Industry-sponsored cardiovascular cell therapies. Some metrics.

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Cell therapies for cardiovascular-related conditions is a closely watched, much studied, oft-discussed, and hotly contested segment of the cell therapy industry.


The data to-date are admittedly confusing.  From a clinical perspective, the studies for which we have data have been relatively small involving a mish-mash of indications, endpoints, eligibility criterion, methods and/or route of administration, as well as the time of administration relative to event or disease progression.


Further compounding any interpretation of the data, from a technical perspective, is the fact the products have been widely varied in terms of being autologous vs allogeneic, expanded and not, genetically modified and not, from a plethora of different sources, and utilizing a wide variety of cell types from skelatal myoblasts, cardiomyocytes, mesenchymal stromal cells, mononuclear cells, etc. 


All this makes it extremely difficult to draw any conclusions with respect to what's working and what's not.  We will not attempt to do so.


All we do below is attempt to give a snapshot of the industry-sponsored cell therapy trials currently ongoing for cardiovascular-related conditions.  So here it is:


Commercial:
Pharmicell's Heartcelligram is the only cell therapy to have received regulatory approval for commercial distribution for the treatment of a cardiac-related indication.  Heartcelligram is an autologous cell therapy approved in 2011 by the Korean Food and Drug Administration (KFDA) for the treatment of Acute Mycardial Infarction (AMI).  The price is reportedly $19,000 and the trial data behind the approval has not yet been published in a peer-reviewed journal.


Phase III or II/III:
There are currently only 3 active and recruiting cardiac-related, industry-sponsored cell therapy trials.  Interestingly they all involve autologous products, two involve devices, two involve centralized manufacturing, two involve bone marrow cells as a source, two are only in European clinical sites, and two are targeting ischemic-related conditions.

• Baxter Therapeutics' Auto-CD34+ cells
• phase III trial actively recruiting
• Indication:  refractory angina and chronic myocardial ischemia
• Estimated enrollment:  444
• Estimated primary completion: June 2016 
• Cytori
• phase II/III trial actively recruiting
• Indication: ST-elevation acute myocardial infarction
• Estimated enrollment: 360
• Estimated primary completion: July 2014

• Miltenyi Biotec
• phase III trial actively recruiting
• Indication: myocardial ischemia or coronary artery disease
• Estimated enrollment: 142
• Estimated primary completion: July 2012

Two companies warrant particular mention at this stage as they appear to be in transition between phases II and III.

Cardio3 Biosciences initially designed a trial of their autologous C-Cure in heart failure secondary to ischemic cardiomyopathy to be a phase II/III trial enrolling 240 patients.  While the trial began in late 2008 and is still registered as active but no longer recruiting on ClinicalTrials.gov the entry has not been updated for almost a year.  

In 2010 the company announced that after enrolling 45 patients - of which 21 were in the treatment arm (24 in the control arm) - they decided to close the study to future enrollment and prepare for a phase III trial.  This decision was reportedly based on "very encouraging data". 

Dr. Christian Homsy, CEO of Cardio3 BioSciences provided the following guidance: “The highly promising data we report today build on the favourable safety profile we have observed through this Phase II trial and documents in patients our belief that we have with  C-Cure a product candidate with the potential to make a real difference in the treatment of heart failure... As noted in the company’s press release of 29 June 2010, with the Phase II stage completed and to allow for potential modifications to the trial protocol, Cardio3 BioSciences has not proceeded to Phase III recruitment into the trial but has continued to gather all data for the six month analysis. Through the Phase II trial, we gained significant  experience in working with a highly innovative stem cell therapy in a clinical setting, and we are using this acquired knowledge in the design of our planned Phase III programme."  The phase III trial of C-Cure is expected to commence in the second half of 2012.

Mesoblast has also announced with its strategic partner, Teva, that they are proceeding with plans to conduct a phase III study of its allogeneic cell therapy product, Revascor, in chronic heart failure.  Most anticipate this clinical trial application to be filed sometime in late 2012.

Phase I or II:
There are over 20 active, industry-sponsored earlier-stage trials (phase I, I/II or II) for cardiovascular-related conditions.  At least 5 of these are expected to have clinical readouts this year.   

Hope this is useful.

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This post has been brought to you by your friends at CTG.  All cell therapy. All the time. :)  

-- Lee @celltherapy

p.s.  As always we welcome your feedback, comments, and corrections.  

Cell therapy products vs cell therapy products; stem cell clinics vs stem cell clinics

I will find a new favorite topic in due course but for now this drum needs a little more beating. The feedback I've been getting is helping me get to the heart of the matter.

Here on these very ephemeral 'pages', I have suggested that the cell therapy industry is not well informed about how many cell therapy products/treatments are currently commercially available worldwide. Some in the industry argue that many of the products I include are not 'real' cell therapy products/treatments (more on that in a minute...) so they shouldn't really be counted.

I have also been sympathetic to unregulated stem cell clinics around the world and the patients that access them while advocating for and supporting the implementation of more stringent ethics, business practices, and therapeutic regulation.

Both sides of this debate have provided useful feedback and perspectives.

Ardent supporters of unregulated stem cell clinics, accuse me of criticizing their pioneering efforts to treat patients that the medical industry can't or won't treat. They believe I tow the party line on the need for rigorous scientific evidence, regulated clinical trials, peer-reviewed publications and a therapeutics review/approval framework. They accuse this view as archaic and not permissive of allowing patients the right to determine their own treatment pathway particularly when there is no harm in the cell-based products being sold.

On the other hand, some of my peers in the cell therapy industry believe I am doing a disservice to the industry by acknowledging that these unregulated stem cell clinics are part of this sector and are doing a robust business with an increasingly large number of American patients.

I happen to believe that just because a company is operating in an unregulated market does not necessarily mean they are unethical, that it may not be fair to characterize all 'stem cell clinics' in unrelated markets as 'the same', and there may be some of these clinics which are conducting business is ways which should be considered acceptable.

In the spirit of informed and informative discussion, I have 4 comments - not in an attempt to be defensive or argumentative but to keep what I believe to be a valuable discussion flowing.

1. There are those that want to believe they know the products available in the market and if there is any gap between their number and mine it is entirely comprised of unregulated products in unregulated markets. Wrong. A large percentage of this gap is comprised of regulated products.

According to my data there continues to be a wide gap between the perception of how many cell therapy products are commercially available in markets around the world and how many there actually are.

For example.

At the 2009 Phacilitate Cell & Gene Therapy Forum the very first speaker of the conference inferred (by mistake) that there was only one cell or gene therapy product approved in the world. He meant gene therapy products. Based on that presentation, however, there were delegates at the conference - people who work in the cell therapy industry and should clearly know better - who were tempted to believe there was only one approved cell or gene therapy product in the world. These are people who would know better if they thought about it for a minute. That's an egregious example but watch the interviews of delegates by BioBusiness.tv and you will see most experts in the field believe there is but a handful of approved cell therapy products worldwide.

According to data in a recent TERMIS newsletter, for example, there are 10 cell therapy products in Korea alone that have been approved by the Korean FDA (KFDA) for treatment of various conditions. This is a regulated market and these are regulated products owned and sold by companies. According to my data there are at least another ten approved products between Australia and Germany. Again both regulated markets. That is already more approved products than most people believe are available in the world.

So yes... I certainly have included unregulated products/treatments in previous data. Nonetheless, but even when I exclude these, the number is larger than most believe.

This is the gap I want to close the most. The more I interact with people now as they react to my data and perspective, I believe I am starting to get a clearer picture about what is behind some of this gap.

2. There may be some who disagree with my definition of 'product' and/or use of the adjective 'approved'.

I have to-date considered it a 'product' whether it is cGMP or cGTP and whether or not it is the subject of an IND/BLA (or equivalent) . I'm certain the FDA CBER shares that view. 'Approval' of a product does not only come by way of BLA/MAA (or equivalent), it also comes from tacit approval in regulated markets where a product falls within a category which is allowed without formal application for review and approval by the regulatory authority.

So, for example, the Xcell-Center clinic in Germany currently provides bone-marrow derived, minimally-manipulated stem cell 'products' under the authority of the German regulatory authorities. They do so on a commercial basis. The products ('treatment' some might prefer) are currently being sold to treat patients with the following (degenerative) diseases: ALS, alzheimer's disease, cardiovascular diseases, cerebral palsy, diabetes mellitus (type 1 & type 2), erectile dysfunction, macular degeneration, multiple sclerosis, osteoarthritis, Parkinson's disease, spinal cord injuries, and stroke.

It's not clear to me whether there is any unique IP around these treatments and the business model here is clearly more of service model than product model but the products/treatment may each be somewhat different and may be administered differently depending on the indication. By at least some people's definition, that is at least 12 different 'products' - all being sold with complete regulatory approval (though not an MAA because of the nature of the products/treatments) - with prices starting at around 12,000 euros depending on the procedures required. Some might argue it's only 1 product but isn't it at least that?

In regulated markets stem cell transplantation is a regulated cell therapy in that there is a regulatory framework within which the service falls and one cannot simply transplant stem cells for any indication one wants (let's say pump them into the brain) even if one simply takes them from the bone marrow, isolates the cells of interest and puts them straight back in.

Stem cell transplantation is commonly perceived to be a medical procedure rather than a product but this does not make it any less a cell therapy. If the cells are more than minimally manipulated they become defined as a cGMP product (in the US). At what point in between does it cross the line and become a 'product'?

Is it whether or not there is IP around the product or process used to make it? Is it whether or not it is characterized primarilyy as a 'service' rather than a 'product'? Certainly some cGMP products will require an extensive clinical service model. It certainly seems to me that at least some cGTP products will be no less cell therapy products than a cGMP product in that they may be the subject of IP and may involve no more of a service element than some cGMP cell therapies.

3. There must be a way to have an informed discussion in which we distinguish between cell therapy products and cell therapy products; stem cell clinics and stem cell clinics.

The Xcell-Center, for instance, operating under complete regulated authority in a regulated market providing treatments for a limited number of conditions and conducting at least some type of long-term follow-up must be considered in a substantially different light than a clinic providing stem cell injections for almost any condition in an unregulated market, without any long-term follow-up, and with no transparency as to their product or process.

I believe the ISSCR and many others share my desire to create the foundation for what will become for patients - in an informed and global medical market - a very important discussion upon which they can discriminate between legit and shoddy clinics and make informed decisions.

4. As for those clinics arguing they should not be not be subjected to standards requiring rigorous scientific evidence, regulated clinical trials, external audits, and peer-reviewed publications within a therapeutics review/approval framework... please stop. Stop now.

Cell therapy is not inherently safe regardless of what kind of cells you use, how you treat them, and what you do with them. As recent reports suggest, this can be as dangerous and deadly as any drug.

__

As to point #1, I am still working on my list of products which I hope to publish soon for all to see and review.

As to point #2, I hope some of you will comment on how to best define 'product' for this discussion. There is a similar and very informative discussion thread in the LinkedIn Cell Therapy Industry Group focused around different therapeutic business models. Although the question is framed differently, the discussion hinges on similar distinctions and issues.

As always... I reserve the right to be wrong. I welcome any and all feedback. My only goal here is an informed and informative exchange of ideas and information.

--Lee