Single and multiple ascending-dose study of glucagon-receptor antagonist RN909 in type 2 diabetes: a phase 1, randomized, double-blind, placebo-controlled trial.

Abstract

PURPOSE:

This first-in-human study assessed safety, immunogenicity, pharmacokinetics, and pharmacodynamics of RN909, a monoclonal antibody antagonist of the glucagon receptor, in type 2 diabetes (T2DM) subjects.

METHODS:

This study enrolled 84 T2DM subjects receiving stable metformin regimens. Forty-four subjects were randomized to receive single escalating doses of RN909 (0.3 to 6 mg/kg subcutaneously (SC), or 1 mg/kg intravenously (IV)), or placebo; 40 subjects were randomized to receive multiple escalating doses (50 to 150 mg SC) or placebo every 4 weeks for 12 weeks.

RESULTS:

RN909 was well tolerated; treatment-related elevated liver function tests (LFTs) were observed in 4/33 (12.1%) and 5/32 (15.6%) subjects treated with single and multiple doses, respectively, versus 1/10 (10%) and 0 in the respective placebo groups. RN909 dose-normalized AUCinf increased more than dose-proportionally following single SC doses, and after multiple doses, accumulation ratios ranged from 1.3 to 3.4. The incidence of antidrug antibodies (ADA) was 33% after single doses and 50% after multiple doses. RN909 produced dose-dependent, durable fasting plasma glucose (FPG)-lowering at day 29 (mean change -20.6 to -97.5 mg/dL) and day 85 (mean change; -27.2 to -43.5 mg/dL) after single and multiple doses, respectively. HbA1c also was reduced after single (mean change -0.30% to -1.44%), and multiple doses (-0.83% to -1.56%).

CONCLUSION:

RN909 was well tolerated after single and multiple doses in T2DM subjects, with diarrhea and elevated LFTs the most frequent adverse events. The appearance of ADA did not affect pharmacokinetics or efficacy. Robust lowering of FPG and HbA1c was observed.

• Authors: Barry Gumbiner, Brooke Esteves, Vanessa Dell, Tenshang Joh, Pamela D Garzone, Alison Forgie, Chandrasekhar Udata
• Journal: Endocrine (Endocrine) Vol. 62 Issue 2 Pg. 371-380 (11 2018) ISSN: 1559-0100 [Electronic] United States
• PMID: 30203123 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antibodies, Monoclonal, Humanized
• Blood Glucose
• Hypoglycemic Agents
• Placebos
• RN909
• Receptors, Glucagon
• Metformin

Topics

• Adolescent
• Adult
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Blood Glucose (drug effects)
• Diabetes Mellitus, Type 2 (drug therapy, immunology)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Hypoglycemic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Male
• Metformin (therapeutic use)
• Middle Aged
• Placebos
• Receptors, Glucagon (antagonists & inhibitors, immunology)
• Young Adult