Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers

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).

Figures

Fig. 1

Trial design for single- and multiple-dose cohorts. Dose escalation in a new cohort, soln solution, caps capsule. *n = 8 per single-dose cohort (6 active, 2 placebo), except for cohort S5 in which one participant withdrew prior to dosing and was not replaced (n = 7; 5 active, 2 placebo). †n = 9 per multiple-dose cohort (6 active, 3 placebo). **There were 3 study periods in cohort S4: period A (10 mg solution); period B (10 mg capsules) and period C (10 mg capsules with food). ‡Single-dose pharmacodynamic population (n = 39; paltusotine n = 29; placebo n = 10) included participants in S1, S2, S3, S4A, and S5 cohorts. GHRH challenge was administered on Day 1 and 2 h post-dose on Day 1. §Multiple-dose pharmacodynamic population (n = 31; paltusotine n = 21; placebo n = 10) included participants from the M1, M2, M3, and M4 cohorts who received all doses

Fig. 2

Growth hormone suppression with single-dose paltusotine. Data shown in panels a and b are mean ± SEM. **P GH growth hormone, GHRH growth hormone-releasing hormone, AUC0-2 area under the serum concentration time curve from 0 to 2 h; EC80 = 80% GH suppression. On Day 1, GHRH was administered 2 h post paltusotine dose. On Day -1, GHRH was administered at approximately the same time of the day as Day 1. a Plasma GH concentrations upon GHRH challenge on Day -1, and Day 1 on paltusotine 10 mg. GH levels were measured at the same time of the day after a GHRH challenge on Day -1 (open circles) and on Day 1 (closed circles). Plasma paltusotine concentrations are shown in black squares. Mean peak GH response on Day 1 and Day 1 were 21 ng/mL and 1.7 ng/mL, respectively. b Mean GHRH-stimulated GH AUC0-2 percent of baseline (Day 1/Day 1) by each dose group. P values were calculated for each dose of paltusotine compared to placebo using ANOVA with Dunnett multiple comparison adjustment. c. Suppression of GH AUC0-2 post GHRH (Day-1–Day 1)/Day-1 as a function of paltusotine concentration (average of 2-, 3-, and 4-h post-dose)

Fig. 3

Suppression of IGF-1 with repeated administration of paltusotine. Data shown are mean ± SEM. *P IGF-1 insulin-like growth factor-1; GHRH = growth hormone-releasing hormone. a Plasma paltusotine (open squares) and serum IGF-1 (closed circles) concentrations at 10 mg multiple dose from baseline (Day 1) to 10–11 days post-dose (Days 20–21). For this dose group, IGF-1 samples were obtained pre-dose, 6 and 12 h post-dose on Days 1, 1 and 10; pre-dose and 12 h post-dose on Days 2–9; and a single sample at approximately the same time as dosing on Days 11, 14, and 21. Arrows represent days on which paltusotine was administered (Days 1 to 10). Paltusotine concentrations are trough plasma concentrations 24 h post-dose on Days 2 to 11 and measured concentrations on Day 12 to 20 after the last dose on Day 10. Baseline IGF-1 was the average of all pre-first dose values. For each of the subsequent days, during the treatment period, each day’s pre-dose IGF-1 value was averaged with the previous day’s value (e.g., Day 2 pre-dose value was averaged with Day 1 post-dose value). b Dose–response for IGF-1 suppression relative to baseline with multiple-dose paltusotine. Values are IGF-1 percent of baseline 12 h post-dose on Day 7 (5 mg dose group) and on Day 10 (10 mg, 20 mg, 30 mg dose groups). Baseline was the average of Day -1 and Day 1 pre-dose IGF-1 results. P-values were calculated for each dose of paltusotine compared to placebo using ANOVA with Dunnett multiple comparison adjustment