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ARA-290

ARA-290

Cibinetide, an 11-amino-acid pyroglutamate helix B surface peptide (pHBSP) derived from erythropoietin. more info
ARA-290 (also known as cibinetide) is a synthetic 11-amino-acid peptide corresponding to the aqueous outer face of helix B of erythropoietin (EPO). It was engineered as a non-erythropoietic, tissue-protective peptide that does not stimulate red-blood-cell production, and it has been studied primarily in rodent models and small clinical cohorts of small fiber neuropathy, neuropathic pain, and metabolic and organ-protection research. The published ARA-290 literature is concentrated in the research program of its developer, Araim Pharmaceuticals, and no study has advanced beyond Phase 2.

Available for laboratory research use only.

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  • Identity
  • Purity (HPLC)
  • Endotoxin (USP <85>)
  • Sterility (USP <71>)
  • Heavy metals (ICP-MS per USP <233>)

Lot 14-2607 · Independent testing in progress

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Biochemical Profile

CAS Number
1208243-50-8
Molecular Formula
C51H84N16O21
Molecular Weight
1257.3 g/mol
Purity
≥99% (HPLC-UV (220 nm))
PubChem CID
91810664
Amino Acid Sequence
pGlu-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser (QEQLERALNSS)

Receptor Targets and Signaling Pathway Context

ARA-290 (cibinetide) was engineered to selectively engage a proposed non-hematopoietic receptor that Brines and Cerami termed the innate repair receptor (IRR), described as a heterocomplex of the erythropoietin receptor (EPOR) and the beta-common receptor (CD131, gene CSF2RB) that is shared across the GM-CSF, interleukin-3, and interleukin-5 receptor families[1][4]. This model grew out of the observation that the tissue-protective action of erythropoietin can be separated from its red-blood-cell-stimulating action. Carbamylated erythropoietin and asialo-erythropoietin retained tissue-protective activity in rodent injury models without stimulating erythropoiesis[2], and the activity was subsequently localized to an 11-amino-acid sequence corresponding to the solvent-exposed outer face of erythropoietin helix B, the helix B surface peptide (HBSP)[3]. Stabilizing that sequence with an N-terminal pyroglutamate yields the pyroglutamate helix B surface peptide (pHBSP), which is ARA-290.

Because ARA-290 mimics only the outer helix B face and does not engage the classical (EPOR)2 homodimer that drives erythropoiesis, it does not raise hematocrit, the property that motivated its development as a non-erythropoietic counterpart to erythropoietin[3]. Dependence on the beta-common receptor was shown pharmacologically: ARA-290 attenuated neuropathic pain behaviors in nerve-injured rats, and the effect was absent in beta-common-receptor knockout mice[5]. Reported downstream events in model systems include lower nerve tumor necrosis factor alpha and CCL2, suppression of spinal microglial and astrocyte markers, and dampened innate immune cell signaling[6].

The IRR is a functional model rather than a fully resolved physical receptor. No high-resolution co-crystal structure of ARA-290 with an EPOR/CD131 complex has been deposited in the Protein Data Bank, and one independent study reported that erythropoietin does not drive a physical interaction between the erythropoietin and beta-common receptors, questioning the heterodimer as classically drawn[15]. The receptor characterization and the majority of the mechanism literature originate within the research program of the developer, Araim Pharmaceuticals, and independent replication of the receptor biology by unaffiliated groups is limited.

Research Applications

Small Fiber Neuropathy and Sarcoidosis Research

The most developed clinical line of ARA-290 research concerns small fiber neuropathy, particularly in sarcoidosis. A double-blind randomized pilot study in sarcoidosis patients with symptoms of small fiber neuropathy was the first human evaluation and reported acceptable tolerability with exploratory symptom endpoints in a small cohort (n=22)[7]. A subsequent double-blind randomized Phase 2 study (n=38) reported changes in patient-reported neuropathic symptom scores and an increase in corneal nerve fiber density measured by corneal confocal microscopy, a non-invasive proxy for small fiber integrity[8]. A larger dose-ranging Phase 2b study (n=64) reported an increase in corneal nerve fiber area at the intermediate dose over a 28-day course[9]. Across these studies the cohorts were small, the treatment periods were short, and the trials were conducted by the developer together with its academic collaborators at Leiden University Medical Center and the Cleveland Clinic. No Phase 3 study of ARA-290 in small fiber neuropathy has been registered or published, and the corneal-nerve readouts remain surrogate endpoints rather than validated clinical outcomes.

Neuropathic Pain Model Research

In preclinical neuropathic pain research, ARA-290 has been studied mainly in rodent peripheral nerve injury preparations. In a nerve-injury model, systemic ARA-290 produced durable attenuation of mechanical allodynia after only a short course of administration, and the antinociceptive effect was abolished in beta-common-receptor knockout mice, establishing receptor dependence[5]. In a rat neuritis model, ARA-290 attenuated mechanical allodynia and was associated with lower local levels of tumor necrosis factor alpha and the chemokine CCL2 in the affected nerve[6]. Additional work reported suppression of spinal microglial (Iba-1) and astrocyte (GFAP) markers, consistent with an action on neuroinflammatory signaling rather than classical opioid pathways. These studies used defined injury models with objective behavioral and histological endpoints, which is a methodological strength, but the effect sizes and the receptor mechanism derive from a small number of laboratories. Whether the durable antinociceptive effects observed in rodents correspond to a sustained clinical outcome has not been established in an adequately powered human trial.

Metabolic and Diabetes Research

ARA-290 has been examined in metabolic and diabetes research. A Phase 2 randomized study in adults with type 2 diabetes and painful neuropathy reported changes in glycated hemoglobin (HbA1c), circulating lipid measures, and a neuropathic symptom questionnaire over a 28-day period (n=48 completed)[10]. In a rat model of type 2 diabetes (Goto-Kakizaki), ARA-290 administration was associated with changes in insulin secretion and glucose tolerance[11]. In a model of early diabetic retinopathy, an erythropoietin-derived peptide of this class was reported to protect against neuroglial and vascular changes in the retina[12]. As with the neuropathy program, the human metabolic data come from small, short studies conducted within the developer's research orbit, and the reported endpoints have not been reproduced in independent, adequately powered trials. The findings are best read as hypothesis-generating observations in defined model systems and cohorts rather than as established metabolic effects of the molecule.

Ischemia, Organ Protection, and Transplantation Research

A broad preclinical literature has examined ARA-290 and related non-erythropoietic erythropoietin-derived peptides in ischemia and organ-protection models. Reported work includes cardioprotection with a peptide that mimics the three-dimensional structure of erythropoietin[13], attenuation of renal ischemia-reperfusion injury[14], and organ-protection endpoints in experimental hemorrhagic shock[17]. In transplantation research, ARA-290 has been studied as a tissue-protective agent for isolated human pancreatic islets under stress and for islet engraftment[18], and cibinetide received an EU orphan designation for use in pancreatic islet transplantation (EMA EU/3/16/1721), a designation that is explicitly not a marketing authorisation[16]. These models span several organ systems and multiple laboratories, which broadens the mechanistic picture, but the individual studies are small and model-specific, and no organ-protection or transplantation indication has advanced to a confirmatory human trial or regulatory approval. The breadth of tissue systems reflects the general tissue-protective framing of the erythropoietin-derived peptide class rather than a validated clinical use in any one organ.

Innate Immunity and Inflammatory Signaling Research

Beyond neurons, ARA-290 has been positioned as a modulator of innate immune signaling. Brines and Cerami framed the innate repair receptor as a switch that dampens the tumor-necrosis-factor-driven innate inflammatory response after tissue injury[4]. In an experimental colitis model, cibinetide dampened innate immune cell functions and was associated with a milder disease course[19]. In a rat model of experimental autoimmune encephalomyelitis, the non-erythropoietic analog ARA-290 was reported to modify disease measures[20]. This innate-immunity framing is the mechanistic thread the developer uses to connect the molecule's varied tissue effects, from nerve injury to colitis to transplantation. A frequently repeated claim on vendor pages that ARA-290 drives macrophage repolarization from an M1 to an M2 phenotype is not cleanly anchored to a single strong primary study; the peer-reviewed record documents innate-immune effects through cytokine endpoints and disease-course measures rather than a dedicated polarization study. As elsewhere in this literature, the innate-immune observations are concentrated in the developer's orbit and its close collaborators.

Replication, Conflict of Interest, and Clinical Status

The ARA-290 evidence base is unusually concentrated in the research program of its developer. The receptor model, the pivotal small-fiber-neuropathy trials, the type 2 diabetes study, and the corneal-nerve endpoints originate overwhelmingly from Araim Pharmaceuticals and its academic collaborators at Leiden University Medical Center and the Cleveland Clinic. Michael Brines and Anthony Cerami, who originated the tissue-protective erythropoietin concept and co-invented ARA-290, are officers and shareholders of Araim, a financial interest disclosed in their published work. Independent replication of the clinical results by unaffiliated groups is limited, and two papers in the broader pyroglutamate-helix-B-peptide literature have been retracted, so the sub-literature warrants added scrutiny. Only four ARA-290 or cibinetide studies appear in the ClinicalTrials.gov registry, the highest phase reached is Phase 2b, and no Phase 3 trial, New Drug Application, or Biologics License Application has been filed. The proposed receptor itself remains contested, with at least one independent study questioning the physical erythropoietin and beta-common-receptor interaction[15]. ARA-290 is not approved by any regulatory agency and is offered strictly for laboratory research use only.

Reconstitution & Storage

Recommended Diluent
Sterile water
Storage (lyophilized)
-20°C, dry, dark, 24-36 months
Storage (reconstituted)
2-8°C, use within 28 days
Shelf Life
24-36 months lyophilized

Research References

  1. [1] Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004;101(41):14907-14912. doi:10.1073/pnas.0406491101PMID:15456912
  2. [2] Leist M, Ghezzi P, Grasso G, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004;305(5681):239-242. doi:10.1126/science.1098313PMID:15247477
  3. [3] Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008;105(31):10925-10930. doi:10.1073/pnas.0805594105PMID:18676614
  4. [4] Brines M, Cerami A. The receptor that tames the innate immune response. Mol Med. 2012;18(1):486-496. doi:10.2119/molmed.2011.00414PMID:22183892
  5. [5] 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: an experimental study in rats and beta-common receptor knockout mice. Anesthesiology. 2011;115(5):1084-1092. doi:10.1097/ALN.0b013e31822fcefdPMID:21873879
  6. [6] Pulman KG, Smith M, Mengozzi M, Ghezzi P, Dilley A. The erythropoietin-derived peptide ARA290 reverses mechanical allodynia in the neuritis model. Neuroscience. 2013;233:174-183. doi:10.1016/j.neuroscience.2012.12.022PMID:23262243
  7. [7] 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(1):1430-1436. doi:10.2119/molmed.2012.00332PMID:23168581
  8. [8] 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(1):334-345. doi:10.2119/molmed.2013.00122PMID:24136731
  9. [9] 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.16-21291PMID:28475703
  10. [10] Brines M, Dunne AN, van Velzen M, et al. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2015;20(1):658-666. doi:10.2119/molmed.2014.00215PMID:25387363
  11. [11] Schmidt RE, Green KG, Feng D, et al. ARA290 improves insulin release and glucose tolerance in type 2 diabetic Goto-Kakizaki rats. Mol Med. 2016;21(1):969-978. doi:10.2119/molmed.2015.00267PMID:26736179
  12. [12] McVicar CM, Hamilton R, Colhoun LM, et al. Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy. Diabetes. 2011;60(11):2995-3005. doi:10.2337/db11-0026PMID:21911748
  13. [13] Ueba H, Brines M, Yamin M, et al. Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin. Proc Natl Acad Sci U S A. 2010;107(32):14357-14362. doi:10.1073/pnas.1003019107PMID:20660739
  14. [14] van Rijt WG, Nieuwenhuijs-Moeke GJ, van Goor H, et al. ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury. J Transl Med. 2013;11:9. doi:10.1186/1479-5876-11-9PMID:23302512
  15. [15] Cheung Tung Shing KS, Broughton SE, Nero TL, et al. EPO does not promote interaction between the erythropoietin and beta-common receptors. Sci Rep. 2018;8(1):12457. doi:10.1038/s41598-018-29865-xPMID:30127368
  16. [16] European Medicines Agency. Public summary of opinion on orphan designation: cibinetide for treatment in pancreatic islet transplantation. EU/3/16/1721. Adopted 29 August 2016. An orphan designation is not a marketing authorisation.
  17. [17] Patel NS, Kerr-Peterson HL, Brines M, et al. Delayed administration of pyroglutamate helix B surface peptide (pHBSP), a novel nonerythropoietic analog of erythropoietin, attenuates acute kidney injury. Mol Med. 2011;17(9-10):883-892. doi:10.2119/molmed.2011.00053PMID:21607291
  18. [18] Yao M, Domogatskaya A, Ågren N, et al. Cibinetide protects isolated human islets in a stressful environment and improves engraftment in the presence of ITH. Cell Transplant. 2021;30:9636897211039739. doi:10.1177/09636897211039739PMID:34498509
  19. [19] Nairz M, Haschka D, Dichtl S, et al. Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis. Sci Rep. 2017;7(1):13012. doi:10.1038/s41598-017-13046-3PMID:29026145
  20. [20] Chen H, Luo B, Yang X, et al. Therapeutic effects of nonerythropoietic erythropoietin analog ARA290 in experimental autoimmune encephalomyelitis rat. J Neuroimmunol. 2014;268(1-2):64-70. doi:10.1016/j.jneuroim.2014.01.006PMID:24518674
  21. [21] U.S. Food and Drug Administration. Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act. 'Cibinetide (ARA-290)' is listed under Category 3 (bulk drug substances nominated without adequate support). Updated 2026.
  22. [22] World Anti-Doping Agency. The 2026 Prohibited List, section S2.1.5 'Innate repair receptor agonists' (examples: asialo EPO, carbamylated EPO). ARA-290 is not named explicitly; it is captured by class under the 'similar biological effect' clause. WADA, January 2026.

Scientific Journal Author

Michael Brines, MD, PhD

Araim Pharmaceuticals (originating from the Kenneth S. Warren Institute), with Anthony Cerami, PhD

Landmark Publications

  • Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004;101(41):14907-14912. (PMID 15456912)
  • Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008;105(31):10925-10930. (PMID 18676614)
  • Brines M, Cerami A. The receptor that tames the innate immune response. Mol Med. 2012;18(1):486-496. (PMID 22183892)

Dr. Brines is independently cited here as the co-inventor of ARA-290 and, with Dr. Anthony Cerami, the originator of the non-erythropoietic tissue-protective erythropoietin concept and the innate repair receptor model. Dr. Brines and Dr. Cerami are officers and shareholders of Araim Pharmaceuticals, the company that developed ARA-290, a financial interest disclosed in their published work. There is no affiliation or commercial relationship between Dr. Brines, Dr. Cerami, Araim Pharmaceuticals, and Peerless Peptides.

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