Abstract 16531: Decreased Cardiovascular Events in Familial Hypercholesterolemic Patients Treated With Mipomersen, an Antisense Inhibitor of Apolipoprotein B Translation
Background: Familial hypercholesterolemia (FH) is associated with a 10-20 fold increase in cardiovascular (CV) events. Mipomersen has been shown to significantly lower levels of atherogenic lipoproteins in plasma. Previous safety analysis of all patients in phase 3 trials found no meaningful imbalance in CV events between placebo and mipomersen arms.
Hypothesis: Treatment with mipomersen for at least 1 year will reduce CV events in FH patients taking maximally tolerated lipid-lowering therapy.
Methods: Rates of major adverse CV events (MACE) during 2 years prior to mipomersen treatment were compared to MACE after treatment in 104 FH patients who participated in one of three phase 3 blinded randomized placebo-controlled 6-month trials and an open-label extension study (NCT00607373, NCT00706849, NCT00794664, NCT00694109). One third of patients (n=34) received placebo for the initial 6 months followed by mipomersen for at least 1 year. Two thirds (n=70) received blinded mipomersen for 6 months followed by at least 6 months in open label treatment. MACE were defined as non-fatal MI, stroke, unstable angina, and revascularization procedures (PCI/CABG). MACE occurring before randomization were identified in medical history. On-study MACE, including those for placebo-treated patients, were adjudicated post-hoc by an independent committee.
Findings: MACE were identified in 62% of patients (64 patients with 146 events [39 MI, 99 PCI/CABG, 5 UA, 3 stroke]) during 24 months prior to mipomersen treatment, and 9% of patients (9 patients with 12 events [2 UA+MI, 6 PCI/CABG, 4 UA]) during a mean of 24.4 months after initiation of mipomersen treatment (MACE rate 25.7/1000 patient-months vs 3.6/1000 patient-months, OR = 0.035 [95% CI 0.009 - 0.144], p<0.0001 by exact McNemar’s test). The marked reduction in MACE coincided with the absolute mean reductions in LDL cholesterol levels (-49 to -113 mg/dL) reported for the phase 3 FH clinical trials.
Summary: MACE rates were significantly lower during mipomersen treatment compared with 24 months prior to mipomersen (p<0.0001).
Conclusions: Results from this limited analysis suggest that treatment with mipomersen may reduce cardiovascular events in patients with FH.
Author Disclosures: B. Duell: Research Grant; Significant; Genzyme/Sanofi, Pfizer, Bristol Meyers Squibb/Astra Zeneca (all significant, but paid only to the institution. Honoraria; Significant; Genzyme/Sanofi. Consultant/Advisory Board; Modest; Novartis, Genzyme/Sanofi, Kaneka. R.D. Santos: Research Grant; Modest; Genzyme/Sanofi. Consultant/Advisory Board; Modest; Genzyme/Sanofi. M.P. McGowan: Employment; Significant; Genzyme Corporation. A. Mahmood: Employment; Significant; Genzyme Corporation. B.F. Baker: Employment; Significant; Isis Pharmaceuticals Inc.. Ownership Interest; Significant; Isis Pharmaceuticals Inc. R.S. Geary: Employment; Significant; Isis Pharmaceuticals Inc.. Ownership Interest; Significant; Isis Pharmaceuticals Inc. W. Singleton: Employment; Significant; Isis Pharmaceuticals Inc. J.J. Kastelein: Consultant/Advisory Board; Modest; Genzyme, Aegerion, Sanofi, Regeneron, Amgen, Eli Lilly, Catabasis, Dezima Pharmaceuticals. Consultant/Advisory Board; Significant; Isis Pharmaceuticals.
- © 2014 by American Heart Association, Inc.