Anamorelin

Anamorelin (ONO-7643, RC-1291, ST-1291) is a non-peptidic, orally active, centrally penetrant agonist of the growth hormone secretagogue receptor type 1a (GHSR-1a), the endogenous receptor for ghrelin. Structurally derived from peptidomimetic optimization of the growth hormone-releasing peptide scaffold at Novo Nordisk and subsequently developed by Helsinn Healthcare and Ono Pharmaceutical, anamorelin binds the ghrelin receptor with subnanomolar affinity (Ki 0.70 nM) and produces full agonist activity in fluorescence imaging plate reader (FLIPR) calcium mobilization assays with an EC50 of 0.74 nM, comparable to endogenous ghrelin (Ki 0.58 nM, EC50 0.67 nM) [1]. No antagonist activity has been observed at concentrations up to 1000 nM. The compound is distinguished from endogenous ghrelin by oral bioavailability, a plasma elimination half-life of approximately 7 to 12 hours (compared to approximately 30 minutes for ghrelin), and the absence of peptidic instability. Pharmacodynamically, a single oral dose of 100 mg produces rapid and sustained elevation of circulating growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 3 (IGFBP-3), with secondary increases in appetite, caloric intake, and body weight observed on chronic dosing. The principal clinical application is cancer anorexia-cachexia syndrome (CACS). Two pivotal Phase 3 randomized, double-blind, placebo-controlled trials (ROMANA 1 and ROMANA 2), conducted in 979 patients with inoperable stage III or IV non-small cell lung cancer and cachexia across 93 sites in 19 countries, demonstrated that anamorelin 100 mg daily for 12 weeks significantly increased lean body mass (median change +1.10 kg versus -0.44 kg on placebo in ROMANA 1; +0.75 kg versus -0.96 kg in ROMANA 2; both P < 0.001) and body weight, with concurrent improvement in anorexia-cachexia symptoms and quality of life measures [2]. However, both trials failed to demonstrate statistically significant improvement in the co-primary endpoint of handgrip strength, a finding that became the basis for the European Medicines Agency refusal of marketing authorization in 2017 [3]. In Japan, where a separate Phase 2 trial (ONO-7643-04) in Japanese non-small cell lung cancer patients with cachexia and a Phase 3 open-label study (ONO-7643-05) in gastrointestinal cancer cachexia confirmed lean body mass and body weight increases, anamorelin received manufacturing and marketing approval from the Pharmaceuticals and Medical Devices Agency on December 11, 2020, as the first ghrelin receptor agonist approved worldwide for cancer cachexia [4]. It is marketed as Adlumiz tablets (50 mg) by Ono Pharmaceutical and has been available since April 2021 for the treatment of cachexia in patients with non-small cell lung cancer, gastric cancer, pancreatic cancer, or colorectal cancer. Pharmacokinetics are characterized by rapid oral absorption (time to peak concentration 0.5 to 2.0 hours), a pronounced food effect (4-fold reduction in area under the curve when administered with food), hepatic metabolism predominantly through cytochrome P450 3A4 (CYP3A4) with minor contributions from CYP2C8 and CYP2D6, and fecal excretion of approximately 92 percent of the administered dose [5, 6]. The CYP3A4 dependence produces clinically significant drug-drug interaction potential with strong CYP3A4 inhibitors (ketoconazole increases the AUC of anamorelin by approximately 4-fold). The compound depresses cardiac conduction and has sodium channel-blocking activity; prolongation of the PR interval, QRS complex, and QT interval has been observed in clinical trials, with a frequency of approximately 10.7 percent for conduction system abnormalities in Japanese registration studies [7, 8]. Contraindications include congestive heart failure, recent myocardial infarction or angina pectoris, and severe cardiac conduction defects. The most frequent adverse events are hyperglycemia (5 to 6 percent overall, substantially higher in patients with pre-existing diabetes), elevated gamma-glutamyl transpeptidase, and gastrointestinal symptoms. This monograph reviews the chemistry, synthesis, and structural pharmacology of anamorelin; the ghrelin receptor mechanism in molecular and physiological detail; comprehensive pharmacokinetics including food effect and CYP3A4 interaction; the preclinical pharmacology in rat, pig, and tumor xenograft models; the clinical evidence base across the ROMANA program, Japanese registration studies, and the osteosarcopenia indication; sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety signals; and a comparative assessment of five cachexia and wasting treatment candidates (ibutamoren, enobosarm, megestrol acetate, mirtazapine, and espindolol) against anamorelin on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).