Abstract
PurposeEvaluate 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.MethodsA 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.ResultsSingle-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.ConclusionsPaltusotine 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 registrationNCT03276858, registered September 8, 2017, retrospectively registered.
Highlights
Somatostatin is produced by a variety of cell types in the central nervous system and gut and has pleiotropic effects, many of which are related to inhibiting the secretion of other hormones
The type 2 receptor, somatostatin receptor subtype 2 (SST2), is expressed in pituitary somatotrophic cells where it mediates the inhibition of growth hormone (GH) secretion, which in turn causes secretion of insulin-like growth factor 1 (IGF-1) from the liver and is highly expressed in gut enteroendocrine and pancreatic islet cells, as well as neuroendocrine tumors that arise from these tissues [3]
Two multiple-dose participants discontinued the study before completion—one participant receiving paltusotine 5 mg withdrew due to a Treatment-emergent adverse events (TEAEs), and one participant receiving paltusotine 10 mg discontinued due to schedule conflicts
Summary
Somatostatin is produced by a variety of cell types in the central nervous system and gut and has pleiotropic effects, many of which are related to inhibiting the secretion of other hormones. The type 2 receptor, SST2, is expressed in pituitary somatotrophic cells where it mediates the inhibition of growth hormone (GH) secretion, which in turn causes secretion of insulin-like growth factor 1 (IGF-1) from the liver and is highly expressed in gut enteroendocrine and pancreatic islet cells, as well as neuroendocrine tumors that arise from these tissues [3]. Synthetic peptide SST2 receptor ligands, such as octreotide and lanreotide, inhibit secretory activity of somatotrophs and gastroenteropancreatic neuroendocrine tumors (GEPNETs) and improve progression free survival in patients with GEPNETs [4, 5]. Pasireotide, a synthetic peptide pan somatostatin receptor ligand (SRL) with activity at SST2, SST3, and SST5 receptors is approved for acromegaly. The efficacy of pasireotide in acromegaly is in part attributed to
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