REPORTING FROM ENDO 2018
CHICAGO (FRONTLINE MEDICAL NEWS) – Testosterone levels dropped by one third for women with polycystic ovary syndrome (PCOS) and hyperandrogenemia when they received a centrally acting medication currently in development. The proof-of-concept phase 2 trial, which saw no concerning safety signals for the medication, fezolinetant, sets the stage for a larger, and perhaps longer, study to learn more about the neurokinin 3 receptor antagonist’s efficacy against PCOS.
“The primary outcome for this phase 2 trial was to see if we could lower testosterone levels in these PCOS patients,” said Graeme Fraser, PhD, chief scientific officer for Ogeda, discussing the poster he and his colleagues presented at the annual meeting of the Endocrine Society.
“Testosterone levels decreased: Measured at about 3 hours postdose, which is the approximate pharmacokinetic Cmax [maximum serum concentration], there was … a more than 30% decrease in testosterone levels,” said Dr. Fraser. By week 12, he said, “there was a very consistent decrease of 30% of testosterone levels. So that was quite good; we successfully hit the primary outcome.”
At 12 weeks, the higher dose of fezolinetant decreased testosterone by 0.64 nmol/L, compared with the 0.04 nmol/L seen with placebo (P less than .01).
Fezolinetant downregulates the activity of candy neurons in the hypothalamus, said Dr. Fraser in an interview. In turn, gonadotropin-releasing hormone (GNRH) pulse frequency is reduced, lowering luteinizing hormone (LH) levels. Since LH drives testosterone levels, this drops as well – a beneficial effect in PCOS, with its cardinal symptom of hyperandrogenism.
The double-blind, placebo-controlled study was conducted in Western Europe; 73 participants were randomized into three groups: 27 to a placebo group, 23 to a treatment group given 60 mg of fezolinetant once daily, and 23 to a treatment group given 180 mg of fezolinetant once daily. All groups received treatment for 12 weeks.
A total of 26 patients on placebo, 21 on 60-mg fezolinetant, and 17 on 180-mg fezolinetant completed the study. Patients who completed the study were included in the safety analysis, while all who took the study medication were included in the intent-to-treat analysis for primary and secondary outcome measures.
All participants had PCOS with hyperandrogenism, mean age was about 31 years, and about three quarters of enrollees were white, though local regulations restricted the collection of race and ethnicity data in some cases. One secondary outcome measure of the study was how fezolinetant affected the LH:FSH (follicle-stimulating hormone) ratio. “Patients with PCOS tend to have a very high GNRH [gonadotropin-releasing hormone] pulse frequency, which leads to a very high LH:FSH ratio,” said Dr. Fraser.
At baseline, the LH:FSH ratio was about 3. “With treatment, that ratio normalized to about 1, which is where it is in healthy women,” he said. The decrease in LH:FSH ratio occurred in a dose-dependent fashion and was statistically significant (P less than .001 for 180 mg fezolinetant versus placebo).
Dr. Fraser and his collaborators also tracked anti-müllerian hormone (AMH) levels, ovarian volume, and number of follicles. Although the investigators saw trends toward reduction in AMH levels and toward smaller ovarian volumes, these trends weren’t significant. “It was somewhat ambitious, I guess, to consider we’d hit these endpoints within 12 weeks,” he said. There were no serious drug-related adverse events.
“Most importantly, I would say, we did not get an increase in menses frequency, and, of course, that’s an important marker for fertility,” said Dr. Fraser. “There’s a debate in PCOS about whether this disease is driven by a malfunction in the brain or a malfunction in the ovaries. I guess on face value, perhaps this problem is in the ovaries.”
With the trends toward lower AMH and ovarian volumes, the research team is left wondering what would happen if the duration of therapy were extended. “Perhaps, the system would have been reset, and the frequency would have been restored. … So one thought that we have is to prolong the study in future trials and see if that could lead to an increase in fertility in PCOS,” said Dr. Fraser.
Fezolinetant is also being studied for menopause-related hot flashes in the United States and Europe.
Dr. Fraser is an employee of Ogeda, which sponsored the trial. Ogeda is a wholly owned subsidiary of Astelas.
SOURCE: Fraser G et al. ENDO 2018, Abstract SAT-305-LB .