Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue

This 2007 *Basic and Clinical Pharmacology & Toxicology* paper is the foundational design and preclinical characterization paper for TH9507 — the molecule that would become tesamorelin (Egrifta) once it cleared the regulatory program in HIV-associated lipodystrophy. The paper documents the modifications applied to native human growth-hormone-releasing factor (hGRF1-44NH₂): a trans-3-hexenoyl moiety attached to Tyr¹ at the N-terminus, which conferred resistance to dipeptidyl-aminopeptidase-IV cleavage while preserving the GHRH-receptor pharmacology of the native hormone. In animal models — pigs, rats, and dogs — TH9507 produced marked elevations in plasma growth hormone and downstream IGF-1, with apparent elimination half-lives in dogs ranging from 21 to 45 minutes. Subchronic four-month toxicity studies in dogs revealed reversible adverse effects — liver and kidney changes, anemia, clinical chemistry alterations — that the authors attributed to prolonged exposure to elevated growth hormone and IGF-1 levels rather than to direct molecule-specific toxicity, a key framing that informed the dose-selection logic for the human trial program. The combined design, pharmacokinetic, and safety findings supported advancement to Phase I in humans, ultimately yielding the Falutz NEJM 2007 trial and the FDA approval that followed.

The dose ranges used in the subchronic toxicology studies are well above the human therapeutic dose; the reversible toxicities observed are at supratherapeutic exposure rather than at the 2 mg daily clinical dose. The "GH/IGF-1 effect rather than molecule-specific toxicity" framing is plausible from the data but is not directly demonstrable — distinguishing the two requires comparison studies that the paper does not include. The half-life range cited (21–45 minutes in dogs) is species-specific; the human plasma half-life that turned up in subsequent clinical pharmacology was 26–38 minutes, broadly consistent with the canine data but not directly equivalent. Industry origin (Theratechnologies, the developer) is the operative context. Read this paper as the preclinical design rationale that justified the human program rather than as direct evidence for clinical efficacy or safety.