Erythropoietin in Spinocerebellar Ataxia Type 2: Feasibility and Proof‐of‐Principle Issues from a Randomized Controlled Study

Abstract

Background Several pieces of evidence have shown the neurotrophic effect of erythropoietin (EPO) and its introduction in the therapeutic practice of neurological diseases. However, its usefulness in the treatment of spinocerebellar ataxia type 2 (SCA2) has not been proven despite the fact that it is endogenously reduced in these patients. Objective The study aims to investigate the safety, tolerability, and clinical effects of a nasally administered recombinant EPO in SCA2 patients. Methods Thirty‐four patients were enrolled in this double‐blind, randomized, placebo‐controlled, phase I–II clinical trial of the nasally administered human‐recombinant EPO (NeuroEPO) for 6 months. The primary outcome was the change in the spinocerebellar ataxia functional index (SCAFI), while other motor, neuropsychological, and oculomotor measures were assessed. Results The 6‐month changes in SCAFI score were slightly higher in the patients allocated to NeuroEPO treatment than placebo in spite of the important placebo effect observed for this parameter. However, saccade latency was significantly decreased in the NeuroEPO group but not in placebo. The frequency and severity of adverse events were similar between both groups, without evidences of hematopoietic activity of the drug. Conclusions This study demonstrated the safety and tolerability of NeuroEPO in SCA2 patients after 6 months of treatments and suggested a small clinical effect of this drug on motor and cognitive abnormalities, but confirmatory studies are warranted. © 2022 International Parkinson and Movement Disorder Society.

Evidence of the neuroprotective potential of NeuroEPO in preclinical studies and clinical trials: A systematic review

“…To organize the information obtained from the articles and their relevance, tables were prepared in which preclinical studies (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) (Table 1) and clinical trials (24)(25)(26)(27)(28)(29)(30) (Table 2) were grouped.…”

“…Their results show that IN administration did not produce local structural damage (15,22,23) or outside the nasal cavity (15), nor hematological alterations (15,24,29) or serious adverse events, and was well tolerated by patients (24,26,29) . After IN administration, it reached the brain (11,12) and exerted neuroprotective effects in biomodels of cerebral ischemia (11,13,14,16,17) and Alzheimer's disease (18, 1 9) , as well as in patients with Parkinson's disease (25,26,27,29) , spinocerebellar ataxia type 2 (29) or Alzheimer's disease (30) . Neuroprotective effects were manifested by decreased neuronal mortality and damaged tissue (11,(13)(14)(15)(16)(17)(18)(19)(20)(21) , as well as improved functional integrity (11,13,14,(16)(17)(18)(19) .…”

NeuroEPO plus (NeuralCIM®) in mild-to-moderate Alzheimer’s clinical syndrome: the ATHENEA randomized clinical trial

“…Direct evidence of neuroEPO plus in the CNS has been demonstrated in Mongolian gerbils using radiolabeled neuroEPO plus [ 25 , 26 ]. Indirect evidence of neuroEPO plus in the cerebral spinal fluid (CSF) is supported by studies measuring total EPO in the CSF of non-human primates [ 26 ] and in patients with Spinocerebellar ataxia type 2 (SCA2) [ 27 ]. These studies suggest that neuroEPO plus is reaching the intended target when delivered intranasally.…”

“…NeuroEPO plus has been safely evaluated in healthy volunteers [ 28 ], patients with SCA2 [ 27 ] and patients with Parkinson disease [ 29 ]. We conducted a phase 2–3 trial (ATHENEA), to assess the safety and efficacy of neuroEPO plus in participants with mild-to-moderate Alzheimer’s clinical syndrome.…”

Effect of intranasal administration of neuroEPO in the histological structure of the olfactory mucosa of rats Wistar

“…Preclinical studies have demonstrated the effects of NeuroEPO on CNS protection in models of Alzheimer's, stroke, and glutamate-induced excitotoxicity (6)(7)(8)(9). In clinical studies, intranasal administration has shown to be safe and well tolerated in healthy volunteers and shows favorable effects with clinical improvement in patients with Parkinson's disease, Alzheimer's, and spinocerebellar ataxia type 2 (10)(11)(12)(13)(14). In addition, NeuroEPO has beneficial effects on glycemia and reproduction in diabetic rats.…”