Efﬁcacy and Safety of Mipomersen

JACCEfﬁcacy and Safety of Mipomersen

Fatima Akdim, MD,* Erik S. G. Stroes, MD, PHD,* Eric J. G. Sijbrands, MD, PHD,‡ Diane L. Tribble, PHD,† Mieke D. Trip, MD, PHD,* J. Wouter Jukema, MD, PHD,§ JoAnn D. Flaim, PHD,† John Su, PHD,† Rosie Yu, PHD,† Brenda F. Baker, PHD,† Mark K. Wedel, MD,† John J. P. Kastelein, MD, PHD* Amsterdam, Rotterdam, and Leiden, the Netherlands; and Carlsbad, California

Efﬁcacy and Safety of Mipomersen, an Antisense Inhibitor of Apolipoprotein B, in Hypercholesterolemic Subjects Receiving Stable Statin Therapy Objectives The aim of this study was to evaluate the efﬁcacy and safety of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Background Mipomersen is an apolipoprotein (apo) B synthesis inhibitor that has demonstrated signiﬁcant reductions in apo B and low-density lipoprotein (LDL) cholesterol in Phase 1 clinical trials in healthy volunteers. Methods A randomized, placebo-controlled, dose-escalation Phase 2 study was designed to evaluate the effects of mi- pomersen in hypercholesterolemic subjects taking stable statin therapy. Seventy-four subjects were enrolled se- quentially into 1 of 6 dose cohorts at a 4:1 (active/placebo) ratio. Subjects received 7 doses of 30 to 400 mg over 5 weeks in the ﬁrst 5 cohorts and 15 doses of 200 mg over 13 weeks in the sixth cohort. Pre-speciﬁed end points included percentage change from baseline in apo B and LDL cholesterol. Safety was assessed with labo- ratory test results and by the incidence and severity of adverse events. Results The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week mipomersen and higher in the 5-week treatment cohorts. Efﬁcacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema [90%]) and he- patic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 sub- jects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations 3 the upper limit of normal, 4 of which persisted on 2 consecutive occasions. Conclusions Mipomersen might hold promise for treatment of patients not reaching target LDL cholesterol levels on stable statin therapy. Further studies are needed to address the mechanisms and clinical relevance of transaminase changes after mipomersen administration. (Dose-Escalating Safety Study in Subjects on Stable Statin Therapy; NCT00231569) (J Am Coll Cardiol 2010;55:1611–8) © 2010 by the American College of Cardiology Foundation

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