AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes

L Katz; N Manamley; W J Snyder; M Dodds; N Agafonova; J Sierra-Johnson; M Cruz; P Kaur; S Mudaliar; P Raskin; R Kewalramani; A Pellacani

doi:10.1111/dom.12586

AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes

Diabetes Obes Metab. 2016 Feb;18(2):191-5. doi: 10.1111/dom.12586. Epub 2015 Dec 14.

Authors

L Katz¹, N Manamley², W J Snyder¹, M Dodds³, N Agafonova¹, J Sierra-Johnson¹, M Cruz¹, P Kaur¹, S Mudaliar⁴, P Raskin⁵, R Kewalramani¹, A Pellacani¹

Affiliations

¹ Amgen Inc., Thousand Oaks, CA, USA.
² Amgen Ltd, Cambridge, UK.
³ Amgen Inc., Seattle, WA, USA.
⁴ Center for Metabolic Research, Veterans Administration San Diego Healthcare System, San Diego, CA, USA.
⁵ University of Texas Southwestern Medical Center, Dallas, TX, USA.

PMID: 26434934
DOI: 10.1111/dom.12586

Abstract

Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose-effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33-35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose-effect trend was observed with the twice-daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.

Keywords: antidiabetic drug; clinical trial; dose-response relationship; glucokinase activator; type 2 diabetes.

Publication types

Clinical Trial, Phase II
Letter
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aminopyridines / administration & dosage*
Aminopyridines / adverse effects
Aminopyridines / therapeutic use
Blood Glucose / analysis
Diabetes Mellitus, Type 2 / blood
Diabetes Mellitus, Type 2 / drug therapy*
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Drugs, Investigational / administration & dosage*
Drugs, Investigational / adverse effects
Drugs, Investigational / therapeutic use
Enzyme Activators / administration & dosage*
Enzyme Activators / adverse effects
Enzyme Activators / therapeutic use
Follow-Up Studies
Glucokinase / chemistry
Glucokinase / metabolism*
Glycated Hemoglobin / analysis
Headache / chemically induced
Headache / epidemiology
Humans
Hyperglycemia / epidemiology
Hyperglycemia / prevention & control*
Hypertriglyceridemia / chemically induced
Hypertriglyceridemia / epidemiology
Hypoglycemia / chemically induced
Hypoglycemia / epidemiology
Hypoglycemia / prevention & control*
Hypoglycemic Agents / administration & dosage*
Hypoglycemic Agents / adverse effects
Hypoglycemic Agents / therapeutic use
Incidence
Least-Squares Analysis
Postprandial Period
Thiadiazoles / administration & dosage*
Thiadiazoles / adverse effects
Thiadiazoles / therapeutic use
Triglycerides / blood

Substances

ARRY-403
Aminopyridines
Blood Glucose
Drugs, Investigational
Enzyme Activators
Glycated Hemoglobin A
Hypoglycemic Agents
Thiadiazoles
Triglycerides
hemoglobin A1c protein, human
Glucokinase