Anamorelin

An orally active small-molecule ghrelin receptor agonist approved in Japan as Adlumiz for cancer cachexia, refused by European regulators in 2017, and never approved in the United States despite a completed phase 3 program.

Also referenced as: ONO-7643, RC-1291, ST-1291, Adlumiz, anamorelin hydrochloride

Also appears in: Metabolic

What is Anamorelin?

Anamorelin is not a peptide. It is a synthetic small molecule, a piperidine-based peptidomimetic developed as an orally active agonist of the growth hormone secretagogue receptor (GHS-R1a), the same receptor that the stomach-derived peptide hormone ghrelin binds. It was developed under the codes RC-1291 and ST-1291 in the United States, where the earliest trials were run by Sapphire Therapeutics and then Helsinn Therapeutics, and under ONO-7643 by Ono Pharmaceutical in Japan, with cancer anorexia-cachexia syndrome as the target indication, since loss of appetite and lean mass track with poor outcomes in advanced cancer. It appears in peptide-adjacent research circles because it reproduces the appetite and growth hormone effects of ghrelin and the injectable growth hormone secretagogues (GHRP-6, ipamorelin) in a tablet.

How it works

• Selective ghrelin receptor agonism. Anamorelin binds and activates GHS-R1a with sub-nanomolar potency in cell-based assays (EC50 and Ki values of roughly 0.6-0.7 nM), shows no significant antagonist activity at concentrations up to 1,000 nM, and stimulates growth hormone release from rat pituitary cells and in rats and pigs (Pietra et al., Journal of Cachexia, Sarcopenia and Muscle, 2014).
• Growth hormone and IGF-1 release. In a phase 1 multiple-dose study in healthy volunteers, RC-1291 at 50 mg and 75 mg produced dose-related weight gain of about 1.2 kg after six days with no dose-limiting adverse effects (Garcia and Polvino, The Oncologist, 2007). A companion placebo-controlled study in 32 healthy volunteers showed increased growth hormone at every dose and sustained rises in IGF-1 and IGFBP-3 after five to six days, with weight change correlating with the IGF-1 response (Garcia and Polvino, Growth Hormone & IGF Research, 2009). In a three-day randomized crossover pilot in 16 patients with cancer cachexia, anamorelin increased body weight, growth hormone, IGF-1 and IGFBP-3 relative to placebo (Garcia et al., Supportive Care in Cancer, 2013).
• Central appetite stimulation. Ghrelin receptor activation in the hypothalamus drives orexigenic signaling, and anamorelin increased food intake and body weight in rats at every dose tested (Pietra et al., Journal of Cachexia, Sarcopenia and Muscle, 2014). In patients, this registers as improved scores on the anorexia-cachexia subscale of the FAACT questionnaire (Temel et al., The Lancet Oncology, 2016).

Research status

Anamorelin has one of the deepest clinical records of any ghrelin-pathway compound, and one of the most contested.

ROMANA 1 and ROMANA 2 (Temel et al., The Lancet Oncology, 2016, 17(4):519-531) were twin randomized, double-blind, placebo-controlled phase 3 trials at 93 sites in 19 countries, enrolling 484 and 495 patients with inoperable stage III/IV non-small cell lung cancer (NSCLC) and cachexia. Over 12 weeks, anamorelin 100 mg increased lean body mass versus placebo in both trials (median change 0.99 kg versus -0.47 kg in ROMANA 1; 0.65 kg versus -0.98 kg in ROMANA 2), but failed the co-primary endpoint of handgrip strength in both. Hyperglycemia was the most common grade 3-4 adverse event, occurring in about 1% of anamorelin-treated patients. ROMANA 3 (Currow et al., Annals of Oncology, 2017, 28(8):1949-1956), a 12-week double-blind safety extension that enrolled 513 completers of the parent trials, found adverse-event rates similar to placebo, maintained weight gain and symptom improvement through 24 weeks, and again no handgrip benefit. A 2025 post hoc analysis of 795 pooled ROMANA patients found the weight and body-composition gains held across all strata and were largest in patients with systemic inflammation, body mass index below 20 kg/m2 or weight loss of 10% or more (Laird et al., Journal of Cachexia, Sarcopenia and Muscle, 2025).

European refusal. The European Medicines Agency accepted Helsinn’s marketing application for Adlumiz 100 mg tablets for review in December 2015. The CHMP adopted a negative opinion on May 18, 2017, citing a marginal effect on lean body mass, no proven effect on handgrip strength or quality of life, and clinical-site inspection findings that safety data had not been recorded adequately. The refusal was confirmed on re-examination on September 14, 2017, and took effect on November 16, 2017.

Japanese program and approval. Ono ran its own trials under the code ONO-7643: a randomized phase 2 in 181 Japanese NSCLC patients (Takayama et al., Supportive Care in Cancer, 2016, 24(8):3495-3505), the pivotal ONO-7643-04 placebo-controlled trial in 174 NSCLC patients, which met its lean body mass endpoint (1.38 kg versus -0.17 kg over 12 weeks) and improved anorexia symptoms and nutritional markers but not handgrip strength or six-minute walk distance (Katakami et al., Cancer, 2018, 124(3):606-616), and ONO-7643-05, a multicenter open-label single-arm phase 3 study in 50 patients with advanced gastric, pancreatic or colorectal cancer (Hamauchi et al., Cancer, 2019, 125(23):4294-4302). On January 22, 2021, Japan’s Ministry of Health, Labour and Welfare approved Adlumiz Tablets 50 mg for cancer cachexia in NSCLC, gastric, pancreatic and colorectal cancer, conditional on a risk management plan and an all-case post-marketing survey. An interim analysis of that survey with a data cutoff of January 21, 2023, covering 6,016 patients in the safety set, reported treatment-related hyperglycemia in 3.9% and nausea in 2.6%, hepatic impairment in 1.2% and conduction disorders in 1.1%, and a mean weight gain of 1.19 kg at week 12 (Takayama et al., Cancer Medicine, 2024).

SCALA and the United States. After the European refusal, Helsinn launched two further identical phase 3 trials, SCALA-1 (NCT03743051) and SCALA-2 (NCT03743064), each enrolling 318 patients with advanced NSCLC at sites that included the United States, with body weight and the 5-item anorexia symptom subscale as co-primary endpoints over 12 weeks. SCALA-2 completed on December 27, 2022, SCALA-1 on February 11, 2023, and both posted results on June 26, 2024. Per the ESMO 2023 late-breaking abstract (LBA95), anamorelin increased body weight by 1.37 kg in SCALA-1 and 1.30 kg in SCALA-2 versus placebo, but the anorexia symptom endpoint did not separate from placebo in either. No US marketing application has been announced through November 2026. The only US studies still listed as active are two NCI-supported, investigator-initiated studies at MD Anderson Cancer Center, both active but no longer recruiting: a phase 2 trial of anamorelin for cancer-related fatigue (NCT03035409, 129 patients, estimated completion February 28, 2028) and a 25-patient qualitative study of anorexia experiences on anamorelin versus placebo (NCT03637816, estimated completion December 31, 2026). Neither is designed to support a registration.

Common dosage forms

The approved product is Adlumiz, a 50 mg film-coated oral tablet dispensed by prescription in Japan. The European application and the ROMANA and SCALA trials used a 100 mg film-coated tablet. Anamorelin hydrochloride is also listed by research-chemical suppliers, where it typically appears as a powder or in capsules rather than as a finished tablet.

Key considerations

• Regulatory status. The Research Market status reflects a regional approval in Japan, a confirmed European refusal, no US marketing application in nearly two decades of development and no registered US-approval-directed trial still running, while the molecule remains available through research suppliers.
• Not a peptide. Anamorelin is a small-molecule ghrelin mimetic, not a peptide and not ghrelin itself; the codes ONO-7643, RC-1291 and ST-1291 all refer to the same compound, and “Adlumiz” is the Japanese brand, not a distinct formulation.
• What the evidence shows. The drug reliably adds roughly 1-2 kg of lean mass or body weight and, in most trials, improves appetite scores, but across ROMANA, ONO-7643-04 and SCALA it has never shown a benefit on handgrip strength, motor function or survival, SCALA did not replicate the appetite-score benefit, and the two regulators weighed that record differently.
• Safety signals. Hyperglycemia is the most common grade 3-4 adverse event in ROMANA and the leading treatment-related reaction in Japanese surveillance, followed by nausea and less frequent hepatic impairment and cardiac conduction disorders; the Japanese label contraindicates strong CYP3A4 inhibitors because anamorelin is cleared by CYP3A4.
• Population studied. Almost all efficacy data come from patients with advanced cancer and documented cachexia; the only data in healthy adults are short phase 1 studies of a week or less, and there are no controlled studies in athletes or non-cachectic populations, so extrapolating lean-mass gains outside cachexia is unsupported.