AT ENDO 2017
ORLANDO –
After 12 weeks of treatment with the oral small molecule, women had a 93% reduction in moderate to severe hot flashes, compared with a 23% reduction for those taking placebo (P less than .0001). The effects of fezolinetant were seen earlier as well, with an 88% reduction in hot flashes at 4 weeks into the trial, compared with a 12% reduction for the placebo group (P less than .001).
Kari Oakes/Frontline Medical News
Dr. Graeme Fraser
The eight-site study enrolled 87 patients in a double-blind, randomized, placebo-controlled trial that assessed hot flash frequency and severity at study weeks 4 and 12. Postmenopausal women had to have frequent, moderate to severe hot flashes to qualify for enrollment, and they had to be otherwise healthy.
To capture data for a secondary endpoint, participants also completed a quality of life questionnaire. Dr. Fraser and his coinvestigators tracked safety and pharmacokinetic data by measuring levels of luteinizing hormone, follicle-stimulating hormone, estradiol, and sex hormone–binding globulin at baseline and 12 weeks, as well.
Evenly divided between study arms, 80 patients completed the trial. Two patients withdrew because of adverse events, one patient violated inclusion criteria, and the others withdrew for a variety of reasons. Mean age was similar between the two groups, at 53.7 years for those on placebo and 53.3 years for the fezolinetant group. Other anthropometric characteristics were similar, as well.
At baseline, patients taking placebo experienced a mean 10.3 moderate to severe hot flashes daily, compared with the fezolinetant group at a mean of 11.5. By study week 4, 14 of the 40 patients in the active arm had zero hot flashes, compared with 2 of 40 in the in the placebo arm, when the intention-to-treat population was examined. Hot flash severity dropped by 70% (P less than .0001).
Quality of life was assessed with the Hot Flash Related Daily Interference Scale (HFRDIS). When the two groups were compared, a significant (P less than .001) reduction in HFRDIS score was seen by week 4 and continued through to week 12 in the group on active treatment. Lower HFRDIS scores mean improved hot flash–related quality of life.
Using the Leeds Sleep Evaluation Questionnaire allowed Dr. Fraser and his colleagues to ask about how long it took patients to get to sleep while they were participating in the study, compared with their normal sleep latency. Patients taking fezolinetant reported getting to sleep significantly more quickly (P less than .01) than the placebo group. They also reported better quality of sleep (P less than .001) and a better awakening experience (P less than .05). However, they did not report feeling better after awakening (P = .08).
Women taking fezolinetant also showed significant improvement, compared with the placebo group, on other quality of life questionnaires, the Greene Climacteric Scale and the Sheehan Disability Scale. By week 8, a significant (P less than .001) improvement was seen on both scales and specifically at week 4 on the Sheehan Disability Scale.
Among the hormone biomarkers that were followed in the study, only plasma luteinizing-hormone levels dropped, compared with patients’ baseline levels. These were reduced 20% 12 hours after one of the two daily 60-mg oral doses, and 50% at 3 hours post dose, a point at which maximum serum fezolinetant concentration would be seen. These were all statistically significant reductions and expected effects of the drug’s mechanism of action.
Further pharmacokinetic analysis, said Dr. Fraser, “supports testing of once-daily dosing for vasomotor symptoms,” given that, when the drug was tested in premenopausal women in phase I clinical trials, there was no difference in peak and trough drug concentration.
The safety profile was good overall, said Dr. Fraser. No patients in the fezolinetant group reported serious treatment-emergent adverse events. “More patients reported treatment-emergent adverse events in the placebo group than in the fezolinetant group,” he said.
The NK3R antagonist is also under investigation for use in the treatment of polycystic ovary syndrome and uterine fibroids.
The study was funded by Ogeda, which employs Dr. Fraser. Another author reported serving as a clinical adviser for Ogeda.
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