Treatment of Homozygous Familial Hypercholesterolemia: Challenges and Latest Development

Familial hypercholesterolemia (FH) is an autosomal codominant genetic disorder of lipoprotein metabolism. Patients can be heterozygous (HeFH) with one mutated allele, homozygous (HoFH) with two identical mutations, or compound heterozygous with different mutations in each allele. HoFH is the more severe form of the disease and is associated with extremely elevated levels of total cholesterol and low‐density lipoprotein cholesterol (LDL‐C). These lipid abnormalities are associated with accelerated atherosclerosis and cardiovascular disease (CVD) and an increased risk of cardiac events and early death. The prevalence of HoFH has been estimated to be 1 in 1 million; however, this is likely an underestimation as the disease is substantially underdiagnosed and undertreated. Early diagnosis and treatment are important to reduce CVD events. Aggressive therapy with conventional agents such as statins and ezetimibe produce substantial reductions in LDL‐C, but patients rarely reach target goals. Apheresis should be considered in all patients with HoFH, although LDL‐C levels rapidly rebound to baseline levels. Three recently introduced novel agents (mipomersen, lomitapide, and evolocumab)—each with a unique mechanism of action—have increased therapeutic options in this difficult‐to‐treat population. When added to standard therapy, these agents produce significant additional LDL‐C lowering and can potentially improve clinical outcomes

Detection of mutations in symptomatic patients with hypertrophic cardiomyopathy in Taiwan

AbstractBackgroundHypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder associated with sudden death, heart failure, and stroke. The aim of the present study was to evaluate the prevalence and types of mutations in symptomatic patients with HCM in Taiwan.MethodsThirty-eight HCM index patients (mean age 60±16 years) underwent systematic mutation screening of eight sarcomeric genes: β-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), troponin T (TNNT2), troponin I (TNNI3), myosin ventricular regulatory light chain 2 (MYL2), myosin ventricular essential light chain 1 (MYL3), α-tropomyosin (TPM1), and cardiac α-actin (ACTC), using direct DNA sequencing. In silico programs predicted damaging amino acids. In the positive families, genotype–phenotype correlation studies were done.ResultsOverall, 13 mutations were identified in 13 index patients (34.2%). The three most frequently mutated genes were MYH7, MYBPC3, and TNNT2. One patient carried double mutations. Five mutations (MYH7 R147S; MYBPC3 R597Q; MYBPC3 W1007R; TNNI3 E124Q; MYL3 R63C) were novel; all were missense mutations. Analysis using in silico tools showed near consensus to classify these five novel mutations as pathological. Family pedigree analysis showed the presence of cosegregation in at least two affected members in each proband family, but incomplete penetrance in young family members with a positive genotype.ConclusionsWe identified 13 HCM pedigrees, including 5 carrying novel mutations and 1 with a double mutation. The three most commonly mutated genes were MYH7, MYBPC3, and TNNT2. These results, together with genetic counseling, could lead to earlier diagnosis and better management of family members at risk of HCM

5A/6A Polymorphism of the Stromelysin-1 Gene and Angiographic Restenosis After Coronary Artery Stenting

Coronary stent deployment is a major advance in interventional treatment, but 20–40% of patients still develop instent restenosis (ISR) due to neointimal hyperplasia. Genetic factors play a role in restenosis. This study investigated the frequency of 5A/6A polymorphism in the promoter of the stromelysin-1 gene, and the issue of whether it contributes to restenosis among patients receiving coronary stent in the Chinese population in Taiwan. Methods: We investigated 344 symptomatic patients after successful coronary stent placement. All patients received repeated angiography after 6 months, or earlier if clinically indicated. Angiographic restenosis was defined as = 50% diameter stenosis at follow-up. Genotyping for stromelysin-1 promoter was based on a polymerase chain reaction technique. Results: The stromelysin-1 gene promoter genotypes 5A5A, 5A6A, and 6A6A were distributed in 3.5%, 22.7%, and 73.8% of patients, respectively. The frequency of the 6A allele was 0.85. There was no significant difference in angiographic ISR between the non-6A6A and 6A6A groups (28.9% and 37.0%, respectively, p = 0.165). However, subgroup analysis revealed a significant difference in patients according to angina status. Among the 5A5A and 5A6A genotype groups, patients with unstable angina had significantly higher ISR rates than those with stable angina (48% vs 21.5%, p = 0.013). On the other hand, among patients with stable angina, those with a 6A6A genotype had a higher ISR rate than those with a non-6A6A genotype (p = 0.029), making the 6A6A genotype an independent predictor of ISR (odds ratio, 2.57; 95% confidence interval, 1.22–5.41; p = 0.013). Conclusion: There is a low frequency of the stromelysin-1 promoter 5A allele in the Chinese population in Taiwan. How stromelysin-1 5A/6A polymorphism affects ISR appears to be linked to angina status. These results merit further study to identify patients carrying genotypes which put them at increased risk of ISR, and which matrix metalloproteinase inhibitors or drug-eluting stents are more effective for those at risk

Efficacy and Safety of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia: Phase 3, Multinational Open-Label Study

Background: Despite progress in treating homozygous familial hypercholesterolemia, most patients do not achieve low-density lipoprotein cholesterol (LDL-C) targets. This study examined efficacy and safety of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, alirocumab, in pediatric patients (aged 8-17 years) with inadequately controlled homozygous familial hypercholesterolemia. Methods: In this open-label, single-arm, multinational, Phase 3 study, patients (n=18) received alirocumab 75 mg or 150 mg (bodyweight <50 kg/≥50 kg) every 2 weeks as an adjunct to background treatment. The primary endpoint was percent change in LDL-C from baseline to Week 12. Secondary endpoints included changes in LDL-C and other lipid parameters up to 48 weeks, safety/tolerability, and alirocumab pharmacokinetics. Results: The mean age of patients was 12.4 years; 16/18 (89%) had mutations in the low-density lipoprotein receptor gene (LDLR) and 2/18 (11%) had mutations in the LDLR adapter protein 1 gene (LDLRAP1). At baseline, mean LDL-C (standard deviation) was 373.0 (193.5) mg/dL, which decreased by 4.1% at Week 12 (primary endpoint) and 11.4%, 13.2%, and 0.4% at Weeks 4, 24, and 48, respectively. At Week 12, 9/18 (50%) patients achieved LDL-C reductions ≥15%. Mean absolute LDL-C decreases ranged from 25 to 52 mg/dL over follow-up. A post hoc analysis demonstrated heterogeneity of responses according to genotype. There were no unexpected safety/tolerability findings. Free PCSK9 was reduced to near zero for all patients at Weeks 12 and 24. Conclusions: The study supports the efficacy and safety of alirocumab as a potential adjunct to treatment for some pediatric patients with homozygous familial hypercholesterolemia. Registration: URL: https://www.clinicaltrials.gov; NCT03510715

Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder, is characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerotic cardiovascular disease. Statin treatment starts at diagnosis, but no statin has been formally evaluated in, or approved for, HoFH children. OBJECTIVES: The authors sought to assess the LDL-C efficacy of rosuvastatin versus placebo in HoFH children, and the relationship with underlying genetic mutations. METHODS: This was a randomized, double-blind, 12-week, crossover study of rosuvastatin 20 mg versus placebo, followed by 12 weeks of open-label rosuvastatin. Patients discontinued all lipid-lowering treatment except ezetimibe and/or apheresis. Clinical and laboratory assessments were performed every 6 weeks. The relationship between LDL-C response and genetic mutations was assessed by adding children and adults from a prior HoFH rosuvastatin trial. RESULTS: Twenty patients were screened, 14 randomized, and 13 completed the study. The mean age was 10.9 years; 8 patients were on ezetimibe and 7 on apheresis. Mean LDL-C was 481 mg/dl (range: 229 to 742 mg/dl) on placebo and 396 mg/dl (range: 130 to 700 mg/dl) on rosuvastatin, producing a mean 85.4 mg/dl (22.3%) difference (p = 0.005). Efficacy was similar regardless of age or use of ezetimibe or apheresis, and was maintained for 12 weeks. Adverse events were few and not serious. Patients with 2 defective versus 2 negative LDL receptor mutations had mean LDL-C reductions of 23.5% (p = 0.0044) and 14% (p = 0.038), respectively. CONCLUSIONS: This first-ever pediatric HoFH statin trial demonstrated safe and effective LDL-C reduction with rosuvastatin 20 mg alone or added to ezetimibe and/or apheresis. The LDL-C response in children and adults was related to underlying genetic mutations. (A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia [HYDRA]; NCT02226198)

Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein–cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment. Objectives: This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH. Methods: This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment. Results: Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was −35.6% (alirocumab [−26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, −29.8%; non–high-density lipoprotein cholesterol, −32.9%; total cholesterol, −26.5%; and lipoprotein(a), −28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period. Conclusions: In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.

Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial

Background Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease. Methods This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs >= 50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373. Findings 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11.4 mmol/L (SD 3.6) in the mipomersen group and 10.4 mmol/L (3.7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (-24.7%, 95% CI 31.6 to 17.7) than with placebo (-3.3%, 12.1 to 5.5; p=0.0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal. Interpretation Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins.ISIS PharmaceuticalsGenzyme Corporatio