Tabimorelin
NN703, NN-703, NNC 26-0703, Tabimorelinum, Abandoned oral growth hormone secretagogue
Tabimorelin is an orally active growth hormone secretagogue developed by Novo Nordisk in the late 1990s and abandoned in phase 2. It reached human trials in growth-hormone-deficient adults, where only 11% of patients mounted a meaningful growth hormone response, and it turned out to be a mechanism-based inhibitor of the liver enzyme CYP3A4. It has never been approved anywhere and is prohibited in sport.
Mechanism
Tabimorelin is an agonist at the growth hormone secretagogue receptor 1a (GHS-R1a), the ghrelin receptor, expressed on pituitary somatotrophs and on hypothalamic arcuate neurones. Receptor activation couples through Gq/11 to phospholipase C, mobilising intracellular calcium and activating protein kinase C, driving exocytosis of stored growth hormone. As with other ghrelin mimetics, part of the effect is central: reduced hypothalamic somatostatin tone and amplified growth hormone-releasing hormone signalling mean the pituitary response exceeds what direct somatotroph stimulation alone would produce. Growth hormone released in this way drives hepatic IGF-1 production, which was the intended therapeutic readout in growth hormone deficiency.
The design goal was oral bioavailability, and structurally tabimorelin achieved oral activity: N-methylation of the amide backbone and D-configuration aromatic residues remove peptidase recognition, and single oral doses produced dose-dependent growth hormone and IGF-1 rises in healthy men. What defeated the programme was a combination of insufficient efficacy and an unfortunate metabolic property. In vitro work in human liver microsomes identified tabimorelin as a mechanism-based (irreversible, suicide) inhibitor of CYP3A4, meaning it forms a reactive intermediate that permanently inactivates the enzyme rather than competing reversibly. A dedicated clinical study using midazolam as a CYP3A4 probe confirmed the interaction in humans, with midazolam exposure rising 93% at steady state and remaining 45% above baseline a week after tabimorelin was stopped. Since CYP3A4 metabolises a very large share of prescription medicines, a chronically administered drug with this property carries an unmanageable interaction burden. That, alongside a modest clinical effect, ended development.
What the research shows
Tabimorelin is a useful case study in why an orally active growth hormone secretagogue is harder to turn into a medicine than it looks. The chemistry worked: single oral doses in healthy men produced dose-dependent rises in growth hormone over 24 hours and, at the highest doses, in IGF-1, without significantly disturbing ACTH, luteinising hormone, follicle-stimulating hormone, thyrotropin, prolactin or cortisol. That is a clean pharmacological result for an oral molecule targeting a receptor normally addressed by an acylated 28-residue peptide.
The clinical result did not follow. In the only substantial patient trial, 97 growth-hormone-deficient adults treated for one week, just 9 of 83 on active drug (11%) reached a peak growth hormone of 5 micrograms/l or above, none on placebo did, the apparent first-dose advantage lost significance once body mass index was accounted for, and by the end of the week the growth hormone response to tabimorelin was indistinguishable from placebo. IGF-I, the outcome that would matter therapeutically, did not move at all over the week. Set against that weak signal was a hard pharmacological obstacle: tabimorelin irreversibly inactivates CYP3A4, and a dedicated study in 17 men showed midazolam exposure almost doubling at steady state and remaining substantially elevated a week after dosing stopped. For a drug intended for years of daily use in patients likely to be taking other medicines, that interaction profile is close to disqualifying on its own. Development stopped, and no company has taken the molecule forward since. Nothing has been published to suggest the compound would perform better in healthy people seeking body composition effects; the only patient data available show a response in roughly one in nine, fading within a week.
Evidence assessment
Limited evidence
Human data exist but are sparse and low-yield: a single ascending dose phase 1 study in healthy men, a CYP3A4 interaction study in 17 men using midazolam, and one randomised placebo-controlled trial of 97 growth-hormone-deficient adults over just one week, in which only 9 of 83 treated patients (11%) reached the prespecified growth hormone response threshold and growth hormone responses after a week of therapy were no different from placebo. There are no trials with clinical endpoints, no long-term data, and development was abandoned before phase 3. This is isolated, short-duration human data of limited quality, which is exactly what the limited tier describes.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Oral administration of the growth hormone secretagogue NN703 in adult patients with growth hormone deficiency Preclinical only
The key clinical trial, and a disappointing one. Nine of the 83 treated patients (11%) achieved a peak growth hormone of 5 micrograms/l or above after the first and/or last dose, and no placebo patient did. Growth hormone peak and area under the curve after the first dose were higher than placebo, but the difference lost statistical significance after correcting for the lower body mass index in the treated group, and after a week of therapy the responses to the final dose were no different from placebo. Serum IGF-I was unaffected by a week of treatment. The authors framed the result as possible utility in a selected subgroup with moderately severe deficiency, but the overall response rate was far too low to support development.
The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN703, a novel orally active growth hormone secretagogue in healthy male volunteers Preclinical only
Corrected during audit. The draft cited this paper as the source for 'oral bioavailability approximately 30% and plasma half-life 4.1 plus or minus 0.4 hours'; the abstract reports neither figure, and those numbers have been removed from the half-life field as unverified. What the paper does report: growth hormone area under the curve over 0-24 hours was significantly higher than placebo at the three highest doses, peak growth hormone at the four highest doses, and IGF-1 rose significantly at 6.0 and 12.0 mg/kg. No significant increases were seen in ACTH, LH, FSH, TSH, prolactin or cortisol, though subtle individual changes in ACTH, cortisol and prolactin were noted above 3.0 mg/kg. The compound was well tolerated.
A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a growth hormone secretagogue, and midazolam, a cytochrome P450 3A4 substrate Preclinical only
The study that made tabimorelin undevelopable as a chronic oral medicine. Midazolam exposure rose 64% after a single NN703 dose and 93% at steady state relative to baseline (both P=0.0001), and was still 45% above baseline after the washout, consistent with the irreversible, mechanism-based CYP3A4 inhibition seen in human liver microsomes. Alpha-hydroxymidazolam did not rise proportionately, as expected when the metabolising enzyme is being inactivated rather than saturated.
Safety
There is very little safety data on tabimorelin, and that scarcity is itself the most important safety fact about it. The phase 1 and phase 2 studies described it as generally well tolerated over exposures of one week or less, with no significant disturbance of other anterior pituitary hormones at the doses studied, although subtle individual changes in ACTH, cortisol and prolactin were noted at higher doses. No data exist on exposure beyond a week, on any clinical outcome, or in women, since the pharmacokinetic work was done in male volunteers only.
The defined hazard is the drug interaction. Tabimorelin is a mechanism-based inhibitor of CYP3A4, the enzyme responsible for metabolising a large fraction of prescription medicines, and the effect persists after dosing stops because the enzyme must be resynthesised rather than simply released. Anyone taking tabimorelin alongside statins, many benzodiazepines, calcium channel blockers, immunosuppressants, certain antivirals, hormonal contraceptives or numerous other CYP3A4 substrates would be exposed to unpredictable and prolonged increases in those drugs' levels. Beyond that, growth hormone secretagogues as a class raise growth hormone and IGF-1, with the attendant theoretical concerns about insulin resistance and about IGF-1 signalling. Tabimorelin is not a licensed medicine anywhere; anything sold under the name is a research chemical of unverified identity, purity, sterility and content, with no manufacturer accountability and no pharmacovigilance. It is prohibited at all times in sport under WADA S2.2.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Never licensed by the MHRA and never marketed in the United Kingdom or European Union. Any tabimorelin available is sold as a research chemical, outside pharmaceutical regulation, with no verified identity, purity, sterility or content, and no pharmacovigilance. |
| United States | Never approved by the FDA. Development was abandoned in phase 2 and no marketing application was submitted. It is not a controlled substance, but it is an unapproved investigational compound with no legal route to human therapeutic use in the United States; selling it for human consumption would be unlawful. |
| WADA (sport) | Prohibited at all times, in and out of competition. WADA category S2.2 covers growth hormone secretagogues and names tabimorelin explicitly, alongside anamorelin, macimorelin, ipamorelin, ibutamoren and lenomorelin (ghrelin). Its abandoned development status confers no exemption whatsoever. |
Questions
Two reasons, either of which would have been enough. The efficacy was poor: in the only substantial patient trial, only 11% of growth-hormone-deficient adults mounted a meaningful growth hormone response, and after a week of treatment the response was no different from placebo while IGF-I had not changed at all. And the pharmacology was awkward: tabimorelin irreversibly inactivates CYP3A4, the liver enzyme that metabolises a large share of prescription drugs, with effects persisting a week after the last dose. A daily medicine with that interaction profile is not viable.
No, though all three act at the same receptor, GHS-R1a. Ipamorelin is an injectable pentapeptide, ibutamoren is an orally active non-peptide, and tabimorelin is an orally active peptidomimetic built from N-methylated D-amino acid residues. All four of these compounds, along with anamorelin and macimorelin, are named explicitly on the WADA Prohibited List under S2.2. Tabimorelin is distinguished mainly by having been tested in patients and found wanting.
Yes, at all times, in and out of competition. WADA category S2.2 covers growth hormone secretagogues and names tabimorelin explicitly. The fact that development was abandoned and the compound was never approved anywhere makes no difference to its prohibited status.
None. It was never tested for body composition, athletic performance or physique in any published trial. The only patient data available come from a one-week study in growth hormone deficiency, where IGF-I, the mediator through which growth hormone exerts its anabolic effects, did not change at all. Development stopped more than twenty years ago and nothing has been published since to change that picture.