Roche's Genentech Reports 22.5% Weight Loss in Phase II Trial of Obesity Drug CT-388
Genentech announced positive Phase II results for CT-388, a dual GLP-1/GIP receptor agonist, showing 22.5% placebo-adjusted weight loss at 48 weeks in people with obesity. The treatment was well-tolerated with low discontinuation rates.
Genentech, a member of the Roche Group, announced positive topline results from CT388-103, a Phase II clinical trial of CT-388, an investigational dual GLP-1/GIP receptor agonist being developed for the treatment of obesity. The study found that once-weekly subcutaneous injections of CT-388 (titrated up to 24 mg) resulted in significant and clinically meaningful placebo-adjusted weight loss of 22.5% (efficacy estimand) without reaching a weight loss plateau at 48 weeks.
A clear dose-response relationship on the weight loss was observed. For the treatment-regimen estimand, the placebo-adjusted weight loss achieved with CT-388 was 18.3% (p-value < 0.001). At week 48 for the 24 mg dose, 95.7% of CT-388 treated participants achieved a weight loss of ≥5%, 87% achieved ≥10%, 47.8% achieved ≥20%, and 26.1% achieved ≥30%. 73% of participants who were pre-diabetic at baseline and treated with CT-388 at 24 mg achieved normal blood glucose levels at week 48 compared to 7.5% in the placebo group.
The treatment was well-tolerated, with the majority of gastrointestinal-related adverse events being mild-to-moderate, generally consistent with the incretin class of medicines. The treatment discontinuation rate due to adverse events was low (5.9% in CT-388 arms; 1.3% in placebo arm).
The multi-center, randomized, double-blind, placebo-controlled, parallel group dose-finding Phase II trial was designed to evaluate the efficacy and safety of CT-388 at low, middle, and high doses in 469 people with obesity. It includes adults with obesity (BMI≥30.0 kg/m2) or overweight (BMI ≥27.0 and <30.0 kg/m2) with at least one weight-related comorbidity without type 2 diabetes and evaluated five dosing cohorts with different up-titration schemes with 24 mg being the highest dose tested. The primary endpoint was percent change in body weight from baseline to week 48.
CT-388 is currently being investigated in an additional Phase II study (CT388-104) to evaluate the efficacy, safety and tolerability of CT-388 in participants who are living with obesity or are overweight and have type 2 diabetes. The Phase III clinical trial program of CT-388 in obesity (Enith1 and Enith2) is expected to start this quarter. In addition to offering robust efficacy as a standalone therapy, CT-388 also plays a key role in unlocking the promise of the obesity pipeline and is considered as a combination asset for petrelintide.
CT-388 is an investigational once-weekly subcutaneous injectable, dual GLP-1/GIP receptor agonist being developed for the treatment of obesity, type 2 diabetes, and other obesity-related comorbidities. It aims to reduce appetite and regulate blood sugar by selectively targeting and activating both receptors which integrate nutrient-derived signals to control energy homeostasis. CT-388 was designed to have potent activation of both GLP-1 and GIP receptors, but with minimal to no ß-arrestin recruitment on either receptor. This biased signaling significantly minimizes receptor internalization and consequent desensitization, which is expected to lead to prolonged pharmacological activity.
The CEO stated that the company expects to be among the top three players in the weight-loss drug market at a minimum, aiming to secure a double-digit market share in the sector. Roche's cardiometabolic portfolio includes multiple weight-loss drugs: CT-388 (a GLP-1/GIP dual receptor agonist) acquired through the acquisition of Carmot, CT-996 (an oral small-molecule GLP-1 receptor agonist), and CT-868 (an oral GLP-1/GIP dual receptor agonist). Additionally, it has Petrelintide, a long-acting amylin analog licensed from Zealand Pharma, Pegozafermin, a MASH drug obtained from the acquisition of 89bio, and Emugrobart, a self-developed MSTN monoclonal antibody.
According to phase 1b clinical data, a fixed-dose combination of CT-388 with petrelintide achieved an average weight loss of 8.6% over 16 weeks. CT-996 is a biased GLP-1R agonist oral small molecule currently in phase II trials for treating obesity and type 2 diabetes. Phase I trial results showed that CT-996 led to an average weight loss of 7.3% in obese patients without type 2 diabetes after four weeks of treatment. CT-868 is expected to enter phase III clinical trials for type 1 diabetes treatment by 2026.
By 2035, over four billion people (more than half of the global population) are projected to be living with excess weight or obesity, a trend affecting nearly every country. This rise is driven by a complex mix of genetics and biology as well as behavioral, environmental and socioeconomic factors, placing an increased strain on healthcare systems due to the associated burden of comorbidities and reduced quality of life.