Human diabetic neuropathy is the commonest long-term complication of diabetes and leads to pain, impotence, foot ulceration and amputation. Currently there are no FDA approved therapies for human diabetic neuropathy. ARA 290 is a novel non-hematopoietic peptide designed from the structure of erythropoietin to preferentially interact with the innate repair receptor that mediates tissue protection and repair. It has shown efficacy in preclinical animal models of neuropathy and in patients with small fiber neuropathy due to sarcoidosis and was granted FDA designation as an orphan drug product for the treatment of neuropathic pain in sarcoidosis. To evaluate the efficacy and safety of ARA 290 in patients with painful diabetic neuropathy, subjects were enrolled in this phase 2 study (EUCTR2012-005590-32-NL). ARA 290 (4 mg) (n=24) or placebo (n=24), were self-administered subcutaneously daily for 28 days and the subjects followed for an additional month without further treatment. No potential safety issues were identified. Patients receiving ARA 290 exhibited an improvement in HbA1c (P<0.002) and cholesterol/HDL ratio (P=0.04), HDL (P=0.06) and triglycerides (P=0.04). In the ARA 290 group neuropathic symptoms as assessed by the PainDetect questionnaire improved significantly (P=0.037) in particular for "tingling" (P=0.01), "thermal pain" (P=0.04), and “allodynia” (P=0.04). There was no change in thermal or vibration perception thresholds in the ARA290 group. Corneal nerve fiber density was significantly reduced (24.4 ± 1.1 v 37.2 ± 0.9 fibers/mm2; p < 0.001) in diabetic patients at baseline and in those with a mean CNFD > 1 standard deviation from normal there was a mean increase (+2.6 ± 1.0 fibers/mm2 for ARA 290 (n=18; p=0.02; paired t test) versus +0.7 ± 1.3 fibers/mm2 for placebo (n=19; p = ns). The improvement in PainDetect correlated significantly with the increase in CNFD in the ARA 290 (r2 = 0.48, P=0.004) but not the placebo group. These observations suggest that ARA 290 may benefit glycemic and lipid control and also has an impact on neuropathic symptoms and small fiber repair which can be detected using our pioneering technique of CCM in diabetic patients with painful neuropathy. These data warrant further larger clinical trials of ARA 290 in diabetic neuropathy.


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