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      ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia

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          Abstract

          Aims

          To assess long-term (78 weeks) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT).

          Methods and results

          In two randomized, double-blind studies (ODYSSEY FH I, n = 486; FH II, n = 249), patients were randomized 2 : 1 to alirocumab 75 mg or placebo every 2 weeks (Q2W). Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was ≥1.8 mmol/L (70 mg/dL). Primary endpoint (both studies) was percentage change in calculated LDL-C from baseline to Week 24. Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; −57.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; −51.4% vs. placebo) in FH II ( P < 0.0001). These reductions were maintained through Week 78. LDL-C <1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively. Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo).

          Conclusion

          In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin ± other LLT, alirocumab treatment resulted in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated.

          Clinical trial registration

          Cinicaltrials.gov (identifiers: NCT01623115; NCT01709500).

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          Most cited references10

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          Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial.

          Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia. This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876. 77 patients were randomly assigned to study groups (15-16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment. REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. Sanofi US and Regeneron Pharmaceuticals Incorporated. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group.

            (a) To determine the excess mortality from all causes and from coronary heart disease in patients with familial hypercholesterolaemia; (b) to examine how useful various criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes are in identifying these patients. Prospective cohort study. Eleven hospital outpatient lipid clinics in the United Kingdom. 282 men and 244 women aged 20-74 with heterozygous familial hypercholesterolaemia. Standardised mortality ratio, all adults in England and Wales being taken as standard (standardised mortality ratio = 100 for standard population). The cohort was followed up for 2234 person years during 1980-9. Fifteen of the 24 deaths were due to coronary heart disease, giving a standardised mortality ratio of 386 (95% confidence interval 210 to 639). The excess mortality from this cause was highest at age 20-39 (standardised mortality ratio 9686; 3670 to 21,800) and decreased significantly with age. The standardised mortality ratio for all causes was 183 (117 to 273) and also was highest at age 20-39 (standardised mortality ratio 902; 329 to 1950). There was no significant difference between men and women. Criteria for measurement of cholesterol concentration in cardiovascular screening programmes (family history, presence of myocardial infarction, angina, stroke, corneal arcus, xanthelasma, obesity, hypertension, diabetes, or any of these) were present in 78% of patients. Familial hypercholesterolaemia is associated with a substantial excess mortality from coronary heart disease in young adults but may not be associated with a substantial excess mortality in older patients. Criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes identify about three quarters of patients with the clinically overt condition.
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              Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands.

              Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels or=2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c >or=2.5mmol/l and not using maximum therapy. Only a small proportion of patients with heFH reaches the LDL-c treatment target of <2.5mmol/l. These results emphasize the need for better monitoring, better utilization of available medication and for new treatment options in heFH to further decrease LDL-c levels.
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                Author and article information

                Journal
                Eur Heart J
                Eur. Heart J
                eurheartj
                ehj
                European Heart Journal
                Oxford University Press
                0195-668X
                1522-9645
                14 November 2015
                01 September 2015
                01 September 2015
                : 36
                : 43 , Focus Issue on Lipids
                : 2996-3003
                Affiliations
                [1 ]Department of Vascular Medicine, Academic Medical Center, University of Amsterdam , Meibergdreef 9, Room F4-159.2, 1105 AZ Amsterdam, The Netherlands
                [2 ]Columbia University , New York, NY, USA
                [3 ]Lipid Clinic, Oslo University Hospital , Oslo, Norway
                [4 ]Center of Preventive Cardiology, 1st School of Medicine and University Hospital, Charles University , Prague, Czech Republic
                [5 ]Institut de Recherches Cliniques de Montréal , Montréal, Canada
                [6 ]Division of Lipidology, Department of Medicine, University of Cape Town and MRC Cape Heart Group , Cape Town, South Africa
                [7 ]Lipid Unit, Hospital Universitario Miguel Servet , Zaragoza, Spain
                [8 ]CHU de Nantes—Hôpital Nord Laennec , Saint-Herblain, France
                [9 ]Sanofi , Paris, France
                [10 ]Regeneron Pharmaceuticals, Inc. , Basking Ridge, NJ, USA
                [11 ]Regeneron Pharmaceuticals, Inc. , Tarrytown, NY, USA
                [12 ]Sanofi , Montpellier, France
                [13 ]Point Médical , Dijon, France
                Author notes
                [* ]Corresponding author. Tel: +31 20 566 6612, Fax: +31 20 566 9343, Email: j.j.kastelein@ 123456amc.uva.nl
                Article
                ehv370
                10.1093/eurheartj/ehv370
                4644253
                26330422
                b7b5ea8c-71fd-47c2-b332-1b4388575a34
                © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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                FASTTrack Esc Clinical Trial Update
                Lipids
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                Cardiovascular Medicine
                alirocumab,pcsk9,heterozygous familial hypercholesterolaemia,cardiovascular risk,ldl-c

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