Topical application of the antimuscarinic pirenzepine increased lower limb nerve fibre density in a phase 2a study in type 2 patients with diabetes with peripheral neuropathy

BACKGROUND: There is no effective definitive treatment for diabetic peripheral neuropathy (DPN). Strategies that target nerve pathology, limit nerve degeneration, and promote axon regeneration can potentially be beneficial. Topical pirenzepine promotes nerve fibre protection and repair in rodent models of type 1 and type 2 diabetes. We assessed the efficacy and safety of topical pirenzepine for the treatment of DPN. METHODS: Preclinical studies were performed to determine efficacy of a topical formulation of 4% pirenzepine against indices of neuropathy in adult female Sprague-Dawley rats with streptozotocin (STZ)-induced diabetes. We then did a proof-of-concept randomised Phase 2a, double-blind, placebo-controlled, clinical trial conducted across 5 university centres in Canada. Participants (aged 18-75 years) with definite type-2 DPN, as defined by the Toronto Consensus Guidelines, who were on stable anti-diabetic and analgesic therapy prior to screening and during the study were enrolled. Participants were randomised to 1 of 4 treatment groups in a 1:1:4:4 ratio, where placebo (2 mL), placebo (4 mL); pirenzepine (2 mL of 4% formulation); and pirenzepine (4 mL of 4% formulation) were self-administered topically by the participants for a 24 weeks period. Safety and tolerability of 2 dose levels of 4% pirenzepine for 24 weeks was the primary objective. The primary efficacy endpoints were the change at 24 weeks from baseline in the intraepidermal nerve fibre density (IENFD) collected from the treated skin (ankle) and the impact on the Norfolk-quality of life-diabetic neuropathy (QOL-DN). Punch biopsies (3 mm) were collected and shipped to a centralised facility for processing and reading. The trial was approved by Health Canada (226063) and registered with ClinicalTrials.govNCT04005287. FINDINGS: In rats, topically administered 4% pirenzepine (100 μl) to the hind paws applied 5 days per week for 6 weeks of diabetes prevented large fibre conduction slowing, touch-evoked allodynia, reduced mean axonal diameter, and small fibre mediated heat hypoalgesia and cold hyperalgesia. Two doses of topical pirenzepine or placebo were administered to 58 DPN individuals for 24 weeks, between October 15, 2019 and December 15, 2021. The least squares mean difference in change from baseline to week 24 in the IENFD at the ankle was 2.32 (p = 0.006) in the pirenzepine 4 mL group; 1.50 (p = 0.048) in the pirenzepine 2 mL group and -0.71 (p = 0.39) in placebo patients on the modified-intent-to-treat analysis (mITT). The change in IENFD at the ankle was significant in the combined pirenzepine groups compared to placebo (p = 0.012). No differences were observed in other parameters in the mITT population. There was a 10.4-point improvement in the Norfolk QOL-DN score in the combined treatment groups over placebo (p < 0.001) in the per protocol (PP) analysis set, but no difference was observed in the modified intention-to-treat analysis, suggesting the need for cautious interpretation of the PP result due to potential bias. Systemic adverse events with possible/probable/definite relation to study drug were similar between the treatment groups. Administration site reactions were the most common reported treatment emergent adverse events among the pirenzepine treatment groups (pirenzepine 4 mL 41.7%, pirenzepine 2 mL 22.6% and placebo 8.3%). There were no deaths. INTERPRETATION: The efficacy of topical pirenzepine in preclinical studies was translated to a clinical study. The overall systemic safety profile was similar between patient groups. However, local topical reactions were more prevalent in the active dose groups than in the placebo group. Topical pirenzepine administered once daily for 24 weeks in patients with DPN resulted in a statistically significant growth of nerve fibres as measured by IENFD at the ankle. This study in humans with DPN demonstrates that selective targeting of the muscarinic acetylcholine type 1 receptor promotes regeneration of distal axons. Future phase 2b, and phase 3 studies are needed to substantiate these observations. FUNDING: The study was funded by the CIHR, Research Manitoba and WinSanTor.

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