Abstract 1312: Mipomersen, a First-in-Class Apolipoprotein B Synthesis Inhibitor, Lowers Lp(a) in Patients With Homozygous Familial Hypercholesterolemia and High Baseline Lp(a): Results of a Phase III Study
Mipomersen (MIPO, ISIS301012) is an antisense oligonucleotide apo B synthesis inhibitor. In Lp(a) transgenic mice, MIPO reduced Lp(a) levels without impacting apo(a) synthesis. Reductions in Lp(a) also were observed in a pilot study in 3 patients with homozygous familial hypercholesterolemia (HoFH). We separately report results of a double-blind, placebo (PBO)-controlled, phase III study in which 51 patients with HoFH were randomized to 26 wks of PBO (n=17) or MIPO 200 mg/wk s.c (n=34) in addition to stable lipid-lowering therapies (LLT). Mean baseline (BL) LDL-C values were 400 mg/dL (PBO) and 439 mg/dL (MIPO). MIPO produced a significant mean % reduction from BL of 25% in LDL-C (primary endpoint); mean absolute LDL-C reduction was 113 mg/dL (both p<0.001 vs PBO, ITT). Significant reductions also were observed for secondary endpoints [apo B (27%), total cholesterol (21%), non-HDL-C (24%), all p<0.001 vs PBO]. Herein we report results for Lp(a), a tertiary endpoint and proposed independent risk factor for CVD in FH patients. The majority of patients (32/34 MIPO; 13/17 PBO) had abnormal Lp(a) levels (>20 mg/dL) at BL. Median BL Lp(a) levels were 58 (range, 3 to 164) mg/dL for PBO and 56 (10 to 176) mg/dL for MIPO. MIPO produced a significant % reduction in Lp(a) from BL (median 32%, p=0.001 vs. PBO); median absolute reduction was 20.5 mg/dL (p=0.0016 vs. PBO). Accordingly, following treatment, median Lp(a) values were 53 (range, 3–150) mg/dL (PBO) vs. 33 (4 –133) mg/dL (MIPO). The % reduction in Lp(a) exceeded that for all other lipids and 8/34 [24%] of MIPO-treated patients had Lp(a) reductions >50%. High Lp(a) has been treated by targeting reductions in LDL, a key component of the Lp(a) particle, with statins±other LLT, or with niacin, but these agents are only modestly effective. Given the safety and tolerability profile of MIPO in this study (28/34 MIPO patients completed treatment; the most common adverse event was injection site reaction [MIPO 26/34, PBO 4/17]; ALT >=3XULN occurred in 4/34 of MIPO patients without clinically significant elevations in bilirubin), the present results suggest that mipomersen could represent an effective therapeutic option for use in conjunction with existing LLT to improve management of Lp(a) in patients with high LDL-C and Lp(a) levels.