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

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2023-04, Vol.25 (4), p.1080-1090
• Main Authors: Heise, Tim, Chien, Jenny, Beals, John M., Benson, Charles, Klein, Oliver, Moyers, Julie S., Haupt, Axel, Pratt, Edward John
• Format: Article
• Language: English
• Subjects: basal insulin; Blood glucose; Blood Glucose - metabolism; Body mass index; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Dosage; Double-Blind Method; Drug dosages; Drug therapy; Fusion protein; Glucose; Glucose - therapeutic use; Humans; Hypoglycemia; Hypoglycemic Agents - therapeutic use; Immunoglobulin G; Insulin; Insulin - therapeutic use; Insulin Glargine - therapeutic use; Insulin, Regular, Human - therapeutic use; Pharmacodynamics; Pharmacokinetics; type 2 diabetes
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.14956

Aim 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. Materials and Methods 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 (1‐10 mg). Safety, tolerability and PK and glucose PD were examined. Results 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 26.1 kg/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. Conclusions BIF was well tolerated and the PK/PD profile enabled once‐weekly dosing with minimal variation in exposure in a treatment interval of 1 week. The findings suggest BIF is suitable for further development as a weekly basal insulin in people with diabetes.