ARA-290 10mg

ARA-290, also called cibinetide, is an 11-residue peptide modelled on the face of erythropoietin’s helix B that points into the surrounding water when the hormone sits on its receptor. This listing is a single 10 mg vial of freeze-dried powder. Research on the peptide has asked whether erythropoietin’s tissue-protective effects can be separated from red-cell production, first in rodent injury models and then in small trials in people with small nerve fibre loss.

Specifications

Sequence and amount in the vial

The certificate gives the sequence as pGlu-EQLERALNSS-OH: eleven residues, starting with an N-terminal pyroglutamate and ending in a free C-terminus. The formula is C51H84N16O21 and the theoretical mass 1257.3 Da, the figure to compare with the LC-MS identity result on the lot certificate. In molar terms the 10 mg fill is about 8.0 µmol, slightly less once the certificate’s water content is allowed for.

The same peptide is sold already dissolved, as an ARA-290 preloaded pen holding 10 mg in 3 mL and an ARA-290 nasal spray holding 10 mg per bottle.

What the research covers

Two receptors for one hormone

Erythropoietin (EPO) controls red-cell production as a circulating hormone, and it also acts locally, in a paracrine and autocrine way, to protect many tissues from injury¹. Brines and colleagues argued that the two jobs use different receptors: red-cell production goes through a homodimer of the EPO receptor, tissue protection through a complex of the EPO receptor with CD131, the beta common receptor subunit shared with the GM-CSF, IL-3 and IL-5 receptors¹,². Their 2004 evidence was biochemical and genetic. Membrane proteins from rat brain, heart, liver and kidney passed over EPO columns came out enriched in EPO receptor bound in a complex with CD131, antibodies to the EPO receptor pulled down CD131 from neuronal-like P-19 cells, and in CD131 knockout mice neither EPO nor carbamylated EPO, a derivative that does not stimulate red-cell production, was active in cardiomyocyte or spinal cord injury models².

Why this mattered was set out in a 2008 review by Brines and Cerami: protecting tissue with recombinant EPO needs more of it than red-cell production does, with a risk of serious adverse effects, and a separate tissue-protective receptor made it possible to design derivatives, including peptides that mimic EPO’s tertiary structure, without the haematopoietic action³.

The helix B peptide

In 2008 the same group narrowed the protective region to helix B of EPO, residues 58 to 82, which faces the aqueous medium when EPO is bound to the receptor homodimer¹. Helix B was neuroprotective in cell culture and protective in animal models of ischaemic stroke, diabetes-induced retinal oedema and peripheral nerve trauma¹. An 11-amino-acid peptide built from the adjacent residues that form helix B’s aqueous face was also protective, in models of stroke and renal ischaemia-reperfusion, and it sped wound healing and improved cognitive function in rodents¹. Neither helix B nor the 11-residue peptide stimulated red-cell production in vitro or in vivo¹. The clinical papers call this peptide ARA 290 or cibinetide⁴,⁵.

Small trials in neuropathy

Most of the human work is in sarcoidosis complicated by small nerve fibre loss. A double-blind, placebo-controlled pilot in 22 people with sarcoidosis and symptoms of small fibre neuropathy raised no safety concerns over four weeks. The ARA 290 group improved more than placebo on a small fibre neuropathy screening score and changed significantly from baseline on the SF-36 pain and physical functioning scales, while pain inventory and fatigue scores improved equally in both groups⁶. A blinded 28-day trial in sarcoidosis-associated small nerve fibre loss reported better neuropathic symptoms, higher corneal small nerve fibre density, changes in skin temperature sensitivity and a longer six-minute walk⁷. In a phase 2 study in type 2 diabetes with painful neuropathy, HbA1c and lipid profiles improved over a 56-day observation period, PainDetect scores improved, and corneal nerve fibre density rose in participants whose baseline was more than one standard deviation from normal⁴.

The largest trial, a phase 2b study, randomised 64 people with sarcoidosis-associated small nerve fibre loss and neuropathic pain to one of three cibinetide arms or placebo for 28 days⁵. On the primary endpoint, change in corneal nerve fibre area, one of the three active arms differed significantly from placebo (placebo-corrected change 697 µm², 95% CI 159 to 1,236); that arm also showed more regenerating GAP-43-positive fibres in the skin, and changes in corneal fibre area tracked changes in those fibres and in six-minute walk distance⁵. Pain improved significantly in all groups⁵.

What is not established

Every trial here ran for about a month, the two that report their size enrolled 22 and 64 people, and the corneal measurements are surrogate markers rather than clinical outcomes, a use the phase 2b authors argued for in their conclusions⁵. Placebo groups improved on some symptom measures too⁶,⁵.The receptor model comes mainly from one group, Brines and Cerami’s, and rests on co-precipitation and knockout experiments rather than a structure of the complex²,³; Brines is also an author of the type 2 diabetes trial⁴. None of these studies used PrymaLab material. The guide to peptides for inflammation research compares cibinetide with KPV and other anti-inflammatory peptides.

How each lot is tested

Every lot is tested in PrymaLab’s own laboratory in Ashland, Kentucky before release: RP-HPLC for purity, LC-MS for identity, Karl Fischer titration for water, LAL for endotoxin and USP <71> for sterility. The results for the lot now shipping are in the certificate panel on this page, and the certificate number, key and QR code can be checked on the verify page. These are in-house results from PrymaLab Analytical, not an independent test, and the lab is not accredited to ISO 17025. The third-party testing guarantee on this page still applies: if any independent laboratory finds the wrong compound, or less than the stated purity or amount, the order is refunded and the cost of the test is reimbursed.

Frequently asked questions

References

1. 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):10925-30. DOI · PubMed
2. Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004;101(41):14907-12. DOI · PubMed
3. Brines M, Cerami A. Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Intern Med. 2008;264(5):405-32. DOI · PubMed
4. 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):658-66. DOI · PubMed
5. 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. DOI · PubMed
6. 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):1430-6. DOI · PubMed
7. 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):334-45. DOI · PubMed