丹麦诺和诺德公司Lone B Enebo团队研究了不同剂量Cagrilitinide联合索马鲁肽2.4 mg用于体重控制的安全性、耐受性、药代动力学和药效学。2021年4月22日，该研究发表在《柳叶刀》杂志上。
人们研究长效胰淀素类似物Cagrilitinide和胰高血糖素样肽-1类似物索马鲁肽2.4 mg作为体重管理的选择。为了确定这种药物组合的安全性、耐受性、药代动力学和药效学，研究组在美国进行了一项随机、安慰剂对照、多次递增剂量、临床1b期试验，招募年龄为18-55岁、体重指数为27.0−39.9 kg/m2的参与者和其他健康人群。
试验包括6个连续重叠组，在每个队列中，参与者被按3：1的比例随机分配，分别接受每周一次皮下注射cagrilitinide（0.16、0.30、0.60、1.2、2.4或4.5 mg）或匹配的安慰剂，同时每周一次皮下注射索马鲁肽2.4 mg，均无生活方式干预。在每个队列中，每4周将cagrilitinide和索马鲁肽的剂量共同增加至16周的期望剂量，参与者以目标剂量治疗4周，然后随访5周。
主要终点为从基线检查到随访结束期间因治疗引起的不良事件的数量。次要药代动力学终点为0到168小时（AUC0–168h）血浆浓度-时间曲线下面积以及cagrilitinide和索马鲁肽的最大浓度（Cmax）；探索性药代动力学终点为半衰期、达到Cmax的时间（tmax）、血浆清除率、cagrilitinide和索马鲁肽的分布体积；探索性药效学终点是体重、血糖参数和激素的变化。
2018年7月25日至2019年12月17日，研究组将符合条件的96名参与者随机分配，其中cagrilitinide组中0.16–2.4 mg组各12名，4.5 mg组11名，安慰剂组24名，均联合2.4 mg索马鲁肽治疗，95例接受治疗的参与者均纳入安全性和全面分析数据集。参与者的平均年龄为40.6岁，男性56例（59%），黑人或非裔美国人51例（54%）。在92名受试者报告的566例不良事件中（cagrilitinide组的发生率为97%，安慰剂组为96%），207例（37%）为胃肠道疾病。
大多数不良事件的严重程度为轻度至中度，各治疗组中出现一种或多种不良事件的参与者比例相似。暴露与cagrilitinide剂量成正比，且不影响索马鲁肽暴露或消除。Cagrilitinide 0.16–4.5 mg的AUC0–168h为926–24 271 nmol × h/L，Cmax为6.14–170 nmol/L。索马鲁肽2.4 mg的AUC0–168h为12757–15305 nmol × h/L，Cmax为96.4–120 nmol/L。
Cagrilitinide 0.16–4.5 mg的半衰期为159-195小时，中位tmax为24-72小时。索马鲁肽2.4 mg的半衰期为145-165小时，中位tmax为12-24小时。不同治疗组的血浆清除率和分布体积相似。第20周时，Cagrilitinide 1.2 mg、2.4 mg和4.5 mg组的平均体重减轻百分比均大于安慰剂组，且均与2.4 mg索马鲁肽联用。所有治疗组的血糖参数均得到改善，与cagrilitinide剂量无关。各治疗组的激素变化相似。
研究结果表明，cagrilitinide和索马鲁肽2.4mg联合治疗超重者耐受性良好，安全性可接受。
附：英文原文
Title: Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial
Author: Lone B Enebo, Kasper K Berthelsen, Martin Kankam, Michael T Lund, Domenica M Rubino, Altynai Satylganova, David C W Lau
Issue&Volume: 2021-04-22
Abstract:
Background
Cagrilintide, a long-acting amylin analogue, and semaglutide 2·4 mg, a glucagon-like peptide-1 analogue, are both being investigated as options for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of this drug combination.
Methods
In this randomised, placebo-controlled, multiple-ascending dose, phase 1b trial, individuals aged 18–55 years with a body-mass index 27·039·9 kg/m2 and who were otherwise healthy were recruited from a single centre in the USA. The trial included six sequential overlapping cohorts, and in each cohort eligible participants were randomly assigned (3:1) to once-weekly subcutaneous cagrilintide (0·16, 0·30, 0·60, 1·2, 2·4, or 4·5 mg) or matched placebo, in combination with once-weekly subcutaneous semaglutide 2·4 mg, without lifestyle interventions. In each cohort, the doses of cagrilintide and semaglutide were co-escalated in 4-week intervals to the desired dose over 16 weeks, participants were treated at the target dose for 4 weeks, and then followed up for 5 weeks. Participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was number of treatment-emergent adverse events from baseline to end of follow-up. Secondary pharmacokinetic endpoints assessed from day of last dose (week 19) to end of treatment (week 20) were area under the plasma concentration-time curve from 0 to 168 h (AUC0–168 h) and maximum concentration [Cmax] of cagrilintide and semaglutide; exploratory pharmacokinetic endpoints were half-life, time to Cmax [tmax], plasma clearance, and volume of distribution of cagrilintide and semaglutide; and exploratory pharmacodynamic endpoints were changes in bodyweight, glycaemic parameters, and hormones. Safety, pharmacokinetic, and pharmacodynamic endpoints were assessed in all participants who were exposed to at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03600480, and is now complete.
Findings
Between July 25, 2018, and Dec 17, 2019, 285 individuals were screened and 96 were randomly assigned to cagrilintide (0·16–2·4 mg group n=12; 4·5 mg group n=11) or placebo (n=24), in combination with semaglutide 2·4 mg, of whom 95 were exposed to treatment (one patient in 0·60 mg cagrilintide group was not exposed) and included in the safety and full analysis datasets. The mean age was 40·6 years (SD 9·2), 56 (59%) of 95 participants were men and 51 (54%) were Black or African American. Of 566 adverse events reported in 92 participants (69 [97%] of 71 participants assigned to 0·16–4·5 mg cagrilintide and 23 [96%] of 24 assigned to placebo), 207 (37%) were gastrointestinal disorders. Most adverse events were mild to moderate in severity and the proportion of participants with one or more adverse event was similar across treatment groups. Exposure was proportional to cagrilintide dose and did not affect semaglutide exposure or elimination. AUC0–168 h ranged from 926 nmol×h/L to 24271 nmol×h/L, and Cmax ranged from 6·14 nmol/L to 170 nmol/L with cagrilintide 0·16–4·5 mg. AUC0–168 h ranged from 12757 nmol×h/L to 15305 nmol×h/L, and Cmax ranged from 96·4 nmol/L to 120 nmol/L with semaglutide 2·4 mg. Cagrilintide 0·164·5 mg had a half-life of 159–195 h, with a median tmax of 24–72 h. Semaglutide 2·4 mg had a half-life of 145–165 h, with a median tmax of 12–24 h. Plasma clearance and volume of distribution for both cagrilintide and semaglutide were similar across treatment groups. At week 20, mean percentage bodyweight reductions were greater with cagrilintide 1·2 and 2·4 mg than with placebo (15·7% [SE 1·6] for cagrilintide 1·2 mg and 17·1% [1·5] for cagrilintide 2·4 mg vs 9·8% [1·2] for pooled placebo cohorts 1–5; estimated treatment difference of 6·0% [95% CI 9·9 to 2·0] for cagrilintide 1·2 mg and 7·4% [11·2 to 3·5] for cagrilintide 2·4 mg vs pooled placebo), and with cagrilintide 4·5 mg than with matched placebo (15·4% [1·3] vs 8·0% [2·2]; estimated treatment difference 7·4% [12·8 to 2·1]), all in combination with semaglutide 2·4 mg. Glycaemic parameters improved in all treatment groups, independently of cagrilintide dose. Changes in hormones were similar across treatment groups.
Interpretation
Concomitant treatment with cagrilintide and semaglutide 2·4 mg was well tolerated with an acceptable safety profile. Future larger and longer trials are needed to fully assess the efficacy and safety of this treatment combination.
DOI: 10.1016/S0140-6736(21)00845-X
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00845-X/fulltext
LANCET：《柳叶刀》，创刊于1823年。隶属于爱思唯尔出版社，最新IF：202.731
官方网址：http://www.thelancet.com/
投稿链接：http://ees.elsevier.com/thelancet
本期文章：《柳叶刀》：Online/在线发表
