ISIS 449884 Injection Add-On to Metformin in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase II Clinical Study.

IF 3.8 3区医学 Q2 Medicine Diabetes Therapy Pub Date : 2024-10-01 Epub Date: 2024-07-15 DOI:10.1007/s13300-024-01617-3

Linong Ji, Leili Gao, Zhikai Feng, Guoliang Chen, Jing Fu, Erin Morgan, Sanjay Bhanot, Shan Gao, Hongyan Zhang, Zicai Liang, Li-Ming Gan

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Abstract

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.

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ISIS 449884 注射液加用二甲双胍治疗 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。

简介：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，已被证明能够减少肝糖输出并降低血糖水平。本研究的主要目的是探讨 ISIS 449884 作为二甲双胍的附加药在中国 2 型糖尿病（T2DM）患者中的安全性和有效性：这是一项针对中国2型糖尿病患者的多中心、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 名接受二甲双胍单药治疗但病情未得到稳定控制的患者被随机分为三组。每组 30 名受试者按 2:1 的比例皮下注射 ISIS 449884（每周 50 毫克或 60 毫克，或每隔一周 100 毫克）或相应剂量的安慰剂（每周 0.25 毫升和 0.3 毫升，或每隔一周 0.5 毫升），共注射 16 周：对 88 例受试者（ISIS 449884，59 例；安慰剂，29 例）的主要疗效终点进行了分析。ISIS 449884治疗组第17周糖化血红蛋白（HbA1c）与基线相比的校正LS平均值变化为-1.31% (95% CI - 1.66%, - 0.96%)，而安慰剂组的校正LS平均值变化为0.15% (95% CI - 0.37%, 0.66%)。两组之间的LS平均差异为-1.46%（95% CI - 1.92%，- 1.00%，P 结论：ISIS 449884注射液加用二甲双胍可显著降低二甲双胍单药治疗无法控制的T2DM患者的HbA1c，其获益/风险状况可接受。临床试验注册：www.chinadrugtrials.org.cn , CTR20191096。

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来源期刊

Diabetes Therapy Medicine-Endocrinology, Diabetes and Metabolism

CiteScore

6.90

自引率

7.90%

发文量

130

审稿时长

6 weeks

期刊介绍： Diabetes Therapy is an international, peer reviewed, rapid-publication (peer review in 2 weeks, published 3–4 weeks from acceptance) journal dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of therapeutics and interventions (including devices) across all areas of diabetes. Studies relating to diagnostics and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged. The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, communications and letters. The journal is read by a global audience and receives submissions from all over the world. Diabetes Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of all scientifically and ethically sound research.