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John J.p. Kastelein - One of the best experts on this subject based on the ideXlab platform.
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Safety and efficacy of Mipomersen in patients with heterozygous familial hypercholesterolemia.
Atherosclerosis, 2018Co-Authors: L.f. Reeskamp, John J.p. Kastelein, Raul D Santos, P.m. Moriarty, P.b. Duell, A.l. Catapano, C.m. BallantyneAbstract:Abstract Background and aims Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular disease risk. Despite multiple LDL-C–lowering therapies, many HeFH patients do not reach LDL-C targets. Mipomersen, an antisense oligonucleotide against apolipoprotein B (apoB), might further lower LDL-C in HeFH patients. We assessed the efficacy and safety of two Mipomersen dosing regimens in HeFH patients and explored whether thrice-weekly dosing improves the benefit-risk profile. Methods In this double-blind trial, HeFH patients (LDL-C >160 mg/dL) on maximal tolerated LDL-lowering therapy were randomized to Mipomersen 200 mg once weekly (n = 104), Mipomersen 70 mg thrice weekly (n = 102), or placebo in matching frequency (n = 103) for 60 weeks. Main outcomes were LDL-C, apoB, and lipoprotein(a) levels after 60 weeks of treatment. Results Mipomersen 200 mg once weekly and Mipomersen 70 mg thrice weekly significantly lowered LDL-C compared with placebo by 21.0% and 18.8%, respectively, and apoB by 22.1% and 21.7% (all p Conclusions Mipomersen 200 mg once weekly and 70 mg thrice weekly are effective in lowering apoB-containing lipoproteins in HeFH patients. This is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. The thrice-weekly dosing regimen was associated with lower frequency of flu-like symptoms, which might help avert discontinuation in some patients, but otherwise had no major benefits.
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Long-term Mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia
Journal of clinical lipidology, 2016Co-Authors: P.b. Duell, Joseph L. Witztum, Sotirios Tsimikas, Raul D Santos, Bridget-anne Kirwan, John J.p. KasteleinAbstract:Background Familial hypercholesterolemia (FH) is characterized by severely elevated LDL-cholesterol and up to a 20-fold increase in premature cardiovascular disease (CVD). Objective Mipomersen has been shown to lower the levels of these atherogenic lipoproteins, but whether it lowers major adverse cardiac events (MACEs) has not been addressed. Methods This post hoc analysis of prospectively collected data of three randomized trials and an open-label extension phase included patients that were exposed to ≥12 months of Mipomersen. MACE rates that occurred during 24 months before randomization in the Mipomersen group were compared to MACE rates after initiation of Mipomersen. Data from the trials included in this report are registered in Clinicaltrials.gov (NCT00607373, NCT00706849, NCT00794664, NCT00694109). The occurrence of MACE events, defined as cardiovascular death, nonfatal acute myocardial infarction, hospitalization for unstable angina, coronary revascularization and nonfatal ischemic stroke, was obtained from medical history data pre-treatment and adjudicated by an independent adjudication committee for events occurring post-treatment with Mipomersen. Results MACEs were identified in 61.5% of patients (64 patients with 146 events [39 myocardial infarctions, 99 coronary revascularizations, 5 unstable angina episodes, 3 ischemic strokes]) during 24 months before Mipomersen treatment, and in 9.6% of patients (10 patients with 13 events [1 cardiovascular death, 2 myocardial infarctions, 6 coronary interventions, 4 unstable angina episodes]) during a mean of 24.4 months after initiation of Mipomersen (MACE rate 25.7 of 1000 patient-months vs 3.9 of 1000 patient-months, OR = 0.053 [95% CI, 0.016–0.168], P Conclusion Long-term Mipomersen treatment not only lowers levels of atherogenic lipoproteins but may also lead to a reduction in cardiovascular events in FH patients.
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Pediatric experience with Mipomersen as adjunctive therapy for homozygous familial hypercholesterolemia
Journal of clinical lipidology, 2016Co-Authors: Frederick J. Raal, Marjet J.a.m. Braamskamp, Sheryl Selvey, Charlotte Sensinger, John J.p. KasteleinAbstract:Background Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited condition resulting in severely elevated low-density lipoprotein cholesterol levels (LDL-C) leading to premature cardiovascular disease and, often, death. Mipomersen is an antisense oligonucleotide that inhibits apolipoprotein B (apo B) synthesis, lowering LDL-C levels. Mipomersen has demonstrated efficacy in adult HoFH patients, possibly providing a therapeutic option for pediatric patients. Study objectives were to summarize Mipomersen efficacy and safety in the pediatric cohort of a phase 3 randomized controlled trial (RCT) and subsequent open-label extension study (OLE). Methods Seven patients aged 12–18 years were randomized to 200-mg Mipomersen or placebo weekly (26 weeks) and received Mipomersen in the OLE (52 or 104 weeks). Plasma LDL-C and apo B concentrations and adverse events were assessed. Results All pediatric patients completed the RCT and entered OLE. The 3 Mipomersen patients in the RCT experienced mean reductions from baseline to RCT end of 42.7% and 46.1% for LDL-C and apo B, respectively. Of the 4 placebo patients, 3 responded well to Mipomersen during OLE, with reductions in LDL-C of 26.5%–42.1%. Three patients completed OLE treatment, and 4 patients discontinued therapy due to adverse events. Lipid level fluctuations were observed and were likely due to poor compliance. Conclusions Long-term Mipomersen treatment was successful regarding efficacy parameters for pediatric HoFH patients. The safety profile was consistent with other phase 3 clinical trials. Long-term compliance was an issue. Measures supporting adherence should be encouraged.
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Abstract 16531: Decreased Cardiovascular Events in Familial Hypercholesterolemic Patients Treated With Mipomersen, an Antisense Inhibitor of Apolipoprotein B Translation
Circulation, 2014Co-Authors: Bart Duell, Richard S. Geary, Mary P Mcgowan, Raul D Santos, Asif Mahmood, Brenda F. Baker, Walter Singleton, John J.p. KasteleinAbstract:Background: Familial hypercholesterolemia (FH) is associated with a 10-20 fold increase in cardiovascular (CV) events. Mipomersen has been shown to significantly lower levels of atherogenic lipoproteins in plasma. Previous safety analysis of all patients in phase 3 trials found no meaningful imbalance in CV events between placebo and Mipomersen arms. Hypothesis: Treatment with Mipomersen for at least 1 year will reduce CV events in FH patients taking maximally tolerated lipid-lowering therapy. Methods: Rates of major adverse CV events (MACE) during 2 years prior to Mipomersen treatment were compared to MACE after treatment in 104 FH patients who participated in one of three phase 3 blinded randomized placebo-controlled 6-month trials and an open-label extension study (NCT00607373, NCT00706849, NCT00794664, NCT00694109). One third of patients (n=34) received placebo for the initial 6 months followed by Mipomersen for at least 1 year. Two thirds (n=70) received blinded Mipomersen for 6 months followed by at...
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Changes in Mipomersen dosing regimen provide similar exposure with improved tolerability in randomized placebo-controlled study of healthy volunteers.
Journal of the American Heart Association, 2014Co-Authors: Joann Flaim, John S. Grundy, Mary P Mcgowan, Brenda F. Baker, John J.p. KasteleinAbstract:Background Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low-density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA-approved subcutaneous dose of 200 mg once weekly. Methods and Results A short-term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of Mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty-four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then Mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable Mipomersen post-distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post-dose elevation of C-reactive protein (CRP) in the Mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers. Conclusions This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to Mipomersen treatment. These results support assessment of alternative dose regimens in longer-term studies. Clinical Trial Registration URL: . Unique identifier: [NCT01061814][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01061814&atom=%2Fahaoa%2F3%2F2%2Fe000560.atom
Richard S. Geary - One of the best experts on this subject based on the ideXlab platform.
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no effect on qt intervals of Mipomersen a 2 o methoxyethyl modified antisense oligonucleotide targeting apob 100 mrna in a phase i dose escalation placebo controlled study and confirmed by a thorough qt tqt study in healthy subjects
European Journal of Clinical Pharmacology, 2016Co-Authors: Rudy Gunawan, Richard S. Geary, John S. Grundy, Asif Mahmood, Walter Singleton, Robert S. Mittleman, Yanfeng WangAbstract:Purpose The aim of this study to evaluate the effect of Mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects.
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Clinical and Preclinical Pharmacokinetics and Pharmacodynamics of Mipomersen (Kynamro^®): A Second-Generation Antisense Oligonucleotide Inhibitor of Apolipoprotein B
Clinical Pharmacokinetics, 2015Co-Authors: Richard S. Geary, Brenda F. Baker, Stanley T. CrookeAbstract:Mipomersen (Kynamro^®), a second-generation 2′- O -methoxyethyl chimeric antisense oligonucleotide (ASO), inhibits the synthesis of apolipoprotein B (apoB) and is indicated in the US as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH) at a dose of 200 mg subcutaneously (SC) once weekly. The pharmacokinetic (PK) properties of Mipomersen are generally consistent across all species studied, including mouse, rat, monkey, and humans. After SC administration, Mipomersen is rapidly and extensively absorbed. It has an apparent plasma and tissue terminal elimination half-life of approximately 30 days. Mipomersen achieves steady-state tissue concentrations within approximately 4–6 months of once-weekly dosing. It does not exhibit PK-based drug–drug interactions with other concomitant medications, either involving competition for plasma protein binding or alterations in disposition of any evaluated drugs. Furthermore, Mipomersen does not prolong the corrected QT (QTc) interval. There have been no ethnic- or gender-related differences in PK observed. In clinical trials, both as a single agent and in the presence of maximal lipid-lowering therapy, Mipomersen has demonstrated significant dose-dependent reductions in all measured apoB-containing atherogenic lipoproteins. Overall, Mipomersen has well-characterized PK and pharmacodynamic properties in both animals and humans, and is an efficacious adjunct treatment for patients with HoFH.
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Abstract 16531: Decreased Cardiovascular Events in Familial Hypercholesterolemic Patients Treated With Mipomersen, an Antisense Inhibitor of Apolipoprotein B Translation
Circulation, 2014Co-Authors: Bart Duell, Richard S. Geary, Mary P Mcgowan, Raul D Santos, Asif Mahmood, Brenda F. Baker, Walter Singleton, John J.p. KasteleinAbstract:Background: Familial hypercholesterolemia (FH) is associated with a 10-20 fold increase in cardiovascular (CV) events. Mipomersen has been shown to significantly lower levels of atherogenic lipoproteins in plasma. Previous safety analysis of all patients in phase 3 trials found no meaningful imbalance in CV events between placebo and Mipomersen arms. Hypothesis: Treatment with Mipomersen for at least 1 year will reduce CV events in FH patients taking maximally tolerated lipid-lowering therapy. Methods: Rates of major adverse CV events (MACE) during 2 years prior to Mipomersen treatment were compared to MACE after treatment in 104 FH patients who participated in one of three phase 3 blinded randomized placebo-controlled 6-month trials and an open-label extension study (NCT00607373, NCT00706849, NCT00794664, NCT00694109). One third of patients (n=34) received placebo for the initial 6 months followed by Mipomersen for at least 1 year. Two thirds (n=70) received blinded Mipomersen for 6 months followed by at...
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Clinical pharmacological properties of Mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B.
British journal of clinical pharmacology, 2013Co-Authors: Stanley T. Crooke, Richard S. GearyAbstract:Mipomersen is a second generation antisense oligonucleotide that targets apolipoprotein B. It has been studied thoroughly in clinical trials (more than 800 subjects), including four randomized double-blind placebo controlled phase 3 studies involving 391 patients, and is in registration for the treatment of severe hypercholesterolaemia. The pharmacokinetic and pharmacodynamic properties of Mipomersen are well characterized. Mipomersen is rapidly and extensively absorbed after subcutaneous administration and has an elimination half-life of approximately 30 days across species. It is cleared by nuclease metabolism and renal excretion of the metabolites. Mipomersen reduces all apolipoprotein B containing atherogenic particles and displays dose dependent reductions between 50-400 mg week⁻¹ , both as a single agent and in the presence of maximal lipid lowering therapy. No drug-drug interactions have been identified. Mipomersen is a representative of second generation antisense drugs, all of which have similar properties, and is thus representative of the behaviour of the class of drugs.
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Mipomersen an apolipoprotein b synthesis inhibitor lowers low density lipoprotein cholesterol in high risk statin intolerant patients a randomized double blind placebo controlled trial
European Heart Journal, 2012Co-Authors: Maartje E. Visser, Richard S. Geary, Aart J. Nederveen, Mieke D. Trip, Gilbert Wagener, Ulrich Beuers, Brenda F. Baker, Joanne M. Donovan, Joanne Verheij, Dick C BasartAbstract:Aims A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of Mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD). Methods and results Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg Mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of Mipomersen administration, LDL-c was reduced by 47 ± 18% ( P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively ( P < 0.001 vs. placebo). Four Mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases ≥3× the upper limit of normal were observed in seven (33%) subjects assigned to Mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis. Conclusion The present data suggest that Mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required. Clinical Trial Registration: ClinicalTrials.gov identifier: [NCT00707746][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00707746&atom=%2Fehj%2Fearly%2F2012%2F04%2F16%2Feurheartj.ehs023.atom
Raul D Santos - One of the best experts on this subject based on the ideXlab platform.
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Lomitapide and Mipomersen—Inhibiting Microsomal Triglyceride Transfer Protein (MTP) and apoB100 Synthesis
Current Atherosclerosis Reports, 2019Co-Authors: Dirk J Blom, Raul D Santos, Frederick J. Raal, A. David MaraisAbstract:Purpose of Review The goal of this review is to evaluate the role of inhibiting the synthesis of lipoproteins when there is no or little residual LDL-receptor function as in patients with homozygous familial hypercholesterolaemia. Lomitapide is administered orally once a day while Mipomersen is given by subcutaneous injection once a week. Lomitapide inhibits microsomal triglyceride transfer protein while Mipomersen is an antisense oligonucleotide directed against apoB100. Recent Findings The pivotal registration trials for lomitapide and Mipomersen were published in 2013 and 2010, respectively. More recently published data from extension trials and cohort studies provides additional information on long-term safety and efficacy. Summary The mean LDL cholesterol reduction was 50% with lomitapide in its single-arm open-label registration trial. Mipomersen reduced LDL cholesterol by approximately 25% in its double-blind, placebo-controlled registration study. Both lomitapide and Mipomersen therapy are associated with variable increases in hepatic fat content. The long-term safety of increased hepatic fat content in patients receiving these therapies is uncertain and requires further study. Both drugs may cause elevated transaminase in some patients, but no cases of severe liver injury have been reported. Lomitapide may also cause gastrointestinal discomfort and diarrhoea, especially if patients consume high-fat meals and patients are advised to follow a low-fat diet supplemented with essential fatty acids and fat-soluble vitamins. Mipomersen may cause injection-site and influenza-like reactions. The effect of lomitapide and Mipomersen on cardiovascular outcomes has not been studied, but circumstantial evidence suggests that the LDL cholesterol lowering achieved with these two agents may reduce cardiovascular event rates.
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Lomitapide and Mipomersen-Inhibiting Microsomal Triglyceride Transfer Protein (MTP) and apoB100 Synthesis.
Current atherosclerosis reports, 2019Co-Authors: Dirk J Blom, Raul D Santos, Frederick J. Raal, A. David MaraisAbstract:Purpose of review The goal of this review is to evaluate the role of inhibiting the synthesis of lipoproteins when there is no or little residual LDL-receptor function as in patients with homozygous familial hypercholesterolaemia. Lomitapide is administered orally once a day while Mipomersen is given by subcutaneous injection once a week. Lomitapide inhibits microsomal triglyceride transfer protein while Mipomersen is an antisense oligonucleotide directed against apoB100. Recent findings The pivotal registration trials for lomitapide and Mipomersen were published in 2013 and 2010, respectively. More recently published data from extension trials and cohort studies provides additional information on long-term safety and efficacy. The mean LDL cholesterol reduction was 50% with lomitapide in its single-arm open-label registration trial. Mipomersen reduced LDL cholesterol by approximately 25% in its double-blind, placebo-controlled registration study. Both lomitapide and Mipomersen therapy are associated with variable increases in hepatic fat content. The long-term safety of increased hepatic fat content in patients receiving these therapies is uncertain and requires further study. Both drugs may cause elevated transaminase in some patients, but no cases of severe liver injury have been reported. Lomitapide may also cause gastrointestinal discomfort and diarrhoea, especially if patients consume high-fat meals and patients are advised to follow a low-fat diet supplemented with essential fatty acids and fat-soluble vitamins. Mipomersen may cause injection-site and influenza-like reactions. The effect of lomitapide and Mipomersen on cardiovascular outcomes has not been studied, but circumstantial evidence suggests that the LDL cholesterol lowering achieved with these two agents may reduce cardiovascular event rates.
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Safety and efficacy of Mipomersen in patients with heterozygous familial hypercholesterolemia.
Atherosclerosis, 2018Co-Authors: L.f. Reeskamp, John J.p. Kastelein, Raul D Santos, P.m. Moriarty, P.b. Duell, A.l. Catapano, C.m. BallantyneAbstract:Abstract Background and aims Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular disease risk. Despite multiple LDL-C–lowering therapies, many HeFH patients do not reach LDL-C targets. Mipomersen, an antisense oligonucleotide against apolipoprotein B (apoB), might further lower LDL-C in HeFH patients. We assessed the efficacy and safety of two Mipomersen dosing regimens in HeFH patients and explored whether thrice-weekly dosing improves the benefit-risk profile. Methods In this double-blind trial, HeFH patients (LDL-C >160 mg/dL) on maximal tolerated LDL-lowering therapy were randomized to Mipomersen 200 mg once weekly (n = 104), Mipomersen 70 mg thrice weekly (n = 102), or placebo in matching frequency (n = 103) for 60 weeks. Main outcomes were LDL-C, apoB, and lipoprotein(a) levels after 60 weeks of treatment. Results Mipomersen 200 mg once weekly and Mipomersen 70 mg thrice weekly significantly lowered LDL-C compared with placebo by 21.0% and 18.8%, respectively, and apoB by 22.1% and 21.7% (all p Conclusions Mipomersen 200 mg once weekly and 70 mg thrice weekly are effective in lowering apoB-containing lipoproteins in HeFH patients. This is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. The thrice-weekly dosing regimen was associated with lower frequency of flu-like symptoms, which might help avert discontinuation in some patients, but otherwise had no major benefits.
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Disease management
2016Co-Authors: Raul D Santos, Wai Chin, P.m. Moriarty, Cara East, John R. Guyton, Barton P. Duell, Robert S. MittlemanAbstract:Long-term efficacy and safety of Mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extensio
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Long-term Mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia
Journal of clinical lipidology, 2016Co-Authors: P.b. Duell, Joseph L. Witztum, Sotirios Tsimikas, Raul D Santos, Bridget-anne Kirwan, John J.p. KasteleinAbstract:Background Familial hypercholesterolemia (FH) is characterized by severely elevated LDL-cholesterol and up to a 20-fold increase in premature cardiovascular disease (CVD). Objective Mipomersen has been shown to lower the levels of these atherogenic lipoproteins, but whether it lowers major adverse cardiac events (MACEs) has not been addressed. Methods This post hoc analysis of prospectively collected data of three randomized trials and an open-label extension phase included patients that were exposed to ≥12 months of Mipomersen. MACE rates that occurred during 24 months before randomization in the Mipomersen group were compared to MACE rates after initiation of Mipomersen. Data from the trials included in this report are registered in Clinicaltrials.gov (NCT00607373, NCT00706849, NCT00794664, NCT00694109). The occurrence of MACE events, defined as cardiovascular death, nonfatal acute myocardial infarction, hospitalization for unstable angina, coronary revascularization and nonfatal ischemic stroke, was obtained from medical history data pre-treatment and adjudicated by an independent adjudication committee for events occurring post-treatment with Mipomersen. Results MACEs were identified in 61.5% of patients (64 patients with 146 events [39 myocardial infarctions, 99 coronary revascularizations, 5 unstable angina episodes, 3 ischemic strokes]) during 24 months before Mipomersen treatment, and in 9.6% of patients (10 patients with 13 events [1 cardiovascular death, 2 myocardial infarctions, 6 coronary interventions, 4 unstable angina episodes]) during a mean of 24.4 months after initiation of Mipomersen (MACE rate 25.7 of 1000 patient-months vs 3.9 of 1000 patient-months, OR = 0.053 [95% CI, 0.016–0.168], P Conclusion Long-term Mipomersen treatment not only lowers levels of atherogenic lipoproteins but may also lead to a reduction in cardiovascular events in FH patients.
Mark K Wedel - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia
European heart journal, 2011Co-Authors: Fatima Akdim, Richard S. Geary, Mark K Wedel, Diane Tribble, Joann Flaim, Brenda F. Baker, Rainard Fuhr, John J.p. KasteleinAbstract:Aims Mipomersen, an apolipoprotein (apo) B synthesis inhibitor, has been shown to produce potent reductions in apoB and LDL-cholesterol levels in animal models as well as healthy human volunteers. A randomized, double-blind, placebo-controlled, dose-escalation study was designed to evaluate the efficacy and safety of Mipomersen monotherapy with or without dose loading in subjects with mild-to-moderate hyperlipidaemia. Methods and results Fifty subjects with LDL-cholesterol levels between 119 and 266 mg/dL were enrolled into five cohorts at a 4:1 randomization ratio of active to placebo. Two 13-week dose regimens were evaluated at doses ranging from 50 to 400 mg/week. Mipomersen produced dose-dependent reductions in all apoB containing lipoproteins. In the 200 and 300 mg/week dose cohorts, mean reductions from baseline in LDL cholesterol were −45 ± 10% ( P = 0.000) and −61 ± 8% ( P = 0.000), corresponding to a −46 ± 11% ( P = 0.000) and −61 ± 7% ( P = 0.000) decrease in apoB levels. Triglyceride levels were also lowered with median reductions up to 53% ( P = 0.021). The most common adverse events were injection site reactions. Seven of 40 subjects (18%) showed consecutive trans -aminase elevations >3× upper limit of normal. Five of these subjects received 400 mg/week, four of whom had apoB levels below the limit of detection. As a consequence, the 400 mg/week cohort was discontinued. Conclusions Mipomersen administered as monotherapy in subjects with mild-to-moderate hyperlipidaemia produced potent reductions in all apoB-containing lipoproteins. Higher doses were associated with hepatic trans -aminase increases. This trial is registered at clinicaltrials.gov as [NCT00216463][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00216463&atom=%2Fehj%2Fearly%2F2011%2F05%2F18%2Feurheartj.ehr148.atom
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efficacy and safety of Mipomersen an antisense inhibitor of apolipoprotein b in hypercholesterolemic subjects receiving stable statin therapy
Journal of the American College of Cardiology, 2010Co-Authors: Fatima Akdim, Mark K Wedel, Diane Tribble, Joann Flaim, Mieke D. Trip, Erik S.g. Stroes, Brenda F. Baker, Eric J G Sijbrands, Wouter J Jukema, John J.p. KasteleinAbstract:Objectives The aim of this study was to evaluate the efficacy and safety of Mipomersen in hypercholesterolemic subjects taking stable statin therapy. Background Mipomersen is an apolipoprotein (apo) B synthesis inhibitor that has demonstrated significant reductions in apo B and low-density lipoprotein (LDL) cholesterol in Phase 1 clinical trials in healthy volunteers. Methods A randomized, placebo-controlled, dose-escalation Phase 2 study was designed to evaluate the effects of Mipomersen in hypercholesterolemic subjects taking stable statin therapy. Seventy-four subjects were enrolled sequentially into 1 of 6 dose cohorts at a 4:1 (active/placebo) ratio. Subjects received 7 doses of 30 to 400 mg over 5 weeks in the first 5 cohorts and 15 doses of 200 mg over 13 weeks in the sixth cohort. Pre-specified end points included percentage change from baseline in apo B and LDL cholesterol. Safety was assessed with laboratory test results and by the incidence and severity of adverse events. Results The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week Mipomersen and higher in the 5-week treatment cohorts. Efficacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema [90%]) and hepatic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 subjects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations ≥3× the upper limit of normal, 4 of which persisted on 2 consecutive occasions. Conclusions Mipomersen might hold promise for treatment of patients not reaching target LDL cholesterol levels on stable statin therapy. Further studies are needed to address the mechanisms and clinical relevance of transaminase changes after Mipomersen administration. (Dose-Escalating Safety Study in Subjects on Stable Statin Therapy; NCT00231569 )
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Lack of Pharmacokinetic Interaction of Mipomersen Sodium (ISIS 301012), a 2′-—O-Methoxyethyl Modified Antisense Oligonucleotide Targeting Apolipoprotein B-100 Messenger RNA, with Simvastatin and Ezetimibe
Clinical Pharmacokinetics, 2009Co-Authors: Rosie Z. Yu, Richard S. Geary, Jo Ann D. Flaim, Gina C. Riley, André A. Vanvliet, Diane L. Tribble, Mark K WedelAbstract:Background and objectives Mipomersen sodium (ISIS 301012) is a 20-mer phosphorothioate antisense oligonucleotide that is complementary to human apolipoprotein B-100 (apoB-100) messenger RNA and subsequently reduces translation of ApoB-100 protein, the major apolipoprotein of very low-density lipoprotein, intermediate-density lipoprotein and low-density lipoprotein (LDL). Mipomersen sodium is currently being studied in phase II/III clinical studies to determine its clinical utility as add-on therapy to HMG-CoA reductase inhibitors or other lipid-lowering agents in subjects with hypercholesterolaemia. The aim of this study was to characterize the pharmacokinetic interactions of Mipomersen sodium with simvastatin and ezetimibe. Another aim was to evaluate the ability of Mipomersen sodium to inhibit major cytochrome P450 (CYP) isoenzymes in vitro . Methods In a phase I clinical study, ten healthy subjects per cohort received a single oral dose of simvastatin 40 mg or ezetimibe 10 mg followed by four 2-hour intravenous doses of Mipomersen sodium 200 mg over an 8-day period, with simvastatin 40 mg or ezetimibe 10 mg being administered again with the last dose of Mipomersen sodium. Mipomersen sodium pharmacokinetic profiles were assessed following the first dose (Mipomersen sodium alone) and the last dose (Mipomersen sodium in combination with simvastatin or ezetimibe). Plasma samples for measurement of simvastatin, simvastatin acid, and free and total ezetimibe concentrations were collected at various timepoints following their first and last oral dosing. A comparative pharmacokinetic analysis was performed to determine if there were any effects resulting from coadministration of Mipomersen sodium with these lipid-lowering drugs. In addition to the clinical pharmacokinetic analysis, the ability of Mipomersen sodium to inhibit the major CYP isoform enzymes (namely CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was evaluated in cryo-preserved human hepatocytes in vitro . Results The area under the plasma concentration-time curve (AUC) from 0 to 24 hours (AUC24), maximum plasma concentration and apparent elimination half-life values of Mipomersen sodium were similar when administered alone and in combination with oral simvastatin or oral ezetimibe. The 90% confidence intervals of the geometric least squares means ratios (%Reference) of the Mipomersen sodium AUC24 values were 93.6, 107 when administered together with simvastatin, and 92.4, 111 when administered with ezetimibe. Therefore, there were no large deviations outside the default no-effect boundaries (80–125%) for total exposure (the AUC) of Mipomersen sodium in combination with either simvastatin or ezetimibe. Similarly, large deviations outside the default no-effect boundaries were not observed for simvastatin, simvastatin acid, or free and total ezetimibe exposure in combination with Mipomersen sodium. In cryo-preserved human hepatocytes, Mipomersen sodium exhibited no cytotoxicity. Significant cell uptake was demonstrated by analysing cell-associated concentrations of Mipomersen sodium. All evaluated enzyme activities had
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lack of pharmacokinetic interaction of Mipomersen sodium isis 301012 a 2 o methoxyethyl modified antisense oligonucleotide targeting apolipoprotein b 100 messenger rna with simvastatin and ezetimibe
Clinical Pharmacokinectics, 2009Co-Authors: Richard S. Geary, Jo Ann D. Flaim, Gina C. Riley, André A. Vanvliet, Diane Tribble, Mark K WedelAbstract:Background and objectives Mipomersen sodium (ISIS 301012) is a 20-mer phosphorothioate antisense oligonucleotide that is complementary to human apolipoprotein B-100 (apoB-100) messenger RNA and subsequently reduces translation of ApoB-100 protein, the major apolipoprotein of very low-density lipoprotein, intermediate-density lipoprotein and low-density lipoprotein (LDL). Mipomersen sodium is currently being studied in phase II/III clinical studies to determine its clinical utility as add-on therapy to HMG-CoA reductase inhibitors or other lipid-lowering agents in subjects with hypercholesterolaemia. The aim of this study was to characterize the pharmacokinetic interactions of Mipomersen sodium with simvastatin and ezetimibe. Another aim was to evaluate the ability of Mipomersen sodium to inhibit major cytochrome P450 (CYP) isoenzymes in vitro.
Brenda F. Baker - One of the best experts on this subject based on the ideXlab platform.
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Abstract 52: Efficacy and Safety of Mipomersen in Patients with Familial Hypercholesterolemia and Inadequately Controlled LDL-C Levels
Arteriosclerosis Thrombosis and Vascular Biology, 2016Co-Authors: C.m. Ballantyne, Michael H Davidson, Raul D Santos, Walter Singleton, P.m. Moriarty, A.l. Catapano, Charlotte Sensinger, Robert S. Mittleman, Samarita De Banerjee, Brenda F. BakerAbstract:Aim: Mipomersen is an antisense oligonucleotide inhibitor of apolipoprotein B-100 synthesis, FDA-approved to treat homozygous familial hypercholesterolemia. The primary objective of this study was to determine whether Mipomersen significantly reduced atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (HeFH). Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study comprised of two cohorts (NCT01475825). Cohort 1 had severe HeFH (LDL-C ≥200 mg/dL + coronary heart disease, or LDL-C ≥300 mg/dL) and Cohort 2 had milder HeFH (LDL-C ≥160 and Results: Mean baseline LDL-C levels were 265 mg/dL in Cohort 1 (N=200) and 176 mg/dL in Cohort 2 (N=109). In Cohort 1, Mipomersen 200 mg weekly reduced LDL-C levels by -29.7% (vs -7.9% placebo, P P Conclusions: The primary analysis showed a significant reduction in LDL-C levels in patients with severe HeFH who received Mipomersen 200 mg once weekly versus placebo. A highly relevant absolute reduction in LDL-C was achieved over time.
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Clinical and Preclinical Pharmacokinetics and Pharmacodynamics of Mipomersen (Kynamro^®): A Second-Generation Antisense Oligonucleotide Inhibitor of Apolipoprotein B
Clinical Pharmacokinetics, 2015Co-Authors: Richard S. Geary, Brenda F. Baker, Stanley T. CrookeAbstract:Mipomersen (Kynamro^®), a second-generation 2′- O -methoxyethyl chimeric antisense oligonucleotide (ASO), inhibits the synthesis of apolipoprotein B (apoB) and is indicated in the US as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH) at a dose of 200 mg subcutaneously (SC) once weekly. The pharmacokinetic (PK) properties of Mipomersen are generally consistent across all species studied, including mouse, rat, monkey, and humans. After SC administration, Mipomersen is rapidly and extensively absorbed. It has an apparent plasma and tissue terminal elimination half-life of approximately 30 days. Mipomersen achieves steady-state tissue concentrations within approximately 4–6 months of once-weekly dosing. It does not exhibit PK-based drug–drug interactions with other concomitant medications, either involving competition for plasma protein binding or alterations in disposition of any evaluated drugs. Furthermore, Mipomersen does not prolong the corrected QT (QTc) interval. There have been no ethnic- or gender-related differences in PK observed. In clinical trials, both as a single agent and in the presence of maximal lipid-lowering therapy, Mipomersen has demonstrated significant dose-dependent reductions in all measured apoB-containing atherogenic lipoproteins. Overall, Mipomersen has well-characterized PK and pharmacodynamic properties in both animals and humans, and is an efficacious adjunct treatment for patients with HoFH.
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Abstract 16531: Decreased Cardiovascular Events in Familial Hypercholesterolemic Patients Treated With Mipomersen, an Antisense Inhibitor of Apolipoprotein B Translation
Circulation, 2014Co-Authors: Bart Duell, Richard S. Geary, Mary P Mcgowan, Raul D Santos, Asif Mahmood, Brenda F. Baker, Walter Singleton, John J.p. KasteleinAbstract:Background: Familial hypercholesterolemia (FH) is associated with a 10-20 fold increase in cardiovascular (CV) events. Mipomersen has been shown to significantly lower levels of atherogenic lipoproteins in plasma. Previous safety analysis of all patients in phase 3 trials found no meaningful imbalance in CV events between placebo and Mipomersen arms. Hypothesis: Treatment with Mipomersen for at least 1 year will reduce CV events in FH patients taking maximally tolerated lipid-lowering therapy. Methods: Rates of major adverse CV events (MACE) during 2 years prior to Mipomersen treatment were compared to MACE after treatment in 104 FH patients who participated in one of three phase 3 blinded randomized placebo-controlled 6-month trials and an open-label extension study (NCT00607373, NCT00706849, NCT00794664, NCT00694109). One third of patients (n=34) received placebo for the initial 6 months followed by Mipomersen for at least 1 year. Two thirds (n=70) received blinded Mipomersen for 6 months followed by at...
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Changes in Mipomersen dosing regimen provide similar exposure with improved tolerability in randomized placebo-controlled study of healthy volunteers.
Journal of the American Heart Association, 2014Co-Authors: Joann Flaim, John S. Grundy, Mary P Mcgowan, Brenda F. Baker, John J.p. KasteleinAbstract:Background Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low-density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA-approved subcutaneous dose of 200 mg once weekly. Methods and Results A short-term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of Mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty-four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then Mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable Mipomersen post-distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post-dose elevation of C-reactive protein (CRP) in the Mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers. Conclusions This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to Mipomersen treatment. These results support assessment of alternative dose regimens in longer-term studies. Clinical Trial Registration URL: . Unique identifier: [NCT01061814][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01061814&atom=%2Fahaoa%2F3%2F2%2Fe000560.atom
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Antisense technology: an emerging platform for cardiovascular disease therapeutics.
Journal of cardiovascular translational research, 2013Co-Authors: Richard G. Lee, Mark J. Graham, Brenda F. Baker, Jeff Crosby, Rosanne M. CrookeAbstract:Antisense oligonucleotides and small interfering RNAs, which suppress the translation of specific mRNA target proteins, are emerging as important therapeutic modalities for the treatment of cardiovascular disease. Over the last 25 years, the advances in all aspects of antisense technology, as well as a detailed understanding of the mechanism of action of antisense drugs, have enabled their use as therapeutic agents. These advancements culminated in the FDA approval of the first chronically administered cardiovascular antisense therapeutic, Mipomersen, which targets hepatic apolipoprotein B mRNA. This review provides a brief history of antisense technology, highlights the progression of Mipomersen from preclinical studies to multiple Phase III registration trials, and gives an update on the status of other cardiovascular antisense therapeutics currently in the clinic.