FDA would allow refractory heterozygous FH trial, but AEGR also must do high risk HeFH trial, and may need clinical outcomes trial. AEGR has not pursued any of these options, at least in part due to financial constraints.
• including patients with 300 LDL mimics the severe refractory HeFH population and shifts risk/benefit (untreated HoFH have LDL 650 mg/dL) -this would be a REMS issue
• safety, but not effiacy data for weeks 56 through 78 have been submitted to the NDA
• It seems unclear whether lomitapide would be approved for patients with liver related abnormalities based on clinical pharmacology comments - what portion of the market would this represent?
• 24/28 patients (86%) had 10% increase in % hepatic fat (absolute points, see figure below) - patients with diabetes or alcohol consumption were excluded from study but have greater risk of steatosis. 26% missing data - may be biased and missing subjects with large amounts of fat at follow-up. appears reversible (not always), at least after short term use
• substantial fat accumulation even in the clinical trial with lower risk patients at lower doses of 2.5-10 mg.
• investigators were not blinded to LDL levels - potential bias source