Abstracts - Orals, Featured Poster Presentations, and Posters
SAT 109-133-GHRH, GH & IGF Biology & Signaling
Bench to Bedside
Expo Halls ABC (Moscone Center)
Poster Board SAT-111
ALRN-5281, a 29 amino acid analog of human growth hormone releasing hormone (GHRH), is being developed to treat orphan diseases including adult growth hormone (GH) deficiencies amenable to GHRH therapy, with the potential to address broader endocrine and metabolic disorders. Relative to GH injections, GHRH therapy produces a more physiological, pulsatile GH release, thereby minimizing safety and tolerability issues associated with chronic, excess GH replacement. ALRN-5281, a member of a new class of therapeutics known as Stapled Peptides, is stabilized with hydrocarbon covalent cross-links (“staples”) that maintain the alpha-helical structure, thereby improving protease resistance. The resulting longer in vivo plasma t½ addresses a major limitation of short-acting GHRH analogs such as sermorelin and tesamorelin. In rat plasma stability assays, 97% of ALRN-5281 remained intact and pharmacologically active after 24 h incubation, compared with the complete degradation of sermorelin after 13 h, and in an in vitro cell-based assay ALRN-5281 displayed strong, dose-dependent activity. As evidence of potency and improved stability in vivo, ALRN-5281 exhibited a plasma t½ of 18 h after intravenous (IV) administration in rats, with rapid increases in peak plasma GH of up to 8632% after either single or repeat IV administration of 0.5 mg/kg ALRN-5281. In dogs, single subcutaneous (SC) injections of ALRN-5281, the proposed clinical route of administration, generated not only the expected elevations in peak GH but more importantly resulted in increases in serum IGF-1, a clinically relevant marker of downstream pharmacologic activity. At 5, 10 or 25 mg/kg, ALRN-5281 produced a marked exposure-dependent rise in serum IGF-1, with a maximum peak increase of 182% 6 days post treatment. Twice-weekly SC administration of 1, 3 or 10 mg/kg of ALRN-5281 to dogs for 40 days was well-tolerated and resulted in exposure-proportional increases in serum IGF-1, with a maximum peak increase of 151% over pre-treatment levels. In addition, mild elevations in body weight were observed, corroborating the anticipated consequences of physiologic serum GH elevations. Overall, these results indicate that ALRN-5281 has enhanced pharmacokinetic and pharmacological properties relative to short-acting GHRH analogs. These findings support the planned Phase 1 investigation of ALRN-5281 as a once-weekly injectable agent for the treatment of adult GH deficiencies amenable to GHRH therapy.
Disclosure: KAO: Employee, Aileron Therapeutics. HC: Employee, Aileron Therapeutics. SJD: Employee, Aileron Therapeutics. NK: Employee, Aileron Therapeutics. AM: Employee, Aileron Therapeutics. ES: Employee, Aileron Therapeutics. AMM: Employee, Aileron Therapeutics. DAA: Employee, Aileron Therapeutics. HCC: Employee, Aileron Therapeutics.
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