Anamorelin (Adlumiz): oral ghrelin agonist and cancer cachexia research overview

Anamorelin (brand name: Adlumiz) is an orally active small-molecule ghrelin receptor agonist developed for the treatment of cancer cachexia-anorexia syndrome — the loss of muscle mass, appetite, and body weight that accompanies advanced cancer and substantially impairs quality of life. Anamorelin is notable on several fronts: it is orally bioavailable (a rare property for a ghrelin-mimetic), it gained regulatory approval in Japan in December 2020, and it was rejected by the FDA in 2017 following submission of the ROMANA-1 and ROMANA-2 phase 3 trials in non-small-cell lung cancer. This guide reviews the compound's pharmacology, the ROMANA trial results, the regulatory history on both sides of the Pacific, and the important distinction between anamorelin and the injectable growth hormone-releasing peptides (GHRPs) also covered on Pepticker.

What is anamorelin?

Anamorelin is a non-peptide, orally bioavailable small molecule agonist of the growth hormone secretagogue receptor type 1a (GHSR-1a), which is also the receptor for ghrelin, an endogenous 28-amino acid peptide hormone produced by the stomach. Anamorelin's molecular formula is C31H42N6O3; its molecular weight is approximately 550.7 Da. Unlike the injectable GHRP peptides (GHRP-2, GHRP-6, hexarelin, ipamorelin) that also act at GHSR-1a, anamorelin is a synthetic organic small molecule that is orally absorbed via the gastrointestinal tract. This oral bioavailability distinguishes it fundamentally from the peptide-based GHRPs, which cannot survive GI proteolysis and must be injected.

Cancer cachexia affects approximately 50–80% of cancer patients and is responsible for an estimated 20% of cancer deaths. Its pathophysiology involves elevated proinflammatory cytokines (TNF-α, IL-6, IL-1β), increased muscle protein catabolism via the ubiquitin-proteasome pathway, and suppression of appetite-stimulating signals. Ghrelin and ghrelin-receptor agonists address this syndrome through multiple mechanisms: stimulating appetite and food intake, promoting growth hormone secretion (with anabolic effects on lean body mass), and potentially suppressing inflammatory cytokine production. Anamorelin was designed to exploit these mechanisms in an orally deliverable form.

Mechanism of action

Anamorelin binds GHSR-1a with high affinity and selectivity, acting as a full agonist at this receptor. GHSR-1a is expressed in the hypothalamus (arcuate nucleus), pituitary, stomach, heart, and peripheral tissues. In the hypothalamus, receptor activation stimulates neuropeptide Y (NPY) and agouti-related peptide (AgRP) release, producing potent orexigenic (appetite-stimulating) effects and suppressing pro-inflammatory signaling. In the pituitary, GHSR-1a activation drives GH pulse amplitude, which in turn drives IGF-1 production in the liver and muscle, promoting lean body mass accretion. In addition to these central and endocrine effects, ghrelin receptor signaling has been reported to suppress TNF-α and IL-6 in some models, potentially attenuating the inflammatory component of cachexia. The net result in cachexic cancer patients is increased appetite, increased caloric intake, and modest gains in lean body mass.

What the research shows: ROMANA-1 and ROMANA-2

The pivotal phase 3 trials were ROMANA-1 and ROMANA-2, both randomized, double-blind, placebo-controlled trials in patients with advanced (stage III/IV) non-small-cell lung cancer (NSCLC) and cachexia. ROMANA-1 enrolled 484 patients (July 2011 – January 2014; 323 anamorelin, 161 placebo); ROMANA-2 enrolled 495 patients (July 2011 – October 2013; 330 anamorelin, 165 placebo). Patients received anamorelin 100 mg orally once daily or placebo for 12 weeks. Results were published by Temel et al. in The Lancet Oncology in 2016 (PMID 26906526).

The two co-primary endpoints were change in lean body mass (LBM, measured by DXA) and change in handgrip strength over 12 weeks. On LBM, anamorelin significantly outperformed placebo in both ROMANA-1 (median LBM increase 0.99 kg vs. −0.47 kg) and ROMANA-2 (0.65 kg vs. −0.98 kg). However, on handgrip strength — the functional muscle strength endpoint — anamorelin showed no significant improvement over placebo in either trial. Secondary endpoints including quality of life scores showed modest or non-significant improvements. Anamorelin was generally well tolerated; the most common adverse events were hyperglycemia and nausea.

The FDA reviewed the anamorelin NDA in 2017 and issued a Complete Response Letter (CRL) declining approval. The FDA's position was that the improvement in lean body mass was not accompanied by meaningful functional benefit (no handgrip strength improvement), and that the drug had not demonstrated a clinically meaningful effect in a symptomatic endpoint important to patients. The EMA's Committee for Medicinal Products for Human Use (CHMP) similarly rejected anamorelin for the European market in 2017, citing inadequate effect on handgrip strength, quality of life, and also raising concerns about data integrity following inspection findings at some clinical trial sites. These rejections underscored a broader regulatory challenge in cancer cachexia: the difficulty of translating body composition improvements into functional or survival endpoints acceptable to regulators.

Despite the Western regulatory rejections, anamorelin (Adlumiz) received approval in Japan on December 11, 2020 — the first regulatory approval of any drug specifically for cancer cachexia anywhere in the world — for cachexia associated with four tumor types: NSCLC, gastric cancer, pancreatic cancer, and colorectal cancer. The Japanese approval was based on the ROMANA data and supplementary Japanese bridging studies. Post-approval studies in Japan have provided additional real-world and clinical data on anamorelin's effects in gastric cancer cachexia. A 2025 Lancet eClinicalMedicine trial (DOI: S2589-5370(25)00433-X) confirmed efficacy in unresectable or recurrent gastric cancer in a multicentre randomized controlled trial.

Pharmacokinetics

Anamorelin is orally bioavailable, which is its defining pharmacokinetic distinction from peptide GHRPs. Following oral administration of the approved 100 mg dose, peak plasma concentration (Cmax) is achieved within approximately 1–2 hours (Tmax). The elimination half-life is approximately 7 hours, supporting once-daily dosing. Anamorelin is metabolized primarily by CYP3A4, and dose adjustments may be required with strong CYP3A4 inhibitors or inducers. Food intake affects absorption; the drug should be taken in a fasting state (at least 1 hour before a meal) per the Japanese prescribing information. Unlike the peptide GHRPs that are cleared within minutes by proteolysis, anamorelin's small-molecule structure confers resistance to gastrointestinal proteases and allows absorption through the intestinal epithelium.

Approved indication and dose (Japan)

Not medical advice. These are ranges reported in research literature, not personalized recommendations. Consult your physician.

Adlumiz (anamorelin hydrochloride) is approved in Japan at an oral dose of 100 mg once daily, taken on an empty stomach at least 1 hour before a meal, for cachexia associated with NSCLC, gastric cancer, pancreatic cancer, and colorectal cancer. This approval is specific to Japan; anamorelin is not FDA-approved in the United States, not EMA-approved in Europe, and not approved by the TGA in Australia. Use in the US would be off-label or investigational. The Phase 3 ROMANA trials used 100 mg once daily over 12 weeks; the Japanese label reflects this dose and schedule.

Storage and handling

Adlumiz tablets should be stored at room temperature (below 25 °C), protected from moisture and light, per the Japanese approved product labeling. As a small organic molecule rather than a peptide, anamorelin tablets have a conventional pharmaceutical shelf life (24–36 months under appropriate conditions) and do not require cold-chain handling or reconstitution. This contrasts sharply with the lyophilized injectable peptide GHRPs, which require cold storage and reconstitution with bacteriostatic water.

What anamorelin is NOT

Anamorelin is not a peptide. It is a synthetic organic small molecule that mimics ghrelin's receptor activation; it shares the receptor target of the injectable GHRPs (GHRP-2, GHRP-6, hexarelin, ipamorelin) but is structurally and pharmacokinetically a completely different class of compound. The oral route, small-molecule scaffold, CYP3A4 metabolism, and conventional tablet formulation distinguish it categorically from the peptide GHRPs on Pepticker. Anamorelin is not FDA-approved; its Japan approval does not create any basis for therapeutic use in the United States without physician oversight and does not imply FDA endorsement. Anamorelin is not a performance-enhancement compound; its clinical use is specifically for the serious medical context of cancer cachexia in patients with advanced malignancies. It is not related to the GLP-1 receptor agonist class (semaglutide, tirzepatide, etc.) and does not cause GLP-1-mediated weight loss; its mechanism, indication, and patient population are entirely different.

References

Key sources include the ROMANA-1 and ROMANA-2 trial publication (Temel et al., Lancet Oncology 2016; PMID 26906526), the Japan regulatory approval review (PMC7890143), the 2025 Lancet eClinicalMedicine gastric cancer trial, the EMA rejection commentary in Lancet Oncology (2022), and the 'What's Next After Anamorelin?' review (PMC5776683).