By Lisa Seachrist

Washington Editor

Faced with unusual animal results, the FDA has told Zonagen Inc. the company would need to conduct an additional two-year rodent study before the agency could consider the approval of Vasomax for the treatment of erectile dysfunction.

The Woodlands, Texas-based company will exercise its right to appeal the decision instead of launching the new rodent study. The agency also said the clinical hold on Vasomax had been upgraded to a partial clinical hold in order to allow the company to conduct 12-week clinical trials.

"From the FDA's perspective, they are conservative," said Joe Podolski, president and CEO of Zonagen. "As an American consumer, I'm glad they are conservative. It really is incumbent upon us to show them this drug is safe. We think the data shows that."

Vasomax works by stimulating smooth muscle relaxation and causing vasodilation. The drug is an immediate-release oral formulation of phentolamine mesylate, which is a short-term alpha-adrenergic receptor blocker. Phentolamine mesylate has been approved for 50 years, first as a treatment for hypertension and then for the diagnosis of certain tumors of the adrenal gland. Recently, however, phentolamine has been used off label as an injectable therapy for erectile dysfunction.

A reformulation of a 50-year old drug may at first glance appear to be a slam-dunk. The sticking point for FDA is the fact the drug was approved when drug surveillance wasn't nearly as rigorous, and Zonagen wants to market the drug not for a life-threatening condition, but for a lifestyle issue. As a result, FDA requested Zonagen conduct a series of animal studies including a genotoxicity profile, a six-month p53 assay, and a six-month daily usage study in dogs and rats. None of these studies raised any red flags.

However, a preliminary look in September at a two-year rat study showed rats receiving Vasomax had a higher incidence of proliferation of brown fat than the control rats. As a result of these findings, FDA placed a clinical hold on Vasomax and Vasofem (a phentolamine mesylate formulation in development for women). The company's stock (NASDAQ:ZONA) plunged 30 percent on that news to close at $5 a share. (See BioWorld Today, Sept. 15, 1999, p. 1.)

Zonagen and marketing partner Schering-Plough Corp., of Madison, N.J., earlier decided to forego a scheduled FDA advisory panel hearing that was to review Vasomax. The companies decided instead to amend their new drug application once 12-week studies of the drug had been completed. (See BioWorld Today, May 11, 1999, p. 1.)

Zonagen's stock closed Wednesday at $3.812, down 93.75 cents.

Just last month, Zonagen submitted the final results of the two-year rat study to FDA along with an independent analysis of the data. Consultants the agency itself uses conducted the independent analysis. (See BioWorld Today, April 19, 2000, p. 1.)

"We think we have an adequate explanation for the brown fat masses in these male rats," Podolski said. "And, we're pretty sure what we see in the rats won't occur in humans."

The company claims experiments conducted both by itself and its outside experts show rat alpha-adrenergic receptors and human alpha-adrenergic receptors have a different affinity for phentolamine. As a result, what is found in the rat isn't likely to be found in the human. In addition, the rats used for this study are prone to the proliferation of brown fat as a response to stress. Humans, on the other hand, are not.

In fact, there are only 80 documented cases of brown fat proliferation in humans in the last century, none of which relates to phentolamine, Podolski said.

Zonagen intends to request the FDA's Cancer Assessment Committee review the data rather than embarking on another two-year rat study. The company also doesn't plan to conduct any 12-week clinical studies of the drug, noting that Schering-Plough has already conducted such a study.