By Debbie Strickland

GenVec Inc. has secured a $100 million-plus deal for its lead program: adenoviral delivery to the heart of a gene that induces the body to build its own arterial bypasses.

The privately held Rockville, Md., company landed the Parke-Davis division of Morris Plains, N.J.-based Warner-Lambert Co. as development and marketing partner for its ischemic heart disease therapy, BioByPass, which is now at the preclinical stage but expected to move into clinical trials in 1998.

"We are in the process of putting together an IND [investgational new drug application] now and anticipate it being filed this year," said Paul Fischer, GenVec's president and CEO.

Parke-Davis' $100 million investment consists of an equity purchase, along with an up-front payment, milestones, and research and development funding over five years. The equity investment will be made in multiple tranches, including the purchase of stock when the company does an initial public offering.

In exchange, Parke-Davis receives marketing rights everywhere except Asia for BioByPass and related therapeutic angiogenesis products. GenVec will receive royalties and certain manufacturing and copromotion rights.

Scios Inc., of Mountain View, Calif., also stands to benefit financially if the therapy hits the market. Scios licensed the gene-transfer applications of the vascular endothelial growth factor gene (VEGF 121) to GenVec in June 1996. The two companies agreed to share profits from products that result from the technology.

The BioByPass therapeutic agent — a modified, replication-deficient adenoviral vector that delivers VEGF into the muscle cells — will be delivered by injection directly into the heart muscle. As development progresses, however, the agent may be delivered in a minimally invasive manner.

The gene expresses the VEGF protein, which acts on endothelial cells to promote new collateral blood vessels that detour the blood traffic around blockages. The short-term introduction of pharmacological levels of VEGF augments the body's normal, angiogenic response to ischemia.

These new blood vessels create a so-called "biological bypass" for providing sufficient oxygen and nutrients to ischemic tissues. BioByPass could potentially be used alone or as an adjunct to existing therapies such as bypass surgery and angioplasty for the treatment of coronary artery disease and peripheral vascular disease.

"Preclinical research in established models of cardiovascular disease shows BioByPass to be effective in creating significant neovascularization in ischemic tissues," said Ron Crystal, chief of the division of pulmonary and critical care medicine at The New York Hospital-Cornell University Medical Center, in New York. "This product is a tangible example of applying gene therapy technology to address important clinical problems."

In preclinical studies using pigs, the procedure restored blood flow and cardiac function as measured by echocardiograms.

"In the pig model, it's very clear that the delivery of VEGF for a period of approximately a week induces new blood vessel formation that actually restores blood flow, even in animals in which one of the coronary arteries is completely blocked off," Fischer said. "It's remarkable."

According to GenVec, the therapy could reach human pivotal trials by 1999 or 2000.

"GenVec will probably be more involved in the Phase I testing, and then as the drug moves through development Parke-Davis will assume a greater role, and as we move into pivotal, Phase III trials, it will be fully Parke-Davis' responsibility," Fischer added.

The angiogenesis product has bypassed GenVec's clinical gene transfer programs in cystic fibrosis and cancer to become the company's lead therapeutic project.

"In many ways the BioByPass program is the most advanced," Fischer said, "because it has a very clear product potential. In terms of clinical studies, the cystic fibrosis program has been in the clinic for a couple of years and we are learning a great deal in the clinical research setting . . . but we believe that BioByPass is a much nearer-term product."

The cystic fibrosis treatment, dubbed GV-1101, is in Phase I studies. Testing has moved into repeat dosing paradigms, with the primary focus on efficiency of transfection and the length of gene expression.

The GV-1301 colon cancer/liver metastasis program also is in a Phase I trial, with researchers about two-thirds through dose escalation.

Founded in 1993, GenVec has raised more than $35 million to date, and with the Parke-Davis deal is sufficiently capitalized to fund operations for "several years," Fischer said. *