Novo Nordisk Submits sBLA for Once-Weekly Semaglutide 2.4 mg for Chronic Weight Management in Adults with Obesity or Overweight

On December 4, Novo Nordisk announced that it had submitted a marketing application to the U.S. Food and Drug Administration (FDA) for once-weekly subcutaneous semaglutide 2.4 mg, as an adjunct to a reduced-calorie diet and increased physical activity, for chronic weight management in adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) who have at least one weight-related comorbidity. To expedite the approval of semaglutide for the obesity indication, Novo Nordisk also utilized a priority review voucher, thereby shortening the review cycle for this supplemental Biologics License Application (sBLA) from the standard 10 months to 6 months.

Obesity is a chronic disease requiring long-term treatment and is associated with many serious health consequences and reduced life expectancy. Obesity also leads to numerous complications, including type 2 diabetes, heart disease, obstructive sleep apnea, chronic kidney disease, non-alcoholic fatty liver disease, and cancer. Semaglutide is a long-acting GLP-1 receptor agonist that has been developed and marketed for the treatment of type 2 diabetes. Novo Nordisk is also developing semaglutide as a new weight-loss medication, as it can reduce hunger and increase satiety, thereby helping patients eat less and reduce calorie intake.

Novo Nordisk’s submission of the marketing application for the weight-loss indication of semaglutide is primarily based on data from the Phase IIIa stage of the STEP clinical program. The STEP program mainly evaluates the therapeutic efficacy of once-weekly subcutaneous injection of 2.4 mg semaglutide versus placebo in patients with obesity. The Phase IIIa stage comprises four trials, which collectively enrolled approximately 4,500 adult patients with overweight or obesity, including:

STEP 1 Trial (Adjunctive Lifestyle Intervention) compared the 68-week safety and efficacy of once-weekly subcutaneous semaglutide 2.4 mg versus placebo in 1,961 adults with obesity or overweight. The results showed that patients in the intention-to-treat population achieved a 16.9% reduction in body weight after 68 weeks of treatment with semaglutide.

STEP 2 Trial (in obese patients with type 2 diabetes) compared the 68-week safety and efficacy of once-weekly subcutaneous semaglutide 2.4 mg versus placebo and semaglutide 1.0 mg in 1,210 adults with obesity or overweight. The results showed that patients in the intention-to-treat population experienced a 10.6% reduction in body weight after 68 weeks of semaglutide treatment.

The STEP 3 trial (adjunctive intensive behavioral therapy) compared the 68-week safety and efficacy of once-weekly subcutaneous semaglutide 2.4 mg versus placebo, both combined with intensive behavioral therapy, in 611 adults with obesity or overweight. The results showed that patients receiving semaglutide plus intensive behavioral therapy achieved a 17.6% reduction in body weight from a baseline mean of 105.8 kg.

STEP 4 Study (Randomized Withdrawal): In 803 adults with obesity or overweight who adhered to the 2.4 mg target dose (after a 20-week lead-in treatment period), the study compared the 48-week safety and efficacy differences between once-weekly subcutaneous semaglutide 2.4 mg and placebo. The results showed that patients who continued treatment with semaglutide 2.4 mg for 68 weeks achieved a total weight reduction of 18.2%.

The above data demonstrate that once-weekly subcutaneous injection of semaglutide 2.4 mg results in a statistically significant improvement in weight loss compared with placebo. In the STEP 1, STEP 3, and STEP 4 trials, semaglutide achieved a weight reduction of 16%–18%. Regarding safety, semaglutide exhibited a favorable safety and tolerability profile across the STEP program, with the most common adverse reactions being mild and transient gastrointestinal events.

Semaglutide was first approved by the FDA on December 5, 2017, as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. It is available as a subcutaneous injection at doses of 0.5 mg and 1 mg, administered once weekly. On September 20, 2019, the FDA approved once-daily oral semaglutide, available in 7 mg and 14 mg strengths. According to the company’s financial reports, global sales of Ozempic (semaglutide subcutaneous injection) reached $1.685 billion in 2019, with approximately $2.4 billion in sales during the first nine months of 2020. Sales of Rybelsus (oral semaglutide) amounted to approximately $166 million during the first nine months of 2020.

The weight-loss drug market represents a significant segment of the pharmaceutical industry. In the United States, more than two-thirds of the population is overweight or obese, with 40% having a body mass index (BMI) of 30 or higher. Since 2012, the U.S. Food and Drug Administration (FDA) has approved five new drugs for weight management: Vivus’s Qsymia (phentermine/topiramate, approved on July 17, 2012), Arena Pharmaceuticals’ Belviq (lorcaserin, approved on June 27, 2012), Orexigen Therapeutics’ Contrave (bupropion/naltrexone, approved on September 10, 2014), Novo Nordisk’s Saxenda (liraglutide, approved on December 23, 2014), and Rhythm Pharmaceuticals’ Imcivree (setmelanotide, approved on November 27, 2020). However, with the exception of Saxenda, the market performance of these drugs has fallen short of expectations.

To date, GLP-1 receptor agonist weight-loss drugs, represented by Saxenda, account for approximately 56% of the global market for prescription obesity medications. In 2019, global sales of Saxenda surged by 47%, reaching DKK 5.68 billion (approximately USD 850 million).

In terms of weight loss efficacy, 52 weeks (1 year) of treatment with Saxenda 3 mg reduced body weight by 4.5% compared with placebo in obese patients without diabetes, and by 3.7% compared with placebo in obese patients with diabetes. One year of treatment with Roche’s over-the-counter weight-loss medication Xenical (orlistat), combined with lifestyle interventions, resulted in a weight reduction of 11.4 kg, which was not significantly greater than the 7.5 kg reduction achieved with lifestyle interventions alone over one year.

Weekly subcutaneous injections of 2.4 mg for 68 weeks resulted in a total weight loss of 15%–18%, with the weight-loss benefit exceeding that of placebo by more than 25%. On May 8, Eli Lilly also released 36-week weight-loss data for the GLP-1 receptor agonist dulaglutide, showing that weekly subcutaneous injections of dulaglutide at doses of 1.5 mg, 3 mg, and 4.5 mg led to weight reductions of 3.1 kg, 4.0 kg, and 4.7 kg, respectively, from a baseline weight of 95.9 kg at week 36. Clearly, semaglutide is poised to be a disruptor in the weight-loss drug market.

Mads Krogsgaard Thomsen, Executive Vice President and Chief Scientific Officer at Novo Nordisk, stated: “Obesity is associated with a wide range of serious complications, yet many healthcare institutions still lack sufficiently effective means to help individuals living with this chronic disease. We are excited to have submitted the marketing application for semaglutide 2.4 mg to the U.S. regulatory authorities for weight management, and we believe that once-weekly semaglutide 2.4 mg has the potential to transform obesity care.”