title: First proof of pharmacology in humans of a novel glucagon receptor antisense drug.
abstract: 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.
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Marloes G J
authors.initials: MG
authors.lastname: van Dongen
authors.affiliation: Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Bart F
authors.initials: BF
authors.lastname: Geerts
authors.affiliation: ISIS Pharmaceuticals Inc. Carlsbad, CA, USA.
authors.forename: Erin S
authors.initials: ES
authors.lastname: Morgan
authors.affiliation: ISIS Pharmaceuticals Inc. Carlsbad, CA, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Brandt
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Marieke L
authors.initials: ML
authors.lastname: de Kam
authors.affiliation: Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cohen
authors.affiliation: ISIS Pharmaceuticals Inc. Carlsbad, CA, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015536:Down-Regulation; D004334:Drug Administration Schedule; D005934:Glucagon / Q000097:blood; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D054735:Phosphorothioate Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018027:Receptors, Glucagon / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D054735:Phosphorothioate Oligonucleotides; D018027:Receptors, Glucagon; D005934:Glucagon
keywords: antisense oligonucleotides (ASO); diabetes mellitus type 2; glucagon; glucagon receptor (GCGR); glucose