Basal Insulin Fc (BIF), A Novel Insulin Suited For Once Weekly Dosing For The Treatment of Patients With Diabetes Mellitus

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Abstract An optimally designed once-weekly basal insulin with reduced day-to-day pharmacokinetic (PK)/pharmacodynamic (PD) fluctuations compared to daily basal insulins should have a low peak-to-trough ratio at steady state. An insulin with this flat profile could improve glycemic efficacy while reducing hypoglycemia. Basal insulin Fc (BIF; LY3209590) is an insulin IgG Fc-fusion protein developed for once weekly dosing. The results of the first in-human studies of BIF assessing the safety, tolerability, PK, and PD following single and once-weekly doses of BIF are presented below. The single ascending dose (SAD) study assessed 6 dose levels of BIF, administered to healthy subjects or patients with type 2 diabetes mellitus (T2DM). In the multiple ascending dose (MAD) study, patients with T2DM previously treated with basal insulin received a one-time loading dose at Week 1 followed by a once-weekly maintenance dose for 5 additional weeks. Four fixed-dose maintenance dose levels were evaluated. The loading dose was implemented to rapidly achieve steady-state BIF concentration at each dose level. Patients with T2DM in the control group received insulin glargine at the same dose as their previous daily insulin dose. Key objectives were safety and tolerability, PK endpoints with a focus on half-life and peak-to-trough ratio at steady state, and finally PD measures. The SAD study included 57 patients with T2DM and 16 healthy subjects. The mean age of patients with T2DM was 58.4 years and the mean BMI was 29.5±3.2 kg/m2. The mean age of healthy subjects was 35.8±9.3 years and the mean BMI was 26.1±3.1 kg/m2. In the SAD study, BIF demonstrated linear PK with dose-proportional concentration profiles in healthy subjects and patients with T2DM. The maximum BIF concentration was reached on Day 4. BIF had a mean half-life of approximately 17 days in patients with T2DM. Following a single dose of BIF, a decrease in FBG was observed on Day 1 and was sustained until at least 5 days post-dose. In the MAD study in 33 subjects with T2DM aged between 40 and 69 years, BIF demonstrated a nearly peak-less PK profile over a one-week dosing interval with a peak-to-trough ratio of ~1.1 at steady state. This flat profile is in contrast to insulin glargine. Following once-daily dosing, insulin glargine has a daily peak-to-trough ratio of ~2. Over the 6-week duration, the 7-point glucose profiles remained constant over time and were similar to insulin glargine profiles. BIF was well tolerated and had a safety profile similar to insulin glargine-treated subjects. In particular, hypoglycemia rates were also similar to insulin glargine and there was no occurrence of hypoglycemic events with cognitive dysfunction. These data support continued development of BIF as a once-weekly insulin treatment of diabetes mellitus.