Mipomersen Lowers LDL-c in High-risk Statin-intolerant Patients
Mipomersen Lowers LDL-c in High-risk Statin-intolerant Patients
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
Whereas statins, the first-line treatment in patients at increased risk for cardiovascular disease (CVD), are well tolerated, adverse events (AEs) such as liver transaminase increases and myalgia occur. In a minority, side effects may even lead to discontinuation of therapy. The incidence of statin 'intolerance' is rising, most likely reflecting the use of higher statin doses required to achieve more stringent LDL cholesterol (LDL-c) targets. Available alternatives to lower LDL-c levels in statin-intolerant patients include switching to other statins, non-daily or low-dosing regimens, and the use of non-statin LDL-lowering drugs such as ezetimibe and bile acid-binding resins. The efficacy of these therapeutic strategies is, however, limited.
Mipomersen is a second-generation antisense oligonucleotide which inhibits the synthesis of apolipoprotein B-100 (apoB). apoB is the main structural component of all atherogenic lipid particles and is required for the secretion of very low-density lipoprotein (VLDL) from the liver. In previous clinical trials, mipomersen has been shown to induce dose-dependent reductions in LDL-c and all other apoB-containing lipoproteins, in patients with various extents of hypercholesterolaemia including patients with familial hypercholesterolaemia (FH). Injection site reactions and flu-like symptoms are the most common AEs with mipomersen. In addition, liver transaminase increases have been observed. Since previous attempts to inhibit VLDL production with microsomal transport protein inhibitors were complicated by profound increases in intrahepatic triglyceride (IHTG) content, safety concerns regarding mipomersen have focused on the liver.
In the present report, we describe the results of a randomized, double-blind, placebo-controlled Phase 2 study designed to evaluate the safety and efficacy of mipomersen in statin-intolerant subjects at high risk for CVD.
Abstract and Introduction
Abstract
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
Introduction
Whereas statins, the first-line treatment in patients at increased risk for cardiovascular disease (CVD), are well tolerated, adverse events (AEs) such as liver transaminase increases and myalgia occur. In a minority, side effects may even lead to discontinuation of therapy. The incidence of statin 'intolerance' is rising, most likely reflecting the use of higher statin doses required to achieve more stringent LDL cholesterol (LDL-c) targets. Available alternatives to lower LDL-c levels in statin-intolerant patients include switching to other statins, non-daily or low-dosing regimens, and the use of non-statin LDL-lowering drugs such as ezetimibe and bile acid-binding resins. The efficacy of these therapeutic strategies is, however, limited.
Mipomersen is a second-generation antisense oligonucleotide which inhibits the synthesis of apolipoprotein B-100 (apoB). apoB is the main structural component of all atherogenic lipid particles and is required for the secretion of very low-density lipoprotein (VLDL) from the liver. In previous clinical trials, mipomersen has been shown to induce dose-dependent reductions in LDL-c and all other apoB-containing lipoproteins, in patients with various extents of hypercholesterolaemia including patients with familial hypercholesterolaemia (FH). Injection site reactions and flu-like symptoms are the most common AEs with mipomersen. In addition, liver transaminase increases have been observed. Since previous attempts to inhibit VLDL production with microsomal transport protein inhibitors were complicated by profound increases in intrahepatic triglyceride (IHTG) content, safety concerns regarding mipomersen have focused on the liver.
In the present report, we describe the results of a randomized, double-blind, placebo-controlled Phase 2 study designed to evaluate the safety and efficacy of mipomersen in statin-intolerant subjects at high risk for CVD.