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EXCEED Trial: Efpeglenatide Displays Significant Reduction in HbA1c and Body Weight

Oct 15, 2019
 
Editor: Steve Freed, R.PH., CDE

Author: Amber Satz, PharmD Candidate, LECOM School of Pharmacy

Efpeglenatide, a new GLP-1 receptor agonist, referenced to liraglutide in Phase II trial.

Diabetes treatment has evolved tremendously over the past century with advancing science and research to develop new medications. From the sole use of insulin for treatment beginning in the 1920s to the development of the first oral antidiabetic drug class, sulfonylureas, in the 1950s, we now have a wealth of options, oral and injectable, to improve glucose control and the quality of life for those affected by diabetes. One of the most popular and effective antidiabetic drug classes is the GLP-1 receptor agonists. The first GLP-1 receptor agonist, exenatide (Byetta) was approved in the United States in 2005. Since then, continuing innovation has led to the development of many more additional drugs in this class.

GLP-1 receptor agonists work by increasing glucose-dependent insulin secretion, suppressing unnecessary glucagon secretion, increasing satiety, and slowing gastric emptying. These unique mechanisms of action result in several positive effects and therefore we are seeing the development of more and more medications in this drug class. The major benefits from GLP-1 receptor agonists are an average estimated decrease in HbA1c of about 1%-1.5%, weight loss, and improved cardiovascular outcomes. Recent cardiovascular outcomes trials such as LEADER and SUSTAIN-6 have provided evidence to support the American Diabetes  Association’s decision to recommend GLP-1 receptor agonists as well as SGLT2 inhibitors for diabetes patients with high risk for ASCVD. Currently, phase III clinical trials are in progress for one of Sanofi’s newest antidiabetic drugs, efpeglenatide; a recent phase II trial’s results for the drug have been released.

EXCEED 203 was a 12-week, randomized, placebo-controlled, double-blind, parallel-group, dose-ranging study of efpeglenatide once weekly, referenced to open-label liraglutide 1.8 mg as an exploratory analysis. The objective was to analyze the efficacy, safety, and tolerability of efpeglenatide. 252 patients were randomized to one of five efpeglenatide doses (0.3 mg, 1 mg, 2 mg, 3 mg, 4 mg, n = 181), placebo (n = 37), or liraglutide 1.8 mg (n = 36). Most patients were taking metformin while others were not on any other diabetes medications. The primary efficacy endpoint was the change in HbA1c from baseline, and HbA1c was also used to assess non-inferiority to open-label liraglutide. Secondary efficacy endpoints consisted of the percentage of patients who achieved HbA1c <7% or 6.5% at week 13, change from baseline in fasting blood glucose, 7-point blood glucose profiles, body weight, and lipid profiles. Safety assessments included treatment-emergent adverse effects (TEAEs), clinical laboratory assessments, vital signs, electrocardiogram (ECG) variables, and injection-site reactions. A mixed-model repeated measures (MMRM) analysis was used for both the primary and secondary endpoints.

Results displayed a significant dose-dependent reduction in HbA1c from baseline to week 13 in patients taking efpeglenatide. The 3 mg group experienced an average decrease of 1.41%  0.12 (LS mean) (p < 0.05) and the 4 mg group experienced an average decrease in HbA1c of 1.61  0.12 (LS mean) (p < 0.05). This compares to the placebo group who experienced a decrease of 0.40%  0.11 (LS mean). Efpeglenatide also displayed a significant dose-dependent reduction in body weight. The 3 mg group displayed an average weight loss of 2.73 kg  0.55 (LS mean) (p < 0.05) and the 4 mg group displayed an average weight loss of 0.31 kg 0.54 (LS mean) (p < 0.05). The placebo group showed an average weight loss of 1.29 kg  0.51 (LS mean). For reference, the liraglutide group experienced an average decrease in HbA1c of 1.38  0.12 and an average weight loss of 3.21 kg  0.56.

In regards to safety and tolerability, the most common TEAEs within the efpeglenatide group were nausea (20.1%), vomiting (9.5%) and headache (8.9%) compared to placebo TEAEs of nausea (16.2%) and headache (13.5%). The liraglutide group experienced nausea (33.3%), injection-site bruising (19.4%) and vomiting (13.9%) most often.

In summary, in the EXCEED study, efpeglenatide  1 mg once weekly demonstrated significant, dose-dependent reductions in HbA1c and efpeglenatide  1 mg led to significant reductions in body weight in patients with type 2 diabetes, with or without metformin. The safety profile of efpeglenatide was consistent with the GLP-1 receptor agonist drug class. Efpeglenatide 4 mg was non-inferior to liraglutide.

Practice Pearls:

  • Efpeglenatide is a GLP-1 receptor agonist currently in phase III clinical trials.
  •  In the EXCEED phase II study, efpeglenatide was shown to be both effective, safe and tolerable.
  •  When approved, efpeglenatide may be an effective option for patients with type 2 diabetes.

Rosenstock, Julio, et al. “Once-Weekly Efpeglenatide Dose-Range Effects on Glycemic Control and Body Weight in Patients With Type 2 Diabetes on Metformin or Drug Naive, Referenced to Liraglutide.” Diabetes Care, 2019, p. dc182648., doi:10.2337/dc18-2648.

Amber Satz, PharmD Candidate, LECOM School of Pharmacy