Abstract: SA-PO650

Apabetalone (RVX-208) Impacts Key Markers and Pathways Associated with CKD in Patients with Severe Renal Impairment

Session Information

Category: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

  • 1601 Pharmacokinetics, Pharmacodynamics, Pharmacogenomics

Authors

  • Kulikowski, Ewelina, Resverlogix Corp, Calgary, Alberta, Canada
  • Sweeney, Michael, Resverlogix Inc, San Francisco, California, United States
  • Johansson, Jan O., Resverlogix Corp., San Francisco, California, United States
  • Wong, Norman C. W., Resverlogix Corp., San Francisco, California, United States
  • Wasiak, Sylwia, Resverlogix Corp, Calgary, Alberta, Canada
  • Tsujikawa, Laura, Resverlogix Corp, Calgary, Alberta, Canada
  • Halliday, Christopher, Resverlogix Corp, Calgary, Alberta, Canada
  • Stotz, Stephanie, Resverlogix Corp, Calgary, Alberta, Canada
  • Gilham, Dean, Resverlogix, Calgary, Alberta, Canada
  • Jahagirdar, Ravi, Resverlogix Corp, Calgary, Alberta, Canada
  • Kalantar-Zadeh, Kamyar, University of California Irvine, School of Medicine, Orange, California, United States
  • Robson, Richard Austin, CHristchurch Clinical Studies Trust, Christchurch, New Zealand
Background

Chronic kidney disease (CKD) is associated with a progressive loss of renal function and a high risk of cardiovascular disease (CVD). Apabetalone is an orally active BET protein inhibitor that decreased major adverse cardiac events (MACE) in CVD patients in phase 2 clinical trials. Thus, a phase 1, open-label, parallel group study of patients with impaired kidney function was conducted to determine the effect of apabetalone on plasma proteins associated with CVD complications in CKD.

Methods

8 subjects with stage 4 CKD not on dialysis (mean eGFR=20 ml/min/1.73m2) and 8 matched controls (mean eGFR=78.5 ml/min/1.73m2) received a single 100 mg dose of apabetalone. Plasma was collected over 48h for PK analysis and at 12h post dose for proteomics analysis using the SOMAscan® platform (1305 proteins). Data were analysed with Ingenuity® Pathway Analysis (IPA®) to identify pathways regulated by apabetalone.

Results

PK parameters were similar in CKD patients and controls. Plasma proteomics in CKD patients showed that after 12h apabetalone altered levels of 261 proteins by 10-58% (p<0.05), versus baseline. 257/261 proteins were downregulated, consistent with inhibition of BET sensitive genes. IPA® revealed a robust effect of apabetalone on pathways involved in immunity and inflammation, acute phase response, diabetes, endothelial dysfunction, vascular calcification, fibrosis, and hypertension. Apabetalone also reduced circulating CKD and CVD markers, including IL-6, TNFα, IL-1, ICAM-1, VCAM-1, CRP, PAI-1, L-selectin, E-selectin, MMP-3, MMP-10, fibronectin and SPP1 (p<0.05).

Conclusion

In stage 4 CKD patients, apabetalone rapidly downregulates plasma markers and molecular pathways linked to renal disease and CVD complications. The long term impact of apabetalone is currently being studied in a subpopulation with impaired kidney function of the phase 3 BETonMACE CVD outcomes trial.