Management of Dyslipidaemias: PCSK9 Inhibition Alberico L. Catapano Professor President EAS University of Milano Italy
Conflict of interest Grants, consulting fees and/or honoraria and delivering lectures from: Aegerion, BMS, Genzyme, Kowa, Merck, Novartis, Pfizer, Recordati, Roche, and Sanofi- Aventis
Event rate (%) Relationship between LDL-C and CVD 30 25 20 Rx - Statin therapy Pl Placebo Pra pravastatin Atv - atorvastatin Secondary Prevention 4S - Rx 4S - Pl 15 10 5 0 LIPID - Pl LIPID - Rx CARE - Pl CARE - Rx HPS - Rx TNT Atv10 TNT Atv80 PROVE-IT - Pra HPS-Pl WOSCOPS Pl PROVE-IT Atv AFCAPS - Pl 6 AFCAPS - RxIDEAL-Sim WOSCOPS - Rx ASCOT - Pl IDEAL-Atv ASCOT - Rx 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) LDL-C achieved, mg/dl (mmol/l) 160 (4.1) Primary Prevention 180 (4.7) 200 (5.2) AFCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; CARE = Cholesterol and Recurrent Events; HPS = Heart Protection Study; LIPID = Long-term Intervention With Pravastatin in Ischemic Disease; PROVE-IT = Pravastatin or Atorvastatin Evaluation and Infection Therapy; 4S = Scandinavian Simvastatin Survival Study; TNT = Treating to New Targets; WOSCOPS = West of Scotland Coronary Prevention Study. Adapted from Rosenson RS. Exp Opin Emerg Drugs. 2004;9:269-279. LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
CTT: More Intensive LDL Lowering can Decrease CV Events by 40-50 % Event (% per annum) Statin/more Control/less RR (CI) per1 mmol/l reduction in LDL-C Trend test More vs less statin <2 mmol/l 2 to <2.5 mmol/l 2.5 to <3.0 mmol/l 3 to <3.5 mmol/l 3.5 mmol/l Total 704 (4.6%) 1189 (4.2%) 1065 (4.5%) 517 (4.5%) 303 (5.7%) 3837 (4.5%) 795 (5.2%) 1317 (4.8%) 1203 (5.0%) 633 (5.8%) 398 (7.8%) 4416 (5.3%) 0.71 (0.52-0.98) 0.77 (0.64-0.94) 0.81 (0.67-0.97) 0.61 (0.46-0.81) 0.64 (0.47-0.86) 0.72 (0.66-0.78) X 2 =2.04 1 (p=0.2) Statin vs contol <2 mmol/l 2 to <2.5 mmol/l 2.5 to <3.0 mmol/l 3 to <3.5 mmol/l 3.5 mmol/l Total All trials combined 206 (2.9%) 339 (2.4%) 801 (2.5%) 1490 (2.9%) 4205 (2.9%) 7136 (2.8%) 217 (3.2%) 412 (2.9%) 1022 (3.2%) 1821 (3.6%) 5338 (3.7%) 8934 (3.6%) 0.87 (0.60-1.28) 0.77 (0.62-0.97) 0.76 (0.67-0.86) 0.77 (0.71-0.84) 0.80 (0.77-0.84) 0.79 (0.77-0.81) X 2 =0.80 1 (p=0.4) <2 mmol/l 2 to <2.5 mmol/l 2.5 to <3.0 mmol/l 3 to <3.5 mmol/l 3.5 mmol/l Total 910 (4.1%) 1528 (3.6%) 1866 (3.3%) 2007 (3.2%) 4508 (3.0%) 10973 (3.2%) 1012 (4.6%) 1729 (4.2%) 2225 (4.0%) 2454 (4.0%) 5736 (3.9%) 13350 (4.0%) 0.78 (0.61-0.99) 0.77 (0.67-0.89) 0.77 (0.70-0.85) 0.76 (0.70-0.82) 0.80 (0.76-0.83) 0.78 (0.76-0.80) X 2 =1.08 1 (p=0.3) 99% or 95% CI 0.45 0.75 1 1.3 Statin/more better Control/less better Lancet 2010; 376: 1670
Nonfatal MI and CHD death relative risk reduction, % Consistent relationship between LDL-C reduction and CHD relative risk 100 80 60 London Oslo MRC Los Angeles Upjohn LRC NHLBI POSCH 4S WOSCOPS CARE LIPID AF/TexCAPS HPS ALERT PROSPER ASCOT-LLA CARDS 40 20 0 20 Robinson JG et al. J Am Coll Cardiol. 2005;46:1855 1862. 15 20 25 30 35 40 LDL-C reduction, %
LDL during statins and CV risk JACC 2014;64:485
Variable response to intensive statin therapy: 40 % do not get to LDL below 70 :A metaanalysis of 38153 patients JACC 2014;64:485
Density Despite Statin Therapy, Many High-Risk Patients Have Marked LDL Elevations 0,6 0,5 0,4 0,3 1,8 mmol/l (70 mg/dl) Non high-risk High-risk LDL-C 2,6 mmol/l (100 mg/dl) 46,8% 0,2 0,1 0 0 1 2 3 4 5 6 7 LDL-C (mmol/l) Gitt AK et al. Eur J Prev Cardiol 2012; 19: 221 30
NEW APPROACHES FOR THE (NEAR) FUTURE?
The PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) Story From discovery to clinical applications Strategies for inhibition of PCSK9
PCSK9 : Rapid Progress from Discovery to Clinic 2003 PCSK9 (NARC-1) discovered Seidah et al. PNAS 2003; 100: 928-33 PCSK9 GOF mutations (missense mutations) cause Autosomal Dominant Hypercholesterolemia Abifadel et al. Nat Genet 2003; 34: 154-6
LDLR Protein Levels are Increased in Livers of Mice with No PCSK9 PCSK9 Ldlr -/- WT Pcsk9 -/- LDLR P and C denote the proprotein and cleaved forms of PCSK9 Rashid S et al. PNAS 2005; 102: 5374-9
PCSK9 : Rapid Progress from Discovery to Clinic 2005 PCSK9 KO mice LDL-C Rashid et al. PNAS 2005; 102: 5374-9 PCSK9 LOF mutations (nonsense mutations) associated with low LDL-C and large reduction in the incidence of CHD Cohen et al. Nat Genet 2005; 37:161-5 & N Engl J Med 2006; 354:1264-72
LOF (Nonsense) Mutations in PCSK9 PCSK9 Prodomain Y142X Catalytic domain C679X C-terminal % <5% LDL-C Dallas Heart Study n = 3,557 Cohen et al. 2005. Nat. Genet. 37:161-165. LDL Cholesterol
Coronary Heart Disease (%) ARIC: 28% Reduction in LDL - 88% Reduction in CHD in AA with PCSK9 (Y142X or C679X) 12 n = 3,364 HTN - 55% Diabetes - 18% Smoking - 30% 8 4 88% PCSK9 mutations * Y142X or C679X - + * P = 0.008 Cohen et al. 2006. N. Engl. J. Med. 354:1264-1272.
PCSK9 LOF, LDL-C and Risk of CHD Population ARIC Study 1 (US) or PCSK9 Mutation Y142X C679X LDL-C Reduction CHD Reduction 28% 88% R46L 15% 47% 3 independent Danish Studies 2 R46L 14% 34% 1. Cohen et al. 2006. N Engl J Med; 354:1264-1272 2. Benn et al. 2010. J Am Coll Cardiol; 55: 2833-42
FH exposes patients to high cholesterol from birth, with CHD earlier in life Cumulative exposure (cholesterol-yrs) by age: FH vs. unaffected (healthy) individuals Threshold for CHD: Reached on average by: Age 15 for HoFH Age 40 for HeFH Age >60 in healthy individuals Evidence of CVD early in life MI and CHD death at an average age of 42 and 45 years, respectively 1 Carotid arterial wall atherosclerosis progression noted from age 12 onwards 2 Horton et al. J Lipid Res. 2009;50:S172-S177. 1. Williams RR et al, JAMA. 1986;255(2):219-224. 2. Weigman J Lancet 2004; 363: 369-37.
PCSK9 / NARC-1 Subtilisin subfamily Tissue expression: liver, small intestine, kidney (other tissues?) Crystal structure (Piper et al. Structure 2007) PCSK9 is secreted into plasma Its acts primarily as a secreted factor
PCSK9: structure
PCSK9: cellular biology VLDLR ApoER2 (LRP8) LRP1 CD36
PCSK9: cellular biology
PCSK9: cellular biology Presence of PCSK9 Less LDLR Higher plasma LDL-C
Impact of PCSK9 on the LDL receptor Secreted PCSK9 binds to the first EGF-A repeat of the LDL-R at the cell surface Internalization of the PCSK9/LDLR complex Directing the LDLR for degradation in lysosome rather than being recycled Decrease of LDLR on hepatic cell surface
Modulation of PCSK9 levels by lipid-lowering drugs Statins increase human serum levels of PCSK9 Ezetimibe in combination with statins induces a complementary increase in PCSK9 levels Impact of fibrates is controversial
Paradoxical effect of statin treatment Statin SREBP-2 LDL-R + PCSK9 - Hepatocytes LDL-R numbers Farnier M. Am J Cardiovasc Drugs 2011; 11: 145-52
Regulation of the hepatocyte LDL Receptor Farnier M. Am J Cardiovasc Drugs 2011; 11: 145-52 LDL-R LDL Plasma PCSK9 secretion PCSK9 protein LDL protein at cell surface Plasma LDL uptake Endocytosis LDL, LDL-R and PCSK9 degradation Endosome PCSK9 expression LDL-R expression Golgi apparatus SREBP activation Cholesterol internalization Hepatocyte cholesterol content Lysosome Statins
The PCSK9 Story From discovery to clinical applications Strategies for inhibition of PCSK9
PCSK9 inhibitors in development Compound Company Phase of clinical development mabs Alirocumab (REGN727/ Sanofi/Regeneron Phase 3 SAR236553) 1 Evolocumab (AMG 145) 2 Amgen Phase 3 RN-316 (PF-04950615) 3 Pfizer/Rinat Phase 2 (completed) RG 7652 4 Roche/Genentech Phase 2 (on hold looking for partner) LY3015014 5 Eli Lilly Phase 2 LGT209 6 Novartis Phase 2 (discontinued) (1) http://clinicaltrials.gov/ct2/results?term=regn727%2f+sar236553&search=search (2) http://clinicaltrials.gov/ct2/results?term=amg+145&search=search (3) http://clinicaltrials.gov/ct2/results?term=pf-04950615&search=search (4) www.roche.com/irp2q12e-annex.pdf p131 (5) http://clinicaltrials.gov/ct2/show/nct01890967?term=ly3015014&rank=3&submit_fld_opt= (6) http://clinicaltrials.gov/ct2/results?term=lgt209&search=search 28
PCSK9 inhibitors in development Compound Company Phase of clinical development (si)rna ALN-PCS 1 Alnylam Pharmaceuticals Phase I (IV formulation) Adnectin Pre-clinical (SC formulation) BMS-962476 2 BMS Phase I Mimetic Peptides EGF-A peptide 3 Prodomain and C-terminal domain interaction disruption 4 Department of Cardiovascular and Metabolic Disease Research, Schering-Plough Research Institute Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina Pre-clinical Pre-clinical (1) http://clinicaltrials.gov/ct2/results?term=aln-pcs&search=search (2) http://www.clinicaltrials.gov/ct2/show/nct01587365 (3) Shan L, et al. Biochem Biophys Res Commun. 2008.10;375(1):69-73. (4) Du F, et al. J Biol Chem. 2011 286, 43054-43061. 29
Impact of PCSK9 inhibition on LDL receptor expression For illustration purposes only 30
Free/Total PCSK9 Conc. (ng/ml) Total REGN727 (ng/ml) X 0.01 LDL--C mean % change Alirocumab : relationship between mab levels, PCSK9 and LDL-C Free PCSK9, Total REGN727/SAR236553 Concentration and Mean % Change LDL-C vs Time 200 180 160 140 120 0-10 -20-30 100 80-40 60 40 20 0 0 500 1000 1500 2000 2500 2 W 4 W Time (hours) Total REGN727/SAR236553 free PCSK9 LDL-c -50-60 -70
PCSK-9 antibody reduces LDL-C Stein EA et al. N Engl J Med. 2012;366:1108 1118.
Multiple-dose Phase 1 Trial with Alirocumab Subcutaneous dose of 150 mg with Atorvastatin SC injections Days 1 29 43 Stein et al; N Engl J Med 2012; 366: 1108-18 33
Multiple-dose Phase 1 Trial with Alirocumab Subcutaneous dose of 150 mg with Atorvastatin SC injections Days 1 29 43 Stein et al; N Engl J Med 2012; 366: 1108-18 34
Effect of Alirocumab mab 150 mg Every 2 Weeks (data from phase 2 trials) Patient population LDL-C (%) ApoB (%) Lp(a) (%) TG (%) On stable atorvastatin therapy 1-67,3-58,3-28,6-28,6 On atorvastatin 10 mg 2-66,2-54,4-34,7-4,0 Heterozygous FH 3-57,3-43,8-19,5-5,7 Data expressed as % change vs placebo (except ref. 2 : % change vs baseline) 1. Mc Kenney et al. J Am Coll Cardiol 2012; 59: 2344-53 2. Roth et al. N Engl J Med 2012; 367: 1891-900 3. Stein et al. Lancet 2012; 380: 29-36 35
Efficacy of Alirocumab in patients with HC on stable Atorvastatin therapy % change in LDL-C by stratified Atorvastatin dose McKenney et al. J Am Coll Cardiol 2012; 59: 2344-53
Mean (±SE) % change in LDL-C from baseline Change in Calculated LDL-C at Two Weekly Intervals From Baseline to Week 20 Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 16 Week 20 20 10 0-10 -20-30 -40-50 -60-70 -80 Placebo 150mg Q4W 200mg Q4W 300mg Q4W 150mg Q2W Stein EA et al. Lancet. 2012;380:29 36.
Mean % Change in LDL-C from Baseline LAPLACE-2: Percent Reduction LDL-C Mean of Weeks 10/12 (N=1899) 30 20 10 0-10 -20-30 -40-50 -60-70 -80-90 -100 Evolocumab Q2W & Q4W 59 66% reductions LDL-C vs baseline Ezetimibe 17 24% reductions LDL-C vs baseline Atorvastatin 80 mg Rosuvastatin 40 mg All p<0,001 for Weeks 10/12 vs Placebo + Ezetimibe Treatment arm Placebo Q2W Placebo Q4W Atorvastatin 10 mg Ezetimibe QD + Placebo Q2W Ezetimibe QD + Placebo Q4W Adapted from: Robinson JG, et al. JAMA 2014 [In press]. Rosuvastatin 5 mg Simvastatin 40 mg Evolocumab 140 mg Q2W Evolocumab 420 mg Q4W
LAPLACE-2 Safety n (%) Any Statin + Placebo (n=558) Atorvastatin + Ezetimibe (n=221) Any Statin + Evolocumab (n=1117) Any TEAEs 219 (39) 89 (40) 406 (36) Most common AEs a Back pain Arthralgia Headache Muscle spasms Pain in extremity 14 (3) 9 (2) 15 (3) 6 (1) 7 (1) 7 (3) 4 (2) 5 (2) 6 (3) 3 (1) 20 (2) 19 (2) 19 (2) 17 (2) 17 (2) Serious AEs 13 (2) 2 (1) 23 (2) AEs leading to study drug discontinuation 12 (2) 4 (2) 21 (2) Deaths 1 (0,2) 0 (0) b 0 (0) CK >5 x ULN 2 (0,4) 0 (0) 1 (0,1) ALT or AST > 3 x ULN 6 (1) 3 (1) 4 (0,4) Potential injection site reactions c 8 (1) 2 (1) 15 (1) Neurocognitive AEs Cognitive deterioration Disorientation 0 (0) 0 (0) 1 (0,5) 1 (0,5) Post-baseline binding antibodies NA NA 1 (0,1) d 0 (0) 0 (0) a Top 5 in evolocumab treatment group. b One subject died after the end of study. c Reported using high-level term groupings which included injection site (IS) rash, IS inflammation, IS pruritus, IS reaction, and IS urticaria. d Binding antibody was present at baseline and at the end of study. No neutralizing antibodies were detected. Robinson JG, et al. JAMA 2014 [In press].
LDL goal achievement LAPLACE trial showed that AMG 145 reduced LDL-C by up to 64% at week 12 and up to 90% of patients achieving LDL-C <70 mg/dl* High risk patients treated with statins + 140mg Q2W AMG 145 GOAL High risk patients treated with statins *NCEP-ATP III LDL-C goals Amgen data on file. 25 50 75 100 125 150 175 200 225 LDL-cholesterol (mg/dl)
41 ODYSSEY MONO Phase 3 Trial Mean LDL-C and free PCSK9 levels in patients treated with alirocumab according to uptitration status LDL-C Free PCSK9 M. Farnier et al Poster EAS Madrid 2014
PK/PD of Alirocumab 150mg Q4W in Combination with Fenofibrate Dotted lines indicate no measurement taken for this period J. Rey et al Poster #1183/131 ACC 2014 42
ODYSSEY MONO Phase 3 Trial Safety Ezetimibe 10 (N=51) Alirocumab 75 Q2W/150 Q2W (N=52) Patients with any TEAE 40 (78,4%) 36 (69,2%) Patients with any treatment emergent SAE 1 (2,0%) 1 (1,9%) Patients with any TEAE leading to death 0 0 Patients with any TEAE leading to permanent treatment discontinuation 4 (7,8%) 5 (9,6%) n (%) = number and percentage of patients with at least one TEAE Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became serious during the TEAE period TEAE period: The TEAE observation period is defined as the time from the first dose of double-blind IMP to the last dose of double-blind IMP injection + 70 days (10 weeks) as residual effect of alirocumab is expected until 10 weeks after the stop of double-blind IMP injection. M. Farnier et al Poster EAS Madrid 2014
Phase 3 Trials: Alirocumab, Evolocumab, Bococizumab Trial Type HeFH Combo Therapy Monotherapy Statin Intolerance LTS Alirocumab Double- Blinded Trials ODYSSEY FH I ODYSSEY FH II ODYSSEY HIGH FH ODYSSEY COMBO I ODYSSEY COMBO II ODYSSEY OPTIONS I ODYSSEY OPTIONS II ODYSSEY MONO ODYSSEY ALTERNATIVE ODYSSEY LONG- TERM Total Number of Patients 4892 N Duration (Mos) Patient Exposure (Yrs) Minimum LDL-C Levels (mg/dl) 471 18 496 100 250 18 250,5 100 105 18 106,5 160 306 12 210 70 660 24 960 70 350 6 50 70 300 6 50 70 Evolocumab Double- Blinded Trials N Duration (Mos) Patient Exposure (Yrs) Minimum LDL-C Levels (mg/dl) Bococizumab Double- Blinded Trials N Duration (Mos) Patient Exposure (Yrs) Minimum LDL-C Levels (mg/dl) RUTHERFORD-2 300 3 46 100 SPIRE-HF 300 12 200 70 LAPLACE-2 1700 3 231 80 100 6 25.5 100 MENDEL-2 600 3 92 100 250 6 50 70 2100 18 2340 70 4538 patient-years In double-blind placebo controlled trials GAUSS-2 300 3 46 None GAUSS-3 500 3 NA NA DESCARTES 905 12 602 75 OSLER Open label 3515 12+ TBD TBD Total Number of Patients 7820 1017 patient-years In double-blind placebo controlled trials SPIRE-HR 600 18 600 70 SPIRE-LDL 1600 18 1600 70 PLANNED SPIRE-LL 939 12 626 >100 Total Number of Patients 3439 ~3000 patient-years (assumes 2:1 randomization, final number likely to be larger as anticipate additional trials) CVD Outcomes Trials ODYSSEY OUTCOMES 18000 Event Driven N/A 70 FOURIER 22500 Event Driven N/A 70 SPIRE-1 12000 SPIRE-2 6300 Event Driven Event Driven N/A 70 & <100 N/A >100 ClinicalTrials.gov. available at: http://clinicaltrials.gov. Accessed May 20, 2014. 44
PCSK9 Monoclonal Antibody Therapy Evidence to date Very effective lowering of LDL-C, non HDL-C, ApoB Positive effects on Lp(a), TG Lipid effects in monotherapy and additive to other LDL lowering drugs No short-term safety issues (months) Unanswered issues Longer term lipid efficacy (dosing interval) Longer term safety profile Immune effects over time CVD outcome trial efficacy Other issues Relevance of other therapies at very low LDL-C levels Cost
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