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Message: AD/PD 2019 March 26-31, 2019
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14th International Conference on Alzheimer's and Parkinson's Diseases (AD/PD 2019): March 26-31, 2019; Lisbon, Portugal
March 27th, 2019: THE EPIGENETIC INHIBITOR APABETALONE DOWNREGULATES BRAIN ENDOTHELIAL AND MICROGLIAL CELL ACTIVATION THAT CONTRIBUTES TO NEURODEGENERATIVE DISEASE
E. Kulikowski1, E. Daze1, S. Wasiak1, D. Gilham1, L. Tsujikawa M.1, B. Rakai1, S. Stotz C.1, H. Christopher2, R. Jahagirdar1, N. Wong C.W.1, M. Sweeney3, J. Johansson O.3.
1Resverlogix Corp., Scientific Development, Calgary, Canada.
2Resverlogix Corp., Business Development, Calgary, Canada.
3Resverlogix Inc., Scientific Development, San Francisco, USA.
Abstract body
Objectives: Vascular endothelial cells transmit inflammatory responses from the periphery to the central nervous system, where activated microglia propagate inflammation, leading to neuronal injury. Here we evaluate anti-inflammatory characteristics of apabetalone, a small molecule inhibitor of epigenetic transcriptional modulators bromodomain and extraterminal domain (BET) proteins, in pre-clinical models of neuroinflammation.
Methods: Human brain microvascular endothelial cells (HBMVECs) were stimulated with TNFalpha, IFNgamma (IFNg) +/- apabetalone and assayed for gene expression, surface protein levels, and THP-1 monocyte adhesion under flow. BV-2 microglia responses to lipopolysaccharide (LPS), IFNg +/- apabetalone were examined. C57BL/6 mice treated with 150mg/kg apabetalone for 7 days received 10mg LPS intraperitoneally, followed by brain mRNA analysis on day 8.
Results: In cytokine stimulated HBMVECs, apabetalone dose dependently reduced the induction of vascular activation marker mRNAs including IL-6, IL-1beta, MCP-1, VCAM and E-selectin. Surface expression of VCAM and E-selectin was also reduced, leading to decreased adhesion of HBMVECs with THP-1 monocytes. In BV-2 microglial cells, apabetalone opposed LPS and IFNg mediated induction of IL -6, IL-1beta, MCP-1, complement C3 and C1q. Peripheral LPS injection in mice provokes inflammatory responses in the brain, where apabetalone attenuated the LPS-induced mRNA expression of endothelial, monocyte and macrophage adhesion molecules E-selectin, ICAM, CCR2, and CD68.
Conclusions: Apabetalone mediated BET inhibition counters the expression of cytokines and endothelial adhesion molecules associated with neuroinflammation and cognitive impairment. Apabetalone’s effect on cognition is being evaluated by repeat MoCAs in diabetic patients ≥70 years old in the phase 3 BETonMACE trial (completion in 2019).
March 30th, 2019: APABETALONE (AN EPIGENETIC BET-INHIBITOR SMALL MOLECULE): A SUB-STUDY EVALUATING EFFECTS ON COGNITION IN DIABETES PATIENTS WITH CARDIOVASCULAR DISEASE
J. Cummings1, J. Johansson2, M. Sweeney2, E. Kulikowski3, N. Wong3, C. Halliday3, K. Lebioda3, B. Winblad4, H. Zetterberg5, K. Kalantar-Zadeh6, S. Nicholls7, G. Schwartz8, K. Ray9.
1Cleveland Clinic Lou Ruvo, Center for Brain Health, Las Vegas, USA.
2Resverlogix Inc., Research and Development, San Francisco, USA.
3Resverlogix Corp., Research and Development, Calgary, Canada.
4Karolinska Institute, Swedish Brain Power, Stockholm, Sweden.
5University of Gothenburg, Department of Psychiatry and Neurochemistry at Institute of Neuroscience and Physiology, Gothenburg, Sweden.
6University of California- Irvine, School of Medicine- Division of Nephrology & Hypertension, Irvine, USA.
7University of Adelaide, South Australian Health & Medical Research, Adelaide, Australia.
8University of Colorado, School of Medicine, Denver, USA.
9Imperial College London, Department of Primary Care and Public Health, London, United Kingdom.
Abstract body
Objectives: Type 2 diabetes (T2D) and cardiovascular disease (CVD) associate with cognitive impairment. Epigenetic dysregulation by bromodomain and extraterminal domain (BET) proteins is implicated in CVD, T2D, and dementia. Apabetalone is a selective BET inhibitor. Effects of apabetalone on cognition are unknown.
Methods: The ongoing phase 3 trial BETonMACE compares apabetalone (100 mg orally twice daily) with placebo in 2,425 patients with recent acute coronary syndrome (ACS), T2D, and low HDL cholesterol, at 195 sites in 13 countries. The primary outcome is time-to-first-occurrence of CV-death, myocardial infarction, or stroke. Cognition, a pre-specified exploratory outcome, is assessed at baseline and annually in patients 70 years and older by the Montreal Cognition Assessment (MoCA). A score of ≤25 indicates cognitive impairment.
Results: Baseline MoCA (versions 7.1, 7.2, and 7.3 depending on language) was performed in 19% of BETonMACE participants (n=466, mean age 74). At baseline 53% show a MoCA score ≤25, indicating cognitive impairment. Demographics and basic serum chemistry in the MoCA score ≤25 population does not differ significantly from the whole MoCA population.
MoCA score change from historical data shows a standard deviation of 3.2 points predicting a necessary sample size of 54 subjects per arm to provide a 90% power to detect a mean between-group difference of 2 points at p<0.05.
Conclusions: Cognitive impairment is common among elderly patients with T2D and ACS. BETonMACE will determine whether the first-in-class BET-inhibitor apabetalone affects the time course of cognitive function in these patients, as well as macrovascular CV events.
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