Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy

Abstract

Objectives: Mipomersen, an antisense oligonucleotide targeting apolipoprotein B synthesis, significantly reduces LDL-C and other atherogenic lipoproteins in familial hypercholesterolemia when added to ongoing maximally tolerated lipid-lowering therapy. Safety and efficacy of mipomersen in patients with severe hypercholesterolemia was evaluated.

Methods and results: Randomized, double-blind, placebo-controlled, multicenter trial. Patients (n = 58) were ≥18 years with LDL-C ≥7.8 mmol/L or LDL-C ≥5.1 mmol/L plus CHD disease, on maximally tolerated lipid-lowering therapy that excluded apheresis. Weekly subcutaneous injections of mipomersen 200 mg (n = 39) or placebo (n = 19) were added to lipid-lowering therapy for 26 weeks.

Main outcome: percent reduction in LDL-C from baseline to 2 weeks after the last dose of treatment. Mipomersen (n = 27) reduced LDL-C by 36%, from a baseline of 7.2 mmol/L, for a mean absolute reduction of 2.6 mmol/L. Conversely, mean LDL-C increased 13% in placebo (n = 18) from a baseline of 6.5 mmol/L (mipomersen vs placebo p<0.001). Mipomersen produced statistically significant (p<0.001) reductions in apolipoprotein B and lipoprotein(a), with no change in high-density lipoprotein cholesterol. Mild-to-moderate injection site reactions were the most frequently reported adverse events with mipomersen. Mild-to-moderate flu-like symptoms were reported more often with mipomersen. Alanine transaminase increase, aspartate transaminase increase, and hepatic steatosis occurred in 21%, 13% and 13% of mipomersen treated patients, respectively. Adverse events by category for the placebo and mipomersen groups respectively were: total adverse events, 16(84.2%), 39(100%); serious adverse events, 0(0%), 6(15.4%); discontinuations due to adverse events, 1(5.3%), 8(20.5%) and cardiac adverse events, 1(5.3%), 5(12.8%).

Conclusion: Mipomersen significantly reduced LDL-C, apolipoprotein B, total cholesterol and non-HDL-cholesterol, and lipoprotein(a). Mounting evidence suggests it may be a potential pharmacologic option for lowering LDL-C in patients with severe hypercholesterolemia not adequately controlled using existing therapies. Future studies will explore alternative dosing schedules aimed at minimizing side effects.

Trial registration: ClinicalTrials.gov NCT00794664.

Conflict of interest statement

Competing Interests: MPM has consulted for and participated in two Genzyme Advisory Board Meetings. She is currently an employee of Genzyme; however, this manuscript was completed prior to this employment. MPM was the lead investigator and developed the manuscript. She has served on the following speaker's bureaus: Glaxo Smith Kline and Merck-Schering Plough. JCT acknowledges grants from Genzyme to his institution. RC is an advisory board member for: Genzyme, KOWA, and MSD; and is a speaker for Abbott, ASTRA-ZENECA, MSD, Pfizer, and Sanofi. LJB reports no conflicts. HS received fees for lectures and consultancy work from Genzyme as well as research grants from MSD Sharp & Dohme and Pfizer. IGB received payments for lectures and speakers bureaus from MSD Sharp & Dohme and Genzyme. She has received travel expenses and meeting expenses from Otsuka and Novartis as well as a grant for research from Bayer Healthcare. GW and is an employee of Genzyme, a Sanofi Company. SCT is a past employee of Genzyme. This does not alter the authors’ adherence to all PLOS One policies on sharing data and materials.

Figures

Figure 1. Patient Disposition – Consort Diagram.

Figure 2. Mean Absolute Reduction in LDL-C (value closest to 2 weeks after the end of study treatment).

Figure 3. Mean Percent Change from Baseline to Week 28.

Error bars indicate 95% CI. Placebo (n  = 18); mipomersen 200 mg weekly (n  = 39). (A) Low-density lipoprotein cholesterol (LDL-C) (B) Apolipoprotein B (Apo B) (C) Lipoprotein(a) (Lp(a)) (D) Non-high density lipoprotein cholesterol (non-HDL-C) (E) Total Cholesterol.