Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain

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

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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 (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-43þ 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 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.

Original languageEnglish
Pages (from-to)BIO52-BIO60
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number6
DOIs
Publication statusPublished - 1 May 2017

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Neuralgia
Sarcoidosis
Nerve Fibers
GAP-43 Protein
Pain
Biomarkers
Placebos
Confocal Microscopy
Cornea
Confidence Intervals
Skin

Keywords

  • ARA 290
  • Helix B surface peptide
  • Inflammation
  • Neuropathy
  • Tissue protection

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. / Culver, Daniel A.; Dahan, Albert; Bajorunas, Daiva; Jeziorska, Maria; van Velzen, Monique; Aarts, Leon P.H.J.; Tavee, Jinny; Tannemaat, Martijn R.; Dunne, Ann N.; Kirk, Rita I.; Petropoulos, Ioannis N.; Cerami, Anthony; Malik, Rayaz; Brines, Michael.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 6, 01.05.2017, p. BIO52-BIO60.

Research output: Contribution to journalArticle

Culver, DA, Dahan, A, Bajorunas, D, Jeziorska, M, van Velzen, M, Aarts, LPHJ, Tavee, J, Tannemaat, MR, Dunne, AN, Kirk, RI, Petropoulos, IN, Cerami, A, Malik, R & Brines, M 2017, 'Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain', Investigative Ophthalmology and Visual Science, vol. 58, no. 6, pp. BIO52-BIO60. https://doi.org/10.1167/iovs.16-21291
Culver, Daniel A. ; Dahan, Albert ; Bajorunas, Daiva ; Jeziorska, Maria ; van Velzen, Monique ; Aarts, Leon P.H.J. ; Tavee, Jinny ; Tannemaat, Martijn R. ; Dunne, Ann N. ; Kirk, Rita I. ; Petropoulos, Ioannis N. ; Cerami, Anthony ; Malik, Rayaz ; Brines, Michael. / Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. In: Investigative Ophthalmology and Visual Science. 2017 ; Vol. 58, No. 6. pp. BIO52-BIO60.
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abstract = "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 (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{\th} 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 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.",
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T1 - Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain

AU - Culver, Daniel A.

AU - Dahan, Albert

AU - Bajorunas, Daiva

AU - Jeziorska, Maria

AU - van Velzen, Monique

AU - Aarts, Leon P.H.J.

AU - Tavee, Jinny

AU - Tannemaat, Martijn R.

AU - Dunne, Ann N.

AU - Kirk, Rita I.

AU - Petropoulos, Ioannis N.

AU - Cerami, Anthony

AU - Malik, Rayaz

AU - Brines, Michael

PY - 2017/5/1

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N2 - 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 (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-43þ 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 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.

AB - 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 (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-43þ 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 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.

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KW - Tissue protection

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