Kidney Week

Abstract: FR-PO1048

Apabetalone Lowers Serum Alkaline Phosphatase in CVD Patients with and Without CKD and Improves Cardiovascular Risk

Session Information

• Hypertension and CVD: Clinical Outcomes, Trials
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1402 Hypertension and CVD: Clinical, Outcomes, and Trials

Authors

• Haarhaus, Mathias, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Mathias Haarhaus,

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

Jan O. Johansson,

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

Michael Sweeney,

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

Ewelina Kulikowski,

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

Norman Cw Wong,

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

Christopher Halliday,

• Khan, Aziz, Resverlogix Corp., Calgary, Alberta, Canada

Aziz Khan,

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

Kenneth E. Lebioda,

• Brandenburg, Vincent, Rhein-Maas-Klinikum, Würselen, Germany

Vincent Brandenburg,

• Beddhu, Srinivasan, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, United States

Srinivasan Beddhu,

• Tonelli, Marcello, University of Calgary, Calgary, Alberta, Canada

Marcello Tonelli,

• Zoccali, Carmine, CNR IFC, Clinical Epidemiology of Renal Diseases and Hypertension, Reggio Calabria, Italy

Carmine Zoccali,

• Kalantar-Zadeh, Kamyar, Harold Simmons Center for Kidney Disease Research and Epidemiology, University of California Irvine, School of Medicine, Orange, California, United States

Kamyar Kalantar-Zadeh,

Background

Patients with cardiovascular disease (CVD) with or without chronic kidney disease (CKD) have considerable residual risk despite optimal standard of care. Alkaline phosphatase (ALP) has been suggested as a modifiable CVD risk factor. Apabetalone, a bromodomain and extraterminal (BET) inhibitor selective for bromodomain 2 (BD2) lowers ALP in a dose-response fashion. In phase 2 studies apabetalone treatment was associate with a significant 44% reduction in CVD events. We sought to determine whether this CVD risk reduction by apabetalone is associated with the concomitant lowering of serum ALP.

Methods

In a pooled phase 2 post-hoc analysis of 795 CVD patients on standard of care treatment including statins, of which 11.8% had CKD as defined by eGFR <60 m/min/1.73m² (n=94; 71=apabetalone; 23=placebo) we assessed the effect of apabetalone vs. placebo treatment for up to 24 weeks on the incidence of CVD events and serum ALP.

Results

Apabetalone treatment decreased serum ALP in CKD and non-CKD CVD patients by 10.2% and 6.5%, respectively (12 weeks), and 7.7% and 7.2%, respectively (24 weeks) (all p<0.01). Further analysis on the whole population showed that baseline ALP (median 72 U/L) predicted MACE (death, non-fatal myocardial infarction, coronary revascularization, or hospitalization for cardiovascular causes), independent of high-sensitivity C-reactive protein (hsCRP), sex, age, study, established CVD risk factors, CKD, and treatment allocation (hazard ratio [HR] per standard deviation [SD] 1.6, 95% CI 1.2-2.1, p<0.001). In the apabetalone group, a 1 SD reduction in ALP was associated with a HR for MACE of 0.58 (95% CI 0.43-0.78, p<0.001).

Conclusion

Serum ALP predicts strongly the residual cardiovascular risk, independent of hsCRP, established cardiovascular risk factors and CKD, in patients with cardiovascular disease on statin treatment. Apabetalone lowers serum ALP and may prevent the incidence of new cardiovascular events. The phase 3 BETonMACE CVD outcomes study reporting H2 2019, will provide further insights about apabetalone’s ALP reduction and potential causality for CVD events.