Abstract 12999: A Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Weekly Subcutaneous Injections of Mipomersen, an Apolipoprotein B-100 Synthesis Inhibitor, on Low Density Lipoprotein Cholesterol in High-Risk Statin-Intolerant Patients with Hypercholesterolemia
Objective: To determine the safety and efficacy of 26 weeks of mipomersen (MIPO) in statin ntolerant (unable to tolerate any dose of ≥2 statins) patients at high risk for coronary heart disease (CHD) or with familial hypercholesterolemia (FH).
Methods: In this study, 33 patients received weekly doses of 200 mg MIPO (n=21) or placebo (n=12). The primary endpoint was percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to Week 28. Other endpoints included changes in apolipoprotein B (apo B), lipoprotein(a) [Lp(a)], high density lipoprotein (HDL) and lipoprotein particle size. Safety was determined via adverse events (AEs) and clinical laboratory evaluations.
Results: Weekly treatment with 200 mg MIPO reduced LDL-C by a mean of 47.3% from a baseline of 6.3 mmol/L to Week 28, (p<.001 v. placebo). Lp(a) and apo B were also significantly reduced in MIPO patients (-27.1% and -46.2%, respectively; both p<.001 v. placebo). HDL increased in MIPO patients but the difference was not statistically significant compared to placebo. MIPO differentially lowered LDL-particle numbers with largest reductions in the small LDL particles (-56.1%, p<.001). Four MIPO (19%) and 2 placebo patients (17%) discontinued dosing due to AEs. The most common AEs in both groups were injection site reactions and flu-like symptoms. Persistent transaminase increases ≥3x ULN occurred in 7 (33%) MIPO patients. Post-baseline magnetic resonance spectroscopy in 14 MIPO and 1 placebo patient showed intrahepatic triglyceride content ranging from 0.8% to 47.3%, which decreased after completion of therapy in most patients. Liver needle biopsies performed in 2 MIPO patients showed severe hepatic steatosis with minimal inflammation and minimal to no fibrosis.
Conclusion: MIPO 200 mg weekly significantly decreased LDL-C, Lp(a) and Apo B compared to placebo. Injection site reactions were frequently reported, but none led to discontinuation of dosing. Persistent transaminase increases and intrahepatic fat accumulation were observed in some MIPO patients; however, inflammatory changes appeared minimal. Inhibition of ApoB synthesis with MIPO may offer an effective strategy to lower LDL-C in statin intolerant patients at high risk for CHD or with FH.
- © 2011 by American Heart Association, Inc.