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Endocrine Abstracts (2021) 73 OC15.4 | DOI: 10.1530/endoabs.73.OC15.4

ECE2021 Oral Communications Oral Communications 15: Late Breaking (6 abstracts)

Identification of a dose range for once daily oral paltusotine in patients with acromegaly that maintains IGF-1 levels when switching from long-acting somatostatin receptor ligand therapy

Murray B. Gordon 1 , Monica Gadelha 2 , Miklos Toth 3 , Mirjana Doknic 4 , Emese Mezosi 5 , Harpal Randeva 6 , Tonya Marmon 7 , Rosa Luo 7 , Michael Monahan 7 , Ajay Madan 7 , Scott Struthers 7 & Alan Krasner 7


1Allegheny General Hospital, Allegheny Neuroendocrinology Center, Pittsburgh, United States; 2Hospital Universitário Clementino Fraga Filho, Neuroendocrinology Research Center/Endocrinology Division, Brazil; 3Semmelweis University, Department of Internal Medicine and Oncology, Budapest, Hungary; 4University Clinical Centre of Serbia, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Beograd, Serbia; 5University of Pécs Medical School, Department of Internal Medicine, Pécs, Hungary; 6University Hospitals Coventry and Warwickshire NHS Trust, United Kingdom; 7Crinetics Pharmaceuticals, San Diego, United States


Long-acting somatostatin receptor ligands (LA-SRLs) are a first line medical treatment for acromegaly but require monthly parenteral administration. Paltusotine (CRN00808) is a nonpeptide, small molecule somatostatin type 2 (SST2) receptor agonist with high oral bioavailability (70%), suitable for once daily, oral dosing. The recently reported results of the ACROBAT Edge study (NCT03789656) suggest that patients with acromegaly treated with injected SRLs can switch to once daily oral paltusotine while maintaining IGF-1 and that paltusotine appeared to be well tolerated. The dose-response relationship for paltusotine was explored using pooled data from patients with acromegaly who participated in the ACROBAT Phase 2 Edge and Evolve (NCT03792555) studies. Both studies were designed to evaluate the safety and efficacy of switching acromegaly patients receiving LA-SRLs to once-daily, oral paltusotine (n = 60). The switch to paltusotine occurred 4 weeks after last LA-SRL injection. Patients were treated with paltusotine at doses titrated upward based on target IGF-1 starting at 10 mg to a maximum of 40 mg per day for up to 13 weeks, followed by a 4-week paltusotine wash-out period. The change from baseline in IGF-1 during the treatment period and the rise in IGF-1 after paltusotine wash-out were used to measure the magnitude of paltusotine-related IGF-1 suppression. An evaluation of steady state IGF-1 changes as a function of paltusotine dose showed that 10 and 20 mg per day resulted in IGF-1 levels that were above baseline, whereas doses of 30 and 40 mg result in changes from baseline of near zero, indicating the 30 and 40 mg doses were equally effective in suppressing IGF-1 as prior monotherapy with injected LA-SRLs. A dose-response relationship was also observed when evaluating the magnitude of the rise of IGF-1 during paltusotine washout. Exposure-response modeling estimated the paltusotine concentration at which 80% of maximal pharmacological response (EC80) is achieved. Simulations of 3 doses (20, 40 and 60 mg/day) of an improved formulation were performed to evaluate the likelihood of achieving this trough concentration of paltusotine in a population of patients. These simulations suggest that a dose range of 40 to 60 mg/day would result in daily trough concentrations that exceed EC80 and result in consistent IGF-1 suppression in patients with acromegaly. In summary, dose and exposure response analyses of clinical trial data in patients with acromegaly has identified a dose range of oral paltusotine expected to result in IGF-1 suppression similar to that of injected LA-SRLs.

Volume 73

European Congress of Endocrinology 2021

Online
22 May 2021 - 26 May 2021

European Society of Endocrinology 

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