ARA-290 (Cibinetide)

What it is

Erythropoietin, EPO for short, can do more than form blood. It also protects tissue, especially nerves. The catch is blood formation itself: more red blood cells mean thicker blood, which is why EPO was never practical as a tissue protector.

ARA-290 is the attempt to separate these two sides. It is a small peptide designed on the model of a section of the EPO molecule that binds selectively to the so-called innate repair receptor, the receptor for the tissue-protective effect. It does not stimulate blood formation. It was developed by Araim Pharmaceuticals and studied mainly in small fiber neuropathy, that is, the loss of and damage to small nerve fibers, as occurs in sarcoidosis and in diabetes.

How it is supposed to work

The receptor sits on cells that become active when tissue is damaged, including macrophages. The idea: the peptide dampens the inflammatory response there and promotes repair, instead of merely suppressing pain.

In animal and cell models, this picture has been widely reproduced: protection of the kidneys from a chemotherapy drug, inhibition of macrophage activation with protection of transplanted islet cells, protection in the mouse model of systemic lupus, higher bone density in mice, pain relief via the TRPV1 channel, and slowed Alzheimer-like disease progression in mice.

In humans, measurement ends earlier. The chain of action via the receptor has not been quantified. What was measured were symptom questionnaires, the density of small nerve fibers in the cornea and skin, temperature sensitivity, walking distance, and blood glucose and blood lipid values.

Why development came to a standstill

The early positive studies were followed by the real test: a randomized, quadruple-blinded study with 64 participants with sarcoidosis-associated small fiber neuropathy, 3 dose levels against placebo over 28 days, conducted from 2014 to 2015. Its results are in the trial registry; a publication on it cannot be found.

The figures explain the silence. For the primary endpoint, the nerve fiber area in the cornea, the mean change in the middle dose group was plus 533.8 compared with minus 170.0 under placebo, with standard deviations between 633.0 and 1110.02. No statistical analysis has been posted. On the symptom questionnaires, placebo was just as good or better: the SFNSL symptom scale fell by 7.3 points under placebo and by 4.9, 8.7 and 5.5 in the active groups. In the skin biopsy, nerve fiber density increased by 0.8 under placebo, and by 0.5, by 0.4 and by minus 0.3 in the active groups. Only the 6-minute walk test came out similarly better in all 3 dose groups, plus 17.7 to 19.3 meters compared with plus 1.2 meters.

After that, nothing larger followed. The registry lists a total of 4 studies, no phase 3, none ongoing. A study on cognitive and neural effects in depression with 36 participants has been completed but never posted results. A trial in diabetic macular edema was terminated early.

What the studies show

Dahan et al., Mol Med 2013

Blinded and placebo-controlled, 28 days of daily subcutaneous administration in sarcoidosis patients with documented loss of small nerve fibers. Endpoints: patient-reported symptoms, corneal nerve fiber density, temperature sensitivity and 6-minute walk test. All came out in favor of the active substance. The number of participants is not stated in the abstract, and the full text is not freely available.

Brines et al., Mol Med 2015

Phase 2 in type 2 diabetes with painful neuropathy, 28 days of self-injection against placebo, followed by one month of follow-up. HbA1c, blood lipids and symptoms in the PainDetect questionnaire improved. The increase in corneal nerve fiber density was seen only in the subgroup with markedly reduced baseline density. The authors themselves phrase their conclusions cautiously.

Phase 2 study with 64 participants (NCT02039687)

The largest and most rigorous study: randomized, parallel groups, quadruple-blinded, 3 dose levels against placebo over 28 days, 16 participants per arm, conducted from January 2014 to February 2015. The primary endpoint was corneal nerve fiber area, with very large scatter and without a posted statistical analysis. On questionnaires and skin biopsy, placebo was equally good or better. Not published.

Lois et al., J Clin Med 2020

Phase 2 in diabetic macular edema over 12 weeks. 9 patients were enrolled, 8 completed the study, and it is listed in the registry as terminated early. Visual acuity, retinal thickness, retinal sensitivity and tear production did not improve on average; only the visual function questionnaire improved. No serious side effects, no antibodies.

Where the data stop

The decisive point is the contrast between the early studies and the largest one. On the symptom questionnaires and nerve fiber density in the skin, ARA-290 brought no advantage over placebo in the study with 64 participants, and for the primary endpoint there are only mean values with very large scatter and no statistical analysis. This study has not been published. Anyone who describes ARA-290 as a proven regeneration peptide relies on the smaller, older papers and leaves out the larger one.

In addition: all published studies treated for 28 days, the eye study for 12 weeks with 9 patients. There are no long-term data. What was measured were surrogate markers and questionnaires, not hard endpoints. Several key papers come from authors with ties to the developing company, and an independent replication of the positive findings is lacking. In diabetic macular edema there was no effect, and the depression study with 36 participants never published results.

And it is not going any further: no phase 3, no ongoing study, no approval. For an active substance that has been tested in humans for years, that is a finding in itself. The many animal and cell models on kidney, bone, lupus and Alzheimer’s are interesting, but they say nothing about what a human gets out of it.

Status, approval and legal

ARA-290 is not approved as a medicine anywhere and may not be marketed in Germany. Its development stage is phase 2; a phase 3 trial was never started, and no study is still running in the trial registry. We therefore do not give dosage information. In sport, the situation is stricter than for many other research peptides: the 2026 doping list, in section S2.1.5, explicitly prohibits agonists of the body’s own repair receptor, with asialo-EPO and carbamylated EPO as examples, and according to its introduction this section also applies to substances with a similar structure or similar biological effect. ARA-290 was developed precisely as an agonist of this receptor. According to the wording, it therefore falls into a class of non-specified prohibited substances, in addition to the catch-all class S0 for substances without approval. The fact that the active substance does not stimulate blood formation does not help here.

Safety

Over the periods tested, the picture is unremarkable: no safety problems in the publications, and in the eye trial over 12 weeks no serious side effects and no antibodies against the active substance. In the posted results of the largest study, however, serious events occurred exclusively in the active arms, each in one participant: fainting, headache, chest tightness, shortness of breath and inflammation of the small intestine in the lowest dose group, and suicidal thoughts in the highest. With 64 participants and individual cases, no causal relationship can be derived from this, but it should not be concealed either. Diarrhea, nausea and abdominal pain occurred with similar frequency in all arms; 4 participants discontinued the study, all in active arms. The classic EPO drawback does not apply, because blood formation is not stimulated, but there is no long-term monitoring like that for approved medicines. Upper limits from EFSA, BfR or NIH do not exist, because this is not a nutrient. Outside a study, ARA-290 is not suitable for anyone, and products from the gray market have not been tested for purity and sterility.

Sources

• Dahan et al., Mol Med 2013 (sarcoidosis, placebo-controlled)
• Brines et al., Mol Med 2015 (type 2 diabetes, phase 2)
• ClinicalTrials.gov, NCT02039687 (phase 2 with 64 participants, results posted)
• Lois et al., J Clin Med 2020 (diabetic macular edema)
• van Velzen et al., Expert Opin Investig Drugs 2014 (review of the phase 2 data)
• Brines et al., Sci Rep 2018 (corneal microscopy as a measurement method)
• Watanabe et al., Transplantation 2016 (macrophage inhibition, animal model)
• Zhang et al., Peptides 2016 (pain relief via TRPV1, animal model)
• WADA Prohibited List 2026, BGBl. III No. 219/2025