RegenMed, stem cell and cell therapy industry in 2015

by Alexey Bersenev on December 30, 2015 · 3 comments

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This is annual overview of the most interesting, in my humble opinion, events and trends in stem cell/ RegenMed/ cell therapy industry. As always, I’d like to welcome everyone to share impressions and opinions about industry performance in 2015.

1. From “stem-” to “immuno-” shift
One of the most interesting trends this year was shifting industry focus from “stem-” or “regenerative” cell therapies to immunocellular therapies. And the most possible reason for this is inspiration by success of CAR T-cell therapies and disappointing results of some stem cell trials. This trend was visible at many levels. First, such companies as Celyad (former Cardio3 Bio) and Caladrius (former NeoStem) changed their names to reflect acquisition (Celyad) or focusing (Caladrius) on immunocellular therapy programs. Second, other “stem cell companies” entered into collaborations on immunotherapies with academic institutions. For example, Fate therapeutics with University of Minnesota and Cesca Therapeutics with MSKCC. Finally, this trend was also obvious in funding and financing. CIRM (California’s stem cell agency) proudly announced funding of two industry-led immunotherapy Phase 3 clinical trials (Caladrius and ImmunoCellular Therapeutics).

2. First stem cell-based medicinal product approved in Europe
At the beginning of this year, Italian company Chiesi Farmaceutici S.p.A announced conditional market authorization by EMA of stem cell-based medicine Holoclar for limbal stem cell deficiency. Holoclar is manufactured by Holostem Advanced Therapies – a joint venture between University of Modena and Chiesi. Holoclar is “ex vivo expanded autologous human corneal epithelial cells containing stem cells”. This approval is a result of two decades of hard work by Graziella Pellegrini and Michele De Luca research group at University of Modena. The key study, which allowed to win EMA approval, was published in 2010.

3. Despite few setbacks gene therapy sector was very strong
It was very very interesting year for gene therapy sector. There were few failures in advanced stages of clinical trials. Despite “Breakthrough Therapy” designation by FDA last year, Celladon failed in Phase 2 cardiac gene therapy trial. It was a disaster for Celladon – trial and preclinical development were suspended, company announced potential sale, merger or liquidation. Announcements by Avalanche Biotechnologies and Sangamo Biosciences are also disappointed investors. Interestingly, these setbacks did not drag other gene therapy companies down. The field was solid as rock and continued to attract interest from investors. Audentes raised more than $100k in financing, Voyager, Dimension and RegenX had successful IPOs. Biogen and AGTC signed $1B deal. But on top of all, there was an exciting news from Spark Therapeutics – great results from pivotal Phase 3 gene therapy trial for eye disease. Spark’s success kept interest to gene therapy sector afloat.

4. Approvals under Japan’s Regenerative Medicine Law
Two years ago Japan has created and passed new law for regulation of Regenerative Medicine (law became effective in November of 2014). Under this law, accelerated marketing approval of cell-based regenerative medicine products is possible after demonstration of safety and some signs of efficacy (Phase 1/2 trials). In September of this year, the first two products were approved in Japan under new law. The first product is TemCell (developed by JCR Pharmaceuticals and Mesoblast) – allogeneic mesenchymal stromal cells for therapy of Graft-Versus-Host-Disease. The second product is HeartSheet (by Terumo) – autologous skeletal muscle cells for heart failure. About two months after market authorization, both product have received price tags and reimbursement decision. TemCell is priced ~ $115,000 – $170,000 USD (depending on total number of doses infused) and HeartSheet is priced ~ $120,000 USD. Another interesting “approval” under new law was PMDA’s first license to R-Japan for manufacturing service of cell-based products.

5. Athersys failure
In April of 2015, US-based company Athersys announced results from Phase 2 clinical trial of their stem cell product MultiStem in ischemic stroke. The study missed both – primary and secondary efficacy endpoints. About a month later, Pfizer terminated agreement with Athersys and stopped investment in stem cell therapy programs. Pfizer supported another Athersys trial – MultiStem for ulcerative colitis, which also failed in 2014. It was a big blow for the whole field, because (1) adult bone marrow stem cells may not work as expected and (2) Pharma giant was ditching investment in stem cell therapy.

6. Japan is solidifying its authority in stem cell industry
This year Japan increased acquisition of stem cell/ regenerative medicine assets and made multiple deals. First, many tech giants went to shop for stem cell assets. As result of it, we saw Nikon – Lonza, Hitachi – CiRA deals and acquisition of Cellular Dynamics International by Fujifilm. Second, Japanese Pharma companies started to jump on “stem cell bandwagon”. Takeda and Sumitomo Dainippon made deals with CiRA this year. But the real bomb was a proposal by Astellas to acquire US-based Ocata Therapeutics. Ocata’s buyout proposal met a huge resistance from investors in US. The deal will be finalized next year.
Will this movement accelerate stem cell industrialization and bring faster marketing approvals in Japan? Definitely!

7. Expectations for cure
One very interesting trend that I’ve observed this year was a great expectations from investors for gene therapy. They thought that in order to transform healthcare and to justify projected high prices, gene therapy must deliver a cure, nothing less! Unfortunately, it is not the case. Investor’s favorite cell/ gene therapy biotech Bluebird bio, announced on annual ASH meeting that 3 sickle disease patients, treated with gene therapy Lentiglobin, did not achieve transfusion independence due to insufficient gene correction. Bluebird data from ASH did not meet high expectations from investors and they dropped the company’s stock shares next day (-40%). On “anticipation of cure” bluebird stock has reached almost $200 per share this year (in May-June), but right now it is trading around $50-60s. Taking into account very short follow-up, presented by bluebird, investors are over-reacted.
CAR T-cell therapy developers are also updated investors on trials outcome at ASH. And again, there was some kind of disappointment about delivery of cure by CAR T-cells. Steve Grupp from Children’s Hospital of Philadelphia (who works in alliance with Novartis on commercialization) reported that relapse rate in pediatric ALL is accelerating after 1 month of CAR T-cell therapy. Thus, at 1 months complete response rate was 93%, at 6 months – relapse-free survival was 76% and at 1 year – 55%. So, these therapies will not be curative for all patients. Investors are being too naive to assume that CART- and gene therapies are magic bullets with 100% curative effects. Reality is more complex.

8. Investment in facilities
It was a year of massive investment to cell/ gene therapy facilities. This trend was especially prominent in immunocellular therapy field. Kite Pharma broke ground on production plant in California. AdaptImmune and WuXi AppTec are invested in leasing of manufacturing facilities in Philadelphia. Lonza is expanding manufacturing capabilities by building cell/gene manufacturing facility in Houston. Korean company Green Cross announced plans to build cell therapy facility in China. Another type of facilities, such as Cell Therapy Catapult and Mayo Clinic, will host multiple commercial cell therapy developers in the future. Probably the world’s biggest gene therapy production facility was constructed by Dutch company UniQure in Massachusetts and opened this year. All these facilities will add hundreds of jobs and form new type of industry to fuel the regional economy. This trend shows maturity of the field. Companies are starting to feel confident and getting their own manufacturing instead of contracting. I think, this year was just a beginning and trend will get even stronger in the next 10 years.

9. Industry is ready to embrace CRISPR gene editing for therapies
In the past two years, a few companies were created to commercialize new gene editing tool – CRISPR/Cas9. This year, “CRISPR companies” were trying to (unsuccessfully) figure out IP mess and were making multiple deals with Pharma and cell therapy companies. These deals could explain how CRISPR-based gene editing may become a therapeutic tool. CART cell therapeutic companies first showed an interest to CRISPR-based gene editing. Novartis announced collaboration with Intellia Therapeutics on development of CRISPR-modified CAR T-cells and hematopoietic cells. Editas Medicine will collaborate with Juno Therapeutics on development of new CART- and TCR cell therapies. Big Pharma also stepped in to the “CRISPR water”. Vertex Pharmaceuticals and Bayer entered into strategic collaboration with CRISPR Therapeutics. Novartis will utilize Caribou Biosciences technologies in drug discovery.

10. Regulators and industry want to clarify autologous cell therapies
At the end of 2014, FDA released drafts of 3 guidance documents for industry, which clarify definitions of minimal manipulation, same surgical procedure and adipose tissue-derived products. This year, FDA added one more guidance – on homologous use of cell/ tissue products. The period for public comments for first 3 documents expired earlier this year, but Agency did not issue final versions. Apparently, FDA got too many comments, which could not be easily addressed. Such industry organizations as ARM and  medical societies submitted comments to FDA on these documents. FDA is planning to have public hearing on all 4 drafts in 2016. This is very interesting situation, because regulation of autologous cell therapies may be confusing for both – regulators and developers. On the other side of the world, Australian TGA proposed few approaches to specific regulation of autologous cell therapies. Public consultation is closed, but no final guidance or rules were released as of today. It will be very interesting to watch how FDA and TGA will finalize their regulations for the most confusing types of cell therapies.

{ 3 comments… read them below or add one }

Camillo Ricordi, MD December 31, 2015 at 1:40 pm

Beautiful Alexey, I’ll share your link on The Cure Alliance FB page and Twitter @CureAlliance. It is interesting to see how breakthrough pilot clinical trials, such as Graziella Pellegrini’s one, were not done under cGMP conditions. This is a first level of innovative pilot clinical testing of potentially breakthrough strategies, where you separate the hypes (or the frauds) from the hopes. We have to find the right balance between safety and the ability to perform innovative pilot clinical trials without raising the bar to an unsustainable and unaffordable level. Graziella who I admire immensely, would not have had the opportunity to get substantial Pharma funding without those initial non-cGMP trials that provided key evidence to support any subsequent investment. This should become a case study towards improving the current system to allow for initial testing and rigorous validation of potential new cures, rather than blocking them. Thank you and Happy New Year !!!


Alberto Zaragoza Comendador January 1, 2016 at 7:29 am

Is there any news on Holoclar commercialization? I found news releases and such when it was approved but barely a peep since then.


Arturo Gomez January 5, 2016 at 7:20 pm

Many thanks from Nicaragua Mr. Alexey. I look forward the answer about point 10 (autologous cell therapies’s regulations!) regards!


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