Adults with obesity treated with semaglutide 2.4 mg achieved and maintained a significant amount of weight loss in a 68-

Data presented at ENDO 2021 demonstrate clinically relevant weight loss, without weight regain, in people treated with semaglutide 2.4 mg vs placebo in combination with lifestyle intervention.

BAGSVRD, Denmark, March 23, 2021 /PRNewswire/ -- New results from the STEP phase 3a clinical trial programme demonstrated weight loss with investigational treatment of once-weekly subcutaneous semaglutide 2.4 mg versus placebo. In the STEP 4 trial, study participants who reached the maintenance dose of semaglutide 2.4 mg during a 20-week run-in period were randomised to either continue treatment with semaglutide 2.4 mg or switch to placebo for 48 weeks.⁽¹⁾ The full results of the STEP 4 trial were presented today at the virtual Endocrine Society (ENDO) 2021 Annual Meeting and published in the Journal of the American Medical Association.

"For people with obesity, maintaining weight loss in the long term is challenging as both physiological and hormonal changes that occur following an initial weight loss can lead to weight regain. These changes, known as metabolic adaptation, result in lasting increased levels of hunger and desire to eat while reducing energy expenditure," said Dr Domenica Rubino, lead investigator of the STEP 4 trial and Director of Washington Center for Weight Management and Research. "Like any other chronic disease, obesity requires a long-term, individualised approach to care, inclusive of medication and lifestyle components."

Following the 20-week run-in period, people who continued treatment with semaglutide 2.4 mg for an additional 48 weeks continued to lose weight with a statistically significant additional mean weight loss of 7.9% ⁽¹⁾ (8.8% for the trial product estimand ⁽²⁾) from week 20 to week 68. People who were switched to placebo following the 20-week run-in period regained 6.9% ⁽¹⁾ of their body weight from week 20 to 68 (6.5% for the trial product estimand ⁽²⁾). The estimated treatment difference [ETD] for the treatment policy estimand was -14.8% (95% confidence interval [CI]: -16.0, -13.5; p<0.0001). People who stayed on semaglutide 2.4 mg throughout the entire 68-week trial achieved a total weight loss of 17.4% ⁽¹⁾ (18.2% for the trial product estimand ⁽²⁾). Both treatment groups followed a reduced-calorie diet and increased physical activity programme throughout the study.⁽¹⁾

"Obesity is a chronic disease that requires ongoing management and the results from STEP 4 trial strengthens the evidence around the potential of semaglutide 2.4 mg to transform the medical management of obesity," said Martin Holst Lange, executive vice president, Development at Novo Nordisk. "Millions of people living with obesity are in need of additional treatment options to help them lose weight and keep it off. The results from STEP 4 show that to sustain weight loss it is important to maintain treatment and that semaglutide 2.4 mg has the potential to offer sustained weight loss of more than 17% after 68 weeks of treatment."

The semaglutide 2.4 mg safety profile is in line with observations seen previously with GLP-1 receptor agonists. It is generally well-tolerated, and the most common adverse events among people treated with semaglutide 2.4 mg were gastrointestinal events.⁽¹⁾

About STEP 4 and the STEP clinical trial programme

STEP 4 was a 68-week phase 3a randomised, double-blind, multicentre, placebo-controlled trial that compared the safety and efficacy of once-weekly subcutaneous semaglutide 2.4 mg versus placebo on change in body weight. The trial was designed to assess the effect of continuing versus discontinuing semaglutide 2.4 mg in adults with obesity (BMI 30 kg/m²), or overweight (BMI 27 kg/m²) with at least one weight-related comorbidity and without type 2 diabetes (HbA_1c <6.5%). During the 20-week run-in period (Week 0 to Week 20), participants were treated with semaglutide (16 weeks escalation, followed by 4 weeks at the target dose) as an adjunct to lifestyle intervention (500 kcal/day diet together with 150 minutes/week of physical activity). Following the run-in period, the 803 people who reached the maintenance dose of semaglutide (2.4 mg) reduced their mean body weight from 107.2 kg (Week 0) to 96.1 kg (Week 20) and were randomised (in a 2:1 ratio) to continue treatment with semaglutide 2.4 mg or switch to placebo for a further 48 weeks (Week 20 to Week 68) with lifestyle intervention.⁽²⁾

The primary endpoint of the trial was the percentage change in body weight from randomisation (Week 20) to the end of treatment (Week 68). Confirmatory secondary endpoints included change in waist circumference, systolic blood pressure, and physical functioning score on the 36-item Short Form Survey (SF-36), assessed from randomisation (Week 20) to the end of treatment (Week 68). Supportive secondary endpoints included percent change in body weight from baseline (Week 0) to the end of treatment (Week 68).⁽²⁾

STEP (Semaglutide Treatment Effect in People with obesity) is a phase 3 clinical development programme with once-weekly subcutaneous semaglutide 2.4 mg in obesity. The global clinical phase 3a programme consists of four trials and has enrolled approximately 4,500 adults with overweight or obesity.⁽³⁾

About subcutaneous semaglutide 2.4 mg for weight management

Once-weekly semaglutide 2.4 mg is under investigation for chronic weight management and not yet approved for people with obesity. It is currently under regulatory review in several countries, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

Semaglutide is an analogue of the human glucagon-like peptide-1 (GLP-1) hormone, with 94% similarity to the native human GLP-1 molecule. ^(4,5) It induces weight loss by reducing hunger, increasing feelings of fullness and thereby helping people eat less and reduce their food cravings.⁽⁴⁾

About obesity

Obesity is a chronic disease that requires long-term management.^(6,7) It is associated with many serious health complications and decreased life expectancy.^(8,9) Obesity-related complications are numerous and include type 2 diabetes,⁽⁷⁾ heart disease,⁽⁷⁾obstructive sleep apnoea,⁽¹⁰⁾ non-alcoholic fatty liver disease⁽¹¹⁾ and certain types of cancer.⁽¹²⁾ The current COVID-19 pandemic has highlighted that obesity also increases the risk for severe illness and hospitalisation due to COVID-19.^(13,14)

The global increase in the prevalence of obesity is a public health issue that has severe cost implications to healthcare systems. In 2016, 13% of adults, or approximately 650 million adults, were living with obesity worldwide.⁽¹⁵⁾

About Novo Nordisk

Novo Nordisk is a leading global healthcare company, founded in 1923 and headquartered in Denmark. Our purpose is to drive change to defeat diabetes and other serious chronic diseases such as obesity and rare blood and endocrine disorders. We do so by pioneering scientific breakthroughs, expanding access to our medicines and working to prevent and ultimately cure disease. Novo Nordisk employs about 45,000 people in 80 countries and markets its products in around 170 countries. For more information, visit novonordisk.com, Facebook, Twitter, LinkedIn, YouTube.

References:

1. Domenica R, Abrahamsson N, et al. Weight loss maintenance with once-weekly semaglutide 2.4 mg in adults with overweight or obesity reaching maintenance dose. Presented at ENDO Annual Meeting. March 20-23, 2021.
2. Warkentin LM, Das D, Majumdar SR, et al. The effect of weight loss on health-related quality of life: systematic review and meta-analysis of randomized trials. Obes Rev. 2014; 15:169182.
3. Kushner RF, Calanna S, Davies M, et al. Semaglutide 2.4 mg for the Treatment of Obesity: Key Elements of the STEP Trials 1 to 5. Obesity. 2020; 28:1050-1061.
4. Blundell J, Finlayson G, Axelsen M, et al. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab. 2017; 19:1242-1251.
5. Lau J, Bloch P, Schaffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 2015; 58:7370-7380.
6. Wadden TA, et al. Intensive Behavioral Therapy for Obesity Combined with Liraglutide 3.0 mg: A Randomized Controlled Trial. Obesity 2019;21:7586.
7. WHO. Obesity: Preventing and managing the global epidemic. Available at: http://www.who.int/iris/handle/10665/423... Last accessed: March 2021.
8. Peeters A, Barendregt JJ, Willekens F, et al. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med. 2003; 138:24-32.
9. Guh DP, Zhang W, Bansback N, et al. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009; 9:88.
10. Gami AS, Caples SM and Somers VK. Obesity and obstructive sleep apnea. Endocrinology and Metabolism Clinics of North America. 2003; 32:869-894.
11. Vernon G, Baranova A and Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011; 34:274-285.
12. Whitlock G, Lewington S, Sherliker P, et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009; 373:10831096.
13. Finer N, Garnett SP and Bruun JM. COVID-19 and obesity. Clin Obes. 2020; 10:e12365.
14. Ryan DH, Ravussin E and Heymsfield S. COVID 19 and the Patient with Obesity - The Editors Speak Out. Obesity (Silver Spring). 2020; 28:847.
15. Durrer Schutz D, Busetto L, Dicker D, et al. European Practical and Patient-Centred Guidelines for Adult Obesity Management in Primary Care. Obes Facts. 2019; 12:40-66.

(1) Based on the treatment policy estimand (primary statistical approach): treatment effect regardless of treatment adherence or initiation of other anti-obesity therapies

(2) Based on the trial product estimand (secondary statistical approach): treatment effect if all people adhered to treatment and did not initiate other anti-obesity therapies