A Phase IIa Randomized Control Trial of VEL015 (Sodium Selenate) in Mild-Moderate Alzheimer’s Disease

Article type: Research Article

Authors: Malpas, Charles B.^{a; b} | Vivash, Lucy^a | Genc, Sila^{a; f} | Saling, Michael M.^{b; c; d} | Desmond, Patricia^{e; f} | Steward, Christopher^{e; f} | Hicks, Rodney J.^{e; l} | Callahan, Jason^l | Brodtmann, Amy^{d; g} | Collins, Steven^{m; n} | Macfarlane, Stephenⁱ | Corcoran, Niall M.^h | Hovens, Christopher M.^h | Velakoulis, Dennis^{j; k} | O’Brien, Terence J.^{a; m}

Affiliations: [a] Melbourne Brain Centre, The Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia | [b] Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia | [c] Department of Neuropsychology, Austin Health, Melbourne, VIC, Australia | [d] Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Hospital, Melbourne, VIC, Australia | [e] Department of Radiology, University of Melbourne, Melbourne, VIC, Australia | [f] Department of Radiology, Royal Melbourne Hospital, Melbourne, VIC, Australia | [g] Eastern Cognitive Disorders Clinic, Department of Neurology, Eastern Health, Monash University, Melbourne, VIC, Australia | [h] Department of Surgery, Royal Melbourne Hospital, Melbourne, VIC, Australia | [i] Caulfield Hospital, Alfred Health, Melbourne, VIC, Australia | [j] Melbourne Neuropsychiatry Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia | [k] Department of Psychiatry, Melbourne, VIC, Australia | [l] Centre for Molecular Imaging, Peter MacCallum Cancer Institute, Melbourne, VIC, Australia | [m] Department of Medicine, Royal Melbourne Hospital, Melbourne, VIC, Australia | [n] Department of Clinical Neurosciences and Neurological Research, St Vincent’s Hospital, Melbourne, Australia

Correspondence: [*] Correspondence to: Terence J. O’Brien, Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, 3010, Australia. E-mail: obrientj@unimelb.edu.au.

Abstract: Background: There is increasing interest in targeting hyperphosphorylated tau (h-tau) as a disease modifying approach for Alzheimer’s disease (AD). Sodium selenate directly stimulates the activity of PP2A, the main enzyme responsible for h-tau dephosphorylation in the brain. Objective: This study assessed the safety and tolerability of 24-week treatment with VEL015 (sodium selenate) in AD. Investigating the effects of VEL015 on cognitive, CSF, and neuroimaging biomarkers of AD were secondary, exploratory objectives. Data were used to identify biomarkers showing most promise for use in subsequent efficacy trials. Methods: A 24-week, multicenter, Phase IIa, double-blinded randomized controlled trial. Forty patients aged ≥55 y with mild-moderate AD (MMSE 14–26) were randomized to supranutritional (VEL015 10 mg tds [n = 20]) and control (VEL015 320μg tds [n = 10] or placebo [n = 10]) groups. Patients were regularly monitored for safety, adverse events (AEs), and protocol compliance. Exploratory biomarkers included cognitive tests, neuroimaging (diffusion MR), and CSF (p-tau, t-tau, and Aβ1-42). Results: Thirty-six (90%; [supranutritional n = 18, control/placebo n = 18]) patients completed the trial. There were no differences in the incidence of specific AEs between groups. Only one secondary biomarker, diffusion MR measures, showed group differences, with less deterioration in the supranutritional group (p < 0.05). Conclusion: Treatment with VEL015 at doses up to 30 mg per day for 24 weeks was safe and well-tolerated in patients with AD. Diffusion MR measures appear to be the most sensitive biomarkers to assess disease progression over 24 weeks.

Keywords: Alzheimer’s disease, clinical trial, dementia, sodium selenate

DOI: 10.3233/JAD-160544

Journal: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 223-232, 2016