NN703, oral GHS derived from ipamorelin, achieves 30% bioavailability and 35-fold GH peak in dogs
Background
Growth hormone deficiency and related metabolic conditions have historically required injectable GH or GH-releasing peptides, limiting chronic therapeutic use. GH secretagogues (GHS) act through the GHS-R 1A receptor to stimulate pituitary GH release independently of GH-releasing hormone (GHRH), offering a distinct route to elevating the GH axis. Ipamorelin established that selective, GHRH-independent GH release was achievable with peptide-based GHS compounds, but oral bioavailability remained a critical bottleneck. NN703 was developed as a structural derivative of ipamorelin specifically engineered for oral activity, addressing the delivery gap that has prevented GHS peptides from reaching practical once-daily dosing regimens.
Study Design
NN703 was characterised across multiple models: GH release was quantified from rat primary pituitary cells in vitro across a dose range, with GHS antagonists and a GHRH antagonist used as pharmacological probes. (35)S-MK677 radioligand binding and inositol phosphate turnover assays were run on BHK cells stably expressing human GHS-R 1A. In vivo, i.v. administration was tested in swine for GH and cortisol endpoints. Beagle dogs received single i.v. (1 µmol/kg) or escalating oral doses up to 20 µmol/kg to determine oral bioavailability and plasma half-life. A 14-day rat study with once-daily oral 100 µmol/kg versus vehicle assessed long-term body weight gain.
Results
In rat pituitary cells, NN703 stimulated GH release dose-dependently with potency and efficacy similar to GHRP-6, and the effect was blocked by known GHS antagonists but not by a GHRH antagonist, confirming GHS-R-mediated action. In the GHS-R 1A binding assay, NN703 inhibited (35)S-MK677 binding but with a lower K(i) than expected from its pituitary cell potency; similarly, inositol phosphate turnover assays yielded lower potency than GHRP-6 and MK677 relative to the pituitary data, indicating divergent receptor pharmacology. In swine, i.v. NN703 achieved an efficacy of 91 ± 7 ng GH/mL plasma at a potency of 155 ± 23 nmol/kg; cortisol rose approximately 50% above basal at all tested doses without dose-dependency, suggesting a ceiling effect on the HPA axis.
In beagle dogs, oral NN703 at the highest dose of 20 µmol/kg produced a 35-fold increase in peak GH concentration, reaching 49.5 ± 17.8 ng/mL, with an oral bioavailability of 30% and a plasma half-life of 4.1 ± 0.4 h.
After a single i.v. dose of 1 µmol/kg in dogs, peak GH reached 38.5 ± 19.6 ng/mL at approximately 30 min, returning to basal by 360 min. In rats dosed orally at 100 µmol/kg once daily for 14 days, body weight gain was significantly greater versus vehicle, demonstrating durable anabolic efficacy.
Key Findings
- Oral NN703 at 20 µmol/kg produced a 35-fold peak GH increase (49.5 ± 17.8 ng/mL) in beagle dogs
- Oral bioavailability in dogs was 30%; plasma half-life was 4.1 ± 0.4 h
- i.v. NN703 in swine: GH efficacy 91 ± 7 ng/mL at potency 155 ± 23 nmol/kg
- Cortisol rose ~50% above basal in swine with no dose-dependency across all tested doses
- Once-daily oral 100 µmol/kg for 14 days significantly increased body weight gain in rats vs vehicle
Why It Matters
NN703 demonstrates that oral GH secretagogue therapy is pharmacologically viable, with a 30% bioavailability and 4.1-hour half-life that are compatible with once-daily dosing — a profile ipamorelin itself cannot achieve orally. The divergent GHS-R 1A receptor pharmacology relative to pituitary cell potency suggests NN703 may engage tissue-specific signalling differently from GHRP-6 and MK677, which is relevant to clinicians evaluating on-target versus off-target risk. The cortisol data from swine — a non-dose-dependent ~50% rise — indicate a dissociation between GH and HPA activation at higher doses, a safety consideration for protocols targeting minimal cortisol interference. The 14-day rat weight-gain data provide a preclinical anchor for anabolic durability, but translation to human dosing regimens requires clinical PK/PD bridging studies.
