Repros Seeks To Develop Low-Dose Proellex To Avoid Liver Toxicity

Repros Therapeutics has requested that FDA lift the clinical hold on its uterine fibroid and endometriosis drug Proellex so it can conduct a single clinical trial using several lower doses of the progesterone receptor blocker, the company announced April 5.

The new trial would use 3 mg, 6 mg, 9 mg and 12.5 mg doses, Repros said. Higher doses of 25 mg and 50 mg were used in the Phase III trials that prompted the clinical hold in August 2009 because of an increase in liver enzymes.

"This is a low-risk study to satisfy the FDA's concerns," CEO Joseph Podolski said in an interview.

The Woodlands, Texas company is in a precarious financial situation, however, and time isn't exactly on its side. Proellex is one of two clinical stage drugs the company has in development. The other, Androxal , in development for the treatment of men wishing to preserve fertility while being treated for hypogonadism, is also in a regulatory holding pattern, while the company awaits input from FDA on the clinical program.

"The company believes the data obtained to date [on Proellex] indicates a clear dose relationship when viewed from the perspective of liver injury," the firm said in a statement. "The company further believes that the risk of liver injury can be avoided by use of lower doses while still retaining a significant amount of the benefit of the drug."

In September, Repros met with FDA to discuss how it could move forward with the development of a low-dose version (¹ (Also see "For Sale: Repros Suffers An FDA Clinical Hold And Potential NASDAQ Delisting" - Pink Sheet, 29 Sep, 2009.)). Repros now says it has met FDA's requirements, although whether the agency will agree remains to be seen.

Among the actions requested by FDA at the time of the meeting was that Repros provide follow-up clinical safety data on patients treated with Proellex showing that liver injury has resolved or stabilized, as well as data on serum concentrations of Proellex in patients. In response, the company has provided FDA with the results of a six-month safety follow-up of subjects exposed to Proellex, and all of the subjects in the follow-up database have exhibited liver enzymes with in the normal range, including seven subjects that previously experienced serious adverse events. Of those, six were exposed to the 50 mg dose and one to the 25 mg dose, although that patient had received the 50 mg dose for two weeks.

With regard to the serum concentrations, FDA is looking for data demonstrating there is a serum concentration of Proellex below which there was no increase in liver enzymes. However, Repros said serum concentrations were not routinely obtained in the Phase III program. The firm maintains Proellex's dose-effect is "apparent" in a review of liver enzyme elevations that fell outside the normal range in the clinical program.

The fact that Repros wasn't able to provide FDA with serum concentration data could be a sticking point. The agency specifically requested the company provide an appropriate dosing regimen resulting in serum concentrations of Proellex that are sufficiently safe. FDA had previously said it would be difficult for the company to determine a dose that would be safe and effective.

Nonetheless, Repros maintains that a 12.5 mg dose would be efficacious while limiting the liver side effects, based upon earlier Phase II trial results and the results of an exposure model conducted using pharmacokinetic data from previous studies.

"Women need alternative therapies for uterine fibroids and endometriosis that is away from surgery," Podolski said. According to Repos, 200,000 to 300,000 hysterectomies are performed annually in the U.S. for the two conditions.

As of Dec. 31, the company had only $1.9 million in cash and equivalents on hand, an amount that was insufficient to fund the future development of Androxal or Proellex. But Podolski said, "We're in a better position now."

The company has been able to raise enough money to cover its burn, the CEO said, through the establishment of an at-the-market program under which it can sell common stock at an aggregate offering price of up to $10 million.

The company's securities were moved to the Nasdaq Capital Market from the NASDAQ Global Market effective Jan. 14; the firm has to maintain a minimum share price of $1 per share and stockholder equity of at least $2.5 million as of May 5 or risk being delisted.

- Jessica Merrill ( ² [email protected] )