DISCUSSION
NAFLD, hepatic alterations, hepatic inflammation, cirrhosis, fibrosis, liver disease, hepatic stiffness, NASH, hepatic steatosis, liver inflammation, metabolic syndrome, steatohepatitis
HOFH, GENETIC CONDITION, CVD, LIVER, CIRRHOSIS, LIVER DAMAGE, LIVER FIBROSIS, FIBROSIS, EVENT, LIVER DISEASE, METABOLIC SYNDROME, HEPATIC STEATOSIS, EVENTS, HEPATIC FIBROSIS, STEATOHEPATITIS
In the present study, we examined the long‐term hepatic safety of lomitapide based on a range of data available from various sources, which enabled the evaluation of follow‐up for more than 9 years. The data show that lomitapide results in some hepatic alterations, but that overall, there were no clinically meaningful signals of liver damage.Liver transaminases are routinely measured in patients receiving lomitapide for HoFH. In the present analysis of data from multiple sources, a minority of patients experienced increases in liver transaminase levels >3xULN. In LOWER, the majority of first events occurred within the first 12 months of treatment and all first events occurred within 20 months, which coincides with the period of lomitapide dose titration. The transaminase profile for lomitapide is similar to the profile seen in the early years with statins and has not been associated with an increase in other hepatic events with either medication. The number of hepatic transaminase elevations >3x ULN that persist >4 weeks despite dose reduction or interruption has remained unchanged since 2019.Evaluation of liver safety included assessment of biomarkers of liver inflammation, CK‐18 and CK‐18 fragments, in samples taken from patients in the phase 3 trial up to 126 weeks (>2 years). Studies have demonstrated that circulating levels of CK‐18 and CK‐18 fragments are correlated with the degree of hepatocyte apoptosis.Levels of HA, P3NP, and TIMP, and the ELF score (which combines all three independent markers) have been shown to correlate with the extent of hepatic fibrosis in several different conditions.The biomarker results were further supported by the analysis of FIB‐4 scores. FIB‐4 score is a useful, non‐invasive marker of liver fibrosis that uses a calculation based on platelet and transaminase levels to provide a validated measure of the risk of liver fibrosis.A FIB‐4 score above 2.67 is considered predictive for clinically meaningful fibrosis in NAFLD in all age groups >35 years old.Data from the Italian cohort also provided the opportunity to evaluate the effect of lomitapide on the liver using hepatic imaging (ultrasound and/or elastography) in patients exposed to long‐term treatment (more than 9 years). There was evidence of a mild to moderate increase in hepatic fat, which is not unexpected due to the mode of action of lomitapide that reduces the formation of VLDL and thereby the export of triglycerides from the liver, leading to a reduction in LDL‐C. However, elastography data demonstrated that the mild to moderate increase in hepatic fat observed in the HoFH patients treated with lomitapide did not translate into an increase in hepatic stiffness or fibrosis. Therefore, the long‐term, real‐world evidence in this cohort of 34 patients with >9 years support the notion that there are no signs of steatohepatitis or fibrosis in HoFH patients treated with lomitapide to date.The results described above indicate that, despite alterations in some liver parameters with lomitapide treatment, no HoFH patient progressed to develop NASH or cirrhosis. One hypothesis is that the mechanism of hepatic steatosis seen in some patients receiving lomitapide may be different to hepatic fat accumulation consequent to metabolic syndrome or genetic conditions. Hepatic fat accumulation is multi‐factorial, and contributing processes include MTP inhibition (e.g. lomitapidePatients receiving lomitapide were on a low‐fat diet with <20% energy from fat, with vitamin E and essential fatty acids supplemented to maintain normal levels. Data from the phase 3 trial, were collected on the fat‐soluble vitamins A, D, E and K, beta‐carotene and essential fatty acids. During the study period, there were no deficiencies in any of these key micronutrients and some increased slightly, indicating that the supplementation levels were sufficient, and no additional fat‐soluble vitamins required supplementation. The observed decrease in the mean levels of vitamin E from baseline to weeks 26 and 78 is not unexpected given the profound lipid‐lowering effect with lomitapide and the fact that vitamin E is transported to the peripheral tissues via LDL‐C.At baseline, patients in the Italian cohort had high LDL‐C levels (mean [IQR] 276.5 mg/dl [196.0–386.2 mg/dl]), despite having access to statins, ezetimibe, apheresis and PCSK9 inhibitors. More than half of patients had experienced a major adverse cardiovascular event by the time of their pre‐lomitapide baseline assessment. This represents a population with a high risk of cardiovascular events driven by very high cholesterol levels that are not controlled with standard lipid‐lowering therapy, which is a classic hallmark of HoFH. We noted in this cohort that only 35% were receiving apheresis at baseline, which is lower than that documented in some past studies.The present study has several limitations. Validation of CK‐18, CK‐18 fragments and ELF have been conducted in NAFLD and NASH.In conclusion, the MTP inhibitor lomitapide can cause temporary elevations in liver transaminases and mild to moderate accumulation of hepatic fat. Across the data sets analysed, biomarkers of hepatic inflammation or fibrosis do not suggest progressive liver disease over the course of the study and hepatic elastography remained normal after more than 9 years of lomitapide treatment. HoFH patients are at high risk of CVD events and premature mortality due to their extremely high LDL‐C exposure since birth.