Efficacy Of Mipomersen Research Articles

Safety and efficacy of mipomersen in patients with heterozygous familial hypercholesterolemia

Background and aimsHeterozygous 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. MethodsIn 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. ResultsMipomersen 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 < 0.001). Lipoprotein(a) was significantly lowered by 27.7% (p < 0.001) with thrice-weekly dosing. Injection-site reactions and flu-like symptoms led to discontinuation in 21.2% (200 mg), 17.6% (70 mg), and 5.8% (placebo) of participants. Alanine transaminase was elevated (≥3× upper limit of normal at least once) in 21.2%, 21.6%, and 1.0% of subjects, respectively. ConclusionsMipomersen 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.

Efficacy and safety of mipomersen in treatment of dyslipidemia: A meta-analysis of randomized controlled trials

Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid-lowering therapy in people at risk for cardiovascular diseases. Mipomersen inhibits apolipoprotein B-100 (apoB) synthesis and causes reduction in LDL-C by reducing apoB. We aimed to perform a meta-analysis of all published randomized controlled trials comparing safety and efficacy of mipomersen with placebo in adults with dyslipidemia. We searched PUBMED, CENTRAL, and EMBASE from inception through March 2014 and used random-effects model to compute the effect size. We identified 8 randomized controlled trials (n=462). Mipomersen compared with placebo significantly reduced LDL-C by 32.37% (95% confidence interval, 25.55-39.18; P<.00001), total cholesterol by 24.18% (18.54-29.83; P<.00001), very low-density lipoprotein cholesterol by 21.59% (9.16-34.02; P=.0007), non-high-density lipoprotein cholesterol (HDL-C) by 30.83% (23.92-37.74; P<.00001), and triglycerides by 36.26% (22-50.54; P<.00001). It also significantly reduced apoB, lipoprotein(a), and apolipoprotein A1. However, mipomersen did not significantly change HDL-C levels. In safety analysis, mipomersen compared with placebo increased the risks of injection-site reaction (risk ratio, 2.05; 95% confidence interval, 1.39-3.04; P=.0003), flu-like symptoms (1.63; 1.22-2.17; P=.0008), alanine aminotransferase ≥3X upper limit of normal (4.44; 1.67-11.86; P=.003), and hepatic steatosis (3.85, 1.39-10.67; P=.01). The risks of alanine aminotransferase ≥10X upper limit of normal did not reach statistical significance (1.57; 0.32-7.6, P=.58). Mipomersen resulted in a significant improvement in lipid parameters except for HDL-C and increased the risks of injection-site reactions, flu-like symptoms, and hepatic steatosis compared with placebo.

Mipomersen, an Apolipoprotein B Synthesis Inhibitor, Reduces Atherogenic Lipoproteins in Patients With Severe Hypercholesterolemia at High Cardiovascular Risk: A Randomized, Double-Blind, Placebo-Controlled Trial

This study sought to examine the efficacy and safety of mipomersen for reducing atherogenic lipids and lipoproteins in patients with hypercholesterolemia. Many patients on lipid-lowering therapies remain unable to achieve target low-density lipoprotein (LDL) cholesterol levels. Mipomersen, an antisense oligonucleotide inhibitor of apolipoprotein B, reduces LDL cholesterol and atherogenic lipoproteins. This randomized, double-blind, multicenter study enrolled 158 patients with baseline LDL cholesterol levels ≥100 mg/dl with, or at high risk for, coronary heart disease who were receiving maximally tolerated lipid-lowering therapy. Patients received weekly subcutaneous mipomersen 200 mg (n = 105) or placebo (n = 52) for 26 weeks, with a 24-week follow-up period. Randomization was stratified by type 2 diabetes status. Sixty mipomersen and 44 placebo patients completed treatment. Mean baseline LDL cholesterol levels were 122.7 and 122.6 mg/dl in the placebo and mipomersen patients, respectively. Mipomersen reduced LDL cholesterol by -36.9% compared with placebo at -4.5% (p < 0.001). Target LDL cholesterol <100 mg/dl was attained in 76% of mipomersen and 38% of placebo patients. Mipomersen also significantly reduced apolipoprotein B (-38%) and lipoprotein(a) (-24%) (p < 0.001). Common adverse events included injection site reactions (78% with mipomersen, 31% with placebo) and flu-like symptoms (34% with mipomersen, 21% with placebo). Elevations in transaminases and liver fat also occurred in some patients, and these levels returned toward baseline after treatment cessation. Mipomersen significantly reduced LDL cholesterol, apolipoprotein B, and lipoprotein(a) in patients with hypercholesterolemia with, or at risk for, coronary heart disease not controlled by existing therapies. (Safety and Efficacy of Mipomersen [ISIS 301012] as Add-On Therapy in High Risk Hypercholesterolemic Patients; NCT00770146).

The role of mipomersen therapy in the treatment of familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder that results in elevated LDL levels and is associated with an increased risk of cardiovascular disease. HMG-CoA reductase inhibitors are recommended as first-line treatment for FH, but often multiple lipid-lowering agents are required to achieve desired reductions in LDL-C in this patient population. The purpose of our review is to discuss the role of mipomersen in the treatment of FH. A PubMed search revealed three published studies and three abstracts of Phase III extension studies evaluating mipomersen in the treatment of FH, and one study evaluating the safety and efficacy of mipomersen in statin-intolerant patients at high risk for cardiovascular disease, wherein a little more than half of the enrolled patients were diagnosed with FH. Mipomersen, an antisense single-strand synthetic oligonucleotide, may become a potential treatment option for patients with FH that require either additional lipid-lowering or as an alternative to statins in intol...

Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial

AimsA 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 resultsThirty-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.ConclusionThe 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

Long-Term Safety and Efficacy of Mipomersen in Patients with Familial Hypercholesterolemia Uncontrolled by Maximally Tolerated Lipid Lowering Therapy

s 291 Apo B, P , .0001 for all; Table 1). Age $65 years, abdominal obesity, and lower baseline high-sensitivity C-reactive protein (hs-CRP) were significant predictors of greater reductions in LDL-C, non-HDL-C, Apo B, total C, VLDL-C, TGs, and all lipid-lipoprotein ratios but not for changes in HDL-C or ApoAI. Age $65 years was associated with significantly greater attainment of LDL-C (,70 mg/dL, ,100 mg/dL) and non-HDL-C (,100 mg/dL, ,130 mg/dL) targets; abdominal obesity predicted higher attainment of nonHDL-C ,130 mg/dL, and lower baseline hs-CRP was associated with greater attainment of LDL-C ,70 mg/ dL and non-HDL-C ,100 mg/dL. The number of MetS factors (1-5) did not predict LDL-C–lowering treatment efficacy. Effects of gender, race, baseline TGs, baseline HDL-C, and concomitant therapy were limited. MetS, diabetes, blood pressure, fasting glucose, and HOMA IR tertiles were not predictive of any treatment response. Conclusions: This post hoc study in MetS subjects with CHD risk identified age $65 years, abdominal obesity, and lower baseline hs-CRP as factors that significantly influence treatment effects of E/S and atorvastatin on changes in LDL-C, non-HDL-C and Apo B, the current treatment targets suggested for reduction of CMR. The clinical benefits of simvastatin and atorvastatin have been established; the effect of ezetimibe on cardiovascular outcomes awaits results from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial.

Mipomersen sodium: A new option for the treatment of familial hypercholesterolemia

In collaboration with Genzyme, Isis Pharmaceuticals has developed mipomersen sodium (ISIS-310312), a synthetic second-generation 20-base phosphorothioate antisense oligonucleotide (ASO) that targets messenger RNA encoding apolipoprotein B-100 (Apo B-100). Elevated cholesterol levels, in particular low-density lipoprotein cholesterol (LDL-C) which contains a single apolipoprotein B (ApoB) molecule, have been directly correlated with the incidence of cardiovascular events. Preclinical investigations in transgenic mice have demonstrated that lowering LDL-C or ApoB can reduce aortic plaque formation associated with atherosclerosis. Mipomersen pharmacokinetics showed a wide and rapid tissue distribution and a slow prolonged elimination phase of several days in a range of species. Mipomersen displayed dose-dependent efficacy in lowering LDL-C, ApoB, triglycerides, total cholesterol and other low-density lipoproteins in healthy volunteers with mild hyperlipidemia. Similar decreases were observed in patients on stable lipid-lowering therapy for familial hypercholesterolemia with baseline LDL-C levels declining towards clinically desirable concentrations of 70 mg/dL. The efficacy of mipomersen in treating patients with severe heterozygous or homozygous familial hypercholesterolemia with cardiovascular complications has been recently assessed. There have been no serious adverse events noted with treatment and mipomersen can be administered in combination with other lipid-lowering therapies. One concern noted was an elevation in liver transaminase concentrations, although these increases were reversible.

Mipomersen as a potential adjunctive therapy for hypercholesterolemia

Mipomersen, an antisense oligonucleotide directed against apolipoprotein B-100 (apoB), was investigated for its safety and efficacy in reducing low-density lipoprotein (LDL) cholesterol (C) as adjunctive treatment for patients with homozygous familial hypercholesterolemia (HoFH) in a Phase III, double-blind, randomized, controlled trial. HoFH patients are very rare in the general population (∼ 1:1,000,000) and have very high risk for cardiovascular events. HoFH patients respond poorly to statins and most other existing lipid-lowering therapies. Mipomersen (200 or 160 mg) administered subcutaneously to 34 HoFH patients for 26 weeks significantly reduced LDL-C by 24.7% from baseline. In addition, mipomersen lowered plasma lipoprotein (a). In most patients, mipomersen administration was most associated with injection-site reactions; influenza-like symptoms were also more common in mipomersen-treated patients. Four patients had elevated serum alanine aminotransferase (ALT) concentrations, one of whom also had a significant increase in intrahepatic triglyceride content. Another patient met the stopping rules for increased ALT concentrations. No patient developed steatohepatitis during the study. Thus, so far short-term data indicate that mipomersen is safe and effective as an adjunctive drug for lowering LDL-C. Despite these promising results, the longer-term safety and efficacy of mipomersen still needs to be determined.