Liver Safety of the Dual Neurokinin-1/-3 Receptor Antagonist Elinzanetant.

backgroundElinzanetant is a selective dual neurokinin (NK)-1/-3 receptor antagonist for the treatment of moderate-to-severe vasomotor symptoms associated with menopause or caused by endocrine therapy. Elinzanetant has been approved by health authorities in several countries. The occurrence of elevated liver enzymes has been observed in clinical use with NK-3 receptor antagonists, e.g., fezolinetant and pavinetant, with recommendations for liver monitoring in the fezolinetant labeling information. Therefore, a thorough evaluation of the liver safety data from clinical trials with elinzanetant was undertaken.

objectiveTo summarize available hepatic safety data from the clinical development program of elinzanetant.

methodsThe potential risk of drug-induced liver injury (DILI) associated with elinzanetant was evaluated on the basis of the analysis of 24 phase 1 studies, three phase 2 studies (RELENT-1, SWITCH-1, NIRVANA), and four randomized, placebo-controlled phase 3 studies (OASIS 1‒4). Liver safety assessments were conducted throughout the studies as per protocol. In the phase 3 studies, a liver safety monitoring board (LSMB) performed an independent and blinded review of cases meeting close liver observation criteria, in alignment with US Food and Drug Administration DILI Guidance and the Council for International Organizations of Medical Sciences 2020 consensus on DILI. An independent data and safety monitoring board monitored the general safety of the participants.

resultsIn the clinical program (phases 1‒3), there was no imbalance between the elinzanetant and placebo groups in alanine aminotransferase (ALT) elevations up to 5×, 10×, or 20× the upper limit of normal (ULN). In the pooled studies that included postmenopausal women, during weeks 1‒52 of treatment, ALT or aspartate transaminase (AST) elevations ≥ 3× ULN were observed in 1.2% of participants treated with elinzanetant 120 mg and in 1.0% of participants treated with placebo. In addition, there were no cases meeting Hy's law, and no indication of cholestatic injury. The LSMB assessed two cases on elinzanetant (2 out of 1697 participants, 0.12%) and one case on placebo (1 out of 1028, 0.10%) as probably related to study drug. For the cases on elinzanetant, one participant had a peak ALT level 7.4× ULN and the other had a peak ALT 3.5× ULN. Alkaline phosphatase and total bilirubin levels remained within reference range; both cases were mild and reversible. The peak ALT for the participant on placebo was 3.6× ULN. No case was classified as highly likely or definite.

conclusionsThe 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).