Genzyme Corporation announced today that the first patient has been treated in a new phase 2 clinical trial examining the safety and effectiveness of locally delivered gene transfer for patients with peripheral arterial disease. Genzyme's experimental therapy, using Ad2/HIF-1 alpha, an engineered form of the HIF-1 alpha gene, is designed to promote the growth of new blood vessels and improve circulation in patients' limbs.
The trial, a randomized double blind placebo controlled study, will take place at up to 35 medical centers in the United States and Europe. It will enroll up to 300 patients diagnosed with severe intermittent claudication, a type of peripheral arterial disease that results in disabling pain or fatigue in the legs, brought on by exercise. Plans are to enroll 75 patients each into one of three dosing groups or a placebo arm. Participants will receive either Ad2/HIF-1 alpha or placebo through a series of injections into the limbs.
In addition to safety, the trial will evaluate the effectiveness of each dose in several measures of efficacy. The primary endpoint is change in the maximum amount of time a patient can walk on a treadmill without stopping due to claudication symptoms. Other endpoints include the amount of time it takes while walking for the onset of claudication pain; change in blood flow to the limbs, as measured using the ankle-brachial index; and various quality of life assessments. The primary endpoint will be evaluated at six months and study participants will be followed for two years.
The Phase 2 clinical trial builds on a successful Phase 1 trial, which demonstrated evidence of safety at several doses in patients with critical limb ischemia, a more severe form of peripheral arterial disease. Investigators also reported preliminary evidence of bioactivity, with a trend in favor of the higher doses studied. Preliminary results of the Phase 1 trial were presented at the 2003 annual meeting of the American Heart Association.
Intermittent claudication is estimated to affect up to five percent of all males 60 years of age and older, and about half as many women, according to the American Heart Association. It is caused by a loss of oxygen to the muscles due to narrowed or blocked arteries, which causes the leg muscles to cramp and causes pain upon walking or exercise. With continued progression, peripheral arterial disease may progress to critical limb ischemia, which is characterized by pain at rest, non-healing ischemic ulcers, and gangrene. Critical limb ischemia is associated with extremely diminished quality of life, a high rate of limb amputation, and a marked increase in short term mortality from cardiovascular disease.
Hypoxia Inducible Factor-1 alpha, or HIF-1 alpha, is a transcription factor, or "master gene," which has been shown to activate a cascade of proteins associated with blood vessel formation. This comprehensive approach contrasts with pro-angiogenic therapies that employ a single protein, such as VEGF isoform, given as a gene or as a recombinant protein. Because the Genzyme-engineered version of HIF-1 alpha turns on the expression of many angiogenic proteins -- including all known VEGF isoforms, angiopoietins 2 and 4 and placenta growth factor among others -- Genzyme believes it may produce a more robust and longer lasting pro-angiogenic effect than gene therapies based on a single growth factor. Pre-clinical studies have demonstrated that HIF-1 alpha can turn on the expression of proteins associated with the body's response to tissue ischemia, including many associated with blood vessel formation. In Genzyme's clinical studies, the gene is delivered using an adenovirus vector.
The HIF-1 alpha clinical effort is the most advanced program in Genzyme's gene therapy portfolio, which also includes pre-clinical work related to lysosomal storage disorders, and research into the applicability of gene therapy to other conditions.