Kidney Week

Abstract: FR-PO132

Apabetalone Downregulates Factors and Pathways Associated with Vascular Calcification

Session Information

• Molecular Mechanisms of CKD - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Gilham, Dean, Resverlogix Corp., Calgary, Alberta, Canada

Dean Gilham,

• Wasiak, Sylwia, Resverlogix Corp., Calgary, Alberta, Canada

Sylwia Wasiak,

• Tsujikawa, Laura, Resverlogix Corp., Calgary, Alberta, Canada

Laura Tsujikawa,

• Sarsons, Christopher D., Resverlogix Corp., Calgary, Alberta, Canada

Christopher D. Sarsons,

• Halliday, Christopher, Resverlogix Corp., Calgary, Alberta, Canada

Christopher Halliday,

• Stotz, Stephanie, Resverlogix Corp., Calgary, Alberta, Canada

Stephanie Stotz,

• Lebioda, Kenneth E., Resverlogix Corp., Calgary, Alberta, Canada

Kenneth E. Lebioda,

• Jahagirdar, Ravi, Resverlogix Corp., Calgary, Alberta, Canada

Ravi Jahagirdar,

• Sweeney, Michael, Resverlogix Inc., San Francisco, California, United States

Michael Sweeney,

• Johansson, Jan O., Resverlogix Inc., San Francisco, California, United States

Jan O. Johansson,

• Wong, Norman Cw, Resverlogix Corp., Calgary, Alberta, Canada

Norman Cw Wong,

• Robson, Richard Austin, CHristchurch Clinical Studies Trust, Christchurch, New Zealand

Richard Austin Robson,

• Kalantar-Zadeh, Kamyar, University of California Irvine, School of Medicine, Orange, California, United States

Kamyar Kalantar-Zadeh,

• Kulikowski, Ewelina, Resverlogix Corp., Calgary, Alberta, Canada

Ewelina Kulikowski,

Background

Apabetalone, an oral small molecule BET inhibitor, reduced the incidence of major adverse cardiac events (MACE) in patients with CVD and improved eGFR in a subgroup with CKD in phase 2 trials. Because vascular calcification (VC) is associated with MACE, effects of apabetalone on processes associated with VC were examined.

Methods

Plasma proteomics was conducted in CVD patients receiving apabetalone in the 3 month (ASSERT) and 6 month (SUSTAIN & ASSURE) phase 2 trials, as well as patients with stage 4/5 CKD that received a single 100mg dose. Coronary artery VSMCs were used to examine effects of apabetalone on transdifferentiation & calcium deposition.

Results

Apabetalone significantly reduced circulating levels of VC markers in CVD patients in phase 2 trials, including alkaline phosphatase, osteopontin and osteoprotegerin. Plasma proteomics of CKD patients (n=8) indicated activation of molecular pathways driving VC including IL-6 signaling, BMP-2 signaling & RANK signaling in osteoclasts. Downregulation of these pathways by apabetalone was predicted in the CKD cohort 12hrs post-dose.

In VSMCs cultured in osteogenic conditions, apabetalone opposed induction of transdifferentiation markers & inhibited calcium deposition. BRD4 is a transcriptional regulator & target of apabetalone. ChIP-seq showed transdifferentiation of VSMCs to a calcifying phenotype promoted re-distribution of BRD4 on chromatin, resulting in fewer BRD4-rich enhancers (118 in osteogenic, 288 in basal). 38 genes were uniquely associated with BRD4-rich enhancers in osteogenic vs basal conditions; several of the genes have been linked to calcification. Apabetalone reduced BRD4 on many of these enhancers, which correlated with decreased gene expression. Bioinformatics indicated BRD4 may cooperate with specific transcription factors to promote calcification.

Conclusion

Involvement of BRD4 in VSMC transdifferentiation & calcification is a novel discovery. Further assessment of apabetalone as a therapeutic for VC is warranted. The impact of apabetalone on biomarkers, renal function & CVD outcomes in patients with impaired kidney function is being evaluated in a subgroup of the phase 3 BETonMACE trial.

Funding

• Commercial Support –