Macimorelin

Macimorelin (JMV-1843, EP-1572, AEZS-130), a synthetic peptidomimetic agonist of the growth hormone secretagogue receptor type 1a (GHS-R1a, the ghrelin receptor), is the first and only orally administered diagnostic agent approved by the United States Food and Drug Administration (December 2017) and the European Medicines Agency (January 2019) for the evaluation of adult growth hormone deficiency (AGHD). The compound was invented and first synthesized at the University of Montpellier and the Centre National de la Recherche Scientifique (CNRS) in France by Fehrentz, Martinez, Guerlavais, and colleagues as part of a structure-activity program seeking orally bioavailable growth hormone secretagogues derived from the hexarelin scaffold, and was subsequently licensed to Aeterna Zentaris for clinical development and marketed under the trade names Macrilen (United States, Novo Nordisk) and Ghryvelin (European Union, Consilient Health and subsequently Pharmanovia) [1, 2]. Structurally, macimorelin is a modified tripeptide containing two indole (tryptophan-derived) moieties linked through a central peptidomimetic backbone with a terminal formamide group and an N-terminal alpha-aminoisobutyric acid cap, conferring oral bioavailability and resistance to proteolytic degradation that distinguish it from the earlier peptide-based growth hormone secretagogues such as GHRP-6 and hexarelin.

The compound binds the GHS-R1a receptor on pituitary somatotroph cells with an IC50 of 22.9 nanomolar in human pituitary tissue and activates the Gq/11-phospholipase C signaling cascade, stimulating endogenous growth hormone release into the systemic circulation in a manner pharmacologically analogous to the endogenous ligand ghrelin [2, 3]. Following oral administration at the diagnostic dose of 0.5 mg/kg body weight, macimorelin produces a robust and reproducible rise in serum growth hormone concentration that peaks between 30 and 90 minutes post-dose, permitting diagnostic discrimination between growth hormone-sufficient and growth hormone-deficient adults through serial blood sampling over a 90-minute test window. The Phase 3 confirmatory trial (Garcia et al., 2018) in 157 adults demonstrated 87 percent sensitivity and 96 percent specificity at a growth hormone cutoff of 2.8 ng/mL, with 97 percent reproducibility on repeat testing, establishing macimorelin as a clinically validated alternative to the insulin tolerance test with the practical advantages of oral administration, absence of hypoglycemia risk, and a shorter, simpler test protocol [4, 5].

Pharmacokinetics are characterized by rapid oral absorption (median time to peak plasma concentration approximately 0.75 hours), hepatic metabolism predominantly through cytochrome P450 3A4 (CYP3A4) to a partially active O-demethylated metabolite, a terminal elimination half-life of approximately 4.1 hours, approximately 70 percent plasma protein binding, and predominantly fecal excretion [6, 7]. Food substantially reduces both the rate and extent of absorption (Cmax reduction of approximately 55 percent, AUC reduction of approximately 44 to 49 percent with a high-fat meal), mandating overnight fasting before the diagnostic test. The principal drug interaction concern is with strong CYP3A4 inducers (which may reduce macimorelin exposure and produce false-positive diagnostic results) and strong CYP3A4 inhibitors (which may elevate exposure). The compound produces a mean increase in the corrected QT interval of approximately 11 milliseconds at the diagnostic dose, requiring avoidance of concomitant QT-prolonging medications during the test [8].

Adverse events in clinical trials were mild and transient, with dysgeusia (bitter or metallic taste), dizziness, headache, nausea, fatigue, hunger, and diarrhea reported at low frequencies. No serious adverse events attributable to macimorelin were reported in the pivotal trials across more than 1000 administered subjects [5, 8]. The compound is administered as a single diagnostic dose rather than as a chronic therapeutic regimen, and the safety profile reflects this acute exposure context. Beyond the diagnostic indication, macimorelin has been investigated in cancer cachexia (pilot trial demonstrating safety and numerical weight improvement) and in pharmacoresistant epilepsy (preclinical seizure suppression through GHS-R1a-mediated neuroprotection), though the compound is not approved for any therapeutic application [9, 10].

This monograph reviews the chemistry, synthesis, and structural pharmacology of macimorelin; the GHS-R1a receptor mechanism in molecular detail; the comprehensive human pharmacokinetic record; the preclinical and clinical evidence base across diagnostic and investigational applications; reconstitution and handling considerations; stack interactions and drug-drug interaction considerations; the adverse-event and safety signal; and a comparative assessment of five growth hormone secretagogue or diagnostic candidates (insulin tolerance test, glucagon stimulation test, anamorelin, ibutamoren, and GHRH-arginine test) against macimorelin on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).