Ara-290 (with Bacteriostatic Water)

ARA-290 (international nonproprietary name: cibinetide) is an 11-amino-acid linear synthetic peptide derived from a region of the erythropoietin (EPO) B-helix. The molecule was designed to retain the tissue-protective, anti-inflammatory, and pro-regenerative signaling activity of erythropoietin while removing its erythropoietic (red-blood-cell-stimulating) activity. The mechanistic rationale is that erythropoietin has two distinct receptor-signaling activities: classical hematopoietic signaling through the homodimeric EPO receptor (EPOR-EPOR) on erythroid progenitor cells, and tissue-protective signaling through a heterocomplex of EPOR and the β-common receptor (βCR, also called CD131, the shared β chain of the IL-3, IL-5, and GM-CSF receptors) that is sometimes referred to as the "innate repair receptor" or IRR. ARA-290 was engineered as a B-helix-derived peptide that engages the IRR without engaging the homodimeric EPOR — separating the tissue-protective signaling from the erythropoietic signaling.

The peptide was developed by Araim Pharmaceuticals (the originator) and has been investigated in published preclinical research for tissue-protective effects in models of ischemia-reperfusion injury, neuropathy, and inflammatory tissue damage, and in published small-cohort clinical-research studies (chiefly in sarcoidosis-related small-fiber neuropathy and in diabetic neuropathic pain).

This page is a research-only educational reference for ARA-290 / cibinetide. The peptide has not been approved as a medicine for any indication. No medical or therapeutic claims are made on this page.

ARA-290 (cibinetide) is a linear 11-amino-acid synthetic peptide with sequence pyroGlu-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser (pyroglutamylated at the N-terminus). The sequence corresponds to a portion of the B-helix region of erythropoietin — a structural region that the peptide-engineering rationale identifies as a contributor to the heterocomplex receptor interface (EPOR-βCR) rather than to the homodimeric EPOR signaling. The molecular weight is approximately 1257 g/mol. The molecule is supplied as a sterile lyophilized peptide for reconstitution in aqueous diluent.

The mechanistic basis for ARA-290 design comes from the work of Brines and colleagues, who proposed and characterized the distinction between hematopoietic and tissue-protective erythropoietin signaling. Erythropoietin is the master regulator of red-blood-cell production: produced primarily by renal interstitial cells in response to hypoxia, EPO binds the homodimeric EPOR on bone-marrow erythroid progenitors and signals through JAK2/STAT5 to drive erythropoiesis. This hematopoietic signaling is the basis for the use of recombinant human EPO (epoetin alfa, epoetin beta, darbepoetin alfa) in the treatment of anemias of chronic kidney disease and chemotherapy.

In addition to hematopoietic signaling, erythropoietin and EPOR are expressed in a wide range of non-erythroid tissues including neurons, vascular endothelium, cardiomyocytes, renal tubular cells, and immune cells, where EPO has been characterized as a tissue-protective and anti-inflammatory signal in models of ischemia-reperfusion injury, traumatic injury, and inflammatory tissue damage. Brines and colleagues proposed that this tissue-protective signaling occurs through a different receptor complex than the homodimeric EPOR — specifically a heterocomplex of EPOR with the β-common receptor (βCR/CD131), sometimes called the innate repair receptor. ARA-290 was designed as a B-helix-derived peptide that selectively engages this IRR without engaging the homodimeric EPOR; in preclinical models, the peptide reproduces the tissue-protective effects of erythropoietin without producing erythropoietic effects.

The clinical-research program for cibinetide has focused primarily on sarcoidosis-related small-fiber neuropathy (a debilitating sensory neuropathy seen in some sarcoidosis patients) and on diabetic painful peripheral neuropathy. Published phase 2 clinical-research studies have reported effects on neuropathic pain measures, on small-fiber regenerative endpoints (intraepidermal nerve fiber density measured by skin biopsy), and on neuropathy-related quality-of-life measures. The clinical-research program has not advanced to phase 3 approval for any indication as of the publication of this reference; cibinetide is not a marketed medicine.

It is important to be clear about what ARA-290 / cibinetide is not. It is not an approved medicine — there is no FDA, EMA, or equivalent approval for any indication. It is not an erythropoietin substitute for anemia — by design, the peptide does not produce erythropoietic effects and would not be useful as an anti-anemic agent. It is not a "research-supply EPO" — the molecule is structurally and functionally distinct from full-length recombinant erythropoietin. And it is not a peptide for sports performance — the design specifically removes the red-blood-cell-stimulating activity of EPO that would be relevant to endurance-performance contexts.

Recombinant human erythropoietin became available as a therapeutic in the late 1980s with the approval of epoetin alfa (Epogen, Procrit) for anemia of chronic kidney disease. Through the 1990s, EPO became a foundational treatment for various anemias of chronic disease. In parallel, research groups characterized EPO and EPOR expression in non-hematopoietic tissues including brain, heart, kidney, and vascular endothelium, and began to investigate the tissue-protective and anti-apoptotic effects of EPO in models of stroke, myocardial infarction, and other ischemic injuries.

By the early 2000s, a body of preclinical evidence supported the concept that EPO had distinct tissue-protective signaling beyond its hematopoietic function. Clinical translation of this concept faced a challenge: chronic administration of erythropoietic doses of EPO would produce unwanted erythropoietic effects (elevated hematocrit, risk of thrombotic complications, contraindication in cancer-related contexts where EPO use has been associated with adverse outcomes). The conceptual solution was to engineer EPO derivatives that retained tissue-protective signaling without erythropoietic signaling.

Brines, Cerami, and colleagues at the Kenneth S. Warren Institute and subsequently at Araim Pharmaceuticals developed several candidate molecules pursuing this engineering rationale, including carbamylated erythropoietin (CEPO, also called asialoCEPO) — a chemically modified EPO with retained tissue-protective activity and abolished erythropoietic activity — and ARA-290, a small B-helix-derived peptide designed to engage the proposed innate repair receptor. ARA-290 was characterized in preclinical models of nephropathy, neuropathy, ischemia-reperfusion injury, and inflammatory tissue damage with published preclinical findings supporting the tissue-protective and anti-inflammatory effects.

Clinical-research evaluation of cibinetide has been pursued by Araim Pharmaceuticals in collaboration with academic investigators. Published phase 2 studies in sarcoidosis-related small-fiber neuropathy (Dahan, Brines, and colleagues at Leiden University Medical Center) reported effects on neuropathic pain and on intraepidermal nerve fiber density. A phase 2 study in painful diabetic peripheral neuropathy similarly reported effects on pain measures and on small-fiber endpoints. These studies typically involved subcutaneous administration of the peptide over multi-week periods in small patient cohorts and were designed as proof-of-concept evaluations of the IRR-engagement hypothesis.

The clinical-research program has not advanced to phase 3 pivotal trials for any indication as of the publication of this reference, and cibinetide is not an approved medicine in any jurisdiction. The peptide remains a research compound and an active subject of clinical-research investigation in sarcoidosis-related neuropathy and related contexts. Independent academic groups continue to investigate the IRR concept and its potential therapeutic relevance.

Erythropoietin (EPO) is a 165-amino-acid glycoprotein hormone produced principally by renal interstitial fibroblasts in response to hypoxia. EPO is the master regulator of erythropoiesis: it binds the homodimeric EPO receptor (EPOR-EPOR) on bone-marrow erythroid progenitor cells and signals through JAK2-mediated phosphorylation of STAT5, supporting survival, proliferation, and differentiation of the erythroid lineage. Recombinant EPO (epoetins) are foundational therapeutics for anemia of chronic kidney disease and chemotherapy-induced anemia.

Beyond hematopoiesis, EPO and EPOR are expressed in many non-erythroid tissues. Preclinical work in models of cerebral ischemia (stroke), myocardial ischemia, renal ischemia-reperfusion, peripheral neuropathy, and inflammatory tissue damage has reported tissue-protective and anti-inflammatory effects of EPO administration. The mechanistic characterization of these non-hematopoietic effects has identified a heterocomplex receptor — EPOR paired with the β-common receptor (βCR, CD131, encoded by CSF2RB) — as the molecular basis for the tissue-protective signaling. The βCR is the shared β chain of the receptors for IL-3, IL-5, and GM-CSF in their canonical signaling contexts; its pairing with EPOR in tissue-protective signaling defines the "innate repair receptor" (IRR) concept.

Engagement of the IRR by EPO or by IRR-selective ligands like ARA-290 signals through pathways including JAK2/STAT3 (distinct from the JAK2/STAT5 of erythropoietic signaling), PI3K/Akt, and MAPK, with downstream effects including anti-apoptotic signaling in injured cells, suppression of inflammatory cytokine production in immune cells (particularly macrophages), and promotion of tissue regenerative processes. In peripheral nerve research, IRR engagement has been associated with effects on small-fiber regenerative capacity in models of nerve injury and neuropathy.

ARA-290 was designed as a small B-helix-derived peptide ligand of the IRR. The 11-amino-acid sequence corresponds to a region of the EPO B-helix that the IRR receptor-interface hypothesis identifies as a contributor to βCR engagement. The peptide engages the IRR with measurable affinity in receptor-binding studies and reproduces EPO's tissue-protective signaling in cell-based and in-vivo models without engaging the homodimeric EPOR and without producing erythropoietic activity. The pharmacokinetic profile of the small peptide is short (plasma half-life on the order of minutes after subcutaneous administration), but the tissue-protective effects in preclinical models persist beyond the plasma exposure window, consistent with a signaling-pathway engagement rather than continuous receptor occupancy mechanism.

Clinical-research evaluation in sarcoidosis-related small-fiber neuropathy and in diabetic painful peripheral neuropathy has used subcutaneous administration over multi-week periods. Reported endpoints include neuropathic pain scores, intraepidermal nerve fiber density measured by skin biopsy (a small-fiber regenerative endpoint), and quality-of-life measures. Effect sizes reported in phase 2 studies vary across endpoints and across studies; the published clinical-research evidence is small-cohort phase 2 work and does not establish efficacy and safety for any approved indication.

Distinguishing ARA-290 from related areas: the peptide is not a full-length EPO substitute (it lacks the erythropoietic activity and is structurally much smaller); it is not an EPO mimetic in the broad sense (specific designs like EMP1 are non-erythroid EPOR engagers with different properties); and it is not a "general anti-inflammatory peptide" in the way that some other research peptides are framed — the proposed mechanism is specifically IRR engagement with downstream anti-inflammatory and regenerative signaling.

ARA-290 (cibinetide) is a linear 11-amino-acid peptide with sequence pyroGlu-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser. The N-terminal pyroglutamate (pGlu) is a cyclized glutamic-acid derivative that confers resistance to N-terminal exopeptidase degradation. The molecular weight is approximately 1257 g/mol. The peptide corresponds to a portion of the erythropoietin B-helix sequence — the structural region implicated in the βCR-engagement interface of the proposed IRR heterocomplex.

The choice of the B-helix region for the peptide-engineering rationale comes from structural and mutational characterization of the EPO/EPOR-βCR interaction. EPO is a four-helix-bundle cytokine (analogous in fold to growth hormone, IL-3, IL-5, and GM-CSF — the latter three sharing the βCR in their canonical homo-receptor signaling). The receptor-interface mapping has identified specific helix-A and helix-D residues as principally involved in EPOR engagement and B-helix and AB-loop residues as contributors to the proposed βCR engagement of the IRR heterocomplex.

Research-grade ARA-290 / cibinetide is produced by solid-phase peptide synthesis (SPPS), purified by reversed-phase HPLC to ≥98% purity, and verified by analytical HPLC and mass spectrometry. The product is supplied as a sterile lyophilized peptide in a sealed vial. Lyophilized storage is at -20 °C or below; reconstituted solutions in aqueous diluent are typically stored refrigerated and used within a short window per peptide-stability practice for short linear peptides.

In published preclinical and small-cohort clinical-research literature, ARA-290 / cibinetide has been investigated in several principal application areas:

Sarcoidosis-related small-fiber neuropathy. Small-fiber neuropathy is a debilitating sensory neuropathy seen in a subset of patients with sarcoidosis, characterized by painful and autonomic symptoms with reduced intraepidermal nerve fiber density on skin biopsy. Published phase 2 clinical-research studies of cibinetide in this patient population have reported effects on neuropathic pain measures, on intraepidermal nerve fiber density, and on quality-of-life endpoints over multi-week subcutaneous administration.

Diabetic painful peripheral neuropathy. Diabetic peripheral neuropathy is a common complication of long-standing diabetes with both small-fiber and large-fiber components. Published phase 2 clinical-research studies have evaluated cibinetide in patients with painful diabetic neuropathy with endpoints similar to those used in the sarcoidosis-neuropathy work.

Preclinical ischemia-reperfusion models. Cibinetide has been investigated in preclinical rodent models of cerebral ischemia, myocardial ischemia-reperfusion, renal ischemia-reperfusion, and hindlimb ischemia for tissue-protective and regenerative effects. The mechanistic rationale is engagement of the innate repair receptor in injured tissues.

Preclinical models of inflammatory tissue damage. Models of inflammatory bowel disease, kidney injury, and other inflammatory tissue-damage contexts have been used to investigate cibinetide's anti-inflammatory and tissue-protective effects through proposed IRR-mediated suppression of macrophage inflammatory signaling.

Cardiac surgery / kidney protection research. Limited clinical-research evaluation has explored cibinetide in the context of cardiac surgery for cardiac and renal protection, building on the preclinical ischemia-reperfusion literature. This research is exploratory and does not establish a clinical indication.

Receptor pharmacology research. ARA-290 is used as a pharmacological tool in research investigating the molecular characterization of the EPOR/βCR heterocomplex (innate repair receptor), the signaling pathways downstream of IRR engagement, and the comparison with EPOR-homodimer signaling. This pharmacological-tool use is mechanistic research distinct from any therapeutic application.

All applications described in this section are research-supply context: laboratory work in cell culture, isolated proteins, and preclinical animal models, or clinical-research studies conducted under regulatory oversight in defined patient populations. The peptide is not approved for any therapeutic use, and nothing on this page describes a clinical protocol or therapeutic recommendation.

ARA-290 / cibinetide sits within the EPO-derived tissue-protective signaling landscape alongside several related molecular approaches.

ARA-290 (cibinetide) is an 11-amino-acid peptide derived from a region of the erythropoietin B-helix, designed to engage the proposed innate repair receptor (EPOR/βCR heterocomplex) and reproduce EPO's tissue-protective and anti-inflammatory signaling without engaging the homodimeric EPO receptor that drives red blood cell production. The molecule was developed by Araim Pharmaceuticals based on the mechanistic distinction between EPO's hematopoietic and tissue-protective signaling axes characterized by Brines, Cerami, and colleagues.

In published preclinical research, ARA-290 reproduces EPO's tissue-protective effects in models of ischemia-reperfusion injury, neuropathy, and inflammatory tissue damage without producing erythropoietic effects. In published phase 2 clinical research in sarcoidosis-related small-fiber neuropathy and painful diabetic peripheral neuropathy, the peptide has been evaluated with endpoints including neuropathic pain, intraepidermal nerve fiber density, and quality-of-life measures.

This page is research educational only. ARA-290 / cibinetide is not approved as a medicine in any jurisdiction. The clinical-research program is at phase 2 and has not advanced to regulatory approval. Research-supply ARA-290 is intended for laboratory and analytical research-only use; no medical or therapeutic claims are made.