Charles B Malpas1,2, Lucy Vivash1, Sila Genc1,3, Michael M Saling2,4,5, Patricia Desmond6,3, Christopher Steward6,3, Rodney J Hicks6,7, Jason Callahan7, Amy Brodtmann5,8, Steven Collins9,10, Stephen Macfarlane11, Niall M Corcoran12, Christopher M Hovens12, Dennis Velakoulis13,14, Terence J O'Brien1,9. 1. Melbourne Brain Centre, The Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia. 2. Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia. 3. Department of Radiology, Royal Melbourne Hospital, Melbourne, VIC, Australia. 4. Department of Neuropsychology, Austin Health, Melbourne, VIC, Australia. 5. Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Hospital, Melbourne, VIC, Australia. 6. Department of Radiology, University of Melbourne, Melbourne, VIC, Australia. 7. Centre for Molecular Imaging, Peter MacCallum Cancer Institute, Melbourne, VIC, Australia. 8. Eastern Cognitive Disorders Clinic, Department of Neurology, Eastern Health, Monash University, Melbourne, VIC, Australia. 9. Department of Medicine, Royal Melbourne Hospital, Melbourne, VIC, Australia. 10. Department of Clinical Neurosciences and Neurological Research, St Vincent's Hospital, Melbourne, Australia. 11. Caulfield Hospital, Alfred Health, Melbourne, VIC, Australia. 12. Department of Surgery, Royal Melbourne Hospital, Melbourne, VIC, Australia. 13. Melbourne Neuropsychiatry Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia. 14. Department of Psychiatry, Melbourne, VIC, Australia.
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.
RCT Entities:
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.
Authors: Barbara R Cardoso; Blaine R Roberts; Charles B Malpas; Lucy Vivash; Sila Genc; Michael M Saling; Patricia Desmond; Christopher Steward; Rodney J Hicks; Jason Callahan; Amy Brodtmann; Steven Collins; Stephen Macfarlane; Niall M Corcoran; Christopher M Hovens; Dennis Velakoulis; Terence J O'Brien; Dominic J Hare; Ashley I Bush Journal: Neurotherapeutics Date: 2019-01 Impact factor: 7.620
Authors: Ann Van der Jeugd; Arnaldo Parra-Damas; Raquel Baeta-Corral; Carlos M Soto-Faguás; Tariq Ahmed; Frank M LaFerla; Lydia Giménez-Llort; Rudi D'Hooge; Carlos A Saura Journal: Sci Rep Date: 2018-04-24 Impact factor: 4.379
Authors: Lucy Vivash; Charles B Malpas; Leonid Churilov; Mark Walterfang; Amy Brodtmann; Olivier Piguet; Rebekah M Ahmed; Ashley I Bush; Christopher M Hovens; T Kalincik; David Darby; Dennis Velakoulis; Terence J O'Brien Journal: BMJ Open Date: 2020-11-16 Impact factor: 2.692