333-OR: Oxyntomodulin Analog LY3305677 (LY) Improves Glycemic Control and Weight Loss in Healthy Volunteers and Subjects with Type 2 Diabetes (T2D)

LY is an acylated peptide analog of oxyntomodulin, a dual glucagon and GLP-1 receptor agonist. We conducted 2 randomized, double-blind, phase 1 multiple ascending subcutaneous dosing studies in healthy subjects (S1, NCT03325387) and in T2D patients (S2, NCT03928379) to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics. In S1, 4 cohorts of healthy subjects received placebo or LY once-weekly (QW) for 4 weeks. In S2, T2D subjects received placebo or LY QW in 2 cohorts with doses escalated over 12 or 16 weeks. A total of 54 subjects completed S1 and 24 patients completed S2. The most common treatment-emergent adverse events in both studies (decreased appetite, nausea, and diarrhea) were mostly mild in severity, and no deaths or serious adverse events were reported. Pharmacokinetic results were consistent between healthy subjects and T2D patients and supported weekly dosing. In healthy subjects, fasting glucose levels were decreased from baseline with increasing LY doses, and reductions in mean body weight from baseline were generally seen with increasing doses, with the largest change observed on Day 29. In T2D subjects during weeks 12-16, preliminary results of mean HbA1c changes from baseline ranged from -1.56% to -2.16% in LY-treated vs. -0.43% to -0.70% in placebo subjects, and mean body weight changes from baseline ranged from -2.30 kg to -11.24 kg in LY-treated vs. -0.35 kg to -2.03 kg in placebo subjects. Fasting glucose, triglycerides, cholesterol, and glucagon levels were decreased from baseline with LY vs. placebo at weeks 12-16. We conclude that LY was well tolerated in both studies, with a safety profile similar to selective GLP-1 receptor agonists. LY has a promising pharmacodynamic profile with potential for therapeutic benefit in T2D, obesity, or other metabolic diseases.