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Ara3.5
ARA-290 Research
Mostly mechanism / observationalLimited safety
12 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most ARA-290 studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from mixed-quality randomised trials published 2012–2021 with a typical study size of 22 participants.
Based on 12 studies · 3 RCTs · 95 total participants
Confidence
Moderate
By outcome
Pain & analgesia
Mostly mechanism / observational7 studies
Nerve-fibre repair & neuroprotection
Mostly mechanism / observational5 studies
Safety profile
Too few graded studies2 studies
Slowing down
Only 1 study in the last 5 years
20122021
1RCTn=64 · small study2017
Cibinetide significantly increased small nerve fiber abundance in the cornea and skin, consistent with a disease modifying effect.
Culver DA, Dahan A, Bajorunas D, Jeziorska M, van Velzen M, Aarts LPHJ, et al. · Invest Ophthalmol Vis Sci (2017)
Phase-2b, 28-day, multicenter randomized trial of 64 subjects with sarcoid-associated small-nerve-fibre loss and neuropathic pain
Doses of 1, 4 or 8 mg/day SC vs placebo; primary endpoint was change in corneal nerve-fibre area (CNFA) at day 28
Placebo-corrected CNFA increased significantly in the 4 mg group (697; 95% CI 159-1236; P = 0.012); intraepidermal regenerating GAP-43+ fibres also increased (P = 0.035)
Subjects receiving ARA 290 exhibited an improvement in hemoglobin A1c and lipid profiles... Neuropathic symptoms as assessed by the PainDetect questionnaire improved significantly in the ARA 290 group.
Brines M, Dunne AN, van Velzen M, Proto PL, Ostenson CG, Kirk RI, et al. · Mol Med (2015)
Phase-2 study in type-2 diabetes; ARA 290 4 mg/day SC self-administered for 28 days, followed for a further month
Improved HbA1c and lipid profile over the 56-day observation period; neuropathic symptoms (PainDetect) improved significantly vs placebo
Subjects with low baseline corneal nerve-fibre density showed a significant increase in CNFD vs no change on placebo
There was no improvement in mean change baseline-week 12 in BCVA, CRT, central retinal sensitivity or tear production... The cibinetide 12-week course was safe.
Lois N, Gardner E, McFarland M, Armstrong D, McNally C, Lavery NJ, et al. · J Clin Med (2020)
Open-label phase-2 trial; nine patients with diabetic macular edema self-administered cibinetide 4 mg/day SC for 12 weeks (eight completed)
Negative on primary visual endpoints — no improvement in best-corrected visual acuity or central retinal thickness
Improvement seen in NEI VFQ-25 quality-of-life composite and, in some participants, in CRT, tear production, diabetic control and albuminuria
In patients with sarcoidosis, ARA290 significantly improved neuropathic and autonomic symptoms, as well as quality of life... In both populations, ARA290 lacked significant adverse effects.
Dahan A, Brines M, Niesters M, Cerami A, van Velzen M. · Pain Rep (2016)
Narrative review of the innate-repair-receptor rationale and the ARA290 neuropathy program
Summarizes that ARA290 relieved mechanical/cold allodynia in mice but not in beta-common-receptor knockouts, supporting the IRR mechanism
Reviews human findings in sarcoidosis- and type-2-diabetes-associated small-fibre neuropathy, including 28-day corneal small-nerve-fibre regrowth
ARA 290 treatment was consistently associated with a significant improvement of neuropathic pain symptoms in sarcoidosis patients... Given the excellent safety profile while reducing neuropathy symptoms, the prospects of ARA 290 treatment in sarcoid neuropathy seem promising.
van Velzen M, Heij L, Niesters M, Cerami A, Dunne A, Dahan A. · Expert Opin Investig Drugs (2014)
Review of two phase-2 clinical trials of ARA 290 in painful small-fibre neuropathy (sarcoidosis and diabetes)
Reports decreased pain scores on validated questionnaires plus increased corneal nerve fibres and improved sensory thresholds and quality of life
Highlights ARA 290's tissue-protective, non-erythropoietic profile and favorable short-term safety
CNF area is a useful variable for quantifying change in CNF morphology... in patients with SFN following cibinetide administration, an agent which promotes nerve repair.
Brines M, Culver DA, Ferdousi M, Tannemaat MR, van Velzen M, Dahan A, et al. · Sci Rep (2018)
Methodology study on corneal confocal microscopy as a non-invasive readout of small-fibre-neuropathy severity and nerve repair
Pools diabetic-polyneuropathy and sarcoidosis-SFN patients, including those treated with cibinetide
Shows corneal-nerve-fibre area tracks neuropathy severity and treatment-associated change
ARA 290 could effectively suppress EAN by attenuating inflammation and exerting direct cell protection... haematopoiesis was not induced by ARA 290 during EAN treatment.
Liu Y, Luo B, Han F, Li X, Xiong J, Jiang M, et al. · PLoS One (2014)
Preclinical study in experimental autoimmune neuritis (a model of inflammatory peripheral demyelinating disease)
ARA 290 improved recovery, nerve regeneration and remyelination, and suppressed inflammation without inducing haematopoiesis
Shifted T-cell differentiation toward regulatory/Th2 phenotypes and promoted Schwann-cell proliferation
Cibinetide activation of the IRR exerts potent anti-inflammatory effects, especially within the myeloid population, reduces disease activity and mortality in mice.
Nairz M, Haschka D, Dichtl S, Sonnweber T, Schroll A, Asshoff M, et al. · Sci Rep (2017)
Preclinical DSS-induced colitis model in mice
Cibinetide (and EPO) improved weight gain and survival and preserved tissue integrity by reducing myeloid-cell infiltration and pro-inflammatory mediators
Anti-inflammatory effect depended on CD131 and JAK2 and was mediated via inhibition of NF-kB p65 — mechanistic support for the IRR pathway