Antisense and Antibodies as Game changers in refractory dyslipidemia. Erik Stroes AMC

Transcription

1 Antisense and Antibodies as Game changers in refractory dyslipidemia Erik Stroes AMC

2 Asymptomatic phase Plaque rupture There is a significant residual CVD risk at least partially modifiable Postponement of coronary event Clinical event horizon Gain in event free years Statin Combination therapy Primordial prevention of atherogenesis Total modifiable risk Residual modifiable risk Probability of a clinical event without prevention with first-line statins combination therapy with optimal risk factors Non-modifiable Non-modifiable risk risk age, sex, age, genetics sex, genetics Packard et al. Vascul Pharmacol 2015;71: Age

3 Lipid disorders are major risk factors for atherosclerotic CVD LDL-C: primary risk factor in CHD and causative for development of coronary atherosclerosis 6 Hypertension 1 Smoking, physical inactivity 1 Prior CV event/manifest atherosclerosis 3 Age, ethnicity, gender, family history/genetic variations 1 Lipid disorders 1 (LDL, HDL, TG ) Increased CV risk Metabolic syndrome 2 Type 2 diabetes 1 High CRP, 4 chronic kidney disease 5 Obesity 1 1. World Heart Federation. Cardiovascular disease risk factors. 2. Dekker et al. Circulation 2005;112: Bhatt et al. JAMA 2010;304: Lagrand et al. Circulation 1999;100: Go et al. N Engl J Med 2004;351: Grundy et al. J Am Coll Cardiol 1999;34:

4 Major lipid targets for CVD prevention Genetic test of LDL and HDL hypothesis Do people with more LDL-raising alleles have higher MI risk? Change in MI risk YES 113% P=10-10 Do people with more HDL-raising alleles have lower MI risk? Change in MI risk NO No effect P=0.63 Voight et al. Lancet. 2012; 380:

5 Mutations in major LPL-pathway genes affect [TG] and risk for CVD-risk Remnant cholesterol Triglycerides Cholesterol

6 MI Risk MI Risk Lipoprotein Pathways for CVD-risk Epidemiology Genetics Therapy LDL Plasma Level LDLR PCSK9 NPC1L1 Statins PCSK9 Abs Ezetimibe HDL Plasma Level Common variants: no effect on MI Rare variants: no effect on MI HDLraising therapy Failed TG Plasma Level Common variants: Yes Rare variants: LPL, APOC3, APOA5, ANGPTL4?

7 There are multiple reasons why Lipid targets are not achieved Absence of effective therapy 1,2 Triglyceride-rich remnants, Lipoprotein(a) Lack of potency 1 81% of patients with Familial Hypercholesterolemia do not reach target LDL-C despite maximal lipid-lowering therapy Low tolerance to available therapy % of statin users experience muscle complaints, whereas ~2% discontinues statins due to muscle-related complaints 1. Béliard et al. Atherosclerosis 2014;234: NCEP Expert Panel. Circulation 2002;106: Cohen et al. J Clin Lipidol 2012;6: Kuklina et al. MMWR Morb Mortal Wkly Rep 2011;60:

8 What is a game-changer for refractory dyslipidemia? Definition: Something that affects an area very much: - having a powerfull effect - unfailing Candidate game-changers Compound Target I] PCSK9- antibodies LDLc reduction II] Apo(a)-antisense Lp(a) reduction III] ApoCIII-antisense TG/TRL reduction

9 I] PCSK9 A serine proprotein convertase 1 Expressed in hepatocytes, kidney mesenchymal cells, intestinal ileum and colon epithelia, CNS 2 Regulates hepatic LDLRs, which bind and internalise LDL particles LDLR PCSK9 1. Catalytic domain 2. Prodomain 3. C-terminus 1. Abifadel et al. Hum Mutat 2009;30: Seidah et al. Proc Natl Acad Sci USA 2003;100: Horton et al. J Lipid Res 2009;50:S172 S177.

10 Plasma LDL-C is controlled by hepatic low density lipoprotein receptor (LDLR) levels LDL particles Increased LDL-R surface concentration LDL-R Recycling of LDL-R Brown et al. Proc Natl Acad Sci USA 1979;76:

11 PCSK9 reduces LDLR recycling, thereby increasing plasma LDL-C LDL particles LDL-R PCSK9 routes LDL-R for lysosomal degradation LDL-R recycling blocked PCSK9 secretion Horton et al. J Lipid Res 2009;50:S172 S177.

12 Genetic variants of PCSK9 demonstrate its importance in regulating LDL levels PCSK9 gain of function (GOF) = Fewer LDLRs 1 (rare 2 ) GOF variant Population Characteristics D374Y British, Norwegian families, 1 Utah family Premature CHD, tendon xanthomas, severe hypercholesterolaemia S127R French, South African, Norwegian patients Tendon xanthomas; CHD, early MI, stroke D129G New Zealand family Brother died at 31 from MI; strong family history of CVD PCSK9 loss of function (LOF) = More LDLRs 3 (more common 2 ) LOF variant Population LDL-C CHD risk R46L ARIC, DHS 15% 47% Y142X or C679X ARIC, DHS 28% 40% 88% R46L CGPS 11% 46% 1. Abifadel et al. Hum Mutat 2009;30: Dadu et al. Nat Rev Cardiol 2014;11: Benn et al. J Am Coll Cardiol 2010;55:

13 Frequency (%) CHD (%) Loss-of-function variants in PCSK9, with lifetime low LDL-C, are associated with a lower risk of CV events Genetic PCSK9 LDL-R Serum LDL-C CHD Plasma LDL-C in black subjects (mg/dl) Nonsense mutation 12 P= (N=85) th percentile with no nonsense mutation 4 88% No Yes Nonsense mutation Cohen et al. N Engl J Med 2006;354;

14 Antibody-based therapeutics have a long history Discovery milestones Serum therapy used as treatment against diphtheria and tetanus Side-chain theory predicted substances today called antibodies First idea of a "magic bullet" Discovery of antibody chemical structure Development of hybridoma technology Production of first monoclonal antibody Nobel prizes Emil Adolf von Behring Paul Ehrlich Gerald Edelman Rodney Porter Georges Köhler Accessed 10 Jan Accessed 10 Jan Zhou et al. Annu Rev Pharmacol Toxicol 2011;51: Accessed 10 Jan Caravella et al. Curr Comput Aided Drug Des 2010;6: Accessed 10 Jan Ecker et al. MAbs 2015;7:9 14. César Milstein >40 Ab-based therapies approved in the EU >300 in development

15 Fully human antibodies are less immunogenic than those containing elements of mouse antibodies Mouse (0% human) Chimeric (65% human) Humanised (> 90% human) Fully human (100% human) Generic suffix -omab -ximab -zumab -umab Examples: Infliximab Bococizumab Evolocumab Alirocumab High Potential for immunogenicity Low Weiner. J Immunother 2006;29:1 9. Yang et al. Crit Rev Oncol Hematol 2001;38: WHO INN (International Nonproprietary Names) Working Document

16 % change in LDL-C from baseline at mean of Weeks 10 and 12 Evolocumab reduces LDL-C by 60% by 1 injection per 2-4 weeks Moderate-intensity statin 1 (simvastatin 40mg) High-intensity statin 1 (atorvastatin 80mg) Statin + ezetimibe 2 Primary hypercholesterolaemia or mixed dyslipidaemia HeFH Evolocumab 140mg Q2W Placebo Q2W 1. Robinson et al. JAMA 2014;311: Raal et al. Lancet 2015;385:

17 Mean % change in LDL-C from baseline Evolocumab significantly reduces LDL-C in patients with heterozygous FH % % vs placebo % -80 Baseline Study week Placebo Q2W (n=54) Evolocumab 140 mg Q2W (n=110) Raal et al. Lancet 2015;385:

18 Mean % change in LDL-C from baseline Evolocumab significantly reduces LDL-C in patients unable to tolerate statins % 40 37% vs ezetimibe 60 56% 80 BL Day Study week Ezetimibe QD + placebo Q2W (n=51) Evolocumab 140 mg Q2W + placebo oral QD (n=103) Stroes et al. J Am Coll Cardiol 2014;63:

19 ODYSSEY LONG TERM Study Design HeFH or High CV-risk patients On max-tolerated statin other lipid-lowering therapy LDL-C 1.81 mmol/l [70 mg/dl] R n=1553 n=788 Double-blind treatment (18 months) Alirocumab 150 mg Q2W SC (single 1-mL injection using prefilled syringe for self-administration) Placebo Q2W SC Follow-up (8 weeks) Assessments W0 W4 W8 W12 W16 W24 W36 W52 W64 W78 Primary efficacy endpoint Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W78 (all patients at least W52) 86% (2011/2341) completed 52 weeks (both treatment arms) 26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) had completed 78 weeks by time of this analysis Mean treatment duration: 65 weeks (both treatment arms) ClinicalTrials.gov identifier: NCT Robinson J, Stroes E, et N Engl J Med 2015

20 LDL-C, LS mean (SE), mmol/l mg/dl ODDYSSEY Outcomes: Long term LDL-C reduction with alirocumab 150 mg Q2W Achieved LDL-C Over Time All patients on background of maximally-tolerated statin ±other lipid-lowering therapy 4 3,5 3 Placebo Alirocumab 3.1 mmol/l mg/dl 3.2 mmol/l mg/dl , ,5 1.3 mmol/l 48.3 mg/dl 1.4 mmol/l 53.1 mg/dl Week 39 Intent-to-treat (ITT) analysis Robinson J, Stroes E, et al N Engl J Med 2015

21 Percent of subjects achieving LDL-C <70mg/dL (1.8 mmol/l) (95% CI) Substantial proportion of patients achieve LDL-C < 1.8mmol/L High-risk patients on high-intensity statin 1 Patients with HeFH 2 Statin-intolerant patients 3 Placebo Q2W Ezetimibe + placebo Q2W Evolocumab 140mg Q2W 1. Robinson et al. JAMA 2014;311: Raal et al. Lancet 2015;385: Stroes et al. J Am Coll Cardiol 2014;63:

22 CVD Event rate (%) CVD events from ODYSSEY LONG TERM and OSLER Trials HR 0.52 (95% CI ) HR 0.47 (95% CI ) Placebo Alirocumab SOC Evolocumab ODYSSEY LONG-TERM OSLER 1 & 2 Robinson JG et al. NEJM 2015; 372: Sabatine MS et al. N Engl J Med 2015;372:

23 No increases in adverse events at very low LDL-C Evolocumab-treated subjects in OSLER programme were stratified by minimum achieved LDL-C Adverse events (AEs), % LDL-C <25 mg/dl (N=773) LDL-C 25 to <40 mg/dl (N=759) LDL-C <40 mg/dl (N=1532) LDL-C 40 mg/dl (N=1426) Any AE Serious AEs Muscle-related AE CK >5 x ULN ALT or AST >3 x ULN Neurocognitive AE Sabatine et al. N Engl J Med 2015;372: Supplementary Appendix.

24 Robinson JG et al. N Engl J Med 2015;372: ODYSSEY Outcomes: Summary of Adverse Events (AEs) by achieved LDL-C: number of patients (%) Alirocumab (N=1550) Alirocumab with 2 consecutive LDL-C <25 mg/dl (N=575) Placebo (N=788) Any AE 1255 (81.0%) 435 (75.7) 650 (82.5%) Serious AE 290 (18.7%) 98 (17.0) 154 (19.5%) AE leading to death 8 (0.5%) 4 (0.7%) 10 (1.3%) AE leading to study drug discontinuation 111 (7.2%) 26 (4.5%) 46 (5.8%)

25 PCSK9 Inhibitor CVD Outcomes Trials Evolocumab Alirocumab Bococizumab Sponsor Amgen Sanofi / Regeneron Pfizer Trial FOURIER ODYSSEY Outcomes SPIRE I SPIRE II Sample size 27,500 18,000 17,000 9,000 Patients MI, stroke or PAD 4-52 wks post-acs High risk of CV event Statin Atorva 20 mg or equiv Evid-based med Rx Lipid-lowering Rx LDL-C mg/dl(mmol/l) 70 ( 1.8) 70 ( 1.8) ( ) PCSK9i Dosing Q2W or Q4W Q2W Q2W 100 ( 2.6) Endpoint 1 : CV death, MI, stroke, revasc or hosp for UA, Key 2 : CV death, MI, or stroke CHD death, MI, ischemic stroke, or hosp for UA CV death, MI, stroke, or urgent revasc Recruitment Status Completed June 2015 Projected for Dec 2015? Completion? /2016? /2017? /2017

26 What is a game-changer for refractory dyslipidemia? Candidate game-changers Compound Target I] PCSK9- antibodies LDLc reduction II] Apo(a)-antisense Lp(a) reduction III] ApoCIII-antisense TG/TRL reduction

27 II] Targeting Apo(a) to Reduce Lp(a) Apo(a) is liver-derived protein linked to an LDL Apo(a) + LDL = Lp(a) Lp(a) is a genetically determined Various apo(a) isoforms with 10 to > 50 kringle IV repeats Schematic of Lp(a) (Koschinsky & Marcovina (2004) Curr Opin Lipol. 15: )

28 Consistent Evidence Demonstrates High Lp(a) as Key Driver of CVD Linear relationship between Lp(a) levels and CVD-risk Modest increases in Lp(a) CVD-risk increase Very high Lp(a) > 2-fold CVD risk increase

29 OxPL-apoB predicts CVD and stroke risk Tsimikas S, J Am Coll Cardiol 2012

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31 Potent & selective Lp(a) reduction by apo(a) antisense once a week

32 LICA Technology LICA increases tissue-specific delivery and efficacy ligand technology utilizing N-Acetylgalactosamine (GalNAc), a highly efficient ligand for the asialoglycoprotein receptor (ASGPR) Much lower ASO drug exposure leads to better tolerability Hepatocyte oligonucleotide concentration at 30 mg Total liver exposure > 10-fold lower

33 What is a game-changer for refractory dyslipidemia? Candidate game-changers Compound Target I] PCSK9- antibodies LDLc reduction II] Apo(a)-antisense Lp(a) reduction III] ApoCIII-antisense TG/TRL reduction

34 III] Apolipoprotein C-III 8.8 kd 79 amino-acids Synthesized in Predominantly in liver Intestine Carried by lipoproteins: Large VLDL 60-90% Small VLDL 40-70% LDL 5-15% Role: Inhibits lipoprotein lipase Inhibits hepatic lipase Inhibits hepatic uptake of TG-rich particles ApoC-III in a complex with an SDS micelle as derived by NMR V. Alexander et al. J Am Coll Cardiol 2012; M. Wyler von Ballmoos et al. J Clin Lipidol 2015

35 Apo-CIII antisense potently reduces ApoC-III (Mean % Change) Gaudet et al. NEJM 2015

36 Apo-CIII antisense potently reduces TG levels (Mean % Change) Gaudet et al. NEJM 2015

37 Apo-CIII antisense also reduces TG levels in patients with LPL-deficiency Gaudet et al. NEJM 2014

38 ApoCIII-as increases hepatic TRL removal in LPL deficient patients Gaudet, N Engl J Med 2014

39 Conclusions in refractory dyslipidemia by antibodies/antisense Revolution for potency and efficacy Even in FH > 70% on LDLc target Even Lp(a)<100g/l in extreme Lp(a) patients Even TG < 5 mmol/l in LPL-deficiency patients Revolution for therapy adherance Sc injection once every 2 4 (12) weeks Very few side effects with ab and LICA-as Refractory dyslipidemias likely to be wiped out in 2019 (?) Real game-changers if prices are realistic!