ARA-290 Research, Specifications & Scientific Information

Introduction

ARA-290 began as an answer to a specific problem: erythropoietin protects tissue, and erythropoietin also makes red blood cells, and the second effect is what stops the first from being useful.

The resolution came from noticing that the two functions travel through different receptors. Erythropoiesis proceeds through the erythropoietin receptor homodimer. Local tissue protection proceeds through a heterocomplex of that receptor with CD131, the beta common receptor. A molecule that engaged only the second would separate the two ^[1].

The design followed from the structure. When erythropoietin sits in its homodimeric receptor, helix B faces the surrounding water rather than the receptor — so the residues on that face are, by construction, not the ones doing the erythropoietic work. Eleven of them, synthesised as a peptide, turned out to retain tissue protection in models of ischaemic stroke and renal ischaemia-reperfusion while being neither erythropoietic in vitro nor in vivo ^[1]. That peptide is ARA-290, and it carries the International Nonproprietary Name cibinetide.

It went into randomised, placebo-controlled human trials and reached phase 2b. This page is a reference record of that work. It describes research, and it contains no guidance of any kind on handling the material.

What Is ARA-290?

An eleven-residue synthetic peptide: pGlu-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser. The first residue is pyroglutamate, a cyclised glutamate with no free N-terminal amine and no single-letter representation, which is why the sequence is written in three-letter code throughout this page.

Its other names describe its origin. Pyroglutamate helix B surface peptide, often abbreviated pHBSP, says exactly what it is: the surface of helix B, with a pyroglutamate at the front. Cibinetide is the International Nonproprietary Name. ARA 290 is the development code from Araim Pharmaceuticals.

The register record is unusually complete for a compound in this library: UNII 9W5677JKDA, CAS registry number 1208243-50-8, PubChem compound identifier 91810664, four FDA orphan drug designations and a European orphan designation, plus ChEMBL and DrugBank identifiers. Those are the marks of formal pharmaceutical development rather than of a research chemical.

It is not an approved medicine anywhere. Orphan designation is a development incentive granted long before any approval decision, and it is not a finding about efficacy.

ARA-290 Specifications

ARA-290 carries the International Nonproprietary Name cibinetide and is recorded in the FDA/NCATS Global Substance Registration System under UNII 9W5677JKDA with CAS registry number 1208243-50-8, PubChem compound identifier 91810664, molecular formula C51H84N16O21 and a molecular weight of 1257.3 g/mol. The register also carries four FDA orphan drug designations and a European orphan designation for the substance, together with ChEMBL and DrugBank identifiers, which reflects that this compound went through formal pharmaceutical development rather than circulating only as a research chemical. The eleven residues correspond to amino acids that form the aqueous face of helix B of erythropoietin — the face that points away from the receptor when erythropoietin is bound to its homodimeric receptor — which is the design premise the compound was built on. The first residue is pyroglutamate, a cyclised glutamate that cannot be written in single-letter code and that removes the free N-terminal amine, which is why the sequence above is given in three-letter notation. The peptide is not erythropoietic and does not stimulate erythrocyte production.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does ARA-290 Work?

By agonism at one receptor and not at another that shares a subunit with it.

Erythropoietin is a type 1 cytokine that plays two roles. As a hormone it regulates erythrocyte production. As a locally produced paracrine and autocrine factor it protects a wide range of tissues from a wide range of insults. Those roles are mediated by distinct receptors: the erythropoietin receptor homodimer for the first, and a heterocomplex of the erythropoietin receptor with CD131 — the beta common receptor, shared with the receptors for several other cytokines — for the second ^[1]. The literature refers to the heterocomplex as the innate repair receptor.

ARA-290 is an agonist at the heterocomplex and is not erythropoietic. The separation is structural rather than a matter of selectivity tuning: the peptide reproduces a surface of erythropoietin that is solvent-facing when erythropoietin occupies the homodimer, so it is not a partial version of the erythropoietic ligand but a different contact surface altogether ^[1].

What the receptor does downstream is described in the review literature as a switch between a damage response and a repair response — antagonising inflammatory processes and initiating tissue repair rather than blocking a single mediator ^[5]. That is a systems-level description, and this page reports it as such rather than as a resolved signalling pathway.

ARA-290 Mechanism of Action

In vitro research

The founding work narrowed erythropoietin's tissue-protective activity down to progressively shorter sequences and checked at each step that erythropoietic activity had not come along with it.

Helix B, residues 58 to 82 of erythropoietin, was neuroprotective in cell culture. An eleven-amino-acid peptide composed of the adjacent residues forming the aqueous face of that helix retained the activity. Neither the helix nor the eleven-residue peptide was erythropoietic in vitro ^[1].

That negative result is the load-bearing one. A tissue-protective peptide derived from erythropoietin would be of limited interest if it also raised haematocrit, because the haematological effect is what constrains erythropoietin's own use for this purpose. Demonstrating absence of the unwanted activity in the same experiments that demonstrate presence of the wanted one is what makes the separation credible.

Work on innate immune cells extended the mechanistic picture: in an experimental colitis system the compound dampened innate immune cell functions, consistent with the receptor's proposed role in resolving rather than merely suppressing inflammation ^[7].

What Is ARA-290 Being Researched For?

Three lines, of which two have reached randomised controlled trials in patients.

• Small nerve fibre loss in sarcoidosis. The most developed line: an exploratory randomised trial, a placebo-controlled trial adding an objective imaging endpoint, and a phase 2b trial of 64 subjects ^{[2, 3, 6, 10]}.
• Painful neuropathy in type 2 diabetes. A phase 2 study of metabolic and neuropathic measures, with a further registered study in prediabetes and type 2 diabetes ^{[4, 11]}.
• Preclinical tissue protection. Ischaemia, nerve trauma, retinal oedema, cutaneous repair in diabetic mice and experimental colitis ^{[1, 7, 8]}.

A further registered phase 2 study in diabetic macular oedema was terminated after enrolling nine participants ^[12].

Every one of those trials studied pharmaceutical investigational material administered under a protocol in a defined patient population. None of them concerns research-grade material supplied for laboratory use.

Human Research on ARA-290

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Exploratory randomised trial in sarcoidosis

Population. 22 patients with sarcoidosis and symptoms of small fibre neuropathy, with a spontaneous pain score of 5 or more on the Brief Pain Inventory. Twelve received the compound intravenously three times weekly for four weeks; ten received placebo ^[2].

Result. The treated group showed a significant improvement at week 4 in the small fibre neuropathy screening list score against placebo (−11.5 ± 3.04 against −2.9 ± 3.34). Within-group change from baseline was significant in the pain and physical functioning dimensions of the SF-36. Brief Pain Inventory and Fatigue Assessment Scale scores improved significantly but equivalently in both groups, and the depressive symptom inventory did not change. No safety concerns were raised by clinical or laboratory assessment ^[2].

Why the equivalence matters. Two of the endpoints moved in the placebo arm as much as in the treated arm. In a 22-person exploratory trial of a symptom-based condition, that is the expected shape of the data and it is the reason the later trials added an objective imaging measure.

Randomised placebo-controlled trial with corneal imaging

Population and design. Patients with documented sarcoidosis-associated small nerve fibre loss, in a blinded placebo-controlled trial of 28 days of daily subcutaneous administration ^[3].

Result. Neuropathic symptoms improved significantly. Alongside the symptom outcomes, corneal small nerve fibre density increased significantly, cutaneous temperature sensitivity changed, and six-minute walk distance increased ^[3].

What changed methodologically. Corneal confocal microscopy counts nerve fibres in a densely innervated, non-invasively imageable tissue. Adding it converts a trial of self-reported symptoms into one with an anatomical readout that a participant cannot influence.

Phase 2b in sarcoidosis-associated small nerve fibre loss

Population and design. 64 subjects with sarcoid-associated small nerve fibre loss and neuropathic pain, randomised over 28 days to 1, 4 or 8 mg per day or placebo. Primary endpoint: change in corneal nerve fibre area at day 28 ^{[6, 10]}.

Result. The placebo-corrected mean change from baseline in corneal nerve fibre area, in square micrometres, was 109 (95% CI −429 to 647) at 1 mg, 697 (159 to 1236; p = 0.012) at 4 mg, and 431 (−130 to 992) at 8 mg. Intraepidermal GAP-43-positive fibres increased in the 4 mg group (p = 0.035). Changes in corneal nerve fibre area correlated with changes in GAP-43-positive fibres (ρ = 0.575; p = 0.025) and with six-minute walk distance (ρ = 0.645; p = 0.009). Pain improved significantly in all groups; among subjects with moderate to severe pain the placebo-corrected decrease in the 4 mg group did not reach significance (p = 0.157) ^[6].

Limitations, stated plainly. Only the middle group met the primary endpoint; the highest group did not, and the confidence interval for the 8 mg group crossed zero. A response that is significant at 4 mg and not at 8 mg is not a clean relationship with the amount administered, and a 64-subject trial cannot resolve whether that pattern is real. Pain improved in every arm including placebo. What the trial establishes most firmly is the correlation structure supporting corneal nerve fibre area as a surrogate endpoint — which is what its authors emphasised.

Phase 2 in type 2 diabetes with painful neuropathy

Population and design. Subjects with type 2 diabetes and painful neuropathy, self-administering 4 mg subcutaneously daily or placebo for 28 days, then followed for a further month without administration ^{[4, 11]}.

Result. No potential safety issues were identified. Glycated haemoglobin and lipid profiles improved in the treated group across the 56-day observation period. Neuropathic symptoms assessed by the PainDetect questionnaire improved significantly. Mean corneal nerve fibre density was significantly reduced compared with normal controls at baseline; among subjects whose baseline density was more than one standard deviation from normal, density increased significantly, against no change on placebo ^[4].

Limitations. A phase 2 study over 28 days of administration. The corneal nerve fibre result applies to a subgroup defined by baseline severity rather than to the whole cohort, and the authors framed the findings as suggesting the compound deserves continued clinical evaluation rather than as establishing benefit.

The overall position

No phase 3 programme has been identified, and the compound is not approved anywhere. A phase 2b trial that meets its primary endpoint in one of three groups is a reason to run a larger trial, not a conclusion.

Preclinical Research on ARA-290

Animal research

The animal work is broad, and its breadth is the point: a receptor described as an innate repair switch should show effects across unrelated kinds of injury, and that is what was tested.

In the founding study, helix B itself was tissue-protective in models of ischaemic stroke, diabetes-induced retinal oedema and peripheral nerve trauma. The eleven-residue peptide was then confirmed as protective in models of ischaemic stroke and renal ischaemia-reperfusion, and was also reported to accelerate cutaneous repair and to augment cognitive function in rodents. Neither was erythropoietic in vivo ^[1].

Later work returned to cutaneous repair with the receptor specified: activation of the erythropoietin receptor and beta common receptor complex by cibinetide improved impaired healing in mice with genetic diabetes ^[8]. Naming the receptor complex in the title reflects that by then the mechanism was the claim being tested rather than assumed.

In experimental colitis the compound dampened innate immune cell functions and ameliorated the course of the disease ^[7] — a different organ, a different injury, and the same proposed receptor.

Findings described in this section were observed in animals, and nothing in them establishes anything about humans.

Current Research Status

Status as of September 22, 2026. This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

ARA-290 vs Related Compounds

The comparisons below are structural and evidential. No comparison of effect is made on this page.

Erythropoietin

The parent molecule, a 165-residue glycoprotein hormone and an approved medicine in several indications. ARA-290 is eleven residues from one solvent-facing surface of it, and is not erythropoietic. Approval of the parent confers nothing on the fragment.

Receptor specificity

Where most compounds in this library have no identified receptor, this one has a named heterocomplex — the erythropoietin receptor with CD131 — and a structural rationale for why it engages that complex and not the homodimer ^[1]. That is an unusually well-specified mechanism for a compound of this size.

BPC-157 and TB-500 :: Grouped alongside ARA-290 under repair and regenerative research in this library. Neither has an identified receptor, and neither has a completed and reported randomised phase 2b trial. The grouping reflects the research question, not shared pharmacology.

Evidence base

ARA-290 has the most developed clinical record of any compound in its category here: four randomised placebo-controlled trials, an objective imaging endpoint, orphan designations, and no approval. It is also the clearest illustration in this library of how far a compound can travel on phase 2 evidence without arriving.

Chemical & Molecular Characteristics

The register record is complete and consistent. UNII 9W5677JKDA, CAS registry number 1208243-50-8, PubChem compound identifier 91810664, molecular formula C51H84N16O21, molecular weight 1257.3 g/mol. The FDA/NCATS record and PubChem agree on formula and mass, which is not true of every compound in this library.

The first residue cannot be written in single-letter code. Pyroglutamate is a glutamate whose side chain has cyclised onto its own alpha-amino group, forming a five-membered lactam. The consequence is that the peptide has no free N-terminal amine — which removes one route of aminopeptidase attack and changes the molecule's charge at the N-terminus. It is part of the structure, not a formatting detail, and a preparation lacking the cyclisation is a different substance.

The sequence is a surface, not a domain. The eleven residues are those forming the aqueous face of erythropoietin's helix B. They are adjacent in the folded protein's surface and contiguous in the primary sequence, which is what makes a linear peptide a plausible mimic of that surface at all. Reading the sequence as a functional fragment of erythropoietin in the usual sense would be a mistake: it reproduces a face, not a subdomain.

The orphan designations are register facts, not efficacy findings. Four FDA orphan drug designations and one European orphan designation are recorded against the substance. Designation is granted on the basis of the rarity of the target condition and a plausible rationale, well before efficacy is established, and it is recorded here because it is part of the substance's register identity rather than because it says anything about results.

Frequently Asked Questions

Scientific References

1. Brines M, Patel NS, Villa P, et al.. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin Proceedings of the National Academy of Sciences of the United States of America; 2008. PMID 18676614 doi:10.1073/pnas.0805594105
2. 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 Molecular medicine (Cambridge, Mass.); 2012. PMID 23168581 doi:10.2119/molmed.2012.00332
3. 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 Molecular medicine (Cambridge, Mass.); 2013. PMID 24136731 doi:10.2119/molmed.2013.00122
4. 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 Molecular medicine (Cambridge, Mass.); 2015. PMID 25387363 doi:10.2119/molmed.2014.00215
5. Collino M, Thiemermann C, Cerami A, et al.. Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin Pharmacology & therapeutics; 2015. PMID 25728128 doi:10.1016/j.pharmthera.2015.02.005
6. 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 Investigative ophthalmology & visual science; 2017. PMID 28475703 doi:10.1167/iovs.16-21291
7. Nairz M, Haschka D, Dichtl S, et al.. Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis Scientific reports; 2017. PMID 29026145 doi:10.1038/s41598-017-13046-3
8. Bitto A, Irrera N, Pizzino G, et al.. Activation of the EPOR-β common receptor complex by cibinetide ameliorates impaired wound healing in mice with genetic diabetes Biochimica et biophysica acta. Molecular basis of disease; 2018. PMID 29223734 doi:10.1016/j.bbadis.2017.12.006
9. Brines M, Culver DA, Ferdousi M, et al.. Corneal nerve fiber size adds utility to the diagnosis and assessment of therapeutic response in patients with small fiber neuropathy Scientific reports; 2018. PMID 29549285 doi:10.1038/s41598-018-23107-w
10. Study of Efficacy of ARA 290 on Corneal Nerve Fiber Density and Neuropathic Symptoms of Subjects With Sarcoidosis 2014. NCT02039687
11. ARA290 in T2D (Effects of ARA 290, an Erythropoietin Analogue) in Prediabetes and Type 2 Diabetes) 2013. NCT01933529
12. The Use of ARA290 for the Treatment of Diabetic Macular Oedema 2016. NCT06626971

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.