Key papers ✓ 5~ 3

• ~ Mixed human RCTInvest Ophthalmol Vis Sci · 2017

  Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain.

  Humans64 peopleRandomizedPlacebo-controlled28 days

  Phase 2b randomized trial, cibinetide 1, 4 or 8 mg/day vs placebo

  Phase 2b trial in 64 sarcoidosis patients with small-fiber nerve loss: 28 days of cibinetide increased corneal nerve fiber area at 4 mg/day (significant) but not at 1 or 8 mg; pain improved in all groups including placebo.

  Key resultPlacebo-corrected CNFA change 109 (1 mg), 697 (4 mg; 95% CI 159 to 1236; P=0.012) and 431 (8 mg) um2; GAP-43+ fibers increased in the 4 mg group (P=0.035)

  Study details

  Studied

  Patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain

  Compared with

  Placebo

  Main outcome

  Change in corneal nerve fiber area (CNFA) at day 28

  Sample

  64 subjects randomized

  Authors' conclusion

  Cibinetide significantly increased small nerve fiber abundance in cornea and skin, consistent with a disease-modifying effect; CNFA supports use as a surrogate endpoint.

  Limitations

  Pain improved significantly in all groups; only the 4 mg dose reached significance for CNFA.

  DOI 10.1167/iovs.16-21291PubMed 28475703
• ✓ Positive human RCTMol Med · 2012

  Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study.

  Humans22 peopleRandomizedPlacebo-controlledDouble-blind4 weeks (2 mg IV three times weekly)

  Double-blind, placebo-controlled exploratory pilot trial

  Double-blind pilot in 22 sarcoidosis patients with small-fiber neuropathy: 4 weeks of IV ARA 290 improved neuropathy symptom scores vs placebo; pain and fatigue scores improved equally in both groups; no safety concerns.

  Key resultSFNSL change at week 4: -11.5 +/- 3.04 with ARA 290 vs -2.9 +/- 3.34 with placebo (p < 0.05); BPI and FAS improved significantly but equivalently in both groups

  Study details

  Studied

  Patients with sarcoidosis and symptoms of small fiber neuropathy (spontaneous pain score >=5)

  Compared with

  Placebo

  Main outcome

  Small fiber neuropathy screening list (SFNSL) score, pain intensity, SF-36, fatigue

  Sample

  22 patients (ARA 290 n=12, placebo n=10)

  Authors' conclusion

  ARA 290 appears to be safe in patients with sarcoidosis and can reduce neuropathic symptoms.

  Limitations

  Small exploratory pilot.

  DOI 10.2119/molmed.2012.00332PubMed 23168581Free full text
• ✓ Positive human RCTMol Med · 2015

  ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes.

  Humanssize not reportedRandomizedPlacebo-controlled28 days of treatment plus one month follow-up

  Phase 2 placebo-controlled study, ARA 290 4 mg self-administered subcutaneously daily

  Phase 2 placebo-controlled study in type 2 diabetes with painful neuropathy: 28 days of ARA 290 improved HbA1c, lipids and neuropathic symptom scores; no safety issues identified.

  Key resultImproved HbA1c and lipid profiles throughout the 56-day observation period and significantly improved PainDetect scores in the ARA 290 group; no numeric values in abstract

  Study details

  Studied

  Subjects with type 2 diabetes and painful neuropathy

  Compared with

  Placebo

  Main outcome

  HbA1c, lipid profiles, PainDetect neuropathic symptoms, corneal nerve fiber density

  Sample

  Number of subjects not stated in abstract

  Authors' conclusion

  ARA 290 may benefit both metabolic control and neuropathy in type 2 diabetes and deserves continued clinical evaluation.

  Limitations

  Sample size not stated in abstract.

  DOI 10.2119/molmed.2014.00215PubMed 25387363Free full text
• ~ Mixed human RCTEur Neuropsychopharmacol · 2015

  Testing the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action.

  Humans36 peopleRandomizedPlacebo-controlledDouble-blindAssessed one week after administration

  Double-blind, randomized, parallel-group, single 2 mg dose

  In 36 healthy volunteers, a single 2 mg dose altered some measures of emotional processing but had no effect on mood, and results did not clearly support an antidepressant effect.

  Key resultARA290 lowered neural responses to happy faces in the fusiform gyrus; no effects on mood or affective symptoms

  Study details

  Studied

  Healthy volunteers

  Compared with

  Placebo

  Main outcome

  Neural processing of fearful vs happy faces and recognition of emotional facial expressions

  Sample

  36 healthy participants

  Authors' conclusion

  ARA290 may modulate some aspects of emotional processing, but the direction and strength of effects do not unequivocally support an antidepressant-like profile.

  Limitations

  Healthy volunteers, single dose; authors suggest testing different timing and dose.

  DOI 10.1016/j.euroneuro.2015.09.005PubMed 26431906
• ✓ Positive reviewExpert Opin Investig Drugs · 2014

  ARA 290 for treatment of small fiber neuropathy in sarcoidosis.

  No new dataReview of two phase II trials

  Narrative review of two Phase II clinical trials

  Review of two phase II sarcoidosis trials (by trial investigators): ARA 290 was associated with reduced neuropathic pain, more corneal nerve fibers and better quality of life, with an excellent safety profile.

  Study details

  Studied

  Sarcoidosis patients with small fiber neuropathy (from two phase II trials)

  Authors' conclusion

  ARA 290 was consistently associated with improved neuropathic pain symptoms, more corneal nerve fibers and better quality of life with an excellent safety profile; the authors call prospects promising.

  Limitations

  Narrative review of two phase II trials, written by the trial investigators.

  DOI 10.1517/13543784.2014.892072PubMed 24555851
• ✓ Positive animalFront Cardiovasc Med · 2022

  A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan.

  Animalssize not reportedRandomized15 months

  Randomized controlled trial, chronic ARA290 vs saline

  In aging rats treated for 15 months, ARA290 reduced cardiac inflammation, preserved heart function and blood pressure, and reduced frailty measures vs saline.

  Study details

  Studied

  18-month-old Fischer 344 x Brown Norway rats

  Compared with

  Saline

  Main outcome

  Cardiac inflammation, echocardiography, blood pressure, frailty index

  Sample

  Longitudinal n=48 and cross-sectional n=144 rats

  Authors' conclusion

  ARA290 reduced cell and tissue inflammation, mitigated cardiovascular structural and functional changes, reduced frailty and preserved healthspan.

  Limitations

  Rat study.

  DOI 10.3389/fcvm.2022.1096887PubMed 36741836Free full text
  FIGURE 1
• ~ Mixed animalNeuroscience · 2013

  The erythropoietin-derived peptide ARA290 reverses mechanical allodynia in the neuritis model.

  Animalssize not reportedSham/vehicle control

  Daily intraperitoneal ARA290 (30 or 120 ug/kg) vs saline vehicle from day 1 after surgery

  In a rat nerve-inflammation pain model, daily ARA290 prevented touch-evoked pain (allodynia) but did not affect heat sensitivity.

  Key resultBoth doses prevented development of mechanical allodynia; no significant effect on heat hyperalgesia; CCL2 and TNF-alpha mRNA not significantly different (p=0.24)

  Study details

  Studied

  Rats with neuritis model

  Compared with

  Saline vehicle

  Main outcome

  Mechanical allodynia, heat hyperalgesia, TNF-alpha and CCL2 mRNA

  Sample

  Groups: vehicle n=20, 30 ug/kg n=11, 120 ug/kg n=9

  Authors' conclusion

  ARA290 may be beneficial for neuropathic pain symptoms where signs of nerve injury are absent; mechanism does not appear to involve inhibiting TNF-alpha or CCL2.

  Limitations

  Rat study; small group sizes for mRNA analysis (n=3-7).

  DOI 10.1016/j.neuroscience.2012.12.022PubMed 23262243
• ✓ Positive animalJ Transl Med · 2013

  Renoprotective capacities of non-erythropoietic EPO derivative, ARA290, following renal ischemia/reperfusion injury.

  AnimalsTwenty-six male Lewis/HanHsd ratsSham/vehicle control3 days

  ARA290 given early (1 h), late (4 h) or repetitively (1 and 4 h) post-reperfusion vs saline

  In rats with kidney ischemia-reperfusion injury, ARA290 given 1 hour after reperfusion improved kidney function and reduced inflammation; later dosing was less effective.

  Study details

  Studied

  Male Lewis rats with unilateral renal ischemia (30 min) plus contralateral nephrectomy

  Compared with

  Saline vehicle

  Main outcome

  Renal function and renal inflammation / acute kidney injury

  Authors' conclusion

  ARA290 attenuated renal ischemia/reperfusion injury; early post-reperfusion administration appears most effective.

  Limitations

  Rat study; late or repetitive dosing only tended to improve markers.

  DOI 10.1186/1479-5876-11-286PubMed 24225194Free full text
  Figure 1 Figure 2

Reported side effects

Small trials of up to 4 weeks reported no safety concerns; long-term human safety data are lacking.

4 registered human trials (0 active)

✓ positive · ✗ negative · ~ mixed · ? inconclusive, judged on each paper's own main outcome. Grades: A strong human evidence → D little or none. Papers and verdicts are drawn from PubMed, Europe PMC and Russian journals (CyberLeninka); not medical advice.