Treatment with efpeglenatide, a once-weekly glucagon-like peptide-1 receptor agonist (GLP-1ra), was associated with a dose-dependent reduction in glucose levels and body weight in patients with early type 2 diabetes (T2D), according to study results published in Diabetes Care. Furthermore, the safety profile was consistent with the GLP-1ra class.
Currently in development, efpeglenatide has a long half-life (5.6-7.5 days) and low peak-to-trough ratio in T2D. Preclinical studies have shown that efpeglenatide led to greater glycemic improvement and weight loss than liraglutide or dulaglutide. The EXCEED 203 trial (ClinicalTrials.gov Identifier: NCT02057172) was a phase 2 study that aimed to assess the efficacy, safety, and tolerability of 5 doses of once-weekly efpeglenatide over 12 weeks in patients with T2D.
The randomized, placebo-controlled, double-blind, parallel-group study of efpeglenatide once weekly included an active control group who received liraglutide. Randomization was stratified by the presence or absence of metformin treatment at baseline. The patients were randomly assigned in equal ratios to efpeglenatide 0.3 mg, 1 mg, 2 mg, 3 mg, or 4 mg once weekly (179 patients); placebo (37 patients); or open-label liraglutide 1.8 mg daily (36 patients).
The primary efficacy end point was defined as the change in glycated hemoglobin (HbA1c) from baseline to week 13 for efpeglenatide compared with placebo. An exploratory assessment evaluated noninferiority to open-label liraglutide. Safety assessment included treatment-emergent adverse events, clinical laboratory assessments, vital signs, electrocardiogram variables, and injection-site reactions.
The final cohort included 252 patients who received at least one dose of the study drug. Efpeglenatide led to dose-dependent reductions in HbA1c levels over the 12-week study. All efpeglenatide doses ≥1 mg resulted in significantly greater reduction in HbA1c levels vs placebo (least squares mean change, 0.6%-1.2%; P <.05 for all), from a baseline HbA1c of 7.7% to 8.0% to a final HbA1c of 6.3% to 6.8%.
The exploratory analysis comparing efpeglenatide with liraglutide showed that efpeglenatide 4 mg was noninferior to liraglutide (least squares mean difference in change in HbA1c, -0.23%; 95% CI, -0.56% to 0.10%).
Compared with placebo, the proportion of patients receiving efpeglenatide doses ≥1 mg who achieved an HbA1c <7% (24% vs 70%-81%, respectively) or HbA1c ≤6.5% (5% vs 22%-53%, respectively) was significantly greater.
Efpeglenatide provided a dose-dependent, rapid, and sustained reduction in fasting plasma glucose, mean self-measured plasma glucose, and weight loss over the study period. Body weight reductions from baseline were significantly greater with efpeglenatide 3 mg and 4 mg (2.7 kg and 3.3 kg, respectively) compared with placebo (1.3 kg; P <.05 for both comparisons).
In general, all doses of efpeglenatide were well tolerated. Rates of gastrointestinal adverse effects with efpeglenatide were similar to those of other long-acting GLP-1ra drugs and subsided after the first 2 weeks. Immunogenicity, which can affect the clinical safety and efficacy of treatment, was low with efpeglenatide, and there was no evidence for neutralizing antibodies.
The researchers acknowledged several limitations of the study, including the open-label liraglutide treatment, inability to assess for statistically significant differences between efpeglenatide and liraglutide, lack of dose titration of efpeglenatide, and lack of evaluation of efpeglenatide in a 6-mg formulation, which is also being investigated and might have greater efficacy.
“[I]n the EXCEED study, efpeglenatide once weekly demonstrated dose-dependent reductions in glucose and body weight in patients with early T2D with and without metformin,” concluded the researchers.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Rosenstock J, Sorli CH, Trautman ME, et al. Once-weekly efpeglenatide dose-range effects on glycemic control and body weight in patients with type 2 diabetes on metformin or drug naïve, referenced to liraglutide [published online July 18, 2019]. Diabetes Care. doi:10.2337/dc18-2648