West Coast Editor

Researchers in the UK and Germany enrolled their first patients in Phase II trials to test a gene therapy developed by Genzyme Corp. targeting intermittent claudication, a common form of peripheral arterial disease (PAD) that causes pain and difficulty walking.

Cambridge, Mass.-based Genzyme in February 2005 treated the first patient in its ongoing Phase II study with locally delivered Ad2/HIF-1 alpha, an engineered form of the HIF-1 alpha gene, for patients with PAD. The trial, intended to show a tendency to promote new blood vessel growth, has as its primary endpoint the amount of time a patient can walk on a treadmill without stopping due to pain. In its 2005 annual report, Genzyme forecast a launch date of 2013 for the product.

"Our [gene-therapy] program has been evolving for a number of years," noted Genzyme spokesman Dan Quinn, and the PAD effort is the most advanced. Other gene therapy efforts at Genzyme include preclinical work related to lysosomal storage disorders, such as Gaucher's disease, as well as preclinical study taking aim at age-related macular degeneration in collaboration with Applied Genetic Technologies Corp., of Alachua, Fla.

Genzyme's buyout late last year of Alameda, Calif.-based Avigen Inc. for $12 million up front plus milestones and royalties brought aboard a Phase I/II gene-therapy program in Parkinson's disease. (See BioWorld Today, Dec. 22, 2005.)

PAD is caused by poor blood flow to the muscles due to narrowed or blocked arteries, which leads to cramping and pain. Left untreated, intermittent claudication can worsen and could lead to loss of limbs through amputation. Scientists at 40 institutions around the world, including 25 in the U.S., are teaming up to experiment with the Genzyme approach.

"We're still excited about the opportunity of gene therapy, and we're large enough now that we can continue to invest and not bet the company on it," Quinn told BioWorld Today.

Emile Mohler, associate professor of medicine at the University of Pennsylvania School of Medicine in Philadelphia, is an expert on PAD.

"The [Genzyme] strategy is a transcription factor upstream of several growth factors," he said. "I'm a little suspect. I think you need cells and the cytokine both, but we'll see."

Mohler was the second author of a gene-therapy PAD study published in Circulation in 2003, involving Gaithersburg, Md.-based GenVec Inc.'s adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication.

"It didn't seem to work," he said. "We had a low-dose and a high-dose virus, and they were no better than placebo."

Others working in the space include Vasogen Inc., which in March reported that its pivotal Phase III study with Celacade technology against PAD missed its primary endpoint in improving patients' walking distance over placebo. (See BioWorld Today, March 14, 2006.)

With Celacade, a small blood sample is collected from the patient during a monthly outpatient procedure and placed into a disposable cartridge, where it is exposed to oxidative stress before being re-administered to the patient through an intramuscular injection.

"I was on the steering committee for that study," Mohler said. "We wanted to modify the immune system to suppress atherosclerosis. It's a new strategy and looked like it had some favorable Phase I data, but not enough to tell if it would work."

Scientists "really need to have a mechanism nailed," he said. "You have to grow new blood vessels or open that artery somehow. Celacade was not going to improve blood flow."

Toronto-based Vasogen noted a good anti-inflammatory effect in the PAD study, though, and hopes to see better results later this year from the larger Phase III trial in chronic heart failure patients.

Reporting success in January was Valentis Inc., of Burlingame, Calif., which unveiled positive Phase IIb data with VLTS 934 for PAD. An earlier Phase II study of the gene-based product known as Deltavasc against intermittent claudication led Valentis to VLTS 934, a non-ionic block copolymer known as a poloxamer that apparently acts as an anti-inflammatory agent. Deltavasc failed in a Phase II study to perform better than a control polymer, which caused Valentis to peg the polymer itself as the beneficial agent. (See BioWorld Today, Jan. 12, 2006.)

Specifically, Deltavasc was a formulation of 5 percent solution of PINC polymer mixed with the Del-1 gene, which was believed to be an angiogenic agent. The control was a 5 percent solution of the PINC polymer alone, which has traits of cell membranes and was supposed to help the uptake of the gene - but turned out itself to be the more important part of the drug.

The poloxamer VLTS 934, expected to enter Phase III trials in less than a year, seems to help repair compromised cell membranes and reduce levels of specific mediators of inflammation - IL-6, IL-8 and MCP-1 - to boost blood flow and exercise tolerance.

Also in the PAD game is ActivBiotics Inc., of Lexington, Mass., which made news at the start of the year by way of its merger with Ft. Lee, N.J.-based Metaphore Pharmaceuticals Inc. The former's lead candidate, rifalazil, is being studied in what the merged company hopes the FDA will consider a pivotal trial for intermittent claudication. (See BioWorld Today, Dec. 15, 2005.)

Given fast-track designation by the FDA, rifalazil is a bactericidal anti-chlamydial agent, going after a possible underlying cause of PAD: infection with Chlamydia pneumonia.

Mohler, also a member of the steering committee for the PAD Coalition, a not-for-profit alliance based in Lakewood, Colo., said angioplasty, the invasive treatment for PAD, "doesn't work. You have re-occlusions within a year or two."

Blockages particularly are tricky below the groin, where patients develop more restenosis, he added. Mohler recommended medical therapy, such as cholesterol-lowering drugs to slow disease progression, and exercise. People, especially those not advanced in age, who get moving three or four times per week can double their walking distance in six months, he said.

"The problem is, they have to walk until they get pain," Mohler said. "Patients don't want to do that."