ARA-290 Research Peptide

Erythropoietin is famous as the kidney hormone that drives red-cell production, yet laboratory work also showed that erythropoietin made locally inside tissues helps them withstand injury. Separating those two jobs was the challenge. In a 2008 paper in PNAS, Michael Brines, Anthony Cerami and colleagues traced the protective activity to helix B (residues 58–82), one of the hormone’s four helices and the one that points out into the surrounding fluid when erythropoietin sits on its classic receptor. Helix B by itself protected neurons in culture and showed tissue-protective activity in rodent models of stroke, diabetic retinal oedema and peripheral nerve trauma.

The team then shrank it further. An 11-residue peptide assembled from the amino acids along that water-facing surface kept the protective signal in rodent stroke and kidney ischaemia–reperfusion models, and also accelerated wound closure and improved performance in cognitive tasks in rodents. Crucially, neither helix B nor the short peptide stimulated red-cell formation in vitro or in vivo. With a pyroglutamate ring closing its N-terminus, that peptide is ARA-290, later given the international non-proprietary name cibinetide.

Red-cell production runs through a homodimer, two erythropoietin receptors (EPOR) paired together on bone-marrow progenitor cells. The tissue-protective effect is attributed to a different pairing, in which EPOR teams up with CD131, the beta common receptor better known as the shared signalling chain of the IL-3, IL-5 and GM-CSF receptors. Researchers call this heterocomplex the innate repair receptor, and ARA-290 was designed to engage it while leaving the homodimer alone.

Some of the clearest genetic evidence comes from neuropathic pain models. After spared nerve injury, ARA-290 relieved touch- and cold-evoked allodynia in rats for as long as 15 weeks, and it was active in normal mice, yet it produced no effect at all in mice lacking the beta common receptor (Swartjes and colleagues, Anesthesiology, 2011). A follow-up rat study connected the long-lasting effect with a damped-down response from spinal microglia, the immune cells of the spinal cord.

Sarcoidosis-associated small fibre neuropathy has been the main clinical research setting. A double-blind pilot in 22 patients (Heij and colleagues, Molecular Medicine, 2012) compared four weeks of ARA-290 with placebo. The Small Fiber Neuropathy Screening List score and the SF-36 pain and physical-functioning scores improved more with ARA-290, but Brief Pain Inventory and fatigue scores improved equally in both arms.

The larger phase 2b study (Culver and colleagues, Investigative Ophthalmology & Visual Science, 2017) randomised 64 people to one of three cibinetide levels or placebo for 28 days. Its primary endpoint, change in corneal nerve fibre area, reached significance in the middle group (P = 0.012), with smaller changes in the lowest and highest groups. Skin-biopsy counts of GAP-43-positive nerve fibres also rose in the middle group. Pain scores fell in every arm, placebo included; in people with moderate-to-severe pain the placebo-corrected drop was described as clinically meaningful but was not statistically significant (P = 0.157).

A phase 2 study in type 2 diabetes with painful neuropathy (Brines and colleagues, Molecular Medicine, 2015) gave ARA-290 or placebo daily for 28 days and followed participants for a further month. The ARA-290 group showed improved HbA1c and lipid profiles across the 56-day observation window and a significant improvement on the PainDetect neuropathy questionnaire. Corneal nerve fibre density was below that of healthy controls at baseline, and among participants with the lowest density it rose significantly with ARA-290 while staying flat on placebo.

Not every eye endpoint moved. A small phase 2 study in diabetic macular oedema (Lois and colleagues, Journal of Clinical Medicine, 2020) recruited nine patients, eight of whom completed 12 weeks. There was no mean improvement in visual acuity, central retinal thickness, retinal sensitivity or tear production, the four primary endpoints, although the composite visual-function questionnaire score improved slightly and no anti-cibinetide antibodies were detected.