Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain

PURPOSE. Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL), which can be quantified using corneal confocal microscopy (CCM). Prior studies suggest that the innate repair receptor agonist cibinetide reverses corneal nerve loss. This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43(+)) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT]). METHODS. Cibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in CNFA at 28 days. RESULTS. The placebo-corrected mean change from baseline CNFA (mu m(2)) at day 28 was 109 (95% confidence interval [CI], similar to 429, 647), 697 (159, 1236; P = 0.012), and 431 (similar to 130, 992) in the 1, 4, and 8 mg groups, respectively. Intraepidermal GAP-43(+) fibers increased in the 4 mg group (P = 0.035). Further, changes in CNFA correlated with changes in GAP-43(+) (q = 0.575; P = 0.025) and 6MWT (q = 0.645; P + 0.009). Pain improved significantly in all groups, with subjects having moderate-severe pain reporting a clinically meaningful placebocorrected decrease in pain intensity in the 4 mg group (P = 0.157). CONCLUSIONS. Cibinetide significantly increased small nerve fiber abundance in the cornea and skin, consistent with a disease modifying effect. The relationships between CNFA and other clinical measures of disease support its use as a surrogate endpoint to assess potential disease modifying therapies for neuropathy.