Background

Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue under investigation for weight management. We assessed the dose–response relationship of cagrilintide regarding the effects on bodyweight, safety, and tolerability.

Methods

We conducted a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial at 57 sites including hospitals, specialist clinics, and primary care centres in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA). Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m² or at least 27 kg/m² with hypertension or dyslipidaemia. Participants were randomly assigned (6:1) to subcutaneous self-injections of once-weekly cagrilintide (0·3, 0·6, 1·2, 2·4, or 4·5 mg), once-daily liraglutide 3·0 mg, or volume-matched placebo (for six placebo groups). The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked to the assigned study treatment with respect to active versus pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in bodyweight from baseline to week 26, assessed in all randomly assigned participants according to the trial product estimand (assuming all participants were adherent to treatment) and to the treatment policy estimand (regardless of adherence to treatment). Safety was assessed in all participants who received at least one dose of randomised treatment. This trial is registered with ClinicalTrials.gov, NCT03856047, and is closed to new participants.

Findings

Between March 1 and Aug 19, 2019, we randomly assigned 706 participants to cagrilintide 0·3–4·5 mg (100–102 per dose group), 99 to liraglutide 3·0 mg, and 101 to placebo. Permanent treatment discontinuation (n=73 [10%]) occurred similarly across treatment groups, mostly due to adverse events (n=30 [4%]). In total, 29 participants (4%) withdrew from the trial. According to the trial product estimand, mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0·3–4·5 mg, 6·0%–10·8% [6·4–11·5 kg]) versus placebo (3·0% [3·3 kg]; estimated treatment difference range 3·0%–7·8%; p<0·001). Weight reductions were also greater with cagrilintide 4·5 mg versus liraglutide 3·0 mg (10·8% [11·5 kg] vs 9·0% [9·6 kg]; estimated treatment difference 1·8%, p=0·03). Similar weight loss reductions were observed with the treatment policy estimand. The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0·3–4·5 mg had gastrointestinal adverse events compared with placebo (41%–63% vs 32%), primarily nausea (20%–47% vs 18%).

Interpretation

Treatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management.

Funding

Novo Nordisk A/S.

中文翻译：

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每周一次的卡格瑞肽用于超重和肥胖人群的体重管理：一项多中心、随机、双盲、安慰剂对照和活性药物对照的剂量发现 2 期试验

背景

天然胰淀素是一种诱导饱腹感的胰腺激素。卡格瑞肽是一种长效胰淀素类似物，正在研究用于体重管理。我们评估了卡格列肽对体重、安全性和耐受性影响的剂量反应关系。

方法

我们在 10 个国家（加拿大、丹麦、芬兰、爱尔兰、日本、波兰、塞尔维亚、南非、英国和美国）。符合条件的参与者是至少 18 岁且没有糖尿病的成年人，体重指数至少为 30 kg/m ²或至少 27 kg/m ²患有高血压或血脂异常。参与者被随机分配 (6:1) 皮下自行注射每周一次的卡格瑞肽（0·3、0·6、1·2、2·4 或 4·5 毫克），每天一次的利拉鲁肽 3·0毫克，或体积匹配的安慰剂（六个安慰剂组）。该试验有 26 周的治疗期，包括长达 6 周的剂量递增期和 6 周的无治疗随访期。参与者和研究人员被蒙蔽到分配的研究治疗与活性治疗与合并安慰剂治疗的比较，但不了解不同的活性治疗。主要终点是体重从基线到第 26 周的百分比变化，根据试验产品估计值（假设所有参与者都坚持治疗）和治疗政策估计值（无论是否坚持治疗）对所有随机分配的参与者进行评估。在接受至少一剂随机治疗的所有参与者中评估了安全性。该试验已在 ClinicalTrials.gov 注册，NCT03856047，不对新参与者开放。

发现

在 2019 年 3 月 1 日至 8 月 19 日期间，我们将 706 名参与者随机分配到卡格瑞肽 0·3-4·5 毫克组（每个剂量组 100-102 名），99 名参与者分配到利拉鲁肽 3·0 毫克组，101 名参与者分配到安慰剂组。治疗组的永久治疗终止（n=73 [10%]）相似，主要是由于不良事件（n=30 [4%]）。总共有 29 名参与者 (4%) 退出了试验。根据试验产品估计，所有剂量的卡格列肽（0·3–4·5 mg，6·0%–10·8% [6·4–11·5 kg]）从基线的平均体重减轻百分比更大与安慰剂相比（3·0% [3·3 kg]；估计的治疗差异范围为 3·0%–7·8%；p<0·001）。卡格瑞肽 4·5 mg 与利拉鲁肽 3·0 mg 相比，体重减轻也更大（10·8% [11·5 kg] vs9·0% [9·6公斤]；估计处理差异 1·8%，p=0·03)。治疗策略估计也观察到类似的体重减轻。最常见的不良事件是胃肠道疾病（如恶心、便秘和腹泻）和给药部位反应。与安慰剂相比，接受卡格列肽 0·3–4·5 mg 的参与者更多出现胃肠道不良事件（41%–63% vs 32%），主要是恶心（20%–47% vs 18%）。

解释

在超重和肥胖患者中使用卡格列肽治疗导致体重显着减轻并且耐受性良好。这些发现支持开发具有新的体重管理作用机制的分子。

资金

诺和诺德 A/S。