Macimorelin
AEZS-130, EP-1572, JMV 1843, Macimorelin acetate, Oral ghrelin receptor agonist
Macimorelin is an orally active ghrelin receptor agonist licensed as a diagnostic test for adult growth hormone deficiency. It is the only oral growth hormone stimulation test approved anywhere, and its clinical purpose is to replace the insulin tolerance test, which is effective but requires deliberately inducing hypoglycaemia under close supervision.
Mechanism
Macimorelin is a potent, orally bioavailable agonist at the growth hormone secretagogue receptor 1a (GHS-R1a), the receptor for endogenous ghrelin, expressed on pituitary somatotrophs and on hypothalamic arcuate nucleus neurones. GHS-R1a is a class A G-protein-coupled receptor with unusually high constitutive activity, coupling through Gq/11 to phospholipase C, generating inositol trisphosphate and diacylglycerol, mobilising intracellular calcium and activating protein kinase C. In the pituitary this drives immediate exocytosis of stored growth hormone. Macimorelin also acts centrally, amplifying growth hormone-releasing hormone neurone activity and suppressing hypothalamic somatostatin tone, so the net secretory stimulus is larger than direct pituitary action alone would produce. Cryo-electron microscopy work published in 2025 has since resolved how macimorelin sits in a bifurcated GHS-R1a binding pocket divided by a conserved salt bridge, and why it binds less tightly than anamorelin does.
The diagnostic logic follows directly. In a healthy pituitary, GHS-R1a stimulation produces a brisk growth hormone surge; in genuine somatotroph deficiency the reserve is absent and the response is blunted or flat. The approved labelling uses a peak growth hormone cut-off of 2.8 nanograms per millilitre, while the pivotal trial's own post hoc analysis favoured 5.1 nanograms per millilitre as giving the better balance of sensitivity and specificity. Chemically, macimorelin is not a true peptide but a peptidomimetic: replacing natural L-amino acids with aminoisobutyric acid and D-tryptophan residues, and capping the molecule with a formamide, removes the cleavage sites that would otherwise destroy it in the gut. That is the entire engineering achievement here, and it is why an oral growth hormone stimulation test exists at all.
What the research shows
The pivotal question for macimorelin was never whether it releases growth hormone, which was established years earlier, but whether an oral test could safely replace the insulin tolerance test. The crossover trial answered that with reasonable clarity, and the exact figures matter because they are frequently misquoted. In the primary analysis, negative agreement with the insulin tolerance test was 95%, meaning macimorelin rarely produces a false positive, which is the more important property when the consequence of a positive result is lifelong growth hormone replacement. Positive agreement was 74%, meaning about a quarter of patients classified as deficient by the insulin tolerance test were not so classified by macimorelin. Applying the same 5.1 ng/ml cut-off to both tests in a post hoc analysis improved positive agreement to 82% while keeping negative agreement at 94%, which is why the paper's own conclusion favours that threshold. The asymmetry is the honest headline: this is a test built to avoid overdiagnosis, and it will miss some genuine cases.
The practical case for macimorelin rests less on superior accuracy than on safety and acceptability. The insulin tolerance test requires deliberately inducing symptomatic hypoglycaemia, needs continuous medical supervision, and is contraindicated in patients with ischaemic heart disease, seizure disorders and in the elderly, which is a substantial fraction of the population being evaluated. Macimorelin is a single oral dose with blood sampling over 90 minutes, and 99% of macimorelin tests were evaluable after the first attempt against 82% of insulin tolerance tests. The trial found it reproducible on repeat testing (97%), which matters because growth hormone stimulation tests are notoriously variable. Limitations remain: obesity blunts growth hormone responses to all stimulation tests including this one, cut-off values may need adjustment by body mass index, and the test is not established in children. Macimorelin is a diagnostic agent, and there is no evidence base supporting its use as a growth hormone therapy or as a physique or performance aid.
Evidence assessment
High-quality evidence
Macimorelin holds approved labelling from the FDA (December 2017) and an EU marketing authorisation granted on 11 January 2019, based on a pivotal randomised two-way crossover trial against the insulin tolerance test. Diagnostic performance, reproducibility and safety were characterised prospectively, and regulators on both sides of the Atlantic independently accepted the data. This meets the criterion of regulator-approved labelling supported by an adequate human trial. The tier should be read as covering diagnostic use only; there is no therapeutic evidence for this compound and none is claimed.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Macimorelin as a Diagnostic Test for Adult GH Deficiency Preclinical only
Corrected during audit, because the draft conflated two different analyses. In the primary analysis, using cut-offs of 2.8 ng/ml for macimorelin and 5.1 ng/ml for the insulin tolerance test, negative agreement was 95.38% (95% CI 87-99), positive agreement 74.32% (63-84), sensitivity 87% and specificity 96%. In a post hoc analysis applying 5.1 ng/ml to both tests, negative agreement was 94% and positive agreement rose to 82%, with 92% sensitivity and 96% specificity. The draft paired the 94% from the post hoc analysis with the 74% from the primary analysis, which is not a combination the paper reports. After the first test, 99% of macimorelin tests were evaluable against 82% of insulin tolerance tests; reproducibility on retesting was 97% (n=33); no serious adverse events were reported.
Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor Preclinical only
Both drugs occupy a bifurcated binding pocket divided by a conserved salt bridge between E124 and R283, and the mutagenesis identified the residues responsible for anamorelin's higher binding affinity relative to macimorelin. Structural comparison across G protein subtypes clarified the basis of G protein selectivity. Mechanistic and preclinical work, included to support the pharmacology section; it carries no clinical implications on its own.
Safety
Macimorelin is well tolerated in the diagnostic setting, which is the principal argument for it over the insulin tolerance test; no serious adverse events were reported in the pivotal trial. Reported effects are mild and transient: dysgeusia, an unusual metallic or bitter taste, is the most characteristic; headache, fatigue, nausea, dizziness and hunger also occur. Unlike the insulin tolerance test, it does not induce hypoglycaemia, which removes the seizure and cardiac risk that restricts the older test.
The most clinically important consideration is QT interval prolongation. Macimorelin causes a modest increase in the corrected QT interval, so concomitant use with other QT-prolonging medicines should be avoided, and drugs that inhibit or induce CYP3A4 can alter macimorelin exposure and affect test interpretation. Growth hormone secretagogues also produce transient rises in cortisol and prolactin. False test results occur in defined situations: recent growth hormone treatment, untreated hypothyroidism, hypercortisolism and significant obesity all distort the response, and the test should not be performed until these are addressed. Athletes should be aware that macimorelin is prohibited at all times under WADA S2.2 and that a therapeutic use exemption is required even for genuine diagnostic use. Products sold outside the licensed supply chain as macimorelin have no verified identity, purity or content.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | An EU marketing authorisation for the diagnosis of growth hormone deficiency in adults was granted on 11 January 2019, following a positive CHMP opinion in 2018; the European Medicines Agency lists the product as authorised and for diagnostic use only. Because that authorisation predated the end of the Brexit transition period, it fell within the arrangements under which existing EU authorisations were converted to Great Britain marketing authorisations from 1 January 2021, though the current MHRA listing status was not independently confirmed in this audit. Availability in UK practice has in any case been limited, and the insulin tolerance test and glucagon stimulation test remain in common use. |
| United States | Approved by the FDA in December 2017 for the diagnosis of adult growth hormone deficiency. It is a diagnostic agent only, and is not approved for treating growth hormone deficiency or for any therapeutic purpose. Prescription-only, administered under medical supervision. |
| WADA (sport) | Prohibited at all times, in and out of competition. WADA category S2.2 covers growth hormone secretagogues and names macimorelin explicitly alongside anamorelin, ipamorelin, tabimorelin, ibutamoren and lenomorelin (ghrelin). An athlete requiring the diagnostic test would need a therapeutic use exemption. |
Questions
It is comparably accurate and considerably safer. In the pivotal crossover trial, negative agreement with the insulin tolerance test was 95% and positive agreement 74% at the licensed cut-off, so it is better at avoiding false diagnoses than at catching every case; applying a common 5.1 ng/ml threshold to both tests improved positive agreement to 82%. Its practical advantage is that it does not require deliberately inducing hypoglycaemia, so it can be used in patients with heart disease, seizure disorders or advanced age, in whom the insulin tolerance test is contraindicated.
No. It is licensed solely as a diagnostic test. It provokes a single burst of growth hormone release to reveal whether the pituitary has reserve; it is not approved, and has not been trialled, as a therapy for growth hormone deficiency, ageing, body composition or athletic performance. Treatment of confirmed deficiency uses recombinant growth hormone.
Because it is not really a peptide. It is a pseudotripeptide built from unnatural building blocks: aminoisobutyric acid, D-configuration tryptophan residues and a terminal formamide cap. Gut and plasma peptidases recognise L-amino acid sequences and free termini, and macimorelin presents neither, so it survives the gastrointestinal tract intact enough to reach the pituitary.
Yes, at all times, in and out of competition. WADA category S2.2 covers growth hormone secretagogues and names macimorelin explicitly, alongside anamorelin, ipamorelin, tabimorelin and ibutamoren. An athlete who genuinely needs the diagnostic test must obtain a therapeutic use exemption in advance.