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.
Level 2 - randomized trial
Individual randomized controlled phase 2a trial
PubMed 41352124 · doi:10.1016/j.ebiom.2025.106055
What was done
Researchers evaluated a topical 4% pirenzepine formulation in female Sprague-Dawley rats with streptozotocin-induced diabetes and in a randomized, double-blind, placebo-controlled Phase 2a trial across 5 Canadian centers. Fifty-eight participants (aged 18–75) with definite type 2 diabetic peripheral neuropathy on stable therapy were randomized 1:1:4:4 to self-administer topical placebo (2 mL or 4 mL) or 4% pirenzepine (2 mL or 4 mL) once daily for 24 weeks. The primary objective was safety and tolerability; primary efficacy endpoints were 24-week changes from baseline in intraepidermal nerve fibre density (IENFD) from ankle punch biopsies and the Norfolk QOL-DN score.
What was found
In diabetic rats, topical pirenzepine prevented large-fibre conduction slowing, touch-evoked allodynia, reduced axonal diameter, heat hypoalgesia, and cold hyperalgesia. In the clinical trial modified intent-to-treat (mITT) analysis of 58 patients, the least squares mean difference in ankle IENFD change at 24 weeks was 2.32 (p = 0.006) for pirenzepine 4 mL, 1.50 (p = 0.048) for pirenzepine 2 mL, and -0.71 (p = 0.39) for placebo, with the combined pirenzepine groups significantly superior to placebo (p = 0.012). No differences were observed in Norfolk QOL-DN or other clinical parameters in the mITT population, though a 10.4-point QOL-DN improvement occurred in the per-protocol subset (p < 0.001). Treatment-related systemic adverse events were similar across groups, but administration-site reactions were higher in active groups (41.7% in 4 mL, 22.6% in 2 mL vs 8.3% in placebo).
Why it matters
This study provides early clinical proof-of-concept that targeting muscarinic acetylcholine type 1 receptors topically can stimulate distal axon regrowth in diabetic neuropathy, an indication currently lacking disease-modifying therapies.
Limits
The clinical sample size was small (58 participants distributed across four arms). Although histological axon regrowth was demonstrated, functional and quality-of-life endpoints failed to show benefit in the primary mITT population, and local skin reactions were common in the active treatment groups.
Cited by
- partial WinSanTor has completed two Phase 2 clinical trials showing that topical pirenzepine stimulates nerve regrowth and improves patient-reported outcomes in neuropathy.