ESPE Abstracts (2022) 95 FC11.4

ESPE2022 Free Communications Late Breaking (6 abstracts)

CRN04777, an oral, nonpeptide selective SST5 receptor agonist, dose-dependently suppresses both fasting and stimulated insulin secretion: results from a first in human study

Christine Ferrara-Cook 1 , Rosa Luo 1 , Eduardo De la Torre 1 , Yang Wang 1 , Stephen Betz 1 , Hjalmar Lagast 1 , Scott Struthers 1 , Ultike Hovelmann 2 , Tim Heise 2 & Alan Krasner 1

1Crinetics Pharmaceuticals, San Diego, USA; 2Profil, Nuess, Germany

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in neonates, infants, and children, and is caused by genetic mutations in pancreatic beta-cells. Current therapies are burdensome, have limited efficacy, and are associated with significant morbidity. CRN04777 is a potent, orally-bioavailable, selective SST5 agonist that suppresses insulin secretion in the terminal steps of the insulin secretion pathway and could be useful for patients with congenital HI. We report results from a first in human randomized, double-blind, placebo-controlled study evaluating the safety, pharmacokinetics, and pharmacodynamics of CRN04777 in healthy volunteers. In multiple ascending dose cohorts, 30, 60 and 120 mg of CRN04777 or placebo was orally administered once daily for 10 days (6:3 active:placebo/cohort). Endogenous insulin secretion was stimulated on separate days with a mixed meal tolerance test (MMTT) and a sulfonylurea (SU) challenge, the latter simulating the most common form of congenital HI. In the MMTT (Day -1 [baseline] and Day 6), 400 mL Resource Energy® was consumed 4 hours after study drug dosing. For the SU challenge (Day -2 [baseline] and Day 10), CRN04777 was administered one hour after SU dosing (10 mg glibenclamide/glyburide), followed by continuous IV glucose infusion rate (GIR) measurement under automated euglycemic clamp conditions. CRN04777 was well tolerated with mild/moderate GI side effects being the most common adverse effects and no serious adverse events. CRN04777 was rapidly orally absorbed (Tmax 1-3 hours), demonstrating dose-dependent increases in systemic exposures and apparent terminal elimination t1/2 of ~40-60 hours. Daily doses of CRN04777 suppressed fasting insulin and C-peptide and increased fasting plasma glucose starting after a single dose at all doses tested. CRN04777 at 60 and 120 mg reduced MMTT stimulated insulin by 33-38% and C-peptide by 20-24% compared to baseline, with increased MMTT-stimulated plasma glucose in all dosing groups. Daily oral doses of 30, 60, and 120 mg CRN04777 also dose-dependently reduced SU-induced insulin and C-peptide concentrations, and dose-dependently decreased the GIR required to maintain euglycemia (-73, -81, -97% with 30, 60, 120 mg respectively; Day 10 vs baseline). These data demonstrate that once daily dosing with CRN04777 suppresses insulin secretion under both basal and stimulated conditions, including a pharmacologic model of congenital HI and presents an acceptable safety profile. The results from this study support the potential for CRN04777 as a novel oral therapy for patients with congenital HI. Planning for patient studies is currently underway.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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