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

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.

Figure 1

Flow chart of study participants.

Figure 2

Effect of mipomersen on apolipoprotein B-100 (A) and low-density lipoprotein cholesterol (B) over time. Low-density lipoprotein cholesterol is presented as the mean per cent change from baseline ± 95% confidence interval. Dotted line represents the end of the treatment period.

Figure 3

Effect of mipomersen on low-density lipoprotein particle subclass distribution.

Figure 4

Change in intrahepatic triglyceride (IHTG) content. Intrahepatic triglyceride content for all subjects with increases in alanine aminotransferase >2× the upper limit of normal (ULN) (n = 15). I, the highest measurement performed; filled circle, measurements performed between Weeks 24 and 31; filled triangle, measurement performed after Week 35; filled square, measurements performed at early termination in Weeks 7 and 15; open square, measurement in a patient from the placebo group who refused follow-up because of claustrophobia; II, the lowest value measured during follow-up between Weeks 50 and 90. Horizontal dotted line represents the upper limit of normal of 5.6% for intrahepatic triglyceride content. The median absolute change from highest intrahepatic triglyceride content to lowest intrahepatic triglyceride content at follow-up was −17.7% (−6.4 to −38.0; n= 12, P= 0.0005).