Date: 2016-09-16
Type of information: Results
phase: 3
Announcement: results
Company: Novo Nordisk (Denmark)
Product: semaglutide
Action
mechanism: glucagon-like Peptide 1 (GLP-1) analogue. Semaglutide is a human GLP-1 (Glucagon-Like Peptide-1) analogue developed for once-weekly treatment of type 2 diabetes patients. The mechanism behind blood glucose lowering and reduction of body weight follows the same principles as liraglutide (Victoza®); however, with a longer intrinsic circulation half-life. Hence, the semaglutide molecule has a pharmacokinetic profile particularly suitable for once-weekly subcutaneous administration.
Disease: type 2 diabetes
Therapeutic area: Metabolic diseases
Country: Canada, Italy, Japan, Mexico, Russian Federation, South Africa, UK, USA
Trial
details: The SUSTAIN programme is a phase 3 clinical programme comprising six global trials of semaglutide administered once-weekly encompassing more than 7,000 people with type 2 diabetes. SUSTAIN 1 - a 30-week efficacy and safety trial of semaglutide versus placebo in 388 drug-naïve people with type 2 diabetes. This trial is conducted globally. The aim of this trial is to investigate efficacy and safety of semaglutide once-weekly versus placebo in drug-naïve subjects with type 2 diabetes. (SUSTAIN™ 1-Monotherapy). (NCT02054897) SUSTAIN 2 - a 56-week efficacy and safety trial of semaglutide versus sitagliptin once-daily as add-on to metformin and/or TZD in 1,231 people with type 2 diabetes. The aim of the trial is to evaluate efficacy and safety of semaglutide once-weekly versus sitagliptin once-daily as add-on to metformin and/or TZD (thiazolidinedione) in subjects with type 2 diabetes.(NCT01930188) SUSTAIN 3 - a 56-week efficacy and safety trial of semaglutide versus exenatide ER 2.0 mg once-weekly as add-on to 1-2 oral antidiabetic drugs in 811 people with type 2 diabetes. This trial is conducted in Europe and North and South America. The aim of the trial is to investigate the efficacy and safety of semaglutide once-weekly versus exenatide ER (extended release) 2.0 mg once-weekly as add-on to 1-2 oral antidiabetic drugs (OADs) in subjects with type 2 diabetes. (NCT01885208) SUSTAIN 4 - a 30-week efficacy and safety trial of semaglutide versus insulin glargine once-daily as add-on to metformin with or without sulphonylurea in 1,089 insulin-naïve people with type 2 diabetes. This trial is conducted in Africa, North and South America, Asia and Europe. The purpose of the trial is to compare the effect of once-weekly dosing of two dose levels of semaglutide versus insulin glargine once-daily on glycaemic control after 30 weeks of treatment in insulin-naïve subjects with type 2 diabetes. (NCT02128932) SUSTAIN 5 - a 30-week efficacy and safety trial of semaglutide versus placebo as add-on to basal insulin alone or basal insulin in combination with metformin in 397 people with type 2 diabetes. This trial is conducted in Asia, Europe and the United States of America (USA). The aim of the trial is to investigate efficacy and safety of semaglutide once weekly versus placebo as add-on to basal insulin alone or basal insulin in combination with metformin in subjects with type 2 diabetes. (NCT02305381) SUSTAIN 6 - a 2-year trial to evaluate cardiovascular and other long-term outcomes with semaglutide in 3,297 people with type 2 diabetes. This trial is conducted globally. The aim of the trial is to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes. The trial is event-driven, i.e. the maximum trial duration (up to max. 148 weeks) will depend on the accrual of major adverse cardiovascular events (MACE) in this trial and the remaining research programme. The incidence of MACE will be monitored throughout the trial which will be terminated according to plan when pre-specified stopping criteria are met. (NCT01720446)
Latest
news: * On September 16, 2016, Novo Nordisk announced that semaglutide administered once-weekly significantly reduced the risk of the primary composite endpoint of time to first occurrence of either cardiovascular (CV) death, non-fatal myocardial infarction (heart attack) or non-fatal stroke by 26% vs placebo, when added to standard of care in 3,297 adults with type 2 diabetes at high CV risk. These results were based on an accumulation of first major adverse CV events (MACE) in 254 people. The main results from SUSTAIN 6 were presented at the 52nd Annual Meeting of the European Association for the Study of Diabetes (EASD) 20162 and also published in the New England Journal of Medicine . * On April 28, 2016, Novo Nordisk announced the top-line results from the sixth and last global phase 3a trial, SUSTAIN6, for semaglutide. This double-blinded trial investigated the long-term cardiovascular and other safety outcomes of 0.5 mg and 1.0 mg semaglutide compared with placebo, both in addition to standard-of-care. In the trial, approximately 3,300 people with type 2 diabetes were treated for 104 weeks. The trial achieved its primary endpoint of showing non-inferiority of major cardiovascular events (MACE) with semaglutide compared with placebo, as well as a statistically significant reduction in cardiovascular risk. In the trial, around 250 MACE were accrued. The primary endpoint of the study was defined as the composite outcome of the first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.The safety profile of semaglutide in SUSTAIN 6 was as expected and consistent with previous semaglutide clinical studies. * On April 2, 2016, Novo Nordisk announced that findings from the first phase 3a clinical trial for semaglutide, an investigational glucagon-like peptide-1 (GLP-1) analogue, demonstrated that treatment with semaglutide administered once-weekly, significantly improved glycaemic control compared to placebo in adults with type 2 diabetes previously managed with diet and exercise alone. Results from the SUSTAIN 1 trial were presented * On September 25, 2015, Novo Nordisk announced the headline results from the second phase 3a trial for semaglutide, SUSTAIN3. The trial investigated the efficacy and safety of 1.0 mg semaglutide compared with 2.0 mg exenatide once-weekly after 56 weeks of treatment added on to 1-2 oral antidiabetic drugs in 813 people with type 2 diabetes. The trial achieved its objective by demonstrating that from a mean baseline HbA1c of 8.4%, people treated with 1.0 mg semaglutide achieved a statistically significant and superior improvement in HbA1c of 1.5% compared to the improvement in HbA1c of 0.9% with 2.0 mg exenatide once-weekly. * On July 10, 2015, Novo Nordisk announced the headline results from SUSTAIN1, the first phase 3a trial for semaglutide, a new GLP-1 analogue administered once-weekly. The trial investigated the efficacy and safety of 0.5 mg and 1.0 mg semaglutide as monotherapy during 30 weeks of treatment compared with placebo in 388 people with type 2 diabetes previously on diet and exercise. The trial achieved its primary objective by demonstrating that from a mean baseline HbA1c of 8.1%, people treated with doses of 0.5 mg and 1.0 mg semaglutide, achieved superior improvements in HbA1c of 1.5% and 1.6%, respectively, compared to no change in HbA1c in the placebo group. 74% and 73% of the people treated with 0.5 mg and 1.0 mg semaglutide, respectively, achieved the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) treatment target of HbA1c below 7% compared with 25% of the people treated with placebo. Furthermore, from a mean baseline of 92 kg, people treated with semaglutide in both doses of 0.5 mg and 1.0 mg experienced a superior weight loss of 3.8 kg and 4.6 kg, respectively, compared with a weight loss of 1.0 kg for people treated with placebo. In the trial, semaglutide appeared to have a safe and well-tolerated profile. The most common adverse events were related to the gastrointestinal system, primarily nausea, were comparable to Victoza® in similar trials and diminished over time. The discontinuation rates due to all adverse events for 0.5 mg and 1.0 mg semaglutide were 6% and 5% compared to a discontinuation rate of 2% for placebo. Novo Nordisk expects to announce headline results of the five remaining SUSTAIN trials within the next nine months. * On June 21, 2012, Novo Nordisk has announced the decision to initiate the global phase 3 development programme for semaglutide, a once-weekly human GLP-1 (Glucagon-Like Peptide-1) analogue. Semaglutide successfully completed phase 2 development in 2010. At that time, it was decided to compare semaglutide with a once-weekly formulation of liraglutide (Victoza®) being studied in phase 1 trials before selecting a candidate for phase 3 development. These, now completed, phase 1 trials reconfirmed the safety profile of liraglutide, but semaglutide has been assessed to have a more attractive profile for once-weekly administration. Consequently, Novo Nordisk has decided to focus on further development of semaglutide, while no further clinical activities with the once-weekly version of liraglutide are expected.
There was a significant 39% decrease in non-fatal stroke and a nonsignificant 26% decrease in non-fatal myocardial infarction and a neutral outcome (2% decrease) in CV death after only two years of treatment.
In this outcomes trial, from an overall mean baseline of 8.7%, semaglutide 0.5 mg and 1.0 mg significantly reduced HbA1c by -1.1% and -1.4% vs -0.4% for both placebo 0.5 mg and 1.0 mg at 104 weeks, when added to standard of care. In addition, from a mean baseline of 92.1 kg, adults treated with semaglutide 0.5 mg and 1.0 mg experienced superior and sustained weight loss of -3.6 kg and -4.9 kg, vs -0.7 kg for placebo 0.5 mg and -0.5 kg for placebo 1.0 mg.1
Fewer serious adverse events were seen with semaglutide vs placebo; however, treatment discontinuation due to adverse events was more frequent with semaglutide, mainly due to gastrointestinal events. The incidence of pancreatitis was lower with semaglutide vs placebo. In terms of microvascular complications, significantly fewer people treated with semaglutide (62 [3.8%]) vs placebo (100 [6.1%]) had new onset or worsening nephropathy while significantly more people treated with semaglutide (50 [3.0%]) vs placebo (29 [1.8%]) experienced diabetic retinopathy complications.1
Novo Nordisk expects to file semaglutide for regulatory review in the US and EU in the fourth quarter of 2016.
at the Endocrine Society’s 98th Annual Meeting and Expo (ENDO 2016) in Boston,MA, US. The 30-week SUSTAIN 1 trial, evaluating the efficacy and safety of semaglutide monotherapy vs placebo in 388 adults with type 2 diabetes,1 showed that, from a mean baseline HbA1c of 8.1%, adults treated with 0.5 mg and 1.0 mg semaglutide achieved
significantly greater HbA1c reductions of 1.5% and 1.6%, respectively, vs <0.1% with placebo. In addition, more adults treated with 0.5 mg and 1.0 mg semaglutide achieved HbA1c targets compared with placebo: HbA1c <7% (74% and 72% vs 25%) and ?6.5% (59% and 60% vs 13%). The trial also demonstrated that adults treated with 0.5 mg and 1.0
mg semaglutide achieved significantly greater reductions from baseline in mean body weight of 3.7 kg/8.16 lb and 4.5 kg/9.92 lb, respectively, vs 1.0 kg/2.20 lb with placebo. Furthermore, adults treated with both doses of semaglutide demonstrated significantly greater reductions from baseline in fasting plasma glucose compared with placebo
(2.5 mmol/L or 45.2 mg/dL and 2.3 mmol/L or 42.1 mg/dL, respectively, vs 0.6 mmol/L or 9.9 mg/dL).1
The most common adverse events observed for adults treated with 0.5 mg and 1.0 mg semaglutide and placebo were gastrointestinal, which were mainly mild or moderate (nausea: 20.3% and 23.8% vs 7.8%; vomiting: 3.9% and 6.9% vs 1.6%; diarrhoea: 12.5% and 10.8% vs 2.3%). The rate of nausea diminished over time. Comparable rates of severe adverse events were observed for adults treated with 0.5 mg and 1.0 mg semaglutide compared with placebo (5.5% and 5.4% vs 3.9%). The proportion of adults discontinuing due to adverse events was low across treatment groups (6.3% and 5.4% vs 2.3%).
* On December 17, 2015, Novo Nordisk announced the headline results from the fourth phase 3a trial for semaglutide, SUSTAIN2. The double-blinded trial investigated the efficacy and safety of 0.5 mg and 1.0 mg semaglutide compared with 100 mg sitagliptin, a once-daily DPP-IV inhibitor, after 56 weeks of treatment in 1,231 people with type 2 diabetes, where both drugs were added on to metformin, thiazolidinedione (TZD) or a combination of metformin/TZD. The trial successfully achieved its objective by demonstrating that from a mean baseline HbA1c of 8.1%, people treated with 0.5 mg or 1.0 mg semaglutide achieved a statistically significant and superior improvement in HbA1c of 1.3% and 1.6% respectively, compared to an improvement in HbA1c of 0.5% with 100 mg sitagliptin.
69% of the people treated with 0.5 mg semaglutide and 78% of the people treated with 1.0 mg semaglutide achieved the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) treatment target of HbA1c below 7% compared with 36% of the people treated with 100 mg sitagliptin.
Furthermore, from a mean baseline body weight of 89 kg, people treated with 0.5 mg and 1.0 mg semaglutide experienced a statistically significant and superior weight loss of 4.3 kg and 6.1 kg respectively, compared with a weight loss of 1.9 kg for people treated with 100 mg sitagliptin.
In the trial, semaglutide appeared to have a safe and well-tolerated profile. The most common adverse event was nausea which diminished over time. Nausea was reported by 18% of the people treated with 0.5 mg semaglutide and by 18% of the people treated with 1.0 mg semaglutide, compared with 7% of people treated with 100 mg sitagliptin. The discontinuation rate due to adverse events was 8% and 10% for people treated with 0.5 mg semaglutide and 1.0 mg semaglutide respectively, compared to 3% for people treated with 100 mg sitagliptin.
Novo Nordisk expects to announce headline results of the two remaining SUSTAIN trials in the first half of 2016.
66% of the people treated with 1.0 mg semaglutide achieved the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) treatment target of HbA1c below 7% compared with 40% of the people treated with 2.0 mg exenatide once-weekly.
Furthermore, from a mean baseline body weight of 96 kg, people treated with 1.0 mg semaglutide experienced a statistically significant and superior weight loss of 5.6 kg compared with a weight loss of 1.8 kg for people treated with 2.0 mg exenatide once-weekly.
In the trial, semaglutide appeared to have a safe and well-tolerated profile. The most common adverse event was nausea which diminished over time. Nausea was reported by 22% of people treated with 1.0 mg semaglutide once-weekly compared with 11% of people treated with 2.0 mg exenatide once-weekly. The discontinuation rate due to all adverse events for 1.0 mg semaglutide was 9.4% compared to 7.2% for 2.0 mg exenatide.
Novo Nordisk expects to announce headline results of the four remaining SUSTAIN trials within the next coming quarters.
Novo Nordisk now plans to initiate the first phase 3 study in the SUSTAIN™ programme in the first half of 2013. The global clinical development programme is expected to include more than 8,000 patients.
