My top takeaways from #WSCS15 so far: IPS cells, #CRISPR, CAR-T, Patients

Mahendra RaoIt’s been a great couple days so far here at the World Stem Cell Summit in Atlanta. You can follow it on Twitter using the #WSCS15 hash tag. S.

I first attended it 5 years ago in Pasadena. One of the special aspects of WSCS is it brings together diverse stakeholders in a way that just doesn’t happen elsewhere. For instance, you can have the FDA, patients, physicians, scientists, and funding agency people all in one room together.

Some strong impressions so far include the following.

IPS cells. There is a great deal of excitement here about IPS cells of course, but Mahendra Rao providing a more sobering perspective. I’m more optimistic than he is. Here are his six “realities” of IPS cells, which I interpreted as his view of the top challenges.

  • Allogeneic therapy is not going to work unless HLA matched.
  • HLA matching requires a larger number of patients.
  • There is not enough cGMP capacity to make all the lines required.
  • The cost of making a line and the time required to make one make this an expensive therapy and probably not useful for a large number of diseases.
  • Cells may not be mature enough for use even if one could solve all of the above problems.
  • No real model for true autologous therapy where manufacturing is involved (no amortization and no comparability).

CRISPR and human germline modification. I was on a panel yesterday on human germline modification that I enjoyed a great deal. I was on the panel with Aubrey de Grey and Aaron Levine, who both gave fantastic talks. The audience asked spot on probing questions as well. There was some disagreement regarding the appropriate level of urgency for developing policies and/or regulations on human germline modification, but overall my sense was that us three panelists perceive that attempts at CRISPR-based human heritable modification are almost certain to occur in the near future.

There’s real promise for CRISPR-based therapies in the future for rare genetic diseases (not to mention all the great in vitro CRISPR research on humans cells in the lab that should continue), but to get from point A where we are now to point B where we might as a field hypothetically be ready to responsibly use CRISPR in the germline for humans is a long road. Thus, irresponsible clinical attempts in the next few years would be very dangerous and could be harmful to the field and society.

Still, patients in the audience passionately pointed out that in many cases there is a profound need for helpful therapies now and in the immediate future. That “patient drive” as it was termed at the Washington DC meeting last week on human germline modification is powerful and must be part of the discussion.

Innovation in brain cancer treatment including CAR-T. We also heard earlier about transformative approaching such as stem cells loaded with toxins and CAR-T therapies for cancer. Very exciting stuff!

Patients and stem cell clinics. In a session today that I chaired, we heard much more from patients. They articulated better than anyone else could about how difficult it is to get reliable information. How does one know if a certain therapy is legit, safe, and worth getting? Where are sources of information? I’d recommend some of the websites list in the link section of this blog (scroll down the right side of the page).

Dr. Steven A. Davis, co-founder of SymBioSys, Inc. gave a great talk using the example of the Texas stem cell clinic CellTex, now operating in Mexico, as a test case and as a way to introduce the key issues that need discussion more broadly. We then spent a good 45 minutes have questions and discussions. It’s clear that there are many gray areas and difficulties in this arena.

The leader of the Mexican Stem Cell Foundation (unfortunately I didn’t catch his name, but if I find it I will add it in here later) gave some helpful context for understanding where things stand in Mexico. His sense was that the Mexican equivalent of the FDA (COFEPRIS) is not currently equipped to carefully evaluate all the stem cell clinics there (often clustered on the border and catering mainly to American patients). However, he did indicate that his perception was that things are improving.

Overall. I have to thank Bernie Siegel, who is the organizer of this amazing meeting, and his team at the Genetics Policy Institute (GPI). They do a phenomenal job every year on the WSCS.

More talks are ongoing right now including a fascinating one on cord blood and its potential use for neurological disorders….stay tuned.

Bioheart on the edge in 2015?

Bioheart logoStem cell biotech company Bioheart ($BHRT) has had a rough 2015 so far.

Could this year be a decisive, negative tipping point for the company?

It has a number of clinical trials going, but from my view things seem increasingly uncertain.

An oddity amongst stem cell biotechs, Bioheart and its leadership have at times seemed to toy with what some might view as controversial projects. Kristin Comella, CSO of Bioheart, has played a major role in other ventures including in the past with the Ageless Institute, a stem cell clinic. Earlier this year, investors reportedly including Brenda Leonhardt (ex-wife of Bioheart founder, Howard Leonhardt) filed a lawsuit against Bioheart for millions in alleged unpaid debt.

Comella and Bioheart are also involved in what I view as concerning training of physicians in the use of a fat-based stem cell product that might be an unapproved biological drug from the FDA’s perspective. Comella provided some insights on Bioheart and the doctor stem cell training in a recent interview I did with her. She didn’t seem concerned with the FDA.

Bioheart has another puzzling venture, US Stem Cell Clinic, LLC, (“SCC”), which it describes in this way:

“a partially owned investment of Bioheart, Inc., is a physician run regenerative medicine / cell therapy clinic providing cellular treatments for patients afflicted with neurological, autoimmune, orthopedic and degenerative diseases. SCC is operating in compliance with the FDA 1271s which allow for same day medical procedures to be considered the practice of medicine. We isolate stem cells from bone marrow and adipose tissue and also utilize platelet rich plasma.”

Recent FDA draft guidances at the very least call into some doubt the compliance of some of the offerings of US Stem Cell Clinic, LLC. The FDA could back down on the requirement for the fat-based stem cell product SVF to be approved in advance as a biological drug, but then again it might not.

Investors seemed worried. Bioheart stock has taken a beating recently, down almost 60% in the last 3 months and almost 7% just today. Overall it seems that something has got to give soon.

Disclosure: I own no stock in Bioheart or its direct competitors. This piece is not financial advice.

Interview with Bioheart CSO, Kristin Comella: trial update, MD stem cell training & FDA

Kristin ComellaI invited the Chief Scientific Officer (CSO) of Bioheart, Kristin Comella, to do an interview after hearing some buzz that this could be a critical time for the company and that it might have been recently visited by the FDA.

Note that Comella not just Bioheart CSO, but also the primary instructor for physician training in stem cell methods offered by the company US Stem Cell Training.

Can you update us on how Bioheart is doing with its clinical trials/INDs?

Comella: Our completed clinical trials of MyoCell to date have been primarily targeted to patients with severe, chronic damage to the heart who are in Class II or Class III heart failure according to the New York Heart Association, or NYHA, heart failure classification system. We have completed various clinical trials for MyoCell including the SEISMIC Trial, a 40­patient, randomized, multicenter, controlled, Phase II­a study conducted in Europe and the MYOHEART Trial, a 20­patient, multicenter, Phase I dose­escalation trial conducted in the United States. We were approved by the FDA, to proceed with a 330­patient, multicenter Phase II/III trial of MyoCell in North America and Europe, or the “MARVEL Trial”. Thus far, 20 patients, including 6 control patients, have been treated. Initial results for the 20 patients were released at the Heart Failure Society of American meeting, showing a significant (35%) improvement in the 6 minute walk for those patients who were treated, and no improvement for those who received a placebo. On the basis of these results, we have applied for and received approval from the FDA to reduce the number of additional patients in the trial to 134, for a total of 154 patients. The SEISMIC, MYOHEART, and MARVEL Trials have been designed to test the safety and efficacy of MyoCell in treating patients with severe, chronic damage to the heart.

In addition, we  received approval from the FDA to conduct a Phase I safety study on 15 patients of a combined therapy (MyoCell with SDF­1) called the REGEN trial. Advancement of the MyoCell and MyoCell SDF­1 clinical development programs is contingent, among many factors, upon the Company obtaining access to sufficient funding to execute the necessary clinical trials to achieve proof of efficacy and regulatory authorization to market such products.

Bioheart has spent over $125 million researching cellular therapies for patients and supporting clinical trials. We are committed to bringing more treatments forward and all revenue that is brought into the company is put towards advancing this science. Our FDA phase 3 MARVEL Trial for congestive heart failure patients is budgeted to cost $10 million dollars for 100 patients. Trying to complete double blind placebo controlled trials is very expensive and there is limited funding for companies who are trying to complete these trials.

How did you and Bioheart get interested in stem cell training courses for MDs? Is US Stem Cell Training owned by Bioheart? Is there some common ground between the missions of the two?

Comella: We are currently offering courses for physicians through US Stem Cell Training which is a wholly owned subsidiary of Bioheart. The field of regenerative medicine is expanding very rapidly and physicians may not have adequate exposure to these topics during medical school. Our goal is to provide physicians with the latest research in cellular medicine. The course includes didactic lecture and hands on demonstration with topics including:

  • Stem Cell Biology
  • Embryonic Cells
  • Induced Pluripotent Stem Cells
  • Bone Marrow Stem Cells
  • Adipose Stem Cells
  • Platelet Rich Plasma
  • GMP Training
  • Regulatory Environment
  • Fat Harvesting Procedure
  • Bone marrow isolation Procedure

The course is constantly updated with new research and data as more studies are published. The goal is to familiarize physicians with the latest research and how this may affect their practice. We also host a monthly webinar series which includes journal clubs and guest lecturers. This field is growing and we want to provide physicians an opportunity to learn more about regenerative medicine. Many patients are asking their physicians questions about regenerative medicine and our hope is to bridge the gap between basic research and clinical practice.

What are your views on the recent FDA draft guidances including on adipose in which the FDA suggested that SVF is a biological drug?

Comella: The FDA has recently released a draft guidance document regarding the use of human cell and tissue products used during the same surgical procedure from adipose tissue and has requested comments from the public on this guidance. Please note that guidance documents represent the FDA’s “current thinking on the scope” of the topic. “FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA’s guidances means that something is suggested or recommended, but not required.”

We do not believe that the current draft guidance document will affect our ability to offer in-clinic cell therapy from fat to our patients. We understand that the FDA’s draft document has elicited much resistance from the public and highly respected organizations such as AABB Center for Cellular Therapies and The Academy of Regenerative Medicine have voiced their opposition.

It is impossible to predict what the FDA will do regarding any in clinic therapies so I can only tell you what has happened in the past. In December of 2014, the FDA visited our lab as well as three physicians who are doing SVF procedures. The FDA took no action against anyone and did not stop the SVF procedures. Many of you have seen that these procedures can provide benefit to patients who have failed other therapies. Our primary goal has been and will continue to be safety and well-being for our patients.

Oftentimes, emerging technologies are met with skepticism and criticism. When stents were first introduced as an option for patients having a heart attack, many famous cardiologists criticized them because of the risk of restenosis (blockage). Yet stenting is now a common cardiac procedure. Cellular medicine has existed since the 1960s and is commonly used for cancer patients under the term Bone Marrow Transplant. These treatments were never put through double blind placebo controlled trials; nevertheless, we accept them as the standard of care. In addition, cellular medicine for degenerative diseases has been the subject of thousands of animal studies and clinical trials. Many of these studies date back to the 1980s. I think a fair question to ask a patient who has failed to benefit from traditional medicines and therapies is “how many studies would you like to see before you try to harness your body’s own healing potential”. Most patients are willing to try something experimental and, provided that companies are clear on the possible risks versus rewards, these therapies should not be withheld from the public.

I think that the body’s natural healing mechanisms are fascinating. The ability to harness this natural healing potential to reverse the effects of degenerative diseases or injuries is very powerful. We have a lot to learn about regenerative medicine but we are now starting to realize the potential by bringing these therapies to clinic. With any new therapies, there are challenges to bringing them to market. In addition, it is difficult to navigate the regulatory environment because these therapies are unlike any others currently available to patients. Cellular therapies should not be regulated in the same way as drugs and devices and many regulatory bodies are trying to establish new rules and guidelines. I am not sure that a person’s own cells should be regulated in the same way as a drug that is manufactured. It is important to advance science with patient safety as the primary interest. We have treated patients whose lives have completely changed for the better because of regenerative medicine and this is why I love this field!

Was US Stem Cell Training or Bioheart recently visited by the FDA? If so, how did the visit go and could you please provide a copy of the 483 form?

Comella: In December of 2014, we had an unannounced inspection from the FDA of our lab as well as three physicians who are doing SVF procedures. The FDA requested copies of our protocols and information about all of the materials that are utilized in the SVF process. They also specifically requested information regarding several IRB protocols. The FDA toured our lab facilities as well as the facilities of three different physicians. The FDA took no action against anyone and did not stop the SVF procedures. No warning letters (i.e. 483s) were issued. We received notice that all the documents were sent to CBER who reviewed and at this time they have no additional questions. Therefore the investigation was closed. Please note that this is the second investigation for Bioheart and we have not received any warning letters (483s). Our lab is a registered FDA tissue bank (FEI: 3005825762) and we are subject to unannounced FDA inspections.

Was Fujifilm CDI acquisition a good move by the companies?

The big stem cell news already this week is the acquisition by Fujifilm of Cellular Dynamics International (CDI) for a whopping $307 million dollars or about $16.50 per CDI share. You can read the press release here.

It was less than two years ago that CDI did its IPO with an initial offering of about $46 million.Cellular Dynamics

Fujifilm reportedly has a multibillion-dollar war chest for buying into the life sciences sector and a growing interest in regenerative medicine. Note that there’s some fun, but perhaps over the top speculation going on in terms of whom they might snap up next.

CDI is an unusual company in the sense that it began about a decade ago with a very sexy idea of using human pluripotent stem cells to cure disease, but now as refers to it is focused more in the “unsexy” business of manufacturing cellular products from stem cells.Fujifilm Logo

Although the production side of regenerative medicine may not sound very innovative, it turns out that the reality is that making high-quality, functional, and pure differentiated cell products from pluripotent stem cells is no easy task. Throw in making such products from human induced pluripotent stem cells (IPSC) and it starts to become very exciting and important.

So was this a good move by Fujifilm and CDI?

Good news for the stem cell/regenerative medicine field overall?

My sense is an initial “yes” all around overall, but with some remaining questions.

If Fujifilm wants to grow a presence in IPSC and more generally the regen med arena, it now has made a big step forward. CDI has worked with CIRM, NIH, and a number of biotech companies. Again, the process of making the “real deal” pure, functional cellular products from IPSC is very important and valuable. The evolving CDI “superdonor” IPSC bank is very cool and could have huge value.

Perhaps something we could learn more about is how Fujifilm will make use of the unique IP of CDI specifically. Also how does the fact that CDI has to license IPSC technology via the Yamanaka Patents come into play? What about the overall price tag just over $300 million?

From the press release comes the Fujifilm perspective:

Commenting on the transaction, Shigetaka Komori, Chairman and CEO of Fujifilm, said, “We are delighted to be able to pursue the business from drug discovery to regenerative medicine with CDI, which develops and manufactures iPS cells. We have optimal scaffolding material, ‘recombinant peptides’, for cell generation and technologies useful for regenerative medicines such as material science and engineering. Our group company, Japan Tissue Engineering, markets regenerative medicine products in Japan. By welcoming CDI to the Fujifilm Group and by combining the technologies and knowhow of both companies, we will seek synergies and efficiencies to be more competitive in the field of drug discovery and regenerative medicine.”

From a CDI perspective, this seems like a major win for their team, who will benefit greatly financially from this deal. Although Fujifilm intends to maintain CDI as a Wisconsin-based subsidiary, as points out it’s not clear what this deal means for the employment of the 150+ CDI workers there longer term. “Synergies” and “efficiencies” after an acquisition can mean reductions in employees. It seems likely that Fujifilm will continue the momentum of CDI and help to give clinical meaning to the efforts of the CDI scientists:

Robert J. Palay, Chairman and CEO of CDI, added, “CDI has become a leader in the development and manufacture of fully functioning human cells in industrial quantities to precise specifications. CDI and Fujifilm share a common strategic vision for achieving leadership in the field of regenerative medicine. The combination of CDI’s technology with Fujifilm’s technologies, know-how, and resources brings us ever closer to realizing the promise of discovering better, safer medicines and developing new cell therapies based on iPSCs.”

For the field overall, this deal is good news. It would seem a clear, strong indicator of the great, concrete value of regenerative medicine and cellular therapies. Nearly a third of a billion dollars is nothing to sneeze at. Notably, this is not about clinical trials or that kind of specific pipeline, but more about concrete cellular products and technology. That’s an important distinction because in this sector oftentimes most of the value and growth emphasis is placed on rapid bedside potential.

Disclaimer: this post is not financial advice and the author has no financial interest in either company.

Stem Cell Pioneer Masayo Takahashi Interview on iPS cells, clinical studies, & more

Masayo TakahashiIn the interview below I talk with Dr. Masayo Takahashi, who is leading a team conducting the first ever in-human clinical study based on iPS cells. The work began with patient enrollment on Aug. 1, 2013 in Japan.

1. Can you tell us a bit about your background? As an M.D./Ph.D. and ophthalmologist do you also see patients in addition to doing research? How did you first get interested in stem cells? Are your interests primarily in iPS cells?

Yes, I have outpatient clinics in two hospitals next to RIKEN and see the patients with retinal degeneration.

I encountered the concept of stem cells at Prof. Gage’s lab in the Salk Institute in 1995. At that time I decided to make treatment for retinal degenerative diseases using stem cells. So I applied the concept of stem cells for retinal transplantation for the first time (Mol. Cell. Neuroscience 1998)

After several years of research in Japan I moved to ES cells because I realized that somatic stem cells cannot be expand enough for many patients as a standard treatment. With help of Dr. Sasai we made retinal pigment epithelial cells from ES cells ( PNAS 2002). When I saw the pigmented clumps of cells in the dish that Dr. Sasai asked me to evaluate in 2000,  I was confident that RPE will be the first ES-derived cell used in a successful clinical treatment and it will be industrialized.  I reported the first treatment of animal model using primate ES cells (Invest. Ophthalmol. Vis. Sci. 2004)

But I hesitated to develop a treatment with ES cells because I myself as an ophthalmologist did not want to use immune suppressant for the elder patients with tiny eye diseases. So it was natural that I immediately moved to iPS cells in 2005 when I heard about iPS cells before the article came out.

2. As the leader of the pioneering first ever in human study of an iPS cell-based therapy, can you fill us in on the process that went into making the trial a reality beginning with patient enrollment on Aug. 1? How long ago did you start preparing for the trial? What steps did you have to go through? Do you think some of your pre-clinical data may be published soon?

As reported in the Invest. Ophthalmol. Vis. Sci 2004, we had Proof of Concept with ES-derived RPE and ready to go into the preparation for the clinical trial. So that we started preclinical study with human iPS cells from 2007. Then we confirmed that the hiPS-RPE have the suitable characteristics for the clinical use in the aspect of quality, quantity, consistency and safety. These data was finally accepted in the Stem Cell Report.

3. Can you tell us how many patients have been enrolled so far? Are autologous iPS cells from any enrolled patients already being made? For the average patient how long do you predict it will take from their enrollment to their treatment?

We cannot announce the enrollment because of the confidentiality of the patients.

The surgery will be held 10-12 months after enrollment.

4. What method is being used or will be used to make the iPS cells? Sendai Virus for example or another approach? Why did you pick this method?

We decided to use a plasmid (episomal vector) according to the discussion with CiRA

5. How will you validate the new iPS cells from each patient? Will you, for example, do a whole range of tests such as genomics, gene expression, epigenetics, in vitro differentiation, and in vivo behavior in animal models? Do such validation tests present challenges such as being costly and time consuming? Why are they important?

We will choose suitable iPS lines severely from genomics, morphology, stem cell markers and karyotype. CiRA will help us.  We have technique for good RPE cell differentiation from 100% of iPS cell lines we choose so far.

We did in vivo efficacy test in the preclinical research but we will not do it again in the clinical research. On the other hand, we will do the tumorigenicity test for each patient’s iPS-RPE at least for the first several patients’ iPS-RPE.

They are very much  time and money consuming. However, it is important to evaluate thoroughly because it will be the first trial.

6. It would be very helpful if you could explain to us the difference between a clinical study and a clinical trial? I understand you are starting with a clinical study. How does that work and assuming all goes well with this study, what would be the next step? A clinical trial?

A clinical study is under the medical practitioner’s law. It is a unique system in Japan that is like a practitioner’s exemption.

Clinical trial is the ordinary system in the world under the pharmaceutical law. The pharmaceutical law has been changed to be more regenerative medicine friendly, so that in the next clinical application we will use the ‘clinical trial’ track.

Our first auto-transplantation of iPS-RPE sheets might become ‘an advanced therapy’ (that is also unique system in Japan). I do not think it will go under clinical trial because it is too expensive to be a commercialized standard treatment.

7. Many patients have asked me how many years it might take before we have iPS cell-based therapies for macular degeneration are fully approved and in common use. What’s your take on that?

It depends on the regulation in each country. However, it will not become in common use before 10 years. ( In Japan, by chance,  it will be 5 years or so.)

8. In the long run, do you think patients can be treated via iPS cell-approaches entirely in an autologous fashion or is it important to establish iPS cell banks for potential matching and allogeneic use? 

To make the treatment as a standard one, the cost should be decreased. In that sense allogeneic transplantation will be necessary. Also we should think about how to bring the cost down of autologous transplantation.

9. Advanced Cell Technology is conducting a similar kind of clinical approach but using hESC. Can you comment on that and how your study and theirs are similar or different?

We will treat wet type Age related macular degeneration (AMD) with RPE sheets, while ACT are treating dry type AMD with cell suspension.

10. What excites you most about stem cells and where do you see the field in general say in 5-10 years?

With ES or iPS cells, the regenerative medicine will go into the industrialized stage at least in the field of RPE.

The effect of regenerative medicine will not depend on the donor cells but depend on the host condition and the surgery skill. We should think of it as medical treatments. Furthermore, the regenerative medicine therapies, especially retinal regenerative medicine, will be completed with rehabilitation (low vision care), so we should think about total medical system.

As for the stem cells, the potential of evaluating patients’ iPS-derived retinal cells is exciting. We have never evaluated patients’ retinal cells.