PCSK9 Inhibitors Current Status Ryan T. Whitney, MD FACC Bryan Heart Fall Conference 2015 Disclosures, Conflicts, and Nefarious Connections I own no stock in the companies mentioned in this talk. I am not a speaker, consultant or hired gun for any device or pharmaceutical company. I am the co-founder of Together+Clinic, a local healthcare IT company. We can help you better optimize patient management and capture CCM revenue. Stop by our booth to learn more.(yes, that was a shameless plug) Proprotein convertase subtilisin/kexin type 9 (PCSK9) Plays a pivotal role in LDL metabolism Promotes the degradation of the LDL receptor and prevents it from recycling to the membrane 1
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Current PCSK9 Inhibitors Alirocumab(Praluent) Sanofi, Regeneron Evolocumab(Repatha) Amgen Bococizumab Pfizer 4
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Alirocumab (Praluent) Indications as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. 8
Evolocumab (Repatha) Indications Indicated as an adjunct to diet and maximally tolerated statin therapyfor the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic CVD, who require additional lowering of LDL-C. Indicated as an adjunct to diet and other LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C Dosing Alirocumab(Praluent) 75 mg SC q2weeks 150 mg SC q2weeks Evolocumab(Repatha) Primary hyperlipidemia: 140 mg SC q2weeks 420 mg SC once monthly HoFH 420 mg SC once monthly Yearly Cost Alirocumab(Praluent) $14,600 Evolocumab(Repatha) $14,100 9
CVS: Costs Could Potentially Reach $150 Billion Annually Approximately 25 million statin users Indication creep 10 million users Most initial estimates closer to $20 billion Research at Bryan Heart FOURIER SPIRE-1 SPIRE-2 Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) A Double-blind, Randomized, Placebo-controlled, Multicenter Study Assessing the Impact of Additional LDL- Cholesterol Reduction on Major Cardiovascular Events When AMG 145 is Used in Combination With Statin Therapy In Patients with Clinically Evident Cardiovascular Disease 10
FOURIER Criteria Inclusion Criteria: Male or female 40 to 80 years of age History of clinically evident cardiovascular disease at high risk for a recurrent event Fasting LDL-C 70 mg/dlor non-hdl-c 100 mg/dl Fasting triglycerides 400 mg/dl Exclusion Criteria: NYHA class III or IV, or last known EF < 30% Uncontrolled HTN, VT, hyper/hypothyroidism HoFH LDL or plasma apheresis FOURIER Arms Evolocumab q2wk or qmonth with atorvastatin 20 80mg Vs Placebo q2wk or qmonthwith atorvastatin 20 80mg Outcomes (5 years) Primary Outcome Measures: Time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization Secondary Outcome Measures: Time to cardiovascular death, myocardial infarction, or stroke Time to death by any cause Time to cardiovascular death or hospitalization for worsening heart failure Time to ischemic fatal or non-fatal stroke or TIA 11
The Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects SPIRE-1 and SPIRE-2 SPIRE-1 (Bococizumab) Inclusion Criteria: Must be on background lipid lowering treatment. Must be at high risk of a CV event. Must have an LDL C >=70 mg/dland < 100 mg/dlor non-hdl-c >= 100 mg/dl and < 130 mg/dl. Exclusion Criteria: An LDL C < 70 mg/dlor >= 100 mg/dlor non HDL-C < 100 mg/dlor >=130 mg/dl. Planned coronary (PCI or CABG) or other arterial revascularization. New York Heart Association Class IV congestive heart failure or left ventricular ejection fraction < 25% by cardiac imaging. Chronic renal insufficiency with creatinine clearance of <30 or with end state renal disease on dialysis. History of hemorrhagic stroke. Prior exposure to bococizumabor other investigational PCSK9 inhibitor. SPIRE-2 (Bococizumab) Inclusion Criteria: Must be on background lipid lowering treatment. Must be at high risk of a CV event. Must have an LDL C >=100 mg/dlor non HDL C >=130. Exclusion Criteria: An LDL C <100 mg/dl or non HDL C <130 mg/dl. Planned coronary (PCI or CABG) or other arterial revascularization. New York Heart Association Class IV congestive heart failure or left ventricular ejection fraction < 25% by cardiac imaging. Chronic renal insufficiency with creatinine clearance of <30 or with end state renal disease on dialysis. History of hemorrhagic stroke. Prior exposure to bococizumabor other investigational PCSK9 inhibitor. 12
August 30, 2015: European Society of Cardiology (ESC A Subcutaneously Administered Investigational RNAiTherapeutic (ALN-PCSsc), Targeting PCSK9 for the Treatment of Hypercholesterolemia: Initial Phase 1 Study Results Kevin Fitzgerald, PhD Co-authors: Amy Simon 1, SuellenWhite 1, Anna Borodovsky 1, NiravPatel 1, Brian Bettencourt 1, Valerie Clausen 1, Jay Horton 3, Peter Wijngaard 2, Robert Kauffman 1, David Kallend 2 1 AlnylamPharmaceuticals, 300 Third Street, Cambridge, MA 02142 USA 2 The Medicines Company, 8 Sylvan Way, Parsippany, NJ 07054 USA 3 Universityof Texas South Western, 5323 Harry Hines Blvd, Dallas, TX 75390 USA Declaration of Interest: Employees of AlnylamPharmaceuticals 1 Employees of The Medicines Company 2 38 PCSK9 Therapeutic Hypothesis LDL LDLR Endosome Lysosomal degradation Anti-PCSK9 Mabs Transiently block PCSK9 binding To LDL receptor (LDLR) LDLR synthesis PCSK9 Synthesis Inhibitors Durably block PCSK9 synthesis and all intracellular and extracellular PCSK9 functions ALN-PCS PCSK9 synthesis PCSK9 mrna Nucleus PCSK9 39 13
Initial ALN-PCSsc Phase 1 Study Results SAD PCSK9 Knockdown Relative to Baseline Mean (SEM) % PCSK9 Knockdown (Change from Baseline) -40-20 0 20 40 60 80 Treatment Placebo 25 mg 100 mg 300 mg 500 mg 800 mg 100 0 1 2 3 4 5 Months Day/Treatment combinations where N=1 not displayed 40 Data in database as of 04 August 2015 Initial ALN-PCSsc Phase 1 Study Results SAD LDL-C Lowering Relative to Baseline Mean (SEM) % LDL-C Lowering (Change from Baseline) 0 20 40 60 Treatment Placebo 25 mg 100 mg 300 mg 500 mg 800 mg 80 0 1 2 3 4 5 Months Days/Treatments where N=1 not displayed LDL-C analyzed by Beta-Quantification 41 Data in database as of 04 August 2015 Initial ALN-PCSsc Phase 1 Study Results MD PCSK9 Knockdown Relative to Baseline Mean (SEM) % PCSK9 Knockdown (Change from Baseline) -60-40 -20 0 20 40 60 80 Treatment Placebo 125 mg qwx4 250 mg q2wx2 300 mg qmx2 300 mg S^qMX2 500 mg qmx2 500 mg S^qMX2 100 0 1 2 3 4 5 Months qw, q2w, or qm S^ =On stable dose of statin Two subjects excluded from all MD analyses: One placebo subject elected to discontinue; One subject in 300 mg statin group was incarcerated on Day 14 42 Data in database as of 04 August 2015 14
Initial ALN-PCSsc Phase 1 Study Results MD LDL-C Lowering Relative to Baseline 0 Mean (SEM) % LDL-C Lowering (Change from Baseline) 20 40 60 Treatment Placebo 300 mg S^qMX2 125 mg qwx4 500 mg qmx2 250 mg q2wx2 500 mg S^qMX2 300 mg qmx2 80 0 1 2 3 4 5 Month qw, q2w, or qm 43 Data in database as of 04 August 2015 S^ =On a stable dose of statins Two subjects excluded from all MD analyses: One placebo subject elected to discontinue; One subject in 300 mg statin group was incarcerated on Day 14 PCSK9 Inhibitors Current Status Ryan T. Whitney, MD FACC Bryan Heart Fall Conference 2015 44 15