Semaglutide Achieves Primary Endpoint in Phase III STEP 4 Trial with 17.4% Weight Loss at 68 Weeks

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Novo Nordisk recently announced the top-line results of the STEP 4 Phase IIIa clinical trial, which evaluated the weight-loss efficacy of semaglutide. This randomized, double-blind, multicenter, placebo-controlled withdrawal study assessed the efficacy and safety of semaglutide for continuous weight management. The 68-week trial, comprising a 20-week run-in period and a 48-week maintenance period, enrolled 902 patients with obesity or overweight and comorbidities to investigate the effects of semaglutide versus placebo on body weight.

During the 20-week dose-escalation period, 803 patients who received once-weekly subcutaneous semaglutide injections with dose titration reached the target dose of 2.4 mg, with mean body weight decreasing from 107.2 kg to 96.1 kg. Subsequently, these patients entered a maintenance phase and were randomized into two groups: one receiving semaglutide and the other receiving placebo, for continued treatment over 48 weeks.

Two statistical methods were employed in this study: (1) treatment strategy assessment (primary statistical method), which evaluates the treatment effect regardless of treatment adherence or the use of other weight-loss medications; and (2) trial product assessment (secondary statistical method), which evaluates the treatment effect under the assumption that all patients adhered to the study medication and did not use any other weight-loss medications.

The results demonstrated that the trial achieved its primary objective: the primary statistical analysis showed that, among all randomized patients, those who continued semaglutide treatment for 48 weeks experienced a further mean weight reduction of 7.9% from baseline at randomization; in contrast, patients in the placebo group had a mean weight increase of 6.9% from baseline at randomization, with the treatment difference between the two groups being statistically significant. Patients who received continuous semaglutide treatment for 68 weeks (20-week lead-in period + 48-week maintenance period) achieved a mean weight reduction of 17.4%.

Secondary statistical analyses showed that patients who continued semaglutide treatment for 48 weeks experienced a further mean weight reduction of 8.8% from the baseline at randomization, whereas the placebo group gained 6.5%, with a statistically significant difference between the two treatment groups. Patients who received continuous semaglutide treatment for 68 weeks achieved a mean weight reduction of 18.2%.

In the trial, semaglutide demonstrated a favorable safety and tolerability profile. Among patients receiving semaglutide treatment, the most common adverse events were gastrointestinal events. Consistent with previously published clinical trials of GLP-1 receptor agonists, most events were transient and mild to moderate in severity.

Obesity is a chronic disease requiring long-term treatment and is associated with many serious health consequences and reduced life expectancy. Obesity-related complications are numerous, including type 2 diabetes, heart disease, obstructive sleep apnea, chronic kidney disease, non-alcoholic fatty liver disease, and cancer.

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1 is a hormone that stimulates insulin secretion. Semaglutide lowers blood glucose levels and promotes weight loss by reducing hunger, increasing satiety, and decreasing food intake. Furthermore, semaglutide reduces the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

Novo Nordisk has developed two formulations of semaglutide: Ozempic, a once-weekly subcutaneous injection (0.5 mg, 1.0 mg), and Rybelsus, a once-daily oral formulation. Both products have been approved for the treatment of type 2 diabetes, and Ozempic has also been approved to reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

Currently, Novo Nordisk is investigating subcutaneous injection of semaglutide at a 2.4 mg dose as a treatment for obesity in adults. The STEP program is a Phase III clinical development project comprising four Phase IIIa trials, enrolling approximately 4,500 adults with overweight or obesity.

Furthermore, Novo Nordisk is also developing semaglutide for the treatment of other metabolic diseases, including non-alcoholic steatohepatitis (NASH). Last week, the company disclosed data from its Phase II clinical study on NASH in its first-quarter earnings report, showing that compared with placebo, semaglutide significantly resolved histological features of NASH in patients without exacerbating liver fibrosis.

Reference Source: Semaglutide 2.4 mg demonstrates superior and sustained weight loss versus placebo, with a 17.4% weight loss after 68 weeks in the STEP 4 trial