New Therapeutic Approaches Affecting Low-density Lipoprotein Production
Lomitapide and mipomersen were recently approved by the Food and Drug Administration (FDA) as adjunct therapy for HoFH in patients aged ≥18 and ≥12 years, respectively; lomitapide is also approved by the European Medicines Agency. Although targeting different proteins via different strategies, both drugs affect the production and secretion of apoB-containing lipoproteins, rather than increasing their removal from circulation. As HoFH is characterized by severely impaired removal of LDL from the bloodstream, these new agents represent a promising approach for treatment of hypercholesterolaemia.
Lomitapide
Lomitapide is an oral inhibitor of the microsomal triglyceride transport protein (MTP), which is responsible for transferring triglycerides and phospholipids onto chylomicron and VLDL during their assembly in the intestine and the liver, respectively. Inhibiting MTP leads to reduced secretion of these lipoproteins into the circulation. In an open-label trial in HoFH patients, lomitapide at maximally tolerated doses, in addition to the standard of care including LDL apheresis, reduced plasma LDL-C and apoB levels by ~50% and Lp(a) by ~15% at 26 weeks, with durable LDL-C lowering over a further 12 months follow-up. The most frequently observed adverse events were gastrointestinal symptoms and liver fat accumulation. Gastrointestinal adverse events (e.g. nausea, flatulence, and diarrhoea) were reduced by a gradual dose-escalation regimen combined with adherence to a low-fat diet (<20% of energy from fat) and dosing outside of mealtimes. Elevations in alanine aminotransaminase (ALT) >3 × upper limit of normal (ULN) were reported for 10 patients (34%). Accumulation of liver fat up to a median level of 9% (range 0–34%) at 26 weeks and 8% (0–19%) at 78 weeks was observed.
Mipomersen
Mipomersen is a second generation antisense oligonucleotide, administered by subcutaneous injection, that targets the messenger ribonucleic acid (mRNA) of apoB, the main protein of LDL, and its precursor, VLDL. Mipomersen reduces translation of apoB mRNA and the synthesis of apoB by the ribosome, leading to reduced secretion of VLDL. In a placebo-controlled double-blind trial in HoFH patients, mipomersen (weekly 200 mg, on top of standard lipid-lowering therapy), resulted in further reductions from baseline at 26 weeks in plasma levels of LDL-C (mean 25%), apoB (27%), and Lp(a) (31%) vs. placebo. The most frequently reported adverse events were injection site reactions (76% of patients), some of which were long-lasting, and flu-like symptoms, typically appearing 2 days after injection. Elevations in ALT have been reported during mipomersen treatment; in 12% of patients, increases >3 × ULN, with or without concomitant increases in liver fat content, were observed although most subsequently decreased while continuing treatment. Liver fat content was not routinely measured in the HoFH study with mipomersen, although in hypercholesterolaemic patients, including those with HeFH, a median increase of ~5% (range −1 to 37%) after 28 weeks treatment was observed.
Increased liver fat content observed during both lomitapide and mipomersen treatment may be correlated with the degree of efficacy. The limited available data suggest that this effect is reversible following suspension of treatment. Owing to the potential risk for hepatic toxicity, both agents have been approved for restricted use. Although the potential CV benefits associated with substantial LDL-C lowering possibly outweigh the theoretical increased risk of steatohepatitis and fibrosis in such very high-risk patients, a systematic evaluation of long-term efficacy, outcome and hepatic safety is clearly necessary. Additionally, both drugs have adverse events that may limit long-term use. Lomitapide is also contraindicated with strong and moderate CYP3A4 inhibitors. Furthermore, as lomitapide has not been evaluated in HoFH patients aged <18 years, and mipomersen in those <12 years or receiving apheresis, treatment in such patients should only be considered via a special access scheme in the event of rapidly progressive atherosclerosis and if other options have been utilized.
Undoubtedly, statins and other conventional lipid-lowering drugs are available worldwide and affordable, compared with apheresis and recent therapeutic options. Although the high costs of these approaches may be a concern, the overall cost to adequately treat HoFH remains low due to its rarity and may be counterbalanced by the cost of treating associated CV complications.