Hypercholesterolaemia is there a place for PCSK9-inhibitor therapy?

Transcription

1 Hypercholesterolaemia is there a place for PCSK9-inhibitor therapy? Derick Raal FCP(SA), FRCP, FRCPC, Cert Endo, MMED, PHD Head, Division of Endocrinology & Metabolism Director, Carbohydrate and Lipid Metabolism Research Unit Faculty of Health Sciences, University of the Witwatersrand

2 200 YEARS AGO CHOLESTEROL Cholesterol, from the Ancient Greek chole (bile) and stereos (solid) is a steroid synthesised by all animal cells which is essential for life. Francois Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769 but it was not until 1815 that the chemist Michel Eugene Chevreul named the compound cholesterine. Steinberg D. J Lipid Res 2004;45:

3 Lipids and lipoprotein metabolism TRIGLYCERIDE Energy Storage Energy Production Steroid Synthesis CHOLESTEROL Cell Membranes Bile Acids Steinberg D. J Lipid Res 2004;45:

4 100 YEARS AGO Atherosclerosis in experimental animals The fact that rabbits could be made hypercholesterolaemic just by feeding them pure cholesterol and that their arteries then showed lesions closely resembling those of human atherosclerosis, was beautifully demonstrated in 1913 by Nikolai Anitschkow. Anischkow N.N, Chalatov S. Zentralbl Allg Pathol 1913;24:1 9

5 75 YEARS AGO Hypercholesterolaemia as a causative factor in the human disease In 1939, the Norwegian scientist Carl Müller pulled together many case reports of hereditary xanthomatosis and concluded that the marked hypercholesterolaemia in these cases was the cause of both the skin lesions and the lesions in the coronary arteries. Muller C. Arch Int Med 1939;64:

6 50 YEARS AGO In 1964 Khachadurian, at the American University in Beirut, described FH as an autosomal dominant disease and showed that FH exists in two forms: the less severe heterozygous form and the more severe homozygous form. Khachadurian A. Am J Med 1964;37:402 7

7 30 YEARS AGO Goldstein and Brown s discovery of the LDL receptor genes as the specific mutation in familial hypercholesterolaemia in 1985, was a major milestone. Science ;34 47

8 LDL RECEPTORS Most cells in the human body have 20,000 to LDL receptors on their cell surface. Each LDL receptor makes one round trip to and from the cell membrane every 10 minutes in its 20 hour lifespan. As each LDL particle contains 1600 molecules of cholesterol, this rapid recycling of LDL receptors provides an efficient mechanism for delivery of cholesterol to the cell. Goldstein & Brown. The LDL receptor ATVB 2009;29:431-38

9 The Human LDL Receptor Chromosome LIGAND BINDING DOMAIN 292 Amino Acids NH 2 C B A 2. EGF PRECURSOR HOMOLOGY ~ 400 Amino Acids C 3. O-LINKED SUGARS 58 Amino Acids Cysteine COOH 4. MEMBRANE-SPANNING 22 Amino Acids 5. CYTOPLASMIC 50 Amino Acids Goldstein & Brown. The LDL receptor ATVB 2009;29:431-38

10 Familial hypercholesterolaemia Mother Father Offspring X X X X X X LDL receptor locus on chromosome 19 X FH Heterozygote 1 in in population Half normal number of LDL receptors 2 fold increase in plasma LDL C Heart attacks begin at age 35 FH Homozygote 1 in to 1 million in population Few or no LDL receptors 4 to 6 fold increase in plasma LDL C Heart attacks begin in childhood Cuchel M et al. Eur Heart J 2014;35:

11 13 YEARS AGO In 2003 Marianne Abifadel from Lebanon described two gain of function mutations in the PCSK9 gene which resulted in a FH phenotype. It was subsequently found that PCSK9 was involved in the regulation of the LDLR and that it binds to the LDLR LDL complex extracellularly and, following endocytosis, targets the LDLR for lysosomal degradation. Abifadel M. Nat Genet 2003;34:154 6

12 PCSK9 Rapid progress from discovery to clinic First MAD phase 1b trials with PCSK9 mab started including FH, non-fh, statin Rx Phase 2 trials in-progress published for REGN727 including FH, Q2W/Q4W dosing Phase 3 trials complete for 2 mabs, BLA* filed and CVD outcome trials started First subjects treated with PCSK9 mab in SAD studies 1st publications MAD POC in FH, nonfh on statin or diet Phase 2 trials published for AMG145 including HoFH, Statin intol, Q2W/Q4W Early data on CVD benefit Marketing approval USA/Europe *BLA Biologics licensing application Seidah. Circ Res 2014:114:

13 PCSK9 Inhibitors (Proprotein convertase subtilisin/kexin type 9) PCSK9 is a serine protease that is an extracellular regulator of LDL receptors PCSK9 binds to the EGF-A extracellular domain of the LDLR. After binding and internalisation, PCSK9 directs the LDLR to lysosomal degradation rather than for recycling

14 Liver The Role of PCSK9 (proprotein convertase subtilisin/kexin 9) in the regulation of the LDL Receptor LDL Apo B Hepatocyte LDLR proteins LDLR Proteolysis PCSK9 Internalization and degradation LDL mrna SREBP2 activation Statins Decreased free cholesterol diet low in saturated fat and cholesterol Alan Tall, N Engl J Med 2006;354:1310-2

15 Hypercholesterolemia Associated With PCSK9 GOF Mutations F216L mutation 1 French proband died from MI Age: 49 years R218S mutation 2 French proband presented with tendinous xanthoma and arcus corneae Age: 45 years TC: 10.4 mmol/l LDL-C: 7.8 mmol/l TC: 11.4 mmol/l LDL-C: 9.2 mmol/l Tendon xanthoma 3 TC = total cholesterol. 1. Abifadel M, et al. Nat Genet. 2003;34: Abifadel M, et al. Hum Mutat. 2009;30: Durrington P. Lancet. 2003;362: Podrid PJ. UpToDate; March 1, Reprinted from The Lancet, Vol. 362, Durrington P, Copyright 2003, with permission from Elsevier.

16 Genetics and genetic heterogeneity of FH A B x x LDLRAP1 PCSK9 APOB x x x x LDLR Normal subject FH heterozygote FH homozygote x Normal allele FH mutationbearing allele Chr 1 Chr 2 Chr 19 LDLRAP1=Low density lipoprotein receptor adapter protein 1 PCSK9=Proprotein convertase subtilisin/kexin type 9 APOB=Apolipoprotein B LDLR=Low density lipoprotein receptor Cuchel M et al. Eur Heart J 2014;35:

17 Mean LDL C Levels (mmol/l) in Patients with GOF and LOF PCSK9 Mutations D35Y 6.4 L108R 6.9 GOF mutations S127R F216L R218S D374Y Control LOF mutations R46L R97 G106R Y142X C679X GOF = Gain of function; LOF = loss of function. Modified from Poirier,. Drug Des Devel Ther 2013; 7:

18 Distribution of plasma LDL cholesterol levels and incidence of CHD among black subjects according to the presence or absence of PCSK9 142X or PCSK9 679X allele No Nonsense Mutation (N=3278) 50 th Percentile 12 88% reduction in 15-year coronary event rate!! Frequency (%) PCSK9 142X or PCSK9 579X (N=85) 28% lower LDL-C level Coronary heart disease (%) No P=0.008 Yes 10 PCSK9 142X or PCSK9 679X Plasma LDL cholesterol in black subjects (mmol/l) J Cohen et al, N Engl J Med 2006; 354:

19 Case Reports of Patients Double Loss-of-Function PCSK9 Mutations 32 year-old Caucasian woman had no measurable PCSK9 and a LDL-C of 0.36 mmol/l. (Am J Hum Genet. 2006;79: ). 21 year-old Zimbabwean woman had no measurable PCSK9 and a LDL-C of 0.39 mmol/l. (Atherosclerosis. 2007;193: ) 49 year-old French male had no detectable PCSK9 levels and a LDL-C of 0.41 mmol/l. (Arterioscler Thromb Vasc Biol. 2009;29: )

20 Relation between proportional reduction in incidence of major CAD and vascular events and mean absolute reduction in LDL cholesterol at 1 year N= subjects from 14 statin trials For every 1 mmol/l reduction in LDL cholesterol there is : a) a % reduction in major CAD or vascular events b) a 12% reduction in overall mortality Proportional reduction in event rate (SE) 50% 40% 30% 20% 10% 0% -10% 50% 40% 30% 20% 10% Major coronary events Major vascular events CTT Collaborators Lancet 2005;366: % -10%

21 With each doubling of statin dose only results in a further 6% reduction in cholesterol 25 Change in Serum Cholesterol Concentration (%) Rule of 6! LDL cholesterol with statin Statin (mg/day)

22 Statin therapy and upregulation of PCSK9 Statins SREBP 2 PCSK9 LDLR SREBP2 = Sterol regulatory element binding protein 2 LDLC Zhang L. Int J Biol Sci 2012;8:

23 Proportion of FH patients on LDL-C targets for different treatment goals 100 Attainment of target (%) N= LDL-C target (mmol/l) Pijlman AH, Atherosclerosis 2010;209:189-94

24 PCSK9 inhibitors currently available or under development Company Drug Mechanism of Action Phase of development Amgen Evolocumab AMG 145 mab III Sanofi/Regeneron Pharmaceuticals Alirocumab REGN727(SAR236553) mab III Pfizer Bristol Myers Squibb/Adnexus Bococizumab RN316(PF ) mab BMS Adnectin II III Alnylam Pharmaceuticals ALN PCS02 sirna II ALN PCS02sc sirna Idera Pharmaceuticals N/A Antisense oligonucleotide Serometrix SX PCK9 Small peptide mimetic Shifa Biomedical Corporation N/A Small molecule inhibitor of autocatalytic processing Preclinical Preclinical Preclinical mab=monoclonal Antibody Adapted from Blom D et al. Clin Lipidol 2013;8(2):243 56

25 Catabolism of LDL, the role of PCSK9 and antibody to PCSK9 LDL LDL receptor Endocytosis LDL R synthesis Endosome Clathrin coated vesicle PCSK9 processing/ export Endoplasmic reticulum Golgi apparatus Nucleus SREBP Hepatocyte Lysosome modified from Hovingh G K, et al. Eur Heart J 2013;34:962-71

26 Catabolism of LDL, the role of PCSK9 and antibody to PCSK9 mab LDL LDL receptor Endocytosis Recycling of LDL R LDL R synthesis Clathrin coated vesicle Golgi apparatus Endosome PCSK9 processing/ export sirna or ASO Endoplasmic reticulum Nucleus SREBP Hepatocyte Lysosome modified from Hovingh G K, et al. Eur Heart J 2013;34:962-71

27 Mean percent change from baseline in LDL-C values among healthy volunteers in single-dose studies Subcutaneous administration of Alirocumab Mean change from baseline in LDL-C (%) Placebo 50 mg 100 mg 150 mg 250 mg Study Day Stein E. N Engl J Med 2012;366:

28 RCTs (Phase III trials) with PCSK9 inhibitors recently published or presented RCT DESCARTES LAPLACE-2 GAUSS-2 MENDEL-2 RUTHERFORD 2 TESLA ODYSSEY MONO ODYSSEY COMBO II ODYSSEY FH I and II ODYSSEY long-term ODYSSEY ALTERNATIVE ODYSSEY High FH ODYSSEY COMBO I Study Design Long-term efficacy & safety Combination therapy with statins Statin intolerance Monotherapy Heterozygous FH Homozygous FH Comparison with ezetimibe in pts with hypercholesterolaemia at mod CV risk Comparison with ezetimibe Heterozygous FH Combination with statins Statin intolerance Severe heterozygous FH On top of maximally tolerated statins ± other lipid-lowering drugs in high risk patients Net LDL-C reduction (%) -49 to to to to to to to -49 ODYSSEY OPTIONS I and II Comparison of different strategies to further reduce LDL-C in high-risk pts. not a goal -20 to -37 De Backer et al. Eur Heart J 2015;36:

29 The Rutherford 2 Study Reduction of LDL C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Design: A 12 week, randomized, double blind, placebo controlled, multicenter phase 3 study Objective: To evaluate the efficacy and safety of evolocumab (AMG 145) 140 mg Q2W and 420 mg QM administered subcutaneously in a large cohort of HeFH patients unable to achieve an LDL C < 2.6 mmol/l despite statin therapy with or without ezetimibe Raal et al. Lancet 2015;385:331 40

30 Rutherford 2 Study design Evolocumab 140 mg SC Q2W N = 111 a Screening Period with Placebo Injection Randomization 2:2:1:1 Evolocumab 420 mg SC QM N = 110 Placebo SC Q2W N = 55 a End of Study Placebo SC QM N = 55 Max. 6 weeks Day 1 Week 2 Week 4 b Week 6 b Week 8 Week 10 Week 12 Week 14 c Evolocumab or placebo SC Q2W Evolocumab or placebo SC QM a N s are number of patients randomized. One patient in each of the placebo Q2W and evolocumab Q2W groups did not receive any doses of the study drug and were not included in the analyses b Injections at weeks 4 and 6 were done at home c Week 14 was a follow up call for Q2W patients to capture adverse events and concomitant medications Raal et al. Lancet 2015;385:331 40

31 Rutherford 2 Mean percentage change from baseline in LDL cholesterol in the four groups. Mean LDL C baseline = 4 mmol/l Change from baseline in LDL cholesterol (%) Baseline Evolocumab every 2 wks.. Evolocumab monthly.. Week 2 Placebo monthly (n=55) Placebo every 2 weeks (n=54) 140 mg evolocumab every 2 weeks (n=110) 420 mg evolocumab monthly (n=110).. Study Week Week 8.. Week 10 Week 12.. Raal et al. Lancet 2015;385:331 40

32 LDL C goal achievement < 1.8 mmol/l week % 60.9% Percent achieving LDL C < 1.8 mmol/l % 63.1% 0 2.0% 2.2% Placebo Q2W (n=54) Evolocumab 140 mg Q2W (n=110) Placebo QM (n=55) Evolocumab 420 mg QM (n=110) Raal et al. Lancet 2015;385:331 40

33 RUTHERFORD 2 study: Reduction in LDL C according to LDL receptor status B Percent changes from baseline in LDL C Negative Defective Unclassified No mutation identified 80 Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Raal et al. Lancet 2015;385:331 40

34 The TESLA Part B Study Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities Part B Design A 12 week randomized, double blind, placebocontrolled multicenter phase 3 study Objective To evaluate the efficacy and safety of evolocumab in patients with HoFH Raal et al. Lancet 2015;385:341 50

35 TESLA Study design Screening period Fasting LDL C 5 10 days before randomization Randomization * 2:1 Evolocumab 420 mg SC QM (N = 33) Placebo SC QM (N = 17) End of Study Visits: Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Dosing QM: Study drug administration *Randomization stratified by screening LDL C (<10.9 mmol/l or 10.9 mmol/l). Week 2 and week 10 study visits were optional. Primary endpoint: Percent change from baseline in Ultracentrifugation LDL C at week 12 Raal et al. Lancet 2015;385:341 50

36 TESLA Percent change in UC LDL C from baseline to week 12 Percent change from baseline in UC LDL C, Mean (%) Placebo (N = 16) Evolocumab 420 mg QM (N = 33 ) Baseline Week 4 Week 6 Week 8 Week 12 Study drug administration Study Week Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values. Raal et al. Lancet 2015;385:341 50

37 TESLA LDL C lowering by type of mutation Percent Change from Baseline in UC LDL C at Week 12, Mean (SE) Mutation status N Placebo Evolocumab 420 mg QM Treatment difference All LDLR Defec ve/any Defective/defective Negative/Defective Unclassified Median (Q1, Q3) Negative/negative LDLR heterozygous Apolipoprotein B ARH (5.3) 11.2 (5.1) 15.1 (7.3) 3.5 (5.8) 3.8 (11.7) 7.2 (0.0, 9.9) 10.8, (3.4) 31.8 (5.8) 21.0 (4.0) 17.9 (8.8) 39.2 (48.8, 14.6) (6.4)* 40.8 (6.1) 46.9 (9.4) 24.5 (7.0) # 21.7 (13.9) Data are least squares (LS) mean for groups with sufficient data; otherwise actual value at week 12. LS mean is from the repeated measures model, which includes treatment group, screening LDL, scheduled visit and the interaction of treatment with scheduled visit as covariates. * Adjusted P value < 0.001; Receptor defective in at least one of two affected alleles. Nominal P value < 0.001; # Nominal P value = 0.013; ǁ Function of one or both LDLR mutations is unknown (includes 6 patients from the defective/any group). Raal et al. Lancet 2015;385:341 50

38 LDL-cholesterol levels in FH From a lethal disorder to a manageable dyslipidaemia LDL-C levels (mmol/l) First synvinolin study ASAP ENHANCE RUTHERFORD TESLA ODYSSEY FH I & II No therapy Simva 40 mg Atorva 80 mg Simva 40 mg Simva 80 mg Simva + Eze 10 mg + Evolocumab or Alirocumab Kastelein JJP. Nat Rev Cardiol. 2014;11:

39 Treatment algorithm for FH Severe FH patients Initiation of high-intensity statin monotherapy is standard of care Statin Ezetimibe is added when patient is not at LDL-C threshold Cholesterol absorption inhibitor Bile acid sequestrants,? fibrates and niacin are added alone or in combination for those not at LDL threshold Add a PCSK9 inhibitor Apheresis for patients on maximally tolerated therapy and LDL-C > 7.8 mmol/l or CAD and LDL-C > 5.2 mmol/l. Mipomersen and lomitapide for HoFH Bile acid? Fibrate sequestrant? Niacin PCSK9 inhibitor Apheresis Mipomersen Lomitapide Adapted from Sniderman A, et al JACC 2014;63:

40 Patients with progressive coronary artery disease despite high dose statin +/- ezetimibe therapy - Is there a place for of PCSK9 Inhibitors in non-fh patients? Patients unable to tolerate statins or effective doses of statins - statin intolerance

41 PCSK9 Inhibitor CVD Outcomes Trials Evolocumab Alirocumab Bococizumab Sponsor Amgen Sanofi / Regeneron Pfizer Trial FOURIER ODYSSET outcomes SPIRE I SPIRE II Sample size 27,500 17,000 17,000 9,000 Patients MI, stroke or PAD 4052 wks post-acs High risk of CV event Statin Atorva 20 mg or equiv Evid.-based med Rx Lipid-lowering Rx LDL-C (mmol/l) PCSK9i Dosing Q2W or Q4W Q2W Q2W Endpoint 1º: CV death, MI stroke, revasc. or hosp for UA Key 2º: CV death, MI or stroke CHD death, MI, ischaemic stroke, or hospital for UA CV death, MI, stroke, or urgent revasc. Recruitment status Completed June 2015 Projected for Dec 2015? Completion 2016/2017 1/2018 8/ (accessed September 6, 2015)

42 The Role of PCSK9 Inhibitors Inhibition of PCSK9 with fully human mabs is a very promising, and very effective, approach to reducing LDL cholesterol further in: Severe heterozygous FH or non-fh patients who have not responded adequately to statin +/- ezetimibe therapy alone The 70-95% of HoFH patients with defective LDLR activity Patients with progressive coronary artery disease despite high dose statin +/- ezetimibe therapy Patients unable to tolerate statins or effective doses of statins - statin intolerance Adapted from Stein EA, Raal FJ. Endocrinol Metab Clin N Am 2014;43: