Case Study. Case Study. Case Study

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1 Case Study Patrick M Moriarty, M.D., Professor of Medicine Director of Clinical Pharmacology and the Atherosclerosis/Lipoprotein-apheresis Center University of Kansas Medical Center Aurora May 4 th 2018 Case Study 55 year old male with 5 year history of CAD (2 stents). PMHX: hypertension, dyslipidemia, CVD Family History: CVD (F age 54) PE: BP 140/85, Pulse 72, WT 190, BMI 28, WC 42 Labs: CBC and Chem Profile unremarkable, TC=280mg/dL, Trigs=150mg/dL, HDL=38, LDL-C=212mg/dL. Meds: ASA, ACEi, NTG, Statin intolerant. Case Study 55 year old male with 5 year history of CAD (2 stents). PMHX: hypertension, dyslipidemia, CVD Family History: CVD (F age 54) PE: BP 140/85, Pulse 72, WT 190, BMI 28, WC 42 Labs: CBC and Chem Profile unremarkable, TC=280mg/dL, Trigs=150mg/dL, HDL=38, LDL-C=212mg/dL. Meds: ASA, ACEi, NTG, Statin intolerant. Question: What would you do for the patients statin intolerance?

2 Statin Intolerance (SI): Limits Many Patients from Achieving LDL-C Goals SI: Inability to use statins for long-term reduction of lipids and/or CV risk because of significant symptoms and/or biomarker abnormalities that can be temporally attributed to the initiation or dose escalation of statins 1 ~10 25% patients in clinical practice report SI 2,3 Cleveland Clinic Myalgia was most common complaint However, 63.2% patients with previous SI were able to tolerate daily statin therapy 4 1. Mancini GBJ et al. Can J Cardiol. 2013;29: ; 2. Bruckert E et al. Cardiovasc Drugs Ther. 2005;19: Cohen JD et al. J Clin Lipidol. 2012;6: Mampuya WM et al. Am Heart J. 2013;166: Guyton JR et al. J Clin Lipidol. 2014;8:S72 S81. Possible Mechanisms of SI Muscle Injury 1. Reduced Sarcolemmal Cholesterol. 2. Reduced T-Tubule & Sarcoplamic Recticulum Cholesterol. 3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q Reduced Prenylation of GTP Binding Proteins - Ras, Rac and Rho - Cell Maintenance, Growth & Reduced Apoptosis. 5. Changes in Fat Metabolism. 6. Increased Muscle Cholesterol &? Plant Sterol 2 nd to LDL-Receptor Activity Failure to Appropriately Repair damaged muscle Vitamin D Deficiency. 7. Inflammation (Inflammatory Myopathy). Draeger JPath 2006, Coleman Cell Death Differ 2002, Phillips P Atherosclerosis 2005, Paiva Clin Pharmacol Ther 2005, Urso. Thompson ATVB 2005 PCSK9 Inhibitor Trials In Statin Intolerant Patients 1) GAUSS 2) GAUSS 2 3) ALTERNATIVE 4) GAUSS 3 5) SPIRE Statin Intolerant

3 PCSK9 Inhibitor Trials In Statin Intolerant Patients 1) ALTERNATIVE 2) GAUSS 3 ODYSSEY ALTERNATIVE: Efficacy and safety of alirocumab versus ezetimibe, in patients with statin intolerance defined by placebo run-in and statin rechallenge arm Patrick M. Moriarty 1, Paul D. Thompson 2, Christopher P. Cannon 3, John R. Guyton 4, Jean Bergeron 5, Franklin J. Zieve 6, Eric Bruckert 7, Terry A. Jacobson 8, Marie T. Baccara-Dinet 9, Jian Zhao 10, Yunling Du 10, Robert Pordy 11, Daniel Gipe 11 1 Department of Internal Medicine, Division of Clinical Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA; 2 Hartford Hospital, Hartford, CT, USA; 3 Harvard Clinical Research Institute, Boston, MA, USA; 4 Duke University Medical Center, Durham, NC, USA; 5 Clinique des Maladies Lipidiques de Québec Inc., Québec, Canada; 6 McGuire VA Medical Center, Richmond, VA, USA; 7 Hospitalier Pitié-Salpêtrière, Paris, France; 8 Emory University, Atlanta, GA, USA; 9 Sanofi, Montpellier, France; 10 Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA; 11 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA 8 ALTERNATIVE: Participants - Moderate risk (10 year CVD risk score >1 and <5%) 11-16%. - High risk (10 year CVD risk score >5%, CKD, DM without target organ damage, HeFH) 21-38%. - Very high risk (CVD, carotid endarterectomy or stent, renal artery stenosis, DM with target organ damage) 50-58%. - LDL-C about 190 mg/dl. - Unable to tolerate at least two different statins, including one at the lowest daily dose, due to muscle-related symptom. - Patients who were on a non-daily dose of a statin or ezetimibe were washed out (2 weeks) prior to initiating the trial. - History of rhabdomyolysis was an exclusion from study. Moriarty PM, et al. JCL. 2015

4 ODYSSEY ALTERNATIVE Study Design Statin intolerant patients* (by medical history) with LDL-C 70 mg/dl (very-high CV risk) or 100 mg/dl (moderate/ high risk) Placebo PO QD + Placebo SC Q2W R N=100 N=100 N=50 Double-Blind Treatment Period (24 Weeks) Alirocumab 75/150 mg SC Q2W + placebo PO QD administered via single 1 ml injection using prefilled pen for self-administration Per-protocol dose possible depending on W8 LDL-C Ezetimibe 10 mg PO QD + placebo SC Q2W Atorvastatin 20 mg PO QD + placebo SC Q2W OLTP/8 week FU Assessments W -4 W0 W4 W8 W12 W16 W24 Patients discontinued if musclerelated AEs reported with placebos during run-in Per-protocol dose increase if Week 8 LDL-C 70 or 100 mg/dl (depending on CV risk) Primary endpoint (LDL-C % change from baseline, ALI and EZE only) Safety analysis (all groups) 4-week single-blind placebo run-in follows 2-week washout of statins, ezetimibe and red yeast rice. OLTP: Alirocumab open-label treatment period; W, Week. Moriarty PM, et al. JCL ALTERNATIVE Trial Efficacy 250 Alirocumab Maintained LDL-C Reductions Week 4 24 Achieved calculated LDL-C over time on-treatment analysis (modified ITT observed data only) Alirocumab Ezetimibe LDL-C, mean (SE), mg/dl mg/dl 157 mg/dl 150 Δ 59 mg/dl Δ 65 mg/dl mg/dl 92 mg/dl % received 150 mg Q2W at W Week Moriarty PM, et al. JCL. 2015

5 ALTERNATIVE Trial Safety Cumulative probability of event Fewer Skeletal Muscle AEs with Alirocumab than with Atorvastatin Kaplan-Meier estimates for time to first skeletal muscle event Atorvastatin Ezetimibe Alirocumab Cox model analysis: HRATV vs ALI =1.63 (95% CI: 1.01 to 2.62), nominal P=0.042 HR EZE vs ALI = 1.41 (95% CI: 0.94 to 2.13), nominal P= Week 1 Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue. ALI, alirocumab; ATV, atorvastatin, EZE, ezetimibe. Safety Analysis: Additional AEs of Interest % (n) of patients Safety analysis from double-blind treatment period Alirocumab (N=126) Ezetimibe (N=124) Atorvastatin (N=63) Adjudicated CV events 2.4% (n=3) 0.8% (n=1) 1.6% (n=1) Ischemia-driven coronary revascularization procedure 2.4% (n=3) 0.8% (n=1) 1.6% (n=1) Non-fatal MI 0.8% (n=1) 0 0 Injection-site reactions 4.8% (n=6) 4.8% (n=6) 1.6% (n=1) Neurocognitive disorders 2.4% (n=3) 1.6% (n=2) 0 Creatine kinase >3x ULN, % (n/n) 2.4% (3/126) 1.6% (2/123) 4.8% (3/62) Myositis* % (n=1) ALT >3x ULN, % (n/n) Adjudicated CV events categories: CHD death, non-fatal MI, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization, congestive heart failure requiring hospitalization, ischemia-driven revascularization procedure (PCI, CABG). *Muscle symptoms with CK 3 x ULN and <10 x ULN. Patients can be reported as having more than one CV event. ALT, alanine transaminase; ULN, upper limit of normal.

6 ODYSSEY ALTERNATIVE: Safety % of patients Alirocumab (N=126) Double-blind Treatment Period Ezetimibe (N=124) Atorvastatin (N=63) TEAEs 82% 81% 86% TEAEs leading to discontinuation 18% 25% 25% Any skeletal-muscle related TEAE 32% 41% 46% Skeletal-muscle related TEAE leading to discontinuation 16% 20% 22% TEAE (treatment emergent adverse event) period = time from first to last injection of study treatment + 70 days. Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue. Moriarty PM, et al. JCL 2015 Interim Safety Results from the Ongoing 3-Year OLTP Safety analysis from start of OLTP up to 52 weeks 89.5% of randomized patients entered the OLTP (including 94% of those randomized to atorvastatin). All patients in OLTP receive alirocumab 75 mg Q2W (with dose increase possible to 150 mg Q2W after 12 weeks OLTP treatment). Alirocumab (N=281) Mean (SD) exposure during OLTP (weeks) 13.9 (6.8) Any TEAE 56% Myalgia 4.3% Muscle spasms 1.8% Musculoskeletal stiffness 0.7% TEAE leading to discontinuation 3% Myalgia (leading to discontinuation) 1% The two patients who discontinued due to myalgia originally came from the alirocumab and ezetimibe arms. ALTERNATIVE Trial Sensitivity

7 ALTERNATIVE: Muscle-Related AE s During Single-Blind, Placebo Run-in Period Run-in failures (n=47) At least one skeletal-muscle symptom during run-in period 49% Myalgia 19% Muscle spasms 15% Pain in extremity 6% Musculoskeletal pain 2% Musculoskeletal stiffness 4% Back pain 2% Muscular weakness 2% Moriarty PM, et al. JCL 2015 ODYSSEY ALTERNATIVE: Safety Double-blind Open Label Treatment Period Treatment Period Alirocumab Ezetimibe Atorvastatin Alirocumab % of patients (N=126) (N=124) (N=63) (N=281) TEAEs 82% 81% 86% 56% TEAEs leading to discontinuation 18% 25% 25% 3% Any skeletal-muscle related TEAE 32% 41% 46% 14% Skeletal-muscle related TEAE leading to discontinuation 16% 20% 22% 1% TEAE (treatment emergent adverse event) period = time from first to last injection of study treatment + 70 days. Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue. Moriarty PM, et al. JCL 2015 Ezetimibe Patients on Ezetimibe at Screen Who Developed Skeletal Muscle Events (SME) Description # of subjects in ezetimibe # (%) of subjects with arm who were previously on SMEs in double-blind ezetimibe at screening period Incidence of skeletal-muscle events (SME) (43%)

8 GAUSS 3: Participants - Moderate risk (10 year CVD risk score >1 and <5%) 11-15%. - High risk (10 year CVD risk score >5%, CKD, DM without target organ damage, HeFH) 21-38%. - Very high risk (CVD, carotid endarterectomy or stent, renal artery stenosis, DM with target organ damage). - LDL-C about 190 mg/dl. - Unable to tolerate at least two different statins, including one at the lowest dose, due to muscle-related symptom.

9 What is Occurring in Statin Intolerance Patients?

10 Statin-Intolerance: The Elephant in The Room Mancini et al, DOI: Negative Statin-Related News Stories in Denmark ( ) and Increase MI and CV Mortality Eur Heart J. 2015;37(11): Negative Statin-Related News Stories in Denmark ( ) and Increase MI and CV Mortality Eur Heart J. 2015;37(11):

11 What we have learned about PCSK9i in Statin-Intolerant Patients - More efficacious than ezetimibe in lowering LDL-C. - Has minimal impact on plasma levels of hepatic and muscle enzymes. - Are generally safe and tolerable, especially when prescribed as an open label therapy, for patients who are statin intolerant. - Statin-intolerant patients may be overly sensitive to statin therapy and may need extra nurturing and counseling to achieve improved compliance with their medical management. What is a delicate flower? If you touch it, tamper with it, forget to water it, or do not provide it with it's necessary light and good soil It ends up withering and dying. Examples of delicate Flowers Orchids (Vanda tricolor) Venus flytrap (Dionaea muscipula).

12 Examples of delicate Flowers Orchids (Vanda tricolor) Venus flytrap (Dionaea muscipula). Statin intolerant patient (Hominis deliciarum). Alternative Therapy for statin Intolerant Patients Try another statin. Use lower dose statin. Try alternative dosing of statin. Co-Q10 before adding statin. Vitamin D before adding statin. Ezetimibe. Bile acid sequestrants. Red Yeast Rice. PCSK9i. Use of Nutraceuticals (viscous fiber, plant sterols, fish oil, flax seed oil, berberine, others)? Mipomersen or lomitapide if HoFH. Lipid-apheresis. Case Study 55 year old male with 5 year history of CAD (2 stents). PMHX: hypertension, dyslipidemia, CVD Family History: CVD (F age 54) PE: BP 140/85, Pulse 72, WT 190, BMI 28, WC 42 Labs: CBC and Chem Profile unremarkable, TC=280mg/dL, Trigs=150mg/dL, HDL=38, LDL-C=212mg/dL. Meds: ASA, ACEi, NTG, Statin intolerant.

13 Case Study 55 year old male with 5 year history of CAD (2 stents). PMHX: hypertension, dyslipidemia, CVD Family History: CVD (F age 54) PE: BP 140/85, Pulse 72, WT 190, BMI 28, WC 42 Labs: CBC and Chem Profile unremarkable, TC=280mg/dL, Trigs=150mg/dL, HDL=38, LDL-C=212mg/dL. Meds: ASA, ACEi, NTG, Statin intolerant. Patient most likely has Familial Hypercholesterolemia thus measure family members for dyslipidemia. Case Study 55 year old male with 5 year history of CAD (2 stents). PMHX: hypertension, dyslipidemia, CVD Family History: CVD (F age 54) PE: BP 140/85, Pulse 72, WT 190, BMI 28, WC 42 Labs: CBC and Chem Profile unremarkable, TC=280mg/dL, Trigs=150mg/dL, HDL=38, LDL-C=212mg/dL. Meds: ASA, ACEi, NTG, Statin intolerant. Patient most likely has Familial Hypercholesterolemia thus measure family members for dyslipidemia. Would also measure an Lp(a). Case Study 55 year old male with 5 year history of CAD (2 stents). PMHX: hypertension, dyslipidemia, CVD Family History: CVD (F age 54) PE: BP 140/85, Pulse 72, WT 190, BMI 28, WC 42 Labs: CBC and Chem Profile unremarkable, TC=280mg/dL, Trigs=150mg/dL, HDL=38, LDL-C=212mg/dL. Meds: ASA, ACEi, NTG, Statin intolerant. Patient most likely has Familial Hypercholesterolemia thus measure family members for dyslipidemia. Would also measure an Lp(a). With a waist circumference of 42, would order dietary consult.