Angiotensin (1-7) vs ARA-290

Binds Mas receptor (MasR), activating nitric oxide synthase and reducing oxidative stress. Opposes TGF-β and angiotensin II signaling to reduce fibrosis. Enhances insulin sensitivity and provides cardiovascular protection.

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone generated primarily through cleavage of angiotensin II by ACE2, functioning as a counter-regulatory arm of the renin-angiotensin system (RAS) by binding the Mas receptor to promote vasodilation, anti-fibrotic, anti-inflammatory, and cardioprotective effects that oppose the vasoconstrictive actions of angiotensin II. Ang-(1-7) acts through the ACE2/Mas receptor axis to reduce oxidative stress, attenuate NF-kB-mediated inflammation, and suppress TGF-beta fibrosis signaling; the ACE2/Ang-(1-7)/Mas axis has emerged as a key regulatory pathway in cardiovascular and metabolic disease, and gained renewed research attention given ACE2's role as the SARS-CoV-2 entry receptor. A Phase 1-2 randomized clinical trial of Ang-(1-7) infusion in COVID-19 ICU patients reported preliminary safety, tolerability, and dose-response data, providing the primary indexed human pharmacokinetic evidence; broader cardiovascular protective applications are supported by preclinical data but have not been established by completed Phase 3 trials. Ang-(1-7) has no FDA approval and no approved therapeutic indication in any jurisdiction; it is an endogenous peptide under active clinical investigation as a candidate for cardiovascular, metabolic, and inflammatory conditions, with emerging human safety data but an incomplete evidence base for any specific approved clinical use.

Non-hematopoietic EPO analogue; activates innate repair receptor (IRR/EPOR/CD131 complex) without erythropoietic effects; promotes tissue repair and nerve healing

ARA 290 (cibinetide) is a synthetic 11-amino-acid peptide derived from the helix B region of erythropoietin (EPO), engineered to activate the innate repair receptor (IRR) — a tissue-protective heteroreceptor complex comprising the EPO receptor and the β-common receptor (CD131) — without engaging the classical erythropoietic EpoR homodimer, thereby separating EPO's tissue-protective signaling from its hematopoietic effects. By selectively engaging the IRR rather than the erythropoietic receptor, cibinetide activates anti-inflammatory and anti-apoptotic intracellular pathways in neurons, endothelium, and other metabolically active tissues without causing erythrocytosis, hypertension, or thrombosis, making it a candidate for neuropathy and inflammatory tissue injury contexts. Randomized, double-blind Phase 2 clinical trials have demonstrated that cibinetide improves metabolic control and neuropathic symptom scores in patients with type 2 diabetes, and a separate study demonstrated improved corneal nerve fiber abundance in patients with sarcoidosis-associated small fiber neuropathy — providing human proof-of-concept for both diabetic and inflammatory peripheral neuropathy applications. Cibinetide (ARA 290) is an investigational compound that has not received FDA approval for any indication; Phase 2 data supports further investigation in peripheral neuropathies, but no Phase 3 completion or regulatory filing has occurred as of 2025.