ACCP Cardiology PRN Journal Club Announcements Thank you

ACCP Cardiology PRN Journal Club

Announcements • Thank you attending the ACCP Cardiology PRN Journal Club – Thank you if you attended last time or have been attending • I have created a PB Works Site that will house our recorded calls, handouts, and Summary/Q&A documents. The link is https: //accpcardsprnjournalclub. pbworks. com/ • If there any suggestions, please let us know.

Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events: OSLER-1 & OSLER-2 Laura Halder, Pharm. D PGY 2 Cardiology Abbott Northwestern Hospital April 30, 2015

Disclosure and Acknowledgement • I have no financial or nonfinancial conflicts of interest regarding the subject matter of this presentation. • Mentor acknowledgement: Dave L. Dixon, Pharm. D, BCPS, CDE, CLS, AACC, FNLA Assistant Professor, Ambulatory Care VCU School of Pharmacy, Richmond, Virginia

Trial Background March 15, 2015: • Published in the New England Journal of Medicine • Presented at the ACC. 15 Scientific Session

Evolocumab Background • Loss-of-function variant shown to have lower LDL and CV events • Provisional brand name: Repatha™ • Fully human monoclonal antibody • Inhibits proprotein convertase subtilisinkexin type 9 (PCSK 9) • Lowers LDL by 60%

Evolocumab Mechanism of Action

Trial Design Open label longer-term extension trials to evaluate safety, side-effect profile and LDL reduction Phase 2 OSLER-1 Evolocumab Parent Trial Phase 3 OSLER-2 420 mg monthly 140 mg every 2 wks

Intervention • Open label to patients, investigators, and care providers • No placebo for standard therapy group • Standard-of-care background therapy was based on local guidelines • Cardiovascular outcomes adjudicated until January 21, 2015 • Other data collected from 2011 to October 31, 2014 • OSLER-1 and OSLER-2 data combined into one data set

Trial End Points • Primary: incidence of adverse effects • Additional safety: – Serious adverse events – Adverse events leading to discontinuation – Abnormal creatinine kinase or LFTs – Development of binding and neutralizing antibodies • Secondary: percent change in LDL • Additional efficacy: – Non-HDL, total cholesterol, triglycerides, HDL – Apolipoproteins A 1 and B – Lipoprotein (a)

Trial End Points Prespecified exploratory outcome: adjudicated CV events • Death • Coronary events – Myocardial infarction – Unstable angina requiring hospitalization – Coronary revascularization • Cerebrovascular events – Stroke – TIA • Heart failure requiring hospitalization

Results • LDL reduction of 61 % (95% CI 59 -63, P<0. 001) • Mean absolute reduction of 73 mg/d. L to median 48 mg/d. L • Similar data in OSLER-1 and OSLER-2 • Consistent LDL effect over time LDL Targets <100 mg/d. L <70 mg/d. L Evolocumab Standard of Care 90. 2% 26. 0% 73. 6% 3. 8%

LDL Cholesterol Levels

Effect on Other Lipids

Cumulative Incidence of Cardiovascular Events NNT = 81

No neutralizing antibodies detected and no difference in evolocumab binding antibodies

Author’s Conclusions • Evolocumab reduced LDL cholesterol by 61% from 120 to 48 mg/d. L in 12 weeks • Effect persisted for 48 weeks • Evolocumab likely reduces CV outcomes – Large decrease in LDL – Synergistic mechanism for LDL reduction as statins – Genetic loss-of-function gene variants show lower risk of CV events – Supported by exploratory analysis in this trial

Study Critiques • Open-label trial design with more frequent follow up than standard of care • Low number of CV and adverse events • Variation in patient population in CV risk and statin intensity • Need a longer term follow up trial of neurocognitive outcomes • Question of impact on cardiovascular outcomes – Future trial with 27, 500 patients on horizon (FOURIER)

Role of PCSK 9 Inhibitors • Possible application of PCSK 9 inhibitors: 1. Preferred in place of a statin 2. Alternative for statin-intolerant patients 3. Add-on therapy to achieve adequate LDL reduction on statin therapy • Adherence impact of monthly or twice weekly injections versus daily pill • Cost of monoclonal antibody therapy

Questions? ? • Special thanks to: – Dr. Dave Dixon – Dr. Craig Beavers

Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events: OSLER-1 & OSLER-2 Laura Halder, Pharm. D PGY 2 Cardiology Abbott Northwestern Hospital April 30, 2015

Thank you for attending! • If you would like to have your resident present, would like to be a mentor, or have questions or comments please e-mail the journal club at accpcardsprnjournalclub@gmail. com or craig. beaverspharmd@gmail. com • Our next Journal Club will be in late April – Sheena Mathew from Tri. Star Centennial will be presenting on PEGASUS TIMI Trial from ACC. 15