July 28, 2026 · 3 min read
ARA-290 (cibinetide): an erythropoietin-derived peptide and the small fiber neuropathy trials
What ARA-290 is, how it is designed to engage the innate repair receptor without raising red cells, and what phase 2 sarcoidosis and diabetes trials report.
ARA-290, also called cibinetide and pHBSP (pyroglutamate helix B surface peptide), is an 11-amino-acid peptide designed from the three-dimensional structure of erythropoietin (EPO). EPO treats anemia by stimulating red blood cell production, but it also protects tissue after injury, and the two effects use different receptors. ARA-290 was engineered to keep the second effect and leave out the first.
The ARA-290 sequence
Sequence: Pyroglutamic acid, Glutamic acid, Glutamine, Leucine, Glutamic acid, Arginine, Alanine, Leucine, Asparagine, Serine, Serine.
- Modified residue
- Negatively charged
- Polar
- Hydrophobic
- Positively charged
- Length
- 11 amino acids
- Average mass
- 1,257.3 Da
- Formula
- C51H84N16O21
Two receptors for one hormone
A 2015 review explains why recombinant EPO is a poor tool for tissue protection: it raises hematocrit, activates platelets and increases selectin expression, which carries a risk of thrombosis. Peptides that engage only the innate repair receptor were developed to avoid those effects. The review also points out that ARA-290 is cleared from plasma within minutes while its effects last longer, and it discusses the molecular mechanisms proposed for that mismatch.
How ARA-290 differs from EPO
EPO receptor homodimer
Binding stimulates red blood cell progenitors.
Innate repair receptor
A heterodimer of the EPO receptor and the beta common receptor. Normal tissue rarely expresses it, injury and inflammation induce it, and it activates protection and repair.
ARA-290
Modeled on helix B of EPO to activate the innate repair receptor without interacting with the EPO receptor homodimer.
Short half-life
Plasma half-life is about 2 minutes, yet effects in animal models and trials outlast it.
Sarcoidosis and small fiber loss
Sarcoidosis often causes loss of small nerve fibers, which can be measured in the cornea with confocal microscopy. A 2014 review of two phase 2 trials in sarcoidosis reported improved neuropathic pain scores, more corneal nerve fibers, better sensory pain thresholds and improved quality of life and physical functioning.
The 2017 phase 2b trial followed 64 people with sarcoidosis, small fiber loss and neuropathic pain for 28 days. The primary endpoint was the change in corneal nerve fiber area. Only the middle dose group reached statistical significance on it. In that group, regenerating GAP-43 positive fibers in the skin also increased (P = 0.035), and changes in corneal nerve area correlated with changes in those fibers and with the six-minute walk test. Pain improved in all groups. In people with moderate to severe pain the authors describe a clinically meaningful placebo-corrected decrease in the middle group, although the reported P value for that comparison was 0.157.
Corneal nerve fiber area after 28 days
- Lowest dose group95% CI -429 to 647109 µm²
- Middle dose group95% CI 159 to 1,236; P = 0.012697 µm²
- Highest dose group95% CI -130 to 992431 µm²
Type 2 diabetes
A 2015 phase 2 trial in people with type 2 diabetes and painful neuropathy compared ARA-290 with placebo for 28 days and then followed participants for a further month without treatment. No potential safety issues were identified. Hemoglobin A1c and lipid profiles improved through the 56-day observation period, and neuropathic symptoms on the PainDetect questionnaire improved significantly. In participants whose corneal nerve fiber density was more than one standard deviation from normal, density increased compared with no change on placebo. The authors concluded that the peptide deserves continued clinical evaluation.
Reading these results
Several features of the trials shape how far they can be read.
- The endpoints are surrogates. Corneal nerve area and fiber counts are imaging and biopsy measures, and the authors propose them as markers of disease modification.
- The dose pattern was not a straight line. In the 2017 trial the middle group did better than the highest.
- The trials were short. Both ran for 28 days of treatment.
- The groups were small, and both trials were phase 2 studies.
An 11-residue peptide with an N-terminal pyroglutamate has a calculated average mass of about 1,257 Da, which is the figure a certificate of analysis should show.
References
- Collino M et al. Flipping the molecular switch for innate protection and repair of tissues: long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Pharmacol Ther 2015.
- van Velzen M et al. ARA 290 for treatment of small fiber neuropathy in sarcoidosis. Expert Opin Investig Drugs 2014.
- Culver DA 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.
- Brines 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.
Related research notes
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