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Home » Angiogenesis Center » Randall W. Moreadith, MD, PhD

Randall W. Moreadith, MD, PhD

Dr. Moreadith is Executive Vice President and Chief Medical Officer of Cardium Therapeutics. Before joining Cardium in 2006, Dr. Moreadith served as Chief Medical Officer of Renovis, Inc., a co-founder of ThromboGenics Ltd., and served in a number of positions and companies in the fields of medicine, genetics, and biochemistry. Dr. Moreadith holds an M.D. from Duke University and a Ph.D. in Biochemistry from Johns Hopkins University. His complete bio can be found on the Cardium Therapeutics web site.

Angioplasty.Org recently discussed with Dr. Moreadith the AWARE clinical trial (Angiogenesis in Women With Angina Pectoris Who Are Not Candidates for Revascularization), a Phase 3 randomized clinical trial for which he is principal investigator.

 

 

Randall W. Moreadith, MD, PhD
Dr. Randall W. Moreadith

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Click here for more information about the AWARE clinical trial (Angiogenesis in Women With Angina Pectoris Who Are Not Candidates for Revascularization)
    Q: Could you briefly go over the description of what the AWARE trial is, what type of patient you're looking for, and what the goal is?
Dr. Moreadith: The AWARE trial is a Phase 3 trial -- a pivotal stage trial - that's going to be evaluating patients, women between the ages of 18 and 75 who have Canadian Cardiovascular Society (CCS) Class III or IV angina. They are women who are not candidates for, or would be unlikely to benefit from, a standard revascularization procedure. Typically, that means these are women who have undergone angioplasty and/or bypass surgery; they're on maximal medical therapy; and yet their life is still limited by chronic angina. So this study will evaluate and enroll them, in a randomized fashion, to a placebo group or one of two dose groups, and evaluate the effect of Ad5FGF-4, also known as Generx, on exercise endpoints that indicate ischemia. The key primary end point in the study will be the time to onset of myocardial ischemia that is typically done with a routine exercise treadmill test.

The key secondary end point will be SPECT perfusion, a non-invasive method that measures myocardial blood flow in the region of the heart that is ischemic. What we hope to find is that not only do women who receive the drug experience prolongation of time to onset of myocardial ischemia – that is – they can walk longer on the test before developing ECG changes indicating ischemia, but also a reduction in that perfusion deficit as measured by SPECT perfusion.

Q: You’re delivering the Ad5FGF-4, or Generx, using a virus. Tell us about that.
Dr. Moreadith: Sure. This is a crippled virus called Adenovirus Type 5. This is a very common virus; most of the people in the United States have had a mild flu-like syndrome, or sniffles, and it's often caused by this type of virus. We've genetically engineered this virus to cripple it so it cannot reproduce, and it's been shown to be safe following administration into the coronary arteries. It carries a gene known as fibroblast growth factor 4. We've studied this in 450 patients who have received an active dose of this via infusion into the coronaries, and we've found no adverse events associated with doing that. What we have found is it's taken up almost exclusively by the heart. So, it delivers the gene and appears to stimulate the growth of new blood vessels in the ischemic region of the heart.

Q: What is the procedure -- just sort of a “step one through five” – that participants will undergo?
Dr. Moreadith: Patients will be randomized at multiple centers in the United States. We will be working closely with approximately 50 major medical centers in the United States, and eventually enroll about 300 patients in this study. They'll undergo routine screening with an exercise test, and they'll have a SPECT perfusion study done as well. In many cases, the women who are candidates for this study are used to these procedures, because they've had these done at some point during the course of their disease. If they are eligible for the study, they'll be randomized, come into the cath lab, and they'll undergo a controlled infusion of this product down the coronary arteries. Our aim is to put 60% of the dose in the left side of the heart, in both native vessels or bypass vessels, and 40% of the dose in the right side of the heart. In this manner we expose the coronary circulation in the heart with the virus so that wherever there is ischemia in the heart, hopefully this will stimulate the growth of new blood vessels.

Q: The AWARE trial has already begun -- how many centers do you have actually online at this point?
Dr. Moreadith: We update that almost weekly now, on our Clinicaltrials.gov site. Most of the sites have already been given approval by their Internal Review Boards.

Q: What is the time frame right now? When do you see this being completed, and how long will you be following patients once they are given the Generx?
Dr. Moreadith: The key primary end point, as I mentioned, is time to onset of ST segment changes diagnostic of myocardial ischemia. That time point will be recorded at 6 months after the dosing. At the same time point, we'll measure the key secondary end point, which is the adenosine SPECT perfusion study. It kind of depends on how quickly we get patients in the study. We certainly hope to have the vast majority of these patients enrolled in the study within the next two years, and then secondary efficacy end points will go out to one year past the last patient in the study.

Q: This isn’t the first clinical trial you’ve conducted with Generx. You’ve had previous experience with it.
Dr. Moreadith: Actually, we have the largest safety and efficacy database of a DNA-based cardiovascular therapeutic in the world. We've studied 663 patients: 213 of those patients received placebo, and 450 received an active dose. That is the result of four angiogenic gene therapy trials, AGENT-I, II, III and IV -- and all of those were randomized, placebo-controlled, double-blind studies at over 100 medical centers worldwide. So, the safety and efficacy database of those four programs is very extensive, and we feel very comfortable advancing this to Phase 3 development in women with refractory angina. I might add that the FDA also feels very comfortable with that, and they've highlighted this program by giving it Fast Track designation as addressing a large unmet clinical need.

Q: Can you expand on that? This is a very important potential therapy and, while there have been studies in the past, it’s my understanding that no one has gotten to this phase of research previously.
Dr. Moreadith: That is correct. This is the first time that a DNA-based cardiovascular therapeutic has advanced to pivotal Phase 3 development. And, to my knowledge, this is one of very few programs in cardiovascular disease that has ever been given fast track status by the FDA. That means that the FDA recognizes this as a large unmet clinical need, and will give this priority review once we go back to the Agency with the data. So, it is a precedent-setting trial: it's the first Phase 3 study of its kind and it's one of the very few cardiovascular interventional studies conducted in women only.

This really represented a sea change in the Agency’s thinking, as well as ours – the recognition that this product produces a permanent change in the heart. It's not a typical anti-anginal. This product grows new blood vessels in the heart and is thus a disease-modifying agent. We were encouraged to explore a primary end point that reflected that. So in discussions with the FDA, we agreed that the time to ST segment depression, indicative of myocardial ischemia, was an adequate end point for that effect, and we will pursue the indication of myocardial ischemia in patients with refractory angina.

Q: Why is this trial for women only?
Dr. Moreadith: That's a very good question. The pooled analysis of our data from all of the AGENT studies, in particular AGENT III and IV, indicated that a large proportion of the patients who were randomized in AGENT III and IV were mostly men, and over half of those patients had mild angina. So, because of a profound placebo response, largely in men with Class II angina, we were unable to measure a true treatment response. However, it was pre-specified in the analysis plan that we would perform a gender analysis as well, and when we did, we were surprised to see a profound treatment effect in women. What we found was a very low placebo response rate in women, largely because these women were sicker: they had more symptom-limited disease, there was a higher percentage of patients with CCS Class II and IV, and the vast majority of these women were on triple therapy as well. So, it appeared that in female patients with more severe disease, who were more symptom-limited and exercise-limited, that the intra-coronary infusion of Ad5FGF-4 did in fact promote a profound treatment response. In fact, on every clinical endpoint in women we observed a concordance of treatment effects – time to onset of ischemia, total exercise duration, time to onset of angina, and change in functional CCS class out to one year. So, we took that data to the FDA, and the Agency agreed with us that we had sufficient evidence, in terms of both safety and efficacy, to proceed to a Phase 3 trial.

Q: This is an interesting example of a trial that looked like it had not succeeded, had not produced results, but when you looked at the data by gender, you discovered that in fact it did work in women.
Dr. Moreadith: Yes. But I want to point out - we don't think this drug works only in women. It appears to work in women with this particular end point – time to changes diagnostic of myocardial ischemia, but in our AGENT-II study, which was largely men, we found a very significant reversal in perfusion deficit size by SPECT. So, even in men who have a perfusion deficit, who may not show a change in their exercise treadmill times, there was a reversal in the perfusion deficit. So, the AWARE study is designed with SPECT as a key secondary end point, and in the future, we hope to be able to take this data back to the Agency and perhaps use SPECT as a surrogate end point in both men and women.

Q: An interesting piece of data from the controversial COURAGE trial, one that's not talked about very much, is that 25% of the patients studied, whether they had angioplasty or medical therapy, were still experiencing angina after a five-year period. Does that have relevance to the trial you're working on?
Dr. Moreadith: The COURAGE trial was a precedent-setting study in many respects and I think what it underscores is that the treatment of patients with chronic angina represents a very large and growing population of patients. Despite what we consider to be optimal medical therapy in many of these patients, including stable medical regimens as well as interventional approaches, while it may diminish the risk of death, or myocardial infarction, or re-hospitalization acutely, it does not really change the natural history of the disease. So, these patients are forced to live with chronic angina. And I think that we'll find in the next decade that, as we continue to improve at putting stents in and doing bypass surgery, we'll need another approach to treat chronic stable angina in these patients, because it really does severely limit their lifestyle.

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The Four "T"s of adenovector gene therapy.
(Click to enlarge)
    Q: The mechanism by which this works is not an unnatural one to the body-- my understanding is that you're kind of inducing the body to do what it would normally do in many cases?
Dr. Moreadith: That's exactly right. In fact, in many respects, it seems that this therapy is uniquely designed at this point in adulthood to stimulate the growth of new vessels. FGF4, the ligand for the FGF4 receptor, is the gene that we express in the myocardium from the virus. It turns out that the adult heart has plenty of FGF4 receptors that would bind the ligand. But soon after embryogenesis FGF4 levels drop to zero throughout the adult body. It appears FGF4 is very important in laying down the embryonic vascular bed, but soon thereafter FGF4 is no longer expressed. Yet, the receptor stays at very high levels in the heart throughout adulthood.

And so, we deliver the ligand through the Ad5FGF-4 adenovector, and it binds to the FGF4 receptor that's at high levels of expression in the heart. So, we “re-trigger” the growth of blood vessels within the myocardium. We're simply taking advantage of a biological architecture within the body that is designed to grow new blood vessels if the ligand is present. About 90% of the adenovector stays within the myocardium, and that which leaves the myocardium is gone within a day or two without any consequence.

So, we get very high levels of expression of the adenovector within the heart resulting in high levels of expression of FGF4. It appears to bind to the receptor and stimulate the growth of new blood vessels throughout the ischemic region of the heart. That makes this approach unique compared to the other approaches, which have tried to deliver both the protein, which has a very short half-life, or multiple injections of the plasmid DNA, which are not taken up by a receptor system. So, we think this system is actually the best in terms of the approach for growing new blood vessels in the myocardium, and also very safe.

Finally, the degree of change we see in terms of increased myocardial perfusion on SPECT is similar in magnitude to that we see when we do an angioplasty procedure or a bypass procedure. In some respects, we are essentially performing a “biological bypass” in these patients.

Q: This year marks the 30th anniversary of coronary angioplasty and its inventor, Andreas Gruentzig, said of his catheter-based technique that what he really did was to demonstrate for the first time that one could work safely inside the artery of an awake, alert human being. Would you say that the technique that you're developing is an outgrowth of that? Could this therapy be delivered in any other fashion?
Dr. Moreadith: It really could not -- without the advent of safe percutaneous interventions within patients with coronary disease. Number one, we wouldn't be able to save the lives of patients coming in with an acute myocardial infarction, and so the restoration of blood flow to the myocardium has been the one thing that's been proven to be of great benefit to these patients. But, as you know, they have progression of disease, and reach a point where you can no longer do these percutaneous interventions or bypass surgery. And that population of patients is large – perhaps several hundred thousand – and growing. Eventually, these patients all succumb to refractory angina. This approach, using a catheter down the coronary to deliver an angiogenic gene, could not be done without the precedent-setting work of many people including Dr. Gruentzig, and Dr. Schatz, who was involved in the development of these stents early on, and many others who have spent much of their careers advancing approaches of treatments of patients with acute MI and refractory angina.

What we're finding is that the body has a lot of innate mechanisms that, if we can find a way to stimulate those endogenous and innate mechanisms, we may be able to safely grow new blood vessels within specific parts of the body. This approach, angiogenic gene therapy, and other approaches, including the recent advances in cell therapy, are all catheter-based systems that allow us to put these products safely and effectively in the myocardium.

Q: What should people who think they might be candidates for this study do?
Dr. Moreadith: If someone reads this site and feels they may be a candidate for this study, they can go directly to the Clinicaltrials.gov site <LINK TO AWARE PAGE>, and they can call me directly as the Chief Medical Officer of Cardium Therapeutics, as the study's principal investigator, and I can refer them, potentially, to a site nearby where they could be evaluated for entry in the study.

We also encourage not only patients who potentially might be candidates for the study, but also investigators who would be interested in participating in the study, who feel they have a large population of patients with refractory angina, particularly female patients, they are encouraged to contact us through the clinicaltrials.gov website as well.

Q: So, at this point, but you're welcoming other centers to get involved as investigators?
Dr. Moreadith: Yes, we are continually evaluating centers that are both very experienced, and have a large population of refractory angina patients.

Q: This is an exciting frontier and we’ll all be watching how this turns out. Hopefully patients or physicians reading this, who may want to get involved, will contact you.
Dr. Moreadith: Well, I think you've done a great job with your website, educating people on multiple issues with cardiovascular health, so I want to applaud you for doing that. It's a great effort, and we definitely need more of that, because people need to become aware that there are experimental approaches out there in late stage development - and maybe one day there will be a therapy for these patients as well. So, the more patients are informed, the better.


This interview was conducted by Burt Cohen of Angioplasty.Org in October 2007

** photo and graphics courtesy of Cardium Therapeutics, Inc.

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