RepliCel -- Treating Functional Cellular Deficits. An Interview with CEO, David Hall

Despite us both living in the Vancouver area and both being involved in cell therapy, I didn't meet David Hall until we were both in La Jolla late last year for the Alliance for Regenerative Medicine's Stem Cell on the Mesa meeting.  Since then we've been keeping in close contact and I have had opportunity to learn a lot more about him, his team, RepliCel, and the company's technology.  

The company is by all appearances a company on the tail end of a number of significant transitions in terms of its structure, finance, clinical pipeline, and even the breadth of its underlying technology.  The company is now unveiling RepliCel 2.0 (my term, not theirs) which builds on the company's core expertise and platform technology but combines newly added assets and clinical strategies that create end-to-end solutions and multiple pillars around which shareholder value is being created.

David presents a sound logic for the transitions through which he has taken the company in the past 18 months and the pace of that change.  He does, perhaps more than many CEO's I have had the opportunity to interview, present a strong and focused vision for the company with a clear goal and a well-defined pathway for how he intends to get the company there.  From my vantage point, this vision permeates into most aspects of the company from clinical trial design, to patent strategy, to defining collaborations, and even recruiting.

Suffice it to say I have been increasingly impressed by what I see and welcome the opportunity to share the interview below with you.  I hope you enjoy learning a little more about RepliCel as much as I have.

CTB:  Tell us a little about your background, David, and how you got involved in a cell therapy company?

DH: My initial career was in finance working on both sides of the street as a money manager and as a banker and analyst.  It was as a banker that I came to join ID Biomedical which then led to my joining Angiotech Pharmaceuticals not long after it was started.  During my time there I served as Chief Financial Officer, Chief Compliance Officer and Treasurer and Corporate Secretary.  After 20 years in life sciences, I spent time focused on public policy in BC and Canada as it related to developing our BC life sciences industry.   During that time I was approached to look at a cell therapy company developing a treatment for pattern baldness.  Despite my lack of empathy at that time for pattern baldness as a disease, I was struck by the elegance of this group’s scientific approach and how that might be expanded into other treatments where there was a deficit of healthy active cells.

CTB: Can you give us a snapshot of RepliCel as a company?

DH: RepliCel is treating cellular deficits in two main areas. The first is addressing conditions where there is a deficit of healthy functioning fibroblasts such as chronic tendinosis and damaged skin. 

The second is in treating pattern baldness where there is a deficit of dermal sheath cup cells that are responsible for maintaining a hair follicle cycle of fiber production.  

In addition, we have developed cell manufacturing technology and procedures to support the potential commercialization of these indications as well as specialised delivery devices which in themselves are unique and have the potential for licensing for other medical and cosmetic uses.  We believe the manufacturing and delivery assets are very important to the company as you need to be able to demonstrate scalability and commercial delivery.

CTB: What is the company’s technology?

DH: RCH-01 is our treatment for pattern baldness.  This technology specifically focuses on replacing a deficit of healthy active dermal sheath cup cells (DSCs).  Our product thesis is that these DSC cells control and maintain the population of dermal papillae (DP) cells in a hair follicle and the number of DPs determine the length and thickness of the hair fibre.  In patients with pattern baldness (men and women), DSCs are compromised by the androgen hormone for no known reason.  It is kind of like the reverse of unwanted or aggressive hair growth.  Some people have five-o-clock shadows when they are 15 and others don’t shave until they are 20+.  In pattern baldness, the androgen hormone compromises hair growth.  RCH-01 addresses the deficit of the active DSC cells in the areas of pattern baldness in the scalp.

The RCT family of products* are for the treatment of chronic tendinosis including Achilles, patellar  and both golfer’s and tennis elbow.  In each case we are addressing a deficit of healthy active fibroblasts.  The scientific thesis is that this chronic disease is the result of incomplete healing cycles due to a deficit of healthy functioning fibroblasts.  Our early human clinical work on chronic tendinosis was done by our collaborator, Dr. David Connell, using fibroblasts isolated from the dermis.  Our program is based on using fibroblasts isolated from the hair follicle due to their ability to express higher levels of type I collagen than dermal fibroblasts.  Type I collagen is the main cell constituent of a tendon.  (*RCT-A-01, RCT-P-01, RCT-G-01 and RCT-T-01)

RCS-01 is focused on replacing damaged or non-functioning fibroblasts in the dermis.  Fibroblasts damaged by UV irradiation, smoking and other factors stop producing healthy amounts of collagen and the constituents of the skin’s extracellular matrix.  As a result, the skin loses its texture.  Similarly, acne and burn scars are targets for us to deliver highly expressive fibroblasts to initiate remodelling of the damaged skin. 

The supporting manufacturing technology is also a critical asset to the company as we believe our process is scalable.  

In addition, we have developed a very unique injection cell injection device for dermal injections for both our derm and pattern baldness program.  This device minimizes shear force, optimizes staged cell delivery, and has a built in freezing element that obviates the need for any kind of anesthetic and can control both volume and depth of injection.

CTB: Where are you doing your trials?  Why Europe and Canada?

DH: All of our trials are being conducted under the terms of reference from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).   Each trial is designed to meet these international standards of which all of the western nations are members.  As such, all of our data up to Phase 2 are admissible towards Phase 3 pivotal programs in each jurisdiction.  

Our RCS-01 trial is being done in Germany.  The co-founder of the Company Dr. Rolf Hoffmann, is located in Germany and he is leading this initiative.  Similarly, our RCH-1 treatment is being conducted in Germany at the Charité Hospital in Berlin.  The Charité is one of the largest teaching and research hospitals in Europe.  In addition, the technology itself was first developed in Dr. Hoffmann and Dr. McElwee’ s lab at the University of Marburg in Germany.  There is history with these technologies in Germany and in addition, the cells are being processed by our contract manufacturer in Austria.

The clinical trial for RCT-A-01 will  be conducted at the University of British Columbia because it is a world centre of excellence for sports medicine research including tendinosis.  We have three very special advisers leading the development of the clinical trial protocol including Dr. Ross Davidson, Dr. Jack Taunton and Dr. David Connell.  Each of them are key opinion leaders in sports medicine.  It is also convenient to have this trial in our own city, but it was not the deciding factor.  Reputation, skills and the ability to recruit patients were the deciding factors.  The cells will be processed in Austria; however, we are moving to bring online a second contract facility validated in North America at the Centre for Commercialization for Regenerative Medicine in Toronto. 

CTB: What is the strategy for the U.S. market?

DH: The US market will be addressed from two angles.  First, we are presenting our fibroblast program to the US military under their peer reviewed medical research program.  The DoD has a great interest in musculoskeletal research to deal with damaged tendons and skin.   We believe our programs are ideally suited for their needs and are preparing filings for funding for clinical programs both in Canada and the US.  The second approach is to undertake phase 2 clinical work on other target tendons in the US after we have gotten our RCT-A-01 program launched.  Importantly, all of our trials are being conducted under ICH standards with the US regulatory pathways in mind. 

CTB: Tell us about the deal you did recently with Shiseido and what your drivers were for that kind of deal?

DH: In 2013 we completed a geographic license with the Shiseido Company.  Shiseido has its own hair research lab and they had come to the conclusion that our approach was the leading cell therapy technology for treating pattern baldness.  

We were interested in doing a geographic license for Japan and parts of Asia for three main reasons.  The first was to have a third party validation of our science and technology which is always important to a start-up company.  The second was to be partnered with a large company whom had the resources (both human and financial) to conduct their own clinical program which along with our program would more than double the data being collected as we work towards establishing our dosing and other protocols for the technology in humans.  Thirdly, Shiseido has committed to cell therapy in a significant manner including having commissioned and now opened a purpose-built cell processing centre in Kobe Japan, in the heart of the country’s regenerative medicine initiative.   

Our ongoing collaboration will see technology improvements shared between parties.   Financially, we received $4 million up front, future milestones totaling approximately $30 million as well as middle single digit royalties on sales.  We are very pleased with our collaboration with Shiseido.  They are a focused and dependable collaborator.

CTB: From our perspective, the company is significantly under-exposed both in the regenerative medicine industry and investment communities.  Can you give us a sense of why you think that might be and your plans in that regard?

DH: Every company has its own chronological pathway to develop a profile in its industry and in the public domain.  During the later stages of 2012 and through 2013 RepliCel was very concentrated on completing the Shiseido transaction as well as completing the filing of PCT patent applications on its fibroblast platform.  Until we had completed the task of protecting our expanded technology, it did not serve the company to disclose these activities.  

Now in 2014, we are completing the next round of financing, pushing hard on our clinical filings to launch 3 clinical trials and now have the freedom to discuss our programs.  As such, we are going to be out in the public domain at conferences and doing roadshows in order to get the RepliCel story known and followed both in industry and in the capital markets.

CTB: While many of the companies in the cell therapy sector are focused on indications like cardiovascular disease, oncology, autoimmune disorders, or diseases of the central nervous system, RepliCel is going after sports injuries, baldness, and wrinkles.  Do you see these indications as low-hanging fruit?  Do these indications battle problems of lower-margin and/or reimbursement challenges?

DH: I would agree that our programs are low hanging fruit in the regenerative medicine business and that is an attractive distinction.  Furthermore, as an autologous therapy, there is less risk of rejection than an allogeneic therapy. 

Our therapies are designed to simply multiply a patient’s particular cells that are in deficit and then deliver it to the area of deficit.  We are not differentiating or inducing cell change, we are simply letting the cells do what they normally do when placed in the area of the wound or damage.  

A lot of regenerative medicine is focused on very complex processes that take a source cell and then engage in extensive cell manipulation and/or differentiation.  While these treatments are going to arrive in the future, today they are very difficult therapies to perfect both in assuring that the cell differentiations are exact and controlled and that the cells are delivered in volume and stay and function where they are needed.  Our process is just simpler.  So, yes, this is low hanging fruit in terms of safety risk and the commercial development timeline.

In terms of margins, we are quite confident in our ability to demonstrate manufacturing scalability.  In terms of reimbursement, initially we have only one product that would need pharmacoeconomic validation and that is the tendon program.  However, we know that we can replicate and deliver a tendon program at a reasonable cost and that there is no current clinically established solution for chronic tendinosis.  Therefore, we do not anticipate any problem pricing at a good margin.  In terms of the derm program, the initial focus is a cosmetic therapy and I think pricing a solution for sun damaged skin, wrinkles, etc. should not be an issue.  A treatment with good efficacy will have no problem getting a premium price. In terms of margins on a treatment for pattern baldness, it would be priced against the current standard of care which is hair transplant surgery.  And at that price, we can make good margins.

CTB: Many of the cell therapy products already approved are in the musculoskeletal, dermatology, and wound repair space and none are a run-away success.  Does it worry you to be also focused on these areas for your near-term opportunities?

DH: That is a statement on the relative efficacy and difficulty of delivery.  Approval does not necessarily equate to commercial success.  We believe that our programs will have significant efficacy for their targeted indications, be easily delivered and they will become the gold standards.  But that is the nature of product development; you have go out and demonstrate efficacy!  One comment on wound repair is that we are not at this time interested in pursuing open wound repair as that space has many solutions ranging from complex cell therapies to medical devices.  It is a crowded space and we prefer at this time to prove our platforms where we are confident in our success and are not populated by other treatments.  

CTB: Your initial focus is on autologous applications of the hair follicle-derived cells, what are plans to address some of the commercial (cost) challenges presented by autologous cell therapies already on the market?

DH: As mentioned above, we are focused in parallel to our clinical development programs, on developing a scalable process for our cell manufacturing.  We see this as a process engineering program and not a development process requiring scientific breakthroughs.  This development program is underway.  It is also true that we believe that our hair follicle derived cells are immune privileged and that in the future, our technologies could well become an allogeneic offering.  But that is down the road. 

CTB: Few companies of ReplCel’s size and market cap are simultaneously tackling multiple products in clinical trials let alone also the concurrent development of a proprietary delivery device.  Some might argue it would be more prudent to preserve capital to ensure you have what it takes to move one product further down the line.   Can you give us a sense of your why you prefer this multi-pronged strategy?

DH: Our programs are inherently cheaper to develop and test than more complex cell therapies and for that matter, new chemical entities or biologics.  We are simply expanding a patient's cells and giving them back to them.  It is just cheaper to do than other therapies.  As such, we can undertake more programs and I would argue that for shareholders, more shots on goal helps to mitigate risks associated with clinical programs.  We believe we have a single focus on leveraging our core expertise around cells derived from the hair follicle organ and finding meaningful clinical applications for those cells.  Optimizing the manufacturing and delivery of those cells just makes sense as part of the risk mitigation and value optimization of those assets.

CTB: To those investors interested in the regenerative medicine and cell therapy sector, where does RepliCel fit in the industry and how do you think it stacks up against sector comparables as an investment opportunity?

DH: I would characterize RepliCel as a mid-stage development company that exists between earlier approved products like Apligraf and Dermagraft for wound healing, and much more complex cell therapy clinical development programs.  There are other mid-stage programs like Athersys' MultiStem and Mesoblast’s Mesenchymal Precursor Cells.   However, I would argue that our simple cell replication process of a target cell deficit is simpler to manufacture and deliver than many cell therapies.  So, I would characterize our development programs as lower risk.  Nevertheless, I would also say to investors that regenerative medicine is going to be a huge field in the future as science and technologies evolve.  This industry will be delivering incredible medical solutions for patients in the future.  

 CTB: Talk to us a little about the stock.  It’s very lightly traded on both the Toronto venture exchange and over-the-counter bulletin board.  What’s the plan going forward in terms of its listing and liquidity?

DH: Yes, it is true our trading has been low.  That is a direct function of our tightly held stock, (management, founders, etc., own approximately 45% of the stock) and the fact that we were very focused in 2103 on our partnership and the patent filings.  As discussed above, we are now launching our story on a focused basis that will see the company out on road shows delivering its message to potential investors.  We think that RepliCel is an attractive and unknown story which will have a good reception.  That effort is focused on addressing the valuation and liquidity.  In terms of listing, the natural progression as we develop assets and valuation is to up list which we will be pursuing.

CTB: Where do you see RepliCel in 18-24 months?

DH: On a clinical basis, we will have data in both our tendon and derm programs and will be closing in on the clinical trial data for our treatment for pattern baldness.  We should at that time be initiating at least one other tendon program and a phase 2 derm program.  We will have developed clinical protocols for two new indications for our fibroblast platform (not yet being disclosed due to patent work) and we will have demonstrated scalability of our manufacturing platform.   If we accomplish this as planned, we will have established an extremely valuable group of assets.   

CTB:  Thank you, David, for the opportunity to spend some time learning more about RepliCel and your plans for the company.

Potential far-reaching implications of the ongoing fight over point-of-care autologous cell therapy

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The FDA recently issued an untitled letter to Parcell Laboratories and its contract manufacturing organization, New England Cryogenic Center (NECC), pertaining to the product PureGen™ Osteoprogenitor Cell Allograft intended for the "repair, replacement, reconstruction of musculoskeletal defects". The letter stated:

"The PureGen™ Osteoprogenitor Cell Allograft is not the subject of an approved biologics license application (BLA) nor is there an IND in effect. Based on this information, we have determined that your actions have violated the Act and the PHS Act."

This would appear to be an indicator that the FDA does not intend to relax enforcement of its view of how autologous cell therapies are to be regulated despite its ongoing litigation on this very subject with RSI.

As followers of this blog know, since the battle's inception in 2008 I have followed the case of Regenerative Sciences, Inc and their war with the FDA over their right to provide certain autologous cell therapy treatments to patients in certain circumstances without FDA approval. My first blog entry on the topic was in September 2008 in which I pointed out that the FDA had written a letter to RSI that July taking issue with some of their practices.

My next blog on the subject was February 2009 in which I concluded "I think the FDA is building its case and a showdown is on its way to Denver-town."

At the advice of legal counsel, I pointed out in a March 2010 blog entry that my reference to FDA's July 2008 letter to RSI was not officially a "warning letter" as that is defined and as I had referred to it but rather an "untitled letter". I also commented that FDA's lack of enforcement action against RSI to-date was emboldening medical practitioners into thinking FDA was reconsidering their position on the legality of providing autologous, expanded cells to patients outside of an FDA-cleared IND or BLA.

I took some satisfaction in announcing on my blog in August 2010 that the FDA had finally taken action against RSI. My satisfaction was not rooted in a belief that the FDA is right (I've always been agnostic as to which side is right) but in the sense that things had occurred as I had predicted they would.

The action the FDA chose to take against RSI was to seek an injunction against RSI from continuing to provide the "offending" treatment - a version of the Regenexx™ procedure using mesenchymal stem cells (“MSCs”) grown outside the body after harvest for the later infusion back into the donor-patient for the treatment of various orthopedic conditions - which the FDA alleges is a "product" falling under its regulatory authority but for which RSI has never received any FDA clearance to provide to patients.

RSI counterclaimed against the United States, challenging the FDA’s authority to regulate the Regenexx™ Procedure in question and challenging certain FDA regulations. The United States moved to dismiss Defendants’counterclaims and for summary judgment.

I have continued to follow the case relatively closely through a number of source (see this sample media coverage in OthosSpineNews) as it continued to progress. Last month, for example, a blog I follow posted an eloquent case in support of RSI's position with the help of Mary Ann Chirba, J.D., D.Sc., M.P.H. of Boston College Law School.

So it was with much interest that I was recently notified of an order issued by the court which appears to have the potential to take the case in a very unexpected direction with enormous potential ramifications.

The context is that the judge was reviewing the FDA's motion for summary judgment, RSI's response, and FDA's reply when the judge issued this order to show cause.

At its essence the Judge has ordered the FDA to file a brief no later than 26 September showing the court why the term “chemical action” applies to stem cells. It is is a short Order the core of which reads as follows:

The Government finds its definition for a “drug” in the FDCA: “The term ‘drug’means . . . articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” 21 U.S.C. § 321(g)(1)(B)&(C).

This definition, at least as to subsection (C), would be broad enough to encompass a boot on a patient’s ankle to hold it secure after ankle surgery. The Court doubts that was Congress’s intent.

Neither party references the definition for “device,” found in the statute at 21 U.S.C. § 321(h). A “device,” is a certain kind of “article” used in diagnosis, cure, mitigation, treatment or prevention of disease, 21 U.S.C. § 321(h)(2), but which, presumably unlike a drug, “does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.” 21 U.S.C. § 321(h).

These contrasting definitions immediately raise the question of why the Court should not interpret the meaning of the word “drug” to include not only an article for use in diagnosis, etc., and intended to affect the structure or function of a patient, but also an article that “achieve[s] its primary intended purposes through chemical action” and which is “dependent upon being metabolized for the achievement of its primary intended purposes.” Id.

The United States is ORDERED TO SHOW CAUSE why the Court should not read the definition of “device” at 21 U.S.C. § 321(h) as informing and restricting the definition of “drug” at 21 U.S.C. § 321(g)(1)(B)&(C).

It will be most curious to see how the FDA argues out of the corner that many believe the Judge has painted the agency. The FDA recently defined “chemical action” in its draft "Guidance for Industry and FDA Staff: Interpretation of the Term “Chemical Action” in the Definition of Device under Section 201(h)of the Federal Food, Drug, and Cosmetic Act". What is curiously absent from the document is any mention of cells or HCT/P’s despite CBER’s approval stamp on the document.

Another line of argument centers around whether cells - notably 'stem' cells - are “metabolized" as that term is defind.

If one extrapolates the ramifications of where the court appears to be currently leaning, the implications of this judgment may have far-reaching implications for biologics in general well beyond cell therapy and certainly well beyond autologous cell therapy.

As some quite logically argue, one potential scenario is that this judge rules all biologics fail to fall within the legislative "drug" definition. The argument goes like this. The drug regulations live under title 21, which has narrow definitions for what constitutes a drug. The FDA’s authority over biologics comes from title 42, which is merely to control communicable disease transmission in transplants, with no authority to take the drug provisions from title 21 and apply them to title 42. So the agency is risking a loss of control over all biologics.

What’s curious here - and perhaps somewhat ironic for RSI at this stage - is that they only ever set out to challenge their ability to regulate autologous cells used by a physician as part of his or her medical practice yet now the FDA's authority to govern all biologics is currently under question.

The fact that I cannot fathom the courts striking FDA's jurisdiction over all biologics when the dust settles on this case does not make the arguments any less compelling and it does leave open the possibility that a lower court Judge such as the one presiding over this case may be inclined to make a ruling which essentially ensures the issues are punted to the appellate courts for a more considered ruling. In such circumstances, even if the FDA were to prevail at the end of the day (perhaps a decade down road) the uncertainty such a ruling would rain down on the sector would be commercially stifling - even if if were just limited to autologous cell therapy let alone if were any broader.

My dated and unpolished law degree can only take this analysis so far and anyone interested in some further but delightfully light and practical reading on the potential ramifications of the case could do no better than read a paper published recently by the relevant practice groups at the law firm K&L Gates entitled "Cultured Stem Cells for Autologous Use:Practice of Medicine or FDA Regulated Drug and Biological Product in which they review the case and its potential implications - the latter of which the authors are not guilty of underestimating in the following concluding sentence of their analysis:

The court’s decision will, to a large degree, dictate the types of legal strategies and business models that will be necessary to successfully perform stem cell procedures in the future.

_____________

post-script: The potential stink of commercial uncertainty wafting from this case is even more egregious when combined with the uncertainty around what to expect from the FDA in its much-anticipated and typically overdue guidance on adipose-derived cell therapies.

Rumor has it that the FDA is leaning toward considering most (if not all) means of deriving cell populations from adipose tissue (typically lipoaspirate) to be governed as what we colloquially refer to as a '351' thus taking it out of the purview of the practicing physician and into the hands of companies prepared to follow the traditional "drug development' model for new medicines. The rationale here is that the mechanical and/or enzymatic digestion required to separate the desired cell populations from the stroma take the process beyond "minimal manipulation'.

Watch for this guidance from CBER OCTGT in the weeks to come and/or any relevant rulings by the Tissue Reference Group. This would be a serious blow to those building business models around point-of-care, autologous adipose-derived cell therapy treatments.

What makes this even more interesting is the pace of which US-based medical practitioners (and/or companies supporting them) are adopting and selling autologous cell-based products, services and/or treatments for sundry indications in ways which many would argue are apparently in obvious and flagrant disregard for the FDA's regulatory authority over such treatments. Included for consideration on such a list would be the following:

IntelliCell Biosceinces

eternaMD

Arizona Stem Cell Center

.

Latest Cell Therapy Approval by FDA. Dendreon's Provenge.

It has been a long-time coming. It has been hyped and scoffed, bet against and hoped for, but now none of that matters. It's here. Dendreon has brought Provenge to market. Here, in the word's of the FDA...


FDA NEWS RELEASE

For Immediate Release: April 29, 2010

FDA Approves a Cellular Immunotherapy for Men with Advanced Prostate Cancer

The U.S. Food and Drug Administration today approved Provenge (sipuleucel-T), a new therapy for certain men with advanced prostate cancer that uses their own immune system to fight the disease.

Provenge is indicated for the treatment of asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment.

Prostate cancer is the second most common type of cancer among men in the United States, behind skin cancer, and usually occurs in older men. In 2009, an estimated 192,000 new cases of prostate cancer were diagnosed and about 27,000 men died from the disease, according to the National Cancer Institute.

“The availability of Provenge provides a new treatment option for men with advanced prostate cancer, who currently have limited effective therapies available,” said Karen Midthun, M.D., acting director of the FDA’s Center for Biologics Evaluation and Research.

Provenge is an autologous cellular immunotherapy, designed to stimulate a patient’s own immune system to respond against the cancer. Each dose of Provenge is manufactured by obtaining a patient’s immune cells from the blood, using a machine in a process known as leukapheresis. To enhance their response against the cancer, the immune cells are then exposed to a protein that is found in most prostate cancers, linked to an immune stimulating substance. After this process, the patient’s own cells are returned to the patient to treat the prostate cancer. Provenge is administered intravenously in a three-dose schedule given at about two-week intervals.

The effectiveness of Provenge was studied in 512 patients with metastatic hormone treatment refractory prostate cancer in a randomized, double-blind, placebo-controlled, multicenter trial, which showed an increase in overall survival of 4.1 months. The median survival for patients receiving Provenge treatments was 25.8 months, as compared to 21.7 months for those who did not receive the treatment.

Almost all of the patients who received Provenge had some type of adverse reaction. Common adverse reactions reported included chills, fatigue, fever, back pain, nausea, joint ache and headache. The majority of adverse reactions were mild or moderate in severity. Serious adverse reactions, reported in approximately one quarter of the patients receiving Provenge, included some acute infusion reactions and stroke. Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5 percent of patients in the Provenge group compared with 2.6 percent of patients in the control group.

Provenge is manufactured by Seattle-based Dendreon Corp.

Will the real regenmed association please stand up?

Further to my post on this topic back in September last year and ongoing discussions I have been having, I have decided to create a quick 4-question poll to get your opinion.

I am not representing anyone or any organization with this survey. I'm out on a limb on my own. I'm curious to see your response to this quick 4-question survey.

Click here to see the survey.

Cell Therapy HiLites 2008-11-14

Here's what caught my attention this week:

Celgene received FDA clearance to proceed with its placenta-derived stem cell clinical ttudy - a phase I, multi-center trial for moderate-to-severe Crohn's disease.

MiscroIslet filed for Chapter 11 bankruptcy protection but expects to restructure as a private company, continue operations, and file its first IND by year's end for an encapsulated porcine-islet product to treat diabetes.

Celladon released promising phase I results for the first gene therapy trial for advanced heart failure.

Cytori is starts to sell some of its StemSource® cell banking systems for collecting, processing, and storing adipose-derived cells. The company received its first order from Asian distributor Green Hospital Supply. The cell bank is to be set up in Japan. Despite all the continued skepticism about the value of cell banking to the donor-potential-patient, cell banking businesses are popping up prolifically around the world on the promise of short-term revenue to fund long-term R&D while providing a service some believe to be of irreplaceable value.

Although technically not a company-related cell therapy story, one of the more interesting developments this week was the announcement out of Charite in Berlin that they have a patient who is AIDS-free following a unique stem cell transplant. The patient developed leukemia which the docs were going to treat with a stem cell transplant. But rather than do the routine transplant by finding a match and treating just his leukemia they dared to be a little different. They went looking for a donor that matched and also had a CCR5-gene mutation (a naturally-occurring mutation which makes life difficult for the HIV virus according to some studies). The Berlin team found 80 compatible bone marrow donors for their patient, an unusually high sum, two of whom had the CCR5-Gene mutation. One of these they used with surprising and heartening results. What I like about this story almost as much as the happy ending and exciting discovery is how the doctors are trying to control the hype around this single-patient data and early results. It's not likely that this kind of transplant is a future treatmtent (for reasons related to supply, demand, and other commercial realities) but perhaps there is a kernal of a cell therapy product here somewhere that someone as innovative as these doctors will develop in time.

Ok I'm late on the draw here but it just came to my attention that in August NovaRx initiated a pivotal phase III in lung cancer patients. Watch on this blog in the coming days for more on the perception-vs-reality gap related to the number of industry-sponsored cell and gene therapy trials currently active worldwide.

Introgen may disappear while on the brink of success. Despite have an MAA being reviewed in the EU for their gene therapy for head and neck cancer, their BLA submission for the same therapy was rejected by the FDA as incomplete (currently under appeal). The company is now "exploring options" after a troubled Q3.

While not for its cell therapy program, Athersys announced it had achieved a clinical development milestone in its Bristol-Myers Squibb alliance. The amount of the milestone payment has not yet been revealed but any revenue is good revenue to offset the cell therapy development burn.

Bucking recent trends, StemCells Inc. (STEM) announced it will raise $20M in a stock sale to select institutional investors. Good news for any company in these times. Even better news for the cell therapy sector!

Finally, in the most over-reported news of the day, Pfizer opens up a regenerative medicine shop. I agree this is big news. This is not a minor investment; it's not throwing some money at a portfolio of biotechs in hopes that something will stick; it's not using stem cells as tools for drug testing or discovery. This is evidence of a belief by those in the halls of some of the tallest towers in life sciences, that cell therapies are going to change the way we treat people. Here are a couple quotes:

“Pfizer Regenerative Medicine represents a great opportunity to focus world-class research in a field that holds considerable promise for biomedical science and for the treatment of many debilitating conditions such as diabetes and neurodegenerative disorders.” said Rod MacKenzie, PhD, head of Worldwide Research at Pfizer.

The unit will be led by Chief Scientific Officer, Ruth McKernan, PhD, who said “I’m very excited to lead this new research unit. While there is still a lot to understand about how stem cells can be used therapeutically, we believe it is one of the most promising areas of scientific research.”

Ok, one more. Corey Goodman, PhD, President of Pfizer’s Biotherapeutics and Bioinnovation Center, said, “The formation of this new unit represents another key step forward in Pfizer’s commitment to be at the forefront of new approaches in biotherapeutics and bioinnovation and to expand our research efforts and expertise into emerging areas of biomedical science, like regenerative medicine, that have great potential for human health.”

Apparently the unit will operate independently (in the fashion of smaller biotechs) with about 70 researchers when fully staffed - in both Cambridge, UK and Cambridge, Mass - and work collaboratively with "leading academic, biotech and pharmaceutical partners around the world.


That's the cell therapy industry as I saw it this week. Happy weekend.

Cell therapy is not the practice of medicine

I have several doctor friends who in the early days of cell therapy years ago argued that autologous cell therapies should be considered the practice of medicine - like stem cell transplants - and not require regulatory approval like drugs or devices. Indeed some of the motivation for the creation of industry self-accreditation bodies like FACT was to attempt to convince regulatory agencies that cell therapy products were best regulated by medical industry bodies. The FDA and other regulatory agencies were engaged in this discussion - they heard, they listened...and in large part they disagreed. My doctor friends came to grips with that reality and worked with the FDA to help create a regulatory framework that they now work within.

Even under the strictest regulatory frameworks there are some types of products which do not require formal approval. This blog will not be an overview of the regulatory distinctions between - for instance - s.351 and s.361 products (per FDA) but suffice it to say the differences between the products which do and do not require formal approval are, by now, fairly well defined in both US and Europe (albeit the latter only more recently). Furthermore, the regulatory agencies are eager to engage in dialogue with anyone who has questions about the proper regulatory pathway for their product.

And yet...there are those even now in the US and Europe who attempt to skirt the regulatory framework by conducting unauthorized and/or non-compliant clinical research and/or offering for sale commercial products without regulatory approval despite them falling clearly under the rubric of the regulatory requirements that such products be approved for such purposes.

It's one thing to be offering clinical products in unregulated markets that would would be or are regulated in other markets. I've previously opined here about the medical tourism industry and the issues it raises. But trying to conduct clinical research or sell clinical therapies that are not approved, in markets where there are clear rules governing the authorization to do so? Really?

Regrettably, yes. Two recent examples are described below. I'm not here to cast aspersions, don't want to spark any skirmishes, and certainly have no basis for suggesting impropriety on the part of those involved in these examples. I refer to these examples because they are recent, part of the public record, and, in my opinion, exemplify actions which should justifiably be called out and discouraged (if not penalized).

1. The first example comes out of Europe as described in recent reports in Science, MedPage Today, etc where the Lancet recently retracts a published article stating "... the editors rejected Dr. Strasser's assertion that products of tissue engineering are not medical products and therefore not subject to the Good Clinical Practice requirements."

Following is the report from MedPage Today (5 Sept 2008) :


Lancet Retratct Article on Incontinence Cell Therapy - Free Legal Forms

2. The second example comes from the US. Below is a copy of a recent letter sent to Regenerative Sciences, Inc (doing business as Regenexx) by the FDA .


FDA Warning Letter to Regenexx (Regenerative Sciences Inc - RSI) - Free Legal Forms

There are only three possible explanations I can come up with for why anyone would act as these two teams of people have done in clear contravention of the guidelines regulating their actions: (a) they simply don't understand, (b) they are looking to wage a fight or make a point, and/or (c) they believe their license to practice medicine supersedes regulatory authority (an argument long-ago tried, tested, and proven a loser). None of those reasons are justifiable in the circumstances.


In some instances, those who push the envelope help to shift the paradigm and improve the system they buck against. Even civil disobedience can - at least in retrospect - be occasionally justified if not even heralded as the impetus for positive change. This is not that.

This is playing with people's lives in clear contravention of the rules. That's not to say the FDA always has it right or that there are not issues to discuss or changes to make. The fact that neither of these treatments appear to pose any real risk to patient safety is certainly part of the argument for relaxed regulatory controls - I understand. But does that justify flagrant contravention of the guidelines as they exist using patients as pawns in the argument?

There are other ways to make this case. Go to a jurisdiction where the treatment is permitted, employ patient groups to lobby or litigate, engage industry and FDA in discussions to affect change in the regulatory regime.

Dear Doctor. The fact these therapies may be relatively harmless is no excuse for acting outside the regulatory framework and guidelines created to protect those people you're treating - agree with it or not, like it or not. Thanks.

--Lee

Does Cell Therapy Demand a Different Investigatory-to-Commercial Paradigm?

I've just finished reading a great post by blogger Sonya Fatah. It's a very balanced and thorough post (click here to read it) on the stem cell medical tourism phenomenon complete with ample anecdotal patient testimonials - including some longer-term follow-up stories - as well as content from interviews of Indian embryonic stem cell transplant [pioneer / capitalist / fraud / savior - depending who you ask] Dr. Geeta Shroff (pictured here). Sonya's post also outlines the reaction of Dr. Stephen Minger et al (including colleagues in India) who tow the more western medicine party line that all this treating patients commercially prior to the rigor of clinical trials, peer review, and regulatory compliance/approval is...well, just wrong.

Word is that ISSCR is busy preparing a public policy statement regarding the stem cell medical tourism industry. It will be curious to see how they balance the various perspectives here given that they are an 'international' society with a clearly 'western' bent. They apparently had a very lively session at their latest conference on this topic.

I'm a firm advocate of regulatory frameworks to protect people from the predators, fraudsters, or even just the sloppy. I'm also an ardent believer in the benefits of peer review, transparency, and accountability. As a product of western inculcation (education) I also believe in the benefits of the clinical trial system and long-term follow-up as a means of vetting therapies before we let them loose on a 'suspeptible' public, regardless how well-meaning or even beneficial the efforts to make such therapies available earlier might be.

Having said all that, even in the West we make certain - albeit regulated - exceptions for no-option patients, etc. And patients - upset they cannot access what are perceived to be relatively safe, low-risk, potentially life -saving/altering stem cell treatments in the US - are voting with their feet and checkbooks traveling to Central America, the Caribbean, India, Asia, and anywhere else they can pay for the privilege to access unproven treatments. It's hard to argue with patients suffering from crippling, painful, and/or terminal ailments that they should be denied the right to choose their treatment.

Would it be better if these treatment providers - most of them companies charging amply for their treatments - would publish their science, conduct clinical trials even whilst they charge patients for treatment, be more transparent with their products/protocols, and/or conduct and publish the results of long-term follow-up? Sure. But this is not as much a part of the culture of eastern medicine. Clinical trials, regulatory approval, peer review...are all hallmarks of western science. Furthermore, different attitudes toward IP protection means transparency and publication are more easily exchanged for trade secret protection.

Has this therapeutics globalization triggered more a clash of cultures than one science and medicine? Could it be said that cell therapies - not unlike herbal remedies, acupuncture, chiropractic regimes or other forms of relatively harmless treatment modalities - do not require as strict a regime of clinical trial and regulatory oversight prior to commercial access? Are they inherently safe enough to allow for a different investigatory pathway or have we just not yet discovered the potentially harmful - if not deadly - side effects presented by predecessor pharmaceuticals, biotechnologies, and even the sister gene therapy which mandate the kind of process we've invented? Would our efforts be better spent on patient education rather than opposing the development and practices of such clinics?

Perhaps only time will tell. I definitely don't have the answers but I can most certainly understand those who - when faced with unbearable alternatives and a perception of very little downside - decide to travel and pay for treatments that cannot be accessed in North America. I am also sure that we in the West must be more than careful in judging or attempting to impose our values or worse - our systems - on those who think differently.

It is easy to accuse companies charging amply for these treatment of being fraudulent or, at the very least, of being motived solely by profit to sell something unproven to those with no options. This is tricky position to take while sitting in a country noted for its free enterprise with its predatory lending practices, legalized gambling, credit card companies charging double-digit interest rates, capitalist institutions more than eager to take advantage of the purchaser's freedom of choice to buy beyond their means, and a health care system with some of the highest costs in the world while allowing a majority of its citizens to go without coverage.

In this world of increasingly globalized medicine there will be medical jurisdiction shopping just like there are havens for taxes, drugs, weapons, etc. We must find ways to work together to a better, harmonized end. The FDA - at least at CBER - is open to accepting data produced outside the US in trials that follow basic strictures. Innovative organizations, academic institutions, and companies should seek ways to collaborate with the companies providing these treatments to attempt to "validate" them to western standards while opening them up to peer review.

Let's keep an open mind and discourse as we seek global solutions to balancing patient protection, choice, education, and access.

We must do everything we can to encourage all involved to conduct clinical trials, perform long-term follow-up, publish their science, and be open to peer review. We should try to better understand what is happening in these jurisdictions rather then simply expecting or demanding they comply with our systems. We should be cautious in our criticism and open in our consideration of whether new treatment modalities open the door for different regulatory pathways that provide safe choices for patients as soon as reasonably possible.

Drug Companies Ready for Cell Therapies?

Ok I won't title every blog in the form of a questions but this one seems a fitting follow-up to my last blog re: VCs.

Today Pfizer announced an investment in an early-stage (pre-clinical) cell therapy company. Forbes' commetary on the deal begins: "Big drug companies have largely stayed away from testing exotic stem-cell treatments. But now Pfizer is betting that a radical new adult stem-cell treatment may be able to stave off diabetes-induced retina damage, a leading cause of blindness. In an unusual deal, the big drug maker is funding the creation of a biotech company in San Diego called EyeCyte, which will develop stem-cell treatments for eye diseases." (click here for full Forbes article).

The press release states "The financing will fund the company into 2010 [the target date for phase I] and will be primarily used to drive product development of the company’s initial clinical target, diabetic retinopathy."

Friedlander and El-Kalay have a fascinating technology and it looks very promising in mouse models. It is, I believe, now being tested in primates. The approach is unique in that it encourages vascularization in a disease states often marked by overvascularization on the premise (borne out in very nice pre-clinical data) that using a highly purified progenitor cell population isolated from the patient’s own bone marrow using proprietary reagents and processes then injected to support healthy vascularization, prevents ineffective vascular proliferation.

In a conference this spring they also spoke of their efforts in looking at not only their scientific methodology but also already working on scale-up (bioreactor me-thinks?) technologies and closed production systems. This is uncharacteristically forward thinking (and admirable) for a company in early development stage.

There have been some encouraging signs recently regarding Pharma's involvement (or potential involvement) in the field.

As Langreth alludes in the Forbes article, J&J is indeed more involved than any other pharma peer. In fact, by my account they are by far the largest cell therapy company in the world if you add up their diverse projects around the globe. They have wisely diversified their investments to internal and external, therapuetic and tools, early and later-stage companies.

There were some, of late, who even presiently opined (or at least wondered aloud) about Pfizer's potential interest in cell therapy (see fellow-blogger J. Rowley's Dec 2007 post at http://tinyurl.com/3kj93m) given the creation of a new Bioinnovation Center "to focus on discovering and developing new medicines". Then in April Pfizer announced the creation of Pfizer Regenerative Medicine "a new research unit focused on stem cells and modulators of regenerative processes".

For the most part, pharma's interest in the sector to-date has been largely focused on the use of stem cells for discovery or testing. Understandable.

Pfizer's investment is modest: $3 million - with rights of first refusal to buy it outright. Hopefully with Pfizer on the board, the team finds a way to ensure that the fact EyeCyte can now leverage Pfizer's "prowess" is a positive influence on prudent development rather than a drag on momentum.

This is an encouraging notch on the bed post of cell therapy. Particularly autologous cell therapy at a time when many are - rather prematurely in my opinion - writing autologous therapies off in favor of allogeneic models. The venture might be a one-off and it might fail, but to me, this is just another small checkmark in the 'reasons-to-be-positive-about-cell-therapy-going-forward' column.

Stay tuned...