Excess body weight is driven in part by dysregulation of the gut-brain hormone signaling that controls appetite, energy intake and glucose metabolism. Roche has reported topline Phase II results from a randomized, placebo-controlled study of its investigational dual GLP-1/GIP receptor agonist CT-388 in adults living with obesity, showing statistically significant reductions in body weight at 48 weeks compared with placebo.
The once-weekly, subcutaneous therapy is being developed for chronic weight management and related cardiometabolic conditions.
The announcement covers the CT388-103 trial, a dose-finding Phase II study evaluating multiple up-titrated dose levels of CT-388, including a highest dose of 24 mg.
Obesity is a chronic disease associated with increased risk of type 2 diabetes, cardiovascular disease and other complications, and current pharmacologic options are largely centered on incretin-based therapies that target the GLP-1 pathway, with some newer agents also engaging the GIP receptor.
CT-388 is designed to activate both GLP-1 and GIP receptors, gut-derived hormone pathways involved in appetite regulation and glucose metabolism.
The molecule was engineered to favor sustained receptor signaling by limiting β-arrestin-mediated receptor internalization and desensitization, a design feature intended to support prolonged pharmacologic activity.
The Phase II study was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that enrolled 469 adults with obesity or who were overweight with at least one weight-related comorbidity, excluding type 2 diabetes.
Participants were assigned to one of five CT-388 dose groups using different up-titration regimens, or to placebo, and were treated for 48 weeks.
The primary endpoint was percent change in body weight from baseline to Week 48. Secondary endpoints included categorical weight-loss thresholds and metabolic measures.
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At the highest tested dose of 24 mg, CT-388 achieved a placebo-adjusted mean body-weight reduction of 22.5% at 48 weeks based on the efficacy estimand, which reflects outcomes assuming participants remained on their assigned treatment.
Using the treatment-regimen estimand, which accounts for treatment discontinuation, the placebo-adjusted weight loss was 18.3%.
Roche reported a clear dose-response relationship across the evaluated dose levels and noted that a weight-loss plateau was not observed by Week 48 in the 24-mg group.
Categorical analyses showed a graded, dose-related pattern of weight loss at Week 48 in the 24-mg cohort. Almost all participants (95.7%) achieved at least a 5% weight reduction, and 26.1% achieved a weight loss of 30% or greater.
More than half of participants receiving 24 mg had a body mass index below 30 at Week 48, compared with 13% in the placebo group.
Among those with prediabetes at baseline, 73% in the 24-mg group had normal blood glucose levels at Week 48, versus 7.5% with placebo.
Safety findings were described as generally consistent with the known profile of incretin-based therapies and the most common adverse events were gastrointestinal and were mostly mild to moderate in severity.
Whether weight loss continues beyond 48 weeks, plateaus with longer follow-up or differs across cardiometabolic subgroups will be evaluated in ongoing and planned Phase III studies, according to the sponsor.
Roche stated that the full data set from CT388-103 will be presented at an upcoming medical congress. The company also noted that CT-388 is being evaluated in an additional Phase II study (CT388-104) in individuals with obesity or overweight and type 2 diabetes and that a Phase III clinical program in obesity is expected to begin in the current quarter.
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Incretin and Combination Strategies in Development
Other incretin-based and incretin-adjacent approaches are also advancing in mid- to late-stage development for obesity.
Viking Therapeutics is evaluating its dual GLP-1/GIP receptor agonist VK2735 as a once-weekly subcutaneous injection in ongoing Phase III VANQUISH trials for chronic weight management, while an oral formulation is in earlier-stage development.
Programs are also exploring combination strategies with tirzepatide. Last year, Palatin Technologies reported Phase II data for the melanocortin-4 receptor agonist bremelanotide, administered daily by subcutaneous injection, in combination with weekly tirzepatide, examining whether central appetite-regulation pathways can augment incretin-mediated weight loss and support weight-loss maintenance.
OrsoBio is developing the oral, liver-targeted mitochondrial protonophore TLC-6740 as an add-on to tirzepatide to increase energy expenditure, with a larger Phase IIb study planned.
Beyond incretin signaling, Arrowhead Pharmaceuticals is evaluating RNA interference therapies targeting the Activin E and ALK7 pathways in early-stage trials, administered by subcutaneous injection, to modify adipose tissue biology and body composition in people with obesity and type 2 diabetes.
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