ARA-290 Explained: What Do the Human Trials in Neuropathy Actually Show?

Using full length recombinant erythropoietin for nerve repair is difficult. To solve this, researchers engineered ARA-290. Mechanistic 1

ARA-290 was designed to bind selectively to the innate repair receptor. Mechanistic 1

By targeting this specific receptor complex, ARA-290 activates tissue repair signals. Mechanistic 1

The problem of small fibre neuropathy

Small nerve fibres are unmyelinated or thinly myelinated sensory nerves. They are responsible for transmitting pain and temperature sensations, as well as controlling autonomic functions like heart rate, digestion and sweating. When these fibres are damaged, patients experience chronic burning pain, tingling, numbness and autonomic dysfunction.

Human evidence in sarcoidosis

Sarcoidosis is an inflammatory disease that frequently causes small nerve fibre loss. Several clinical trials have tested ARA-290 in this population, looking for both symptom relief and structural nerve changes. Human 2

A pilot study published in 2012 enrolled 22 patients with sarcoidosis and symptoms of small fibre neuropathy. The ARA-290 group showed a significant improvement in their neuropathy screening list scores compared with placebo. They also reported significant positive changes from baseline in the pain and physical functioning dimensions of the SF-36 quality of life questionnaire. Human 3

A subsequent blinded placebo controlled trial tested administration. The researchers reported that ARA-290 significantly improved neuropathic symptoms. The treatment was also associated with an increase in corneal small nerve fibre density, changes in cutaneous temperature sensitivity and an increased exercise capacity measured by a six minute walk test. Human 2

The largest of these studies, a phase 2b randomised trial published in 2017, enrolled 64 subjects. The researchers also found an increase in regenerating intraepidermal nerve fibres in the skin, which correlated with the corneal changes and walk test improvements. Human 4

Human evidence in type 2 diabetes

Small fibre neuropathy is also a major complication of type 2 diabetes, driven by chronic high blood sugar and metabolic stress. A phase 2 study published in 2015 evaluated ARA-290 in patients with type 2 diabetes and painful neuropathy. Human 1

The researchers reported that neuropathic symptoms improved significantly in the ARA-290 group. Patients with severe baseline nerve loss showed a significant increase in corneal nerve fibre density, while the placebo group showed no change. Human 1

The study also noted that subjects receiving ARA-290 exhibited improvements in HbA1c and lipid profiles throughout the 56 day observation period. This suggests a potential metabolic effect alongside the nerve repair findings. Human 1

Why measure corneal nerve fibres?

The trials for ARA-290 frequently use corneal confocal microscopy to measure nerve fibre density. Human 4

Using a specialised microscope, researchers can non invasively image and count the small nerve fibres in the eye. This acts as a surrogate marker for systemic small fibre neuropathy. If nerve fibres are regenerating in the cornea, it provides objective physical evidence of repair that supports the subjective improvements reported in patient pain questionnaires. Human 4

The 2017 trial confirmed this relationship by showing that changes in the cornea correlated with the regrowth of nerve fibres in skin biopsies. Specifically, the researchers measured GAP-43 positive fibres. Human 4

Pharmacokinetics and the switch mechanism

Safety and side effects in clinical trials

In the 2012 sarcoidosis pilot study, the researchers noted that no safety concerns were raised by clinical or laboratory assessments. Human 3 Similarly, the 2015 type 2 diabetes study reported that no potential safety issues were identified during the 56 day observation period. Human 1

ARA-290 is designed as a nonerythropoietic peptide, meaning it does not stimulate red blood cell production. Mechanistic 1

Limitations and the need for larger trials

While the phase 2 data provides objective evidence of nerve repair, the research has clear limitations. The published human trials involve small patient populations, ranging from 22 to 64 subjects. Human 3 4

The study durations are short. The longest continuous dosing period in the published neuropathy trials is 28 days, with observation extending to 56 days. Small fibre neuropathy is a chronic condition that develops over years. A 28 day intervention proves that the biological mechanism can be activated, but it does not answer how the treatment performs over the long term. Human 1

UK regulatory and WADA status

In the UK, medicines are regulated under the Human Medicines Regulations 2012. ⁵ The MHRA is the agency responsible for regulating medicines. ⁶ The EMA and FDA have previously granted orphan drug designation for ARA-290 in sarcoidosis and neuropathic pain due to sarcoidosis, respectively, but this designation is designed to support development research and is not a marketing authorisation. ⁷

For athletes, the World Anti-Doping Agency maintains strict rules on unapproved substances. ARA-290 is explicitly named on the WADA Prohibited List under section S2, though WADA also maintains an S0 category for non approved substances. This category prohibits any pharmacological substance in clinical development that lacks current approval by a governmental regulatory health authority. Therefore, ARA-290 is prohibited at all times in WADA tested sports. ⁸

The BioRx conclusion

For more information on how peptides are regulated, see What Are Peptides?. For details on how these molecules are manufactured, see How Peptides Are Actually Made.

Frequently asked questions

What is ARA-290?

ARA-290 is a synthetic peptide engineered from erythropoietin. It is designed to activate tissue repair pathways without stimulating red blood cell production.

How is ARA-290 different from erythropoietin?

Erythropoietin stimulates the production of red blood cells. ARA-290 was modified so that it only binds to the innate repair receptor, meaning it does not increase red blood cell counts.

What is small fibre neuropathy?

It is a condition where the small unmyelinated nerve fibres that control pain, temperature sensation and autonomic functions are damaged. This leads to chronic burning pain, tingling and numbness.

What do the human trials show?

Phase 2 trials in patients with sarcoidosis and type 2 diabetes have reported that ARA-290 improves neuropathic pain scores and increases the physical density of small nerve fibres measured in the cornea and skin.

Is ARA-290 an approved medicine?

No. ARA-290 is an investigational compound. It is not approved by the FDA or EMA for human therapeutic use, and it remains prohibited in sport under WADA rules.

More peptide questions

References

Studies marked "View study in BioRx" sit in the clinical studies index with their design and evidence grade.

1. Brines M et al. (2015). ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Molecular Medicine.PubMed · DOI · View study in BioRx
2. Dahan A et al. (2013). ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Molecular Medicine.PubMed · DOI · View study in BioRx
3. PubMed, PMID 23168581
4. Culver DA et al. (2017). Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain. Investigative Ophthalmology and Visual Science.PubMed · DOI · ClinicalTrials.gov · View study in BioRx
5. Legislation.gov.uk, The Human Medicines Regulations 2012
6. GOV.UK, Medicines and Healthcare products Regulatory Agency
7. EMA, EU/3/13/1191 Orphan designation for sarcoidosis
8. WADA, Prohibited List S0 Non-approved Substances