07.18JULY 2018 : VOLUME 14 : NUMBER 7

CONTRACT SERVICES 34

SYBODIES ON THE SCENE leadXpro and University of Zurich collaboration to generate membrane protein target-directed sybodiesBY MEL J. YEATES

VILLIGEN, Switzerland—In early June, leadXpro and the University of Zurich (UZH) announced a collaboration to generate sybodies as molecular discovery tools, therapeutic lead compounds and diagnostic reagents against disease-relevant membrane protein targets.

Membrane proteins such as transport-ers, ion channels and GPCRs are therapeu-tic targets for highly successful medicines. leadXpro’s expertise lies in the generation of membrane protein samples for biophysi-cal analysis and structural investigation by X-ray crystallography and cryo-electron microscopy, and the company generates and applies such samples to the discovery and optimization of small-molecule and bio-therapeutic lead compounds. The intent is to extend drug discovery options for previously intractable or challenging membrane protein drug targets.

According to Michael Hennig, CEO and chairman of the board of leadXpro, “leadXpro

is located in a region with excellent research facilities like the ETH institutes (PSI, ETH Zürich) and Universities of Basel and Zürich. Prof. Markus Seeger and I have known each other for many years, and we had previous

collaborations already. I approached Markus three years ago to use sybodies as chaperones in crystallization experiments for X-ray struc-ture determination.”

The war against resistance advancesU.K. and FIND team up to combat global threat of antimicrobial resistanceBY JEFFREY BOULEY

LONDON & GENEVA—The 71st World Health Assembly, held recently in Switzerland, served as the venue for a side event at which an important announcement was made: the signing of a memorandum of understanding (MOU) that establishes a three-year proj-ect focusing on connecting vital data from patients’ diagnostic test results to national antimicrobial resistance (AMR) surveillance programs in low- and middle-income coun-tries (LMICs). The goal: to help combat the growing threat of drug-resistant infections.

More specifically, it was the U.K. govern-ment’s Global Antimicrobial Resistance Inno-vation Fund (GAMRIF)—part of the Depart-ment of Health and Social Care—and the Foundation for Innovative New Diagnostics (FIND) that signed the MOU on connectivity for diagnostics that can combat AMR.

To improve worldwide surveillance of AMR, FIND and its partners will develop tools and solutions to connect vital informa-

tion from AMR-related diagnostic testing of patients and ensure it reaches national surveillance programs in LMICs, extending their scope to include routine hospital and community data.

Some 700,000 global deaths each year are estimated to be caused by drug-resistant

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Cracking the codeScripps uncovers new transcription factor combos to reprogram skin cells into different neuronsBY KELSEY KAUSTINEN

LA JOLLA, Calif.—In the latest advance-ment for cellular reprogramming tech-nology, a team of researchers from The Scripps Research Institute have reported on the discovery of several new transcrip-tion codes for di¡erentiating skin cells into multiple di¡erent types of neurons. Their work, detailed in a paper titled “Diverse reprogramming codes for neu-ronal identity,” was published in Nature.

A meeting of the minds ........................................................6Underuse of specimens concerns biobanks .................12Grant awarded for continuous modular manufacturing ....34On the cutting edge.............................................................35

SPECIAL FOCUS ON NEUROLOGY AND NEUROSCIENCE:

Neurodegenerative disease

16

WHAT’S INSIDEDISCOVERY 6

TOOLS & TECHNOLOGY

PRECLINICAL 20

RESEARCH & DEVELOPMENT 12

CLINICAL TRIALS 23

DIAGNOSTICS 32

BUSINESS & GOVERNMENT POLICY 35

MARKET NEWS 3EDITORIAL/COMMENTARY 10LATE-BREAKING NEWS 38

CODE CONTINUED ON PAGE 14

IMMUNO-ONCOLOGY: IO Summit 2018 preview ....................................27Immuno-oncology news......................................29

THE HUNT FOR BIOMARKERS HAS NO PEER

See the back cover.

TSRI scientists recently developed and tested a set of two factor codes to determine which ones were capable of programming skin cells to become neurons instead.

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The expertise of leadXpro is in generating membrane protein samples for biophysical analysis and structural investigation by X-ray crystallography and cryo-electron microscopy—the company generates and applies such samples to the discovery and optimization of small-molecule and biotherapeutic lead compounds.

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Drug-resistant microbes, or “superbugs,” are an ever-growing threat. While the quest for new antimicrobial therapies is a key need in mitigating this threat, so too are better diagnostics options.

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LONDON—Gene therapy combines a reduced treatment duration with a higher chance of cure, unlike conventional oncology treatments such as chemotherapy. However, this novel therapeutic approach requires the delivery of genetic material to the patient, an unchart-ed territory in oncology which will necessitate the implementation of new regulatory guidelines and the restructuring of existing treatment

GlobalData: Immune-based gene therapy candidates should prevail in oncology

UP AND COMINGFinancing news from young and emerging companies in pharma and biotechBY DDNEWS STAFF

SAN DIEGO—Leading off our financing news roundup this issue is Metacrine Inc., a biotechnology company developing therapies to benefit patients with liver, gastro-intestinal and metabolic diseases, which recently completed a Series C financing that raised $65 million in new funds. The investment was led by Venrock Healthcare Partners and includes new investors Frank-lin Templeton Investments, Deer-field Management, Arrowmark Partners, Invus, Lilly Asia Ventures, Vivo Capital and other undisclosed investors. Existing investors Arch Venture Partners, venBio, Polaris Partners, NEA and Alexandria Venture Investments participated in the financing as well.

Founded in 2015, Metacrine has now raised a total of $125 million in equity financing. According to the company, since inception it has leveraged its highly experienced internal team in biology, chemis-try and protein engineering to dis-cover and develop novel therapies and has “judiciously expanded” its capabilities to include early devel-opment, clinical and regulatory expertise. With these capabilities, Metacrine says it has built the

algorithms in various oncology indications, notes data and analyt-ics company GlobalData.

The company’s recent report, “Gene Therapy in Oncology,” covers the competitive landscape of gene therapies in oncology and the regu-latory framework concerning their clinical development and commer-cialization across the eight major markets (United States, France, Germany, Italy, Spain, United

Kingdom, Japan and China), look-ing in detail at the Phase 3 and Phase 2 cancer gene therapy can-didates that are expected to enter the oncology space within the next decade.

According to GlobalData, the cur-rent clinical development of gene therapies in oncology is dominated by smaller biotech and pharma-ceutical companies—AstraZeneca

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“Ample opportunity remains in the oncology space for gene therapies. One of the most promising therapeutic strategies is developing combination regimens of gene therapies with immune checkpoint inhibitors.”Volkan Gunduz, an analyst at GlobalData

MARKET NEWS4 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.com

with a new brand name: Saxenda. Novo Nor-disk is already dominating the T2D space, as not only are many T2D patients obese, but also most obese patients are at high risk of getting T2D. Novo Nordisk found a way of entering this space without risking much. Its Phase II asset for obesity, semaglutide, is also a T2D drug and shows weight-loss e¢ects on top of its glycemic benefits.

“The early-stage assets show a variety of novel mechanisms of action, so there is hope that science has come up with ways of tackling obesity that are ingenious enough to convince big pharma players to develop these assets despite the failings of the last three drugs,” said Dr. Valentina Gburcik, director of cardiovascular and metabolic disorders at GlobalData.

U.S. DOMINATES BIOSIMILARS MARKET, BUT BRAZIL AND SOUTH KOREA ARE GAININGBiosimilars are becoming increasingly pop-ular with pharmaceutical companies; how-ever, knowing which markets have been saturated with biosimilars and which are open remains an important consideration for pharma companies, observes GlobalData.

“The deal activity can provide a useful indication of which biosimilar drugs are in development. The recent strategic alli-ance deals show the potential of bringing these biosimilar monoclonal antibodies to market for therapy areas such as cancer or autoimmune diseases,” noted Lisa Marris, a healthcare analyst at GlobalData, adding that emerging markets such as Brazil and South Korea have been involved in a growing number of deals for the development or com-

mercialization of biosimilars, thus gaining a foothold for these countries in the future of the biosimilar market.

The countries with the highest deal val-ues and highest number of deals in the past five years reveals that the U.S. continues to dominate biosimilar activity, with the highest total deal value and highest per-centage of deals for an individual country. The European Union as a whole has a larger proportion of deals compared to the United States, and these are predominately made up of Germany and the United Kingdom. Brazil and South Korea are also active in the biosimilar market, as noted earlier. �

Spring cleaningA roundup of recent GlobalData prognostications on specific therapeutic marketsBY DDNEWS STAFF

O NE OF THE CHALLENGES at times is keeping up with the various pieces of market news in this magazine with only one small section in which to highlight them. But with a larger-than-normal section this issue to play with, we thought we’d do a little “spring cleaning” (even if it is early summer) and share some spring predictions from

data and analytics firm GlobalData that have long-term implications.

OSTEOPOROSIS MARKET WILL GROW TO $11.2B BY 2027Despite being dominated by generic bispho-sphates, the osteoporosis market is likely to undergo significant changes over the next 10 years, growing at a compound annual growth rate (CAGR) of 4.3 percent and reaching $11.2 billion by 2027, according to Global-Data. The launch of two key products will diversify physicians’ anabolic arsenal, mov-ing the use of these bone-forming agents up the treatment paradigm. The impact of these agents has already been noted with the launch of Radius Health’s Tymlos in the United States last year.

Despite current setbacks with the FDA related to potential cardiovascular adverse events, Amgen’s novel sclerostin inhibi-tor, Evenity, is forecast to enter the Unit-ed States and other markets from 2019 onwards. It will o¢er a much-needed alter-native therapy with a more appealing once-monthly dosing regimen, novel mechanism of action and strong e¨cacy profile. Evenity is forecast to become the leading branded product in the market by 2027, command-ing a 17-percent market share.

“We expect uptake of these new anabolic agents to be strongest in more severe patients who have or are considered at high risk of developing a fracture,” said Alice Stevens, a healthcare analyst at GlobalData. “For many years the only anabolic therapy on the market has been Forteo, which due to its high price tag has been restricted to the later lines of therapy and more severe patients. However, the diversification of the anabolic o¢ering is likely to increase competition within this space, driving down prices and potentially bolstering the use of these therapies up the treatment paradigm.

“The arrival of the new anabolic therapies, and biosimilars to current market-leading branded products, are likely to shape the osteoporosis market over the next 10 years, potentially moving treatment paradigms away from standard generic bisphosphate therapies.”

AMD MARKET WILL ROCKET TO $11.5B BY 2026Pharmaceutical sales within the age-related macular degeneration (AMD) markets were estimated to be $4.9 billion across the seven major markets (United States, France, Germa-ny, Italy, Spain, United Kingdom and Japan) in 2016. This is expected to reach $11.5 billion in 2026, with an impressive CAGR of 8.9 per-cent, according to GlobalData. The company states that this growth will be driven by new therapies entering the market and a global aging society, which will lead to increasing numbers of elderly people developing AMD.

GlobalData predicts the launches of three drugs for the treatment of geographic atro-phy (GA), the late stage of dry age-related macular degeneration (dAMD), and three late-stage pipeline drugs for wet AMD (wAMD). In particular, the launch of drugs into the AMD market to treat dAMD will be a large driver of growth, as there are cur-rently no prescription medications available for these patients.

“We expect that with the launch of bro-lucizumab in the wAMD market, Novartis will offset the losses to Eylea and regain dominance in the AMD market,” said Dr. Edit Kovalcsik, a healthcare analyst at Glo-balData. “Once more e¨cacy and safety data accumulates and physicians become more accustomed to the use of brolucizumab, its advantage of less-frequent dosing will allow it to claim an increasing share and become a first-line therapy if reimbursed.”

New drugs entering the dAMD market will include two anti-complement agents—Apellis’ APL-2 and Ophthotech’s Zimura—and one neuroprotective agent: Allergan’s Brimo DDS, which together will drive an increase of the treated AMD cases, expand-ing the AMD market.

Kovalcsik adds: “Following the failure of both Phase 3 trials of lampalizumab for the treatment of GA, Apellis’ APL-2 emerged as the most promising GA drug after its positive Phase 2a results were announced. Provided that the planned Phase 3 trial of APL-2 for GA will confirm these results, we forecast that Apellis’ drug will reach blockbuster status within a few years of its launch, by 2025.”

OBESITY MARKET PROVING TO BE A CHALLENGE TO PENETRATEThe obesity market may not be the mega-blockbuster market some were predicting, according to GlobalData. The latest bank-ruptcy filing by Orexigen Therapeutics, whose Contrave proved a disappointment, shows how hard it is to enter this poten-tially lucrative market, the firm notes, and despite the obesity epidemic, Vivus’ Qsymia and Arena Pharmaceuticals’ Belviq, two other once-promising drugs, also failed.

One question is why this market is so severely skewed towards the early-stage pipe-line, given the failure of these drugs. Accord-ing to GlobalData’s Pharma Intelligence Center, there are two drugs in Phase 3, 17 in Phase 2 and 33 in Phase 1. Novo Nordisk, Eli Lilly, Amgen, Boehringer Ingelheim, Johnson & Johnson, AstraZeneca, Sanofi and Novartis all have early-stage assets in this space.

Particularly active is Novo Nordisk, with one asset in Phase 2 and six in Phase 1. It suc-cessfully repurposed one of its type 2 diabetes (T2D) drugs, Victoza, into an anti-obesity pill

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“The arrival of the new anabolic therapies, and biosimilars to current market-leading branded products, are likely to shape the osteoporosis market over the next 10 years, potentially moving treatment paradigms away from standard generic bisphosphate therapies.”Alice Stevens, an analyst at GlobalData

For more information, visit www.DDN-News.com JULY 2018 | | DDNEWS 5MARKET NEWS

PACE OF PHARMA INNOVATION ACCELERATES Record number of new blockbuster drugs forecast to hit the market in 2018PHILADELPHIA—Clarivate Analytics announced recently the launch of its annual “Drugs to Watch” report. The analysis identified 12 new drugs forecast to achieve annual sales of $1 billion or more (blockbuster status) by 2022 using the Cortellis database, which includes information gathered from diverse sourc-es including drug pipelines, patents, clini-cal trials, chemistry, deals and company announcements. More blockbuster drugs

have been predicted to launch in 2018 than in any other year since the “Drugs to Watch” report began in 2013.

“Despite political and regulatory uncertainties in the USA and EU mar-kets, the annual ‘Drugs to Watch’ report 2018 shows that the pace of pharma-ceutical innovation continues to accel-erate,” explained Mukhtar Ahmed, president of life sciences at Clarivate Analytics. “2018 is on track to see many new potential game-changing drugs come to market, which will benefit the lives of millions of patients around the world.” �

The full report is available at: http://info.clarivate.com/drugstowatch2018

infrastructure to advance potential best-in-class novel medicines from discovery through full clinical development.

“The team at Metacrine has repeatedly proven to be scientifically driven, highly pro-ductive and very creative,” said Dr. Rich Hey-man, chairman of Metacrine. “We are very pleased to have a leading syndicate of inves-tors to partner with the company to build a lasting enterprise that aims to develop drugs than can materially benefit patients.”

Metacrine’s lead program is focused on the farnesoid X receptor (FXR). FXR represents a promising target to treat non-alcoholic steato-hepatitis (NASH), a debilitating condition that is becoming a leading cause for liver transplant and for which no approved therapies exist today. In addition to NASH, Metacrine has identified a potential role for FXR in diarrhea-predominant irritable bowel syndrome (IBS-D) and inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

Through Metacrine’s discovery e¢orts and extensive characterization of a broad set of FXR agonists, MET409 has been selected as the lead clinical candidate. MET409 is a non-bile acid FXR agonist and has demonstrated robust preclinical e¨cacy with a predicted favorable safety profile. While there are a number of FXR agonists in development, Metacrine believes it has identified key fac-tors in regards to FXR engagement that are important for e¨cacy as well as safety.

Rain flows through $18M Series AFREMONT, Calif.—Rain Therapeutics Inc., a privately held, clinical-stage biotechnol-ogy company focused on biomarker-driven, small-molecule therapeutics for patients with cancer, in May announced the closing of a tranched Series A financing of $18.4 million and emerged from stealth mode. The financ-ing was led by San Francisco-based Biotech-nology Value Fund (BVF) and followed by Perceptive Advisors, Auckland UniServices Limited’s Inventors Fund and other private investors. BVF’s Dr. Gorjan Hrustanovic will join the Rain board of directors in conjunc-tion with the financing. The Series A round follows a $1-million convertible note financ-ing completed late last year.

Rain plans to use the proceeds to advance the clinical development of its lead program, tarlox-otinib (Tarlox), in patients with EGFR and ErbB Exon 20 insertion mutations in non-small cell lung cancer (NSCLC). The company intends to commence a Phase 2 study in patients with EGFR and ErbB Exon 20 insertion mutations in NSCLC in the first half of 2019.

“With the proceeds from recent financings, we can complete a Phase 2 proof-of-concept study and continue to advance tarloxotinib,” said Avanish Vellanki, Rain’s co-founder and CEO. “Our goal is to provide Exon 20 patients with a novel treatment option that results in strong antitumor responses while avoiding the debilitating, dose-limiting EGFR toxici-ties in the gut and skin that are associated with conventional small-molecule inhibitors.”

Rain has worldwide development and commercialization rights for Tarlox through an exclusive license to technology developed at the University of Auckland.

PhoreMost’s $15M round leads it to discoveryCAMBRIDGE, U.K.—PhoreMost, a United Kingdom-based biopharmaceutical company

dedicated to drugging previously “undrugga-ble” disease targets, announced recently that it had completed an £11-million ($15-million) Series A investment round. The investment will be used to expand operations on the Babraham Research Campus and progress several novel drug targets from its next-gen-eration SITESEEKER phenotypic screening platform into first-in-class drug discovery programs.

The new investment follows a successful validation phase, which saw PhoreMost grow from a Cambridge University spinout in 2015 with early proof-of-concept data to a techni-cally and commercially validated enterprise in 2017. The SITESEEKER platform is said to be able to identify the best new therapeutic targets for any chosen disease setting and rapidly identify how to develop novel drugs to them, which has the potential to signifi-cantly increase the diversity and a¢ordabil-ity of novel treatments for cancer and other unmet diseases.

Using its platform, PhoreMost has built a proprietary novel target pipeline, signed two pharma collaboration deals and spun out a new company, NeoPhore, to progress a novel target for cancer immunotherapy into the small-molecule development stage. The funding will enable PhoreMost to expand the range and depth of other proprietary targets into the drug discovery process.

HiFiBiO secures $37.5 million in Series BCAMBRIDGE, Mass., HANGZHOU, China & PARIS—May saw HiFiBiO Therapeutics, a company focused on the discovery of ther-apeutic antibodies through single-B-cell screening and analysis, announce the com-pletion of a $37.5-million Series B financing round and the company’s transformation into “a multinational biopharmaceutical enter-prise with an experienced management team, stronger global presence and rich pipe-line of novel antibody drugs to treat cancer and autoimmune disorders.”

“With our oversubscribed Series B fund-ing, expanded drug development team and new facilitates on three continents, HiFiBiO Therapeutics is now poised to generate breakthrough immune modulators to address unmet medical needs around the world,” said HiFiBiO Therapeutics President and CEO Dr. Liang Schweizer. “Our rapid pipeline progression is supported by our leadership’s commitment to open innovation generating new biological insights from multiple collab-orations with leading global academic insti-tutions and biopharmaceutical companies.”

Zomedica announces private offeringANN ARBOR, Mich.—Zomedica Pharmaceu-ticals Corp., a veterinary diagnostic and phar-maceutical company, announced recently the commencement of a private o¢ering of its common shares, without par value. To that point, the company had sold an aggregate of 255,815 common shares for gross proceeds of $550,000 in the o¢ering. All of the common shares sold in the new o¢ering were to be subject to a statutory four-month hold peri-od in accordance with applicable Canadian securities laws, which will expire on Sept. 16, 2018.

The common shares had not been regis-tered under the Securities Act and were not able to be o¢ered or sold in the United States absent registration or an applicable exemp-tion from such registration requirements. �

is the only large pharmaceutical company with an in-house gene therapy in late-stage clinical development. Other major play-ers, such as Johnson & Johnson, have the exclusive worldwide rights to develop other companies’ products.

Viral gene therapies dominate the late-stage pipeline, with 25 gene therapy candidates in clinical development in a variety of oncology indications. The most commonly targeted tumor types include melanoma, which is highly responsive to immunotherapies, and hard-to-treat tumors such as colorectal cancer, glio-bastoma multiforme, pancreatic cancer and prostate cancer.

Oligonucleotide and viral gene thera-pies dominate the Phase 3 pipeline, while oncolytic viral gene therapies are more commonly represented in the Phase 2 pipeline. In contrast, there is limited clin-

ical development of other types of gene therapies such as bacterial gene therapies and transgenes.

“Ample opportunity remains in the oncology space for gene therapies. One of the most promising therapeutic strate-gies is developing combination regimens of gene therapies with immune check-point inhibitors,” said Volkan Gunduz, senior oncology and hematology analyst at GlobalData. “To this end, significant opportunity exists, as half of the Phase 3 pipeline is evaluated as a monotherapy and only one candidate is evaluated in combination with a checkpoint inhibitor.”

According to GlobalData, the use of novel cancer gene therapies in combina-tion with immune checkpoint inhibitors will provide more clinical benefit to can-cer patients, increasing treatment dura-tions significantly. The high cost of novel therapies and longer treatment durations are major factors that will increase the cost of care in the oncology space. �

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BR IEFS

DISCOVERY6 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.com

Cannabinoids vs. C. di�.LOS ANGELES—Vitality Biopharma Inc. has reported new findings detailing the antimicrobial activity of cannabinoids and their potential for treating C. difficile-associated diarrhea and colitis. Vital-ity has demonstrated that cannabinoids includ-ing THC can serve as effective antibiotics for C. diff., vancomycin-resistant Enterococci and other pathogens. The company has submitted a patent application for related intellectual property and plans to evaluate VBX-100—a proprietary gas-trointestinal-targeted THC compound—as a treat-ment for C. diff.-associated diarrhea and colitis.

Dr. Brandon Zipp, Vitality’s Director of R&D, commented that “Our recent studies show that cannabinoids may be useful for both addressing the inflammatory state of the colon, as well as confronting the microbial dysbiosis at the root of the problem.”

Kv1.3 ion channel blocker shows potential in rare disease

SEATTLE—Kv1.3 Therapeutics Inc. shared data at the recent American Academy of Neurology Meeting from sporadic inclusion body myositis patients (sIBM) showing high expression of the Kv1.3 ion channel on lymphocytes from their skeletal muscle biopsies. Kv1.3 is often found on T effector memory cells, which play a role in several T cell-mediated autoimmune disorders. The presence of this ion cannel on lymphocytes in this patient population supports the use of Kv1.3 Therapeutics’ dalazatide as a potential treatment for sIBM. Dalazatide is a highly selective and near-ly irreversible inhibitor of the Kv1.3 ion channel.

“Dalazatide has demonstrated preclinical activity in multiple preclinical animal models of T cell autoimmune disease and has been found to be safe in early clinical trials. We look forward to clinical trials of dalazatide in sIBM patients,” said Dr. Tahseen Mozaffar, lead investigator on the research.

IN THIS SECTIONArtificial intelligenceA meeting of the minds ............................ 6

Infectious diseaseCannabinoids vs. C. diff. ........................... 6Infections under fire ................................. 6

Integrated discovery servicesCapitalizing on connection ....................... 6

Natural productsMoss polysaccharide discovery likened to beta glucen .............................. 9

Neurology/Rare diseaseKv1.3 ion channel blocker shows potential in rare disease ............... 6

Protein targetsSybodies on the scene (MEMBRANE jump from cover) ................................................ 9

Infections under fireAiCuris, Max Planck Institute look to natural products for new weapons against viral, bacterial infectionsBY KELSEY KAUSTINEN

WUPPERTAL & DORTMUND, Ger-many—Antibiotic resistance is one of the biggest and most pressing health issues today, both in the United States and worldwide. While some anti-biotic resistance is a natural occur-rence—vulnerable bacteria are killed by antibiotics, while resistant strains survive to reproduce, making them the predominant forms—it is exacerbated these days due to factors such as inter-national travel and the overprescrip-tion of antibiotics. While the problem has been around for a while now, many have noted that too few pharma and biotechs seem willing to step up to it.

The U.S. Centers for Disease Con-trol and Prevention (CDC) estimates that in up to 50 percent of cases, anti-biotics are not optimally prescribed or are prescribed when not needed. According to the CDC, some two mil-lion illnesses and 23,000 deaths are attributed to antibiotic resistance, with a majority of infections and

Capitalizing on connectionBioAscent and XenoGesis combine core capabilitiesBY ILENE SCHNEIDER

NEWHOUSE & NOTTINGHAM, U.K.—Bio-Ascent Discovery is collaborating with XenoGesis to offer an enhanced range of integrated drug discovery services, includ-ing medicinal chemistry, biology and drug metabolism and pharmacokinetics (DMPK). Both companies also have a track record of producing a series of viable candidates. The collaboration is dedicated to delivering tai-lored solutions for clients and a more person-alized service ranging from target evaluation to candidate nomination and predicted clini-cal pharmacokinetics and dose.

XenoGesis—a provider of DMPK services,

quantitative bioanalysis, in-vitro pharmacol-ogy, modeling and simulation for human pharmacokinetic and dose prediction—has a history of delivery in drug discovery. Through a consultative approach, the XenoGesis team helps to identify the potential “winners” and “losers” in a selection of compounds synthe-sized in drug discovery campaigns, provid-ing significant time and cost savings for R&D companies. Providing iterative feedback to the research team based on the results and recommending next steps is a key focus for XenoGesis. The company’s laboratory tests build a full picture of the ADME properties of a molecule, including required human drug exposure, backed up with advice on how to modify the chemical structure of a compound to make it more “drug-like.”

BioAscent has integrated drug discovery services, including de-novo assay develop-ment, target analysis, bespoke screening strategies, compound screening, medicinal and synthetic chemistry, computational chemistry and data management. Scientists at the company have experience with work-ing from assay development through to pre-clinical and clinical candidates across all bio-logical target classes and major therapeutic indications. As part of its compound manage-ment service, BioAscent currently holds and manages more than one million compounds for customers, in liquid and solid formats. Through its Compound Cloud service, the company provides rapid access to an IP-free library of more than 125,000 lead-like com-

SERVICES CONTINUED ON PAGE 7

A meeting of the mindsInsilico and WuXi AppTec use AI in drug discoveryBY RACHEL FLEHINGER

SHANGHAI & BALTIMORE—Insilico Medi-cine, a company using artificial intelligence (AI) in their drug discovery efforts, has completed a strategic round of funding spearheaded by WuXi AppTec. The funding is intended to further Insilico’s capacity to apply deep learning for target identification, drug discovery and aging research. The collaboration will serve to integrate the AI technology at Insilico with the laboratory infrastructure and expertise presented by WuXi AppTec.

The initial round of funding was aimed at forming a strategic collaboration between

the two companies, which validated a part of Insilico’s generative pipeline—perform-ing several experiments that would irrefut-ably demonstrate the performance of the

generative adversarial networks and reinforcement learning in generating novel molecular entities for the di�cult orphan molecular targets. The first phase of the investment required suc-cessful experimental validation

of Insilico’s generative adversarial networks, or GANS, and reinforcement learning-based discovery.

WuXi AppTec is the largest global provider AI CONTINUED ON PAGE 8 INFECTION CONTINUED ON PAGE 8

TOOLS & TECHNOLOGY

WuXi AppTec hopes to use Insilico Medicine’s artificial intelligence technology to predict pharmacological properties of drugs and supplements and identify novel biomarkers.

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pounds in screening-ready format. XenoGesis and BioAscent have

both received investment from BioCity Group and are based at BioCity Group sites in Notting-ham and Glasgow. BioCity Group, a U.K.-based business incubator that supports the growth of ambi-tious life-sciences businesses, was founded in 2002. It is home to more than 250 businesses across locations in Nottingham, Glasgow and Alderley Park.

According to Paul Smith, CEO of BioAscent, “There is a longstand-ing connection between BioAscent and XenoGesis, with a deep under-standing of each other’s capabilities and how these interrelate. We saw a gap in the market for a focused, tailored service where the provid-ers have genuine expertise in the three key drug discovery disciplines of biosciences, medicinal chemis-try and DMPK.”

Richard Weaver, managing direc-tor of XenoGesis, added, “Each company sees a benefit to its cli-ents in the collaboration, allowing us together to o�er a truly compre-hensive integrated drug discovery service. Both companies share an ethos of putting science and the client first, offering high-quality laboratory services with the best impartial advice from our experts. Based on the complementarity of our expertise and our shared cul-tural values, we expect this collabo-ration to thrive over time.”

As Smith explained, “Activities are project-specific and tailored for each discovery program, as no two drug discovery programs are alike. Projects might start with (for example) upfront DMPK con-sultancy advice from the team at XenoGesis or assay development and high-throughput screening from the team at BioAscent. Cli-ents can then place parts or all of their discovery activities with us, secure in the knowledge they have access to a comprehensive but science-driven drug discovery service.”

“Due to our consultative approach, XenoGesis and Bio-Ascent will work closely together to handle account management in a way that suits the specific project requirements. Furthermore, our dedicated client relationship man-agement teams have the systems and processes in place to manage all client projects from start to finish,” Weaver continued. “The focus will always be science-led, bringing together our combined DMPK, medicinal chemistry and biosciences expertise to benefit our clients’ drug discovery projects. Of course, we are also working togeth-er on joint business development e�orts.”

Both companies describe the commercial potential of the alli-ance as “huge.” The global drug discovery market is currently val-

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ued at $22 billion, with double-digit growth forecast over the next five years. This growth is driven by a trend towards outsourcing with an increasing need for integrated drug discovery services, and the two companies have identified that there is room in the market for a comprehensive, science-driv-en drug discovery service. They believe that the combination of capabilities and expertise makes the team unique in the market. �EDITCONNECT: E071804

“There is a longstanding connection between BioAscent and XenoGesis, with a deep understanding of each other’s capabilities and how these interrelate,” says Paul Smith, CEO of BioAscent. “We saw a gap in the market for a focused, tailored service where the providers have genuine expertise in the three key drug discovery disciplines of biosciences, medicinal chemistry and DMPK.”

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deaths occurring in hospital settings.In the latest installment of an ongoing part-

nership, AiCuris Anti-infective Cures GmbH and the Max Planck Institute of Molecular Physiology (MPI) announced a collaborative agreement in the second quarter of 2018 to address the issue of antibiotic resistance. The organizations will work together for the iden-tification of novel compounds for treating viral and bacterial infections.

Per the terms of the deal, AiCuris will be granted access to the MPI’s proprietary col-lection of natural product-inspired substanc-es and, together with the research group of Dr. h.c. Waldmann, will investigate and opti-mize compounds that prove active against bacteria or viruses and could be developed into anti-infective drugs. No financial details were disclosed.

“Novel antibiotics are in high demand due to the global rise of resistance to exist-ing drugs,” Waldmann noted in a press release. “Natural products have been an invaluable source of novel antibiotics, and the concepts developed at MPI Dortmund for the design and synthesis of novel natu-ral product-inspired compounds could pave the way to the discovery of new drugs. The expertise of MPI scientists in chemical biol-ogy partnered with AiCuris’ proven experi-ence in drug development could result in the discovery and development of innova-tive approaches to fight bacterial and viral resistance.”

Waldmann’s research group, as noted on the MPI website, focuses on “the organic chemistry-biology interface. Grounded in chem- and bioinformatic charting of biolog-ically relevant chemical space, we develop novel strategies for the synthesis of natural product-inspired compound collections and use them for the study of biological phenom-ena. Natural products and their structural sca�olds represent the biologically relevant and prevalidated regions of chemical struc-ture space explored by nature.”

In January, the World Health Organiza-tion (WHO) shared surveillance data from its Global Antimicrobial Surveillance Sys-tem, detailing some sobering specifics with regards to antibiotic resistance across the globe. In patients with suspected blood-

stream infections, those with resistance to at least one commonly used antibiotic ranged from zero to as high as 82 percent. Penicillin resistance fell between zero and 51 percent, and individuals with E. coli bac-teria associated with urinary tract infec-tions showed resistance to ciprofloxacin anywhere between 8 and 65 percent of the time.

WHO issued a 2017 report titled “Antibac-terial agents in clinical development—an analysis of the antibacterial clinical develop-ment pipeline, including tuberculosis” that showed there is a critical lack of new antibiot-ic being advanced clinically. The report found 51 new antibiotics and biologicals meant to treat priority antibiotic-resistant pathogens, but only eight were defined by WHO as “innovative treatments that will add value to the current antibiotic treatment arsenal.” The majority “are modifications of existing classes of antibiotics and are only short-term solutions,” as noted in a WHO press release.

“We strongly believe the development of new antibacterial drugs is crucial to combat antibiotic-resistant bacteria that is killing around 25,000 people every year in Europe,” commented Dr. Holger Zimmermann, CEO of AiCuris Anti-infective Cures GmbH. “One way to develop a resistance-breaking drug is to disregard well-trodden paths and explore new opportunities. We are very excited to be working with the MPI and its propri-etary library of nature-derived compounds, as nature has often proven to be the perfect blueprint for innovative concepts.”

This isn’t the only news from AiCuris on the topic of infections and collaborations. The second quarter of the year also saw the company announce that the Japanese Ministry of Health, Labor and Welfare had granted MSD (known as Merck & Co. in the United States and Canada) marketing autho-rization for PREVYMIS for the prevention of cytomegalovirus infections in allogeneic hematopoietic stem cell transplant patients. AiCuris licensed the drug, a first-in-class non-nucleoside CMV inhibitor, to MSD in 2012, and per AiCuris’ agreement with MSD, it receives milestone payments and royalties on net sales of PREVYMIS. Securing Japa-nese marketing approval triggered a €15-mil-lion payment to AiCuris. �EDITCONNECT: E071806

of R&D services, and one of its core strengths is its chemistry capacity, allow-ing collaboration on chemical synthesis and experimental validation of the molecules generated by Insilico AI from scratch. The companies complemented each other’s capacity, with Insilico doing the work in the digital space while WuXi provided the solid experimental base.

“Insilico has a very strong AI team, but it does not have a group of seasoned drug development or business develop-ment professionals in-house,” according to Lennart Lee, a principal venture capital

investor at WuXi AppTec. “Alex Zhavor-onkov is currently building out the [Insili-co] team, and he will need to build the right team of people around him.”

WuXi AppTec’s investment came from its Corporate Venture Fund and was bolstered by several additional financ-ing partners including Pavilion Capital, BOLD Capital Partners and Juvenescence. The joint project represents a significant win for both companies.

“We will significantly accelerate both the AI development and the biology and chemistry e�orts and expand the teams at Insilico,” says Dr. Alex Zhavoronkov, founder and CEO of Insilico Medicine. “We will also collaborate with the WuXi’s leading scientists very closely. Currently we are also planning to open a company in China ... because an AI company without a substantial R&D presence in China will not be able to lead in the long-term.”

The companies anticipate another round of funding coming forth in the third quarter of 2018, pending the estab-lishment of some new goals and a success-ful outcome in the preclinical validation exercises.

“WuXi AppTec hopes to use Insilico’s AI technology to predict pharmacological properties of drugs and supplements and identify novel biomarkers. We hope the technology would allow our researchers to generate novel therapeutic candidates, with a focus on aging and age-related dis-eases,” asserts Lee. “We are hopeful that our partnership will accelerate our drug discovery process.”

“Our team is very dedicated, and if something happens along the way and we

fail with one of the experiments, there are always many others in parallel. And our AI pipelines are constantly improv-ing,” says Zhavoronkov. “In the case that we fail in one experiment, we will be able to rapidly re-engineer our AI and do better.”

Adding to the current excitement and promise at Insilico, they have also just been named as a recipient of the North American Technology Innovation Award from Frost & Sullivan, for a product with innovative features and functionality that is gaining rapid market acceptance.

“Technology leadership in artificial intelligence for drug discovery and bio-

marker development, academic excel-lence, extensive collaborations with phar-maceutical and consumer companies, novel methods of attracting top talent and increasing global reach have allowed Insilico Medicine to build a credible and sustainable business model in the nascent longevity biotechnology industry,” noted Neelotpal Goswami, senior industry ana-lyst at Frost & Sullivan. “In recognition of its pioneering research and ability to introduce novel products and solutions for age management, Frost & Sullivan is pleased to present it with the 2018 Tech-nology Innovation Award.” �EDITCONNECT: E071805

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The Waldmann research group at the Max Planck Institute of Molecular Physiology will investigate and optimize compounds that prove active against bacteria or viruses and could be developed into anti-infective drugs, in concert with ongoing R&D partner AiCuris. Pictured here is Max Planck Innovation, the technology transfer arm of the Max Planck Society.

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“We will significantly accelerate both the AI development and the biology and chemistry e�orts and expand the teams at Insilico. We will also collaborate with the WuXi’s leading scientists very closely. Currently we are also planning to open a company in China ... because an AI company without a substantial R&D presence in China will not be able to lead in the long-term.”Dr. Alex Zhavoronkov, CEO of Insilico Medicine

A new collaboration will integrate the artificial intelligence technology at Insilico with the laboratory infrastructure and expertise presented by WuXi AppTec (pictured here).

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Moss polysaccharide discovery likened to beta glucenCompound discovered in moss could have potential for health and medical usesBY DDNEWS STAFF

ADELAIDE, Australia—An inter-national team of scientists, led by Prof. Rachel Burton from the University of Adelaide in South Australia and Prof. Alison Roberts of the University of Rhode Island, was looking into the evolutionary history of beta glucan when they

made a discovery that could have potential in therapeutics options and drug delivery, among other areas.

Beta glucan, a polysaccha-ride, is a dietary fiber that is known to have various health benefits—in fact, it is used in some medicines for such condi-tions as diabetes, hypercholes-terolemia and cancer—and the compound is abundant in cere-als such as oats and barley. But thus far it is not known to have been found in moss, despite the

plants having similar relevant genes.

But, scientific curiosity being what it is, the researchers took one of these similar genes from moss to see if it would lead to the production of beta glucan as in the case of oats and barley.

“What we found was a new polysaccharide made up of the sugars glucose and arabinose—not just glucose as in beta glu-can,” said Burton. “We have called it arabinoglucan and believe the way the two di�erent sugars link

together will make it structurally similar to beta glucan.”

The researchers, whose find-ings were recently published in the journal The Plant Cell, think that there might be “great potential” for this new polysac-charide as has been seen with other types.

Burton said while the function of the arabinoglucan was not yet known, it may have properties of value to the health, industrial and medical fields, like well-known polysaccharides such as

cellulose for paper and cotton, or xylans that can be used for as dietary supplements or drug delivery. She said the discovery led researchers to question how many other undiscovered plant polysaccharides were out there.

“We don’t know what’s there because we can’t always see it,” Burton noted. “Scientists will need new tools to be able to find them, which might include new antibodies and microscopy tech-niques.” �EDITCONNECT: E071807

Under this research and development collaboration, leadXpro will provide puri-fied membrane protein and UZH will apply their sybody platform, which is unique in generating synthetic single-domain anti-bodies (dubbed sybodies) against challeng-ing membrane proteins. leadXpro has the option to acquire any resulting commercial applications of the developed products.

“In this challenging project, we apply our recently developed sybody selection plat-form to enable drug discovery on a disease-relevant membrane protein. As an academic innovator lab, we have a strong interest in making our technology accessible to skilled and experienced industry partners, like leadXpro,” remarked Markus Seeger, project leader and a professor at UZH.

Iwan Zimmermann, co-inventor of the sybody technology, UZH, added, “The proj-ect gained quickly momentum, due to the combination of the excellent target quality delivered by leadXpro and our highly e�-cient sybody platform. The collaboration is an excellent validation of our binder technol-ogy towards future therapeutic applications.”

Sybodies are synthetic single-domain antibodies that have been developed in the Seeger research group at UZH. “Some ani-mals like camels, llamas and sharks gener-ate so-called nanobodies. They are smaller in size compared to antibodies and can be produced easily,” says Hennig.

According to the research published in eLife, the sybodies are “designed to mimic the natural shape diversity of camelid nano-bodies, thus allowing for an optimal surface complementarity to the limited hydrophilic epitopes on membrane proteins. The applica-tion of ribosome display for synthetic nano-body libraries allows processing of very large diversities, thus compensating for the incre-mental antibody maturation taking place in

vivo. Our approach permits the selection and preparative production of sybodies within three weeks and requires only standard labo-ratory materials.”

Sybodies have been engineered for target-ing challenging integral membrane proteins and are selected entirely in vitro, thereby enabling rapid binder generation in the pres-ence of non-covalent ligands against delicate targets. Due to their high thermal stabilities and low production costs, sybodies show

promise for diagnostic as well as therapeutic applications. Sybodies are ideally suited to trap intrinsically flexible membrane proteins in defined conformational states and thereby facilitate structure determination by X-ray crystallography and cryo-EM.

Mathieu Botte, senior scientist and proj-ect leader at leadXpro, said, “Generation of high-quality membrane protein samples is a core competence of leadXpro’s lead discovery platform. Within only three weeks, our col-laboration partners at UZH have successfully generated a highly diverse set of sybodies that are directed against our challenging target protein. Binding properties were character-ized with our platform of biophysical meth-ods (e.g. Creoptix’s wave-guided interferom-etry) and revealed up to pM a�nities and favorably slow dissociation rates for several binders. Sybodies are therefore ideal candi-dates for the formation of stable complexes for structural studies, and they represent excellent therapeutic lead compounds.”

“In addition to employing our membrane protein samples for our biophysical and struc-

ture-based analytical tool set, we can now expand the utility of our samples as antigens for the generation of sybodies or antibodies,” Hennig adds. “While this collaboration is our first entry into the biologics discovery space, benefits from the generated sybodies as sta-bilization, crystallization and tools to aid our structure guided small-molecule platform are also very welcome and contribute additional value to our existing membrane protein gen-eration platform.”

When asked about the types of possible commercial applications the researchers hope might come out of this collaboration, he notes, “Sybodies are great facilitators to crystallize challenging drug target proteins like membrane proteins. This will enable structure-based drug discovery for disease mechanisms that have not benefitted from these modern methods to discover new treat-ment options for patients. In addition, sybod-ies could be drug molecules themselves, like the many antibody treatments that are cur-rently available.” �EDITCONNECT: E071801

MEMBRANECONTINUED FROM PAGE 1

“The project gained quickly momentum, due to the combination of the excellent target quality delivered by leadXpro and our highly e�cient sybody platform. The collaboration is an excellent validation of our binder technology towards future therapeutic applications.”Iwan Zimmermann of the University of Zurich

The University of Zurich (pictured here) will apply its sybody platform against challenging membrane proteins using purified membrane proteins provided by collaborating company leadXpro.

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OUT OF ORDER: RIGHT NOT TO TRY?BY RANDALL C WILLIS

W HEN FACED with a terminal illness, the last thing anyone wants to hear is that the med-ical establishment has noth-ing left in its arsenal to help

you. Yet, for so many patients, this is precisely the case, and with no alternatives in front of them, many are tempted to try the unorthodox and the unproven.

To some extent, medical tour-ism is built on that desperation; the hope that a treatment that has not found domestic approval might yet be worth a try somewhere else—locations where regulations aren’t as strictly enforced, perhaps.

With the recently signed Right-to-Try legislation, however, these patients might have another option. Rather than spend their remaining few dollars on travel to distant lands, they can spend that money at home, paying out of pocket for experimental therapies-on-demand, if those treatments have passed Phase 1 clinical trials.

The patient doesn’t have to enroll in the drug company’s clinical trials to receive therapy, and the results of right-to-try treatment will not be used in regulatory review of the treatment for ultimate approval.

If we set aside the cost issue for a moment, this seems like a wonderful opportunity for patients who see the risk of death as more worrisome than the risk of adverse events. And it indemnifies the drug companies from the risk of having their experimental therapeutics tagged with negative outcomes from uses they likely never intended.

There is, however, another perspective.In May, I questioned the clinical and scien-

tific utility of single-arm clinical trials, suggest-ing that without a comparator (e.g., placebo or

standard of care), there could be no statistical understanding of the resulting data.

A counter-argument for that could be that the sheer numbers of patients achieving similar results suggests that something was happening, and if most of those responses were positive, was that not a good thing?

In the more distant past, I also questioned the validity of o¢-label prescribing of approved

drugs. To me, clinicians were hold-ing unregulated clinical trials based on personal prescribing experience with a treatment, clinical hearsay in the form of case studies or logic exercises based on suspected modes of action.

Again, the counter could be that because the treatment has already been approved, even if not for this specific patient population, it has been well characterized through

numerous clinical trials and post-marketing monitoring. Thus, the relative risk profile of receiving treatment is largely known and the clinician can make a well-informed decision about the risk to his or her patient.

What is being proposed through Right-To-Try, however, invalidates both counter-arguments.

Rather than o¢ering whatever statistical validity comes from sheer numbers of participants, when the patient exercises his or her right-to-try, N = 1. Thus, whatever happens once treatment starts o¢ers essentially zero scientific or clinical insight.

And because treatment is being given with a drug that has likely not been tested on very many people even if it has passed Phase 1 testing, the risk profile is still largely unknown. Just look at the numbers of drugs that fail post-Phase 1 or even post-approval due to safety concerns.

Again, I understand that for the patient who is facing death, none of this likely matters.

If the treatment fails, it doesn’t change the patient’s outcome; but if it positively impacts the disease course and extends the patient’s life, it was worth the risks.

All of this should matter, however, to those in the healthcare, drug and allied industries.

Even if these patients are being given Right-To-Try experimental treatments outside of the patient selection processes, should we not still try to learn everything we can from that treat-ment of that patient?

In choosing to participate in a “clinical trial of one,” should the patient not be expected to par-ticipate in the same scientific analysis as patients who enroll in clinical trials of dozens, hundreds or thousands?

If the treatment fails, then perhaps we can learn something that helps us better select other patient populations. If the treatment succeeds, then we may have the basis of future trials and other indications.

But without examining endpoints and bio-markers, without profiling patient -omics, without monitoring metabolic chemistries and adverse events, the failure or success of treat-ment stands as completely meaningless to the scientific and clinical communities.

I appreciate that what I am suggesting would require great clarity on a variety of fronts, not the least of which is corporate and medical liability of having such information. But how is that ulti-mately di¢erent from the clinical trials process as it stands?

The hope of experimentation is to better understand the situation after the experiment than you did before it.

No matter how you parse it, Right-to-Try is an experiment. �

Randall C Willis can be reached by email at willis@ddn-news.com

Editor’s focus: Cancer should not be a ‘popularity contest’BY JEFFREY BOULEY

U P UNTIL THE MOMENT I sat down to ponder this month’s edito-rial, I was undecided about using neglect of ovarian cancer as my topic this month, although I had

in my queue of potential topics a news release about an Australian oncology researcher, Dr. Jim Coward, who says ovarian cancer patients are losing out as badly needed funds and clinical attention are focused on more prominent—yet not as deadly—women’s diseases.

Then came the retweet on my Twitter feed, of someone talking about how ovarian cancer often goes undetected because the tendency is to assume women simply need to lose weight, instead of actually considering weight gain and pain as possible symptoms.

Given that my mom died roughly two decades ago in her early 50s—of ovarian cancer that went undiagnosed until the very late stages because her physician repeatedly accused her of secret binge-eating when she visited multiple times for unexplained bloating, weight gain and pain—I decided to take that as a sign.

As noted by Coward, an associate professor and oncologist who is leading the first clini-cal trial of the Australian therapy Cantrixil for recurrent ovarian cancer, ovarian cancer treatment lags far behind that of the more publicized breast and cervical cancers.

“More needs to be done in devel-oping novel clinical trials to help enhance the survival rates for women with ovarian cancer,” he said. “We’re really only gaining small steps in understanding ovarian cancer—how it evolves, how the tumor behaves once its established, where it origi-nates—and making small gains subsequently in developing e¢ective treatments.”

As a pharma/biotech market journalist and as a compassionate human, I am pleased to see progress on any cancer front, breast and cervical very much among them. But also as a journalist, I know how headlines can command attention. I know that when a lot of people demand action on an issue because it a¢ects more people than some other issue, the bigger group and louder

voices will likely prevail. And while I have tried as chief editor here to make sure I have a good mix of coverage of the common to the rare and

the deadly to the simply annoying, I cannot say for certain that I have not contributed in some way to elevat-ing attention for some diseases at the expense of deadlier ones.

There is a lot of attention on com-mon diseases (in the general public and the scientific one), and there is a lot of attention on very rare diseases (in life sciences and pharma/biotech at least). But what about those dis-eases in between, those that are not

so common as to garner the bulk of attention and funding and not so potentially lucrative as truly orphan indications can be for pharma and biotech companies.

Perhaps it’s time to rethink some of our pri-orities publically and privately. Perhaps it’s time for those areas that have received attention for decades and made progress to give a little way. Enough for deadlier and less-understood ones to get more attention and make more progress. �

Jeffrey Bouley, DDNews Chief Editor

Randall C Willis

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For more information, visit www.DDN-News.com JULY 2018 | | DDNEWS 11EDITORIAL

COMMENTARY: Improving results after hematopoietic stem cell transplantationBY DR. KARINE KLEINHAUS OF PLURISTEM THERAPEUTICS

HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) is a broad term that covers the transplantation of blood progeni-tor/stem cells from any source. It has become a powerful tool to treat numerous conditions. Indeed, physicians perform more than 50,000 first HSCTs annually; of these, 53 percent are autologous (taken from the patient) and 47 percent are allogenic (taken from

a donor other than the patient). Among the conditions HSCT can treat are: acute myeloid leukemia, acute lym-

phoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, myelodysplastic syndromes, multiple myeloma, non-Hodgkin lymphoma, Hodgkin disease, aplastic anemia and pure red-cell aplasia—but this list is not exhaustive.

HSCT has four possible outcomes: failure (when the transplanted cells just don’t take, a rare result); partial success (commonly called incomplete engraftment, when the cells are living inside the patient’s bone, but they are not active enough to keep the patient transfusion-independent); success with complications (when the cells are active enough to make the patient transfusion-independent but other health issues arise); and success without complications. In the first case, a second transplant is possible or other therapies can be considered, but the prognosis is usually disheartening.

Incomplete engraftmentIncomplete engraftment (poor graft func-tion) requires the patient to undergo more transfusions of red cells or platelets. There are complications of serial transfusions of either of these cell types, and a patient needs intense prophylactic treatments to protect from infections if his or her white counts are low. The current treatment for incomplete hematopoietic recovery includes adminis-tration of factors stimulating white and red blood cell growth, such as granulocyte-colo-ny stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin.

However, a significant number of patients do not respond to growth factors and may continue to require frequent transfusions, which expose them to transfusion-related risks such as allo-sensitization and infec-tions, without providing a definitive cure. Regular transfusions are also associated with significant costs. Thus, there is an unmet need for additional treatment options for these patients.

Several groups are conducting trials to determine whether cellular therapy could be the treatment of choice for poor graft function after HSCT. Pluristem Thera-peutics, based in Haifa, Israel, is currently recruiting patients in the United States and Israel for its Phase 1 trial of PLX-R18 cells in this unmet need. PLX-R18 cells, derived from mesenchymal-like cells collected from donated placentas, are designed to release a combination of therapeutic proteins to jump-start the regeneration of a poorly function-ing hematopoietic system. The cells are also being evaluated in a variety of other hema-tologic indications.

Other groups are also working on cell therapies for the treatment of poor graft function after HSCT. These include a group of researchers from multiple academic insti-tutions in Belgium, headed by Yves Beguin from the University Hospital of Liege. Their

ongoing Phase 2 study is evaluating whether infusion of mesenchymal stem cells (MSCs) can treat steroid-resistant acute graft-versus-host disease (GVHD) or poor graft function after HSCT. The study is expected to be com-pleted in December 2019. Researchers from several academic institutions in China—headed by Qifa Liu, of the Nanfang Hospital of Southern Medical University—are also studying MSCs as a therapy for poor graft function. One trial is testing whether MSCs with or without peripheral blood stem cells could treat poor graft function and delayed platelet engraftment. In another trial, this group is evaluating whether peripheral blood stem cells combined with MSCs can treat poor graft function.

Side effects of HSCTEven when successful, HSCT can have some potentially dangerous side e¢ects. Infections are quite common, though antibiotic treat-ments are usually successful. Organ damage and, among female patients, infertility are more di¨cult to address but can be managed in some cases. GVHD, which is common among allogenic HSCT and rare in autolo-gous HSCT, can be acute or chronic. This complication can be lethal and is often very di¨cult to treat.

GVHDGVHD develops when the donor’s immune cells mistakenly attack the patient’s nor-mal cells. GVHD can be mild, moderate or severe—even life-threatening. An ounce of prevention is always worth a pound of cure, so patients usually receive a regimen of preven-tative immune suppressors a day or two before their infusion. The regimen may include: Cyclosporine and methotrexate, Tacrolimus (Prograf) and methotrexate, Tacrolimus and mycophenolate mofetil (CellCept) as well as Prograf and sirolimus (Rapamune).

However, GVHD still happens, and it comes in two varieties, acute and chronic.

Acute GVHD usually manifests within 100 days following HSCT. It is induced by donor T cells responding to the mismatched host polymorphic histocompatibility antigens. Chronic GVHD generally manifests later (>100 days) and has some features of autoimmune diseases. It may develop either de novo or following resolution of—or as an extension of—acute GVHD.

Acute GVHDTreating aGVHD can take many forms. Topi-cal corticosteroids (e.g., triamcinolone 0.1%) have proven e¢ective for some skin aGVHD. Often, physicians will continue the original immunosuppressive prophylaxis (cyclospo-rine or tacrolimus [FK506]) while adding methylprednisolone.

Additional therapies, which can be used alone or in combination, include: anti-CD5-specific immunotoxin, anti-interleukin-2 (IL-2) receptor, ATG, mycophenolate mofetil, sirolimus and XomaZyme (a pan T-Cell ricin A-chain immunotoxin). There is no data from a well-conducted controlled trial showing that any of these is more e¢ective than any other.

If these initial therapies fail, secondary therapies include ATG or multiple pulses of methylprednisolone Sirolimus, Infliximab, Etanercept, Mycophenolate mofetil (MMF) and Ruxolitinab, among others.

In August 2017, the FDA expanded the approval of Imbruvica (ibrutinib) for the treatment of adult patients with chronic GVHD (cGVHD) after failure of one or more treatments. This is the first FDA-approved therapy for the treatment of cGVHD. Dr. Richard Pazdur, director of the FDA’s Oncolo-gy Center of Excellence and acting director of the O¨ce of Hematology and Oncology Prod-ucts in the FDA’s Center for Drug Evaluation and Research, was quoted in the announce-ment by the FDA as saying, “Patients with cGVHD who do not respond to other forms of therapy—typically corticosteroids to sup-press their immune system—now have a treatment option specifically indicated to treat their condition.” Imbruvica, a kinase inhibitor, was previously approved for treat-ing certain chronic lymphocytic leukemias, Waldenström’s macroglobulinemia and mar-ginal zone lymphoma. It is under accelerated approval status for mantle cell lymphoma.

However, some aGVHD is steroid refracto-ry. Currently, there are no approved therapies for patients with steroid-refractory aGVHD in the United States, and o¢-label options have demonstrated mixed efficacy. These include mycophenolate mofetil (MMF), etanercept, photopheresis, mesenchymal stromal cells, sirolimus and pentostatin. Other agents that can be tried include mono-clonal antibodies directed against such tar-gets as CD25, TNF-alpha, the T cell receptor, and the IL-2 receptor. There are limited data to guide the choice of therapy. Mesoblast is developing MSC-100-IV to treat these cases, and it has demonstrated immunomodulatory properties to regulate T cell-mediated inflam-matory responses by inhibiting T cell prolif-eration and down-regulating the production of the pro-inflammatory cytokines, including

tumor necrosis factor-alpha, or TNF-alpha, and interferon gamma.

Chronic GVHDAlthough the clinical presentation of cGVHD mostly resembles scleroderma, it can mimic any other autoimmune disease. Immunosup-pression with corticosteroids, tacrolimus and mycophenolate mofetil are the mainstays of treatment. Hydroxychloroquine, an antima-larial drug, is effective in several autoim-mune disorders, including cGVHD. A major cause of death in cGVHD is infection from profound immunodeficiency associated with the disease. All patients require prophylaxis against encapsulated organisms, and patients with frequent infections and low immuno-globulin levels should receive intravenous immunoglobulin replacement.

Mary E.D. Flowers and Paul J. Martin noted in Blood, “Management of chronic GVHD has relied on corticosteroids as the mainstay of treatment of >3 decades … Pro-longed systemic corticosteroid treatment causes significant toxicity, including weight gain, bone loss, myopathy, diabetes, hyper-tension, mood swings, cataract formation and increased risk of infection.”

Approximately 50 to 60 percent of cGVHD patients who undergo systemic treatment require a secondary treatment within two years of their initial treatment. “No consen-sus has been reached regarding the optimal choice of agents for secondary treatment of chronic GVHD, and the published literature provides little useful guidance.” Physicians generally use ECP, Rituximab, Imatinib, Pen-tostatin, mesenchymal stem cells, mycophe-nolate mofetil, mTOR inhibitor and Interleu-kin-2—and again, this list is not exhaustive.

As with the acute variety, some cGVHD is steroid refractory. Research into treat-ments again includes Pluristem’s PLX-PAD cell therapy. Last November, the company signed an agreement with Tel Aviv Sourasky Medical Center (Ichilov Hospital) to conduct a Phase 1/2 trial.

Conclusion HSCT represents a revolution in the treat-ment of many maladies, but it is an incom-plete revolution at present. Treatments of incomplete engraftment as well as acute and chronic GVHD are advancing but our understanding of the causes is far from complete. Studies to improve treatment are underway. However, our ability to prevent or quickly and easily remedy these health issues remains over the horizon. �

Karine Kleinhaus, M.D., M.P.H., is divisional vice president, North America at Pluristem Therapeutics.

“Several groups are conducting trials to determine whether cellular therapy could be the treatment of choice for poor graft function after HSCT.”

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RESEARCH & DEVELOPMENT

12 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.com

Recalibrating Mendelian randomization

NEW YORK—Mendelian randomization (MR), a common method that looks at genetic variation to determine how risk factors affect disease and mortality risk, may not be as straightfor-ward as believed, according to scientists from the Department of Genetics and Genomics Sci-ences at the Icahn School of Medicine at Mount Sinai, Massachusetts General Hospital and the Broad Institute. The collaborators found that in 48 percent of cases of MR, horizontal pleiotropy was present.

Horizontal pleiotropy is a phenomenon in which genetic variants affect disease by differ-ent pathways than those being tested, and the researchers found that its presence distorted MR results by -131 to 201 percent on average, and that widespread horizontal pleiotropy induces false-positive causal relationships in as much as 10 percent of results in some cases. These results highlight the need to evaluate all MR studies for horizontal pleiotropy, according to the authors, who have developed MR-PRESSO, open-source software to detect and correct for this phenomenon. Their work was published in Nature Genetics.

FDNA’s Face2Gene hits milestoneBOSTON—FDNA recently announced that more than 100,000 patients had been evaluated with Face2Gene, AI-based technology that uses deep learning algorithms to search photos for facial descriptors and traits that could be indicative of genetic diseases. According to FDNA, it has one of the fastest-growing and most comprehensive genomic databases, with more than 70 percent of geneticists and more than 2,000 clinical, research and lab sites adding Face2Gene to their workflow and further expanding the database. The company reports that it is expecting this momentum to con-tinue, estimating that it will evaluate more than 4,000 patients a month over the next few months.

IN THIS SECTIONBiospecimensUnderuse of specimens concerns biobanks .................................. 12

Genetics/GenomicsFDNA’s Face2Gene hits milestone ......... 12Recalibrating Mendelian randomization ............................................12

NeurologyCracking the code (CODE from cover) .... 14

Infectious diseaseBacterial DNA uptake has IU scientists hooked ............................... 12NETs of neutrophils ................................ 12Veterinary drug could curb malaria and Zika outbreaks .................... 15

NETs of neutrophilsUniversity of Bristol researcher investigates immune cell defense against microbesBY ILENE SCHNEIDER

BRISTOL, U.K.—Dr. Borko Amulic, a researcher who recently moved from the Max Planck Institute in Germany to the University of Bris-tol, received a £1.2-million Career Development Award from the Medi-cal Research Council. The five-year award will enable Amulic and his team of researchers in the School of Cellular and Molecular Medicine to study how and whether the natural ability of neutrophil immune cells can be increased to fight infection “in the post-antibiotic age,” according to the University of Bristol.

Neutrophils—immune cells that protect the body from infection by bacteria, fungi and parasites—are the most abundant immune cells in humans. Without these cells, humans would be defenseless against

Bacterial DNA uptake has IU scientists hookedThe first direct observation of the DNA uptake process could help advance e�orts against drug-resistant bacteriaMEL J. YEATES

BLOOMINGTON, Ind.—Indiana University scientists have made the first direct observa-tion of a key step in the process that bacteria use to rapidly evolve new traits, including antibiotic resistance.

Using methods invented at IU, research-ers recorded the first images of bacterial appendages—over 10,000 times thinner than human hair—as they stretched out to catch DNA. These DNA fragments can then be incorporated into bacteria’s own genome through a process called DNA uptake, or hor-izontal gene transfer. The work was reported on June 11 in the journal Nature Microbiology.

“Horizontal gene transfer is an important

way that antibiotic resistance moves between bacterial species, but the process has never been observed before, since the structures

involved are so incredibly small,” said senior author Ankur Dalia, an assistant professor in the IU Bloomington College of Arts and Sci-ences’ Department of Biology. “It’s important to understand this process, since the more we understand awbout how bacteria share DNA, the better our chances are of thwarting it.”

The bacterium used in the study was Vib-rio cholerae, the microbe that causes cholera. The bacterial structures used to catch DNA in the environment are extremely thin, hair-like appendages called pili.

“We chose to study Vibrio cholerae because it undergoes natural transformation readily in the environment. We also know a lot about the regulation of how Vibrio cholerae turns on the genes required for natural transforma-tion, and so we can use that as a tool to make them take up DNA from the environment more often. It is also a very easy organism to work with and grows quickly, which makes it a great tool for studying basic biological questions,” according to Dalia and IU Ph.D.

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Underuse of specimens concerns biobanksEconomic sustainability also challenges biobanks, even as outside researchers struggle to find the specimens they needBY DDNEWS STAFF

LEXINGTON, Mass.—Recently, iSpecimen released its latest biobanking survey report, finding that a majority of global biobanks—collectors of human fluids, cells and tissue for biomedical research—are underutilizing their specimens while struggling with financial pressures that threaten their long-term viability.

Forty-two biobanks answered an iSpecimen online questionnaire about their work in March, and 67 percent of the participating biobanks cited underutilization of samples as a major or moderate biobank challenge—the most frequently cited of 13 choices. More than half (53 percent) of the participants said they collect more samples than they release to researchers.

Meanwhile, 64 percent of respondents cited economic sustainability as a major or moderate biobank challenge, the second-high-est of 13 choices and the top major challenge.

Although biobanks can charge fees for distributing specimens, many are leaving revenue on the table, according to iSpeci-

men. Only 44 percent of respondents release specimens to external researchers from for-profit organizations (e.g., pharma and biotech companies) with whom they are not actively

collaborating. Only 24 percent of respondents said specimens are released to specimen brokers or commercial biorepositories.

“These findings are impor-tant,” said iSpecimen founder and CEO Dr. Christopher Ianelli.

“We already know that researchers struggle to obtain the samples they need for their important research. Our review confirms that there’s a pent-up supply of biospeci-mens in storage, and that biobanks want to do something about it. Broader sample shar-ing would address both the underutilization and specimen availability problems, as well as the challenge of economic sustainability.”

As iSpecimen notes, one National Cancer Institute study found that four out of five researchers reported limiting the scope of their work due to the di£culty of procuring high-quality specimens.

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Clockwise from upper left: This series of four still images shows a pilus stretch out from a bacterium (in green) to catch a piece of DNA in the environment (in red). This is the first step in the DNA uptake process.

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student Courtney Ellison. Although scientists were aware that pili

play a role in DNA uptake, direct evidence demonstrating how they work was lacking until this study. In order to observe pili in action, the scientists used a new method invented at IU to “paint” both the pili and DNA fragments with special glowing dyes. The team that developed this new method to label pili with dyes was led by IU Distin-guished Professor Yves Brun and Ellison.

Dalia and Ellison explained that, “In order to record cells binding onto DNA using their pili, we first had to fluorescently label both the pili and DNA. While labeling DNA is very straightforward and can be easily achieved using commercially available dyes, we had to develop a method to label the pili because these tools did not exist. To label the pili, we genetically engineered them so that we could add a fluorescent dye that would bind to this modification. The kinds of dyes used to label the pili are called maleimide dyes. These dyes work by specifically binding to the thiol group of the amino acid cyste-ine, which we genetically engineered into the pili.

This method for labeling pili was devel-oped by the first author of this study, Court-ney Ellison in Yves Brun’s lab, and it was initially published last year in collaboration with Ankur Dalia in the journal Science.

The new study uses these dyes to reveal that pili act like microscopic “harpooners” that cast their line through pores in the cell’s wall to “spear” a stray piece of DNA at the very tip. The pili then “reel” the DNA into the bacterial cell through the same pore. Dalia said the pore is so small that the DNA would need to fold in half to fit through the opening in the cell.

“It’s like threading a needle,” said Ellison. “The size of the hole in the outer membrane is almost the exact width of a DNA helix bent in half, which is likely what is coming across. If there weren’t a pilus to guide it, the chance the DNA would hit the pore at just the right angle to pass into the cell is basically zero.”

“[We] like to think of the pili as bacterial fishing rods,” Dalia and Ellison tell DDNews. “The pili are extended (or ‘cast’) and retract-ed (or ‘reeled’) back into the cell through tiny machines inside of the cell. The pili have specific proteins on their tips called minor pilins that they use as ‘fishing hooks’ to bind onto DNA, and when the pili are reeled back in they bring the attached DNA back with them.”

“One really exciting aspect of this research is that we found that the machinery used to retract or ‘reel’ in the pili is not actually required for this to occur. This was very sur-prising, since it was always thought before that this machinery was needed for retrac-tion to happen,” they note. “This is another future direction that we are pursuing by try-ing to determine how the cells are able to reel in their pili when that machine is missing.”

According to Ellison and Dalia, “One area directly related to this work will be to try to understand how the protein associated with the tip of the fiber latches onto DNA and what interactions are occurring between those proteins and the DNA. We are very interested in the role and range of forces required for bending DNA to pull it into the cell, and we hope to learn more about these factors in the future by studying the machines that extend and retract the pili.

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A new study used dyes to reveal that pili act like microscopic “harpooners” that cast their line through pores in the cell’s wall to “spear” a stray piece of DNA at the very tip. The pili then “reel” the DNA into the bacterial cell through the same pore. According to reseacher Ankur Dalia (pictured here), the pore is so small that the DNA would need to fold in half to fit through the opening in the cell.

“Also, type IV pili can carry out very diverse processes, including attachment to surfaces, virulence and horizontal gene transfer. The pilus labeling method used here is allowing us to pursue many unanswered questions about these structures, so another major area of focus moving forward is to apply this method to study other pilus systems in Vibrio cholerae and beyond.”

“These are really versatile appendages,” Dalia said. “This method invented at IU is really opening up our basic understanding about a whole range of bacterial functions.” �EDITCONNECT: E071808

14 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.comRESEARCH & DEVELOPMENT

Perennial biospecimen underuti-lization means that biospecimens—the sample itself and the related data—age out of usefulness. The aver-age specimen age for 42 percent of the respondents was more than five years, a period in which many important medical advances have occurred. The medical data attached to a six-year-old sample would not reflect, say, new cancer biomarkers—a data gap poten-tially rendering the sample obsolete.

The biobank review also explored technology, finding that biobanks have a “hodgepodge” of software, data and search capabilities that likely impede specimen utilization.

Search capabilities in biobanks are especially primitive, according to the survey, with many researchers having trouble finding specimens within their own organizations. Internal research-ers can access an online inventory list of specimens at only 27 percent of the participating biobanking organi-zations. Seventy-three percent of the participating biobanks have no online system in place for their researchers to search their catalog for the cases and specimens they require.

More than half of respondents said their biobanks are using primitive ad-hoc systems, such as spreadsheets, to manage their specimen inventory and data. And more than half of the respondents use internal data stan-dards to describe their collections. Only 14 percent of respondents use externally defined biorepository stan-dards such as Minimum Information About Biobank Data Sharing or Ontol-ogy for Biobanking, which enhance data sharing.

“On the whole, the biobanking land-scape is fractured, and current practices impede both biomedical research and future sustainability,” said Ianelli. “Bio-banks need strategies for making their collections available and searchable, processing requests and reinvesting the revenue. The result will be advances in biomedical research and precision medicine, honoring the intentions of philanthropic donor patients.” �

The report can be found at http://pages.ispecimen.com/Worldwide-Biobanking-Survey-Download.htmlEDITCONNECT: E071809

BIOCONTINUED FROM PAGE 12

The scientists developed and tested a set of two factor codes to determine which ones were capable of programming skin cells to become neurons instead, particularly ones that recreate neuronal shape and electri-cal excitability. They tested 598 pairs of transcription factors altogether, and found that more than 12 percent were capable of producing neurons. This provides research-ers with 76 new codes for the production of neurons.

Equally encouraging was the behav-ior of what Dr. Kristin Baldwin, a profes-sor at Scripps Research and senior author of the study, referred to as the “synthetic neurons”—the converted neurons began to grow synapses and attempt to communicate with each other in the span of just a couple weeks.

To determine whether the new codes would produce di¬erent variations of neu-rons, Sohyon Lee, a co-first author on this research and recent Ph.D. graduate at Scripps Research, and Dr. Rachel Tsunemoto, also co-first author, turned to the “outputs” of the codes they’d worked with using electri-cal recording methods as well as new sensi-tive sequencing methods. Tsunemoto was a researcher with Scripps Research and the University of California, San Diego, at the time of the study.

They discovered that each code did indeed result in neurons with di¬erent properties. As the authors reported in their abstract, “By comparing the transcriptomes of these induced neuronal cells (iN cells) with those of endogenous neurons, we define a ‘core’ cell-autonomous neuronal signature. The iN cells also exhibit diversity; each transcrip-tion factor pair produces iN cells with unique transcriptional patterns that can predict their pharmacological responses. By linking dis-tinct transcription factor input ‘codes’ to defined transcriptional outputs, this study delineates cell-autonomous features of neu-ronal identity and diversity and expands the reprogramming toolbox to facilitate engi-neering of induced neurons with desired patterns of gene expression and related func-tional properties.”

Baldwin called the results “a big step for-

ward in cellular reprogramming,” as the use of the transcription factor “codes” means scientists can generate the exact types of neurons they want ad nauseam. This is particularly momentous when it comes to neurons, since, as noted online by Baldwin’s lab, “[N]eurons are primarily generated at birth and are maintained without cell divi-sion for the life of an individual. Neurons do not divide and have not been shown to generate tumors, for unknown reasons. The inability to generate cell lines from neurons precludes a number of important studies including analyses of neuronal genomic

stability in di¬erentiation and disease, and has impeded the generation of appropri-ate in-vitro models of disease.” At present, researchers tend to rely on samples obtained via brain surgery, which only remain viable for a matter of hours.

According to Baldwin, this research comes on the heels of years of work by her lab and others around the world. Nobel laure-ate Shinya Yamanaka and Marius Wernig’s group at Stanford University demonstrated that using sets of three to four factors enabled the conversion of skin cells into pluripotent stem cells and straight into neurons, and Baldwin’s lab had proved that applying sets of two factors enabled them to produce specific neurons that respond to stimuli such as itchi-ness or pain. That work, published in Nature Neuroscience in November 2014, described how Baldwin’s lab converted skin cells into the neurons responsible for registering sen-sation. These neurons are normally found in clusters known as dorsal root ganglia along the outer spine, and are a¬ected by spinal cord injury and linked with Friedrich’s ataxia. Recent research has also tied them to aging and autoimmune disease.

“The brain is incredibly complex, with thousands of different types of cells that are each involved in di¬erent diseases,” says Baldwin, who was senior author of the study. “The problem with understanding and treat-ing the many disorders of the brain is that we cannot reproducibly produce the right types of brain cells. Now we have found more than 75 new ways to rapidly and reproducibly turn skin cells into neurons that we think will be much better representatives of di¬erent neu-rologic diseases than were previously avail-able.” �EDITCONNECT: E071802

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“The problem with understanding and treating the many disorders of the brain is that we cannot reproducibly produce the right types of brain cells. Now we have found more than 75 new ways to rapidly and reproducibly turn skin cells into neurons that we think will be much better representatives of di�erent neurologic diseases than were previously available.”Dr. Kristin Baldwin, a professor at Scripps Research

Pictured here are human-induced neurons generated from a novel transcription factor pair Neurog3/Pit1. Colors represent a nuclear stain (DAPI) in blue, synaptic marker expression (Synapsin1) in green and neuron-specific beta-III tubulin expression (Tuj1) in red.

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Mouse-induced neurons generated from a novel transcription factor pair Neurog2/Brn2 are pictured here, with cells stained for neuron-specific beta-III tubulin expression (Tuj1).

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“We already know that researchers struggle to obtain the samples they need for their important research. Our review confirms that there’s a pent-up supply of biospecimens in storage, and that biobanks want to do something about it.”Dr. Christopher Ianelli, CEO of iSpecimen

For more information, visit www.DDN-News.com JULY 2018 | | DDNEWS 15RESEARCH & DEVELOPMENT

pathogens. The researchers will investigate how neutrophil responses are regulated and how they carry out tasks such as engulfing parasites or entrapping them in neutrophil extracellular traps (NETs), webs of DNA that neutrophils release in a kamikaze cell death attempt to control infections.

According to Amulic, NETs are composed of extruded chromatin with antimicrobial and immunostimulatory properties. Released by an active process called NETosis, the NETs are believed to trap microbes as well as signal to the rest of the immune system. However, excessive or dysregulated neutrophil responses are destructive and contribute to pathology in malaria, autoimmunity and cancer. Thus, mechanisms that fine-tune neutrophil responses are critical for health.

In defining the role of NETs in immunity, Amulic explained that NETosis is an anti-microbial strategy that causes neutrophil death and helps to achieve pathogen control and elimination. As he explained in an article published in Current Biology, “In vitro, the microbicidal properties of NETs have been clearly demonstrated: they trap pathogens and prevent them from dispersing, while simultaneously destroying them through exposure to a high concentration of

antimicrobial e¬ectors. These antimicrobial effectors include, as expected, the anti-microbial proteins of the neutrophil granules. Perhaps unexpectedly, the histones in NETs are also key components of the anti-microbial repertoire. It has long been known that histones are some of the most powerful antimicrobial agents that exist.

“Nevertheless, exactly how this anti-microbial activity of histones could be effectively harnessed was a long-standing and intractable mystery. The discovery of NETs presents a satisfying explanation for this apparent dilemma. Through NET formation, neutrophils provide histones with an opportunity to execute their alternative, non-structural function: microbial killing.”

Amulic and his team “want to understand how neutrophils are regulated at the molecular level and to use these insights to interrogate their function in immunity and inflammation,” he said. The researchers “also aim to develop therapies targeting neutrophils in malaria, a devastating disease that a¬ects millions of people in developing countries.”

In Bristol, Amulic will work with key collaborators in the Faculty of Biomedical Science, including experts in the fields of immunology, microbiology and biochemistry. He will also have access to cutting-edge facilities such as the Wolfson Bioimaging facility. With research that spans cell biology

and immunology, the team will use molecular biology techniques such as CRISPR/Cas9 knockout to characterize genes regulating human neutrophil behavior. The researchers will employ various disease models and patient samples to investigate neutrophils in vivo.

As Amulic said, “Our goal is to propose targets for therapies in inflammatory diseases (including malaria, autoimmunity and cancer), as well as to discover ways to boost neutrophil microbicidal activity in settings such as immunodeficiency and antimicrobial resistance. The emergence of antimicrobial resistance threatens human

health, and one strategy to combat infection is to boost the natural ability of neutrophils to kill pathogens. It is my hope that this award will allow us to discover the genes and biochemical pathways regulating neutrophil functions so we can do just that.”

He added, “I am also very keen to understand how neutrophils contribute to inflammatory diseases. Excessive neutrophil activation often damages our own tissues and contributes to diseases such as autoimmunity and cancer. By better understanding the link, we can begin to investigate how to negate this impact.” �EDITCONNECT: E071810

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Veterinary drug could curb malaria and Zika outbreaksCalibr researchers look at a class of drugs called isoxazolines with an eye toward human useBY DDNEWS STAFF

LA JOLLA, Calif.—Medicines given to house-hold pets to kill fleas and ticks might be e¬ec-tive for preventing outbreaks of malaria, Zika virus infection and other dangerous insect-borne diseases that a²ict millions of people worldwide, according to a new study led by scientists at Calibr, a non-profit drug discov-ery institute closely a£liated with Scripps Research, and TropIQ Health Sciences, a Dutch social enterprise.

The researchers found that a class of drugs called isoxazolines, sold in veterinary prod-ucts such as fluralaner (Bravecto) and afoxo-laner (NexGard) to protect pets from fleas and ticks, also kill species of disease-carrying mosquitos that feed on human blood.

The research team, led by TropIQ’s Dr. Koen Dechering and Calibr’s Dr. Matt Trem-blay, determined via experimental studies on mosquitoes and computer modeling that giv-ing isoxazoline drugs to less than a third of the population in areas prone to seasonal out-breaks of insect-borne diseases could prevent up to 97 percent of all cases of infection. The results of the study were published recently in the Proceedings of the National Academy of Sciences (PNAS).

“Insect-borne infectious diseases remain primary causes of severe illnesses and fatali-ties worldwide, and new approaches to pre-venting outbreaks of these diseases are criti-cally needed,” said Dr. Peter Schultz, CEO of Calibr and Scripps Research. “Our findings suggest that isoxazolines might be e¬ective at controlling outbreaks of diseases carried

by mosquitoes and other insects in regions with limited medical infrastructure.”

Millions of people each year contract malaria, Zika fever and other insect-borne diseases that are particularly prevalent in tropical and sub-tropical regions. In 2016, an estimated 216 million people contracted malaria worldwide and 445,000 died from the disease (mostly children in the African Region), according the U.S. Centers for Dis-ease Control and Prevention. Zika, a mosqui-to-borne disease that can cause birth defects in infants born to infected mothers, has spread rapidly around the planet in recent years and is now found in 90 countries.

“Research on insect-borne diseases has predominantly focused on control of insect

populations through use of insecticides and prevention of bites through distribution of bednets, but these approaches have not been fully e¬ective in controlling outbreaks,” says Koen Dechering, CEO of TropIQ Health Sci-ences. “Vaccines are largely lacking for most diseases and drugs to treat people who have contracted the disease are losing efficacy because of emerging resistance.”

The international research team investi-gated a new strategy, the possibility of giving humans isoxazolines to block transmission of diseases by insect vectors.

When administered orally, the drugs are absorbed into the bloodstream and spread throughout the animal’s body, where they remain active for up to three months. While

well tolerated in dogs and cats, the drugs kill blood-sucking fleas and ticks that feed on the blood of treated animals by damaging the insects’ nervous systems.

The Calibr and TropIQ scientists and their collaborators tested two of the drugs, fluralaner and afoxolaner, and found they also kill species of disease-carrying mosqui-tos and sand flies that feed on human blood infused with the insecticides. The drugs also were e¬ective against insect strains that are resistant to common insecticides.

Based on existing data from studies of the drugs in animals, the researchers estimated that a single human dose of the drugs would convey an insecticide e¬ect against mosqui-tos and sand flies lasting 50 to 90 days.

“In many regions where seasonal out-breaks are endemic, medical infrastructure is such that delivery of medical care is on an intermittent basis,” said Tremblay, chief oper-ating o£cer of Calibr and Scripps Research and a senior author on the PNAS paper. “Isox-azolines could be administered prior to the beginning of seasonal disease outbreaks to convey protection until the threat diminishes at the end of the season.”

The drugs may not work as vaccines, since a treated person could still contract a disease from an insect bite. But an insect that bites an infected person taking the drugs would die before it could transmit the disease to other people, an e¬ect that, when multiplied over a large population, would reduce the overall number of infections.

Based on safety studies of isoxazoline use in animals, the drugs have a good chance of being safe if repurposed for human use, according to Calibr. The research team is planning to evaluate the e£cacy of the drugs in humans, and anticipates that these studies will take around two years. �EDITCONNECT: E071811

This image shows a female Aedes aegypti, a species of mosquito that carries the Zika virus. Researchers at Calibr, a non-profit drug discovery institute closely affiliated with Scripps Research, and TropIQ Health Sciences found that drugs given to pets to kill fleas and ticks might be effective at stopping transmission of insect-borne diseases such as Zika fever and malaria in humans.

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Dr. Borko Amulic will use a £1.2-million, five-year award to study the natural ability of neutrophil immune cells (pictured here) to fight infection and perhaps boost them for therapeutic uses “in the post-antibiotic age.”

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Druggability of tauSo, fast forwarding back to the present day—or June 28, 2018, at least—we see one company con-tinuing the trend toward more focus on tau as news came out of Cantabio Pharmaceuticals Inc. that the company, which is working on therapeutics for AD, Parkinson’s disease and related neurological disorders, had seen publication of a peer-reviewed article. Lead authored by Cantabio’s CEO Dr. Gergely Toth, along with collabo-rators at the Hungarian Academy of Sciences and German Center for Neurodegenerative Diseases (DZNE), the work appeared in the journal ACS Chemical Neuroscience.

The paper was titled “The structural basis of small molecule targetability of monomeric Tau protein” and reported structure-based evidence that native monomeric tau can be a viable target for drug-like small molecules despite its heterogeneous structure.

As the company noted of the

news, the aggregation of monomer-ic tau protein is linked to the onset and progression of Alzheimer’s disease and other tauopathies, and this study and the scientific team’s previous findings provide theoreti-cal and experimental evidence for the ability of monomeric tau to be a receptor of small molecules designed to prevent the aggrega-tion, which leads to toxicity and cell death.

As per Prof. Eckhard Mandelkow, a co-author of the publication and group leader at DZNE in Bonn, this is further evidence that inhibition of tau aggregation by small molecules may be a viable therapeutic approach for tauopathies such as Alzheimer’s disease. He noted that “These molecules are currently being evaluated in animal models of tau-induced pathology.”

“We are excited to publish further scientific evidence that establishes a structural biology basis for Cantabio’s tau small-m o l e c u l e p h a r m a c o l o g i c a l

chaperone program, which aims to prevent and reduce aggregation of tau protein as a therapeutic strategy for Alzheimer’s disease and other tauopathies such as concussion-related chronic traumatic encephalopathy,” said Cantabio’s CEO, Dr. Gergely Toth. “The tau protein has long been a major target for Alzheimer’s drug development, but due to the nature of its structure, it has historically proven to be a di�cult target for small-molecule drug candidates. Our work at Cantabio represents a significant step forward in developing a therapy that is able to prevent the formation of the toxic protein aggregates that are associated with neurodegeneration in these diseases.”

Tau as a therapeutic and diagnostic targetAnd, perhaps in a sign of how much tau research remains in the shadow of amyloid research, our next piece of fairly recent news comes from

There is no resolution as to whether amyloid plaques or tau tangles are more important in the etiology of Alzheimer’s disease—or if either is more important than the other—but tau continues to gain interest as a target even as the shadow of amyloid research continues to loom over it.

The ‘Tao’ of tau?In the recurring debate of tau vs. amyloid, we take a look at how anti-tau research is progressingBY JEFFREY BOULEY

I N LOOKING AT NEURODEGENERATIVE DISEASES for this special focus section on neuroscience, it seemed fitting to check in not just on the consistently hot topic of Alzheimer’s disease, but more specifically the issue of the tau protein and some of the recent insights and progress

on the anti-tau front.Alzheimer’s has already proven to be a particularly complex

and challenging disease for life-sciences researchers and pharma/biotech companies. And in a disease where sticky tangles of pro-teins seems to atrophy the brain and choke o� cognition, one of the stickiest areas has been the issue of the amyloid protein vs. the tau protein. The aggregation of the tau protein is a hallmark of Alzheimer’s disease, but traditionally much of the energy and e�ort has gone toward focusing on ways to reduce the number of amyloid plaques.

As Emily Underwood wrote in a 2016 article in Science, “One of the telltale signs of Alzheimer’s disease (AD) is sticky plaques of ß-amyloid protein, which form around neurons and are thought by a large number of scientists to bog down information pro-cessing and kill cells. For more than a decade, however, other researchers have fingered a second protein called tau, found inside brain cells, as a possible culprit.”

The topic Underwood was addressing was an imaging study of 10 people with mild AD that indicated tau deposits, rather than amyloid, are closely linked to memory loss, dementia and other AD symptoms. It wasn’t evidence that actually resolved the amyloid-tau debate—almost certainly both proteins play major roles, and perhaps other factors as well—but the findings did serve as a potential jumping-o� point for additional e�ort on tau-targeting treatments and better diagnostic tools.

And on the subject that tau and amyloid likely represent more of a “pair of culprits” rather than an “either-or” situation, we can go back a couple years to a JAMA Neurology paper by G.S. Bloom that cast ß-amyloid protein and tau in a “trigger and bullet” meta-phor. As the author noted in the abstract, “During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic proper-ties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop.”

For more information, visit www.DDN-News.com JULY 2018 | | DDNEWS 17NEUROSCIENCE/NEUROLOGY

� RO7105705, an anti-tau antibody in Phase 2 and developed in collaboration with Genentech under a 2012 licensing agreement

� Morphomer Tau, a small molecule in preclinical development and developed in-house

� PI-2620, a Tau-PET imaging agent developed in collaboration with Piramal Imaging under a 2014 licensing agreement.

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AC Immune is heavily invested in neurodegenerative research and conducted a key opinion leader luncheon last year at which experts weighed in on the importance of the tau protein both as a therapeutic and diagnostic target.

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the end of last year, when AC Immune SA, a clinical-stage biopharmaceutical company with a broad pipeline focused on neurodegenerative diseases, shared the top-level insights from a key opinion leader (KOL) luncheon meeting on the importance of tau as a target in Alzheimer’s disease and other neurodegenerative diseases. The meeting featured presentations by KOLs Dr. Khalid Iqbal of the New York State Institute for Basic Research in Developmental Disabilities and Dr. Michael Rafii of the University of California, San Diego, and the University of Southern California.

Iqbal highlighted the critical importance of tau as a therapeutic target in Alzheimer’s disease and other neurodegenerative diseases and how inhibition and prevention of the Tau pathology can potentially rescue the pathology of Alzheimer’s disease and cognitive impairment, commenting: “Neurodegeneration leads to tau pathology, and tau pathology leads to neurodegeneration. Where there is no tau pathology, there is no Alzheimer’s disease. Tau-based therapeutic approaches have significant potential to treat a range of neurodegenerative diseases.”

Rafii discussed tau-mediated pathology and the importance of tau diagnostics in people with Down syndrome, a population with a genetic predisposition to develop Alzheimer’s-related neuropathological changes, including ß-amyloid plaques and tau tangles.

“Biomarkers of Alzheimer’s, including Tau-PET, can be readily studied in adults with Down syndrome as in other preclinical AD populations,” Rafii noted. “By understanding the link between Alzheimer’s and Down syndrome, we may not only be able to help the Down syndrome community, but the broader population as well. People with Down syndrome are an important population to study as we enhance our understanding of early intervention and prevention of Alzheimer’s disease in general.”

Also at the KOL meeting, Dr. Andreas Muhs, chief scientific o�cer of AC Immune, highlighted the company’s relevant Tau programs:

� ACI-35, an anti-tau vaccine in Phase 1b and developed in collaboration with Jans-sen Pharmaceuticals under a 2014 licensing agreement

“We are excited to publish further scientific evidence that establishes a structural biology basis for Cantabio’s tau small-molecule pharmacological chaperone program, which aims to prevent and reduce aggregation of tau protein as a therapeutic strategy for Alzheimer’s disease and other tauopathies such as concussion related chronic traumatic encephalopathy.”Dr. Gergely Toth, CEO of Cantabio Pharmaceuticals

TAU CONTINUED ON PAGE 18

NEUROSCIENCE/NEUROLOGY18 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.com

Picking apart PDA roundup of recent news on R&D related to Parkinson’s diseaseBY JEFFREY BOULEY

NEW YORK—A recent study from researchers at the Icahn School of Medicine at Mount Sinai provides new insights into a link between inflammatory bowel disease (IBD) and Parkinson’s disease (PD), and may have significant implications for the treatment and prevention of PD.

The study, published in JAMA Neurology, shows that individuals with IBD are at a 28-percent higher risk of developing PD than those without IBD. However, if they are treated with anti-tumor necrosis factor alpha (anti-TNFα) therapy, a monoclonal antibody that is commonly used to control inflammation in IBD patients, then their risk of developing Parkinson’s goes down significantly, and becomes even lower than that in the general population.

These new insights may allow for better screening of IBD patients for Parkinson’s disease, given that IBD onset usually precedes that of PD by decades, and they also offer evidence to support exploring anti-TNFα therapy to prevent PD in at-risk individuals.

While previous research had shown genetic and functional connections between IBD and Parkinson’s disease, clinical evidence linking the two has been scarce. The authors of the study previously identified a number of genetic variants that contributed to either an increased risk of both PD and of Crohn’s disease, a type of IBD, or a decreased risk of both diseases, which prompted them to further study the co-occurrence of the two diseases.

“Systemic inflammation is a major component of IBD, and it’s also thought to contribute to the neuronal inflammation found in Parkinson’s disease,” explained Inga Peter, a professor in the Department of Genetics and Genomic Sciences at Mount Sinai and lead investigator in the study. “We wanted to determine if anti-TNFα therapy, could mitigate a patient’s risk in developing Parkinson’s disease.”

The Mount Sinai team found a 78-percent reduction in the incidence of Parkinson’s disease among IBD patients who were treated with anti-TNFα therapy when compared to those who were not.

It was previously thought that anti-TNFα therapies had limited e�ects on the central nervous system, the site where molecular mechanisms of PD are found, because the large molecules in the anti-TNFα compounds cannot independently pass through the blood-brain barrier. The outcomes of this study suggest that it may not be necessary for the drug to pass through the blood-brain barrier to treat or prevent inflammation within the central nervous system, or that the blood-brain barrier in patients with IBD may be compromised, allowing the large molecules of the compound to pass through.

Preclinical evidence for DJ-1 protein targetingSAN FRANCISCO—Cantabio Pharmaceuticals Inc. recently presented results of the company’s DJ-1 protein-targeting small-

molecule pharmacological chaperone therapeutic program at the Neuro4D Conference (Advances in Drug Discovery for Proteopathic Neurodegenerative Diseases) in Mainz, Germany.

Loss of DJ-1 protein function has been linked to the onset of a variety of diseases, such as Parkinson’s disease, Alzheimer’s disease, stroke, amyotrophic lateral sclerosis, chronic obstructive pulmonary disease and type 2 diabetes. The DJ-1 protein is considered to be one of the primary therapeutic targets for Parkinson’s disease, as it is genetically linked to the onset of familial PD.

The presentations described the positive therapeutic activity in cellular models and in an MPTP mouse model of PD of Cantabio’s novel DJ-1 candidates.

“We are excited to present positive in-vivo e�cacy results of one of our orally bioavailable DJ-1 protein targeting small-molecule pharmacological chaperones. This drug candidate has shown excellent drug-like characteristics and its significant protective function in a recognized mammalian disease model for Parkinson’s disease is a major step forward for Cantabio’s drug development programs,” said Cantabio’s CEO, Dr. Gergely Toth. “We are looking forward to testing this molecule in further disease models of Parkinson’s and Alzheimer’s disease and to the further development of multiple candidates from our other programs. These results also provide excellent validation of our in-house DJ-1 drug discovery platform’s ability to generate prospective drug candidates and for our DJ-1 targeting therapeutic program’s potential for becoming a disease-modifying therapeutic for Parkinson’s and Alzheimer’s disease.”

Axovant licenses investigational gene therapyBASEL, Switzerland—Axovant Sciences in early June announced that it had licensed the exclusive worldwide rights to develop and commercialize OXB-102, now AXO-Lenti-PD, from Oxford BioMedica. AXO-Lenti-PD is an investigational gene therapy for Parkinson’s disease that delivers three genes encoding a critical set of enzymes required for dopamine synthesis in the brain. Oxford BioMedica is a world leader in lentiviral vector product development and manufacturing, and will be the clinical and commercial supplier of AXO-Lenti-PD. Axovant expects to initiate a Phase 1/2 dose escalation study of AXO-Lenti-PD in patients with advanced PD by the end of 2018.

Under the terms of the license agreement with Oxford BioMedica, Axovant obtained rights to AXO-Lenti-PD, as well as its predecessor product ProSavin, for an initial payment of $30 million in cash, $5 million of which will be applied as a credit against the process development work and clinical supply that Oxford BioMedica will provide to Axovant. Oxford BioMedica is also eligible to receive additional development, regulatory and commercial milestone payments potentially in excess of $812 million, and tiered royalties on net sales of AXO-Lenti-PD, if approved. Roivant has agreed to purchase $25 million of Axovant common shares, which will support the clinical development of AXO-Lenti-PD and additional business development activities. �

e�ectively together to achieve the common goal of an approved disease-modifying therapeutic and earlier diagnosis of Alzheimer’s disease—one of society’s biggest challenges of the century,” said Prof. Andrea Pfeifer, CEO of AC Immune.

Potential monotherapy?Also late in 2017, TauRx Therapeutics Ltd. reported the full results from its second Phase 3 clinical study of LMTX, a tau aggregation inhibitor for Alzheimer’s disease, which were published online in the Journal of Alzheimer’s Disease. The company noted that results from this study (TRx-237-005) are consistent with those from the first Phase 3 study, recently published in The Lancet in mild to moderate Alzheimer’s disease, in supporting the hypothesis that LMTX might be e�ective as monotherapy at a dose as low as 4 mg twice daily.

The results of the earlier study showed significant differences in favor of two higher doses of LMTX (75 mg and 125 mg twice daily) when taken as monotherapy compared with the intended 4 mg control dose taken as monotherapy or as add-on therapy to currently approved treatments for AD in prespecified post-hoc analyses. In a further analysis, the same di�erence in favor of monotherapy compared with add-on treatment was found in patients taking the 4 mg twice-daily dose.

According to TauRx, in both the LMTX monotherapy and add-on therapy groups, whole brain atrophy (measured via MRI scans) initially progressed as expected for patients with mild Alzheimer’s disease. However, after nine months of treatment, the annualized rate of whole brain atrophy in monotherapy patients reduced significantly and became typical of that reported in normal elderly controls without Alzheimer’s disease. The comparable rate seen in the add-on therapy group progressed as reported for patients with mild Alzheimer’s disease.

And early this year, the company reported preclinical study results,

published online in Frontiers in Molecular Neuroscience, showing that LMTM, the active pharmaceutical ingredient in the LMTX product developed for the treatment of Alzheimer’s disease, may also be useful for the treatment of Parkinson’s disease.

It is worth noting that in 2016, there was some significant disagreement regarding LMTM when Phase 3 results were presented showing that the drug missed its co-primary endpoints of slowing cognitive and functional decline in mild to moderate AD. Some had argued that the placebo and drug results were nearly identical and, as a commentator on the Alzforum website argued, a scientist involved in the trial presented “a subgroup analysis that held no statistical credence yet purported to show a strong benefit on cognition and brain atrophy.”

Some other takes around the same time contended that LMTM might not benefit AD patients who are receiving standard of care but, as a monotherapy, the drug might stabilize cognition and reduce brain atrophy. �EDITCONNECT: E071832

TAUCONTINUED FROM PAGE 17

Cantabio researchers recently published evidence that native monomeric tau can be a viable target for drug-like small molecules despite its heterogeneous structure.

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“By understanding the link between Alzheimer’s and Down syndrome, we may not only be able to help the Down syndrome community, but the broader population as well. People with Down syndrome are an important population to study as we enhance our understanding of early intervention and prevention of Alzheimer’s disease in general.”Dr. Michael Rafii of UC San Diego and USC

For more information, visit www.DDN-News.com JULY 2018 | | DDNEWS 19NEUROSCIENCE/NEUROLOGY

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Study may reveal why people with the APOE4 gene have higher risk of the diseaseBY ANNE TRAFTON, MIT NEWS OFFICE

CAMBRIDGE, Mass.—People with a gene vari-ant called APOE4 have a higher risk of devel-oping late-onset Alzheimer’s disease; in fact, APOE4 is three times more common among Alzheimer’s patients than it is among the general population. However, little is known about why this version of the APOE gene, which is normally involved in metabolism and transport of fatty molecules such as cho-lesterol, confers higher risk for Alzheimer’s.

To shed light on this question, MIT neuro-scientists have performed a comprehensive study of APOE4 and the more common form of the gene, APOE3. Studying brain cells derived from a type of induced human stem cells, the researchers found that APOE4 pro-motes the accumulation of the beta amyloid proteins that cause the characteristic plaques seen in the brains of Alzheimer’s patients.

“APOE4 influences every cell type that we studied, to facilitate the development of Alzheimer’s pathology, especially amyloid accumulation,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study.

The researchers also found that they could eliminate the signs of Alzheimer’s in brain cells with APOE4 by editing the gene to turn it into the APOE3 variant.

Picower Institute Research Scientist Yuan-Ta Lin and former postdoc Jinsoo Seo are the lead authors of the paper, which appears in the May 31 online edition of Neuron.

Amyloid accumulationAPOE, also called apolipoprotein E, comes in three variants, known as 2, 3 and 4. APOE binds to cholesterol and lipids in cells’ environments, enabling the cells to absorb the lipids. In the brain, cells known as astrocytes produce lipids, which are then secreted and taken up by neurons with the help of APOE.

Among the general population, about 8 percent of people have APOE2, 78 percent have APOE3 and 14 percent have APOE4. However, among people with late-onset, nonfamilial Alzheimer’s, which accounts for 95 percent of all cases, the profile is very di�erent: only 4 percent have APOE2, and the percentage with APOE3 drops to 60 percent. APOE4 shows a dramatic increase—37 percent of late-onset Alzheimer’s patients

Neuroscientists discover roles of AD-linked gene

carry this version of the gene.“APOE4 is by far the most significant risk

gene for late-onset, sporadic Alzheimer’s disease,” Tsai says. “However, despite that, there really has not been a whole lot of research done on it. We still don’t have a very good idea of why APOE4 increases the disease risk.”

Previous studies have shown that people with the APOE4 gene have higher levels of amyloid proteins, but little is known about why that is.

In this study, the MIT team set out to answer that question using human induced pluripotent stem cells—stem cells derived from skin or other cell types. They were able to stimulate those stem cells to di�erentiate into three different types of brain cells: neurons, astrocytes and microglia.

Using the gene-editing system CRISPR/Cas9, the researchers genetically converted APOE3 in stem cells derived from a healthy

subject to APOE4. Because the cells were genetically identical except for the APOE gene, any differences seen between them could be attributed to that gene.

In neurons, the researchers found that cells expressing APOE3 and APOE4 di�ered in the expression of hundreds of genes—about 250 genes went down and 190 went up in cells with APOE4. In astrocytes, the numbers were even higher, and they were highest of all in microglia: in APOE4 microglia, more than 1,100 genes showed reduced activity, while 300 became more active.

These genetic changes also translated to di�erences in cell behavior. Neurons with APOE4 formed more synapses, and they secreted higher levels of amyloid protein.

In APOE4 astrocytes, the researchers found that cholesterol metabolism was highly dysregulated. The cells produced twice as much cholesterol as APOE3 astrocytes, and their ability to remove amyloid proteins from

their surroundings was dramatically impaired.Microglia were similarly a�ected. These

cells, whose normal function is to help remove foreign matter, including amyloid proteins and pathogens such as bacteria, became much slower at this task when they had the APOE4 gene.

The researchers also found that they could reverse most of these effects by using CRISPR/Cas9 to convert the APOE4 gene to APOE3 in brain cells derived from induced stem cells from a patient with late-onset Alzheimer’s disease.

Disrupting cell behaviorIn another experiment, the researchers created three-dimensional “organoids,” or miniature brains, from cells with genes that are known to cause early-onset Alzheimer’s. These organoids had high levels of amyloid aggregates, but when they were exposed to APOE3 microglia, most of the aggregates were cleared away. In contrast, APOE4 microglia did not e�ciently clear the aggregates.

Tsai said she believes that APOE4 may disrupt specific signaling pathways within brain cells, leading to the changes in behavior that the researchers saw in this study.

“From this gene expression profiling, we can narrow down to certain signaling pathways that are dysregulated by APOE4,” she says. “I think that this definitely can reveal potential targets for therapeutic intervention.”

The findings also suggest that if gene-editing technology could be made to work in humans, which many biotechnology companies are now trying to achieve, it could o�er a way to treat Alzheimer’s patients who carry the APOE4 gene.

“If you can convert the gene from E4 to E3, a lot of the Alzheimer’s-associated characteristics can be diminished,” Tsai says. �

The APOE4 variant of the APOE gene is known to be associated with Alzheimer’s disease, but MIT researchers recently delved deeper to try to understand why that is the case.

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“APOE4 influences every cell type that we studied, to facilitate the development of Alzheimer’s pathology, especially amyloid accumulation.”Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory

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PRECLINICAL20 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.com

CRV431 tackles liver fibrosisEDISON, N.J.—ContraVir Pharmaceuticals Inc. has reported that a preclinical study of CRV431, a cyclophilin inhibitor, appeared to decrease the extent of fibrosis in an animal model by 46 percent compared to a control. Mice were treated with streptozotocin, then fed a high-fat diet. CRV431 was administered orally for eight weeks, during which time it had no effect on body weight, liver weight or blood glucose levels. Previous studies of the compound have shown it to have antiviral effects by reducing HBV DNA, surface antigen and other viral markers of HBV infections and/or liver disease.

“With these results, we have data indicating that CRV431 has an independent effect on reduc-ing the formation of fibrosis that is over and above the effects on the hepatitis B virus,” James Sapir-stein, CEO of ContraVir Pharmaceuticals, noted in a press release.

New implants to improve data collection, animal welfare

ST. PAUL, Minn. & HOLLISTON, Mass.—The second quarter of 2018 saw Data Sciences International, a subsidiary of Harvard Bioscience Inc., announce the launch of two telemetry implants: the Physio-Tel Digital L03 and L04. The implants record data from conscious, unrestrained lab animals and can record any combination of up to four biopotential channels (such as EEG, EMG or ECG), temperature and activity in large animal models.

Jeffrey Duchemin, president and CEO of Har-vard Bioscience, said, “DSI is committed to pro-viding solutions for researchers that can improve the collection of high-quality physiologic signals from unrestrained, conscious experimental ani-mals in a low-stress environment. DSI’s PhysioTel Digital platform has been adopted by research-ers involved with cardiovascular studies, and we anticipate its latest products will be an essential tool for scientists who aim to solve complex neu-rological diseases.”

IN THIS SECTIONAnimal modelsDo animal studies predict human safety? ............................ 20New implants to improve data collection, animal welfare ............. 20

Autoimmune/ inflammatory diseaseA unique mechanism of action for delivering IL-10 ....................................... 22

Liver diseaseCRV431 tackles liver fibrosis .................. 20

NeurologyMANF protein may ease TBI symptoms ...20

PainSignal stopper ........................................ 20

MANF protein may ease TBI symptomsMANF Therapeutics restarts IND-enabling work in light of new resultsBY RACHEL FLEHINGER

NEW YORK—MANF Therapeutics Inc., a subsidiary of Amarantus Bio-science Holdings named after the promising protein integral to its pri-mary research and indication, has announced the publication of a new article promising significant results in the treatment of traumatic brain inju-ry (TBI). The study, entitled “MANF prevents traumatic brain injury in rats by inhibiting inflammatory activation and protecting Blood Brain Barrier,” was published in World Neurosurgery by researchers at Anhui Medical Uni-versity and the University of Science & Technology of China Hefei. The results suggest that MANF may pro-vide noteworthy protection against long-term neurological e�ects of TBI.

MANF refers to a naturally occur-ring protein in the human body—mesencephalic-astrocyte-derived neu-rotrophic factor. MANF is considered a highly promising regenerative can-didate, showing positive outcomes on a number of orphan diseases includ-ing retinitis pigmentosa, Parkinson’s diseases, diabetes and Wolfram’s syndrome. MANF Therapeutics is currently looking at its potential for treatment of Alzheimer’s disease, myocardial infarction and antibiotic-induced ototoxicity (being toxic to the ear, namely the inner ear) in addition to the traumatic brain injury findings recently reported.

Research shows that MANF seems to work through the unfolded pro-tein response to reduce or prevent cell death following trauma or injury. According the company’s press release, “MANF provides neuroprotective e�ect against acute brain injury after TBI, via attenuating BBB disruption and intracranial neuroinflammation,

SIGNAL STOPPERMolecule blocks neuropathic pain without negative side e�ectsBY ILENE SCHNEIDER

BLOOMINGTON, Ind.—Neuropathic pain—the chronic, pathological pain that continues even when the cause of the pain has been removed—can be caused by damage to nerve cells, as well as by medicines used to treat cancer. This issue is very common, a�ecting 5 to 10 percent of people worldwide, and no cures or e�ective treatments are currently available. Chemotherapy-induced pain can be so intense that it causes some cancer patients to stop treatment and others to suf-fer damaging side e�ects.

A collaboration between research groups from Indiana University and the Turku Centre for Biotechnology in Finland has collaborated in discovering an experimen-tal molecule that appears to interrupt the signaling cascades in the body that cause multiple forms of neuropathic pain without producing unwanted side e�ects. The study was reported in the May 2018 issue of the journal Pain. The research was funded by the National Institutes of Health’s National Cancer Institute.

The researchers, who met at a Society for Neuroscience meeting, were led by Andrea

Hohmann of Indiana University and Michael Courtney from the Turku Centre for Bio-technology. Hohmann explained that the approach o�ers potential for maximizing the therapeutic e�cacy of novel inhibitors likely to exhibit favorable analgesic profiles without

SIGNAL CONTINUED ON PAGE 21

Do animal studies predict human safety?Study of FDA and EMA reports analyzes predictivity of animal-human relationship in relation to patient safetyBY MEL J. YEATES

NEW YORK—A big data analysis conducted by Elsevier has evaluated the ability of ani-mal studies to predict human safety. The study examined the consistency between preclinical animal testing and observations made in human clinical trials. The study ana-lyzed 1,637,449 adverse events reported for both humans and the five most commonly used animals in FDA and EMA regulatory documents for 3,290 approved drugs and formulations.

The results revealed that some animal tests are far more predictive of human response than others, depending on the species and symptom being reported. This finding, which has considerable implications for improving patient safety, could help pharmaceutical firms decide which tests are appropriate and which might be ruled out to reduce unneces-sary animal testing.

“All life-science companies have a desire to decrease animal testing, and with contin-ued pressure from governments, societies and animal welfare groups, pharmaceutical organizations are exploring ways to do that,” says Dr. Matthew Clark, director of scientific services at Elsevier.

“Through this study, Elsevier has demon-strated that applying a big data approach to very large data sets has potential for huge

ANIMAL CONTINUED ON PAGE 22 MANF CONTINUED ON PAGE 21

Indiana University (pictured here), along with the Turku Centre for Biotechnology in Finland, has collaborated in discovering an experimental molecule that appears to interrupt the signaling cascades in the body that cause multiple forms of neuropathic pain without producing unwanted side effects.

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the unwanted side effects of conventional treatments on motor function or memory.

The molecule described in the study tar-gets a glutamate receptor called N-methyl-D-aspartate receptor (NMDAR). Previ-ous experimental drugs used to block the NMDAR receptor caused side e�ects such as memory impairment and motor dysfunction, thus limiting their therapeutic potential. In the study, which was performed with mice, the designer molecule used did not cause negative side e�ects nor typical motor side e�ects observed with previous experimental molecules that directly target NMDARs.

According to Hohmann, chemotherapy-induced peripheral neuropathy, which can be permanent, limits life-saving anticancer treatment and negatively impacts quality of life. By understanding the critical signal-ing pathways involved in development and maintenance of the neuropathy, researchers can find therapeutic strategies to prevent or treat it. The NMDAR signaling complex plays a vital role in central sensitization of chronic pain. While NMDAR antagonists are e�ective in reducing pain sensitization, they disrupt normal physiological processes, such as motor function, memory and cognition. The NMDAR signaling complex consists of many protein partners including the scaf-fold postsynaptic density 95 kDA (PSD95) protein, the neuronal enzyme nitric oxide synthase (nNOS) and its adaptor protein NOS1AP. By disrupting specific steps down-stream of NMDAR activation, it is possible to reduce pain sensitization while eliminating side e�ects associated with upstream recep-tor blockade.

The study’s goal was to block signals caused by the binding of nNOS to the protein NOS1AP during the process of neurotrans-mission, as a new approach to treating chron-ic pain. NOS1AP is present in fine structures of living neurons, including structures that may be synaptic spines.

The team in Finland designed the mol-ecule after discovering that NOS1AP, which is downstream of nNOS, triggers several biological pathways that are associated with abnormal glutamate signaling, including neuropathic pain. That molecule gave the Indiana University group the tools to ask questions about suppressing pain, Hohmann explained.

The Indiana University group showed that an experimental molecule designed by the Turku group to prevent nNOS signaling to NOS1AP reduced two forms of neuropathic pain in rodents. These forms of pain usually develop because of the chemotherapeutic agent paclitaxel or nerve damage.

The treatment also disrupted markers of nociceptive signaling in the spinal cord when the test drug was injected at that site into mice.

“Importantly, the chemical that prevents this signaling did not cause the negative side e�ects observed in previous experiments,” Hohmann said. “Our studies suggest that the nNOS-NOS1AP interaction site is a previ-ously unrecognized target for pain therapies.”

“The results imply that the protein NOS1AP might be a valuable novel target in the development of more e�ective medicines to treat neuropathic pain,” Courtney added. “NOS1AP should be studied in more detail to find the best way to prevent this protein from contributing to chronic pain.” �EDITCONNECT: E071812

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while the inhibition of NF-B signaling pathway could be a potential mecha-nism.” In other words, after a brain injury, heightened amounts of the MANF protein lessened the egregious e�ects of impact on the blood-brain-barrier (BBB), and thus lowered the risks of cerebral edema and inflammation.

Scientists found that in immediate aftermath of traumatic brain injury in rats, the body naturally flooded the brain with endogenous MANF. By adding a high dose of recombinant human MANF, the impact of TBI was dramatically reduced. Specifi-cally, MRI’s conducted after the injury and following a high dose of exogenously produced MANF indicated a lower brain-water-content measurement. Likewise, the testing showed an increase in their modified Garcia score, which measures six indices of sensorimotor deficits, while also alleviating the blood-brain barrier per-meability—a finding of particular interest to the scientists.

“The fact that MANF acts to restore the blood-brain barrier is highly consequen-tial in terms of restoring one of the body’s crucial protective mechanisms. Further studies are required to understand how

this mechanism would a�ect drug develop-ment,” asserts Gerald Commissiong, CEO of MANF Therapeutics.

MANF was initially identified by parent company Amarantus’ own platform, the PhenoGuard protein discovery engine. In 2017, Amarantus formed MANF Therapeu-tics as a wholly owned subsidiary to con-tinue preclinical development of MANF, initially for the treatment of ophthalmo-logical disorders. Amarantus entered into a manufacturing agreement with Catal-ent Pharma Solutions for clinical-grade production of MANF, with Catalent pro-viding all cell line engineering, process development and clinical Good Manufac-turing Practices (cGMP) biomanufactur-ing activities. Through that partnership, MANF Therapeutics had the tools for the rapid development of a high-performance cell line expressing the MANF protein, thus enabling them to scale up for cGMP production.

The MANF protein has proven to be e�ective in managing other diseases attrib-uted to inflammatory response, and had begun Investigational New Drug (IND)-enabling development to utilize MANF for ophthalmological conditions, includ-ing RAO and retinitis pigmentosa, back in 2016. It has already been granted orphan drug designations from the FDA for these

conditions and has shown promise as a potential treatment for glaucoma, Parkin-son’s, Alzheimer’s, diabetes and cardiovas-cular issues such as stroke and myocardial infarction. The results regarding its use in treating TBI, however, suggest a potential new indication, and has prompted the company to restart the IND preparations. Amarantus has retained regulatory exper-tise to identify the fastest path to human proof-of-concept data by evaluating well-respected regulatory pathways available worldwide and is targeting the initiation of first-in-man clinical studies for MANF in 2019.

“These findings mean we will re-initiate cGMP manufacturing for MANF,” states Commissiong. “This news is important because it speaks to MANF’s broad poten-tial to protect brain cells from injury, and outlines key mechanisms into MANF’s biological function. Amarantus is devel-oping the therapeutic protein MANF for various indications of the central nervous system, primarily ophthalmology and Parkinson’s. We may expand that list of indications over time as resources become available.” �EDITCONNECT: E071814

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The MANF protein was discovered by MANF Therapeutics’ chief scientific o�cer, Dr. John Commissiong, thanks to AMBS’ proprietary discovery engine PhenoGuard. MANF Therapeutics is developing MANF-based products as treatments for brain and ophthalmic disorders, and owns IP rights and licenses from a number of universities related to the development of the protein.

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“These findings mean we will re-initiate cGMP manufacturing for MANF. This news is important because it speaks to MANF’s broad potential to protect brain cells from injury, and outlines key mechanisms into MANF’s biological function.”Gerald Commissiong, CEO of MANF Therapeutics

PRECLINICAL22 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.com

benefits—in this case, in reducing animal testing and improving patient safety. The findings from the study have consider-able implications for improving patient safety and can help pharmaceutical teams decide which animal tests are appropriate throughout drug development and testing, and which might be ruled out as unneces-sarily testing on animals,” continues Clark. “Elsevier is pleased to be playing a role in directly addressing this important issue, by not just publishing research but nor-malizing data from di�erent sources and performing analytics.”

One of the main conclusions of the study, published in the Journal of Regulatory Toxicol-ogy and Pharmacology, is that when it comes to cardiac events such as arrhythmia, there is a high degree of concordance between ani-mal and human responses. However, at the other end of the spectrum, some events iden-tified have never been reported in a human, and some events observed in humans have never been reported in an animal study.

As a result of the analysis, Elsevier has created a dataset that will o�er researchers a way to more accurately predict human risk, based on parameters such as species, adverse event and drug formulation, allow-ing them to design safer and more robust clinical trials. This knowledge of which spe-cies are most predictive for each adverse event is key to avoiding safety issues.

“This kind of analysis has important implications for safety of patients, as it allows researchers to more accurately esti-mate the implied risk to humans from a given observed e�ect in an animal. With access to this kind of data and understand-ing, future researchers can design safer clinical trials,” Clark notes.

“Just because there are no findings in

animals, this often does not mean that no adverse events will occur when the trial is undertaken on humans,” he adds. “The study showed that, for many adverse events, the negative predictive value is low. There is an entire class of events that require verbal descriptions of sensation—head-ache and nausea are among the most com-mon—which are not well represented in animal studies. One of the most important issues seen in humans but not animals is cholestatic hepatitis. There is also a cluster of other liver issues not represented well in animal models, which have not been reported in animal studies in drug approv-al documents. This points out that human biology has some unique points, especially around the liver, and research is continu-ing to better understand and predict drug-induced liver injury.”

Clark tells DDNews that the data analysis was performed over the span of a year. “The discussions about what should be done and how the results should be interpreted took the largest period of time. Our team loaded the data, and the preparation of the actual queries and data analytics was refined dur-

ing that time. Once the queries and analytics had been defined, re-running the analysis to generate the updates and looking at the selected subsets was done in under an hour.”

The statistical study was carried out in conjunction with the Bayer AG Pharma-ceuticals Investigational Toxicology depart-ment and is the broadest published to date using publicly available data.

Elsevier will continue to develop the analysis it has created as part of this study by working on projects with customers and their proprietary datasets, and the team also plans to add additional datasets on dosing to further improve accuracy. The full study, “A Big Data Approach to the Concordance of the Toxicity of Pharmaceuticals in Animals and Humans,” has also been made available through open access via ScienceDirect.

“Elsevier works very closely with phar-maceutical researchers worldwide, dis-cussing issues faced and how we can help address them,” Clark points out. “As a result, this study was launched after sev-eral discussions with Bayer identified this topic as a significant issue—and one which Elsevier had the data to address and Bayer’s

toxicology expertise could support. Bayer also has an ongoing interest in assessing how predictive animal studies are of human outcomes, as one of the best ways to reduce the amount of animal testing is by using studies that only have a high predictivity of outcomes.”

“Already, the industry is committed to reducing the number of animal tests that take place, yet standards regarding patient safety are paramount. Our study demon-strates how big data can help navigate that dilemma by building trials that account for potential risks and can better refine the stratification of patients for the trial,” he remarks. “It is possible to reduce animal testing by focusing on those species that best predict human risks for the adverse events in question. Moreover, these data are key to supporting the shift to adopt evidence-based medicine. My hope is that the life-science industry notes this kind of big data analysis that shows how the con-tinued application of technology will help us to make even more safe and humane breakthroughs in the future.” �EDITCONNECT: E071813

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A unique mechanism of action for delivering IL-10APVO210 holds promise in the treatment of autoimmune diseases BY DDNEWS STAFF

SEATTLE—Aptevo Therapeutics Inc., a bio-technology company focused on developing novel oncology and hematology therapeutics, recently announced the publication of pre-clinical data in Frontiers in Immunology. The data highlight the activity of APVO210 as a potent and selective immunosuppressive agent with potential utility in the treatment of multiple autoimmune and inflammatory conditions, such as psoriasis, inflammatory bowel disease, rheumatoid arthritis, graft-versus-host disease and lupus, as well as other diseases where there is antigen-driven activa-tion of T lymphocyte-mediated disease.

APVO210 is a bispecific antibody candi-date built on Aptevo’s ADAPTIR therapeutic protein platform. It is designed to modulate and suppress pathological immune activa-tion without lymphocyte activation by selec-tively delivering a modified form of IL-10 to antigen-presenting cells via CD86 without stimulating IL-10 responses on resting and activated lymphocytes.

Cytokines are pleiotropic and function by promoting or suppressing a variety of cellular

functions, including inflammatory respons-es. Unregulated inflammation is believed to be responsible for a variety of chronic and acute inflammatory and autoimmune disor-ders. The cytokine IL-10 is known to play a key role in suppressing inflammation and, as a result, has been studied extensively by other companies in di�erent clinical trials for autoimmune and inflammatory disorders. Unfortunately, the results of these studies

have been disappointing. This may be due to the undesired stimulatory properties of IL-10, which exerts stimulatory e�ects on lympho-cytes, promoting B-cell proliferation, immu-noglobulin production and cytotoxic T cell function, thus potentially reducing its overall therapeutic utility for immunosuppression.

Conversely, APVO210 is designed to deliver a modified form of IL-10 to suppress inflammation and immune activation with-

out lymphocyte stimulation. Importantly, APVO210 also retains the ability to mediate the di�erentiation of tolerogenic dendritic cells and antigen-specific T regulatory cells (Tr1).

“There is a growing body of data to support APVO210 as a novel, first-in-class targeted cytokine immunotherapy,” said Dr. Jane Gross, chief scientific officer for Aptevo. “Our data highlight the unique attributes of

this molecule, demonstrating its ability in vitro to selectively target antigen presenting cells without triggering IL-10R signaling in T or B cells. If these results are confirmed in the clinic, APVO210 could represent an improved version of IL-10 by maintaining its suppressive properties while reducing the stimulatory properties observed with other investigational IL-10 therapies. Most impor-tantly, our data demonstrate that APVO210

induces tolerogenic dendritic cells and anti-gen-specific T regulatory cells, which may also act to suppress autoimmune and inflam-matory disease processes.”

“We believe APVO210 represents a potentially groundbreaking new approach in immune-suppressive therapy with impli-cations for the treatment of a wide variety of IL-10-mediated diseases characterized by pathological immune activation and inflam-mation,” continued Gross. “The preclinical data published in Frontiers in Immunology demonstrate the potent immunomodula-tory properties of APVO210, showing that it can selectively suppress antigen presenting function and T cell activation and induce regulatory dendritic cell production without stimulating the function of naïve or activated B and T cells.”

“We are very encouraged by the mount-ing body of evidence for APVO210 support-ing targeted cytokine delivery as a novel therapeutic approach for inflammatory and autoimmune diseases,” said Marvin L. White, president and CEO of Aptevo. “We have submitted our pre-IND package to the FDA and have received their feedback. Based on this, we are pleased to rea�rm our previous guidance that we anticipate filing an IND for APVO210 in the fourth quarter of 2018.” �EDITCONNECT: E071815

“There is a growing body of data to support APVO210 as a novel, first-in-class targeted cytokine immunotherapy. “Our data highlight the unique attributes of this molecule, demonstrating its ability in vitro to selectively target antigen presenting cells without triggering IL-10R signaling in T or B cells.”Dr. Jane Gross, chief scientific o�cer for Aptevo

Recently published research indicates that some animal tests are far more predictive of human response than others, depending on the species and symptom being reported, and that better data analysis may help make animal testing more accurate and efficient.

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CLINICAL TRIALS

IN THIS SECTIONInfectious diseaseNew investment in treating superbugs ... 23Paratek highlights omadacycline efficacy ............................ 23

Inflammatory diseaseIMO-8400 falls short of primary endpoint ................................ 23

MigraineThe new migraine muffler(s) .................. 23

NeurologyCannabis vs. Lennox-Gastaut syndrome ... 24REVERSE-ing vision loss ......................... 23

REVERSE-ing vision lossGenSight’s GS010 improves vision in Phase 3 trial of patients with rare genetic diseaseBY KELSEY KAUSTINEN

PARIS—Additional results shared in June from GenSight Biologics’ Phase 3 clinical trial, REVERSE, are build-ing on previous encouraging data for its GS010 compound. REVERSE is a randomized, double-masked, sham-controlled pivotal Phase 3 trial evalu-ating the e�cacy of a single intravit-real injection of GS010 (rAAV2/2-ND4) in 37 Leber hereditary optic neuropathy (LHON) patients with the G11778A mutation in the mito-chondrial ND4 gene.

LHON is a rare maternally inher-ited mitochondrial genetic disease in which the degeneration of retinal

New investment in treating superbugsMelinta Therapeutics seeks to move investigational pyrrolocytosine compounds into clinical stageBY RACHEL FLEHINGER

NEW HAVEN, Conn.—Backed by funding from CARB-X, Melinta Therapeutics is seek-ing a prime compound candidate to begin Investigational New Drug (IND) testing to treat drug-resistant bacterial infections. Development will continue on the company’s investigational pyrrolocytosine compounds, which are a novel class of antibiotics target-ing bacterial ribosomes in entirely new ways.

“Our structure-based design e�orts to cre-ate and optimize the pyrrolocytosine class of antibiotics have shown exciting promise, with several compounds demonstrating comprehensive activity and preclinical e�ect across the full set of bacterial ‘superbugs,’” said Dr. Erin Du�y, chief scientific o�cer at Melinta. “We believe this new class of antibi-otics could be transformational in the fight against these urgent threats. The support and

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THE NEW MIGRAINE MUFFLER(S)Allergan’s oral CGRP receptor antagonist demonstrates robust efficacy and safety in episodic migraine preventionBY MEL J. YEATES

DUBLIN—In early June, Allergan plc announced positive results from CGP-MD-01, a Phase 2b/3 clinical trial evaluating the e�cacy, safety and tolerability of orally administered atogepant. All active treatment arms of atogepant met the primary endpoint across all doses and dose regimens, with a statistically significant reduction from base-line in monthly migraine/probable migraine (MPM) headache days in patients with epi-sodic migraine treated with atogepant com-pared with placebo for 12 weeks.

Atogepant is Allergan’s second orally-

administered investigational calcitonin gene-related peptide (CGRP) receptor antagonist in development for migraine prevention. Atogepant follows ubrogepant, Allergan’s first oral investigational CGRP antagonist for the acute treatment of migraine, which reported two positive Phase 3 pivotal trial results ear-lier this year. Allergan will continue with its Phase 3 program for atogepant, following dis-cussions with regulatory authorities.

“We are extremely pleased to share these positive results for atogepant—our first Phase 2b/3 study in episodic migraine—which

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Paratek highlights omadacycline e cacy

BOSTON—Biopharma company Paratek Pharma-ceuticals Inc. recently shared a new analysis of its Phase 3 OPTIC study of omadacycline vs. moxifloxacin in treating community-acquired bacterial pneumonia, with the results presented at this year’s American Thoracic Society 2018 International Conference. Efficacy results for the study were presented by measurements of disease severity, and similar high response rates were seen for the early clinical response and post-therapy evaluation endpoints in both treatment groups regardless of disease severity.

“This analysis underscores that across the range of disease severity studied, omadacycline demonstrated high rates of clinical success at the early response timepoint in hospitalized CABP patients. The implications for clinical prac-tice are that achieving clinical success at an early timepoint could potentially result in transition from intravenous to oral omadacycline, allow-ing for hospital discharge,” said Paul McGovern, Paratek’s vice president of clinical affairs.

IMO-8400 falls short of primary endpoint

EXTON, Pa.—Idera Pharmaceuticals Inc.’s recent Phase 2 clinical trial of IMO-8400 in adult patients with dermatomyositis vs. placebo failed to meet its primary endpoint of a statistically significant reduction of patients’ Cutaneous Der-matomyositis Disease Area and Severity Index (CDASI) activity scores, the company announced. The trial sought to evaluate the safety, efficacy, tolerability, pharmacokinetics, pharmacodynam-ics, disease-specific autoantibodies and immu-nogenicity of IMO-8400 in the target population in 30 subjects. The participants received either once-weekly subcutaneous injections of 0.6 mg/kg of IMO-8400, 1.8 mg/kg of IMO-8400 or pla-cebo for up to 24 weeks. Mean CDASI activity scores were in the severe range for all cohorts, despite 17 of 30 participants having received background treatment with immunosuppressive drugs and/or systemic corticosteroids.

Melinta is making the push to get its pyrrolocytosine class of antibiotics into clinical trials soon, aided by funding from CARB-X.

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Allergan recently announced positive results from a Phase 2b/3 clinical trial of atogepant for migraine prevention and Phase 3 results related to ubrogepant for migraine episode treatment.

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Cannabis vs. Lennox-Gastaut syndromePositive results published in NEJM for clinical trial of Epidiolex in LGSBY DDNEWS STAFF

BOHEMIA, N.Y.—The New England Journal of Medicine (NEJM) recently published posi-tive results from a clinical trial of cannabi-diol in Lennox-Gastaut syndrome (LGS). Cannabidiol (CBD), a compound derived from the cannabis plant that does not pro-duce a “high,” has been an increasing focus of medical research in epilepsy. New study results from the clinical trial of Epidiolex, the lead cannabinoid product candidate for GW Pharmaceuticals, indicate that the compound significantly reduced the num-ber of seizures in patients with LGS.

Lennox-Gastaut syndrome is a rare and severe form of childhood-onset epilepsy that typically persists into adulthood. Despite currently available medications and a polytherapy approach to treatment, most individuals with LGS will continue to have lifelong, debilitating seizures.

The results of the study published in NEJM compared two doses of CBD to pla-cebo. Researchers reported a 41.9-percent reduction in “drop seizures” for those tak-ing a 20 mg/kg/d regimen and a 37.2-per-cent reduction in drop seizures in those on a 10 mg/kg/d regimen. Drop seizures are a type of seizure that results in a loss of muscle control and often leads to falls.

Researchers enrolled 225 patients ages 2 to 55 with LGS across 30 international sites in a randomized, double-blind, placebo-con-trolled trial to assess the e�cacy and safety

of cannabidiol in patients. Side e�ects were reported in 94 percent of the patients in the 20 mg CBD group, 84 percent in the 10 mg group, and 72 percent of those taking the placebo. Side e�ects were generally reported as mild or moderate in severity and included sleepiness, decreased appetite, diarrhea, upper respiratory infection, fever, vomit-ing, nasopharyngitis and status epilepticus.

“This landmark study provides data and evidence that Epidiolex can be an e�ective and safe treatment for seizures seen in patients with Lennox-Gastaut Syndrome,” said Dr. Anup Patel, chair of the LGS Foun-dation’s professional advisory board, chief of neurology at Nationwide Children’s Hos-pital and the study’s co-first author says.

Added Christina SanInocencio, executive director of the LGS Foundation: “LGS is devastating. While it is rare to achieve com-plete seizure control in this patient popula-tion, we sincerely hope that more safe and e�ective treatment options become avail-able so that patients and their families can have relief from unrelenting seizures.”

In other, unrelated news of cannabis extracts and journal publications, Phyto-plant Research S.L. participated in a first-ever pioneering collaborative project to investigate the ability of cannabinoid can-nabigerol (CBG), the molecular precursor of 9-tetrahydrocannabinol ( 9-THC) and cannabidiol (CBD). The study investi-gated the ability of the above to modulate the a�nity and functionality of type-1 and type-2 cannabinoid receptors (CB1 and CB2, respectively) and CB1–CB2 hetero-receptor complexes. It concluded that CBG significantly modulates CB2R- and CB1R/

CB2R-mediated endocannabinoid action, while the e�ects are weak in CB1R-express-ing cells.

The results of this research, published in the journal Frontiers in Pharmacology, suggest that CBG, a non-psychotropic phy-tocannabinoid, at nanomolar concentra-tions, is capable of acting as a competitive partial agonist of the CB2R. Regarding its action on CB1R, it is not possible to rule out a potential allosteric action, since the blocking of intracellular signalling of CB1R agonists occurs at concentrations of CBG lower than those necessary for its binding to the orthostatic site of the receptor.

These findings, the company says, “reopen the discussion” about the ability of other phytocannabinoids to bind directly to cannabinoid receptors as 9-THC does. In the study, researchers obtained results using different approaches that include the classic radioligand ligand binding, new fluorescent-based binding techniques and the measurement of signaling pathways. In these assays, CBG was able to modify

the a�nity and activity of selective CB1R and CB2R agonists at concentrations with physiological relevance (nanomolar).

The results also suggest that the partial agonism on the CB2R is regulated by the presence of the CB1R. However, more com-plex alternative scenarios cannot be ruled out as CBG may act on the orthosteric site of the CB1R protomer and as protean ago-nist of the CB1R protomer within the CB1R/CB2R heteromer.

“With these findings, we demonstrate clearly that CBG is active at the cannabi-noid receptors CB1 and CB2 and that it exerts its e�ects through those receptors. We have deepened the knowledge about phytocannabinoids and reopened the dis-cussion about the interaction between the Cannabis plant compounds,” said Dr. Xavier Nadal, director of the R&D–Extraction Department at Phytoplant Research, not-ing that the findings also point to signifi-cant potential for therapeutic uses of such compounds. �EDITCONNECT: E071819

resources available through CARB-X will provide important assistance as we move to advance one or more pyrrolocytosines into clinical development.”

Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) was established by the Biomedical Advanced Research and Development Authority (BARDA), a branch of the U.S. Department of Health and Human Services, to protect the country from a variety of chemical, biologi-cal, radiological and nuclear threats, as well as from pandemic influenza and emerging infectious diseases.

BARDA has not generally invested in products in advance of the establishment of

human data testing, but knew that the pre-clinical drug discovery pipeline was a cru-cial investment in finding new protections against biological threats. In collaboration with the Wellcome Trust, a global charitable foundation dedicated to improving health, BARDA funded CARB-X to help address the threat of antibiotic resistance that will com-plicate any public health emergency. CARB-X is now one of the world’s largest public-private partnerships focused on preclinical discovery and development of new antibac-terial products to help address the threat of antibiotic resistance.

Under the terms of the recently announced funding, Melinta will receive an initial $2.3 million to isolate its best candidate to prog-ress to IND testing with the FDA. Once the best option is chosen, which Melinta expects

to do by the end of the year, CARB-X will invest more money to help the company prep for IND testing—funding a battery of tests regarding safety, e�cacy and toxicology in rodents and a non-rodent species, and finally in-vitro and in-vivo testing. Successful IND testing will trigger another round of fund-ing to support the first-in-human testing program, with the possibility of up to $6.2 million to support the development.

What makes the Melinta candidates excit-ing is their focus on novel ways to target the bacterial ribosome in response to the alarm-ing emergence of bacteria that have devel-oped resistance to all existing drug classes. Currently these pathogens cause mortality rates approaching 50 percent in some infec-tion types, making “superbugs” the most serious hospital-treated bacterial threat. In addition, the causative pathogen is often unknown, creating the need for therapies that cover the full range of potential bacte-ria. Melinta’s pyrrolocytosines have demon-strated comprehensive activity across the full set of bacterial “superbugs.”

“We are very enthusiastic about our two top candidates. We have done a thorough

job with our candidate compounds, ascer-taining characterization and optimization activity, and we have very promising early safety results. But, of course, the proof is in the pudding,” asserts Du�y. “While we are very enthusiastic about our candidates pro-gressing with CARB-X support, we are also being good stewards of the program and the company by also continuing to develop new products behind our existing candidates in the event of an unanticipated setback.”

The ribosome has been the focus of ongo-ing research into its structure and workings for decades, as a prime target for immunolo-gists and drug discovery pipelines. Antibi-otics have proven e�ective against disease by attacking bacteria, disrupting their ribo-somes and thus preventing the bacteria’s ability to create proteins needed to survive and reproduce. However, bacteria have devel-oped resistance to many antibiotics that have targeted the same ribosome sites via similar mechanisms. While an estimated 60 to 70 percent of antibiotics work through target-ing ribosomes, Melinta is focused on finding novel approaches.

“We are exploring an entirely new class of antibiotics, using a novel target site that has not yet shown antibiotic resistance, and one that is not currently targeted by existing anti-biotics,” said Du�y. “We are using what we know, and an iterative structure design game to zoom in on the canvas, identify adjacent sites, and engineer an entirely new class of treatments.” �EDITCONNECT: E071816

MELINTACONTINUED FROM PAGE 23

“With these findings, we demonstrate clearly that CBG is active at the cannabinoid receptors CB1 and CB2 and that it exerts its e�ects through those receptors. We have deepened the knowledge about phytocannabinoids and reopened the discussion about the interaction between the Cannabis plant compounds.”Dr. Xavier Nadal of Phytoplant Research

“We have done a thorough job with our candidate compounds, ascertaining characterization and optimization activity, and we have very promising early safety results. But, of course, the proof is in the pudding. While we are very enthusiastic about our candidates progressing with CARB-X support, we are also being good stewards of the program and the company by also continuing to develop new products behind our existing candidates.”Dr. Erin Du�y, chief scientific o�cer at Melinta

CARB-X is one of the world’s largest public-private partnerships focused on discovery and development of new antibacterials to fight antibiotic resistance.

For more information, visit www.DDN-News.com JULY 2018 | | DDNEWS 25CLINICAL TRIALS

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ganglion cells leads to irreversible vision loss. Vision is suddenly lost in one eye, and the second eye is sequentially impaired—while 97 percent of patients experience bilateral involvement at less than one year of the beginning of their vision loss, a quarter of patients lose vision in both eyes simultane-ously. An estimated 1,400 to 1,500 individu-als lose their sight as a result of LHON in the United States and Europe every year.

GS010 uses a mitochondrial targeting sequence proprietary technology platform that resulted from research performed at the Institut de la Vision. When linked with a gene of interest, the platform can specifi-cally target defects in mitochondria using an AAV vector. The gene of interest is trans-ported into the cell, where it is expressed and produces a functional protein, which is then moved to the mitochondria to restore miss-ing/deficient mitochondrial function.

GenSight shared top-line results in April that demonstrated that the improvement of +11 ETDRS letters (-0.218 logMar on aver-age) in GS010-treated eyes, which was clini-cally significant, was matched by an improve-ment of +10 ETDRS letters (-0.211 LogMAR) in the sham-treated eyes. This fell short of the study’s primary endpoint of a +15 ETDRS letters di�erence in visual acuity between GS010- and sham-treated eyes.

The study did meet its secondary end-points based on spectral-domain optical coherence tomography (SD-OCT) param-eters, such as the change in ganglion cell layer macular volume from baseline to week 48, and the change in thickness of the tem-poral quadrant of the retinal nerve fiber layer from baseline to week 48. In addition, contrast sensitivity—per Pelli-Robson low-vision testing, a more sensitive method of evaluating visual function—almost doubled in GS010-treated eyes compared to sham-treated eyes.

“-0.21 log units is about 11 to 12 letters,” Dr. Robert Sergott, professor of neurology and ophthalmology at Thomas Je�erson Univer-sity, remarked in the webcast. “We set a high bar this trial—15 letters. If you get a 15-letter improvement, you double your visual angle, and regulatory agencies will allow you to label your product as one that gives vision improvement. The most common intravit-real injections are the anti-VEGF agents in the retinal community, for diabetes, macular degeneration of the wet variety. How much improvement do they get? Seven letters; this far exceeded [that].” Sergott is also the direc-tor of neuro-ophthalmology at Wills Eye Hos-pital and director of the William H. Annesley, Jr. EyeBrain Center.

The exact cause of the improvement in the sham-treated eyes is unknown, but it could be based in part on the fact that molecules can travel from one eye to the contralateral optic nerve, GenSight noted in its presenta-tion. The company hypothesizes that GS010 is systemically absorbed, and as such, a small-er dose makes its way to the untreated eye.

As noted in the presentation, this is the first demonstration of neuro-protection of both central nervous system AXONS and neurons in a human genetic disease.

“Examining the totality of the data, the REVERSE results suggest a therapy that may provide meaningful bilateral improve-ment of vision for our subjects, which is not what would be expected from the natural

REVERSECONTINUED FROM PAGE 23

history of this disease. Our planned follow-up of REVERSE subjects will enable us to monitor the observed continuous bilateral improvement after another year,” said Dr. Barrett Katz, chief medical o�cer of Gen-Sight. “GS010-treated eyes were significantly more likely to achieve vision of 20/200 or better when compared to sham-treated eyes. In addition, trends suggest a potentially larger benefit for subjects at earlier stages of LHON. We eagerly await what data from the RESCUE trial will show.”

Based on post-hoc analyses, it is thought

that patients at less advanced stages of LHON could see a better benefit from GS010. Par-ticipants who enrolled with better vision had better clinical outcomes, and 75 percent of GS010-treated eyes that saw improvement at week 48 were those that had had vision loss for less than nine months at the time of treatment.

Study subjects will be evaluated again at 96 weeks, with that data set to be available in the first quarter of 2019.

“The company—myself, and the manage-ment of this company—is absolutely deter-

mined to move this product into the approval process,” Bernard Gilly, co-founder and CEO of GenSight, said in the webcast, add-ing later: “We will move this forward to the European Agency, and to the FDA as well. We are going to make all e�ort possible to make this happen, to make this become a product available to the patient as soon as we can.” Per the presentation, GenSight intended to send out a Scientific Advice packet on June 5 to regulatory bodies, with a response expected in the third or fourth quarter. �EDITCONNECT: E071818

GenSight’s GS010 uses a mitochondrial targeting sequence proprietary technology platform—linked with a gene of interest, the platform can specifically target defects in mitochondria using an AAV vector. The company hopes the therapy will greatly benefit Leber hereditary optic neuropathy patients.

CLINICAL TRIALS26 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.com

represent a tremendous opportunity in the prevention of migraine, with a convenient oral dosage form that is currently unavail-able,” says David Nicholson, chief research and development o�cer at Allergan. “Atogepant is a novel, highly potent, orally-administered CGRP receptor antagonist in development for the prevention of migraine. CGRP and its receptors are expressed in regions of the nervous system associated with migraine pathophysiology.

“Antagonism of these receptors reduces pain and the other symptoms of migraine.Atogepant is chemically distinct from ubro-gepant, our orally-administered CGRP recep-tor antagonist for the acute treatment of migraine, with a higher potency and longer half-life, making it suitable for preventive treatment.”

In the CGP-MD-01 study, 834 U.S. adult patients were randomized to placebo, 10-mg once per day (QD), 30-mg QD, 30-mg BID, 60-mg QD or 60-mg twice per day (BID) and treated under double-blind conditions for 12 weeks, for the prevention of episodic migraine. E�cacy analyses were based on the modified intent-to-treat population of 795 patients.

The primary efficacy endpoint was the change from baseline in mean MPM headache days across the 12-week treatment period.

All active treatment groups demonstrat-

ed a statistically significant reduction from baseline in the primary e�cacy parameter (10 mg QD vs. placebo, p=0.0236; 30 mg QD vs. placebo, p=0.0390; 60 mg QD vs. placebo, p=0.0390; 30 mg BID vs. pla-cebo; p=0.0034, 60 mg BID vs. placebo, p=0.0031).

The reported p-values are adjusted for mul-tiple comparisons by controlling the overall type I error rate of the study at 5 percent, two-sided. Additional details and results from other endpoints are anticipated to be presented at upcoming scientific meetings.

“Atogepant is an oral CGRP antagonist that will allow us to address the preventive treat-ment of episodic migraine and subsequently, chronic migraine. Given its safety and heri-tage in chronic migraine as well as its unique mechanism of action and HCP administra-tion, we expect Botox to continue to the be the foundation of chronic migraine therapy,” notes Nicholson.

“Atogepant will provide an oral CGRP antagonistic option; this is important given the preference of many patients for an oral formulation,” he continues. “While atoge-pant will allow us to address the preventive treatment of episodic migraine and chronic migraine, many migraine sufferers will still experience breakthrough headaches on preventive medications, and there-fore, will need an acute treatment option such as ubrogepant. Allergan recognizes that many migraine su�erers may require multiple treatment options to help pre-vent migraines/headaches and also address

moments when they have a breakthrough headache/migraine.”

In the CGP-MD-01 trial, atogepant was well tolerated. The most common adverse events were nausea, fatigue, constipation, nasopharyngitis and urinary tract infection, which were reported with a frequency of more than 5 percent in at least one atoge-pant treatment arm and greater than placebo. There was no signal of hepatotoxicity with atogepant in this study with daily adminis-tration over 12 weeks. The liver safety profile for atogepant was similar when compared to placebo.

“The positive results from this study show that oral atogepant has a compelling profile relative to other treatment options on the market and in development for the preven-tion of migraine. We are excited about the prospects for this product and rapidly mov-ing to the next stage of development,” said Bill Meury, chief commercial o�cer at Aller-gan. “Allergan has one of the most innova-tive and deepest product lines for migraine in the industry, with Botox approved for the prevention of chronic migraine and oral atogepant and ubrogepant in development for the prevention and acute treatment of migraine.”

“These exciting results demonstrate the potential for atogepant for a broad spectrum of migraine patients. The e�cacy and safety across doses and dose regimens show prom-ise in a patient population with high unmet treatment needs,” said Dr. Peter Goadsby, a neurologist and professor at Kings College London and the University of California, San Francisco. “Results from this atogepant trial provide continued evidence for the clinical potential of oral CGRP antagonists and the substantial value of progressing research and developing new treatments for migraine patients.”

“We are excited about advancing our migraine program with two investigational small molecule oral CGRP receptor antago-nists ... These are expected to be the first oral CGRP receptor antagonists to market,” Nicholson concludes. �EDITCONNECT: E071817

UBROGEPANT ENTERS PHASE 3DU B L I N —In Ap r i l , A l l e rg a n announced positive results from ACHIEVE II (UBR-MD-02), the sec-ond of two pivotal Phase 3 clinical tri-als evaluating the e�cacy, safety and tolerability of orally administered ubrogepant 25 mg and 50 mg com-pared to placebo in a single migraine attack in adults. The ACHIEVE II study included 1,686 U.S. adult patients ran-domized to placebo, ubrogepant 25 mg and 50 mg, to treat a single migraine attack of moderate-to-severe headache intensity.

“We are pleased to share these posi-tive results from ACHIEVE II, our second Phase 3 study supporting the efficacy, safety, and tolerability of 50 mg ubrogepant. The consistency in response between both ACHIEVE I and ACHIEVE II provides further evidence that ubrogepant, an oral calcitonin gene-related peptide (CGRP) receptor antago-nist, o�ers a promising opportunity for the acute treatment of migraine,” said David Nicholson, chief research and development o�cer of Allergan.

Both dosages showed a statisti-cally significant greater percentage of ubrogepant patients achieving pain freedom at two hours after the initial dose as compared to placebo patients, and the 50 mg dose demonstrated a statistically significant greater per-centage of ubrogepant patients achiev-ing absence of the most bothersome migraine-associated symptom at two hours after the initial dose.

The 25 mg dose demonstrated improvement, but failed to demon-strate statistical significance.

The 50 mg dose of ubrogepant also showed a statistically significant greater percentage of patients achiev-ing pain relief at two hours, sustained pain relief from two to 24 hours, and sustained pain freedom from two to 24 hours after the initial dose as com-pared to placebo. In addition, ubro-gepant 50 mg also showed a statisti-cally significant greater percentage of patients achieving absence of photo-phobia and phonophobia at two hours after the initial dose as compared to placebo. Ubrogepant 25 mg failed to demonstrate statistical significance in these endpoints.

In ACHIEVE II, ubrogepant was well tolerated and demonstrated a safety profile similar to placebo. There was no signal of hepatotoxicity for ubrogepant.

The most common adverse events were nausea and dizziness, neither of which was reported with a frequency more than 2.5 percent. Additional results from this study are anticipated to be released at upcoming scientific meetings throughout 2018, and Aller-gan anticipates filing of a New Drug Application to the FDA in 2019. �

ALLERGANCONTINUED FROM PAGE 23

“We are extremely pleased to share these positive results for atogepant—our first Phase 2b/3 study in episodic migraine—which represent a tremendous opportunity in the prevention of migraine, with a convenient oral dosage form that is currently unavailable.”David Nicholson, chief research and development o�cer at Allergan

“The positive results from this study show that oral atogepant has a compelling profile relative to other treatment options on the market and in development for the prevention of migraine. We are excited about the prospects for this product and rapidly moving to the next stage of development,” said Bill Meury, chief commercial officer at Allergan.

For more information, visit www.DDN-News.com JULY 2018 | | DDNEWS 27

August 27–31, 2018 � Boston � Seaport World Trade Center

Be Boston-bound for erudition in the newest science, technology and techniques in cancer immunotherapyBY MEL J. YEATES

CAMBRIDGE HEALTHTECH Institute’s Immuno-Oncology Summit once again graces Boston with its sixth annual outing, though this time head-ing to the Seaport Hotel and World Trade Center. Situated

just across Fort Point Channel from down-town Boston, this year’s location is closer to the heart of the city, giving attendees myriad options for food, beverages and entertain-ment—when they aren’t busy gleaning new information.

So what’s new for the Immuno-Oncology Summit in 2018? Cambridge Healthtech Institute (CHI) notes that the summit now has a track on bispecific antibodies, as well

as a new neoantigen-targeted therapies track, which highlights personalized immunother-apy approaches. Immuno-oncology (IO) bio-markers coverage has been expanded to three days in order to cover predictive biomarkers, companion diagnostics and immune profil-ing, and coverage of adoptive T cell therapy has been expanded to three days to span dis-covery and development.

With an expanded exhibit hall and a new “Partnering Forum” to highlight emerging companies and investment opportunities, there’s plenty of opportunity to acquire new information, according to CHI, which emphasizes that the annual meeting focuses on the latest applied research. The compre-

SUMMIT CONTINUED ON PAGE 28

CAMBRIDGE HEALTHTECH INSTITUTE

Sixth Annual Immuno-Oncology SummitAugust 27–31, 2018BOSTON, SEAPORT WORLD TRADE CENTER

This year’s Immuno-Oncology Summit from Cambridge Healthtech Institute will be held at the Seaport Boston Hotel and World Trade Center.

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Informing immuno-oncologyCONFERENCE PROGRAMS

AUGUST 27-28

Immunomodulatory Therapeutic Antibodies for CancerEMERGING TARGETS, COMBINATIONS AND ANTIBODY ENGINEERING FOR NEXT-GENERATION IMMUNOTHERAPYFeatured Presentations:

� “New Immune Checkpoints for Human Cancer Immunotherapy” by Dr. Xingxing Zang of Albert Einstein College of Medicine

� “The Development of Agonist OX40 Monoclonal Antibody for Cancer Immunotherapy—Navigating the Bench to Bedside Journey” by Dr. Niranjan Yanamandra of GlaxoSmithKline

Rational Combination Cancer ImmunotherapyDATA DRIVES COMBINATORIAL STRATEGIES AND SUCCESSESFeatured Presentation:

� “Rational Combination of Immunotherapy, It Is Science, Not Logic” by Dr. Samir N. Khleif of Georgetown University Medical Center

Immuno-Oncology Biomarkers 1 QUANTITATIVE IMMUNE PROFILING AND IMMUNE MONITORINGFeatured Presentation:

� “Exosomes and Their Cargo as Tumor Biomarkers” by Dr. Samir Hanash of MD Anderson Cancer Center

Oncolytic Virus ImmunotherapyCOMMERCIALIZING THE EXCITING POTENTIAL OF ONCOLYTIC VIROTHERAPYFeatured Presentations:

� “Unlocking the Full Potential of Cancer Immunotherapy” by Dr. David Kirn of IGNITE Immunotherapy

Training Seminar 1CAR-T ENGINEERING FOR PROTEIN SCIENTISTS

� Dr. Dina Schneider of Lentigen Technology Inc.

AUGUST 28-29

Bispecific Antibodies for Cancer ImmunotherapyENGINEERING NEXT-GENERATION BIOTHERAPEUTICS IN IMMUNO-ONCOLOGYFeatured Presentations:

� “The Immune Force Awakens with Novel Bispecific Biotherapeutics: Challenges and Opportunities” by Dr. Rakesh Dixit of MedImmune

� “Bispecific Technology for Multiple Avenues of T Cell Activation” by Dr. John Desjarlais of Xencor

� “Mechanisms of Action for the Application of BiTE Antibodies in Immunotherapy Combinations” by Dr. Tara Arvedson of Amgen

Preclinical and Translational Immuno-OncologyPREDICTIVE PRECLINICAL MODELS AND TRANSLATIONAL STRATEGIES FOR CANCER IMMUNOTHERAPYFeatured Presentations:

� “3D Model to Mimic the Microenvironment” by Dr. Litao Zhang of Bristol-Myers Squibb

� “The Role of Genetically Engineered Mouse Models of Cancer in Profiling Novel Immune Targeting Therapies” by Dr. Elizabeth Hardaker of AstraZeneca

Immuno-Oncology Biomarkers 2 PREDICTIVE BIOMARKERS AND COMPANION DIAGNOSTICSFeatured Presentations:

� “Immunophenotyping to Differentiate Responder and Non-Responder Patients in Cancer Immunotherapy” by Dr. George Poste of Arizona State University

� “Predictive Biomarkers in Colon Cancer and Mismatch Repair Deficient Tumors” by Dr. Robert Anders of Johns Hopkins University

Adoptive T Cell Therapy 1: DiscoveryENGINEERING IMMUNE CELLS FOR MORE EFFECTIVE IMMUNOTHERAPIES

PROGRAM CONTINUED ON PAGE 28

28 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.comIO SUMMIT 2018

Visit www.ddncancer.com today and every day you need to know more about the world of oncology.

YOUR PORTALTO A PLACE OF MOREONCOLOGY AWARENESSONCOLOGY AWARENESS

There are many access points for news and knowledge of the world of oncology therapeutics R&D and diagnostics, but in your multitude of choices, don’t overlook DDNews’ Cancer Research News site.

Both overlapping with and distinct from the main DDNews website, Cancer Research News provides a doorway to news of those making strides in cancer drug development, from individual groundbreaking scientists to big-name companies; a gateway to recent research studies and academic efforts in oncology; and a pathway to fi nd pointed commentaries on issues related to cancer therapeutics and diagnostics.

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hensive five-day, 12-track pro-gram covers immunomodulatory antibody engineering, emerging immuno-oncology targets, combi-nation immunotherapy, preclini-cal and translational IO, predic-tive biomarkers and companion diagnostics, adoptive T cell ther-apy, oncolytic viruses and person-alized cancer vaccines.

“The Immuno-Oncology Sum-mit brings together a unique and international mix of large and medium pharmaceutical and bio-tech companies, leading univer-sities and clinical research insti-tutions, government and nation-al labs, CROs, emerging compa-nies and tool providers—making the summit a perfect meeting place to share experience, fos-ter collaborations across indus-try and academia and evaluate

emerging technologies,” CHI notes of the event. “Now in its sixth year, the IO Summit consistently delivers a cutting-edge agenda, 600-plus senior delegates and a sold-out exhibit hall. Please join us in Boston for comprehensive scientific cover-age and unparalleled networking opportunities.”

Also among the highlights this year is the plenary keynote ses-sion, which kicks o� on Tuesday,

Aug. 28, at 4:15 p.m. Dr. Jenni-fer Brogdon, the director of the Exploratory Immuno-Oncology operations at Novartis, will pres-ent “CAR-T Therapy for B Cell Malignancies,” followed by “Walk-ing on the Moon: Reflections on the Work of the Cancer Moonshot and the Future of the Biden Can-cer Initiative” by Dr. Gregory C. Simon, president of the Biden Cancer Initiative. �EDITCONNECT: E071833

Training Seminar 2IMMUNOLOGY FOR DRUG DISCOVERY SCIENTISTS

� Dr. Masha Fridkis-Hareli and Dr. Tatiana Novobrantseva of Verseau Therapeutics

AUGUST 30-31

Emerging Immuno-Oncology TargetsNOVEL TARGETS AND PATHWAYS FOR CANCER IMMUNOTHERAPY AND COMBINATIONSFeatured Presentation:

� “T Cells against Tumor Neoantigens: How Many Are Likely Needed for Clinical Efficacy and Can Contemporary Vaccines Get Us There?” by Dr. Andrew Allen of Gritstone Oncology

Personalized Cancer VaccinesFeatured Presentations:

� “Neoantigen-Based Vaccines for Breast Cancer” by Dr. Keith Knutson of the Mayo Clinic

� “Neoantigen Approaches as Personal and Precision Cancer Therapeutics” by Dr. Richard Gaynor of Neon Therapeutics

Neoantigen Targeted TherapiesPERSONALIZED CANCER IMMUNOTHERAPY IN THE GENOMIC ERAFeatured Presentations:

� “Neoantigen-Based Vaccines for Breast Cancer” by Dr. Keith Knutson of the Mayo Clinic

� “T Cells against Tumor Neoantigens: How Many Are Likely Needed for Clinical Efficacy and Can Contemporary Vaccines Get Us There?” by Dr. Andrew Allen of Gritstone Oncology

Adoptive T Cell Therapy 2: DevelopmentCASE STUDIES AND CLINICAL PROGRESS OF CAR, NK, TCR, AND TILFeatured Presentations:

� “A Translational Perspective of Development of Yescarta (Axicabtagene Ciloleucel), a First-in-Class CAR T Cell Product for Diffuse Large B Cell Lymphoma” by Dr. Adrian Bot of Kite, a Gilead Company

� “Stress-Resistant T Cell Therapy for Solid Tumors” by Dr. Prasad S. Adusumilli of Memorial Sloan Kettering Cancer Center

� “Tricked-Out CARs: Next-Generation Approaches to Enhance and Optimize CAR T Cell Function” by Dr. Benjamin Boyerinas of bluebird bio

Immuno-Oncology Investing & Partnering ForumFACILITATING PARTNERING, FUNDING & INVESTMENT TO ADVANCE IMMUNO-ONCOLOGY DRUGS

� “State of the Industry Keynote Presentation” by Dr. Ilan Zipkin of the Parker Institute for Cancer Immunotherapy

SUMMITCONTINUED FROM PAGE 27

For more information, visit www.DDN-News.com JULY 2018 | | DDNEWS 29

THE FIRST OF THEIR KIND

Immuno-Oncology NewsA cancer news feature to accompany our IO Summit 2018 coverage, plus a guest commentary

Researchers test a new immunotherapy combo and a pioneering approach to cancer vaccinationBY MEL J. YEATES & JEFFREY BOULEY

S IGNALING DOUBLE trouble for some cancers, researchers in Augusta, Ga., have paired two immuno-therapies together as a novel way to tackle tumors. Specifically,

pembrolizumab, which enables the T cells a patient already has to better attack a tumor, and poly-IC, which can produce an inde-pendent and vigorous immune response, are being given together for the first time to help more patients wage a stronger war on a wide range of solid tumors, researchers say.

The first phase of the clinical trial of this unique pairing is looking at the safety of com-bining the two drugs in a dozen patients with solid tumors, like lung or liver cancer, which have not responded to standard therapy. A second phase will commence at its comple-tion in about 30 patients with nonresponsive metastatic colon cancer.

“We have experiments in mice that show that the combined use of PD-1 antibody and poly-IC is synergistic for the recognition of tumors and an antitumor response mediated by T cells,” noted Dr. Esteban Celis, co-leader of the Cancer Immunology, Inflammation and Tolerance program at the Georgia Can-cer Center at Augusta University.

“Now we want to see if this synergy can also work for patients,” added Dr. Sharad Gha-mande, associate director for clinical research and trials at the Georgia Cancer Center—as well as chief of the Division of Gynecologic Oncology and executive vice chair of the

Department of Obstetrics and Gynecology at the Medical College of Georgia. Ghamande is principal investigator on the first trial. Dr. Asha Nayak-Kapoor, hematologist/oncologist at MCG and the Georgia Cancer Center, will lead the colon cancer trial.

Celis’ lab has shown how poly-IC, which behaves like the genetic material of viruses to get the attention of the immune system, can improve the e�ectiveness of therapeu-tic cancer vaccines. During those studies, he found the synergy between these two immu-

notherapy agents as well.PD-1 is a molecule naturally expressed by T

cells, a type of white blood cell that can fight infections and cancers, to help prevent an overzealous immune response. But tumors have a ligand for the molecule, called PD-LI, and their interaction inhibits the activity of the T cells that kill tumors, Celis explained.

“The antibody blocks the interaction and allows those T cells that are already at the tumor site to be more e�ective,” he noted. The synthetic PD-1 antibody, pembrolizumab, is already used by physicians to help treat a wide range of cancers by releasing the brakes on T-cells that recognize tumors, Celis added.

But a caveat is that many patients have few if any T cells in their tumors, which means the treatment is e�ective in only about 20 percent of patients who also have high mic-rosatellite instability. That means that their tumor has a lot of genetic mutations, which are likely to get the attention of the immune system despite scarce T cells. These tumors are characterized as immunogenic.

“The idea is that tumors that have a lot of mutations are more immunogenic, so that is why they tend to be infiltrated by T cells,” Celis said. “In tumors that are less immuno-genic, we hope that poly-IC will make them more immunogenic.”

In other unique immuno-oncology news—and going “across the pond” to Europe—a

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Cancer Research UK is testing a first-of-its-kind vaccine for non-small cell lung cancer.

Pictured here are Dr. Esteban Celis (left), co-leader of the Cancer Immunology, Inflammation and Tolerance program at the Georgia Cancer Center at Augusta University, and Dr. Sharad Ghamande, associate director for clinical research and trials at the Georgia Cancer Center.

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Demonstrating response of IL-12 platform in breast cancer and glioblastomaBOSTON—Ziopharm Oncology Inc., a biotechnology company focused on development of next-generation immu-notherapies utilizing gene- and cell-based therapies to treat patients with cancer, in June presented clinical data showing the company’s Controlled IL-12 platform as monotherapy achieved anti-tumor responses in patients with meta-static breast cancer (mBC) and patients with recurrent glioblastoma (rGBM) at the 2018 American Society of Clinical Oncology Annual Meeting.

The poster, “Demonstration of Anti-Tumor Immunity via Intratumoral Regulated Platform Ad-RTS-hIL-12 in Advanced Breast Cancer and Recur-rent Glioblastoma Patients,” present-ed data from two open-label trials that evaluated Ad-RTS-hIL-12 plus veledimex, a gene therapy designed to induce and control the expression of the powerful cytokine interleukin 12 (IL-12). Updated data from the company’s Phase 1 rGBM study shows median overall survival (mOS) of 12.7 months has been sustained for patients treated with Ad-RTS-hIL-12 plus 20 mg of veledimex at a mean follow-up time of 12.9 months as of May 4, 2018. This mOS of 12.7 months continues to compare favorably to the five to eight months survival established in histori-cal controls for patients with rGBM.

“We remain excited that Ad-RTS-hIL-12 plus veledimex as monothera-py demonstrates promising antitumor responses and makes cold tumors hot with new immune-infiltrating cells and overexpression of checkpoints,” said Dr. Francois Lebel, Ziopharm’s chief medical officer and executive vice president for research and devel-opment. “We look forward to further development of our Controlled IL-12 platform in combination with immune checkpoint inhibitors, with one com-bination trial initiated in brain cancer and plans to advance a similar treat-ment regimen in a second tumor type later this year.” �

ONCOLOGY SPOTLIGHT30 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.com

Commentary: Immuno-Oncology —Gold Rush or a Golden Age?BY DR. ANDY KINLEY OF NOVELLA CLINICAL

T HE LAST FEW YEARS saw the success of checkpoint inhibitor drugs like pembrolizumab and nivolumab in treating cancer and brought on a whole new mean-

ing to the field of immunotherapy. Modulat-ing the immune system to kill tumor cells became a main focus of many drug sponsors and the term “immuno-oncology” became a new buzzword. Estimates show1 that cur-rently hundreds of clinical trials involving immuno-oncology therapies are being car-ried out with the recruitment of over a hun-dred thousand patients.

As excitement builds in the field, concerns have also arisen about poorly designed trials, patient safety and ine�cient use of research funds and patient volunteers. In this com-mentary, we take a deeper look at the status of the crowded immuno-oncology field and explain how drug sponsors (and the scientific world in general) can derive the best ben-efit from a multitude of clinical trials and the information so gathered.

INTRODUCTION

A feverish hype has surrounded the field of immuno-oncology (IO) over the past decade with the discovery and approval of several checkpoint inhibitors. Keytruda (pembroli-zumab), perhaps the most notable checkpoint inhibitor, has been approved for the treat-ment of melanoma, lung cancer, head and neck cancer and several other cancer types.

The concept of cancer immunotherapy is not new, and the beginnings of the field can be traced back to findings made more than a century ago. However, incredible progress has been made recently, and with the suc-cess of drugs like Keytruda, which generated greater than $1 billion in sales in the third quarter of 2017 alone, the business case for industry focus on immuno-oncology thera-peutics is clear.

IS IO EXPERIENCING A GOLD RUSH?

Keytruda is one of six FDA-approved check-point inhibitors2 for the treatment of a wide variety of cancers. Due to their market and medical success, there has been great interest from both academia and pharmaceutical com-panies in these classes of drugs. This interest has translated into a populous drug develop-ment pipeline for cancer immunotherapeu-tics: 50 checkpoint inhibitors are being evalu-ated in 1,502 studies, 1,105 of which are in combination with other treatments.3 Thought leaders in the field, however, have criticized the massive number of trials, calling it a “gold rush”4 with pharmaceutical companies seek-ing to take advantage of the clinical and com-mercial success of these drugs.

Do these criticisms hold merit? Many claim that this rush has led to hastily planned trials that lack su�cient scientific rationale and/or preclinical investigation. These types of trials, as experts note, do not advance our scientific understanding of how these thera-peutics work or cancer’s ability to develop resistance. The failed ECHO-301 study5 of IDO inhibitor epacadostat in combination with pembrolizumab in advanced melanoma is often highlighted as an example of rushing into a (Phase 3) clinical trial without robust

early-phase and e�cacy data. One additional criticism of the excessive

number of trials being run is that they are quickly exhausting oncology’s most precious and important resource—eligible patients.6

Many trials call for a very specific patient type—patients who have relapsed, are in a specific stage or have a specific biomarker—and enrolling them in trials that are essential-ly testing similar drugs could make it di�cult for other trials studying more innovative and novel therapies to find enough subjects.

So, it may be worth asking the question: Since there are already six FDA-approved checkpoint inhibitors, five of which inhibit the same PD-1 signaling pathway, do patients really need additional treatment options that have a similar mechanism of action?

NOT A GOLD RUSH, BUT A GOLDEN AGE?

Answering this question, like studying can-cer, is no easy task. Cancer is a complex dis-ease capable of altering a patient’s immune system in a variety of ways. While research-ers and clinicians have gained deep insights over the past century, there are still many unanswered questions. Preclinical research and tumor models can help to answer some of these questions; however, they may not be a good predictor of safety or e�cacy in humans. Thus, performing well-designed clinical trials allows researchers to formulate a more unifying hypothesis for how di�erent cancers, and the immunotherapies that treat them, work.

For this reason, other thought leaders in immuno-oncology have taken a view oppos-ing those criticizing the “gold rush,” calling the current era a “golden age of oncology drug development.”7 Only 10 to 30 percent of patients respond to checkpoint inhibitors, and with the extraordinary cost of drugs like Keytruda, which is priced at $150,000 a year, it seems there is plenty of room for innova-tion to create more e�ective drugs, or combi-nations, that are cheaper for patients.

In addition, some of the critiques of the IO “gold rush” may not be 100-percent accurate. With the massive number of trials and the seemingly small number of eligible patients, it is easy to believe that patients are being enrolled in trials that will not necessarily pro-vide additional information or simply repeat similar studies. However, about 60 percent of the 1,500 studies mentioned above are small, single-site trials. Many of these are dose-escalation or expansion studies, and while they can expand to include a large number of patients, typically enrollment is gated, based on preliminary safety and e�cacy data. These exploratory trials usually involve only 15 to 20 patients in each treatment arm and will not expand to enroll more. Therefore, trial databases may artificially overestimate patient demand.

One additional argument for companies developing their own PD-L1 inhibitors is financial. PD-L1 inhibitors are the foun-dation for the treatment of many types of cancer. Their continuously growing success in a variety of indications and their use in combination with other treatments means that any emerging company looking to break into the immunotherapy market will either need to partner with large pharmaceutical

companies with approved PD-L1 therapies, or develop their own checkpoint inhibitor.

BEYOND CHECKPOINT INHIBITORS TO NOVEL THERAPIES

The crowded IO field can also lead to the development of innovative new approaches for the treatment of cancer. A few years ago, researchers proposed a framework called the Cancer-Immunity Cycle8 for thinking about the steps by which immune cells (specifically T cells) are primed to attack cancer cells, infiltrate the tumor microenvironment,9

recognize which cells are cancerous and kill them. This framework has helped research-ers identify new targets and pathways that could be exploited by novel cancer therapeu-tic strategies.

Many inventive companies have done just that, exploring second- and third-generation therapies. Some of these are a new wave of checkpoint inhibitors, either antibodies or small molecules, that “release the brakes” of the immune system by inhibiting molecules which prevent immune attacks against can-cer cells (i.e., TIM-3, VISTA, LAG-3, IDO or KIR). Simultaneously, there is also active research into molecules that “step on the gas” by stimulating cellular targets (i.e. CD40, GITR, OX40, CD137 and ICOS) to kill cancer cells.

A GOLD STANDARD

With the hype and activity in the immuno-oncology field increasing, there are sure to be additional successes and failures, adding fuel to the fire for each side of this argument. One thing that both sides can agree on is that clinicians and researchers want clinical tri-als to be run with solid, scientific rationales that have the greatest potential to benefit patients. As we’ve described above, there is certainly a “gold rush” in the field, but it may not be as bad for patients as some have point-ed out. The activity in this area has helped, and will continue to help, answer critical research questions and push revolutionary cancer therapeutics to market. �

Andy Kinley, Ph.D., is senior director of oncology strategy at Novella Clinical, where he provides strategic guidance to the oncology and operational teams as well as consultative oversight for biopharma sponsors developing cancer therapeutics.

REFERENCES1. https://www.ft.com/content/00092dde-578c-11e7-9fed-c19e2700005f2. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html3. https://www.cancerresearch.org/news/2017/cri-immuno-oncology-landscape-analysis-publication4. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30521-1/fulltext5. https://lifescivc.com/2018/04/life-after-echo-301-lessons-learned-about-modulating-ido-tdo-to-treat-cancer/6. https://www.nytimes.com/2017/08/12/health/cancer-drug-trials-encounter-a-problem-too-few-patients.html7. https://www.focr.org/news/science-too-much-good-thing8. https://www.cell.com/immunity/fulltext/S1074-7613(13)00296-39. https://www.nature.com/articles/nature21349

first-of-its-kind treatment vaccine has moved into a Phase 1 clinical trial for patients with non-small cell lung can-cer (NSCLC), under a collaboration agreement between Cancer Research UK and Asterias B iotherapeutics Inc.

Cancer Research UK will manage the initial clinical development of AST-VAC2, which it describes as “a promising immunotherapy candidate derived from a standardized human embryonic stem cell line.”

If shown to be safe and e�ective, the hope is that AST-VAC2 could serve as an additional treatment for patients who no longer have advanced disease but whose lung cancer is at high risk of returning. Also, it could possibly be of use in combination with other treat-ments for patients who have advanced disease.

“This vaccine trial is a pioneering approach to improving treatment for lung cancer, the biggest cause of can-cer death worldwide,” said Dr. Nigel Blackburn, Cancer Research UK’s director of drug development. “By coupling our expertise with a leading biotechnology company, we’ve accel-erated the development of this experi-mental treatment by years.”

The vaccine is made from dendritic cells that are able to “kick-start” the body’s immune system, according to Cancer Research UK—they present antigens on their surface and orches-trate a T cell immune response against cells bearing the same antigens. AST-VAC2 dendritic cells are engineered to express a modified form of a protein called telomerase, which is almost always present at high levels in various types of cancer cells, but rarely found in healthy cells.

This modified form of telomerase, called hTERT, can stimulate a natural immune response targeted at cancer cells. High levels of telomerase are a common feature of many cancers, so AST-VAC2 has the potential to become an immunotherapy option for other types of cancer beyond NSCLC, according to the collaborators.

Previous dendritic cell therapies have been made using patients’ own cells, but this process is costly, slow and ine�cient. By using a pioneering approach of growing mature dendritic cells from a single human embryonic stem cell line in the laboratory, it’s hoped AST-VAC2 will overcome these challenges.

Michael Mulroy, president and CEO of Asterias, commented that: “The experience and expertise of Cancer Research UK’s Centre for Drug Devel-opment and Biotherapeutics Devel-opment Unit have brought us a step closer to realizing the clinical poten-tial of this exciting experimental treat-ment ... In the future, there’s also the potential to utilize this novel platform technology to produce treatments that could, in theory, target multiple tumor antigens and thereby treat a whole range of di�erent cancers and tumor types.” �EDITCONNECT: E071834

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For more information, visit www.DDN-News.com JULY 2018 | | DDNEWS 31ONCOLOGY SPOTLIGHT

lio,” said Dr. Luciano Rossetti, global head of research and development at the biopharma business of Merck KGaA. “The unique design of this fusion protein o�ers the potential to optimally engage the TGF-β path-way. This is one example of the cre-

ative approaches we are taking to address challenging cancers where we believe we can deliver a transfor-mational change for patients.”

In patients with second-line (no prior immunotherapy) advanced NSCLC from the cohort of the

ongoing Phase 1 clinical trial, signs of clinical activity were seen across PD-L1 expression levels. At the rec-ommended Phase 2 dose (1,200 mg every two weeks), an inves-tigator-assessed confirmed over-all response rate of 40.7 percent

(11 of 27 patients) was observed. In patients with high PD-L1+ express-ing tumors, ORR was 71.4 percent (five of seven patients). A median progression-free survival (PFS) of 6.8 months was observed for PD-L1+ patients (1,200 mg every two weeks), and the median PFS was not reached for the high PD-L1-expressing population, owing to the number of patients still responding at the time of analysis.

These data build on a number of recent readouts for M7824, including preliminary data in gas-tric cancer at the ASCO 2018 Gas-trointestinal Cancers Symposium. Merck KGaA will present data from additional cohorts in hard-to-treat cancer types in the coming year. �

Germany’s Merck KGaA presents updated clinical results for M7824 at ASCO meetingDARMSTADT, Germany—In early June, Merck KGaA—based in Darmstadt, Germany, and tradi-tionally known as EMD in the Unit-ed States and Canada to distinguish it from Merck & Co.—announced results from expansion cohorts of the ongoing M7824 Phase 1 clinical trial program at the American Soci-ety of Clinical Oncology (ASCO) 2018 Annual Meeting in Chicago.

These data include results in patients with advanced non-small cell lung cancer (NSCLC) and in human papillomavirus-associated cancers, presented in collaboration with the National Cancer Institute, providing further evidence that bringing together a transforming growth factor-β (TGF-β) trap with the anti-PD-L1 mechanism may generate clinically relevant antitu-mor activity.

“M7824’s dual approach to fight-ing cancer, which brings together a TGF-β trap with the anti-PD-L1 mechanism, complements our existing immuno-oncology portfo-

Positive clinical data shared for DeCidE1 vs. ovarian cancerHALIFAX, Nova Scotia—June brought news that IMV Inc. shared new positive data in an oral presentation for its DeCidE1 (DPX-Sur-vivac with low-dose CyclophosphamIDe and Epacadostat) clinical study at the 2018 Ameri-can Society of Clinical Oncology annual meeting. These data from the ongoing Phase 1b/2 trial evaluated the safety and e�cacy of the combination of IMV’s lead candidate DPX-Survivac and low-dose cyclophospha-mide, with Incyte’s IDO1 enzyme inhibitor epacadostat, in patients with advanced recur-rent ovarian cancer.

DPX-Survivac consists of survivin-based peptide antigens formulated in IMV’s pro-prietary DPX drug development platform. DPX-Survivac is believed to work by eliciting a cytotoxic T cell immune response against cells presenting survivin peptides. Survivin, recognized by the National Cancer Institute as a promising tumor-associated antigen, is broadly overexpressed in most cancer types and plays an essential role in antagonizing cell death, supporting tumor-associated angiogenesis and promoting resistance to anti-cancer therapies. IMV has identified over 15 cancer indications in which the over-expression of survivin can be targeted by DPX-Survivac.

During the presentation, Dr. Oliver Dorigo, an associate professor of obstetrics and gynecology (oncology) at Stanford Uni-versity Medical Center, provided an update on the clinical benefits from the first 18 evaluable participants among 26 enrolled (including 10 from the 100 mg epacadostat

dosing cohort and eight from the 300 mg epacadostat cohort), as well as blood sample and tumor biopsy analyses from the study’s first dosing cohort. IMV is conducting the Phase 1b/2 trial in an ongoing collaboration with Incyte Corp.

“We continue to be impressed by the safety and e�cacy signals we see from this clinical trial, especially in this heavily pre-treated patient population with advanced ovarian disease and very limited treatment options,” said Frederic Ors, CEO of IMV Inc. “We designed DPX-Survivac to program immune cells in vivo in order to heighten and sustain anticancer T cell responses. Thus, we are especially pleased to be able to demonstrate, for the first time, a clear correlation between partial regressions and T cell infiltration in the tumors.”

At the time of data cut-o�, 39 patients were enrolled (including 25 new participants in the 300 mg cohort, with eight evaluable from

day 56 first CT scan). Data from the first 18 evaluable patients across both dosing cohorts showed seven tumor regressions, including four partial responses (PR) reported so far (defined as 30-percent decrease in tumor lesion size). Study participants generally tolerated treatments well, with no related significant adverse events reported.

Data from the first eight evaluable par-ticipants in the 300 mg epacadostat dosing cohort at first CT scan included six patients demonstrating stable disease at day 56, with four still on trial at data cut-o�. Two patients with tumor regressions were observed so far, including one PR with a tumor regression ongoing for more than nine months. IMV plans to report updated results on these patients and others when data from at least 16 evaluable participants in the second dos-ing cohort are available.

Researchers also analyzed patient data to study the combination’s mechanism of

action. They examined blood samples and tumor biopsies for the 10 evaluable patients treated in the first dosing cohort. These data showed that survivin-specific T cell responses were detected in 100 percent of patients. There was an increase in T cell infiltration post-treatment in 37 percent of the analyzable tumor biopsies based on two complementary testing methodologies (RNA sequencing and immunohistochem-istry). Two of the three patients with T cell infiltration showed PRs with significant and durable tumor regressions lasting more than one year. The third patient with T cell infil-tration exhibited progressive disease with evidence of downregulation of the major histocompatibility presentation pathway and significant increases in suppressive markers, both indicative of mechanisms of resistance.

“We know how important T cells are to controlling gynecological cancers, particu-larly in advanced ovarian disease, where it has been estimated that less than 20 percent of patients are responsive to monotherapies like checkpoint inhibitors,” said Dr. Gabriela Nicola Rosu, chief medical o�cer at IMV Inc. “IMV’s approach to program T cells in vivo is showing promising results that have been able to connect the dots between T cell infiltration and tumor response in these patients, many of whom have rapidly growing tumors. We believe this data is an important milestone toward our goal of significantly increasing the number of indi-viduals able to benefit from immunotherapy treatments.” �

“We continue to be impressed by the safety and ecacy signals we see from this clinical trial, especially in this heavily pre-treated patient population with advanced ovarian disease and very limited treatment options.”Frederic Ors, CEO of IMV Inc.

“The unique design of this fusion protein o­ers the potential to optimally engage the TGF-β pathway.”Dr. Luciano Rossetti of Merck KGaA, Darmstadt, Germany

Germany’s Merck KGaA recently shared ongoing M7824 Phase 1 clinical data from patients with advanced non-small cell lung cancer and human papillomavirus-associated cancers.

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Abcam, Shuwen Biotech link up for CDx kits

CAMBRIDGE, U.K. & DEQING, China—Abcam and Shuwen Biotech have signed a memorandum of understanding under which they will jointly apply their expertise in the production of high-quality antibodies and the development and commercial-ization of companion diagnostic kits.

“Shuwen has a long-standing reputation amongst pharmaceutical companies for com-panion diagnostic kit development and central lab testing, and Abcam is a recognized leader in quality antibody development. This alliance will undoubtedly further strengthen Shuwen’s capabilities in developing quality companion diagnostic kits especially immunoassay kits,” said Jay Z. Zhang, Shuwen’s chairman and CEO. “We have seen continuous advances at all levels in personalized medicine over the past few years and these can only continue through innovative technologies like those that will be born out of joint efforts between Shuwen and Abcam.”

More work on the way for W0101CASTRES, France—Mid-May saw an extension of the collaboration between Pierre Fabre and Roche to develop a companion diagnostic (CDx) for W0101. The partnership now extends from developing a prototype immunohistochemistry assay as a CDx for W0101 to include the retro-spective determination of IGF-1R expression in patients enrolled in a Phase 1/2 clinical study of the compound. W0101 is an antibody-drug conjugate product candidate that targets the insulin-like growth factor 1 (IGF-1) receptor, and is presently being evaluated in a Phase 1/2 clinical study in patients with relapsed/refractory solid tumors.

“It is noteworthy that the IGR-1R antibody used in the diagnostic assay binds a different epitope than the antibody from the therapeutic construct, both developed by Pierre Fabre Research Insti-tute,” said Dr. Alexandre Passioukov, vice presi-dent of translational medicine at Pierre Fabre Research Institute.

IN THIS SECTIONCompanion diagnosticsAbcam, Shuwen Biotech link up for CDx kits ................................. 32More work on the way for W0101 ......... 32

Infectious disease/Drug resistanceThe war against resistance advances (AMR from cover) ................... 33

OncologyProper prediction in prostate cancer ...... 32

Pulmonary/AsthmaThe nose knows ...................................... 32

PROPER PREDICTION IN PROSTATE CANCERNew studies indicate a valid, predictive biomarker for mCRPCBY JIM CIRIGLIANO

SAN DIEGO—California-based cancer diag-nostic development company Epic Sciences Inc. announced in June two promising new sets of data evaluating their assays for the nuclear-localized androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells as a predictive biomarker for metastatic castration-resistant prostate can-cer (mCRPC).

The first of these data sets was presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting from June 1 to 5 in Chicago. The company and its collaborators presented a total of five studies,

EPIC CONTINUED ON PAGE 33

The nose knows Mount Sinai researchers use nasal brush test to diagnose asthma BY LORI LESKO

NEW YORK—Armed with a simple nasal brush, Mount Sinai researchers have identi-fied a genetic biomarker of asthma that can di�erentiate asthma from other respiratory conditions such as allergic rhinitis, smok-ing, upper respiratory infection and cystic fibrosis.

Led by clinical and computational sci-entists in the Department of Genetics and Genomic Sciences, the Icahn Institute for Genomics and Multi-scale Biology and the Department of Pediatrics at the Icahn School of Medicine at Mount Sinai, the research team published its results in the June 2018 issue of Scientific Reports.

In the journal article, Mount Sinai Health System researchers described using a “nasal brushing” technique to collect RNA from the noses of 190 volunteers, 66 of whom had asthma and 124 of whom did not. After those samples were sequenced, machine learning algorithms were used to analyze the data to determine the di�erences between the RNA of the two groups.

As a result, a 90-gene biomarker was iden-tified that is specific to people with asthma. It is hoped that soon doctors will be able

to simply swab the inside of patients’ noses, then analyze the sample to see if the bio-marker is present. The next step involves plans for a follow-up study involving a larger sample size.

“Mild to moderate asthma can be di£cult to diagnose because symptoms change over time and can be complicated by other respi-ratory conditions,” Dr. Supinda Bunyavanich, a researcher at the Icahn School of Medicine, states. “Our nasal brush test takes seconds to collect. For time-strapped clinicians, par-ticularly primary care providers at the front lines of asthma diagnosis, this could greatly improve patient outcomes through early and accurate diagnosis.”

Bunyavanich told DDNews that asthma “can be challenging to diagnose given its wax-ing and waning symptoms. Individuals may not recognize that they have asthma, and individuals may not be symptomatic when they see their doctor.”

“Studies have shown substantial propor-tions of the population have asthma-like symptoms without being diagnosed with asthma,” she adds. “Some of these people may actually have asthma and would benefit from diagnosis and appropriate treatment.” At the same time, “some of these people may not have asthma and would benefit from know-ing asthma is unlikely, thus avoiding unnec-essary treatment with asthma medications. Current guidelines recommend incorporat-

ing pulmonary function testing with clini-cal assessment to diagnose asthma, but such testing is frequently not available in primary care settings. Limited time and expertise also often preclude pulmonary function testing.”

“Our nasal brush-based classifier would be quick and easy to implement, yielding an

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Epic Sciences says that its Oncotype DX AR-V7 Nucleus Detect test is the first and only liquid biopsy test of its kind designed to prolong the lives of men with metastatic castration-resistant prostate cancer by helping their physician identify the most effective treatment.

“One of the most exciting components of this study is demonstrating the power of machine learning when applied to biomedical data,” says Dr. Gaurav Pandey of the Mount Sinai Health System. “Collaborations between computational scientists and biomedical researchers and clinicians are advancing medicine at an inspiring pace.”

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including an oral abstract of a study conducted in partnership with the Duke Cancer Institute titled “The PROPHECY trial: Multicenter pro-spective trial of circulating tumor cell (CTC) AR-V7 detection in men with mCRPC receiving abiraterone (A) or enzalutamide (E).”

According to Ryan Dittamore, chief of medical innovation at Epic Sciences, the studies demonstrate the further validation and clinical utility of their nuclear-localized AR-V7 test, as well as other liquid biopsy tests under development.

Following this announcement, a second study published June 28 in JAMA Oncology validated the predictive value of a liquid biopsy test and demonstrated a survival benefit for patients. The results chronicled an independent, multi-center, blinded study conducted by an international team of research-ers from Memorial Sloan Ketter-ing Cancer Center (MSK), Epic Sciences, the Institute of Cancer Research and London Health Sci-ences Centre collected over four years. The study followed 142 mCRPC patients treated at either MSK, The Royal Marsden or the London Health Sciences Centre, and concluded that nuclear-local-ized AR-V7 protein in circulating tumor cells can identify patients who may live longer with taxane chemotherapy versus androgen receptor signaling inhibitor (ARSi) treatment.

“This liquid biopsy test addresses a critical unmet need at a decision point in management to predict and select the therapy that is most likely to extend a patient’s life,” said Dr. Howard Scher, who led the study. Scher is the co-chair for the Center for Mechanism Based Ther-apy and the head of the Biomarker Development Initiative at MSK. “During the treatment of metastat-ic prostate cancer, physicians will now be able to use AR-V7 status to determine when a patient’s cancer has become resistant to androgen receptor-directed therapy and will respond better to chemotherapy, enabling the patient to live longer.”

The blood test, called Oncotype DX AR-V7 Nucleus Detect, is com-mercially available in the United States through Epic Science’s part-nership with Genomic Health Inc.

“The PROPHECY data focused on validating AR-V7 as a nega-tive predictive biomarker for use of abiraterone or enzalutamide,” says Dittamore. “Given that every patient who was positive for nucle-ar-localized AR-V7 in our test has no patient benefit, the natural question is: ‘Will these patients live longer on chemotherapy?’ The Scher et al. publication vali-dates this—that patients who test positive with the Oncotype DX AR-V7 Nucleus Detect test will live longer on chemotherapy than when treated with ARSi inhibitors, abiraterone or enzalutamide. Given the two datasets, the test has been validated in the context of the clini-cal question being asked.”

The results address an impor-tant unmet need for physicians and patients faced with a choice about how to approach treatment of metastatic castration-resistant prostate cancer.

“Prior to AR-V7, physician intu-ition was the primary decision-making strategy in determining a therapeutic sequencing for patients with mCRPC,” Dittamore explains. “Validating nuclear-localized AR-V7 protein as a predictive test in this decision demonstrates a survival advantage of AR-V7 over physician intuition. The data sup-port that the use of Oncotype DX AR-V7 Nucleus Detect test has the ability to increase patient survival through better decision making.”

A specific, predictive biomarker for prostate cancer has been di£-cult to isolate, with the male equiva-lent of the breast cancer biomarker HER-2 proving to be elusive. Dit-tamore credits his team’s success on their approach to the challenge.

“Our approach was to lead not with the biomarker, but with an important unmet, relevant clinical question,” he tells DDNews. “The clinical question and test perfor-mance requirements dictated the biomarker, rather than the other way around. During our journey with MSK, we ended up looking at 20 di�erent biomarkers before we landed on nuclear-localized AR-V7 protein. After initial feasibility with AR-V7, we locked down the assay and tested in multiple cohorts to validate the test.” �EDITCONNECT: E071820

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automatable output of yes or no asthma for the clinician to consid-er,” Bunyavanich continues. “The potential outcomes of this include appropriate treatment of asthma if asthma is likely—and avoidance of unnecessary asthma treatment if asthma is unlikely.”

Currently, pulmonary function testing (PFT) is the most reliable diagnostic tool for asthma. How-ever, the equipment and expertise needed to perform these tests are not always available in primary care settings where asthma is frequently

diagnosed and treated. It is also dif-ficult to di�erentiate between asth-ma and other respiratory diseases using PFT alone, while the nasal brush and subsequent analysis for

this asthma biomarker provides a binary result of asthma or not asthma.

“One of the most exciting com-ponents of this study is demon-

strating the power of machine learning when applied to biomedi-cal data,” said Dr. Gaurav Pandey, who led data science efforts to develop the biomarker. “Collabo-rations between computational scientists and biomedical research-ers and clinicians are advancing medicine at an inspiring pace. We have the power of many insights we didn’t have in the past, and that opens a window to an entirely new world of diagnostic tools and treatments.”

Pandey was lead researcher in the study, which was titled “Nasal Brush-based Classifier of Asthma Identified by Machine Learning

Analysis of Nasal RNA Sequence Data.”

This classifier reportedly per-formed with strong predictive value and sensitivity across eight test sets, including a test set of independent asthmatic and con-trol subjects profiled by RNA sequencing, two independent case-control cohorts of asthma profiled by microarray and five cohorts with other respiratory conditions (allergic rhinitis, upper respiratory infection, cystic fibro-sis, smoking), where the classifier had a low to zero misclassification rate. �EDITCONNECT: E071821

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“Mild to moderate asthma can be difficult to diagnose because symptoms change over time and can be complicated by other respiratory conditions,” says Dr. Supinda Bunyavanich, a researcher at the Icahn School of Medicine. “Our nasal brush test takes seconds to collect.”

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Pictured here are representative AR-V7-positive circulating tumor cells. Recent studies reportedly demonstrate the further validation and clinical utility of Epic Sciences’ nuclear-localized AR-V7 test, as well as other liquid biopsy tests under development.

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pathogens. If nothing is done to stem the tide of growing AMR, that number is expected to bal-loon to 10 million deaths per year by 2050, with the econom-ic harm and human loss falling disproportionately on LMICs.

As FIND noted in announc-ing the MOU signing, Lord Jim O’Neill’s independent review on AMR in 2016 underlined the importance of a coordi-nated global e�ort to tackle the AMR threat, with the review describing it as “shocking” the way in which prescribing deci-sions today have not fundamen-tally changed since the 1950s—owing to a lack of suitable diag-nostic tools and technologies.

Better diagnostics, of course, are a critical component of the e�ort to rein in drug-resistant bacteria, viruses, parasites and fungi. As FIND notes, “Wide-spread, consistent use of diag-nostic tests to identify disease-causing pathogens and deter-mine the presence of drug resis-tance enables healthcare profes-sionals to provide patients with the most appropriate treatment regimens. Data from connected diagnostics enable surveillance of drug resistance at national, regional and international lev-els and inform precision global health interventions.”

Teaming up the U.K. govern-ment and FIND will further GAMRIF’s goal of fostering innovations to tackle AMR for the benefit of people in LMICs. Three workstreams will be delivered: end-to-end data transfer and reporting from point-of-care testing for AMR surveillance; a mobile phone app to enable the transfer of a range of rapid diagnostic test results for surveillance; and clinical decision aids via mobile phones, also linked to AMR sur-veillance systems.

“Diagnostics are critical to tracking and monitoring dis-eases and the spread of drug

resistance,” said Catharina Boehme, CEO of FIND. “Con-necting diagnostics to surveil-lance systems at various levels from local to global will allow surveillance to be strengthened in LMICs, where the burden of infectious diseases is highest but data are currently limited.”

“This partnership with FIND is part of the U.K. government’s continued commitment to fight drug-resistant infections,” com-mented Steve Brine, the United Kingdom’s health minister. “Supporting work on diagnostic technologies is an essential part of this, and will have a key role to play in mitigating the impact of superbugs on the health and eco-nomic prosperity of the world’s poorest. This partnership will contribute to saving lives in areas of the world that are dispropor-tionally a�ected by this threat.”

Over the past decade, the U.K. government, through the Department for International Development, has been a major donor to FIND, supporting the initiation of the development of critical diagnostic assays for pri-oritized target product profiles using innovative technology platforms and business mod-els. This recently signed MOU extends the ongoing relation-ship between FIND and the government, specifically to sup-port diagnostic connectivity for AMR as part of the Global AMR Innovation Fund.

“Diagnostic technologies play a key role in tackling AMR,” said Prof. Dame Sally Davies, England’s chief medical o£cer. “I welcome the Global AMR Innovation Fund’s collabora-tion with FIND, which aims to connect diagnostics to national and global surveillance sys-tems. Collecting this valuable information will improve sur-veillance, which is crucial to monitoring trends of infection, linking data on antibiotic use in di�erent sectors and allowing assessment of interventions to reduce AMR.” �EDITCONNECT: E071803

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CONTRACT SERVICESOutsourcing on the rise

NEW YORK—According to Kalorama Informa-tion, roughly half of drug discovery research will be contracted out to contract research organiza-tions (CROs) in three to four years, as reported in the company’s latest report, “Outsourcing in Drug Discovery: The Contract Research Organization Market, 8th Edition.”

Kalorama estimates that the market for outsourced drug discovery is currently valued at $24 billion, noting that this market grew 17 percent in 2017. The organization states that “Between the $2.6-billion cost for a new drug, $117 billion of drug products with patent expi-rations and the thousands of pharmaceutical industry layoffs, the only way to fill the gap is outsourcing.” Bruce Carlson, publisher of Kal-orama Information, said that “We believe the industry is at roughly 40 percent outsourcing for discovery services, and the outsourcing is on the increase.” Among the trends associated with this industry change is the selection of out-sourcing partners in Asia and Eastern Europe, according to the report.

Millennium Biosciences tapped for consulting

by Nu-MedSALT LAKE CITY—Medical device company Nu-Med Plus Inc. recently enlisted Millennium Biosciences as its strategic partner for company quality and regulatory service. N-Med specializes in investigating and developing applications of nitric oxide technologies for the medical field.

“For the past 30 plus years, Mr. D’Amico [head of Millennium Biosciences] has been a successful professional in the Quality and Regulatory field in the capacities of quality project management and regulatory affairs. We are excited to have retained Millennium Biosciences as we aggressively step forward, pursuing ISO 13485 training and certification for our company along with approvals for our products,” said Jeff Robins, president and CEO of Nu-Med-Plus.

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Processing/ New chemical entitiesGrant awarded for continuous modular manufacturing ........................................ 34

Quality/RegulatoryMillennium Biosciences tapped for consulting by Nu-Med .............................................. 34

Grant awarded for continuous modular manufacturingBY MEL J. YEATES

ALNWICK, U.K.—The contract research and development organization Arcinova recently received a grant award of £1.5 million from Innovate UK for the development of new flexible modular manufacturing technolo-gies, a project which is set to demonstrate the operating feasibility of innovative continu-ous production tools. The goal for Arcinova: establish itself as a world leader in defining continuous modular manufacturing technol-ogy for the support of new chemical entities’ development, scale up and manufacture.

According to Dr. Paul Quigley, head of API development and bioanalytical services at Arcinova, “Arcinova felt that the current Innovate UK funding round for the develop-ment of new medicines manufacturing tech-nology was an ideal opportunity to enhance our technological capabilities ... The initial focus was on the development of new con-tinuous manufacturing technologies, and this was an area of particular importance to Arcinova and an area where the University of Nottingham has particular strengths. Our previous successful track record of collabora-tion, allied to the skill sets of the Nottingham and Arcinova teams in the area of continuous processing technology development, made this collaboration a natural evolution of the current relationship.”

The project, which will span a three-year period, will be under-taken in collaboration with a team led by Prof. Mike George, with Prof. Pete Licence and Prof. Sir Martyn Poliako� at the Uni-versity of Nottingham. The aim of the project is to develop a continuous, flexible modular manufacturing technology platform which will enable Arcinova to handle increasingly complex chemistries with more discrete manufacturing steps.

“In response to the development of new and more targeted pharmaceutical treat-ments, small-molecule drug substances are becoming more complex in nature, more potent and, as a consequence, the drug sub-stance requirements for a candidate drug—both through the clinical development phase and at commercial launch—has reduced sig-nificantly,” Quigley notes.

“Our vision for this project is the devel-opment of a continuous, flexible modular manufacturing technology platform which will enable Arcinova to meet this technol-ogy need and to be a leading player in the development, scale-up and manufacture of new small-molecule drugs. Initially, a num-

ber of key technology areas will be chosen for development,” continues Quigley. “These areas will be chosen on the basis of expected technical need from Arcinova and on the basis of demonstrated expertise from the aca-demic partner (University of Nottingham).”

“My colleagues and I at Nottingham are firmly convinced that flow chemistry can transform chemical manufacture in the U.K., and this partnership with Arcinova is

an opportunity to turn our vision into reality,” added George, a pro-fessor of chemistry at the Univer-sity of Nottingham.

The developed continuous modular manufacturing technol-ogy reportedly will be easily scal-

able, with a reduced manufacturing footprint when compared to more traditional batch reactor approaches. The developed technolo-gies will enable Arcinova to enhance manu-facturing capacity and minimize invento-ries for highly reactive hazardous processes whereas for a batch process the reaction scale would be severely constrained. The developed flexible modular manufacturing technology platform will enhance Arcinova’s existing infrastructure in GMP and non-GMP assets, which include five-liter and 20-liter GMP ves-sel streams, and builds on its current capa-bilities in continuous processing technology.

“The growth in novel, increasingly potent and technically complex small molecules as new candidate drug substances necessitates a radical rethink in terms of the technology required to generate them. Currently the need is for technologies which will provide the capability to manufacture drug substanc-es in small volume, with the facility of rapid

changeover of production, with high process intensity and product yield, generating high purity materials and with the ability to han-dle potentially hazardous reagent conditions. Additional requirements would include the need for improved process economics when compared to traditional batch processing conditions, and the ability to minimize pro-cess solvents, reagents and catalysts as fur-ther drivers,” Quigley tells DDNews.

“Continuous processing technologies o�er a solution to this unmet need, yet the technology is still evolving and in many areas (oxidation, thermal processing [high and low] and in solvent reuse) the technolo-gies available are not, as yet, scalable,” he notes. “Arcinova in particular has a need for a technology which could o�er the capabil-ity to satisfy long-term demand for new chemical entities as drug substances on an existing site footprint without the need to use large chemical reactors, with low inven-tories and with the ability to o�er world-class chemical processing technologies that would di�erentiate us from the global competitor base and enhance our business growth prospects.”

When asked how the project has been since the announcement of the grant, Quigley says, “The project is going well, with the Univer-sity recruitment phase in an advanced state. We have good project management discipline in place and regularized meetings to ensure that the project outputs are well managed and metricated. Our intention is to rapidly apply the developed manufacturing technologies to real case projects which can rapidly enhance Arcinova’s technological competitiveness.” �EDITCONNECT: E071824

TOOLS & TECHNOLOGY

Arcinova will use a grant to help fund development of new flexible modular manufacturing technologies.

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BRIEFS ON THE CUTTING EDGEA roundup of instrumentation, software and other tools and technology newsBY JEFFREY BOULEY

CAMBRIDGE, Mass.—CAMP4 Thera-peutics recently launched with a plat-form “to discover e ective treatment approaches for every disease” and at the same time announced a $30-mil-lion Series A financing. Operating at

what it calls “the intersec-tion of biology and computa-tion,” CAMP4 is building on seminal dis-

coveries in gene regulation circuitry made by company founders Dr. Rich-ard Young of the Whitehead Institute of Biomedical Research and MIT and Dr. Leonard Zon of Boston Children’s Hospital and Harvard University.

To enable its vision, CAMP4 is focusing e orts to scale its proprietary 4-D Gene Circuity Platform across all human cell types relevant to disease.

“The machinery that controls activation of the 24,000 genes in the human body can be codified by CAMP4’s platform into a discrete set of combinatorial rules using signaling pathways,” said Josh Mandel-Brehm, CEO of CAMP4. “By combining novel experimental data and computational capabilities, our platform solves the control code for any gene and cell type central to disease pathology.”

CAMP4 believes the impact of its activities can substantially de-risk and shorten the drug development process, which the company notes is “otherwise historically characterized by poor productivity and long approval timelines.” Proceeds from the recent financing will be used to expand the use of its platform to other human cell types and accelerate collaborations with partners toward novel target discoveries and new applications for existing chemistries, extending their

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Biogen to acquire TMS-007CAMBRIDGE, Mass.—June saw the beginning of an exclusive option agreement between Biogen and TMS Co. Ltd., under which Biogen will acquire TMS-007—a plasminogen activator with a novel mechanism of action that helps to break down blood clots and is thought to inhibit inflamma-tion at the site of thrombosis—and backup compounds. Biogen will pay TMS $4 million up front and $18 million if Biogen exercises its option. TMS also stands to receive up to $335 million in potential development and commer-cialization milestones, as well as tiered royal-ties. TMS-007 has reduced infarct volume (dead tissue due to lack of blood supply) in rodent and primate models of embolic and thrombotic stroke. A double-blind, placebo-controlled Phase 2 study is underway to determine the safety and efficacy of a single intravenous administration up to 12 hours after stroke onset in patients with acute ischemic stroke.

NIH to fund animal testing centers for genome editing

BETHESDA, Md.—The National Institutes of Health recently announced funding for a new program that will establish two large-animal testing cen-ters, one of which will test genome-editing deliv-ery technologies and editors developed by the NIH Somatic Cell Genome Editing program. One center will test the technologies in pigs, and the other in monkeys (specifically rhesus and marmosets). It is expected that the first center will have the capacity to test roughly 250 animals a year as of April 2021, while the second center is expected to test roughly 110 animals per year. The NIH Common Fund Office of Strategic Coordination will provide $2.5 million in fiscal year 2019-2020 and $4.5 million in fiscal years 2021-2023 for this effort. The NIH grant also states that the centers will be expected to “Establish assays and SOPs to evaluate on-target and off-target genome edit-ing in target cells and tissues, including germline cells, in wild-type animals.”

IN THIS SECTIONAnimal testing/GeneticsNIH to fund animal testing centers for genome editing .................... 35

Licensing and acquisition dealsBiogen to acquire TMS-007 ................... 35Strengthening its immuno-oncology portfolio .................... 35

Neurology/Stem cellsiPSC interest ........................................... 35

Startups7 Hills launches with $2M SBIR grant ...................................... 36

Tools and technologyOn the cutting edge ................................ 35

iPSC interestFCDI licenses technology from UC Irvine to develop iPSC-derived microglia for neurological disease modelsBY KELSEY KAUSTINEN

MADISON, Wis.—Fujifilm Cellular Dynamics Inc. (FCDI) and the University of California, Irvine (UCI) have begun an exclusive patent license agreement centered on UCI technology for deriving microglia from induced pluripotent stem cells (iPSCs). Facilitated through the UCI Applied Innovation offices, the agreement covers the licensing and commercialization of UCI’s technology in the commercial research field, as well as a non-exclusive patent license agreement for commercializing microglia media formulation. Financial details for the deal were not released.

This technology is relatively new, all things considered, having only been detailed in a paper in Neuron in April 2017. Commercial

interest from a company like FCDI, which is a market leader in the development and manufacture of human iPSCs and differentiated tissue-specific iPSCs, is an encouraging sign for UCI. FCDI is looking to leverage this technology to produce better models for studying degenerative neurological diseases.

“Until now researchers have relied predominantly on animal models, which do not sufficiently mimic the human disease, to study the role microglia play in neurodegeneration,” said Seimi Satake, chairman and CEO of FCDI. “With UCI’s technology, FCDI will bring to market iPSC-derived microglia that will provide researchers with better tools to characterize microglia from donors with neurological diseases, to develop assays that distinguish between normal and diseased behaviors and to advance e orts in discovering new therapies.”

“We are delighted that FCDI has recognized the importance of iPSC-derived

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Strengthening its immuno-oncology portfolioApeiron signs licensing deal for new checkpoint inhibitor with the Medical University of Vienna and IMB BY DDNEWS STAFF

VIENNA—Apeiron Biologics AG, a clinical-stage company focused on cancer immuno-therapy, announced near the end of June the signing of an agreement with the Institute of Molecular Biotechnology GmbH (IMBA) of the Austrian Academy of Sciences and the Medical University of Vienna. The agree-ment grants Apeiron an exclusive world-wide license to a novel technology targeting casitas B cell lymphoma-b (Cbl-b). Cbl-b is an intracellular checkpoint limiting the immune reactivity in various immune cells, such as T cells and natural killer cells, and was originally discovered by Dr. Josef Pen-ninger, scientific director of IMBA.

According to Apeiron, inhibiting Cbl-b not only distinctly activates immune cells but o ers the opportunity to deactivate other relevant checkpoints—including CTLA-4 and PD-L1/PD-1—and thus can be regarded as the “master checkpoint” in cancer immu-

notherapy. Apeiron is engaged in an innova-tive cellular immunotherapy project based on the knockdown of Cbl-b (APN401), which

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TOOLS & TECHNOLOGY

Speaking of a deal between his company and the Medical University of Vienna, Peter Llewellyn-Davies, chief financial and business officer of Apeiron, said: “The agreement expands our portfolio of immunotherapies targeting Cbl-b and is also an excellent example of an academic-industrial partnership maximizing the strengths of both parties.”

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microglia to model and study human neurological disease and advance our understanding of microglia biology,” Matt Blurton-Jones, a UCI associate professor and co-inventor of the technology, said in a press release. “We hope that, by making this new technology readily available to the scientific community, researchers worldwide will uncover important new findings and accelerate the discovery of promising therapies.”

Blurton-Jones’ UCI faculty page notes that in his research group, “[We]are using iPSCs to generate human microglia and understand the e ects of disease-associated genetic risk factors on microglial function and AD [Alzheimer’s disease] pathology. Working with immune-deficient AD mouse models, we have also recently uncovered an important role for the adaptive immune system in AD, finding that peripheral immune populations slow the development of beta-amyloid pathology by modulating microglial function.”

A 2017 press release penned by Kirsten M. Klein, assistant education coordinator of the UCI Mind institute, covered the publication of the iPSC-derived microglia technology in Neuron, noting that “In the brain, microglia mediate inflammation and the removal of dead cells and debris. These cells make up 10 to 15 percent of brain cells and are needed for the development and maintenance of neural networks.”

“Microglia play an important role in Alzheimer’s and other diseases of the central nervous system. Recent research has revealed that newly discovered Alzheimer’s risk genes influence microglia behavior. Using these cells, we can understand the biology of these genes and test potential new therapies,” Blurton-Jones explained at the time.

Details of this technology appeared in the 2017 Neuron paper titled “iPSC-derived Human Microglia-like Cells to Study Neurological Diseases.” As noted in the abstract, “We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals

that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients and robustly phagocytose CNS substrates. iMGLs were used to examine the e ects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo.”

“We are pleased that FCDI has licensed our protocol to make and distribute microglia to the scientific community. As leaders in the field of providing iPSC-derived products, we are confident that FCDI will provide researchers and scien-tists with a reliable product in large scale to carry out quality studies,” Wayne Poon and

Edsel Abud, UCI co-inventors of the tech-nology, said of the recent licensing deal.

This isn’t the first iPSC-focused deal for Fujifilm Corp. so far this year. In Febru-ary, the company launched a collaboration with Takeda Pharmaceutical Co. Ltd. for the development of regenerative medicine therapies using iPSC-derived cardiomyo-cytes to treat heart failure.

Takeda gains a “right of first negotiation” to collaboratively and globally commercial-ize regenerative medicine products featur-ing iPSC-derived cardiomyocytes currently being developed by FCDI. The companies will work together to investigate the safety and efficacy of any produced therapies. While no specific financial details were disclosed, Takeda will make a one-time payment to Fujifilm. �EDITCONNECT: E071827

is currently in clinical development.Scientists at IMBA, in cooperation

with the Max F Perutz Laboratories of Medical University of Vienna, recently discovered a further novel approach targeting Cbl-b by cell-permeable cbl-b inhibiting peptides.

Apeiron has now licensed this promising new research technology from IMBA, to expand the Cbl-b based checkpoint blockade project portfolio. Under the terms of the agreement, Apeiron will be responsible for fur-ther preclinical and clinical develop-ment of this IMBA technology. IMBA and Medical University of Vienna will receive an upfront payment and will be eligible to receive development, regu-latory and commercialization mile-stone payments and royalties. Further financial terms were not disclosed.

“The in-licensing of this innova-tive technology allows us to further enhance our presence in the prom-ising area of immune-oncology and strengthens our position in the field of checkpoint inhibitors,” said Peter Llewellyn-Davies, chief financial and business officer of Apeiron. “The agreement expands our port-folio of immunotherapies targeting Cbl-b and is also an excellent exam-ple of an academic-industrial part-nership maximizing the strengths of both parties.”

Michael Krebs, managing director of IMBA added: “We at IMBA see our-selves as an important player in the value chain of biomedical innovations. The IMBA is developing completely new approaches for the treatment of human diseases and thereby enabling potentially alternative treatment options for patients. This collabora-tion with Apeiron shows once again that it is worthwhile for the Austrian government to invest in science and that the geographical proximity of excellent academic research and com-panies, as can be found at the Vienna BioCenter, represents a promising business model.” �EDITCONNECT: E071828

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7 Hills launches with $2M SBIR grantAn additional $4 million in seed capital will help new company pursue novel cancer therapeuticsBY DDNEWS STAFF

HOUSTON—7 Hills Pharma, a privately-held immunotherapy company focused on devel-opment of novel tumor-targeting cell adhe-sion agents, announced today that it has been awarded a $2-million Small Business Innova-tion Research (SBIR) grant by the National Institutes of Health (NIH).

This is the second NIH grant awarded to the company for the advancement of its integrin activator. The first grant supported the successful completion of the proof-of-concept study. The SBIR award is based on a

competitive federal grant program aimed at supporting scientific excellence and techno-logical innovation. The NIH grant is in addi-tion to $4 million in seed capital provided to 7 Hills from private investors.

“We are honored by the NCI’s support of our important work in making tough-to-treat, non-immunogenic solid tumors more susceptible to antitumor attacks by the immune system and check point inhibitors,” said Dr. Upendra Marathi, president and CEO of 7 Hills. “With this funding and the financial support from our angel investors, we plan to conduct key IND-enabling preclinical studies for our lead compound 7HP349 and related compounds for the treatment of drug-resistant tumors with defective T cell-tumor cell adhesion.”

“The fundamental problem in disease progression with cancer is that solid tumors

evade the immune system by preventing the infiltration, function and ultimate attack of T cells and other tumoricidal immune cells,” said Dr. Darren Woodside, co-founder of 7 Hills and chairman of the NIH Innovative Immunology Research Study Section. “It’s an adhesion problem. We have known that solid tumors create an immunosuppressive microenvironment that prevents killer T cells from adhering to the tumor blood vessel lin-ing and working their way into the tumor to do their job. 7 Hills is optimizing novel integrin activators to address and reverse the inherent tumor protective environment, promoting T cell destruction of the tumor while maintaining a favorable overall safety profile by leveraging the natural biological mechanism of integrins.” �EDITCONNECT: E071830

“The fundamental problem in disease progression with cancer is that solid tumors evade the immune system by preventing the infiltration, function and ultimate attack of T cells and other tumoricidal immune cells.”Dr. Darren Woodside, co-founder of 7 Hills

Fujifilm Cellular Dynamics Inc. (FCDI) is looking to leverage a technology for deriving microglia from iPSCs, with the aim to produce better models for studying degenerative neurological diseases. Pictured here is FDCI’s parent company, Fujifilm.

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life cycle and value into areas previously not considered.

“By combining the power of epigenom-ics, computational biology and machine learning, CAMP4’s platform has the unique potential to elucidate the mechanisms and rules governing gene regulation across dis-ease,” said Jorge Conde, general partner at Andreessen Horowitz, one of the investors in the financing round. “This is an extraordi-nary opportunity to transform how we think about discovering new therapies and treating patients.”

Shimadzu enhances MS platform with with new Q-TOF SystemCOLUMBIA, Md.—In other recent tools and technology news, Shimadzu announced the launch of the quadrupole time-of-flight (Q-TOF) LCMS-9030 system. The Shimadzu LCMS-9030 is a research-grade mass spec-trometer designed to deliver high-resolution, accurate-mass detection with incredibly fast data acquisition rates, allowing scientists to identify and quantify more compounds with greater confidence.

Ultra-fast (UF) acquisition rates and core ion beam technologies developed for the triple quadrupole platform are said by the company to have created new possibilities in quantitative mass spectrometry by delivering exceptional sensitivity, specific quantitation and enhanced target compound verification. Also in the new system, core ion beam tech-nologies transition toward a unique approach in ion gating using UFaccumulation to create a precise pulse of ions into the flight tube optimized for high sensitivity and high reso-lution using iRefTOF reflectron technology. The iRefTOF generates an ideal reflectron field, delivering the highest resolution for the flight path with highly stable mass accuracy.

“Our Q-TOF technology on the LCMS-9030 will push the boundaries further for high mass accuracy and high mass resolution detection and will make an impact across all applications, from small-molecule quantita-tion to complex intact protein analysis. This technology highlights Shimadzu’s passion for making something new and innovative as well as our commitment to making analy-sis better and promoting better science,” said Shuzo Maruyama, general manager of the Analytical & Measuring Instruments Divi-sion at Shimadzu.

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Turn data into action for clinical and translational genomics researchRIJSWIJK, Netherlands & CAMBRIDGE, Mass.—Bluebee Corp. announced in May the release of BLUEBASE, a complete data management solution designed to transform next-generation sequencing (NGS) and meta-data into actionable genomic knowledge with e®ciency and clinical-grade security. BLUE-BASE runs on the Bluebee core data analysis platform and provides post-sequencing intel-ligent data aggregation, ease of querying and deep knowledge mining. BLUEBASE is aimed at diagnostic assay developers, pharmaceuti-cal researchers, clinical trial operators and investigators of population-scale initiatives, offering a turnkey solution to efficiently realize clinically-relevant information from large-scale genomic data.

BLUEBASE aggregates, organizes and stores combined genomic data sets, phe-notypes and other metadata from a vast ecosystem of curated public and private databases. With a customizable data model, BLUEBASE accommodates a wide scope of user-defined metadata and ontology frameworks, including the integration of a dynamic public knowledge base of 150 data sources and hundreds of millions of data records, composed of publications, variant datasets, clinical studies and other data sources. Private data sets and metadata are said to be easily integrated within the system.

A range of applications are enabled by BLUEBASE, including discovery and valida-tion of biomarkers, insight into patient strati-fication approaches, cross-study analyses by multidisciplinary teams, identification of drug candidates for clinical trials and more. Having data mined and readily accessible in BLUEBASE within the Bluebee platform reportedly eliminates data redundancy and risks associated with physically transferring large, private datasets, further streamlining clinical genomics applications.

“BLUEBASE was created as part of our

mission to further serve precision medicine initiatives,” says Hans Cobben, CEO of Blue-bee. “As part of the Bluebee platform, volume to value from genomic data is now achiev-able, with high e®ciency and clinical-grade security.”

Discovery in real time with NLPCAMBRIDGE, U.K. & BOSTON—Lingua-matics, a leading natural language process-ing (NLP) text analytics provider, in May announced the latest release of its I2E AMP platform to automate the discovery of critical insights from text using NLP.

The I2E Asynchronous Messaging Pipe-line (AMP) platform reportedly delivers high-throughput, fault tolerant workflow management for real-time document and record processing, addressing the NLP text-mining and ETL (extract transform load) requirements for healthcare and life-sciences organizations of all sizes by allowing users to plug I2E into enterprise workflows and rapidly process streams of data at scale.

“I2E’s flexible NLP platform goes far beyond traditional entity mark-up, providing semantically enriched data that normalizes concepts and relationships based on the rele-vant context,” said David Milward, chief tech-nology o®cer for Linguamatics. “With AMP, clients now have an enterprise class, high-throughput solution that provides secure, fault-tolerant, scalable and real-time ETL from unstructured text to structured data.”

“AMP provides for the rapid transactional processing of unstructured data for a variety of workflows, including document markup and data extraction to feed enterprise search engines, machine learning, data warehouses and dashboards,” said Phil Hastings, chief business development o®cer for Lingua-matics. “The 2.0 release includes new options that make it an even more valuable solution that can be applied to multiple use cases across life sciences and healthcare.” �EDITCONNECT: E071829

EDITCONNECT:Appearing as an online-only extra this issue is a new Patent Docs column by Kevin Noonan giving you a brief roundup of the happenings at this year’s BIO International meeting. You can find it by going to our home page at www.ddn-news.com and entering the Editconnect number E071831 in the “search our archives” field at the top of the page.

“Our Q-TOF technology on the LCMS-9030 will push the boundaries further for high mass accuracy and high mass resolution detection and will make an impact across all applications, from small molecule quantitation to complex intact protein analysis.”Shuzo Maruyama, a general manager at Shimadzu

“BLUEBASE was created as part of our mission to further serve precision medicine initiatives. As part of the Bluebee platform, volume to value from genomic data is now achievable, with high e�ciency and clinical-grade security.”Hans Cobben, CEO of Bluebee

38 DDNEWS | | JULY 2018 For more information, visit www.DDN-News.comLATE-BREAKING NEWS

COMPUTATIONAL MODELS PROVIDE INSIGHTS INTO ATHEROSCLEROSISFRANKFURT, Germany & NEW YORK—Researchers have identi-fied a new gene-activation path-way caused by lipids associated with coronary artery disease, a finding that could help identify new directions in research and drug development. The study was published in June in Nature Communications.

The discovery—that expo-sure to lipids activates a gene called MTHFD2 in the walls of blood vessels—was made by researchers from the Institute for Cardiovascular Physiology of Goethe University in Frankfurt, Germany, and the Department of Genetics and Genomic Sciences of the Icahn School of Medicine at Mount Sinai in New York. The researchers used a computational model of the cells lining blood vessels in the human heart devel-

oped at Mount Sinai.Oxidized phospholipids are

abundant in the arterial plaque that causes atherosclerosis, and they are thought to promote ath-erosclerosis progression. Howev-er, the specific cellular processes caused by these lipids on the

arterial surface are still not well understood. The cells composing the inner surface of blood vessels, called endothelial cells, are at the forefront of the atherosclerotic process and therefore are a major focus of research into coronary artery disease.

“Endothelial cell response to lipids has been studied extensive-ly over the years, but it was still unknown that MTHFD2 was even functional in these cells,” said Dr. Jun Zhu, a professor of genetics and genomic sciences at the Icahn School of Medicine and head of data science at Sema4, a patient-centered predictive health compa-ny that is a Mount Sinai venture. Zhu is also co-senior author of the study. “Computational biological models such as the one we used in this study are allowing us to uncover a wealth of knowledge about complex diseases that we never could before.”

The international research team predicted and validated in follow-up experiments that the MTHFD2 gene plays a key role in endothelial cell response to oxi-dized phospholipids, and found

that MTHFD2 was also activated in endothelial cells in response to other factors, such as inflam-mation or a change in amino acid concentration.

“Our study showed that when the MTHFD2 gene is activated in endothelial cells in response to oxidized lipids, it sends out molecular ‘danger signals’ promot-ing inflammation and stimulating the atherosclerotic process,” said Dr. Ralf Brandes, director of the Institute for Cardiovascular Physi-ology and a professor of physiol-ogy at Goethe University. “These findings suggest that MTHFD2 could be a novel target to disrupt development and progression of atherosclerosis.”

The gene is known to be consis-tently activated in cancer, making it a promising target for cancer therapies as well. �

Late-Breaking NewsHERE ARE SOME NEWS ITEMS THAT ARRIVED TOWARD THE TAIL END OF THIS ISSUE’S PLANNING AND PRODUCTION PROCESS

Teamwork between cells fuels aggressive childhood brain tumorLONDON—Scientists have dis-covered that cancerous cells in an aggressive type of childhood brain tumor work together to infiltrate the brain, and this finding could ultimately lead to much-needed new treatments, according to a new study titled “Functional diversity and cooperativity between sub-clonal populations of pediatric glio-blastoma and di�use intrinsic pon-tine glioma cells” and published in Nature Medicine at the end of June.

In the study, funded by Cancer Research UK with support from Abbie’s Army and the DIPG Col-laborative, the researchers inves-tigated a type of childhood brain tumor called diffuse intrinsic pontine glioma (DIPG), shining a light on its most aggressive char-acteristic—its ability to leave the brain stem and send cancer cells to invade the rest of the brain. DIPG is incredibly di�cult to treat, and nearly all children with this type of cancer die within two years.

The researchers, led by a team at The Institute of Cancer Research in London, used donations of biopsy tissue and the brains of children who had died as a consequence of

DIPG to look deep into the tumor and learn more about its cells.

They found that DIPGs are het-erogenous, meaning they are made up of more than one type of cell. This enables the cells to “work” together to leave the original tumor and travel into the brain. The sci-entists say this shows how complex the genetic make-up of the disease is and that a multipronged attack is likely to be necessary for treatment.

As of yet, there is no cure for this illness. Children usually can’t have surgery because of the tumor’s loca-tion in the brain stem, which con-trols functions such as breathing, heart rate, blood pressure and swal-lowing. Moreover, other treatment options such as chemotherapy don’t work because of di�culty in getting the drugs into the brain, and many DIPG tumors have a resistance to chemotherapy.

“This is the first time we’ve observed this sort of interaction between different tumor cells in DIPG,” said Prof. Chris Jones, who led the study at The Institute of Cancer Research. “The idea that the cells are working together to make the disease grow and become

aggressive is new and surprising. Childhood cancers were thought to be very simple, but this shows us that isn’t always the case. Cru-cially, this gives us hope that we can develop new treatments.”

The study also shows that even cells that exist in relatively small

numbers in DIPG can exert a pro-found influence by leading cells from the main tumor into the rest of the brain to stimulate tumor growth and infiltration. In the case of one kind of cell, as it migrates it releases a chemical messen-ger called CXCL2, which has the

e�ect of calling other cells from the tumor to follow it.

The next stage of research will see the researchers looking for treatments that target the most important subpopulations of cells in the tumor and/or interfere with the cooperation between cells. �

In DIPG, tumor cells that begin in the brain stem can migrate throughout the brain because of “cooperation” between cells, with some types of tumor cells guiding other types to other locations in the brain.

Goethe University (pictured here) researchers in Frankfurt, Germany, along with scientists at Mount Sinai in New York, recently identified a new gene-activation pathway caused by lipids associated with coronary artery disease.

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Zika suppresses virus fighting cells

TALLAHASSEE, Fla.—More than two years after reports of skyrocketing Zika rates surfaced worldwide, questions still loom about this complicated virus—but Florida State University researchers think they are one step closer to finding answers. In an article published in the journal Stem Cell Reports, Dr. Hengli Tang, a professor of biological science, and his postdoctoral researcher Jianshe Lang took what the university called a “deep dive” into the differences between Zika and the Dengue viruses.

On the surface, these viruses are very similar—they are both delivered by mosquitoes and their genetic mate-rial is organized similarly. Yet, Zika is much more effective at penetrating the body’s natural barriers against infections and leaves behind a trail of devastating effects on infected fetuses.

“We were really looking at one spe-cific aspect,” Tang said. “Does Zika virus get to more sites because of the ability to disseminate through the body better than Dengue?”

Tang and Lang found Zika has a unique ability to ferry the virus throughout the body when most viruses would be stopped, and that seems to be due to a specific type of immune cell: the macro-phage. Macrophages float throughout the bloodstream and when a virus invades, they typically flock to the site of the dis-ease to fight it. This is the case in Dengue as with so many other invasions, but it’s not what happens when Zika enters the body, researchers found.

Researchers grew macrophages

from stem cells in Tang’s lab. They then exposed these cells to either the Zika virus or the Dengue virus. The macro-phages were then subjected to a test that measured the mobility of the infected cells. In the Dengue experiment, the mac-rophages were essentially immobilized as they stayed in one spot to fight the infection. The ones infected with Zika virus, however, maintained their ability to migrate on glass slides.

That could be why the Zika virus is so effective, Tang said, noting: “They’re hitching a ride on macrophages to other parts of the body.”

Furthermore, Tang said, it appears that the Zika virus is actively suppressing the macrophage’s ability to carry out its typical duties in fighting disease.

“Now the question is, with the increased ability to spread throughout the body, does Zika virus also use these infected macrophages to cross the pla-centa barrier, the blood-brain barrier and the testicular barrier?” Tang said. “If you understand how they cross these barri-ers, then you can develop more effective countermeasures to protect people.”

Broad and Bayer launch new efforts against heart failure

CAMBRIDGE, Mass.—The Broad Institute of MIT and Harvard has teamed up with Bayer to launch the Precision Cardiology Laboratory (PCL), a new endeavor that will pursue scientific insights aimed at developing new therapies for heart failure. According to the American Heart Association, more than 900,000 people are diagnosed with heart failure every year in the United States. The condition, which results from the failure of the heart to pump enough blood, is one of the most common reasons for hospitalization among adults. There are many causes of heart failure, and the PCL will use new tools and methods to more fully understand and treat them.

Research in the PCL will bring sci-entists from both organizations into an integrated work space at the Broad Institute, effectively combining Broad’s innovative methods for basic scientific discovery and the clinical expertise of its practicing physician/researchers with Bayer’s long history of drug develop-ment. The effort will be led by Broad Associate Member Patrick Ellinor, who directs the Cardiac Arrhythmia Service

at Massachusetts General Hospital and is a professor of medicine at Harvard Medical School.

The PCL’s initial goal is to develop high-resolution, single-cell maps of cardiovascular tissues in human and animal models. Using tissue samples donated by healthy individuals as well as people suffering from cardiovascular disease, researchers will build datasets to accelerate insights into heart failure.

“Such high-resolution maps of cells and tissues will be a profound asset for understanding heart failure and for developing new and better drugs,” said Ellinor. “I am extremely excited by the potential of this expanded partnership to benefit patients.”

The Broad-Bayer partnership began in 2013 with an oncology program. In 2015, the organizations launched a cardiovascular-specific collaboration aimed at using genomics to better under-stand cardiovascular disease. Now, the

PCL will use non-genomic approaches to jumpstart the development of new therapeutics for heart failure. Through this expanded partnership, Bayer is dedicating an additional $22 million to the collaboration over the next five years.

“The Broad Institute is an important and strategic partner for Bayer, enabling us to deepen our understanding in the area of cardiovascular diseases, and we are looking forward to extending our col-laboration even further,” said Dr. Joerg Moeller, member of the executive com-mittee of Bayer AG’s Pharmaceuticals Division and Head of Research and Development. “Joint laboratories are a novel partnering model for industry and academia and will bring Bayer and Broad Institute cardiovascular research to the next level.”

A new collaboration to discover new antibiotics

MONTPELLIER, France—Deinove, a biotech company that discovers, develops and produces high-value compounds from rare bacteria, has announced a col-laboration with bioMérieux, a major player in in-vitro diagnostics, to explore new strains and multiply opportunities to discover new antibiotics.

The AGIR (Antibiotics against Resistant Infectious Germs) program,

led by Deinove and its subsidiary Deinobiotics, is supported by the Investments for the Future Program. It aims to discover new antibiotics by systematically exploring the potential of living systems—specifically, the great diversity of microorganisms.

As the holder of one of the largest bac-terial strain banks in the world, bioMéri-eux, which specializes in the diagnosis of infectious diseases, will provide Deinove with more than 250 strains representing 130 different species.

Deinove and bioMérieux have jointly selected the strains for this project tar-geting a biological diversity. While most current research focuses on a small number of known strains, Deinove has structured its AGIR program around the exploration of an extensive and diverse range of bacteria. Capitalizing on its technology allowing it to automate and accelerate the analysis of large quanti-ties of strains, Deinove aims to maximize

the opportunities for discovering new antibiotic structures.

“For more than 55 years, bioMérieux has taken forward the diagnosis of infec-tious diseases to improve patient care. We are very pleased to share our deep bacteria knowledge with Deinove to support discovery of new antibiotics. Given the threat to public health repre-sented by the rise in bacterial resistance, the search for new treatment options is essential and we are proud to be involved,” said Marie-Françoise Gros, medical director of bioMérieux.

Added Emmanuel Petiot, CEO of Deinove, added: “This is a new example

of our approach that aims to explore, as widely and as quickly as possible, the diversity of the living world, thanks to the power of our platform. Working with bioMérieux, one of the leading infectious disease experts, is truly exciting for us.”

The AGIR project, operated by Bpifrance, is carried out by the Deinove Group together with the Charles Viollette Institute. It aims to implement an innova-tive strategy for the discovery of new antimicrobials—antibiotics and antifun-gal agents—through an integrated and automated approach. Its objective is to develop new technologies to optimize the platform for selecting, identifying and developing new antimicrobial molecules of natural origin.

APTO-253 can resume hematologic cancer trial

SAN DIEGO & TORONTO—June 29 saw Aptose Biosciences Inc. announce that the U.S. Food and Drug Administration had lifted the clinical hold on APTO-253, Aptose’s investigational drug for hematologic cancers. APTO-253 is said to be the only known clinical-stage mol-ecule that has the potential to directly inhibit expression of the MYC oncogene, shown to be a causative factor in many malignancies, including acute myeloid leukemia.

Up to 15 clinical centers are expect-ed to participate in the Phase 1b trial, and the screening and dosing will resume as soon as practicable for patients with relapsed or refractory AML or with high-risk myelodysplastic syndromes. Recent data also highlight the role of MYC gene dysregulation in B cell malignancies1, and Aptose hopes to pursue this patient population in the coming months.

The Phase 1b trial of APTO-253 had been placed on clinical hold as a con-sequence of an event that occurred at a clinical site with the infusion procedure. Ultimately, a root cause investigation determined that the event resulted from chemistry- and manufacturing-based issues, all of which were incorporated into a chemistry, manufacturing and control amendment to the Investigational New Drug application.

“We are eager to return APTO-253 back into the clinic,” said Dr. William G. Rice, chairman, president and CEO of Aptose. “Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.” �

American Society for Cell Biology (ASCB).....37 www.ascb.org

BD Biosciences ....................................................13 www.bdbiosciences.com

Bethyl Laboratories, Inc......................................25 www.bethyl.com

Cayman Chemical Co...........................................17 www.caymanchem.com

Horizon Discovery Ltd............................................7 www.horizondiscovery.com

INTEGRA Biosciences AG..................................19 www.integra-biosciences.com

PerkinElmer Corporation ......................................2 www.perkinelmer.com

Quanterix Corporation.....................................1, 40 www.quanterix.com

Sarstedt, Inc...........................................................21 www.sarstedt.com

Thermo Fisher Corporation...................................3 www.thermoscientific.com

A D V E R T I S E R ’ S I N D E X

“We were really looking at one specific aspect. Does Zika virus get to more sites because of the ability to isseminate through the body better than engue?”Dr. Hengli Tang of Florida State University

Zika and Dengue viruses may both be spread by mosquitoes and have similar genetic organization, but Zika seems to have special abilities to thwart attacks by mammalian macrophages.

Pharma giant Bayer will work with the Broad Institute to better understand and treat the causes of heart failure.

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