106-LB: Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MK-1092 in Subjects with T1DM and T2DM

Abstract

Background: MK-1092, a first-in-class insulin receptor partial agonist, is being developed as a novel basal insulin to treat diabetes. Primary objectives were to assess safety and tolerability of single subcutaneous (SC) doses of MK-1092 in T1DM and T2DM and to determine safe single SC doses of MK-1092 in T1DM with a maximum glucose infusion rate (GIRmax) between 1.5 and 4.5 mg/kg/min. Secondary objectives were to estimate PK profiles in T1DM and T2DM and to determine the GIRmax in T2DM. Methods: All subjects received blinded treatments of MK-1092 or glargine and placebo matched to the alternative active treatment under euglycemic clamp conditions. T1DM: 2 cohorts (n=8/cohort) were each randomized (3:1) to receive MK-1092 (8 nmol/kg in cohort 1 or 32 nmol/kg in cohort 2) or glargine (3 nmol/kg [0.5 units/kg]). T2DM: 1 cohort (n=9) was randomized to receive either MK-1092 (n=6) or glargine (n=3). Each subject underwent 3 dosing periods. MK-1092 was dosed at 32, 16 and 64 nmol/kg in periods 1, 2, and 3, respectively and glargine was dosed at 3 nmol/kg in all periods. Results: All doses tested were safe and well tolerated. There were no SAEs or discontinuations due to AEs. AEs were mild or moderate and resolved spontaneously. No anti-MK-1092 or anti-insulin antibodies were observed. In T1DM, the geometric mean of apparent terminal t1/2 was 8.54 and 6.70 hr; Tmax was 15.00 and 15.04 hr; AUC0-∞ was 21.5 and 74.9 nM*hr and Cmax was 0.79 and 3.43 nM for 8 and 32 nmol/kg MK-1092, respectively. PK parameters for 32 nmol/kg MK-1092 were comparable for T1DM and T2DM except for a ~40-50% lower AUC0-∞ and Cmax in T2DM. In T1DM, the mean GIRmax was 1.33 and 2.74 mg/kg/min for 8 and 32 nmol/kg MK-1092, respectively and 2.32 mg/kg/min for glargine. In T2DM, the mean GIRmax was 1.90, 1.40 and 2.83 mg/kg/min for 32, 16 and 64 nmol/kg MK-1092, respectively and ~ 1.2 mg/kg/min for glargine. Conclusion: Single doses of MK-1092 are well-tolerated and lower glucose in patients with diabetes. 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.