car-t therapy report september 2017 · 2017-09-14 · bpi car-t therapy report - september 2017 4...

1BPI CAR-T Therapy Report - September 2017

CAR-T Therapy ReportSeptember 2017News Spotlight This report highlights some of the major recent developments and important catalysts occurring in the CAR-T therapy field. It includes BPI news as well as predictive and competitive intelligence on clinical events in the space.


Report Contents

Development and commercial complexities of the cutting-edge therapy

EfficacyNovartis’ CAR-T triggers durability questions in pediatric ALL; Phase II ELIANA response rates likely to hold – experts

Novartis’ JULIET study in DLBCL unlikely to show differentiation to CAR-T competitors but potential for better toxicity profile – experts

Novartis, bluebird bio’s Phase I BCMA-targeting CAR-Ts favored over Adaptimmune’s NY-ESO-1-targeting TCR therapy for MM – experts

Nanjing Legend’s myeloma CAR-T yields comparable data to bluebird’s bb2121, but bluebird-Celgene partnership offers bigger boost – experts

CAR-Ts in solid tumors to be defined by combinations, targeted delivery mechanisms – experts

Safety EventsNovartis’ FDA AdCom safety discussion on CAR-T for pediatric ALL draws expert attention on long-term genotoxicity but concerns remain distant

Novartis’ reported lack of cerebral edema in CAR-T lymphoma study difficult to pinpoint, but potentially a clinical/cost advantage – experts

Kite Pharma’s CAR-T study cerebral edema death gives experts pause but may not adversely affect long-term outlook

Kite’s KTE-C19 likely to overcome toxicity fears for FDA approval in relapsed/refractory DLBCL, label may exclude TFL/PMBCL subgroups – experts

Manufacturing HurdlesNovartis CAR-T Phase II JULIET study in DLBCL briefly hit with manufacturing hiccup in Europe; experts say unlikely a long-term problem

Bluebird bio has capacity to make myeloma CAR-T for 10 patients per month – source

bluebird faces CAR-T manufacturing scale-out challenges in MM, but obstacles easily surmountable with large investment, Celgene partnership – experts

Kite’s success in DLBCL CAR-T rollout hinges on logistics, physician education, but uptake enthusiasm prevails – experts

ReimbursementKite’s KTE-C19 to encounter tough negotiations with payers despite unlikely hurdles to on-label reimbursement – experts

CAR-T pursuits in China face pricing headache for broad coverage, likely restriction to urban regions – experts

CAR-Ts’ place in lymphoma therapy uncertain given well-served treatment landscape, high cost – experts

Development UpdatesKite Phase I/II pediatric ALL study sees amendment to include patients treated with Amgen’s Blincyto to speed recruitment; Phase I portion has two slots left – source

Servier’s Phase I off-the-shelf CAR-T protocol amended to include ALL only, excluding CLL - sources

Western CAR-T companies pursuing China will face IP hurdles, but may gain branding edge – experts

Western CAR-Ts face Chinese development hurdles due to uncertain regulatory landscape – experts

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DEVELOPMENT AND COMMERCIAL COMPLEXITIES OF THE CUTTING-EDGE THERAPY

In recent years, hematology-oncology drug development has been abuzz with the potential of chimeric antigen receptor T-cell (CAR-T) therapies. That potential became a reality on 30 August when the FDA gave its first approval to a CAR-T therapy, Novartis’ Kymriah (tisagenlecleucel), for acute lymphoblastic leukemia (ALL) in children and young adults. The approval followed a unanimously favorable 12 July vote by the FDA Oncologic Drugs Advisory Committee (ODAC) and happened well ahead of the 3 October approval verdict date the agency had set. Novartis’ stock rose 2% on the news amid significant industry, investor and media excitement. Also nearing approval is Kite Pharma’s axicabtagene ciloleucel (or “axi-cel”) for aggressive non-Hodgkin’s lymphoma (NHL), as Kite said in August that the FDA will not hold an ODAC meeting for the drug.

Yet, beyond the usual talk of dazzling efficacy and blockbuster potential, BioPharm Insight (BPI) looks at some of the lingering issues and expert deliberations on how these transformational CAR-Ts will be both accepted and logistically implemented in the clinic. Besides Novartis and Kite, the other major players are Juno Therapeutics and bluebird bio, but other big oncology companies are watching eagerly to see how these new therapeutics will pan out commercially following accelerated development and potential approvals.

BPI data shows the global combined sales of Kite’s axi-cel, Juno’s JCAR017 and Novartis’ tisagenlecleucel-T are expected to reach more than USD 2.6bn in 2022. Diseases that these CAR-T therapies are targeting include pediatric and adult ALL, diffuse large B-cell lymphoma, multiple myeloma and chronic lymphocytic leukemia. The field is also slowly branching into solid tumors like glioblastoma, though these are much further behind in development.

BioPham Insight coverage dives into the debate among clinical trial investigators and other Key Opinion Leaders (KOLs) on durability of responses in specific indications along with questions on relapse rates after infusion. With such expedited development paths, experts point to many unknowns on how efficacy may play out in the clinic. Meanwhile, cases of deaths in patients and safety events like cerebral edema, have also placed a cloud on the therapies’ safety profiles, and experts have discussed the potential for these events to be a class effect versus specific to the competing CAR-T constructs. Manufacturing is also an anxiety when it comes to scaling up for a commercial launch, as sources have told BPI of manufacturing issues during trials that in turn have led to logistical issues with administration to patients. Lastly, as a new, highly innovative and transformational therapy, reimbursement experts question potential pricing models, which may come under heavy scrutiny in front of payers post launch. Lastly, as a new, highly innovative and transformational therapy, reimbursement experts question potential pricing models, which may come under heavy scrutiny in front of payers post launch. Novartis announced the therapy would cost USD 475,000, which does not include ancillary costs -- including hospitalization and the use of Roche’s Actemra to treat cytokine release syndrome (CRS) -- and cost benefit discussions are likely to intensify.

Introduction


30 SEPT 2016

• Remission durability uncertainty underlines likely need for therapy after CAR-T

• Yet, CD19-negative relapse concerns muted due to post-CAR-T treatments

Novartis’ (VTX:NOVN) Phase II CTL019 (tisagenlecleucel-T) has experts impressed with its response rates in pediatric acute lymphoblastic leukemia (ALL), but the ongoing question is how durable those responses will be.

The Phase II ELIANA study (NCT02435849) will likely show complete remission (CR) rates consistent with what has been shown so far, some experts said, though CR rates and relapse-free survival (RFS), a measure of durability, could drop somewhat as time goes on.

An ongoing concern is that many patients relapse, and often the disease that comes back is negative for CD19 antigen expression, experts agreed. However, it is likely patients will continue to receive additional therapies after tisagenlecleucel-T such as allogeneic stem cell transplant (alloSCT) and other CAR-Ts, some added.

This news service reported 28 September a Novartis spokesperson’s statement that the company intends to present data from ELIANA at the 2016 ASH meeting, despite an analyst report nine days before saying data was expected in 2017.

The spokesperson declined to comment on the data further except to reiterate that the company plans to continue moving ahead with tisagenlecleucel-T in pediatric relapsed/refractory ALL as planned, with anticipated FDA and EMA regulatory filings next year. ELIANA’s primary endpoint is percentage of patients getting CRs and CRs with incomplete hematological recovery (CRi) six months after administration.

CRS IMPRESSIVE, BUT CONCERN OVER DURABILITY

The CR rates seen with CTL019 in studies like a Phase I pediatric ALL trial (NCT02374333) presented at the 2015 ASH meeting are likely to persist in ELIANA, said Dr William Slayton, division chief, Pediatric Hematology/Oncology, University of Florida Shands Children’s Hospital, Gainesville. Even in older Phase I studies (NCT01626495; NCT01029366), the Novartis CAR-T still produced a 90% CR rate in children and adults, noted Dr Cameron Tebbi, professor, pediatrics, College of Medicine, University of South Florida, Tampa, agreeing that ELIANA would probably show a similar rate.

Compared with overall response rates (ORR) in the 70s

among non-Hodgkin’s lymphoma patients, CTL019 has shown ALL CR rates in the 90% range, Tebbi noted, pointing to published data that also included 15 patients with prior alloSCT (Maude et al. N Engl J Med. 2014 Oct 16;371(16):1507-17). A follow-up to one of the studies (NCT01626495) included in the publication presented at the 2016 ASCO meeting showed a 93% CR rate among 59 pediatric ALL patients one month after infusion.

The RFS rate at 12 months in the ASH abstract marks a bit of a drop from RFS at six months, but it is still good considering how heavily pretreated patients in the study were, said Dr Hanumantha Pokala, assistant professor of pediatric hematology/oncology, College of Medicine, University of Oklahoma, Oklahoma City. There will likely be a further drop at 24 months, and further drops in RFS would seem to validate some physicians’ concerns that alloSCT is needed after successful CAR-T therapy for long-term survival in most patients, he added.

While some patients could be cured of ALL from taking CAR-T, the cure rate could be expected to fall a little more as time goes on, Slayton said. Rather than just CR rates, the question is how durable those CRs will be, he added.

At the same time, in the group of patients receiving CAR-T, just getting into remission is a feat unto itself, considering how pretreated the patients are and that remission is being achieved with a single intervention, Slayton said. As such, durability is not in and of itself as important as achieving remission.

Among 53 patients in the Phase I study presented as ASH, the CR rate was 94%. CR/CRi rates were measured in that study at 12 months, according to ClinicalTrials.gov, though at

An ongoing concern is that many patients relapse, and often the disease that comes back is negative for CD19 antigen expression, experts agreed. However, it is likely patients will continue to receive additional therapies after tisagenlecleucel-T such as allogeneic stem cell transplant (alloSCT) and other CAR-Ts, some added.

Novartis’ CAR-T triggers durability questions in pediatric ALL; Phase II ELIANA response rates likely to hold - experts

Intelligence | Efficacy


median follow-up of 10.6 months (range 1-39 months), only six of 29 patients remained in CR had received subsequent treatment like donor lymphocyte infusion or alloSCT, according to the abstract. Forty-five responding patients became minimal residual disease (MRD) negative by Day 28, followed by two more who became negative by three months.

Patients in the Phase I study received a median dosage of 4.3x10^6/kg cells, ranging from 1 to 17.4x10^6/kg. ELIANA doses them at 2 to 5x10^6/kg and allows up to 2.5x10^8/kg.

There has been a lot of deserved excitement about CAR-T approaches in lymphoid malignancies like ALL, which have resulted in responses among patients with highly refractory and relapsed disease, said Dr Mikkael Sekeres, director, Leukemia Program, Cleveland Clinic Taussig Cancer Institute, Ohio. Patients in ELIANA are required to be in their second or greater bone marrow (BM) relapse, any BM relapse after alloSCT, refractory to chemotherapy, ineligible for alloSCT or intolerant or failed after two lines of tyrosine kinase inhibitor therapy if they have Philadelphia chromosome-positive ALL.

Despite the high CR rates, however, it does seem that about 50% of pediatric ALL patients taking tisagenlecleucel-T relapse after a year, Sekeres said. As such, despite the amazing CR rates, when one takes the long view on it, it is not a panacea and not for everyone, he added.

The response rates are definitely great, but the concerns are about the disease relapsing and the clone transforming, Pokala said.

Among the 50 patients who responded, 20 who had a CR at one month subsequently relapsed, with three relapses occurring after subsequent alloSCT. Thirteen of those 20 relapses occurred with CD19-negative blasts. Furthermore, four of five patients previously refractory to Amgen’s (NASDAQ:AMGN) CD19-targeted monoclonal antibody Blincyto (blinatumomab) went into CR with tisagenlecleucel-T, but three subsequently relapsed with CD19-negative disease.

Yet, the risk of patients’ disease coming back as CD19-negative is not a risk to tisagenlecleucel-T overall because it is only one part of the treatment paradigm, Tebbi said. Indeed, most people would be very hesitant not to perform an alloSCT subsequent to the CAR-T therapy for curative purposes, assuming patients did not have a transplant in the past, Pokala said.

While there have been cases of children who stayed in remission after CAR-T treatment, most doctors would be nervous about only giving a CAR-T, he added. Meanwhile, Slayton cited an anecdote of a patient he had referred for treatment with tisagenlecleucel-T, subsequently relapsed and is now receiving an experimental CD22-based CAR-T that, like its CD19-targeting cousin, was also developed at the University of Pennsylvania, though he was uncertain if that patient had a CD19-negative relapse. A Phase I study (NCT02650414) of the CD22-targeting CAR-T in pediatric ALL, initiated in December 2015, is under way at the Children’s Hospital of Philadelphia.

In addition to the high CR rate, all but five patients in the ASH 2015 abstract developed Grade 1-4 cytokine release syndrome (CRS). However, treatment with Roche’s

(VTX:ROG) autoimmune disease treatment Actemra (tocilizumab) and the steroid dexamethasone has been able to reduce incidence of that toxicity, Tebbi and Pokala noted.

Novartis’ market cap is CHF 199.7bn (EUR 183bn).

by Alaric DeArment in New York



12 MAY 2017

• Tisagenlecleucel-T's efficacy appears in line with Kite's axi-cel

• Neurotoxicity potentially better, but confirmatory data neede

Novartis’ (VTX:NOVN) Phase II JULIET data for tisagenlecleucel-T in diffuse large B-cell lymphoma (DLBCL) is not expected to show any differentiation from its chimeric antigen receptor T-cell (CAR-T) therapy competitors, namely Kite Pharma’s (NASDAQ:KITE) axicabtagene ciloleucel (axi-cel).

Experts pointed to hints that Novartis’ CAR-T may have a better neurological toxicity profile over axi-cel based on presented data and the recent cerebral edema-linked death of a patient taking axi-cel. Still, they cautioned that more data was needed to clearly demonstrate any difference, and it likewise is unclear if the designs of the constructs have any bearing on their clinical performance.

Analysts expect JULIET (NCT02445248) data, due on 14 June, to be similar to that of Kite’s Phase I/II ZUMA-1 study (NCT02348216), but Kite shares may be volatile around the data release, according to reports. Kite completed its rolling BLA filing for axi-cel’s FDA approval in March, while Novartis is seeking FDA approval for tisagenlecleucel-T in pediatric ALL.

Tisagenlecleucel-T-- with its most advanced area of development in pediatric acute lymphoblastic leukemia (ALL) -- is expected to see sales across indications peak at USD 1.5bn in YE26, according to BioPharm Insight data. Axi-cel’s sales across indications are expected to reach USD 1.7bn at YE25, and Juno Therapeutics’ (NASDAQ:JUNO) JCAR017 is expected to generate lymphoma sales of USD 1.3bn at the same time. Data from JULIET is expected at the International Conference on Malignant Lymphoma (ICML) meeting in June in Lugano, Switzerland.

A Novartis spokesperson confirmed the JULIET presentation date, adding the company does not comment on other companies’ products, and data is embargoed ahead of ICML. Tisagenlecleucel-T, axi-cel and JCAR017 all target the CD19 antigen.

DIFFERENTIATION UNCLEAR, BUT HINTS OF BETTER TOXICITY

From the available data, the case remains that there does not seem to be any significant differences between tisagenlecleucel-T and the other anti-CD19 CAR-T products in terms of efficacy/toxicity, and JULIET will unlikely unveil

any more differentiation, said Dr Amanda Cashen, associate professor, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. The companies each designed their trials with somewhat different inclusion criteria, and while there appears to be differences in efficacy and toxicity between the DLBCL and ALL populations as well as between adult and pediatric patients, she said nothing had emerged to differentiate between the constructs themselves.

Patients in JULIET have at least two prior therapy lines, according to ClinicalTrials.Gov, while ASH data presentations stated patients in the Phase I Transcend NHL 001 study of JCAR017 and ZUMA-1, respectively, received at least three and a median five prior therapy lines (abstract nos. 4192 and LBA-6).

Even if differences in efficacy or toxicity do arise, it does not mean one therapy is better or worse, but rather depends on factors like how many prior lines of therapy patients have had, even though patients in the studies are heavily pretreated in general, said Dr Vijaya Bhatt, assistant professor, Internal Medicine, University of Nebraska Medical Center, Omaha, who is participating in ZUMA-1 and Transcend NHL 001.

Durability of responses will be the bigger question in JULIET and how tisagenlecleucel-T holds up against axi-cel and JCAR017 at 3-6 months, agreed Cashen and Dr Vaishalee Kenkre, assistant professor of medicine, University of Wisconsin Carbone Cancer Center, Madison. Complete responses (CRs) at 3-6 months have held up in ZUMA-1, so an educated guess would be that this would be the case in JULIET too, Cashen said.

A 57-patient Phase IIa study (NCT02030834) of tisagenlecleucel-T in lymphomas had data on 13 patients

The companies each designed their trials with somewhat different inclusion criteria, and while there appears to be differences in efficacy and toxicity between the DLBCL and ALL populations as well as between adult and pediatric patients, she said nothing had emerged to differentiate between the constructs themselves.

Novartis’ JULIET study in DLBCL unlikely to show differentiation to CAR-T competitors but potential for better toxicity profile – experts



presented at ASH 2016, showing a 52% overall response rate (ORR), including a CR rate of 38% at three months.

Generally, Cashen said, if patients remain in complete remission at three months, they will still be in remission at six months. It is hard to know if there will be a winner, but overall the CAR-Ts seem comparable in terms of response rates, Bhatt added.

Based on the ORR from tisagenlecleucel-T’s ASH data, along with the three- and six-month response rates reported in ZUMA-1, Kenkre said a reasonable hope would be to see at least 40% of patients in JULIET remaining in CR several months out from administration of therapy.

At the level of costimulatory domains used by the different constructs, there are some theoretical differences, Bhatt said. In particular, Cashen explained, it has been proposed that the 4-1BB costimulatory domain, which tisagenlecleucel-T uses, confers better persistence of CAR-T cells, while axi-cel’s CD28 costimulatory domain has a faster onset of action. However, Cashen and Bhatt said it remains unclear if those theoretical differences will translate into clinical differences between the constructs.

On the other hand, based on published data there does seem to be the possibility of greater neurotoxicity risk with axi-cel, said ZUMA-1 investigator Dr Jonathan Friedberg, director, James P. Wilmot Cancer Center, University of Rochester, New York. With the recent report of a fatal cerebral edema event in the ZUMA-1 study, it is possible that tisagenlecleucel-T’s neurotoxicity could be better than axi-cel’s, said Dr Fabio Benedetti, physician, Division of Hematology and Bone Marrow Transplantation, G.B. Rossi Polyclinic Hospital, Verona, Italy, although it will have to be confirmed in a larger sample size.

At the same time, the neurotoxicity treatment has improved over time with experience, Benedetti added. In ZUMA-1, levetiracetam has been used to mitigate neurotoxicity, and BPI previously reported the study is also experimenting with using the drug prophylactically.

While the report of fatal cerebral edema with axi-cel drew expert concern, this news service reported 11 May, it did not alter axi-cel’s overall risk/benefit ratio. The Kite news prompted a 15% drop in that company’s share price after release on 8 May.

According to the tisagenlecleucel-T data from ASH, transient neurotoxicity included Grade 2-3 delirium in two patients and Grade 1 cognitive disturbance in another. ZUMA-1 reported neurotoxicity in 29% of 101 patients at ASH, according to a 6 December press release.

Still, on the topic of potential differentiation on toxicity, Bhatt said the main differences in toxicity over all appear to be not between the constructs, but between NHL and ALL patients, with toxicity in ALL being much higher. Another factor that makes a difference in terms of toxicity is tumor bulk, he added.

Novartis’ market cap is CHF 212.3bn (EUR 194.1bn).




20 SEPT 2016

• Anti-NY-ESO-1 TCR broad reach limited due to less frequent HLA expression

• Data premature to confirm superior efficacy of BCMA-CARTs over TCRs

• Exploration of additional antigens for most favorable target remains elusive

bluebird bio (NASDAQ:BLUE) and Novartis’ (VTX:NOVN) Phase I BCMA-targeting CAR-T therapies -- bb2121 and CART-BCMA, respectively -- will be the T-cell therapies likely to have the broadest applicability in multiple myeloma (MM), experts said.

Comparatively, T-cell receptor (TCR) therapies targeting the NY-ESO-1 antigen, such as Adaptimmune (NASDAQ:ADAP) and GlaxoSmithKline’s (LON:GSK) NY-ESO TCR will depend on patient expression of HLA-A2, and relatively limited expression of that antigen among MM patients thus limits the ability to apply it across the patient population, some experts noted.

B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) therapy development programs in MM include bluebird and partner Celgene’s (NASDAQ:CELG) 50-patient Phase I study CRB-401 (NCT02658929) of bb2121, which started in February this year. In addition, a 15-patient Phase I study (NCT02546167) of Novartis’ CART-BCMA is also underway, led by the University of Pennsylvania Abramson Cancer Center in Philadelphia.

Adaptimmune is running a Phase I/IIa study (NCT01352286) of NY-ESO TCR in 26 patients, with a primary completion date of April 2021.

Sales for bb2121 are expected to reach USD 459m by YE25, according to an analyst report, while sales for Adaptimmune’s NY-ESO-1 in MM are expected to reach USD 601m by YE21, according to another report. Data from the bb2121 study is expected in 2017, while updated data for NY-ESO TCR in MM may be at the European Society of Medical Oncology meeting in October, according to analyst reports.

Adaptimmune did not offer comment, and bluebird did not respond to a request for comment. A Novartis spokesperson noted that the company continues to focus on the CAR-T programs where it sees meaningful benefit to patients, and early research programs like the one for the BCMA CAR-T continue.

BCMA CARRIES BROADER APPLICABILITY

BCMA is a better target for MM because NY-ESO-1 is HLA-restricted given only about 20% of the population is HLA-expressing, said Dr Amrita Krishnan, director, Multiple Myeloma Program, City of Hope, Duarte, California. Indeed, NY-ESO-1’s HLA dependence means it has limited applicability and utility, and BCMA is also more widely expressed than NY-ESO-1, agreed Dr Rachid Baz, associate member, Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, Florida. However, it is still not clear how many patients will ultimately have NY-ESO-1, nor is it known whether BCMA-targeting CAR-Ts or NY-ESO-1-targeting TCRs will be more effective in MM, he said.

In the ongoing Adaptimmune TCR study, 34% of patients positive for HLA-A2 also expressed NY-ESO-1 and/or LAGE-1 antigens, making them eligible for the study (Rapoport et al. Nat Med. 2015 Aug; 21(8): 914-921). Clinical responses were seen in 16 of 20 advanced MM patients who took NY-ESO TCR, with a median progression-free survival (PFS) of 19.1 months. Targeting more than one antigen combined with tumor-specific TCRs restricted to additional common HLA antigens should make the therapy available to most patients, according to the study. However, a review stated that because the cells are HLA-dependent, the approach has limited utility compared to CAR-T cells (Kocoglu, Badros. Pharmaceuticals (Basel). 2016 Mar; 9(1): 3).

BCMA is almost ubiquitously expressed on plasma cells, without many other sites of expression, and it represents the most logical choice of antigen to target in MM, said Dr Sagar Lonial, chair, Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia. There is more expression of BCMA on the majority of malignant plasma cells, which thus makes it a more applicable target

Indeed, NY-ESO-1’s HLA dependence means it has limited applicability and utility, and BCMA is also more widely expressed than NY-ESO-1, agreed Dr Rachid Baz, associate member, Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, Florida.

Novartis, bluebird bio’s Phase I BCMA-targeting CAR-Ts favored over Adaptimmune’s NY-ESO-1-targeting TCR therapy for MM - experts



than NY-ESO-1, agreed Dr Mecide Gharibo, hematologist/oncologist, Cancer Institute of New Jersey, Rutgers University, New Brunswick.

Study investigator for CRB-401 Dr Jacob Laubach, clinical director, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts, roughly estimated that bluebird’s study of bb2121 is enrolling patients who have 80% of MM plasma cells expressing BCMA.

INTEREST IN ADDITIONAL TARGETS

It is unclear which targets should be favored for MM at this early stage, said Gharibo, adding additional targets should be explored, and targeting more than one antigen could help make T-cell therapies more effective.

For example, another target that could be explored is the CS1 antigen, said Dr Sundar Jagannath, director, Multiple Myeloma Program, Tisch Cancer Institute at Mount Sinai, New York. Chimeric antigen receptor natural killer (CAR-NK) cells targeting CS1 have been shown to enhance in vitro and in vivo activity against MM (Chu et al. Leukemia. 2014 Apr; 28(4): 917- 927). Even CD19 could be a target worth exploring because CD19-targeting CAR-Ts have provided some benefit in MM patients despite that antigen not being widely expressed in MM, Baz noted, pointing to cases in a Phase I study done by Novartis showing MM patients benefiting from CD19 CAR-T therapy, (N Engl J Med 2015; 373:1040-1047).

An advantage to targeting multiple antigens is to reduce the potential for antigen escape, which is one mechanism of antigen resistance, Baz said. A Phase I study (NCT02374333) of Novartis’ CD19-targeting CTL019 in children and young adults with acute lymphoblastic leukemia (ALL), concluded that disease recurrence with cells that have lost CD19 expression is an important mechanism of resistance to the therapy, according to a 2015 ASH abstract (no. 681). In the abstract, 13 of 20 relapsing patients - out of 50 who achieved complete remissions - had lost CD19 expression at recurrence.

For now, at least in myeloma, it remains unknown how levels of expression of a particular epitope or target will influence the activity of the CAR-T construct, Laubach said.

Novartis’ market cap is CHF 210.3bn (EUR 192bn). Celgene’s is USD 83.4bn, while bluebird’s is USD 2.7bn. Adaptimmune’s is USD 484.8m.




7 JULY 2017

• Efficacy differences may be due to number of prior therapies, not constructs

• Celgene’s myeloma connections, reputation gives bluebird market advantage

• LCAR-B38M’s bispecific targeting may lessen risk of resistance to therapy

Nanjing Legend Pharmaceutical’s chimeric antigen-receptor T-cell (CAR-T) LCAR-B38M has impressive Phase I/II multiple myeloma (MM) data, but experts found little to distinguish its safety or efficacy from competitor bluebird bio’s (NASDAQ:BLUE) bb2121, which has a significant head start on Western development.

While the 100-patient Phase I/II LCAR-B38M study (NCT03090659) showed a slightly higher overall response rate (ORR) than bb2121’s Phase I study (NCT02658929) and slightly higher toxicity, experts said the toxicity differences between the B-cell maturation antigen (BCMA)-targeting CAR-T therapies were not dramatic enough to be clinically significant, and the efficacy differences may be due to bb2121 patients being more heavily pretreated. While analysts have said Legend’s data positions LCAR-B38M as a potential competitor to bb2121, experts said, bluebird has an upper hand in the US market owing to its manufacturing partnership with Celgene (NASDAQ:CELG) -- a company with a strong connection to the MM community. Therefore Nanjing, China-based Legend faces the burden of forming similar partnerships if it wishes to bring its CAR-T into the more lucrative western markets.

Both companies exhibited data from their Phase I studies in oral and poster presentations at last month’s American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) annual meetings in Chicago and Madrid, respectively.

Legend plans to start a US clinical trial in early 2018, according to an ASCO press release. Legend, whose parent is GenScript (HKG:1548), originally planned to do the US trial by itself, however, CEO Frank Fan said it would likely seek a partner, but did not elaborate further. bluebird did not respond to requests for comment.

DATA IMPRESSIVE, COMPARABLE TO BLUEBIRD’S

While Legend’s data is not yet very mature, it was impressive, especially in light of patients showing a high response rate after a single infusion, said Dr Stathis Kastritis, professor of hematology, University of Athens, Greece.

As of a 20 February data cutoff, 100% of 22 patients in the LCAR-B38M study had achieved an objective response, including six minimal residual disease-negative complete responses (MRD-negative CRs) and 14 very good partial responses (VGPRs), according to data presented at the EHA meeting (abstract no. S103). Meanwhile, bluebird presented data on 18 patients showing an ORR of 89%, including four CRs, seven VGPRs and five PRs, according to its ASCO data (abstract no. 3010). LCAR-B38M’s safety was also quite good and not very high, even though it appeared slightly higher than bluebird’s toxicity, Kastritis added.

However, the toxicity profiles of the two CAR-T constructs are not dramatically different with no high incidence of cytokine release syndrome (CRS) with either, said Dr Ashutosh Wechalekar, consultant hematologist, University College London.

CRS was the most common toxicity from LCAR-B38M, with two patients experiencing it at severe Grade 3 and one at life-threatening Grade 4, while other cases were mild, and all were controllable with anti-inflammatory drugs or Roche’s (VTX:ROG) Actemra (tocilizumab). In the bb2121 study, Grade 1-2 (mild-moderate) CRS occurred in 73% of 11 patients, while no toxicities greater than Grade 2 occurred.

The efficacy overall appears comparable between the two therapies, and even though Legend had a higher CRS rate, it is likely that with time there will be more CRS with bluebird’s product as the patient sample size grows, said Dr Saad Usmani, director of plasma cell disorders, Levine Cancer Institute, Charlotte, North Carolina. While one difference between the two constructs is that LCAR-B38M has epitope bispecific targeting – which bb2121 does not – bb2121 investigator Dr Noopur Raje, director, Center for Multiple

The efficacy overall appears comparable between the two therapies, and even though Legend had a higher CRS rate, it is likely that with time there will be more CRS with bluebird’s product as the patient sample size grows, said Dr Saad Usmani, director of plasma cell disorders, Levine Cancer Institute, Charlotte, North Carolina.

Nanjing Legend’s myeloma CAR-T yields comparable data to bluebird’s bb2121, but bluebird-Celgene partnership offers bigger boost – experts



Myeloma, Massachusetts General Hospital, Boston, said the two constructs’ efficacy and toxicity did not appear to differ.

It is unclear if the different targeting explains the slight difference in response rates, which may be due not to the constructs themselves but the patients, Kastritis said, noting that patients in the Chinese study were less heavily pretreated than those in the bb2121 trial.

Among patients in the Chinese study, 11 patients were refractory to chemotherapy, proteasome inhibitors and immunomodulators, while 11 were resistant to double prior treatments – chemotherapy and proteasome inhibitors or immunomodulators – and four had relapsed after autologous stem cell transplant, according to the EHA abstract. In the bb2121 study, patients had received a median seven prior lines of therapy, according to the bluebird press release. Even one more prior line of therapy can make a huge difference in how a patient responds to a therapy like CAR-T, Kastritis added.

Yet, the bispecific targeting could raise the chances of inducing responses to the therapy, Wechalekar said, because it can lessen the chances of cells becoming resistant. It has been the case that MM patients resistant to Roche’s Rituxan (rituximab) can still respond to Roche’s other antibody Gazyva (obinutuzumab) because the drugs target different receptors of CD20, he explained.

CELGENE PARTNERSHIP GIVES BLUEBIRD A BOOST

Legend will need to partner in order to bring its therapy to the US, Wechalekar said. The bluebird-Celgene partnership has the advantage of Celgene’s links to the entire myeloma community, whereas Legend lacks those links, he added. Celgene’s immunomodulatory drugs Thalomid (thalidomide), Revlimid (lenalidomide) and Pomalyst (pomalidomide) – marketed as Imnovid in Europe – are widely used as backbone therapies for MM. Celgene and bluebird formed the partnership focused on BCMA-targeting product candidates in March 2013.

Indeed, it is not only connections with the myeloma community but also Celgene’s history of running validated US and European trials that has resulted in doctor confidence in the results, said Dr Evangelos Terpos, associate professor of hematology, University of Athens, Greece. He added, he would feel more confident if the study was run by a company with an established reputation in clinical trials, like Celgene, as opposed to a relatively unknown one. Even with strong data, a trial in the US or Europe will still be necessary to be marketed in the western world, and the CAR-T will not likely be used based on Chinese data. However, he said that did not mean Legend’s data was not good, as he had seen impressive data from some Chinese companies like BeiGene (NASDAQ:BGNE), with its Phase III Bruton’s tyrosine kinase inhibitor, BGB-3111. Celgene and Beigene announced 6 July that Celgene had acquired ex-Asia rights to its Phase II PD-1 inhibitor, BGB-A317.

GenScript’s market cap is HKD 7.7bn (USD 988.2m).




22 MAR 2016

• Checkpoint blockade, survival factors addition to combat immunosuppression

• Direct delivery routes in head and neck and peritoneal cancers being explored

The potential for chimeric antigen receptor T-cell (CAR-T) research in solid tumors will be improved with combinatorial approaches that target the unique set of challenges in these cancers, experts said.

Additionally, the potential to directly deliver the CAR-T cells to the tumor in certain cancers present an opportunity to enhance the immune response compared to liquid tumors, they noted.

While research in solid tumors remains behind hematological cancers, some preclinical strategies under exploration include using CAR-Ts to prime the tumor microenvironment before adding checkpoint blockades and other immunotherapies, experts said.

A number of Phase I trials exploring CAR-Ts in solid tumors like glioblastoma, head and neck cancer and breast cancer are under way at large cancer centers like Memorial Sloan-Kettering Cancer Center, New York; University of Pennsylvania; Moffitt Cancer Center, California, and University of Texas MD Anderson Cancer center. Additionally biotechs including Emeryville, California-based Eureka Therapeutics, Ziopharm Oncology (NASDAQ:ZIOP), Bellicum Pharma (NASDAQ:BLCM) and larger players like Novartis (VTX: NOVN), Juno Therapeutics (NASDAQ:JUNO) and Kite Pharma (NASDAQ:KITE) are exploring the potential of CAR-Ts in solid tumors.

The University of Pennsylvania/Novartis alliance, presented Phase I safety data at the American Association for Cancer Research annual meeting in 2015. The results were from five patients with mesothelin-expressing solid tumors who received CAR-T therapy and showed the therapy to be well tolerated.

It is likely that in a years’ time, up to 20 additional industry- and investigator -sponsored studies could initiate for CAR-T therapies in solid tumors, noted Dr Sophie Papa, clinical scientist, King’s College London, UK.

COMBINATORIAL APPROACHES

To make the CAR-Ts less susceptible to an immunosuppressive environment, a combination with checkpoint blockades can be useful, said Bruce Levine, professor, Cancer Gene Therapy, University of Pennsylvania

Abramson Cancer Center, Philadelphia. CAR-Ts can cause the initial damage, and then checkpoint inhibition can support the tumor killing and prevent T cells from being anergized, a state when they’re present but inactive, explained Papa. Also, previously anergized T cells can then recognize the tumor cells, she added.

Combinations with checkpoint inhibitors can activate certain pathways leading to the secretion of pro-inflammatory cytokines, which serve as a signal for other immune cells -- possibly having an avalanche effect, said Dr Stephen Gottschalk, director, Basic & Translational Research Division, Texas Children’s Cancer Center, Houston.

Additionally, once CAR-Ts are engaged with the target, many solid tumors either already express PD-1 or can be induced to, noted Saul Priceman, assistant research professor, City of Hope National Medical Center, Los Angeles, California. Suppressing that through checkpoint inhibitors would be important for the overall response, he added.

Also, CAR-Ts can be inhibited by the same mechanisms as normal T cells, and blocking checkpoints like PD-1 may be able to turn those mechanisms off, said Charles Sentman, professor, Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.

Under the Penn/Novartis alliance, a research group published preclinical data on the addition of a switch receptor to CAR-T cells blocking PD-1 mediated immune suppression in solid tumors, according to a 15 March press release.

However, the combination approach still needs to be tested, because so far, only preclinical studies have been done, Gottschalk said. Even though checkpoint inhibitors have been promising in other cancers, only a subset of patients achieve long-term remissions, added Papa.

While research in solid tumors remains behind hematological cancers, some preclinical strategies under exploration include using CAR-Ts to prime the tumor microenvironment before adding checkpoint blockades and other immunotherapies, experts said.

CAR-Ts in solid tumors to be defined by combinations, targeted delivery mechanisms - experts



The potential toxicity issues that exist any time two powerful therapies are combined also need to be looked at, said Sentman. However, physicians have learned to manage the side effects due to checkpoint inhibitors, so the risk associated with combination therapies can be taken on, noted Papa.

Experts also pointed out that combination approaches would go beyond the approved PD-1/CTLA-4 inhibitors. PD-1 is just one of several suppressive pathways that could be targeted, Priceman said, adding that possible combinations could include those with chemotactic or survival factors. Cancers like prostate cancer are less immunogenic, but the balance can be tipped in the favor of immunotherapy working if it is combined with other approaches like a vaccine, Papa noted. The art is in finding things that can make tumors more immunogenic, perhaps by combining CAR-Ts with checkpoint inhibition or oncolytic viruses, she added.

DELIVERY MECHANISMS

Delivery will not be one size fits all, but if off-tumor toxicity is an issue, then directly delivering the CAR-Ts to the tumor might be a pragmatic approach, Papa said. Local delivery has been unique to the field because of its impact on safety, since it allows us to bypass a lot of side effects, Priceman said. This is an option in cancers that cause local damage like head and neck, ovarian, prostate, melanoma, brain tumors and mesothelioma, Papa said.

Intratumoral administration may help, but it requires a lot of skill because it is difficult to know the right spot for administration, Levine said. In indications like ovarian cancer, intraperitoneal administration is probably a bit easier, he added. Intravenous administration is convenient to use, since cells can go everywhere in the blood system, Sentman said. Local delivery requires a little more invasive work, but it can deal with some of the issues of systemic toxicity, he added.

While one theory is that CAR-Ts delivered intravenously can get any micro-metastases associated with the tumor, another states that targeting the tumor would induce the immune system to kill the micro-metastases, Sentman said.

However, targeting metastatic disease becomes difficult with local delivery of CAR-Ts, Gottschalk noted. In certain diseases like glioblastoma or head and neck cancer, local delivery can be explored, but that does not tackle the big problems with metastatic solid tumors, he added. There is also the question of how to ensure delivery mechanisms are consistent while conducting multicenter trials, Levine said.

In mesothelioma, the disease does not metastasize in the same way as other tumors and has a relatively contained environment, Papa said, making it easier to deliver therapies directly to the tumor region. In cervical cancer, even though patients die of metastatic disease, they have a lot of local regional tumor growth, so there could be some scope for immunotherapy there, she added.

Certain diseases are well suited to systemic delivery of CAR-Ts, Gottschalk said. In sarcoma, the lung is the primary site of metastases and all T cells end up there, which makes

it convenient for systemic administration, he added. Also, since the liver is so well-perfused, T-cell homing to the tumor site in hepatocellular carcinoma may not be problematic, Gottschalk said.

by Manasi Vaidya and Alaric DeArment in New York and Hamish McDougall in London



18 JULY 2017

• Viral vectors used in tisagenlecleucel-T cut risk of insertional mutagenesis

• Replication-competent retrovirus risks remain a remote concern

• Risk of genotoxicity remains, but experience does not bear it out

Genotoxicity and insertional mutagenesis flags raised during Novartis’ (VTX:NOVN) FDA AdCom meeting for tisagenlecleucel-T are valid for long-term safety but still just theoretical and should not be a concern for a final approval, experts said.

The 10 members of the Oncologic Drugs Advisory Committee (ODAC) voted unanimously on 12 July to recommend that tisagenlecleucel-T – a CD19-targeting chimeric antigen receptor T-cell (CAR-T) therapy – be approved for pediatric acute lymphoblastic leukemia (ALL) based on results of the 72-patient Phase II ELIANA study (NCT02435849).

Novartis’ stock rose 2% following the news, which also drew praise from Arie Belldegrun, CEO of competitor Kite Pharma (NASDAQ:KITE), which is developing the CD19-targeting CAR-T axicabtagene ciloleucel (axi-cel). The PDUFA date for Novartis’ BLA is 3 October, and tisagenlecleucel-T’s sales are expected to peak at USD 1.5bn at YE26, according to BioPharm Insight data.

Vector-associated risks from tisagenlecleucel-T are low but not entirely eliminated, according to an FDA summary of potential risks, which included replication-competent retrovirus (RCR) and insertional mutagenesis. Analysts said the ODAC’s discussion was overall very positive with potential concerns ultimately trumped by outstanding clinical results, according to a report.

GENOTOXICITY CONCERN PRESENT BUT PERIPHERAL

Long-term it remains unknown what the outcome will be with CAR-T cells and its safety, hence the long-term follow-up study (NCT02445222) and registry, which monitors patients for 15 years and requires families to consent to receive the product, said Dr Michelle Hermiston, associate professor, Pediatrics, University of California San Francisco Benioff Children’s Hospital. Approval for tisagenlecleucel-T based on the ELIANA data is likely, Dr William Slayton, division chief, Pediatric Hematology/Oncology, University of Florida, Gainesville. All experts agreed on a likely approval, noting it as an important therapeutic step forward for pediatric ALL.

The registry will monitor patients for long-term safety signals like secondary malignancies and B-cell aplasia as well as short-term toxicities like cytokine release syndrome and neurotoxicity, a Novartis spokesperson said.

HIV-based vectors are relatively random in terms of where they insert genetic material, and there is the risk that if the insertion is random then it could promote other malignancies down the line, said Slayton.

Still, while the lentiviral vector spurs concerns about insertional mutagenesis, tisagenlecleucel-T’s developers have taken out the LMO2 gene that helped the gene be transcribed in the new cell, thus raising chances of insertional mutagenesis, noted Slayton and Hermiston. For all batches of tisagenlecleucel-T used in the AdCom’s analysis, integration sites were found to be highly polyclonal, with no evidence for integration favoring certain sites or for integration near specific oncogenes of concern like LMO2, the FDA backgrounder states.

The vectors used today indeed are much safer than the ones used in earlier generations of cell therapy studies, which caused a lot of transformational mutagenesis, but one would still worry about genetically altered T cells becoming cancerous in the long run, said Slayton. There have been numerous T-cell therapy trials in which cells were transduced with a gammaretroviral or lentiviral vector, with many using CAR-Ts for cancers, but to date there have been no reports of vector-related genotoxicity in trials using T cells, according to a backgrounder for the ODAC meeting. The reasons for the lack of vector genotoxicity are unknown, but may be related to T cells being differentiated, while stem cells are not.

In addition, one thing that is different from the earlier problems with insertional mutagenesis is that when earlier

Still, while the lentiviral vector spurs concerns about insertional mutagenesis, tisagenlecleucel-T’s developers have taken out the LMO2 gene that helped the gene be transcribed in the new cell, thus raising chances of insertional mutagenesis, noted Slayton and Hermiston.

Novartis’ FDA AdCom safety discussion on CAR-T for pediatric ALL draws expert attention on long-term genotoxicity but concerns remain distant

Intelligence | Safety


cell therapies were being tested in the 1990s and early 2000s, the transduction was being done into stem cells, whereas now it is being done into differentiated cells, namely T cells, Hermiston said. The Novartis spokesperson said earlier viral vectors were prone to genetic changes that could lead to the formation of a RCR vector, but tisagenlecleucel-T uses a vector with many improved safety features, and replication-competent viruses have not been observed with the CAR-T. There has also been no evidence of insertional mutagenesis and no cases of secondary cancers, she added.

Genotoxicity is possible, but in contrast with stem cells, the CAR-T cells are fairly short-lived, the spokesperson said. While there is evidence that tisagenlecleucel-T’s cells persist longer than axi-cel’s, there is no evidence of the lentivirus escaping outside the cells, she explained. Tisagenlecleucel-T uses the 4-1BB costimulatory domain, which has been associated with longer persistence of CAR-T cells in the blood relative to the CD28 domain, which axi-cel uses.

Tisagenlecleucel-T’s CAR protein comprises an extracellular portion that has a murine anti-CD19 single-chain antibody fragment and an intracellular portion containing CD3-zeta T-cell signaling and 4-1BB costimulatory domain, according to the FDA backgrounder. It is manufactured using a self-inactivating lentiviral vector containing modified sequences from HIV-1.

The risk is “not completely zero,” but small nonetheless, said Dr Ann Woolfrey, director, Unrelated Donor Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, highlighting the need to watch patients carefully following approval. But so far, she added, there have been no reports of RCR or genotoxicity associated with CD19-targeting CAR-T cells.

Additionally, Dr Edmund Waller, director, Bone Marrow and Stem Cell Transplant Center, Emory University, Atlanta, Georgia, said that while genotoxicity and RCR may be long-term safety concerns, the patients for whom Novartis is seeking a label for tisagenlecleucel-T would otherwise be dead from ALL so approval should not be at risk. On the other hand, he said there can be off-target integration of the CAR into other cells -- meaning ALL cells can express the CAR -- but the lentiviral vector overall is less genotoxic than gamma retrovirus constructs, said Waller, an investigator in the Phase II JULIET study (NCT02445248) of tisagenlecleucel-T in aggressive non-Hodgkin’s lymphoma.

By contrast, RCR -- even resulting from the lentiviral vector mutating and picking up additional material --is still just a theoretical concern, because the lentivirus is engineered to lack the necessary machinery for replication, Slayton said.





20 JULY 2017

• Speculation that cerebral edema differences may be related to constructs

• Potential for cerebral edema to appear later nevertheless could still exist

• If Novartis CAR-T’s edema is lower than Kite’s, could yield cost advantag

Novartis’ (VTX:NOVN) reported lack of cerebral edema in the Phase II JULIET study of CAR-T tisagenlecleucel-T in diffuse large B-cell lymphoma (DLBCL) has experts questioning whether it is due to the construct or some other factor, but it may give the cell therapy postapproval clinical and cost advantages over competitors, experts said.

Furthermore, one expert cautioned that some neurotoxicity that nevertheless occurred in JULIET (NCT02445248) could be mild forms of cerebral edema that went undetected, while another said more severe events were a future possibility.

The company said in a 7 June announcement of the interim JULIET data presentation that it had not produced any incidents of cerebral edema, let alone fatal ones. Following the presentation at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland last month, analysts said adverse events in JULIET were acceptable, but did not address cerebral edema specifically.

Reasons for the lack of cerebral edema with tisagenlecleucel-T – despite its appearance with other chimeric antigen receptor T-cell (CAR-T) therapies – have not been clearly determined, a Novartis spokesperson said. There are many differences between Novartis’ and other manufacturers’ production processes, as well as technical differences such as tisagenlecleucel-T’s 4-1BB costimulatory domain, versus the CD28 costimulatory domains used by Kite Pharma’s (NASDAQ:KITE) axicabtagene ciloleucel (axi-cel), she added.

LACK OF EDEMA POSSIBLY CONSTRUCT-RELATED

It is not clear why there is no cerebral edema with the Novartis construct versus what has been seen with axi-cel and Juno Therapeutics’ (NASDAQ:JUNO) now-defunct JCAR015, agreed investigators Dr Veronika Bachanova, associate professor of medicine, University of Minnesota, Minneapolis, and Dr Edmund Waller, professor, hematology and medical oncology, Emory University, Atlanta, Georgia. It could be a result of there simply not being enough patients who have been treated with it for a signal to appear, said Bachanova. The JULIET interim data included 85 patients,

according to Novartis’ press release. In Kite’s 142-patient Phase I/II ZUMA-1 study (NCT02348216) of axi-cel in DLBCL, the company noted it enrolled 111 and successfully treated 101, as of its April 2017 AACR presentation. Juno presented data on 44 patients in its Phase I Transcend NHL study (NCT02631044) at the ICML conference, according to a 17 June press releases.

However, Bachanova said it is difficult to confirm the events are due to the construct itself because there is no clear biological link. Meanwhile, Waller said cerebral edema and central nervous system toxicity generally may be due to activation by the CAR-T of microglia in the brain.

Bachanova also said cerebral edema is probably related to the patients and factors like their age, given that cerebral edema is more common in younger patients, whereas DLBCL patients’ median age tends to be 50-60. The median age in JULIET was 56 (range 24-75), according to an abstract at EHA 2017 annual conference (LBA2604). The median age among 111 patients in ZUMA-1 was 58 (range 25-76), according to data at the 2016 ASH meeting (abstract no. LBA-6). Among 39 patients in Juno’s Phase I study, it was 61 (range 37-79), according to data from the same ASH conference (abstract no. 4192).

According to the JULIET data, 11 of 85 patients experienced Grade 3-4 neurotoxicity. Previously, it was reported that one patient in ZUMA-1 developed cerebral edema and died, though this news service reported 11 May that despite giving experts pause, it may not adversely affect axi-cel’s long-term outlook. Prior to that, Juno announced 23 November 2016 that it placed the Phase II ROCKET study (NCT02535364) of JCAR015 in adult acute lymphoblastic leukemia (ALL) on clinical hold after multiple patients died from cerebral edema. However, Transcend NHL has reported that 18% of 44 patients in the trial’s main cohort experienced severe

Furthermore, one expert cautioned that some neurotoxicity that nevertheless occurred in JULIET (NCT02445248) could be mild forms of cerebral edema that went undetected, while another said more severe events were a future possibility.

Novartis’ reported lack of cerebral edema in CAR-T lymphoma study difficult to pinpoint, but potentially a clinical/cost advantage – experts



neurotoxicity, according to a 17 June press release, with no mention of cerebral edema.

Yet, Amorette Barber, assistant professor of biology, Longwood University, Farmville, Virginia, and JULIET investigator Dr Harald Holte, leader, Lymphoma Program, Oslo University Hospital, Norway, said the difference in cerebral edema incidence probably is due to construct design, in particular different costimulatory domains, which are involved with T-cell activation. Barber highlighted axi-cel’s CD28 costimulatory domain giving stronger and quicker but less enduring responses, versus tisagenlecleucel-T’s weaker but more persistent responses from its 4-1BB costimulatory domain as reason for the difference in cerebral edema. Nevertheless, it is hard to say what causes the cerebral edema, which could also be influenced by factors like tumor type, size and location, she added. For example, JCAR015 also used the 4-1BB costimulatory domain, but as it was studied in leukemia – often more spread throughout the body than DLBCL – that likely also contributed to the observation of cerebral edema in ROCKET, she said.

Dr William Slayton, division chief, Pediatric Hematology/Oncology, University of Florida College of Medicine, Gainesville, said he believes cerebral edema is related to cytokine release syndrome, a well-known side effect of CD19-targeting CAR-Ts related to their tumor cell-killing MOA.

The constructs themselves may indeed influence inflammatory signals because the different costimulatory domains may produce different intracellular events, said JULIET co-lead investigator Dr Richard Maziarz, professor of medicine, Oregon Health and Science University, Portland, who noted that early studies showed the cells can cross the blood-brain barrier.

Bachanova said some of the neurotoxicity commonly seen with CD19-targeting CAR-Ts may in fact be cerebral edema that has gone undetected, milder forms of edema that do not progress to more severe herniation (pressure in the skull). She expressed worry about underdiagnosing of cerebral edema in CAR-T trials like JULIET because it may not be easy to diagnose, as patients may not know they have herniation and hence not report it. Maziarz, meanwhile, left open the possibility that cerebral edema could show up later on in patients taking tisagenlecleucel-T.

Nevertheless, Holte said it is a clinical and cost advantage if patients do not have cerebral edema. For example, if Kite has confirmed cerebral edema links and prices axi-cel tens of thousands of dollars lower than tisagenlecleucel-T, the cost advantage is negated if patients nevertheless have to stay in the hospital for cerebral edema, which can cost USD 2,000 per day or even USD 5-10,000 per day in the intensive care unit, Maziarz said. That is where the toxicity profile comes into play, he said, as centers may select which CAR-T therapy to offer based on those factors.





11 MAY 2017

• Trial design or CAR-T formulation may require changes to mitigate toxicity

• Number of deaths vs population size within acceptable risk/benefit

Kite Pharma’s (NASDAQ:KITE) disclosure of a patient death from cerebral edema in the Phase I/II ZUMA-1 study of axicabtagene ciloleucel (axi-cel) in aggressive non-Hodgkin’s lymphoma has sparked some trepidation but is unlikely to doom the product, experts said.

The death could be problematic and may force changes to either the trial’s (NCT02348216) protocol or the formulation of the product itself, in the context of similar events that derailed Juno Therapeutics’ (NASDAQ:JUNO) competitor chimeric antigen receptor T cell (CAR-T) JCAR015 last year. However, experts said, it may not pose a significant problem from a risk/benefit and future market standpoint.

News of the patient death triggered a 15% decline in Kite’s stock price after the 8 May morning announcement. Axi-cel is anticipated to reach global sales of USD 1.7bn by YE25, according to BioPharm Insight data. Kite announced the completion of its rolling BLA filing on 31 March, and this news service reported 21 December 2016 that the FDA would likely approve the CAR-T. Analysts see the death as a potential speed bump but likely an isolated event.

A patient in the 142-patient ZUMA-1 trial experienced a neurologic event that progressed to fatal cerebral edema that was deemed related to axi-cel, according to the company’s 1Q17 quarterly earnings filing. Juno announced in its 4Q16 earnings that it would discontinue JCAR015’s development after five deaths from cerebral edema in the Phase II ROCKET study (NCT02535364) of adult acute lymphoblastic leukemia (ALL), according to a 1 March press release.

Kite did not respond to a request for comment.

EVENTS CAUSE CONCERN, BUT PROGRAM WILL LIKELY SURVIVE

While cautioning against extrapolation of the experience in Juno’s program to Kite’s, Dr Daniel Persky, director, Clinical Trials Office, University of Arizona Cancer Center, Tucson, said the news of the deaths from Kite’s product nevertheless gave him pause. It will be necessary, therefore, to find predictors of toxicity and, failing that, reformulate the product, he noted.

According to analysts, following Juno’s death announcement, the company suggested -- in an April 2017 presentation at the American Association for Cancer Research conference -- incorporating CD19-directed CAR-T therapy into the front-line, minimal residual disease setting could maximize benefit and minimize toxicity. However, the company has not indicated next steps to revive the program.

One patient death may not mean much for the overall risk/benefit profile, agreed investigator Dr Vijaya Bhatt, assistant professor, Internal Medicine, University of Nebraska Medical Center, Omaha, and Dr Barbara Savoldo, professor, Immunology, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill. Neurological toxicity is already known to occur with CAR-Ts like axi-cel, Bhatt added.

Data on 101 patients in ZUMA-1 presented at ASH 2016 showed Grade 3 or higher cytokine release syndrome (CRS) occurred in 13% of patients, while neurotoxicity at the same grades occurred in 29%, according to a 6 December 2016 press release. This news service reported 21 December 2016 that while axi-cel’s toxicity profile would likely draw attention from the FDA, it would not likely derail its approval potential.

In terms of its competitors, Phase I safety data showed Juno’s other CAR-T, JCAR017 in DLBCL, triggered Grade 4 neurotoxicity in two out of 14 patients (ASH 2016 abstract no. 4192), while transient neurotoxicity appeared in two of 13 patients receiving Novartis’ (VTX:NOVN) tisagenlecleucel-T (ASH 2016 abstract no. 3026).

As more patients took part in clinical trials of axi-cel, it was inevitable that the risk of fatal toxicities like cerebral edema increased, thereby allowing for such risks, Savoldo said. But

One patient death may not mean much for the overall risk/benefit profile, agreed investigator Dr Vijaya Bhatt, assistant professor, Internal Medicine, University of Nebraska Medical Center, Omaha, and Dr Barbara Savoldo, professor, Immunology, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill.

Kite Pharma’s CAR-T study cerebral edema death gives experts pause but may not adversely affect long-term outlook



even a single case of cerebral edema - generally a rare event - could be viewed as problematic for the axi-cel program, said Dr Fabio Benedetti, physician, Division of Hematology and Bone Marrow Transplantation, G.B. Rossi Polyclinic Hospital, Verona, Italy.

The more important thing is ensuring that the medical team administering CAR-Ts is properly trained in what toxicities to expect. Steroids and drugs like Roche’s (VTX:ROG) Actemra (tocilizumab) are typically used to manage CRS, while antiepileptic drugs are used for neurotoxicity, this news service has previously reported.

Indeed, mortality from CAR-Ts like axi-cel is still far below that of allogeneic stem cell transplantation (alloSCT), which is frequently used in NHL patients as heavily pretreated as those in ZUMA-1, so CAR-T is still likely to add significant value to the treatment armamentarium, said ZUMA-1 investigator Dr Jonathan Friedberg, director, James P. Wilmot Cancer Center, University of Rochester, New York.

According to a 2011 analysis of 3,788 patients receiving alloSCT for lymphoma and other hematological cancers as well as aplastic anemia, 85% were alive at 10 years, with graft-versus-host disease cited as a frequent cause of alloSCT-related death (Wingard et al. J Clin Oncol. 2011 Jun 1; 29(16): 2230-2239).

Ongoing research will be needed to determine risk factors and mitigation strategies for CAR-Ts, Friedberg added. ZUMA-1 includes an experimental cohort of patients receiving Actemra and levetiracetam prophylaxis to prevent CRS and neurotoxicity, respectively.

In the company’s 8 May earnings call, Kite chief medical officer David Chang noted that since ZUMA-1’s initiation, nearly 200 patients have been treated in trials of axi-cel, more than 300 if including patients in the original National Cancer Institute studies of the CAR-T, therefore the rate of deaths from the CAR-T is tracking at about 2%, consistent with the ZUMA-1 study itself.

In addition to ZUMA-1, Kite is investigating axi-cel in adult and pediatric ALL and in a DLBCL study combined with Roche’s PD-L1 inhibitor Tecentriq (atezolizumab).

Kite’s market cap is USD 4.4bn.




21 DEC 2016

• Number of patients may be insufficient to warrant subgroup approval

• Efficacy data, unmet need bolster approval chances

• Toxicity will draw attention, but unlikely to derail approval overall

Kite Pharma’s (NASDAQ:KITE) axicabtagene ciloleucel (axi-cel) will likely draw FDA scrutiny over safety, but the chimeric antigen receptor T-cell (CAR-T) therapy’s efficacy nevertheless bolsters approval prospects, experts said.

Data on relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and the subtypes transformed follicular lymphoma (TFL) and primary mediastinal B-cell lymphoma (PMBCL) from the 142-patient Phase I/II ZUMA-1 study (NCT02348216) shows high efficacy among patients who otherwise lack options, experts said, agreeing the data makes approval likely. However, given the small number of TFL/PMBCL patients, the label may only include DLBCL, an expert said, while another said the subtypes are similar enough that it may include all the subtypes.

The company announced 4 December the submission of a rolling BLA for axi-cel, also known as KTE-C19, for relapsed/refractory DLBCL, PMBCL and TFL patients ineligible for autologous stem cell transplant (autoSCT), with the expectation of completing the submission by the end of 1Q17.

While analysts lean in favor of an approval, expectations are for a broad label encompassing DLBCL as well as the TFL and PMBCL subtypes. Toxicity including patient deaths has been viewed as manageable given their small number and deadly nature of the disease, according to a report. The CAR-T is expected to achieve global sales of USD 1.3bn by YE25, according to BioPharm Insight data.

AXI-CEL APPROVAL

Cytokine release syndrome (CRS) and neurotoxicity observed in ZUMA-1 will focus much of the FDA’s attention on axi-cel’s toxicity, said a US expert and Dr Chaitra Ujjani, assistant professor, Division of Hematology and Oncology, Georgetown University Medical Center, Washington, DC.

The question will boil down to safety and whether the FDA will approve it after well-publicized deaths in Juno Therapeutics’ (NASDAQ:JUNO) currently halted Phase II ROCKET study (NCT02535364) of JCAR015 in acute lymphoblastic leukemia (ALL), said Dr David Aboulafia, section head, Department of Hematology/Oncology, Virginia

Mason Medical Center, Seattle, Washington. Brian Malkin, senior counsel, law firm McGuireWoods, Washington, DC, also noted the FDA appeared to have concerns about JCAR015’s safety, as well as durability of responses.

Durability is ultimately a bigger clinical question over ZUMA-1’s response rates, said investigator Dr Deepa Jagadeesh, associate staff, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, Ohio, adding any responses longer than one to two years would be great, with axi-cel’s durability currently at around three months. Short pediatric ALL responses from Novartis’ (VTX:NOVN) tisagenlecleucel-T raised experts’ durability concerns, this news service reported 30 September.

Grade 3 or higher CRS and neurotoxicity occurred in a respective 13% and 29% of 93 patients, according to a 6 December press release. Three patients died from treatment-emergent toxicities, including cardiac arrest in the setting of CRS, pulmonary embolism and hemophagocytic lymphohistiocytosis.

Yet, axi-cel’s high efficacy will likely outweigh FDA toxicity concerns, Ujjani and Aboulafia agreed.

The deaths represent a small number of patients out of many who otherwise have low chance of survival, and it is possible the hemophagocytic lymphohistiocytosis was not axi-cel-related, Aboulafia said. Furthermore, notwithstanding CAR-T toxicity’s importance, even allogeneic SCT produces fatality rates of 15%-40%, said Dr Joshua Brody, assistant professor, Hematology and Medical Oncology, The Mount Sinai Hospital, New York.

In contrast with the 93-patient toxicity data, the toxicity data for 62 patients announced in September showed respective 18% and 34% CRS and neurotoxicity rates, and the current data represent the ability to manage toxicity across ZUMA-1’s 24 US and Israeli centers, the spokesperson said.

The deaths represent a small number of patients out of many who otherwise have low chance of survival, and it is possible the hemophagocytic lymphohistiocytosis was not axi-cel-related, Aboulafia said.

Kite’s KTE-C19 likely to overcome toxicity fears for FDA approval in relapsed/refractory DLBCL, label may exclude TFL/PMBCL subgroups – experts



The Phase I/II CR rate warrants FDA approval with its superiority to current therapies and possibility of improvement at six and nine months, Brody said. The data will likely pressure the FDA to approve the therapy given the efficacy and unmet need, Aboulafia and Ujjani said.

Among 51 DLBCL and 11 TFL/PMBCL patients, the overall response rate (ORR) was 79%, including a 52% complete response (CR) rate, according to a 6 December press release. DLBCL rates were 76% and 47%, while TFL/PMBCL rates were 91% and 73%. The company ultimately will submit a 101-patient dataset to the FDA, the spokesperson said.

The benchmark for ZUMA-1 is the SCHOLAR-1 meta-analysis of four studies, she noted, which showed ORRs of 20%-30% and CR rates of 2%-18% among 861 patients, according to a presentation at the 2016 American Society of Clinical Oncology annual meeting (abstract no. 7516). Therapies in the analysis included Roche’s (VTX:ROG) Rituxan (rituximab) and chemotherapy.

AXI-CEL LABEL

The label for axi-cel will likely be consistent with the design of the ZUMA-1 study, meaning for highly refractory patients, Ujjani said. The label will likely be for third-line DLBCL after autoSCT and perhaps second-line, transplant-ineligible disease, Brody and Jagadeesh said.

ZUMA-1 is being studied in patients who have had no response to their last line of therapy and refractoriness to autoSCT, as well as an anti-CD20 monoclonal antibody, an anthracycline-containing chemotherapy regimen and - in TFL patients - prior chemotherapy for FL and subsequent chemotherapy refractoriness after transformation to DLBCL, according to ClinicalTrials.gov.

Still, the 11 TFL/PMBCL patients in ZUMA-1 are few compared with the 51 DLBCL patients, Ujjani said. Yet, while DLBCL comprises the predominant number of patients in the study, TFL and PMBCL are merely subsets of that disease, Aboulafia said. The FDA could very well start off by only granting a label for DLBCL, but in practice the treatments for all three are the same, so it is unlikely the agency will nitpick, he said.

If axi-cel works in TFL/PMBCL based on the same mechanism of action that it does in DLBCL, then that may support a broader label, Malkin said. On the other hand, given the novelty of CAR-T technology, the FDA may be hesitant to make that conclusion without data on more patients from an expansion cohort or additional, proof-of-concept study to confirm that is the case, he said.

Combining the 62-patient efficacy analysis and additional patients in the one-month toxicity follow-up yields 20 TFL/PMBCL patients, the spokesperson noted. Discussions with the FDA makes the company confident it has the appropriate number of patients for the label to include all three subtypes, she said.





13 JULY 2017

Novartis (VTX:NOVN) temporarily encountered manufacturing problems at its European chimeric antigen receptor T-cell (CAR-T) manufacturing facility, forcing at least one site in the Phase II JULIET trial of tisagenlecleucel-T in diffuse large B-cell lymphoma (DLBCL) to go through the US facility, a source with knowledge of the situation said. The logistical issue occurred after the European sites’ activation and resulted in lengthening the time between apheresis and reinfusion, the source added.

However, other experts said such issues would not likely create insurmountable logistical hurdles in the future.

While not providing details about the problems that occurred or when, the source said Novartis resolved the issue within a few weeks. Yet, the need to ship the product back and forth across national borders can create import-export hurdles that take time to overcome, which can be a problem for patients with an aggressive disease like DLBCL, the source said. Experts said there is confidence that such issues could be resolved and that international shipping of live cells is already a familiar practice in allogeneic stem cell transplantation (alloSCT), though the fragility of cell products means it is important to ensure smooth logistics.

A Novartis spokesperson said the company was not aware of the manufacturing issues. Novartis formed a manufacturing partnership with the Fraunhofer Institute for Cell Therapy and Immunology in Leipzig, which Fraunhofer announced 19 January 2015. A Novartis spokesperson said the European portion of JULIET got up and running in September 2016.

Data from JULIET (NCT02445248) was presented at the International Conference on Malignant Lymphoma (ICML) conference last month in Lugano, Switzerland (abstract no. 7). The 130-patient study includes 27 sites across four continents, including seven sites in Europe, 14 in the US and two each in Canada, Japan and Australia.

While Novartis is initially seeking FDA approval for tisagenlecleucel-T in pediatric acute lymphoblastic leukemia (ALL) with a PDUFA date of 3 October, it is also developing it for DLBCL, and the CAR-T’s sales across indications are forecasted to peak at USD 1.5bn by YE26, according to BioPharm Insight data. An analyst report stated that tisagenlecleucel-T will need to take 20-30% market share to achieve USD 1bn sales, but the competitiveness of the DLBCL market will affect its ability to reach that. The agency’s Oncologic Drugs Advisory Committee voted unanimously 12 July to recommend its approval in ALL.

The process of shipping cells for alloSCT between countries has been worked out pretty well, agreed JULIET

lead investigator Dr Richard Maziarz, medical director, Adult Blood and Marrow Stem Cell Transplant Program, Oregon Health and Science University, Portland, and Dr Ann Woolfrey, director, Unrelated Donor Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Woolfrey added about 25% of the 200 alloSCTs her center does each year are sourced from outside the US without major hiccups. On the other hand, she said it could be that CAR-T cells are subject to EU regulations different from the ones for alloSCT cells, and because cell products are so sensitive to even small glitches, Novartis will have to ensure it expands its ability to ship the product internationally if the need arises.

Additionally, Maziarz said that with the cold-storage devices used to ship cell therapies able to keep them at constant temperatures for up to 14 days, it is unlikely that a finished CAR-T product being stuck at the airport for a day will cause problems. Indeed, problems such as import-export hurdles routinely arise in oncology and, while not trivial, are not insurmountable, said Dr. Michelle Hermiston, associate professor, Pediatrics, University of California San Francisco Benioff Children’s Hospital.



The logistical issue occurred after the European sites’ activation and resulted in lengthening the time between apheresis and reinfusion, the source added.

Novartis CAR-T Phase II JULIET study in DLBCL briefly hit with manufacturing hiccup in Europe; experts say unlikely a long-term problem

Intelligence | Manufacturing Hurdles


6 JUNE 2017

• High-risk patients or those with residual disease most likely to get neratinib

• Efficacy in HR+ patients a positive trend, but would likely not influence label

Bluebird bio (NASDAQ:BLUE) has a current capacity to manufacture bb2121 -- its BCMA-targeting chimeric antigen receptor T-cell (CAR-T) therapy -- for 10 multiple myeloma patients nationwide per month, said a source briefed on the matter on the sidelines of the 2017 ASCO meeting in Chicago, Illinois.

The long waiting list to get into bluebird’s Phase I study (NCT02658929) of the CAR-T illustrated the need for significantly higher manufacturing capacity if the therapy is to be commercially viable, the source said. However, the company’s two-year-old partnership with Celgene (NASDAQ:CELG) may later help with capacity as the CAR-T moves into Phase II testing.

This news service reported on 9 December 2016 that wait times of six weeks between enrollment onto the study and administration of bluebird’s CAR-T could be a problem in the real-world treatment of patients, particularly for those patients who have aggressive disease.

By contrast, the source noted, Kite Pharma’s (NASDAQ:KITE) CD-19 targeting CAR-T axicabtagene ciloleucel is manufactured in an enormous, warehouse-style facility. Kite has previously announced it plans to roll its therapy out at more than 70 centers nationwide after FDA approval.

Data on bluebird’s Phase I study was presented at ASCO, showing an 89% overall response rate in 18 patients, including four complete responses, seven very good partial responses and five partial responses, along with cytokine release syndrome in 15/21 patients that was mostly Grade 1-2, except for two Grade 3 cases (abstract no. 3010). Analysts called the data impressive and have maintained an outperform rating on bluebird’s stock. The company’s market cap is USD 4.1bn.

Another CAR-T developer that has struggled with manufacturing is Novartis (VTX:NOVN), which this news service reported on 5 December 2016 that it closed enrollment of its Phase II JULIET study (NCT02445248) for anti-CD19 CAR-T tisagenlecleucel-T in non-Hodgkin’s lymphoma due to a large enrollment backlog.

In February, JULIET’s primary completion date was pushed from May 2022 to January 2024. Novartis is also developing a competitor to bb2121.

bluebird did not respond to a request for comment.

by Alaric DeArment in Chicago

Bluebird bio has capacity to make myeloma CAR-T for 10 patients per month – source



26 JUNE 2017

• Automated manufacturing cheaper than clean rooms

• Hybrid in-house, contract manufacturing a likely future scenario

• Manufacturing capacity should grow to 150 therapies/ month

bluebird bio (NASDAQ:BLUE) will be challenged to ramp up manufacturing of bb2121 in multiple myeloma (MM) perhaps more than tenfold in order to bring the therapy into Phase II and eventually commercial development, experts said. While the process is achievable, it’s also challenging to scale out manufacturing in terms of making many small batches in parallel, as well as expensive, experts said.

The process will likely consist of scaling out rather than scaling up, meaning expanding parallel production of many small batches of the BCMA-targeting chimeric antigen receptor T-cell (CAR-T) therapy rather than producing very large batches in one setting, some experts said. This would mean buying numerous machines to automate production, which would require significant space and funding, they said. However, an expert added that while it is highly questionable whether the company would be able to scale out with any existing CMO, it would probably move forward with a hybrid model, as other biotechnology companies do.

The company currently relies on CMOs to produce its products, according to its 1Q17 earnings statement, and CMOs do not have the capacity to manufacture bb2121’s components at commercial levels. This news service reported 6 June that the company has capacity to make about 10 patient therapies per month for the entire country. Sales for bb2121 are expected to peak at USD 1.1bn at YE24, according to BioPharm Insight data. bluebird has a development and commercialization relationship with Celgene (NASDAQ:CELG) for bb2121.

Data from the 50-patient Phase I study (NCT02658929) of bb2121 appeared in a poster at the 2017 ASCO meeting in Chicago, Illinois, and is included in an oral presentation at the European Hematology Association meeting in Madrid, Spain. bluebird did not respond to requests for comment.

MANUFACTURING SCALE-OUT FACES CHALLENGES

The overall challenge for CAR-Ts is that their early development was through manual manufacturing processes, a legacy of their invention in academic rather than bioindustrial settings, said Anthony Davies, executive chairman, Dark Horse Consulting, Campbell, California. At the time, the complexity of CAR-Ts’ manufacturing surpassed

the options then available for automation of manufacturing, he said.

Currently available equipment for automating CAR-T manufacturing – particularly Cologne, Germany-based Miltenyi Biotec’s Prodigy machines – is relatively expensive, typically more than USD 100k apiece, and capable of producing therapies for perhaps 30-50 patients per year, Davies said. Such a capital investment – buying a large number of Prodigy-type machines – is nontrivial, he said, but cheaper than doing open manipulation that would require a clean room as the Prodigy is a closed system.

Indeed, scaling out with Miltenyi-type machines has the advantage of making it possible to process lots of patient products in parallel, minimizing the need for a HEPA-filtered clean room and thus reducing costs associated with construction, validation and upkeep of a traditional clean room facility, said Robert Orr, president, Orr Pharmaceutical Consulting, West End, North Carolina. However, a robust quality-control system would need to be in place with so many individual batches being made in parallel, he added. Indeed, the partnership with Celgene could be advantageous for bluebird in creating robust systems with better control and documentation, he said.

Another question is what approach to take in developing manufacturing facilities, Davies said. Kite Pharma (NASDAQ:KITE) announced in a 20 June 2016 press release the opening of a newly built 43,500-square-foot manufacturing plant near Los Angeles International Airport capable of processing 5,000 patient cell therapies per year. By contrast, Novartis (VTX:NOVN) in December 2012, purchased a 173,000-square-foot plant in New Jersey formerly owned by Dendreon for producing its Provenge (sipuleucel-T) cell therapy for prostate cancer.

Time will tell, Davies said, whether Kite’s strategy will work, though he noted the Dendreon plant came with the legacy

However, an expert added that while it is highly questionable whether the company would be able to scale out with any existing CMO, it would probably move forward with a hybrid model, as other biotechnology companies do.

bluebird faces CAR-T manufacturing scale-out challenges in MM, but obstacles easily surmountable with large investment, Celgene partnership - experts



of older, manual manufacturing processes. Yet, another question is whether to pursue a centralized manufacturing approach like Kite’s and Dendreon’s or a decentralized approach that has tertiary-care centers making the therapies themselves, he said. However, while simpler than the centralized model, such a decentralized manufacturing approach would still leave open logistical issues because of the shipping of raw materials and quality-control problems, he said.

Moreover, Davies said, if a company wants to go from making CAR-T therapies for 10 patients a month to 150, it is highly questionable whether it would be able to do so with any existing CMO. It is more likely that companies like bluebird will use a combination of in-house manufacturing and working with CMOs with surge capacity, he said. That has already been taking place in the biotechnology industry, as is the case with Roche’s (VTX:ROG) Genentech, which has numerous CMO contracts in addition to its own in-house manufacturing, he noted.

CURRENT CAPACITY MAY NOT SUPPORT FURTHER DEVELOPMENT

The company needs to increase manufacturing capacity to 150 therapies per month from the approximately 10 it makes, a source familiar with matter said. There is a waiting list to get into the ongoing Phase I study, suggesting that capacity is an issue, the source added.

However, Phase I investigator Dr Noopur Raje, director, Center for Multiple Myeloma, Massachusetts General Hospital, Boston, said capacity to process therapies for 10-20 patients per month is acceptable as a starting point. There is a need to process a greater number of patients over time, she said, though she did not specify an exact number. Meanwhile, Dr Laura Rosinol, hematologist, Hospital Clinic of Barcelona, Spain, also was hesitant to specify the exact number of patient therapies the company would need to generate per month, but she said the figure of 10 was low and that subsequent trials would likely generate significant interest in the trial, thereby necessitating a much greater capacity.

bluebird’s market cap is USD 4.5bn.

by Alaric DeArment in Madrid



6 JAN 2017

• Company's emphasis on manufacturing, education draws expert confidence

• Restricted rollout prudent as site logistics, administration know-how crucial

• Therapy an attractive option, but durability of responses will remain important

Kite Pharma (NASDAQ:KITE) has delicate logistics and physician education hurdles to overcome if it is to be successful in launching axicabtagene ciloleucel (axi-cel) for aggressive non-Hodgkin’s lymphoma, experts said.

While there will be difficulties to meet the high demand for the extremely complex therapy, experts expected the company to be able to ensure quick delivery to patients. Kite’s decision to focus on 72 cancer centers with experience in giving chimeric antigen receptor T-cell (CAR-T) therapies like axi-cel and its push to educate physicians will benefit its roll out, experts said. Sales are expected to reach USD 1.3bn by YE25, according to BioPharm Insight data.

Otherwise, they said axi-cel is an attractive option for diffuse large B-cell lymphoma (DLBCL) given its impressive complete remission (CR) rate, though in the long run durability of remissions will be crucial.

Demand at launch is anticipated to be strong, and logistics will be key, according to analyst notes. Approval is anticipated in 4Q17, which this news service has previously reported as likely - following the Phase I/II ZUMA-1 study (NCT02348216) -- despite neurotoxicity fears. An advisory committee meeting is expected in the fall.

LOGISTICS AND EDUCATION

Administering axi-cel requires significant coordination, more akin to an allogeneic stem cell transplant (SCT) than an autologous SCT, a ZUMA-1 investigator said. CAR-T involves extracting patients’ T cells and shipping them to the manufacturer, which uses a viral vector to make them recognize the cancer cell-surface antigen CD19 and grows them before shipment back to the clinic for administration.

The company is confident in its manufacturing process, a Kite spokesperson said, noting a report at the American Society of Hematology meeting that in ZUMA-1 had a 99% manufacturing success rate and average 17-day turnaround from apheresis to delivery. Overall, the investigator said, the company seems to emphasize logistics and physician education around axi-cel’s safety and management. The company appears prepared in terms of manufacturing

capacity to handle the rollout, the investigator said, adding mainstream acceptance will hinge on sufficient physician education about axi-cel’s safety profile.

Meanwhile, cancer centers have been gearing up to deliver CAR-T, hiring people and identifying space for the treatments, said Dr David Aboulafia, section head, Department of Hematology/Oncology, Virginia Mason Medical Center, Seattle, Washington. These steps are intended to counteract timeline hurdles expected following patient referrals from hospitals not offering CAR-T to the ones that do. Because DLBCL progresses rapidly, the couple of weeks between cell collection and administration adds to timeline complexities, he said. Despite those challenges, he said he was confident that Kite and other CAR-T companies had sufficient funding and ingenuity to quicken production and delivery.

This news service reported 4 December that of the three major CAR-T clinical trial programs in aggressive NHL -- the others being Juno Therapeutics’ (NASDAQ:JUNO) Phase I TRANSCEND study (NCT02631044) of JCAR017 and Novartis’ (VTX:NOVN) Phase II JULIET study (NCT02445248) of tisagenlecleucel-T -- ZUMA-1 had a “reasonable” turnaround time of two to three weeks, compared with the backlogs experienced in JULIET.

The company would probably not have to restrict axi-cel’s rollout to the 23 US sites involved in the ZUMA-1 study, but it would be important to ensure sites are logistically equipped to handle CAR-T administration, the investigator said. That could mean some kind of feasibility study with sites demonstrating the capacity to give CAR-T, the investigator added, noting that Kite was in the process of identifying sites.

The company appears prepared in terms of manufacturing capacity to handle the rollout, the investigator said, adding mainstream acceptance will hinge on sufficient physician education about axi-cel’s safety profile.

Kite’s success in DLBCL CAR-T rollout hinges on logistics, physician education, but uptake enthusiasm prevails - experts



It is understandable that the company is initially restricting axi-cel’s rollout to 72 sites because it is such a new technology and has a significant side-effect profile, making it important to ensure that centres can safely manage patients, said ZUMA-1 investigator Dr Deepa Jagadeesh, associate staff, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, Ohio.

The question is whether community cancer centers will be able to offer axi-cel later on, Jagadeesh and Aboulafia said. Initially, the therapy will be in those patients able to get to large cancer centers and stay for post-treatment monitoring, but it may later be possible to give it at larger community centers with adequate intensive care units and ability to ameliorate its toxicity, Aboulafia said.

THERAPY AN ATTRACTIVE OPTION

Axi-cel showed a 52% CR rate in ZUMA-1, compared with rates as low as 2%-18% in the same population for existing options like chemotherapy and anti-CD20 monoclonal antibodies.

ZUMA-1 showed a superior CR rate to existing treatments, said Dr Joshua Brody, assistant professor, Hematology and Medical Oncology, The Mount Sinai Hospital, New York, adding he would use axi-cel in his patients, assuming approval in third-line disease or perhaps second-line, transplant-ineligible patients.

Meanwhile, Dr Chaitra Ujjani, assistant professor, Division of Hematology and Oncology, Georgetown University Medical Center, Washington, DC, said she would refer “appropriate patients” - meaning those who are highly refractory - to physicians who administer CAR-T, adding that she would not give it herself as she does not do stem cell transplants (SCT).

This news service previously reported, initially it is possible the agency will only grant a label for DLBCL and not the subtypes primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL) given the small number of patients in those subgroups.

Another factor influencing uptake is whether patients will be able to have long, disease-free intervals, Aboulafia and Jagadeesh said. While reluctant to cite a particular number, Jagadeesh said any prolongation of duration will be important, with something longer than a year being ideal. Existing therapies do not provide anything that long or even the possibility of a cure, she added.

Assuming accelerated approval, a randomized confirmatory trial is ideal, but randomization would require significant patient numbers and time, Jagadeesh said. Kite’s management has said the pre-IND ZUMA-7 study is confirmatory and will need to be ongoing by 2H17 in anticipation of axi-cel’s approval, according to an analyst report.

However, the spokesperson said the company has not discussed details about confirmatory studies and will not do so until it has finalized its BLA submission. This news service reported 26 May that the FDA may show flexibility in CAR-T confirmatory study design, potentially allowing long-term follow-up instead of randomization.





9 JAN 2017

• Negative publicity risk would deter coverage denial, even if label narrow

• Payers will have little leverage, but could restrict to centers of excellence

• Concern about hospital financial losses makes strong negotiations likely

Kite Pharma’s [NASDAQ:KITE] axicabtagene ciloleucel (axi-cel) for aggressive non-Hodgkin’s lymphoma (NHL) will not likely encounter reimbursement hurdles for on-label use, but will face tough manufacturer-payer negotiations, experts said.

A high price tag will likely encourage payers to limit the chimeric antigen receptor T-cell (CAR-T) therapy’s usage to centers of excellence, but axi-cel’s strong efficacy and Kite’s monopoly position will otherwise give payers little leverage. Meanwhile, hospitals’ concerns about taking losses will force negotiations with the manufacturer to will focus on ancillary services as well as the branding advantage of being a CAR-T center, experts said. In the long run, the unlikelihood of axi-cel facing future biosimilar competition means price reductions will have to come from next-generation CAR-Ts and other treatments with better efficacy or safety, experts said.

This news service reported on 12 November 2015 that the high costs of CAR-Ts - estimates ranging from USD 150,000 to USD 300,000 - would elicit strong payer restrictions, particularly barring off-label use. An approval is expected in 4Q17, and this new service reported an accelerated approval is likely based on results of the Phase I/II ZUMA-1 study (NCT02348216). The ability to get reimbursement from private and public payers is a primary risk factor for axi-cel, according to an analyst report.

Kite is highly confident that reimbursement will be available for axi-cel, but it is too soon to discuss the therapy’s price, a spokesperson said, adding the company is currently having discussions with payers.

REIMBURSEMENT NEGOTIATIONS

Axi-cel will be an incredibly expensive treatment and, at least initially, will not be easily generalized to a large number of centers, said Dr David Aboulafia, section head, Department of Hematology/Oncology, Virginia Mason Medical Center, Seattle, Washington. The company plans to have axi-cel made available at 72 centers with CAR-T experience.

Based on on-label usage, it is not likely payers will turn it down given it would be for patients who have exhausted all other options, said Dr Chaitra Ujjani, assistant professor, Division of Hematology and Oncology, Georgetown

University Medical Center, Washington, DC. Instead, they could restrict its reimbursable use to centers of excellence, similarly to stem cell transplants (SCTs), she said.

Because of axi-cel’s high efficacy in a patient population otherwise lacking viable treatment options, the risk of negative publicity could be a potentially powerful deterrent to payers turning down patients who need axi-cel, said Craig Garthwaite, associate professor of strategy, co-director, Health Enterprise Management Program, Northwestern University Kellogg School of Management, Chicago, Illinois. Such a risk could even persuade payers to cover axi-cel for the DLBCL subtypes -- primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL) -- if the CAR-T received a narrow label that only included DLBCL, Garthwaite said. This news service previously reported that such a narrow label was possible given the small number of PMBCL and TFL patients in ZUMA-1, though the agency still might grant a broad label given that treatments for them are the same as for DLBCL.

Because of axi-cel’s efficacy addressing an unmet need and effective monopoly - at least until Novartis’ (VTX:NOVN) Phase II tisagenlecleucel-T and Juno Therapeutics’ (NASDAQ:JUNO) Phase I JCAR017 become available - payers otherwise will not have much leverage to hold back on Kite, Garthwaite said. Instead, they probably have to pass the extra costs onto consumers through higher premiums, he said.

While it is possible that axi-cel’s high price could trigger

Because of axi-cel’s high efficacy in a patient population otherwise lacking viable treatment options, the risk of negative publicity could be a potentially powerful deterrent to payers turning down patients who need axi-cel, said Craig Garthwaite, associate professor of strategy, co-director, Health Enterprise Management Program, Northwestern University Kellogg School of Management, Chicago, Illinois.

Kite’s KTE-C19 to encounter tough negotiations with payers despite unlikely hurdles to on-label reimbursement – experts

Intelligence | Reimbursement


payer resistance similar to Gilead Sciences’ (NASDAQ:GILD) Sovaldi (sofosbuvir) for hepatitis C, the CAR-T would nevertheless show huge value by potentially extending survival among patients otherwise likely to die as long as toxicities were kept in check, said Matthew Grennan, assistant professor, Health Care Management, University of Pennsylvania Wharton School of Business, Philadelphia. Patients in ZUMA-1 showed a 52% CR rate, according to data from the American Society of Hematology’s 2016 conference.

However, the problem with Sovaldi wasn’t just the price tag but that it was for millions of patients, whereas axi-cel’s population is much smaller, Garthwaite said. In the US, about 10,000 DLBCL patients per year are not cured by chemotherapy, most of them dying from the disease, according to an analyst report.

The problem for payers with axi-cel will not be the per-year cost, but the cumulative cost over many years, he said. Because there will be no biosimilar competition to drive down costs, payers will find themselves paying high prices for it until something better comes along. As axi-cel is not just a drug, but an entire process it is unlikely to face biosimilar competition and what will bring the price down in the future will be competition from future, next-generation CAR-T constructs or other products that can work better, similar to what happened with coronary stents, Grennan said.

Rather than a traditional setup like with pharmaceutical and biotech drugs, whereby the clinic gets a check in the mail from the insurance company, reimbursement may involve alternative deals between Kite, payers and hospitals, said Garthwaite and Dr Joshua Brody, assistant professor, Hematology and Medical Oncology, The Mount Sinai Hospital, New York.

These deals will likely involve a bundle of items that include not just the CAR-T itself but the ancillary services and products that come with it, Garthwaite said. Such deals will arise because CAR-Ts will not be a significant money maker for hospitals, leading to concerns that they could incur a loss due to the high cost, Brody said. At the same time, while the patient population indeed will not be large, another factor potentially affecting negotiations will be the benefit that hospitals’ brands will derive from becoming known as centers for the therapies, Garthwaite said.





16 FEB 2017

• Six-digit Chinese yuan price tags likely, similar to stem-cell transplant

• Private reinsurance and reformed plan potential may accomodate high price

Chimeric antigen receptor T-cell (CAR-T) developers eyeing Chinese markets -- like Kite Pharma (NASDAQ:KITE) and Juno Therapeutics (NASDAQ:JUNO) -- are likely to face complicated pricing considerations given the evolving insurance landscape, experts said.

With strong pricing pressure likely, these therapies will remain out of most Chinese patients’ reach due to inadequate health insurance coverage, experts said.

While CAR-Ts in the US are expected to cost hundreds of thousands of dollars, their price in China likely cannot exceed CNY 50k-300k (USD 7,280-43,683) for the therapies themselves, not including ancillary services that will push costs past CNY 200k (USD 29,122) or more, experts said.

At the same time, constrained health care budgets even in wealthier areas and wide disparities in coverage between affluent and poorer parts of the country make broad insurance coverage unlikely, at least in the near term, forcing patients to pay out of pocket, they said. Nevertheless, in at least some wealthier areas, insurance may eventually cover part of the cost of CAR-Ts, as it does for other expensive therapies like stem cell transplant (SCT) and organ transplants.

Kite announced 10 January that it formed a Shanghai-based joint venture ( JV) with Fosun Pharmaceutical (SHA:600196) called Fosun Pharma Kite Biotechnology, which will develop Kite’s axicabtagene ciloleucel (axi-cel) and other products for the Chinese market. Juno formed a similar JV, JW Biotechnology, with Shanghai-based WuXi AppTec last year.

While the JV moves are still early and not being factored into models for Kite and Juno, analysts believe there is substantial opportunity for cell therapies in China given health care reforms and a more favorable landscape for local partnering deals with foreign companies.

A Kite spokesperson said the 50/50-owned JV will operate as a Chinese company, developing and manufacturing axi-cel locally. Juno did not respond to specific inquiries, and neither Fosun nor WuXi responded to requests for comment.

PRICING PRESSURES LIKELY

Generally, there is a solid market for CAR-T in China given that the patients who are candidates will be those for whom the only other alternative is death, but the problem is how

to price the therapies, said Alex Chang, professor, Tongji University School of Medicine, Shanghai. As such, the price will have to be lowered for the Chinese market to realistically around CNY 50k, not including ancillary services, said Dr Weidong Han, Department of Hematology, Chinese People’s Liberation Army Hospital, Beijing.

Including ancillary services like hospitalization, chemotherapy conditioning and immune-suppressant drugs, the cost will vary from patient to patient but will likely rise to CNY 200k or more, said Jianqiang Li, formerly Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington.

On the other hand, the price could go as high as CNY 300k, based on conversations with CAR-T companies in China, assuming a price of around USD 300k in the US, said Peng Li, principal investigator, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences. Chang also noted CNY 300k could be justified because that is the cost of SCT, but in this case CAR-Ts would have to replace SCT as many patients who achieve complete remission from CAR-T ultimately relapse.

INSURANCE COVERAGE INADEQUATE

The majority of insured patients would not able to afford CAR-T in China, Peng Li said. Even SCT is unaffordable for many patients, who often have to rely on donations and charity, Chang said.

There are three public insurance programs that cover most of the Chinese population, namely the urban-employee plan, another for retirees and children and a third for rural citizens, noted Dr Shenglan Tang, associate director for Duke Kunshan University and China Initiatives, Duke Global Health Institute, Durham, North Carolina. The amount of coverage

At the same time, constrained health care budgets even in wealthier areas and wide disparities in coverage between affluent and poorer parts of the country make broad insurance coverage unlikely, at least in the near term, forcing patients to pay out of pocket, they said.

CAR-T pursuits in China face pricing headache for broad coverage, likely restriction to urban regions – experts



patients receive depends on their plan as well as locale, with the urban-employee plan in wealthier cities like Shanghai and Beijing offering the best coverage, he said. Even still, for procedures like SCT patients may be steered into using ancillary drugs that are inappropriate in order to keep costs down, said Lung-Ji Chang, Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville.

CAR-Ts’ availability would be limited to wealthier, urban areas where people can pay copays or out of pocket, said Winnie Yip, professor of health policy and economics, Harvard University School of Public Health, Boston, Massachusetts. By contrast, Blair Gifford, professor of management and health administration, University of Colorado Business School, Denver, said rural residents receive only a small subsidy that would not cover CAR-T.

To the extent urban-employee insurance covers expensive treatments for catastrophic care like SCT, patients must still pay copays of 30-50% even in wealthier areas, Gifford and Yip said.

It is conceivable that in the next few years - once CAR-Ts are approved in China -- a similar arrangement could exist for this therapeutic option, Tang said. Indeed, notwithstanding sharp regional differences, benefit packages have slowly increased over the last several years, he and Yip said.

The government-funded insurance programs have an annual cap equal to six times the average employee’s income, and as such would not likely cover CAR-T because of the threefold to fivefold gaps in the amount of coverage between regions or even between two parts of the same province thanks to regional income disparities, said Hao Yu, senior policy researcher, RAND Corporation, Pittsburgh, Pennsylvania. In 2015, Beijing had the highest average salary, at 9,227 yuan per month (approximately USD 16K/year), followed by Shanghai with 8,664 yuan and Shenzhen at 7,728 yuan, according to a 21 January 2016 China Daily report.

The government has also sought to promote private reinsurance to supplement government insurance for when insurance caps kick in, Yu said. However, reinsurance to offset copays for CAR-T would likely be available only for the very wealthy or expatriates, Yip said.

Families usually pool money for high-cost treatment for a relative, owing to cultural values in China, said Tang. Yet, this cost still seems excessive for Chinese patients, said Gifford.

Yet even though the percentage of Chinese households able to pay out of pocket for CAR-T is small - perhaps 1-2% - in absolute terms it would be a large number given China’s 1.4bn population, Tang said.

Furthermore, it is mainly in northern and southern China that the middle class is shaping up, thus representing millions of people and a very large market despite being concentrated in a relatively small geographic portion of the country, added Yu.

Shanghai, the largest city, has a population of 20.2m, followed by Beijing and Guangzhou at 16.4m and 10.6m, respectively, according to 2010 census data.

Kite and Juno have respective USD 2.8bn and USD 2.6bn market caps. Fosun’s is CNY 60bn (USD 8.7bn).




12 APR 2016

• High efficacy in NHL, HL treatments make CAR-T's role uncertain

• CAR-T production, preparation requirements hinder uptake

• Lower response rates in NHL than ALL necessitate biomarkers

Chimeric antigen receptor T-cell (CAR-T) therapies have drawn expert uncertainty about their potential place in non-Hodgkin’s lymphoma (NHL) treatment due to factors like a highly competitive market, cost concerns and infrastructure requirements.

Given that response rates in many NHL histologies have been much lower than the complete response (CR) rates of often 80% or more seen in acute lymphoblastic leukemia (ALL), some experts added it would be important to find biomarkers to better predict which NHL patients might respond and thus increase response rates.

In terms of CAR-T development targeted at NHL, Juno Therapeutics (NASDAQ:JUNO) plans to launch a registration-directed study of JCAR017 in NHL in 1Q17, according to an analyst note. Kite Pharma (NASDAQ:KITE) will present updated results from the Phase I ZUMA-1 study (NCT02348216) of KTE-C19 at the American Association of Cancer Research’s annual meeting in 16-20 April, according to a 17 March press release. Novartis (VTX:NOVN) presented CTL019 Phase IIa data in the NHL subtypes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL) at the American Society of Hematology’s (ASH’s) 2015 annual conference in December.

This news service reported 23 March that while CAR-T produced less robust outcomes in NHL than in ALL, cell design adjustments and combinations could provide a way forward, and responses vary by NHL histology. Novartis’ CTL019 has produced a 100% response rate among seven patients with FL, but 54% in 13 DLBCL patients, while a study of Juno’s JCAR014 showed a 42% response rate in 12 NHL patients, this news service noted.

Kite and Novartis declined to comment, while Juno did not respond to a request for comment.

CAR-TS VENTURE INTO CROWDED NHL ENVIRONMENT

In contrast with ALL, lymphomas do not lack effective and curative therapies, said Dr Yi-Bin Chen, director of clinical research, Bone Marrow Transplant Program, Massachusetts General Hospital, Boston. For example, it would be difficult

to see the need a new drug for Hodgkin’s lymphoma (HL) because current therapies are so effective, he and Dr Urban Novak, lead physician, Clinic and Polyclinic for Medical Oncology, Bern University Hospital, Switzerland, agreed.

Seattle Genetics’ (NASDAQ:SGEN) Adcetris (brentuximab vedotin) is a CD30-targeting monoclonal antibody used for HL, while Bristol-Myers Squibb’s (NYSE:BMY) Opdivo (nivolumab) and Merck ’s (NYSE:MRK) Keytruda (pembrolizumab) for HL are respectively in the registration-directed Phase II CheckMate 205 (NCT02181738) and Keynote-087 (NCT02453594) studies.

Before considering CAR-Ts in NHL, doctors will need to sort out how to use all the other drugs available for various histologies, said Dr Andreas Lohri, director, Oncology Hematology Immunotherapy, Baselland Canton Hospital, Liestal, Switzerland. Some histologies like MCL are not curable, but existing therapies can extend median overall survival to more than 10 years, Chen said, while half the patients with DLBCL can be cured with standard chemotherapy-based approaches. Roche (VTX:ROG) and Biogen’s (NASDAQ:BIIB) Rituxan (rituximab), a CD20-targeting monoclonal antibody, is commonly used for NHLs, and AbbVie (NYSE:ABBV) and Johnson & Johnson’s (NYSE:JNJ) Imbruvica (ibrutinib) is approved for MCL specifically.

CAR-Ts will probably take a long time to find their niche in NHLs because they are among the least mature in development, Lohri said, compared with more well-established drugs like Imbruvica, Gilead Sciences’ (NASDAQ:GILD) Zydelig (idelalisib) in FL and AbbVie and Roche’s Venclexta (venetoclax). Venclexta received FDA approval on 11 April for chronic lymphocytic leukemia (CLL), and the drug is in a Phase II study in FL (NCT02187861) and a Phase I/II study (NCT02055820) of NHLs, including DLBCL, in

For example, it would be difficult to see the need a new drug for Hodgkin’s lymphoma (HL) because current therapies are so effective, he and Dr Urban Novak, lead physician, Clinic and Polyclinic for Medical Oncology, Bern University Hospital, Switzerland, agreed.

CAR-Ts’ place in lymphoma therapy uncertain given well-served treatment landscape, high cost – experts



combination with Rituxan or Roche’s Gazyva (obinutuzumab) and cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP).It is nevertheless possible that CAR-T could replace autologous stem cell transplant (SCT) or become a bridge to allogeneic SCT, said Dr Gilles Salles, professor, hematology, South Lyon Hospital Center, France. The drug industry is probably investing in CAR-T as a lymphoma treatment because the market is much bigger than ALL, he added.

COST, INFRASTRUCTURE REQUIREMENTS PRESENT CHALLENGES

At the moment, in addition to high drug costs, it is difficult to expand CAR-T use more widely because the infrastructure required to produce it is prohibitive, while the individual dose preparation for each patient creates time constraints, said Dr Leslie Popplewell, associate clinical professor, Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California. An off-the-shelf product without individual preparation would be ideal, she said. For example, Cellectis (EPA:ALCLS) has plans to develop off-the-shelf CAR-Ts in lymphomas with its current CAR-T pipeline under a partnership with Pfizer (NYSE:PFE).

The infrastructure requirements will be a barrier, and cost is a very critical issue in oncology generally, Novak said. In addition to high cost, the toxicity is significant as well, Chen added. If CAR-T is proven to be better than currently available therapies in NHL, then the high cost would be justifiable, he said. Still, Novak said, insurance companies and governments would probably want to see predictive markers to ensure clinical success. Chen added he would like to see predictive markers to gauge who would respond to CAR-Ts and in order to bring NHL response rates closer to the high rates seen in ALL. This news service reported 12 November 2015 that CAR-Ts would face strong payer restrictions given they require inpatient care, and their use would likely remain confined to academic medical centers. Cost estimates for CAR-Ts range from the USD 150,000 that Kite said it might charge to the USD 300,000 or more forecasted by financial analysts.

Novartis’ market cap is CHF 191bn (USD 200.26bn). Juno’s is USD 4.1bn. Kite’s is USD 2.4bn.




13 JULY 2017

Kite Pharma’s (NASDAQ:KITE) Phase I/II ZUMA-4 study of axicabtagene ciloleucel (axi-cel) in pediatric acute lymphoblastic leukemia (ALL) has a protocol amendment that allows patients who have previously received Amgen’s (NASDAQ:AMGN) Blincyto (blinatumomab) to enter the study, a source said.

According to the amended protocol, patients who have received Blincyto can enter as long as they have at least 90% expression of CD19 on their cancer cells, the source added. Axi-cel is a chimeric antigen receptor T-cell (CAR-T) therapy that, like Blincyto, targets CD19.

The company has not publicly disclosed the amendment. ZUMA-4’s (NCT02625480) ClinicalTrials.gov page was last updated in January and still lists prior treatment with CD19-targeting therapies - including BiTE antibodies- the class to which Blincyto belongs – as an exclusion criterion. The source said the amendment was put in place after the last trial page update.

The amendment has helped with enrollment in ZUMA-4 despite competition from Novartis’ (VTX:NOVN) Phase II ELIANA study (NCT02435849) of tisagenlecleucel-T in pediatric ALL, the source said, given that ELIANA continues to exclude patients with prior treatment with Blincyto. The source added that ZUMA-4’s Phase I portion had two slots left as of the last week of June and that the enrollment figure is in the “double digits.”

A Kite spokesperson said the Phase I portion’s target enrollment is 12 patients, while ClinicalTrials.gov states the Phase I/II trial’s full patient enrollment target as 75. Ten members of the FDA’s Oncologic Drugs Advisory Committee voted unanimously Wednesday to recommend

tisagenlecleucel-T’s approval for pediatric ALL, and the PDUFA date for Novartis’ BLA is 3 October. Analysts forecasted Novartis would likely establish a dominant market presence in CAR-T despite tisagenlecleucel-T being second to market after axi-cel in the more lucrative diffuse large B-cell lymphoma (DLBCL) indication.

The PDUFA date for axi-cel in DLBCL is 29 November. Axi-cel’s sales are expected to reach USD 1.6bn by YE27, with leukemia sales expected to reach USD 322m by YE20, according to BioPharm Insight data. The Kite spokesperson said data from the Phase I portion of ZUMA-4 and also ZUMA-3 (NCT02614066) in adult ALL is expected at the American Society of Hematology’s (ASH’s) meeting in December. Preliminary data from both studies was presented at the 2016 ASH meeting (abstract no. 2803).

Kite’s market cap is USD 6bn.


Kite Phase I/II pediatric ALL study sees amendment to include patients treated with Amgen’s Blincyto to speed recruitment; Phase I portion has two slots left – source

Intelligence | Development Updates

The amendment has helped with enrollment in ZUMA-4 despite competition from Novartis’ (VTX:NOVN) Phase II ELIANA study (NCT02435849) of tisagenlecleucel-T in pediatric ALL, the source said, given that ELIANA continues to exclude patients with prior treatment with Blincyto.


23 FEB 2017

Les Laboratoires Servier has amended the protocol of its Phase I study of UCART19 to no longer enroll patients with chronic lymphocytic leukemia (CLL) and only enroll those with acute lymphoblastic leukemia (ALL), two sources said.

The study’s (NCT02746952) ClinicalTrials.gov page states that it is expected to enroll 12 patients aged 16 and older from both populations at a single site in London. However, a source said it had not enrolled any CLL patients, and the Neuilly-sur-Seine, France-based company had decided to enroll only ALL patients in order to ensure cleaner data. The trial started in August 2016, and the trial page was last modified on 10 November 2016. The amendment is currently in place.

Cellectis (EPA:ALCLS) was the originator of the “off-the-shelf” CAR-T, for which Servier gained worldwide development and commercialization rights in November 2015 under a February 2014 option agreement. Servier paid Cellectis USD 38.2m, and Cellectis is eligible for more than USD 300m in milestone payments for the deal.

Pfizer (NYSE:PFE) gained US commercialization rights as well as worldwide co-development and commercialization rights, according to a 19 November 2015 press release.

UCART19 attracted widespread media attention in November 2015 when it induced a complete remission in a heavily pretreated British infant with ALL. A parallel 10-patient Phase I study in pediatric ALL (NCT02808442) is also underway at London’s Great Ormond Hospital.

UCART19 is an allogeneic chimeric antigen receptor T-cell (CAR-T) therapy that targets the CD19 antigen. By contrast, other CAR-Ts in development - such as Novartis’ (VTX:NOVN) tisagenlecleucel-T, Kite Pharma’s (NASDAQ:KITE) axicabtagene ciloleucel and Juno Therapeutics’ (NASDAQ:JUNO) - are produced using autologous T cells from the patient.

An analyst report stated that initial UCART19 data in three adult ALL patients is premature to interpret, with one minimal residual disease-negative complete remission (MRD-negative CR) and Grade 2 cytokine release syndrome (CRS), an MRD-negative CR with Grade 4 CRS and the third case receiving UCART19 on a compassionate use basis, which resulted in disease progression and death. The report cited data presented at a 14 December 2016 National Institutes of Health Recombinant DNA Advisory Committee meeting.

Peak net sales for UCART19 in ALL, CLL and diffuse large B-cell lymphoma are expected to reach USD 1.1bn, according to an analyst report.

Servier said the information is confidential and declined to comment further.

Cellectis’ market cap is EUR 745.9m. Pfizer’s is USD 204.3bn.


Servier’s Phase I off-the-shelf CAR-T protocol amended to include ALL only, excluding CLL - sources



17 FEB 2017

• Loose IP-protection presents challenge amid all the CAR-T in China

• Western branding, publicized data to boost demand over local CAR-Ts

• Western branding, publicized data to boost demand over local CAR-Ts

Chimeric antigen receptor T-cell (CAR-T) developers entering the Chinese market will find a complex intellectual property (IP) landscape with looser local protection than in the US, yet could capitalize on competitive advantages, experts said.

IP protection in China is improving, but remains weaker than in the US as some Chinese CAR-T companies appear to have already copied Western companies’ CAR-T viral vectors, experts said. At the same time, companies like Kite Pharma (NASDAQ:KITE) and Juno Therapeutics (NASDAQ:JUNO) may have a competitive advantage over local competitors thanks to stronger reputations among Chinese consumers. While protectionist instincts may drive the government to give preferential treatment to homegrown CAR-Ts, some experts said that was unlikely in the near term.

A Shanghai-based joint venture ( JV) announced 10 January by Kite and Fosun Pharmaceutical (SHA:600196) - as well as one that Juno and Shanghai-based WuXi AppTec formed last year - triggered positive analyst sentiment. However, this news service recently reported that Western CAR-Ts would face numerous regulatory and economic hurdles prior to being marketed in China.

The Kite/Fosun JV will operate as a Chinese company to develop and manufacture Kite’s axicabtagene ciloleucel (axi-cel) and other products locally, a Kite spokesperson said. Juno did not respond to specific inquiries, and Fosun and WuXi did not respond to requests for comment.

IP PROTECTIONS IMPROVED, BUT STILL DEVELOPING

While the government has sought to boost IP protections in China in recent years, some features of US patent law that companies may take for granted remain weak, apparently allowing Chinese companies to already copy Western CAR-T patents, experts said.

Most Chinese CAR-T companies seem to use viral vectors using IP from Kite, Juno or Novartis (VTX:NOVN), said Peng Li, principal investigator, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences. Li said he ascertained that from seeing clinical trial data, but declined to name the Chinese developers. Vectors can be reproduced in the lab in weeks, but proprietary research platforms are harder to copy, Li and Lung-Ji Chang,

Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville added.

Chinese CAR-T companies with trials on ClinicalTrials.gov include Beijing Sanwater Biological Technology, Hefei-based Sinobioway Cell Therapy, Suzhou-based iCarTAB BioMed, Union Stem Cell & Gene Engineering (SHA:600645), Shijiazhuang-based Hebei Senlang Biotechnology, Suzhou-based PersonGen BioTherapeutics, Shanghai-based Innovative Cellular Therapeutics, Shanghai-based Carsgen Therapeutics, and Shanghai GeneChem.

While it is possible that some Chinese companies have copied IP from Western companies, litigation -- and high legal costs for the patent holder -- may not be worthwhile at such an early stage of development and the companies’ small size, said Weihong Hsing, partner, law firm, Panitch Schwarze, Philadelphia, Pennsylvania. Damages may come into play once an infringing product starts generating revenue, but a patent holder could still sue a company earlier to stop infringement, maintain patent enforceability or sue in exchange for a licensing fee from the infringer, she said. Still, because Chinese courts lack the robust legal discovery system that US courts have for obtaining information pertinent to a case, proving patent infringement in a lawsuit can be more difficult there, thus making it more important to safeguard trade secrets, she said.

The Kite spokesperson said that outside the Fosun deal, the company had not licensed any of its technology to Chinese companies. Juno and Novartis did not specifically address similar inquiries.

Losing control of IP in China is possible, but probably not a major worry because of China’s World Trade Organization membership and government efforts to protect patents. The

While the government has sought to boost IP protections in China in recent years, some features of US patent law that companies may take for granted remain weak, apparently allowing Chinese companies to already copy Western CAR-T patents, experts said.

Western CAR-T companies pursuing China will face IP hurdles, but may gain branding edge – experts



companies are undoubtedly aware of the IP issue and keen to protect their IP, as evidenced by Kite asking for USD 40m from Fosun just for it to in-license its technology, said Hao Yu, senior policy researcher, RAND Corporation, Pittsburgh, Pennsylvania.

Numerous patent law revisions that make it easier to obtain some patent claims -- with a meaningful scope of protections -- show the IP situation is improving in China as the government seeks to show it cares about IP protection, Hsing said. However, claims with a broad scope of protections are still not as easily obtained in China like the US, she added. Overall, the IP issue is not unique to China, and Kite and Juno should be confident their IP will be protected under the JVs given that Fosun and WuXi AppTec care about IP, she said.

FOREIGN VS LOCAL COMPETITIVE CONSIDERATIONS

One potential competitive advantage for Western CAR-T companies is the better reputations Western products have over their Chinese counterparts, agreed Peng Li and Hebei Senlang founder Jianqiang Li, formerly Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington. If a product has a US pedigree or comes from a company like Novartis, consumers will assume it has higher quality and prefer it, Chang added. A reputable Western company’s trademark has value in China, and teaming up with a Chinese company that also has a good reputation there can help as well, Hsing said.

Jianqiang Li said some patients with whom he spoke with revealed that the ostensible CAR-T therapies they had received from some Chinese companies bore closer resemblance to dendritic cell/cytokine-induced killer (DC-CIK) therapy, which previously was widely used in China but is now under restrictions by the government.

Kite can benefit from its strong global reputation as well as clinical data showing strong response rates among patients, said Dr Weidong Han, Department of Hematology, Chinese People’s Liberation Army Hospital, Beijing.

Kite is in the middle of an FDA BLA review of axi-cel on the back of data from the Phase I/II ZUMA-1 study (NCT02348216) showing a 79% overall response rate among patients with aggressive non-Hodgkin’s lymphoma (ASH 2016 abstract no. LBA-6). This news service reported 20 December 2016 that approval was likely.

However, Alex Chang, professor, Tongji University School of Medicine, Shanghai, said he was less certain on Western CAR-Ts having much of an advantage over Chinese competitors due to their cost and data from Chinese-developed CAR-Ts showing equivalent efficacy.

Chang pointed to Shanghai Yake Biotechnology’s - a company Chang is affiliated with -- Phase I study (ChiCTR-IIh-16008711) data on YK-CART19 showing an 88.6% complete remission/complete remission with incomplete hematological recovery (CR/CRi) rate among 35 patients, 82.9% of whom achieved minimal residual disease negativity (ASH 2016 abstract no. 649).

There is still the potential for the Chinese government to disproportionately support local CAR-T companies or institute policies that could obstruct Western companies, Jianqiang Li said. One such strategy to make it harder for Western products to enter the market would be to

make their sponsors do extra clinical trials within China, Lung-Ji Chang said. But while such a scenario is possible, protectionist measurements generally are unlikely in the near term because the government is focused on spurring CAR-T development in China.

Kite and Juno’s respective market caps are USD 2.6bn and USD 2.4bn. Fosun’s is CNY 60bn (USD 8.7bn).




10 FEB 2017

• Hospital sites with different trial standards require scrutiny

• Regulations unclear but CAR-Ts could fall under CFDA oversight

Western-origin chimeric antigen receptor T-cell (CAR-T) therapies being developed in China face an uncertain regulatory landscape at the national level, as well as disparities between hospitals’ practices at the local level, experts said.

While regulation of cell therapies like CAR-Ts may fall under Chinese Food and Drug Administration (CFDA) regulations, details of these regulations remain unclear, experts said. However, Ministry of Health-imposed restrictions on commercialization of cell therapies -- put in place after a scandal last year -- appear likely to be lifted, experts said, and potential approval of CAR-Ts in the US may spur the Chinese government to liberalize policies. Meanwhile, widely different hospital-level skillsets and approaches to institutional review board (IRB) approvals mean CAR-T manufacturers must be careful about which centers they use, experts said.

Kite Pharma (NASDAQ:KITE) announced 10 January the formation of a Shanghai-based joint venture ( JV), Fosun Pharma Kite Biotechnology, with Fosun Pharmaceutical (SHA:600196), to will license and develop Kite’s axicabtagene ciloleucel (axi-cel) in China. The deal gives the JV options to license other Kite CAR-Ts and T-cell receptor (TCR) therapies. Juno Therapeutics (NASDAQ:JUNO) announced 7 April 2016 a similar JV, JW Biotechnology, with Shanghai-based WuXi AppTec.

Analysts have noted recent health care reform developments and a favorable landscape for in-licensing and partnering of foreign cell therapies in China, especially CAR-Ts, describing the Kite-Fosun JV as positing substantial cell therapy development opportunities there.

A Kite spokesperson noted the CFDA has drafted guidelines for cell therapies that are under review, but it does not currently regulate them, and the company has not disclosed timing or other details regarding clinical trials in China. The spokesperson added the 50/50-owned JV will be a separate Chinese company that will manufacture and develop axi-cel there. Juno did not address specific inquiries, and neither Fosun nor WuXi AppTec responded to requests for comment.

UNCERTAIN REGULATORY LANDSCAPE

A hurdle remaining to be cleared is Ministry of Health-imposed restrictions on commercial use of cell therapies in cancer - though clinical trials are still allowed - following

a high-profile scandal last year in which a synovial sarcoma patient died after receiving dendritic cell cytokine-induced killer (DC-CIK) therapy, noted Alex Chang, professor, School of Medicine, Tongji University, Shanghai, and Lung-Ji Chang, Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville. Despite being ineffective, the therapies had become widespread in China, leading to many patients being defrauded, Lung-Ji Chang added.

However, based on documentation, the government appears to be moving toward allowing commercialization, said Jianqiang Li, formerly Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, and now working on a startup in China. Dr Weidong Han, Department of Hematology, Chinese People’s Liberation Army Hospital, Beijing, said the government is treating CAR-T development as a priority.

Draft guidance that the CFDA released for public comment on 16 December 2016 proposed a CFDA-led regulatory framework for stem cell therapy, immune cell therapy and gene editing. The draft guidance has sparked industry debate and indicates the CFDA is gradually establishing a more flexible and pragmatic approach to cell therapy, according to a 20 December press release by Innovative Cellular Therapeutics, a Shanghai-based CAR-T company.

Thus, cell therapy development, which previously fell under the authority of the Ministry of Health, will likely now fall specifically under CFDA oversight, Jianqiang Li said. In general, cell therapies had previously not been regulated much, Lung-Ji Chang said.

FDA approval of CAR-Ts would be proof of concept for clinical application and could thus spur the Chinese government to open the market faster, said Peng Li, principal investigator, Guangzhou Institutes of Biomedicine and Health, Chinese

FDA approval of CAR-Ts would be proof of concept for clinical application and could thus spur the Chinese government to open the market faster, said Peng Li, principal investigator, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.

Western CAR-Ts face Chinese development hurdles due to uncertain regulatory landscape – experts



Academy of Sciences. This news service previously reported that axi-cel would likely win FDA approval for aggressive non-Hodgkin’s lymphoma, while acute lymphoblastic leukemia (ALL) data on Novartis’ (VTX:NOVN) opened a decent approval path for tisagenlecleucel-T.

But for the moment, there are no specific development regulations for CAR-T, Lung-Ji Chang said, thereby presenting a hurdle to Western CAR-Ts entering the market. For example, it is unclear if initiating a clinical trial would require filing an IND-type application, and who would look at such an application if it was filed, he said.

Given regulatory uncertainties and the greater difficulties of developing drugs in China than in the US, Kite and Juno were smart enough to know it would not be a good idea to try and enter the Chinese market by themselves, Alex Chang said. A lot of companies previously opened research facilities in China when the government opened the pharmaceutical market, but closed them after discovering drug development there was more difficult than anticipated due to unpredictable regulations, Lung-Ji Chang said.

HOSPITAL PRACTICE DISPARITIES

Beyond regulatory hurdles, there are also development disparities in terms of different hospitals’ practices during trials, Lung-Ji Chang said. While some will make sure to get IRB approval before starting a study, others will not until after the study has started, he explained, adding some still will not seek IRB approval at all, he explained.

With time, he said, hospitals in China may catch up to international standards and ensure IRB approval before enrolling patients. But until then, companies developing CAR-Ts will have to be very picky about which hospitals they use for clinical trials, he said, adding that even working with CROs in China can sometimes be hectic because they do not do a good enough job facilitating communication between trial sites and sponsors.

Many hospitals have also insisted on doing manufacturing on-site, whereas others do not, Peng Li said. Because of this, he said, the CAR-T development program he is running set up central GMP facilities in Guangzhou and Changsha, as well as smaller facilities at some of the centers.

ClinicalTrials.gov lists one Phase I study (NCT02822326) -- in which he is taking part -- of a CD19-targeting CAR-T in acute leukemia, sponsored by Guangdong General Hospital.

In terms of centers’ abilities to handle the toxicities associated with CAR-T and required inpatient care, Peng Li, Lung-Ji Chang and Alex Chang agreed there were significant disparities between some hospitals, with some being exemplary in their treatment of patients and others ill-equipped to handle CAR-T toxicities due to lack of skills, while doctors at other hospitals were too harried to communicate efficiently with sponsors.

Kite and Juno’s market caps are USD 2.6bn and 2.2bn, respectively. Fosun’s is CNY 60.9bn (USD 8.9bn).




EDITOR, NORTH AMERICA Surani Fernando

EDITOR, EMEA Jennifer C Smith-Parker

SENIOR REPORTERS Alaric DeArment

Hamish McDougall

REPORTERS Manasi Vaidya

Reynald Castaneda

Fiona Barry

Shuan Sim

SENIOR EDITORIAL ANALYSTS Peter Murphy

Kelly Lambrinos

EDITORIAL ANALYSTS Supa Chantschool

Querida Anderson EDITOR IN CHIEF

Editorial Team

http://www.biopharminsight.com/surani-fernando

http://www.biopharminsight.com/jennifer-smith-parker

http://www.biopharminsight.com/alaric-dearment

http://www.biopharminsight.com/hamish-mcdougall

http://www.biopharminsight.com/peter-murphy

http://www.biopharminsight.com/querida-anderson


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