Macimorelin

Mechanism (as reported)

A study using high-resolution cryo-electron microscopy reported structures of the growth hormone secretagogue receptor (GHSR) bound to macimorelin, and described a bifurcated binding pocket divided by a conserved salt bridge (E1243.33–R2836.55). The same study reported that systematic mutagenesis and functional studies identified key residues underlying differences in binding affinity between macimorelin and another ligand (anamorelin) and provided structural comparison supporting mechanisms of G protein selectivity. (PMID: 40542284)

Key findings (each cites a source)

• Research on AVP deficiency diagnostic strategies reported that oral growth hormone secretagogue macimorelin failed to provide a sufficient stimulus in that context. (PMID: 38087160) [PMID 38087160]
• A multicenter, open-label, randomized two-way crossover trial reported that macimorelin could be used as a diagnostic test for adult GH deficiency by measuring stimulated GH levels after a single oral dose, and reported diagnostic agreement, sensitivity/specificity values, reproducibility, and that no serious adverse events were reported for macimorelin. (PMID: 29860473) [PMID 29860473]
• A review of evidence reported that macimorelin increases GH levels acutely via the ghrelin receptor GHSR1-a and that it has been shown to have good sensitivity and specificity for diagnosing adult GH deficiency. (PMID: 24834478) [PMID 24834478]
• A Delphi survey by the GH research society reported that there was consensus to recommend the macimorelin test for diagnosing GH deficiency in adults, while the insulin tolerance test was considered the gold standard in adults. (PMID: 40335774) [PMID 40335774]
• Structural biology research reported determination of cryo-EM structures of GHSR bound to macimorelin and described that both drugs occupied a bifurcated binding pocket divided by a conserved salt bridge (E1243.33 and R2836.55), with additional mutagenesis and functional studies identifying key residues involved in binding affinity and supporting mechanisms of G protein selectivity. (PMID: 40542284) [PMID 40542284]
• A pilot clinical trial reported that cancer cachexia patients randomized to macimorelin had efficacy-criterion results that were described as numerically improved body weight and quality of life compared with placebo over 1 week, and reported that no related serious or non-serious adverse events were reported; the source also described relationships between changes in patient outcomes in macimorelin recipients. (PMID: 36860137) [PMID 36860137]
• A phase 1 single-dose randomized controlled study in healthy adults reported macimorelin safety/tolerability, pharmacokinetics, and pharmacodynamics, including that GH levels increased after dosing, that transient increases were observed in certain endocrine markers, and that all reported treatment-emergent adverse events were mild or moderate and resolved; it also reported mean QTcF prolongation and that there were no clinically meaningful changes in vital signs or laboratory parameters. (PMID: 32325373) [PMID 32325373]