Abstract: SA-PO782
Apabetalone Downregulates Alkaline Phosphatase and Improves Cardiovascular Risk
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Gilham, Dean, Resverlogix, Calgary, Alberta, Canada
- Tsujikawa, Laura, Resverlogix, Calgary, Alberta, Canada
- Wasiak, Sylwia, Resverlogix, Calgary, Alberta, Canada
- Halliday, Christopher, Resverlogix, Calgary, Alberta, Canada
- Fu, Li, Resverlogix, Calgary, Alberta, Canada
- Sarsons, Chris, Resverlogix, Calgary, Alberta, Canada
- Ho, Phoebe S., Resverlogix, Calgary, Alberta, Canada
- Stotz, Stephanie, Resverlogix, Calgary, Alberta, Canada
- Rakai, Brooke D., Resverlogix, Calgary, Alberta, Canada
- Lebioda, Kenneth E., Resverlogix, Calgary, Alberta, Canada
- Jahagirdar, Ravi, Resverlogix, Calgary, Alberta, Canada
- Sweeney, Michael, Resverlogix, San Francisco, California, United States
- Johansson, Jan O., Resverlogix, Calgary, Alberta, Canada
- Wong, Norman Cw, Resverlogix, Calgary, Alberta, Canada
- Kalantar-Zadeh, Kamyar, University of California Irvine, School of Medicine, Orange, California, United States
- Haarhaus, Mathias, Karolinska University Hospital, Stockholm, Sweden
- Kulikowski, Ewelina, Resverlogix, Calgary, Alberta, Canada
Background
Apabetalone is an inhibitor of BET proteins - epigenetic readers modulating gene expression. In phase 2 trials, apabetalone reduced major adverse cardiac events (MACE) in patients with cardiovascular disease (CVD) & improved eGFR in those with chronic kidney disease (CKD). Elevated serum alkaline phosphatase (ALP) is a risk factor for MACE, as it contributes to vascular calcification & endothelial dysfunction. We examined apabetalone-mediated effects on ALP in CVD patients post-hoc & determined apabetalone’s impact on tissue non-specific ALP (TNAP) expression in cell culture systems.
Methods
Circulating ALP was measured in CVD patients receiving apabetalone in the 3-month (ASSERT) and 6-month (SUSTAIN & ASSURE) trials. Apabetalone’s effect on expression of TNAP (gene symbol ALPL) was determined in cultured primary human hepatocytes (PHH), HepaRG, HepG2, calcifying vascular smooth muscle cells (VSMCs) & vascular endothelial cells. Protein abundance & ALP enzyme activity were also measured.
Results
In phase 2 trials, baseline serum ALP correlated with MACE (R2=0.87). In ASSERT, apabetalone dose dependently reduced serum ALP (p<0.001 vs placebo). In ASSURE & SUSTAIN, patients on apabetalone (n=331) had greater reduction in serum ALP than placebo (n=166; median % change -3.2 vs -11; p<0.001), including those with CKD, i.e. eGFR<60 (apabetalone n=35 placebo n=13 median % change -6.3 vs -14; p<0.02). In vitro, apabetalone suppressed ALPL expression in PHH, HepaRG & HepG2 cells by 60-80%. Trans-differentiation of VSMCs to calcifying cells resulted in 2.5-fold increase in ALPL gene expression. Apabetalone countered calcium deposition & suppressed ALPL/TNAP gene expression, protein levels & enzyme activity. Apabetalone also downregulated ALPL in aortic endothelial cells, umbilical vein endothelial cells & brain microvascular endothelial cells 50-70%.
Conclusion
In phase 2 trials, apabetalone lowered serum ALP. Mechanistically, apabetalone downregulates ALPL/TNAP expression in multiple cell types, which may contribute to reductions in MACE observed in patients. The impact of apabetalone on biomarkers, renal function & CVD outcomes is being evaluated in the phase 3 BETonMACE trial.
Funding
- Commercial Support –