PCSK9-i Nový léčebný přístup nejen pro familiární HLP Richard Češka Centrum preventivní kardiologie III.Interní klinika 1.LF UK a VFN Praha
Cíle léčby HLP: Včera, dnes i zítra Ø Ovlivnění koncentrace aterogenních lipidů Ø Maximální snížení LDL-C Ø Ovlivnění koncentrace dalších lipidových RF Snížení Lp/a/ Ø Ovlivnění nelipidových RF Kouření Hypertenze? Ø Snížení KV rizika Ø Snížení mortality 3
Cíle léčby FH: Včera, dnes i zítra Ø Ovlivnění koncentrace aterogenních lipidů ØSnížení LDL-C Alespoň o 5%? Dosažení cílových hodnot? Maximální možné snížení Ø Ovlivnění koncentrace dalších lipidových RF Snížení Lp/a/ Ovlivnění dalších složek lipidového spektra 4
Cíle léčby FH: Včera, dnes i zítra Ø Maximální snížení LDL-C Ø Ovlivnění nelipidových RF Kouření Hypertenze Komplexní terapie (sekundární prevence) ØSnížení KV rizika ØSnížení mortality 5
Pokles celkové mortality dlouhodobý účinek snížení LDL-C WOSCOPS CHD mortality All-cause mortality Percentage with event Over entire period 27% risk reduction P<.1 12 1 8 Placebo 6 Pravastatin 4 Original trial 2 2 4 6 8 1 12 14 16 18 2 22 Years since randomisation 55 65 75 y Average age of cohort Percentage with event 4 5 4 3 5 3 2 5 2 1 5 1 Over entire period 13% risk reduction P<.1 Years since randomisation Placebo Pravastatin 2 4 6 8 1 12 14 16 18 2 22 5
Prevence ICHS 2 let studie WOSCOPS Non-fatal MI/ CHD death Percentage with event 24 21 18 15 12 9 6 3 Gain in event free years 5 years placeb o pravastatin 2 4 6 8 1 12 14 16 18 2 22 Years since randomisation
Léčba nemocných s HLP Sniderman AD, et al. JACC 214;63(19):1935-47.
Lomitapid pro homozygoty FH Diet Source triglyceride cholesterol Liver Source triglyceride cholesterol Intestinal Cell MTP Apo B-48 Liver Cell MTP Apo B-1 Chylomicron Lomitapide Decreases Secretion into the Blood VLDL Courtesy of Aegerion
Mipomersen pro homozygoty FH???
CETP inhibitor??? Myslíme tedy Anacetrapib 11
PCSK-9 inhibitory (MAB) 12
Funkce LDL receptoru LDL 1. Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 1979;76:333-3337. 2. Steinberg D, Witztum JL. Proc Natl Acad Sci U S A. 29;16:9546-9547. 3. Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 29;29:431-438.
PCSK9 reguluje expresi LDL-R v játrech 1. Qian YW, Schmidt RJ, Zhang Y, et al. J Lipid Res. 27;48:1488-1498. 2. Horton JD, Cohen JC, Hobbs HH. J Lipid Res. 29;5(suppl):S172-S177
Genetické varianty PCSK9 regulují hladiny LDL PCSK9 Gain of Function (GoF) = Less LDL-Rs 1,3,5 PCSK9 Loss of Function (LoF) = More LDL-Rs 1,4,5 Mutations in the human PCSK9 gene that lead to a loss of PCSK9 function are found in 1 3% of the population 1 3 LDL-C, low-density lipoprotein cholesterol; LDL-R, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9. 1. Horton JD, et al. J Lipid Res 29;5:S172 7; 2. Lakoski SG, et al. J Clin Endocrinol Metab 29;94:2537 43; 3. Abifadel M, et al. Hum Mutat 29;3:52 9; 4. Cohen J, et al. Nat Genet 25;37:161 5; 5. Steinberg D, et al. PNAS 29;16:9546 7.
Snižení KV rizika v důsledku genetických variant PCSK9 ovlivňujících LDL-C Proportional Risk Reduction (SE) 3% 2% 1% % HMGCR rs12916 SORT1 rs646776 LDL-R rs2228671 PCSK9 rs112651 ABCG5/8 rs12916 APOE rs442638 LDL-R rs651172 SORT1 rs599839 PCSK9 rs11591147 2 4 6 8 1 12 14 16 18 Lower LDL-C (mg/dl) CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; SE, standard error. Ference BA, et al. J Am Coll Cardiol 212;6:2631 9.
PCSK9 Allely snižují LDL-C o 28% u Afroameričanů a 15% bělochů (a 9 resp5% KVO) 12 Hypertension - 55% Smoking - 3% Diabetes - 18% 12 Hypertension - 25% Smoking - 25% Diabetes - 8% n=3,364 n=9,524 Coronary Heart Disease (%) 8 4 Coronary Heart Disease (%) 8 4 * p =.3 * p =.8 Y142X or C679X - + R46L - + African Americans Hazard ratio =.11 (CI:.2-.8, p =.3) Caucasians Hazard Ratio=.5 (CI:.32-.79, p =.3) Courtesy of Helen Hobbs
Anti-PCSK9 Monoclonal Antibodies block interaction PCSK9/LDL-R and lower LDL-C in plasma 1. Chan JC, Piper DE, Cao Q, et al. Proc Natl Acad Sci U S A. 29;16:982-9825.
The RUTHERFORD-2 Study Ø Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (NCT211117) Ø Design: A 12-week, randomized, double-blind, placebo-controlled, multicenter phase 3 study Ø Objective: To evaluate the efficacy and safety of evolocumab (AMG 145) 14 mg Q2W and 42 mg QM administered subcutaneously in a large cohort of HeFH patients unable to achieve an LDL-C < 1 mg/dl despite statin therapy with or without ezetimibe 19
RUTHERFORD-2: Mean % Change in LDL-C a from Baseline to the Mean of Weeks 1 and 12, and Week 12 Alone Weeks 1 and 12 Week 12 Adjusted Mean Percent Change ± SE from Baseline 1-1 -2-3 -4-5 -6-7 -1% -6% b -61% 2% -63% 2 1-1 -2-3 -4-5 -6-7 -2% -61% -66% b -59% b -61% b 6% -56% Placebo Q2W (N = 54) Placebo QM (N = 55) Evolocumab 14 mg Q2W (N = 11) Evolocumab 42 mg QM (N = 11) a Determined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was < 4 mg/dl or triglyceride levels were > 4 mg/dl b P <.1; placebo-adjusted treatment difference analyzed using repeated measures model which included treatment group, stratification factors (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates 2 LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly; SE, standard error
Proportion of Patients (%) RUTHERFORD-2: LDL-C a Goal Achievement < 7 mg/dl 9 8 7 6 5 4 3 2 1 2% Weeks 1 and 12 Week 12 65% b 67% 79% b 66% b 8% 8 7 6 5 4 3 2 1 2% 2% Placebo Q2W (N = 54) Placebo QM (N = 55) Evolocumab 14 mg Q2W (N = 11) Evolocumab 42 mg QM (N = 11) a Determined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was < 4 mg/dl or triglyceride levels were > 4 mg/dl b P <.1; analyzed using CMH test, stratified by the stratification factors LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly 68% 2% 61% b 63% 21
RUTHERFORD-2: Placebo-adjusted Treatment Differences in Other Lipids from Baseline to Week 12 ApoB Treatment Difference % Mean ± SE HDL-C Treatment Difference % Mean ± SE ApoA1 Treatment Difference % Mean ± SE -4-14 -24-34 -44-54 14 12 1 8 6 4 2 12 1 8 6 4 2-49% -49% 9% 9% 9% 4% Triglycerides Lp(a) Treatment Difference % Mean ± SE Treatment Difference % Mean ± SE -5-1 -15-2 -25-3 -5-1 -15-2 -25-3 -35-4 -2% -32% Evolocumab 14 mg Q2W vs. placebo Evolocumab 42 mg QM vs. placebo -12% -28% All evolocumab vs. placebo treatment differences were statistically significant at the P <.1 level (except for ApoA1, which was not part of the testing hierarchy); adjusted for multiplicity No notable difference were observed between the means of Weeks 1 and 12 and Week 12 alone Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; Lp(a), lipoprotein (a); SE, standard error 22
LS mean (SE) % change from baseline to Week 24 Alirocumab, Praluent významně snižuje LDL-C v týdnu 24 versus placebo Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background max-tolerated statin other lipid-lowering therapy LS mean difference (SE) vs. placebo: N=322 Intent-to-treat (ITT) Analysis FH I N=163 43.4% had dose increase at W12 57.9% (2.7) P<.1 N=166 FH II N=81 51.4% (3.4) P<.1 38.6% had dose increase at W12 Alirocumab Placebo 23
Alirocumab, Praluent významně snižuje LDL-C v týdnu 24 (Pooled Data from FH I and FH II) Alirocumab + max-tolerated statin other LLT N=488 N=244 Placebo + max-tolerated statin other LLT LS mean (SE) % change from baseline to Week 24 u Only 42% of alirocumab patients required a dose increase at Week 12 to the 15 mg Q2W dose LS mean difference (SE) vs. placebo: 55.8% (2.1); P<.1 LLT = lipid-lowering therapy Intent-to-treat (ITT) Analysis 24
Alirocumab, Praluent snižuje u FH konzistentně LDL-C během 52 týdnů Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin Other LLT Placebo: FH I Alirocumab: FH I FH II FH II LDL-C, LS mean (SE), mmol/l 4. mmol/l 4. mmol/l 3.7 mmol/l 3.5 mmol/l 1.8 mmol/l 1.9 mmol/l 1.8 mmol/l 1.7 mmol/l mg/dl 25 Dose if LDL-C >7 mg/dl at W8 Week Intent-to-treat (ITT) Analysis, LLT = lipid-lowering therapy
Většina hefh léčených alirocumabem dosahuje cílových hodnot LDL-C Proportion of patients reaching LDL-C goal at Week 24 FH I FH II Alirocumab Placebo % patients P<.1 Very high-risk: <1.81 mmol/l (7 mg/dl); high-risk: <2.59 mmol/l (1 mg/dl). LLT = lipid-lowering therapy. Intent-to-treat (ITT) Analysis 26
FH I a FH II studie alirocumab, Praluent LS mean (SE) % change from baseline to Week 24 Non-HDL-C Apo B Lp(a) FH I FH II FH I FH II FH I FH II All comparisons vs. placebo are P<.1 Alirocumab + max-tolerated statin other LLT Placebo + max-tolerated statin other LLT Adjusted mean (SE) shown for Lp(a). LLT = lipid-lowering therapy Intent-to-treat (ITT) Analysis 27
Bezpečnost alirocumabu, Praluent u FH % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Alirocumab (N=489) Placebo (N=244) TEAEs 74.8% (366) 75.4% (184) Treatment-emergent SAEs 1.% (49) 9.% (22) TEAEs leading to death.8% (4) TEAEs leading to discontinuation 3.1% (15) 3.7% (9) Adverse Events of Interest Adjudicated CV events 1.6% (8) 1.2% (3) Injection-site reactions 11.5% (56) 9.% (22) Neurocognitive disorders.2% (1) 1.2% (3) ALT >3 x ULN 2.1% (1/488) 1.2% (3/244) Creatine kinase >3 x ULN 3.5% (17/483) 6.2% (15/243) u 4 TEAE-related deaths were all in alirocumab arm, 2 due to metastatic cancer (non-small cell lung and pancreatic), 2 due to MI (1 acute, 1 sudden cardiac death) Adjudicated CV events include all CV AEs positively adjudicated. The adjudication categories are the following: CHD death, non-fatal MI, fatal and non-fatal ischaemic stroke, unstable angina requiring hospitalisation, congestive heart failure requiring hospitalisation, ischaemia-driven revascularisation procedure (PCI, CABG). Statistical analyses have not been performed. 28
Bezpečnost alirocumabu, Praluent u FH % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Alirocumab (N=489) Placebo (N=244) Injection-site reaction 11.5% (56) 9.% (22) Nasopharyngitis 1.2% (5) 11.1% (27) Influenza 8.8% (43) 6.1% (15) Headache 5.5% (27) 6.6% (16) Statistical analyses have not been performed. 29
Zpátky ke kořenům. Co je cílem léčby? Morbidity Mortality
No. at Risk Placebo Alirocumab Post-hoc analýza- alirocumab snižuje Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Safety Analysis (at least 52 weeks for all patients continuing treatment, including 67 patients who completed W78 visit) Cumulative probability of event.6.5.4.3.2.1. 788 155 velké KV příhody o 54% Placebo + max-tolerated statin ± other LLT Alirocumab + max-tolerated statin ± other LLT Cox model analysis: HR=.46 (95% CI:.26 to.82) Nominal p-value = <.1 12 776 1534 24 731 1446 Mean treatment duration: 65 weeks Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy 36 73 1393 48 682 1352 6 667 1335 72 321 642 84 127 252 Weeks
Kardiovaskulární příhody ve studii OSLER 3 Combined endpoint: Death, MI, NAP hospitalization, coronary revascularization, stroke, TIA, CHF hosp. Kumulativní Incidence (%) 2 1 HR.47 95% CI.28-.78 P=.3 Standard therapy (N=1489) 2.18%.95% Evolocumab + standard therapy (N=2976) 3 6 9 12 15 18 21 24 27 3 33 365 Days from randomisation Sabatine MS et al. NEJM 215;March 15:
Zítřky léčby HLP Ø Nonfarmakologická léčba Dieta Režim Extrakorpoální přístupy (homozygoti) Genová či chirurgická léčba Ø Farmakoterapie Statiny (vysokodávkované) Kombinační léčba Statin + ezetimib Statin + PCSK9-i PCSK9-i (za určitých situací)
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