STOCKHOLM – The ultra-long-acting GLP-1 receptor agonist efpeglenatide was efficacious when given once a month and improved glycemic control versus placebo, according to interim data from a 16-week, phase II study involving just over 200 patients with type 2 diabetes.
However, “tolerability and safety seem critical for final dose selection of a monthly regimen,” said Dr. Stefano Del Prato of the University of Pisa in Italy. He presented the findings at the annual meeting of the European Association for the Study of Diabetes.
Efpeglenatide is a new incretin-based therapy being developed by the South Korea–based company Hanmi Pharmaceutical. It has been created via the company’s LAPSCOVERY (Long Acting Protein/Peptide Discovery Platform) Technology whereby the therapeutic agent (GLP-1) is conjugated with a human immunoglobulin G Fc fragment via a linking molecule. This makes a larger molecule that extends the half-life to make it suitable for less frequent (weekly or monthly) dosing.
Dr. Del Prato noted that in a previous study reported at the American Diabetes Association annual scientific sessions in June (Diabetes. 2015;64:A73), efpeglenatide administered once weekly had been shown to be noninferior to once-daily liraglutide in terms of improved hemoglobin A1c from baseline. The aim of the present study was to see whether the interval between doses could be extended further and what might be the optimal dose for monthly administration.
Data were presented on 209 patients enrolled in the trial. The mean age was 56 years and mean diabetes duration, 7 years. Patients had been treated with metformin for an average of 4 years but had unsatisfactory glycemic control despite being on stable doses for at least 3 months.
Patients were randomized to treatment with one of three monthly doses of efpeglenatide (8 mg, 12 mg, or 16 mg) or to placebo. Initially all patients randomized to the active treatment received a 4-mg weekly dose for 4 weeks before the dose was increased to a monthly 8-mg dose for 4 weeks, then either continued (n = 51) or raised again to 12 mg (n = 52) or 16 mg (n = 53) for the remainder of the study.
Overall, 158 patients completed the 16-week trial and a 6-week follow-up phase. The main reasons for treatment discontinuation was patient decision (n = 11), nausea (n = 5), or vomiting (n = 7) in the active treatment groups, or serious adverse event (n = 4).
The mean change in HbA1c over time was the primary endpoint and all three doses of efpeglenatide significantly reduced HbA1c to a greater extent than did placebo, with final recorded values of 6.92%, 6.64%, and 6.74% for the 8-mg, 12-mg, and 16-mg doses, respectively, and 7.56% for placebo. There was no significant difference seen between the three efpeglenatide doses. The respective mean changes in HbA1c from baseline to week 17 were –0.66%, –0.67%, –0.79%, and –0.32%.
The percentage of patients achieving an HbA1c of less than 7% or 6.5% or lower were 57.7% and 34.6% for the 8-mg dose, 63.5% and 50% for the 12-mg dose, 57.7% and 36.5% for the 16-mg dose, and 30.6% and 12.2% for placebo. The differences between the doses were not significant, but all values were significant versus placebo.
Greater reductions in fasting plasma glucose were seen comparing active treatment (–0.78, –0.45, –0.79 mmol/L) versus placebo (–0.07 mmol/L). Body weight was lowered to a greater extent by all doses of efpeglenatide when compared to placebo (–1.78, –3.05, –2.20 kg vs. –0.34 kg).
Dr. Del Prato noted that all three doses seemed effective and were likely to be within the maximal dosage range. There might be some differences in tolerability, however, with patient-reported hypoglycemia occurring more frequently with the highest dose use (17% vs. 2% for placebo and 11.5% for the 8-mg and 13.5% for the 12-mg doses). Nausea and vomiting, which subsided over the course of treatment, tended to recur after the second monthly dose and thereafter with the highest doses of efpeglenatide.
A slight increase of five to eight or nine beats per minute was observed in the patients who received efpeglenatide versus placebo, and there was a slight drop in systolic blood pressure over time.
“The use of GLP-1 receptor agonists, in particular long-acting GLP-1 receptor agonists, is becoming more common, because of their well-known effects on glucose-dependent insulin secretion and glucose-dependent inhibitor of glucagon release,” Dr. Del Prato observed. “These effects, together with the reduction in body weight and effect on gastric emptying results in very appealing possibilities or opportunities for treatment in type 2 diabetes.”
He concluded: “Once-monthly efpeglenatide therapy is efficacious in type 2 diabetic patients inadequately controlled with metformin.”