Section 01
What it's used for
Phase 2: Improved Nerve Health
In Phase 2 clinical trials in people with diabetic nerve damage, researchers observed improved corneal nerve fiber density, a marker of nerve health measured in the eye, along with better neuropathic pain scores on standard rating scales.
▸Clinical wording
Phase 2 trials showed improved corneal nerve fiber density and neuropathic pain scores.
Less Inflammation, Better Nerves
In people with sarcoidosis, an inflammatory disease that can affect multiple organs, researchers observed reduced inflammation and improved small-fiber neuropathy, nerve damage affecting the smallest nerves that causes pain and numbness.
▸Clinical wording
Reduced inflammation and improved small fiber neuropathy.
Studied for Nerve Pain Relief
ARA-290 is being studied for chronic pain for two reasons: it may reduce inflammation, and it may help damaged nerves regenerate. These are general properties described for the peptide, not results from a specific chronic pain trial.
▸Clinical wording
Anti-inflammatory and nerve-regenerative properties.
Section 02
Mechanism of Action
A repair fragment of a blood hormone
- Erythropoietin's tissue-protecting action can be separated from its red-blood-cell-making action.
- Researchers traced the protective part to one stretch of the molecule (helix B).
- An eleven-amino-acid copy of that surface kept protection in stroke, retina and nerve-injury models.
- It produced no stimulation of red blood cell production and acts on a different receptor pairing.
▸Clinical wording
Helix B surface peptide design and IRR selectivity
Erythropoietin's tissue-protective role is pharmacologically separable from its haematopoietic one, and ARA 290 was engineered from that split. Mapping protective activity onto the EPO molecule localised it to helix B (residues 58-82), which was neuroprotective in vitro and tissue protective in vivo in stroke, retinal damage and peripheral nerve injury models. An 11-amino-acid peptide reproducing the water-facing surface of helix B — the molecule now called ARA 290 or cibinetide — retained the same protective profile in those models and additionally improved wound healing and cognitive performance, while producing no stimulation of red blood cell production (Brines et al., 2008). The target is a heterocomplex of the EPO receptor with CD131, the beta-common receptor, distinct from the EPOR homodimer that drives erythropoiesis.
A receptor that appears only after injury
- The target receptor is absent from healthy tissue and switches on after injury, low oxygen or metabolic stress.
- So the peptide can only signal where damage has already turned the receptor on.
- In nerve-injured rats and mice it relieved touch and cold pain for up to fifteen weeks.
- Mice genetically lacking one receptor subunit showed no effect at all.
▸Clinical wording
Injury-restricted innate repair receptor expression
The innate repair receptor is not a constitutive feature of healthy tissue; it is locally upregulated in response to injury, hypoxia or metabolic stress, which makes ARA 290 a context-restricted agonist whose signal exists only where damage has already switched the receptor on (Dahan et al., 2016). The dependence on the beta-common subunit is genetic rather than correlative. After spared nerve injury, ARA 290 relieved tactile and cold allodynia for as long as 15 weeks in rats and wild-type mice, while in beta-common receptor knockout mice no effect was observed at all (Swartjes et al., 2011). In mice subjected to middle cerebral artery occlusion, siRNA suppression of the beta-common receptor significantly attenuated ARA 290's tissue-protective effect, and peripheral blood erythropoietic parameters were unchanged throughout (Wang et al., 2024).
How it calms immune cells from inside
- In mice with induced colitis, the peptide acted mainly on scavenger immune cells, barely on T cells.
- Fewer inflammatory cells accumulated and several inflammatory messengers fell.
- It blocked the master inflammation switch (NF-κB p65) through two internal signalling proteins.
- Knockout mice missing either of those proteins confirmed both were required.
▸Clinical wording
JAK2 and PI3K signalling that suppresses NF-kB p65
The clearest intracellular chain published for cibinetide comes from experimental colitis. In DSS-treated mice and in bone-marrow-derived macrophages, cibinetide acted mainly on myeloid cells, reducing accumulation of neutrophils, monocytes and eosinophils with little effect on T cells, and lowering TNF, IL-1beta, IL-6, IL-12/IL-23, the chemokines Ccl2, Ccl3 and Ccl11, and Nos2 expression. Mechanistically it inhibited p65 DNA-binding activity through JAK2 and PI3K signalling, and the requirement for each node was confirmed in CD131-knockout and JAK2-knockout mice (Nairz et al., 2017). A parallel cytokine profile appeared in the stroke model, where ARA 290 reduced TNF-alpha, IL-1beta and IL-6 and neuronal apoptosis at seven days (Wang et al., 2024).
Calmer spinal cells, regrown nerve fibres
- In nerve-injured rats, pain relief tracked with less activation of spinal immune cells.
- Higher doses prevented that activation at two weeks and again at twenty weeks.
- In sarcoidosis patients with nerve fibre loss, 28 days of daily injections improved symptoms and walking distance.
- Corneal nerve fibre density rose on microscopy, with fibre area up about 14% in four weeks.
▸Clinical wording
Microglial quieting and small nerve fibre regrowth
In rats with spared nerve injury, ARA 290 reduced allodynia dose-dependently and this tracked with suppression of the spinal microglial response measured as Iba-1 immunoreactivity: at two weeks vehicle animals showed activation localised to L5 that 10-30 ug/kg prevented, and by 20 weeks vehicle animals showed activation spread across L2-L5 that 30 ug/kg prevented (Swartjes et al., 2014). The human observation is regenerative rather than purely analgesic. In patients with sarcoidosis and documented small nerve fibre loss, 28 days of daily subcutaneous ARA 290 improved neuropathic symptom scores, increased corneal nerve fibre density on confocal microscopy, altered thermal pain thresholds and increased six-minute walk distance (Dahan et al., 2013); corneal nerve fibre area rose about 14% within four weeks (Dahan et al., 2016).
Section 03
Biological Pathways
No data for this section yet.
Section 04
Dosage Information
| Route / system | Context | Range studied | Limitation |
|---|---|---|---|
| Subcutaneous — sarcoidosis trial | Phase 2b, 64 patients with painful nerve damage | 1, 4 or 8 mg once a day for 28 days — roughly 11–115 µg/kg at 70–90 kg. Only 4 mg beat placebo, on eye nerve fibres, about 23% up. | 8 mg did no better than 4 mg: more drug, no more effect. Twenty-eight days, an imaging measure, and a sponsor that closed without filing — nothing confirmed. |
| Subcutaneous — diabetes trial | Phase 2, type 2 diabetes with nerve symptoms | 4 mg self-injected once a day for 28 days — roughly 44–57 µg/kg for a 70–90 kg adult, with follow-up to day 56 | Only side measures moved: average blood sugar, blood fats, a pain score. Eye nerve density rose only in the subgroup that started worst; nothing was repeated. |
| Intravenous | Randomised pilot, 22 sarcoidosis patients | 2 mg three times a week for 4 weeks — roughly 22–29 µg/kg per dose for a 70–90 kg adult | Twelve patients on drug against ten on placebo, with questionnaires as the outcome: scores moved, nothing objective measured. Later trials dropped this route. |
| Subcutaneous — self-administration | Self-administration outside any trial | 1–4 mg per day is the circulating figure — roughly 11–57 µg/kg for a 70–90 kg adult; a 2 mg twice-weekly pattern is also quoted | The daily figures are copied from the trial arms; the twice-weekly pattern was never tested. Orphan and fast-track status is not approval: no label exists. |
Results
Syringe Fill Level (100u syringe)
Set positive values for: Recommended dose per kg.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Section 05
Protocols
No protocols featuring this peptide yet. Browse All Protocols
Section 06
Stability & Storage
Lyophilised powder
In clinical trials the vials were kept refrigerated at 2–8 °C. The subcutaneous product is a vial of 5.6 mg lyophilisate reconstituted with 0.66 ml of sterile water for injection. For the research-grade material, reagent catalogues give −20 °C for the powder and claim 2 years at −80 °C.
After reconstitution
The solution is prepared shortly before use: in the intravenous trial 2 mg was diluted in 6 ml of saline immediately before infusion. A preclinical study aliquoted a phosphate-buffered stock and held it at 4 °C; reagent catalogues give −80 °C for up to 6 months or −20 °C for up to 1 month.
Section 07
Side Effects & Precautions
ARA-290 (cibinetide) has completed and published human trials, unlike most research peptides. Total published human exposure is roughly 220 people in studies of 28 days to 12 weeks; no single trial exceeded 64 participants and no Phase 3 trial exists.
Serious adverse events in the diabetes trial
- Four serious adverse events occurred in the diabetes trial on ARA-290.
- One was worsening kidney function in a patient with borderline renal insufficiency whose furosemide dose had just been raised; it never recovered by 6 weeks.
- Another was a fatal heart attack in a 70-year-old man, judged unrelated to treatment.
- The same paper's abstract nonetheless states that no safety issues were identified.
Suicidal ideation triggered added monitoring
One participant with a prior history of depression developed suicidal ideation on ARA-290, recorded as a serious adverse event in a sarcoidosis trial, out of more than 200 people treated with the peptide by that point. The next trial added formal monitoring for suicidal thoughts as a result.
Overall rate matched placebo, serious events didn't
- Most patients in every arm, including placebo, reported at least one adverse event overall, at broadly similar rates.
- Serious adverse events occurred only on active doses: 2 of 16 patients at 1 mg and 1 of 14 at 8 mg, versus 0 of 16 on placebo and 0 of 16 at 4 mg.
- Those serious events were syncope, headache, chest tightness, shortness of breath and small bowel enteritis, all in the 1 mg group.
- One patient in the 8 mg group also discontinued because of an adverse event.
- Headache and nausea both exceeded placebo, and the excess did not depend on dose.
- Injection-site pain, by contrast, was reported more often on placebo than on any ARA-290 dose.
Erythropoiesis claim rests on thin evidence
ARA-290 is designed not to stimulate red blood cell production, unlike erythropoietin. Only one published trial reports actual hemoglobin numbers, unchanged after 4 weeks. Other trials give only a general no-changes statement, and the original animal study lists its result as data not shown.
No toxicology data, no special-population studies
No published preclinical toxicology study was found for ARA-290. No human safety data exist for pregnancy, breastfeeding, children, over-70s, or significant kidney or liver impairment; trials excluded these groups. ARA-290 has no marketing approval anywhere, only EU orphan drug designation.
Section 08
Regulatory Status
It holds orphan drug status in the US and EU for a rare neurological complication of sarcoidosis, but orphan status is a development incentive, not a marketing approval, and its original developer appears to have halted work around 2020.
FDA / United States
Orphan drug and fast track, not approved
In July 2016 the FDA granted ARA-290 orphan drug designation, later adding Fast Track status, for sarcoidosis-associated small fiber neuropathy. Neither is a marketing approval: no New Drug Application has been filed, and no company currently holds an active IND for the compound.
EMA / European Union
Two orphan designations, no approval
The European Commission granted orphan designation EU/3/13/1191 for sarcoidosis in 2013 and EU/3/16/1721 for preventing pancreatic islet graft loss in 2016. Both remain designations only — no marketing authorisation application has reached the EMA.
Clinical trials
Phase 2 completed, no Phase 3 followed
A randomised, placebo-controlled Phase 2b trial (NCT02039687) in sarcoidosis patients showed improvement in neuropathy symptom scores at four weeks. No Phase 3 study was ever registered, and public activity from the sponsor, Araim Pharmaceuticals, stopped around 2020.
WADA
Not named on the list; the S0 catch-all fits
ARA-290 is not listed by name on the WADA Prohibited List. As an investigational compound with no approval anywhere for human therapeutic use, it meets the definition of category S0 (Non-Approved Substances), which covers substances not addressed elsewhere on the List.
Orphan drug status marks a disease as rare enough to merit development incentives — it says nothing about whether the drug works or is safe, and it is not a licence to prescribe or sell. Regulatory status differs by jurisdiction and can change; check current official sources before relying on any of this.
Section 09
Research Studies
- [1]Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietinBrines M, Patel NSA, Villa P, Brines C, Mennini T, De Paola M, et al. · Proceedings of the National Academy of Sciences USA · 2008
- [2]Targeting the innate repair receptor to treat neuropathyDahan A, Brines M, Niesters M, Cerami A, van Velzen M. · Pain Reports · 2016
- [3]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 miceSwartjes M, Morariu A, Niesters M, Brines M, Cerami A, Aarts L, Dahan A. · Anesthesiology · 2011
- [4]Erythropoietin-derived peptide ARA290 mediates brain tissue protection through the beta-common receptor in mice with cerebral ischemic strokeWang RL, Yang ZH, Huang YY, et al. · CNS Neuroscience & Therapeutics · 2024
- [5]Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitisNairz M, Haschka D, Dichtl S, Sonnweber T, Schroll A, Aßhoff M, et al. · Scientific Reports · 2017
- [6]ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia responseSwartjes M, van Velzen M, Niesters M, Aarts L, Brines M, Dunne A, Cerami A, Dahan A. · Molecular Pain · 2014
- [7]ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber densityDahan A, Dunne A, Swartjes M, Proto PL, Heij L, Vogels O, et al. · Molecular Medicine · 2013
- [8]Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot studyHeij L, Niesters M, Swartjes M, Hoitsma E, Drent M, Dunne A, et al. · Molecular Medicine · 2012
Section 10
Frequently Asked Questions
Eleven amino acids reproducing a region of the tertiary structure of erythropoietin. Unlike EPO itself it acts through the innate repair receptor — a pairing of EPOR and βcR — rather than the classical erythropoietin receptor. The practical consequence is that it does not stimulate red blood cell production, so the blood thickening that EPO is doped for does not apply here.
There were phase 2 signals and no confirmation. In 64 patients with sarcoidosis-related nerve pain only the 4 mg dose beat placebo, and only on corneal nerve fibre density, by about 23%; 8 mg added nothing over 4 mg. In the diabetes trial only secondary measures moved. Nothing was replicated, and the sponsor closed without ever filing for approval.
This was never studied on its own. Every trial ran 28 days of daily injections and measured at the end of that window, with follow-up to day 56 in the diabetes study. When an effect starts, and whether it outlasts dosing, does not follow from what was published.
Trials used 1, 4 or 8 mg subcutaneously once a day for 28 days, and only the 4 mg arm produced a result; an intravenous pilot gave 2 mg three times a week for four weeks, a route later dropped. The 1 to 4 mg a day figure circulating outside trials leans on those protocols and is not supported by any documented human practice of its own.
Unknown — no carcinogenicity study of ARA-290 has been run. The question comes from its EPO ancestry: erythropoiesis-stimulating agents accelerated tumour progression in several trials in cancer patients. ARA-290 does not activate the classical EPO receptor and does not stimulate erythropoiesis, but that is an argument from mechanism, not a measurement.
No, and no other regulator has approved it either. It reached phase 2 and went no further: no application for approval was ever filed. There is no approved indication, no approved dose and no pharmaceutical quality standard behind it.
Clinical trials kept the vials at 2–8 °C. Reagent catalogues give −20 °C for research-grade powder. The solution was prepared shortly before use — the intravenous study diluted 2 mg in 6 ml of saline immediately before infusion — so a reconstituted vial is not meant for long storage.