When doses were increased rapidly in a Phase I study, patients on Roche’s investigational oral GLP-1 receptor agonist experienced nausea, vomiting, constipation, diarrhea, as well as abdominal distension.
Roche’s investigational obesity pill CT-996 appears to have substantial safety concerns, according to data presented on Wednesday at the 2024 annual meeting of the European Association for the Study of Diabetes.
After four weeks, patients whose CT-996 doses were ramped up rapidly lost 7.3% of their body weight, while placebo comparators saw weight loss of 1.2% in the same time frame. Patients treated with the more aggressive schedule were given CT-996 at an initial dose of 10 mg, which was gradually increased every three to seven days to a peak of 120 mg.
Rapid dose escalation appeared to carry safety concerns, according to the pharma’s presentation. Nausea arose in around 85% of these patients, as did gastrointestinal esophageal reflux disease (GERD). Vomiting, constipation, diarrhea and abdominal and distention were all common in patients who were treated more aggressively.
By comparison, a more gradual up-titration of CT-996 dose appeared to improve its tolerability, Roche noted. GERD and vomiting, in particular, all arose much less frequently in patients whose doses were increased slowly. The efficacy of this gentler schedule, however, was markedly weaker with patients losing 2.3% of their body weight at four weeks. This effect did not represent a significant advantage over placebo.
Roche highlighted in its presentation that all adverse events were mild or moderate across all dosing cohorts. The prevalence of gastrointestinal side effects was also consistent with the safety profile of the incretin drug class, and despite the rapid up-titration of doses in some patients, there were no unexpected safety signals. None of the patients dropped out of the study due to toxicities.
Despite the company’s efforts to allay concerns about CT-996’s safety profile, investors were still disappointed and company’s shares dropped 5% in reaction to the data drop, according to SeekingAlpha. Obesity frontrunners Novo Nordisk and Eli Lilly gained 4% and 2%, respectively.
Analysts are ambivalent about CT-996’s prospects. Truist Securities analyst Joon Lee wrote in a note to investors that “while efficacy looks strong relative to peers, we think CT-996 came up short on safety and tolerability.”
BMO Capital Markets analyst Evan Seigerman also acknowledged that CT-996’s safety data “leaves questions for some investors,” who will likely choose to stay “on the sidelines as they wait to see if the company can improve tolerability” in Phase II studies. Still, he concedes that Wednesday’s data are still “very early” and come from a “small sample size of patients.”
Roche will start Phase II studies for CT-996 next year.
CT-996 is an orally available, once-daily investigational obesity pill that activates the GLP-1 receptor, in turn promoting the secretion of insulin from the pancreas. The drug candidate also helps suppress appetite. CT-996 was originally developed by Carmot Therapeutics, which Roche acquired in December 2023 for $2.7 billion.
In July 2024, the company released initial data for CT-996, first revealing that treatment resulted in a 7.3% drop in body weight.
