Randomized, double-blind, placebo-controlled trial of ISC 17536, an oral inhibitor of transient receptor potential ankyrin 1, in patients with painful diabetic peripheral neuropathy: impact of preserved small nerve fiber function

Abstract

Patients with chronic pain syndromes, such as those with painful peripheral neuropathy due to diabetes mellitus, have limited treatment options and suffer ongoing attrition of their quality of life. Safer and more effective treatment options are needed. One therapeutic approach encompasses phenotypic characterization of the neuropathic pain subtype, combined with the selection of agents that act on relevant mechanisms. ISC 17536 is a novel, orally available inhibitor of the widely expressed pain receptor, transient receptor potential ankyrin 1, which mediates nociceptive signaling in peripheral small nerve fibers. In this randomized, placebo-controlled, proof-of-concept trial, we assessed the safety and efficacy of 28-day administration of ISC 17536 in 138 patients with chronic, painful diabetic peripheral neuropathy and used quantitative sensory testing to characterize the baseline phenotype of patients. The primary end point was the change from baseline to end of treatment in the mean 24-hour average pain intensity score based on an 11-point pain intensity numeric rating scale. The study did not meet the primary end point in the overall patient population. However, statistically significant and clinically meaningful improvement in pain were seen with ISC 17536 in an exploratory hypothesis-generating subpopulation of patients with preserved small nerve fiber function defined by quantitative sensory testing. These results may provide a mechanistic basis for targeted therapy in specific pain phenotypes in line with current approaches of "precision medicine" or personalized pain therapeutics. The hypothesis is planned to be tested in a larger phase 2 study.

Trial registration: ClinicalTrials.gov NCT01726413.

Conflict of interest statement

S.M. Jain and R. Balamurugan were principal investigators in the study and received an investigator grant. M. Tandon is a full-time employee of Glenmark Pharmaceuticals Limited. N. Mozaffarian is a full-time employee of Janssen Pharmaceuticals, Inc, and G. Gudi and Y. Salhi are full-time employees of Ichnos Sciences, Inc. R. Holland, R. Freeman, and R. Baron are not employees of Glenmark Pharmaceuticals or Ichnos Sciences and were not compensated for this manuscript.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

Figures

Figure 1.

Study design schematic. BID, twice daily; R, randomization.

Figure 2.

Patient disposition.

Figure 3.

Mean 24-hour API score change from baseline, ITT population. API, average pain intensity; ITT, intent-to-treat.

Figure 4.

Mean change from baseline in the 24-hour API score: exploratory hypothesis subgroup analysis; P < 0.05, descriptive.

Figure 5.

Mean PK Profile on days 1 and 28 with ISC 17536 250 mg BID; mean + SD plotted on a semilogarithmic scale is shown.