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

Daniel A Culver,Monique Van Velzen,Maria Jeziorska,Leon P H J Aarts,Ioannis N Petropoulos,Rita I Kirk,Michael Brines,Anthony Cerami,Daiva Bajorunas,Rayaz A Malik,Ann N Dunne,Jinny Tavee,Albert Dahan,Martijn R Tannemaat

doi:10.1167/iovs.16-21291

Abstract

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]). Cibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in CNFA at 28 days. The placebo-corrected mean change from baseline CNFA (μm2) at day 28 was 109 (95% confidence interval [CI], -429, 647), 697 (159, 1236; P = 0.012), and 431 (-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+ (ρ = 0.575; P = 0.025) and 6MWT (ρ = 0.645; P = 0.009). Pain improved significantly in all groups, with subjects having moderate-severe pain reporting a clinically meaningful placebo-corrected decrease in pain intensity in the 4 mg group (P = 0.157). 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.

Highlights

MethodsCibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in corneal nerve fiber area (CNFA) at 28 days
This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated small nerve fiber loss (SNFL) and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43þ) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT])
Intraepidermal GAP-43þ fibers increased in the 4 mg group (P 1⁄4 0.035)

Summary

Methods

Cibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in CNFA at 28 days. The study was a double-blind, randomized, placebo-controlled, two-center assessment of the effects of daily SC administration of 3 doses of cibinetide or placebo for 28 days in sarcoidosis subjects with painful SNFL. After a 28-day screening period, the subjects were randomized (1:1:1:1) to 4 treatment groups: 1, 4, or 8 mg cibinetide or placebo daily from a block randomization scheme generated by a unit independent from the study sites. The 8 mg dose was expected to be similar to 4 mg, as preclinical neuropathy data suggest that higher doses of cibinetide do not further decrease pain behaviors if a threshold dose is exceeded.[6] The first subcutaneous administration of study drug occurred at the research site and thereafter it was self-administered daily for an additional 27 days. Vials were returned to the pharmacy to determine study drug compliance

Results

Discussion

Conclusion