islet defense in bio century week of 5 28-12

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BioCenturyTHETHETHETHETHE B B B B BERNSTEINERNSTEINERNSTEINERNSTEINERNSTEIN R R R R REPORTEPORTEPORTEPORTEPORT ONONONONON B B B B BIOIOIOIOIOBBBBBUSINESSUSINESSUSINESSUSINESSUSINESS

Volume 20 • Number 22 • Page A1 of 20

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WEEK OF MAY 28, 2012

BioCentury This Week

This Week in SciBX

Reviving Ras — Genentech and Vanderbilt teams have independently identified a new smallmolecule binding site that blocks activation of Ras, which has been considered undruggable.Please see Table of Contents on A9.

Cover Story

Devil is in the Dosing — Dosing andpharmacokinetics, not specificity, are likely tobe the key to avoiding cardiac effects withsecond-generation S1P agonists that arefollowing Gilenya for multiple sclerosis.

Product Discovery & Development

c-Met’s Highs and Lows — Differencesin tumor types and study designs mayexplain apparently contradictory resultsfor two mAbs against human hepatocytegrowth factor/scatter factor from Amgen andAveo./A5

Islet Defense — Sernova’s Cell Pouch Systemand Sertolin technology is designed to providethe necessary setting for donor islet cells toproduce insulin while being protected from thehost immune system./A8

Emerging Company Profile

Disabling Immune Escape — iTeos is devel-oping small molecules to block tumor immuno-suppressive mechanisms, and hopes to combineits immunomodulators with cancer vaccinesfrom the Ludwig Institute./A10

Implantable Antipsychotics — Delpor’sProzor implantable device aims to deliver ex-

This Week on BioCentury TV

ASCO Preview — ISI’s Mark Schoenebaumon investor highlights; Johns Hopkins’Thomas Smith on bending the cancer costcurve. Please see Program Notes on A13.

www.biocenturytv.com


Devil is in the dosingBy Erin McCallister

Senior WriterData released in April suggest the

theory behind second-generation sphin-gosine 1-phosphate receptor agonists indevelopment for multiple sclerosis waswrong. However, two companies are find-ing that improved pharmacokinetics and/or dose titration could achieve the origi-nal goal of improving safety comparedwith first-generation S1P receptor agonistGilenya fingolimod from Novartis AG.

Gilenya, the first oral drug for relaps-ing-remitting multiple sclerosis (RRMS),was approved in September 2010, but hasstruggled to gain a foothold in first-line usedue to concerns over cardiovascular safety(see BioCentury, Sept. 27, 2010).

In April, Novartis updated the drug’sU.S. and EU labels to recommend addi-tional cardiac testing before treating pa-tients and additional cardiac monitoringonce dosing begins.

Gilenya’s therapeutic effect in MS ismediated by its interaction with S1PR1 onlymphocytes. But it binds with high affinityto all of the five known S1P receptorsexcept S1PR2.

According to Gordon Francis, VP ofNovartis’ neurosciences and ophthalmol-ogy clinical science unit, rodent data hadsuggested Gilenya’s interaction with S1PR3was responsible for reductions in heartrate and atrioventricular (AV) block.

tended-release antipsychotics without drugspikes to reduce side effects and improvepatient compliance compared with depot for-mulations./A11

Regulation

Rare Win — An FDA panel agreed with Pfizerthat surrogate secondary endpoints in a failedPhase II/III trial justify approval of tafamidis totreat transthyretin familial amyloid polyneur-opathy, an Orphan disease./A12

Finance

Ebb & Flow — Pontifex seeks shelter. AbbottBiotech venturing upstream. Strategic VCswithout carried interest. Accelerator refuelingthe tank. Also: Furiex; Medivation; Onyx;Achillion; Chelsea; MediciNova; Peregrine;Active Biotech; Auxilium; Veloxis, et al./A15

Featured links this week/A7

Stock charts & tables/A20

Company index/A14

BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS MAY 28, 2012 PAGE A2 OF 20

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The idea behind second-generationS1P receptor agonists thus was to dial inspecificity for S1PR1, while dialing outinteraction with S1PR3.

However, Phase II data reported inApril for ONO-4641 from Ono Pharma-ceutical Co. Ltd. and Merck KGaA,show cardiovascular signals similar toGilenya’s.

ONO-4641 is selective for S1PR1 andS1PR5.

Meanwhile, preclinical data on sec-ond-generation compounds from Novartisand Receptos Inc., as well as additionalstudies of Gilenya have negated the S1PR3hypothesis.

“The rodent l ied,” Francis toldBioCentury. “We thought that was thekey receptor, but it turns out it is not thesame across species, and the same types ofcardiac effects are seen with an S1PR1-exclusive agonist.”

Novartis and Receptos now believeslowing the time to peak drug concentra-tion could reduce the CV effects of sec-ond-generation agonists without compro-mising efficacy.

Receptos expects the PK profile of itsRPC1063 will accomplish this goal, whileNovartis is exploring dose titration inPhase II trials of its siponimod (BAF312).

Actelion Ltd. also has some skin inthe game with its second-generation S1PR1agonist, ponesimod. The company is say-ing little about how it plans to mitigate thecardiovascular effects, but plans to startPhase III testing this year.

Regardless of how the scenarios playout, it appears likely that S1P1R-specificagonists would be used behind BG-12from Biogen Idec Inc. because of itscleaner safety profile and history of use.Fumarate, the parent compound of BG-12, is already used in Germany to treatpsoriasis without any serious side effects.

S1P signalsCardiovascular side effects emerged

during clinical development of Gilenya,and postmarketing reports of CV eventshave led to increased warnings on thedrug’s label.

In clinical trials, Gilenya was associ-ated with a mean decrease in heart rate of13 bpm, which occurred six hours afterthe first dose. Bradycardia following thefirst dose was reported in 0.5% of patientsin the Gilenya groups of the clinical pro-gram vs. none in the placebo groups.

“We’re going to have BG-12before these new S1P ago-nists come online. I thinkBG-12 will be hard to beat

for a while.”

David Brandes, Hope MultipleSclerosis Center

With continued dosing, the heart ratereturns to baseline within a month.

The original label for Gilenya recom-mended that doctors observe all patientsfor six hours after the first dose for de-creases in heart rate. Baseline ECGs wererecommended in patients at higher risk forbradyarrhythmia. The label also suggesteddoctors “carefully monitor” patients onbeta blockers, or Class Ia or Class III anti-arrhythmic drugs.

In December, FDA issued a safety alertfor Gilenya after receiving a report of anMS patient who died within 24 hours ofthe first dose of the drug for unknownreasons.

In January, EMA’s CHMP began a safetyreview following reports of serious cardio-vascular events in patients receivingGilenya as well as the unexplained deathof the U.S. patient. At the time, CHMP saidthere had been 10 additional deaths. Six,including three sudden deaths, were un-explained. Three were due to heart attack,and one was due to disruption of heartrhythm.

While FDA did not conclude thatGilenya contributed to the patient deaths,Novartis reached agreements with theagency and EMA to change the drug’slabel.

The new U.S. label recommends thatall patients receive an electrocardiogramprior to starting Gilenya and six hoursafter the first dose in addition to hourlyblood pressure and heart rate measure-ments. The drug is contraindicated inpatients with preexisting cardiac condi-tions or taking concomitant anti-arrhyth-mic drugs.

The new European label contains lan-guage similar to the U.S. label and alsorecommends that monitoring be extendedfor at least two hours in patients whoseheart rate is lowest at six hours.

According to Francis, the new labelsare intended to “highlight for physiciansand patients that there are groups ofpatients for whom this drug might be lesssuited than others due to the heart rate

Product Discovery & Development,from previous page

effects.”In any case, sales of Gilenya have been

rising as Novartis launches the drug inadditional territories and as physiciansbecome more familiar with the product.Novartis reported 1Q12 worldwide salesof $247 million and worldwide annualsales for 2011 of $494 million, including afull year of sales in the U.S. and about ninemonths of sales in Europe. The drug waslaunched in Europe shortly after its ap-proval last March, followed by a Decem-ber launch in Japan. Novartis licensedrights to Gilenya from MitsubishiTanabe Pharma Corp.

Second-generation surprisePhase I and II data on second-genera-

tion S1P receptor agonists show the samekinds of cardiovascular signals as Gilenya,although too little data have been dis-closed to know whether the signal is asstrong.

Merck and Ono presented their PhaseII data for ONO-4641 at the AmericanAcademy of Neurology meeting in NewOrleans in April.

In the double-blind, internationalDreaMS trial in 407 patients with RRMS,all three doses met the primary endpointof reducing the number of gadolinium-enhancing lesions obtained by MRI infour-week intervals for 26 weeks. Patientsreceiving 0.05 mg had a reduction of 82%vs. placebo. Reductions vs. placebo were92% for the 0.1 mg group and 77% for the0.15 mg group (p<0.0001 for all threedoses).

In a Phase II trial of Gilenya in 281patients with RRMS, patients receiving1.25 mg Gilenya had a reduction of 42%vs. placebo in the number of gadolinium-enhancing lesions based on a mean num-ber of lesions at six months of 1.29 forGilenya and 2.21 for placebo. Reductionsvs. placebo were 87.8% for the 5 mg dosewhere mean number of lesions was 0.27 atsix months.

The ONO-4641 data appear to becomparable to Phase II data on lesions forGilenya, given that the patients in theGilenya trial were likely sicker: despitesimilar enrollment criteria, there was ahigher number of mean gadolinium-en-hancing lesions at baseline in the GilenyaPhase II trial (2.8-3.4) vs. the ONO-4641trial (0.9-1.4). However, ONO-4641, likeother second-generation S1P receptoragonists, can be given at considerablylower doses.

No patients in the 0.05 mg group or


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Product Discovery & Development,from previous page “The rodent lied.”

Gordon Francis, Novartisplacebo group had secondary AV block.But 1% of patients in the 0.1 mg ONO-4641 group and 3% in the 0.15 mg groupexperienced secondary AV block. Therealso was a decrease in heart rate, with themaximum mean drop of 8.4 bpm seen inthe 0.15 mg group.

Andrew Galazka, Merck’s SVP of exter-nal scientific affairs, global developmentand medical, declined to compare theONO-4641 data on CV side effects withdata from similar placebo-controlled trialsof Gilenya.

“We need to complete the analysis ofthe Phase II results. We are looking at allsorts of analyses to detect any differencethat may be there between our compoundand available treatments, and we will de-sign a program around those differences,”he said.

Novartis also has seen heart rate eleva-tions in its Phase I and Phase II trials forsiponimod. The pharma designed the com-pound to be an S1PR1-specific agonist,but now believes the original hypothesiswas flawed.

“We thought we were going to beclever by getting rid of the S1PR3 compo-nent,” Francis said.

However, a 2007 publication byNovartis in Pharmacology & Therapeuticsnoted experiments with isolated guineapig atrial myocytes revealed both fingolimodand an S1PR1-specific tool compoundcalled AUY954 activated potassium ionchannels, resulting in a decrease in heartrate.

Also in 2007, Novartis realized thatS1PR1 was the dominant player behindCV effects based on Phase I results forsiponimod.

The animal data, Phase I results andresearch in human cardiovascular tissuethat showed a higher concentration ofS1PR1 mRNA and protein vs. S1PR3, ledNovartis to conclude S1PR1 played agreater role in heart rate elevation.

Receptos agrees. “S1PR1 appears tobe the predominant receptor in humancardiomyocytes, so any S1PR agonist islikely going to have some effect on heartrate,” said CMO Sheila Gujrathi.

Tweaking deliveryReceptos and Novartis believe they

can mitigate the cardiac effects based onthe physiologic properties of their com-pounds and/or by tweaking the dosingschedule.

According to Gujrathi, RPC1063 isnot only highly specific for S1PR, but alsohas a pharmacokinetic profile that couldhelp to desensitize cardiomyocytes to thecompound’s heart rate-lowering effects.

“We have a slower time to reach thehighest therapeutic concentration, andthis allows for gradual onset of our drug,”she told BioCentury.

The increase in heart rate seen withGilenya was dose dependent and occurredwithin the first six hours of administration.Receptos therefore believes that if thetime to peak concentration is slowed,cardiomyocytes may not become over-whelmed and heart rate would not drop,or the drop would not be as severe.

“Our goal is to make the cardiovascu-lar profile of RPC1063 as benign as pos-sible so that patients will not have adverseevents and only a minimal drop in heartrate that could be well tolerated. If wecould show a benign cardiac profile, hope-fully we could remove the need for cardiacmonitoring,” Gujrathi said.

Receptos has completed a Phase I study,and the company plans to release thepharmacokinetics data as well as safetydata showing “a more benign” profile atthe European Committee for Treat-ment and Research in Multiple Scle-rosis (ECTRIMS) meeting in October,Gujrathi said.

“We are very encouraged by this dataand we believe RPC1063 has the potentialto be best in class,” she said.

Novartis hopes to achieve a similarreduction in cardiovascular side effectswith titrated dosing of siponimod, withoutsacrificing any of the efficacy seen withGilenya.

The pharma tested a titrated dosingregimen in a Phase II trial in 297 RRMSpatients. On the primary endpoint, the

titrated 1.25 mg dose arm had an 86.1%reduction vs. placebo in new gadolinium-enhancing lesions on T1-weighted andnon-enhancing new/newly enlarging le-sions on T2-weighted MRI scans (p<0.001).

The trial also tested the effect of atitrated dose vs. stable dosing of siponimodon cardiac effects. Cohort 1 received stabledoses of 0.5, 2, or 10 mg of siponimod orplacebo, over six months. A second groupof patients, which included placebo pa-tients from cohort 1 who were allowed tocross over after six months, were random-ized to test titrated doses of 0.5, 1.25, 2and 10 mg siponimod vs. placebo overthree months. Cohort 2 also included astable dose arm of 0.25 mg.

In cohort 2, siponimod was started at0.25 mg on day one and titrated up to thefinal dose over the course of 3-10 daysdepending on the final dose.

In cohort 1 on day one, a dose-depen-dent reduction in mean heart rate wasseen; secondary AV block occurred in 19patients in the treatment arms, includingfive symptomatic AV blocks.

In the titration group, the reduction inmean heart rate was less pronounced, andthere were no symptomatic second-de-gree AV blocks. There were five events ofasymptomatic AV block in patients onplacebo and two events in the titrated 2mg arm.

“Although the patient numbers aresmall, it appears that the titration sched-ule abrogates the cardiac effects,” Francissaid.

Novartis expects to start Phase III test-ing of siponimod late this year or in early2013. It also is considering a titrationstudy of Gilenya, he added.

Receptos also may do dose titrationwith RPC1063, Gujrathi said. The biotechis planning on an end-of-Phase I meetingwith FDA before deciding on the Phase IIprogram.

Merck said it is exploring possibilitiesfor its Phase III program of ONO-4641,including dose titration.

Actelion has its S1PR1 agonist in PhaseII testing. Last August, the company an-nounced Phase IIb data for ponesimod in464 RRMS patients. The compound metthe primary endpoint of reducing the num-ber of new active inflammatory lesions asmeasured by T1-weighted MRI brain scansat weeks 12, 16, 20 and 24 vs. placebo(p<0.0001).

In 2007, the company observed first-dose cardiovascular effects of ponesimodand has been studying how to adapt treat-ment protocols to minimize these effects,

“We fundamentally believethat there will be a high

need for another effectiveand safe agent to go afterBG-12 and in place of it in

some patients.”

Faheem Hasnain, Receptos


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which spokesperson Roland Haefeli did not provide.He did say the company’s compound exhibited an adverse

event pattern in the Phase IIb trial that, “if confirmed, would giveponesimod a competitive safety and tolerability profile.”

Actelion plans to start Phase III testing this year.

Besting BG-12Even with similar efficacy and better safety than Gilenya,

Receptos President and CEO Faheem Hasnain expects second-generation S1P receptor agonists will slot in behind Biogen’s BG-12 because of the latter’s clean safety profile.

This month, Biogen Idec announced FDA and EMA acceptedfor review regulatory applications for oral BG-12. BG-12 is adimethyl fumarate that activates the NF-E2-related factor 2(Nrf2) pathway.

In the Phase III DEFINE trial, the drug met the primaryendpoint with 49% reduction in the proportion of patients withRRMS who relapsed at two years vs. placebo (p<0.0001). BG-12also reduced the number of gadolinium-enhancing lesions, asecondary endpoint, by 90% vs. placebo.

In the Phase III program, the major side effects were flushing,gastrointestinal disorders, headache and nasopharyngitis.

“There is a lot of cycling that goes on in MS, with patientsgoing to relapse and cycling through different therapies, and BG-12 looks interesting. But we fundamentally believe that there willbe a high need for another effective and safe agent to go after BG-12 and in place of it in some patients,” Hasnain said.

David Brandes, a physician at Hope Multiple SclerosisCenter and assistant professor at David Geffen School ofMedicine, agreed.

“We’re going to have BG-12 before these new S1P agonistscome online. I think BG-12 will be hard to beat for a while,” hesaid. “There might be some patients who can’t tolerate the GI orflushing side effects, but those will be minimal.”

COMPANIES AND INSTITUTIONS MENTIONEDActelion Ltd. (SIX:ATLN), Allschwil, Switzerland.American Academy of Neurology, St. Paul, Minn.Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.David Geffen School of Medicine, Los Angeles, Calif.European Committee for Treatment and Research in MultipleSclerosis (ECTRIMS), Basel, SwitzerlandHope Multiple Sclerosis Center, Knoxville, Tenn.Merck KGaA (Xetra:MRK), Darmstadt, GermanyMitsubishi Tanabe Pharma Corp. (Tokyo:4508; Osaka:4508), Osaka,JapanNovartis AG (NYSE:NVS; SIX:NOVN), Basel, SwitzerlandOno Pharmaceutical Co. Ltd. (Tokyo:4528; Osaka:4528), Osaka,JapanReceptos Inc., San Diego, Calif.


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By Michael FlanaganSenior Writer

Differences in the manner of c-Met inhi-bition and EGFR mutation status may helpexplain apparently contradictory biomarkerresults in non-small cell lung cancer re-ported for two anti-c-Met mAbs, one fromAveo Pharmaceuticals Inc. and the otherfrom Genentech Inc.

Activation of c-Met is thought to triggertumor cell survival, growth and metastasisin a variety of tumor types.

Aveo’s ficlatuzumab binds human hepa-tocyte growth factor/scatter factor (HGF/SF) and prevents the ligand from interactingwith and activating c-Met.

By contrast, Genentech’s MetMAbonartuzumab binds c-Met directly and blocksits interaction with HGF/SF.

The Phase II results from Roche and itsGenentech unit showed MetMAb plus theEGFR inhibitor Tarceva erlotinib met oneco-primary endpoint by improving progres-sion-free survival in patients with high c-Metexpression.

This month, however, Aveo said that asubset of patients with low c-Met expressionhad longer PFS than patients with high c-Met expression in its Phase Ib/II trial officlatuzumab in NSCLC.

Aveo’s data also differed from results forAmgen Inc.’s rilotumumab in gastric andgastroesophageal junction cancer. The mAbshave the exact same mechanism, and in thatcase researchers expect the divergent datareflect the different tumor types in which themolecules were tested (see “Amgen’s c-MetExperience”).

Going lowAveo’s open-label study compared Iressa

gefitinib, a small molecule EGFR1 inhibitor,with and without ficlatuzumab as front-linetherapy for NSCLC.

The company’s rationale for combiningficlatuzumab and an EGFR inhibitor wasbased on preclinical evidence of synergisticactivity and a clinical precedent for target-ing the c-Met and EGFR pathways together(see BioCentury, Nov. 1, 2010).

Preliminary data from an intent-to-treat(ITT) analysis showed ficlatuzumab plusIressa missed the primary endpoint of over-all response rate vs. Iressa alone in 188patients with previously untreated NSCLC


c-Met’s highs and lows

Amgen’s c-Met experienceAmgen Inc.’s rilotumumab improved survival in patients with gastric and gastroesoph-

ageal junction cancer whose tumors expressed high levels of c-Met, but not in patients withlow c-Met expression.

Amgen selected advanced gastric cancer in part because c-Met expression is particularlyhigh in this setting, according to David Chang, VP of global oncology.

Phase II results presented at the 2011 European Multidisciplinary Cancer Congress inStockholm showed a positive trend on the primary endpoint of median PFS for chemother-apy plus rilotumumab vs. chemotherapy plus placebo (5.6 vs. 4.2 months, HR=0.64).

The secondary endpoint of overall survival (OS) also showed a trend in favor of therilotumumab group (11.1 vs. 8.9 months, HR=0.73).

In an abstract released this month, Amgen reported a post hoc biomarker analysisshowing that in patients whose tumors had high c-Met expression, adding rilotumumab tochemotherapy significantly improved median OS vs. chemotherapy plus placebo (11.1 vs.5.7 months, p=0.012).

In patients with low c-Met expression, the company saw a trend toward unfavorable OSin the rilotumumab group. Data will be presented at the American Society of ClinicalOncology meeting in Chicago.

Amgen spokesperson Ashleigh Koss said patients were not stratified prospectivelybecause gastric cancer is a setting with high c-Met expression.

Researchers who spoke to BioCentury agreed that different tumor types could explainthe seeming disconnect between results for rilotumumab and Aveo Pharmaceuticals Inc.’sficlatuzumab, which was studied in NSCLC.

Amgen plans to move rilotumumab into Phase III testing this year to treat advancedgastric and gastroesophageal junction cancer in patients whose tumors have high c-Metexpression.

Earlier this year, Amgen and Dako A/S partnered to develop and evaluate the use ofa companion diagnostic measuring c-Met expression in the development of rilotumumab.

Dako is being acquired by Agilent Technologies Inc.

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(43% vs. 40%). The combination also missedthe secondary endpoint of median PFS vs.Iressa alone (5.6 vs. 4.7 months).

In Genentech’s case, its combination ofMetMAb and Tarcva missed the co-primaryendpoint of PFS in the ITT population. Butit did hit the endpoint in the high c-Metsubset: PFS was 2.9 months for MetMAb incombination with Tarceva vs. 1.5 monthsfor placebo plus Tarceva (p=0.04).

In Aveo’s case, however, a post hocsubgroup analyses showed ficlatuzumab didbest in patients with low c-Met expression.

The Aveo analyses segmented patientsbased on EGFR mutation status (wild-typeor sensitizing mutations) and c-Met expres-sion levels (high or low).

Rather than focusing on c-Met expres-

sion, where the preclinical evidence wasunclear about which subgroup might re-spond better, Aveo SVP and CSO JenoGyuris said the company’s main hypothesesgoing into the study related to whether theaddition of ficlatuzumab to Iressa wouldwork in patients with EGFR wild-type and/or EGFR sensitizing mutations (SM+).

“The translational research evidence wasin fact stronger in the EGFR SM+ setting,where c-Met amplification or elevated HGFwas demonstrated as the mechanism ofresistance for EGFR inhibitor in SM+ tumorsat the time,” he told BioCentury. “Thereason for the inclusion of the exploratoryc-Met biomarker was to assess if HGF/c-Metpathway activity, as measured by c-Met


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expression levels by IHC, could also impact the activity of thecombination.”

According to Gyuris, Genentech’s definition of high c-Metincluded all patients with tumors that were positive for c-Metbased on a diagnostic test, which was amuch less stringent definition than wasused by Aveo.

“Neither Genentech nor Aveo wouldlikely have known precisely which c-Metsubset, if there were one, would preferen-tially benefit” from the respective combina-tion, he said.

As it turned out, the most favorableeffect of ficlatuzumab and Iressa was in 10patients who were EGFR SM+ and low c-Met. These patients had median PFS of 11 months vs. 5.5 monthsin nine SM+, low c-Met patients receiving Iressa alone. The resultwas not statistically significant.

In the high c-Met arms, the addition of ficlatuzumab offered nobenefit.

Wild-type patients receiving either regimen had PFS of 1.8months while those with EGFR SM+ had PFS of 9.2 months. Patientswith wild-type EGFR and low c-Met had slightly worse PFS in thecombination arm (1.3 vs. 2.3 months).

Elan Ezickson, Aveo’s EVP and COO, said an internal review ofthe data suggested ficlatuzumab did not have an impact — positiveor negative — on any of the groups except the EGFR SM+/low c-Met group.

He said the slightly worse PFS in EGFR wild-type/low c-Metpatients was simply a matter of chance.

“This was an exploratory study designed to look at theintersection of EGFR mutation status and c-Met expression levelswith the goal of using the biomarkers to identify patient populationswhere we could see a strong signal of activity,” said Gyuris. “Wethink we have done just that.”

Ezickson suggested there might be an inverse correlationbetween HGF and c-Met in NSCLC. If this were the case, thenpatients with high c-Met expression might benefit less from an HGF/SF inhibitor because c-Met is activated largely independently of theligand.

On the flipside, it could be that tumors in patients with low c-Met expression are more dependent on HGF/SF for activation,which Ezickson said would explain why ficlatuzumab appearedmore active in this subgroup.

Edurne Arriola, a medical oncologist at the Hospital del Mar,said she is working with preclinical models of small cell lung cancerthat have high levels of HGF/SF and no c-Met expression. “Thismight not necessarily be the case in NSCLC,” she said, but itsuggests there can be situations with an inverse correlation inexpression levels of c-Met and its ligand.

Arriola’s group has yet to put Aveo’s theory about ficlatuzumab’sactivity in low c-Met patients to the test. “We are trying to figureout if these would be sensitive to an HGF inhibitor,” she said, notingthat the tumors have proven resistant to a small molecule inhibitorof c-Met.

Jill Siegfried of the University of Pittsburgh said that ifficlatuzumab’s signal in EGFR SM+/low c-Met patients is real, thenEzickson’s theory of an inverse correlation between c-Met and HGF/SF could make sense.

Ficlatuzumab prevents “ligand-dependent signaling of c-Met

only. At high c-Met levels, tumors can be activated either byconstitutive dimerization that occurs without needing the ligand orit can be trans-activated by EGFR itself,” or even by otheroncogenes like Src kinase, said Siegfried, who is a professor ofpharmacology and chemical biology at the university’s school ofmedicine.

“One might argue that it is the low c-Met patients who canachieve the best blockade of c-Met signalingthrough inhibition of the ligand,” she added.

Jin Kim, CSO of Galaxy BiotechLLC, expressed doubt as to whether theefficacy signal for ficlatuzumab was real,noting that significance had not beenachieved in the retrospective analyses ofthe biomarker data.

There are several possible explanationsfor ficlatuzumab’s “seemingly counterintuitiveeffects” in the high and low c-Met groups,

said Kim. “It is certainly possible that ficlatuzumab is simply not apotent drug, or that HGF is not a good therapeutic target inNSCLC.”

Genentech’s positive MetMAb data in NSCLC seem to refute thelatter explanation, he noted.

Another potential explanation, said Kim, is that the highproportion of EGFR SM+ patients in the ficlatuzumab study had anegative impact on the mAb’s efficacy.

A total of 58% of patients in the Phase II trial of ficlatuzumabwere defined as EGFR SM+ compared with only 13% of those inthe MetMAb arm and 11% in the placebo arm in Genentech’sstudy.

“The Aveo patient population may have been more enrichedfor EGFR mutant patients than the Genentech patient popula-tion, and it’s possible that these patients are not good candidatesfor treatment with HGF/c-Met antagonists. After all, what isdriving the cancer in these patients is the EGFR mutation and notthe HGF/c-Met pathway,” said Kim.

Galaxy’s TAK-701, a mAb against HGF/SF that Kim co-discov-ered, is being developed by partner Takeda PharmaceuticalCo. Ltd. It is in Phase I testing in solid tumors.

Arriola of Hospital del Mar noted that Genentech’s study had ahigh proportion of EGFR wild-type patients, a group that tends notto achieve much benefit from use of Tarceva alone. “So it should bequite easy to observe a benefit” from the addition of MetMAb, shenoted.

Seiji Yano, a professor of medical oncology at the CancerResearch Institute of Kanazawa University, believes an impor-tant question that Aveo will need to answer is “whether the doseof its anti-HGF antibody was enough to neutralize HGF activity invivo.”

Indeed, unlike MetMAb, which binds the receptor, ficlatuzumabneeds to mop up all the HGF ligand in circulation.

Yano said the available data are insufficient to draw anyconclusions about whether and how ficlatuzumab’s activity differsfrom the other mAbs. “Without the level of HGF in the tumors, I donot think we can make a correct interpretation on these data,” hesaid.

Leveling upAveo is collecting data on HGF expression levels, which

Ezickson said could go a long way toward explaining the results. Hehopes to report these at a scientific meeting next half.

“Without the level of HGF inthe tumors, I do not think wecan make a correct interpre-

tation on these data.”

Seiji Yano, Kanazawa University



The company has not settled on a plan for moving ficlatuzumabforward in NSCLC, he said, though “based on the strength andconsistency of response rate and magnitude of the PFS benefit inmutation-positive, c-Met-low patients, we think that is a strongsignal of activity that warrants further development in that sub-group.”

“Going forward it will be very important to incorporate c-Metand HGF biomarker analyses in all clinical trials with this class ofagents,” noted Gyuris.

In the meantime, Aveo plans to start a Phase II trial officlatuzumab in head and neck cancer around mid-year.

Genentech’s MetMAb is in Phase III testing to treat NSCLC inpatients with high c-Met expression, with marketing applicationsexpected in 2014.

Tarceva is marketed in the U.S. by Genentech and OSI Pharma-

ceuticals Inc., now part of Astellas Pharma Inc., and elsewhereby Roche. AstraZeneca plc markets Iressa for NSCLC in the EU.

COMPANIES AND INSTITUTIONS MENTIONEDAgilent Technologies Inc. (NYSE:A), Santa Clara, Calif.American Society of Clinical Oncology (ASCO), Arlington, Va.Amgen Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.Astellas Pharma Inc. (Tokyo:4503), Tokyo, JapanAstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K.Aveo Pharmaceuticals Inc. (NASDAQ:AVEO), Cambridge, Mass.Dako A/S, Glostrup, DenmarkGalaxy Biotech LLC, Mountain View, Calif.Genentech Inc., South San Francisco, Calif.Hospital del Mar, Barcelona, SpainKanazawa University, Kanazawa, JapanRoche (SIX:ROG; OTCQX:RHHBY), Basel, SwitzerlandTakeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, JapanUniversity of Pittsburgh School of Medicine, Pittsburgh, Pa.

Featured links this weekLinks to the following documents reside onlineon the BioCentury on BioBusiness page ofwww.biocentury.com.

Epilepsy

Not-for-profit Epilepsy Therapy Project pipe-line documenting investigational and ap-proved products for epilepsy.

Heart failure

European Society of Cardiology 2012 guide-lines for diagnosis and treatment of acuteand chronic heart failure.

Opioids

NICE clinical guidelines on use of opioidsfor pain in palliative care.

Orphan products

Summary of actions taken at the May 10-11plenary meeting of EMA’s Committee forOrphan Medicinal Products (COMP).

Ovarian cancer

NICE quality standard on recognizing earlysymptoms of ovarian cancer.

PCORI

Patient Centered Outcomes ResearchInstitute (PCORI) funding announce-ment to award $120 million in grants in2012 after its board voted to formallyadopt a revised set of research priori-ties and agenda (see BioCentury Extra,Tuesday, May 22).

PDUFA

— Text of the Food and Drug Administra-tion Safety and Innovation Act (S. 3187)passed by the U.S. Senate to reauthorize

PDUFA that includes several amendments,including one from Sen. Tom Coburn (R-Okla.) that would require independentassessment of the drug review and ap-proval process (see BioCentury Extra, Fri-day, May 25).— White House statement of administra-tion policy supporting S. 3187 to reautho-rize PDUFA (see BioCentury Extra, Thursday,May 24).

Pediatric drugs

Summary of actions taken at the April 11-13meeting of EMA’s Pediatric Committee.

Pharmacovigilance

EMA Q&A on implementation of pharma-covigilance legislation.

Prostate cancer

U.S. Preventative Services Task Force (USP-STF) final recommendation againstusing prostate-specific antigen (PSA)-basedscreening for prostate cancer in all agegroups (see BioCentury Extra, Monday, May21).

Safety

EMA’s CHMP draft orientation paper of2013 priorities for adverse drug reac-tion research under Framework Pro-gramme 7 (FP7), including long-termsafety effects of antipsychotics in de-mentia patients, long-term adverse skel-etal effects of bisphosphonates, andDNA collection and studies on the ge-netic causes of adverse drug reactionssuch as angiotensin-converting enzymeinhibitor-related angioedema and sta-tin-induced myopathy.

Startups

Text of the Startup Act 2.0 (S. 3217) thataims to change tax requirements for startupinvestments and amend visa regulations tocreate new businesses and jobs (see BioCen-tury Extra, Tuesday, May 22).

Product documentation

— Nimenrix: CHMP EPAR for Nimenrix tovaccinate patients ages 12 months and old-er against invasive meningococcal diseasescaused by Neisseria meningitidis serogroupsA, C, W-135 and Y; from GlaxoSmith-Kline plc (LSE:GSK; NYSE:GSK).— Tafamidis: Briefing documents for theMay 24 meeting of FDA’s Peripheral andCentral Nervous System Drugs AdvisoryCommittee, which voted 13-4 that surro-gate endpoint data for tafamidis were robustenough to predict a clinical benefit in pa-tients with transthyretin (TTR) familial amy-loid polyneuropathy (FAP); from PfizerInc. (NYSE:PFE) (see “A Rare Win,” A12).— Vimpat: CHMP revised EPAR updatingSPC to include hallucination as an adversedrug reaction for Vimpat lacosamide as anadjunctive therapy for partial-onset seizures;from UCB Group (Euronext:UCB).— Xarelto: Briefing documents for the May23 meeting of FDA’s Cardiovascular andRenal Drugs Advisory Committee, whichvoted 6-4, with one abstention, againstrecommending approval of 2.5 mg twice-daily Xarelto rivaroxaban to reduce the riskof cardiovascular events in patients withacute coronary syndrome (ACS), non-ST-elevation myocardial infarction or unstableangina; from Bayer AG (Xetra:BAYN) andJohnson & Johnson (NYSE:JNJ) (see Bio-Century Extra, Wednesday, May 23)



See next page

By Stephen HansenSenior Writer

Sernova Corp. is developing its Sertolin cell technologyand Cell Pouch System device to provide an immune-privileged,vascularized environment for donor islet cells to produce insulinin insulin-dependent diabetes patients. The approach is intendedto overcome problems with traditionalislet cell transplantation, including poorrates of cell survival and engraftment, andunwanted immune responses.

Standard islet transplantation involvesusing a catheter to infuse islet cells intothe portal vein of the liver. While mini-mally invasive, the procedure carries therisk of portal vein thrombosis and intrap-eritoneal bleeding.

According to Sernova President andCEO Philip Toleikis, about 50% of thecells die immediately. In addition, becausedonor islet cells are particularly sensitiveto hypoxic conditions, it is unclear howmany of the remaining cells actually en-graft and are able to provide a therapeutic benefit.

“The islet cells don’t like to be bathed in blood. They wantto be next to microvessels so they can interact with them,”Toleikis said.

Donor cells also are recognized by the body as foreign andelicit an inflammatory immune response. Patients thus requireimmunosuppressive drugs to prevent graft rejection. Thesedrugs not only carry the risk of serious infections and malignan-cies, but also can impair the revascularization and function ofgrafted islets.

Sernova protects islet cells from immediate death and ensuressufficient oxygen is available to the cells using its Cell PouchSystem, a matchbook-sized polymer device with several cham-bers for therapeutic cells.

Initially, the empty device is implanted subcutaneously in theabdomen with the chambers plugged. The device contains pores,which allow microvessels and collagen tissues to move in andgrow up to the edge of the plugs over a period of two to 12 weeks,Toleikis said.

Once the device has been vascularized, the plugs are re-moved in an outpatient procedure and donor islet cells areinserted into the chambers. Toleikis said both inserting thedevice and removing the plugs requires a minimally invasive onecentimeter keyhole subcutaneous incision.

“The islet cells naturally release growth factors when theymove into an environment to stimulate angiogenesis andmicrovessel formation,” he said.

The microvessels not only supply the islet cells with theoxygen and nutrients needed to survive, but also provide theconnection to the host for glucose regulation.

Sernova says its unpublished preclinical data show islet cellsremain viable in the Cell Pouch System after a single transplan-tation. In a diabetic pig model, the Cell Pouch System maintainedglucose levels in the normal range during the six-month study.


Islet defenseAll transplanted animals were positive for insulin C-peptide, ameasure that Toleikis said shows insulin released from islet cellsis regulating glucose.

At the end of the study period, the devices were removed andthe pigs returned to a diabetic state. Toleikis said analysis of thedevices showed the vast majority of islet cells were still healthy

and functioning.“Our six-month preclinical data is not

because we lost the islets at six months.That is just when the study ended,” hesaid.

Immune privilegedSernova has a second technology

dubbed Sertolin that uses the naturalability of Sertoli cells to create an immune-privileged environment.

Sertoli cells are naturally found in thetestes. In addition to secreting growthfactors, they synthesize the cytokines nec-essary to protect developing spermatozoa

from being attacked by the immune system. Toleikis said it hasbeen known for over 60 years that it is possible to transplant cellsfrom other species into the testes without them being rejected.

“By combining the Sertoli cells with the islet cells, the CellPouch System becomes an immune-privileged environment.That’s the ideal situation for the therapeutic cells,” Toleikis said.“It’s local immunosuppression without the need for systemictreatment.”

The company cited unpublished data in a diabetic rat modelco-transplanted with porcine islets and Sertoli cells in the kidneycapsule, showing the immune response was significantly inhib-ited compared with rats that received only the porcine islets.

In co-transplanted animals, islets produced “robust” levels ofinsulin up to 180 days following implantation, Toleikis said. Inanimals receiving islets without the Sertolin technology, an IgG-mediated immune response destroyed the islets by day 14.

Toleikis said Sernova also has unpublished data in multiplediabetic animal models that combine the Sertolin technology andislet cells in the Cell Pouch System. He said these data show thatnormal glucose levels were achieved in two weeks and main-tained for the duration of the studies — more than 100 days.

Beta-O2 Technologies Ltd. is developing another devicethat uses a mechanical barrier to prevent the immune systemfrom reaching the implanted islet cells. The bioartificial pancreashas two chambers, one for the islet cells and another for anoxygen supply for the cells. Both chambers are encapsulated ina polymer barrier with nanopores large enough to let insulin out,but small enough to prevent immune system components fromentering.

Preclinical data were recently published showing thebioartificial pancreas can restore blood glucose levels in diabeticmice (see SciBX: Science-Business eXchange, March 22).

According to Toleikis, previous approaches that have used a

“By combining the Sertolicells with the islet cells,the Cell Pouch Systembecomes an immune-

privileged environment.That’s the ideal situationfor the therapeutic cells.”

Philip Toleikis, Sernova


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ANALYSIS

COVER STORYReviving RasGenentech and Vanderbilt teams have independently usedfragment-based drug discovery to identify a new smallmolecule binding site that blocks activation of Ras, a highlyprevalent oncoprotein that has previously been consideredundruggable. The results could reinvigorate drug discoveryefforts against the target.

TARGETS & MECHANISMSCooling down ADA Johns Hopkins University team has clinical proof-of-concept data for slowing the progression of Alzheimer’sdisease by reducing activity in the hippocampus withantiepileptic drugs. AgeneBio has licensed the IP and isplanning a Phase II trial of an antiepileptic to prevent AD.

Getting around peripartum cardiomyopathyA Harvard Medical School–led team has shown that asoluble form of FLT1 causes about one-third of peripartumcardiomyopathy cases—those associated with pre-eclampsia. Ongoing studies are seeking to identify smallmolecule inhibitors of the protein and determine whetherthe mechanism also underlies the other two-thirds ofcases.

Getting selective for gCellzome and Exelixis have independently designed thefirst highly selective inhibitors of the g-isoform of PI3K.Exelixis hopes to out-license its inhibitors, whereas therecent acquisition of Cellzome by GlaxoSmithKline givesthe pharma a new class of compounds for inflammatoryand autoimmune diseases.

THE DISTILLERYThis week in therapeuticsTreating melanoma by antagonizing PREX2; preventingthrombosis with PDI inhibitors; ameliorating hyperalgesia indiabetic neuropathy by blocking methylglyoxal; and more…

This week in techniquesHigh throughput sequencing of TCRs to detect minimalresidual disease in T cell acute lymphoblastic leukemia; aproteomic method for developing rational combinations ofkinase inhibitors; synthesis of biologically activemeroterpenoids; and more…


mechanical barrier to sequester donor islet cells have preventedthe cells from interacting with microvessels, thus potentiallyreducing their therapeutic effect.

Into humansIn May Sernova began a Canadian open-label, single-arm

Phase I/II trial of the Cell Pouch System without the Sertolintechnology. The trial will enroll 20 patients with insulin-depen-dent diabetes who will receive immunosuppressive drugs.

The primary endpoint will be safety, and the secondaryendpoint will be the proportion of patients who achieve andmaintain insulin independence at three months after transplan-tation. Data are expected this year.

Patients will be followed for up to three years to provideadditional information on the long-term viability of the islet cells.

A second Phase I/II trial will then combine the Sertolintechnology with the Cell Pouch System. Toleikis said the Sertolintechnology is still 12-18 months from the clinic.

While Sernova is focused on diabetes, Toleikis said otherprotein or hormone-producing cells, or stem cells, could be usedin the Cell Pouch System. Some examples the company isconsidering include human growth hormone (hGH) and FactorVIII.

“Essentially anything that can produce a hormone or proteinthat is missing from the body, we’ll be able to work with,” he said.“We are currently looking at neurological diseases, metabolicdiseases and blood diseases.”

Sernova, which is listed on the TSX Venture Exchange, raisedC$3.6 million ($3.5 million) in a private placement in April.Toleikis said the company has C$5 million in cash, which shouldprovide a two-year runway.

COMPANIES AND INSTITUTIONS MENTIONEDBeta-O2 Technologies Ltd., Petah Tikva, IsraelSernova Corp. (TSX-V:SVA), London, Ontario

The search for intelligent lifeWe know you have many choices forheadlines. But finding real intelligence is a lotharder. That’s why top managers andinvestors in the life sciences communitydepend on BioCentury, the Bernstein Reporton BioBusinessTM for its leading perspective onthe strategic issues essential to the formation,development and sustainability of life scienceventures in 2012 and beyond.



By Kai-Jye LouStaff Writer

Tumor cells exploit many signalingpathways to avoid detection by the hostimmune system, thereby limiting the po-tential of cancer immunotherapies. iTeosTherapeutics S.A. is developing smallmolecule immunomodulators that blockthese escape pathways, which could po-tentially boost and prolong the effects ofcancer vaccines.

iTeos spun out of the Ludwig Insti-tute for Cancer Research Ltd. (LICR)and the de Duve Inst itute at theUniversité catholique de Louvain lastAugust to translate the LICR’s scientificassets into immunomodulatory cancertherapies.

iTeos initially will focus on pancreatic,liver, lung and colorectal cancers. Thecompany is pursuing three targets, two ofwhich have been disclosed: tryptophan2,3-dioxygenase (TDO2; TDO) andindoleamine 2,3-dioxygenase (INDO;IDO). The company has exclusive rightsto the targets from LICR and could receiverights to future targets discovered at theinstitute.

The rationale for targeting IDO andTDO stems from the research of iTeos co-founder and CSO Benoit Van den Eynde,who also is director of the LICR BrusselsBranch. Since 2003, his group and othershave shown that degradation of tryptophanby IDO and by TDO is a strategy manytumors employ to disarm immune cells.

iTeos CEO Michel Detheux said thecompany has an undisclosed number ofsmall molecule IDO and TDO inhibitorsin preclinical development.

Aside from iTeos, there are no dis-closed TDO inhibitors in development.

At least two other companies, IncyteCorp. and NewLink Genetics Corp.,are developing small molecule IDO inhibi-tors. Incyte’s INCB24360 is in Phase IIdevelopment for solid tumors. NewLink’s

iTeos Therapeutics S.A.

Gosselies, BelgiumTechnology: Smal l moleculeimmunomodulators that block tumorimmunosuppressive mechanismsDisease focus: CancerClinical status: PreclinicalFounded: 2011 by Michel Detheuxand Benoit Van den EyndeUniversity collaborators: Ludwig Insti-tute for Cancer Research, de DuveInstitute at the Universite catholiquede LouvainCorporate partners: NoneNumber of employees: 5Funds raised: €3 million ($4 million)Investors: Ludwig Institute for CancerResearch; Hunza Ventures; Life Sci-ence Research Partners; Vives LouvainTechnology Fund; and angel investorsCEO: Michel DetheuxPatents: None issued


iTeos: Disabling tumor immune escape

1-methyl-d-tryptophan is in a pair of PhaseIb/II trials in solid tumors.

Detheux said iTeos plans to developIDO inhibitors that will be more potentand selective than the clinical-stage com-pounds but declined to disclose whetherthe company already has candidates thatmeet such criteria.

The company plans to start a proof-of-concept Phase I/II trial of a lead candidateagainst one of the two targets in combina-tion with a cancer vaccine from LICRwithin two years.

Detheux said the company will select“the most advanced Ludwig Institute can-cer vaccine suitable for the human cancerwe want to target.”

He said the institute already has mul-tiple cancer vaccine candidates in the

clinic and that one could be approved bythe time the company is ready to start itsPhase I/II trial. He declined to providespecific details on LICR’s vaccine candi-dates and the planned trial.

iTeos is aiming to complete the PhaseI/II study and to submit an IND for asecond candidate in four years. Decisionson whether to partner, out-license orcontinue developing the lead candidatein-house will be made after completing thePhase I/II.

Detheux said iTeos is exploring thepossibility of developing a dual inhibitorthat targets both IDO and TDO.

In January, Van den Eynde’s grouppublished data showing that tumor cellscould express IDO, TDO or both. Thosedata suggest inhibition of IDO and TDOcould have a complementary effect (seeSciBX: Science-Business eXchange, Feb. 23).

iTeos this month raised €3 million ($4million) in a series A round, which comple-ments a €6 million non-dilutive researchgrant the company received last Decem-ber from Belgium’s Walloon regional gov-ernment.

Detheux said the funding gives iTeosrunway until 2015 and that the funds willallow the biotech to build out its therapeuticplatform and to discover and develop addi-tional small molecule immunomodulators.

iTeos will outsource some drug dis-covery efforts, such as those related tomedicinal chemistry, pharmacokinetics andlead optimization.

COMPANIES AND INSTITUTIONS MENTIONEDIncyte Corp. (NASDAQ:INCY), Wilmington,Del.iTeos Therapeutics S.A., Gosselies, BelgiumLudwig Institute for Cancer ResearchLtd., New York, N.Y.NewLink Genetics Corp. (NASDAQ:NLNK), Ames, IowaUniversite catholique de Louvain, Brus-sels, Belgium

BioCentury makes people thinkThere is only one journal — BioCentury, the Bernstein Report on BioBusinessTM — that is recognized by key decision makers asthe best source of perspective, interpretation and analysis for top managers and investors in the biotech community.


By Stephen HansenSenior Writer

While extended-release antipsychoticshave been a commercial success, they stillhave a limited therapeutic duration andpoor pharmacokinetics, resulting in poorcompliance. Delpor Inc. is aiming toimprove all three of these characteristicswith its implantable Prozor drug deliverydevice.

Prozor is a tubular device 40 mm longand 4 mm in diameter that is subcutane-ously implanted in the arm to provide con-tinuous drug delivery via passive diffusion.

To deliver drugs with poor water solu-bility, such as antipsychotics, Delpor hasdeveloped undisclosed excipients thaterode over time, creating an acidic pHenvironment within the device. This acidgeneration improves solubility and estab-lishes a concentration gradient betweenthe device reservoir and the external en-vironment. The drug then passively dif-fuses into the body at a steady rate.

Delpor’s lead program is DLP-114, aProzor device loaded with risperidone.Delpor plans to submit an IND by yearend.

DLP-115, a Prozor device deliveringpaliperidone, is in preclinical testing.

According to President and CEOTassos Nicolaou, Delpor would competewith depot formulations of antipsychoticsdelivered via intramuscular injection, suchas Johnson & Johnson’s Risperdal Constar isperidone and Invega Sustennapaliperidone palmitate. Both are approvedfor schizophrenia; Risperdal Consta is alsoapproved to treat bipolar disorder.

In 2011, Risperdal Consta had sales of$1.6 billion. Sales of Invega Sustenna werenot disclosed.

Risperdal Consta is given every twoweeks, and Invega Sustenna is given oncemonthly. Nicolaou said drug levels spikefollowing injections, which can lead toextrapyramidal side effects.

The company says unpublished pre-clinical data show Prozor can deliverrisperidone at a constant rate, resulting in

Delpor Inc.

San Francisco, Calif.Technology: Prozor and Nanopor drugdelivery devicesDisease focus: Neurology, infectiousClinical status: PreclinicalFounded: 2009 by Tassos Nicolaou,Frank Martin and Nick ArvanitidisCorporate partners: NoneNumber of employees: 4Funds raised: UndisclosedInvestors: Angel investorsCEO: Tassos NicolaouPatents: 2 issued covering Nanoportechnology and Delos pump technol-ogy for drug delivery


Delpor: Implantable antipsychotics

a flat PK profile. Nicolaou thinks thesmooth PK profile could diminish or elimi-nate the extrapyramidal side effects.

Nicolaou added the amount of drugused in DLP-114 should allow for three- tosix-month dosing. This schedule shouldimprove patient compliance comparedwith injectable depot formulations, whichrequire patients to visit the doctor’s officefor more frequent injections.

Nicolaou noted the implant also couldbe safer because it can be removed if apatient has a bad reaction to the drug,whereas a depot cannot.

Delpor also is developing a relatedtechnology for biologics, called Nanopor.

Nicolaou said the biologics device alsorelies on passive diffusion, but unlikeProzor, Nanopor devices have membranesat each end containing nanopores. Thesize and number of nanopores dictateshow much therapeutic is released.

He said the challenge is to keepbiologics stable within the device at bodytemperature. Nicolaou said Delpor has anundisclosed formulation technology thatprevents the proteins from aggregating.

Delpor’s lead Nanopor program is DLP-

201, a preclinical interferon alpha implantto treat HCV. Similar to Prozor, DLP-201’ssteady PK profile could reduce side effectsassociated with daily IFN alpha injections.

Delpor also has DLP-202, which con-tains human growth hormone (hGH), inpreclinical testing.

Intarcia Therapeutics Inc. andDurect Corp. are developing productsusing an implantable device called Durosunder licenses from J&J’s Alza Corp. sub-sidiary.

The difference between Delpor’s de-vices and Duros implantable devices isthat Prozor and Nanopor have no movingparts, while Duros is an osmotic mini-pump that uses osmotic pressure and apiston to slowly push drug out of thedevice.

According to Nicolaou, Prozor alsohas a larger drug capacity and lower costof goods. Moreover, he said, if the devicebecomes clogged, there is no risk of drugdumping.

Durect markets Alzet implantable os-motic pumps for research use to deliverdrugs in animal models. Intarcia’s ITCA650, a continuous subcutaneous deliveryof exenatide from an implantable Durosdevice, is in Phase III testing for Type IIdiabetes (see BioCentury, July 11, 2011).

Intarcia also has ITCA 638, a Durosdevice containing IFN alpha, in Phase I forHCV.

Delpor also has a pump technologycalled Delos that can deliver therapeuticsat timed intervals. The company is notdeveloping programs using the technol-ogy, but Nicolaou said it could be usefulfor fertility hormones, parathyroid hor-mone or pain medications.

COMPANIES AND INSTITUTIONS MENTIONEDDelpor Inc., San Francisco, Calif.Durect Corp. (NASDAQ:DRRX), Cupertino,Calif.Intarcia Therapeutics Inc., Hayward, Calif.Johnson & Johnson (NYSE:JNJ) , NewBrunswick, N.J.

All press releases, news announcements and story inquiries should be submitted to ournews room at [email protected]. Editorial announcements emailed to the Editor-in-Chief

and/or the Publisher may not receive immediate attention and potential stories will be delayed.


By Erin McCallisterSenior Writer

Pfizer Inc. saw value in a failed Phase II/III trial of tafamidisas a treatment for transthyretin familial amyloid polyneuropathywhen it acquired FoldRX Pharmaceuticals Inc. in 2010. Lastweek, FDA’s Peripheral and Central Nervous System DrugsAdvisory Committee agreed, voting 13-4 that data on surrogateendpoints in the study were sufficiently robust to predict clinicalbenefit.

The vote paves the way for accelerated approval in theOrphan disease.

If FDA approves tafamidis, Pfizer would have two approvedOrphan drugs only two years after thepharma said it was creating a business unitfocused on rare diseases. The PDFUA dateis June 16.

Approval also would validate thepharma’s decision to purchase FoldRx foran undisclosed sum, despite knowing thecompound had missed the primary end-points (see BioCentury, Sept. 6, 2010).

Stabilizing TTRTTR FAP is an autosomal dominant

disease characterized by deposition ofabnormal amyloid proteins primarily inthe peripheral nerves and other organs.Symptoms include sensorimotor and auto-nomic neuropathy as well as heart, kidneyand eye dysfunction.

According to FDA’s briefing documents, there are about2,500 patients with TTR FAP in the U.S. and 5,000-10,000worldwide.

The disease is caused by mutations in the gene that codes fortransthyretin (TTR).The most frequent mutation leads to misfoldingof TTR monomers, which form toxic intermediates. The result isthe formation and deposition of amyloid.

Patients die within about 11 years of onset of symptoms.Current treatment in the U.S. is liver transplant, which

removes abnormal TTR from circulation. The five-year survivalfor liver transplant is 80%, with about 60% who stabilize, 20%who improve and 20% who do poorly.

FoldRx discovered and developed tafamidis as an alternativefor patients who are not eligible for or do not respond to livertransplant. The compound is a small molecule that stabilizes theTTR protein and prevents misfolding.

In 2009, tafamidis missed the co-primary composite end-points of disease progression and quality of life in the intent-totreat (ITT) population in Fx-005, a randomized double-blind,placebo-controlled Phase II/III trial. The ITT population included64 patients on tafamidis and 61 on placebo.

The trial also included multiple secondary endpoints includ-ing large nerve fiber score, small nerve fiber score, modified BMI(mBMI), muscle weakness and TTR stabilization status.

See next page

Small fiber function was one of five components of the qualityof life endpoint; and muscle weakness was one of three compo-nents of disease progression.

Small fiber function and muscle weakness have been usedpreviously in studies for diabetic peripheral neuropathy, whilethe surrogate of TTR stability was designed specifically fortafamidis.

Tafamidis had a statistically significant improvement on thesecondary outcomes of small nerve fiber score (p=0.005), mBMI(p<0.0001), muscle weakness (p=0.01) and TTR stabilization(p<0.0001).

Pfizer submitted an NDA last December with the understand-ing that the regulatory pathway — tradi-tional or accelerated — would be deter-mined at a later date.

Applying flexibilityIn briefing documents, FDA reviewers

recommended that the agency issue acomplete response letter because tafamidismissed the primary endpoints and theclinical significance of the secondary end-points was uncertain.

However, in a memo to the panelincluded in the review documents and inhis opening statement at the meeting,Russell Katz, director of the Division ofNeurology Products at the Center forDrug Evaluation and Research (CDER),said FDA is “willing to apply as much

flexibility as we can, but within the standards of the law.”Katz told the panel robust clinical data from at least two well-

controlled clinical trials was necessary for full approval. Alterna-tively, a single well-controlled trial could satisfy the criteria forfull approval if the results were “robust,” with a p-value 0.05,as well as multiple subgroups and locations showing equallyrobust results.

Alternatively, Katz said, FDA can grant accelerated approvalbased on an unvalidated surrogate endpoint if it believes theeffect on the surrogate is reasonably likely to predict a clinicalbenefit.

He added that the definition of reasonably likely will dependon a “detailed understanding of efficacy and safety and thebiological activity or pathophysiology of the drug.”

The panel voted 13-4 that the data from Fx-005 did notsupport full approval because 58% of patients were enrolled ina single site in Portugal, and there was a higher than expecteddropout rate due to liver transplant, leaving the study underpow-ered.

Fx-005 had 90% power to detect a significant treatmentdifference and assumed a 5-10% dropout rate, including drop-outs for liver transplant.

The dropout rate from transplant alone was 20%, which boththe agency and Pfizer agreed left the study underpowered.

Regulation

A rare win

“As I understand it,surrogate data has to besubstantial and the effect

reasonably likely to predictbenefit. One could makethat argument for muscle

strength and smallfiber function.”

Eric Logigian,University of Rochester

Medical Center


Regulation,from previous page

Tens of thousands of physicians and research-ers are crowding into Chicago this week for“ASCO” — the annual meeting of the AmericanSociety of Clinical Oncology.

In its ASCO preview, BioCentury This Weektelevision looks beyond the medical science tothe economics of cancer, from investors lookingfor upside to healthcare providers grapplingwith the mounting cost of care.

Dr. Mark Schoenebaum, Senior Managing Director and Head of HealthcareResearch at ISI Group, joins BioCentury This Week from Wall Street todiscuss the sustainability of oncology drug prices, the rise of “immune-oncology” and the showcase presentations at this year’s ASCO meeting.

In a Web Exclusive segment, Dr. Schoenebaum describes why drug pricing isa “big, big overhang” on biopharma stocks,saying the Street sees a “declining marginindustry.”

On the cost side, Dr. Thomas Smith, Director ofPalliative Medicine and Professor of Oncology atJohns Hopkins University, joins BioCentury ThisWeek to preview his ASCO session on theaffordability of care, and argue why and howoncologists must find ways to bend the costcurve in medical spending.

Watch Any Time on the Webwww.biocenturytv.com

New weekly shows go online at 9:00 a.m. EDT on Sundays.Prior shows available 24/7 in the online Program Archive.

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Substantial surrogatesDespite these shortcomings, panel

members did feel secondary endpointspointed to some level of clinical benefit.

Temporary voting member CliftonGooch was especially impressed by thesmall nerve fiber function score.

“Since this is the first population ofnerve fibers to be affected in this condition,it is, in effect, a canary in the coal mine. Soto see [efficacy] in a part of the nervoussystem where you would see the earliestsigns of disease, it is significant,” he said.

Gooch is chair of the department of

neurology at the University of SouthFlorida.

In response to Gooch, Katz remindedthe panel that FDA’s analysis showed thelevel of response on small nerve fiberfunction peaked at 18 months, and thenleveled off. Patients on placebo continuedto do worse, with the curves remainingseparated, but patients on treatment alsogot worse, he said.

Gooch countered that it is not surpris-ing to see a high initial response on smallnerve fiber function followed by a plateau.

“There are some nerves, in this casesmall fibers, that are barely alive, and adrug like this salvages them and enablesthe repair process to kick in, which gives

the patient an early bump before progres-sion starts,” but that doesn’t mean thedrug isn’t working, he said.

Gooch also noted that in diabetic neur-opathy, decreases in small fiber functionhave been associated with “significant mor-bidity.”

According to FDA’s briefing documents,small fiber function is an objective measureof peripheral nerve function and a surrogatemeasure of peripheral neuropathy.

The panel also felt the mean changefrom baseline in muscle weakness of 0.8 fortafamidis vs. 3.4 for placebo (p=0.013) wasan important marker of clinical benefit.

“As I understand it, surrogate data hasto be substantial and the effect reasonablylikely to predict benefit. One could makethat argument for muscle strength andsmall fiber function,” said Eric Logigian, atemporary voting member and professorof neurology at the University of Roch-ester Medical Center.

The panel also was impressed with theTTR stabilization score, which measuredthe proportion of stabilized TTR proteinin the plasma upon exposure to tafamidisvs. TTR ratio at baseline.

In the treatment group, the TTR stabi-lization ratio was 97% vs. 0% for placebo(p<0.0001).

Because TTR stabilization correlateswith amyloid fiber inhibition in vitro, Pfizerconsidered it to be a plausible biomarkerthat could predict clinical benefit.

Panel members agreed.“TTR stabilization was robust and just

makes sense,” temporary voting memberDavid Preston said.

Preston is vice chairman of neurologyand professor of neurology at UniversityHospitals — Case Medical Center.

Additionally, the panel felt that accel-erated approval was warranted due to theabsence of major adverse events in thetafamidis program and the lack of treat-ments beyond liver transplants.

ConfirmationAs Pfizer would need to have a confir-

matory trial started prior to acceleratedapproval, the pharma presented threepotential studies.

Donna Grogan, former CMO atFoldRx and a consultant to Pfizer, saidthese might include an open-label trialof tafamidis vs. historical controls, or aplacebo-controlled study of tafamidis inTTR FAP with muscle weakness at month12 as the primary endpoint.

Grogan also suggested the companySee next page


Regulation,from previous page

could use its TTR FAP patient registry tohelp confirm tafamidis’ clinical benefit.

The Transthyretin-Associated Amyloi-dosis Outcomes Survey (THAOS) is aninternational, multicenter disease registryopen to all patients with TTR FAP. Thelongitudinal registry collects data on symp-toms, symptom onset, ambulatory status, BMI and mBMI, neuro-logical examination, reflexes and sensory and cardiac tests.

Pfizer is using the registry to satisfy its postmarketing commit-ment with EMA, which approved tafamidis last November under theexceptional circumstances clause.

As of February, THAOS had enrolled more than 1,200patients with TTR FAP, including 99 patients on tafamidis and221 patients who have had liver transplant.

Business buildingIf the agency approves tafamidis in June, it would be Pfizer’s

second FDA-approved rare disease drug in as many months.On May 1, FDA approved Elelyso taliglucerase alfa for

Gaucher’s disease. Pfizer has exclusive rights outside of Israel toElelyso from Protalix Biotherapeutics Inc. (see BioCentury,Dec. 7, 2010).

Even if FDA issues a complete response letter for tafamidis,it may not be long before Pfizer adds to its stable of approvedOrphan drugs. Bosutinib, the pharma’s next most-advancedOrphan program, is under FDA review to treat Philadelphiachromosome-positive (Ph) chronic myelogenous leukemia (CML).

In January, FDA accepted Pfizer’s NDA for the dual inhibitorof BCR-ABL and Src kinase. The PDUFA date is undisclosed.

Pfizer announced its plans to expandits presence in rare disease in June 2010when the pharma established its Orphanand Genetic Diseases Research Unit. Atthe time, the pharma already had anestablished business in hemophilia.

Since the announcement, Pfizer hasbeen buying up or licensing new pro-grams.

Besides the FoldRx and Protalix deals,Pfizer announced a partnership last April with lysosomal storagedisease company Zacharon Pharmaceuticals Inc. to collab-orate on R&D for the biotech’s preclinical compounds formucopolysaccharidosis I, II and IIIA-C. Pfizer has an option totake over the program (see BioCentury, May 9, 2011).

In October, GlycoMimetics Inc. granted Pfizer exclusive,worldwide rights to GMI-1070 for sickle cell disease. Theglycomimetic inhibitor of E selectin (SELE; CD62E), P selectin(SELP; CD62P) and L selectin is in Phase II testing for vaso-occlusive crises associated with sickle cell disease. Results areexpected next half.

Pfizer takes over development after Phase II (see BioCentury,Oct. 31, 2011).

COMPANIES AND INSTITUTIONS MENTIONEDGlycoMimetics Inc., Gaithersburg, Md.Pfizer Inc. (NYSE:PFE), New York, N.Y.Protalix Biotherapeutics Inc. (NYSE-A:PLX; Tel Aviv:PLX), Carmiel,IsraelUniversity Hospitals — Case Medical Center, Cleveland, OhioUniversity of Rochester Medical Center, Rochester, N.Y.University of South Florida, Tampa, Fla.U.S. Food and Drug Administration (FDA), Silver Spring, Md.Zacharon Pharmaceuticals Inc., San Diego, Calif.

“TTR stabilizationwas robust and just

makes sense.”

David Preston, University Hospitals— Case Medical Center

BioCenturyCompany IndexMay 28, 2012

Abbott Biotech Ventures A16Abbott Labs A15Acadia Pharma A16Accelerator A16Achillion A17Actelion A2Active Bio A17Acylin Therap A16Affymax A19Alexandria Real Estate Equities A16Allozyne A16Almirall A19Am Academy of Neuro A2Amgen A5Amgen Ventures A16Arch Venture Partners A16Astellas A7, A19AstraZeneca A7, A16AuraSense A15Auxilium A18Aveo A5Bayer A7, A17, A19

Beta-O2 Technologies A8Biogen Idec A2Boehringer Ingelheim A19Celldex A17Chelsea Therap A17Cortec Group A16David Geffen Schl of Medi A4Delcath A18Delpor A11Dendreon A19Durect A11European Committee for Re-search and Treat A3FDA A12Furiex A16Galaxy Biotech A6Genentech A5GE A16Gilead A15, A16GlaxoSmithKline A7, A16, A18,A19GW Pharma A19Hope Multiple Sclerosis Ctr A4Hospital del Mar A6Human Genome Sci A19Incyte A10

Intarcia A11InterMune A19Ipsen A18iTeos Therap A10J&J A7, A11, A19Kanazawa U A6Kissei A19Ludwig Inst for Cancer Res A10Marnac A19MediciNova A17, A19MedImmune Ventures A16Medivation A16, A19Merck KGaA A2Merck Serono A16Mitsubishi Tanabe A2Myriad A19Nektar A16NeuroGenetic Pharma A15New Leaf Venture Partners A16NewLink Genetics A10Novartis A1Novavax A18Ono Pharma A2Onyx A17OVP A16Peregrine A17

Pfizer A7, A12Pharmaxis A17Pontifex A15Pozen A16PPD A16Protalix A14Receptos A2Roche A5Sernova A8SR One A16Syrrx A16Takeda A6, A16, A19Teva Pharma A18Theraclone A16U catholique de Louvain A10U Hospitals — Case Med Ctr A13U of Pittsburgh A6U of Rochester Med Ctr A13U of South Florida A13Veloxis A18Vertex A17VLST A16Waters A19Wilex A17WRF Capital A16Zacharon A14


See next page

By Stacy LawrenceSenior Writer

Pontifex Venture Partners has anovel strategy with its new fund — inten-tionally investing in U.S. biotechs that willhave losses for about three to five years toreceive a tax credit from an undisclosedother country and to offset gains fromother investments.

The $60 million fund is from an undis-closed investor domiciled outside the U.S.

“The country of jurisdiction places ahigh regard on U.S.-based biotech invest-ment opportunities,” Pontifex co-founderand Managing Member Andrew Fontaninitold BioCentury.

The new fund will invest in three to fivemid- to late-stage therapeutics companiesthis year. He expects to invest about $10-$20 million per deal, either alone or aspart of a syndicate, for a total of about $60million this year on behalf of the investor.

The primary criterion for investment isa company with roughly three to five yearsof net operating losses.

Secondary criteria include the scien-tific and business merits of a company,Fontanini said. He hopes to work withfundamental co-investors, allowing him topiggyback on their due diligence.

Pontifex is looking for biotechs withcompounds in Phase II or Phase III testingthat can achieve profitability or an exitafter the investor has taken advantage ofthe tax benefits.

Fontanini noted that Pontifex wouldalso help a portfolio company take advan-tage of the foreign tax jurisdiction if it wereto have substantial revenues or be ac-quired.

“We can work to move the companyinto the jurisdiction before there’s revenue or an exit to shelterthe money offshore,” he said.

Last year, the investor that Pontifex represents put $20million in an undisclosed Phase III company.

AbbVie earlierEarly stage investor Abbott Biotech Ventures will start

investing even earlier after parent company Abbott Laborato-ries (NYSE:ABT) splits in two, the firm’s head of ventureinvestment, Steven Kuemmerle, said at last week’s C21BioVentures conference in Napa, Calif.

Abbott Biotech Ventures will be part of AbbVie, a research-based pharmaceutical company. The other public company willhouse Abbott’s generics, devices, diagnostic and nutritionalbusinesses and retain Abbott’s name. The split is expected to

Ebb & Flow

Seeking sheltercomplete by year end.

Abbott Biotech Ventures typically in-vests in companies that are 12-18 monthsahead of an IND. Kuemmerle said the firmwill be able to push even earlier givenAbbVie’s exclusive focus on therapeutics.

The firm focuses on indications strate-gic to Abbott, including neuroscience,immunology, cardiology, virology and on-cology.

The firm, which does not have a de-fined fund, invested in at least two compa-nies in the past six months, neither ofwhich was in the clinic: Alzheimer’s dis-ease (AD) play NeuroGenetic Phar-maceuticals Inc. and nucleic acid thera-peutics company AuraSense Therapeu-tics LLC.

Kuemmerle said the firm has madenine investments since its inception twoand a half years ago.

The firm has had one exit: the 2010acquisition of Arresto BioSciences Inc. byGilead Sciences Inc. (NASDAQ:GILD)for $225 million in cash, plus potentialpayments based on sales. When it wasacquired, Arresto’s lead candidate was inPhase I testing for idiopathic pulmonaryfibrosis (IPF) and advanced solid tumors.The compound, AB0024, is a humanizedmAb against lysyl oxidase-like 2 (LOXL2).

Abbott Biotech Ventures typically in-vests $500,000-$15 million per deal witha 20% reserve, said Kuemmerle.

The firm typically limits its stake in acompany to a maximum of 15% and usu-ally is not interested in being a leadinvestor. It has, however, acted as the leada few times to keep a syndicate together.

Corporate VCs participated in 16% oflife science venture financings in the past

two years, according to data from PricewaterhouseCoopers, theNational Venture Capital Association (NVCA) and ThomsonReuters.

Kuemmerle cautioned, however, that “corporate VCs will becyclical because of management fatigue when they don’t see thekinds of returns they want or because of strategic realignment.”

Carried awayThree out of four corporate VCs on a panel at last week’s C21

BioVentures conference in Napa, Calif., said their compensationdoes not include carried interest. Any upside stays with thefunds, which could help relieve pharmas from further infusingthem with cash.

Most private equity players including VCs and hedge funds

Source: BCIQ: BioCentury Online Intelligence

Money Raised in 2012Last week, the biotech industry raised $191million, bringing to $12.5 billion the totalraised year-to-date. In 2011, a total of $49.5billion was raised, including $37.2 billion indebt and other fundraising, $4.2 billion infollow-ons, $1.8 billion in PIPEs, $1 billion inIPOs, and $5.3 billion in venture capital. Totalsinclude overallotments and warrants, and arerounded to the nearest millions.

Source: BCIQ: BioCentury Online Intelligence


Ebb & Flow,from previous page

See next page

are paid about a 2% management fee on a fund, plus a carriedinterest that is usually about 20% of any eventual profits in agiven fund.

Samuel Wu of MedImmune Ventures said compensationfor VCs at his firm consists of salary, bonus and shares in parentcompany AstraZeneca plc (LSE:AZN; NYSE:AZN).

The firm has a $400 million fund, and the team is “highlyincented to establish strong returns,” Wu said. “We’ve made itinto a true evergreen fund. If it shrinks, I shrink myself out of ajob.”

Wu joined MedImmune Ventures in 2010 from venture firmSV Life Sciences.

Nilesh Kumar of Merck Serono Ventures said that sincehis firm is only threeyears old, it is stillin validation modeand its VCs do notreceive carried in-terest. He joinedthe firm in 2009,the year of its in-ception. Among hisprior positions, hewas a VC with Atlas Ventures.

Steven Kuemmerle of Abbott Biotech Ventures said hereceives a salary and a bonus. “We can’t have a carry, althoughsome days I wish we did,” he said.

He has been with Abbott since 1987 and previously was inthe licensing group.

The outlier was Rajeev Dadoo of SR One, the venture armof GlaxoSmithKline plc (LSE:GSK; NYSE:GSK). He said hisfirm uses a mix of corporate and traditional VC compensationstructures. SR One, an evergreen fund, creates virtual funds orbaskets of investments and VC compensation includes carriedinterest tied to those.

Since its inception in 1985, SR One has invested more than$650 million in private and public biotechs.

Pressing the AcceleratorVenture-backed incubator Accelerator Corp. is raising a

fourth fund that it expects to close by year end, Chairman andCEO Carl Weissman told BioCentury.

Weissman, who also is a managing director at OVP VenturePartners, expects the fund to total $22.5 million, the same sizeas the prior fund and enough for about six investments, unlessinvestors opt to expand Accelerator into another geographicalregion from the Pacific Northwest.

Investors include Amgen Ventures, Arch Venture Part-ners, OVP, PPD Inc., WRF Capital and Alexandria RealEstate Equities Inc. The syndicate invests pro rata in everyseries A round, but investment in a series B round or beyond isoptional.

Accelerator gets a contractual first look at innovationscoming out of Leroy Hood’s Institute for Systems Biology (ISB).

Accelerator has invested in 12 life sciences companies since2003, five of which have graduated from Accelerator and itsfacilities.

One investment came from ISB; two were from introductionsmade by Hood and ISB; another two came from the Accelerator

“We’ve made it into a trueevergreen fund. If it shrinks,I shrink myself out of a job.”

Samuel Wu, MedImmune Ventures

syndicate; and one came from a cold proposal. Acceleratorsourced the remaining six deals, Weissman said.

He added that only two investments — protein therapeuticsplay Allozyne Inc. and acylation inhibitor company AcylinTherapeutics Inc. — were deals that were evaluated byseveral other VCs prior to an investment. The remaining dealflow was evaluated solely by Accelerator.

In total, Accelerator companies have raised more than $216million, with about $45 million in series A investments. Of that,about $12 million was invested in series A financings forcompanies that didn’t advance.

Five of the Accelerator companies have raised series Brounds, including autoimmune and inflammation play VLSTCorp. ; infectious disease and inf lammation companyTheraclone Sciences Inc.; and Allozyne.

Although Accelerator has yet to see any exits, Weissman saidhe expects some this year.

Venture tracksSue Siegel joined healthymagination, the $6 billion healthcare

initiative of General Electric Co. (NYSE:GE), as CEO. Siegelwas a general partner at Mohr Davidow. She replaces MikeBarber, who becomes VP and general manager of GE’s GEHealthcare unit.

Mohr Davidow is one of four VC firms that partnered with GEto launch a healthymagination grant program last September forresearch on breast cancer diagnostics.

Jeremy Lack joined healthcare-focused private equity firmCortec Group as managing director. He was a principal atNew Leaf Venture Partners.

Analyst tracksRobert Hazlett joined Roth Capital Partners LLC as

senior research analyst for biopharmaceuticals. He was a man-aging partner at RCH Ventures LLC. Prior to that, he was amanaging director at BMO Capital Markets.

Since joining Roth, he has started coverage of three compa-nies: neurology play Acadia Pharmaceuticals Inc.(NASDAQ:ACAD); Nektar Therapeutics (NASDAQ:NKTR),which develops therapeutics based on its PEGylation andpolymer conjugation technologies; and pain company PozenInc. (NASDAQ:POZN).

Regulatory milestonesFuriex Pharmaceuticals Inc. (NASDAQ:FURX) gained

$3.34 (21%) to $19.10 last week after EMA accepted for reviewan MAA from Takeda Pharmaceutical Co. Ltd. (Tokyo:4502)for alogliptin to treat Type II diabetes. The acceptance triggersa $10 million milestone payment to Furiex, which co-developedalogliptin with Syrrx Inc. Takeda acquired Syrrx in 2005.

Gilead Sciences Inc. (NASDAQ:GILD) was up $0.55 to$50.49 last week after EMA accepted for review an MAAfor cobicistat as a boosting agent for HIV treatment with pro-tease inhibitors. The application was submitted in April. Gileadplans to submit an application to FDA next quarter.

Medivation Inc. (NASDAQ:MDVN) gained $4.23 to $87.38last week after submitting an NDA to FDA for enzalutamide(formerly MDV3100) to treat castration-resistant prostate can-cer in patients previously treated with docetaxel. The company



requested Priority Review.Onyx Pharmaceuticals Inc.

(NASDAQ:ONXX) gained $4.98 (12%)to $46.80 last week after it and BayerAG (Xetra:BAYN) submitted regulatoryapplications in the EU and U.S. for rego-rafenib to treat metastatic colorectalcancer. Onyx has co-promotion rights inthe U.S. and is eligible for a 20% royalty onworldwide sales.

Separately, Onyx and Bayer saidNexavar sorafenib plus best supportivecare missed the primary endpoint of over-all survival vs. placebo plus best support-ive care in the Phase III MISSION trial totreat relapsed or refractory non-squa-mous non-small cell lung cancer (NSCLC).

Onyx said MISSION is the third failedPhase III trial of Nexavar for lung cancer.The partners do not plan to continuedeveloping the product in the indication.Nexavar is marketed for liver and ad-vanced kidney cancers.

Pharmaxis Ltd. (ASX:PXS; Pink:PXSLY) lost A$0.09 to A$1.02 last weekafter submitt ing an NDA to FDAfor Bronchitol mannitol to treat cystic fi-brosis (CF). Bronchitol is approved inAustralia and the EU.

Vertex Pharmaceuticals Inc.(NASDAQ:VRTX) gained $0.76 to $64.85on Friday after EMA’s CHMP recom-mended approval of Kalydeco ivacaftor totreat cystic fibrosis (CF) in patients agessix years and older who have at least onecopy of the G551D mutation in the cysticfibrosis transmembrane conductance regu-lator (CFTR). The company expects a finaldecision from the EC in three to fourmonths. Vertex was up $3.51 for theweek.

Wilex AG (Xetra:WL6) was up €0.06to €3.85 on Friday after announcing FDA’sOncologic Drugs Advisory Committee(ODAC) will meet on July 25 and reviewthe development strategy of kidney can-cer diagnostic Redectane. Wilex gained€0.29 for the week.

Clinical milestonesAchillion Pharmaceuticals Inc.

(NASDAQ:ACHN) gained $0.71 (11%) to$7.21 on Monday after ACH-2684 led toa mean maximum reduction in HCV RNAlevels from baseline to day three of 3.36log10 IU/mL vs. 0.68 log10 IU/mL forplacebo in a Phase Ib trial in patients withHCV genotype 1 infection. Full data areexpected in 4Q12 (see B13). See next page

BioCenturyTHETHETHETHETHE B B B B BERNSTEINERNSTEINERNSTEINERNSTEINERNSTEIN R R R R REPORTEPORTEPORTEPORTEPORT ONONONONON B B B B BIOIOIOIOIOBBBBBUSINESSUSINESSUSINESSUSINESSUSINESS

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Achillion gained $0.85 (13%) to $7.35last week.

Celldex Therapeutics Inc. (NASDAQ:CLDX) gained $0.39 to $4.50last week after reporting data from thePhase IIb EMERGE trial showing glem-batumumab vedotin (CDX-011) led to anoverall response rate of 19% vs. 14% forchemotherapy in patients with advanced,refractory or resistant glycoproteinNMB (GPNMB)-expressing breast cancer.The company will decide on next stepsafter receiving updated data expected in4Q12 (see B16).

Chelsea Therapeutics Internation-al Ltd. (NASDAQ CHTP) was off $0.25(12%) to $1.84 on Tuesday after announc-ing plans to modify the ongoing Phase IIIStudy 306B of Northera droxidopa basedon a meeting with FDA about a completeresponse letter for the neurogenic orthos-tatic hypotension product. The companyplans to resubmit an NDA in 1Q13 (seeB11).

Chelsea was off $0.12 to $1.87 lastweek.

MediciNova Inc. (NASDAQ:MNOV;Osaka:4875) fell $1.18 (43%) to $1.57 onThursday after MN-221 as an adjunct tostandard of care missed the primary end-point of improving percent predicted forcedexpiratory volume in one second (FEV1)at three hours vs. standard of care alonein a Phase IIb trial to treat severe acuteexacerbations of asthma. The companyplans to continue development in theindication and has requested an end-of-Phase II meeting with FDA (see B22).

The stock was off $1.32 (43%) to $1.75last week.

Peregrine PharmaceuticalsInc. (NASDAQ:PPHM) gained $0.09(21%) to $0.53 on Monday after reportingpositive top-line data from a Phase IIb trialof bavituximab as a second-line treatmentfor locally advanced or metastatic non-squamous non-small cell lung cancer(NSCLC). Overall response rate (ORR),the primary endpoint, was higher in pa-tients receiving bavituximab plus docetaxelvs. placebo plus docetaxel. Peregrine saidthe trial was not powered to detect statis-tical significance but the results supportPhase III development for NSCLC.

Peregrine was up $0.12 (28%) to $0.56last week.

Ebb & FlowActive Biotech AB (SSE:ACTI) rose

CHF5 (12%) to CHF45.80 on Mondayafter receiving a €10 million ($12.8 mil-


lion) milestone payment from Ipsen Group (Euronext:IPN)triggered by the completion of 50% of the planned enrollment ina Phase III trial of oral tasquinimod to treat metastatic castra-tion-resistant prostate cancer (CRPC). Top-line data are ex-pected by YE13.

Active Biotech gained CHF1.50 to CHF42.30 last week. Ipsengained €0.39 to €20.74.

Auxilium Pharmaceuticals Inc. (NASDAQ:AUXL) wasup $1.64 to $19.27 last week after granting GlaxoSmithKlineplc (LSE:GSK; NYSE:GSK) exclusive U.S. rights to co-promoteTestim, a testosterone replacement therapy. As a result, Auxiliumraised its 2012 global Testim revenue guidance to $225-$235million from $215-$225 million. The company now expects totalrevenues for the year of $293-$315 million, up from $283-$305million.

Drug delivery company Delcath Systems Inc. (NASDAQ:DCTH) fell $0.88 (37%) to $1.50 on Friday after raising $20million through the sale of 13.3 million units at $1.50 per unitin a follow-on. Each unit comprises a share and a three-yearwarrant to purchase 0.3 shares, with each whole warrantexercisable at $1.65. The stock lost $0.49 (25%) last week.

Neurology company D-Pharm Ltd. (Tel Aviv:DPRM) gainedNIS0.01 to NIS0.90 last week after announcing it will merge withstroke company Thrombotech Ltd. in a stock deal. Shareholdersof Thrombotech will own 60% of the combined company.

In February, D-Pharm said it was in negotiations for the deal

after discontinuing development of stroke therapy DP-b99 dueto lack of efficacy.

Vaccines company Novavax Inc. (NASDAQ:NVAX) gained$0.11 to $1.27 last week after raising $12.2 million through thesale of 10 million shares at $1.22 in a private placement. Theprice is a 5% premium to Novavax’s close of $1.16 on May 18,before the offering was announced.

Teva Pharmaceutical Industries Ltd. (NASDAQ:TEVA)lost $0.29 to $38.61 last week after new President and CEOJeremy Levin cut 2012 guidance in a business update butstopped short of revealing details of his strategy for the company.

Levin expects to present a full plan by year end. Teva nowexpects $20-$21 billion in sales, down from previous expecta-tions of $22 billion, and non-GAAP EPS of $5.30-$5.40, downfrom $5.48-$5.68 (see B8).

Veloxis Pharmaceuticals A/S (CSE:VELO) fell DKK0.12(16%) to DKK0.65 on Wednesday after announcing plans toreduce headcount by 40-50% to conserve resources to developand commercialize LCP-Tacro to prevent organ rejection. Thecompany said it will discontinue other pipeline activities, includ-ing early phase research, but did not provide details.

Veloxis expects the restructuring to save about DKK35-DKK40 million ($6-$6.9 million) annually starting in 2013. AtMarch 31, the company had DKK213.8 million ($36.7 million)in cash. Its 2011 operating loss was DKK269.9 million ($47million). The stock was off DKK0.13 (17%) to DKK0.64 for theweek.

— Staff Writers Andrew Fisher, Kevin Lehnbeuter & Jon Wollebencontributed to this week’s Ebb & Flow


Save the DateFriday, September 7th in New York City

Celebrating its 19th year as the premiere Wall Street collaborative gathering of the life science investment and corporatecommunities, organizers BioCentury and Thomson Reuters remind you to save the date to kick off the fall investmentseason at NewsMakers in the Biotech Industry.

NewsMakers remains the best opportunity — in a single day — for the investment community to assess the prospects of48 news-driven public biotech and mid-tier pharma companies with ample runway, unpartnered assets and major productand earnings events.

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Presenting CompaniesThe NewsMakers Class of 2012 will include up to 48publicly traded companies independently selected byBioCentury based on objective selection criteria, includinginvestor validation, unpartnered assets and upcoming, value-creating milestones, informed by the collective intelligence ofThomson Reuters and the conference sponsors. Forinformation on presenting company opportunities, pleaseemail [email protected].

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Analyst picks & changesCompany Bank Analyst Coverage Opinion Wk chg 5/25 cls

Affymax Inc. (NASDAQ:AFFY) MLV Ed Arce Price target Buy 8% $14.07

Arce raised his target to $21 from $12 after Affymax and partner Takeda Pharmaceutical Co. Ltd. (Tokyo:4502) launched once-monthlyOmontys peginesatide in the U.S. to treat anemia in chronic kidney disease (CKD) patients who are on dialysis (see BioCentury, April 30). Hebelieves the net overall cost of Omontys will be lower than anemia drug Epogen epoetin alfa from Amgen Inc. (NASDAQ:AMGN), and thatnephrologists will view Omontys’ label as comparable to Epogen in terms of efficacy and risk. Arce also anticipates an EU launch of thesynthetic peptide-based erythropoiesis-stimulating agent (ESA) in early 2013.

Dendreon Corp. (NASDAQ:DNDN) Jefferies Biren Amin New Underperform -2% $7.11

Biren also set a $5 target. He believes Dendreon’s Provenge sipuleucel-T is likely to be a “distant third in terms of market share” in asymptom-atic/minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). He sees Zytiga abiraterone acetate and enzalutamide(formerly MDV3100) “potentially offering a more compelling value proposition of improved clinical benefits with lower cost densities, fewerreimbursement issues, and greater ease of use.” Zytiga is marketed by Johnson & Johnson (NYSE:JNJ). Medivation Inc. (NASDAQ:MDVN) lastweek submitted an NDA for enzalutamide, an oral androgen receptor antagonist partnered with Astellas Pharma Inc. (Tokyo:4503).

GW Pharmaceuticals plc (LSE:GWP) Nomura Samir Devani Downgrade Neutral (from buy) 1% 78.50p

Devani also lowered his target to 100p-105p from 110p-115p after the company reported Sativex sales for fiscal 1H ended March 31, 2012 of£1.7M ($2.7M), below his estimate of £2.4M ($3.8M). GW also announced Sativex sales guidance for the fiscal year of about £2.5M, belowDevani’s estimate of £5.6M. The sublingual cannabis extract spray containing tetrahydrocannabinol (THC) and cannabidiol (CBD) is approvedto treat spasticity due to multiple sclerosis (MS) in Canada, Spain, New Zealand, Germany, Denmark and the U.K., and was recommended forapproval under the EU Mutual Recognition Procedure in 10 additional countries in May. Bayer AG (Xetra:BAYN) has rights to market Sativexin Canada and the U.K. from GW, while Almirall S.A. (Madrid:ALM) has rights in the rest of Europe and Mexico.

Human Genome Sciences BMO Capital Jim Birchenough Downgrade Market perform -3% $13.61Inc. (NASDAQ:HGSI) Markets (from outperform)

Birchenough also lowered his target to $13 from $17 after GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) amended its hostile offer to acquirepartner Human Genome for $13 per share to require that the biotech invalidate or redeem its recently-adopted poison pill (see B4). He said theprocess between the companies has become “more adversarial” and believes the chances of a price bump or the addition of a contingent valueright tied to darapladib has diminished. He also believes there is an increased risk GSK will drop the offer and that a competitive process isunlikely to yield an alternate offer in the near term. Darapladib, a small molecule inhibitor of vascular inflammation mediator lipoprotein-associated phospholipase A2 (Lp-PLA2) coronary, is in Phase III testing for coronary heart disease.

InterMune Inc. (NASDAQ:ITMN) Canaccord Ritu Baral Price target Buy 6% $10.73

Baral lowered her target to $15 from $24 on strong future competition and lower sales prospects for InterMune’s Esbriet pirfenidone to treatidiopathic pulmonary fibrosis. She believes competing IPF product Vargatef nintedanib (formerly BIBF 1120) from Boehringer IngelheimGmbH may be approved in the U.S. before Esbriet. Baral believes Esbriet still has blockbuster potential, but reduced her worldwide peak salesestimate in 2025 to $2.1B from $3.6B. InterMune has rights to Esbriet from Marnac Inc. in the U.S., Europe and other territories. BI’s Vargatefis a triple kinase inhibitor in Phase III testing for IPF.

MediciNova Inc. MLV Ed Arce Downgrade Hold (from buy) -43% $1.75(NASDAQ:MNOV; Osaka:4875)

Arce also removed his target after MediciNova reported that MN-221 missed the primary endpoint in a Phase IIb trial to treat severe acuteexacerbations of asthma (see B22). MediciNova said it still plans to develop MN-221 for the indication, but Arce is “not convinced” the companywill be able to improve the probability of success for future trials. MediciNova has exclusive, ex-Japanese rights to the selective adrenergicreceptor beta 2 (ADRB2) agonist from Kissei Pharmaceutical Co. Ltd. (Tokyo:4547).

Myriad Genetics Inc. Leerink Dan Leonard Upgrade Outperform (from 4% $25.53(NASDAQ:MYGN) market perform)

Leonard also raised his target to $30-$31 from $27-$30, saying he thinks concerns related to diagnostic company’s reimbursement risk and IPconcerns are “overdone” based on his calls with clinicians and reimbursement specialists, as well as a literature review. Leonard thinks newCMS payment codes, expected to be set before year end, will be in the ballpark of Myriad’s current pricing. He also thinks the U.S. Court ofAppeals for the Federal Circuit will affirm a July 2011 ruling that Myriad’s composition patents covering the breast cancer 1 early onset(BRCA1) and BRCA2 genes are valid.

Waters Corp. (NYSE:WAT) Mizuho Peter Lawson Upgrade Buy (from neutral) 2% $82.10

Lawson also raised his target to $92 from $84, saying he favors pharma vs. academic exposure “due to a lack of visibility into 2013 funding andthe NIH overhang.” He noted that the research tool supplier has about a 55% exposure to drug discovery organizations (pharma, biotech,CRO, etc.), and about a 15% exposure to government/academic institutions.

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BioCentury tracks 579 issues that report prices and volume daily. TheBioCentury 100 is a subset used to monitor price and volume trends.

BioCentury 100 Price & Volume TrendCumulative weekly performance of 100 bioscience stocks. 12-week period.Line shows Price Level change (Left scale. Index base=1000 on May 10,1996). Bars show cumulative volume in millions (right scale).

Price GainsStocks with greatest % price increase in the week ended May 25.(Priced above $2; 5,000 minimum share volume)Company Ticker $Close $Chg %Chg Vol(00)Rosetta Genomics1 ROSG 13.240 7.740 141% 251699Complete Genomics GNOM 3.000 1.360 83% 257777Amyris AMRS 2.570 0.980 62% 44091Telik TELK 5.230 1.560 43% 5831Neptune Tech2 NEPT 3.840 0.960 33% 31080Vermillion VRML 2.220 0.460 26% 60663Pacific Biosciences PACB 2.600 0.490 23% 33524Repros RPRX 9.010 1.610 22% 17867Furiex Pharma FURX 19.100 3.340 21% 3692Idenix IDIX 9.680 1.600 20% 80501Galectin Therap GALT 2.380 0.340 17% 5173CytRx CYTR 3.450 0.490 17% 22473

Price DeclinesStocks with greatest % price decline (criteria as above).Company Ticker $Close $Chg %Chg Vol(00)ECI 4567 ¥6650.00 -¥5350 -45% 135Prima BioMed3 PBMD 4.110 -0.730 -15% 302858CellSeed 7776 ¥665.000 -¥115 -15% 2348Santhera SANN CHF4.010 -CHF0.64 -14% 400Novogen4 NVGN 2.070 -0.260 -11% 31172Albany Mol Res AMRI 2.710 -0.300 -10% 3735Deinove ALDEI €8.140 -€0.760 -9% 100Cumberland CPIX 6.090 -0.500 -8% 1025Lonza LONN CHF35.13 -CHF2.59 -7% 18863Curasan CUR €2.790 -€0.199 -7% 70Senomyx SNMX 2.330 -0.165 -7% 7050

Volume GainsGreatest changes in volume above 5,000 shares.Company Ticker Vol(00) %Chg $Close $ChgOrexo ORX 51308 9930% SEK25.3 SEK3.50PCI PCIB 835 2145% NOK36 -NOK1Complete Genomics GNOM 257777 761% 3.000 1.360Evogene EVGN 10026 524% NIS16.47 -NIS0.37Alexion ALXN 397233 490% 92.420 8.160Vermillion VRML 60663 475% 2.220 0.460Telik TELK 5831 443% 5.230 1.560Flamel FLML 6728 428% 4.380 -0.250Novogen4 NVGN 31172 342% 2.070 -0.260

BioCentury 100 Advance-Decline TrendBC100 BC100 BC100

Week Price Stocks Gaining Stocks Decliningended level gaining vol. (00) declining vol. (00)

Apr 20 2766.23 80 10137590 17 1120821May 04 2674.79 15 2373235 85 5617862May 11 2749.85 67 4756570 33 2440138May 18 2615.21 13 645325 87 6088088May 25 2720.76 81 4712381 18 1474079

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BioCentury London IndexWeekly change in the combined market capitalization for 14 biosciencestocks listed on the LSE or AIM, 12-week period. Index base =1000 onMay 10, 1996.

May 25

1 Volume figure is of ADSs (ADS = 1 share)2 Includes volume from Toronto Stock Exchange3 Includes volume from Australian Stock Exchange with converted ADSs(ADS = 30 shares)4 Includes volume from Australian Stock Exchange with converted ADSs(ADS = 25 shares)

BioCenturyBioBusiness for the week ended May 25

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week's corporate, clinical and financial news.BioCentury Week in Review is a com-

prehensive compendium of business newsfor management and investors in biosciencecompanies. It is organized into three de-partments: Company News, Clinical Newsand Financial News.

The index on this page lists all thecompanies covered this week. The newsitems in each department are organizedalphabetically by company. When morethan one company is listed, the biotechcompany is shown first. Each brief is la-beled with one or more applicable busi-ness categories from the following list:

ADMET; Agbio/Environmental; Anti-bodies; Autoimmune; Bioinformatics;Biomanufacturing; Biopharmaceuticals;Biosimilars; Cancer; Cardiovascular;Chemistry; Combinatorial biology; Com-putational chemistry/biology; Dental; Der-matology; Diagnostic; Drug delivery; En-docrine/Metabolic; Finance; Functional ge-nomics; Gastrointestinal; Gene/Cell ther-apy; Generics; Genitourinary; Genomics;Hematology; Hepatic; High throughputscreening; Infectious; Inflammation; Mi-croarrays; Microfluidics; Musculoskeletal;Neurology; Nutraceuticals; Ophthalmic;Other; Pharmaceuticals; Pharmacogenet-ics; Proteomics; Pulmonary; Renal; Supply/Service; Transplant; Veterinary

WWWWWEEKEEKEEKEEKEEK INININININ R R R R REVIEWEVIEWEVIEWEVIEWEVIEW

Volume 20 • Number 22 • Page B1 of 31

WEEK OF MAY 28, 2012

COMPANY NEWS

Deals (Page B2)

Active Bio (SSE:ACTI)/Ipsen (Euronext:IPN)Almirall (Madrid:ALM)/Aslan PharmaAlnylam (NASDAQ:ALNY)/Plant BioscienceAnGes (Tokyo:4563)/MorishitaBioDelivery (NASDAQ:BDSI)/Meda (SSE:

MEDAA)BioTime (NYSE-A:BTX)/XenneXCodexis (NASDAQ:CDXS)/Merck (NYSE:MRK)D-Pharm (Tel Aviv:DPRM)/ThrombotechDaiichi Sankyo (Tokyo:4568; Osaka:4568)/Japa-

nese Natl Cancer CntrEpitargetEverist Genomics/ManipalExact Sciences (NASDAQ:EXAS)/Mayo ClinicGen-Probe (NASDAQ:GPRO)/Roche (SIX:

ROG; OTCQX:RHHBY)GE (NYSE:GE)/Karolinska U HospitalGenmab (CSE:GEN)/GlaxoSmithKline (LSE:

GSK; NYSE:GSK)H. Lundbeck (CSE:LUN)/CHDI FoundationHuman Genome (NASDAQ:HGSI)/Glaxo-

SmithKline (LSE:GSK; NYSE:GSK)Immune Pharmaceuticals/Weizmann Inst of

ScienceIntelliCell (OTCQB:SVFC)/U of FloridaInterMune (NASDAQ:ITMN)/VidaraKinex/Xiangxue (Shenzhen:300147)Laboratory Corp. (NYSE:LH)/XDxMarina (OTCQX:MRNA)/Solvay (Euronext:SOLB)Multilab/Takeda (Tokyo:4502)

Sales & Marketing (Page B5)

AkrimaxAllergy (LSE:AGY)/Lincoln MedicalAuxilium (NASDAQ:AUXL)/GlaxoSmithKline

(LSE:GSK; NYSE:GSK)BTG (LSE:BGC)/WellstatCellectis (Euronext:ALCLS)CellectriconDyax (NASDAQ:DYAX)Eisai (Tokyo:4523; Osaka:4523)Kyowa Hakko (Tokyo:4151)Pfizer (NYSE:PFE)

Other News (Page B6)

Auxilium (NASDAQ:AUXL)/Watson (NYSE:WPI)

AstraZeneca (LSE:AZN; NYSE:AZN)/Glaxo-SmithKline (LSE:GSK; NYSE:GSK)

Bavarian Nordic (CSE:BAVA)BioPorto (CSE:BIOPOR)ElexoPharm/Khondrion/Pharmacelsus/Radboud UHaloiPierianNeuroSearch (CSE:NEUR)OpGen

QLT (TSX:QLT; NASDAQ:QLTI)Takeda (Tokyo:4502)Teva (NASDAQ:TEVA)Veloxis (CSE:VELO)Vertex (NASDAQ:VRTX)/Crohn’s and Colitis

Fndtn

Management Tracks (Page B8)

Achillion (NASDAQ:ACHN)Albany Molecular (NASDAQ:AMRI)AlkeusAspenBio (NASDAQ:APPY)AvrahamBecton Dickinson (NYSE:BDX)GenVec (NASDAQ:GNVC)Organovo (OTCQB:ONVO)ParatekPfizer (NYSE:PFE)PPDS1 BiopharmaSigmoid PharmaTalon (OTCBB:TLON)

CLINICAL NEWS

Regulatory (Page B9)

Aerocrine (SSE:AERO)Almirall (Madrid:ALM)/Forest (NYSE:FRX)/

Kyorin (Tokyo:4569)Bayer (Xetra:BAYN)Bayer (Xetra:BAYN)/J&J (NYSE:JNJ)Biogen Idec (NASDAQ:BIIB)/Elan (NYSE:ELN)Boehringer IngelheimCelgene (NASDAQ:CELG)Cepheid (NASDAQ:CPHD)Chelsea (NASDAQ:CHTP)/Dainippon (To-

kyo:4506; Osaka:4506)Dafra PharmaEisai (Tokyo:4523; Osaka:4523)Emergent BioSolutions (NYSE:EBS)Furiex (NASDAQ:FURX)/Takeda (Tokyo:4502)Genentech/Chugai (Tokyo:4519)/Roche

(SIX:ROG; OTCQX:RHHBY)Gilead (NASDAQ:GILD)/Japan Tobacco (To-

kyo:2914; Osaka:2914)GlaxoSmithKline (LSE:GSK; NYSE:GSK)Medivation (NASDAQ:MDVN)/Astellas (To-

kyo:4503)

BioCentury Week in Review MAY 28, 2012 PAGE B2 OF 31

COMPANY NEWS/Deals, Sales & Marketing, Other News, Management Tracks

Regulatory,from previous page

See next page

DEALS

Active Biotech AB (SSE:ACTI), Lund, SwedenIpsen Group (Euronext:IPN), Boulogne-Billancourt, FranceBusiness: Cancer

Active Biotech said it received a €10 million ($12.8 million)milestone payment from partner Ipsen under a 2011 deal to co-developand commercialize Active Biotech’s tasquinimod. The milestone wastriggered by the completion of 50% planned enrollment — 600 of 1,200patients — in a Phase III trial of oral tasquinimod to treat metastaticcastration-resistant prostate cancer (CRPC). Top-line data from thetrial are expected by year end 2013. The milestone payment is the firstunder the deal. Active Biotech is eligible for about an additional €165million ($210.7 million), plus tiered double-digit royalties.Tasquinimod is a quinoline-3-carboxamide derivative that binds S100calcium binding protein A9 (S100A9; calgranulin B; MRP14) (see BioCentury,April 25, 2011).

Almirall S.A. (Madrid:ALM), Barcelona, SpainAslan Pharmaceuticals Pte. Ltd., SingaporeBusiness: Autoimmune

Almirall granted Aslan exclusive, worldwide rights to developLAS186323, a dihydroorotate dehydrogenase (DHODH) inhibitor inPhase I testing for rheumatoid arthritis. Aslan will conduct and funddevelopment through the end of Phase II trials, after which Aslan willfind a partner for Phase III development and commercialization. Detailswere not disclosed.

Aslan’s business model is to pick up molecules to developthrough Phase II proof-of-concept (POC) trials and then return aPhase III-ready compound to the originator or find a partner to take

it to commercialization. The company was founded in 2010. InNovember, Bristol-Myers Squibb Co. (NYSE:BMY, New York,N.Y.) granted Aslan rights to develop and commercialize BMS-777607. The c-Met tyrosine kinase inhibitor is in Phase I/II forcancer (see BioCentury, Nov. 7, 2011).

Alnylam Pharmaceuticals Inc. (NASDAQ:ALNY), Cambridge, Mass.Plant Bioscience Ltd., Norwich, U.K.Business: Pharmaceuticals

Tech development and IP management company Plant Biosciencegranted Alnylam a non-exclusive, worldwide license to U.S. patent No.8,097,710 — the Baulcombe patent — for use in developing RNAitherapeutics. The patent, which was issued in January, covers a post-transcriptional gene silencing method using short RNA molecules.Details were not disclosed.

AnGes MG Inc. (Tokyo:4563), Osaka, JapanMorishita Jintan Co. Ltd. (Tokyo:4524; Osaka:4524), Osaka, JapanBusiness: Infectious, Drug delivery

AnGes said Morishita will use its enteric-coated capsule drugdelivery technology with AnGes’ HPV vaccine targeting E7 transformingprotein (human papillomavirus-16; HpV16gp1). AnGes is developingthe preclinical vaccine with GenoLac BL Corp. (Okinawa, Japan) undera 2011 deal. Details were not disclosed (see BioCentury, Aug. 15, 2011).

BioDelivery Sciences International Inc. (NASDAQ:BDSI), Raleigh, N.C.Meda AB (SSE:MEDAA), Solna, SwedenBusiness: Neurology

BioDelivery received a $2.5 million milestone payment from

Merck (NYSE:MRK)Novo Nordisk (CSE:NVO; NYSE:NVO)Novo Nordisk (CSE:NVO; NYSE:NVO)/

Bristol-Myers (NYSE:BMY)OceraPfizer (NYSE:PFE)Pharmaxis (ASX:PXS; Pink:PXSLY)ProRetinaProsensa/GlaxoSmithKline (LSE:GSK; NYSE:

GSK)Repros Therapeutics (NASDAQ:RPRX)Seattle Genetics (NASDAQ:SGEN)/Takeda

(Tokyo:4502)Transgenomic (OTCBB:TBIO)Vertex (NASDAQ:VRTX)

Clinical Results (Page B13)

Achaogen/Isis (NASDAQ:ISIS)Achillion (NASDAQ:ACHN)Ardea (NASDAQ:RDEA)/Bayer (Xetra:BAYN)ArQule (NASDAQ:ARQL)/Daiichi Sankyo (To-

kyo:4568; Osaka:4568)/Kyowa (Tokyo:4151)

Array (NASDAQ:ARRY)/AstraZeneca (LSE:AZN; NYSE:AZN)

Array (NASDAQ:ARRY)/Genentech/Roche(SIX:ROG; OTCQX:RHHBY)

Astex (NASDAQ:ASTX)Aveo (NASDAQ:AVEO)/Astellas (Tokyo:

4503)/Kyowa (Tokyo:4151)Boehringer IngelheimCelldex (NASDAQ:CLDX)Chugai (Tokyo:4519)/Daiichi Sankyo (To-

kyo:4568; Osaka:4568)/Roche (SIX:ROG;OTCQX:RHHBY)

Curis (NASDAQ:CRIS)/DebiopharmCuris (NASDAQ:CRIS)/Genentech/Chugai

(Tokyo:4519)/Roche (SIX:ROG; OTCQX:RHHBY)

Eisai (Tokyo:4523; Osaka:4523)Eisai (Tokyo:4523; Osaka:4523)/SFJ PharmaEli Lilly (NYSE:LLY)EtubicsGlaxoSmithKline (LSE:GSK; NYSE:GSK)Horizon (NASDAQ:HZNP)/SkyePharma

(LSE:SKP)ImmunoGen (NASDAQ:IMGN)/Sanofi (Euron-

ext: SAN; NYSE:SNY)Inovio (NYSE-A:INO)Ipsen (Euronext:IPN)/Rhythm PharmaJ&J (NYSE:JNJ)MediciNova (NASDAQ:MNOV; Osaka:4875)/

Kissei (Tokyo:4547)

Merck (NYSE:MRK)MolMed (Milan:MLM)Neurocrine (NASDAQ:NBIX)Oncothyreon (NASDAQ:ONTY)Onyx (NASDAQ:ONXX)/Bayer (Xetra:BAYN)Onyx (NASDAQ:ONXX)/Ono Pharmaceuti-

cal (Tokyo:4528; Osaka:4528)Peregrine (NASDAQ:PPHM)Pharmacyclics (NASDAQ:PCYC)/J&J (NYSE:

JNJ)Piramal (BSE:500302; NSE:PIRHEALTH)Roche (SIX:ROG; OTCQX:RHHBY)Takeda (Tokyo:4502)Theravance (NASDAQ:THRX)/GlaxoSmith-

Kline (LSE:GSK; NYSE:GSK)U of Michigan

Preclinical Results (Page B26)

Arrowhead (NASDAQ:ARWR)

Clinical Status (Page B26x)

Amgen (NASDAQ:AMGN)/Cytokinetics(NASDAQ:CYTK)

ArQule (NASDAQ:ARQL)/Daiichi Sankyo (To-kyo:4568; Osaka:4568)/Kyowa Hakko (To-kyo:4151),

Aveo (NASDAQ:AVEO)See next page


See next page

Deals,from previous page

Meda under a 2006 deal granting Meda exclusive European rights todevelop and commercialize Breakyl fentanyl. The payment wastriggered by the pricing approval and registration in Finland, thefirst European country. BioDelivery is eligible for another $2.5million milestone payment at launch, which is slated for later thisyear. The adhesive disc formulation of fentanyl is approved to treatbreakthrough pain in opioid-tolerant adult cancer patients. Earlierthis year, BioDelivery postponed the relaunch of Onsolis fentanylin the U.S. so that two appearance issues raised by FDA can beaddressed (see BioCentury, March 19).

BioTime Inc. (NYSE-A:BTX), Alameda, Calif.XenneX Inc., Cambridge, Mass.Business: Genomics, Bioinformatics

BioTime’s LifeMap Sciences Inc. subsidiary completed its acquisi-tion of XenneX in a stock deal. XenneX shareholders received 1.4million shares, or about 13% of the common shares of LifeMap, as wellas 448,431 shares of BioTime valued at $1.8 million based on BioTime’sclose of $4.02 on May 18, before the deal closed.

LifeMap also acquired exclusive, worldwide rights to MalaCardsfrom Yeda Research and Development Co. Ltd. (Rehovot, Israel).LifeMap expects to launch the database of human diseases by year end.Yeda is the tech transfer arm of the Weizmann Institute of Science(Rehovot, Israel). Details were not disclosed (see BioCentury, April 30).

Codexis Inc. (NASDAQ:CDXS), Redwood City, Calif.Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J.Business: Supply/Service

The partners extended by three years to 2015 a 2007 deal grantingnon-exclusive rights to Codexis’ enzyme products for manufacturingundisclosed compounds. Details were not disclosed (see BioCentury,April 9, 2007).

D-Pharm Ltd. (Tel Aviv:DPRM), Rehovot, IsraelThrombotech Ltd., Ness Ziona, IsraelBusiness: Neurology, Cardiovascular

D-Pharm will merge with stroke company Thrombotech in astock deal. Shareholders of Thrombotech will own 60% of thecombined company, while D-Pharm shareholders will own 40%. InFebruary, D-Pharm said it was in negotiations for the deal afterdiscontinuing development of its own stroke therapy DP-b99 dueto lack of efficacy. The combined company’s pipeline will include:

Thrombotech’s THR-18, a short peptide plasminogen activatorinhibitor-1 (PAI-1) in Phase II testing to treat acute ischemicstroke; and D-Pharm’s DP-VPA, a phospholipid derivative of valproicacid that completed a Phase II trial in patients with complex partialepilepsy (see BioCentury, March 5).

Daiichi Sankyo Co. Ltd. (Tokyo:4568; Osaka:4568), Tokyo, JapanJapanese National Cancer Center, Tokyo, JapanBusiness: Cancer

In February, Daiichi Sankyo and the center partnered to dis-cover and develop anti-cancer agents. Under the three-year deal,the center will provide Daiichi Sankyo with research results thatare in line with broad research topics to expand Daiichi’s pipelineincluding its survival signals and epigenetics programs. Daiichi willdecide whether to collaborate with the center on targets. Daiichiwill conduct high throughput screening of viable targets. Thecenter will receive funding from Daiichi for the provided research,plus additional funding for each collaborative research projectimplemented. The partners will negotiate ownership of IP gener-ated under the deal based on each partners’ contribution. Detailswere not disclosed.

Epitarget A/S, Oslo, NorwayBusiness: Drug delivery

An undisclosed pharma company will supply custom short interfer-ing RNA molecules for Epitarget to test on its ultrasound triggeredsiRNA delivery platform. Epitarget and its academic partner FrenchNational Institute of Health and Medical Research (Inserm) are respon-sible for in vivo testing. Details were not disclosed.

Epitarget’s technology allows for the encapsulation of active sub-stances in nano-sized liposomes, which can be released in tumors byexposure to a targeted ultrasound field.

Everist Genomics Inc., Ann Arbor, Mich.Manipal Education and Medical Group International India Pvt.Ltd., Bangalore, IndiaBusiness: Diagnostic

Everist and Manipal formed a JV to market Everist’s AngioDefenderand CardioDefender diagnostics for cardiovascular disease in India, aswell as Everist’s gene-based molecular assays to predict cancer recur-rence. Everist said it expects the JV will have $100 million in revenuesover the next 36 months. Details were not disclosed. Everist has rightsto AngioDefender through its acquisition of Angiologix Inc. in October(see BioCentury, Nov. 7, 2011).

Clinical Status,from previous page

AvrahamCatalyst (NASDAQ:CPRX)CerecorClinuvel (ASX:CUV; Xetra:UR9)Diamyd Medical (SSE:DIAM B)EsperanceGeoVax (OTCBB:GOVX)GW Pharma (LSE:GWP)/OtsukaInsmed (NASDAQ:INSM)Kaketsuken/GlaxoSmithKline (LSE:GSK;

NYSE:GSK)MorphoSys (Xetra:MOR; Pink:MPSYF)/XencorNorthwest Biotherapeutics (OTCBB:NWBO)

NovaBay (NYSE-A:NBY)Pluristem (NASDAQ:PSTI; Tel Aviv:PSTI)SangartStemCells (NASDAQ:STEM)Trimel (TSX:TRL)

FINANCIAL NEWS

Completed Offerings (Page B30)

Advaxis (OTCBB:ADXS)ApepticoCatalyst (NASDAQ:CPRX)Delcath Systems (NASDAQ:DCTH)Flowonix MedicalGenovis (NASDAQ:GENO)

KiyatecNovavax (NASDAQ:NVAX)Sigmoid

Amended Offerings (Page B30)

Trovagene (Pink:TROV)

Other Financial News (Page B30)

Arena (NASDAQ:ARNA)Emergent (NYSE:EBS)Inserm TransfertProsonixRecipharmSangartSynageva (NASDAQ:GEVA)Tengion (NASDAQ:TNGN)


See next page


Exact Sciences Corp. (NASDAQ:EXAS), Madison, Wis.Mayo Clinic, Rochester, Minn.Business: Diagnostic

The partners expanded a 2009 deal to give Exact Sciences exclusive,worldwide rights to develop and commercialize IP covering sampleprocessing, analytical testing and data analysis associated with screen-ing for gastrointestinal cancers and diseases, as well as stool- andblood-based testing for other cancers. The clinic will receive an upfrontpayment and research funding, and is eligible for milestones androyalties. Details were not disclosed.

In 2009, Mayo granted Exact Sciences an exclusive, worldwidelicense to develop and commercialize IP covering non-invasive, stool-based DNA screening for colorectal cancer diagnostics and screens (seeBioCentury, June 22, 2009).

Gen-Probe Inc. (NASDAQ:GPRO), San Diego, Calif.Roche (SIX:ROG; OTCQX:RHHBY), Basel, SwitzerlandBusiness: Diagnostic

Gen-Probe sub-licensed to Roche’s Ventana Medical SystemsInc. tissue diagnostic unit co-exclusive, worldwide rights to IPcovering the measurement of ERG expression through immunohis-tochemistry (IHC) in prostate tissue for an in vitro diagnostic.Ventana said it believes testing for the ERG biomarker will beimportant for diagnostic, prognostic and predictive prostate can-cer tests. Details were not disclosed. ERG is an oncogene thatrearranges and fuses with androgen response elements in abouthalf of prostate cancer patients but not in healthy tissue.

General Electric Co. (NYSE:GE), Fairfield, Conn.Karolinska University Hospital, Stockholm, SwedenBusiness: Gene/Cell therapy

General Electric’s GE Healthcare unit partnered with the hos-pital to study future technology and workflow needs for celltherapies in a clinical setting. Under the three-year deal, GE and thehospital will identify technologies needed to grow, handle, processand analyze cells. The partners also are seeking to identify repro-ducible and standardized protocols and workflows for manufactur-ing and quality control. Details were not disclosed.

Genmab A/S (CSE:GEN), Copenhagen, DenmarkGlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.Business: Cancer

Genmab said it received a DKK20 million ($3.4 million) milestonepayment from partner GlaxoSmithKline under a 2006 deal to co-develop and commercialize Arzerra ofatumumab. The payment wastriggered by the submission of an NDA to Japan’s Ministry of Health,Labor and Welfare (MHLW) for Arzerra to treat chronic lymphocyticleukemia (CLL). GSK, which has worldwide co-development and com-mercialization rights, markets the anti-CD20 mAb in the U.S. and EU forthe indication (see BioCentury, Jan. 1, 2007 & April 30, 2012).

H. Lundbeck A/S (CSE:LUN), Copenhagen, DenmarkCHDI Foundation Inc., New York, N.Y.Business: Neurology

Not-for-profit foundation CHDI and Lundbeck partnered to inves-tigate a targeted therapy for Huntington’s disease. CHDI will conductpreclinical studies on an undisclosed compound from Lundbeck andfocus on the compound’s effect on purinergic receptor P2X, which thepartners say may be involved in HD. Details were not disclosed.

Human Genome Sciences Inc. (NASDAQ:HGSI), Rockville, Md.GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.Business: Autoimmune, Cardiovascular, Endocrine/Metabolic

GlaxoSmithKline added a condition to its hostile tender offer toacquire Human Genome for $13 per share that the biotech redeem itsshareholder rights plan or satisfy GSK that the plan has been invalidatedor does not apply to the pharma. The plan, announced earlier thismonth, gives shareholders the right to purchase additional shares if ahostile group acquires 15% or more of the company’s shares. GSKannounced plans for the tender offer earlier this month after refusingto participate in Human Genome’s strategic review process (seeBioCentury, April 23; May 14 & May 21).

Immune Pharmaceuticals Ltd., Herzliya-Pituach, IsraelWeizmann Institute of Science, Rehovot, IsraelBusiness: Cancer, Antibodies

Immune partnered with Yeda Research and Development CompanyLtd., the institute’s technology transfer arm, to develop antibodiesagainst epidermal growth factor receptor 3 (EGFR3; HER3; ErbB3) forcancer. Immune will develop and evaluate multiple antibody formats,including human mAbs, dual epitope-targeting bi-specific antibodies andantibody nanoparticle conjugates. Immune, which is leading and fundingdevelopment, will have exclusive rights to Yeda’s IP. Immune will alsoprovide research funding to the institute and contribute its IP. Yeda iseligible for undisclosed milestones and royalties for each productdeveloped under the deal. Details were not disclosed.

IntelliCell BioSciences Inc. (OTCQB:SVFC), New York, N.Y.University of Florida, Gainesville, Fla.Business: Gene/Cell therapy

IntelliCell partnered with the university’s Institute for CellEngineering and Regenerative Medicine to research the physiologi-cal characteristics of stromal vascular fraction cells. IntelliCell alsointends to develop combination therapies with other bio-engi-neering products under development. IntelliCell’s technology sepa-rates stromal vascular fraction to produce adipose-derived adultstem cells for use in tissue processing centers and doctor’s offices.Details were not disclosed.

InterMune Inc. (NASDAQ:ITMN), Brisbane, Calif.Vidara Therapeutics International Ltd., IrelandBusiness: Inflammation, Musculoskeletal

InterMune will divest to Vidara worldwide rights to developand commercialize Actimmune interferon (IFN) gamma-1b for $55million in cash. InterMune is also eligible for tiered royalties fortwo years, which the company said could add about 5% to thepurchase price. InterMune said the deal will provide additionalcapital for the registration and commercialization of its idiopathicpulmonary fibrosis (IPF) drug Esbriet pirfenidone, as well as for itsR&D programs. The deal is expected to close this quarter. LocustWalk Partners is advising InterMune.

InterMune markets Actimmune to treat chronic granulomatousdisease and severe, malignant osteopetrosis. The company re-corded 2011 sales for Actimmune of $20.2 million. InterMune hasrights to Esbriet from Marnac Inc. (Dallas, Texas) in the U.S.,Europe and other territories. Shionogi & Co. Ltd. (Tokyo:4507;Osaka:4507, Osaka, Japan) has rights in South Korea and Taiwan,and markets it as Pirespa for IPF in Japan. Esbriet is a small moleculeinhibitor of proinflammatory cytokines such as tumor necrosisfactor (TNF) alpha and IL-1 beta, as well as pro-fibrotic cytokines,including platelet derived growth factor (PDGF) and transforminggrowth factor (TGF) beta.


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Kinex Pharmaceuticals LLC, Buffalo, N.Y.Xiangxue Pharmaceutical Co. Ltd. (Shenzhen:300147), Guangzhou,ChinaBusiness: Cancer

Kinex granted Xiangxue exclusive rights in China, Taiwan andSingapore to develop and commercialize KX02 for cancer. KX02 is alipophilic dual inhibitor of Src and pretubulin. In the U.S., Kinex said itplans to submit an IND early next quarter. Kinex said the deal will allowit access to a large population of patients with brain tumors — theintended indication for KX02. Kinex will receive an upfront paymentand is eligible for milestones and royalties. Xiangxue will make an equityinvestment in Kinex. Details were not disclosed.

Laboratory Corp. of America Holdings (NYSE:LH), Burlington, N.C.XDx Inc., Brisbane, Calif.Business: Diagnostic

LabCorp and XDx partnered to discover biomarkers to predictflares of systemic lupus erythematosus (SLE) and develop a predictivetest based on the markers. The partners said the deal combines XDx’sSLE blood sample database and LabCorp’s diagnostic development andcommercialization resources. XDx will be responsible for biomarkerdiscovery, while the partners will collaborate on development. LabCorpwill be responsible for commercialization. Details were not disclosed.

Marina Biotech Inc. (OTCQX:MRNA), Bothell, Wash.Solvay S.A. (Euronext:SOLB), Brussels, BelgiumBusiness: Chemistry

Girindus AG (Hannover, Germany), a contract manufacturing or-ganization and member of Solvay, received exclusive, worldwide rightsto develop and commercialize oligonucleotides using Marina’s Confor-mationally Restricted Nucleotide (CRN) chemistry. Marina will beeligible royalties and will receive cGMP material from Girindus forMarina’s internal programs. Details were not disclosed.

Multilab Industria e Comercio de Produtos Farmaceuticos Ltda.,Sao Jeronimo, BrazilTakeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, JapanBusiness: Generics

Takeda will acquire branded generics and OTC company Multilab forBRL500 million ($247.6 million) up front and up to BRL40 million ($19.8million) in milestones. According to Takeda, Multilab reported netrevenues of BRL140 million ($69.3 million) in 2011. Takeda, whichreported EUR 260 million ($347 million) in Brazilian sales for the fiscalyear ending March 31, 2012, said the deal will strengthen its positionin the country and diversify its OTC portfolio.

The deal is expected to close by the end of next quarter. JPMorganadvised Takeda, while BTG Pactual advised Multilab. Mattos Filho VeigaFilho Marrey Jr. e Quiroga Advogados was legal advisor for Takeda,while Pinheiro Neto Advogados was legal advisor for Multilab.

SALES & MARKETING

Akrimax Pharmaceuticals LLC, Cranford, N.J.Business: Endocrine/Metabolic

Akrimax launched Suprenza phentermine orally disintegrating tab-lets in the U.S. as a short-term adjunct to treat obesity. The wholesaleacquisition cost is $45 for the 15 mg dose and $67.50 for the 30 mg dose.Akrimax has rights to market the sympathomimetic amine anorecticfrom Citius Pharmaceuticals LLC (Maynard, Mass.).

Allergy Therapeutics plc (LSE:AGY), London, U.K.Lincoln Medical Ltd., Salisbury, U.K.Business: Drug delivery, Inflammation

Allergy said Lincoln is recalling Anapen adrenaline for injectionin the U.K. to treat anaphylactic shock due to a potential problemwith delivery time and auto-injector dose volume. Lincoln said itreceived no reports of defects or adverse events related to theissues. Allergy markets the product in the U.K., Ireland, theNetherlands and Poland. Sales of Anapen in the territories were£845,000 ($1.3 million) for 2H11. Lincoln is required to reimburseAllergy for assisting with the recall. Allergy has rights to distributeAnapen from Lincoln. The issue was discovered by manufacturerOwen Mumford Ltd. (Oxford, U.K.).

Auxilium Pharmaceuticals Inc. (NASDAQ:AUXL), Malvern, Pa.GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.Business: Endocrine/Metabolic

Auxilium granted GlaxoSmithKline exclusive rights in the U.S. toco-promote testosterone replacement therapy Testim. Auxilium willbook all sales of the topical 1% testosterone gel and pay GSK apercentage of net sales above an undisclosed baseline. GSK is expectedto begin promoting Testim early next quarter. Auxilium will remainresponsible for all manufacturing, supply and regulatory activities. Thedeal expires on Sept. 30, 2015.

As a result of the GSK deal, Auxilium raised its 2012 global Testimrevenue guidance to $225-$235 million from $215-$225 million.Auxilium now expects total revenues for the year of $293-$315 million,up from previous expectations of $283-$305 million. Auxilium re-ported 2011 net revenues for Testim of $207.9 million worldwide.

BTG plc (LSE:BGC), London, U.K.Wellstat Therapeutics Corp., Gaithersburg, Md.Business: Other

Wellstat granted BTG exclusive rights to distribute uridine triac-etate in the EU on a named-patient basis to treat an overdose of thechemotherapy 5-fluorouracil (5-FU). BTG also received an option tolicense EU marketing rights for the indication. Wellstat will be respon-sible for regulatory filings and will receive an upfront payment. Wellstatwill receive an upfront payment, and is eligible for a payment uponexercise of the option as well as transfer pricing payments based onmanufacturing costs and a “significant” percentage of net sales. Detailswere not disclosed.

Last year, Wellstat granted BTG marketing rights to the product in theU.S., where it is available under emergency-use IND provisions and anexpanded access protocol. Uridine triacetate has Orphan Drug designa-tion in the U.S. and the EU for the indication (see BioCentury, July 11, 2011).

Cellectis S.A. (Euronext:ALCLS), Paris, FranceBusiness: Gene/Cell therapy, ADMET

Cellectis’ Cellectis stem cells business unit launched hips-HEP.The hepatocyte-like cells are derived from human induced pluripo-tent stem (iPS) cells and used for in vitro drug discovery, toxicitytesting and vaccine development.

Cellectricon AB, Moelndal, SwedenBusiness: Supply/Service

Cellectricon launched its Cellaxess Elektra Discovery technology foradherent cell electroporation. The technology can be used for stimulationand voltage control of cultures in small molecule screening, transfectionof short interfering RNA (siRNA) and cDNA to primary cell cultures ingenomic screening applications, as well as delivery of small molecules andantibodies in lead identification and target validation.


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Dyax Corp. (NASDAQ:DYAX), Burlington, Mass.Business: Cardiovascular

Dyax launched a refund program for patients receiving diagnostictesting for hereditary angioedema (HAE). Patients who do not havehealth insurance coverage or have a copay, coinsurance or deductiblefor HAE diagnostic testing are eligible to have expenses refunded.Those not eligible include patients enrolled in any government healthcareprogram, such as Medicare, Medicaid or Tricare, and patients residingin Massachusetts, Michigan, Minnesota or Rhode Island. Dyax marketsKalbitor ecallantide, a subcutaneously delivered yeast-derived recom-binant plasma kallikrein inhibitor, to treat HAE in the U.S. Last Novem-ber, Dyax withdrew an MAA in Europe for Kalbitor in the indicationbecause EMA’s CHMP indicated that the information provided was notsufficient to demonstrate a positive benefit-risk balance (see BioCentury,Nov. 21, 2011).

Defiante Farmaceutica S.A., an affiliate of Sigma-Tau Group (Pomezia,Italy), has commercialization rights to the product in Europe, NorthAfrica, the Middle East, Russia, Taiwan, Singapore, South Korea, LatinAmerica, Australia and New Zealand (see BioCentury, June 6, 2011).

Eisai Co. Ltd. (Tokyo:4523; Osaka:4523), Tokyo, JapanBusiness: Neurology

Eisai’s Eisai Europe Ltd. subsidiary launched Zebinix eslicarbazepineacetate in Sweden as an adjunct therapy for epilepsy in adults withpartial-onset seizures with or without secondary generalization. Thecompany said the product will receive full reimbursement from Swedishhealth authorities. Details were not disclosed.

Eisai has marketing rights to the once-daily sodium channelblocker from Bial-Portela & Ca. S.A. (S. Mamede do Coronado, Portu-gal) in Europe under a 2009 deal (see BioCentury, Feb. 23, 2009).

Kyowa Hakko Kirin Co. Ltd. (Tokyo:4151), Tokyo, JapanBusiness: Pharmacogenetics

Kyowa’s Kyowa Medex Co. Ltd. subsidiary launched the PoteligeoTest IHC and Poteligeo Test FCM companion diagnostics in Japan toidentify subpopulations of adult T cell leukemia-lymphoma patientslikely to respond to treatment with the company’s Poteligeomogamulizumab. Poteligeo Test IHC, an immunohistochemistry (IHC)test, is used with tissue samples such as lymph nodes or skins of ATLpatients. Poteligeo Test FCM, a flow cytometry (FCM) test, is used toevaluate blood samples.

Potel igeo, a humanized ant i-CC chemokine receptor4 (CCR4; CD194) mAb, is approved to treat relapsed orrefractory CCR4-positive T cell leukemia-lymphoma. Amgen Inc.(NASDAQ:AMGN, Thousand Oaks, Calif.) has exclusive rightsfrom Kyowa to develop and commercialize Poteligeo for all non-cancer indications outside of Japan, Korea, China and Taiwan (seeBioCentury, March 10, 2008).

Pfizer Inc. (NYSE:PFE), New York, N.Y.Business: Hematology, Drug delivery

Pfizer launched its Xyntha Solofuse in Canada to control and preventbleeding episodes and for surgical prophylaxis in hemophilia Apatients. The prefilled, dual-chamber syringe that is used to deliver IVXyntha recombinant Factor VIII is available in 1,000, 2,000 and 3,000 IUdoses. The product is also approved in the U.S.

Pfizer gained the product through its 2009 acquisition of Wyeth,which licensed exclusive rights to the peptide ligands used in thepurification process from Dyax Corp. (NASDAQ:DYAX, Burlington,Mass.) in 2001 (see BioCentury, May 29, 2001).

OTHER NEWS

Auxilium Pharmaceuticals Inc. (NASDAQ:AUXL), Malvern, Pa.Watson Pharmaceuticals Inc. (NYSE:WPI), Parsippany, N.J.Business: Endocrine/Metabolic

Auxilium and FCB I Holdings Inc. filed suit in the U.S. District Courtfor the District of New Jersey alleging an ANDA from Watson for ageneric version of Auxilium’s Testim infringes patents covering thetopical 1% testosterone gel. The patents, which expire on various datesfrom April 21, 2023 through Jan. 18, 2025, include U.S. Patent Nos.7,320,968; 7,608,605; 7,608,606; 7,608,607; 7,608,608; 7,608,609;7,608,610; 7,935,690; 8,063,029; and 8,178,518. The ANDA containsParagraph IV certifications claiming that the patents are invalid, unen-forceable and/or will not be infringed by the ANDA. Auxilium reported2011 net revenues for Testim of $205.1 million in the U.S. and $207.9million worldwide. FCB, which is controlled by Footstar Corp. (Mahwah,N.J.), is the surviving entity that granted Auxilium rights to a transdermalgel formulation technology containing testosterone under a 2000 deal.

AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K.GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.Business: Infectious

The EU’s Innovative Medicines Initiative launched theNewDrugs4BadBugs grant program to fund development of newantibiotics against antibiotic-resistant bacteria, including productsfrom GlaxoSmithKline and AstraZeneca. The program will alsocreate an information hub to facilitate information sharing. Theprogram wil l in it ia l ly support Phase I I and I I I tr ia ls ofGSK’s GSK1322322, an antibacterial agent that inhibits peptidedeformyalse function. IMI will provide €88 million ($112.4 mil-lion), with an additional in-kind contribution of €103.7 million($132.4 million) from industry partners. An additional €3 million($3.8 million) from IMI and €5 million ($6.4 million) from industrywill be available for projects to improve the efficiency of antibioticclinical trials.

IMI also plans to support the development at a later date of twoproducts from AstraZeneca: AZD9773, a polyclonal sheep antibodyfragment against tumor necrosis factor (TNF) alpha; and MEDI4893, amAb targeting a Staphylococcus aureus toxin. AZD9773 is in Phase IItesting, while MEDI4893 is in early stage development. IMI expects toprovide €92 million ($117.5 million), with an additional in-kind contri-bution of €276 million ($352.4 million) from industry.

IMI is also accepting proposals for a broader research program thataims to improve the permeability of drugs into Gram-negative bacteria.Industry will contribute €8 million ($10.2 million) in kind, while IMI willcontribute €16 million ($20.4 million).

IMI, which said additional projects are in development, expectsthe seven-year ND4BB program to have an overall budget of about€600 million ($766 million). IMI is a joint undertaking by theEuropean Commission and the European Federation of Pharmaceu-tical Industries and Associations (EFPIA). EFPIA participants alsoinclude: Basilea Pharmaceutica AG (SIX:BSLN, Basel, Switzerland),Johnson & Johnson (NYSE:JNJ, New Brunswick, N.J.) and Sanofi(Euronext:SAN; NYSE:SNY, Paris, France).

Bavarian Nordic A/S (CSE:BAVA), Kvistgaard, DenmarkBusiness: Infectious

Bavarian Nordic said the U.S. government expanded by $32million to $544 million a June 2007 contract to supply the company’sImvamune smallpox vaccine to the U.S. Strategic National Stockpile.The company said it requested the additional funding to conduct a


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Phase III trial of Imvamune in 4,000 healthy volunteers, which islarger than was initially proposed. The trial is expected to beingenrolling in 1H13. The company said it has recognized a total of$220 million in revenue under the contract. Bavarian has deliveredmore than 8 million doses of a planned 20 million doses of thevaccine, with the remained doses to be delivered this year and next.Bavarian Nordic is developing Imvamune under FDA’s Animal Rule,which allows marketing approval to be granted based on efficacy inrelevant animal models and an acceptable safety risk profile inhumans (see BioCentury, June 11, 2007).

BioPorto Diagnostics A/S (CSE:BIOPOR), Gentofte, DenmarkBusiness: Diagnostic

BioPorto said that the European Patent Office (EPO) rejected thecompany’s European Patent No. EP1831699, covering a method ofdiagnosing renal disorders by applying a cutoff when measuring theconcentration of the lipocalin (LCN2; NGAL) biomarker. BioPorto andits patent attorney, Suzzane Hoiberg, plan to appeal the decision in lateSeptember. The company said the patent will remain valid until a finaldecision on the appeal, which it expects to be processed in 2014.

The EPO’s opposition division found that the patent is insufficientlydescribed. Specifically, the EPO said that the patent’s cut-off thresholdvalue of 250 ng/mL NGAL is too low, and patients will incorrectly beclassified as having renal affection. However, BioPorto argues that theEPO’s determination is based on an erroneous calculation of thespecificity. The EPO also found that it has not been rendered probablethat the method can diagnose all types of renal affection, such as chronickidney injury, but the company said the purpose of the method is notto differentiate between types of renal affection.

Last August, BioPorto said that a provisional opinion from the EPOfound that the NGAL patent may have been issued too broadly or onan incorrect basis. BioPorto markets its NGAL Test in Canada and theEU. BioPorto disclosed in its 2010 annual report that in 3Q10 the EPOsaid there were four objections to the company’s NGAL patent. Theobjections came from Abbott Laboratories (NYSE:ABT, Abbott Park,Ill.), Alere Inc. (NYSE:ALR, Waltham, Mass.), the Phadia AB subsidiaryof Thermo Fisher Scientific Inc. (NYSE:TMO, Waltham, Mass.) and oneother company. The in vitro diagnostic that detects NGAL produced inthe kidney to diagnose acute kidney injury is also under review in theU.S. Abbott and Alere also market NGAL immunoassays in Europe (seeBioCentury, Sept. 5, 2011).

ElexoPharm GmbH, Saarbruecken, GermanyKhondrion B.V., Nijmegen, the NetherlandsPharmacelsus GmbH, Saarbruecken, GermanyRadboud University Nijmegen Medical Centre, Nijmegen, theNetherlandsBusiness: Pharmaceuticals

A consortium consisting of Khondrion, ElexoPharm, Pharmacelsusand Radboud received a three-year €2.1 million ($2.7 million) grantfrom the German Federal Ministry of Education and Research, under theEurostars R&D program, to discover therapies for mitochondrialdiseases. ElexoPharm is responsible for design and synthesis of smallmolecules using in silico modeling and medicinal chemistry technologies.Khondrion will conduct in vitro evaluation of the new chemical entities,including screening in its cell-based mitochondrial disease models.Pharmacelsus will conduct ADME, toxicity, pharmacokinetic studies,and the university will conduct in vivo preclinical testing on selectedcompounds. Details were not disclosed.

Halo Therapeutics LLC, Newton, Mass.Business: Musculoskeletal

Halo received $1.1 million from 12 not-for-profits comprising a mixof grant money and notes that will be repaid with a fixed return shouldundisclosed pre-defined events occur. Halo will use the funds for itsPhase II trial of HT-100 in Duchenne muscular dystrophy (DMD) slatedto begin next half. HT-100 is an oral analog of halofuginone, a collagentype I (COL1) inhibitor. Details were not disclosed. Halo acquired theproduct, which has Orphan Drug designation in the U.S. and EU for theindication, from Collgard Biopharmaceuticals Ltd. (Petah Tikva, Israel)last year (see BioCentury, Jan. 9).

The not-for-profits are: Action Duchenne; Coalition Duchenne;Cure Duchenne; Duchenne Now; Duchenne Research Fund; Hope forGus; Hope for Javier; Jain Foundation; Michael’s Cause; Parent ProjectMuscular Dystrophy; Ryan’s Quest; and Zubin’s Wish.

iPierian Inc., South San Francisco, Calif.Business: Neurology, Gene/Cell therapy

iPierian announced it selected the first two development pro-grams for its pipeline: mAbs targeting microtubule-associatedprotein tau (MAPT; tau; FTDP-17) and the complement pathway totreat neurodegenerative diseases. The company, which previouslysaid it would focus on neurodegenerative diseases such asAlzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) andspinal muscular atrophy, will use its in vitro disease models tovalidate therapeutic targets or mechanisms of disease. The modelsare based on the company’s patient-derived induced pluripotentstem cells (iPSC) technology and combine human cortical neurons,motor neurons, microglia and astrocytes. iPierian said it expectsto select lead antibodies for both programs “in the near future.”Additionally, the company said it hired Pamela Conley as VP ofresearch, formerly VP of research biology at Portola Pharmaceu-ticals Inc. (South San Francisco, Calif.).

NeuroSearch A/S (CSE:NEUR), Ballerup, DenmarkBusiness: Neurology

NeuroSearch said the State Prosecutor from the Office for Eco-nomic Crime filed preliminary charges alleging share price manipulationfrom a Feb. 3, 2010 announcement of top-line results from the PhaseIII MermaiHD trial that sent NeuroSearch shares soaring DKK83 (98%)to DKK168. The company reported that twice-daily Huntexil pridopidinemet the primary endpoint of significantly improving voluntary motorfunction vs. placebo at week 26 in patients with Huntington’s disease.However, on April 28, 2010, the company released a revised analysisthat showed the dopamine stabilizer did not meet the primary endpointsending shares falling DKK52 (30%) to DKK120. The company is denyingthe charges and is collaborating fully with the authorities to resolve thematter (see BioCentury, Feb. 8, 2010 & May 3, 2010).

Last month, NeuroSearch said it is seeking a worldwide partnershipfor Huntexil after it was unable to secure a deal that would haveexcluded European rights. The company attributed the difficulty infinding an ex-European partner to an increased risk for the program inthe U.S. Last year, FDA and EMA requested additional Phase III data tosupport Huntexil’s previously observed effect on the total motorscore (TMS) and to substantiate the clinical relevance of the effect (seeBioCentury, April 16).

OpGen Inc., Gaithersburg, Md.Business: Genomics, Infectious

OpGen formed a public health consortium to evaluate its wholegenome mapping technology as an enhanced method for strain typingmicroorganisms that cause disease outbreaks. The consortium comprises


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the Association of Public Health Laboratories (APHL), the Centers forDisease Control and Prevention (CDC), the University of MarylandInstitute for Genome Sciences, and 11 U.S. state public health laboratories.

QLT Inc. (TSX:QLT; NASDAQ:QLTI), Vancouver, B.C.Business: Ophthalmic, Drug delivery

QLT postponed its annual meeting to June 4 from May 24 aftershareholders controlling about 22.8 million, or about 40%, of thecompany’s shares submitted proxy statements to the SEC in support ofa dissident slate of directors proposed by NB Public Equity KomplementarApS, which is seeking to replace up to six QLT board members. At April30, the company had 49.1 million shares outstanding.

QLT issued a statement highlighting four initiatives proposed by theboard. The company said a “key priority” will be the development ofQLT091001 for retinal diseases caused by inherited lecithin-retinolacyltransferase (LRAT) or retinal pigment epithelium-specific protein65kDa (RPE65) gene mutations. The synthetic retinoid replacementtherapy for 11-cis-retinal completed Phase Ib trials in retinitispigmentosa (RP) due to inherited LRAT or RPE65 mutations and Leber’scongenital amaurosis (LCA). QLT said it plans to continue developmentof its punctual plug drug delivery technology, but said investmentsbeyond Phase II would not occur without a partner to “significantlyoffset” expenses. The company also plans to repurchase $75-$100million in shares through a Dutch auction tender offer next quarter.Lastly, QLT said it plans to submit a PMA to FDA by mid-year for a newlaser for use with ophthalmic drug Visudyne verteporfin.

QLT markets Visudyne in U.S. for wet age-related macular degenera-tion (AMD), while partner Novartis AG (NYSE:NVS; SIX:NOVN, Basel,Switzerland) markets it elsewhere. Visudyne is a light-activatedbenzoporphyrin derivative used in photodynamic therapy (PDT). In 1Q12,the product had $5.2 million in U.S. sales and $22.5 million in worldwidesales. QLT had $9 million in total 1Q12 revenues. QLT091001 has FastTrack designation in the U.S. and Orphan Drug designation in the U.S. andEU to treat LCA and RP. At March 31, the company had $207.2 million incash, with a three-month operating loss of $11.8 million. QLT had a 2011operating loss of $38.8 million.

Takeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, JapanBusiness: Antibodies, Biopharmaceuticals

Takeda’s California subsidiary said it will close its South SanFrancisco site and relocate the most essential antibody and biologicsresearch to San Diego. In January, Takeda merged its South SanFrancisco and San Diego subsidiaries into one business, called TakedaCalifornia Inc. The company said about half of the about 50 employeesfrom the South San Francisco site will be offered positions in San Diego.

Takeda San Diego was established in March 2005 through the acqui-sition of structural biology company Syrrx, while the South San Franciscosite was formed in 2007 to focus on antibodies. In March, Mary Haak-Frendscho, who was the founding president and former CSO of the SouthSan Francisco business, became executive chair of the newly establishedmAb subsidiary of Compugen Ltd. (NASDAQ:CGEN, Tel Aviv, Israel) inSouth San Francisco (see BioCentury, Feb. 14, 2005 & May 26, 2008).

Teva Pharmaceutical Industries Ltd. (NASDAQ:TEVA), Petah Tikva,IsraelBusiness: Autoimmune, Neurology, Biosimilars

Jeremy Levin, who officially took over as president and CEO of Tevathis month, cut 2012 guidance and announced plans to present a fullstrategic plan for the company by year end after concluding a review ofTeva’s assets, R&D programs and overall strategy. Levin said the

company would be looking to divest businesses that do not fit andpartner pipeline assets that are not in core areas. CFO Eyal Deshehadded that Teva has instituted a cost-cutting and efficiency program. Tevaalso appointed Allan Oberman as head of generics in the U.S., effectivein July. He was previously head of generics in Eastern Europe, Israel,the Middle East and Africa regions. Oberman replaces Timothy Crew,who is transitioning to a new, undisclosed position at the company.

Teva now expects $20-$21 billion in sales and non-GAAP EPS of$5.30-$5.40, down from previous expectations of $22 billion in salesand non-GAAP EPS of $5.48-$5.68. The company said its outlook wasnegatively affected by $600 million due to currency effects in Europe,$400 million due to macroeconomic conditions and healthcare reformsin key European markets, and $540 million due in part to changes toTeva’s U.S. commercial model that resulted in a reduction in wholesaleinventory. Teva also slightly lowered its expected R&D expense for theyear to 6.8-7.2% of net sales from 6.9-7.3% of net sales.

Veloxis Pharmaceuticals A/S (CSE:VELO), Horsholm, DenmarkBusiness: Transplant, Drug delivery

Veloxis said it plans to restructure and reduce headcount by about 40-50% to 30-35 to conserve resources for the development and commer-cialization of LCP-Tacro to prevent organ rejection. The company said itwill discontinue other pipeline activities, including early phase research,but did not provide details. EVP of Pharmaceutical Development and CMCPeter Nielsen is included in the cuts. Veloxis expects the restructuring tosave about DKK35-DKK40 million ($6-$6.9 million) annually starting in2013. At March 31, the company had DKK213.8 million ($36.7 million) incash. Its 2011 operating loss was DKK269.9 million ($47 million).

Veloxis expects top-line data in mid-2013 from the Phase III Study3002 trial comparing once-daily LCP-Tacro, which delivers tacrolimususing the biotech’s MeltDose technology, to twice-daily Prograftacrolimus in de novo kidney transplant patients. The company plans tosubmit regulatory applications for LCP-Tacro in kidney transplantpatients to EMA this year and to FDA in 2H13. Astellas Pharma Inc.(Tokyo:4503, Tokyo, Japan) markets Prograf (see BioCentury, April 2).

As part of the restructuring, the company promoted: Lars Bjorn-Christensen to SVP of technical operations, a newly created position; RonGuido to SVP of global regulatory affairs and quality; Christina Sylvest to SVPof global clinical operations and development; and John Weinberg to chiefcommercial officer from SVP of commercial operations and investor relations.

Vertex Pharmaceuticals Inc. (NASDAQ:VRTX), Cambridge, Mass.Crohn’s and Colitis Foundation of Canada, Toronto, OntarioBusiness: Autoimmune

Vertex and the foundation partnered for three years to providetwo rounds of joint funding to Canadian academics researching theunderlying disease mechanisms and drivers of inflammatory boweldisease (IBD), specifically Crohn’s disease and ulcerative colitis(UC). The partners awarded grants to the Universite de Sherbrooke,McMaster University and the University of Toronto. The universi-ties’ projects will investigate the role of bacteria in IBD and thebody’s response to an imbalance of these bacteria to identifypotential targets for therapies. Details were not disclosed.

MANAGEMENT TRACKS

Boards of Directors

Alkeus Pharmaceuticals Inc., Boston, Mass.Business: OphthalmicAppointed: Joshua Boger, former CEO of Vertex Pharmaceuticals Inc.,as executive chairman


CLINICAL NEWS

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Management Tracks,from previous page

Clinical activities and selected announcements for the week ended May 25.

REGULATORY

Aerocrine AB (SSE:AERO), Solna, SwedenProduct: Niox MinoBusiness: Diagnostic

Australia’s Therapeutic Goods Administration (TGA) approved NioxMino airway inflammation monitor and Niox Mino test kit. Niox Mino, ahandheld point-of-care device, measures fractional exhaled nitric oxide(FeNO) as an assessment of airway inflammation in patients with asthma.The test kit includes a pre-calibrated disposable sensor and disposablefilters. Niox Mino is marketed in the U.S. and Europe for the indication.

Almirall S.A. (Madrid:ALM), Barcelona, SpainForest Laboratories Inc. (NYSE:FRX), New York, N.Y.Kyorin Pharmaceutical Co. Ltd. (Tokyo:4569), Tokyo, JapanProduct: Bretaris Genuair (Eklira Genuair - EU) aclidinium bromideBusiness: Pulmonary

EMA’s CHMP issued a positive opinion recommending approval ofBretaris/Eklira Genuair aclidinium bromide from Almirall as a mainte-nance bronchodilator treatment to relieve symptoms in patients withchronic obstructive pulmonary disease (COPD). The product is underreview in U.S. for the indication, with a PDUFA date in July. The productis an inhalable long-acting, selective M2 and M3 muscarinic receptorantagonist delivered using Almirall’s Genuair inhaler. Forest has U.S.

Avraham Pharmaceuticals Ltd., Tel Aviv, IsraelBusiness: NeurologyAppointed: Yaacov Michlin as chairman, he is CEO of the YissumResearch Development Company Ltd. tech transfer arm of theHebrew University of Jerusalem

Becton Dickinson and Co. (NYSE:BDX), Franklin Lakes, N.J.Business: Diagnostic, Supply/ServiceAppointed: Vincent Forlenza, president and CEO, as chairman, effectiveJuly 1; he will succeed Edward Ludwig, who is retiring

Sigmoid Pharma Ltd., Dublin, IrelandBusiness: GastrointestinalAppointed: Thomas Lynch as chairman

Management

Achillion Pharmaceuticals Inc. (NASDAQ:ACHN), New Haven,Conn.Business: InfectiousPromoted: Gautam Shah to EVP from SVP while remaining chief com-pliance officer

Albany Molecular Research Inc. (NASDAQ:AMRI), Albany, N.Y.Business: Supply/Service, ChemistryHired: Ian Shott as president of AMRI Europe, a newly created position,formerly founder and CEO of Excelsyn Ltd., which AMRI acquired

AspenBio Pharma Inc. (NASDAQ:APPY), Castle Rock, Colo.Business: Veterinary, Diagnostic, Supply/ServiceHired: Don Hurd as chief commercial officer and SVP, a newly createdposition, formerly VP of sales at BioBehavioral Diagnostics Co.

Avraham Pharmaceuticals Ltd., Tel Aviv, IsraelBusiness: NeurologyTransitioned: Yona Geffen to CEO from SVP of clinical affairs and COO

GenVec Inc. (NASDAQ:GNVC), Gaithersburg, Md.Business: Cancer, Cardiovascular, OphthalmicAppointed: Cynthia Collins as president and CEO, formerly group VPof the cellular analysis business at Beckman Coulter Inc., which DanaherCorp. acquired; she replaces Paul Fischer, who retired

Organovo Holdings Inc. (OTCQB:ONVO), San Diego, Calif.Business: Gene/Cell therapy, Supply/ServiceHired: Eric David as chief strategy officer, formerly associate partnerat McKinsey & Co.

Paratek Pharmaceuticals Inc., Boston, Mass.Business: InfectiousHired: Evan Loh as CMO and chairman, formerly SVP of developmentand strategic operations at Pfizer Inc.; he replaces Walter Gilbert aschairman, who remains as vice chairmanTransitioned: Dennis Molnar to president, CEO and a director from VPof corporate development; he replaces Thomas Bigger, who resigned

Pfizer Inc. (NYSE:PFE), New York, N.Y.Business: PharmaceuticalsTransitioning: Olivier Brandicourt to president and general manager ofthe emerging markets and established products business units frompresident and general manager of the primary care business unit,effective June 1; he succeeds David Simmons, who is departing tobecome chairman and CEO of PPD Inc.; John Young, currently regionalpresident of Europe and Canada for the primary care business unit, willsucceed Brandicourt

PPD Inc., Wilmington, N.C.Business: Supply/ServiceHired: David Simmons as chairman and CEO, effective June 4, formerlypresident and general manager of the emerging markets and establishedproducts business units at Pfizer Inc.

Sigmoid Pharma Ltd., Dublin, IrelandBusiness: GastrointestinalHired: David Roblin as CMO, while continuing as CMO of Creabilis S.A.;and Rosemarie Tully as CBO, formerly senior director of corporatedevelopment at Elan Corp. plc

S1 Biopharma Inc., Jersey City, N.J.Business: GenitourinaryHired: Robert Pyke as CMO, formerly director of clinical research atBoehringer Ingelheim GmbH

Talon Therapeutics Inc. (OTCBB:TLON), San Mateo, Calif.Business: Cancer, DermatologyHired: Thomas DeZao as head of commercial operations and planning,formerly SVP and chief commercial officer at ChemGenex Pharmaceu-ticals Ltd., which Cephalon acquired; Teva Pharmaceuticals IndustriesLtd. subsequently acquired Cephalon


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BioCentury Week in ReviewBioCentury Week in Review is published byBIOCENTURY PUBLICATIONS INC.,PO Box 1246 San Carlos CA 94070-1246. Phone 650-595-5333.Fax 650-595-5589. David Flores, President & CEO;Karen Bernstein, Ph.D., Chairman & Editor-in-Chief

BioCentury®; The Bernstein Report on BioBusiness™ ; TheBioCentury 100™ ; and The Clear Route to ROI™ are trademarksof BIOCENTURY PUBLICATIONS INC.All contents © Copyright 2012, BIOCENTURY PUBLICATIONS INC.ALL RIGHTS RESERVED. No part of this publication may bephotocopied or reproduced in any form, retransmitted, or stored in aretrieval system without prior written consent of the publisher.

rights to the product from Almirall, which last year granted Kyorinexclusive rights in Japan. Daewoong Pharmaceutical Co. Ltd.(KSE:069620, Seoul, South Korea) has marketing rights in Korea.

Bayer AG (Xetra:BAYN), Leverkusen, GermanyProduct: Regorafenib (fluoro-sorafenib) (BAY 73-4506)Business: Cancer

Bayer submitted regulatory applications in the EU and U.S. forregorafenib to treat metastatic colorectal cancer (mCRC). Onyx Pharma-ceuticals Inc. (NASDAQ:ONXX, South San Francisco, Calif.) has co-promotion rights to the dual acting signal transduction (DAST) inhibitorof multiple kinases in the U.S. and is eligible for a 20% royalty on worldwidesales (see BioCentury, Oct. 17, 2011). Regorafenib has Fast Track designationin the U.S. to treat mCRC and gastrointestinal stromal tumors (GIST), andOrphan Drug designation in the U.S. to treat GIST.

Bayer AG (Xetra:BAYN), Leverkusen, GermanyJohnson & Johnson (NYSE:JNJ), New Brunswick, N.J.Product: Xarelto rivaroxaban (BAY 59-7939)Business: Cardiovascular

FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 6-4, with 1 abstention, against recommending approval of 2.5 mg twice-dailyXarelto rivaroxaban from Johnson & Johnson to reduce the risk ofcardiovascular events in patients with acute coronary syndrome (ACS),non-ST-elevation myocardial infarction or unstable angina. The panelfound Xarelto’s efficacy data to be underwhelming in light of concernsabout an increased risk of bleeding. Members also were concerned aboutthe statistical design of the Phase III trial as well as the large number ofpatients who withdrew consent and were not included in follow-upanalyses. The sNDA has Priority Review, with a June 29 PDUFA date.

In FDA’s briefing documents released last week, an agency reviewerrecommended in favor of approval, albeit with various contraindicationsand the addition of new information about the risk of bleeding to aboxed warning on Xarelto’s label.

The oral Factor Xa inhibitor is approved in the U.S. to treat deepvein thrombosis (DVT) and pulmonary embolism (PE) in patientsundergoing knee or hip replacement surgery, and to reduce the risk ofstroke and systemic embolism in patients with non-valvular atrialfibrillation (AF). Johnson & Johnson has rights to rivaroxaban fromBayer in the U.S.

Separately, the U.K.’s NICE issued final guidance recommending theuse of Xarelto to prevent stroke and systemic embolism in patients withAF with 1 or more risk factors — its approved indication. Therecommendation is in line with a March final appraisal determination(FAD) (see BioCentury, April 2).

In March, NICE said it needed additional information before it canrecommend the use of Xarelto to treat DVT and prevent recurrent DVTand PE following an acute DVT — its approved indication. The oralFactor Xa inhibitor is also approved in Europe to prevent venousthromboembolism (VTE) in patients undergoing hip or knee replace-ment surgery, for which NICE issued final guidance recommending theuse of Xarelto in 2009 (see BioCentury, March 19). Xarelto is also underreview in the EU to treat PE and to prevent recurrent DVT and PE (seeBioCentury, April 16).

Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.Elan Corp. plc (NYSE:ELN), Dublin, IrelandProduct: Tysabri natalizumabBusiness: Autoimmune

Biogen Idec said Health Canada approved an updated label forautoimmune drug Tysabri natalizumab to identify that anti-JC virus (JCV)antibody status as a risk factor for developing progressive multifocalleukoencephalopathy (PML). FDA and the European Commission al-ready approved similar label updates on anti-JCV antibody status as arisk factor for developing PML (see BioCentury, Jan. 23). Biogen Idec andpartner Elan market Tysabri to treat multiple sclerosis (MS) in the EUand U.S., where the humanized mAb against integrin alpha(4) is alsomarketed to treat Crohn’s disease.

Boehringer Ingelheim GmbH, Ingelheim, GermanyProduct: Pradaxa dabigatran etexilateBusiness: Cardiovascular

EMA’s CHMP completed a review of the risk of bleeding associatedwith Pradaxa dabigatran from Boehringer Ingelheim and recommendedupdating the label of the atrial fibrillation (AF) drug to include clearerguidance on how to reduce and manage bleeding. The committee did sayavailable data confirm the benefit-risk profile of Pradaxa.

The new information describes when Pradaxa should not be usedand identifies the types of lesions or conditions and the concomitantmedications that may place a patient at significant risk of major bleeding.CHMP noted that reports of bleeding with Pradaxa often involve apatient accident or injury, and the committee recommended updatingthe drug’s label to note that patients should seek medical attention ifthey fall or injure themselves while on Pradaxa. The product’s labelalready includes information on bleeding risk.

Pradaxa is a direct thrombin inhibitor approved in the U.S. and EUto prevent stroke and blood clots in patients with AF and in the EU toprevent venous thromboembolic (VTE) events in adults who haveundergone elective total hip or knee replacement surgery and toprevent systemic embolism in patients with non-valvular AF.

Celgene Corp. (NASDAQ:CELG), Summit, N.J.Product: Pomalidomide (CC-4047)Business: Autoimmune

The European Commission granted Orphan Drug designation forCelgene’s pomalidomide to treat systemic sclerosis. The thalidomideanalog is in Phase II testing for the indication. In April, the companysubmitted an NDA to FDA for the product to treat relapsed andrefractory multiple myeloma (MM). Celgene also plans to submit anMAA to EMA for the indication this quarter. Pomalidomide is also inPhase III testing for myelofibrosis, with data slated for year end (seeBioCentury, April 30).

Cepheid Inc. (NASDAQ:CPHD), Sunnyvale, Calif.Product: Xpert CTBusiness: Diagnostic

Cepheid received CE Mark approval for its Xpert CT test to detect


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and differentiate Chlamydia trachomatis. Cepheid plans to immediatelylaunch the rapid in vitro molecular diagnostic test in Europe. The testruns on Cepheid’s GeneXpert System.

Product: Xpert CT/NGBusiness: Diagnostic

Cepheid received CE Mark approval for its Xpert CT/NG test todetect and differentiate Chlamydia trachomatis and Neisseria gonorrhoeae.Cepheid plans to immediately launch the rapid in vitro moleculardiagnostic test in Europe, with a U.S. launch slated for late 2012. Thetest runs on Cepheid’s GeneXpert System.

Chelsea Therapeutics International Ltd. (NASDAQ:CHTP), Char-lotte, N.C.Dainippon Sumitomo Pharma Co. Ltd. (Tokyo:4506; Osaka:4506),Osaka, JapanProduct: Northera droxidopaBusiness: Cardiovascular

Chelsea said it plans to modify the ongoing Phase III Study 306B trialof Northera droxidopa based on a meeting with FDA about a completeresponse letter for the neurogenic orthostatic hypotension (NOH)product. The company, which received the letter in March, hopes toresubmit an NDA in 1Q13.

After reaching “apparent consensus” with the agency, Chelseawill change the trial’s primary endpoint to measure orthostatichypotension symptom assessment scale (OHSA) item 1 score(dizziness or light-headedness) at 2 weeks post-titration; thecurrent endpoint is measuring a reduction in falls. Chelsea alsoplans to increase enrollment to 200 from 160. The trial alreadyenrolled 161 patients.

Chelsea added that FDA is concerned about the disproportion-ate contribution from a single center in the Phase III 301 trial, whichsupported the NDA. Chelsea said it will provide FDA withdocumentation from all patients at the site and information from2 post-study independent site visits. The company also is startinganother inquiry into the data and conduct of the trial. In the letter,FDA asked for data from an additional trial to show durability ofeffect over a 2-3 month period and support the 301 results (seeBioCentury, April 2). Chelsea has rights to Northera from Dainipponoutside of Japan, Korea, China and Taiwan.

Dafra Pharma International, Turnhout, BelgiumProduct: OleylphosphocholineBusiness: Infectious

The European Commission granted Orphan Drug designation forDafra’s oleylphosphocholine to treat leishmaniasis. Dafra has exclu-sive, worldwide rights to the alkylphosphocholine derivative from theMax Planck Society (Munich, Germany) under a 2008 deal (see BioCentury,July 21, 2008).

Eisai Co. Ltd. (Tokyo:4523; Osaka:4523), Tokyo, JapanProduct: Fycompa perampanel (E2007)Business: Neurology

EMA’s CHMP issued a positive opinion recommending approval ofFycompa perampanel from Eisai as an adjunctive treatment for partial-onset seizure in epilepsy patients 12 years and older. In March, FDAaccepted for review an NDA from Eisai for the AMPA-type glutamatereceptor antagonist for the indication. The PDUFA date is Oct. 22 (seeBioCentury, March 12).

Emergent BioSolutions Inc. (NYSE:EBS), Rockville, Md.Product: BioThraxBusiness: Infectious

FDA approved an sBLA from Emergent to change the adminis-tration schedule of BioThrax anthrax vaccine to a 3-dose primaryseries of intramuscular injections at 0, 1 and 6 months followed bya booster series consisting of injections at 12 and 18 months andannual injections thereafter. The previous regimen for the adsorbedanthrax vaccine was a 5-dose primary schedule at 0, 1, 6, 12, 18months with annual booster injections. Last year, the U.S. govern-ment awarded Emergent a new contract worth up to $1.3 billion tosupply 44.8 million doses of BioThrax over 5 years (see BioCentury,Oct. 10, 2011).

Furiex Pharmaceuticals Inc. (NASDAQ:FURX), Morrisville, N.C.Takeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, JapanProduct: Nesina alogliptin (SYR-322)Business: Endocrine/Metabolic

Takeda said EMA accepted for review an MAA for alogliptin to treatType II diabetes. Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitorapproved for the indication in Japan as Nesina. In April, FDA issued acomplete response letter for 2 NDAs from Takeda for alogliptin anda fixed-dose combination of alogliptin and Actos pioglitazone (seeBioCentury, April 30).

The acceptance triggers a $10 million milestone payment to Furiex,which co-developed alogliptin with Syrrx Inc. Takeda acquired Syrrx in2005. Furiex is eligible for royalties in Japan and Europe.

Takeda’s Actos is a thiazolidinedione (TZD) peroxisome prolifera-tion activated receptor (PPAR) gamma agonist insulin sensitizer.

Genentech Inc., South San Francisco, Calif.Chugai Pharmaceutical Co. Ltd. (Tokyo:4519), Tokyo, JapanRoche (SIX:ROG; OTCQX:RHHBY), Basel, SwitzerlandProduct: Pertuzumab (R1273, RG1273)Business: Cancer

Chugai submitted an NDA to the Japanese Ministry of Health, Laborand Welfare (MHLW) for pertuzumab to treat HER2-positive meta-static or recurrent breast cancer. Chugai, which is majority owned byRoche, has Japanese rights to develop and market the mAb HERdimerization inhibitor that prevents HER2 from binding to other HERreceptors (HER1/EGF, HER3 and HER4). A BLA for the product fromRoche’s Genentech unit is under FDA Priority Review as a first-linetreatment for HER2-positive metastatic breast cancer; the PDUFA dateis June 8.

Gilead Sciences Inc. (NASDAQ:GILD), Foster City, Calif.Japan Tobacco Inc. (Tokyo:2914; Osaka:2914), Tokyo, JapanProduct: Cobicistat (formerly GS 9350)Business: Infectious

EMA accepted for review an MAA from Gilead for cobicistat as aboosting agent for HIV treatment with protease inhibitors. The appli-cation was submitted in April. Gilead plans to submit an application toFDA next quarter for the inhibitor of cytochrome P450 family 3subfamily A (CYP3A). Japan Tobacco has exclusive rights in Japan todevelop and commercialize cobicistat (see BioCentury, Jan. 2).

GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.Product: Votrient pazopanibBusiness: Cancer

EMA’s CHMP issued a positive opinion recommending approval ofVotrient pazopanib from GlaxoSmithKline to treat advanced soft tissuesarcoma in patients who received prior chemotherapy. Last month,


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FDA approved the broad spectrum inhibitor of VEGF and othertyrosine kinases for the indication. Votrient is approved in the U.S. andEU to treat renal cell carcinoma (RCC) (see BioCentury, April 30).

Medivation Inc. (NASDAQ:MDVN), San Francisco, Calif.Astellas Pharma Inc. (Tokyo:4503), Tokyo, JapanProduct: Enzalutamide (formerly MDV3100)Business: Cancer

Medivation submitted an NDA to FDA for enzalutamide to treatcastration-resistant prostate cancer (CRPC) in patients previouslytreated with docetaxel. The company requested Priority Review. Theoral androgen receptor antagonist has Fast Track designation in the U.S.to treat advanced prostate cancer in post-chemotherapy patients.Medivation and Astellas partnered in 2009 to develop and commercial-ize the product (see BioCentury, Nov. 2, 2009). Sanofi (Euronext:SAN;NYSE:SNY, Paris, France) markets Taxotere docetaxel.

Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J.Product: Isentress raltegravir (formerly MK-0518)Business: Infectious

Merck said FDA approved an updated label for Isentress raltegravirto include 3-year data from the 5-year, double-blind Phase III STARTMRKtrial of the HIV drug in combination therapy in treatment-naïve adults.Last year, Merck reported data from the trial that showed Isentressmaintained a viral load of <50 copies/mL at week 156 in 75.4% of patients(n=281) vs. 68.1% of patients receiving Sustiva efavirenz (n=282) (seeBioCentury, March 7, 2011). Isentress, an HIV integrase inhibitor, isapproved in the U.S. and EU for use in combination with otherantiretroviral therapies to treat HIV-1 infection. Bristol-Myers SquibbCo. (NYSE:BMY, New York, N.Y.) and Merck market Sustiva.

Novo Nordisk A/S (CSE:NVO; NYSE:NVO), Bagsvaerd, DenmarkProduct: Levemir insulin detemirBusiness: Endocrine/Metabolic

Novo Nordisk said FDA approved an expanded label for Levemirinsulin detemir to include treatment of Type I diabetes in children ages 2-5 years. The long-acting insulin analog is already approved for the indicationin patients ages 6 years and for Type II diabetes in adults. Levemir isapproved in Europe to treat diabetes mellitus in patients ages 2 years.It is also approved as add-on therapy to Victoza liraglutide. Levemir is givenas an add-on to oral diabetes drugs or in combination with short- or rapid-acting insulin injections. Novo Nordisk also markets Victoza, a long-actinganalog of glucagon-like peptide-1 (GLP-1), to treat diabetes.

Novo Nordisk A/S (CSE:NVO; NYSE:NVO), Bagsvaerd, DenmarkBristol-Myers Squibb Co. (NYSE:BMY), New York, N.Y.Product: NovoThirteen catridecacogBusiness: Hematology

EMA’s CHMP issued a positive opinion recommending approval ofNovoThirteen catridecacog from Novo Nordisk to treat congenitalFactor XIII deficiency, a bleeding disorder. Earlier this year, NovoNordisk received a complete response letter from FDA for a BLA forthe recombinant factor XIII (rFXIII). Novo Nordisk has rights to theproduct from ZymoGenetics Inc., which Bristol-Myers Squibb acquiredin 2010 (see BioCentury, Feb. 6).

Ocera Therapeutics Inc., San Diego, Calif.Product: Zysa (Kremezin) (formerly AST-120)Business: Gastrointestinal

Ocera said it received CE Mark approval for Zysa to treat diarrhea-

predominant irritable bowel syndrome (IBS-D). The product is mar-keted in Asia as Kremezin to treat chronic kidney disease. Zysa has FastTrack designation for D-IBS in the U.S., where the product is in PhaseII testing for non-constipating IBS. Ocera licensed Zysa from KurehaCorp. (Tokyo, Japan) in 2005 (see BioCentury, Jan. 23, 2006). Zysa is anorally-delivered spherical carbon adsorbent with a selective adsorp-tion profile for toxins in the gastrointestinal tract.

Pfizer Inc. (NYSE:PFE), New York, N.Y.Product: Inlyta axitinib (formerly AG-013736)Business: Cancer

EMA’s CHMP issued a positive opinion recommending approval ofInlyta axitinib from Pfizer to treat advanced renal cell carcinoma afterfailure of prior treatment with Pfizer’s Sutent sunitinib or a cytokine.In January, FDA approved the inhibitor of VEGF receptors 1, 2 and 3 forthe indication (see BioCentury, Jan. 30).

Product: Vyndaqel tafamidis meglumine (Fx-1006A)Business: Endocrine/Metabolic

FDA’s Peripheral and Central Nervous System Drugs AdvisoryCommittee voted 13-4 that surrogate endpoint data for Pfizer’s tafamidiswere robust enough to predict a clinical benefit in patients withtransthyretin (TTR) familial amyloid polyneuropathy (FAP). The votecould pave the path for accelerated approval of the compound. Thepanel backed the surrogate endpoints to support accelerated approvalafter voting 13-4 that the data on the clinical endpoints in the pivotalPhase II/III Fx-005 trial were not robust enough to support regularapproval. In Fx-005, tafamidis missed the co-primary composite end-points of disease progression and quality of life. However, tafamidis didshow significant improvements in a handful of secondary endpoints.These included small fiber function, 1 of 5 components of quality of life;muscle strength, 1 of 3 components of disease progression; and thestability of the TTR protein.

The panel felt that these 3 secondary endpoints could be predictiveof clinical benefit, with a confirmatory trial conducted postapproval.The panel did not discuss what the endpoint should be in the confirma-tory trial. When Pfizer submitted its NDA for tafamidis, the approvalpathway was yet to be determined. The small molecule that stabilizesthe TTR protein and prevents its misfolding is under Priority Reviewwith a June 16 PDUFA date. Pfizer gained tafamidis, which is approvedin the EU as Vyndaqel under EMA’s exceptional circumstances clause,through its 2010 acquisition of FoldRx Pharmaceuticals Inc. (seeBioCentury, Sept. 6, 2010 & Nov. 21, 2011).

Pharmaxis Ltd. (ASX:PXS; Pink:PXSLY), Frenchs Forest, AustraliaProduct: Bronchitol mannitolBusiness: Pulmonary

Pharmaxis submitted an NDA to FDA for Bronchitol mannitol totreat cystic fibrosis. The formulation of mannitol in a dry powderinhaler system has Orphan Drug and Fast Track designation in the U.S.for the indication. In April, the European Commission approvedBronchitol for use in CF patients aged 18 years and older as an add-ontherapy to best standard of care. The product is also approved inAustralia (see BioCentury, April 23).

ProRetina Therapeutics S.L., Noain, SpainProduct: PRO-001Business: Ophthalmic

The European Commission granted Orphan Drug designation forProRetina’s PRO-001 to treat retinitis pigmentosa. The recombinanthuman proinsulin is in preclinical testing for the indication.


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Prosensa B.V., Leiden, the NetherlandsGlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.Product: PRO045Business: Musculoskeletal

The European Commission granted Orphan Drug designation forProsensa’s PRO045 to treat Duchenne muscular dystrophy (DMD). Theantisense oligoribonucleotides that skips exon 45 on the dystrophingene is in preclinical testing. GlaxoSmithKline has rights to co-developthe compound under last year’s expansion of a 2009 deal (see BioCentury,Oct. 19, 2009; July 5, 2010 & Sept. 19, 2011).

Product: PRO053Business: Musculoskeletal

The European Commission granted Orphan Drug designation forProsensa’s PRO053 to treat Duchenne muscular dystrophy (DMD). Theantisense oligoribonucleotides that skips exon 53 on the dystrophingene is in preclinical testing. GlaxoSmithKline has rights to co-developthe compound under last year’s expansion of a 2009 deal (see BioCentury,Oct. 19, 2009; July 5, 2010 & Sept. 19, 2011).

Repros Therapeutics Inc. (NASDAQ:RPRX), The Woodlands, TexasProduct: Androxal enclomipheneBusiness: Endocrine/Metabolic

Repros modified an SPA for 2 planned Phase III trials with oralAndroxal enclomiphene to treat secondary hypogonadism to includeadditional secondary endpoints specifying the number of men in thestudy that exhibit a single time point of testosterone concentration>1,500, 1,800 and 2,500 ng/dL. The amendment follows additional inputfrom FDA that came after the company’s May 9 meeting with the agency.The company said the agency has 45 days to provide the biotechcomments. Earlier this month, Repros said FDA received the company’ssubmission of required documentation for the SPA for the 2 trials (seeBioCentury, May 14 & May 21).

Seattle Genetics Inc. (NASDAQ:SGEN), Bothell, Wash.Takeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, JapanProduct: Adcetris brentuximab vedotin (SGN-35)Business: Cancer

Seattle Genetics said Health Canada accepted for review an NDS forAdcetris brentuximab vedotin to treat relapsed Hodgkin’s lymphomaand systemic anaplastic large cell lymphoma (ALCL). Seattle Geneticsis seeking conditional approval for the antibody-drug conjugate (ADC)composed of an anti-CD30 mAb and monomethyl auristatin E (MMAE).Seattle hopes to launch the product in Canada by early 2013.

Adcetris has accelerated approval in the U.S. to treat Hodgkin’slymphoma and ALCL. The product is under review in the EU for theindications. Seattle Genetics is co-developing the product worldwidewith Takeda’s Millennium Pharmaceuticals Inc. subsidiary, except inJapan, where Millennium is responsible for development. Millenniumhas marketing rights outside the U.S. and Canada, where SeattleGenetics retains rights. The compound has Orphan Drug designationin the U.S. and EU for Hodgkin’s lymphoma and ALCL, as well as forcutaneous T cell lymphoma (CTCL) in the EU, and Fast Track designationin the U.S. to treat Hodgkin’s lymphoma.

Transgenomic Inc. (OTCBB:TBIO), Omaha, Neb.Product: SURVEYOR Scan K-RAS kitBusiness: Diagnostic

Transgenomic said it received CE Mark approval for its SURVEYORScan K-RAS Kit to detect mutations in K-RAS associated with drug-

resistant tumors. The kit is used exclusively with the company’s WAVEMicrochip Electrophoresis (MCE) System. Menarini Diagnostics, adivision of Menarini Group (Florence, Italy), will distribute the kit inthe U.K., Ireland, Austria, Belgium, France, Germany, Greece, Italy, theNetherlands, Portugal and Spain.

Vertex Pharmaceuticals Inc. (NASDAQ:VRTX), Cambridge, Mass.Product: Kalydeco ivacaftor (VX-770)Business: Pulmonary

EMA’s CHMP issued a positive opinion recommending approval ofKalydeco ivacaftor from Vertex to treat cystic fibrosis in patients ages 6years and older who have at least 1 copy of the G551D mutation in the cysticfibrosis transmembrane conductance regulator (CFTR). Vertex estimatesthat 1,100, or about 3%, of the 35,000 CF patients in Europe have themutation. The company expects a final decision from the EuropeanCommission within 3-4 months. In January, FDA approved the smallmolecule potentiator of CFTR for the indication. Kalydeco was discoveredin partnership with Cystic Fibrosis Foundation Therapeutics Inc., the non-profit drug discovery and development affiliate of the Cystic FibrosisFoundation. The foundation is eligible for a tiered royalty.

CLINICAL RESULTS

Achaogen Inc., South San Francisco, Calif.Isis Pharmaceuticals Inc. (NASDAQ:ISIS), Carlsbad, Calif.Product: Plazomicin (ACHN-490)Business: InfectiousMolecular target: NADescription: Next-generation aminoglycoside antibioticIndication: Treat complicated urinary tract infections (cUTI) and acutepyelonephritisEndpoint: Microbiological eradication rate; clinical cure rateStatus: Phase II dataMilestone: NA

Achaogen said a double-blind, international Phase II trial in 145 patientswith cUTI or acute pyelonephritis showed that once-daily 15 mg/kg IVplazomicin for 5 days “met its objectives of assessing safety and efficacy”by demonstrating “favorable” microbiological eradication and clinical curerates, the primary and secondary endpoints, at the test of cure (TOC) visit5-9 days after the end of treatment compared to levofloxacin. Plazomicinwas well tolerated. Details were not disclosed. Achaogen said it plans tomeet with FDA regarding the design of future studies with plazomicin,which the company plans to start in 1H13. Achaogen acquired exclusiveworldwide rights to Isis’ aminoglycosides antibiotics program in 2006 (seeBioCentury, Feb. 6, 2006).

Achillion Pharmaceuticals Inc. (NASDAQ:ACHN), New Haven,Conn.Product: ACH-2684Business: InfectiousMolecular target: HCV NS3 proteaseDescription: HCV NS3 protease inhibitorIndication: Treat HCV infectionEndpoint: Safety, pharmacokinetics and antiviral activityStatus: Additional Phase Ib dataMilestone: Final Phase I data (4Q12)

Data from 30 patients with HCV genotype 1 infection in the PhaseIb portion of a 3-part, double-blind, U.S. Phase Ia/Ib trial showed thatonce-daily 100 mg oral ACH-2684 led to a mean maximum reduction inHCV RNA levels from baseline to day 3 of 3.36 log10 IU/mL vs. 0.68 log10IU/mL for placebo. Additionally, once-daily 400 mg ACH-2684 led to amean maximum reduction in HCV RNA from baseline to day 3 of 3.73


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Clinical Results,from previous page

log10 IU/mL, while twice-daily 400 mg led to a mean maximum reductionof 4.16 log10 IU/mL. ACH-2684 was well tolerated with no viralbreakthroughs observed during treatment. Additionally, no seriousadverse events were reported and there were no patientdiscontinuations during treatment.

The trial consists of 3 parts — a Phase Ia portion evaluating singleascending-doses of ACH-2684 in healthy volunteers; a 14-day Phase Iaportion evaluating multiple ascending-doses of ACH-2684 in healthyvolunteers; and a Phase Ib portion evaluating ACH-2684 for 3 days inpatients with HCV genotype 1 or 3 infection. The multiple ascending-dose portion of the trial is expected to start this quarter, while full datafrom the trial are expected in 4Q12. In January, Achillion reportedpreliminary data from healthy volunteers and patients with HCVgenotype 1 or 3 infection in the trial (see BioCentury, Jan. 16).

Ardea Biosciences Inc. (NASDAQ:RDEA), San Diego, Calif.Bayer AG (Xetra:BAYN), Leverkusen, GermanyProduct: BAY 86-9766 (formerly RDEA119)Business: CancerMolecular target: MEKDescription: Selective inhibitor of mitogen-activated ERK kinase (MEK)Indication: Treat hepatocellular carcinoma (HCC)Endpoint: Disease control rate (DCR); overall survival (OS), time toprogression (TTP), objective response rate (ORR), duration of re-sponse (DOR), safety and pharmacokineticsStatus: Phase II dataMilestone: NA

An open-label, Asian Phase II trial in 65 evaluable patients withunresectable HCC showed that twice-daily 50 mg oral BAY 86-9766plus sorafenib as first-line treatment produced a DCR of 43%, with 3confirmed partial responses and 25 cases of stable disease for 10weeks. Median TTP was 4.1 months and OS data are not yet mature. Themost common adverse events were rash, diarrhea, elevations in alanineaminotransferase (ALT) and aspartate aminotransferase (AST) levels,vomiting, nausea and anorexia. There were 4 deaths due to hepaticfailure, sepsis/hepatic encephalopathy, tumor lysis and syndrome andunknown cause, respectively. Dose modifications due to adverseevents were necessary in almost all patients. Data will be presented atthe American Society of Clinical Oncology meeting in Chicago in June.

Bayer has exclusive, worldwide rights to develop and commercial-ize BAY 86-9766 from Ardea under a 2009 deal (see BioCentury, May 4,2009). Last month, AstraZeneca plc (LSE:AZN; NYSE:AZN, London,U.K.) said it will acquire Ardea for about $1.3 billion (see BioCentury, April30). Bayer and Onyx Pharmaceuticals Inc. (NASDAQ:ONXX, Emeryville,Calif.) market Nexavar sorafenib.

ArQule Inc. (NASDAQ:ARQL), Woburn, Mass.Daiichi Sankyo Co. Ltd. (Tokyo:4568; Osaka:4568), Tokyo, JapanKyowa Hakko Kirin Co. Ltd. (Tokyo:4151), Tokyo, JapanProduct: Tivantinib (ARQ 197)Business: CancerMolecular target: c-Met receptor tyrosine kinaseDescription: Small molecule inhibitor of c-Met receptor tyrosinekinaseIndication: Treat hepatocellular carcinoma (HCC)Endpoint: Time to progression (TTP); progression-free survival (PFS),overall survival (OS), objective response rate (ORR), disease controlrate (DCR), safety and pharmacokineticsStatus: Additional Phase II dataMilestone: NA

Additional data from a double-blind, international Phase II trial in107 patients with unresectable HCC who failed 1 prior systemictherapy showed that twice-daily oral tivantinib missed the secondaryendpoint of median PFS vs. placebo (1.7 vs. 1.5 months, p=0.06). In asubgroup of 37 patients whose tumors had high c-Met expression,tivantinib led to a median TTP and PFS of 2.9 and 2.4 months, respec-tively, vs. 1.5 and 1.5 months for placebo (p=0.03 and p=0.02). Data willbe presented at the American Society of Clinical Oncology meeting inChicago in June.

ArQule previously reported that tivantinib met the primary end-point of improving TTP vs. placebo. Specifically, tivantinib led to a 56%improvement on the endpoint compared to placebo (p=0.04) (seeBioCentury, Jan. 23). Tivantinib is also in the Phase III ATTENTION trialto treat non-small cell lung cancer (NSCLC). ArQule is co-developingtivantinib with Daiichi Sankyo on a worldwide basis outside of certainAsian countries, where ArQule licensed rights to Kyowa in 2007 (seeBioCentury, April 30, 2007 & Nov. 17, 2008).

Indication: Treat gastric cancerEndpoint: Disease control rate (DCR); tumor response, progression-free survival (PFS), overall survival (OS) and pharmacokineticsStatus: Phase II dataMilestone: NA

An Asian Phase II trial in 30 patients with previously treated metastaticgastric showed that tivantinib led to a DCR of 36.7% with a median PFS of43 days. No objective responses were observed. Grade 3/4 adverse eventsincluded neutropenia and anemia. Data will be presented at the AmericanSociety of Clinical Oncology meeting in Chicago in June.

Tivantinib is also in the Phase III ATTENTION trial to treat non-small cell lung cancer (NSCLC). ArQule is co-developing tivantinib withDaiichi Sankyo on a worldwide basis outside of certain Asian countries,where ArQule licensed rights to Kyowa in 2007 (see BioCentury, April 30,2007 & Nov. 17, 2008).

Array BioPharma Inc. (NASDAQ:ARRY), Boulder, Colo.AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K.Product: Selumetinib (AZD6244, ARRY-886)Business: CancerMolecular target: MEKDescription: Small molecule MEK inhibitorIndication: Treat acute myelogenous leukemia (AML)Endpoint: Response rateStatus: Phase II dataMilestone: NA

An open-label, U.S. Phase II trial in 47 patients with advanced AMLshowed that twice-daily 100 mg selumetinib produced 1 partial re-sponse, 3 minor responses defined as a >50% decrease in blood and/or marrow blasts lasting >4 weeks, 2 unconfirmed minor responsesdefined as >50% decline in marrow blasts without a follow-up confir-matory biopsy, and 4 cases of stable disease. Selumetinib was welltolerated. Grade 3 adverse events possibly related to treatmentincluded fatigue, dyspnea and nausea. Data will be presented at theAmerican Society of Clinical Oncology meeting in Chicago in June. In2003, Array granted AstraZeneca rights to selumetinib for oncologyindications (see BioCentury, Dec. 22, 2003).

Indication: Treat solid tumorsEndpoint: Dose-limiting toxicities (DLTs), maximum tolerated dose(MTD) and antitumor activity; pharmacokinetics and safetyStatus: Phase I dataMilestone: NA

An open-label dose-escalation U.S. Phase I trial in 15 patients with


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refractory solid tumors showed that selumetinib plus Erbitux cetuximabproduced 2 partial responses and 4 cases of stable disease. The MTDwas twice-daily 75 mg selumetinib and once-weekly 250 mg/m2 Erbituxfollowing a 400 mg/m2 loading dose of Erbitux. Grade 4 hypomagnesemiawas the only DLT and grade 3 adverse events included rash, hyponatre-mia and headache. Data will be presented at the American Society ofClinical Oncology meeting in Chicago in June.

In 2003, Array granted AstraZeneca rights to selumetinib foroncology indications (see BioCentury, Dec. 22, 2003). Erbitux is marketedby ImClone Systems Inc., a subsidiary of Eli Lilly and Co. (NYSE:LLY,Indianapolis, Ind.), and Bristol-Myers Squibb Co. (NYSE:BMY, NewYork, N.Y.) in North America. Merck KGaA (Xetra:MRK, Darmstadt,Germany) markets Erbitux elsewhere, except in Japan where the 3companies market the drug.

Indication: Treat hepatocellular cancer (HCC)Endpoint: Maximum tolerated dose (MTD) and dose-limiting toxicities(DLTs) (Phase I portion); time to progression and safety (Phase II portion)Status: Phase I/II dataMilestone: NA

Interim data from 11 evaluable patients with unresectable HCC inan open-label, Chinese Phase I/II trial showed that selumetinib plusNexavar sorafenib led to 3 partial responses and 6 cases of stabledisease. DLTs were grade 3 fatigue and abdominal pain in 2 of 6 patientsreceiving twice-daily 50 mg selumetinib and grade 3 elevated aspartatetransaminase levels and diarrhea in 2 of 3 patients receiving once-daily100 mg selumetinib. The MTD and recommended Phase II dose is once-daily 75 mg selumetinib plus Nexavar. The most common adverse eventsincluded diarrhea, rash, fatigue, hypertension, anorexia, vomiting andthrombocytopenia. Data will be presented at the American Society ofClinical Oncology meeting in Chicago in June.

In 2003, Array granted AstraZeneca rights to selumetinib foroncology indications (see BioCentury, Dec. 22, 2003). Bayer AG(Xetra:BAYN, Leverkusen, Germany) and Onyx Pharmaceuticals Inc.(NASDAQ:ONXX, South San Francisco, Calif.) market Nexavar.

Indication: Treat solid tumorsEndpoint: Maximum tolerated dose (MTD) and safetyStatus: Phase II dataMilestone: NA

An open-label, dose-escalation, U.S. Phase I trial in 16 patients withadvanced solid tumors showed that selumetinib plus cixutumumab(IMC-A12) produced 1 partial response and 4 cases of stable disease in10 evaluable patients. A dose-limiting toxicity (DLT) of visual changesoccurred at the 75 mg selumetinib dose. Grade 3 adverse eventsincluded nausea/vomiting, visual changes/retinopathy, methicillin-re-sistant Staphylococcus aureus (MRSA) skin infection, hyperglycemia andstroke. The recommended Phase II dose is twice-daily 50 mg selumetinibplus twice-weekly 12 mg/kg cixutumumab. Data will be presented at theAmerican Society of Clinical Oncology meeting in Chicago in June.

In 2003, Array granted AstraZeneca rights to selumetinib foroncology indications (see BioCentury, Dec. 22, 2003). Cixutumumab, ahuman mAb against insulin-like growth factor-1 receptor (IGF-1;IGF1R) from Eli Lilly and Co. (NYSE:LLY, Indianapolis, Ind.), is in PhaseII testing for various cancers.

Indication: Treat radioactive iodine-refractory thryoid tumorsEndpoint: Changes in tumor radioactive iodine (RAI) uptake; changesin serum thyroglobulin after RAIStatus: Pilot trial data

Milestone: NAData from 20 evaluable patients in an open-label, U.S. pilot trial

showed that twice-daily 75 mg selumetinib led to increased tumoriodine uptake in 12 patients, 8 of which achieved sufficient iodine avidityto warrant RAI therapy. Of the 7 patients who have received RAItherapy, 5 had partial responses and 2 had stable disease. No selumetinib-related toxicities were >grade 2. Data will be presented at theAmerican Society of Clinical Oncology meeting in Chicago in June. In2003, Array granted AstraZeneca rights to selumetinib for oncologyindications (see BioCentury, Dec. 22, 2003).

Indication: Treat advanced colorectal cancerEndpoint: Biomarker analysisStatus: Phase II dataMilestone: NA

Data from 9 evaluable patients with advanced colorectal cancerrefractory to standard therapy in an open-label, U.S. Phase II trial showedthat once-daily 75 mg selumetinib plus once-weekly 90 mg MK-2206, anAKT inhibitor from Merck & Co. Inc. (NYSE:MRK, Whitehouse Station,N.J.), produced 2 cases of stable disease after two 28-day cycles. No patientshowed 70% inhibition of phosphoylation of both mitogen-activated ERKkinase (MEK) and AKT. The partners said that if repeated dosing does notproduce >70% inhibition in both markers, they will conclude that thecombination cannot provide adequate dual inhibition. Grade 1/2 adverseevents included rash, reversible retinal detachment, liver abnormalities,hypoalbuminemia and lymphopenia. Data will be presented at the Ameri-can Society of Clinical Oncology meeting in Chicago in June.

AstraZeneca and Merck partnered in 2009 to conduct a Phase I trialof the combination in solid tumors (see BioCentury, June 8, 2009). In 2003,Array granted AstraZeneca rights to selumetinib for oncology indica-tions (see BioCentury, Dec. 22, 2003).

Array BioPharma Inc. (NASDAQ:ARRY), Boulder, Colo.Genentech Inc., South San Francisco, Calif.Roche (SIX:ROG; OTCQX:RHHBY), Basel, SwitzerlandProduct: GDC-0068, RG7440Business: CancerMolecular target: Protein kinase B (PKB) (PKBA) (AKT) (AKT1);Protein kinase B beta (PKBB) (AKT2)Description: Small molecule inhibitor of protein kinase B (PKB; PKBA;AKT; AKT1), AKT2 and AKT3Indication: Treat solid tumorsEndpoint: Dose-limiting toxicities (DLTs); safetyStatus: Phase Ib dataMilestone: NA

An open-label, dose-escalation, international Phase Ib trial in 23patients with advanced or metastatic solid tumors showed that 100, 200and 400 mg doses of daily GDC-0068 plus docetaxel and 100 and 200mg doses of daily GDC-0068 plus FOLFOX6 (5-FU, leucovorin, andoxaliplatin) chemotherapy were well tolerated with no DLTs. The mostcommon GDC-0068-related adverse events were grade 1 or 2 diarrhea,nausea, vomiting, fatigue and reduced appetite. Grade 4 neutropeniaoccurred in 1 patient receiving GDC-0068 plus docetaxel. Dose esca-lation continues. Data will be presented at the American Society ofClinical Oncology meeting in Chicago in June. Roche’s Genentech Inc.unit and Array discovered GDC-0068, which is also in a Phase Ib/II trialfor castration-resistant prostate cancer (CRPC).

Astex Pharmaceuticals Inc. (NASDAQ:ASTX), Dublin, Calif.Product: AT13387Business: CancerMolecular target: Heat shock protein 90 (Hsp90)


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Description: Non-ansamycin inhibitor of heat shock protein 90 (Hsp90)Indication: Treat solid tumorsEndpoint: Maximum tolerated dose (MTD); safety, pharmacokineticsand tumor assessments at 12 monthsStatus: Phase I dataMilestone: NA

Data from 53 evaluable patients in a open-label, dose-escalating,U.S. Phase I trial showed that the MTD of once-weekly IV AT13387 was260 mg/m2. AT13387 produced 1 partial response in a patient withgastrointestinal stromal tumor (GIST) and 3 cases of stable disease for6 months in 1 patient with follicular cell thyroid carcinoma, 1 patientwith metastatic uveal melanoma and 1 patient with GIST. Dose-limitingtoxicities (DLTs) of gastrointestinal disturbance, fatigue and infusion-related symptoms occurred at the 310 mg/m2 dose. Patients receivedtwice-weekly 10, 20, 40, 80 or 120 mg/m2 AT13387 on days 1, 4, 8, 11,15 and 18 of a 28-day cycle followed by once-weekly 150, 220, 260 or310 mg/m2 on days 1, 8 and 15. Data will be presented at the AmericanSociety of Clinical Oncology meeting in Chicago in June. AT13387 is inPhase II testing for GIST.

Aveo Pharmaceuticals Inc. (NASDAQ:AVEO), Cambridge, Mass.Astellas Pharma Inc. (Tokyo:4503), Tokyo, JapanKyowa Hakko Kirin Co. Ltd. (Tokyo:4151), Tokyo, JapanProduct: Tivozanib (AV-951) (formerly KRN951)Business: CancerMolecular target: Vascular endothelial growth factor (VEGF)Description: Inhibitor of VEGF receptors 1, 2 and 3Indication: Treat advanced renal cell carcinoma (RCC)Endpoint: Progression-free survival (PFS); overall survival (OS), objec-tive response rate (ORR), duration of response and quality of lifeStatus: Additional Phase III dataMilestone: Submit NDA (3Q12); submit MAA (2H12)

Additional data from the open-label, international Phase III TIVO-1 trial in 517 patients showed that once-daily 1.5 mg oral tivozanib metthe secondary endpoint of improving ORR vs. sorafenib (33% vs. 23%,p=0.014). In a subgroup of patients who had previously receivedsystemic therapy, tivozanib led to a median PFS of 11.9 months vs. 9.1months for sorafenib. OS data, which are not yet mature, are expectedin 2013. Data will be presented at the American Society of ClinicalOncology meeting in Chicago in June. In January, Aveo reported thattivozanib met the primary endpoint of median PFS vs. sorafenib (11.9vs. 9.1 months, p=0.042). In a subgroup of patients who received noprior systemic anti-cancer therapy, tivozanib also significantly im-proved median PFS vs. sorafenib (12.7 vs. 9.1 months, p=0.037) (seeBioCentury, Jan. 9).

Aveo and Astellas plan to submit an NDA to FDA in 3Q12 and anMAA to EMA in 2H12 for tivozanib to treat RCC. Tivozanib has OrphanDrug designation in the EU. Aveo has exclusive ex-Asian rights totivozanib from Kyowa Hakko Kirin. Aveo partnered with Astellas todevelop and commercialize tivozanib outside of Asia (see BioCentury,Feb. 21, 2011). Bayer AG (Xetra:BAYN, Leverkusen, Germany) andOnyx Pharmaceuticals Inc. (NASDAQ:ONXX, Emeryville, Calif.) mar-ket Nexavar sorafenib.

Boehringer Ingelheim GmbH, Ingelheim, GermanyProduct: Afatinib (Tomtovok) (BIBW 2992)Business: CancerMolecular target: Epidermal growth factor receptor (EGFR); Epidermalgrowth factor receptor 2 (EGFR2) (HER2) (ErbB2) (neu)Description: Dual inhibitor of EGFR and HER2

Indication: Treat locally advanced HER2-positive breast cancerEndpoint: Objective response rate (ORR); clinical benefit rate (CBR),safety and pharmacokineticsStatus: Phase II dataMilestone: NA

An open-label, international Phase II trial in 29 patients with locallyadvanced HER2-positive breast cancer showed that neoadjuvant therapywith once-daily 50 mg oral afatinib for 6 weeks produced 7 partialresponses, plus 2 cases of stable disease (n=10). Neoadjuvant therapywith Tykerb lapatinib produced 6 partial responses, plus 1 case of stabledisease (n=8), while treatment with Herceptin trastuzumab produced4 partial responses, plus 6 cases of stable disease (n=11). Treatment-related adverse events occurred in 100%, 75% and 45.5% of patientsreceiving afatinib, Tykerb and Herceptin, respectively. Data will bepresented at the American Society of Clinical Oncology meeting inChicago in June.

Afatinib is being evaluated in the LUX program, which consists ofmore than 10 trials evaluating the compound for the treatment ofvarious solid tumors, including non-small cell lung cancer (NSCLC),breast and head and neck cancer. GlaxoSmithKline plc (LSE:GSK;NYSE:GSK, London, U.K.) markets lapatinib in the U.S. as Tykerb andas Tyverb in the EU. Herceptin is marketed in the U.S. by the GenentechInc. unit of Roche (SIX:ROG; OTCQX:RHHBY, Basel, Switzerland) andby Roche elsewhere.

Indication: Treat non-small cell lung cancer (NSCLC)Endpoint: Progression free survival (PFS); objective response rate(ORR), clinical benefit rate (CBR), time to objective response, qualityof life and safetyStatus: Interim Phase III dataMilestone: NA

Interim data from the open-label, international Phase III LUX-Lung5 trial in 1,154 patients with stage IIIb/IV metastatic NSCLC whoprogressed after receiving 1 line of chemotherapy and also failedTarceva erlotinib and Iressa gefitinib showed that once-daily 50 mg oralafatinib led to a median PFS of 3.3 months. Additionally, afatinib led toan ORR of 8%, while 56% of patients achieved stable disease. Further-more, afatinib led to a median PFS of 4.2 months in 49 EGFR mutation-positive patients vs. 2.6 months in 35 EGFR mutation-negative patients.The most common grade 3/4 adverse events were diarrhea and rash/acne. Data will be presented at the American Society of ClinicalOncology meeting in Chicago in June.

The LUX program consists of more than 10 trials evaluating afatinibfor the treatment of various solid tumors, including NSCLC, breast andhead and neck cancer. Tarceva is marketed in the U.S. by OSI Pharma-ceuticals Inc., now part of Astellas Pharma Inc. (Tokyo:4503, Tokyo,Japan), and the Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY,Basel, Switzerland), and by Roche elsewhere. AstraZeneca plc (LSE:AZN;NYSE:AZN, London, U.K.) markets Iressa.

Celldex Therapeutics Inc. (NASDAQ:CLDX), Needham, Mass.Product: Glembatumumab vedotin (CDX-011) (formerly CR011-vcMMAE)Business: CancerMolecular target: Glycoprotein NMB (GPNMB); TubulinDescription: Human mAb against glycoprotein NMB (GPNMB) linkedto the tubulin inhibitor monomethyl auristatin E (MMAE)Indication: Treat advanced, refractory or resistant GPNMB-expressingbreast cancerEndpoint: Overall response rate (ORR); progression-free survival(PFS), overall survival (OS) and safetyStatus: Preliminary Phase IIb data


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Milestone: Additional Phase IIb data (4Q12)Preliminary data from the open-label, U.S. Phase IIb EMERGE trial

in 117 evaluable patients showed that 1.88 mg/kg IV CDX-011 given onday 1 of each 21-day cycle led to an ORR of 19% vs. 14% for single agentchemotherapy of the investigator’s choosing. Additionally, CDX-011led a disease control rate (DCR) of 59% vs. 50% for chemotherapy. Inpatients with triple-negative breast cancer (TNBC) (n=33), CDX-011led to an ORR and DCR of 21% and 71%, respectively, vs. 0% and 33%for chemotherapy. In patients whose tumors had high GPNMB expres-sion (expression in 25% of tumor cells; n=33), CDX-011 led to an ORRand DCR of 32% and 64%, respectively, vs. 13% and 38% for chemo-therapy. In patients with both TNBC and high GPNMB expression(n=14), CDX-011 led to an ORR and DCR of 36% and 82%, respectively,vs. 0% and 33% for chemotherapy.

Celldex said that while the data are not yet mature, CDX-011 showeda trend of improvement in PFS in patients with high GPNMB expressionvs. chemotherapy, while significantly improving the endpoint in patientswith both TNBC and high GPNMB expression (p=0.0032). The mostcommon adverse events included rash and peripheral neuropathy. Thecompany said next steps will be determined after it receives updated data,which are expected in 4Q12. Celldex did say it has developed a diagnosticassay that identifies GPNMB expression patterns and levels in patientswith breast cancer. CDX-011 has Fast Track designation in the U.S. Theproduct uses antibody-drug conjugate technology from Seattle GeneticsInc. (NASDAQ:SGEN, Bothell, Wash.).

Chugai Pharmaceutical Co. Ltd. (Tokyo:4519), Tokyo, JapanDaiichi Sankyo Co. Ltd. (Tokyo:4568; Osaka:4568), Tokyo, JapanRoche (SIX:ROG; OTCQX:RHHBY), Basel, SwitzerlandProduct: Zelboraf vemurafenib (PLX4032, R7204, RG7204, RO5185426)Business: CancerMolecular target: BRAFDescription: Oral small molecule inhibitor of the oncogenic BRAFV600EIndication: Treat metastatic melanoma in patients with V600E BRAFmutationsEndpoint: Overall survival (OS) and progression-free survival (PFS);overall response rate (ORR), time to response, duration of response,time to treatment failure, safety and pharmacokineticsStatus: Updated Phase III dataMilestone: NA

Updated data from the open-label, international Phase III BRIM3 trialin 675 patients with previously untreated BRAF V600E mutation-positivemetastatic melanoma showed that twice-daily 960 mg oral Zelboraf led toa median OS of 13.2 months vs. 9.6 months for standard of care IVdacarbazine every 3 weeks. Additionally, 12-month OS rates were 55% forZelboraf vs. 43% for dacarbazine. Data will be presented at the AmericanSociety of Clinical Oncology meeting in Chicago in June. Roche previouslyreported that vemurafenib met the co-primary endpoints of OS and PFSvs. dacarbazine (see BioCentury, Jan. 24, 2011 & June 13, 2011).

Zelboraf is approved in the U.S., EU, Switzerland, Brazil, Israel,Canada and New Zealand to treat unresectable or metastatic melanomain patients with BRAF V600E mutations. Roche also has CE Markapproval in Europe for its companion BRAF V600 Mutation Test, whichis a PCR-based nucleic acid test to identify patients whose tumors carrythe mutation. The companion test is also approved in the U.S. Rochehas exclusive, worldwide rights to Zelboraf from Plexxikon Inc., whichwas acquired by Daiichi last year. Chugai, which is majority owned byRoche, has rights in Japan.

Curis Inc. (NASDAQ:CRIS), Lexington, Mass.Debiopharm Group, Lausanne, SwitzerlandProduct: Debio 0932 (formerly CUDC-305)Business: CancerMolecular target: Heat shock protein 90 (Hsp90)Description: Small molecule inhibitor of Hsp90Indication: Treat advanced solid tumors or lymphomaEndpoint: Safety and maximum tolerated dose (MTD); antitumor activ-ity, pharmacokinetics and pharmacodynamicsStatus: Phase I dataMilestone: NA

An open-label, dose-escalation, French Phase I trial in 51evaluable patients with advanced solid tumors or lymphoma whowere resistant to standard therapy showed that Debio 0932 givendaily or every other day was generally well tolerated with no ocularor cardiac toxicity reported. Dose-limiting toxicities (DLTs) in-cluded febrile neutropenia at the once-daily 1,600 mg dose ofDebio 0932 and diarrhea and asthenia at the 1,600 mg every otherday dose. Additionally, rates of partial response and stable diseasein patients receiving once-daily Debio 0932 (n=23) were 4% and17%, respectively. Rates of partial response and stable disease inpatients receiving Debio 0932 every other day (n=28) were 0% and29%, respectively. Data will be presented at the American Societyof Clinical Oncology meeting in Chicago in June.

The recommended Phase II dose was determined to be once-daily 1,000 mg Debio 0932 and is being evaluated in 30 patients inthe expansion phase of the trial. Debiopharm also said it plans tostart a Phase I/II trial evaluating Debio 0932 as first- and second-line treatment of non-small cell lung cancer (NSCLC). Debiopharmhas exclusive, worldwide rights to develop and commercializeCuris’ Hsp90 technology, which includes Debio 0932, under a 2009deal (see BioCentury, Aug. 10, 2009).

Curis Inc. (NASDAQ:CRIS), Lexington, Mass.Genentech Inc., South San Francisco, Calif.Chugai Pharmaceutical Co. Ltd. (Tokyo:4519), Tokyo, JapanRoche (SIX:ROG; OTCQX:RHHBY), Basel, SwitzerlandProduct: Erivedge vismodegib (GDC-0449, RG3616)Business: CancerMolecular target: Smoothened (SMO)Description: Small molecule hedgehog pathway inhibitorIndication: Treat advanced chondrosarcomasEndpoint: 6-month clinical benefit rate (CBR); progression-free sur-vival (PFS), overall survival (OS), duration of response and safetyStatus: Phase II dataMilestone: NA

Interim data from 17 evaluable patients in a single-arm, open-label,French Phase II trial showed that once-daily 150 mg oral vismodegib ledto 4 cases of stable disease at 6 months, meeting the criteria forcontinued enrollment. Vismodegib was well tolerated. The trial, whichhas enrolled 40 patients, is being conducted by the Institut Bergonie.Data will be presented at the American Society of Clinical Oncologymeeting in Chicago in June.

FDA approved vismodegib earlier this year as Erivedge to treatadvanced basal cell carcinoma (BCC) in adults with metastaticdisease or who are not candidates for surgery or radiation (seeBioCentury, Feb. 6). The product is under review in Europe, Canadaand Switzerland for the indication. Roche’s Genentech Inc. unitdiscovered vismodegib and jointly validated the compound withCuris through a series of preclinical studies under a collaborationagreement. Chugai, which is majority owned by Roche, has Japaneserights to the compound.


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Indication: Treat advanced sarcomasEndpoint: Maximum tolerated dose (MTD) of RO4929097 (Phase Ib)and progression-free survival (PFS) (Phase II); protein levels from pre-and post-treatment biopsies, overall response rate (ORR) and overallsurvival (OS) (Phase II)Status: Phase Ib dataMilestone: NA

Data from 34 patients with advanced sarcomas in the Phase Ibportion of an open-label, U.S. Phase Ib/II trial showed that once-daily150 mg oral vismodegib plus once-daily 10 and 15 mg RO4929097 waswell tolerated with no dose-limiting toxicities (DLTs) reported. Sys-temic exposure (peak plasma concentration and area under the curve(AUC) over 0-24 hours) of RO4929097 was about 70% lower in patientswho received vismodegib plus RO4929097 vs. RO4929097 alone. ThePhase II portion of the trial is evaluating once-daily 15 mg RO4929097,the recommended dose from the Phase Ib portion, alone and incombination with once-daily 150 mg vismodegib. The Memorial Sloan-Kettering Cancer Center is sponsoring the trial. Data will be presentedat the American Society of Clinical Oncology meeting in Chicago in June.

FDA approved vismodegib earlier this year as Erivedge to treatadvanced basal cell carcinoma (BCC) in adults with metastatic diseaseor who are not candidates for surgery or radiation (see BioCentury, Feb.6). The product is under review in Europe, Canada and Switzerland forthe indication. Roche’s Genentech Inc. unit discovered vismodegib andjointly validated the compound with Curis through a series of preclini-cal studies under a collaboration agreement. Chugai, which is majorityowned by Roche, has Japanese rights to the compound. Roche’sRO4929097 (R4733), a gamma secretase inhibitor, is in Phase I testingto treat solid tumors.

Indication: Treat advanced basal cell carcinoma (BCC)Endpoint: Overall response rate (ORR); duration of response, pro-gression-free survival (PFS), overall survival (OS) and safetyStatus: Additional Phase II dataMilestone: NA

Additional data from the open-label, international Phase II ERIVANCEBCC trial in 104 patients with inoperable advanced BCC showed thatonce-daily 150 mg oral vismodegib led to a 1-year survival rate of 77.3%in patients with metastatic BCC (n=33) and 93.1% in patients with locallyadvanced BCC (n=63). Data will be presented at the American Societyof Clinical Oncology meeting in Chicago in June.

Last year, Roche’s Genentech Inc. unit reported that vismodegib metthe primary endpoint of ORR as assessed by independent review, with anORR of 43% in patients with locally advanced BCC and 30% in patients withmetastatic BCC (see BioCentury, March 28, 2011 & June 27, 2011). FDAapproved vismodegib earlier this year as Erivedge to treat advanced BCCin adults with metastatic disease or who are not candidates for surgery orradiation (see BioCentury, Feb. 6). The product is under review in Europe,Canada and Switzerland. Genentech discovered vismodegib and jointlyvalidated the compound with Curis through a series of preclinical studiesunder a collaboration agreement. Chugai, which is majority owned byRoche, has Japanese rights to the compound.

Indication: Treat metastatic pancreatic cancerEndpoint: Progression-free survival (PFS); median overall survival (OS),objective response rate (ORR) and safetyStatus: Interim Phase Ib/II dataMilestone: NA

Interim data from 70 evaluable patients with recurrent or metastaticpancreatic cancer in a double-blind, U.S. Phase Ib/II trial showed that

once-daily 150 mg oral vismodegib plus gemcitabine led to a median PFSof 3.7 months vs. 2.4 months for placebo plus gemcitabine. There wereno complete or partial responses and 49 cases of stable disease inpatients receiving vismodegib vs. 3 complete responses, 11 partialresponses and 31 cases of stable disease in patients receiving placebo.Upon disease progression, 23 of 35 patients in the placebo groupcrossed over to receive vismodegib. Median OS was 6.3 months forpatients receiving vismodegib vs. 5.4 months for placebo, and 1-year OSwas 24% for both arms. Grade 3/4 adverse events included neutropenia,hyponatremia, fatigue, hyperglycemia and elevated alkaline phosphatase(ALP) levels. The University of Chicago sponsored the trial, which wasfunded by NIH’s National Cancer Institute (NCI). Data will be presentedat the American Society of Clinical Oncology meeting in Chicago in June.

FDA approved vismodegib earlier this year as Erivedge to treatadvanced basal cell carcinoma (BCC) in adults with metastatic diseaseor who are not candidates for surgery or radiation (see BioCentury, Feb.6). The product is under review in Europe, Canada and Switzerland.Roche’s Genentech Inc. unit discovered vismodegib and jointly vali-dated the compound with Curis through a series of preclinical studiesunder a collaboration agreement. Chugai, which is majority owned byRoche, has Japanese rights to the compound.

Eisai Co. Ltd. (Tokyo:4523; Osaka:4523), Tokyo, JapanProduct: Amatuximab (MORAb-009)Business: CancerMolecular target: Glycoprotein-9 (GP-9) (CD42a)Description: IgG1 antibody against glycoprotein-9 (GP-9; CD42a)Indication: Treat locally advanced malignant pleural mesothelioma(MPM)Endpoint: Progression-free survival (PFS); safety, objective responserate (ORR), duration of survival and overall survival (OS)Status: Interim Phase II dataMilestone: NA

Interim data from the open-label, international Phase II MORAb-009-003 trial in 89 chemotherapy-naïve patients with unresectableepithelial or biphasic pleural MM showed that 5 mg/kg amatuximab ondays 1 and 8 of a 21-day cycle in combination with cisplatin andpemetrexed produced 30 partial responses and 39 cases of stabledisease. Median PFS was 6.1 months and the 6-month PFS rate was 52%.Median OS as of Jan. 10 was 14.5 months. Grade 3/4 hypersensitivityreactions occurred in 4.5% of patients receiving amatuximab. Data willbe presented at the American Society of Clinical Oncology meeting inChicago in June. Eli Lilly and Co. (NYSE:LLY, Indianapolis, Ind.) marketsAlimta pemetrexed.

Product: Farletuzumab (MORAb-003)Business: CancerMolecular target: Folate receptor 1 (FOLR1) (FR-alpha)Description: Humanized IgG1 antibody targeting the folate receptor 1(FOLR1; FR-alpha)Indication: Treat platinum-sensitive ovarian cancer in first relapseEndpoint: Safety; objective response rate (ORR), time to response andduration of responseStatus: Phase I dataMilestone: NA

A single-arm, open-label Phase I trial in 15 patients with platinum-sensitive epithelial ovarian cancer showed that once-weekly 2.5 mg/kgfarletuzumab plus carboplatin and pegylated liposomal doxorubicinevery 4 weeks for 6 cycles produced 1 complete response, 10 partialresponses and 4 cases of stable disease. Median PFS was 11 months.Adverse events deemed to be possibly related to farletuzumab orchemotherapy included 2 cases of small bowel obstruction in the same


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patient and 1 case of fatigue. Data will be presented at the AmericanSociety of Clinical Oncology meeting in Chicago in June.

Last year, Eisai’s Morphotek Inc. subsidiary terminated the Phase IIFAR122 trial in platinum-resistant ovarian cancer after an interim analysisby an independent DMC showed that farletuzumab plus paclitaxel wasunlikely to meet the endpoints of PFS and OS vs. paclitaxel plus placebo(see BioCentury, Jan. 16). Farletuzumab is in a Phase III trial in combinationwith carboplatin and taxane chemotherapy for platinum-sensitive ovariancancer in first relapse and a Phase II trial for first-line treatment of non-small cell lung cancer (NSCLC). Johnson & Johnson (NYSE:JNJ, NewBrunswick, N.J.) markets Caelyx pegylated liposomal doxorubicin.

Eisai Co. Ltd. (Tokyo:4523; Osaka:4523), Tokyo, JapanSFJ Pharmaceuticals Inc., Pleasanton, Calif.Product: Lenvatinib (E7080)Business: CancerMolecular target: Vascular endothelial growth factor (VEGF) receptor;Vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1)(VEGFR-2)Description: Inhibitor of multiple VEGF receptor tyrosine kinasesIndication: Treat unresectable stage III and IV melanomaEndpoint: Safety and maximum tolerated dose (MTD)Status: Phase Ib dataMilestone: NA

An open-label, dose-escalation Phase Ib trial in 32 patients withunresectable stage III/IV melanoma showed that once-daily 20-24 mglenvatinib plus temozolomide produced 6 partial responses. MedianPFS was 5.4 months with a 6-month PFS rate of 37%. The most commontreatment-related adverse events were fatigue, hypertension, pro-teinuria, vomiting, hypothyroidism, anorexia, nausea, diarrhea andthrombocytopenia. Grade 3 adverse events at the 24 mg dose includedfatigue, hypertension and diarrhea. No grade 4 adverse events or dose-limiting toxicities (DLTs) were reported. Data will be presented at theAmerican Society of Clinical Oncology meeting in Chicago in June. Thecompound is in Phase III testing to treat thyroid cancer. Eisai partneredwith SFJ to develop lenvatinib last year (see BioCentury, Sept. 12, 2011).Merck & Co. Inc. (NYSE:MRK, Whitehouse Station, N.J.) marketsTemodar temozolomide.

Eli Lilly and Co. (NYSE:LLY), Indianapolis, Ind.Product: Alimta pemetrexedBusiness: CancerMolecular target: Dihydrofolate reductase (DHFR); Glycinamide ribo-nucleotide formyltransferase (GARFT)Description: Antifolate that inhibits thymidylate synthase, dihydrofolatereductase (DHFR) and glycinamide ribonucleotide formyltransferase(GARFT)Indication: Treat inoperable stage IIIA/B non-small cell lung cancer(NSCLC)Endpoint: 2-year overall survival (OS); median OS, time to progression(TTP), overall response rate (ORR) and safetyStatus: Additional Phase II dataMilestone: NA

Additional data from an open-label Phase II trial in 98 patients withinoperable stage IIIA/B NSCLC showed that 500 mg/m2 IV Alimta givenevery 21 days plus carboplatin and radiation led to a 2-year OS rate, theprimary endpoint, of 45.2% vs. 57.6% for Alimta plus cisplatin andradiation. Median TTP and OS were 8.8 and 18.7 months, respectively,for Alimta plus carboplatin and radiation vs. 13.1 and 27 months forAlimta plus cisplatin and radiation. Additionally, Alimta plus carboplatin

and radiation led to an ORR of 52.2% vs. 46.2% for Alimta plus cisplatinand radiation. Data will be presented at the American Society of ClinicalOncology meeting in Chicago in June.

Eli Lilly reported interim data from the trial in 2010 (see BioCentury,May 31, 2010). Alimta is approved in the U.S. and EU for first- andsecond-line therapy as well as maintenance therapy following platinum-based chemotherapy of locally advanced or metastatic non-squamousNSCLC, and for malignant pleural mesothelioma (MPM).

Product: Cixutumumab (IMC-A12)Business: CancerMolecular target: Insulin-like growth factor 1 (IGF1) receptor (IGF1R)(CD221)Description: Human mAb against insulin-like growth factor-1 (IGF-1)receptor (IGF1R)Indication: Treat solid tumorsEndpoint: Maximum tolerated dose (MTD) and safetyStatus: Phase II dataMilestone: NA

An open-label, dose-escalation, U.S. Phase I trial in 16 patients withadvanced solid tumors showed that selumetinib plus cixutumumabproduced 1 partial response and 4 cases of stable disease in 10 evaluablepatients. A dose-limiting toxicity (DLT) of visual changes occurred atthe 75 mg selumetinib dose. Grade 3 adverse events included nausea/vomiting, visual changes/retinopathy, methicillin-resistant Staphylococ-cus aureus (MRSA) skin infection, hyperglycemia and stroke. Therecommended Phase II dose is twice-daily 50 mg selumetinib plus twice-weekly 12 mg/kg cixutumumab. Data will be presented at the AmericanSociety of Clinical Oncology meeting in Chicago in June.

In 2003, Array BioPharma Inc. (NASDAQ:ARRY, Boulder, Colo.)granted AstraZeneca plc (LSE:AZN; NYSE:AZN, London, U.K.) rightsto selumetinib, a small molecule MEK inhibitor, for oncology indica-tions (see BioCentury, Dec. 22, 2003). Selumetinib and cixutumumab areboth in Phase II testing for various cancers.

Product: Dulaglutide (GLP-1Fc) (LY2189265)Business: Endocrine/MetabolicMolecular target: Glucagon-like peptide-1 (GLP-1)Description: Long-acting glucagon-like peptide-1 (GLP-1) receptoragonistIndication: Treat Type II diabetesEndpoint: Change from baseline in mean 24-hour systolic blood pres-sure (SBP) as measured by ambulatory blood pressure monitoring(ABPM) at week 16; mean 24-hour diastolic blood pressure (DBP) andmean 24-hour heart rateStatus: Phase II dataMilestone: NA

A double-blind, international Phase II trial in 755 Type II diabeticsreceiving 1 oral diabetes medication showed that 0.75 and 1.5 mgdoses of once-weekly subcutaneous dulaglutide each met the primaryendpoint of non-inferiority to placebo in reducing mean 24-hour SBPfrom baseline to week 16 as measured by ABPM. The non-inferioritymargin was 3 mmHg. Additionally, the trial was designed to assesssuperiority if the non-inferiority endpoint was met. High-dosedulaglutide significantly reduced mean 24-hour SBP from baseline toweek 16 by 2.79 mmHg compared to placebo (97.3% CI: -2.83, 0.68),while low-dose dulaglutide non-significantly reduced the endpoint by1.07 mmHg compared to placebo (97.3% CI: -4.58, -1). Eli Lilly saidsimilar results were observed at week 26.

Additionally, both low- and high-dose dulaglutide were non-infe-rior to placebo on the secondary endpoint of reducing mean 24-hourDBP from baseline to week 16 and to week 26. Furthermore, low-dose


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dulaglutide was non-inferior to placebo on the secondary endpoint ofmean 24-hour heart rate at week 16 (1.62 bpm; 97.3% CI: 0.32, 2.92)and at week 26 (1.26 bpm; 97.3% CI: -0.13, 2.64). High-dose dulaglutidedid not meet non-inferiority criteria for 24-hour heart rate at eithertime point (2.84 bpm; 97.3% CI: 1.52, 4.16 and 3.5 bpm; 97.3% CI: 2.1,4.91, respectively). The non-inferiority margins for 24-hour DBP and24-hour heart rate were 2.5 mmHg and 3 bpm, respectively. Both dosesof dulaglutide also significantly reduced HbA1c from baseline at weeks16 and 26 vs. placebo. The most common adverse events were gas-trointestinal and included diarrhea, nausea and vomiting. Data werepresented at the American Society of Hypertension meeting in NewYork. Dulaglutide is in Phase III testing for Type II diabetes.

Product: LY2228820Business: CancerMolecular target: p38 mitogen-activated protein kinase (p38 MAPK)(MAPK14)Description: Small molecule inhibitor of p38 mitogen-activated proteinkinase (p38 MAPK; MAPK14)Indication: Treat cancerEndpoint: Number of patients with clinically significant effects; recom-mended Phase II dose, tumor response and pharmacokineticsStatus: Phase I dataMilestone: NA

An open-label, dose-escalation, U.S. Phase I trial in 54 patients withadvanced cancer showed that LY2228820 produced 15 cases of stabledisease. The maximum tolerated dose (MTD) was twice-daily 420 mgLY2228820, however twice-daily 300 mg LY2228820 was selected asthe recommended Phase II dose because of the frequency of grade 1 and2 adverse events and the observation of clinical activity at lower doselevels. The most common treatment-related adverse events includedfatigue, nausea, rash, constipation, vomiting and pruritus. Dose-limit-ing toxicities (DLTs) included grade 2 dizziness and grade 3 erythemamultiforme and ataxia. Patients received twice-daily 10-200 mgLY2228820 as a capsule or 160-560 mg LY2228820 as a tablet. Data willbe presented at the American Society of Clinical Oncology meeting inChicago in June.

Product: LY2780301Business: CancerMolecular target: S6 kinase (S6K); Protein kinase B (PKB) (PKBA) (AKT)(AKT1)Description: Selective ATP competitive inhibitor against p70S6 kinaseand protein kinase B (PKB; PKBA; AKT; AKT1)Indication: Treat advanced cancerEndpoint: Recommended Phase II dose; best overall response, progres-sion-free survival (PFS), duration of response and pharmacokineticsStatus: Phase I dataMilestone: NA

An open-label, dose-escalation, Spanish Phase I trial in 32 patientswith advanced or metastatic cancer showed that 100-500 mg oralLY2780301 in 28-day cycles was well tolerated. Eli Lilly said therecommended Phase II dose will be in the 300-500 mg range. Therewere no partial or complete responses and the best observed responsewas prolonged stable disease for 6.5 cycles. Grade 3 and 4 toxicitieswere anemia, increased alanine aminotransferase (ALT) and aspartateaminotransferase (AST) levels and increased gamma-glutamyltransferase(GGT). Common toxicities included constipation, fatigue, nausea,diarrhea and vomiting. Data will be presented at the American Societyof Clinical Oncology meeting in Chicago in June.

Product: LY900009Business: CancerMolecular target: Gamma secretaseDescription: Small molecule inhibitor of gamma secretaseIndication: Treat advanced cancerEndpoint: Safety and pharmacokineticsStatus: Phase I dataMilestone: NA

A dose-escalation Phase I trial in 22 patients with advanced cancershowed that 60 mg LY900009 led to grade 3 dose-limiting toxicities (DLTs)of fatigue and diarrhea in 2 patients. The maximum tolerated dose (MTD)was tentatively identified at 30 mg. The most common treatment-emer-gent adverse events were diarrhea, vomiting, nausea, fatigue, anorexia,hypophosphatemia and rash. Patients received thrice-weekly 2-60 mgLY900009 in 28-day cycles. An additional cohort of patients is receiving 45mg LY900009 to refine the MTD. Data will be presented at the AmericanSociety of Clinical Oncology meeting in Chicago in June.

Etubics Corp., Seattle, Wash.Product: ETBX-011Business: CancerMolecular target: NADescription: Vaccine using an adenovirus serotype 5 (Ad5) vectoragainst carcinoembryonic antigen (CEA)Indication: Treat advanced or metastatic carcinoembryonic antigen(CEA)-expressing cancerEndpoint: Safety; CEA-specific immune responses and response rateStatus: Phase I/II dataMilestone: Start Phase III (year end 2012)

An open-label, U.S. Phase I/II trial in 25 patients with refractoryadvanced CEA-expressing colorectal cancer showed that subcutaneousETBX-011 given once every 3 weeks for 3 doses led to a 1-year overallsurvival (OS) rate of 54%. Data will be presented at the AmericanSociety of Clinical Oncology meeting in Chicago in June.

GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.Product: Avandia rosiglitazoneBusiness: Endocrine/MetabolicMolecular target: Peroxisome proliferation activated receptor (PPAR)Description: Oral thiazolidinedione (TZD) peroxisome proliferationactivated receptor (PPAR) gamma agonist to enhance insulin sensitivityIndication: Treat Type II diabetesEndpoint: Loss of glycemic control defined as glycated hemoglobinlevels of 8% for 6 months or sustained metabolic decompensationrequiring insulinStatus: Phase III dataMilestone: NA

Researchers at George Washington University and colleaguesreported data from the double-blind, U.S. Phase III TODAY trial in 699Type II diabetics aged 10-17 showing that twice-daily Avandia plusmetformin met the primary endpoint of a lower rate of treatmentfailure, defined as loss of glycemic control, vs. metformin alone at amean follow-up of 3.86 years (38.6% vs. 51.7%, p=0.006). Metforminplus lifestyle intervention non-significantly reduced the rate of treat-ment failure (46.6%) vs. metformin alone. Patients were initially treatedwith metformin to attain a glycated hemoglobin level of <8% and werethen randomized to receive Avandia plus metformin, metformin aloneor metformin plus the TODAY Lifestyle Program, which focuses onweight loss through eating and activity behaviors. The trial was spon-sored by NIH’s National Institute of Diabetes and Digestive and KidneyDiseases (NIDDK). Data were published in the New England Journal ofMedicine. GlaxoSmithKline markets Avandia.



Horizon Pharma Inc. (NASDAQ:HZNP), Deerfield, Ill.SkyePharma plc (LSE:SKP), London, U.K.Product: Rayos (Lodotra - EU) prednisone (NP01)Business: AutoimmuneMolecular target: Corticoid receptorsDescription: Delayed-release oral formulation of low-dose prednisoneIndication: Treat rheumatoid arthritis (RA)Endpoint: Proportion of patients achieving a 20% improvement in theAmerican College of Rheumatology criteria (ACR20) response at week12; morning joint stiffness, disease activity score using 28 joint counts(DAS28), FACIT-Fatigue score, Short Form 36-Item (SF-36) question-naire and safetyStatus: Additional Phase III dataMilestone: PDUFA date (07/26/2012)

Additional data from the double-blind, international Phase III CAPRA-2 trial in 350 patients with active RA showed that Rayos significantlyimproved ACR50 response rate at week 12 vs. placebo (22% vs. 10%,p=0.006). Rayos also significantly improved DAS28, FACIT-Fatigue andSF-36 scores from baseline to week 12 vs. placebo (p0.003 for all).Patients received once-daily 5 mg Rayos or placebo in combination withstandard DMARD therapy. Data were published in the Annals of theRheumatic Disease. In 2009, Nitec Pharma AG reported that Rayos metthe primary endpoint a greater proportion of patients achieving anACR20 response at week 12 vs. placebo (49% vs. 29%, p=0.0002) (seeBioCentury, Sept. 7, 2009).

Rayos is under FDA review in the U.S. for RA with a July 26 PDUFAdate. The product is approved as Lodotra in Europe and Israel to treatmoderate to severe active RA. Merck KGaA (Xetra:MRK, Darmstadt,Germany) has marketing rights to Lodotra in Germany and Austria,while Mundipharma International Ltd. (Cambridge, U.K.) has marketingrights in the rest of Europe and in certain Asian and Latin Americancountries (see BioCentury, Nov. 15, 2010 & March 12, 2012). Rayos usesGeoclock delivery technology from SkyePharma, which is eligible forsingle-digit royalties. Horizon gained the product through its 2010acquisition of Nitec (see BioCentury, April 12, 2010).

ImmunoGen Inc. (NASDAQ:IMGN), Waltham, Mass.Sanofi (Euronext:SAN; NYSE:SNY), Paris, FranceProduct: SAR3419Business: CancerMolecular target: CD19Description: CD19 mAb linked to DM4Indication: Treat relapsed or refractory B cell non-Hodgkin’s lym-phoma (NHL)Endpoint: Dose-limiting toxicities (DLTs); tumor response, durationof response, safety and pharmacokineticsStatus: Phase I dataMilestone: NA

Data from 21 evaluable patients in an extension cohort of an open-label, French Phase I trial showed that an optimized regimen of 55 mg/m2 IV SAR3419 consisting of 4 once-weekly doses followed by 4 bi-weekly doses led to an objective response in 6 patients, including 3unconfirmed complete responses, plus 9 cases of stable disease.Durations of response ranged from 8-35 weeks. The most commonadverse events were asthenia, including 1 patient with grade 3, andgastrointestinal disorders. Grade 3/4 hematological toxicities includedneutropenia, thrombocytopenia and anemia. Reversible grade 1 blurredvision/corneal event occurred in 1 patient. There were no DLTs. Datawill be presented at the American Society of Clinical Oncology meetingin Chicago in June.

The partners extended the Phase I trial with the optimized dosingcohort after data showed that once-weekly SAR3419 led to late adverseevents and antibody-drug conjugate (ADC) accumulation after 4 weeks.The optimized dosing regimen of SAR3419 is being evaluated in a pairof Phase II trials as a single agent or in combination with rituximab inpatients with diffuse large B cell lymphoma (DLBCL). ImmunoGen andSanofi partnered in 2003 to develop cancer antibodies. Biogen Idec Inc.(NASDAQ:BIIB, Cambridge, Mass.) and Genentech Inc., a unit of Roche(SIX:ROG; OTCQX:RHHBY, Basel, Switzerland), co-market rituximabas Rituxan in the U.S., while Roche markets it as MabThera elsewhere.

Inovio Pharmaceuticals Inc. (NYSE-A:INO), Blue Bell, Pa.Product: SynCon H5N1 influenza DNA vaccineBusiness: InfectiousMolecular target: NADescription: Synthetic DNA consensus influenza (H5N1) vaccineIndication: Treat influenza infectionEndpoint: Safety; humoral and cellular immune responsesStatus: Phase I dataMilestone: NA

An open-label, U.S. Phase I trial in 17 healthy volunteers showedthat SynCon avian influenza vaccine generated hemagglutination inhibi-tion (HAI) against at least 1 of 6 tested H5N1 strains with geometricmean titers 1:40 in 8 subjects (47%) and 1:20 in 12 subjects (71%).Additionally, 5 subjects had HAI titers 1:20 against 3 H5N1 strainsand 2 subjects had HAI titers 1:20 against all 6 strains. Subjectsreceived 2 intramuscular vaccinations followed by 2 intradermal vacci-nations using Inovio’s Cellectra-3P electroporation-based DNA deliv-ery system. The vaccine was well tolerated. Reported adverse eventsand injection site reactions were mild to moderate and required notreatment. Inovio is conducting a Phase I trial of INO-3510, a multi-antigen influenza vaccine that combines SynCon Vaccine constructs forthe H1N1 and H5N1 subtypes and is delivered intradermally using itselectroporation system.

Ipsen Group (Euronext:IPN), Boulogne-Billancourt, FranceRhythm Pharmaceuticals Inc., Boston, Mass.Product: RM-131 (formerly BIM 28131)Business: GastrointestinalMolecular target: GhrelinDescription: Ghrelin agonistIndication: Treat diabetic gastroparesisEndpoint: Pharmacodynamics; safety and tolerabilityStatus: Phase Ib dataMilestone: NA

A double-blind, crossover, U.S. Phase Ib trial in 10 patients withdiabetes and delayed gastric emptying showed that 100 µg RM-131significantly reduced gastric emptying time of solids vs. placebo (59.5vs. 127.8 minutes, p=0.011). RM-131 did not significantly improve theaverage score of combined nausea, bloating, postprandial fullness andupper abdominal pain vs. placebo (0.91 vs. 0.69 points, p>0.05). RM-131was generally well tolerated with no serious adverse events reported.Data were presented at the Digestive Disease Week meeting in SanDiego. Rhythm has exclusive, worldwide rights to RM-131 from Ipsen(see BioCentury, March 15, 2010).

Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.Product: Simponi golimumabBusiness: AutoimmuneMolecular target: Tumor necrosis factor (TNF) alphaDescription: Human mAb against tumor necrosis factor (TNF) alphaIndication: Treat ulcerative colitis (UC)

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Endpoint: Clinical response rate at week 6 defined as a reduction in Mayoscore of 30% and 3 points compared to baseline, with either a reductionfrom baseline in the rectal bleeding subscore of 1 point or a rectalbleeding subscore of 0 or 1; clinical remission defined as a Mayo score of2 points, mucosal healing defined as a Mayo endoscopy score of 0 or 1and Inflammatory Bowel Disease Questionnaire (IBDQ) scoresStatus: Phase III dataMilestone: Submit regulatory application (2012)

The double-blind, international Phase III PURSUIT trial in 774 patientsshowed that induction therapy with low- and high-dose subcutaneousSimponi each met the primary endpoint of a greater proportion of patientsachieving a clinical response at week 6 vs. placebo (51.8% and 55%,respectively, vs. 29.7%, p<0.0001 for both). Both doses of Simponi alsomet the secondary endpoints of a greater proportion of patients achievingclinical remission (18.7% and 17.8%, respectively, vs. 6.3%, p<0.0001 forboth) and mucosal healing vs. placebo (43.2% and 45.3%, respectively, vs.28.5%, p=0.0005 for both). Additionally, a significantly greater proportionof patients receiving low- and high-dose Simponi reported improvementsin health-related quality of life as measured by the mean change frombaseline in IBDQ scores vs. placebo (27.4% and 27%, respectively, vs.14.6%, p<0.0001 for both).

The trial enrolled patients with moderately to severely active UCwho had failed to respond to or tolerate treatment with 6-mercaptopu-rine, azathioprine, corticosteroids and/or 5-aminosalicylate, or werecorticosteroid dependent. Patients received 200 mg Simponi at week0 followed by 100 mg Simponi at week 2; 400 mg Simponi at week 0followed by 200 mg Simponi at week 2; or placebo. Patients respondingto induction treatment with Simponi were eligible to continue in thePhase III PURSUIT maintenance study. Data were presented at theDigestive Disease Week meeting in San Diego.

Johnson & Johnson plans to submit regulatory applications in theU.S. and EU for Simponi to treat UC this year. Simponi is approved in52 countries for rheumatologic indications, including the U.S. wherethe drug is approved for moderate to severe rheumatoid arthritis (RA),psoriatic arthritis and ankylosing spondylitis. J&J licensed UltiMAbtechnology to develop Simponi from Medarex Inc., which was acquiredby Bristol-Myers Squibb Co. (NYSE:BMY, New York, N.Y.).

Last year, Merck & Co. Inc. (NYSE:MRK, Whitehouse Station, N.J.) andJ&J concluded a 2009 arbitration over a dispute related to a 1998 dealbetween J&J’s Janssen Biotech Inc. unit (formerly Centocor Ortho BiotechInc.) and Schering-Plough Corp. for Simponi. Merck’s Schering-Ploughsubsidiary agreed to relinquish distribution rights to Simponi in Canada,Central and South America, the Middle East, Africa and Asia Pacific to J&J,while Merck retains exclusive marketing rights in Europe, Russia andTurkey. J&J has U.S. rights to Simponi and co-markets the drug in Japan,Indonesia and Taiwan with Mitsubishi Tanabe Pharma Corp. (Tokyo:4508;Osaka:4508, Osaka, Japan) (see BioCentury, April 18, 2011).

MediciNova Inc. (NASDAQ:MNOV; Osaka:4875), San Diego, Calif.Kissei Pharmaceutical Co. Ltd. (Tokyo:4547), Nagano, JapanProduct: Bedoradrine (MN-221, KUR-1246)Business: InflammationMolecular target: Adrenergic receptor beta 2 (ADRB2)Description: Selective adrenergic receptor beta 2 (ADRB2) agonistIndication: Treat severe acute exacerbations of asthmaEndpoint: Change from baseline in percent predicted forced expiratoryvolume in 1 second (FEV1) at 3 hours; dyspnea index scale, hospitaladmission rate, ICU admission rate, number of albuterol treatmentsand hospital length of stayStatus: Preliminary Phase IIb data

Milestone: NAPreliminary data from 144 evaluable patients with acute exacerba-

tions of asthma in the double-blind, U.S. Phase IIb MN-221-CL-007 trialshowed that a 1-hour IV infusion with 1,200 µg MN-221 as an adjunctto standard of care (SOC) missed the primary endpoint of improvingpercent predicted FEV1 from baseline at 3 hours vs. placebo plus SOC.On secondary endpoints, MN-221 improved FEV1 area under the curve(AUC) from 0-1 hour (0.065 vs. 0.02 L, p=0.043), 0-2 hours (0.231 L vs.0.085, p=0.05) and 0-3 hours vs. placebo (0.435 vs. 0.24 L, p=0.066).Additionally, MN-221 improved dyspnea score AUC from 0-2 hours by38% over placebo (p=0.062) and from 0-3 hours by 34% over placebo(p=0.055). Furthermore, a non-significantly smaller proportion ofpatients receiving MN-221 were hospitalized compared to placebo(38% vs. 46%). Other than asthma-related events, there were 2 seriousadverse events including 1 case of bronchitis each with MN-221 andplacebo and 1 case of pneumonia with MN-221.

The trial enrolled 175 patients who presented to a hospital emer-gency department with an acute exacerbation of asthma and did notinitially respond to complete SOC treatment, which included inhaledalbuterol, inhaled ipratropium and steroids. According to MediciNova,administration of off-protocol therapies not typically used in treatingacute exacerbations of asthma was over-represented in the placebogroup. The company plans to continue development of MN-221 in theindication and has requested an end-of-Phase II meeting with FDA.MediciNova said it intends to include further controls for off-protocolmedications in the design of its Phase III program. Data from the PhaseII MN-221-CL-002 of MN-221 to treat exacerbations of chronic ob-structive pulmonary disease (COPD) are expected in 4Q12. MediciNovahas exclusive, worldwide rights excluding Japan to MN-221 from Kissei.

Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J.Product: MK-2206Business: CancerMolecular target: Protein kinase B (PKB) (PKBA) (AKT) (AKT1)Description: Protein kinase B (PKB; PKBA; AKT; AKT1) inhibitorIndication: Treat advanced colorectal cancerEndpoint: Biomarker analysisStatus: Phase II dataMilestone: NA

Data from 9 evaluable patients with advanced colorectal cancerrefractory to standard therapy in an open-label, U.S. Phase II trialshowed that once-daily 75 mg selumetinib, a small molecule MEKinhibitor from AstraZeneca plc (LSE:AZN; NYSE:AZN, London, U.K.),plus once-weekly 90 mg MK-2206 in combination with produced 2 casesof stable disease after two 28-day cycles. No patient showed 70%inhibition of phosphorylation of both mitogen-activated ERK kinase(MEK) and AKT. The partners said that if repeated dosing does notproduce >70% inhibition in both markers, they will conclude that thecombination cannot provide adequate dual inhibition. Grade 1/2 ad-verse events included rash, reversible retinal detachment, liver abnor-malities, hypoalbuminemia and lymphopenia. Data will be presented atthe American Society of Clinical Oncology meeting in Chicago in June.

AstraZeneca and Merck partnered in 2009 to conduct a Phase I trialof the combination in solid tumors (see BioCentury, June 8, 2009). In 2003,Array BioPharma Inc. (NASDAQ:ARRY, Boulder, Colo.) grantedAstraZeneca rights to selumetinib for oncology indications (seeBioCentury, Dec. 22, 2003).

MolMed S.p.A. (Milan:MLM), Milan, ItalyProduct: NGR-hTNF (formerly Arenegyr)Business: CancerMolecular target: Alanyl membrane aminopeptidase (ANPEP) (APN) (CD13)


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Description: Recombinant fusion protein that selectively binds toCD13Indication: Treat advanced non-small cell lung cancer (NSCLC)Endpoint: Progression-free survival (PFS); safety, response rate, dura-tion of response and overall survival (OS)Status: Additional Phase II dataMilestone: NA

Additional data from the open-label, Italian Phase II NGR014 trialin 116 chemotherapy-naïve patients with stage IIIb/IV NSCLC showedthat 0.8 µg/m2 NGR-hTNF every 3 weeks plus cisplatin and pemetrexedor gemcitabine led to a median PFS of 5.8 months vs. 5.7 months forcisplatin and pemetrexed or gemcitabine alone. Additionally, NGR-hTNF plus cisplatin and pemetrexed or gemcitabine produced a re-sponse rate of 23% vs. 19% for cisplatin and pemetrexed or gemcitabinealone. One-year OS rates for both treatment groups was 62%. Data willbe presented at the American Society of Clinical Oncology meeting inChicago in June.

MolMed previously reported data from 100 evaluable patients show-ing that NGR-hTNF plus cisplatin and pemetrexed led to a median PFS of6.7 months vs. 4.6 months for cisplatin and pemetrexed alone in patientswith non-squamous NSCLC and a performance status of 1. In patients withsquamous histology, NGR-hTNF plus cisplatin and gemcitabine led tomedian PFS of 4.5 months vs. 2.7 months for cisplatin and gemcitabine alone(see BioCentury, May 30, 2011 & Oct. 17, 2011). Top-line data from the PhaseIII NGR015 trial of NGR-hTNF to treat malignant pleural mesothelioma(MPM) are expected in 2013. Eli Lilly and Co. (NYSE:LLY, Indianapolis, Ind.)markets Alimta pemetrexed and Gemzar gemcitabine.

Neurocrine Biosciences Inc. (NASDAQ:NBIX), San Diego, Calif.Product: Urocortin 2 (formerly NBI-69734)Business: CardiovascularMolecular target: Corticotropin-releasing factor receptor 2 (CRHR2)(CRFR2)Description: Endogenous peptide ligand of corticotropin-releasingfactor 2 (CRF2)Indication: Treat acute decompensated heart failure (ADHF)Endpoint: SafetyStatus: Phase II dataMilestone: NA

The double-blind, New Zealand Phase II UNICORN trial in 53patients with ADHF showed that IV urocortin 2 was generally welltolerated with no treatment-related serious adverse events reported.Urocortin 2 significantly reduced mean arterial pressures from baselineto end of infusion vs. placebo (12 vs. 3 mmHg reductions, p<0.001).Heart rates were higher during urocortin 2 infusion vs. placebo, butremained in the normal range and were comparable in both treatmentgroups post infusion. In patients undergoing right heart catheterization(n=20), urocortin 2 increased cardiac output by >50% vs. 0% for placebo(p=0.003). The most common adverse event reported in both theurocortin 2 and placebo arms was transient flushing (55% vs. 23%,respectively). Patients received standard of care (diuretics and vasodi-lators) plus a continuous IV infusion of either 5ng/kg/min urocortin 2or placebo for up to 4 hours.

Oncothyreon Inc. (NASDAQ:ONTY), Seattle, Wash.Product: PX-866Business: CancerMolecular target: Phosphoinositide 3-kinase (PI3K)Description: Oral phosphoinositide 3-kinase (PI3K) inhibitorIndication: Treat recurrent glioblastoma multiforme (GBM)

Endpoint: Objective response and early progression rates; safetyStatus: Interim Phase II dataMilestone: NA

Interim data from 15 evaluable patients with GBM at first recurrencein a 2-stage, single-arm, open-label, Canadian Phase II trial showed that12 patients discontinued therapy after receiving a median of one 8-weekcycle of once-daily 8 mg oral PX-866. Of the discontinuations, 9 weredue to disease progression and 3 were due to grade 3/4 liver enzymeabnormalities. Other adverse events included fatigue, diarrhea, nausea,vomiting and lymphopenia. According to the trial design, enrollmentwill be discontinued if 0 objective responses and 10 early progres-sions are observed in 15 patients in Stage I of the trial. Oncothyreonsaid Stage I response data are premature and it is not yet known if thetrial will proceed to Stage II. Stage II of the trial plans to enroll anadditional 15 patients. Data will be presented at the American Societyof Clinical Oncology meeting in Chicago in June. PX-866 is also in PhaseII testing to treat head and neck cancer, colorectal cancer, non-small celllung cancer (NSCLC) and chemotherapy-naïve prostate cancer.

Onyx Pharmaceuticals Inc. (NASDAQ:ONXX), South San Fran-cisco, Calif.Bayer AG (Xetra:BAYN), Leverkusen, GermanyProduct: Nexavar sorafenibBusiness: CancerMolecular target: CRAF (RAF1); Vascular endothelial growth factor(VEGF) receptorDescription: Inhibitor of RAF1 and multiple receptor tyrosine kinasesIndication: Treat relapsed or refractory non-squamous non-small celllung cancer (NSCLC)Endpoint: Overall survival (OS); progression-free survival (PFS), over-all response rate (ORR), disease control rate (DCR), time to progres-sion and quality of lifeStatus: Phase III dataMilestone: NA

The double-blind, international Phase III MISSION trial in 703patients with advanced relapsed or refractory non-squamous NSCLCwhose disease progressed after 2 or 3 prior treatments showed thattwice-daily 400 mg oral Nexavar plus best supportive care missed theprimary endpoint of OS vs. placebo plus best supportive care. Thepartners did say that Nexavar showed an improvement over placebo onthe secondary endpoint of PFS, but did not disclose details. Onyx saidMISSION is the third failed Phase III trial of Nexavar for lung cancer andsubsequently the partners do not plan to continue developing theproduct for the indication. Nexavar is approved in more than 100countries to treat liver cancer and advanced kidney cancer. Bayer andOnyx have a worldwide co-development agreement for Nexavar out-side of Japan, where Bayer owns rights.

Onyx Pharmaceuticals Inc. (NASDAQ:ONXX), South San Fran-cisco, Calif.Ono Pharmaceutical Co. Ltd. (Tokyo:4528; Osaka:4528), Osaka,JapanProduct: Kyprolis carfilzomib (PR-171, ONO-7057)Business: CancerMolecular target: ProteasomeDescription: Selective proteasome inhibitorIndication: Treat relapsed and refractory multiple myeloma (MM)Endpoint: Overall response rate (ORR); clinical benefit rate (CBR),safety, time to progression (TTP), duration of response, progression-free survival (PFS) and overall survival (OS)Status: Additional Phase IIb dataMilestone: PDUFA date (07/27/2012)


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Additional data from the open-label, North American pivotal PhaseIIb PX-171-003-A1 trial showed that in a subset of patients refractoryor intolerant to Velcade bortezomib and either thalidomide or Revlimidlenalidomide (n=229), carfilzomib produced an ORR of 20.6% with amedian duration of response of 7.4 months. In patients refractory toVelcade, Revlimid or thalidomide in any prior regimen, carfilzomibproduced ORRs of 16.5%, 17.8% and 22.2%, respectively, with responsedurations of 7.8, 5.6 and 7.8 months. In patients refractory to all 3approved therapies, carfilzomib produced an ORR of 20.5% with aresponse duration of 7.8 months. Data will be presented at theAmerican Society of Clinical Oncology meeting in Chicago in June.

In 2010, final data from 257 evaluable patients in the trial showedthat carfilzomib led to a median OS of 15.5 months and produced an ORRof 24.1%, with a median duration of response of 8.3 months and a CBRof 34.2% (see BioCentury, Dec. 13, 2010). Based on the data, Onyx isseeking accelerated approved of carfilzomib in the U.S. to treat relapsedand refractory MM under the name Kyprolis. The PDUFA date is July 27with an advisory committee meeting scheduled for June 20.

Ono has exclusive, Japanese rights to develop and commercializecarfilzomib from Onyx, which gained the product through its acquisi-tion of Proteolix Inc. in 2009. Millennium Pharmaceuticals Inc., asubsidiary of Takeda Pharmaceutical Co. Ltd. (Tokyo:4502, Osaka,Japan), markets Velcade in the U.S., while Johnson & Johnson (NYSE:JNJ,New Brunswick, N.J.) has rights elsewhere. Celgene Corp.(NASDAQ:CELG, Summit, N.J.) markets Revlimid.

Peregrine Pharmaceuticals Inc. (NASDAQ:PPHM), Tustin, Calif.Product: Bavituximab (3G4)Business: CancerMolecular target: PhosphatidylserineDescription: Chimeric mAb against phosphatidylserineIndication: Second-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC)Endpoint: Overall response rate (ORR); progression-free survival(PFS), duration of response, overall survival (OS) and safetyStatus: Phase IIb dataMilestone: Phase IIb additional data (2012)

Top-line data from a double-blind, international Phase IIb trial in 117evaluable patients showed that ORR, the primary endpoint, was higherin patients receiving once-weekly 1 mg/kg bavituximab plus docetaxel(15%) and 3 mg/kg bavituximab plus docetaxel (17.9%) vs. placebo plusdocetaxel (7.9%). Median PFS, a secondary endpoint, was 4.2 monthsin the low-dose bavituximab group and 4.5 months in the high-dosebavituximab vs. 3 months for placebo. Median OS, also a secondaryendpoint, was <6 months in patients receiving placebo and has not yetbeen reached in either bavituximab arm. No significant safety issues orconcerns were reported. Peregrine said the trial was not powered todetect statistical significance. The trial enrolled 121 patients withpreviously treated locally advanced or metastatic non-squamous stageIIIb/IV non-squamous NSCLC.

This year, Peregrine expects to report OS data from the trial, as wellas OS data from a pair of separate Phase II trials of bavituximab as first-line treatment of NSCLC and as first-line treatment of pancreaticcancer, respectively. Peregrine also said the Phase IIb results supportPhase III development of bavituximab to treat NSCLC, but details werenot disclosed. In March, Peregrine reported PFS and ORR data from aPhase II trial evaluating bavituximab as first-line treatment of stage IIIb/IV NSCLC (see BioCentury, March 19). Sanofi (Euronext:SAN; NYSE:SNY,Paris, France) markets Taxotere docetaxel.

Pharmacyclics Inc. (NASDAQ:PCYC), Sunnyvale, Calif.Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.Product: Ibrutinib (PCI-32765)Business: CancerMolecular target: Bruton’s tyrosine kinase (Btk)Description: Bruton’s tyrosine kinase (Btk) inhibitor that covalentlybinds to cysteine residue 481Indication: Treat relapsed or refractory chronic lymphocytic leukemia(CLL), small cell lymphocytic lymphoma (SLL) and related diseasesEndpoint: Response rate and safety; pharmacokinetics and tumor responseStatus: Interim Phase Ib/II dataMilestone: NA

Interim data from the open-label, U.S. Phase Ib/II PCYC-1109-CAtrial showed that once-daily 420 mg oral PCI-32765 plus ofatumumabled to a partial response in all 24 patients with relapsed or refractoryCLL, SLL or prolymphocytic leukemia (PLL) within six 28-day cycles.Additionally, 2 of 3 patients with Richter’s transformation achieved apartial response. Median follow-up was 6.5 months. Grade 3/4 adverseevents included anemia, pneumonia, urinary tract infection (UTI) andhyponatremia. Data will be presented at the American Society ofClinical Oncology meeting in Chicago in June.

PCI-32765 has Orphan Drug designation in the U.S. for CLL. LastDecember, Pharmacyclics partnered with Johnson & Johnson’s JanssenBiotech Inc. unit to co-develop and co-commercialize Pharmacyclics’PCI-32765 (see BioCentury, Dec. 12, 2011). GlaxoSmithKline plc (LSE:GSK;NYSE:GSK, London, U.K.) markets ofatumumab as Arzerra in the U.S.and EU to treat CLL. GSK has worldwide co-development and commer-cialization rights to ofatumumab from Genmab A/S (CSE:GEN,Copenhagen, Denmark) under a 2006 deal.

Indication: Treat chronic lymphocytic leukemia (CLL) or small celllymphocytic lymphoma (SLL)Endpoint: Prolonged hematologic toxicity; safety and overall response rate(ORR) as measured by disease in the lymph nodes and/or blood test resultsStatus: Interim Phase Ib/II dataMilestone: NA

Interim data from the open-label, U.S. Phase Ib/II PCYC-1108-CAtrial in 30 patients with relapsed or refractory CLL showed that once-daily 420 mg oral PCI-32765 plus bendamustine and rituximab led to anORR of 90%, with 10% of patients achieving a complete response and80% achieving a partial response. Additionally, 2 patients achieved anodal response with residual lymphocytosis. Median follow-up was 4.9months. Grade 3/4 neutropenia and thrombocytopenia were reportedin 47% and 10% of patients, respectively. Grade >3 non-hematologicadverse events that were potentially related to PCI-32765 includedrash, fatigue and tumor lysis. Data will be presented at the AmericanSociety of Clinical Oncology meeting in June. PCI-32765 has OrphanDrug designation in the U.S. for CLL. Last December, Pharmacyclicspartnered with Johnson & Johnson’s Janssen Biotech Inc. unit to co-develop and co-commercialize Pharmacyclics’ PCI-32765 (see BioCentury,Dec. 12, 2011).

Astellas Pharma Inc. (Tokyo:4503, Tokyo, Japan) granted rights tobendamustine to Cephalon Inc. in North America, to MundipharmaInternational Ltd. (Cambridge, U.K.) in Europe and to SymBio Pharma-ceuticals Ltd. (JASDAQ:4582, Tokyo, Japan) in Japan, China, Korea,Taiwan and Singapore. Cephalon, which Teva Pharmaceutical IndustriesLtd. (NASDAQ:TEVA, Petah Tikva, Israel) acquired last year, marketsbendamustine as Treanda in the U.S. to treat CLL and indolent B cellnon-Hodgkin’s lymphoma (NHL). Biogen Idec Inc. (NASDAQ:BIIB,Cambridge, Mass.) and Genentech Inc., a unit of Roche (SIX:ROG;OTCQX:RHHBY, Basel, Switzerland), co-market rituximab as Rituxanin the U.S., while Roche markets it as MabThera elsewhere.


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Piramal Healthcare Ltd. (BSE:500302; NSE:PIRHEALTH), Mumbai,IndiaProduct: BST-CarGelBusiness: MusculoskeletalMolecular target: Not applicableDescription: Chitosan-based liquid bioscaffold mixed with autologouswhole blood which is then implanted into a debrided cartilage defectprepared with bone marrow stimulationIndication: Cartilage repairEndpoint: Quality and quantity of cartilage repair at 12 months asmeasured by percent lesion fill and T2 MRI values; Western Ontario andMcMaster Universities Osteoarthritis Index (WOMAC) assessmentsfor pain, stiffness and functionStatus: Phase III dataMilestone: Market launch (4Q12)

An international, blinded Phase III trial in 80 patients aged 18-55 withsingle symptomatic grade III/IV focal lesions on femoral condylesshowed that BST-CarGel met the co-primary endpoints of greaterlesion filling and superior repair tissue quality at 12 months vs. standardof care microfracture surgery (p=0.0105 and p=0.033, respectively).On secondary endpoints, BST-CarGel was equivalent to microfracturesurgery in significantly improving WOMAC assessments for pain,stiffness and function from baseline to 12 months. Safety was compa-rable between treatment groups. Data were presented at the Interna-tional Cartilage Repair Society meeting in Montreal. In April, BST-CarGel received CE Mark approval in Europe for cartilage repair.Piramal plans to launch the product in 4Q12.

Roche (SIX:ROG; OTCQX:RHHBY), Basel, SwitzerlandProduct: RO4929097 (R4733)Business: CancerMolecular target: Gamma secretaseDescription: Gamma secretase inhibitorIndication: Treat advanced sarcomasEndpoint: Maximum tolerated dose (MTD) of RO4929097 (Phase Ib)and progression-free survival (PFS) (Phase II); protein levels from pre-and post-treatment biopsies, overall response rate (ORR) and overallsurvival (OS) (Phase II)Status: Phase Ib dataMilestone: NA

Data from 34 patients with advanced sarcomas in the Phase Ibportion of an open-label, U.S. Phase Ib/II trial showed that once-daily150 mg oral vismodegib plus once-daily 10 and 15 mg RO4929097 waswell tolerated with no dose-limiting toxicities (DLTs) reported. Sys-temic exposure (peak plasma concentration and area under the curve(AUC) over 0-24 hours) of RO4929097 was about 70% lower in patientswho received vismodegib plus RO4929097 vs. RO4929097 alone. ThePhase II portion of the trial is evaluating once-daily 15 mg RO4929097,the recommended dose from the Phase Ib portion, alone and incombination with once-daily 150 mg vismodegib. The Memorial Sloan-Kettering Cancer Center is sponsoring the trial. Data will be presentedat the American Society of Clinical Oncology meeting in Chicago in June.

FDA approved vismodegib earlier this year as Erivedge to treatadvanced basal cell carcinoma (BCC) in adults with metastatic diseaseor who are not candidates for surgery or radiation (see BioCentury, Feb.6). The small molecule hedgehog pathway inhibitor is under review inEurope, Canada and Switzerland for the indication. Roche’s GenentechInc. unit discovered vismodegib and jointly validated the compound withCuris Inc. (NASDAQ:CRIS, Lexington, Mass.) through a series ofpreclinical studies under a collaboration agreement.

Takeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, JapanProduct: Vedolizumab (MLN0002)Business: AutoimmuneMolecular target: Integrin alpha(4)beta(7)Description: Humanized mAb against integrin alpha(4)beta(7)Indication: Treat moderate to severe ulcerative colitis (UC)Endpoint: Proportion of patients with a clinical response at week 6 andproportion of patients in complete remission at week 52; proportionof patients in clinical remission at week 6 and proportion of patientswith a clinical response at week 52Status: Additional Phase III dataMilestone: NA

Additional data from the double-blind, international Phase III GEMINII trial showed that 47.1% of patients receiving vedolizumab in theblinded induction cohort (n=225) had a clinical response at week 6, aco-primary endpoint, vs. 25.5% for placebo (n=149; p<0.0001). Addi-tionally, 44.8% and 41.8% of patients who responded to vedolizumabat week 6 (in either the blinded or open-label induction cohorts) andsubsequently received vedolizumab every 4 (n=125) and 8 weeks(n=122), respectively, during the maintenance stage of the trial achievedclinical remission at week 52, also a co-primary endpoint, vs. 15.9% forplacebo (n=126; p<0.0001 for both).

The trial enrolled 895 patients with moderately to severely activeUC who have failed 1 conventional therapy, including tumor necrosisfactor (TNF) alpha antagonists. In the blinded induction cohort, 374patients were randomized to receive vedolizumab or placebo at weeks0, 2 and 6. Patients who responded to treatment were re-randomizedto receive placebo or vedolizumab every 4 or 8 weeks for up to 46weeks during the maintenance stage. In the open-label inductioncohort, 521 patients received vedolizumab at weeks 0, 2 and 6 andpatients who responded to treatment were randomized to receiveplacebo or vedolizumab every 4 or 8 weeks for up to 46 weeks duringthe maintenance stage. Patients have an option to continue treatmentfor up to 2 years in the open-label Phase III GEMINI LTS extension study.Data were presented at Digestive Disease Week meeting in San Diego.

In February, Takeda reported top-line data showing that vedolizumabmet the co-primary endpoints of a greater proportion of patients witha clinical response/remission in the induction and maintenance phasesof the trial vs. placebo (see BioCentury, Feb. 27). Earlier this month, thecompany reported top-line data from the Phase III GEMINI II trial in1,115 patients with moderate to severe Crohn’s disease (CD) showingthat vedolizumab met the co-primary endpoints of a greater proportionof patients in clinical remission at week 6 (induction phase) and at week52 (maintenance phase) vs. placebo. However, vedolizumab missed theco-primary endpoint of improving enhanced response rate in theinduction phase vs. placebo (see BioCentury, May 14).

Takeda plans to submit a BLA and MAA to FDA and EMA, respec-tively, for vedolizumab during its fiscal year 2013 ending March 30, 2014.The pharma said that because the CD data are still being analyzed, it hasnot yet been determined whether the initial regulatory submission willbe for just UC or for both UC and CD.

Theravance Inc. (NASDAQ:THRX), South San Francisco, Calif.GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.Product: GSK961081 (961081) (formerly TD-5959)Business: PulmonaryMolecular target: Muscarinic receptor; Adrenergic receptor beta 2(ADRB2)Description: Bifunctional muscarinic receptor antagonist and beta 2agonist (MABA)Indication: Treat chronic obstructive pulmonary disease (COPD)Endpoint: Change from baseline in A.M. trough forced expiratory volume


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in 1 second (FEV1) on day 29; weighted mean FEV1 area under the curve(AUC) from 0-24 hours on day 28 and serial FEV1 on days 1 and 28Status: Phase IIb dataMilestone: NA

A double-blind, placebo- and active-controlled, international PhaseIIb trial in 436 patients with moderate to severe COPD showed that alldoses of GSK961081 met the primary endpoint of improving meanmorning trough FEV1 from baseline to day 29 vs. placebo (p0.001 forall). Specifically, once-daily 100, 400 and 800 µg GSK961081 led to meandifferences from placebo in trough FEV1 of 155, 215 and 277 mL,respectively, while twice-daily 100, 200 and 400 µg GSK961081 led tomean differences from placebo in trough FEV1 of 173, 249 and 258 mL,respectively. Additionally, all doses of GSK96108 (except the once-daily 100 µg dose at 12 hours on day 1) significantly improved weightedmean FEV1 AUC from 0-24 hours on day 28 and serial FEV1 on days 1and 28 vs. placebo. GSK961081 was well tolerated with headache,cough and dysgeusia reported as the most common adverse events.Theravance granted GlaxoSmithKline exclusive rights to its inhaledMABA program in 2005 (see BioCentury, March 28, 2005).

University of Michigan, Ann Arbor, Mich.Product: Prednisone, azathioprine and N-acetylcysteineBusiness: PulmonaryMolecular target: NADescription: Oral combination of prednisone, azathioprine and N-acetylcysteineIndication: Treat idiopathic pulmonary fibrosis (IPF)Endpoint: Change from baseline in serial forced vital capacity (FVC) at week60; time disease progression or death, acute exacerbations and safetyStatus: Phase III discontinuedMilestone: NA

Researchers at the university and colleagues stopped the double-blind, U.S. Phase III PANTHER-IPF trial after an interim analysis of 155patients showed that compared to placebo (n=78), the oral combina-tion of prednisone, azathioprine and N-acetylcysteine (n=77), a widelyused treatment for IPF according to the researchers, led to significantlygreater rates of death (10% vs. 1%, p=0.01), hospitalization (30% vs. 9%,p<0.001), acute exacerbations (6% vs. 0%, p=0.03) and serious adverseevents (31% vs. 10%, p=0.001). Additionally, there was no significantdifference between the 3-drug combination arm and placebo in thechange from baseline in serial FVC at a mean follow-up of 32 weeks (0.24vs. 0.23 L reductions, p=0.85). The researchers said data from patientsreceiving N-acetylcysteine alone are still being gathered and analyzed.The trial, which was sponsored by NIH’s National Heart, Lung andBlood Institute (NHLBI), enrolled IPF patients aged 35-85 with mild tomoderate lung function defined as an FVC of 50% and a carbonmonoxide diffusing capacity of 30% of the predicted value. Data werepublished in the New England Journal of Medicine and were presented atthe American Thoracic Society meeting in San Francisco.

PRECLINICAL RESULTS

Arrowhead Research Corp. (NASDAQ:ARWR), Pasadena, Calif.Product: Anti-HBV siRNA DPCsBusiness: InfectiousIndication: Treat HBV infection

In a mouse model of HBV infection, single injections of hepatocyte-targeted anti-HBV siRNA DPCs delivered using Arrowhead’s DynamicPolyconjugate (DPC) delivery technology resulted in a multi-log reduc-tion of serum hepatitis B surface antigen (HBsAg) and serum HBV DNA.

In mice carrying a hepatocyte-specific reporter gene fused to HBVsequences, 4 biweekly injections of anti-HBV siRNA DPCs led to amulti-log reduction in gene expression over 2 months with no changesin toxicity markers. Data were presented at the European Foundationfor Clinical Medicine meeting in Basel.

CLINICAL STATUS

Amgen Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.Cytokinetics Inc. (NASDAQ:CYTK), South San Francisco, Calif.Product: Omecamtiv mecarbil (AMG 423) (formerly CK-1827452)Business: CardiovascularMolecular target: Cardiac myosinDescription: Cardiac myosin activatorIndication: Treat patients with left ventricular systolic dysfunctionhospitalized for acute heart failureEndpoint: Effect on dyspnea; additional measures of dyspnea, patientglobal assessment (PGA), change in N-terminal pro-brain natriureticpeptide (NT-proBNP), incidence of worsening heart failure, days aliveout of hospital up to day 30 and pharmacokineticsStatus: Phase II ongoingMilestone: NA

Cytokinetics said an IDMC recommended continuation to thesecond cohort of the double-blind, placebo-controlled, internationalPhase IIb ATOMIC-AHF trial of omecamtiv mecarbil based on a safetyreview. The trial, which plans to enroll about 600 patients, is evaluating3 doses of IV omecamtiv mecarbil. Amgen has exclusive, ex-Japaneserights to omecamtiv mecarbil (see BioCentury, June 1, 2009).

ArQule Inc. (NASDAQ:ARQL), Woburn, Mass.Daiichi Sankyo Co. Ltd. (Tokyo:4568; Osaka:4568), Tokyo, JapanKyowa Hakko Kirin Co. Ltd. (Tokyo:4151), Tokyo, JapanProduct: Tivantinib (ARQ 197)Business: CancerMolecular target: c-Met receptor tyrosine kinaseDescription: Small molecule inhibitor of c-Met receptor tyrosine kinaseIndication: Treat non-small cell lung cancer (NSCLC) of non-squamoushistologyEndpoint: Overall survival (OS); progression-free survival (PFS) and OSin the wild-type EGFR sub-populationStatus: Completed Phase III enrollmentMilestone: NA

ArQule and Daiichi Sankyo completed enrollment in the double-blind, international Phase III MARQUEE trial comparing twice-daily 360mg oral tivantinib plus daily 150 mg oral Tarceva erlotinib vs. placeboplus Tarceva in about 1,000 patients with locally advanced or metastaticNSCLC who received 1-2 prior systemic anti-cancer therapies. Thecompany has an SPA from FDA for the trial. ArQule is co-developingtivantinib with Daiichi Sankyo on a worldwide basis outside of certainAsian countries, where ArQule licensed rights to Kyowa in 2007 (seeBioCentury, Nov. 5, 2007 & Nov. 17, 2008).

Tarceva is marketed by OSI Pharmaceuticals Inc., now part ofAstellas Pharma Inc. (Tokyo:4503, Tokyo, Japan), and Genentech Inc.,a unit of Roche (SIX:ROG; OTCQX:RHHBY, Basel, Switzerland), in theU.S., and by Roche elsewhere.

Aveo Pharmaceuticals Inc. (NASDAQ:AVEO), Cambridge, Mass.Product: AV-203Business: CancerMolecular target: Epidermal growth factor receptor 3 (EGFR3) (HER3)(ErbB3)Description: Epidermal growth factor (EGF) receptor 3 (HER3) (ErbB3)


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targeted antibodyIndication: Treat solid tumorsEndpoint: Safety; pharmacokinetics, objective response rate (ORR),disease control rate (DCR), duration of response and time to progres-sion (TTP)Status: Phase I startedMilestone: NA

Aveo began an open-label, dose-escalation, U.S. Phase I trial toevaluate IV AV-203 every 2 weeks in up to 30 patients with metastaticor advanced solid tumors. The company will also enroll up to 60 patientsin a portion of the trial evaluating potential biomarkers that will predictresponse to AV-203. Biogen Idec Inc. (NASDAQ:BIIB, Weston, Mass.)has an exclusive option to co-develop and commercialize the compoundoutside North America under a 2009 deal. Biogen Idec may exercise itsoption upon the completion of Phase II proof-of-concept testing (seeBioCentury, March 30, 2009).

Avraham Pharmaceuticals Ltd., Tel Aviv, IsraelProduct: LadostigilBusiness: NeurologyMolecular target: NADescription: Cholinesterase, brain-selective monoamine oxidase in-hibitor and neuroprotective agentIndication: Treat Alzheimer’s diseaseEndpoint: Alzheimer’s Disease Assessment Scale-Cognitive Subscale(ADAS-Cog) and safety; Neuropsychiatric Inventory (NPI), CornellScale for Depression in Dementia (CSDD), Alzheimer’s Disease Co-operative Study-Activities of Daily Living (ADCS-ADL) and Mini-MentalState Examination (MMSE)Status: Completed Phase II enrollmentMilestone: Phase II data (4Q12)

Avraham completed enrollment of about 200 patients in a double-blind, placebo-controlled, European Phase II trial evaluating 80 mg oralladostigil twice daily for 26 weeks in patients with mild to moderate AD.Avraham has an exclusive, worldwide license to develop and commer-cialize ladostigil to treat AD and other neurodegenerative diseasesfrom the technology transfer arms of the Hebrew University of Jerusa-lem (Jerusalem, Israel) and Technion-Israel Institute of Technology(Haifa, Israel) (see BioCentury, April 26, 2010).

Indication: Treat mild cognitive impairment (MCI)Endpoint: Conversion from mild cognitive impairment to Alzheimer’sdisease as determined by Clinical Dementia Rating (CDR) score;changes in Geriatric Depression Scale, Neuropsychiatric Test Batteryand Disability Assessment in Dementia, safety and mean time todevelopment of probable or possible ADStatus: Phase II startedMilestone: NA

Avraham began a 36-month, double-blind, placebo-controlled, in-ternational Phase II trial to evaluate 10 mg oral ladostigil daily in at least200 patients. Avraham has an exclusive, worldwide license to developand commercialize ladostigil to treat AD and other neurodegenerativediseases from the technology transfer arms of the Hebrew Universityof Jerusalem (Jerusalem, Israel) and Technion-Israel Institute of Tech-nology (Haifa, Israel) (see BioCentury, April 26, 2010).

Catalyst Pharmaceutical Partners Inc. (NASDAQ:CPRX), CoralGables, Fla.Product: Vigabatrin (CPP-109)Business: Neurology

Molecular target: GABA transaminaseDescription: Irreversible inhibitor of GABA transaminaseIndication: Treat cocaine addictionEndpoint: Proportion of patients that are cocaine-abstinent duringweeks 8 and 9Status: Completed Phase IIb enrollmentMilestone: Phase IIb data (1Q13)

Catalyst completed enrollment of about 210 cocaine-dependent pa-tients in a double-blind, placebo-controlled, U.S. Phase IIb trial evaluatingvigabatrin. Patients will receive twice-daily 1.5 g oral vigabatrin or placebofor 9 weeks. NIH’s National Institute on Drug Abuse (NIDA) and theVeteran’s Administration Cooperative Studies Program are collaboratingwith Catalyst for the trial. NIDA will cover most of the site costs for thetrial, while the VA will handle site monitoring and data management.

Vigabatrin has Fast Track designation in the U.S. for the indication.The product is also in Phase II testing to treat cocaine and alcohol co-dependency (see BioCentury, April 4, 2011).

Cerecor Inc., Baltimore, Md.Product: FP01Business: PulmonaryMolecular target: NADescription: Oral small molecule that is centrally actingIndication: Treat acute coughEndpoint: Change in cough count; safetyStatus: Phase II startedMilestone: Phase II data (3Q12)

Cerecor began the double-blind, placebo-controlled, South Ameri-can Phase II CLIN01-002-A trial to evaluate 2 doses of thrice-daily FP01lozenges in about 192 healthy subjects with upper respiratory tractinfections (URTI).

Clinuvel Pharmaceuticals Ltd. (ASX:CUV; Xetra:UR9), Melbourne,AustraliaProduct: Scenesse afamelanotide (CUV1647) (formerly Melanotan)Business: Endocrine/MetabolicMolecular target: Melanocortin 1 receptor (MC1R)Description: Sustained-release subcutaneous implant of synthetic al-pha melanocyte stimulating hormone (MSH)Indication: Treat erythropoietic protoporphyria (EPP)Endpoint: Duration of direct sunlight exposure between 10:00 and18:00 hours on days when no pain was experienced; combined sunexposure and phototoxic pain, sun exposure, quality of life,photoprovocation and safetyStatus: Phase III startedMilestone: NA

Clinuvel began the double-blind, placebo-controlled, U.S. Phase IIICUV039 trial of 16 mg Scenesse every 2 months for 6 months in up to100 EPP patients. In February, the company submitted an MAA to EMAfor Scenesse for the indication. The product has Orphan Drug desig-nation in Australia, Switzerland, EU and the U.S. for EPP, a severe geneticdisorder causing absolute ultraviolet radiation and light intolerance inthe skin (see BioCentury, Feb. 13).

Diamyd Medical AB (SSE:DIAM B), Stockholm, SwedenProduct: NP2 EnkephalinBusiness: NeurologyMolecular target: NADescription: Herpes simplex virus (HSV) vector delivering the en-kephalin gene via the Nerve Targeting Drug Delivery SystemIndication: Treat cancer painEndpoint: Pain scores and concomitant opioid pain medication usage


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Status: Completed Phase II enrollmentMilestone: Phase II data (mid-2012)

Diamyd completed enrollment of about 32 patients with severecancer pain in a double-blind, placebo-controlled, U.S. Phase II trialevaluating NP2 Enkephalin for 4 weeks, after which all patients mayreceive 2 additional doses in an open-label extension.

Esperance Pharmaceuticals Inc., Baton Rouge, La.Product: EP-100Business: CancerMolecular target: Luteinizing hormone-releasing hormone (LHRH)Description: Fusion protein consisting of a luteinizing hormone-releasing hormone (LHRH) ligand conjugated to a membrane-disrupt-ing peptideIndication: Treat ovarian cancerEndpoint: Dose limiting toxicities (DLTs) and overall response rate(ORR); time to progression, progression-free survival (PFS), overallsurvival (OS), duration of response and safetyStatus: Phase II startedMilestone: NA

Esperance began an open-label, U.S. Phase II trial (ESP2011-002) tocompare an IV infusion of EP-100 twice weekly for the first 3 weeks ofa 4-week cycle for up to 6 cycles plus weekly IV paclitaxel vs. paclitaxelalone in about 48 patients. The trial includes a run-in period in 5-8patients to confirm the maximum safe dose of EP-100.

GeoVax Labs Inc. (OTCBB:GOVX), Atlanta, Ga.Product: GM-CSF-adjuvanted DNA/MVA vaccineBusiness: InfectiousMolecular target: NADescription: Granulocyte macrophage colony-stimulating factor (GM-CSF)-adjuvanted 2 component vaccine consisting of a recombinant DNAand a recombinant modified vaccinia Ankara (MVA), both of whichexpress the gag, pol and env proteins of HIV-1Indication: Vaccinate against HIV/AIDS infectionEndpoint: Safety and immunogenicityStatus: Phase I startedMilestone: NA

GeoVax began the double-blind, placebo-controlled, dose-escala-tion, U.S. Phase I HVTN 094 trial to evaluate its GM-CSF-adjuvanted DNA/MVA vaccine in 48 healthy volunteers. The trial is sponsored by the NIH’sNational Institute of Allergy and Infectious Diseases (NIAID) and will beconducted by the NIAID-funded HIV Vaccine Trials Network (HVTN).

GW Pharmaceuticals plc (LSE:GWP), Salisbury, U.K.Otsuka Pharmaceutical Co. Ltd., Tokyo, JapanProduct: Sativex, NabiximolsBusiness: NeurologyMolecular target: Cannabinoid receptorsDescription: Sublingual cannabis extract spray containing tetrahydro-cannabinol (THC) and cannabidiol (CBD)Indication: Treat pain in patients with advanced cancerEndpoint: Mean change from baseline in patient pain assessment asmeasured using a 0-10 Numeric Rating Scale (NRS); percentage im-provement in average NRS pain score, mean 11-point NRS worst painscore and mean sleep disruption NRS score from baseline to the endof treatmentStatus: Phase III startedMilestone: Complete Phase III enrollment (year end 2013)

GW and partner Otsuka began a 2-part Phase III trial to evaluate

twice-daily Sativex for up to 10 sprays per day in patients with advancedcancer who have inadequate analgesia even with optimized chronicopioid therapy. The single-blind first part will evaluate Sativex for 2weeks in about 540 patients. In the double-blind second part, patientswho respond to treatment will be randomized to receive Sativex orplacebo for 5 additional weeks. This is the third Phase III trial of Sativexto treat cancer pain and it will provide supportive data for the first 2trials, which are slated to complete enrollment by the end of 2013.

Sativex is approved to treat spasticity due to multiple sclerosis (MS)in Canada, Spain, New Zealand, Germany, Denmark and the U.K. Earlierthis month, the product was recommended for approval under the EUMutual Recognition Procedure (see BioCentury, May 14). Otsuka hasexclusive rights to Sativex in the U.S. Bayer AG (Xetra:BAYN, Leverkusen,Germany) has rights to market the product in Canada and the U.K. fromGW, while Almirall has rights in the rest of Europe and Mexico. NeopharmLtd. (Petah-Tikva, Israel) has rights in Israel/Palestine.

Insmed Inc. (NASDAQ:INSM), Monmouth Junction, N.J.Product: Arikace (formerly SLIT amikacin)Business: InfectiousMolecular target: Ribosomal 30S subunitDescription: Sustained-release lipid inhaled targeting (SLIT) formula-tion of amikacinIndication: Treat non-tuberculosis mycobacterial (NTM) lung infectionEndpoint: Change in mycobacterial density from baseline to 84 days;proportion of subjects with culture conversion to negative, time to“rescue” anti-mycobacterial drugs, change in 6-minute walk distance,oxygen saturation and Patient Reported Outcomes, and safetyStatus: Phase II startedMilestone: Phase II data (4Q13)

Insmed began the double-blind, placebo-controlled, U.S. Phase IITARGET-NTM trial to evaluate once-daily 560 mg Arikace administeredwith the eFlow Nebulizer System from Pari GmbH (Starnberg, Ger-many) for 84 days in about 100 patients. Following the double-blindportion, patients may enroll in an 84-day, open-label portion. Insmedgained Arikace through its 2010 acquisition of Transave Inc. (seeBioCentury, Dec. 6, 2010).

Kaketsuken, Kumamoto, JapanGlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.Product: Cell culture based pandemic influenza vaccineBusiness: InfectiousMolecular target: NADescription: Cell culture based pandemic influenza vaccine developedusing EB66 cell lineIndication: Vaccinate against pandemic influenza virus infectionEndpoint: NAStatus: Phase II startedMilestone: NA

Vivalis S.A. (Euronext:VLS, Nantes, France) said Kaketsuken beganin April a Japanese Phase II trial to evaluate a cell culture-based pandemicflu vaccine. In 2009, GlaxoSmithKline and Kaketsuken (formerly theChemo-Sero-Therapeutic Research Institute) partnered to co-developa cell-based, adjuvanted pandemic influenza vaccine in Japan usingVivalis’ EB66 cell line (see BioCentury, Oct. 5, 2009).

MorphoSys AG (Xetra:MOR; Pink:MPSYF), Martinsried, GermanyXencor Inc., Monrovia, Calif.Product: MOR208 (formerly XmAb5574)Business: CancerMolecular target: CD19Description: Humanized mAb against CD19



Indication: Treat relapsed or refractory chronic lymphocytic leukemia(CLL)Endpoint: Safety, pharmacokinetics and preliminary antitumor activityStatus: Completed Phase I enrollmentMilestone: Phase I data (4Q12)

The partners completed enrollment of 30 patients in an open-label,dose-escalation, U.S. Phase I trial evaluating MOR208. In June 2010,Xencor granted MorphoSys exclusive, worldwide rights to develop andcommercialize the compound (see BioCentury, July 5, 2010).

Northwest Biotherapeutics Inc. (OTCBB:NWBO), Bethesda, Md.Product: DCVax-Brain (DCVax-L)Business: CancerMolecular target: Not applicableDescription: Autologous dendritic cells treated ex vivo with glioblas-toma tumor fragmentsIndication: Treat newly diagnosed glioblastoma multiforme (GBM)Endpoint: Progression-free survival (PFS); overall survival (OS), timeto disease progression and safetyStatus: Phase II amendedMilestone: NA

Northwest Biotherapeutics amended a double-blind, internationalPhase II trial evaluating DCVax-L to designate it as a Phase III trial, toinclude another cohort and increase enrollment to up to 300 patientsfrom up to 240. Patients with newly diagnosed GBM indicated forsurgery will receive 2 intradermal injections of DCVax-L or placebo ondays 0, 10 and 20, and at weeks 8, 16, 32, 48, 72, 96 and 120. The productis approved in Switzerland for use at selected centers to treat malignantbrain cancers, including GBM. The vaccine has Orphan Drug designationin the U.S. and EU.

NovaBay Pharmaceuticals Inc. (NYSE-A:NBY), Emeryville, Calif.Product: NVC-422Business: InfectiousMolecular target: Not availableDescription: Synthetic analog of the phagocytosis-associated com-pound N, N-dichlorotaurine (NNDCT)Indication: Treat adenoviral conjunctivitisEndpoint: Sustained clinical cureStatus: Phase IIb startedMilestone: Phase IIb data (1H13)

NovaBay began the double-blind, international, pivotal Phase IIbBAYnovation trial to evaluate NVC-422 ophthalmic solution vs. vehicleophthalmic solution in about 450 patients.

Pluristem Therapeutics Inc. (NASDAQ:PSTI; Tel Aviv:PSTI), Haifa,IsraelProduct: PLX-PAD cellsBusiness: CardiovascularMolecular target: NADescription: Allogeneic, placental-derived expanded (PLX) cellsIndication: Treat intermittent claudication (IC)Endpoint: Change in the maximal walking distance from baseline;hemodynamics, quality of life measurements and safetyStatus: Phase II startedMilestone: NA

Pluristem began a placebo-controlled, U.S. Phase II trial to evaluate150 million and 300 million PLX-PAD cells administered via 2 intramus-cular injections 12 weeks apart in about 132 patients.

Sangart Inc., San Diego, Calif.Product: MP4OX (MalPEG-Hb solution) (formerly Hemospan)Business: HematologyMolecular target: Not availableDescription: Oxygenated pegylated hemoglobin-based colloidIndication: Treat lactic acidosis caused by hemorrhagic shock in se-verely injured trauma patientsEndpoint: Proportion of patients discharged alive from the hospitalthrough day 28 and alive at the day 28 follow-up visit; ventilator-, ICU-and hospital-free days, composite endpoint of time to complete organfailure resolution (CTCOFR), proportion of patients who normalizelactate levels and proportion of patients remaining in the hospital, ICUand on the ventilatorStatus: Phase IIb ongoingMilestone: NA

Sangart said an IDMC recommended continuation of a double-blind,placebo-controlled, international Phase IIb trial of MP4OX based onsafety data from the first 122 patients. The trial, which plans to enroll360 patients, is evaluating 250 mL MP4OX.

StemCells Inc. (NASDAQ:STEM), Newark, Calif.Product: Human neural stem cells (HuCNS-SC)Business: NeurologyMolecular target: Not applicableDescription: Purified human neural stem cellsIndication: Treat chronic spinal cord injury (SCI)Endpoint: Safety; changes in sensation, motor and bowel/bladder func-tionStatus: Phase I/II ongoingMilestone: NA

StemCells said an independent DSMB recommended continuationto the next cohort of an open-label, international Phase I/II trial ofHuCNS-SC after an interim safety review of first cohort. The firstcohort enrolled patients with thoracic SCI classified as level A on theAmerican Spinal Injury Association Impairment Scale (AIS). Patientsreceived 20 million cells at the site of injury. StemCells said changes insensitivity to touch were observed in 2 patients. The trial plans to enroll12 patients. Specifically, the second cohort will enroll patients withincomplete neurological injury classified as AIS B, while a third cohortwill enroll patients classified as AIS C. The company said patientsclassified as AIS B and AIS C have less severe injury, in which there issome preservation of sensory motor function.

Trimel Pharmaceuticals Corp. (TSX:TRL), Mississauga, OntarioProduct: Tefina (TBS-2)Business: GenitourinaryMolecular target: NADescription: Bioadhesive intranasal low-dose gel formulation of tes-tosteroneIndication: Treat anorgasmia in womenEndpoint: Increase in occurrence of orgasm compared to baselineStatus: Phase II startedMilestone: NA

Trimel began a double-blind, placebo-controlled, internationalPhase II trial to evaluate Tefina in 240 premenopausal women.



OFFERINGS & SECURITIES TRANSACTIONS

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Week ended 5/25/12. Shares after offer-ing refers to shares outstanding. Proceedsare gross, not net. Shares offered don’tinclude overallotments. Currency ratesused in the week: €=$1.2768; £=$1.5827;SEK=$0.1401

Completed Offerings

Advaxis Inc. (OTCBB:ADXS),North Brunswick, N.J.Business: CancerDate completed: 5/15/12Type: Private placement of con-vertible notesRaised: $740,000Placement agent: RodmanShares outstanding prior: 286.5millionInvestors: Accredited investors;company managementNote: The one-year promissorynotes were purchased at a 25%discount and convert at $0.15. In-vestors also received five-yearwarrants to purchase up to 50% ofthe number of shares receivedthrough conversion of notes at$0.15. Additionally, Advaxis ex-changed $4.5 million in convert-ible debt for 52.2 million sharesand warrants to purchase 5.8 mil-lion shares.

Apeptico Forschung undEntwicklung GmbH, Vienna,AustriaBusiness: PulmonaryDate completed: 5/16/12Type: Venture financingRaised: €2 million ($2.6 million)Investors: BioScience VenturesGroup; V+ GmbH & Co. Fonds 2;V+ GmbH & Co. Fonds 3; privateinvestors

Catalyst Pharmaceutical Part-ners Inc. (NASDAQ:CPRX),Coral Gables, Fla.Business: NeurologyDate completed: 5/24/12Type: Follow-onRaised: $4.8 millionUnits: 6 millionPrice: $0.80 (unit)Shares after offering: 30.7 millionUnderwriters: Cowen; Roth Capi-tal PartnersNote: Each unit comprises a share

and a five-year warrant to pur-chase a share at $1.04.

Delcath Systems Inc. (NASDAQ:DCTH), New York, N.Y.Business: Drug delivery, CancerDate completed: 5/25/12Type: Follow-onRaised: $20 millionUnits: 13.3 millionPrice: $1.50 (unit)Shares after offering: 63.5 millionUnderwriters: Cowen; Wedbush;Roth Capital PartnersOverallotment: 2 millionNote: Each unit comprises a shareand a three-year warrant to pur-chase 0.3 shares, with each wholewarrant exercisable at $1.65.

Flowonix Medical Inc., Mt. Ol-ive, N.J.Business: Drug deliveryDate completed: 5/24/12Type: Venture financingRaised: $25 millionInvestors : RFT Investment ;OmniCapital Fund; Clarus Ven-tures; existing investors

Genovis AB (NASDAQ:GENO),Lund, SwedenBusiness: Supply/ServiceDate completed: 5/22/12Type: Rights offeringRaised: SEK12.1 million ($1.7 mil-lion)Shares: 3.5 millionPrice: SEK3.50Shares after offering: 10.4 millionInvestors: Existing investorsNote: Shareholders were eligibleto purchase a share for every twoheld.

Kiyatec Inc., Pendleton, S.C.Business: ADMETDate completed: 5/23/12Type: Venture financingRaised: Not disclosedInvestors: Nexus Medical Partners;Technology Capital Investors;Upstate Carolina Angel Network;private investors

Novavax Inc. (NASDAQ:NVAX),Rockville, Md.Business: InfectiousDate completed: 5/21/12Type: Private placement

Raised: $12.2 millionShares: 10 millionPrice: $1.22Shares after offering: 132.2 millionInvestor: RA Capital HealthcareFund

Sigmoid Pharma Ltd., Dublin,IrelandBusiness: GastrointestinalDate completed: 5/17/12Type: Venture financingRaised: €3 million ($3.8 million)Note: The company said it raisedover €3 million ($3.8 million) in1Q12.

Amended Offerings

Trovagene Inc. (Pink:TROV),San Diego, Calif.Business: DiagnosticDate announced: 5/23/12Type: Follow-onTo be raised: $20 millionUnits: 2 millionPrice: $9.90 (unit)Underwriters: Aegis Capital; Sum-mer Street; Brean MurrayNote: Trovagene amended its fol-low-on and now hopes to sell 2million units at $9.90. The companyalso added Brean Murray as an un-derwriter. Each unit comprises twoshares and a warrant to purchase ashare. Trovagene also plans toimplement a 1-for-5 reverse stocksplit prior to the offering. Follow-ing the offering and split, the com-pany will have about 17.9 millionshares outstanding.

Other Financial News

Arena Pharmaceuticals Inc.(NASDAQ:ARNA), San Diego,Calif.Business: Endocrine/Metabolic,Neurology, CardiovascularDate announced: 5/21/12

Arena raised $9.1 millionthrough the sale of 1.7 millionshares at $5.50 to cover over-allotments from its May 16 fol-low-on, bringing the total raisedto $69.6 million. Arena, whichclosed Friday at $6, has 197.2 mil-lion shares outstanding.

Emergent BioSolutions Inc.(NYSE:EBS), Rockville, Md.Business: Infectious, Autoim-mune, CancerDate announced: 5/21/12

Emergent BioSolutions said itsboard authorized the repurchase ofup to $35 million of the company’scommon stock. At March 31, thecompany had about $150.4 million incash. Emergent BioSolutions, whichclosed Friday at $13.70, has 36.2million shares outstanding.

Inserm Transfert Initiative,Paris, FranceBusiness: FinanceDate announced: 5/23/12

Inserm Transfert Initiative, theseed investment arm of the FrenchNational Institute of Health andMedical Research (Inserm), raised€2 million ($2.6 million) fromPfizer Inc. (NYSE:PFE, New York,N.Y.) and Shire plc (LSE:SHP;NASDAQ:SHPGY, Dublin, Ire-land), completing the fundraisingat €35.5 million ($45.3 million).The initiative expects to provide15-20 life science companies withan average investment of €2 mil-lion per company over five years.The initiative raised €33.5 million($42.8 million) in January (seeBioCentury, Jan. 16).

Prosonix Ltd., Oxford, U.K.Business: Inflammation, Drug de-liveryDate announced: 5/21/12

Prosonix raised £5.7 million($9 million) in the second close ofa series B round, bringing the totalraised to £17.1 million ($27.2million). New investor Gimvjoined existing investors Ventech;Gilde; Entrepreneurs Fund; Questfor Growth; and Solon Ventures.Prosonix raised £11.4 million($18.2 million) in a first close inJune 2011.

Recipharm AB, Jordbro, SwedenBusiness: Supply/Service, Biom-anufacturingDate announced: 5/22/12

Recipharm secured a five-yearloan facility for €90 million ($114.9million) with Swedbank.


Other Financial News,from previous page

Sangart Inc., San Diego, Calif.Business: HematologyDate announced: 5/24/12

Sangart raised an additional $50million in a series G round fromexisting investor Leucadia Na-tional, bringing the total raised inthe round to more than $100 mil-lion. Last year, Sangart raised morethan $50 million in the round.

Synageva BioPharma Corp.(NASDAQ:GEVA), Lexington,Mass.Business: Endocrine/Metabolic,InfectiousDate announced: 5/23/12

Synageva filed a shelf registra-tion covering the sale of up to$150 million of its securities. Thecompany, which closed Friday at$37.84, has 21.3 million sharesoutstanding.

Tengion Inc. (NASDAQ:TNGN),Winston-Salem, N.C.Business: Genitourinary, Gene/Cell therapy, TransplantDate announced: 5/18/12

Tengion received a letter fromNASDAQ indicating that the com-pany is not in compliance with theminimum $2.5 million in stock-holders’ equity requirement forcontinued listing. The companysaid it expects to submit a plan toregain compliance by June 29. At

Tengion’s annual shareholders’meeting last week, shareholdersapproved a reverse stock split ata ratio between 1-for-6 and 1-for-10. The company said a reversestock split would provide a meansto regain compliance with the $1minimum bid price requirementfor continued listing, with whichthe company is also not in compli-ance. Tengion, which closed Fri-day at $0.30, has 24.7 million sharesoutstanding.

islet defense in bio century week of 5 28-12

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