Anamorelin

Anamorelin is a potent, selective, orally-active ghrelin receptor agonist developed for the treatment of cancer anorexia-cachexia syndrome (CACS). It mimics the N-terminal active core of endogenous ghrelin with high receptor affinity (0.70 nM) and has a longer half-life (approximately 7 hours) compared to natural ghrelin. Anamorelin was approved in Japan in December 2020 for treating cachexia in patients with non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer under the brand name Adlumiz, but has not been approved by the FDA or European regulatory authorities due to insufficient evidence of functional improvements despite increases in lean body mass.

Lean Body Mass and Weight Gain

Anamorelin significantly increases lean body mass and total body weight in patients with cancer-related cachexia. Multiple phase 3 clinical trials demonstrated mean increases in lean body mass ranging from 1.06 to 1.89 kg compared to placebo over 12 weeks ^[1][2][3][4]. The ROMANA 1 and 2 trials showed anamorelin significantly increased lean body mass in patients with advanced non-small cell lung cancer and cachexia ^[2]. A Japanese phase 3 study (ONO-7643-04) reported a least squares mean change in lean body mass of 1.38 ± 0.18 kg versus -0.17 ± 0.17 kg for placebo (P < 0.0001) ^[4]. Meta-analyses confirmed significant body weight increases of approximately 1.73 kg compared to placebo ^[5][6].

Appetite Stimulation and Nutritional Status

The drug significantly improves anorexia symptoms and nutritional markers in cachexia patients ^[4][7]. In gastrointestinal cancer patients, anamorelin improved anorexia and nutritional status, with 63.3% of patients maintaining or gaining lean body mass ^[8]. The compound works by binding to and stimulating growth hormone secretagogue receptors, which triggers production of neuropeptide Y involved in appetite regulation ^[9]. Clinical studies demonstrated significant increases in the total FAACT score (Functional Assessment of Anorexia/Cachexia Therapy), indicating improved quality of life related to appetite and cachexia symptoms ^[6][10].

Growth Hormone and IGF-1 Axis Activation

Anamorelin significantly increases plasma levels of growth hormone, insulin-like growth factor-1 (IGF-1), and IGF-binding protein-3 in a dose-dependent manner ^[11][12]. In healthy volunteers, single doses of 25-75 mg produced significant GH elevations within 1 hour post-dose, with 50-75 mg doses causing sustained increases in IGF-1 levels ^[11]. A study in adults with osteosarcopenia showed serum IGF-1 increased by approximately 50% compared to placebo, alongside improvements in muscle function and bone formation markers ^[13]. These hormonal changes contribute to the anabolic effects on muscle tissue through activation of the mTOR pathway and increased protein synthesis ^[9].

Muscle Function and Strength (Emerging Evidence)

While large cachexia trials did not demonstrate improvements in handgrip strength ^[2][3], newer research suggests potential benefits for specific muscle functions. A 2023 study in osteosarcopenia patients found anamorelin significantly increased knee flexion torque at 240°/s by approximately 20% (P = 0.013), suggesting improvements in dynamic muscle strength ^[13]. The drug's ability to stimulate IGF-1 production promotes satellite cell activity and inhibits myostatin, supporting muscle protein synthesis ^[9][13].

Safety and Tolerability Profile

Anamorelin demonstrates a favorable safety profile with adverse event rates similar to placebo in multiple clinical trials ^[2][5]. The ROMANA 3 safety extension study showed anamorelin and placebo groups had similar incidences of treatment-emergent adverse events (52.2% versus 55.7%), grade ≥3 adverse events (22.4% versus 21.6%), and serious adverse events (12.8% versus 12.6%) over extended treatment periods . The drug exhibits high selectivity for the ghrelin receptor with minimal binding to other receptors such as calcium channels, sodium channels, and serotonin transporters even at elevated concentrations ^[1][9]. Common drug-related adverse events are infrequent and mild, including hyperglycemia, nausea, and transient increases in liver enzymes that are reversible upon discontinuation ^[3][10].

Overall Safety Profile

Clinical data from multiple phase 2 and 3 trials demonstrate that anamorelin is generally well tolerated with a safety profile comparable to placebo ^[2][3][5]. Systematic reviews and meta-analyses confirmed no significant differences in overall adverse events or severe adverse events between anamorelin and placebo groups ^[5][6]. The ROMANA 3 extension study, which followed patients for up to 24 weeks, found no new safety signals and maintained the favorable tolerability profile observed in earlier trials . Although the incidence of adverse drug reactions increased with age and performance status, serious adverse reactions did not increase in elderly patients (≥75 years) or those with performance status 2, with most events being grade 1 or 2 in severity .

Common Adverse Effects

The most frequent drug-related adverse events include hyperglycemia, nausea, and diabetes mellitus, although their incidence remains low at approximately 2-5% ^[3][10]. The most common grade 3-4 adverse events in anamorelin groups included fatigue, asthenia, atrial fibrillation, and dyspnea (approximately 5% each), though these were not necessarily treatment-related ^[3]. Phase 2 integrated analyses reported hyperglycemia occurring in 1.2% of the 100-mg anamorelin group versus 0% in placebo ^[3]. Hepatic enzyme elevations (AST and ALT) can occur at dosages of 50 mg or greater but are reversible with drug discontinuation ^[10]. Cardiovascular effects on heart rate and blood pressure were modest and without clinical consequence in controlled trials ^[10].

Special Populations and Contraindications

Diabetic Patients: Retrospective analysis revealed significantly higher rates of hyperglycemic adverse events in diabetic patients compared to non-diabetic patients (72.2% vs. 6.3%, P < 0.01) ^[10]. Diabetic patients also showed fewer treatment responders (45.2% vs. 81.9%, P < 0.01) and higher discontinuation rates due to adverse events (25.8% vs. 4.2%, P < 0.01), suggesting caution is warranted in this population ^[10]. Anamorelin does not significantly affect fasting glucose levels in non-diabetic populations ^[11].

Drug Interactions: Anamorelin is primarily metabolized via hepatic CYP3A4, and concomitant use of strong CYP3A4 inhibitors such as ketoconazole can increase anamorelin Cmax and AUC approximately 3-fold, potentially requiring dose adjustments ^[9]. Food intake significantly reduces bioavailability, with Cmax and AUC being 0.31-fold and 0.49-fold lower, respectively, when administered 2 hours after a meal compared to fasting ^[9].

Regulatory Considerations and Long-term Safety

The European Medicines Agency (EMA) refused marketing authorization in 2017, citing inadequate safety data recording and insufficient evaluation of potential risks, in addition to concerns about lack of proven efficacy on handgrip strength and quality of life . Both the EMA and FDA have not approved anamorelin, partly due to requirements that muscle strength, physical function, and prognosis be demonstrably improved . Long-term safety beyond 24 weeks remains unknown as extension trials have not exceeded this duration ^[10]. While approved in Japan for cachexia treatment in multiple cancer types, post-marketing surveillance continues to monitor real-world safety outcomes .

Pregnancy and Lactation

No adequate studies exist regarding anamorelin use during pregnancy or lactation. Given the drug's mechanism involving growth hormone and IGF-1 stimulation, theoretical concerns exist about potential effects on fetal development, though specific data are lacking ^[9].

Monitoring Recommendations

Patients receiving anamorelin should be monitored for signs of hyperglycemia, particularly those with diabetes or prediabetes ^[10]. Periodic liver function tests (AST/ALT) may be warranted given the potential for reversible hepatic enzyme elevations at higher doses ^[10]. Cardiovascular monitoring appears unnecessary in most patients given the modest effects observed in clinical trials, though patients with pre-existing cardiac conditions warrant standard clinical vigilance ^[10].