ARA-290, now known by the name cibinetide, is a small synthetic peptide of 11 amino acids. Researchers designed it from the 3D structure of erythropoietin (EPO), the kidney hormone that drives red blood cell production. The aim was to keep EPO’s tissue-protective and anti-inflammatory signaling while removing its effect on red cells.
It has been tested in a handful of small phase 2 trials, mostly for painful small nerve fiber neuropathy in sarcoidosis and type 2 diabetes. It is not an approved medicine, the largest trial enrolled 64 people for 28 days, and there are no human studies on muscle, recovery from training or athletic performance.
This page summarizes what the published trials and preclinical studies report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Class | Non-erythropoietic peptide; innate repair receptor agonist |
| Other names | Cibinetide; pyroglutamate helix B surface peptide (pHBSP); ARA 290 |
| Developer | Warren Pharmaceuticals, later Araim Pharmaceuticals |
| Structure | 11 amino acids, C51H84N16O21, ≈1,257 g/mol |
| Route in trials | Intravenous (2 mg three times weekly) or subcutaneous (1–8 mg daily) |
| Half-life | ≈20 min terminal half-life after 4 mg SC in healthy volunteers; ≈2 min plasma half-life in rats and rabbits |
| Development stage | Phase 2 only; no approved product in Drugs@FDA |
| WADA | Not named, but falls under S2.1.5 innate repair receptor agonists, prohibited at all times |
What it is
EPO acts through two different receptors (Brines et al., PNAS 2008):
- a pair of EPO receptors (a homodimer), which drives red blood cell production;
- a complex of the EPO receptor with CD131, the β-common receptor, which mediates tissue protection.
The developers call the second complex the innate repair receptor. According to a review by the developers, it is normally scarce in healthy tissue and is switched on by injury or inflammation (Collino et al., Pharmacol Ther 2015). Using EPO itself to protect tissue is limited by rising hematocrit (the share of blood made up of red cells), platelet activation and a high risk of blood clots.
To separate the two effects, Brines and colleagues mapped the part of EPO that faces outward when EPO binds its red-cell receptor, a region called helix B. They built an 11-amino-acid peptide from the surface residues of that helix, helix B surface peptide (HBSP), with the sequence QEQLERALNSS. The first glutamine closes spontaneously into pyroglutamate, and that cyclized form (pHBSP) became ARA-290. In their experiments the peptide did not stimulate red blood cell production in vitro or in animals (Brines et al., PNAS 2008).
| Property | Value |
|---|---|
| Molecular formula | C51H84N16O21 |
| Molecular weight | 1,257.3 g/mol |
| PubChem CID | 91810664 |
| Sequence | Pyroglutamate-EQLERALNSS (helix B surface peptide) |
Source: PubChem CID 91810664; Brines et al., PNAS 2008.
Pharmacokinetics
ARA-290 is cleared from the blood very quickly. Because it is a small, unprotected peptide, the developers found a plasma half-life of about 2 minutes in rats and rabbits (Brines et al., PNAS 2008).
Human data come from healthy-volunteer studies summarized in the trial papers:
| Measure | Result | Source |
|---|---|---|
| Peak plasma level after 4 mg SC | ≈3 ng/mL (≈2.4 nmol/L) | Brines et al., Mol Med 2015 |
| Terminal half-life after 4 mg SC | ≈20 min | Brines et al., Mol Med 2015 |
| Exposure above 1.3 ng/mL, 2 mg IV | Median AUC 65 ng/mL × min | Dahan et al., Mol Med 2013 |
| Exposure above 1.3 ng/mL, 2 / 4 / 6 mg SC | Median AUC 23 / 59 / 249 ng/mL × min | Dahan et al., Mol Med 2013 |
The crossover study behind the AUC figures used 10 healthy volunteers. The investigators chose 4 mg subcutaneous daily for later trials because its exposure was similar to the 2 mg intravenous dose used earlier.
The developers argue that a peptide present for only minutes can still have lasting effects, because it switches on downstream repair and anti-inflammatory signaling (Collino et al., Pharmacol Ther 2015). That is a mechanistic hypothesis from the company’s own review, not something established in independent human studies.
Regulatory status
- Not an approved drug. No cibinetide product is listed in Drugs@FDA, and the registered human trials reached phase 2 at most (ClinicalTrials.gov).
- Not a named anabolic steroid. It is a peptide and does not appear in the US Schedule III list of anabolic steroids (21 CFR 1308.13).
- Prohibited in sport. The WADA list bans “innate repair receptor agonists” at all times under S2.1.5, giving asialo EPO and carbamylated EPO as examples, and S2 also covers substances with similar biological effects (WADA 2026 Prohibited List). ARA-290 is not named on the list, but it was designed and is described in its trials as an innate repair receptor agonist.
What the research shows
All human trials were small and short, and most were run by or with the developer (several authors were officers of, and held stock in, Araim Pharmaceuticals). The main outcomes were symptom questionnaires and nerve-fiber imaging, not hard clinical endpoints.
| Trial | Design and n | Dose | Main finding |
|---|---|---|---|
| Heij 2012, sarcoidosis | Randomized, double-blind pilot; 22 patients | 2 mg IV three times weekly, 4 weeks | Better small fiber neuropathy symptom score than placebo |
| Dahan 2013, sarcoidosis | Randomized, double-blind; 38 patients | 4 mg SC daily, 28 days | Better symptom score and corneal nerve fiber area; pain intensity no better than placebo |
| Brines 2015, type 2 diabetes | Randomized, double-blind phase 2; 49 enrolled | 4 mg SC daily, 28 days | Small HbA1c fall; better PainDetect score |
| Culver 2017, sarcoidosis | Randomized phase 2b; 64 patients | 1, 4 or 8 mg SC daily, 28 days | Corneal nerve fiber area up only at 4 mg |
| Lois 2020, diabetic macular edema | Single-arm phase 2; 9 patients | 4 mg SC daily, 12 weeks | No improvement in vision or retinal thickness |
Sarcoidosis-associated small fiber neuropathy
Sarcoidosis is an inflammatory disease that can damage the small sensory and autonomic nerve fibers, causing burning pain and autonomic symptoms.
Pilot trial. In 22 patients, ARA-290 2 mg IV three times weekly for 4 weeks improved the small fiber neuropathy screening list (SFNSL) score more than placebo (change −11.5 vs −2.9 points, p under 0.05). Brief Pain Inventory and fatigue scores improved equally in both groups (Heij et al., Mol Med 2012).
Subcutaneous trial. In 38 patients (21 ARA-290, 17 placebo) given 4 mg SC daily for 28 days (Dahan et al., Mol Med 2013):
| Outcome | ARA-290 | Placebo | p |
|---|---|---|---|
| SFNSL score change, 1 week after dosing | −12.2 points (≈28%) | −3.8 points (≈9%) | 0.005 |
| SFNSL score change, 12 weeks after dosing | −9.7 points | −4.1 points | 0.037 |
| Corneal nerve fiber area, median change at day 28 | +14.5% | −5.3% | 0.022 within the ARA-290 group |
| Skin nerve fiber density, lower leg | +7.2% | −1.3% | Not significant |
| 6-minute walk distance | +18.7 m | −15.1 m | 0.049 |
| Brief Pain Inventory pain intensity | ≈9% lower | ≈9% lower | No difference between groups |
Pain interference scores improved more with ARA-290 during dosing, but by 9 months after the last dose they were no longer different from baseline.
Phase 2b dose-ranging trial. This trial randomized 64 patients to 1, 4 or 8 mg daily or placebo for 28 days. The primary endpoint was the change in corneal nerve fiber area (Culver et al., IOVS 2017):
| Daily dose | Placebo-corrected change in corneal nerve fiber area (95% CI) |
|---|---|
| 1 mg | +109 μm² (−429 to 647) |
| 4 mg | +697 μm² (159 to 1,236); p = 0.012 |
| 8 mg | +431 μm² (−130 to 992) |
Only the 4 mg dose reached significance, and the 8 mg dose did not do better. Pain improved in all groups including placebo. In the subgroup with moderate to severe pain, the placebo-corrected pain reduction at 4 mg was described as clinically meaningful but was not statistically significant (p = 0.157).
Type 2 diabetes and painful neuropathy
In a phase 2 trial, 49 people with type 2 diabetes and painful neuropathy self-injected 4 mg ARA-290 or placebo daily for 28 days and were followed for another 28 days; 48 were analyzed after one stopped early (Brines et al., Mol Med 2015):
| Outcome | ARA-290 | Placebo |
|---|---|---|
| HbA1c change at day 28 | −0.16% | −0.01% |
| HbA1c change at day 56 | −0.21% | +0.21% |
| PainDetect score change at day 28 | −3.3 points | −1.1 points |
| PainDetect score change at day 56 | −4.2 points | −0.74 points |
The HbA1c difference over time was significant (p = 0.002), as was the PainDetect difference (p = 0.037). Triglycerides and the total-to-HDL cholesterol ratio also improved modestly. The SFNSL score did not change in either group, and the Neuropathic Pain Symptom Inventory improved by about 20% in both groups. The HbA1c analysis included 42 participants.
A mouse study reporting that the peptide improved diet-induced insulin resistance was later retracted by the journal, in 2024 (Collino et al., Br J Pharmacol 2014, retracted).
Diabetic macular edema
A 12-week single-arm trial of 4 mg daily enrolled 9 patients with diabetic macular edema (fluid swelling in the center of the retina). Visual acuity, retinal thickness, retinal sensitivity and tear production did not improve on average, though a vision-related quality-of-life score rose slightly. The registry lists the trial as terminated (Lois et al., J Clin Med 2020; ClinicalTrials.gov NCT06626971).
Mood and cognition
The library groups ARA-290 under cognitive function, largely because of animal work: the original rodent study reported improved cognitive function (Brines et al., PNAS 2008). The one human test was a randomized, double-blind study in 36 healthy volunteers given 2 mg or placebo. One week later, ARA-290 changed some measures of emotional processing, but it had no effect on mood, and the authors concluded the results did not clearly support an antidepressant-like profile (Cerit et al., Eur Neuropsychopharmacol 2015).
Animal studies
Most published work on ARA-290 is preclinical. In rats with nerve injury, five injections of 30 μg/kg relieved touch- and cold-evoked pain for up to 15 weeks; the effect was absent in mice lacking the β-common receptor (Swartjes et al., Anesthesiology 2011). The original paper reported protection in rodent models of stroke, kidney injury and wound healing (Brines et al., PNAS 2008). These results do not establish any effect in people.
There are no controlled human studies of ARA-290 for muscle growth, injury repair, tendon or joint healing, or exercise recovery.
Side effects and risks
What the trials reported
The published trials described ARA-290 as well tolerated, but they were few and small, and no one received it for longer than 12 weeks.
- Sarcoidosis trials. No drug-related safety signals in blood chemistry or hematology, no injection-site pain or irritation, and no serious adverse events in the 38-patient trial (Dahan et al., Mol Med 2013).
- Type 2 diabetes trial. Adverse events were similar in number between groups. Four serious adverse events occurred on ARA-290. Two were judged possibly related, including a worsening of borderline kidney function (creatinine 119 to 159 μmol/L) after a diuretic dose increase, which led to stopping the drug. One participant died of a heart attack after hospitalization for cellulitis two weeks after the last dose, which the safety committee judged unrelated (Brines et al., Mol Med 2015).
- Antibodies. No anti-ARA-290 antibodies were detected in the sarcoidosis, diabetes or macular edema trials.
Red blood cells
The peptide was designed not to raise red cell production. In the IV pilot trial, hemoglobin was 8.9 vs 8.6 mmol/L (ARA-290 vs placebo) at baseline and 8.7 vs 8.7 mmol/L after 4 weeks (Heij et al., Mol Med 2012). No published trial has measured red cell effects beyond 12 weeks of use.
Unknowns and product quality
- Long-term safety is unknown. No published trial dosed it for longer than 12 weeks, and the only healthy-volunteer study we found used a single dose.
- Unregulated products. With no approved product, anything sold as ARA-290 is not made under drug-manufacturing oversight, so identity, purity, dose and sterility cannot be assumed.
- Interactions. No formal drug-interaction studies have been published.
Key takeaways
- An EPO-derived peptide that does not make red cells. ARA-290 is an 11-amino-acid peptide modeled on helix B of erythropoietin. It targets the EPO receptor/CD131 “innate repair receptor” rather than the red-cell receptor.
- Very short half-life. About 20 minutes in humans after a 4 mg injection, and about 2 minutes in rats and rabbits.
- Small, short, developer-linked trials. Phase 2 studies in sarcoidosis and type 2 diabetes neuropathy found better symptom scores and more corneal nerve fibers, but pain intensity often improved as much on placebo.
- No human evidence for muscle or recovery. Claims about healing, recovery or cognition rest on animal studies; the one human mood study found no effect on mood.
- Not approved, banned in sport. It has no FDA approval and human testing stopped at phase 2. WADA prohibits innate repair receptor agonists at all times.
Sources
- Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008;105(31):10925–10930. PubMed.
- 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. PubMed.
- National Center for Biotechnology Information. Cibinetide, PubChem CID 91810664. PubChem.
- 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. Mol Med. 2012;18(1):1430–1436. PubMed.
- 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. Mol Med. 2013;19(1):334–345. PubMed.
- 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. Mol Med. 2015;20(1):658–666. PubMed.
- 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. Invest Ophthalmol Vis Sci. 2017;58(6):BIO52–BIO60. PubMed.
- Lois N, Gardner E, McFarland M, et al. A phase 2 clinical trial on the use of cibinetide for the treatment of diabetic macular edema. J Clin Med. 2020;9(7):2225. PubMed.
- Cerit H, Veer IM, Dahan A, et al. Testing the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action. Eur Neuropsychopharmacol. 2015;25(12):2289–2299. PubMed.
- Swartjes M, Morariu A, Niesters M, et al. 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. PubMed.
- Collino M, Benetti E, Rogazzo M, et al. A non-erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet-induced insulin resistance in mice. Br J Pharmacol. 2014;171(24):5802–5815. Retracted in: Br J Pharmacol. 2024;181(8):1341. PubMed.
- ClinicalTrials.gov. Registered studies of cibinetide (ARA 290), including NCT02039687 and NCT06626971. ClinicalTrials.gov; NCT06626971.
- US Food and Drug Administration. Drugs@FDA: FDA-approved drugs. FDA.
- World Anti-Doping Agency. The 2026 Prohibited List, International Standard. Effective January 1, 2026. WADA 2026 Prohibited List.
- Code of Federal Regulations. 21 CFR 1308.13, Schedule III. 21 CFR 1308.13.