Antimuscarinic pirenzepine may promote lower-limb nerve fibre regeneration in diabetic polyneuropathy
Aims: This randomized, phase 2a, double-blind, placebo-controlled clinical trial evaluated the safety and efficacy of topically administered pirenzepine, a muscarinic acetylcholine type 1 selective receptor antagonist, in improving neuropathy-related and clinical measures in individuals with type 2 diabetes (T2D) and confirmed diabetic polyneuropathy (DPN).
Methods: A preclinical study involving streptozotocin-induced rats assessed the efficacy of a topical formulation of 4% pirenzepine on indices of nerve function and structure. Subsequently, in the clinical trial, individuals with DPN were randomly assigned to receive topical formulations containing placebo (2 mL or 4 mL) or pirenzepine (2 mL or 4 mL of 4% pirenzepine), which they self-applied to the legs for 24 weeks. At baseline and follow-up, participants underwent assessment of intraepidermal nerve fibre density (IENFD) at the ankles and thighs, quantitative sensory testing, sural nerve conduction studies, plasma concentrations of pirenzepine, and evaluation with the Norfolk-quality of life-diabetic neuropathy (QOL-DN) questionnaire. Adverse events (AEs) were monitored during treatment and for 2 weeks after the end of treatment.
Results: In rats, pirenzepine prevented diabetes-induced heat hypoalgesia, cold hyperalgesia, tactile allodynia, nerve conduction velocity slowing, and reduction in mean axonal diameter. Two doses of pirenzepine or placebo were administered to 58 subjects with DPN for 24 weeks. Significant increases in IENFD at the ankle, but not at the control sites on the thigh, were observed in both pirenzepine groups (least squares mean difference 2.32 for 4 mL pirenzepine [P=0.006] and 1.50 for 2 mL pirenzepine [P=0.048]). In the modified-intent-to-treat (mITT) population, the combined pirenzepine groups showed a significant increase in IENFD compared to placebo (P=0.012). Moreover, in the per-protocol (PP) population, the combined pirenzepine treatment groups demonstrated improvement over placebo in the Norfolk QOL-DN total score (-10.4 points, P<0.001) and physical function large-fibre subset score (-6 points, P<0.001). Eczema craquele was the most common treatment-related AE and was effectively prevented by daily administration of a moisturizer.
Conclusions: Topical application of pirenzepine once daily for 24 weeks improved IENFD at the ankle in subjects with DPN.
Comments: Multiple studies in diabetic rodent models have shown that antagonism of muscarinic receptors counteracts mitochondrial dysfunction and axonal degeneration, which are key pathogenetic mechanisms in DPN. This study translated preclinical observations to a proof-of-concept clinical trial demonstrating a significant improvement in IENFD after administration of the selective antimuscarinic pirenzepine. Topical administration minimized systemic exposure, and adverse events were localized and possibly due to the lower emollient-to-ethanol ratio in the pirenzepine formulations than in the placebo formulations. However, the authors acknowledge that a considerable number of participants deviated from the study protocol and could not be replaced because of recruitment constraints during the COVID-19 pandemic. Furthermore, the modest sample size may have limited the study’s power to detect treatment effects in clinical measures other than the Norfolk QOL-DN questionnaire, which improved in the per-protocol population Therefore, the findings require confirmation in adequately powered phase 2b and phase 3 trials characterized by larger cohorts with longer treatment durations, stricter protocol adherence, and active and placebo formulations matched for excipient composition.
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Reference. Sivadasan A, Fernyhough P, Calcutt NA, Frizzi KE, Gardner K, Hansen A, Breiner A, Zochodne DW, McInnes N, Punthakee Z, Gosselin S, Perkins BA, Bril V. 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. EBioMedicine. 2026 Jan;123:106055. doi: 10.1016/j.ebiom.2025.106055. Epub 2025 Dec 5. PMID: 41352124; PMCID: PMC12721300.
