Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension

Abstract

Aims: To evaluate the efficacy and safety of extended dosing with mipomersen in patients with familial hypercholesterolaemia (HC) taking maximally tolerated lipid-lowering therapy.

Methods and results: A planned interim analysis of an ongoing, open-label extension trial in patients (n = 141) with familial HC receiving a subcutaneous injection of 200 mg mipomersen weekly plus maximally tolerated lipid-lowering therapy for up to 104 weeks. The mean changes in low-density lipoprotein cholesterol (LDL-C) from baseline to weeks 26 (n = 130), 52 (n = 111), 76 (n = 66), and 104 (n = 53) were -28, -27, -27, and -28%; and in apolipoprotein B -29, -28, -30, and -31%, respectively. Reductions in total cholesterol, non-high-density lipoprotein-cholesterol, and lipoprotein(a) were comparable with decreases in LDL-C and apolipoprotein B levels. Mean high-density lipoprotein cholesterol increased from baseline by 7 and 6% at weeks 26 and 52, respectively. The long-term safety profile of mipomersen was similar to that reported in the associated randomized placebo-controlled Phase 3 trials. Adverse events included injection site reactions and flu-like symptoms. There was an incremental increase in the median liver fat during the initial 6-12 months that appeared to diminish with continued mipomersen exposure beyond 1 year and returned towards baseline 24 weeks after last drug dose suggestive of adaptation. The median alanine aminotransferase level showed a similar trend over time.

Conclusion: Long-term treatment with mipomersen for up to 104 weeks provided sustained reductions in all atherosclerotic lipoproteins measured and a safety profile consistent with prior controlled trials in these high-risk patient populations. CLINICALTRIALS.GOV: NCT00694109.

Keywords: Adverse events; Familial hypercholesterolaemia; Hypercholesterolaemia; Lipid-lowering; Long-term safety.

© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1

Patient disposition. *One patient discontinued after completing the initial treatment period.

Figure 2

Sustained reductions in LDL-C, ApoB, and Lp(a) with long-term mipomersen treatment.

Figure 3

Incidence of injection site reactions (ISRs) and flu-like symptom (FLS) events occurring at least once over time. (A) All patients. (B) Patients completing 2 years of treatment.

Figure 4

Change from baseline in ALT levels and liver fat fraction over time. Values shown represent: (A) box plot of ALT levels (U/L); (B) box plot of change from baseline in liver fat fraction (%).

Figure 5

Evolution of systolic and diastolic blood pressure over time. The horizontal line in the middle of each box indicates the median, an X indicates the mean and the top and the bottom borders of the box mark the 75th and 25th percentiles, respectively. Whiskers are presented to the most extreme value within ±1.5 times the interquartile range. The data points above and below the whiskers are defined as outliers. BL, baseline, PD, post last dose.

Figure 6

Evolution of corrected QT (QTc) intervals over time. The horizontal line in the middle of each box indicates the median, an X indicates the mean and the top and the bottom borders of the box mark the 75th and 25th percentiles, respectively. Whiskers are presented to the most extreme value within ±1.5 times the interquartile range. The data points above and below the whiskers are defined as outliers. BL, baseline; PD, post last dose.