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 (UFs) would suppress estrogenic drive to the endometrium and myometrium, while 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: This work aimed to assess the effects of the novel NK1,3 antagonist elinzanetant on reproductive hormone levels in healthy women.

Methods: A randomized, single-blinded, placebo-controlled study was conducted in 33 women who attended for 2 consecutive menstrual cycles. In each cycle blood samples were taken on days 3 or 4, 9 or 10, 15 or 16, and 21 or 22 to measure serum reproductive hormones. In cycle 2, women were randomly assigned 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 = .038), and luteal-phase progesterone (120 mg change from baseline on day 21 or 22: -19.400 nmol/L, P = .046). Elinzanetant 120 mg prolonged the cycle length by median of 7.0 days (P = .023). Elinzanetant reduced the proportion of women with a luteal-phase serum progesterone concentration greater than 30 nmol/L (a concentration consistent with ovulation) in a dose-related manner in cycle 2 (P = .002). Treatment did not produce vasomotor symptoms.

Conclusion: 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 UFs and EM. As such, elinzanetant may represent a novel therapy to manipulate reproductive hormone levels in women with hormone-driven disorders.

Keywords: GnRH; endometriosis; estradiol; neurokinin B; substance P; uterine fibroids.

Figure 1.

Consolidated Standards of Reporting Trials participant flow depicts the number of participants entered into the study, randomly assigned, and analyzed. Fifty-four women were recruited and screened, of whom 33 were randomly assigned to receive placebo or elinzanetant 40 mg, 80 mg, or 120 mg (N = 8 or 9 per group). The most common reason for screen failure was menstrual period duration or irregularity. One woman in each of the elinzanetant 40-mg and 80-mg groups did not complete the treatment course. A total of 31 participants were included in the pharmacodynamic (PD) per-protocol analyses. Twenty-four participants from the elinzanetant 40-mg, 80-mg, and 120-mg groups were included in the pharmacokinetic (PK) analysis.

Figure 2.

Study protocol diagram. Healthy women attended for 2 consecutive menstrual cycles. In each cycle, blood samples were taken on days 3 or 4, 9 or 10, 15 or 16, and 21 or 22 to measure serum reproductive hormone levels, and plasma elinzanetant levels (cycle 2 only). No treatment was given in cycle 1 (baseline). During cycle 2, participants were randomly assigned to receive placebo or elinzanetant 40 mg, 80 mg, or 120 mg (N = 8 per group [9 for the 80-mg dose]) for up to 21 days.

Figure 3.

Reproductive hormone levels in women receiving placebo or elinzanetant during the study. A, C, and E, The median averaged across all time points during cycles 1 (C1) and 2 (C2) in A, serum luteinizing hormone (LH; IU/L); C, follicle-stimulating hormone (FSH; IU/L); and E, estradiol (pmol/L) in women after placebo (N = 8, red), elinzanetant 40 mg (N = 7, blue), 80 mg (N = 8, green), and 120 mg (N = 8, orange). Data in graphs depict within-participant paired raw data and the group median and interquartile range. ^**P less than .01, Wilcoxon matched-pairs signed rank test. B, D, and F, The median change averaged across all time points between cycles 1 and 2 in B, serum LH (IU/L); D, FSH (IU/L); and F, estradiol (pmol/L) in healthy women after placebo (N = 8, red), elinzanetant 40 mg (N = 7, blue), 80 mg (N = 8, green), and 120 mg (N = 8, orange). *P less than .05, Wilcoxon rank sum test. G, The median change from baseline on day 21 or 22 in serum progesterone (nmol/L) in healthy women after placebo (N = 8, red), elinzanetant 40 mg (N = 7, blue), 80 mg (N = 8, green), and 120 mg (N = 8, orange). Data in graphs depict within-participant paired raw data and the group median and interquartile range. *P less than .05, Wilcoxon matched-pairs signed rank test (comparing cycle 1 and cycle 2) and Wilcoxon rank sum test (comparing placebo vs elinzanetant). H, The median change from baseline on day 21 or 22 in serum progesterone (nmol/L) in healthy women after placebo (N = 8, red), elinzanetant 40 mg (N = 7, blue), 80 mg (N = 8, green), and 120 mg (N = 8, orange). *P less than .05, Wilcoxon rank sum test.

Figure 4.

Menstrual cycle length and biochemical parameters of ovulation in women receiving placebo or elinzanetant during the study. A, The change in menstrual cycle length between cycles 1 (C1) and 2 (C2) after treatment with placebo (N = 8, red), elinzanetant 40 mg (N = 7, blue), 80 mg (N = 8, green), and 120 mg (N = 8, orange) in healthy women. Data in graphs depict within-participant paired raw data and the group median and interquartile range. *P less than .05, Wilcoxon rank sum test. B, The median change between cycles 1 and 2 in menstrual cycle length (days) in healthy women after placebo (N = 8, red), elinzanetant 40 mg (N = 7, blue), 80 mg (N = 8, green), and 120 mg (N = 8, orange). *P less than .05, Wilcoxon rank sum test. C, The percentage of healthy women with a serum progesterone greater than 30 nmol/L in cycle 2 after placebo (N = 8, red), elinzanetant 40 mg (N = 7, blue), 80 mg (N = 8, green), and 120 mg (N = 8, orange). ^**P less than .01, chi-square test.