Abstract: PO0648
Apabetalone, an Inhibitor of BET Proteins, Downregulates Alkaline Phosphatase and Improves Cardiovascular Risk
Session Information
- CKD Mechanisms - 2
October 22, 2020 | Location: On-Demand
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
- Fu, Li, Resverlogix, Calgary, Alberta, Canada
- Wasiak, Sylwia, Resverlogix, Calgary, Alberta, Canada
- Halliday, Christopher, 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, San Francisco, California, United States
- Wong, Norman Cw, Resverlogix, Calgary, Alberta, Canada
- Kalantar-Zadeh, Kamyar, University of California Irvine, Irvine, California, United States
- Haarhaus, Mathias, Karolinska University Hospital, Stockholm, Sweden
- Kulikowski, Ewelina, Resverlogix, Calgary, Alberta, Canada
Background
Elevated serum alkaline phosphatase (ALP) predicts major adverse cardiac events (MACE). ALP is associated with vascular calcification (VC), inflammation & endothelial dysfunction in patients with cardiovascular disease (CVD) &/or chronic kidney disease (CKD). Apabetalone is an inhibitor of BET proteins - epigenetic readers modulating gene expression in pathological VC & inflammation. We studied apabetalone’s impact on tissue non-specific ALP (TNALP) expression in cell culture, then analyzed serum ALP in phase 2 trials.
Methods
Expression of TNALP (gene symbol ALPL) was measured in primary hepatocytes, HepaRG, HepG2, primary mesangial cells (MC), vascular smooth muscle cells (VSMC) & vascular endothelial cells by q-PCR. TNALP was assessed by immunoblot & flow cytometry, ALP activity by enzymatic assays. Serum ALP was measured in CVD patients in phase 2 trials (ASSERT, SUSTAIN & ASSURE). Subpopulations had CKD (eGFR<60).
Results
Apabetalone downregulated ALPL expression in liver cells by 60-80%. HepG2s had lower TNALP protein >55%, enzyme activity >40% & TNALP positive cells 15-30%; renal MCs had >90% decreases in ALPL expression & TNALP enzyme activity (p<0.001). ALPL was suppressed 50-70% in 3 vascular endothelial cell types with apabetalone. In VSMCs, apabetalone lowered ALPL expression, TNALP protein, enzyme activity & extracellular calcium deposition.
In ASSERT, apabetalone dose dependently reduced serum ALP (p<0.001). In combined phase 2 analysis, apabetalone lowered ALP (p<0.001), including patients in the CKD subgroup (p=0.008). Notably, the apabetalone-mediated decreases in serum ALP in phase 2 correlated with reduced MACE at 12-14 weeks (HR 0.64 per 1-SD in ALP, 95% CI 0.46–0.90 p=0.009 1-SD=13U/L); similar associations were observed at 24–26 weeks (HR 0.66 per 1-SD ALP 95% CI 0.43–0.99 p=0.045; 1-SD=14U/L).
Conclusion
Apabetalone lowers serum ALP, consistent with reduced hepatic, renal & vascular TNALP production. Modulation of ALP by apabetalone may affect pathogenetic processes to lower cardiovascular risk. This study provides insight to MACE reductions in phase 2 clinical trials.
Funding
- Commercial Support –