ARA-290 (Cibinetide)

This is ARA-290’s best-evidenced use and the only one with replicated human data. Sarcoidosis frequently damages small sensory and autonomic nerve fibers, producing pain and dysautonomia that immunosuppression treats poorly — a genuine unmet need, and a rare disease, which is why the compound holds orphan status.

Trial one (n=22, intravenous). A double-blind, placebo-controlled exploratory trial gave 22 sarcoidosis patients with documented small-fiber neuropathy ARA-290 2 mg intravenously three times weekly, or placebo, for four weeks. The Small Fiber Neuropathy Screening List score improved significantly versus placebo (Δ −11.5 vs −2.9), as did the pain and physical-functioning dimensions of the SF-36. No safety concerns arose on clinical or laboratory assessment ^{1Reference 1Heij L et al. · 2012RCTSafety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study — human (RCT)View study →}. The result that usually gets dropped: the Brief Pain Inventory and the Fatigue Assessment Scale “improved significantly but equivalently in both patient groups” — that is, they did not separate from placebo — and the depressive-symptom inventory did not move at all. Every endpoint in this trial was a patient-reported questionnaire.

Trial two (subcutaneous, 28 days). A second blinded placebo-controlled trial switched to daily subcutaneous dosing and added an objective measure. Neuropathic symptoms improved, and so did corneal nerve-fiber density, cutaneous temperature sensitivity, and exercise capacity on the six-minute walk test ^{2Reference 2Dahan A et al. · 2013RCTARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density — human (RCT)View study →}. This is the study that first suggested a disease-modifying rather than purely analgesic effect.

Trial three — the Phase 2b (n=64, NCT02039687). Sponsored by Araim Pharmaceuticals, this 28-day randomized trial compared cibinetide 1, 4 and 8 mg/day subcutaneously against placebo, with change in corneal nerve-fiber area (CNFA) as the pre-specified primary endpoint. It was met — but only in part. Placebo-corrected mean change in CNFA was 109 µm² (95% CI −429 to 647) at 1 mg, 697 µm² (159 to 1236; p = 0.012) at 4 mg, and 431 µm² (−130 to 992) at 8 mg. Only the middle dose reached significance, which is not the dose-response you would like to see. Regenerating GAP-43-positive intra-epidermal nerve fibers also increased at 4 mg (p = 0.035), and CNFA change correlated with both GAP-43 change and six-minute-walk change. Pain improved significantly in all groups, including placebo, and the placebo-corrected pain reduction in the moderate-to-severe subgroup at 4 mg reached only p = 0.157 ^{3Reference 3Culver DA et al. · 2017RCTCibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain — human (RCT, Phase 2b)View study →}. Results are posted on ClinicalTrials.gov; serious adverse events occurred in 2 of 16 (1 mg), 0 of 16 (4 mg), 1 of 14 (8 mg) and 0 of 16 (placebo) participants — small numbers, no dose relationship, in a population with active systemic disease.

On the corneal endpoint — read this before reading the result. Corneal confocal microscopy is a genuinely clever, non-invasive way to count and measure the small nerve fibers in the cornea, and it detects regeneration more sensitively than a skin biopsy ^{4Reference 4Brines M et al. · 2018Clinical trialCorneal nerve fiber size adds utility to the diagnosis and assessment of therapeutic response in patients with small fiber neuropathy — human (diagnostic / biomarker study, not a trial)View study →}. That is why it was chosen. But it is a surrogate: it measures nerve morphology, not symptoms, function, or quality of life. A drug can grow nerve fibers that are visible under a microscope without a patient noticing anything. In this program, the morphology endpoints moved and the pain endpoints largely did not — so the surrogate is carrying the case, and whether it predicts clinical benefit is the unanswered question. An expert review of the first two trials framed the prospects as promising ^{5Reference 5van Velzen M et al. · 2014ReviewARA 290 for treatment of small fiber neuropathy in sarcoidosis — reviewView study →}; that review predates the Phase 2b pain result.

Gap: No Phase 3 has ever been registered. All human trials are ≤28 days, the largest is 64 patients, the pivotal endpoint is a surrogate, the clinically meaningful pain endpoint was not significant, and durability beyond a month is untested.

A Phase 2 study had subjects with type 2 diabetes and painful neuropathy self-administer subcutaneous ARA-290 4 mg daily or placebo for 28 days, then followed them a further month. The cibinetide group showed improvement in HbA1c and lipid profiles across the 56-day window; neuropathic symptoms on the PainDetect questionnaire improved significantly; and among subjects whose baseline corneal nerve-fiber density was more than one standard deviation below normal, CNFD rose significantly versus no change on placebo. No safety issues were identified ^{6Reference 6Brines M et al. · 2015RCTARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes — human (RCT, Phase 2)View study →}.

Three cautions the usual summaries omit. The published abstract reports the metabolic improvements descriptively — it does not state a significance level for HbA1c or lipids, and the authors’ own conclusion is that the peptide “may benefit” both and “deserves continued clinical evaluation.” The nerve-density result is a subgroup finding, not the whole cohort. And I could not match this publication to a ClinicalTrials.gov record: the only registered ARA-290 diabetes trial (NCT01933529, Karolinska, 24 subjects estimated) has different primary endpoints — oral glucose tolerance and insulin secretion — its status is listed as UNKNOWN, and no results have ever been posted. The published study appears to be unregistered.

Gap: One small, short, apparently unregistered human Phase 2 with self-reported and surrogate endpoints, not powered for glycemic or hard neuropathy outcomes, never replicated.

Analgesia in rats is the most replicated preclinical finding for this peptide. In a neuritis model, ARA-290 (30 or 120 µg/kg intraperitoneally, daily) prevented the development of mechanical allodynia ^{10Reference 10Pulman KG et al. · 2013AnimalThe erythropoietin-derived peptide ARA290 reverses mechanical allodynia in the neuritis model — animal (rat)View study →}.

In a spared-nerve-injury model it produced dose-dependent relief of mechanical and cold allodynia lasting up to 20 weeks, coupled with suppression of the spinal microglial response ^{9Reference 9Swartjes M et al. · 2014AnimalARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response — animal (rat)View study →}.

Mechanistically, part of the effect may be direct rather than immune-mediated: ARA-290 inhibits the TRPV1 ion channel and relieves capsaicin-induced hypersensitivity in cell and behavioral assays ^{11Reference 11Zhang W et al. · 2016In vitroARA 290 relieves pathophysiological pain by targeting TRPV1 channel: integration between immune system and nociception — in vitro / animal (rodent)View study →}.

The human counterpoint belongs here rather than in a footnote. ARA-290 has never had a dedicated human neuropathic-pain trial. In the two sarcoidosis trials that did carry pain instruments, the Brief Pain Inventory failed to separate from placebo ^{1Reference 1Heij L et al. · 2012RCTSafety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study — human (RCT)View study →} and the placebo-corrected pain reduction in the Phase 2b did not reach significance ^{3Reference 3Culver DA et al. · 2017RCTCibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain — human (RCT, Phase 2b)View study →}.

Rodent allodynia is not human pain relief, and here the human pain data that exist are the weaker part of the file.

Gap: No dedicated human trial for neuropathic or inflammatory pain outside the sarcoidosis and diabetes small-fiber setting; the mechanistic pain data are entirely rodent or cell-based.

The tissue-protective peptide scaffold was first characterized in the heart, and the animal work here is the strongest preclinical block on the page. In cultured neonatal rat cardiomyocytes and a dilated-cardiomyopathy hamster, helix B surface peptide inhibited TNF-α-induced apoptosis by roughly 70–80% through Akt/ERK/STAT3, matching EPO without erythropoiesis ^{12Reference 12Ueba H et al. · 2010In vitroCardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin — animal (rat, hamster) / in vitroView study →}.

A single bolus of pyroglutamate helix B peptide in a rat myocardial-infarction model was cardioprotective against ischemic damage, comparably to EPO ^{13Reference 13Ahmet I et al. · 2011In vitroA small nonerythropoietic helix B surface peptide based upon erythropoietin structure is cardioprotective against ischemic myocardial damage — animal (rat) / in vitroView study →}.

In vitro, ARA-290 also reduced doxorubicin-induced genotoxicity and oxidative stress ^{15Reference 15Shokrzadeh M et al. · 2020In vitroAn engineered non-erythropoietic erythropoietin-derived peptide, ARA290, attenuates doxorubicin-induced genotoxicity and oxidative stress — in vitroView study →}.

The healthspan study deserves separate mention because it is unusually well-built for an animal study: a 15-month randomized controlled trial in aging Fischer 344 × Brown Norway rats (n=48 longitudinal, n=144 cross-sectional) found chronic ARA-290 reduced cardiac inflammatory infiltrate and cytokines, enhanced cardiomyocyte autophagy, blunted the age-associated blood-pressure rise, preserved left-ventricular ejection fraction, and lowered a frailty index at 33 months of age ^{14Reference 14Winicki NM et al. · 2022RCTA small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan — animal (rat, 15-month randomised controlled study)View study →}. This is the entire basis of ARA-290’s “anti-aging” and “longevity” marketing — and it is a rat study.

A naming note: refs ^{12Reference 12Ueba H et al. · 2010In vitroCardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin — animal (rat, hamster) / in vitroView study →} and ^{13Reference 13Ahmet I et al. · 2011In vitroA small nonerythropoietic helix B surface peptide based upon erythropoietin structure is cardioprotective against ischemic myocardial damage — animal (rat) / in vitroView study →} used HBSP and pHBSP respectively. The pyroglutamate-capped form (pHBSP) is ARA-290; the uncapped HBSP is its immediate precursor. They are the same design, not the same molecule, so ^{12Reference 12Ueba H et al. · 2010In vitroCardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin — animal (rat, hamster) / in vitroView study →} is scaffold evidence rather than direct ARA-290 evidence.

Gap: Entirely animal and in vitro. There is no human cardiac, cardiovascular, or longevity trial of ARA-290 of any kind, so every “anti-aging” claim made for it is rodent-only.

Several models show renoprotection. In a pig unilateral renal-ischemia model, intravenous ARA-290 improved glomerular filtration rate over seven days and reduced interstitial fibrosis ^{16Reference 16van Rijt WG et al. · 2013ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury — animal (pig)View study →}.

In rats, ARA-290 given early after reperfusion improved renal function and reduced inflammation, with earlier administration more effective ^{17Reference 17van Rijt WG et al. · 2013AnimalRenoprotective capacities of non-erythropoietic EPO derivative, ARA290, following renal ischemia/reperfusion injury — animal (rat)View study →}.

In a rat renal-allograft model it lowered serum creatinine and urea and reduced macrophage infiltration, apparently by inhibiting NF-κB ^{18Reference 18Yan L et al. · 2018AnimalEPO derivative ARA290 attenuates early renal allograft injury in rats by targeting NF-κB pathway — animal (rat)View study →}.

This cluster carries a specific caution. In 2026, Molecular Medicine published a retraction note for a paper on delayed administration of pHBSP in acute kidney injury ^{29Reference 29Patel NSA et al. · 2026Retraction note: delayed administration of pyroglutamate helix B surface peptide (pHBSP), a novel nonerythropoietic analog of erythropoietin, attenuates acute kidney injury — retraction noticeView study →} — the same molecule, the same research area. The three studies cited above are not retracted, but a retraction inside a small literature is a reason to weight the whole cluster down rather than up.

Gap: Animal-only, with a retraction in the adjacent literature. No human renal or transplant trial of ARA-290 exists.

The peptide’s anti-inflammatory action has been tested across rodent autoimmune models, consistently and by different groups. In rat experimental autoimmune neuritis it improved recovery, reduced nerve inflammation, and shifted T-cell phenotype toward regulatory-T and Th2 and away from Th1 ^{19Reference 19Liu Y et al. · 2014AnimalErythropoietin-derived nonerythropoietic peptide ameliorates experimental autoimmune neuritis by inflammation suppression and tissue protection — animal (rat)View study →}.

In rat experimental autoimmune encephalomyelitis — the standard multiple-sclerosis model — it reduced severity with lower IL-17, TNF-α and IFN-γ ^{20Reference 20Chen H et al. · 2014AnimalTherapeutic effects of nonerythropoietic erythropoietin analog ARA290 in experimental autoimmune encephalomyelitis rat — animal (rat)View study →}.

In mouse experimental colitis, cibinetide dampened innate immune cell function via CD131/JAK2-dependent NF-κB inhibition ^{21Reference 21Nairz M et al. · 2017In vitroCibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis — animal (mouse) / in vitroView study →}.

In mouse lupus models it reduced autoantibodies and nephritis — explicitly without stimulating hematopoiesis ^{22Reference 22Huang B et al. · 2018AnimalNon-erythropoietic erythropoietin-derived peptide protects mice from systemic lupus erythematosus — animal (mouse)View study →}.

Gap: Every model is rodent. There is no human trial of ARA-290 in any autoimmune or inflammatory disease, and none is registered.

Cibinetide protected isolated human islets under cytokine stress — preserving ATP content and reducing caspase-3/7 activity — and reduced the instant blood-mediated inflammatory reaction that destroys islets during intraportal transplantation in a human blood-loop model; in athymic mice it improved human-islet engraftment ^{23Reference 23Yao M et al. · 2021In vitroCibinetide protects isolated human islets in a stressful environment and improves engraftment in the perspective of intraportal islet transplantation — in vitro (human islets) / animal (mouse)View study →}. In an allogeneic mouse islet-transplant model it reduced early inflammation and, combined with tacrolimus, improved graft function ^{24Reference 24Yao M et al. · 2020AnimalImprovement of islet allograft function using cibinetide, an innate repair receptor ligand — animal (mouse)View study →}.

This is the one application where “human” appears in the data, and it is worth being precise about what kind: human tissue in a dish, not human patients. The in-vivo efficacy is mouse.

Gap: No human transplant trial. The human component is in vitro only.

In genetically diabetic (db/db) mice, cibinetide at 30 µg/kg/day subcutaneously improved impaired wound healing — raising VEGF, phospho-Akt, phospho-eNOS and nitrite/nitrate, and improving re-epithelialization, angiogenesis, scar strength and time to closure — through activation of the EPO-receptor/β-common-receptor complex ^{25Reference 25Bitto A et al. · 2018AnimalActivation of the EPOR-β common receptor complex by cibinetide ameliorates impaired wound healing in mice with genetic diabetes — animal (mouse)View study →}.

This single mouse study is the entire evidential basis for ARA-290 being sold as a “healing peptide.”

Gap: One mouse model, one lab, no replication, and no human wound-healing data of any kind.

Cibinetide, which binds only the heteromeric tissue-protective receptor, inhibited osteoclastogenesis in vitro and increased cortical (~5.8%) and trabecular (~5.2%) bone mineral density in wild-type mice over one month; it also blunted EPO-driven expansion of osteoclast progenitors ^{26Reference 26Awida Z et al. · 2021In vitroThe non-erythropoietic EPO analogue cibinetide inhibits osteoclastogenesis in vitro and increases bone mineral density in mice — in vitro / animal (mouse)View study →}. The mechanistic point is interesting — EPO itself reduces bone density by expanding osteoclasts, so splitting the receptors may split that liability too.

Gap: In vitro plus a single short mouse study. No human bone data.

A helix B surface peptide suppressed adipogenesis and macrophage inflammation via an EPO-receptor/PPARγ axis and, in high-fat-diet mice, improved obesity, insulin resistance and adipose inflammation without stimulating hematopoiesis ^{27Reference 27Liu Y et al. · 2015In vitroNonerythropoietic erythropoietin-derived peptide suppresses adipogenesis, inflammation, obesity and insulin resistance — animal (mouse) / in vitroView study →}.

The reason this row is scored so low is a retraction. The most-cited paper in this area — a 2014 British Journal of Pharmacology study reporting that pHBSP decreased susceptibility to diet-induced insulin resistance in mice, improved insulin signaling in skeletal muscle and enhanced mitochondrial biogenesis — has been retracted ^{28Reference 28RETRACTED — Collino M et al. · 2014AnimalA non-erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet-induced insulin resistance in mice — animal (mouse); retracted publication, cited here only as a retractionView study →}. It is cited here only as a retraction, never as evidence. Removing it leaves a single non-retracted mouse paper standing. Note that this is distinct from the type 2 diabetes human trial in application 2, which was a neuropathy-and-metabolic-markers study, not a metabolic-syndrome trial.

Gap: One mouse study after the key paper was withdrawn. No human metabolic-syndrome or obesity trial.

This application was tested in humans and the result was negative. In a double-blind, randomized, parallel-group trial, 36 healthy participants received a single 2 mg dose of ARA-290 or placebo, with neural and cognitive effects assessed one week later (NCT02070783, Leiden University Medical Center, completed; no results posted to the registry). Primary outcomes were neural processing of fearful versus happy faces and behavioral recognition of emotional facial expressions.

The findings did not go the way an antidepressant should. ARA-290-treated individuals showed lower neural responses to happy faces in the fusiform gyrus, and tended toward reduced recognition of happy and disgust expressions. It did produce faster categorization of positive versus negative words and increased attention toward positive images, but no effect on mood or affective symptoms. The authors’ own conclusion: the direction and strength of the effects “do not unequivocally support an antidepressant-like profile” ^{7Reference 7Cerit H et al. · 2015RCTTesting the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action — human (RCT, negative)View study →}.

Development for depressive disorders was subsequently discontinued.

Two limits cut both ways: these were healthy volunteers, not depressed patients, and it was a single dose assessed a week later — so this is a failed proof-of-mechanism rather than a failed treatment trial. But it is the only human depression-relevant data that exist, and it is negative.

Gap: No trial in a clinical depressed population has been run or registered, and the program was abandoned.

Also tested in humans, also negative. A Phase 2 trial at the Belfast Health and Social Care Trust recruited treatment-naïve patients with diabetic macular edema and had them self-administer cibinetide 4 mg/day subcutaneously for 12 weeks. Nine patients were recruited; eight completed. This was an uncontrolled, single-arm study analyzed descriptively — no placebo group.

There was no improvement in best-corrected visual acuity (−2.9 ± 5.0 letters), central retinal thickness (+10 ± 94.6 µm), central retinal sensitivity (−0.53 ± 1.9 dB) or tear production (−0.13 ± 7.7 mm). The one measure that improved was the patient-reported NEI VFQ-25 visual-function questionnaire (+2.7 ± 3.1). Some individual participants showed improvements in retinal thickness, tear production, glycemic control and albuminuria. No serious adverse events and — a genuinely useful safety datum — no anti-cibinetide antibodies were detected ^{8Reference 8Lois N et al. · 2020Clinical trialA Phase 2 clinical trial on the use of cibinetide for the treatment of diabetic macular edema — human (single-arm Phase 2, null on objective endpoints)View study →}.

A double-counting correction. This trial appears in two places and is often presented as two studies. It was published in 2020 under EudraCT 2015-001940-12 / ISRCTN16962255, and separately registered on ClinicalTrials.gov as NCT06626971, which is listed as TERMINATED with the reason “Expiry of study drug — no replacement available.” That registry entry is not a newer, second trial: its actual start date is April 2016 and its completion date August 2017, matching the published study exactly. It was submitted to ClinicalTrials.gov in 2018 and only posted in October 2024. One trial, two registrations, nine patients.

Gap: A single-arm study of nine people with objectively null primary results, which ran out of drug. No controlled DME trial exists and none is planned.