Tabimorelin

Summary

Tabimorelin (NN703) is an orally active growth‑hormone‑releasing peptide investigated as a potential treatment for absolute or relative growth‑hormone (GH) deficiency. In short‑term studies in healthy men it raised circulating GH and downstream IGF‑I levels, while animal work showed it stimulates appetite and fat accumulation via hypothalamic pathways.

Mechanism of Action

Tabimorelin acts as an agonist at the ghrelin (growth‑hormone‑secretagogue) receptor, stimulating pituitary somatotrophs to release GH. The resulting GH surge drives hepatic production of IGF‑I and IGF‑binding protein‑3. In addition, the compound has been shown in vitro to act as a mechanism‑based inhibitor of the cytochrome‑P450 enzyme CYP3A4, altering the metabolism of co‑administered CYP3A4 substrates. In rodents, ghrelin‑receptor activation by tabimorelin modulates hypothalamic neuropeptide expression, increasing orexigenic NPY and decreasing anorectic POMC when leptin signalling is intact.

What the Research Shows

Two randomized, double‑blind, placebo‑controlled studies in healthy male volunteers demonstrated dose‑related increases in GH area‑under‑the‑curve and Cmax after single and 7‑day oral dosing (0.05‑12 mg/kg). IGF‑I rose significantly at higher doses, while other pituitary hormones (ACTH, LH, FSH, TSH, cortisol) showed no consistent changes, though isolated increases in prolactin, TSH and ACTH were noted at specific doses. Repeated dosing led to a modest decline in GH response from day 1 to day 7. A separate interaction study showed that a single and steady‑state dose of tabimorelin increased midazolam exposure by ~64‑93 %, supporting CYP3A4 inhibition in humans. In Zucker diabetic fatty rats, oral tabimorelin (50 mg/kg) induced hyperphagia and increased fat mass in lean controls, accompanied by hypothalamic up‑regulation of NPY and down‑regulation of POMC; these effects were blunted in leptin‑receptor‑deficient rats, indicating dependence on leptin signalling. Metabolite profiling identified 13 urinary metabolites, facilitating future anti‑doping detection.

Reported Benefits

Evidence from early clinical trials indicates that tabimorelin can reliably stimulate GH secretion and elevate IGF‑I, suggesting utility for patients with GH deficiency who prefer oral therapy to daily injections. Its dual action on the ghrelin receptor may also influence appetite regulation, which could be relevant in metabolic research. The oral formulation simplifies administration compared with injectable GH analogues.

Limitations of the Evidence

Human data are limited to short‑term studies in healthy men; long‑term efficacy, safety, and effects in GH‑deficient patients remain untested. The decline in GH response over a week hints at possible tachyphylaxis. CYP3A4 inhibition raises the risk of drug‑drug interactions, and the orexigenic, adipogenic effects observed in rodents may translate to unwanted weight gain in humans. No regulatory approval has been granted, and the compound remains investigational.

Safety Considerations

Both single‑dose and 7‑day studies reported good tolerability, with no serious adverse events. Minor hormonal perturbations included transient increases in prolactin, TSH, and ACTH at certain dose levels, and a decrease in ACTH and cortisol after repeated dosing. CYP3A4 inhibition can raise plasma concentrations of co‑administered substrates, necessitating caution. Animal data revealed hyperphagia and increased adiposity, indicating a potential for weight‑gain side effects. Comprehensive safety profiling in patient populations is lacking.

How It Is Administered

Tabimorelin has been administered orally in single and repeated doses ranging from 0.05 mg/kg to 12 mg/kg in clinical studies. Intravenous and subcutaneous routes have also been investigated experimentally, but oral delivery is the primary focus for potential therapeutic use. Formulation details were not disclosed in the cited literature.

Routes of Administration

Goals & Uses

• Increase lean body massMusculoskeletalModerate
• Diagnostic testing for GH deficiencyDiagnosticsModerate
• Growth hormone deficiency (GHD) treatmentEndocrinologyModerate
• Growth hormone deficiencyEndocrineModerate
• IGF-1 elevationMetabolic / HormonalModerate
• Body composition improvementMetabolicLow

Contraindications

• Active malignancyOncologyHighUse caution or avoid depending on agent and context
• Hypersensitivity to tabimorelinAllergy/ImmunologyHigh
• PregnancyPopulationHighPotential fetal risk or insufficient safety data
• Uncontrolled Diabetes MellitusMetabolic / EndocrineModerate
• Proliferative or severe non-proliferative diabetic retinopathyOphthalmologyHigh

Adverse Effects

• EdemaFluid BalanceUncommonSwelling from fluid retention
• HyperglycemiaMetabolicCommonAbnormally high blood glucose
• Injection site painLocalCommonPain at the injection site
• Elevated blood glucose / insulin resistanceMetabolicUncommon
• Edema / fluid retentionMetabolicUncommon
• Increased appetite / hungerGastrointestinal / MetabolicCommon
• Cortisol elevationEndocrinologyUncommon
• Arthralgia / myalgiaMusculoskeletalUncommon

Drug Interactions

• InsulinLowMay increase risk of low blood sugar
• GlucocorticoidsModerate
• Insulin / antidiabetic agentsModerate
• Somatostatin analogues (e.g., octreotide)High

Population Constraints

• Pediatric patientsAgeRelative
• Pediatric patients < 2 yearsAgeRelative
• Patients with diabetes mellitusMetabolicRelative
• Elderly patientsAgeRelative
• Pregnant womenReproductiveAbsolute
• Patients with History of MalignancyOncologyRelative

Regulatory Status

• European UnionInvestigationalInvestigational medicinal product; no EMA approval.
• United StatesInvestigationalPhase II clinical trials; not FDA approved.
• United KingdomInvestigationalClinical trial use only; not licensed.

Never received marketing approval; development discontinued after Phase II trials.

Evidence & Sources

• The pharmacokinetics, pharmacodynamics, safety and tolerability following 7 days daily oral treatment with NN703 in healthy male subjects
  Journal ArticleModerateZdravkovic M, et al.2001-01-01T00:00:00.000000Z
• A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate
  Journal ArticleModerateZdravkovic M, et al.2003-01-01T00:00:00.000000Z
• Comprehensive insights into the formation of metabolites of the ghrelin mimetics capromorelin, macimorelin and tabimorelin as potential markers for doping control purposes
  Journal ArticleLowLange T, et al.2021-01-01T00:00:00.000000Z
• The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN703, a novel orally active growth hormone secretagogue in healthy male volunteers
  Journal ArticleModerateZdravkovic M, et al.2000-01-01T00:00:00.000000Z
• Adipogenic and orexigenic effects of the ghrelin-receptor ligand tabimorelin are diminished in leptin-signalling-deficient ZDF rats
  Journal ArticleLowHolm AM, et al.2004-01-01T00:00:00.000000Z

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