Elinzanetant (NT-814), a Neurokinin 1,3 Receptor Antagonist, Reduces Estradiol and Progesterone in Healthy Women

Abstract

Context The ideal therapy for endometriosis (EM) and uterine fibroids (UF) would suppress estrogenic drive to the endometrium and myometrium, whilst minimizing vasomotor symptoms and bone loss associated with current treatments. An integrated neurokinin-kisspeptin system involving Substance P and neurokinin B acting at the neurokinin (NK) receptors 1 and 3, respectively, modulates reproductive hormone secretion and represents a therapeutic target. Objective To assess the effects of the novel NK1,3 antagonist elinzanetant on reproductive hormone levels in healthy women. Design Randomized, single-blinded, placebo-controlled study. Participants/Intervention Thirty-three women attended for 2 consecutive menstrual cycles. In each cycle blood samples were taken on days 3/4, 9/10, 15/16 and 21/22 to measure serum reproductive hormones. In cycle 2, women were randomized to receive once daily oral elinzanetant 40, 80, 120 mg or placebo (N=8 or 9 per group). Results Elinzanetant dose-dependently lowered serum luteinizing hormone, estradiol (120 mg median change across cycle: -141.4 pmol/L, P=0.038) and luteal phase progesterone (120 mg change from baseline on day 21/22: -19.400 nmol/L, P=0.046). Elinzanetant 120 mg prolonged the cycle length by median of 7.0 days (P=0.023). Elinzanetant reduced the proportion of women with a luteal phase serum progesterone concentration >30 nmol/L (a concentration consistent with ovulation) in a dose-related manner in cycle 2 (P=0.002). Treatment did not produce vasomotor symptoms. Conclusions NK1,3 receptor antagonism with elinzanetant dose-dependently suppressed the reproductive axis in healthy women, with the 120 mg dose lowering estradiol to potentially ideal levels for UF and EM. As such, elinzanetant may represent a novel therapy to manipulate reproductive hormone levels in women with hormone driven disorders.

Review of human genetic and clinical studies directly relevant to GnRH signalling

“…Elinzanetant has recently been shown to dose‐dependently lower serum LH, oestradiol, and luteal‐phase progesterone in healthy women. At the highest dose tested, Elinzanetant prolonged the cycle length by a median of 7.0 days 107 . Collectively, these data demonstrate the involvement of NKB‐NK3R signalling in the physiological regulation of GnRH/LH secretion in women.…”

“…At the highest dose tested, Elinzanetant prolonged the cycle length by a median of 7.0 days. 107 Collectively, these data demonstrate the involvement of NKB-NK3R signalling in the physiological regulation of GnRH/LH secretion in women.…”

Invited review: Translating kisspeptin and neurokinin B biology into new therapies for reproductive health

“…108 Regarding safety, elinzanetant was well tolerated with no safety concerns identified during the study, nor any clinically relevant changes in blood pressure, heart rate or electrocardiogram parameters. 108 Therefore, further studies are now required in women with hormone driven disorders to examine the effects of NK1 and NK3 receptor antagonism.…”

“…107 A recent study investigated the effects of NK1 and NK3 receptor antagonism (elinzanetant: NT-814) on reproductive hormone secretion across two consecutive menstrual cycles in 33-healthy premenopausal women. 108 Following a baseline assessment cycle, women in the second cycle were randomised to once daily oral elinzanetant (40-120 mg) or placebo. This revealed that elinzanetant reduced oestradiol and progesterone levels in a dose-dependent manner without causing vasomotor symptoms.…”

“…From a therapeutic perspective, the highest dosing arm was observed to lower circulating oestradiol to potentially ideal levels for uterine fibroids and endometriosis 108 . Regarding safety, elinzanetant was well tolerated with no safety concerns identified during the study, nor any clinically relevant changes in blood pressure, heart rate or electrocardiogram parameters 108 . Therefore, further studies are now required in women with hormone driven disorders to examine the effects of NK1 and NK3 receptor antagonism.…”