NEW ORLEANS – Hot flash frequency was reduced by up to threefold in phase 2b results for fezolinetant, a novel nonhormonal therapy.
The neurokinin-3–receptor (NK3R) antagonist showed a significant reduction of 1.8-2.6 mean hot flashes daily from placebo in twice-daily dosing at the end of 12 weeks, despite a strong 55% response rate to placebo, Graeme Fraser, PhD, said at the annual meeting of the Endocrine Society.
Once-daily dosing also significantly dropped the frequency of moderate to severe vasomotor symptoms by 2.1-2.6 events daily, compared with placebo at the end of 12 weeks.
“This phase 2b trial was really about looking at different dose levels and looking at the once-daily versus twice-daily dosing,” Dr. Fraser said in a video interview. “The efficacy of both, with regard to once-daily and twice-daily dosing, was clear.”
The investigators looked at doses ranging from 15 mg to 90 mg twice daily and 30-120 mg daily. Significant reductions in frequency of moderate to severe hot flashes were seen at all doses and frequencies at 4 weeks and 12 weeks.
A coprimary endpoint, vasomotor severity, was also significantly reduced at 12 weeks for the two highest twice-daily doses. Hot flash severity was similarly reduced at 12 weeks for the two highest once-daily doses.
The safety profile was generally good; there were no signs of suicidality, no changes in endometrial thickness judged by ultrasound or endometrial biopsy, and estradiol levels were unchanged. Plasma bone markers, other laboratory values, and electrocardiograms were also unchanged.
A total of nine women experienced asymptomatic elevations in liver enzymes without bilirubin elevation. Most of these elevations were below three times the upper limit of normal.
Across 51 study sites in the United States, a total of 352 women received one dose of study drug and were included in the safety analysis. Efficacy was analyzed for 349 women, and 287 (81%) were considered completers.
Women were included in the randomized, double-blind, placebo-controlled study if they were naturally or surgically menopausal and aged 40-65 years, and experiencing at least 50 moderate to severe hot flashes weekly.
Fezolinetant acts on the KNDy neuron by replacing estrogen’s inhibitory effects. “Normally the firing is controlled by estrogen, but of course, in menopause, estrogen levels drop, and that control is lost,” explained Dr. Fraser. Fezolinetant exerts antagonism on the KNDy neuron’s NK3 receptor. “Why that’s important is that this neuron synapses at the thermoregulatory centers of the brain.”
Dr. Fraser said that discussions are underway with regulatory authorities to proceed to phase 3 clinical trials.
Dr. Fraser is a consultant to Astellas and was formerly a principal in Ogeda, the developer of fezolinetant. Ogeda is now a wholly owned subsidiary of Astellas, which funded the phase 2B trial.