Cofrogliptin

We conducted a multicentre, randomized phase 3 trial in China to evaluate the efficacy and safety of cofrogliptin (HSK7653), a novel long‐acting dipeptidyl peptidase‐4 inhibitor, in patients with drug‐naïve type 2 diabetes (T2D).

Patients with inadequately controlled T2D were randomly assigned (1:1:1) to cofrogliptin 10 mg, cofrogliptin 25 mg or placebo, taken orally once every 2 weeks for a 24‐week double‐blind period. Eligible patients then received cofrogliptin 25 mg in a 28‐week open‐label extension. The primary endpoint was the change in glycated haemoglobin (HbA 1c ) from baseline to week 24.

In total, 475 patients (median age: 54.0 years) were randomized and received at least one dose of cofrogliptin 10 mg ( n  = 158), cofrogliptin 25 mg ( n  = 158) or placebo ( n  = 159); 401 patients entered the open‐label extension. At week 24, the least‐squares (LS) mean difference (95% confidence interval [CI]) in HbA 1c versus placebo was −0.63% (−0.81, −0.46) with cofrogliptin 10 mg and −0.59% (−0.77, −0.42) with cofrogliptin 25 mg (both p  < 0.0001). The LS mean (standard error) change in HbA 1c from baseline was maintained at the end of the study in patients given open‐label cofrogliptin 25 mg for an additional 28 weeks: cofrogliptin 10 mg: −0.86% (0.07); cofrogliptin 25 mg: −0.74% (0.07); placebo: −0.89% (0.07). Over the entire study, common adverse events were hyperuricaemia, hyperlipidaemia, hypertriglyceridaemia, increased lipase, upper respiratory tract infection and urinary tract infection. Hypoglycaemic events did not significantly differ between groups.

Cofrogliptin provided glycaemic control over 52 weeks and was generally well tolerated in patients with T2D.

Registered on Clinicaltrials.gov with the registration number NCT04556851 ( https://clinicaltrials.gov/study/NCT04556851 ).

Cofrogliptin (HSK7653) is a long‐acting dipeptidyl peptidase‐4 inhibitor for the treatment of type 2 diabetes mellitus with a twice‐monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12‐lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration‐QT interval corrected for heart rate (C‐QTc) analysis, we used linear mixed‐effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (ΔQTcF). The result showed that a placebo‐corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice‐monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.