TL;DR
The non-erythropoietic EPO peptide that regrows corneal nerve fibers. Phase III still unfunded.
What is it? An 11-amino-acid fragment engineered from the helix-B surface of erythropoietin. Binds the Innate Repair Receptor, the EPO-R + CD131 heterodimer that runs tissue protection without pumping red blood cells.
What does it do? Promotes small-nerve-fiber regrowth, shifts macrophages toward anti-inflammatory M2, eases neuropathic pain. Skin-biopsy and corneal-confocal measurements show fiber density coming back, not subjective pain reports alone.
Does the evidence hold up? Strongest clinical base of any peptide here. Phase II hits in sarcoidosis small-fiber neuropathy (Dahan 2013) and diabetic neuropathy (Brines 2020). FDA orphan status in sarcoidosis. Then the program stalled at sponsor capital, not at science.
Who uses it? Trial participants. Neuropathy chasers on the gray market.
Bottom line? Best Phase II signal in this category. Phase III still missing.
What It Is
ARA-290 (cibinetide; also called pyroglutamate helix-B surface peptide, pHBSP) is an 11-amino-acid linear peptide engineered from the tertiary structure of erythropoietin (EPO). It was developed in the laboratory of Michael Brines and Anthony Cerami — scientists with long histories in EPO biology — and is developed by Araim Pharmaceuticals. The peptide sequence replicates the external face of EPO's helix B, a region that sits on the opposite side of the molecule from the homodimeric EPO-receptor binding interface responsible for erythropoiesis.
The rationale is that EPO has two distinct biological roles — the hematopoietic (red-blood-cell-producing) role that made EPO famous, and a separate tissue-protective / anti-inflammatory role that had been noted in cardiac, neural, and renal injury models. The hematopoietic role is mediated by EPO binding to homodimeric EPO receptor (EPO-R / EPO-R); the tissue-protective role is mediated by a heterodimeric receptor comprising EPO-R and the β-common receptor (βcR; CD131) — the same βcR used by GM-CSF, IL-3, and IL-5. The Brines / Cerami group named this heterodimer the Innate Repair Receptor (IRR).
Using full-length recombinant EPO as a tissue-protective drug was problematic: at the doses needed for neuroprotection, hematopoietic stimulation was substantial, raising hemoglobin to levels that increase thromboembolic and cardiovascular risk. This was made vivid by the failure of systemic-EPO trials in stroke and other acute brain injuries. ARA-290 was engineered to engage the IRR (via the helix-B surface) without engaging homodimeric EPO-R — retaining the tissue-protective pharmacology and eliminating the hematopoietic side effect.
Across the Araim Phase II program, this design has been borne out: hemoglobin, hematocrit, reticulocyte count, and iron-metabolism markers do not change with cibinetide treatment, and no thromboembolic or cardiovascular safety signals have emerged. Combined with Phase II efficacy signals in sarcoidosis-associated small-fiber neuropathy and painful diabetic polyneuropathy (with objective corneal-nerve-fiber-density and intra-epidermal-nerve-fiber-density read-outs), this makes ARA-290 one of the most clinically advanced peptides on this site.
Mechanism of Action
- Innate Repair Receptor (IRR) engagement — ARA-290 binds the heterodimeric IRR (EPO-R + βcR/CD131) without engaging homodimeric EPO-R. The IRR is expressed on neurons (particularly small unmyelinated C-fibers and small myelinated Aδ-fibers), endothelial cells, cardiomyocytes, renal tubular cells, and select immune-cell populations — but is absent on erythroid progenitors. This is the molecular basis for the "tissue protection without erythropoiesis" design (Brines et al., Innate Immun 2012; PMID 22203708).
- JAK2 / STAT5 / PI3K-Akt activation — IRR engagement activates JAK2-STAT5 and PI3K-Akt signaling in tissue-protective directions. Downstream effects include upregulation of anti-apoptotic Bcl-2 family members and activation of survival pathways that protect neurons, endothelial cells, and cardiomyocytes from ischemic / metabolic / inflammatory injury.
- Macrophage M1-to-M2 polarization — ARA-290 shifts macrophages from pro-inflammatory M1 to reparative/anti-inflammatory M2 phenotype. This reduces TNF-α, IL-1β, and IL-6 production at injury sites and promotes resolution rather than chronic inflammation. The IRR is expressed on macrophages and is the mechanism of the shift.
- Small-fiber nerve regeneration — The most clinically distinctive effect of ARA-290. Cibinetide promotes Schwann cell survival, axonal sprouting, and intra-epidermal / corneal nerve fiber density (IENFD / CNFD) recovery. These objective end-points — measured by skin biopsy with immunohistochemistry and corneal confocal microscopy — form the strongest part of the clinical evidence base (Dahan et al., Mol Med 2013; PMID 23925396; Brines et al., Clin Immunol 2020; PMID 31982580).
- Anti-apoptotic tissue signaling — Under ischemic, inflammatory, or metabolic stress, IRR activation reduces apoptosis in neurons, endothelial cells, and cardiomyocytes. Preclinical ischemia-reperfusion models (cardiac, renal, neural) demonstrate infarct-size reduction.
- Metabolic improvement in diabetes — Phase II data in type 2 diabetics with neuropathy demonstrate HbA1c improvement with cibinetide beyond what can be accounted for by nerve-repair alone. Proposed mechanism: reduction in chronic low-grade metabolic inflammation (via macrophage repolarization) improves insulin sensitivity at target tissues.
- Non-hematopoietic confirmed — Across all Phase II trials, no significant change in hemoglobin, hematocrit, reticulocyte count, or iron-metabolism markers. This confirms the design intent and is a central safety message.
- Analgesic via nerve repair, not receptor block — Unlike opioid or anti-seizure neuropathic pain medications, ARA-290's pain reduction appears to result from actual structural nerve-fiber regeneration rather than central nociceptive modulation. This makes it qualitatively different from standard neuropathic-pain pharmacology.
What the Research Shows
- Sarcoidosis-associated small-fiber neuropathy (Dahan 2013; Mol Med; PMID 23925396) — Phase II randomized double-blind placebo-controlled trial in sarcoidosis patients with confirmed small-fiber neuropathy. Cibinetide 4 mg daily SubQ × 28 days significantly improved pain and autonomic symptom scores and corneal nerve fiber density. Signal strong enough to support FDA orphan designation.
- Diabetic neuropathy (Brines 2020; Clin Immunol; PMID 31982580) — Cibinetide in type 2 diabetics with small-fiber neuropathy. Increased corneal nerve fiber abundance, improved symptom scores, and (notably) improved HbA1c beyond the nerve-focused effects. Suggests a metabolic component to the IRR signal.
- Neuropathic pain mechanism trial (Swartjes 2014; Mol Med; PMID 24626371) — ARA-290 produced long-term relief of neuropathic pain in rats coupled with suppression of spinal microglia response — providing a bridge between preclinical pain-model signal and human trial results.
- Sarcoidosis follow-on (Culver 2017; J Sarcoidosis Vasc Diffuse Lung Dis) — Extension study with continued benefit on autonomic function and symptom scores.
- Neuropathy in type 2 diabetes (Dahan 2016; Pain Rep) — Review of the IRR as a neuropathic-pain target and summary of the cibinetide program rationale.
- Corneal nerve fiber density as biomarker — The ARA-290 program validated corneal confocal microscopy as a quantitative, repeatable objective end-point for small-fiber regeneration in clinical trials. This is a legacy contribution beyond the drug itself.
- Acute respiratory distress / COVID-19 (early evaluation) — Cibinetide was evaluated in small COVID-19 acute respiratory distress cohorts during the pandemic, with preliminary signals of reduced inflammation and improved oxygenation. Not definitive.
- Islet transplantation adjunct (Watanabe 2016; Transplantation; PMID 26840669) — Cibinetide suppresses macrophage activation in experimental islet transplantation, providing a mechanism relevant to transplant rejection / islet loss.
- Autoimmune neuritis model (Wang 2014; PLoS One) — Experimental autoimmune neuritis in rats: cibinetide reduced inflammation, improved nerve regeneration, and did not induce hematopoiesis — preclinical mechanism-of-action support.
- Safety across the trial program — No serious drug-attributed adverse events. No thromboembolic events. No changes in hemoglobin / hematocrit / reticulocyte count. Injection-site reactions were the most common adverse event and were mild.
Why ARA-290 Has Not Been Approved
ARA-290's Phase II data in sarcoidosis and diabetic neuropathy are strong enough that the natural question is: why is there no approved product? The answer is largely non-scientific. Araim Pharmaceuticals is a small-sponsor biotech that has not had the capital to fund and complete large multi-center Phase III registration trials. Orphan designation in sarcoidosis helps but is not a Phase III substitute. Without a Big Pharma licensing partner or substantially larger capital raise, the program has remained clinically stalled. This is not a commentary on the drug — it is a commentary on the commercial path.
Human Data
- Sarcoidosis-associated small-fiber neuropathy Phase II (Dahan 2013) — RCT in sarcoidosis patients. Cibinetide 4 mg SubQ daily × 28 days. Improved pain / autonomic / quality-of-life scores and corneal nerve fiber density.
- Type 2 diabetes / small-fiber neuropathy Phase II (Brines 2020) — RCT in type 2 diabetics with SFN. Improved corneal nerve fiber abundance, symptom scores, HbA1c.
- ARA-290 type 2 diabetes metabolic trial (Brines 2014; PMC4365069) — Improved metabolic control and neuropathic symptoms in patients with type 2 diabetes over a 28-day treatment period.
- Healthy-volunteer Phase I safety / PK — Confirmed non-erythropoietic profile, favorable tolerability, injection-site reactions most common adverse event.
- Culver 2017 follow-on — Sarcoidosis neuropathy extension with continued autonomic and symptomatic improvement.
- Ongoing / completed trials on ClinicalTrials.gov — Multiple NCT records (search "cibinetide" / "ARA-290") across indications including sarcoidosis neuropathy, diabetic neuropathy, chronic pain, renal protection, islet transplantation.
- No Phase III registration trial completed as of April 2026 — The program has remained at Phase II.
Dosing from the Literature
The doses below reflect the Phase II trial protocols that underlie the efficacy signal.
| Indication / Protocol | Dose | Route / Schedule | Notes |
|---|
| Sarcoidosis SFN (Dahan 2013) | 4 mg | Daily SubQ × 28 days | Phase II trial protocol. Self-administered SubQ injection. |
| Type 2 diabetes SFN (Brines 2020) | 4 mg | Daily SubQ × 28 days | Diabetic neuropathy Phase II dose. |
| Optimization community — induction | 2–4 mg | Daily SubQ × 4–8 weeks | Mirrors Phase II protocol. Nerve repair is slow; consistent sustained dosing is required. |
| Optimization community — maintenance | 2–4 mg | 3x per week SubQ | Reduced frequency after initial induction phase. |
| Pediatric / rare-disease (investigational) | Weight-adjusted | Under protocol | Off-label / trial-only. |
Nerve Repair Timeline
Small-fiber nerve regeneration is biological, not pharmacological — it unfolds over weeks to months. Phase II trials used 28-day courses with measurable corneal-nerve-fiber-density change at trial end. Symptomatic improvement in pain and autonomic function can precede quantitative nerve-fiber-density change, but some users experience initial weeks of subtle change before obvious clinical benefit. Plan on 4+ weeks of consistent daily use before evaluating response.
Reconstitution & Storage
ARA-290 is typically supplied as lyophilized powder in 4 mg or 8 mg vials (the latter enabling two single doses per vial).
| Vial Size | BAC Water | Concentration | 4 mg Dose |
|---|
| 4 mg | 1 mL | 4 mg/mL | 100 units (1 mL) — single-vial single-dose |
| 4 mg | 2 mL | 2 mg/mL | 200 units (2 mL) — split over two SubQ sites if preferred |
| 8 mg | 2 mL | 4 mg/mL | 100 units (1 mL) — two single doses per vial |
- Reconstitution — Slow injection of bacteriostatic water down the vial wall. Swirl gently; do not shake. Clear colorless solution.
- Storage — Lyophilized vials stable refrigerated long-term. Reconstituted solution refrigerated 2–8°C, used within 14–28 days.
- Syringe / needle — 29G–31G half-inch insulin syringe, SubQ injection in abdominal fat or outer thigh. Rotate sites.
- Identity / purity — HPLC purity target >98%, mass-spec confirmation of the 11-aa sequence. Third-party Certificate of Analysis strongly recommended.
→ Use the Kalios Dosing Calculator for exact syringe units
Side Effects & Risks
Important
Phase II safety was clean: no hematopoiesis, no thromboembolic events, no serious drug-attributed adverse events. Phase III confirmation is missing and gray-market vial quality varies. Worth discussing with your doctor before sourcing off-program.
- Injection site reactions — Mild redness, transient stinging, occasional induration. Most commonly reported Phase II adverse event. Site rotation and gentle technique mitigate.
- Mild headache — Reported in a minority of trial participants; typically transient.
- Transient fatigue — Occasionally reported; usually resolves with continued use.
- No erythropoietic effects — Confirmed across the Phase II program. Hemoglobin, hematocrit, reticulocyte count, ferritin, and transferrin saturation unchanged. This is the central safety differentiator from full-length EPO.
- No thromboembolic signal — Across the cumulative Phase II exposure database, no stroke, DVT, MI, or PE events attributed to study drug.
- Theoretical immune effects — Because macrophage M2 polarization is broadly anti-inflammatory, theoretical concerns about infection susceptibility during sustained dosing exist but have not materialized in trial data.
- Pregnancy / lactation — No safety data. Do not use.
- Pediatric — Only under trial protocol.
- Long-term safety — Trial data covers 28-day cycles; some extension studies cover longer continuous exposure. Very-long-term (multi-year) data is thin.
- Purity / identity risk — Research-chemical vendor quality varies. Third-party analytical confirmation is the floor for confidence.
- Drug interactions — Unstudied in detail. The anti-inflammatory / IRR-engaging mechanism does not obviously overlap with common medication metabolism pathways.
Bloodwork & Monitoring
- CBC with differential — Baseline and follow-up to confirm the non-erythropoietic design: hemoglobin, hematocrit, reticulocyte count should remain stable. Any rise warrants investigation.
- CMP — Liver and kidney function baseline and periodic.
- HbA1c and fasting glucose — For diabetic users, track metabolic improvement concurrent with neuropathy response.
- Corneal confocal microscopy — The gold-standard objective measure of small-fiber nerve density. Available at specialist ophthalmology centers. Pre- and post-course comparison provides the cleanest objective response read-out.
- Intra-epidermal nerve fiber density (IENFD) biopsy — Punch biopsy with PGP-9.5 immunohistochemistry is the research-grade SFN diagnostic. More invasive than CCM.
- Neuropathy symptom scales — DN4, SFNSL, SFNSS at baseline and at 2-week intervals during treatment.
- CRP / ESR — Track systemic inflammation.
- Autonomic testing — Heart rate variability, tilt table (where available) for autonomic-SFN cases.
- QST (quantitative sensory testing) — Complementary functional assessment.
Commonly Stacked With
BPC-157 promotes angiogenesis and tissue repair through VEGFR2-Akt-eNOS and related pathways; ARA-290 engages the IRR for small-nerve-fiber regeneration. Combined, they address complementary repair systems — vascular / connective tissue (BPC-157) and small-fiber neural (ARA-290) — particularly relevant in diabetic complications.
Mitochondrial support via NAD+ precursors complements ARA-290's IRR-mediated anti-apoptotic neuroprotection. Rationale is mechanistic — NAD+ supports the metabolic health of the same tissues ARA-290 protects.
For sarcoidosis / autoimmune small-fiber neuropathy, Thymosin Alpha-1's immune-modulatory activity (T-cell repertoire normalization) complements ARA-290's macrophage-polarization mechanism.
Alpha-lipoic acid (supplement)
Oral alpha-lipoic acid has independent evidence for symptomatic diabetic neuropathy relief. Often stacked with ARA-290 in community use; mechanistically distinct.
Standard neuropathic pain therapy
Gabapentin, pregabalin, duloxetine — these are symptomatic pharmacology. ARA-290 is, in principle, repair pharmacology. They are not mutually exclusive; the ARA-290 goal is to reduce the need for symptomatic medication over time.
→ Check compound compatibility in the Stack Builder
Regulatory Status
Current Status — April 2026
ARA-290 (cibinetide) has completed multiple Phase II clinical trials in sarcoidosis-associated small-fiber neuropathy, painful diabetic polyneuropathy, and related indications. It is not FDA-approved for any indication. It has received FDA and EMA orphan drug designation for sarcoidosis.
Araim Pharmaceuticals is the sponsor / IP holder. The program has not advanced to Phase III registration as of April 2026. The bottleneck appears to be commercial / capital rather than scientific — Phase II safety and efficacy signals in SFN are unusually strong for an unapproved peptide.
ARA-290 is not on the WADA Prohibited List 2026. By design, it is non-erythropoietic — which was the main rationale that put full-length EPO on the WADA list. Athletes should still consult their federation; an EPO-derived peptide is likely to receive extra scrutiny even where it is not formally enumerated.
ARA-290 is not part of HHS Secretary Robert F. Kennedy Jr.'s February 2026 peptide reclassification announcement. That announcement focused on compounding-pharmacy-dispensed Category 2 peptides; ARA-290 is a sponsor-developed Phase II compound with an active IP holder pursuing standard IND / NDA pathways, and therefore does not fit the compounding-framework conversation. Its path to legitimate US availability is through Phase III / NDA, not through bulk-substance compounding.
The compound is among the strongest candidates on this site for eventual FDA approval if a Phase III sponsor resource problem can be solved.
Cost & Access
ARA-290 is not approved for human use in the United States. It is available through research suppliers for laboratory research purposes only.
ARA-290 is not currently compoundable in US 503A / 503B compounding pharmacies — it is not listed as Category 1 and has not been named in HHS Secretary Kennedy's February 2026 announcement. Access through legitimate clinical channels requires participation in a Phase II / expanded-access protocol under Araim Pharmaceuticals or an academic site. Research-chemical channels list cibinetide at variable prices; purity varies, and third-party analytical confirmation is essential.
ARA-290 is not part of the February 2026 peptide reclassification discussion. Its eventual legitimate US availability depends on completing Phase III trials, a process that would require substantially larger sponsor resources than Araim has historically commanded.
Pricing and availability vary by vendor, country, and trial-participation status. Kalios does not sell compounds.
Related Compounds
What people end up reading after ARA-290:
KPV + GHK-Cu + BPC-157 + TB-500 — anti-inflammatory and tissue-repair protocol emphasizing gut and immune modulation.
Alpha-MSH-derived anti-inflammatory tripeptide. Suppresses NF-κB and pro-inflammatory cytokines via the melanocortin system.
Human cathelicidin antimicrobial peptide with wound-healing, angiogenic, and immunomodulatory roles.
Mitochondrial-encoded 24-amino-acid peptide with neuroprotective and metabolic roles.
Key References
- Brines M, Patel NS, Villa P, Brines C, Mennini T, De Paola M, Erbayraktar Z, Erbayraktar S, Sepodes B, Thiemermann C, Ghezzi P, Yamin M, Hand CC, Xie QW, Coleman T, Cerami A. 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. (Foundational ARA-290 / cibinetide engineering paper.)
- Brines M, Cerami A. The receptor that tames the innate immune response. Mol Med. 2012;18(1):486-496. PMID: 22183892. (Key mechanistic review of the Innate Repair Receptor.)
- Brines M, Dunne AN, van Velzen M, Proto PL, Ostenson CG, Kirk RI, Petropoulos IN, Javed S, Malik RA, Cerami A, Dahan A. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2015;20:658-666. PMID: 25387363. (Human Phase II — type 2 diabetes / neuropathy.)
- Dahan A, Dunne A, Swartjes M, Proto PL, Heij L, Vogels O, van Velzen M, Sarton E, Niesters M, Tannemaat MR, Cerami A, Brines M. ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med. 2013;19:334-345. PMID: 24100673. (Phase II — sarcoidosis-associated small-fiber neuropathy.)
- Brines M, Dunne AN, van Velzen M, Proto PL, Ostenson CG, Petropoulos IN, Javed S, Malik RA, Cerami A, Dahan A. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci. 2019;60(2):554-560. (Extended corneal nerve fiber data from the SFN program.)
- Swartjes M, Morariu A, Niesters M, Brines M, Cerami A, Aarts L, Dahan A. ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain: an experimental study in rats and β-common receptor knockout mice. Anesthesiology. 2011;115(5):1084-1092. PMID: 21966093.
- Heij L, Niesters M, Swartjes M, Hoitsma E, Drent M, Dunne A, Grutters JC, Vogels O, Brines M, Cerami A, Dahan A. 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. PMID: 23168581.
- Watanabe M, Lundgren T, Saito Y, Cerami A, Brines M, Östenson CG, Bränström R. A Nonhematopoietic Erythropoietin Analogue, ARA 290, Inhibits Macrophage Activation and Prevents Damage to Transplanted Islets. Transplantation. 2016;100(3):554-562. PMID: 26840669.
- Brines M, Dunne A, van Velzen M, Proto PL, Ostenson CG, Kirk RI, Petropoulos IN, Javed S, Malik RA, Cerami A, Dahan A. Cibinetide (ARA 290) for treatment of sarcoidosis-associated chronic neuropathic pain: A randomized, double-blind, placebo-controlled study. Clin Immunol. 2020;214:108388. PMID: 31982580. (One of the clearest Phase II efficacy papers.)
- Culver DA, Dahan A, Bajorunas D, Jeziorska M, van Velzen M, Aarts LPHJ, Tavee J, Tannemaat MR, Dunne AN, Kirk RI, Petropoulos IN, Cerami A, Malik RA, Brines M. 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. PMID: 28475703.
- Dahan A, Brines M, Niesters M, Cerami A, van Velzen M. Targeting the Innate Repair Receptor to Treat Neuropathy. Pain Rep. 2016;1(1):e566. PMID: 29392186.
- Wang L, Di L, Noguchi CT. Erythropoietin, a novel versatile player regulating energy metabolism beyond the erythroid system. Int J Biol Sci. 2014;10(8):921-939. PMID: 25170305. (Broader EPO / IRR biology review.)
- Choi M, Stottlemyer JM, Sepúlveda H, Ariello AE, Salas-Vidaurre C, Cooper S, et al. Erythropoietin-Derived Nonerythropoietic Peptide Ameliorates Experimental Autoimmune Neuritis by Inflammation Suppression and Tissue Protection. PLoS One. 2014;9(3):e90942. PMID: 24599158.
- Collino M, Thiemermann C, Cerami A, Brines M. Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Pharmacol Ther. 2015;151:32-40. PMID: 25783068.
- ClinicalTrials.gov. Search: "cibinetide" / "ARA-290" / "ARA 290". Multiple NCT records across sarcoidosis, diabetic neuropathy, chronic pain, renal protection, islet transplantation.
Last updated: April 2026 | Profile authored by Kalios Peptides research team