Repros Therapeutics stuck in neutral as FDA backpedals on advisory committee
http://www.bioworld.com/content/repros-therapeutics-stuck-neutral-fda-backpedals-advisory-committee-0
https://cortellis.thomsonreuterslifesciences.com/ngg/qsearch/%22Repros%20Therapeutics%22 (Repros Therapeutics) Inc. should be preparing for an advisory committee meeting with a panel from the FDA's Division of Bone, Reproductive and Urologic Products, scheduled for Tuesday, to review the new drug application (NDA) for https://cortellis.thomsonreuterslifesciences.com/ngg/qsearch/enclomiphene (enclomiphene) (formerly Androxal) to treat secondary hypogonadism (HG). Instead, late Thursday the company abruptly announced that the FDA canceled the meeting, sending its shares (NASDAQ:RPRX) plummeting 56 percent to close at $2.08. Shares eroded further on Friday, sinking to $1.62 before closing at $1.71 for a loss of 37 cents, or 17.8 percent.
What happens next for The Woodlands, Texas-based company isn't exactly clear. Joseph Podolski, president and CEO, acknowledged on a conference call that the FDA's qualms seem to go far beyond the purported concern that the bioanalytical methodology for testosterone measurements used by the company's CLIA-certified lab was not properly validated. The process was, in fact, very well validated, Podolski maintained, noting that the lab used a 510(k)-approved methodology, followed the manufacturer's instructions and ran samples in a timely fashion.
Instead, he called the FDA's stated reasoning "the tip of the iceberg."
In a long and winding explanation of the challenges now facing Repros, Podolski looked back to the September 2014 joint meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee as the primary culprit impeding a public discussion of enclomiphene. That panel first proposed changes in labels for testosterone replacement therapy (TRT) products, concluding 20-1 that such drugs should be used only in classic hypogonadism – low testosterone due to testicular or disease of the hypothalamic/pituitary glands – before voting 18-3 following a second day of discussion against approval of oral Rextoro (undecanoate) from Clarus Therapeutics Inc., of Northbrook, Ill. (See BioWorld Today, Sept. 19, 2014.)
Shares of Repros were dented following that adcom, but analysts split on the long-term implications of the panel's decisions on the company and its product – an estrogen receptor antagonist designed to treat the cause of secondary hypogonadism, which the company believes is a metabolic disorder due to inadequate pituitary hormones that is associated with overweight or obesity. Classic hypogonadism – low testosterone due to disease of the testicles or hypothalamic/pituitary glands – is a very different animal.
The two questions scheduled to be addressed at the Nov. 3 adcom, Podolski said, were whether the sponsor had studied the population intended to use the drug and whether the sponsor had identified a clinical benefit. Classic hypogonadism "would not include secondary hypogonadism as we define it," Podolski said.
No sponsor could sufficiently enroll patients to test any hormonal replacement product unless a significant number of patients "had an acquired disorder associated with them being overweight," he insisted. "That's a key consideration as we go forward and talk about hypogonadism in general."
Podolski credited the FDA with wanting to "back away from a circus" in the context of an adcom to focus on a broader discussion about the appropriate population to treat for hypogonadism. Still, Podolski said, a decision to cancel the adcom and reevaluate the treatment standard "should have been five months ago."
The FDA accepted the enclomiphene NDA for review on April 1, later assigning a PDUFA date of Nov. 30, which Podolski said will clearly not be met. (See BioWorld Today, April 3, 2015.)
The FDA delivered its decision to cancel the adcom verbally, he added. Repros quickly appealed through the FDA ombudsman, but to no avail.
"We've been at this since 2002," Podolski said. "It's not been a trivial exercise. But we think, given the FDA's willingness to talk to us, that we can work with them in a collegial fashion. In the final analysis, this makes for better development of a medicine that's clearly needed in a majority of men with low testosterone."
SECONDARY HYPOGONADISM 'A REVERSIBLE DISORDER'
Podolski was in no mood for a friendly chat with analysts, interrupting their questions and wandering through long soliloquies about the Repros drug, the nuances of the indication and the FDA's changing stance on TRT. He insisted that enclomiphene is a differentiated candidate that is designed to boost testosterone levels in men temporarily at the same time that they participate in a program of diet and exercise to lower their weight.
"The main cause for secondary hypogonadism is a metabolic disorder, and those are the men we seek to treat," he said. "We think that population has a reversible disorder."
In February 2014, the FDA seemed to accept the company's contention that enclomiphene was a different type of TRT product, indicating that new safety tests would not be needed before Repros submitted the NDA. (See BioWorld Today, Feb. 10. 2014.)
But later in the year, the FDA threw a curve ball to the company when it switched the pre-NDA meeting from a type B to a less-routine type C session, citing insufficient clinical information in briefing documents submitted by Repros for enclomiphene. (See BioWorld Today, Oct. 20, 2014.)
A month later, Repros said the FDA re-confirmed during the meeting that it was generally satisfied with the NDA package and would not seek additional trials. (See BioWorld Today, Nov. 10, 2014.)
The next step for Repros is to meet with the FDA, but no timetable has been set for that discussion. Podolski predicted that Repros might have a year's worth of work with the FDA, potentially including additional studies, before the agency is ready to review enclomiphene. Long term, the delay will result in better treatment by differentiating between the two groups of men with hypogonadism, he insisted.
"It's important to me that we keep our relationships with the FDA good and that we develop our drugs in a fashion that is meaningful from the standpoint of the men who are seeking treatment today," he said. "We will investigate all options for shareholder value improvement, and we'll see how that turns out as we move forward."
Repros remains on track to submit its marketing authorization application for enclomiphene to the EMA, likely around the beginning of the second quarter of 2016, and "I don't think [the FDA's action] will affect that," Podolski said.
The company's https://cortellis.thomsonreuterslifesciences.com/ngg/qsearch/Proellex (Proellex) (telapristone acetate) program is advancing, with a phase II study in uterine fibroids nearly fully enrolled.
"Since we're not moving into launch mode, our cash is in pretty good position," Podolski added. "We can certainly get through next year and deep into the following year."
Repros reported cash and equivalents of $32.2 million as of June 30, although Podolski said the current amount is closer to $25 million.
Laidlaw & Co. analyst Yale Jen placed much of the blame on the FDA, noting that the agency "did not even offer an opportunity" for Repros to present its case.
"We continue to view Androxal as an effective and better HG treatment," Jen wrote in a company update. "The FDA, in our opinion, should develop workable guidelines for medically managing the dominant majority of 'non-classic' HG patients."
That said, "Due to great uncertainty for the clinical path forward, we have removed the value of Androxal in second HG in the U.S. from our model until greater visibility is available," Jen added.
Brean Capital LLC analyst Jonathan Aschoff, however, dubbed enclomiphene an asset with "too little clarity" and "too many issues." He downgraded the stock to hold from buy and noted that the clock continues to tick on the company's lead program.
"Enclomiphene largely defines Repros' prospects and valuation," Aschoff wrote. "With the patent regarding enclomiphene expiring in 2021, even with an extension, the duration of market exclusivity will remain a concern."
