107-LB: Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MK-1092 in Healthy Subjects (HS)

Abstract

Background: MK-1092, a first-in-class insulin receptor partial agonist, is being developed as a novel basal insulin for patients with T1DM and T2DM. The primary objective of this first-in-human study was to assess safety and tolerability of single subcutaneous (SC) doses of MK-1092 in HS. Secondary objectives were to estimate PK profiles, to determine the maximal glucose infusion rate (GIRmax) required to maintain target glucose levels during euglycemic clamp conditions and to explore the glycemic effect of insulin lispro when added to a single dose of MK-1092 in HS. Methods: In part 1 of this single-site study, 5 cohorts of HS (n=8/cohort) were blinded and randomized (3:1) to receive MK-1092 (4, 8, 16, 32 or 64 nmol/kg) or glargine (3 nmol/kg [0.5 units/kg]). Subjects received single SC doses of MK-1092 or glargine and placebo matched to the alternative active treatment under euglycemic clamp conditions. Part 2 of the study was started once a safe and tolerated MK-1092 dose that achieved GIRmax ~1-2 mg/kg/min was identified in Part 1. In the open-label part 2 of the study, 4 HS received lispro (1.2 nmol/kg [0.2 units/kg], IV) approximately 12 hr after a single SC dose of MK-1092 (8 nmol/kg) to confirm high dose lispro could reduce hyperglycemia (defined as GIRmax > 4mg/kg/min) after MK-1092 dosing. Results: All doses tested were safe and well tolerated. There were no SAEs and no discontinuations due to AEs. AEs were mild or moderate and resolved spontaneously. The geometric mean of apparent terminal t1/2 ranged from 5.4 to 9.3 hr, Tmax ranged from 12 to 18 hr, AUC0-∞ ranged from 10.6 to 161 nM*hr and Cmax ranged from 0.38 to 6.82 nM at 4 to 64 nmol/kg MK-1092. Mean GIRmax for glargine was 2.72 mg/kg/min and 0.92, 1.69, 3.10, 3.32 and 4.39 mg/kg/min for 4, 8, 16, 32 and 64 nmol/l MK-1092, respectively. Adding lispro to 8.0 nmol/kg MK-1092 resulted in a mean GIRmax of 11.34 mg/kg/min. Conclusion: Single doses of MK-1092 are well-tolerated and lower glucose in healthy subjects. Disclosure L. Morrow: Employee; Spouse/Partner; Lilly Diabetes. Employee; Self; ProSciento. M. Grimm: None. C. Beysen: Employee; Self; ProSciento. G. Walford: Employee; Self; Merck & Co., Inc. K. Duncan: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. P.K. Mitra: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Bristol-Myers Squibb. P. Vaddady: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. M. Hompesch: Board Member; Self; ProSciento. Employee; Self; ProSciento. Stock/Shareholder; Self; ProSciento.