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Effect and safety of NN9535 in weight management (NN9536-4382)

Effect and safety of NN9535 in weight management (NN9536-4382)

401

The demographic and baseline characteristics for all randomised subjects were generally similar across treatment groups

This was a 68-week, randomised, double-blind, placebo-controlled, four-armed, parallel group, multi-centre, multinational clinical trial comparing semaglutide s.c. 2.4 mg once-weekly with semaglutide placebo once-weekly and semaglutide s.c. 1.7 mg once-weekly with semaglutide placebo once-weekly in subjects with overweight or obesity and with or without T2D. A total of 400 subjects with overweight or obesity were planned to receive treatment with either semaglutide 2.4 mg once weekly, semaglutide 1.7 mg once weekly or placebo once weekly as an adjunct to a reduced-calorie diet and increased physical activity. To mitigate the risk of gastrointestinal side effects, the trial included an initial dose escalation period of 12 weeks for the semaglutide 1.7 mg and of 16 weeks for the semaglutide 2.4 mg treatment group. Treatment was continued on the maintenance dose of 2.4 mg once weekly for an additional 52 weeks, or on semaglutide 1.7 mg for an additional 56 weeks, until week 68 (end of treatment). Accounting for the long half-life of semaglutide, a follow-up visit (end of trial) for safety assessments was scheduled 7 weeks after end of treatment to ensure complete wash-out for antibody assessments. 437 subjects were screened, 401 subjects were randomised, and 400 subjects were exposed to trial product. A total of 98.5% of subjects completed the trial.

Safety results Semaglutide 2.4 mg and 1.7 mg administered once weekly, as adjuncts to a reduced-calorie diet and increased physical　activity, were overall well tolerated in the presented trial conducted in East Asian subjects with overweight or obesity　and weight-related comorbidities. The safety and tolerability profile of semaglutide 2.4 mg and 1.7 mg was as expected　with a glucagon-like peptide-1 receptor agonist (GLP-1 RA). Adverse events The evaluation of AEs showed -Similar overall proportion of subjects with AEs with semaglutide 1.7 mg, semaglutide 2.4 mg and placebo(82.0%, 85.9% and 79.2%); but higher event rates with the two semaglutide doses than for placebo (354.6 and　303.3 vs 165.7 events per 100 PYE), driven primarily by gastrointestinal AEs -Similar proportion of subjects with SAEs with semaglutide 1.7 mg, semaglutide 2.4 mg and placebo (7.0%,5.0% and 6.9%), and event rates were similar but slightly higher for semaglutide 1.7 mg (7.3, 4.4 and 4.9 events per 100 PYE). -The proportion of subjects permanently discontinuing treatment due to AEs was low in all treatment groups, but slightly higher in the two semaglutide treatment groups than in the placebo group (3.0%, 2.5% vs 1.0%), again driven predominantly by gastrointestinal AEs　 -The majority of the AEs in all treatment groups were non-serious, of mild severity and reported as recovered Gastrointestinal AEs were more frequent with any of the semaglutide doses than placebo (59.3% for semaglutide 2.4 mg and 64% for semaglutide 1.7 mg vs 29.7% for placebo): -The difference was driven by constipation, diarrhoea, nausea, vomiting and different kinds of abdominal pain or discomfort -The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered -The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it remained stable throughout the trial The results of the other safety focus areas -None of the subjects without T2D at screening experienced AEs of hypoglycaemia. No severe or blood glucoseconfirmed symptomatic hypoglycaemic episodes were reported in any of the treatment groups in the subjects with T2D at screening. -The proportion of subjects with retinal disorder AEs was larger with semaglutide 2.4 mg than with 1.7 mg and placebo (14.3% for semaglutide 2.4 mg, 8.0% for semaglutide 1.7 mg and 8.0% for placebo) in the subjects with T2D at screening. Only few events of diabetic retinopathy were reported. -For the remaining of the safety focus areas, no noteworthy differences between treatment groups were seen. -There were no AEs of acute pancreatitis or AEs of suspected transmission of an infectious agent via trial product. Clinical laboratory evaluations Treatment with both doses of semaglutide resulted in increases in lipase and amylase vs placebo; the ratio to baseline at week　68 was: -Lipase: 1.56 (56% increase) in both semaglutide 2.4 mg and semaglutide 1.7 mg vs 0.96 (4% decrease) for placebo -Amylase: 1.08 (8% increase) in semaglutide 1.7 mg group, 1.09 (9% increase) in semaglutide 1.7 mg group, vs 0.93 (7% decrease) for placebo -The increase in lipase and amylase occurred during the initial 20 weeks of treatment, with no or little further increase. -Increases in amylase and lipase are well known from other GLP-1 RAs. The mechanism behind is unknown. In terms of risk of pancreatitis, the predictive value of isolated elevations of lipase and/or amylase is low as also seen in this trial. There was no change in calcitonin. The ratio to baseline at week 68 was: semaglutide 2.4 mg 0.95 (5% decrease), semaglutide 1.7 mg 0.98 (2% decrease) vs 0.94 (6% decrease) for placebo. The evaluation of other clinical laboratory parameters did not reveal any safety concerns. Vital signs Treatment with both doses of semaglutide resulted in an increase in pulse. The estimated change from baseline at week 68 was 4.38 beats/min for semaglutide 2.4 mg and 6.29 beats/min for semaglutide 1.7 mg vs 2.43 beats/min for placebo and the treatment differences vs placebo were: 1.95 beats/min ([-0.13; 4.03]95% CI) for semaglutide 2.4 mg and 3.86 beats/min ([1.45; 6.27]95% CI) for semaglutide 1.7 mg.

EFFICACY RESULTS In this trial, the treatment effect of semaglutide 2.4 mg and semaglutide 1.7 mg administered once weekly as adjuncts to a reduced-calorie diet and increased physical activity in subjects with overweight or obesity and with or without type 2 diabetes, was evaluated vs placebo. The treatment policy estimand (intention-to-treat principle) was the primary estimand and reflects the treatment effect of semaglutide 2.4 mg vs placebo and semaglutide 1.7 mg vs placebo regardless of adherence to treatment and regardless of starting anti-obesity therapies. The hypothetical estimand (ontreatment principle) reflects the treatment effect in subjects while on treatment with trial product and excluding the effect of any other anti-obesity therapies. The confirmatory evaluation was based on the treatment policy estimand. From baseline to week 68, superiority of semaglutide 2.4 mg vs placebo and of semaglutide 1.7 mg vs placebo was confirmed in the predefined fixed-sequence statistical testing hierarchy for the following primary and confirmatory secondary endpoints: 1. change in body weight (%) 2. achieving body weight loss >=5% 3. achieving body weight loss >=10% 4. achieving body weight loss >=15% 5. change in waist circumference Results are presented below together with related endpoints. Body weight The results for body weight related endpoints are provided in Table 4 and the conclusions are summarised below. Change in body weight (%) and body weight reduction >=5% at week 68 – primary endpoints -Superiority of semaglutide 2.4 mg vs placebo in body weight change (%) from baseline to week 68 as well as body weight reduction >=5% at week 68 was confirmed. The pre-specified sensitivity analyses supported the conclusion. -Superiority of semaglutide 1.7 mg vs placebo in body weight change (%) from baseline to week 68 as well as body weight reduction >=5% at week 68 was confirmed.

Other efficacy endpoints related to body weight – confirmatory and supportive secondary endpoints Superiority of semaglutide 2.4 mg and semaglutide 1.7 mg vs placebo on body weight was supported by the weightrelated secondary efficacy endpoints: -A statistically significantly greater proportion of subjects achieved a weight loss of >=10% or >=15% with both　semaglutide 2.4 mg and semaglutide 1.7 mg vs placebo. -The decrease in mean waist circumference was statistically significantly greater with semaglutide 2.4 mg and　semaglutide 1.7 mg vs placebo.

"-Semaglutide 2.4 mg and semaglutide 1.7 mg were superior to placebo with respect to weight loss (-13.19% vs-9.65% vs -2.12%; ETD Sema 2.4 mg:-11.06% [-12.88; -9.24]95% CI; ETD Sema 1.7 mg: −7.52% [−9.62; −5.43]95% CI), including 5, 10 and 15% weight loss responders and waist circumference "-Semaglutide 2.4 mg and semaglutide 1.7 mg were overall well tolerated and the safety and tolerability profiles were consistent with the GLP-1 RA class in general

Aug. 31, 2023

Feb. 04, 2022

https://pubmed.ncbi.nlm.nih.gov/35131037/

Yes

According to the Novo Nordisk disclosure commitment on novonordisk-trials.com URL:https://www.novonordisk-trials.com

Novo Nordisk Pharma Ltd.

Meiji Yasuda Seimei Bldg., 2-1-1, Marunouchi, Chiyoda-ku, Tokyo

Novo Nordisk Pharma Ltd.

Meiji Yasuda Seimei Bldg., 2-1-1, Marunouchi, Chiyoda-ku, Tokyo

completed

Jan. 21, 2019

Interventional

randomised, double-blind, parallel group, multi-center

treatment purpose

3

BMI >= 27.0 kg/m2 with >= 2 weight related comorbidities or BMI >= 35.0 kg/m2 with >= 1 weight related comorbidity

Severe heart failure, History of pancreatitis, Severe psychological disorder, other

Both

Overweight or obesity

investigational material(s)
Generic name etc : NN9535
INN of investigational material : -
Therapeutic category code : 249 Other hormone preparations (including antihormone preparations)
Dosage and Administration for Investigational material : once weekly subcutaneously

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

efficacy
Change from baseline in body weight (%)

safety
Number of treatment emergent adverse events (TEAEs) from baseline

Nov. 05, 2018