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Lowering of LDL-c: Novel concepts and novel promises

Lowering of LDL-c: Novel concepts and novel promises. Dr. Evan Stein University of Cincinnati Ohio, USA. Why do we need more LDL reducing drugs?.

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Lowering of LDL-c: Novel concepts and novel promises

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  1. Lowering of LDL-c: Novel concepts and novel promises Dr. Evan Stein University of Cincinnati Ohio, USA

  2. Why do we need more LDL reducing drugs? • Numerous cardiovascular end point trials have confirmed more LDLc reduction results in more CVD reduction • NCEP, AHA, ACC and European guidelines continue to lower LDLc goal in high risk and even lower risk CVD patients • Growing number of statin adverse patients with limited alternatives • Special populations (e.g. FH and severe hypercholesterolemia) do not achieve even old goals

  3. LDL Receptor Function and Life Cycle For illustration purposes only 3

  4. The Role of PCSK9 in the Regulation of LDL Receptor Expression For illustration purposes only 4

  5. Impact of an PCSK9 mAb on LDL Receptor Expression For illustration purposes only mAb 5

  6. PCSK9:Rapid Progress From Discovery to Clinic • Adenoviral  expression in mice • PCSK9 KO mouse  LDL-C • PCSK9 LOF mutations found with 28%  LDL-C and 88%  CHD risk • Humans null for PCSK9 have LDL-C ~15 mg/dL • First subject treated with PCSK9 mAb • First patients with FH & nonFH treated with PCSK9 mAb • PCSK9 (NARC-1) discovered • PCSK9 GOF mutations associated with ADH  LDL-C in mice and non-human primates treated with anti-PCSK9 mAb Plasma PCSK9 binds to LDLr First publication POC in patients 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2012 Seidah NG. Proc Natl Acad Sci USA 2003;100(3):928-33, Abifadel M. Nat Genet 2003;34(2):154-6, Maxwell KN. Proc Natl Acad Sci USA 2004;101(18):7100-5, Rashid S. Proc Natl Acad Sci USA 2005;102(15):5374-79, Lagace TA et al. JCI 2006;116:2995-3005 Cohen JC. N Engl J Med 2006;354(12):1264-72, Zhao Z. AmJ Hum Genet 2006;79(3):514-23, Hooper AJ. Atherosclerosis 2007;193(2):445-8, Chan JC. Proc Natl Acad Sci USA 2009;106(24):9820-5; Stein et al N Engl J Med 2012;366:1108-18 Stein modified from Swergold, Regeneron

  7. Inhibition of PCSK9 with Monoclonal Antibody: First in Man Studies • How effective will a mAb be? • How long will effect last? • Will the mAb be effective in patients treated with statins, whose LDL-R are already upregulated? • As statins increase PCSK9 levels in plasma if effective will LDL-C reduction be less, the same (additive) or enhanced (synergistic) than monotherapy? • In patients with heterozygous familial hypercholesterolemia (HeFH) and a defective LDL-R will PCSK9 inhibition have any significant effect? • Will mAb anti-PCSK9 administration be safe and well tolerated?

  8. Phase Ib: Multidose StudyDouble-Blind, Randomized, Placebo-Controlled NCT01161082 Sequential Cohorts Primary Endpoint incidence and severity of TEAEs SC 50mg / Placebo Men & women, Age 18-65; HeFH+ non-FH LDL-C>100 mg/dl* Atorvastatin 10-40 mg* SC 100mg / Placebo Follow-up 105 days after last dose Exploratory Endpoint changes in lipids and lipoproteins SC 150mg / Placebo 21-day screening period *An additional 150-mg arm was enrolled with no background atorvastatin and baseline LDL-C >130 mg/dL 148 1 29 43 57 Days Dose administered Stein et al NEJM 2012; 366:1108-18

  9. Dose Groups Stein et al NEJM 2012; 366:1108-18

  10. ApoB & LDL-C ResponseMean % Change from Baseline, Day 57 % * * * * * * * * * * † * * * P < 0.0001 vs. Placebo † P < 0.01 vs. Placebo Stein et al NEJM 2012; 366:1108-18

  11. LDL-C Dose ResponseAtorvastatin Combo-Rx, HeFH & Non-FH Combined Mean % Change from Baseline 4 wks 4 wks = Dose administered

  12. Study Design Cohorts 1-5: Low- to moderate-dose statins,no heFH (N = 40) Cohort 6: High-dose statins, no HeFH (N = 12) • Rosuvastatin < 40 mg • Atorvastatin < 80 mg • Simvastatin 20–80 mg • AMG 145: Placebo, 3:1 Cohort 5 N = 8 • Rosuvastatin 40 mg • Atorvastatin 80 mg • AMG 145: placebo 3:1 Cohort 4 N = 8 Cohort 3 N = 8 Cohort 7: Low- to moderate- dose statins, HeFH (N = 6) Cohort 2 N = 8 • Rosuvastatin < 40 mg • Atorvastatin < 80 mg • Simvastatin 20–80 mg • AMG 145: placebo 3:1 Blinded Dose Level Review Team safety review before dose escalation Cohort 1 N = 8 • Men and women 18–70 years of age • BMI 18–32 kg/m2 • LDL-C 70–220 mg/dL • Triglycerides ≤ 400 mg/dL • With or without heterozygous familial hypercholesterolemia (heFH)

  13. Multiple-dose AMG 145 Reduced LDL-C up to 75% vs Placebo in Subjects on Low- to Moderate-dose Statins (Cohorts 1-5) Mean LDL-C reduction at dosing interval trough: • Up to 75% vs placebo at week 6 after 3 biweekly SC doses of AMG 145 (p < 0.001), • Up to 66% vs placebo at week 8 after 2 SC doses given every 4 weeks (p < 0.001) • Maximum reductions at week 4: • 81% for biweekly dosing • 80% for every-4-week dosing

  14. Multiple-dose AMG 145 Reduced LDL-C by Up to 70% vs Placebo in Subjects on High dose Statins (Cohort 6-7) Mean LDL-C reduction in the HeFH cohort at the end of the dosing interval (Day 43): • 65% vs placebo (p<0.001) • 66% from baseline Maximum LDL-C reduction: • 70% vs placebo (p<0.001) • 73% from baseline Comparable to LDL-C reductions in dose-matched non-HeFH subjects

  15. Treatment Emergent AEs by Treatment Group No clinically meaningful injection-site reactions. No clinically meaningful anti-drug antibodies observed. Stein et al NEJM 2012; 366:1108-18

  16. Inhibition of PCSK9 with mAb • How effective will a mAb be? • very effective LDL-C reductions • How long will effect last? • about 2 to 4 weeks at doses tested • Will the mAb be effective in patients treated with statins, whose LDL-R are already upregulated ? • yes – no difference between diet only • As statins increase PCSK9 levels in plasma if effective will LDL-C reduction be less, the same (additive), or enhanced (synergistic) than monotherapy? • probably additive • In patients with heterozygous familial hypercholesterolemia (HeFH) and a defective LDL-R will PCSK9 inhibition have any significant effect? • yes • Will mAb anti-PCSK9 administration be safe and well tolerated? • Well tolerated in small and short term study

  17. Additional Questions after Phase 1 • Will higher doses be more effective? • Will higher doses produce longer lasting effect? • Will LDL-C effect be maintained if added to maximal dose atorvastatin? • Will initial results seen in small group of HeFH from one center be maintained in larger and more diverse HeFH population with additional LDLr defects? • Will patients with history of muscle related side effects on statins tolerate and respond to PCSK9 mAb? • Will PCSK9 mAb at higher doses, longer administration and when added to maximal dose statin still be safe and well tolerated?

  18. Study Design Treatment Period (12 weeks) Follow-up Period (8 weeks) Screening Period (7 weeks) N=31 Placebo Q2W SAR236553 50mg Q2W N=30 Primary Endpoint %  calculated LDL-C from baseline to week 12 N=31 SAR236553 100mg Q2W LDL-C ≥ 100 mg/dL at Wk-1 while taking atorva 10, 20, or 40 mg for ≥ 6wks N=31 SAR236553 150mg Q2W Secondary Endpoints % in other lipoproteins and apolipoproteinsand % patients reaching pre-specified LDL-C levels N=30 SAR236553 200mg Q4W w/alt placebo N=30 SAR236553 300mg Q4W w/alt placebo Diet* W0 V2 W2 V3 W-7 V1a W-1 V1 W6 V5 W8 V6 W4 V4 W10 V7 W12 V8 W16 V9 W20 V10 *NCEP ATP-III TLC or equivalent diet McKenney et al JACC 2012;59:2344-53

  19. SAR236553 Administered 2 weekly (Q2W) SC: Change in Calculated LDL-C from Baseline to Week 12 ∆ - 5.1% ∆ - 8.5% ∆ - 39.6% ∆ - 30.5% LDL-C Mean (SE) % Change from Baseline ∆ - 53.6% ∆ - 72.4% ∆ - 64.2% ∆ - 62.9% Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12 in the modified intent-to-treat (mITT) population, by treatment group. Week 12 estimation using LOCF method. McKenney et al JACC 2012;59:2344-53

  20. SAR236553 Administered 4 weekly (Q4W) SC: Change in Calculated LDL-C from Baseline to Week 12 ∆ - 5.1% ∆ - 39.6% LDL-C Mean (SE) % Change from Baseline ∆ - 43.2% ∆ - 47.7% ∆ - 72.4% ∆ - 64.2% Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12 in the modified intent-to-treat (mITT) population, by treatment group. Week 12 estimation using LOCF method. McKenney et al JACC 2012;59:2344-53

  21. Additional Questions after Phase 1 • Will higher doses be more effective? No • Will higher doses produce longer lasting effect? The higher the dose the longer the effect • Will LDL-C effect be maintained if added to maximal dose atorvastatin? • Will initial results seen in small group of HeFH from one center be maintained in larger and more diverse HeFH population with additional LDLr defects? • Will patients with history of muscle related side effects on statins tolerate and respond to PCSK9 mAb? • Will PCSK9 mAb at higher doses, longer administration and when added to maximal dose statin still be safe and well tolerated?

  22. Study Design Treatment Period (8 weeks) Follow-up Period (8 weeks) Screening and Run-in Period N=31 SAR236553 Placebo + Atorvastatin 80mg Safety Population N=92 Efficacy Population mITT [LOCF] N=88 N=30 N=214 SAR236553 150mg Q2W + Atorvastatin 80mg Atorvastatin 10mg Screening Visit N=31 SAR236553 150mg Q2W + Atorvastatin 10mg (maintenance dose) W16 D113 Diet* SAR 150mg SQ Q2W W2 D15 W12 D85 W-7 D-49 W0 D1 W6 D43 W-1 D-7 W4 D29 W8 D57 * NCEP ATP-III TLC or equivalent diet Roth et al NEJM 2012; 367:1891-1900

  23. Change in Calculated LDL-C 2-Week Intervals from Baseline to Week 8 BSL 121.1 mg/dL WK8 100.0 mg/dL ∆ - 17.3% LDL-C Mean (SE) % Change from Baseline BSL 120.6 mg/dL WK8 40.4 mg/dL ∆ - 66.2% BSL 120.6 WK8 40.4 ∆ - 66.2% BSL 126.9 mg/dL WK8 36.8 mg/dL ∆ - 73.2% * BSL 126.9 WK8 36.8 ∆ - 73.2% * Roth et al NEJM 2012; 367:1891-1900 * P<0.0001 vs Placebo + A80 *P<0.0001 vs PL + A80mg

  24. Additional Questions after Phase 1 • Will higher doses be more effective? No • Will higher doses produce longer lasting effect? The higher the dose the longer the effect • Will LDL-C effect be maintained if added to maximal dose atorvastatin? Yes – but appears to maximum to LDLr upregulation • Will initial results seen in small group of HeFH from one center be maintained in larger and more diverse HeFH population with additional LDLr defects? • Will patients with history of muscle related side effects on statins tolerate and respond to PCSK9 mAb? • Will PCSK9 mAb at higher doses, longer administration and when added to maximal dose statin still be safe and well tolerated?

  25. RUTHERFORD: Study Design Population • Global trial with ~55 pts per group • 18−75 years, with a diagnosis of HeFH by Simon Broome criteria • LDL-C > 100 mg/dL and triglycerides < 400 mg/dL • At least 4 weeks of stable lipid-lowering therapy (eg, statin, ezetimibe, bile-acid sequestants, niacin) Primary endpoint: % change in LDL-C, measured by ultracentrifugation, from baseline at 12 weeks Raal et al Circulation 2012;126:2408-17

  26. RUTHERFORD: LDLc Changes During Treatment LDL-C based on Friedewald calculation Investigational product administration Raal et al Circulation 2012;126:2408-17

  27. Additional Questions after Phase 1 • Will higher doses be more effective? No • Will higher doses produce longer lasting effect? The higher the dose the longer the effect • Will LDL-C effect be maintained if added to maximal dose atorvastatin? Yes – but appears to maximum to LDLr upregulation • Will initial results seen in small group of HeFH from one center be maintained in larger and more diverse HeFH population with additional LDLr defects? Yes • Will patients with history of muscle related side effects on statins tolerate and respond to PCSK9 mAb? • Will PCSK9 mAb at higher doses, longer administration and when added to maximal dose statin still be safe and well tolerated?

  28. GAUSS: Key Entry Criteria • Statin intolerant: defined as intolerable myalgia (muscle pain, soreness, weakness, or cramps) or myopathy (myalgia plus an elevated creatine kinase level); and having symptom improvement or resolution with statin discontinuation and either • unable to tolerate at least 1 statin at any dose or • unable to tolerate an increase in dose above weekly maximums of rosuvastatin 35 mg, atorvastatin 70 mg, simvastatin 140 mg, pravastatin 140 mg, lovastatin 140 mg, or fluvastatin 280 mg • Elevated LDL-C: above risk-based goals recommended by the National Cholesterol Education Program (NCEP): • ≥ 100 mg/dL (2.59 mmol/L) with diagnosed coronary heart disease (CHD) or risk equivalent • ≥ 130 mg/dL (3.4 mmol/L) without CHD or risk equivalent and ≥ 2 risk factors, or • ≥ 160 mg/dL (4.1 mmol/L) without CHD or risk equivalent and with ≤ 1 risk factor. • Background Rx: Eligible patients could receive stable doses (≥ 4 weeks before screening) of one or more of the following: statins less than or equal to the weekly maximums listed above, bile-acid sequestering resins, or plant stanols/sterols. Sullivan et al JAMA 2012;126:2408-17

  29. GAUSS: Study Design & Entry Criteria Screening and Placebo Run-in Period Randomization 1:1:1:1:1 EOS 280 mg AMG 145 SC Q4W Primary endpoint: Percentage change in LDL-C, by ultracentrifugation, from baseline at 12 weeks 350 mg AMG 145 SC Q4W 420 mg AMG 145 SC Q4W 420 mg AMG 145 SC Q4W and ezetimibe 10 mg Placebo SC Q4W and ezetimibe 10 mg Max. 6 weeks Week 12 Day 1 Week 2 Week 4 Week 8 Visits: Q4W: IP Administration (AMG 145 or placebo) NCEP, National Cholesterol Education Program Sullivan et al JAMA 2012;126:2408-17

  30. GAUSS: Baseline Characteristics * LDL-C measured by ultracentrifugation. SD, standard deviation; NCEP, National Cholesterol Education Program Sullivan et al JAMA 2012;126:2408-17

  31. GAUSS: % Change from Baseline in Calculated LDL-C* At All Visits * Calculated LDL-C values. Q4W, every 4 weeks; QD, daily, CI, confidence intervals Sullivan et al JAMA 2012;126:2408-17

  32. GAUSS: Safety and Tolerability * Four serious adverse events were reported for AMG 145: acute pancreatitis, coronary artery disease, hip fracture, and syncope. None were considered treatment related. AE: Adverse event. Some patients experienced more than 1 AE. Sullivan et al JAMA 2012;126:2408-17

  33. Additional Questions after Phase 1 • Will higher doses be more effective? No • Will higher doses produce longer lasting effect? The higher the dose the longer the effect • Will LDL-C effect be maintained if added to maximal dose atorvastatin? Yes – but appears to maximum to LDLr upregulation • Will initial results seen in small group of HeFH from one center be maintained in larger and more diverse HeFH population with additional LDLr defects? Yes • Will patients with history of muscle related side effects on statins tolerate and respond to PCSK9 mAb? Yes • Will PCSK9 mAb at higher doses, longer administration and when added to maximal dose statin still be safe and well tolerated? Although only administered for relatively short period, over 1200 patients have received mAb to PCSK9 , and safety continues to be encouraging.

  34. Therapeutics Targeted to PCSK9 in Development: Conclusion • Inhibition of PCSK9 with fully human mAbs is a very promising, and potentially the most effective, approach to reducing LDL-C including patients: • With nonFH, HeFH and LDLr defective HoFH • On statins or diet alone and • Those unable to tolerate statins, or effective doses of statins. • Additive to all existing therapy • SC delivery every 2 or 4 weeks • In large phase 2 program of 2 agents of over 1200 patients no significant adverse effects have emerged so far • Phase 3 programs including 2 large CVD outcome trials are already underway with the Amgen (AMG 145) and Sanosi (alirocumab) fully human monoclonal antibodies

  35. Status of Current Therapeutics Targeted to PCSK9 in Development Stein & Swergold. Curr Atheroscler Rep (2013) 15:310DOI 10.1007/s11883-013-0310-3 *LNA locked nucleic acid

  36. Thank you

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