Click here for more information about the AWARE clinical trial (Angiogenesis in Women With Angina Pectoris Who Are Not Candidates for Revascularization)

Q: You recently began recruiting for the AWARE Trial which hopes to show that the agent Generx induces angiogenesis which can benefit the coronary circulation to grow new arteries. Dr. Shah: Obviously we don't know the answer to the question, “Does local angiogenic gene therapy actually work, in terms of improving perfusion in symptoms and, if so, how durable is the effect from a one-time delivery of the gene?” These are questions that obviously have to be addressed. I think gene therapy or angiogenesis has had a very tumultuous career, to say the least, with ups and downs and a lot of promise, but more hype than fact. So this will be the first Phase 3 trial that is going to address directly whether local angiogenic therapy works, and if it does work, how long does it work? I think this is the first step in that direction – to bringing gene transfer all the way to a Phase 3 clinical trial.

Q: There have been previous studies of this angiogenetic factor that showed better results in women. Is this because women have smaller arteries that they may experience coronary artery disease differently?
Dr. Shah: The basis for launch of this study in women is, as you know, the data from two previous trials which showed no overall benefit, but a strong suggestion of benefit in women. We still don't understand what is so different that women would respond differently than men. I don't think we have a full understanding. I am a big believer that gender is not simply small versus large. Gender may have some really profound implications in terms of responses to different treatments. So I don't dismiss the idea that this was a fluke. I think it's really quite plausible to suggest that there may be gender differences in the way people respond.

Q: Do you think this may be due to hormonal differences?
Dr. Shah: Well, that's one possibility, and the other is: what else sits on that X chromosome -- besides hormones? What else is making women different from men? Obviously they have two X chromosomes instead of one X chromosome. So it may go beyond hormonal influences. There may be other genetic bases for differential response. But, at the moment, it's a hypothesis, and that can only be proven or disproven with an appropriate placebo-controlled trial.

Q: How is recruiting going?
Dr. Shah: We’ve just put ads, and I think we have two patients identified as potential candidates and they're going to go through the screening process. So we’re excited about it.

Q: There’s a specific protocol for who is eligible -- in general terms what types of patients are being enrolled?
Dr. Shah: These are women with angina, who are having angina or angina-like symptoms despite at least two classes of medications, and are not deemed candidates for mechanical revascularization with either PCI or surgery. So that's the bottom line in terms of what kind of patients, and the primary endpoint is obviously improvement in perfusion and exercise tolerance.

Q: How does this fit together with other anti-anginal therapies? To me, one of the most interesting results of last year's COURAGE Trial was the fact that 25% of the patients still had some angina, whether they had angioplasty or medical therapy.
Dr. Shah: Angina continues to plague patients, and for some of the women, it may be microvascular disease, for others it's going to be diffuse disease and total occlusions that are not amenable to revascularization, or lesions that are not really good candidates for revascularization, or a combination of all of these. At the present time, in absence of candidacies for PCI or CABG, the options for patients with continuing angina are standard medications which is calcium channel blockers, nitrate beta-blockers, and on top of that renolazine, as one of the newer anti-anginal drugs, Enhanced External CounterPulsation, or EECP, and spinal chord stimulation -- that is being used I think more in Europe than in this country for relief of refractory angina. And some places still believe in laser or Trans Myocardial Laser Revascularization although the results have been both up and down. So those are the kinds of options that are currently available. And then obviously the patient in this trial has a novel approach to improve blood flow.

Q: Angiogenetic therapies have been a long time coming. The late Jeffrey Isner was working with this area over a decade ago. What takes such a long time for these therapies to be tested?
Dr. Shah: Well there were several negative studies using VEGF and other things. I think the critical studies had gotten started prematurely before the science had been worked out. And it turned out that to really have good angiogenic response, you need to create mature blood vessels, not leaky capillaries, and when you create leaky capillaries you don't get sustained benefit. And that's was happening with VEGF.

The idea is that with FGF you may get more mature blood vessels, similar to collaterals. And I think it took some time for science to basically catch up until the studies were done with FGF. And although the overall field has not moved very fast, this is the first tangible really progress in years that we have seen in the field. And who knows? We don't know whether this is going to work or not work, and the jury is still out.

Cedars-Sinai Medical Center Los Angeles, CA

The entire field of gene therapy has had fits and starts, and it has not been has easy to translate the simplistic concepts into practical usable treatment, for any disease for that matter. The promise of gene therapy has not been fully realized, although I remain convinced that at the appropriate time, when we have figured out the best vector, the best delivery, and how to address to the immune response, then I think we may have a good platform. But that's what it takes. Look how long it took to finally get our LDL-lowering therapy right. I think the AWARE trial is exciting because this is the first gene therapy trial in cardiac disease that has advanced to Phase 3.

Q: Thank you for your time Dr. Shah. Prospective patients interested in enrolling in the AWARE trial at Cedars-Sinai (one of an estimated 50 centers participating nationwide) can call 1-800-CEDARS1 (1-800-233-2771) for more information about the study and eligibility.

For more information, visit the AWARE study website.