Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers
Ajay Madan, Stacy Markison, Stephen F Betz, Alan Krasner, Rosa Luo, Theresa Jochelson, Jason Lickliter, R Scott Struthers, Ajay Madan, Stacy Markison, Stephen F Betz, Alan Krasner, Rosa Luo, Theresa Jochelson, Jason Lickliter, R Scott Struthers
Abstract
Purpose: Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors.
Methods: A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability.
Results: Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo.
Conclusions: Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors.
Trial registration: NCT03276858, registered September 8, 2017, retrospectively registered.
Keywords: Acromegaly; IGF-1; Paltusotine; SST2; Somatostatin receptor agonist.
Conflict of interest statement
Ajay Madan, Stacy Markison, Stephen F. Betz, Alan Krasner, Rosa Luo, and R. Scott Struthe are employees of Crinetics Pharmaceuticals, Inc. Theresa Jochelson is a consultant for Crinetics Pharmaceuticals, Inc. Jason Lickliter is an employee of Nucleus Network.
© 2021. The Author(s).
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