Novel non-hormonal therapy may reduce hot flashes, improve QoL in postmenopausal women

NT-814, an oral, non-hormonal dual neurokinin 1,3 receptor antagonist may reduce the frequency of hot flashes, while improving quality of life (QoL) and sleep in postmenopausal women, according to results of the phase IIb SWITCH-1 trial presented at NAMS 2020.

SWITCH-1 trial participants were 199 postmenopausal women (age 40–65 years) who experienced ≥7 moderate and/or severe hot flashes per day. They were randomized to receive one of four doses of NT-814 (40, 80, 120, or 160 mg) or placebo once daily for 12 weeks.

Women in all treatment groups experienced reductions in frequency of hot flashes. At week 1, women in the NT-814 40, 80, 120, or 160 mg and placebo groups experienced a mean (least squares [LS]) -1.7, -1.4, -3.2, -3.1 and -1.4 fewer hot flashes per day from baseline, respectively. At week 4, the corresponding reductions were -4.3, -4.1, -6.7, -5.4, and -2.8, respectively, and at week 12, -6.5, -5.6, -7.8, -6.6, and -4.8, respectively.

A dose-related reduction in severity of hot flashes was observed, with higher doses of NT-814 having a greater effect than lower doses compared with placebo, noted the researchers.

Within 1 week of treatment, women who received the 120 or 160 mg doses of NT-814 had significantly greater reductions in frequency of hot flashes compared with placebo recipients ([LS mean difference, -1.80 and -1.69; p=0.0079 and 0.0125, respectively). [NAMS 2020, abstract S-21]

These reductions with NT-814 120 and 160 mg remained greater than that of placebo at week 4 (LS mean difference, -3.93 and -2.63; p=0.0002 and 0.0115, respectively) and with 120 mg at week 12 of treatment (LS mean difference, -2.95; p=0.0116), though not with 160 mg (LS mean difference, -1.78; p=0.1346).

In contrast, reductions in hot flashes with NT-814 at the lower doses (40 or 80 mg) did not significantly differ from that derived with placebo.

Most adverse events (AEs) were mild or moderate. AEs possibly related to higher doses of NT-814 included fatigue and somnolence, though these were rare. No treatment-related serious AEs or NT-814-related elevations in liver enzymes occurred.

In an a priori analysis of the same study, higher doses of NT-814 were also associated with improvements in sleep, mood, and QoL.

At week 12, sleep, assessed using the Insomnia Severity Index (ISI), was improved with NT-814 (80, 120 and 160 mg) vs placebo (LS mean difference, -3.77; p=0.0078, -4.27; p<0.0001, and -4.85; p<0.0001, respectively).

NT-814 at 120 and 160 mg showed significantly greater improvements vs placebo for mood (assessed using the Beck Depression Inventory II; LS mean difference, -3.74; p=0.0115 and -4.32; p=0.0048, respectively) and menopause-specific QoL (LS mean difference, -0.80; p=0.0004 and -0.77; p=0.0009, respectively).

“[S]ignificant improvements were also shown for each domain (Physical, Psychosocial, Vasomotor, and Sexual) of the menopause-specific QoL,” the researchers pointed out.

Hormone therapy, while effective for improving hot flashes and sleep in postmenopausal women, has its own set of risks and potential contraindications, noted the researchers.

“NT-814 … at doses of 120 [or] 160 mg [once/day] reduced the frequency and severity of hot flashes and significantly reduced overall hot flash burden in postmenopausal women. [It] also showed improvement in key secondary endpoints [of] mood, sleep, and QoL,” they said.

Its acceptable safety profile supports further evaluation in phase III trials. “[In addition, the results] demonstrate the potential for the dual NK1R and NK3R antagonism of NT-814 to provide broad benefit on well-being beyond improving hot flashes,” they concluded.