Some investor confusion over the results from Repros Therapeutics Inc.'s first of two identical, pivotal phase III trials with Androxal (enclomiphene), its oral secondary-hypogonadism treatment, did not stop shares of the company from enjoying an uplift based on the data, which could enable a new drug application (NDA) before 2014 is over.

Brean Capital LLC analyst Jonathan Aschoff said he "fully expect[s] the same positive results from the second phase III trial in the first half of October, followed by a pre-NDA meeting by the end of October and an NDA submission by year-end, if the company is not acquired by then."

Repros, of The Woodlands, Texas, offered top-line results from a study called ZA-305, comparing estrogen receptor antagonist Androxal with Androgel (testosterone gel, Abbvie Inc.), showing Repros' therapy to be superior in the pair of co-primary endpoints: percentage of change from baseline in average sperm concentration, and percentage of subjects considered to be responders, defined as men with 24-hour average testosterone in the normal range, with the associated average sperm concentration of 10 million/mL or greater.

The latter "was an endpoint we've always really felt made the most sense," said Joseph Podolski, president and CEO of Repros, noting that the study "hit both of those endpoints handily" and adding that he, too, foresees a similar outcome in the second study. "In the final analysis, the responder is really where it's at," he said. "The placebo is there just as a calibrator for the outcome."

Secondary endpoints also showed statistically significant differences between the Androxal and Androgel groups. Repros' shares (NASDAQ:RPRX) closed Thursday at $21.58, up $3.57, or 18.5 percent.

Piper Jaffray analyst Joshua Schimmer said his firm was "deluged with questions" regarding what Repros-watchers expected would be a third primary endpoint: normalization of testosterone. Repros officials said that, after the company's press release regarding the protocol, the FDA instructed the firm to drop the separate endpoint. But Repros provided the normalization numbers during the conference call: 68 percent with Androxal vs. 52 percent with Androgel. CEO Podolski said a letter arrived "about four to five days" after the press release went out, and the agency "essentially collapsed what looked like three endpoints into two."

Schimmer found that, "while Androgel has clearly underperformed expectations as normalization should have been closer to 80 percent (and Androxal underperformed as well but to a lesser extent), this may have been a result of compliance with a complex double-dummy regimen and potentially longer study duration," he wrote in a research report. "We believe the totality of the data clearly validate[s] the physiology and the profile of Androxal vs. topical testosterone."

Podolski wagered that compliance may have been an issue. "This is a complicated study for the patient," he said, pointing out that "clinical-trial zealots" advising Repros insisted that, "if you're going to compare two modalities of treatment" as ZA-305 did, then the double-dummy design was necessary. "The most readily available agent that we could placebo or double-dummy was the Androgel once-a-day pack," Podolski said. "That meant that almost 50 percent of these guys, every morning, would have to open up four of these packets and lather it on."

ZA-305 was designed to enroll 120 men, 40 each into three parallel arms: Androxal and placebo. All three arms were blinded and "double-dummied," Repros said, with men receiving both an active dose and a placebo mimicking the other active drug. Those on full placebo received two placebos, one for each active. The study lasted 17 weeks, with 16 weeks of dosing and one week of follow-up.

Men, ages 60 years and older, enrolled in the study exhibited sperm counts in the normal range at baseline (greater than 15 million/mL) on two separate days separated by at least two days. Men also showed morning testosterone levels of greater than 300 ng/dL on both of those days to be eligible to enter the study.

Signed up for the study were 127 subjects, of which 117 completed. Of those enrolled, 44, 42 and 41 subjects were randomized to Androxal, Androgel and placebo, respectively. The mean age of the subjects was 47, 45 and 48 years for the groups, respectively, and baseline body mass index was similar for the three groups, 33.8, 33.1 and 33.5, respectively.

In sperm concentration, the percentage change from baseline was found to be unchanged for Androxal-treated subjects, and those treated with Androgel turned up a median 33 percent decrease from their baseline concentration. That difference was found to be statistically different from baseline (p = 0.0007) as well as statistically different from the Androxal results (p = 0.0004).

FDA PANEL NEXT MONTH

Schimmer also cited "a few investors who've speculated that the testosterone normalization level needed to be above 75 percent for the study," but said they are using a data point from the special protocol assessment (SPA) agreement in the first phase III placebo-controlled studies. "These new phase III head-to-head studies did not have an SPA, and so we do not believe that a pre-specified hurdle rate was agreed upon," wrote Schimmer. Anyway, in the earlier phase III studies, conducted with a more traditional study design, Androxal "clearly achieved the pre-specified testosterone response rate hurdle. As such, we aren't concerned at this point." (See BioWorld Today, March 29, 3013.)

Testosterone replacement therapy will be the topic of discussion next month during a joint meeting of the FDA's Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. Specifically, the meeting will take up the NDA for oral undecanoate (Rextoro), submitted by Clarus Therapeutics Inc., of Northbrook, Ill., which seeks approval for conditions associated with a deficiency or absence of endogenous testosterone: primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired). In June, Clarus made public phase III data from two studies showing that the testosterone replacement product met its endpoints in both studies testing the drug in male adults with hypogonadism. In March, Endo International plc, of Dublin, won FDA approval of Aveed, its injectable form of undecanoate for hypogonadism.

Repros has been allotted speaking time at the panel meeting, but only three and a half minutes, Podolski said – long enough, he said, to make the company's main point: Giving exogenous testosterone to men with the reversible condition of secondary hypogonadism (who collectively make up 85 percent to 98 percent of the market, and whose condition often is associated with obesity) only makes them dependent on hormones to keep their levels normal, and can further compromise their already-impaired testicular function.