Neuroprotection
ARA-290 (Cibinetide): Tissue-Protective Peptide for Nerve Regeneration
ARA-290 is an 11-amino acid peptide derived from erythropoietin's structure that provides tissue protection without the dangerous blood-thickening effects of EPO itself. It activates the innate repair receptor (IRR) — a damage-sensor that triggers anti-inflammatory and regenerative responses only where injury exists.
The clinical data is notable: Phase 2 trials showed 23% increases in corneal nerve fiber area in sarcoidosis patients. This is actual nerve regeneration, not symptom suppression — the first drug to demonstrate this in humans. Development has stalled since 2020 due to funding constraints, not scientific failure.
At a Glance
| Property | Value |
|---|---|
| What it is | 11-amino acid synthetic peptide from EPO helix B |
| Mechanism | Activates innate repair receptor (EPOR-CD131) |
| Key outcome | 23% nerve fiber regeneration in Phase 2 trials |
| Dose | 4 mg SC daily (clinical trials) |
| Duration studied | 28–84 days |
| Regulatory status | FDA Fast Track + Orphan Drug; not approved |
What ARA-290 Is
ARA-290 (also called cibinetide) is an engineered peptide that was reverse-engineered from erythropoietin's three-dimensional structure. When researchers mapped EPO's shape, they found that one surface — helix B — faces away from the receptor responsible for making red blood cells. This surface instead contacts a different receptor complex that triggers tissue repair.
The peptide sequence was extracted from this helix B region: 11 amino acids with no sequence similarity to EPO itself, but recapitulating the three-dimensional geometry that activates repair pathways.
The result is a molecule that provides EPO's protective benefits without its liabilities — no blood thickening, no thrombosis risk, no need for hemoglobin monitoring.
How ARA-290 Works
The Innate Repair Receptor
Normal tissues don't express the innate repair receptor (IRR). It appears rapidly in response to injury, inflammation, hypoxia, or metabolic stress — acting as a damage sensor that summons repair resources only where needed.
The IRR is a heterodimer of two receptor subunits: EPOR and CD131 (beta-common receptor). When ARA-290 binds this complex, it triggers signaling cascades that reduce inflammation and support regeneration:
JAK2/STAT signaling: Anti-apoptotic effects — damaged cells are rescued rather than eliminated prematurely.
PI3K/Akt pathway: Modulates cell survival, stem cell migration, and regional blood flow to injured areas.
NF-kB downregulation: Reduces proinflammatory cytokine production, particularly TNF-alpha — quieting the inflammatory response that can become self-perpetuating.
Why It Doesn't Make Red Blood Cells
EPO's blood-making effects require binding to EPOR homodimers in bone marrow — a completely different receptor configuration. ARA-290 doesn't engage this receptor at all. CD131 knockout studies confirm this: animals lacking the beta-common receptor subunit lose all tissue-protective effects from ARA-290, but erythropoiesis continues normally.
This means no polycythemia (thick blood), no thrombosis risk, no hypertension from volume overload — the dangerous side effects that limit EPO use in clinical practice.
| Feature | EPO (Erythropoietic) | ARA-290 (Tissue Protective) |
|---|---|---|
| Receptor | EPOR homodimer | EPOR-CD131 heterodimer (IRR) |
| Primary effect | RBC production | Tissue protection/repair |
| Thrombosis risk | Yes | No |
| Hemoglobin monitoring | Required | Not required |
Clinical Evidence: What Trials Show
Sarcoidosis Small Fiber Neuropathy
The strongest clinical data comes from sarcoidosis patients with painful small fiber neuropathy — a condition where tiny sensory nerves die back, causing burning pain, numbness, and autonomic dysfunction.
DOSARA Trial (Phase 2b, n=64): Patients received 4 mg subcutaneous cibinetide daily for 28 days. The 4 mg dose group showed a 23% increase in corneal nerve fiber area versus baseline, confirmed by confocal microscopy. Skin biopsies showed increases in GAP-43 positive nerve fibers — a marker of active nerve regeneration, not just nerve survival.
Pain intensity decreased significantly in the moderate-to-severe pain subgroup. Walking distance correlated with nerve fiber density improvements.
Pilot Study (n=22): The earlier proof-of-concept trial showed ARA-290 patients achieved an 11.5-point improvement in Small Fiber Neuropathy Screening List scores versus 2.9 points for placebo. 42% of ARA-290 patients achieved clinically meaningful 15+ point improvements versus 0% in the placebo group.
Why This Matters
This is the first drug to demonstrate actual small nerve fiber regeneration in humans. Existing neuropathy treatments only suppress symptoms (gabapentin, duloxetine) or slow progression. ARA-290 shows biological reversal — new nerve fibers growing where old ones had died.
| Trial | Phase | N | Primary Endpoint | Result |
|---|---|---|---|---|
| DOSARA (Sarcoidosis) | 2b | 64 | Corneal nerve fiber area | 23% increase |
| Sarcoidosis Pilot | 2 | 22 | SFNSL score | 11.5 vs 2.9 points |
| Type 2 Diabetes | 2 | ~40 | Metabolic/neuropathy | Improved |
| Diabetic Macular Edema | 2 | 9 | BCVA, retinal thickness | Not met |
Other Indications (Earlier Stage)
Type 2 Diabetes: Subjects receiving ARA-290 showed improvements in HbA1c, lipid profiles, and corneal nerve fiber density in those with baseline deficits.
Diabetic Macular Edema (n=9): This small open-label study failed to meet primary endpoints for visual acuity and retinal thickness, though some participants showed individual improvements. The small sample size limits conclusions.
Preclinical promise: Animal studies show ARA-290 protects kidneys during transplantation (reduced ischemia-reperfusion injury), reduces infarct size after heart attack, and provides neuroprotection in stroke and traumatic brain injury models. The peptide crosses the blood-brain barrier.
Who ARA-290 May Benefit
| Profile | Why ARA-290 Helps |
|---|---|
| Small fiber neuropathy | First drug to show nerve regeneration in this condition |
| Sarcoidosis patients | FDA Fast Track + Orphan Drug designation for this population |
| Diabetic neuropathy | Preclinical and Phase 2 data show nerve fiber improvements |
| Post-viral nerve damage | IRR mechanism targets injury-induced inflammation |
| Chemotherapy-induced neuropathy | Theoretical fit (IRR upregulates with metabolic stress) |
The peptide works best when the innate repair receptor is actually expressed — meaning active injury, inflammation, or metabolic stress. It's less likely to help when nerves have already completely degenerated without ongoing insult.
Dosing
Reconstitution note: Use bacteriostatic water with sodium chloride (isotonic) to reduce injection site sting and prevent welts.
Clinical Trial Protocol
| Parameter | Value |
|---|---|
| Standard dose | 4 mg SC daily |
| Dose range tested | 1–8 mg daily |
| Treatment duration | 28–84 days |
| Route | Subcutaneous (thigh, rotating sites) |
The 4 mg dose showed the clearest efficacy signal. Doses up to 8 mg were tested without dose-limiting toxicity.
Pharmacokinetics
ARA-290 has a paradoxically short plasma half-life of approximately 2–20 minutes. Yet biological effects persist because receptor activation triggers sustained intracellular signaling cascades — the receptor acts as a "molecular switch" that stays on after the ligand clears.
Peak plasma concentration after 4 mg SC reaches approximately 3 ng/mL (2.4 nmol/L), exceeding the minimum effective concentration of 1 nmol/L.
Side Effects and Safety
ARA-290 has an excellent safety profile across multiple Phase 2 trials.
Common:
- Mild injection site reactions
- Transient headache
Serious events:
- Adverse event frequency was comparable between ARA-290 and placebo groups
- No clinically significant hematological changes (confirms no erythropoietic activity)
- No anti-cibinetide antibodies detected
Safety Advantage Over EPO
The critical benefit: ARA-290 eliminates the major risks that limit EPO therapy:
| Concern | EPO | ARA-290 |
|---|---|---|
| Thrombosis | Increased risk | Not observed |
| Polycythemia | Can occur | Not observed |
| Hypertension | Can occur | Not observed |
| Pure red cell aplasia | Risk with antibodies | Not applicable |
This safety profile makes ARA-290 usable in populations where EPO would be dangerous — cardiovascular patients, those with clotting disorders, or anyone at thrombotic risk.
Development Status: The Funding Gap
Despite promising Phase 2 results and regulatory fast-tracking, ARA-290 development has stalled.
Achievements:
- US and EU Orphan Drug Designation for sarcoidosis
- US FDA Fast Track Designation for sarcoidosis-associated small fiber neuropathy
- Successful End-of-Phase 2 FDA meeting (2017)
- EU Orphan Designation for pancreatic islet transplantation
Current status:
- No Phase 3 trials announced or registered
- Araim Pharmaceuticals (the developer) shows no public activity since July 2020
- Total funding of only $8.1M — insufficient for Phase 3 ($50–100M+ typically required)
- 1–10 employees as of last update
The most likely explanation is insufficient capital to fund Phase 3 trials combined with difficulty attracting pharmaceutical partners despite orphan drug designations. The science was successful; the business model wasn't.
Academic research continues: A 2023 study showed ARA-290 reduced cardiac aging hallmarks and preserved ejection fraction in mice. A 2024 study confirmed brain tissue protection through the beta-common receptor in stroke models. The scientific community sees ongoing value in the mechanism.
FAQ
What is ARA-290 used for?
ARA-290's most advanced indication is sarcoidosis-associated small fiber neuropathy, where Phase 2 trials showed nerve regeneration. Preclinical data suggests potential for kidney protection during transplantation, cardiac protection, stroke, and other conditions involving tissue injury.
Is ARA-290 the same as EPO?
No. ARA-290 was derived from EPO's structure but activates a different receptor. It provides tissue protection without making red blood cells — eliminating the thrombosis, polycythemia, and hypertension risks of EPO.
Why isn't ARA-290 FDA approved?
Despite successful Phase 2 trials and FDA Fast Track designation, no Phase 3 trials have been conducted due to funding constraints. The developing company appears to have run out of capital before completing the approval process.
How is ARA-290 administered?
Subcutaneous injection, typically 4 mg daily for 28–84 days in clinical trials. The short half-life (2–20 minutes) doesn't limit efficacy because receptor activation triggers sustained intracellular effects.
Can ARA-290 regenerate nerves?
Clinical data suggests yes — Phase 2 trials showed 23% increases in corneal nerve fiber area and increases in regenerating nerve fibers in skin biopsies. This is the first drug to demonstrate small fiber nerve regeneration in humans.
Where can I get ARA-290?
ARA-290 is not commercially available. The developing company (Araim Pharmaceuticals) appears inactive since 2020. Your options are limited to research peptide suppliers of variable quality. Unlike more common peptides, ARA-290 has fewer suppliers and less quality verification in the market. Some compounding pharmacies may be able to source it, but availability is inconsistent.
Is ARA-290 being developed for other conditions?
Officially, development stalled after Phase 2. However, academic research continues exploring the mechanism. A 2023 study showed cardiac protection effects in aging mice. A 2024 study confirmed neuroprotection in stroke models. The innate repair receptor mechanism has theoretical applications in kidney transplant protection, heart attack, TBI, and diabetic complications—but without commercial development, these remain preclinical observations rather than active drug programs.
How does ARA-290 compare to BPC-157 for nerve healing?
They work through different mechanisms. ARA-290 activates the innate repair receptor specifically at sites of injury, with Phase 2 clinical trial data showing measurable nerve regeneration. BPC-157 has extensive preclinical data on healing (including nerve repair) but no completed human trials for neuropathy. ARA-290 has the stronger human evidence base; BPC-157 has the broader anecdotal use and easier availability. They could theoretically complement each other since their mechanisms don't overlap.
Related Topics
- NAD+ Guide — cellular energy support for nerve function
- SS-31 Guide — mitochondrial repair peptide
- Semax vs Selank — cognitive and neuroprotective peptides
- MOTS-c Guide — mitochondrial-derived peptide
References
- Brines M. Discovery of a Master Regulator of Injury and Healing. Mol Med 2014. https://pmc.ncbi.nlm.nih.gov/articles/PMC4374522/
- Brines M, et al. ARA 290, a Nonerythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control. Mol Med 2015. https://pmc.ncbi.nlm.nih.gov/articles/PMC4365069/
- Dahan A, et al. Targeting the innate repair receptor to treat neuropathy. Pain Rep 2017. https://pmc.ncbi.nlm.nih.gov/articles/PMC5741312/
- Heij L, et al. ARA 290 in Sarcoidosis SFN. Mol Med 2012. https://pmc.ncbi.nlm.nih.gov/articles/PMC3563705/
- Araim Pharmaceuticals. Cibinetide Regenerates Small Nerve Fibers. PRNewswire 2017.
- PMC3567997. ARA290 attenuates renal ischemia/reperfusion injury. 2013.
- CNS Neuroscience & Therapeutics. ARA290 brain tissue protection in cerebral ischemic stroke. 2024. https://onlinelibrary.wiley.com/doi/10.1111/cns.14676
This content is for educational purposes only. ARA-290 (cibinetide) is not FDA-approved. It received Fast Track and Orphan Drug designations but commercial development has stalled since 2020. Access is currently limited to research contexts. Consult a qualified healthcare provider before considering any peptide protocol.