Survodutide passes cardiovascular safety test in Phase 3 obesity trial

Boehringer Ingelheim’s survodutide, a dual agonist at the glucagon and GLP-1 receptors, met its primary cardiovascular safety endpoint in SYNCHRONIZE-CVOT, a Phase 3 study that was the first global cardiovascular safety trial for this drug class, according to results presented Monday during the American Heart Association Scientific Sessions in Chicago and published simultaneously in The Lancet. The double-blind, placebo-controlled trial enrolled 5,530 adults with obesity or overweight who had established cardiovascular disease or chronic kidney disease, or at least two weight-related complications or cardiovascular risk factors. Participants received weekly survodutide 3.6 mg, survodutide 6.0 mg, or placebo. The primary endpoint was time to first occurrence of five-point major adverse cardiovascular events: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, ischemia-related coronary revascularization, or heart failure events.

On the treatment-regimen estimand, which counts events regardless of adherence or use of other therapies, survodutide was associated with a hazard ratio of 0.89 for five-point MACE (95% confidence interval 0.67 to 1.18; p<0.0001 for the non-inferiority test). The key secondary three-point MACE endpoint, comprising cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, also met non-inferiority with a hazard ratio of 0.84 (95% confidence interval 0.60 to 1.18; p<0.0001). Because both confidence intervals crossed 1, the trial met its non-inferiority objective but did not show a statistically significant reduction in cardiovascular events.

Secondary endpoints showed cardiometabolic improvements at 72 weeks. Using the supplementary secondary estimand, systolic blood pressure fell by up to 6.68 mmHg in the survodutide group compared with 1.76 mmHg in the placebo group (P=0.0001), and waist circumference fell by up to 11.96 cm versus 2.74 cm. Body weight fell by up to 13.7% with survodutide compared with 2.0% with placebo in a population at elevated cardiovascular risk that included people with type 2 diabetes. Reductions were also seen in high-sensitivity C-reactive protein and triglycerides.

Fierce Biotech reported that the 13.7% weight loss is slightly below the 15% that Eli Lilly has promoted for Zepbound over a similar time frame, while noting the limitations of cross-trial comparisons. Neerja Balachander, who leads clinical development and medical affairs in Boehringer’s cardio-renal-metabolism division, told Fierce ahead of the readout that she was "super thrilled by the result." She said survodutide targets "those people that want to lose the metabolically bad fat and want to conserve muscle."

Gastrointestinal adverse events were the most common side effects and were mostly mild to moderate, with nausea, vomiting, diarrhea, and constipation reported more often than with placebo. Treatment discontinuation due to gastrointestinal events occurred in 19.3% of participants receiving survodutide 3.6 mg and 20.8% of those receiving 6.0 mg, compared with 1.9% in the placebo group. Most discontinuations happened during dose escalation, when the initial protocol allowed limited flexibility to adjust or interrupt dosing. Boehringer said upcoming Phase 3b studies will use more flexible titration strategies. Fierce Biotech noted that the discontinuation rate compares unfavorably with reported discontinuations due to adverse events of 2.6% to 7.1% for Zepbound or Wegovy, depending on dose.

The results complete the registrational SYNCHRONIZE program for obesity, according to Zealand Pharma. Boehringer plans to proceed with global regulatory submissions in obesity. Balachander told Fierce that the company aims to submit a weight-loss approval application to the FDA "at some time in the next year," and that Boehringer is pursuing approval for both weight loss and MASH. Survodutide remains investigational and has not been approved.

Survodutide is also being evaluated in two global Phase 3 trials, LIVERAGE and LIVERAGE-Cirrhosis, in adults with MASH and fibrosis, and in additional Phase 3b studies in women’s health and fatty liver disease.