Sarcoidosis, an orphan disease characterized by systemic inflammation of the eyes, skin, lungs, and intrathoracic lymph nodes, is often accompanied by small nerve fiber loss and associated painful neuropathy.2 In the absence of adequate treatment for this disorder, the symptoms of patients with sarcoidosis are managed with antidepressants, analgesics, or anticonvulsants.
Pro-inflammatory cytokines and chemokines have been implicated in the maintenance of sarcoidosis-associated inflammation. Activation of the innate repair receptor was found to be beneficial in a number of disorders, including neuropathies, by promoting tissue repair and reducing apoptosis and inflammation through janus kinase-2 activation.3,4
The innate receptor agonist used in this study, cibinetide (ARA 290), was shown to have high affinity and selectivity for this receptor, and to elicit sustained effects, including reversal of neuronal dystrophy, in the nanomolar range, despite its short half-life.3,5 Another mechanism whereby cibinetide may exert these effects is through the blocking of the peripheral nociceptor, transient receptor potential vanilloid-1 ion channel, which was shown to alleviate mechanical hypersensitivity.6
Previous clinical studies indicated that cibinetide is efficacious in alleviating symptoms associated with small fiber neuropathy, and in increasing small nerve fiber density.7,8 The goal of the current study, a phase 2b double-blind, randomized, placebo-controlled clinical trial (Clinicaltrials.gov Identifier: NCT02039687), was to evaluate the safety, efficacy, and dosage of cibinetide administered subcutaneously every day for 28 days to patients with sarcoidosis and painful small nerve fiber loss. Study participants (n=64; aged 17-70 years) were randomly assigned to 1 of 4 groups and treated with 1, 4, or 8 mg cibinetide, or placebo (n=16 in each group; 15 and 14 patients analyzed in the 4- and 8-mg groups, respectively). The initial administration was given at the research center, and all following doses were self-administered.
Corneal nerve fiber area (CNFA) in the subbasal layer of the cornea, determined by analysis of in vivo confocal microscopy images, was increased from baseline after the 4- and 8-mg cibinetide treatments (P =.084 and P =.274, respectively), and CNFA in the 4-mg treatment group showed a significant increase compared with placebo (P =.012). Discontinuation of cibinetide administration led to a return of CNFA to baseline levels.
Intraepidermal nerve fiber density, determined on skin biopsies taken in the vicinity of the lateral malleolus, was not increased by any of the cibinetide treatments, but the least squares mean growth-associated protein-43 (GAP-43, a marker of new or recently generated nerve fibers)-positive fibers, showed a 23% increase from baseline in the group treated with 4 mg cibinetide (P =.035). In addition, a correlation was found between CNFA changes and length of GAP-43-positive fibers (Spearman ρ=0.5750; P =.025), “suggesting that the effects of cibinetide were consistent across two anatomic sites and small nerve fiber assessment methodologies.” Another correlation was found between CNFA changes and a 6-minute walk test designed to assess functional improvements of the treatment (Spearman ρ=0.645; P =.009).
The self-administered RAND 36-item health survey was significantly improved after the 1-mg cibinetide treatment compared with placebo, and the 4-mg cibinetide treatment led to improvements in social and physical functioning, as well as pain. Decreases in pain scores (assessed using the Brief Pain Inventory) in study participants with moderate to severe pain were the most pronounced in the group treated with 4 mg cibinetide (least squares mean difference, −1.01; 95% CI, −2.42 to 0.41; P =.157). Adverse events resulting from cibinetide treatment were mild and included fatigue, nausea, and diarrhea.
The researchers concluded, “The study results show a significant, placebo-corrected increase in CNFA after 28 days of cibinetide administration, which corroborates a similar increase observed in a prior phase 2a trial and provides clinical validation of preclinical data demonstrating neuroprotective and neurotrophic effects of cibinetide.”
Summary and Clinical Applicability
The researchers noted that, although the effects of cibinetide in the current study were assessed on patients with sarcoidosis, small nerve fiber loss occurs in a number of other pathologies, and that cibinetide “may exhibit restorative function in other diseases complicated by [small nerve fiber loss].”
Limitations and Disclosures
Patients with painless small nerve fiber neuropathy were not included in the study.
The duration of the cibinetide treatment was short (28 days), limiting the assessment of the drug’s full effects.
The number of study participants was low.
Several study authors received payments from Araim Pharmaceuticals.
- Culver DA, Dahan A, Bajorunas D, et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci. 2017;58(6):BIO52-BIO60. doi: 10.1167/iovs.16-21291
- Chen ES, Moller DR. Sarcoidosis–scientific progress and clinical challenges. Nat Rev Rheumatol. 2011;7(8):457-467. doi: 10.1038/nrrheum.2011.93
- Collino M, Thiemermann C, Cerami A, Brines M. Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Pharmacol Ther. 2015;151:32-40. doi: http://www.sciencedirect.com/science/article/pii/S0163725815000595
- Swartjes M, Van velzen M, Niesters M, et al. ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain. 2014;10:13. doi: 10.1186/1744-8069-10-13
- Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissueprotective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008;105:10925-10930. doi: 10.1073/pnas.0805594105
- Zhang W, Yu G, Zhang M. ARA 290 relieves pathophysiological pain by targeting TRPV1 channel: Integration between immune system and nociception. Peptides. 2016;76:73-79. doi: 10.1016/j.peptides.2016.01.003
- Heij L, Niesters M, Swartjes M, et al. Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med. 2012;18:1430-1436. doi: 10.1016/j.peptides.2016.01.003
- Dahan A, Dunne A, Swartjes M, et al. ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med. 2013;19:334-345. doi: 10.2119/molmed.2013.00122