SAT-429 Final Results from the First in Man Phase 1 Clinical Trial of CRN00808, an Orally Bioavailable sst2-Selective, Nonpeptide Somatostatin Biased Agonist, for the Treatment of Acromegaly: Safety, Pharmacokinetics, Pharmacodynamics, and Midazolam Drug Interaction in Healthy Volunteers

Abstract

Injected depot formulations of somatostatin peptide analogs are routinely used to treat acromegaly and neuroendocrine tumors (NETs). CRN00808 is a small molecule nonpeptide selective somatostatin receptor 2 agonist whose safety, pharmacokinetics (PK), and pharmacodynamics (PD) has been characterized in preclinical studies. This study describes the final results from a first-in-human, single and multiple ascending dose Phase 1 study in healthy volunteers to measure the safety, PK, PD, and midazolam drug interaction potential of CRN00808 (NCT03276858; preliminary results with blinded safety data presented at ENDO 2018). In the single dose arm of the study, cohorts of 8 subjects (6 active: 2 placebo) received CRN00808 as an oral solution or capsules (1.25 mg to 60 mg, or placebo). The effect of food on CRN00808 PK was also evaluated. In the multiple dose arm, cohorts of 9 subjects (6 active: 3 placebo) received CRN00808 capsules once daily (5 mg to 30 mg, or placebo) for 7-10 days. In the drug-interaction arm, a single cohort of 8 subjects received 20 mg of CRN00808 for 7 days; midazolam PK was assessed before (Day -2) and after (Day 7) administration of CRN00808. Safety and PK were assessed in all phases of the study. Suppression of GHRH-induced GH secretion and suppression of serum IGF-1 were measured as PD endpoints in the single and multiple dose phases of the study, respectively. Once daily administration of 5-30 mg CRN00808 capsules exhibited dose-dependent increases in peak (Cmax) and total (AUC) plasma exposures. The apparent terminal elimination half-life was determined to be of 42-50 hours and steady state was achieved in 3-5 days. Capsules taken with a standard high fat, high calorie meal resulted in a markedly lower plasma CRN00808 AUC (83%). Oral administration of CRN00808 resulted in dose-dependent suppression of both GHRH stimulated GH and IGF-1 secretion; a single 10 mg dose was found to cause 91% suppression of GHRH-stimulated GH and 10 mg once per day for 10 days resulted in maximal suppression of serum IGF-1. Midazolam PK was unaffected by co-administration of 20 mg CRN00808, suggesting little or no risk of drug interaction with CYP3A4/5 substrates. Treatment emergent adverse events associated with CRN00808 were generally mild and transient, and consistent with those reported with other somatostatin agonists. In conclusion, results from this Phase I clinical trial in healthy volunteers support further clinical development of CRN00808 as a once-daily oral treatment of patients with acromegaly.