Ipamorelin

Mécanisme d'action

Ipamorelin binds to the growth hormone secretagogue receptor (GHS-R), the same receptor through which the endogenous hormone ghrelin stimulates growth hormone release from the pituitary. In the original pharmacological characterization (Raun et al., 1998), the peptide released growth hormone from primary rat pituitary cells and in rat and swine models with a potency and efficacy comparable to GHRP-6. Its distinguishing feature was selectivity: unlike GHRP-6 and GHRP-2, ipamorelin did not raise ACTH and cortisol levels in the swine model significantly beyond the GHRH level, even at doses far above those effective for GH release. None of the secretagogues tested, ipamorelin included, affected FSH, LH, prolactin or TSH levels. A dose-escalation study in healthy male volunteers (Gobburu et al., 1999) described dose-proportional pharmacokinetics after intravenous infusion, with a short terminal half-life of about 2 hours and a single, time-limited episode of GH release.

État des preuves

The evidence on ipamorelin consists of the preclinical characterization (Raun et al., 1998), a pharmacokinetic-pharmacodynamic study in healthy volunteers (Gobburu et al., 1999), and two controlled phase 2 trials in postoperative ileus after bowel resection, both sponsored by Helsinn. The first was a multicenter, double-blind, placebo-controlled proof-of-concept trial (NCT00672074, 117 patients, completed 2009, published as Beck et al., 2014). Ipamorelin was well tolerated there but missed the key efficacy endpoint: time from the first dose to tolerance of a standardized solid meal did not differ significantly from placebo, and the secondary efficacy analyses likewise showed no significant differences. The authors themselves name as a limitation that the study was small and enrolled patients with a broad range of underlying conditions. A larger randomized, placebo-controlled phase 2 dose-finding trial followed (NCT01280344, HT-IPAM-202, 320 patients, 2011 to 2014). Development stopped after its completion; the results of this larger trial were never posted on ClinicalTrials.gov nor published, so the largest controlled dataset on ipamorelin is publicly unavailable. Ipamorelin holds no marketing authorization as a medicine in any jurisdiction. Phase 3 data, long-term data and trials in other indications are entirely lacking. No conclusions on efficacy or safety can be drawn from this evidence base, least of all for unregulated research material.

Conservation et manipulation

Lyophilized peptides are generally stored cool, dry and protected from light. After reconstitution, peptide solutions are typically kept refrigerated (2-8 °C) and used within a few days, as stability in solution is limited. Repeated freeze-thaw cycles are considered unfavorable. These are generic handling notes for lyophilized peptides, not product-specific stability data; no substance-specific stability data for research-grade ipamorelin have been published.

Questions sur l'état de la recherche

What has ipamorelin been investigated for in research?

Ipamorelin was characterized in the 1990s as a selective growth hormone secretagogue: the original description examined GH release in cell, rat and swine models, and a follow-up study examined pharmacokinetics and GH response in healthy volunteers. The controlled clinical program tested the substance in two phase 2 trials as a prokinetic in postoperative ileus after bowel resection. Today it mainly serves in research as a pharmacological tool for studying ghrelin receptor-mediated, selective GH release.

What is the state of the evidence on ipamorelin?

There are the preclinical characterization, one study in healthy volunteers and two placebo-controlled phase 2 trials in postoperative ileus: a published proof-of-concept trial in 117 patients, which missed its key efficacy endpoint (time from the first dose to tolerance of a standardized solid meal), and a larger dose-finding trial in 320 patients (2011 to 2014) whose results were never published. Clinical development was discontinued afterwards, a phase 3 program was never started, and ipamorelin is not approved as a medicine in any country. No conclusions on efficacy or safety, including for the unregulated products in circulation, can be drawn from this evidence base.

Sources

1. Raun et al., Eur J Endocrinol 1998DOI: 10.1530/eje.0.1390552PMID: 9849822
2. Gobburu et al., Pharm Res 1999DOI: 10.1023/a:1018955126402PMID: 10496658
3. Beck et al., Int J Colorectal Dis 2014DOI: 10.1007/s00384-014-2030-8PMID: 25331030
4. ClinicalTrials.gov NCT00672074 (phase 2, postoperative ileus, 117 patients)
5. ClinicalTrials.gov NCT01280344 (HT-IPAM-202, phase 2 dose-finding, 320 patients, no results posted)