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07-04-2010 | Cardiometabolic | Article

Mipomersen shows preliminary lipid-lowering efficacy


Free abstract

MedWire News: Mipomersen, an inhibitor of apolipoprotein B-100 (ApoB), has shown preliminary lipid-lowering efficacy when added to conventional therapy in a phase II clinical trial involving patients with familial hypercholesterolemia (FH).

The investigators say that the drug, a second-generation antisense oligonucleotide, merits further evaluation as add-on therapy in people with an inadequate low-density lipoprotein (LDL) cholesterol response to conventional agents.

A team led by John Kastelein (Academic Medical Centre, Amsterdam, The Netherlands) performed a phase II, randomized, double-blind, placebo-controlled, dose-escalation study to assess the safety and efficacy of mipomersen.

The drug was designed to inhibit synthesis of ApoB by the liver and in previous trials produced prolonged, dose-dependent reductions in LDL cholesterol in healthy volunteers and in patients with mild-to-moderate hypercholesterolemia.

The participants in the present study were 44 patients with heterozygous FH who were randomly assigned to receive mipomersen (at doses ranging from 50 to 300 mg) or placebo. All patients continued their pre-existing lipid-lowering therapy, including high-dose statins, and followed a low-fat diet.

Patients received 8 doses subcutaneously over the 6-week study period; those in the 300-mg dose group continued treatment for an additional 7 weeks with once-weekly dosing.

After week 6, LDL cholesterol had fallen by 21% and 34% in the mipomersen 200 and 300-mg groups, respectively, compared with baseline, and ApoB had fallen by 23% and 33%. All reductions were statistically significant versus placebo.

Mipomersen, at doses of 200 and 300 mg, was also associated with reductions in levels of lipoprotein(a) and triglycerides versus baseline, although these changes were not significant.

In the extended-treatment group, LDL cholesterol, ApoB, and lipoprotein(a) had fallen by 3%, 37%, and 29%, respectively, at week 13 compared with baseline. All reductions were statistically significant.

Furthermore, LDL cholesterol and ApoB levels remained below baseline for at least 3 months after the last dose.

In terms of safety, there was one serious adverse event, a single episode of syncope that was considered to be unrelated to the study drug. Other adverse events included injection-site reactions, influenza-like symptoms, and elevations in liver enzymes.

Writing in the American Journal of Cardiology, Kastelein et al conclude: “Although the present findings support the use of mipomersen at a dose of 200-mg/week in a Phase III program, additional studies are warranted to elucidate the relation between the transaminase elevations and steatotic changes in the liver after mipomersen administration.”

These results add to the results of a previous study demonstrating the efficacy of mipomersen for LDL cholesterol reduction in FH patients, as reported by MedWire News.

MedWire ( is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

By Joanna Lyford