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

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

  • Diabetes Ther. 2024 Oct;15(10):2183-2196. doi: 10.1007/s13300-024-01617-3.
Linong Ji # 1,  Leili Gao # 2,  Zhikai Feng 3,  Guoliang Chen 3,  Jing Fu 3,  Erin Morgan 4,  Sanjay Bhanot 4,  Shan Gao 3,  Hongyan Zhang 3,  Zicai Liang 3,  Li-Ming Gan 5 6 7 8
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, Peking University People's Hospital, No. 11 Xi zhi men South Street, Xicheng District, Beijing, 100044, China. jiln@bjmu.edu.cn.
  • 2 Department of Endocrinology and Metabolism, Peking University People's Hospital, No. 11 Xi zhi men South Street, Xicheng District, Beijing, 100044, China.
  • 3 Ribo Life Science Co Ltd, Suzhou, Jiangsu, China.
  • 4 Ionis Pharmaceuticals, Carlsbad, CA, USA.
  • 5 Ribo Life Science Co Ltd, Suzhou, Jiangsu, China. li-ming.gan@ribocure.com.
  • 6 Ribocure Pharmaceuticals AB, Gothenburg, Sweden. li-ming.gan@ribocure.com.
  • 7 Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden. li-ming.gan@ribocure.com.
  • 8 Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. li-ming.gan@ribocure.com.
  • # Contributed equally.
PMID: 39008234 DOI: 10.1007/s13300-024-01617-3
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.

Keywords

Glucagon receptor; ISIS 449884; Metformin; Type 2 diabetes mellitus.

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