Semaglutide Achieves 18.2% Weight Loss Over 68 Weeks: All Four Phase III STEP Trials Successfully Completed

June 14, 2020 News /BioValleyBIOON/ -- Novo Nordisk recently announced semaglutideWeight LossThe final two Phase IIIa studies in the efficacy Phase III STEP programClinical TrialTop-line results of (STEP 2, STEP 3). Among them, the STEP 2 trial in patients with type 2Diabetesconducted in adult patients with type 2 diabetes (T2D) and obesity/overweight; the STEP 3 trial was conducted in adult patients with obesity or overweight and comorbidities, evaluating semaglutide as an adjunct to intensive behavioral therapy (IBT). The results showed that once-weekly subcutaneous (SC) injection of semaglutide 2.4 mg resulted in a statistically significant reduction in body weight compared with placebo.

Semaglutide is a human glucagon-like peptide-1 (GLP-1) analog that promotes insulin secretion and inhibits glucagon secretion in a glucose concentration-dependent manner, enabling type 2DiabetesThe patient’s blood glucose levels improved significantly, with a low risk of hypoglycemia. In addition, semaglutide can induceWeight Loss. In addition, semaglutide can significantly reduce type 2DiabetesRisk of Major Adverse Cardiovascular Events (MACE) in Patients.

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

Novo Nordisk is investigating once-weekly subcutaneous semaglutide 2.4 mg as a treatment for obesity in adults. Semaglutide is a GLP-1 hormone analog that helps people eat less and reduce calorie intake by reducing hunger and increasing satiety, thereby inducingWeight Loss。

The STEP program (Semaglutide Treatment Effect in People with obesity) is a Phase III clinical development program evaluating the efficacy of once-weekly subcutaneous (SC) semaglutide at a 2.4 mg dose for weight management in adult patients with obesity. This global Phase IIIa clinical program comprises four Phase IIIa trials and has enrolled approximately 4,500 adults with overweight or obesity.

This study employed two statistical methods: (1) treatment strategy-based analysis (primary statistical method), which disregards treatment adherence or the initiation of otherWeight Losstherapeutic efficacy of the study drug; (2) evaluation based on the trial product (secondary statistical method), i.e., therapeutic efficacy in patients who adhered to the study drug regimen and did not initiate other weight-loss medications.

STEP 2 (Obesity and Type 2 Diabetes) was a 68-week, randomized, double-blind, multicenter, placebo-controlled trial that enrolled a total of 1,210 adult patients with type 2 diabetes and obesity or overweight. The study compared the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg, placebo, and once-weekly subcutaneous semaglutide 1.0 mg for weight reduction over 68 weeks, with all treatment groups receiving concomitant lifestyle interventions.

The trial met both primary endpoints, with data showing statistically significant differences:

——Key statistical methods showed that among all randomized patients, after 68 weeks of treatment, the SC semaglutide 2.4 mg group experienced a 9.6% reduction from a mean baseline body weight of 99.8 kg, the placebo group had a 3.4% reduction, and the SC semaglutide 1.0 mg group had a 7.0% reduction. After 68 weeks of treatment, 68.8% of patients in the SC semaglutide 2.4 mg group achieved ≥5% weight loss, compared with 28.5% in the placebo group.

—Secondary statistical methods showed that, in the intent-to-treat population, after 68 weeks of treatment, the mean weight reduction was 10.6% in the subcutaneous (SC) semaglutide 2.4 mg group, 3.1% in the placebo group, and 7.5% in the SC semaglutide 1.0 mg group. After 68 weeks of treatment, 73.2% of patients in the SC semaglutide 2.4 mg group achieved a weight loss of ≥5%, compared with 27.6% in the placebo group.

STEP 3 (Adjunctive Intensive Behavioral Therapy [IBT]) was a 68-week, randomized, double-blind, multicenter, placebo-controlled trial that enrolled 611 adult patients with obesity or overweight and comorbidities. The study compared the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo for weight reduction over 68 weeks. Both treatment groups received adjunctive IBT, defined as weekly behavioral support, nutritional counseling, and a reduced-calorie diet.

The trial met both primary endpoints, with data showing statistically significant differences:

——Key statistical methods showed that among all randomized patients, after 68 weeks of treatment, the SC semaglutide 2.4 mg + IBT group experienced a 16.0% reduction from a mean baseline body weight of 105.8 kg, whereas the placebo + IBT group experienced a 5.7% reduction. After 68 weeks of treatment, 86.6% of patients in the SC semaglutide 2.4 mg + IBT group achieved ≥5% weight loss, compared with 47.6% in the placebo + IBT group.

—Secondary statistical methods showed that among patients in the intention-to-treat population, after 68 weeks of treatment, the SC semaglutide 2.4 mg + IBT group experienced a 17.6% reduction in body weight, while the placebo + IBT group experienced a 5.0% reduction. After 68 weeks of treatment, 89.8% of patients in the SC semaglutide 2.4 mg + IBT group achieved ≥5% weight loss, compared to 50.0% in the placebo group.

STEP 4 (Withdrawal) was a 68-week, randomized, double-blind, multicenter, placebo-controlled withdrawal trial that enrolled 902 patients with obesity or overweight and comorbidities to compare the efficacy and safety of semaglutide versus placebo for continued weight management. The trial included a 20-week run-in period and a 48-week maintenance period. During the 20-week run-in period, after receiving dose-escalated semaglutide treatment, 803 patients 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 the maintenance period and were randomized into two groups: one group received once-weekly subcutaneous (SC) semaglutide 2.4 mg, and the other received once-weekly SC placebo, for a duration of 48 weeks.

The trial met both primary endpoints, with data showing statistically significant differences: patients who continued treatment with subcutaneous semaglutide 2.4 mg experienced further substantial weight loss, whereas those switched to placebo exhibited significant weight regain.

—Key statistical methods showed that among all randomized patients, those who continued treatment with subcutaneous (SC) semaglutide 2.4 mg for 48 weeks experienced a further mean weight reduction of 7.9% from the baseline at randomization (weight at the end of the run-in period); whereas patients receiving placebo had a mean weight increase of 6.9% from the baseline at randomization. The difference between the two treatment groups was statistically significant. Patients who received continuous once-weekly SC semaglutide treatment for 68 weeks (20-week run-in period + 48-week maintenance period) achieved a mean weight reduction of 17.4%.

— Secondary statistical analyses showed that among patients in the intent-to-treat population, those who continued treatment with subcutaneous (SC) semaglutide 2.4 mg for 48 weeks achieved a further mean weight reduction of 8.8% from the baseline at randomization (weight at the end of the run-in period); whereas patients receiving placebo experienced a mean weight increase of 6.5% from the baseline at randomization. The difference between the two treatment groups was statistically significant. Patients who received continuous once-weekly SC semaglutide treatment for 68 weeks achieved a mean weight reduction of 18.2%.

STEP 1 (Adjunctive Lifestyle Intervention) was a 68-week, randomized, double-blind, multicenter, placebo-controlled trial that enrolled 1,961 patients with obesity or overweight and comorbidities. The study compared the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo over 68 weeks for weight reduction, with both treatments combined with lifestyle intervention.

The trial met both primary endpoints, with data showing statistically significant differences, demonstrating that after 68 weeks of treatment, SC semaglutide 2.4 mg resulted in a statistically significant and superior reduction in body weight compared with placebo.

—Key statistical methods showed that among all randomized patients, after 68 weeks of treatment, the SC semaglutide 2.4 mg group experienced a 14.9% reduction from a mean baseline body weight of 105.3 kg, compared with a 2.4% reduction in the placebo group; 86.4% of patients in the SC semaglutide 2.4 mg group achieved ≥5% weight loss, versus 31.5% in the placebo group.

—Secondary statistical analyses showed that, in the intention-to-treat population, after 68 weeks of treatment, the subcutaneous semaglutide 2.4 mg group achieved a mean weight reduction of 16.9%, compared with 2.4% in the placebo group; 92.4% of patients in the subcutaneous semaglutide 2.4 mg group achieved ≥5% weight loss versus 33.1% in the placebo group, with statistically significant differences between groups.

In four trials, subcutaneous semaglutide 2.4 mg was safe and well tolerated, consistent with previous trials. Among patients treated with subcutaneous semaglutide 2.4 mg, the most common adverse events were gastrointestinal disorders. Most events were transient and of mild to moderate severity.

Mads Krogsgaard Thomsen, Executive Vice President and Chief Scientific Officer at Novo Nordisk, stated, “The results from STEP 2 and STEP 3 continue to build upon the impressive weight loss outcomes reported in the earlier STEP 1 and STEP 4 trials. In summary, the findings indicate that semaglutide 2.4 mg will play a pivotal role in improving the treatment of patients with obesity. We have now reported the results of all four trials in the STEP program, and we look forward to sharing these data with regulatory authorities.”

Currently, Novo Nordisk has developed both an injectable formulation (Ozempic) and an oral formulation (Rybelsus) of semaglutide:

——Ozempic (semaglutide, injectable formulation): is a once-weekly subcutaneous injection formulation (0.5 mg or 1 mg) indicated for: (1) as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus; (2) to reduce the risk of major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in adult patients with type 2 diabetes mellitus and established cardiovascular disease (CVD).

Ozempic was first approved by the U.S. FDA in December 2017 and is currently marketed and sold in many countries and regions worldwide. The drug’s second indication was approved by the U.S.FDAApproved. Data from the cardiovascular outcomes trial (CVOT) SUSTAIN 6 demonstrated that, in patients with type 2 diabetes at high cardiovascular (CV) risk, Ozempic, when added to standard care, significantly reduced the risk of the composite major adverse cardiovascular events (MACE) endpoint by 26% compared with placebo.

——Rybelsus (semaglutide, oral tablets): is a once-daily oral formulation containing the absorption-enhancing excipient SNAC. This medication is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Rybelsus is the world’s first and only oral GLP-1 receptor agonist, administered once daily, with two therapeutic doses: 7 mg and 14 mg.

In the United States, the label for Rybelsus was updated in January 2020 to include additional information from the PIONEER 6 cardiovascular outcomes trial (CVOT), which demonstrated cardiovascular (CV) safety. Conducted in patients with type 2 diabetes at high CV risk, the trial showed that Rybelsus, when added to standard care, met its primary endpoint of non-inferiority for the composite major adverse cardiovascular events (MACE) endpoint compared with placebo, thereby establishing CV safety. In the study, the proportion of patients who experienced at least one MACE event was 3.8% in the Rybelsus group and 4.8% in the placebo group. (Bioon.com)

Original Source: Semaglutide 2.4 mg shows superior weight loss versus placebo in the phase 3 trials STEP 2 and STEP 3, thereby successfully completing the programme