By Lisa Seachrist

Washington Editor

Zonagen Inc.'s stock plunged more than 30 percent on news the FDA put a clinical hold on its phentolamine-based drugs, Vasomax and Vasofem, based on a preliminary analysis of a two-year rat study.

The Woodlands, Texas-based company saw its stock (NASDAQ:ZONA) close at $4.937 a share, down $2.375, following the FDA's decision to halt all clinical studies of Vasomax to treat erectile-dysfunction in men and Vasofem to treat sexual dysfunction in women. The agency is permitting marketing partner Schering-Plough Corp., of Madison, N.J., to complete a fully enrolled 12-week study of Vasomax in humans.

The setback came just three months after the two companies decided to forgo an FDA advisory committee hearing and take a non-approvable letter for Vasomax in order to develop a database of long-term use of the product. The stock fell 46 percent that day, closing at $10.687. (See BioWorld Today, May 11, 1999, p. 1.)

Preliminary results from the two-year rat study showed male rats receiving Vasomax had a higher incidence of proliferation of brown fat tissue than control rats, triggering the FDA's clinical hold.

"I think the agency is doing the prudent thing here, at least until we convince the agency that the brown fat proliferation doesn't represent a long-term risk in humans," said Joseph Podolski, president and CEO of Zonagen. "We've seen nothing to date to indicate that it would."

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. It has been approved for 50 years, first as a treatment for hypertension and later 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.

Because phentolamine was approved when drug surveillance wasn't as rigorous and Vasomax is considered a "lifestyle" drug, FDA requested that Zonagen conduct a series of animal studies. Prior to the two-year rat studies, Zonagen had submitted a complete genotoxicity profile, a six-month mouse p53 assay, and six-month daily usage studies in dogs and rats. None of the studies showed any abnormal side effects.

The two-year rat study was meant to be a postmarket study to examine the carcinogenicity of Vasomax. Because a rat's life span is roughly two years, the intent was to examine the lifetime risk of cancer from taking Vasomax daily.

"We've really seen nothing remarkable in our toxicology studies," Podolski said. "Brown fat proliferation has never been an issue in these studies."

In fact, Podolski noted there have only been 80 or so cases of brown fat masses in humans this century and none of them has been associated with phentolamine. Only hibernating animals routinely demonstrate brown fat proliferation, that coming during the summer months when they store up energy for the winter.

In the two-year rat study, only the male rats receiving Vasomax experienced brown fat proliferation. The company expects to learn more from that study when it is completed in November. Podolski suspects the issue affects only male rats and isn't applicable to humans. Nevertheless, the studies need to be completed to make that argument.

"We believe that we will be able to convince the agency that this isn't relevant for humans," Podolski said.

In the meantime, the clinical hold has realistically set back the targeted launch date for Vasomax to sometime in 2001.

Zonagen, which focuses on the areas of urology, female health and contraception, has three female contraceptives in development, as well as its Vasomax and Vasofem programs.