Elinzanetant

Elinzanetant (Lynkuet; BAY3427080; formerly NT-814 and GSK1144814) is a potent and selective dual antagonist of the neurokinin-1 (NK1) and neurokinin-3 (NK3) receptors, developed for the non-hormonal treatment of moderate-to-severe vasomotor symptoms (VMS) associated with menopause and with endocrine therapy for hormone receptor-positive breast cancer. The compound received its first regulatory approval in the United Kingdom in July 2025, followed by approvals in Australia, Canada, Switzerland, and the United States, where it was approved by the Food and Drug Administration on October 24, 2025, under the trade name Lynkuet at a recommended dose of 120 mg orally in the published literature. Elinzanetant is the first and only approved dual NK1/NK3 receptor antagonist, mechanistically distinct from fezolinetant (Veozah), which acts solely on the NK3 receptor. The dual mechanism targets kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the hypothalamic arcuate nucleus, where neurokinin B (NKB) acting through NK3 receptors initiates thermoregulatory dysregulation responsible for hot flashes, and substance P (SP) acting through NK1 receptors amplifies KNDy neuronal activity and contributes to sleep disruption, mood disturbance, and peripheral vasodilation. By antagonizing both receptor subtypes, elinzanetant addresses the composite symptom burden of menopause rather than isolated hot flash frequency alone. The compound exhibits high affinity for human NK1 receptors (pKi 8.7 to 10.2) and NK3 receptors (pKi 8.0 to 8.8), with greater than 300-fold selectivity for NK1 and greater than 100-fold selectivity for NK3 over off-target receptors. Pharmacokinetics are characterized by rapid oral absorption (median Tmax approximately 1 hour), absolute oral bioavailability of 52 percent, extensive plasma protein binding (99.7 percent), a large volume of distribution (137 L), and a long elimination half-life of approximately 45 hours that supports dosing. Metabolism is predominantly CYP3A4-mediated, producing three active metabolites with comparable NK1/NK3 potency at approximately 39 percent of parent plasma exposure. Excretion is predominantly fecal (90 percent as metabolites). The clinical evidence base comprises the OASIS Phase 3 program: OASIS 1 and OASIS 2 (12-week placebo-controlled studies in approximately 400 postmenopausal women each), OASIS 3 (52-week long-term study in 628 women), and OASIS 4 (12-week study in women receiving breast cancer endocrine therapy). All trials met primary endpoints, demonstrating statistically significant and clinically meaningful reductions in VMS frequency and severity at weeks 4 and 12, with onset of effect as early as week 1. Secondary endpoints showed significant improvements in sleep disturbances, menopause-related quality of life, and mood. Long-term efficacy was maintained through 52 weeks in OASIS 3 with no signal of hepatotoxicity, endometrial hyperplasia, or endometrial malignancy. The most common adverse events are headache (7.8 percent) and fatigue (5 percent). Elinzanetant is contraindicated in pregnancy, in severe hepatic impairment, and with concomitant strong CYP3A4 inhibitors. This monograph reviews the chemistry, synthesis, and stereochemistry of elinzanetant; the dual-receptor pharmacology in molecular and neurophysiological detail; the comprehensive human pharmacokinetic record; the clinical evidence base across the OASIS program and the dose-finding SWITCH-1 study; sourcing and quality verification considerations; reconstitution and handling; stack-interaction considerations for research applications; the adverse-event and safety signal profile; and a comparative assessment of five alternative compounds for vasomotor symptom management against elinzanetant on five competency standards.