Long-term hepatic safety of lomitapide in homozygous familial hypercholesterolaemia

Abstract

Introduction: Lomitapide is a microsomal triglyceride transfer protein inhibitor for patients with homozygous familial hypercholesterolaemia. Due to its mechanism of action, potential hepatic effects of lomitapide are of clinical interest. This study aimed to determine the long-term hepatic safety of lomitapide.

Methods: Data were aggregated from the pivotal phase 3 and extension phase clinical trial with lomitapide (median 5.1 years; serum total bilirubin, transaminases, cytokeratin-18 [CK-18] and enhanced liver fibrosis [ELF] score, fat-soluble vitamins and essential fatty acids), 8-year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER) and real-world evidence from a cohort of patients treated with lomitapide in Italy (hepatic elastography, and FIB-4 score for hepatic fibrosis).

Results: In the phase 3 trial and the LOWER registry, any asymptomatic excursions in liver transaminase levels were not associated with elevations in bilirubin, and no Hy's law cases were detected in up to 8 years follow-up. There were no clinically relevant increases among hepatic biomarkers CK-18, CK-18 fragments or ELF score and fat-soluble vitamins and essential fatty acids remained above normal levels. In 34 patients treated in Italy with lomita pide for more than 9 years, elevations in hepatic fat were mild-to-moderate; hepatic stiffness remained normal, and the mean FIB-4 score remained below the fibrosis threshold value of 2.67.

Conclusions: These data indicate that the hepatic safety of lomitapide remains favourable with no clinically significant elevations in hepatic biomarkers and hepatic stiffness remained normal for more than 9 years follow-up. PHASE 3 TRIAL: NCT00730236; extension phase: NCT00943306; LOWER: NCT02135705.

Keywords: Lomitapide; hepatic; hepatic biomarkers; hepatic steatosis; homozygous familial hypercholesterolaemia; liver; liver fibrosis.

FIGURE 1

Mean aminotransferase and bilirubin levels from the pivotal phase 3 trial in HoFH. Values represent means ± standard deviation. ULN for bilirubin (all patients) is 1.2 mg/dl; ULN for ALT in females is 33 and males is 40 IU/L; ULN for AST in females is 36 and males is 43 IU/L. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

FIGURE 2

CK‐18 fragments (A) and ELF component (B) biomarkers during lomitapide treatment in the long‐term extension study. Values represent mean (95% CI) CK‐18 and extracellular matrix markers in patients with follow‐up data. *p < .05; **p < .01. CK‐18, cytokeratin‐18 fragment; ELF, enhanced liver fibrosis; HA, hyaluronic acid; P3NP, amino‐terminal propeptide of type III procollagen; TIMP‐1, tissue inhibitor of matrix metalloproteinase; W, week.

FIGURE 3

FIB‐4 scores by months of treatment with lomitapide in patients with baseline and follow‐up data (n = 25). Bars represent individual patient data at baseline and last follow‐up. FIB‐4 score is calculated as age (years) × AST [IU/L]/(platelets [10⁹/L] × (ALT [IU/L])^0.5). *Parametric, two‐tailed t‐test. SD, standard deviation; ^†77‐year‐old patient with short follow‐up; ^#patient with very low platelet counts at follow‐up (74 × 10⁹/L), ^§66‐year‐old patient.

FIGURE 4

Hepatic stiffness according to liver elastography by months of exposure to lomitapide in patients with follow‐up elastography data (n = 21). Bars represent individual patient data at last follow‐up visit. Inset: mean ± SD liver stiffness at baseline and follow‐up for n = 7 patients with baseline and follow‐up data. SD, standard deviation.