ARA-290

Mechanism (as reported)

Across the provided sources, ARA 290 has been associated with modulation of innate immune responses (e.g., macrophage activation/inflammatory cytokine effects) and suppression of central microglia responses, and in preclinical experiments has been shown to inhibit TRPV1 channel activity. (PMIDs: 34343617, 24529189, 26774587, 26683514)

Key findings (each cites a source)

• A study reported that early systemic administration of ARA 290 in an early-onset AD-like mouse model (APP/PS1) decelerated amyloid-β (Aβ) pathology progression and improved cognitive functions. [PMID 34343617]
• In that same preclinical study, ARA 290 was reported to increase total monocytes by stimulating generation of the Ly6C low patrolling subset, which were described as implicated in clearing Aβ from cerebral vasculature, with subsequent reduction in brain Aβ burden. [PMID 34343617]
• In the preclinical study, depletion of the Ly6C low patrolling subset in chimeric APP/PS1 mice was reported to make ARA 290 inefficient at attenuating Aβ pathology and improving cognitive functions in young animals. [PMID 34343617]
• The preclinical study reported that ARA 290 effects were compromised in a late-onset/aged APP1/PS1 model, where ARA 290 failed to reverse Aβ pathology and failed to increase circulating monocytes. [PMID 34343617]
• A phase 2 study in patients with type 2 diabetes and painful neuropathy reported that ARA 290 was self-administered subcutaneously daily for 28 days (with follow-up without further treatment) and that no potential safety issues were identified. [PMID 25387363]
• In that phase 2 study, ARA 290 was reported to improve hemoglobin A1c (HbA1c) and lipid profiles over the 56-day observation period. [PMID 25387363]
• In that phase 2 study, ARA 290 was reported to significantly improve neuropathic symptoms assessed by the PainDetect questionnaire. [PMID 25387363]
• In that phase 2 study, mean corneal nerve fiber density (CNFD) was reported to be reduced significantly compared with normal controls, and subjects with mean CNFD >1 standard deviation from normal were reported to show a significant increase in CNFD compared with no change in placebo. [PMID 25387363]
• An editorial noted that ARA 290 is being discussed in the context of two Phase II clinical trials and was described as an erythropoietin derivative with tissue protective/healing properties that does not stimulate erythropoiesis; it was also summarized as being consistently associated with significant improvement of neuropathic pain symptoms in sarcoidosis patients, along with reported increases in corneal nerve fibers and improvements in sensory pain thresholds and quality of life/physical functioning. [PMID 24555851]
• A preclinical rat study reported that ARA 290 produced a dose-response reduction of mechanical allodynia (up to 20 weeks) and cold allodynia (for multiple doses, up to 20 weeks) compared with vehicle, following a spared nerve injury model. [PMID 24529189]
• In the same preclinical study, animals treated with certain ARA 290 doses were reported not to show an increase in spinal microglia reactivity (iba-1 immunoreactivity) at 2 weeks, and at 20 weeks the study reported that a dose associated with reduced allodynia did not show increased microglia reactivity. [PMID 24529189]
• In the same preclinical study, astrocyte reaction (GFAP immunoreactivity) was reported as not different across conditions examined. [PMID 24529189]