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Daniel Gaudet - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia the odyssey hofh trial
Journal of the American College of Cardiology, 2020Co-Authors: Dirk J. Blom, Daniel Gaudet, John J P Kastelein, Stephen Donahue, Robert Pordy, Mariko Haradashiba, P Rubba, Minji Charng, Shazia Ali, Yuping DongAbstract:Abstract Background Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein–cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment. Objectives This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH. Methods This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment. Results Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on Lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was −35.6% (alirocumab [−26.9%] vs. placebo [8.6%]; p Conclusions In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621 .)
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long term efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in patients with homozygous familial hypercholesterolemia
Circulation, 2017Co-Authors: Dirk J. Blom, Hendrik Du Toit Theron, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Claudia Stefanutti, Maurizio Averna, Giovanni Battista VignaAbstract:Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression.1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins. In a pivotal 78-week open-label trial, Lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia.2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat. Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306). Patients continued on Lomitapide at the maximally tolerated dose until transition to commercial or compassionate Lomitapide. Lipid-lowering therapies, including apheresis, could be modified at the investigator’s discretion if LDL-C was <100 mg/dL. Both studies received institutional review board and regulatory approval, and all participants provided informed consent. Significance of the percent changes from baseline was assessed using a mixed linear model; correlations were assessed with Pearson correlation. Nineteen (mean age, 30.4 years; 10 male/9 female) of the 23 patients who completed the pivotal trial enrolled in the extension trial, and 17 completed week 126 (78 weeks pivotal + 48 weeks extension) assessments (primary efficacy end point). Three patients discontinued prematurely (relocation, elevated transaminases and excess alcohol, sudden cardiac death). The median Lomitapide dose remained mostly consistent at 40 mg (range, 20–60 mg) from week 36 in the pivotal study to week 282 in the extension trial. Overall, the median treatment duration with Lomitapide across both trials was 5.1 years (range, 2.1–5.7 years). Among the 17 patients who completed week 126, LDL-C decreased from 356±127 mg/dL at baseline to …
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the lipid lowering effects of Lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia a post hoc analysis of a phase 3 single arm open label trial
Atherosclerosis, 2015Co-Authors: Claudia Stefanutti, Maurizio R Averna, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Robert A. Hegele, Dt H Theron, A D Marais, C R Sirtori, Daniel GaudetAbstract:Objective Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of Lomitapide.
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abstract 16516 sustained ldl c lowering and stable hepatic fat levels in patients with homozygous familial hypercholesterolemia treated with the microsomal triglyceride transfer protein inhibitor Lomitapide results of an ongoing long term extension study
Circulation, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Maurizio Averna, Claudia StefanuttiAbstract:Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by markedly elevated LDL-C and high CVD risk. Lomitapide is approved in the US to lower LDL-C as ...
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Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study.
Lancet, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Maurizio R Averna, Dirk J. Blom, Emma A Meagher, Adrian David Marais, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel GaudetAbstract:BACKGROUND Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in adults with this disease. METHODS We did a single-arm, open-label, phase 3 study of Lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on Lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. FINDINGS 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of Lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p
Dirk J. Blom - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia the odyssey hofh trial
Journal of the American College of Cardiology, 2020Co-Authors: Dirk J. Blom, Daniel Gaudet, John J P Kastelein, Stephen Donahue, Robert Pordy, Mariko Haradashiba, P Rubba, Minji Charng, Shazia Ali, Yuping DongAbstract:Abstract Background Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein–cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment. Objectives This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH. Methods This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment. Results Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on Lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was −35.6% (alirocumab [−26.9%] vs. placebo [8.6%]; p Conclusions In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621 .)
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long term efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in patients with homozygous familial hypercholesterolemia
Circulation, 2017Co-Authors: Dirk J. Blom, Hendrik Du Toit Theron, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Claudia Stefanutti, Maurizio Averna, Giovanni Battista VignaAbstract:Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression.1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins. In a pivotal 78-week open-label trial, Lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia.2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat. Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306). Patients continued on Lomitapide at the maximally tolerated dose until transition to commercial or compassionate Lomitapide. Lipid-lowering therapies, including apheresis, could be modified at the investigator’s discretion if LDL-C was <100 mg/dL. Both studies received institutional review board and regulatory approval, and all participants provided informed consent. Significance of the percent changes from baseline was assessed using a mixed linear model; correlations were assessed with Pearson correlation. Nineteen (mean age, 30.4 years; 10 male/9 female) of the 23 patients who completed the pivotal trial enrolled in the extension trial, and 17 completed week 126 (78 weeks pivotal + 48 weeks extension) assessments (primary efficacy end point). Three patients discontinued prematurely (relocation, elevated transaminases and excess alcohol, sudden cardiac death). The median Lomitapide dose remained mostly consistent at 40 mg (range, 20–60 mg) from week 36 in the pivotal study to week 282 in the extension trial. Overall, the median treatment duration with Lomitapide across both trials was 5.1 years (range, 2.1–5.7 years). Among the 17 patients who completed week 126, LDL-C decreased from 356±127 mg/dL at baseline to …
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the lipid lowering effects of Lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia a post hoc analysis of a phase 3 single arm open label trial
Atherosclerosis, 2015Co-Authors: Claudia Stefanutti, Maurizio R Averna, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Robert A. Hegele, Dt H Theron, A D Marais, C R Sirtori, Daniel GaudetAbstract:Objective Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of Lomitapide.
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abstract 16516 sustained ldl c lowering and stable hepatic fat levels in patients with homozygous familial hypercholesterolemia treated with the microsomal triglyceride transfer protein inhibitor Lomitapide results of an ongoing long term extension study
Circulation, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Maurizio Averna, Claudia StefanuttiAbstract:Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by markedly elevated LDL-C and high CVD risk. Lomitapide is approved in the US to lower LDL-C as ...
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efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia a single arm open label phase 3 study
The Lancet, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Dirk J. Blom, Emma A Meagher, Robert A. Hegele, Maurizio Averna, David A Marais, Cesare R. SirtoriAbstract:Summary Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of Lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on Lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of Lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p Interpretation Our study suggests that treatment with Lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.
Robert A. Hegele - One of the best experts on this subject based on the ideXlab platform.
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long term efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in patients with homozygous familial hypercholesterolemia
Circulation, 2017Co-Authors: Dirk J. Blom, Hendrik Du Toit Theron, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Claudia Stefanutti, Maurizio Averna, Giovanni Battista VignaAbstract:Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression.1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins. In a pivotal 78-week open-label trial, Lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia.2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat. Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306). Patients continued on Lomitapide at the maximally tolerated dose until transition to commercial or compassionate Lomitapide. Lipid-lowering therapies, including apheresis, could be modified at the investigator’s discretion if LDL-C was <100 mg/dL. Both studies received institutional review board and regulatory approval, and all participants provided informed consent. Significance of the percent changes from baseline was assessed using a mixed linear model; correlations were assessed with Pearson correlation. Nineteen (mean age, 30.4 years; 10 male/9 female) of the 23 patients who completed the pivotal trial enrolled in the extension trial, and 17 completed week 126 (78 weeks pivotal + 48 weeks extension) assessments (primary efficacy end point). Three patients discontinued prematurely (relocation, elevated transaminases and excess alcohol, sudden cardiac death). The median Lomitapide dose remained mostly consistent at 40 mg (range, 20–60 mg) from week 36 in the pivotal study to week 282 in the extension trial. Overall, the median treatment duration with Lomitapide across both trials was 5.1 years (range, 2.1–5.7 years). Among the 17 patients who completed week 126, LDL-C decreased from 356±127 mg/dL at baseline to …
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the lipid lowering effects of Lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia a post hoc analysis of a phase 3 single arm open label trial
Atherosclerosis, 2015Co-Authors: Claudia Stefanutti, Maurizio R Averna, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Robert A. Hegele, Dt H Theron, A D Marais, C R Sirtori, Daniel GaudetAbstract:Objective Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of Lomitapide.
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Homozygous familial hypercholesterolaemia : new insights and guidance for clinicians to improve detection and clinical management. : A position paper fromthe Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society
'Oxford University Press (OUP)', 2014Co-Authors: Marina Cuchel, Robert A. Hegele, E. Bruckert, H.n. Ginsberg, F.j. Raal, R.d. Santos, J.a. Kuivenhoven, B.g. Nordestgaard, O.s. Descamps, Steinhagen E. ThiessenAbstract:Aims: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. Methods and results: Early diagnosis ofHoFHand prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH.We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensiveACVDevaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of Lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary. Conclusion: This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH
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abstract 16516 sustained ldl c lowering and stable hepatic fat levels in patients with homozygous familial hypercholesterolemia treated with the microsomal triglyceride transfer protein inhibitor Lomitapide results of an ongoing long term extension study
Circulation, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Maurizio Averna, Claudia StefanuttiAbstract:Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by markedly elevated LDL-C and high CVD risk. Lomitapide is approved in the US to lower LDL-C as ...
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efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia a single arm open label phase 3 study
The Lancet, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Dirk J. Blom, Emma A Meagher, Robert A. Hegele, Maurizio Averna, David A Marais, Cesare R. SirtoriAbstract:Summary Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of Lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on Lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of Lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p Interpretation Our study suggests that treatment with Lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.
Emma A Meagher - One of the best experts on this subject based on the ideXlab platform.
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long term efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in patients with homozygous familial hypercholesterolemia
Circulation, 2017Co-Authors: Dirk J. Blom, Hendrik Du Toit Theron, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Claudia Stefanutti, Maurizio Averna, Giovanni Battista VignaAbstract:Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression.1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins. In a pivotal 78-week open-label trial, Lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia.2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat. Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306). Patients continued on Lomitapide at the maximally tolerated dose until transition to commercial or compassionate Lomitapide. Lipid-lowering therapies, including apheresis, could be modified at the investigator’s discretion if LDL-C was <100 mg/dL. Both studies received institutional review board and regulatory approval, and all participants provided informed consent. Significance of the percent changes from baseline was assessed using a mixed linear model; correlations were assessed with Pearson correlation. Nineteen (mean age, 30.4 years; 10 male/9 female) of the 23 patients who completed the pivotal trial enrolled in the extension trial, and 17 completed week 126 (78 weeks pivotal + 48 weeks extension) assessments (primary efficacy end point). Three patients discontinued prematurely (relocation, elevated transaminases and excess alcohol, sudden cardiac death). The median Lomitapide dose remained mostly consistent at 40 mg (range, 20–60 mg) from week 36 in the pivotal study to week 282 in the extension trial. Overall, the median treatment duration with Lomitapide across both trials was 5.1 years (range, 2.1–5.7 years). Among the 17 patients who completed week 126, LDL-C decreased from 356±127 mg/dL at baseline to …
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the lipid lowering effects of Lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia a post hoc analysis of a phase 3 single arm open label trial
Atherosclerosis, 2015Co-Authors: Claudia Stefanutti, Maurizio R Averna, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Robert A. Hegele, Dt H Theron, A D Marais, C R Sirtori, Daniel GaudetAbstract:Objective Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of Lomitapide.
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abstract 16516 sustained ldl c lowering and stable hepatic fat levels in patients with homozygous familial hypercholesterolemia treated with the microsomal triglyceride transfer protein inhibitor Lomitapide results of an ongoing long term extension study
Circulation, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Maurizio Averna, Claudia StefanuttiAbstract:Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by markedly elevated LDL-C and high CVD risk. Lomitapide is approved in the US to lower LDL-C as ...
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efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia a single arm open label phase 3 study
The Lancet, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Dirk J. Blom, Emma A Meagher, Robert A. Hegele, Maurizio Averna, David A Marais, Cesare R. SirtoriAbstract:Summary Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of Lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on Lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of Lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p Interpretation Our study suggests that treatment with Lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.
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Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study.
Lancet, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Maurizio R Averna, Dirk J. Blom, Emma A Meagher, Adrian David Marais, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel GaudetAbstract:BACKGROUND Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in adults with this disease. METHODS We did a single-arm, open-label, phase 3 study of Lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on Lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. FINDINGS 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of Lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p
Claudia Stefanutti - One of the best experts on this subject based on the ideXlab platform.
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long term efficacy and safety of the microsomal triglyceride transfer protein inhibitor Lomitapide in patients with homozygous familial hypercholesterolemia
Circulation, 2017Co-Authors: Dirk J. Blom, Hendrik Du Toit Theron, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Claudia Stefanutti, Maurizio Averna, Giovanni Battista VignaAbstract:Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression.1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins. In a pivotal 78-week open-label trial, Lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia.2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat. Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306). Patients continued on Lomitapide at the maximally tolerated dose until transition to commercial or compassionate Lomitapide. Lipid-lowering therapies, including apheresis, could be modified at the investigator’s discretion if LDL-C was <100 mg/dL. Both studies received institutional review board and regulatory approval, and all participants provided informed consent. Significance of the percent changes from baseline was assessed using a mixed linear model; correlations were assessed with Pearson correlation. Nineteen (mean age, 30.4 years; 10 male/9 female) of the 23 patients who completed the pivotal trial enrolled in the extension trial, and 17 completed week 126 (78 weeks pivotal + 48 weeks extension) assessments (primary efficacy end point). Three patients discontinued prematurely (relocation, elevated transaminases and excess alcohol, sudden cardiac death). The median Lomitapide dose remained mostly consistent at 40 mg (range, 20–60 mg) from week 36 in the pivotal study to week 282 in the extension trial. Overall, the median treatment duration with Lomitapide across both trials was 5.1 years (range, 2.1–5.7 years). Among the 17 patients who completed week 126, LDL-C decreased from 356±127 mg/dL at baseline to …
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toward an international consensus integrating lipoprotein apheresis and new lipid lowering drugs
Journal of Clinical Lipidology, 2017Co-Authors: Claudia Stefanutti, Mariko Haradashiba, U Julius, Gerald F Watts, Maria Laura Cossu, V J J Schettler, Giustina De Silvestro, Handrean Soran, Jeanine Roeters E Van Lennep, Livia PisciottaAbstract:Background Despite advances in pharmacotherapy of lipid disorders, many dyslipidemic patients do not attain sufficient lipid lowering to mitigate risk of atherosclerotic cardiovascular disease. Several classes of novel lipid-lowering agents are being evaluated to reduce atherosclerotic cardiovascular disease risk. Lipoprotein apheresis (LA) is effective in acutely lowering the plasma concentrations of atherogenic lipoproteins including low-density lipoprotein cholesterol and lipoprotein(a), and novel lipid-lowering drugs may dampen the lipid rebound effect of LA, with the possibility that LA frequency may be decreased, in some cases even be discontinued. Sources of material This document builds on current American Society for Apheresis guidelines and, for the first time, makes recommendations from summarized data of the emerging lipid-lowering drug classes (inhibitors of proprotein convertase subtilisin/kexin type 9 or microsomal triglyceride transfer protein, high-density lipoprotein mimetic), including the available evidence on combination therapy with LA with respect to the management of patients with dyslipidemia. Abstract of findings Recommendations for different indications are given based on the latest evidence. However, except for Lomitapide in homozygous familial hypercholesterolemia and alirocumab/evolocumab in heterozygous familial hypercholesterolemia subjects, limited data are available on the effectiveness and safety of combination therapy. More studies on combining LA with novel lipid-lowering drugs are needed. Conclusion Novel lipid-lowering agents have potential to improve the performance of LA, but more evidence is needed. The Multidisciplinary International Group for Hemapheresis TherapY and Metabolic DIsturbances Contrast scientific society aims to establish an international registry of clinical experience on LA combination therapy to expand the evidence on this treatment in individuals at high cardiovascular disease risk.
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the lipid lowering effects of Lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia a post hoc analysis of a phase 3 single arm open label trial
Atherosclerosis, 2015Co-Authors: Claudia Stefanutti, Maurizio R Averna, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Robert A. Hegele, Dt H Theron, A D Marais, C R Sirtori, Daniel GaudetAbstract:Objective Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of Lomitapide.
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abstract 16516 sustained ldl c lowering and stable hepatic fat levels in patients with homozygous familial hypercholesterolemia treated with the microsomal triglyceride transfer protein inhibitor Lomitapide results of an ongoing long term extension study
Circulation, 2013Co-Authors: Marina Cuchel, Hendrik Du Toit Theron, Dirk J. Blom, Emma A Meagher, Prediman K Shah, Cesare R. Sirtori, Robert A. Hegele, Daniel Gaudet, Maurizio Averna, Claudia StefanuttiAbstract:Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by markedly elevated LDL-C and high CVD risk. Lomitapide is approved in the US to lower LDL-C as ...
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lipoprotein apheresis state of the art and novelties
Atherosclerosis Supplements, 2013Co-Authors: Claudia Stefanutti, U JuliusAbstract:Abstract Lipoprotein apheresis (LA) is an extracorporeal technique which permits the unselective or specific removal of lipoproteins, namely Low Density Lipoproteins (LDL), as well as other apolipoprotein B100-containing lipoproteins from plasma. LA represents a selective upgrade (with both clinical and metabolic advantages) from conventional forms of extracorporeal therapy such as plasma-exchange (PEX) which was used in the seventies to treat severe hypercholesterolemia. The primary reason for using is the treatment of homo-, double- (or compound) and heterozygous familial hypercholesterolemia (Hoz-, DHtz,- Htz,-FH). This technique has also been shown to be efficacious in the treatment of other severe forms of hyperlipoproteinemia such as: hyperLp(a)lipoproteinemia, the familial combined hyperlipoproteinemia and other varieties associated with an elevated cardiovascular risk (CVR) when used in patients who are poor- or non-responders to pharmacological treatment following specific guidelines for the reduction of cholesterol in plasma. Patients with these severe forms of dyslipidemia and, particularly, those affected by FH are subject to coronary ischemic events and thus require an intensive, efficacious, continuous, and personalized form of therapy. A therapy based solely on current available drugs does not achieve the desired results in the Hoz- and DHtz forms of FH or in approximately 10–20% of the Htz form. For the aforementioned clinical conditions, LA treatment offers a necessary therapeutic approach. LA can also be applied in the prevention of secondary recurrence of coronary ischemic events and of arterial stenosis which appears, rather frequently after vascular surgery (coronary by-pass, percutaneous transluminal angioplasty). Clinical trials have shown that statins provide a major reduction in cardiovascular morbidity and mortality, but often fail to attain desirable LDL-cholesterol target level in Hoz- and DHtz- (Compound) FH high cardiovascular risk patients. Intolerance to statins is also relatively frequent in Htz-FH and non-FH patients. LA has effectively replaced pharmacological cholesterol-lowering therapy for decades. Young high CVR risk patients survived to adulthood thanks only to LA. More recently, promising novel compounds aimed at other molecular targets are being studied for the treatment of severe dyslipidemia: Lomitapide, Mipomersen, PCSK9 inhibitors and HDL-enhancers. It is expected that these potent new agents will be combined with LA in the treatment of the most severe forms of hyperlipidemia.
