NRD.E1, an innovative non-opioid therapy for painful diabetic peripheral neuropathy-A randomized proof of concept study.

BACKGROUND: Painful diabetic peripheral neuropathy (PDPN) affects up to 26% of patients with diabetes mellitus, with major impacts on their general health and well-being. Most available drugs fail to deliver acceptable pain reduction in the majority of patients and are often poorly tolerated. NRD.E1 is a novel product that has shown anti-nociceptive preclinical effects and good tolerability in healthy volunteer studies. METHODS: This phase 2a, randomized, dose-finding, Proof of Concept study enrolled patients with PDPN of ≥3 months duration. After at least one treatment-free week (WO week), 88 patients entered a 1-week single-blind (SB)-placebo run-in period, followed by 3 weeks' double-blind (DB) treatment, during which they received NRD.E1 at 10, 40 or 150 mg/day or placebo. RESULTS: The primary endpoint (change from SB-placebo run-in week to week 3 in weekly mean of daily average numerical rating scale [NRS] pain intensity) showed clinically relevant placebo-corrected treatment effect pain reductions at 40 mg and 150 mg/day of 0.82 (95% CI: 0.07, 1.58, p = 0.034) and 0.66 (95% CI: -0.03, 1.35; p = 0.061) NRS points, respectively, though did not meet the pre-specified value of p = 0.016 required due to multiplicity. An additional post hoc endpoint looking at the change from WO baseline to week 3 in weekly mean of daily average NRS showed the placebo-corrected treatment effect was 1.46 (95% CI: 0.26, 2.66), and 1.20 (95% CI: 0.10, 2.29) NRS points, respectively. Secondary and post hoc analyses of NRS pain data (including 30 & 50% responder rate and NNT), sleep interference, Short-form McGill pain questionnaire (especially pain intensity assessed on Visual Analogue Scale), Patient's and Clinician's Global Impression of Change showed effects consistent with the primary findings. NRD.E1 was well tolerated, with only headache reported in more than two patients and more frequently on NRD.E1 than placebo. CONCLUSIONS: The data suggest that NRD.E1 potentially represents a novel non-opioid therapeutic option for patients with PDPN, with at least similar efficacy and better tolerability than available therapies, justifying its further evaluation in larger-scale confirmatory studies. SIGNIFICANCE: NRD.E1 is a novel non-opioid therapeutic which is being developed for the treatment of PDPN. In this randomized, controlled, dose-finding, Proof of Concept study, NRD.E1 induced a clinically relevant pain reduction and it was well tolerated. Available data suggest that NRD.E1 has at least similar efficacy and better tolerability than the currently available therapies, potentially offering a promising new therapeutic option to patients with PDPN and possibly other neuropathic pain indications.

First-in-Human Single-Ascending-Dose, Multiple-Dose, and Food Interaction Studies of NRD.E1, an Innovative Nonopioid Therapy for Painful Diabetic Peripheral Neuropathy.

Painful diabetic peripheral neuropathy is characterized by burning, stabbing, or electric shock-type pain, which severely impacts day-to-day functioning and quality of life. Here, we report the results of 3 phase I studies with NRD135S.E1 (referred to as NRD.E1), a new, orally available chemical entity, presently developed for the treatment of painful diabetic peripheral neuropathy. The first study was a first-in-human, randomized, placebo-controlled, single-ascending-dose study, where NRD.E1 was administered to healthy male subjects in single dosages ranging from 300 to 1200 mg. The second study was a randomized, placebo-controlled multiple-dose study, where healthy male subjects received 300 mg of NRD.E1 once daily for 5 consecutive days. The third study was an open-label food interaction study in healthy men and women following a crossover design, where NRD.E1 was administered under fed and fasted conditions at 40 mg. The studies revealed dose-dependent absorption, increased exposure to NRD.E1 when administered with food, and no relevant accumulation after once-daily administration. All 3 phase I studies consistently showed rapid absorption of orally administered NRD.E1 followed by fast elimination, mainly via metabolization (glucuronidation), and small secondary increases in plasma concentrations. NRD.E1 was well tolerated, with no subject discontinuation due to treatment-emergent adverse events in any study.