Macimorelin

What is Macimorelin?

Macimorelin is a small peptidomimetic — a tripeptide-based ghrelin (GHSR-1a) receptor agonist re-engineered for oral bioavailability and metabolic stability. It is sold under the brand name Macrilen and is the first and so far only oral growth-hormone secretagogue approved by the FDA (December 2017) and EMA (2019) as a diagnostic test for adult growth hormone deficiency (AGHD). The test is a single-use procedure: a patient fasts overnight, dissolves a 0.5 mg/kg dose of macimorelin granules in roughly 120 mL of water, drinks it within 30 seconds, and serum growth hormone is sampled at 30, 45, 60, and 90 minutes. A peak GH below the FDA-cleared cutoff of 2.8 ng/mL diagnoses AGHD with high concordance against the historic gold-standard insulin tolerance test. Crucially, macimorelin is not a therapy — it is administered exactly once as a stimulation challenge, then the patient is referred for treatment decisions about somatropin replacement on the basis of the GH response.

What Macimorelin Is Investigated For

Macimorelin's role is narrow but unique: it is the first FDA-approved oral GH-secretagogue diagnostic, designed to replace the dangerous insulin tolerance test (ITT) and the now-defunct GHRH-arginine test in evaluating adult growth hormone deficiency. The pivotal head-to-head trial (Garcia 2018) showed it matches ITT performance at a 2.8 ng/mL cutoff with markedly better tolerability and zero hypoglycaemic risk. Outside this single diagnostic indication, macimorelin has no approved therapeutic use — it is a one-dose challenge agent, not a peptide therapy. Pediatric studies are ongoing.

History & Discovery

Macimorelin's lineage traces back to the European peptide-medicinal-chemistry programmes of the late 1990s, when groups led by Romano Deghenghi and Jean Martinez set out to design orally bioavailable ghrelin-receptor agonists from a tripeptide scaffold. The compound first appeared in the literature as EP-1572 (Broglio 2002, Journal of Endocrinological Investigation), a peptidomimetic with potent and selective GH-releasing activity in human subjects. Aeterna Zentaris licensed the asset and re-developed it as AEZS-130, repositioning the molecule away from a chronic-therapy ambition (which had stalled commercially in the wake of MK-677 and other secretagogues) toward a single-use diagnostic indication where competition was thin and unmet need was clear: the insulin tolerance test was dangerous, the GHRH-arginine test depended on GHRH that was disappearing from the US market, and clinicians needed a safer modality. Phase 2 validation (Garcia 2013, JCEM) confirmed the test's pharmacological profile, and the pivotal Phase 3 head-to-head against the ITT (Garcia 2018, JCEM) provided the FDA evidence base. Macimorelin was approved by the FDA in December 2017 under the brand name Macrilen and subsequently by the EMA in 2019. Strongbridge Biopharma (now part of Xeris Biopharma) acquired the US rights, and Novo Nordisk has held distribution rights in selected markets — making macimorelin one of the few peptidomimetic diagnostics to reach commercial scale.

How It Works

Macimorelin binds the ghrelin receptor on the pituitary the same way the natural hunger hormone ghrelin does, telling the gland to release a burst of growth hormone. A healthy pituitary responds strongly; a damaged one cannot.

Macimorelin is a peptidomimetic agonist of the growth hormone secretagogue receptor type 1a (GHSR-1a), the same G-protein-coupled receptor activated by endogenous ghrelin. It is structurally derived from a tripeptide scaffold (a modified D-Trp/Ala/D-2-methyl-Trp backbone) optimised in the Aeterna Zentaris/Europeptides programme (originally as EP-1572) for high oral bioavailability and resistance to peptidase cleavage. On binding GHSR-1a expressed on pituitary somatotrophs, macimorelin activates Gαq/11, mobilising intracellular calcium via phospholipase-C/IP3 signalling and stimulating pulsatile GH release. There is also a hypothalamic component: GHSR-1a is expressed on GHRH neurons in the arcuate nucleus, where ghrelin-receptor activation enhances GHRH tone and suppresses somatostatin output, amplifying the somatotroph signal. The net effect is a brisk, dose-dependent rise in serum GH peaking 30–60 minutes after oral dosing — a response that requires both intact somatotroph reserve and a functional hypothalamic-pituitary axis. AGHD patients, with depleted somatotroph mass or disrupted hypothalamic input, fail to generate a normal peak.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Macimorelin:

• 01Performance in obesity: BMI is a well-known modifier of GH response; whether the 2.8 ng/mL cutoff needs adjustment in patients with BMI >35 remains debated.
• 02Paediatric GHD diagnosis: dose-escalation safety data exist (Csákváry 2021), but a definitive paediatric cutoff and regulatory approval are still pending in the US and EU.
• 03Use after traumatic brain injury, where somatotroph recovery may evolve for years and a single-time-point diagnostic may misclassify patients.
• 04Re-testing childhood-onset GHD at the paediatric-to-adult transition — comparative data against insulin and arginine tests are limited.
• 05Cost-effectiveness vs. the glucagon stimulation test, which is cheaper and widely available but takes 3–4 hours and has its own confounders.
• 06Whether macimorelin response correlates with downstream therapy benefit (i.e. predicts who responds best to somatropin replacement) — currently the test predicts diagnosis, not treatment response.

Forms & Administration

Macimorelin is supplied as Macrilen — single-use sachets of granules to be reconstituted in approximately 120 mL of cold water immediately before dosing. The patient fasts at least 8 hours, drinks the solution within 30 seconds, and remains seated. Blood for serum GH is drawn at 30, 45, 60, and 90 minutes after dosing. Each test consumes one sachet at a weight-based dose of 0.5 mg/kg. There is no chronic, multi-dose, injectable, or compounded formulation: macimorelin exists only as a single-use oral diagnostic product distributed through specialty pharmacies on prescription. Patients should not take it outside a medically supervised endocrinology testing setting; the value of the test depends entirely on standardised conditions (fasting state, no interfering medications, accurate timing of the GH samples).

Common Questions

Who Macimorelin Is NOT For

Drug & Supplement Interactions

The most clinically important interaction is with strong CYP3A4 inducers — rifampin, carbamazepine, phenytoin, St. John's wort, enzalutamide, and similar agents lower macimorelin plasma exposure and have been documented to produce false-positive AGHD test results; these drugs should be discontinued for an appropriate washout period before testing where feasible. CYP3A4 inhibitors (clarithromycin, ketoconazole, ritonavir) raise exposure but have less clear effect on test interpretation. QT-prolonging drugs — including macrolides like clarithromycin, certain antiarrhythmics (sotalol, amiodarone), some antipsychotics, and methadone — can be additive with macimorelin's small QT effect and should be paused where it is safe to do so. Recent glucocorticoid exposure (particularly oral or injected high-dose steroids) blunts the GH response independent of any pharmacokinetic interaction. Levothyroxine should be at steady-state and TSH within range. Of note, opioids and somatostatin analogues (octreotide, lanreotide) can also dampen the response and ideally are held before the test.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions