Roche enicepatide hits both Phase II endpoints in T2D and obesity

Roche has reported positive topline results from CT-388-104, a Phase II trial of enicepatide (CT-388) in 447 adults living with type 2 diabetes and overweight or obesity. The once-weekly subcutaneous injection met both primary endpoints at 48 weeks, delivering statistically meaningful reductions in HbA1c and body weight at the highest titrated dose of 24 mg.

At that dose, patients achieved a mean HbA1c reduction of 2.65 percentage points from a baseline of 8.1%. In a harder-to-treat subgroup with poor baseline glycaemic control (HbA1c above 8.5%), the reduction reached 4.13 percentage points. By week 48, 90% of patients in the 24 mg arm had reached the T2D diagnostic threshold of 6.5% HbA1c, and 62% achieved normoglycaemia below 5.7%, a non-diabetic level. Mean weight loss at the highest dose was 15.5%, with no evidence of a plateau by the end of the study period.

Trial profile and tolerability

The CT-388-104 study (NCT06628362) was a randomised, double-blind, placebo-controlled, multi-centre trial. The discontinuation rate due to adverse events was 2.0% in enicepatide arms, against 0.0% in the placebo arm. The most common adverse events were mild-to-moderate gastrointestinal effects, consistent with the broader incretin drug class. Roche said no new safety signals were identified.

Levi Garraway, Roche's Chief Medical Officer and Head of Global Product Development, said the proportion of patients reaching normalised glucose levels within less than a year of treatment was "highly encouraging," adding that sustained weight loss alongside glycaemic control positions enicepatide as a candidate capable of reducing both acute and long-term metabolic complications.

Roche is already running two Phase III studies of enicepatide in chronic weight management, designated ENITH-1 and ENITH-2. It plans to initiate a Phase III glycaemic-control programme and cardiovascular outcomes trials in the first half of 2027.

Market context and competitive positioning

The GLP-1 agonist market is one of the most intensely contested in pharmaceutical development. Novo Nordisk's semaglutide and Eli Lilly's tirzepatide, a dual GLP-1/GIP agonist, have each set high commercial and clinical bars. Tirzepatide, in particular, is the closest structural comparator to enicepatide, both candidates targeting the same two receptor pathways. Roche acquired enicepatide through its purchase of Carmot Therapeutics in early 2024.

Roche's differentiation argument centres on the molecule's biased signalling design. Enicepatide is engineered to minimise beta-arrestin recruitment at both receptors, which the company says reduces receptor internalisation and desensitisation, potentially sustaining pharmacological activity over longer dosing periods. Whether this mechanistic distinction translates into a durable clinical advantage over tirzepatide or next-generation entrants will depend on head-to-head data, which has not yet been conducted.

The cardiometabolic space is attracting capital and late-stage programmes from a wide range of developers, including several mid-cap biotechs pursuing oral GLP-1 formulations that could shift the competitive landscape further. For Roche, the enicepatide data land at a strategic moment: the company has limited approved presence in the obesity category and is using this programme to build a broader cardiometabolic portfolio that integrates its diagnostics capabilities alongside its pharmaceutical pipeline. Full results from the Phase II study are expected to be presented at a forthcoming medical conference.