Anamorelin
ONO-7643, RC-1291, ST-1291, Anamorelin hydrochloride, Oral ghrelin receptor agonist
Anamorelin is an orally active ghrelin receptor agonist developed for cancer cachexia, the wasting syndrome that accompanies advanced malignancy. Two large phase 3 trials showed it reliably increases lean body mass, and equally reliably fails to improve muscle strength. It was approved in Japan around the turn of 2020-2021 and rejected in Europe, which is a fair summary of where the evidence sits.
Mechanism
Anamorelin is a selective agonist at the growth hormone secretagogue receptor 1a (GHS-R1a), the endogenous receptor for ghrelin, acting through the same Gq/11-phospholipase C-calcium-protein kinase C pathway as macimorelin and the ghrelin peptides; cryo-electron microscopy work published in 2025 showed it occupies a bifurcated pocket in the receptor and binds more tightly than macimorelin does. Its therapeutic rationale in cachexia rests on ghrelin's dual biology. Centrally, GHS-R1a activation on arcuate nucleus neuropeptide Y and agouti-related peptide neurones stimulates appetite and food-seeking, while suppressing hypothalamic somatostatin tone and amplifying growth hormone-releasing hormone drive, thereby raising pulsatile growth hormone secretion and downstream IGF-1. Peripherally, ghrelin signalling has anti-inflammatory effects in preclinical models, reducing production of the pro-inflammatory cytokines that drive cachectic muscle and adipose catabolism, and it promotes gastric emptying, which may improve tolerance of oral intake.
The design intent was therefore to attack cancer cachexia on several fronts simultaneously: increase appetite, increase anabolic hormone drive, and dampen the inflammatory catabolic signalling that distinguishes cachexia from simple starvation. What the trials revealed is that these mechanisms deliver mass without demonstrated function. Anamorelin reliably increases lean body mass as measured by dual-energy X-ray absorptiometry, but this gain did not translate into measurable improvement in handgrip strength in either phase 3 trial or in the extension study. The proposed explanations are that a substantial part of the growth-hormone-mediated gain is fluid and non-contractile tissue rather than functional myofibrillar protein, and that against ongoing tumour-driven inflammation the newly accrued mass is not usably contractile. Those explanations remain hypotheses. What is established is the dissociation itself, which is the central scientific finding of the anamorelin programme and has shaped how regulators think about cachexia endpoints generally.
What the research shows
The ROMANA programme is unusually informative precisely because it was replicated. Two independent phase 3 trials, together enrolling 979 patients with advanced non-small-cell lung cancer and cachexia, produced the same split outcome: lean body mass rose significantly on anamorelin in both, and handgrip strength failed to improve in both. Body weight and anorexia-cachexia symptoms also improved. Neither trial demonstrated a survival benefit. Because both co-primary endpoints were prespecified, this is not a case of a trial being rescued by post hoc analysis; the functional endpoint simply did not move. The 513-patient safety extension out to 24 weeks reproduced exactly this pattern, with sustained weight and symptom gains and still no handgrip improvement in either arm.
Regulators drew opposite conclusions from the same data, which is itself worth understanding. The Japanese authority approved anamorelin for cachexia across four tumour types, accepting increases in lean body mass and appetite as clinically meaningful in a population with few alternatives, and applying eligibility restrictions in practice; the two review papers cited here give slightly different dates for that decision, 11 December 2020 and 22 January 2021, which probably reflect different regulatory steps. The European Medicines Agency's CHMP issued a negative opinion in 2017, confirmed on re-examination, on the grounds that a body composition change without functional or survival benefit does not establish clinical benefit. Neither position is unreasonable, and the disagreement reflects a genuine unsettled question in cachexia research about whether lean mass is a valid surrogate. Japanese post-marketing experience suggests anamorelin does not help patients with the most severe weight loss in pancreatic cancer, and that combining it with nutritional and exercise support may work better than the drug alone, on the hypothesis that anabolic drive without a stimulus for contractile protein synthesis is inherently insufficient. That hypothesis remains under test rather than established. Anyone encountering anamorelin marketed as a bodybuilding or appetite aid should note that its own phase 3 trials found no strength benefit.
Evidence assessment
Mixed evidence
Two adequately powered, double-blind, placebo-controlled phase 3 trials across 93 sites in 19 countries enrolling 979 patients is high-quality evidence, but the trials split their co-primary endpoints: lean body mass improved consistently in both, handgrip strength improved in neither, and no survival benefit was demonstrated. A 513-patient safety extension confirmed the same pattern over 24 weeks. Regulators reached opposite conclusions, with approval in Japan and refusal in the European Union. Substantial human trial data with conflicting and partially negative results is precisely the definition of mixed.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials Preclinical only
A split result, replicated. Lean body mass increased with anamorelin in ROMANA 1 (median +0.99 kg versus -0.47 kg, P<0.0001) and ROMANA 2 (+0.65 kg versus -0.98 kg, P<0.0001). Handgrip strength did not differ in ROMANA 1 (P=0.15) or ROMANA 2 (P=0.65). One co-primary endpoint was met and the other was not, in both replications. Grade 3-4 treatment-related adverse events did not differ between groups; the most common was hyperglycaemia, in under 1% and 1% of anamorelin patients respectively. This is the central dataset for anamorelin and the reason regulatory opinion diverged.
ROMANA 3: a phase 3 safety extension study of anamorelin in advanced non-small-cell lung cancer (NSCLC) patients with cachexia Preclinical only
Extended exposure was well tolerated: treatment-emergent adverse events 52.2% versus 55.7%, grade 3 or higher 22.4% versus 21.6%, serious events 12.8% versus 12.6%, and 36 (10.5%) versus 23 (13.8%) deaths, none drug-related. Anamorelin significantly increased body weight at all time points (P<0.0001) and improved anorexia-cachexia symptoms at several time points. No significant improvement in handgrip strength was seen in either group, so the extension confirmed rather than resolved the functional endpoint problem from the core trials.
The regulatory approval of anamorelin for treatment of cachexia in patients with non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer in Japan: facts and numbers Preclinical only
Documents Japanese approval for cachexia in non-small-cell lung, gastric, pancreatic and colorectal cancer and contrasts it directly with the failure to obtain approval in Europe. Reports lean body mass gains of 1.56 kg in the Japanese phase 2 trial in non-small-cell lung cancer and 1.89 kg in a gastrointestinal cancer study, both by dual-energy X-ray absorptiometry. A useful primary source for the divergence in regulatory judgement on the same underlying evidence.
Anamorelin in Japanese patients with cancer cachexia: an update Preclinical only
States that anamorelin was approved for production and marketing in Japan on 22 January 2021 for cancer cachexia in non-small-cell lung, gastric, pancreatic and colorectal cancer. Reports that real-world use improved lean body mass, body weight and appetite, but that it does not increase body weight in severely weight-losing patients with pancreatic cancer. Importantly for safety, it records case reports of cardiac adverse drug reactions including fatal arrhythmias, advising careful monitoring even from the first dose, and notes that combining anamorelin with nutrition and exercise may be more useful than the drug alone.
Safety
Hyperglycaemia is the most discussed adverse effect and is mechanistically predictable, since raising growth hormone induces insulin resistance. Its severity in the trials should not be overstated, and the draft did overstate it: in ROMANA 1 and 2, hyperglycaemia was the most common grade 3-4 treatment-related adverse event but affected under 1% and 1% of anamorelin-treated patients, and grade 3-4 treatment-related events overall did not differ from placebo. Glucose intolerance and diabetes were reported more often on anamorelin at all grades, and glycaemic monitoring is appropriate, particularly in patients with existing diabetes. Nausea, oedema and hypertension have also been reported. Growth hormone and IGF-1 rise on treatment, which is the intended pharmacology but carries the theoretical concerns that accompany any sustained increase in IGF-1 signalling in a population with active malignancy; the trials did not demonstrate accelerated tumour progression, but they were short and not designed to answer that question definitively.
A post-marketing signal from Japan deserves attention: case reports describe cardiac adverse drug reactions, including fatal arrhythmias, prompting advice to monitor carefully even from the first dose. These are case reports rather than a quantified incidence, but they are the main new safety information since the pivotal trials. Anamorelin is metabolised by CYP3A4, so interactions with strong inhibitors such as azole antifungals and certain antivirals, and with inducers such as rifampicin and carbamazepine, are clinically relevant in oncology patients on complex regimens. Effects on the QT interval warrant caution alongside other QT-prolonging agents. Beyond the pharmacology, the important safety point is regulatory: anamorelin is not licensed in the United Kingdom, the United States or the European Union, so any material obtained is unregulated, of unverified identity and purity, and outside pharmacovigilance. It is also prohibited at all times in sport under WADA S2.2.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Not licensed. The European Medicines Agency's CHMP adopted a negative opinion in 2017, which was confirmed on re-examination, so anamorelin has no marketing authorisation in the European Union or the United Kingdom. Regulators considered the increase in lean body mass insufficient without accompanying functional or survival benefit. |
| United States | Not approved by the FDA. Anamorelin is not available as a licensed medicine in the United States following the ROMANA programme. It is not a controlled substance, but marketing it for human use would be unlawful. |
| WADA (sport) | Prohibited at all times, in and out of competition. WADA category S2.2 covers growth hormone secretagogues and names anamorelin explicitly, alongside macimorelin, ipamorelin, tabimorelin, ibutamoren and lenomorelin (ghrelin). Use is permitted only under a granted therapeutic use exemption. |
Questions
It builds lean body mass but not demonstrated strength. This distinction is the central finding of the ROMANA programme: across two replicated phase 3 trials in 979 patients, lean body mass rose significantly while handgrip strength did not improve in either, and the 513-patient extension out to 24 weeks found the same. The proposed explanation is that a substantial portion of the gain is fluid and non-contractile tissue rather than functional muscle protein, particularly against a background of tumour-driven inflammation, but that explanation is a hypothesis; the dissociation is the established fact.
Because regulators judged the same evidence differently. Japan approved it for cachexia in four cancer types, accepting improvements in lean body mass, weight and appetite as meaningful in a population with essentially no alternatives. The European CHMP issued a negative opinion in 2017, confirmed on re-examination, holding that a change in body composition without functional or survival benefit does not establish clinical benefit. The disagreement reflects an unsettled question about whether lean mass is a valid surrogate endpoint.
They share a target but not a molecule. All three are agonists at the ghrelin receptor GHS-R1a. Ipamorelin is a synthetic pentapeptide requiring injection; ibutamoren is an orally active non-peptide; anamorelin is an orally active peptidomimetic. All three are named explicitly on the WADA Prohibited List under S2.2 as growth hormone secretagogues. Only anamorelin has been through replicated phase 3 trials with hard endpoints, and those trials did not show a strength benefit.
Yes, at all times, both in and out of competition. WADA category S2.2 covers growth hormone secretagogues and names anamorelin explicitly. There is no legitimate competitive context for its use, and it is not licensed as a medicine in the UK, US or EU in any case.