Treatment of Homozygous Familial Hypercholesterolemia with the

1. Treatment of Homozygous Familial Hypercholesterolemia with the Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide C Stefanutti1, M Cuchel, EA Meagher, H dTTheron, DJ Blom, AD Marais, RA Hegele, MR Averna, CR Sirtori,PK Shah, D Gaudet, GB Vigna, AME du Plessis, LeAnne T Bloedon2, and Daniel J Rader for the Phase 3 HoFH Lomitapide Study Investigators 1Extracorporeal Therapeutic Techniques Unit, Immunohematology and Transfusion Medicine, Department of Molecular Medicine, “Sapienza” University of Rome, “Umberto I” Hospital 2Aegerion Pharmaceuticals 32 Screened 31 Entered run-in • 6 Discontinuations • Adverse events (n=4) • Withdrew consent (n=1) • Noncompliance with protocol (n=1) 29 Entered efficacy phase 23 Completed efficacy phase (Week 26) 23 Completed safety phase (Week 78) Results Background & Objectives Results B. A. • Homozygous familial hypercholesterolemia (HoFH) is a life threatening genetic condition typically caused by mutations in the gene encoding the low density lipoprotein (LDL) receptor. • HoFHis characterized by severe hypercholesterolemia from birth and onset of premature cardiovascular disease (CVD) often during childhood. • Patients with HoFH are poorly responsive to conventional drug therapy, which primarily lowers LDL cholesterol levels through up-regulation of the LDL receptor. • Despite maximal doses of existing lipid lowering drugs and apheresis treatment HoFH patients usually cannot reach LDL-C goals. • Lomitapide is an investigational drug in a new class of lipid-lowering agents known as microsomal triglyceride transfer protein (MTP) inhibitors that lower LDL-C by inhibiting the assembly and secretion of apoB. • It was previously demonstrated that high doses of lomitapide (up to 1 mg/kg/day) effectively reduced LDL-C in HoFH when used as monotherapy (Cuchel M et al. N Engl J Med. 356:148-56, 2007). • The objective of the present study was to evaluate the efficacy and long term safety of lomitapide in subjects with HoFH on current lipid-lowering therapy (Cuchel, M. et al. Lancet. Article in press: http://dx.doi.org/10.1016/S0140-6736 (12)61731-0 ) Figure 2:A. ALT, AST and bilirubin levels (mean, 95%CI) measured at baseline and at regular intervals during the study. Laboratory reference ranges were: ALT: Male (10-40 U/L), Female (10-33 U/L); AST: Male (10-43 U/L), Female (10-36 U/L), Bilirubin, 0.1-1.1 mg/dL. B. Percentage of Fat in the Liver (mean, 95%CI), as measured by MRI/NMRS at Baseline and 26, 56 and 78 weeks of lomitapide treatment (safety population). Study Design Figure 1: Mean percent changes in LDL-C TC and apoB levels from baseline to end of study in completers (n=23). Data are mean ± SD. Figure 3: Gastrointestinal adverse events, expressed as % of patients with events and intensity grade, observed during the entire study duration. Table 2: Lipid and lipoprotein concentrations at baseline and weeks 26, 56, and 78 Conclusions • Treatment with the MTP inhibitor lomitapide is highly efficacious in lowering LDL-C in patients with HoFH treated with maximum lipid lowering therapy • Treatment with lomitapide produced significant reductions in apo B, total cholesterol and non-HDL cholesterol • At any time on treatment with lomitapide, 16 (55%) had LDL-C < 100 mg/dL and 9 (31%) had < 70 mg/dL • GI AEs are the most common AE during lomitapide treatment; are usually of mild or moderate intensity with incidence decreasing after patients are established on their maximum tolerated dose • Hepatic fat content at week 26 is increased as compared to baseline and then stabilizes • Single-arm, open-label study with ascending dose of lomitapide, up to 60 mg/day • The primary efficacy endpoint measure was percent change in LDL-C from baseline to the end of the efficacy phase (week 26), for the intent to treat (ITT) population. • Concomitant lipid-lowering therapies fixed through Week 26; low fat diet • Careful LFT monitoring, liver fat evaluation by NMRS Acknowledgments This study was supported by a grant from the FDA Office of Orphan Product Development (FR-R-003098) to Dr. Marina Cuchel and by Aegerion Pharmaceuticals The authors would like to thank their co-investigators, the clinical staff at the study sites as well as the patients who participated in the study and their families. Data are reported in mg/dL. Absolute values are mean ± SD or median (range). % Change from baseline values are mean (95% CI); ^ ITT analysis using LOCF, LDL-C reduced by 40% from baseline to week 26 (190 ± 104 mg/dL, p<0.001). *p values from mixed model; **p values from one-sample t-test