Perimenopausal vasomotor symptoms are triggered by a fall in circulating levels of estrogen and other sex steroids. It has been hypothesized that thermoregulatory centres in the hypothalamus play a crucial role in mediating the hot flash response. Recent research has focused on the hypothalamic hormone neurokinin B (NKB), as a possible mediator linking estrogen deficiency to hot flashes. NKB is a decapeptide and a member of the tachykinin family of peptides. 

In animal and human studies, it has been demonstrated that stimulation of NKB-neurokinin 3 receptor (NK3R) signalling can induce hot flashes, thus researchers have focused on antagonism of this signalling pathway as a potential target for mitigating menopausal symptoms. Several preliminary studies in humans have shown that NK3R antagonists produce significant reductions in menopausal symptoms, with a reduction in the severity and frequency of moderate to severe vasomotor symptoms observed on the first day of treatment.  

In a placebo-controlled, randomized trial, researchers have assessed the efficacy and safety of NT-814, a dual neurokinin 1 and 3 receptor antagonist (Trower et al, 2020).  In this double-blind, randomized, placebo-controlled trial, 76 postmenopausal women with moderate to severe hot flashes were randomized to 14 days of treatment with once-daily NT-814 (50, 100, 150, or 300 mg) or placebo.  

Daily hot flash frequency and severity, as well as frequency of waking due to night sweats, decreased in all groups (including placebo) measured on Day 14. Symptom reduction was the greatest in women receiving doses of NT-814 above 100 mg.  Mean reduction in moderate/severe hot flash frequency was 37% in the placebo group, 24% at 50 mg, 59% at 100 mg, 84% at 150 mg, and 66% at 300 mg of NT-814.  A similar reduction in waking due to hot flashes was observed across the five groups.  

The improvement with NT-814 at doses greater than 150 mg was evident during the first week of treatment. The most common treatment-related adverse events were mild somnolence and headache, which were reported more frequently in the 300 mg group. Safety monitoring identified no concerns.

On their website, KaNDy, the manufacturer of NT-814 has released promising preliminary data from their phase 2b trial.  The SWITCH-1 study was a randomised, double-blind, placebo-controlled trial conducted in the US, UK and Canada, including 199 women with at least 7 moderate or severe hot flashes/flushes (HF) per day.  

Women were randomized and received one of four doses of NT-814 or placebo. After treatment with NT-814 for 12 weeks at the most effective dose, participants experienced statistically significant reductions compared to placebo in average hot flash frequency, observed during the first week of treatment and continuing throughout the 12-week treatment period: -6.7 for NT-814 vs -2.7 for placebo at week 4, and -7.8 vs -4.7 at Week 12 (p<0.0001 and p=0.0092, respectively).  In addition, patients also reported improvements in quality of life, mood and sleep with NT-814

These findings are exciting and herald the development of new non-hormonal approaches for the management of menopausal vasomotor symptoms.  For most, the symptoms are manageable, but for a sizable subset of midlife women, these symptoms can negatively affect sleep, mood, and quality of life.  While clinical guidelines suggest that menopausal vasomotor symptoms typically last from 6 months to 2 years, new research suggests that for many women, the duration of symptoms is much longer and are associated with significant morbidity.  

Ruta Nonacs, MD PhD

 

Trower M, Anderson RA, Ballantyne E, Joffe H, Kerr M, Pawsey S.  Effects of NT-814, a dual neurokinin 1 and 3 receptor antagonist, on vasomotor symptoms in postmenopausal women: a placebo-controlled, randomized trial.  Menopause. 2020 Feb 17.