Cell Therapy 2016 – Year in Review (part 2)

by Alexey Bersenev on January 2, 2017 · 0 comments

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This is the second part of my overview of the most significant events in cell therapy in 2016.

CRISPR-modified cells go clinical
This year, for the first time, CRISPR gene-edited cells were used in human. Chinese oncologists from Sichuan University used CRISPR editing method to knockout PD-1 gene on autologous T-cells of the patient with metastatic lung cancer. The first patient was a part of clinical trial, which partially supported by company Chengdu MedGenCell. The outcome of the first case(s) was not reported as of today. Three more clinical trials, involved CRISPR-based PD-1 knockout of auto- T-cells in bladder, prostate and renal cancer are registered in NCT database. These 3 trials is a collaboration between Peking University and company Cell Biotech.
In US, a group from University of Pennsylvania proposed the first clinical trial, where T-cells from patients with multiple myeloma will be modified with CRISPR-based gene editing technology. The trial design was presented at NIH RAC and was recommended for approval. Parker Institute will fund Penn’s CRISPR project. RAC decision on Penn’s trial triggered debate on ethical and potential safety issues.

CAR-T cell therapy toxicity
Toxicity, related to highly efficacious CAR-T cell therapies, was one of the hottest and highly discussed topics the year. If in previous years, deaths due to cytokine release syndrome led to temporary suspension of few clinical trials by FDA, this year, fatal neurotoxicity came upfront and dominated the news. US-based company Juno Therapeutics reported at least 5 deaths from cerebral edema in their pivotal trial ROCKET. After the first 3 deaths, reported in July, FDA lifted the trial hold in a week after protocol amendment. However, this change did not have beneficial effect and 2 more deaths were reported in November. Unfortunately, the causes of fatal cerebral edema remain unknown. The trial, more likely, will be terminated. Investors dumped Juno’s stock and criticized company’s CEO, who sold $6M worth stock between June and November.
Fatal neurotoxicity added more to heated debate on safety of CAR-T cell therapies. Even though, other developers did not observed fatal cases of cerebral edema, some critics think that field is not ready to go on a market. Despite FDA’s support and effort to understand CAR-T cell-related toxicities through creation of database, Juno’s trial deaths may have negative ripple effect on the whole field.

Big failures of clinical trials
Few academic and industry-sponsored clinical trials failed in late stage. First, pan-European Phase 3 trial, evaluated transplantation of autologous hematopoietic stem/ progenitor cells in patients with refractory Crohn’s disease failed to demonstrate efficacy and was terminated due to toxicity.
Second, Belgian company Celyad released results of their Phase 3 cardiac cell therapy pan-European trial CHART-1. Even though, exploratory analyses suggested potential benefit in fraction of patients, study failed to meet primary end point.
Third, South Korean Phase 3 clinical trial, assessing efficacy if autologous bone marrow-derived mesenchymal stem cells in patients with chronic spinal cord injury was terminated in the middle due to futility. Only 2 patients out of 16 analyzed showed functional improvement. The study was supported by company Pharmicell.
Also, I’d like to note that results of 2 failed cardiac cell therapy clinical trials (both involve autologous CD34+ cells) were published this year: PreSERVE-AMI (Caladrius), RENEW (Baxter).

ChondroCelect withdrawal from European market
This year Belgian cell therapy company Tigenix announced plans for voluntary withdrawal of their autologous chondrocytes implantation product ChondroCelect from European market. This is business decision, due to competitors on a market and lack of reimbursement. ChondroCelect received EMA marketing authorization in 2009 and since that received reimbursement only in 3 countries. ChondroCelect withdrawal brings failure rate of ATMPs post-marketing adoption in Europe to 50%. This is an alarming trend.

CAR-T goes outside of oncology
This year, we saw the first attempts of getting CAR-based technology outside of oncology field. French company TxCell started several collaborations for development of CAR-Tregs for therapy of autoimmune diseases. Their ENTrIA platform describes the concept behind. Researchers from UPenn described so-called CAAR cells , which able to eliminate auto-reactive B-cells.

Best strategic acquisitions
This year was very productive for strategic acquisition in the field. I’d like to mention here the most interesting: Astellas acquired Ocata Therapeutics ($384M), GE acquired Biosafe, Pfizer acquired Bamboo Therapeutics ($150M), Allergan acquired RetroSense ($60M).

Islet transplantation in diabetes to become standard of care
Human pancreatic islets transplantation in type 1 diabetes has been on trials in selected medical centers for about two decades. This year, results of large multicenter Phase 3 clinical trial were reported. Clinical and manufacturing protocols were successfully reproduced by 8 centers. The study met primary end points, demonstrating glycemic control, freedom of severe hypoglycemic events and insulin-independence. Results of this study will be submitted as BLA for marketing authorization. This is historic and intriguing moment for the field! Because trial was academic, it is unclear who will own license and how technology will spread globally.


Cell Therapy 2016 – Year in Review (part 1)

by Alexey Bersenev on December 31, 2016 · 0 comments

in Uncategorized

In the last day of 2016 I’d like to look at back and overview the most interesting events (in my opinion) and trends of the year. I’m going to split this overview for 2 parts without any particular order.

Results of pivotal CAR-T cell trials
Two major commercial developers of CD19 CAR-T cell therapies – Novartis and Kite Pharma, have reported results of pivotal trials, which will lay a foundation of market approvals in 2017 in US.
Novartis registration trial ELIANA in pediatric acute lymphoblastic leukemia (ALL) was conducted in 25 centers of few countries and evaluated 50 children. Complete response at 3 months was 82%. Relapse-free rate among responders was 60% at 6 months (49% survived with CR). Adverse events in a form of cytokine release syndrome were observed in 79% of patients (59% of which were admitted to the intensive care unit) and neurotoxicity – in 21%.
Kite Pharma conducted their registration CAR-T trial ZUMA-1 in patients with Non-Hodgkin Lymphoma (NHL) in 22 US centers. Complete response at 1 month was 47% (76% overall response), but dropped to 33% at 3 months. Severe cytokine release syndrome occurred in 20% of patients and neurotoxicity in 29%.
Both companies feel confident about obtaining market approval in 2017.

Strimvelis approval
There were 7 market approvals of cell-based therapeutic products this year worldwide, but the most interesting, in my opinion, was Strimvelis. It is gene-modified autologous CD34+ cells for therapy of one of the forms of inherited severe combined immunodeficiency – SCID-ADA. The technology was developed by Italian scientists at San Raffaele Scientific Institute and licensed to Pharma giant GSK in 2010. This is the first ex vivo cell-gene therapy product, approved in Europe. Also, Strimvelis is first example of successful development of cell-gene therapy by big Pharma company, licensed from academic institution.
Because of orphan indication, Strimvelis was approved with only n=12, but demonstrated 100% efficacy (survival at 3 years and longer time point) in pivotal trial. The product is priced as 594,000 euros ($665,000 USD). Despite high price tag, the market size for Strimvelis is about 14 patients in Europe and 12 in US, therefore, the product will not be profitable for GSK. Intriguingly, Strimvelis is the first product in cell/ gene therapy history with “money back guarantee” policy.

Attempts to reform regulation in US
Debates about reforming regulation of cell-based therapies have been ongoing in US whole year. The first proposed controversial bill – REGROW Act triggered many discussions and split professionals for 2 camps. REGROW proposes to accelerate development cell of therapy products by skipping phase 3 of clinical trials and granting conditional marketing approval. Many professional organizations opposed REGROW. However, debates on REGROW recently faded away with passing another bill – Cures Act. It was giant “healthcare improvement” bill with few provisions for regenerative medicine/ cell therapy. As gentler alternative to REGROW, Cures Act gained more supporters, passed Congress and was signed by president into law. Read more about potential impact of Cures Act here.
Another historic event was FDA’s public hearing on clarification of some definitions, related to regulation of cell therapies. The field has never seen such big public interest and participation before. FDA received so many controversial comments about their cell therapy draft guidances, that 2-days hearing was necessary. There were many good points made during the hearing, highlighting necessity for education and open discussion between FDA and all stakeholders. FDA’s response in a form of final version of guidances is expected in the first half of 2017.

The end of StemCells Inc
This year, one of the oldest stem cell therapeutic company StemCells Inc ceased its operations. StemCells Inc was founded by Irv Weissman (Stanford U) and Fred Gage (Salk Institute) in 1988 and went public in 1992. Company was not able to deliver therapeutic promise over almost 3 decades of existence. Earlier this year StemCells Inc terminated Phase 2 of spinal cord injury trial, due to lack of efficacy. Poor financial performance (company went from $175 per share in 1995 to 57 cents per share in 2016), lack of trust from investors and some recent CIRM-related controversies also contributed to company’s setbacks. About a month ago, StemCells assets were acquired (through merger) by medical device company MicroBot Medical.
StemCells Inc shutdown is a big blow for the field, because it showed inability to deliver stem cell therapy promise, despite strong scientific foundation and financial support.

The biggest deals made in T-cell therapy space
2016 was a very good year for big deals in cell therapy. The most interesting and potentially impactful deals happened in engineered T-cell therapy space. Two more Biopharma companies entered CAR-T cell field – Baxalta (now part of Shire) and Regeneron. Baxalta (Shire) will pay up to $1.7B to Precision BioSciences for their gene editing platform in development of 6 allo- CAR-T cell therapy targets. Regeneron will collaborate with Adicet Bio on development of off-the-shelf CAR- and TCR- T-cell therapies. Another big deal (with $1B potential) was signed between bluebird bio and Medigen for development of TCR-modified T-cells.
Trend: big players are getting more and more interested in off-the-shelf T-cell therapies, watch how it will get hotter in 2017.

Stay tuned for part 2!


New law, called “21st Century Cures Act”, has been signed this week in US. This is huge legislation, which covers new developments and initiatives, aimed to improve healthcare system. Few sections of the Cures Act specifically dedicated to regenerative medicine. These sections were proposed by industry lobby organization Alliance of Regenerative Medicine (ARM) as the most recent addition to the Cures Act. Unlike highly controversial REGROW Act (which proposed to have conditional approval without Phase 3 clinical trials), Cures Act offers gentler, but potentially significant regulatory changes. In this post, I’ll try to discuss what cell therapy/ regenerative medicine field should expect from this new law.

New definition
Section 3033 of Cures Act defines “Regenerative Medicine Therapy” (RMT) as

… cell therapy, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the Public Health Service Act and part 1271 of title 21, Code of Federal Regulations.

Currently FDA does not use definition “regenerative medicine” or “regenerative medicine product”. It is unclear if FDA will adopt this terminology as new sub-classification of HCT/P. It is unclear to me if gene-modified cells are also falling under RMT. The answer is yes, if all RMT = 351 HCT/P. Cures Act does not say specifically about gene therapy or gene-modified cells as exception. Based on definition, immunocellular therapies in oncology are also RMT. I see this classification as misleading.

New designation
If cell-based product classified as RMT, it is eligible for new designation “Regenerative Advanced Therapy” (RAT), which expedites approval process. Two more criteria must be met for RAT designation (emphases mine): (1) serious or life-threatening disease or condition and (2) preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such a disease or condition. Now, if you familiar with existent FDA’s expedited programs, these criteria sound very similar (almost identical) to Fast Track and Breakthrough Therapy designations. Once RAT is granted, developer will enjoy all the same benefits that Breakthrough Therapy designation offers, including two more existent expedited programs – Accelerated Pathway and Priority Review.
So, why do we need one more designation for expedited approval? Apparently, lobbyists of new legislation thought that FDA is not generous enough with expedited approval designations. Reading through section 3033 of Cures Act, I was not able to find what could lower a bar for RAT designation compared to existent expedited FDA programs (mainly, Breakthrough Therapy).

Postapproval requirements
Unlike existent FDA regulation, Cures Act describes what data could be used if developer of cell-based product is a subject of post-expedited approval requirements. Regulatory monitoring may include confirmatory clinical studies, patient registries and other “real world evidence”, such as electronic health records. I’d like to note that FDA routinely requires postapproval follow-up data. FDA also applies these requirements for approved cell therapy products (see Provenge example). For gene-modified cells it would be 10-15 years of genotocixity safety monitoring. So, it is not something entirely new.

Regulation of RAT-related devices
Section 3034 of Cures Act requires FDA to issue separate guidance for regulation of devices, related to recovery, isolation and delivery of RAT, within one year after law enactment. Currently FDA has no separate guidance for devices, related to HCT/P. Cures Act says that RAT-related devices should be moderate risk (class II) by default, unless specified by FDA in guidance when premarket approval application is required (class III). This section also requires FDA to specify “off label” use of RAT-related devices, means for more than one indication and for more than one cell type.
So, Cures Act requests FDA to simplify regulation of cell therapy isolation devices. If FDA will allow such “freedom”, it will be much easier, for example, to legitimize the use of adipose SVF processing devices for multiple applications. This section may have the biggest short-term impact on cell therapy field.

Reporting on RAT success
Section 3035 of Cures Act requires FDA to report annually to Congress on effectiveness of RAT program. Before, FDA was not required to report on effectiveness of its expedited approval programs. However, FDA regularly reports it on multiple public meetings and conferences. For example, Celia Witten (Deputy Director of CBER) reported on few public meetings this year about success rate of Breakthrough Therapy designation for cell/ gene products as 11 granted/ 32 requested. You can also read GAO report of expedited approval programs.

Developing standards
Section 3036 of Cures Act requires FDA in collaboration with NIST (and other stakeholders) to develop standards and “consensus definition of terms” for RMT and RAT, including manufacturing and control of such products. Cures Act gives FDA 2 years to complete this task and one more year to update regulation to include new standards.
To me, this is the most valuable section for the field. We really need it.

Opinions and controversy
Citing different provisions of the Cures Act, many critics think that the law would weaken regulation of drugs/ devices and current FDA’s standards. I’m going to comment on some quotes below.

From Respectful Insolence blog:

The central premise of the bill is ideological nonsense. It turns out that radical reform involving weakening the FDA is not needed. The FDA already has the tools to do what the 21st Century Cures Act demands without weakening patient protections or scientific rigor. In fact, the FDA, despite being underfunded, is actually remarkably efficient at new drug approvals, evaluating nearly all new drug applications within 6 to 10 months, an impressive turnaround for such complex assessments. It’s been pointed out that the FDA actually acts more rapidly than most European regulatory agencies. Basically, there is no evidence that the FDA hampers overall medical innovation, nor is there evidence that the FDA’s current requirements lead to higher drug prices or cost lives.

I agree, however, regenerative medicine sections have some new and good things, such as a request for standards development. Most of the Cures Act provisions, including those applicable to regenerative medicine, are not offering anything new. The only exception could be use of “real world evidence” (not just confirmatory monitored studies) for postapproval surveillance.

From In the Pipeline blog (emphasis mine):

And there’s some fundamental confusion here. I really don’t think that there’s this huge backlog of wonderful therapies piling up behind a big FDA roadblock. FDA approval is not what shows that a drug works; clinical data do that. You can instruct everyone to collect less data, but then you will approve – and ask people and their insurance companies to pay for – more things that don’t actually work. How we are supposed to spend less on health care by approving expensive medications that don’t do much good escapes me.

Totally agree! As I said before, we are lacking of good products with spectacular clinical performance – blame developers first of all, not FDA.

From ScienceInsider:

But suggesting special treatment to regenerative medicine also sends a troubling signal, says public health policy expert Aaron Kesselheim of Harvard University. “The FDA already has these tools that, if there is a new important regenerative medicine therapeutic, it would apply,” he says. “I just don’t know what this section of the bill does, other than push the FDA to apply these pathways to regenerative medicine therapeutics before there’s any kind of reasonable belief that that would be useful.”

Agree with Kesselheim. As I said above, proposed RAT designation essentially the same as existent Breakthrough Therapy designation (which applies to all drugs, not just to HCT/Ps). I guess, by proposing RAT designation, ARM and stakeholders believe that success rate of Breakthrough Therapy designation, granted to 351 HCT/Ps is too low (currently 34%). Well, maybe there is a good reason for it.

From the same source:

And though Cures stops short of explicitly removing a requirement for phase III trials, winning accelerated approval can make them unnecessary. “Accelerated approval is conditional approval,” Mills says. (Like conditional approval, it comes with the requirement to collect postapproval evidence of efficacy. The Cures bill also specifies that such evidence can come from sources outside a clinical trial, such as electronic health records or patient registries.)
Drugs for rare diseases have long depended on the accelerated pathway to reach the market, Mills notes, and “they’re lucky if they get two trials.” In fact, an analysis of the 20 drugs approved under FDA’s accelerated pathway between 2011 and 2015 found that only 20% relied on phase III data.

Mills nails it, however, accelerated approval is not equal to conditional approval. Even with expedited programs Phase 3 of trials may be required. Also, expedited approval will not necessarily come with requirement of post-market studies. It all depends. We don’t have historic 351 HCT/P approvals data to conclude how frequent accelerated pathways will result in bypassing Phase 3 of trials. But very soon we may witness the first such precedent with approval of CAR-T cell products – both Kite Pharma and Novartis skipped one phase of trials.

Concluding remarks
Taking into account high probability of passing the Cures bill and its gigantism (it combines so many different things together), it was a smart move from ARM to squeeze sections related to regenerative medicine. ARM possibly resolved controversy, related to REGROW Act, by offering gentler alternative with few provisions in Cures Act. It seem to me that REGROW will die.
Importantly, Cures Act is not clarifying the most controversial issues in cell therapy, highly debated on historic FDA public hearing this year. As of now, Cures Act is not changing significantly current regulatory framework for 351 HCT/Ps, but it will be up to FDA to decide how it could be changed in the future (Cures requires FDA to clarify so and so in guidances). It also will largely depend on what course new FDA Commissioner will take.


Presentation: CELL THERAPY – Definitions, Classifications and Trends

October 14, 2016

Here is my talk that I gave on August 15 this year during annual BioProcessing Summit in Boston. Cell Therapy – Definitions and Classifications from nanog Link Transcript: 2. Cell therapy is mostly experimental field right now. So, one of the best ways to track activities in this field is to look at number of […]

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Historic FDA public hearing on regulation of cell therapy in US

September 18, 2016

On September 12 and 13 of 2016, FDA conducted public hearing on clarification of regulatory guidances for cell therapy. In my view, it was historic event, because it was the first-of-its-kind public hearing for cell therapy field. The reason for the hearing was unexpectedly high number of controversial comments about 4 guidances that FDA released […]

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Whom should we blame for the absence of approved stem cell products in US?

September 14, 2016

Few months ago I was watching presentations from Bipartisan Policy Center on support of REGROW Act as alternative regulation for cell therapy, proposed to FDA. I was especially intrigued by presentation of Randal Mills – President and CEO of California Institute for Regenerative Medicine (CIRM). Here is a quote that I’d like to discuss today […]

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Why price for cell/ gene therapy products is so high?

September 6, 2016

The topic of pricing cell and gene therapies is very hot right now. The price tags for the most approved cell/gene therapy products are high and there is no one simple solution to address their reimbursement and adoption. The world’s most expensive drug is gene therapy drug Glybera, has captured a lot of attention in […]

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Is cell therapy failing commercialization in Europe?

August 19, 2016

Christopher Bravery – a consultant on advanced biologicals, has opened Cell Therapy Stream of the annual Bioprocessing Summit with worrisome note: “Half of approved cell and gene therapy products on European market eventually failed commercialization and were withdrawn“. Let’s look at it in details. Since introduction of regulation cell/ gene therapy as Advanced Therapy Medicinal […]

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FDA calls for collaboration on CAR T-cell therapies database

March 16, 2016

CAR T-cell therapy is disruptive technology on many levels. One of such levels is regulation. On the one hand regulators have not seen such impressive efficacy data for long time and it is very inspiring (FDA keeps awarding CAR T-cell developers with “Breakthrough Therapy” designation). On the other hand, high efficacy “comes with a high […]

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Spinal mass formation after auto- transplantation of olfactory cells in patients with spinal cord injury

February 13, 2016

The recent report, published in Acta Neuropathologica, describes 2 cases of spinal tissue mass formation after local transplantation of autologous olfactory mucosa in patients with spinal cord injury. Both patients underwent cell translplantation 7- and 5 years ago in Portugal as part of clinical trial. Patients were evaluated at University of Michigan Medical Center for […]

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