Abstract 1077: A Phase III Study of Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide (AEGR-733) in Patients With Homozygous Familial Hypercholesterolemia: Interim Results at 6 Months
Background: Patients with homozygous familial hypercholesterolemia (HoFH), caused by mutations in both LDL receptor alleles, are poorly responsive to existing cholesterol-lowering therapies and at extremely high risk for premature cardiovascular disease. We previously showed in a small phase II trial that lomitapide (AEGR-733), an inhibitor of the microsomal triglyceride transfer protein (MTP), was effective in reducing LDL-C levels by 50% in these patients when given as monotherapy. We present here available 6 month data in 10 patients with HoFH from a phase III study evaluating the efficacy and safety of lomitapide over 1.5 years.
Methods and Results: HoFH subjects are enrolled in this single-arm, open-label study and allowed to continue their usual lipid lowering treatment, including apheresis. The dose of lomitapide is gradually titrated during the first 14 –18 weeks of the study up to a goal of 60 mg/day (or 80 mg if LDL and safety criteria are met). Lipids, liver function tests (LFTs) and liver MRI with spectroscopy are evaluated regularly during the study. To date 18 subjects have been enrolled (of a planned 25), 10 of which have completed the first 6 months (primary efficacy endpoint) and are the focus of this abstract. The maximal tolerated dose ranged 20 – 80 mg/day. The mean LDL-C level reduction observed at 6 months as compared to baseline was −44% (range +19 to −93%). Four patients achieved LDL-C <100 mg/dl; 2 more achieved LDL-C<170 mg/dl. Mean hepatic fat (n=8) was 1.33% (range 0.0 –5.0%) at baseline and 8.1% (range 0.8 –22.7%) at 6 months. Three subjects experienced transitory transaminases elevations that required dose reduction; however no subjects discontinued due to elevated LFTs. Two subjects discontinued due to gastrointestinal adverse events.
Conclusions: These interim results suggest that treatment of HoFH patients with the MTP inhibitor lomitapide results in substantial LDL-C reduction with minimal to modest hepatic fat accumulation and minimal to moderate LFTs changes. The favorable risk benefit profile of this approach suggests a therapeutic window for lomitapide in HoFH and suggests that it may be a viable treatment for these patients.