Ara 290: Safety Profile & Research Summary
21 PubMed CitationsExpert ReviewedGMP CertifiedLast Reviewed: February 2026
Animal Studies
- Neuropathic Pain (Rats): 30–60 µg/kg IP produced dose-dependent, long-term (20-week) relief of mechanical and cold allodynia with suppressed spinal microglia activation. [7]
- Cardiovascular Aging (Rats): 100 µg/kg IP tri-weekly for 15 months preserved cardiac function (ejection fraction, LV volume), reduced cardiac inflammation (NF-κB, CD45, CD68), improved frailty index, enhanced autophagy flux. No significant lifespan extension (p = 0.182). [1]
- Insulin Resistance (Mice): 30 µg/kg SC ameliorated diet-induced metabolic dysfunction, normalized glucose/lipid profiles, enhanced mitochondrial biogenesis. [12]
- Islet Transplantation (Rats): 120 µg/kg/day protected islets from cytokine-induced apoptosis in vitro (75.2% vs. 54.6% viability, p < 0.05). [14]
- Depression (Mice): Daily ARA-290 ameliorated chronic stress-induced depression-like behavior comparable to fluoxetine, reversing microglia activation. [7]
- Wound Healing (Rats): Topical application in diabetic rats accelerated wound closure, reduced re-epithelialization period, and increased collagen content. [17]
Human Clinical Trials
- Sarcoidosis SFN Pilot (n=22): 2 mg IV 3x/week for 4 weeks — SFNSL score improved −11.5 vs. −2.9 in placebo (p < 0.05); improved SF-36 physical functioning. [6]
- NERVARA Trial (n=38): 4 mg SC daily for 28 days — 14.5% increase in corneal nerve fiber area (p = 0.022); SFNSL improved −12.2 vs. −3.8 (p = 0.005); 6MWT improved +18.7 m vs. −15.1 m (p = 0.049). [4]
- T2D Neuropathy (n=48): 4 mg SC daily for 28 days — HbA1c improved −0.16% vs. −0.01% (p = 0.002); PainDetect improved +3.3 vs +1.1 (p = 0.037); CNFD increased +2.6 fibers/mm² in high-risk group (p = 0.02). [5]
- Diabetic Macular Edema (Phase 2): 4 mg SC daily for 12 weeks improved retinal thickness, tear production, and metabolic control. [10]
Regulatory Status
FDA: Investigational compound. Orphan compound + Fast Track designation for sarcoidosis-associated neuropathy. [9]
EMA: Orphan compound Designation for sarcoidosis.
WADA: Not currently on the Prohibited List, but EPO-related origin may be subject to future review.
reported tolerability profile: No anti-ARA-290 antibodies detected after 28 days of daily dosing. No increase in hematocrit, hemoglobin, or platelet counts. Preclinical toxicology showed no adverse effects at doses up to 1000x the initial human dose. [5]
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References
- Winicki NM, Nanavati AP, Morrell CH, et al. A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan. Front Cardiovasc Med, 9, 1096887, 2023.
- Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. PNAS USA, 105(31), 10925–10930, 2008.
- Swartjes M, Morariu A, Niesters M, et al. ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain. Anesthesiology, 115(5), 1084–1092, 2011.
- Dahan A, Dunne A, Swartjes M, et al. ARA 290 improves symptoms in study subjects with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med, 19(1), 334–345, 2013.
- Brines M, Dunne AN, van Velzen M, et al. ARA 290, a Nonerythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control and Neuropathic Symptoms in study subjects with Type 2 Diabetes. Mol Med, 20(1), 658–666, 2015.
- Heij L, Niesters M, Swartjes M, et al. tolerability and efficacy of ARA 290 in sarcoidosis study subjects with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med, 18(1), 1430–1436, 2012.
- Swartjes M, van Velzen M, Niesters M, et al. ARA 290 produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain, 10, 13, 2014.
- McVicar CM, Hamilton R, Colhoun LM, et al. Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy. Diabetes, 60(11), 2995–3005, 2011.
- Culver DA, Dahan A, Bajorunas D, et al. Cibinetide Improves Corneal Nerve Fiber Abundance in study subjects With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain. Invest Ophthalmol Vis Sci, 58(6), BIO52–BIO60, 2017.
- Lois N, Gardner E, McFarland M, et al. A Phase 2 Clinical Trial on the Use of Cibinetide for the investigation of Diabetic Macular Edema. J Clin Med, 9(7), 2225, 2020.
- Nairz M, Haschka D, Dichtl S, et al. Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis. Sci Rep, 7(1), 13012, 2017.
- Collino M, Benetti E, Rogazzo M, et al. A non-erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet-induced insulin resistance in mice. Br J Pharmacol, 171(24), 5802–5815, 2014.
- Tokodai K, Brines M, Ericzon BG, et al. Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand. Transplantation, 104(10), 2020.
- Kumagai-Braesch M, Cerami A, Ericzon BG, et al. Cibinetide Protects Isolated Human Islets in a Stressful Environment. Cell Transplantation, 30, 2021.
- Schmidt RE, Feng D, Wang Q, et al. Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy in Akita diabetic mouse sympathetic ganglia. Exp Neurol, 232(2), 126–135, 2011.
- Niesters M, Swartjes M, Heij L, et al. The erythropoietin analog ARA 290 for investigation of sarcoidosis-induced chronic neuropathic pain. Expert Opin Orphan Drugs, 1, 77–87, 2013.
- Pulman KG, Smith M, Mengozzi M, et al. The erythropoietin-derived peptide ARA290 reverses mechanical allodynia in the neuritis model. Neuroscience, 233, 174–183, 2013.
- Brines M. Discovery of a Master Regulator of Injury and Healing: Tipping the Outcome from Damage toward Repair. Mol Med, 20(Suppl 1), S10–S16, 2014.
- Ahmet I, Tae H, Brines M, et al. Chronic administration of small nonerythropoietic peptide of erythropoietin ameliorates postmyocardial infarction-dilated cardiomyopathy. J Pharmacol Exp Ther, 345(3), 446–456, 2013.
- Coldewey SM, Khan AI, Kapoor A, et al. Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the β-common receptor. Kidney Int, 84(3), 482–490, 2013.
- Muller C, Yassin K, Li LS, et al. ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats. Mol Med, 21(1), 969–978, 2016.
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