Gone in a Flash: New Drug Class Targets Menopause Symptom

Miriam E Tucker

April 06, 2017

ORLANDO, Florida – Neurokinin 3 (NK3) receptor antagonists may represent a new class of nonhormonal oral treatment options for menopausal hot flashes, phase 2 data from two trials suggest.

Findings from randomized controlled trials of the NK3 receptor blockers MLE4901 (Millendo Therapeutics) and fezolinetant (Ogeda) in women with frequent moderate to severe menopausal hot flashes were presented during a late-breaking abstract session here at ENDO 2017: The Endocrine Society Annual Meeting, and the MLE4901 data were also simultaneously published in the Lancet.

"Treatment with the NK3 receptor antagonist could be practice-changing, as it significantly relieves hot-flash symptoms without the need for estrogen exposure. Larger-scale studies of longer duration are now indicated and planned," Dr Julia K Prague, of Imperial College London, United Kingdom, said of MLE4901 in her presentation.

Ogeda chief scientific officer Dr Graeme L Fraser, who presented the fezolinetant data, said that the company plans to further test the drug in women who have had breast, uterine, and ovarian cancer, for whom hormone-replacement therapy is contraindicated. "This really is a perfect fit for this population, where there is an important unmet need."

In an interview, session moderator Dr Richard J Santen, professor of medicine at the University of Virginia, Charlottesville, told Medscape Medical News, "This is an approach that focuses on the pathophysiology rather than empirical treatment. Nothing else does this.…I think the beauty of these studies is that they're really looking at the part of the brain that controls hot flashes and the possibility that you can very specifically block what turns them on.…To me, this looks quite exciting."

However, he also cautioned, "The question is what happens when you give this to patients for 3 or 4 years? What is the ultimate toxicity? What other tissues in the body have this receptor? We have to have major caution about the long-term effect."

Michelle Warren, MD, an ob/gyn from the Center for Menopause, Hormonal Disorders, and Women's Health at Columbia University, New York, told Medscape Medical News: "I think it's very exciting. It tells us about the mechanism of hot flashes, something we've puzzled about for a long time. This has compelling physiologic and molecular evidence that we can attack the problem from its core."

"Could Be Practice-Changing"

In the MLE4901 trial, 37 women aged 40 to 62 with amenorrhea for at least 12 months who experienced seven or more hot flashes daily were randomized to either 40 mg of the drug taken orally twice daily or placebo twice daily for 4 weeks. After a 2-week washout, they received the other treatment for another 4 weeks, and both groups were followed for another 2 weeks after the intervention ended. Twenty-eight of the women completed the entire protocol.

At baseline, the women were experiencing about 13 hot flashes per 24-hour period and 85 per week. During the fourth study week, in the intention-to-treat analysis, they experienced a total of 49 hot flashes with placebo compared with just 19 while taking MLE4901, a highly statistically significant 45-percentage-point difference (< .0001).

The results didn't differ whether the women took the drug or placebo first or second, Dr Prague added.  

Other significant percentage-point differences in favor of MLE4901 over placebo were hot-flash severity (41), hot-flash bother (45), and hot-flash interference (58) (all < .0001).

Scores on questionnaire-assessed measures of psychosocial and physical domains improved significantly along with the reduction in vasomotor symptoms. One likely reason for that, Dr Prague said, probably relates to improved sleep.

Women are "more able to concentrate, less irritable, less tired, and less lethargic when not awakened by night sweats," she said.  

Scores for the sexual domain didn't change, but that wouldn't be expected from this class of drugs. Also, many of the participants were widowed or just not sexually active, which could confound the findings, she noted.

Objective measurement of hot-flash detection via a skin conductance monitor generally concurred with the women's subjective reporting.

The drug was generally well-tolerated, and there were no serious adverse events. However, three subjects did develop transient transaminase elevations with normal bilirubin following day 28 of MLE4901 treatment. All three remained asymptomatic and the levels returned to baseline.

Trial Meets FDA-Defined End Points

Meanwhile, fezolinetant was studied in a 12-week, double-blind, placebo-controlled multicenter trial in 87 healthy menopausal women experiencing at least 49 moderate to severe hot flashes weekly, as specified by the US Food and Drug Administration for trials of drugs to treat menopausal hot flashes. The women were randomized to 90 mg of the drug twice daily vs placebo.

Among the 80 women who completed the study, hot-flash frequency was significantly reduced compared with placebo at each study week, by 88% vs 38% at week 4 (< .001) and by 93% vs 54% at week 12 (< .001). Also at week 12, there were 14 of 40 women who reported zero hot flashes compared with just two of 40 with placebo.

Hot-flash severity, the co–primary end point, also dropped significantly more with fezolinetant, by 60% vs 12% at week 4 and by 70% vs 23% at week 12 (P < .001).

Scores on questionnaires also revealed significant improvements with fezolinetant in measures of quality of life, sleep, and reduced disability (all P < .001). But as with MLE4901, libido did not improve. "That is to be expected, because after all this isn't estrogen replacement," Dr Fraser noted.  

The drug decreased plasma luteinizing hormone (LH) levels by 20% at 12 hours' postdose and by 50% at 3 hours after dosing (vs 16% for placebo), and LH levels were found to correlate with reduction in hot flashes.

Fezolinetant's onset is more rapid than hormone-replacement therapy, and pharmacokinetic/pharmacodynamic assessments support once-daily dosing, he said.

There were no serious adverse events in the fezolinetant group, and fewer patients reported mild to moderate adverse events compared with placebo (29 vs 35, respectively). However, two patients in the fezolinetant group did experience moderate events that required stopping the drug: fibromyalgia in one case and vertigo in the other. But the vertigo ceased and that subject was able to complete the trial. Overall, Dr Fraser said, "the safety profile was extremely good."  

In response to a question from Dr Santen about other NK3 receptors elsewhere in the body, Dr Fraser replied that they are also expressed in the gastrointestinal tract, the uterus, and the ovaries, but "we haven't seen any endometrial hyperplasia or GI effects."

The MLE4901 study was funded by the UK Medical Research Council and National Institute for Health Research and conducted in collaboration with Millendo Therapeutics and AstraZeneca. Dr Prague has no additional relevant financial relationships. Disclosures for the coauthors are listed in the paper. The fezolinetant trial was funded by Ogeda, of which Dr Fraser is an employee. Disclosures for the coauthors are listed in the abstract. Dr Santen consults for Pfizer.

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Lancet. Published online April 3, 2017. Article

ENDO 2017. April 3, 2017; Orlando, Florida. Abstract OR16-5


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