pavinetant (AZD4901) / AstraZeneca, Tempest Therap - LARVOL DELTA

Liver Safety of the Dual Neurokinin-1/-3 Receptor Antagonist Elinzanetant. (PubMed, Drug Saf) - "The aggregated phase 1‒3 clinical data, supported by preclinical toxicology and individual case adjudications of participants with elevated liver enzymes, suggest that there is a low risk of liver toxicity for elinzanetant. On the basis of these data, liver test monitoring was considered unnecessary in clinical practice by the LSMB (video abstract available online). Supplementary file2 (MP4 73923 KB)."

Journal • Hepatology • Liver Failure

NK3 receptor antagonist alters the centrally controlled perception of menopausal flushing - a pilot study. (PubMed, Climacteric) - "Using functional magnetic resonance imaging (fMRI), this study investigated the central effect of the NK3R antagonist MLE4901 during a flush, particularly functional connectivity changes in the salience network...This pilot study demonstrates decreased connectivity in the salience network during NK3R antagonist treatment. This may indicate areas of interest for further targeted fMRI studies and mechanistic investigation of this novel treatment for flushing."

Journal

Neurokinin 3 Receptor Antagonists Compared With Serotonin Norepinephrine Reuptake Inhibitors for Non-Hormonal Treatment of Menopausal Hot Flushes: A Systematic Qualitative Review. (PubMed, Adv Ther) - "NK3Ras trials show encouraging efficacy and tolerability/safety. Completion of phase 3 NK3Ra trials are required to confirm efficacy and uphold safety/tolerability data but phase 2 results suggest that NK3Ras are more effective than SNRIs for non-hormonal treatment of menopausal HFs."

Journal • Review

[VIRTUAL] Adverse metabolic PCOS traits in a hyperandrogenic PCOS mouse model improved following neurokinin 3 receptor antagonist treatment (Fertility 2021) - "PCOS-like mice were treated with a NK3R antagonist- (MLE4901) at a dose of 25mg/kg/day for 28 days... These results suggest that NK3R antagonism ameliorates some metabolic features of PCOS and may have potential as a future treatment option. Furthermore, the findings support continued research in targeting specific neuroendocrine regions to identify novel"

Preclinical • Polycystic Ovary Syndrome • AR • LEP

Neuropeptide Treatment for Hot Flushes During the Menopause (clinicaltrials.gov) - P2; N=37; Completed; Sponsor: Imperial College London; N=67 ➔ 37

Enrollment change

Neurokinin 3 receptor antagonism ameliorates key metabolic features in a hyperandrogenic PCOS mouse model. (PubMed, Endocrinology) - "Treatment with a NK3R antagonist (MLE4901) did not impact the observed reproductive defects...NK3R antagonism did not improve circulating serum triglyceride or fasted glucose levels. Collectively, these findings demonstrate that NK3R antagonism may be beneficial in the treatment of adverse metabolic features associated with PCOS and support neuroendocrine targeting in the development of novel therapeutic strategies for PCOS."

Journal • Preclinical • Obesity • Polycystic Ovary Syndrome

Kisspeptin and neurokinin B interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome. (PubMed, Hum Reprod) - "The NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7)...and K.S. have nothing to disclose. N/A."

Clinical • Journal • Genetic Disorders • Obesity • Polycystic Ovary Syndrome

Neurokinin B regulates gonadotropin secretion, ovarian follicle growth and the timing of ovulation in healthy women. (PubMed, J Clin Endocrinol Metab) - "...NK3R antagonist MLE4901 40 mg bd oral was taken from cycle day 5-6 for 7 days...Post-ovulatory progesterone rise was similarly delayed (peak cycle day: 30±2 vs 22±1, p=0.002) and cycle length was prolonged (35±1 vs 29±1 days in controls, p=0.0003) but luteal progesterone excretion was unaffected by the NK3Ra (LH surge day +7 urinary progesterone 58±10 vs 48±7 pmol/mol creatinine in controls, ns). These data demonstrate the involvement of NKB-NK3R signalling in the physiological regulation of GnRH/LH secretion, determining normal follicle development in women."

Journal • Biosimilar • Long-acting Reversible Contraceptives

Neurokinin 3 Receptor Antagonists Do Not Increase FSH or Estradiol Secretion in Menopausal Women. (PubMed, J Endocr Soc) - P2 | "Single-center, randomized, double-blind, placebo-controlled, crossover trial of an oral NK3R antagonist (MLE4901) in 28 women aged 40 to 62 years, experiencing >7 hot flashes/24 h; some bothersome or severe (Clinicaltrials.gov, NCT02668185)...NK3R antagonists do not increase serum estradiol or FSH despite their reduction in hot flashes. This is clinically significant and highly reassuring for women who have a contraindication to conventional hormone therapy such as prior/existing breast cancer and/or thromboembolism."

Clinical • Journal • Breast Cancer • Cardiovascular • Oncology • Solid Tumor

Kisspeptin and neurokinin B interactions in modulating gonadotropin secretion in women with PCOS (Fertility 2020) - " Women with PCOS (based on the Rotterdam criteria) were either administered NK3Ra (MLE4901) 40mg bd for 7 days on day 1-2 of induced menstruation (n=8) or received no treatment, acting as controls (n=7)... These data demonstrate the interactive regulation of GnRH/LH secretion by NKB and kisspeptin in PCOS, and that the NKB system mediates aspects of estrogenic feedback."

Clinical