Conference Coverage

Neurokinin receptor antagonist nearly halves hot flashes


 

AT ENDO 2017

– A novel antagonist of a neurokinin pathway effectively reduced hot flashes in postmenopausal women, according to results of a phase II trial.

The neurokinin 3 receptor (NK3R) antagonist, termed MLE4901, cut the number of hot flashes nearly in half compared to the effect of a placebo, and also improved overall menopause-related quality of life symptoms.

The medication has the potential to fulfill an unmet clinical need, since 70% of women experience hot flashes and the median duration of symptoms is more than 7 years, Julia K. Prague, MD, said at the annual meeting of the Endocrine Society.

The study results were published concurrently with Dr. Prague’s presentation (Lancet. 2017 Apr 3. doi: 10.1016/S0140-6736[17]30823-1).

Evidence from postmortem studies of postmenopausal women, said Dr. Prague, pointed to NKB (neurokinin B)/NK3R signaling as playing a role in hot flashes. The brains of these women showed hypertrophy of NKB neurons and increased neuronal activity, as well as increased NKB gene expression. The same effects were seen in monkeys whose ovaries had been removed, and the effect was reversed when the monkeys were given estrogen.

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Also, previous work has shown that administering NKB to premenopausal women gave them hot flashes (Sci Rep. 2015 Feb 6;5:8466). The preclinical work laid the groundwork for the hypothesis that taking an oral NK3R antagonist could mitigate hot flashes in menopausal women.

The randomized, placebo-controlled, double-blind 2-way crossover study enrolled 37 healthy women aged 40-62 who were at least 12 months out from their last menses. To qualify for enrollment, they needed to be experiencing at least seven hot flashes per 24 hours; the actual mean total number in the study group was 13 per 24 hours and 85 per week. A total of 28 women completed the full protocol.

The mean age of the women was 55 years, and the mean body mass index was 25.8 kg/m2. Three quarters of the women were white.

The women had an initial 2-week baseline period, during which they kept a symptom diary, and then were randomized to receive either an oral NK3R antagonist or a placebo twice daily. Then, each patient went through a 2-week washout period, after which they were crossed over to the other arm of the study. Finally, patients were monitored for a further 2 weeks after taking the study drug.

The NK3R antagonist, said Dr. Prague, “significantly reduced the total weekly number of hot [flashes] compared to placebo in the fourth week of treatment.” Patients taking placebo experienced 49.01 hot flashes per week (range, 40.81-58.86), while those taking the NK3R antagonist had 19.35 (range, 15.99-23.42, P less than .0001). This amounted to a 45% reduction in number of hot flashes compared to placebo.

Dr. Prague, a clinical research fellow at Imperial College, London, said that the treatment effect size seen was similar regardless of whether patients received the active study drug or placebo first.

Using the Menopause-Related Quality of Life questionnaire, Dr. Prague and her colleagues determined that when women were taking the NK3R antagonist, in addition to a significant reduction in vasomotor symptoms, menopause-related psychosocial symptoms were reduced by 15% (P = .0083) and physical symptoms by 19% (P = .0002). As expected for the nonhormonal medication, she said, sexual symptoms were reduced by a nonsignificant 8% (P = .24).

A subset of patients received more intensive study, with external validation of hot flashes and a series of 3-day-long stays during which an intravenous catheter was placed for blood sampling every 10 minutes.

Data from this group of patients showed that, while the NK3R antagonist did not significantly affect the number of luteinizing hormone pulses detected compared with placebo (P = .41), it did increase the mean amplitude of each pulse (P = .0243). Also, the active drug made the luteinizing hormone pulses more orderly (P = .0006 compared to placebo).

The NK3R antagonist was well tolerated. Though no serious adverse events were seen, three patients taking the NK3R antagonist did have a transient and asymptomatic elevation of transaminases without hyperbilirubinemia at 28 days after starting treatment. The elevation resolved for all patients within 90 days of stopping the medication.

The novel drug could represent “a potentially practice-changing therapeutic,” said Dr. Prague, since it “significantly relieves hot [flash] symptoms without the need for estrogen exposure.” She added that planning is underway for longer studies involving more patients.

The study was supported by AstraZeneca and Millendo Therapeutics, which are involved with manufacturing MLE4901.

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