Key study points:
1. Lomitapide reduces plasma LDL-C by 50% (at 26 weeks) and 38% (at 78 weeks) in patients with homozygous familial hypercholesterolemia.
2. Lomitapide increases hepatic fat content by 8.3% (at 78 weeks).
Primer: Familial hypercholesterolemia (FH) is a genetic disease with clinically detectable elevated plasma low-density lipoprotein cholesterol (LDL-C) levels from the time of birth and results in premature atherosclerosis. The disease is caused by genetic mutations in genes responsible for clearance of the LDL-particle from the blood via the liver. In the most severe and fatal form, homozygous familial hypercholesterolemia (HoFH), the causative mutations reside in both alleles of the LDL-receptor gene (LDLR).
HoFH often presents with the classic findings of xanthelasma palpebrarum, tendon xanthomata, and arcus senilis. Further, the aggressive atherosclerosis associated with HoFH causes significant coronary artery disease, typically requiring numerous surgical interventions including coronary artery bypass grafting (CABG) and angioplasty, and often results in death prior to age 30. Indeed, this grave prognosis highlights the great need for effective LDL-lowering therapies within the HoFH patient population. The current standard of care is comprised of LDL apheresis (for acute LDL reduction only) and pharmacological interventions, including lipid-lowering statins in combination with ezetimibe. However, the efficacy of these pharmacologics are diminished by the dysfunctional LDL-receptors present in HoFH patients, rendering cells unable to remove circulating LDL-particles from the blood.
Lomitapide is a small-molecule inhibitor of the enzymatic microsomal triglyceride transfer protein (MTP) that is vital to the formation of LDL precursor particles. Thus, pharmacologic inhibition of MTP decreases formation of chylomicrons and very-low-density lipoprotein (VLDL) particles resulting in net LDL-particle reduction. Lomitapide does not depend on functional LDL-receptors, unlike statins, where inhibition of HMG-CoA reductase results in the upregulation of hepatic LDL-receptors and increased clearance of circulating plasma LDL-particles. Thus, lomitapide is a promising treatment strategy for HoFH.
This [phase III] trial: This Phase III, non-randomized, unmasked, single arm study evaluated the efficacy and safety of the oral MTP inhibitor, Lomitapide, in patients with homozygous familial hypercholesterolemia (HoFH). 23 men and women at 11 clinical centers with genetically confirmed cases of HoFH entered the trial. A regimen of lipid-lowering medications (Lopitapide + participants current lipid-reduction therapies), apheresis, supplementations of vitamin E and essential fatty acids, and a low-fat diet was initiated and patients were followed for a total of 78 weeks (26 week second phase for drug efficacy, 52 week third phase for safety). Percent change in LDL-C from baseline to maximum dosage Lomitapide (at week 26 of treatment) was noted for each participant. Percent hepatic fat content was also evaluated at baseline and at 6-month intervals due to previous clinical trial findings of increased hepatic fat content with Lomitapide use.
At 26 weeks of treatment, LDL-C decreased 50% (range -62% to -39%; p-value <0.0001). At 78 weeks, LDL-C levels were decreased by 38% (range -52% to -24%; p-value= 0.001). At 26 weeks, mean hepatic fat content increased to 8.6% (range 0-33.6%) from 1.0% (range 0-5.0%) at baseline. Hepatic fat content stabilized at 8.3% (0-19.0%) at 78 weeks. Elevations of ALT and/or AST greater than three times the upper-limit-of-normal occurred in 10 patients during the study. 80% of patients experienced gastrointestinal side effects.
In sum: Significant unmet medical needs exist for the HoFH patient population. This study demonstrated the safety and efficacy of oral Lomitapide for significant reduction of LDL-C and total cholesterol in adult patients with HoFH. Lomitapide may improve overall patient outcomes and survival, and may even reduce severity of cardiovascular disease within this population. However, this study faces several significant limitations. First, the design of the study lacks a control group, thus it is difficult to truly differentiate improvements due to treatment with Lomitapide versus improvements due to the other aspects of the trial regimen (therapy standardization, diet changes, vitamin supplementation, etc.). Further, while the authors followed the study participants for a total of 78 weeks, long-term studies are needed to ensure increased hepatic fat content does not progress to hepatic fibrosis or cirrhosis. Finally, additional studies are needed to address safety and efficacy in children to extend this pharmacologic agent to a younger but equally high-risk patient population.
By [ME] and [MM]
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