Gene Therapy Yet to Yield Convincing Results in Myocardial Collaterals
High-risk patients and others have benefited from new treatment strategies; more questions than answers remain.
Therapeutic angiogenesis — in which angiogenic growth factors, encoding genes, or stem cells are employed to encourage collateral blood vessel growth — have proven effective in animal models and in unblinded phase-1 trials, but placebo-controlled trial results are not as convincing.
Timothy D. Henry, MD, Director of Research for the Minneapolis Heart Institute Foundation, gave an overview of blinded gene therapy trials during a presentation yesterday.
Many of the blinded trials have produced enough encouraging data to warrant continued investigation of these therapies, Henry said. Placebo-controlled myocardial angiogenesis trials have included approximately 1,200 patients using seven different agents and methods of delivery. Although these analyses have indicated that the treatments are safe, and limited post - hoc analysis has shown benefit for high-risk subgroups, overall efficacy has been modest.
AGENT trials
The AGENT-3 trial investigated the safety and efficacy of two doses of a single intracoronary infusion of replication defective adenovirus (Ad) containing a human fibroblast growth factor (FGF) gene (Ad5FGF-4) in patients with stable angina. Overall, study participants failed to outperform the placebo arm in change in exercise duration from baseline, the primary endpoint of the study. However, in a subgroup of high-risk patients who were older than 55 years of age and had class 3 or 4 angina, a trend for improvement from week 12 to month 6 (P =.07 and P =.08 for the two different study doses) was noted.
An exploratory meta-analysis of the AGENT-3 and AGENT-4 trials found that placebo response was consistently high in men.
In women, there was an observed improvement in time to angina (P < .01). Among women in the high-dose group, there were improvements in the time to 1-mm ST-segment depression at both 12 weeks (P < .05) and six months (P < .05). Canadian Cardiovascular Society class improvements for angina were noted at week 12 (P < .05), month 6 (P =.056) and month 12 (P < .01).
REVASC
In the phase-2 REVASC trial, patients with class 2 to class 4 angina were randomized to receive intramyocardial injections of AdVEGF121 (4x1010 pu) or continue with best medical management. At 12 weeks there was no significant difference in the primary endpoint of time to additional 1-mm ST-segment depression. By week 26, however, investigators noted that patients receiving AdVEGF injections experienced a significant improvement in mean exercise time to ST-depression: over 1 minute compared with no improvement in the medically treated patients (P = .024). Mean Canadian Cardiovascular Society scores also did not change in the medically treated group compared with the progressive improvement noted in those treated with AdVEGF at weeks 6 (P = .001), 12 (P < .001) and 26 (P < .001).
Although Henry noted the promise of gene therapy from these and other trials, he indicated that many questions remain.
“What is the ideal growth factor or combination to use? Should we use proteins, genes, stem cells, etc? Even though we’ve conducted a relatively large number of trials, we still don’t have enough data to know who ideal patients are or to answer these other issues,” Henry said. “Unfortunately, these are the same questions we had five years ago, and still have today.”