First proof of pharmacology in humans of a novel glucagon receptor antisense drug

J Clin Pharmacol. 2015 Mar;55(3):298-306. doi: 10.1002/jcph.396. Epub 2014 Sep 15.


Fasting and postprandial hyperglucagonemia in type 2 diabetes mellitus (T2DM) patients cause excessive hepatic glucose production (HGP), suggesting that attenuation of hepatic glucagon action could be a therapeutic strategy for T2DM. In this study we evaluated the safety, tolerability, PK, and pharmacodynamics in healthy human volunteers of single and multiple doses (50-400 mg) ISIS 325568, a 2'-O-MOE antisense (ASO) developed to reduce hepatic glucagon receptor (GCGR) mRNA expression. In the multiple dose cohorts, treatment consisted of eight doses of ISIS 325568 or placebo over 6-weeks. Drug effects were assessed using serial fasting glucagon measurements and the glycemic response to a glucagon challenge at baseline and at the end of 6-week treatment. ISIS 325568 was not associated with clinically relevant changes. Dose-dependent predominantly mild injection site reactions were the most common side-effect. Active treatment caused a gradual increase in fasting glucagon levels and, compared to placebo, a significantly blunted glucagon-induced increase in plasma glucose AUC (24%, P < 0.0001) and HGP (13%, P = 0.007) at the 400 mg/week dose. Six weeks treatment with ISIS 325568 in healthy volunteers attenuated glucagon-stimulated HGP and glucose excursions, supporting further evaluation of the GCGR antisense approach in patients with T2DM.

Keywords: antisense oligonucleotides (ASO); diabetes mellitus type 2; glucagon; glucagon receptor (GCGR); glucose.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Down-Regulation
  • Drug Administration Schedule
  • Glucagon / blood
  • Healthy Volunteers
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacokinetics
  • Injections, Subcutaneous
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Middle Aged
  • Netherlands
  • Phosphorothioate Oligonucleotides / administration & dosage*
  • Phosphorothioate Oligonucleotides / adverse effects
  • Phosphorothioate Oligonucleotides / pharmacokinetics
  • Receptors, Glucagon / drug effects*
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism
  • Young Adult


  • Biomarkers
  • Blood Glucose
  • Hypoglycemic Agents
  • Phosphorothioate Oligonucleotides
  • Receptors, Glucagon
  • Glucagon