# ARA-290 — Research Peptide Profile

> ARA-290 (cibinetide) is an erythropoietin-derived peptide acting at the innate repair receptor. Phase 2 trials show nerve fiber regrowth in sarcoidosis neuropathy.

Source: https://peptpedia.org/peptide/ara-290 | Published: 2026-09-18 | Last updated: 2026-09-18

ARA-290 (cibinetide) is a small peptide engineered from erythropoietin's helix B that activates the innate repair receptor (EPOR/CD131) without any erythropoietic effect. In Phase 2 trials it increased corneal nerve fiber abundance in sarcoidosis small fiber neuropathy and improved metabolic measures in type 2 diabetes. It is unapproved; sponsor Araim Pharmaceuticals holds FDA orphan drug designation for sarcoidosis.

## Overview

ARA-290 (cibinetide, also called pHBSP for pyroglutamate helix B surface peptide) is an 11-amino-acid peptide engineered from the aqueous face of helix B of erythropoietin. It was designed to retain erythropoietin's tissue-protective signaling while eliminating its red-blood-cell-stimulating activity, which is possible because the two effects are mediated by different receptors: tissue protection is signaled through the innate repair receptor (IRR), a heterocomplex of the erythropoietin receptor (EPOR) and CD131, the beta common receptor. Clinical development by Araim Pharmaceuticals has focused on small fiber neuropathy: pilot and Phase 2 trials in sarcoidosis-associated small nerve fiber loss showed improved neuropathic symptoms and increased corneal nerve fiber density, and a Phase 2 trial in type 2 diabetes showed improved HbA1c, lipid profiles, and neuropathic symptoms. The peptide has an extremely short plasma half-life of about 2 minutes but triggers durable downstream effects. ARA-290 received FDA orphan drug designation for sarcoidosis in 2016 but is not approved for any indication.

## Molecular Profile

- **Category:** recovery-repair
- **Molecular formula:** C51H84N16O21
- **Molecular weight:** 1257.3 g/mol
- **CAS number:** 1208243-50-8
- **Amino acid sequence:** pGlu-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser (pE-EQLERALNSS)
- **Also known as:** Cibinetide, pHBSP, Pyroglutamate Helix B Surface Peptide, ARA 290
- **Half-life:** ~2 minutes plasma half-life, yet triggers durable downstream effects lasting days to weeks (PMID 25728128)

## Mechanism of Action

Erythropoietin acts through two distinct receptor systems: the EPOR homodimer on red cell progenitors drives erythropoiesis, while a heteroreceptor of EPOR and CD131 (the beta common receptor), termed the innate repair receptor, mediates tissue protection. The IRR is minimally expressed in healthy tissue but is rapidly induced by injury and inflammation. ARA-290 mimics the three-dimensional structure of helix B of erythropoietin, the region facing the aqueous medium when erythropoietin is bound to the EPOR homodimer, and selectively activates the IRR without engaging the erythropoietic receptor. IRR activation initiates anti-inflammatory, anti-apoptotic, and reparative programs, including dampening of innate immune cell activation. Preclinical work has also identified direct inhibition of the TRPV1 nociceptive channel as a contributor to analgesia in neuropathic pain models. Despite a plasma half-life of roughly 2 minutes, IRR engagement appears to flip a sustained molecular switch, producing biological effects lasting days to weeks after each dose.

## Key Research Findings

- ARA-290 is an 11-amino-acid peptide from erythropoietin's helix B that activates the innate repair receptor (EPOR/CD131) without any erythropoietic activity.
- The Phase 2b trial (64 patients) showed the 4 mg dose significantly increased corneal nerve fiber area in sarcoidosis small fiber neuropathy, objective evidence of nerve regrowth in humans.
- A Phase 2 trial in type 2 diabetes showed improved HbA1c, lipid profiles, and neuropathic symptoms over 56 days of observation.
- Plasma half-life is about 2 minutes, yet innate repair receptor engagement flips a sustained molecular switch producing effects lasting days to weeks.

## Safety & Tolerability

ARA-290 has a consistently clean early-phase safety record: multiple Phase 1 and Phase 2 trials reported no drug-related serious adverse events, no anti-drug antibodies, and no erythropoietic effects. All completed trials were small (at most 64 participants) and short (at most 12 weeks of dosing), so rare or delayed effects cannot be excluded.

**Human data status:** Several small Phase 1 and Phase 2 trials have been completed in sarcoidosis small fiber neuropathy, type 2 diabetes, and diabetic macular edema; the largest enrolled 64 participants and the longest dosing was 12 weeks. No Phase 3 trial has been published.

**Regulatory status:** Not approved by the FDA, EMA, or any other regulator. FDA orphan drug designation for sarcoidosis was granted to Araim Pharmaceuticals in 2016 (sponsor announcement), and an EU orphan designation for sarcoidosis has been reported; designations are development incentives, not approvals. Anti-doping laboratories treat ARA-290 as a prohibited EPO-derived peptide in sport (PMID 28941172).

- In the 28-day type 2 diabetes trial (4 mg daily subcutaneous), no potential safety issues were identified across the treatment and follow-up period. (evidence tier: human-interventional; [PMID 25387363](https://pubmed.ncbi.nlm.nih.gov/25387363/))
- The 12-week diabetic macular edema trial reported no serious adverse events or reactions and no detectable anti-cibinetide antibodies. (evidence tier: human-interventional; [PMID 32674280](https://pubmed.ncbi.nlm.nih.gov/32674280/))
- The intravenous pilot study in sarcoidosis patients (2 mg three times weekly for 4 weeks) raised no safety concerns on clinical or laboratory assessment. (evidence tier: human-interventional; [PMID 23168581](https://pubmed.ncbi.nlm.nih.gov/23168581/))
- The peptide is non-erythropoietic by design: it does not engage the erythropoietin receptor homodimer that drives red cell production, and showed no erythropoietic activity in vitro or in vivo, avoiding the hematocrit elevation and thrombotic risk that limit erythropoietin's tissue-protective use. (evidence tier: animal; [PMID 18676614](https://pubmed.ncbi.nlm.nih.gov/18676614/))
- Long-term safety beyond 12 weeks of continuous dosing is uncharacterized, and completed trials enrolled at most 64 participants, so the evidence base cannot exclude uncommon adverse effects. (evidence tier: human-interventional; [PMID 28475703](https://pubmed.ncbi.nlm.nih.gov/28475703/))

## Dosing Information (Research Context)

In published human trials, ARA-290 was self-administered subcutaneously at 4 mg once daily for 28 days in type 2 diabetes (PMID 25387363), at 1, 4, or 8 mg once daily for 28 days in the Phase 2b sarcoidosis neuropathy trial (PMID 28475703), and at 4 mg once daily for 12 weeks in diabetic macular edema (PMID 32674280). An earlier pilot study used 2 mg intravenously three times weekly for 4 weeks (PMID 23168581). No dosing outside these trial protocols has published support.

| Route | Dose | Frequency | Notes |
| --- | --- | --- | --- |
| Subcutaneous (Phase 2b sarcoidosis) | 1, 4, or 8 mg | Once daily x 28 days | 4 mg arm significantly increased corneal nerve fiber area (PMID 28475703) |
| Subcutaneous (type 2 diabetes) | 4 mg | Once daily x 28 days | HbA1c and lipid improvements over 56-day observation (PMID 25387363) |
| Subcutaneous (diabetic macular edema) | 4 mg | Once daily x 12 weeks | Safe; no anti-drug antibodies detected (PMID 32674280) |
| Intravenous (pilot sarcoidosis) | 2 mg | 3x weekly x 4 weeks | Improved small fiber neuropathy screening list scores (PMID 23168581) |

## Researched Effects

- **Small Nerve Fiber Regeneration** (evidence: moderate): The most distinctive clinical finding for ARA-290 is measurable regrowth of small nerve fibers in humans. In the Phase 2b trial of 64 patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain, 28 days of once-daily cibinetide produced a placebo-corrected increase in corneal nerve fiber area of 697 micrometers squared at the 4 mg dose (P = 0.012), with parallel increases in regenerating GAP-43-positive intraepidermal skin fibers; corneal nerve changes correlated with improved 6-minute walk distance. Earlier blinded trials in sarcoidosis patients had already shown significant increases in corneal nerve fiber density, making ARA-290 one of the few research peptides with objective histological evidence of nerve regrowth in humans.
- **Neuropathic Symptom Relief** (evidence: moderate): Across the sarcoidosis small fiber neuropathy program, ARA-290 improved patient-reported neuropathic symptoms: the pilot trial showed significant improvement in small fiber neuropathy screening list scores versus placebo after 4 weeks, and subsequent trials showed improvements in symptom-based outcomes and pain measures, with a placebo-corrected pain reduction described as clinically meaningful in subjects with moderate-to-severe pain, though that comparison did not reach statistical significance (P = 0.157). In type 2 diabetes patients with painful neuropathy, 28 days of treatment significantly improved PainDetect questionnaire scores. Preclinical work attributes the analgesia partly to direct TRPV1 channel inhibition and partly to dampening of innate immune activation at injured nerves.
- **Metabolic Control in Type 2 Diabetes** (evidence: preliminary): A Phase 2 trial in patients with type 2 diabetes found that 4 mg daily subcutaneous ARA-290 for 28 days improved hemoglobin A1c and lipid profiles throughout the 56-day observation period, alongside the neuropathic symptom improvements. The metabolic findings are mechanistically interesting because the innate repair receptor is implicated in tissue responses to metabolic stress, but they rest on a single small trial and require confirmation in larger, longer studies before any conclusion about antidiabetic efficacy can be drawn.
- **Tissue Protection and Anti-Inflammatory Signaling** (evidence: moderate): The preclinical literature for ARA-290 and the helix B surface peptide concept spans ischemic stroke, renal ischemia-reperfusion, diabetes-induced retinal edema, peripheral nerve trauma, impaired wound healing in diabetic mice, myocardial infarction, experimental colitis, and protection of transplanted pancreatic islets. In the discovery paper, the 11-amino-acid helix B surface peptide was tissue protective in stroke and kidney ischemia models and accelerated wound healing, without erythropoietic activity. This breadth reflects the innate repair receptor's role as an injury-induced protective system, though most of these applications remain preclinical.

## Research Applications

- Small Fiber Neuropathy Research
- Sarcoidosis Research
- Diabetic Neuropathy Research
- Innate Repair Receptor Biology
- Tissue Protection Research

## Key Studies

### Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Brines M, Patel NS, Villa P, et al. — *Proceedings of the National Academy of Sciences* (2008) — [PMID 18676614](https://pubmed.ncbi.nlm.nih.gov/18676614/) | [doi:10.1073/pnas.0805594105](https://doi.org/10.1073/pnas.0805594105)

The discovery paper establishing that erythropoietin's tissue-protective and erythropoietic functions are mediated by distinct receptors: hematopoiesis via the EPOR homodimer and tissue protection via a heterocomplex of EPOR and CD131 (the beta common receptor). The authors delimited the protective activity to helix B (residues 58-82) and showed an 11-amino-acid peptide simulating its aqueous face is tissue protective in ischemic stroke and renal ischemia-reperfusion models, accelerates wound healing, and augments cognitive function in rodents, all without erythropoietic activity in vitro or in vivo. This work created the compound class to which ARA-290 belongs.

### Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study

Heij L, Niesters M, Swartjes M, et al. — *Molecular Medicine* (2012) — [PMID 23168581](https://pubmed.ncbi.nlm.nih.gov/23168581/) | [doi:10.2119/molmed.2012.00332](https://doi.org/10.2119/molmed.2012.00332)

The first placebo-controlled human study of ARA-290 enrolled 22 sarcoidosis patients with small fiber neuropathy symptoms and spontaneous pain scores of at least 5, dosing 2 mg intravenously three times weekly or placebo for 4 weeks. No safety concerns arose on clinical or laboratory assessment. The ARA-290 group showed significant improvement in small fiber neuropathy screening list scores versus placebo (-11.5 versus -2.9) and significant improvements in the pain and physical functioning dimensions of the SF-36 quality-of-life measure.

### ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density

Dahan A, Dunne A, Swartjes M, et al. — *Molecular Medicine* (2013) — [PMID 24136731](https://pubmed.ncbi.nlm.nih.gov/24136731/) | [doi:10.2119/molmed.2013.00122](https://doi.org/10.2119/molmed.2013.00122)

This blinded, placebo-controlled trial in patients with documented sarcoidosis-associated small nerve fiber loss found that 28 days of daily subcutaneous ARA-290 significantly improved neuropathic symptoms. Beyond patient-reported outcomes, treatment was associated with a significant increase in corneal small nerve fiber density measured by confocal microscopy, changes in cutaneous temperature sensitivity, and increased exercise capacity on the 6-minute walk test, leading the authors to propose ARA-290 as a potential disease-modifying agent for this condition.

### ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes

Brines M, Dunne AN, van Velzen M, et al. — *Molecular Medicine* (2015) — [PMID 25387363](https://pubmed.ncbi.nlm.nih.gov/25387363/) | [doi:10.2119/molmed.2014.00215](https://doi.org/10.2119/molmed.2014.00215)

This Phase 2 study enrolled patients with type 2 diabetes and painful neuropathy to self-administer ARA-290 4 mg or placebo subcutaneously daily for 28 days, with an additional month of untreated follow-up. No potential safety issues were identified. Treated subjects showed improved hemoglobin A1c and lipid profiles throughout the 56-day observation period and significant improvement in neuropathic symptoms on the PainDetect questionnaire. Subjects whose corneal nerve fiber density was more than one standard deviation below normal showed a significant increase versus no change in the placebo group.

### Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain

Culver DA, Dahan A, Bajorunas D, et al. — *Investigative Ophthalmology & Visual Science* (2017) — [PMID 28475703](https://pubmed.ncbi.nlm.nih.gov/28475703/) | [doi:10.1167/iovs.16-21291](https://doi.org/10.1167/iovs.16-21291)

The Phase 2b trial randomized 64 subjects with sarcoidosis-associated small nerve fiber loss and neuropathic pain to cibinetide 1, 4, or 8 mg daily or placebo for 28 days, assessing corneal nerve fiber area by confocal microscopy and regenerating GAP-43-positive intraepidermal fibers. The placebo-corrected mean change in corneal nerve fiber area at day 28 was +697 micrometers squared in the 4 mg group (P = 0.012), with a parallel increase in regenerating skin fibers (P = 0.035); corneal changes correlated with 6-minute walk improvement. Subjects with moderate-to-severe pain reported a clinically meaningful placebo-corrected pain decrease at 4 mg, but this endpoint was not statistically significant (P = 0.157).

### A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema

Lois N, Gardner E, McFarland M, et al. — *Journal of Clinical Medicine* (2020) — [PMID 32674280](https://pubmed.ncbi.nlm.nih.gov/32674280/) | [doi:10.3390/jcm9072225](https://doi.org/10.3390/jcm9072225)

This open-label Phase 2 trial treated 9 patients with diabetic macular edema with cibinetide 4 mg daily subcutaneously for 12 weeks. There was no significant improvement in best-corrected visual acuity, central retinal thickness, retinal sensitivity, or tear production, though quality-of-life scores on the NEI VFQ-25 improved and some participants showed improvements in retinal thickness, diabetic control, and albuminuria. No serious adverse events or reactions occurred, and no anti-cibinetide antibodies were detected, extending the human safety record to 12 weeks of continuous dosing.

## Frequently Asked Questions

### What is ARA-290 (cibinetide)?

ARA-290, also called cibinetide or pHBSP, is an 11-amino-acid peptide modeled on the helix B surface region of erythropoietin. It activates the innate repair receptor, a complex of the erythropoietin receptor and CD131, triggering tissue-protective and anti-inflammatory programs without stimulating red blood cell production. It has completed multiple Phase 2 trials, mainly in small fiber neuropathy, and holds FDA orphan drug designation for sarcoidosis, but it is not an approved drug.

### How is ARA-290 different from erythropoietin (EPO)?

EPO signals through two receptor systems: the EPOR homodimer, which drives red blood cell production, and the innate repair receptor (EPOR plus CD131), which mediates tissue protection. Using EPO as a tissue-protective drug is limited by hematocrit rises, platelet activation, and thrombosis risk from its erythropoietic arm. ARA-290 was engineered from helix B, the region facing away from the EPOR homodimer interface, so it activates only the repair receptor and is non-erythropoietic in vitro and in vivo.

### What did the sarcoidosis small fiber neuropathy trials show?

The Phase 2b trial in 64 patients found that 28 days of cibinetide at 4 mg daily significantly increased corneal nerve fiber area versus placebo (placebo-corrected +697 micrometers squared, P = 0.012) and increased regenerating nerve fibers in skin biopsies, with corneal changes tracking improved 6-minute walk distance. Earlier blinded trials showed improved neuropathic symptom scores and increased corneal nerve fiber density. This is objective evidence of small nerve fiber regrowth in humans, though larger and longer trials are still needed.

### Does ARA-290 help in diabetes?

A Phase 2 trial in type 2 diabetes patients with neuropathy found 4 mg daily for 28 days improved HbA1c and lipid profiles over the 56-day observation period and significantly improved neuropathic symptoms; patients with reduced corneal nerve fiber density at baseline showed significant increases versus placebo. A separate 12-week trial in diabetic macular edema found the treatment safe but without significant improvement in visual acuity or retinal thickness. The metabolic findings come from single small trials and remain preliminary.

### Is ARA-290 FDA approved or legal to use?

ARA-290 is not approved for any indication by the FDA or any other regulator. Araim Pharmaceuticals received FDA orphan drug designation for sarcoidosis in 2016, which provides development incentives but is not an approval, and no Phase 3 program has been published. Anti-doping laboratories treat it as a prohibited EPO-derived peptide in sport. Material sold by research vendors sits outside any regulatory oversight.

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