Biomarkers of hepatic safety
NAFLD, NASH, fibrosis, steatohepatitis
INFLAMMATION, FIBROSIS, STEATOHEPATITIS
During treatment with lomitapide in the pivotal phase 3 and extension trials, circulating levels of CK‐18 and CK‐18 fragments were measured as biomarkers of hepatic inflammation and indicators of non‐alcoholic steatohepatitis (NASH). Mean levels of CK‐18 and CK‐18 fragments exhibited statistically significant mean increases from baseline to week 26, and then remained relatively stable between weeks 26 and 126 (Figure 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. *For HA and TIMP‐1, statistically significant mean elevations over baseline were only evident for HA at week 56 (12.4 ng/ml [95% CI: 1.5, 23.3] Evaluating ELF at the individual patient level showed that there were five patients with ELF scores >−0.6415 post‐baseline through week 78. These elevated scores were mostly at single timepoints—one patient at week 26 (−0.5510), two patients at week 56 (−0.3357 and −0.5731), one patient at week 78 (−0.4715), and one patient at weeks 26, 56 and 78 (−0.3317, −0.3787 and −0.1195). For this latter patient, hepatic fat content was 0.86% at baseline, 11.85% at week 26 and 0.39% at week 56, indicating that NAFLD was not present in this patient. One subject had ELF >−0.6415 at baseline but not thereafter. No subjects exhibited ELF scores that would exceed the threshold whereby the odds of having either moderate or severe fibrosis would exceed the odds of not having moderate or severe fibrosis. During the study, none of the patients underwent post‐baseline liver biopsy due to liver‐related safety concerns.