Long-term treatment of homozygous familial hypercholesterolemia with lomitapide: 11 years of safety and effectiveness findings from the Lomitapide Observational Worldwide Evaluation Registry (LOWER)

Background Lomitapide is an oral microsomal triglyceride transfer protein inhibitor approved for homozygous familial hypercholesterolemia (HoFH). Objective Evaluate data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER; NCT02135705). Methods LOWER is a global, prospective observational registry initiated in March 2014 to evaluate real-world effectiveness and safety of lomitapide in patients with HoFH. Results A total of 246 individuals were enrolled (43.5% male; mean age 50.3 years, SD 15.3; range 18–83). Mean lomitapide daily dose was 12.1 mg (SD 8.7; range 1.4–50.0). Patients received lomitapide for an average 45.6 months (SD 38.4; range 0.3–142.1). Baseline mean LDL-C was 241.1 mg/dL (SD 109.1; range 71–672). Following treatment initiation, 86.8% of patients on lomitapide achieved ≥50% LDL-C reduction at some timepoint (72.2% in the full analysis set [FAS]). In the FAS 74.3% achieved LDL-C <100 mg/dL, 51.0% <70 mg/dL, and 38.4% achieved <55 mg/dL LDL-C at any time. Adverse events were mostly gastrointestinal in nature (n=111; 45.3%). Hepatic events of special interest (ESIs) were reported in 21.6% and gastrointestinal ESIs occurred in 13.9% of patients. Major adverse cardiovascular events (MACE) occurred in 15.9% of patients, and no MACE were attributed to lomitapide. Exposure-adjusted MACE incidence was 2.8 events per 100-person years on lomitapide, versus 4.3 after lomitapide discontinuation. Conclusion LOWER supports lomitapide's long-term effectiveness and safety for up to 11 years, enabling substantial LDL-C reductions and treatment goal achievement in HoFH with a manageable safety profile. Tentative evidence of reduced MACE during lomitapide treatment warrants further investigation.