Pharmacokinetic and pharmacodynamic properties of the novel basal insulin Fc (insulin efsitora alfa), an insulin fusion protein in development for once-weekly dosing for the treatment of patients with diabetes.

Abstract

To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of basal insulin Fc (BIF; LY3209590), a fusion protein combining a novel single-chain insulin variant together with human IgG2 Fc domain, following single and multiple once-weekly BIF administration. The single ascending dose, 15-day study assessed four BIF doses (5-35 mg) in healthy participants and people with type 2 diabetes (T2D). In the 6-week multiple ascending dose study, people with T2D, previously treated with basal insulin, received insulin glargine daily or a one-time loading dose of BIF followed by 5 weeks of once-weekly dosing (1-10mg). Safety, tolerability and PK and glucose PD were examined. Mean ages of people with T2D (N= 57) and healthy participants (N= 16) in the single-dose study were 58.4 and 35.8 years, respectively; mean body mass index values were 29.5 and 26.1kg/m2 . BIF had a PK half-life of approximately 17 days, which led to a sustained, dose-dependent decrease in fasting blood glucose for 5 days or longer. No severe hypoglycaemia was observed. The 6-week ascending dose study included 33 people with T2D aged 40-69 years. BIF showed a low peak-to-trough ratio of 1.14 after the last dose at week 6 (steady state). Over 6 weeks, BIF seven-point glucose profiles remained constant and were similar to insulin glargine. Rates and duration of BIF hypoglycaemic events were similar to insulin glargine. BIF was well tolerated and the PK/PD profile enabled once-weekly dosing with minimal variation in exposure in a treatment interval of 1week. The findings suggest BIF is suitable for further development as a weekly basal insulin in people with diabetes.