First proof of pharmacology in humans of a novel glucagon receptor antisense drug. (15th September 2014)

• Record Type: Journal Article
• Authors: van Dongen, Marloes G. J.; Geerts, Bart F.; Morgan, Erin S.; Brandt, Teresa A.; de Kam, Marieke L.; Romijn, Johannes A.; Cohen, Adam F.; Bhanot, Sanjay; Burggraaf, Jacobus
• Is Part Of: Journal of clinical pharmacology. Volume 55:Number 3(2015:Mar.)
• Page Start: 298
• Page End: 306
• Publication Date: 2014-09-15
• Subjects: Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.396
• Languages: English
• ISSNs: 0091-2700

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jcph396-sec-0001" sec-type="section"> <p>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%, <italic>P</italic> < 0.0001) and HGP (13%, <italic>P</italic> = 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.</p> </sec> </abstract>