ATTENUATION OF INSULIN ACTION BY AN ALLOSTERIC INSULIN RECEPTOR ANTIBODY IN HEALTHY VOLUNTEERS.

ATTENUATION OF INSULIN ACTION BY AN ALLOSTERIC INSULIN RECEPTOR ANTIBODY IN HEALTHY VOLUNTEERS.

J Clin Endocrinol Metab. 2017 Jun 09;:

Authors: Johnson KW, Neale A, Gordon A, Roessig J, Bezwada P, Vukelich S, Goldfine I, Rubin P

Abstract
Background: X358 (X358) is a fully human monoclonal antibody to the insulin receptor (InsR) that acts as a negative allosteric modulator of insulin signaling. It is being developed as a novel treatment for hyperinsulinemic hypoglycemia. This report describes pharmacokinetic (PK), and pharmacodynamic (PD) data from a first-in-human clinical trial.
Methods: A double-blind, placebo-controlled, single ascending dose study was performed with 29 healthy adult males randomized to intravenous infusion of placebo or X358 at 0.1, 0.3, 1, 3, 6 or 9 mg/kg dose levels. The primary objective was to assess safety and tolerability, and secondary objectives included PK and PD analyses. A short insulin tolerance test (ITT) was implemented in the 3-9 mg/kg dose cohorts at baseline and post-infusion.
Results: There were no deaths, SAEs, or subject discontinuations due to adverse events. There were no clinically significant safety findings. X358 exhibited dose-proportional PK with a half-life of 21 days. Dose-dependent elevations of circulating insulin levels, likely related to reduced insulin clearance via mAb action at receptors, represented a sensitive biomarker of X358 exposure. X358-dependent increases in postprandial glucose levels and fasting HOMA-IR values were observed and persisted for at least 1 week at the higher dose levels. In all the ITT cohorts, the slope for glucose lowering was substantially attenuated after X358 infusion of a similar magnitude, but with increasing duration with rising dose level.
Conclusion: Single X358 infusions were well tolerated and resulted in a dose-dependent reduction in insulin sensitivity. Clinical development of X358 in hyperinsulinemic, hypoglycemic conditions is proceeding.

PMID: 28605468 [PubMed - as supplied by publisher]

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