Enclomiphene Ups Testosterone, Maintains Sperm Count

Miriam E Tucker

November 11, 2015

The estrogen antagonist oral enclomiphene citrate (formerly known as Androxal, Repros Therapeutics), raises serum total testosterone levels while maintaining sperm counts in the normal range in men with secondary hypogonadism, two new studies find.

The data were published online October 23 in BJU International by Edward Kim, MD, professor of surgery in the division of urology at the University of Tennessee Graduate School of Medicine, Knoxville, and colleagues.

The benefits of enclomiphene over testosterone-replacement therapy are cited as "restoration instead of replacement" and include the fact it is an oral formulation and maintains spermatogenesis, with no risk for transference (compared with testosterone gel), and preservation of the hypothalamic–pituitary–gonadal axis rather than suppression of it, Dr Kim told Medscape Medical News.

Approval of Enclomiphene in US Unlikely Now

The two studies were phase 3 pivotal trials that the manufacturer, Repros, had submitted to the US Food and Drug Administration (FDA) in hopes of approval for use in the treatment of secondary hypogonadism in men who are overweight or obese, younger than 60 years, and who desire to maintain fertility.

But on October 29, the company announced that the FDA had canceled an advisory committee hearing for the product that had been scheduled for November 3, citing "a laboratory issue" as the reason.

However, the cancellation probably had more to do with the FDA's recent attempts to restrict the use of testosterone products to curb overuse in men who simply have "low T" due to aging, Repros president and chief executive officer Joseph S Podolski told investors in a recent conference call, noting that the company now expects that the FDA will decline to license enclomiphene citrate.

The announcement is expected by the November 30, 2015 Prescription Drug User Fee Act (PDUFA) goal date.

In March 2015, the FDA issued a drug safety communication calling for testosterone product manufacturers to include information about possible increased risk for heart attacks and strokes in patients taking testosterone and also reiterated that such products are approved as replacement therapy "only for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause hypogonadism."

That group accounts for less than 5% of those currently being treated and doesn't include those for whom enclomiphene citrate would be indicated, Dr Kim pointed out.

Hypogonadism Secondary to Obesity: A Reversible Disorder?

Indeed, Mr Podolski pointed out during the investor's call, "Our intended population is overweight and obese men. You couldn't have enrolled enough patients in any testosterone trials without enrolling a significant number with an acquired disorder associated with being overweight or obese….We think that population has a reversible disorder."

Dr Kim, who consults for Repros, told Medscape Medical News that the company "has felt that, based on past discussions with the FDA, the demonstration of improvement in testosterone levels and maintenance of sperm concentrations were appropriate measures of clinical benefit."

Now, however, "science has advanced, and those end points are not what the FDA considers at this point to be appropriate measures of clinical benefit. Then, the question is, what are? There are no accepted criteria — we don't have a validated questionnaire. That's because testosterone-deficiency symptoms can be so variable, so no tool adequately captures it. We don't know the right tool to use," Dr Kim noted.

Now that the advisory committee hearing has been canceled, the company will engage in discussions with the FDA over defining the population that needs to be treated and the expected benefits.

"We intend to work with the FDA over the next year to help define that. I think that's going to result in better medicine," Mr Podolski noted.

Raises Testosterone, Maintains Spermatogenesis

The two parallel phase 3 studies, designed to meet FDA regulatory requirements, were conducted with a total of 256 overweight men aged 18 to 60 years, with secondary hypogonadism (serum total testosterone <300 ng/dL) and a low or inappropriately normal luteinizing hormone (LH) level (<9.4 IU/L) on two morning measurements.

They were randomized to oral enclomiphene citrate, testosterone gel (AndroGel, AbbVie), or placebo for 16 weeks. Half of those receiving enclomiphene citrate received 12.5 mg throughout the study, while the other half were uptitrated to 25 mg. Both studies were three-arm, double-dummy design.

Total testosterone above 400 ng/dL was seen after 4 weeks of treatment with enclomiphene citrate but not with testosterone gel. Testosterone levels remained low in the placebo group.

There were no significant changes between week 4 and week 16, the end of the study, in any of the groups.

Total testosterone remained higher than baseline in the enclomiphene groups for at least 7 days after the end of treatment (P < .001), while remaining unchanged in the placebo group (P = .38) and dropping rapidly in the testosterone gel group to a level below baseline (P = .07).

Levels of LH and follicle-stimulating hormone (FSH) increased in the enclomiphene-citrate groups and decreased in the testosterone-gel group at 16 weeks.

Sperm counts declined significantly in the testosterone-gel group compared with both placebo (P < .001) and enclomiphene citrate (P < .001).

Defining "success" as the achievement of sperm concentrations of 10x106 or greater and total testosterone in the normal range, the two enclomiphene-dosing groups succeeded in 63.5% of patients, compared with 24.7% for testosterone gel and 5.8% with placebo (P < .001).

Enclomiphene Citrate Still on Track for European Submission

Of the 21% of men in the two studies who had adverse events considered to be possibly, probably, or definitely related to study drug, none were severe or serious, and there was no difference in treatment-related adverse events between the study groups.

The persistence of the effects of enclomiphene citrate after the last dose would be an advantage over a topical agent, the authors say, because "skipping a dose would not lead to a rapid bottoming-out that would be seen with the topical agent."

And they add that the elevations in LH, FSH, and total testosterone in the men taking enclomiphene citrate "underpin the positive effects we have seen on sperm counts and are in marked contrast to the suppressive effects of exogenous testosterone-delivery systems on sperm counts.

"This could be an important consideration in the treatment of hypogonadal men wishing to preserve fertility," they observe.

Despite the FDA setback, Repros is "still on track" for a European submission in March or April 2016, Mr Podolski said in the investor call.

In contrast to the FDA, the European Medicines Agency has said it can find scant evidence that the use of testosterone in men with hypogonadism increases the risk for cardiovascular problems.

Dr Kim is a consultant to Repros Therapeutics and an advisor for Apricus Biosciences. Disclosures for the coauthors are listed in the paper. Podolski is a Repros employee.

BJU Int. Published online October 23, 2015. Abstract

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