Abstract 1311: Mipomersen, a First-in-Class Apo-B Synthesis Inhibitor, Lowers LDL-C in Patients With Homozygous Familial Hypercholesterolemia: Results of a Phase III Study
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by an LDL receptor defect resulting in exceedingly high LDL-C levels and premature CAD. Despite available lipid-lowering therapies (LLT), adequate treatment of HoFH remains an unmet medical need. Mipomersen (ISIS 301012, MIPO) is an antisense oligonucleotide that inhibits apoB synthesis. The objective of this double blind, randomized, placebo (PBO) controlled, global multicenter (n=9), phase III trial was to determine if adding MIPO to ongoing LLT is safe and effective in reducing LDL-C in HoFH patients. This is the first phase III clinical study using antisense to lower apo B-containing lipoproteins. Eligible patients (LDL-C ≥130 mg/dL and TG <350 mg/dL, age ≥12) were randomized (2:1) to 200 mg MIPO or PBO, administered s.c weekly for 26 wks. The primary endpoint was LDL-C % change from baseline (BL) at Week 28. The study had >80% power to detect a 20% point difference between groups. Demographics were similar in both groups with mean age 31.3 and 43% males. As shown in the table⇓, MIPO resulted in highly significant mean % reductions in LDL-C and other lipids. Of 51 patients, 45 completed treatment. Of 34 MIPO-treated patients, 6 withdrew from treatment. Reasons for withdrawal were adverse events (AE) [injection site reaction (ISR) (n=2), rash (n=1), and ALT elevation (n=1)]; non-compliance (n=1); withdrawal of consent (n=1). In MIPO-treated patients the most common AE was ISR on ≥1 occasion (26/34). ALT increased to ≥3X ULN in 4/34 patients treated with MIPO without clinically significant bilirubin elevations. In this study, treatment with MIPO produced statistically significant and clinically meaningful reductions in LDL-C and other lipids and was generally well-tolerated. Accordingly, MIPO may represent an effective therapeutic option for use in conjunction with existing LLT for improved management of lipids in this patient population.