The α2-Subunit Preferring GABA Positive Allosteric Modulator, N-Desmethyl-Clobazam in Peripheral Neuropathic Pain Patients: Results of a Phase IIa Randomised Placebo-Controlled Ascending Dose Study.

BACKGROUND

N-desmethyl clobazam (NDMC), an α2-preferring-α1-sparing-GABAA modulator, was promising in preclinical models and Phase I studies, demonstrating antihyperalgesic properties without associated sedation. This Phase IIa trial aimed at exploring the effect of NDMC in peripheral neuropathic pain (NP) patients.

METHOD: Randomised, ascending doses, double-blind, placebo-controlled study, evaluating 40, 60, 120 mg of NDMC. Primary outcome was the change in weekly average daily pain (WADP) on a Numerical Rating Scale (NRS) from baseline (V1) to the end of the study (V7). Secondary outcomes included sedation (subjective NRS), quality of life (SF36), global and patient impression of change (CGI, PCGI). PK and safety data were collected. The study was prematurely terminated due to recruitment challenges related to the COVID-19 pandemic.

RESULTS

Thirty-three out of the planned 76 patients were enrolled. The mean reduction in WADP from V1 to V7 was -1.53 points for placebo and -1.99 across all NDMC doses (delta = 0.46, p = 0.47). When analysed according to NDMC plasma concentrations, the mean WADP reduction was 1.53 (SD 1.58) for placebo 1.78 (SD 1.79) for NDMC < 1000 ng/mL, and 2.40 (SD 1.46) for NDMC ≥ 1000 ng/mL. The prevalence of 30% pain reduction was 38.5% (placebo) and 83.3% (NDMC ≥ 1000 ng/mL). Logistic regression analysis indicated that NDMC ≥ 1000 ng/nL was predictive of a 30% pain reduction (odds ratio = 12.5, p = 0.04). NDMC was well tolerated.

CONCLUSION

Despite being underpowered, this study revealed a consistent exposure-response relationship along with a favourable safety profile for NDMC in patients with NP.

TRIAL REGISTRATION: ClinicalTrial.gov (NCT03375034); kofam.ch (SNCTP000003517).

SIGNIFICANCE STATEMENT: This work presenting the Phase II data of the new antihyperalgesic compound, N-Desmethyl-Clobazam (NDMC) in peripheral neuropathic pain patients support further investigation into the role in modulating GABAergic pathways as a potential therapeutic target for neuropathic pain. This objective is particularly relevant given the limited efficacy of standard pharmacological treatments for neuropathic pain, which often requires a multimodal approach targeting the multiple pathways involved in pain pathophysiology.