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Ichim: Which one was the first stem cell trial for cardiac conditions?

Patel: It is like one of those questions like who did the first heart operation. There is a lot of debate as to what was the first to use cells plus therapy and there have been a number of trials. Myoblasts were performed in 2000, the Chinese reported work performed in 1999 or 2000, and the Ralfstock guys in Germany 2000s. So there are a number of trials, including ours, all in the 2000-2003 period that where being conducted almost simultaneously.

Ichim: Pardon me for asking because I should really know this, which one was yours?

Patel: The original CABG plus cells, which was performed in South America and India.

Ichim: Lets talk about Phase 2 trials in cardiac, we all have seen the excellent co-development deal between Cephalon and Mesoblast that happened in December of last year and we are all interested in how far are they?

Patel: The Cephalon-Mesoblast work is interesting. They are doing a 60 patient randomized trial here in the US in patients with Class II-IV heart failure. From the data thus far released there is a significant reduction in treatment group in terms of adverse events as compared to the placebo control group, they have not reported any efficacy data in terms of ejection fraction and the like.

Something unique from the data they presented was that they showed up to 2/3 of the control group were class III heart failure and 2/3 of the treatment group were class II. The early data was very interesting and promising. The safety of the data was very eloquent and reproducible. One thing that was very unique was Erik Dukker’s European large animal acute MI data which was the best in terms of scar reduction for any allogeneic MSC that I have seen to date. That data, if it pans out, in humans will be very interesting.

Ichim: How did Mesoblast administer their cells? Did they use balloon catheter in the heart failure patients?

Patel: They used NOGA mapping and administration, in chronic heart failure, both ischemic and non-ischemia. They did not do acute myocardial infarction in this trial.

Their trial had similarities with our Phase II Aastrom, which also uses NOGA administration in treatment of patients with ischemic and non ischemic heart failure. It is different in that we were looking only at class III/IV heart failure.

Ichim: How is that trial coming along?

Patel: Ours is completed from the patient recruitment and treatment perspective.

We are waiting 6 month data. Our trial was a three center trial between myself, Tim Henry and Mark O’Costa. These three centers were heavy enrollers. We had low adverse events so far. This study involves patient’s own bone marrow stem cells expanded for 12 days using Aastrom’s proprietary bioreactor system.

Ichim: Lets go back to my question about Mesoblast. Remember we were chatting at the meeting about this. There seems to be a lot of different players in this field that are all using bone marrow derived stem cells. Obviously I believe endometrial derived stem cells possess numerous advantages. But there is Osiris’s mesenchymals, there is Athersys who are using Catherine Verfaille’s cells that seem to be like mesenchymal stem cells except for their smaller size. What is the cell that Mesoblast is using? Are they just another type of mesenchymal stem cell?

Patel: By name they call them the cells mesenchymal precursors. The Mesoblast cells are unique in that they express STRO-1 and VLA-4.

In my opinion everyone’s stem cells have unique properties and surface markers be they Osiris, Mesoblast, Athersys, Allocure, and a couple other products that are bone marrow based.

What is unique to see will be the IP landscape, are they same cells or cousins? This may be a situation like the CD133 versus CD34. In this field we know that all mesenchymal stem cells are not the same but the question will be how similar or different are they when you apply them clinically?

Ichim: Did we forget to mention any other ones?

Patel: I am sure that we did, but not for want to miss them but just because they have not made enough noise. Actually the one trial we forgot to discuss was the Athersys phase I which Warren Sherman from Columbia presented using the Cricket catheter, which is adventitial delivery, that was a very safe trial. It will be interesting to see how they do in the next generation for their phase II AMI study.

Ichim: That was very interesting. That was the one with the bizarre catheter that actually had a couple of needles in it?

Patel: That catheter had one needle, it causes a microperforation to allow for perivascular injection. This is a very innovative concept since people that use the standard intracoronary delivery techniques seem to have a lot of washout of the cells.

Ichim: I don’t get it. So they are making a small hole in the blood vessel, why is it that there is no bleeding or damage?

Patel: The microperforation is way too small. You do not perforate into the pericardium. It only barely perforates. However it does require a well highly trained skill set to manipulate that catheter. If you had been listening to Dr. Sherman’s presentation you would have seen that there were no catheter-related injuries.

Ichim: (Laughing). OK, what about the large Brazilian data? That was also a session that I didn’t listen through in entirety.

Patel: That data was 10 year follow-up on several Brazilian studies. The work was initially performed in heart failure using NOGA by Hans Doneman, then they had Emerson Perin and Jim Willerson. We also had our work which involved CABG. That was groundbreaking work that set the foundations for a lot of the cardiac cell therapy that is being performed today. We are still waiting to hear the outcomes of the studies that were funded by the government of Brazil including the work on Chagas, dilated cardiomyopathy, and CABG.

Ichim: Speaking of South America, what did Jorge Tuma present?

Patel: This was incredible data that had patients who have been followed for 8 years. Cell administration was performed via the retrograde technique which we developed with him. The original experiments involved bone marrow mononuclear cells isolated by ficoll, heap-starch, CD34, etc, he is now using the Harvest system for autologous bone marrow mononuclear cell collection. He presented data on ten patients treated with this.

Ichim: This is what I love about interviews, I can ask all sorts of questions about things that I should know but I don’t. What exactly is this “retrograde technique”? I have heard you mention it several times.

Patel: We access the venous system of the heart. We occlude the outflow and deliver the biologic into the heart. What is unique is that the venous system does not get the same atherosclerosis as the arterial system. This procedure has been around since 1898..its been around from back then…the idea was can we give oxygenated blood back to the heart. It was in the 50s and 60s when Illahi started to implement this. I use this in my heart operations to give chemicals and nutrients into the heart backwards during open heart operations…so I said how

Administration of cells using the retrograde technique takes me half hour to do. This appears to be a safe and cost efficient means to deliver a biologic to the heart on incredibly sick patients.

Ichim: To put in things in perspective regarding cell administration. I know that NOGA is expensive and not too many centers have it. But how long does it take to do a NOGA administration of stem cells into the heart?

Patel: 1-2.5 hours, usually 90 minutes at best, you are manipulating the inside of the heart so there is a risk of irregular rhtyums, also low risk of perforation

Ichim: I still don’t really understand this retrograde technique. How is it that the cells actually enter the heart? Do they actually cross into the tissue?

Patel: You block the outflow of the heart and under pressure you push the cells into the venous system. So you have created a column of cells. You have antegrade blood flow and retrograde stop flow, so the cells either go into the tissue or perforate the sinus…perforate the sinus is very rare, less than 1 % in over a couple hundred patients. These are microperforations in the venous system so it doesn’t require emergent surgery…all of the patients in which this has occurred have done well.

Juventas presented some data in large animals in which the SDF plasmid showed a significant uprgulation using retrograde techniques in contrast to other means of delivery.

Ichim: To switch topics I saw you on CNN about spraying stem cells on poor patients with bad burns, how do the cells go inside of the tissue?

Patel: We add calcium and thrombin, it looks like jello if you were to spray it into the petri disue, so you have retention by tissue adhesion and the mechanical properties of the collagen, thrombin and calcium, so you are creating a matrix for your biologic. So it really is spray on and it actually sticks there.

Ichim: I remember you now based in Utah, what ever happened to that company in your neck of the woods Allocure? How are they doing these days?

Patel: The last I heard they completed Phase I trial here in Utah, they were giving at the time of heart surgery for renal production. They have a bone marrow mesenchymal cell product. The trial is completed, we are looking to see what their next study will be. Will the stick to renal protection or will they follow other companies by entering CLI, heart failure, etc.

Ichim: You know, I was impressed by that company C3 or something like that, they were using differentiated cells for heart?

Patel: That was a Phase I/II trial by Joseph Bartnak where they have a bone marrow mesenchymal cell that was cultured in a procardiac cocktail. It was administered by noga or endocardial mapping. And again the data looked interesting…we look forward to their next trial and when they come to US

Ichim: What they were doing was really new in my humble opinion. It seems to me like everyone in this field is administering undifferentiated cells based on the belief or hope that the damaged tissue will program the undifferentiated stem cell to become a cardiomyocyte. To your knowledge are there other people using differentiated or semi-differentiated cells?

Patel: Yes of course. There is Capricor, Eduardo Marban’s company. They are taking a biopsy of the patient’s own heart, grow up the cells and put them back in. They don’t put the cardiospheres back in because they are too large but put in some cells derived from cardiosphere grown in vitro. One of the issues they are facing is that their procedure is very much dependent on the starting material. They were able to do biopsy but because there was large variability in the weight of the starting tissue, it is important to figure out how to get enough

Ichim: Conceptually it seems counter-intuative to take out heart from a patient with heart failure !

Patel: People do right heart biopsy in transplant patients, doing native heart biopsy you are always concerned about damaging the valve. Raj who was doing the procedure for them is a great interventionalist, but have to make sure that the procedure is designed so that other interventionalists who may not have his skill set can do it. The concept is great but manufacturing and reproducibility is important.