Capromorelin

Capromorelin (CP-424,391) came out of a Pfizer programme on pyrazolinone-piperidine dipeptide growth hormone secretagogues [1], and was characterised preclinically as an orally active agonist [4].

The human trial. Three hundred and ninety-five men and women aged 65-84 with mild functional limitation were randomised to one of four capromorelin schedules (10 mg three times weekly, 3 mg twice daily, 10 mg nightly, 10 mg twice daily) or placebo, intended for two years. It was stopped early under pre-specified treatment-effect criteria, but 315 people completed 6 months and 284 completed 12. IGF-1 rose in a sustained, dose-related way in every active group, and peak nocturnal growth hormone rose, most with the least frequent dosing. At 6 months, body weight was up 1.4 kg on capromorelin against a 0.2 kg fall on placebo, and lean body mass up 1.4 kg against 0.3 kg. Tandem walk improved by 0.9 seconds in the pooled treatment groups, and by 12 months stair climb had improved too [2].

That last part is what makes capromorelin unusual. The recurring failure of this whole class is that lean mass goes up and function does not: MK-677 added a kilogram of fat-free mass over a year and changed nothing measurable about strength, walking or stair climbing [5], and two hip-fracture trials missed their functional endpoints [6][7]. Capromorelin's trial reported two functional measures moving. Its own authors put it carefully — capromorelin "may improve body composition and physical function" [2] — and no confirmatory human trial was ever run.

Where it ended up. Human development stopped. Capromorelin was instead developed as a veterinary appetite stimulant, and is licensed for dogs [3]; a randomised study in healthy beagles showed four days of oral dosing raised food intake and body weight [8], and daily dosing has been assessed for safety in cats [9]; its veterinary discovery, efficacy and safety record has been reviewed [10]. It is also used off-label in laboratory primates [11].

Capromorelin is an agonist at GHS-R1a, the ghrelin receptor [1]. Like the other secretagogues it raises growth hormone in pulses, and from there IGF-1 [2]. The receptor's other main effect — appetite — is what the veterinary product is sold for [3].

One detail from the human trial is worth noting: peak nocturnal growth hormone rose most in the group dosed least often, three times a week [2]. That is consistent with the partial desensitisation seen with frequent dosing elsewhere in this class [12], and it suggests less frequent dosing may preserve the growth hormone response better.

Ghrelin-receptor agonists also lower blood pressure, and work in rodents suggests that this happens through a receptor other than GHS-R1a [13][14].

Capromorelin is a small molecule, not a peptide, and is orally active [1]. The only licensed product is a veterinary oral solution for dogs [3]. It is detectable in urine, including after dermal exposure — relevant to anyone handling the veterinary solution [15] — and its metabolites have been mapped for doping control [16].

In 395 older adults over up to 12 months, the reported adverse events were fatigue, insomnia, and small increases in fasting glucose, glycosylated haemoglobin and indices of insulin resistance [2]. The glucose findings are the same class effect seen with MK-677, where 12 months raised fasting glucose by about 5 mg/dL and HbA1c by 0.2% [5].

The trial was stopped early under pre-specified treatment-effect criteria rather than for safety [2]. There is no human data beyond 12 months. In cats, daily dosing has been evaluated for safety over longer periods [9], but that does not transfer.

No human interaction studies. No interactions with other compounds on this site have been documented.