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Next-Generation Sequencing Transforms Today's Biology

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Next-Generation Sequencing Transforms Today's Biology Evolving new therapies for the prevention of atherosclerosis: a glimpse of the near future G.K. Hovingh MD PhD ([email protected]) Department of Vascular Medicine AMC Amsterdam The Netherlands Today BMJ 2013;347:f544 www.chinadaily.com.cn/life/2009- 04/21/content_7698500.htm What we know - CVD major burden - LDL-C causally related with CVD - LDL-C goals: the lower the better - Statins : corner stone in therapy How well do we do? Reduction in MACE statin vs placebo (%) 0 -30 Potential for further risk reduction -100 Where do we go? Reduction in MACE statin vs placebo (%) 0 Potential for further -30 risk reduction -50 = further LDL-C lowering? and or Additional Rx? -100 A glance at the future… Atherosclerosis • LDL • HDL • TG • Lp(a) • Inflammation Lipid Modifying Drugs • Cholesterol absorption inhibitors • Squalene synthase inhibitors (SSI) • Microsomal triglyceride transfer protein (MTP) inhibitors • Acyl coenzyme A acyltransferase (ACAT) inhibitors • Diacylglycerol acyltransferase (DGAT) inhibitors • Thyroxin receptor agonists • ApoB mRNA antisense drugs • PCSK9 antibodies • ApoA1-based strategies (iv) • Cholesterol ester transfer protein (CETP) inhibitors ApoA-1 based therapy ApoA1 Mimetics, such as APL-180 Novartis Full-length ApoA1, such as ApoA1 Cerenis Therapeutics Pre-Beta HDL, as generated by delipidation, HDL Therapeutics Inc. Reconstituted HDL, CSL Ltd. ApoA1 Milano MDCO216, The Medicines Company Trimeric ApoA1, Borean Pharma and now Roche RVX-208, as developed by Resverlogix Fx-5A, as developed by Kinemed Inc. HDL epidemiology 302K participants in 68 prospective studies Emerging Risk Factors Collaboration, JAMA 2009 HDL intervention; failures Torcetrapib, Dalcetrapib, Niacin HDL intervention; failures Torcetrapib, Dalcetrapib, Niacin HDL intervention; failures Torcetrapib, Dalcetrapib, Niacin HDL intervention; failures Torcetrapib, Dalcetrapib, Niacin HDL intervention; failures Torcetrapib, Dalcetrapib, Niacin HDL cholesterol remains a useful marker of MI risk and should continue to be measured routinely to assess risk Correlation in observational epidemiologic studies does NOT equal causation Result of testing of Observational Hypothesis Raised hypothesis in clinical epidemiology trial (CAST trial 1989) PVCs post MI is Suppression of PVCs Treatment with associated with with medicines will antiarrhythmics increased risk of reduce risk of sudden suppressed PVCs, sudden death death INCREASED risk of arrhythmic death Hormone replacement (HERS, WHI trials) therapy use is HRT will lower risk of HRT INCREASED risk associated with lower CVD of MI and stroke risk of CVD (TREAT trial, 2009) Anemia in patients with Correcting anemia with Epogen administration T2D and CKD is Epo will lower risk of corrected anemia but associated with CVD INCREASED the rate of increased risk of CVD stroke Lipid Modifying Drugs • Cholesterol absorption inhibitors • Squalene synthase inhibitors (SSI) • Microsomal triglyceride transfer protein (MTP) inhibitors • Acyl coenzyme A acyltransferase (ACAT) inhibitors • Diacylglycerol acyltransferase (DGAT) inhibitors • Thyroxin receptor agonists • ApoB mRNA antisense drugs • PCSK9 antibodies • ApoA1-based strategies (iv) • Cholesterol ester transfer protein (CETP) inhibitors CETP inhibitors Torcetrapib Dalcetrapib Anacetrapib Evacetrapib HDL +55-70% +30% +140% +50-130% LDL -15-25% no effect -35% -20-40% apoA1 +25% +10% +40% +20-50% lp(a) no effect no effect -40% na RR increased no effect no effect no effect ACCELERATE Sites in North America, Europe and Asia Evacetrapib 130mg Statin 11.000 CVD pts > 30 days Placebo Primary End Point CV death, MI, stroke, coronary revasc or 3 yrs FU hospitalization for UA completion 2017 TULIP Design N=42 placebo + placebo N=42 TA-8995 1mg + placebo - mild dyslipidemia N=42 TA-8995 2.5mg + placebo - no CVD N=42 TA-8995 5mg + placebo - LDL-C 2.5- 4.5 mmol/L N=42 TA-8995 10mg + placebo - HDL-C 0.8-1.8 N=42 placebo +Atorvastatin 20mg mmol/L N=42 TA-8995 10mg+ Atorvastatin 20mg - TG <4.5 mmol/L N=42 placebo + Rosuvastatin 10mg N=42 TA-8995 10mg + Rosuvastatin 10mg Washout/run in treatment 12 weeks FU HDL-C %change at 12 weeks 200% 180% 166% 150% 122% 100% 76% 50% 2% 0% Placebo 1 2.5 5 10 TA-8995 (mg/day) LDL-C %change at 12 weeks 0% -20% -27% -40% -34% -47% -47% -60% Placebo 1 2.5 5 10 TA-8995 (mg/day) The CETP history Annu Rev Med 2014;65:385 LDL-C is primary target Lipid Modifying Drugs • Cholesterol absorption inhibitors • Squalene synthase inhibitors (SSI) • Microsomal triglyceride transfer protein (MTP) inhibitors • Acyl coenzyme A acyltransferase (ACAT) inhibitors • Diacylglycerol acyltransferase (DGAT) inhibitors • Thyroxin receptor agonists • antisense drugs • PCSK9 antibodies • ApoA1-based strategies (iv) • Cholesterol ester transfer protein (CETP) inhibitors Antisense GENE DNA mRNA RNA Antisense Drug RNAse Antisense Drug Protein Small molecule Antisense drug Disease Disease Disease Human ApoB-100 Ideal Target • ApoB-100: – expressed in liver – essential for synthesis and transport of VLDL and LDL-C – biologically validated – Undruggable for small molecules 68 Dose Dependent Reduction in ApoB 70 Other targets for antisense? 70 Other targets for antisense? http://www.isispharm.com/Pipeline/index.htm status 25-09-2014 70 Lipid Modifying Drugs • Cholesterol absorption inhibitors • Squalene synthase inhibitors (SSI) • Microsomal triglyceride transfer protein (MTP) inhibitors • Acyl coenzyme A acyltransferase (ACAT) inhibitors • Diacylglycerol acyltransferase (DGAT) inhibitors • Thyroxin receptor agonists • ApoB mRNA antisense drugs • PCSK9 antibodies • ApoA1-based strategies (iv) • Cholesterol ester transfer protein (CETP) inhibitors PCSK9; a success story •Affected family members with: •Total cholesterol in 90th percentile •Tendon xanthomas •CHD •Early MI •Stroke Role of PCSK9 in the regulation of LDL receptor expression PCSK9 LOF heterozygosity: impact on lipids and CAD No nonsense mutation (n=3278) 30 50th Percentile 20 10 12 p=0.008 0 8 50 100 150 200 250 300 88% PCSK9142X / PCSK9679X CHD (%) CHD 4 (N=85) Frequency (%) Frequency 30 50th Percentile 20 0 No Yes 10 PCSK9142X or PCSK9679X 0 50 100 150 200 250 300 Plasma LDL-C in black subjects (mg/dL) • LOF, loss of function • Adapted from Cohen JC, et al. New Engl J Med 2006; 354: 1264–72. PCSK9 inhibitors in development Phase of clinical Type Compound Company development mAb Alirocumab Sanofi/Regeneron 3 (REGN7272/SAR236553)1 AMG 1452 Amgen 3 RN-316 (PF-04950615)3 Pfizer/Rinat 2 (completed) RG 76524 Roche/Genentech 2 (on hold) LY30150145 Eli Lilly 2 LGT2096 Novartis 2 (discontinued) siRNA ALN-PCS7 Alnylam Pharmaceuticals Phase I (IV formulation) Pre-clinical (SC formulation) Mimetic EGF-A peptide8 Schering-Plough Pre-clinical peptide Prodomain and C-terminal Dept. of Cell Biology and Anatomy, Pre-clinical •EGFdomain-A, epidermal interaction growth factor -like repeat A;School IV, intravenous; of Medicine, mAb, monoclonal University antibody; of SC, subcutaneous; siRNA, small inhibitory RNA disruption9 South Carolina, SC, USA •1http://clinicaltrials.gov/ct2/results?term=REGN727%2F+SAR236553&Search=Search; 2http://clinicaltrials.gov/ct2/results?term=AMG+145&Search=Search; 3http://clinicaltrials.gov/ct2/results?term=PF-04950615&Search=Search; 4http://www.roche.com/irp2q12e-annex.pdf (p.131); 5http://clinicaltrials.gov/ct2/results?term=LY3015014&Search=Search; •6http://clinicaltrials.gov/ct2/results?term=LGT209&Search=Search; 7http://clinicaltrials.gov/ct2/results?term=ALN-PCS&Search=Search; 40 •8Shan L, et al. Biochem Biophys Res Commun 2008; 375: 69–73; 9Du F, et al. J Biol Chem 2011; 286: 43054–61 (all accessed August 2013). Effects on LDL-C of adding alirocumab to atorvastatin every 2 weeks Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 0 Δ – -10 5.1% -20 SE) % ± -30 Δ –39.6%* -40 -50 Δ – C mean ( - -60 64.2%* -70 Δ – change from baseline change LDL -80 72.4%* Placebo (n=31) Alirocumab 50 mg Q2W (n=30) Alirocumab 100 mg Q2W Alirocumab 150 mg Q2W (n=29) *p<0.0001(n=31) vs placebo 41 •Reproduced with permission from McKenney JM, et al. J Am Coll Cardiol 2012; 59: 2344–53. Effects on LDL-C of adding alirocumab to atorvastatin every 4 weeks Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 0 Δ –5.1% -10 SE) SE) ± -20 -30 -40 Δ – Δ – -50 43.2%* baseline C mean ( 47.7%* - -60 % change % change from -70 LDL -80 *p<0.0001 vs placebo Placebo (n=31) Alirocumab 200 mg Q4W (n=28) Alirocumab 300 mg Q4W (n=30) Safety summary Alirocumab Phase 2 studies 115651 115662 10033 Safety population Placeb Rx Placeb Rx Placeb Rx o groups o groups o groups (n;151) (n=61) (n=62) (n=31) (n=31) (n=15) Overview of all TEAEs, n (%) Patients with any TEAE 14 (45.2) 91 (60.3) 19 (61.3) 32 (52.5) 9 (60.0) 50 (80.6) Patients with any treatment-emergent SAE 1 (3.2) 3 (2.0) 0 (0) 1 (1.6) 1 (6.7) 0 (0) Patients with any TEAE leading to death 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Patients with any TEAE or treatment- emergent SAE leading to permanent 0 (0) 6 (4.0) 4 (12.9) 1 (1.6) 0 (0) 1 (1.6) treatment discontinuation • The most common TEAE was mild injection-site reactions • No persistent or prevalent liver or skeletal muscle safety signals were noted • 5 SAEs were reported in 4 patients in active treatment arms, with 1 patient experiencing 2 SAEs (leukocytoclastic vasculitis and subsequent43 humerus fracture) AMG 145 Phase 2 studies: efficacy Dose Trial Patient LDL-C ApoB Lp(a) TG population (%) (%) (%) (%) LAPLACE-TIMI On stable statin -66.1 -56.4 – -33.7 140 mg 571 ± ezetimibe Q2W MENDEL2 Monotherapy -47.2 -44.2 -29.3 -12.0 (no statin) LAPLACE-TIMI On stable statin -50.3 -42.0 – -19.4 571 ± ezetimibe 420 mg RUTHERFORD3 Heterozygous FH -56.4 -46.2 -31.5 -19.9 Q4W on stable statin MENDEL2 Monotherapy -52.5 -42.5 -29.2 -3.3 (no statin) GAUSS4 Statin intolerance -50.7 -42.1 -23.6 -14.2 (no statin) Data expressed as % change vs placebo (except reference 4: % change vs baseline) 1Giugliano RP, et al.
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