ISIS 449884注射液联合二甲双胍治疗2型糖尿病患者：一项随机、双盲、安慰剂对照的II期临床研究。
ISIS 449884 Injection Add-On to Metformin in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase II Clinical Study.
作者信息
Ji Linong, Gao Leili, Feng Zhikai, Chen Guoliang, Fu Jing, Morgan Erin, Bhanot Sanjay, Gao Shan, Zhang Hongyan, Liang Zicai, Gan Li-Ming
机构信息
Department of Endocrinology and Metabolism, Peking University People's Hospital, No. 11 Xi zhi men South Street, Xicheng District, Beijing, 100044, China.
Ribo Life Science Co Ltd, Suzhou, Jiangsu, China.
出版信息
Diabetes Ther. 2024 Oct;15(10):2183-2196. doi: 10.1007/s13300-024-01617-3. Epub 2024 Jul 15.
INTRODUCTION
ISIS 449884, a 2'-O-methoxyethyl antisense oligonucleotide that targets the glucagon receptor (GCGR), has demonstrated an ability to reduce hepatic glucose output and lower the blood glucose level. The primary objective of this study was to investigate the safety and efficacy of ISIS 449884 as an add-on to metformin in a population of Chinese patients with type 2 diabetes mellitus (T2DM).
METHOD
This was a multicenter, placebo-controlled (2:1), randomized, double-blind, parallel-enrollment, multiple-dose phase II study in Chinese patients with T2DM. A total of 90 patients who were uncontrolled by stable metformin monotherapy were randomized into three cohorts. Thirty subjects were enrolled in each cohort and received injections of ISIS 449884 (50 mg or 60 mg weekly or 100 mg every other week) or a corresponding volume of placebo (0.25 mL and 0.3 mL weekly or 0.5 mL every other week) subcutaneously in a 2:1 ratio for 16 weeks.
RESULTS
The primary efficacy endpoint was analyzed in 88 subjects (ISIS 449884, n = 59; placebo, n = 29). The corrected LS mean change from baseline in glycated hemoglobin (HbA1c) at week 17 in the pooled ISIS 449884 treatment group was - 1.31% (95% CI - 1.66%, - 0.96%), and that in the pooled placebo group was 0.15% (95% CI - 0.37%, 0.66%). The LS mean difference between the two groups was - 1.46% (95% CI - 1.92%, - 1.00%, P < 0.001). Treatment-emergent adverse events (TEAEs) occurred in 53/60 subjects (88.3%) and 25/30 subjects (83.3%) in the pooled ISIS 449884 treatment group and the pooled placebo group, respectively, with similar incidences. Drug-related TEAEs occurred in 41/60 subjects (68.3%) and 9/30 subjects (30.0%), respectively. TEAEs of grade 3 or higher occurred in 5/60 (8.3%) subjects and 2/30 (6.7%) subjects, respectively, and none of them were drug related.
CONCLUSIONS
The ISIS 449884 injection add-on to metformin significantly reduced HbA1c in patients with T2DM uncontrolled by stable metformin monotherapy and showed an acceptable benefit/risk profile.
CLINICAL TRIAL REGISTRATION
www.chinadrugtrials.org.cn , CTR20191096.
引言
ISIS 449884是一种靶向胰高血糖素受体（GCGR）的2'-O-甲氧基乙基反义寡核苷酸，已证明具有降低肝脏葡萄糖输出和降低血糖水平的能力。本研究的主要目的是在中国2型糖尿病（T2DM）患者人群中，研究ISIS 449884作为二甲双胍附加治疗药物的安全性和有效性。
方法
这是一项针对中国T2DM患者的多中心、安慰剂对照（2:1）、随机、双盲、平行入组、多剂量II期研究。共有90例接受稳定二甲双胍单药治疗但血糖控制不佳的患者被随机分为三组。每组招募30名受试者，按2:1的比例皮下注射ISIS 449884（每周50 mg或60 mg或每两周100 mg）或相应体积的安慰剂（每周0.25 mL和0.3 mL或每两周0.5 mL），持续16周。
结果
对88名受试者（ISIS 449884组，n = 59；安慰剂组，n = 29）分析了主要疗效终点。在汇总的ISIS 449884治疗组中，第17周糖化血红蛋白（HbA1c）较基线校正的最小二乘均值变化为-1.31%（95%CI -1.66%，-0.96%），汇总安慰剂组为0.15%（95%CI -0.37%，0.66%）。两组间的最小二乘均值差异为-1.46%（95%CI -1.92%，-1.00%，P < 0.001）。汇总的ISIS 449884治疗组和汇总安慰剂组分别有53/60名受试者（88.3%）和25/30名受试者（83.3%）发生治疗中出现的不良事件（TEAE），发生率相似。与药物相关的TEAE分别发生在41/60名受试者（68.3%）和9/30名受试者（30.0%）中。3级或更高等级的TEAE分别发生在5/60（8.3%）名受试者和2/30（6.7%）名受试者中，且均与药物无关。
结论
在稳定二甲双胍单药治疗血糖控制不佳的T2DM患者中，添加ISIS 449884注射剂可显著降低HbA1c，且显示出可接受的效益/风险比。
临床试验注册
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