By Lisa Seachrist

Washington Editor

Zonagen Inc. said it submitted the final results of a two-year rat study to FDA for the agency's evaluation in the hopes a clinical hold would be lifted on its lead phentolamine-based drugs, Vasomax and Vasofem.

The Woodlands, Texas-based Zonagen was developing Vasomax as a therapy for penile erectile dysfunction and Vasofem to treat sexual dysfunction in women when FDA placed the drugs on clinical hold last August. A rat study showed some male rats developed an unexplained proliferation of brown fat. Filing the two-year rat data study is the first step in getting those clinical trials back on track.

"We feel satisfied with the technical evaluation of the data and we look forward to meeting with FDA," said Joseph Podolski, Zonagen's president and CEO. "We are hopeful the agency comes to the same conclusion."

Podolski declined to discuss the study's findings in detail because the FDA is going to conduct its own review of the data, including analyzing 10 percent of the tissue sample slides. In addition to the two-year rat data, Podolski said Zonagen and development partner Schering-Plough Corp., of Madison, N.J., have submitted 27 additional preclinical and clinical studies of the drugs since the beginning of March. Finally, the company assembled a panel of experts to submit an independent analysis of the data to FDA in May.

"We want to work with FDA, so we tried to use consultants they already use so they are comfortable," Podolski said. "We want them to take a rational approach to assessing the drug."

Vasomax is an immediate-release oral formulation of phentolamine mesylate, which is a short-term alpha-adrenergic receptor blocker that stimulates smooth muscle relaxation and causes vasodilation. The drug was approved 50 years ago as a treatment for hypertension and later as a means to diagnose certain tumors of the adrenal gland. Recently, it's been used off-label as an injectable therapy for erectile dysfunction. Vasofem is a similar formulation in development to treat female sexual dysfunction.

The fact phentolamine was approved during an era when the drug approval process was less rigorous and the fact the drug is a "lifestyle" drug led the agency to recommend a series of animal studies.

The proliferation of brown fat - a fat found in hibernating animals - among male rats in the two-year study shut down the clinical development of the two drugs in August with the exception of a fully-enrolled 12-week study. (See BioWorld Today, August 11, 1999, p. 1.)

"We just don't believe this drug is the cause of the problem," Podolski said. "If the drug is a carcinogen, you would expect to see a dose-dependent effect. We don't see that."

Instead, the increase in brown fat proliferation among the male rats occurred equally at all dosage levels. Podolski noted the drug also caused a 30 percent to 40 percent increase in heart rate in rats, while the studies in humans showed increases of about 1 or 2 beats per minute. In addition, the company noted phentolamine has been on the market for a very long time without the proliferation of brown fat ever being documented.

"The next big event is going to be FDA's decision on the clinical hold," Podolski said. "Lifting the clinical hold is the next major hurdle."

Zonagen's stock (NASDAQ:ZONA) closed Tuesday at $4.968, up 65.62 cents.

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