Current and Emerging Treatment

A main gap in the management of FH is the lack of early detection and appropriate pharmacological intervention. The most severe forms (HoFH) generally exhibit unambiguous physical signs from childhood. However, less severe forms may remain hidden until the occurrence of the first cardiovascular event.1

Current Therapies For Patients With FH

Statin therapy represents the first pharmacological approach for the management of hypercholesterolemia in FH patients, and current guidelines recommend that adults are treated with the maximal tolerated dose of a high potency statin. In most cases, however, statin monotherapy is insufficient to achieve the recommended LDL-C levels.1,2

Given the mechanism of action of statins (lipid-lowering effect by increasing hepatic expression of LDL-R) it is expected that HoFH subjects carrying null mutations on the LDLR gene would not respond. However, these patients are responsive to statins, although to a lesser extent compared with other FH patients, since statins may act via alternative mechanisms of action, such as the reduction of VLDL (and thus LDL) synthesis. Ultimately, the LDL-C reduction observed in FH patients is lower than that observed in non-FH patients (~20% vs. 40%-60%).1,3-6

Ezetimibe inhibits the intestinal uptake of dietary and biliary cholesterol by inhibiting the Niemann-Pick C1 like 1 (NPC1L1) transporter, which leads to a reduced delivery of cholesterol to the liver and upregulates LDL-R expression, resulting in the reduction of LDL-C levels. Data support the recommendation of giving ezetimibe in combination with a statin in FH patients, resulting in an additional reduction (10%-15%) of LDL-C levels. Of note is that the combination of ezetimibe+statin is effective in adolescents with HeFH, who showed a greater LDL-C level reduction compared with the treatment with simvastatin alone. Both treatments were well tolerated and there were no clinically relevant signs of growth, sexual maturation, or steroid hormone perturbation.7-11

PCSK9 is a protein mainly expressed in the liver and plays a relevant role in the expression of LDL-R; in fact, it binds LDLR expressed on the surface of hepatocytes and targets it for degradation. As a consequence, high levels of PCSK9 are associated with hypercholesterolemia, and gain-of-function (GOF) mutations in the PCSK9 gene are a cause of FH and increased cardiovascular risk. On the contrary, loss-of-function (LOF) mutations are associated with reduced LDL-C plasma levels and lower risk of coronary heart disease, indicating PCSK9 as a possible pharmacological target for the treatment of hypercholesterolemia.12,13
Evolocumab is currently approved as an adjunct to diet and maximally tolerated statin therapy in patients with HoFH and those with HeFH. Approval for the treatment of HoFH was based on the TESLA (Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities) Part B study (NCT01588496), which enrolled 50 patients, none of whom received apheresis, and reported that evolocumab reduced LDL-C levels by an average of 31% compared with placebo.14 For HeFH, the larger phase 3 study, RUTHERFORD-2 (Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study-2), found that evolocumab reduced LDL-C levels by approximately 60% compared with placebo.15 In the more recent TAUSSIG study, mean change in LDL-C from baseline to week 12 was −21.2% (−59.8 mg/dL) in patients with HoFH and −54.9% (−104.4 mg/dL) in those with severe HeFH.16
In the ODYSSEY trial, which looked at alirocumab 150 mg every 2 weeks vs. placebo in adult patients with HoFH, Blom and colleagues found that at week 12, the percent change from baseline was −26.9% for alirocumab vs +8.6% for placebo. Reductions in other atherogenic lipids as follows: apolipoprotein B, −29.8%; non–HDL-C, −32.9%; total cholesterol, −26.5%; and lipoprotein(a), −28.4% (all P< .0001 vs. placebo).17 Data suggest that FH patients, in particular HeFH, may benefit most from additional LDL-C-lowering by means of anti-PCSK9 inhibitor therapy, as it may induce an additional ~60% LDL-C reduction in HeFH patients who are already treated with the maximal tolerated lipid-lowering therapy. This translates into over 80% of these patients being able to achieve recommended LDL-C targets.1,18 At this time, alirocumab is approved to treat the heterozygous form of FH only.
Inclisiran was approved by the FDA in December 2021. The agent works by targeting PCSK9; however, as opposed to the two PCSK9 antibodies that inhibit circulating PCSK9, inclisiran is a chemically synthesized small interfering RNA (siRNA) molecule that reduces the production of PCSK9 through gene silencing within hepatocytes. The ORION trials tested inclisiran in patients with FH, ASCVD or ASCVD-risk equivalents. In those studies, the mean placebo-adjusted reduction in LDL cholesterol was approximately 50%.19,20 Inclisiran is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical ASCVD.
Mipomersen is a second-generation antisense oligonucleotide which binds the coding region of human apoB mRNA and triggers its degradation, which results in the reduction of all atherogenic apoB-containing lipoproteins (LDL, but also VLDL and Lp (a)). Due to its mechanism of action being independent of LDL-R expression, it has been developed as adjunct treatment for patients with FH, particularly for those with HoFH.21,22
Lomitapide, a microsomal transfer protein (MTP) inhibitor that has been approved for the treatment of HoFH, reduces LDL-C levels in an LDL-R-independent mechanism. MTP is a lipid transfer protein localized in the endoplasmic reticulum of hepatocytes and enterocytes, playing a key role in the assembly and secretion of apolipoprotein-B-containing lipoproteins in both the liver (VLDL) and intestine (chylomicrons). Individuals carrying loss-of-function mutations in the gene encoding for MTP (MTTP) are characterized by hypocholesterolemia and reduced levels of circulating apoB-containing lipoproteins, suggesting MTP as a pharmacological target for the treatment of hypercholesterolemia.23,24

Angiopoietin-like 3 (ANGPTL3) is a hepatic protein playing a key role in lipoprotein metabolism through the inhibition of both lipoprotein lipase and endothelial lipase activity, and loss of function (LOF) variants of ANGPTL3 gene are associated with reduced plasma levels of TG and LDL-C. Heterozygous carriers of ANGPTL3 LOF mutations have a 34% reduction in odds of developing coronary artery disease, and subjects in the lowest tertile of ANGPTL3 levels have reduced odds of MI compared with subjects in the highest tertile. As a result, ANGPTL3 is a pharmacological target for the treatment of hypercholesterolemia. ANGPTL3 modulates LDL-C levels independently of the LDL-R, which suggests that pharmacological inhibition of ANGPTL3 is an effective target for reducing LDL-C levels in patients with HoFH. Traditional lipid-lowering therapies such as statins and PCSK9 inhibitors act by up-regulating LDL-R expression and subsequently have little efficacy in these patients and virtually no activity in those with two null alleles.25

In February 2021, the FDA approved evinacumab for HoFH supported by data from the ELIPSE HoFH study.26 ELIPSE HoFH assessed 65 patients randomized to either 15 mg/kg evinacumab IV every 4 weeks (n=43) plus lipid-lowering therapies, or lone lipid-lowering therapies (n=22). At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL-C level of 47.1%, as compared with an increase of 1.9% in the placebo group (P<.0001). Additionally, the LDL-C level was lower in the evinacumab group than in the placebo group in patients with null–null variants (–43.4% vs. +16.2%) and in those with non-null variants (–49.1% vs. –3.8%).25

Bempedoic acid, recently approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or established ASCVD who require additional lowering of LDL-C, is an ATP citrate lyase (ACL) inhibitor that reduces cholesterol biosynthesis and lowers LDL-C by up-regulating LDL-R. In 2020, the results of a pooled data analysis from 4 double-blind, placebo-controlled randomized clinical trials conducted from 2016 to 2018 were published.27 At week 12, the LDL-C level percentage change from baseline was −16.0% with bempedoic acid vs 1.8% with placebo (difference, P<.001). The decrease in LDL-C levels with bempedoic acid was sustained during long-term follow-up in both pools (patients with ASCVD or HeFH or both receiving a maximally tolerated statin, difference of −12.7% at week 52; patients with statin intolerance, difference of −22.2% at week 24).
Lipoprotein apheresis is the physical removal of lipoproteins from the blood and represents an important tool for the treatment of FH patients in which the pharmacological approach is not sufficient to reduce significantly LDL-C levels. It is indicated particularly for HoFH patients or severe HeFH who do not respond to or are intolerant of statins. Following apheresis, both LDL-C and Lp(a) levels significantly decrease by 50%-70% but return to baseline levels during the period to the next apheresis procedure. The combination of lipoprotein apheresis with lipid-lowering drugs may thus further improve the lipid profile and reduce the cardiovascular risk. As an invasive procedure, quality of life is a consideration.1,28 With newer therapies, there may be the opportunity to delay apheresis until other options are tried.


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