HoFH presents with a wide spectrum of LDL-C levels in a genetically confirmed cohort of patients Claudia Stefanutti Department of Molecular Medicine, Sapienza University Rome, Italy HoFH, homozygous familial hypercholesterolaemia LDL-C, low-density lipoprotein cholesterol
Disclosures Consulting agreements and research grants from: Aegerion Fresenius Medical Care Kaneka NV
Background and objectives HoFH 1 Prevalence Genetics Phenotype Consequences Rare (1:160,000 300,000) More common in founder populations Autosomal codominant* Two LDL receptor gene mutations Defective/defective; defective/negative; or negative/negative Or, mutations in other genes affecting LDL-R functionality (e.g. apo B, PCSK-9, LDLRAP1) Elevated levels of circulating lowdensity LDL-C levels (often >13mmol/L, but as low as 3.9mmol/L) Cutaneous or tendon xanthomas before the age of 10 Poor response to conventional drug therapies Premature onset cardiovascular disease Untreated patients generally do not survive past 30 years of age Examine the baseline characteristics of a cohort of patients with genetically confirmed HoFH to assess variation in genotype and phenotype *Except LDLRAP1 gene (autosomal recessive); Not universal PCSK-9, proprotein convertase subtilisin/kexin type 9 LDLRAP, LDLR adapter protein-1 1. Cuchel M, et al. Eur Heart J 2014;35:2146-57
Methods Pivotal phase 3 trial of lomitapide in patients with genetically confirmed HoFH The study Open-label, single arm dose-escalation trial of oral lomitapide 5 60mg q.d. Primary endpoint: % change in plasma LDL-C levels at Week 26 Data were also analysed through Week 78 Codes: AEGR-733-005; NCT00730236 The patients (n=29) 18 years At least one of the following diagnostic criteria: Untreated total cholesterol >500mg/dL and triglycerides <300mg/dL AND both parents with documented untreated TC >250mg/dL Functional mutation in both LDLR alleles or alleles known to affect LDLR functionality Skin fibroblast LDL receptor activity <20% normal Stable LLT for at least 6 weeks prior to baseline assessment and then through primary endpoint (Week 26)* Baseline data *Including statins, ezetimibe, nicotinic acid, bile acid sequestrants, fibrates, and Lipoprotein apheresis LLT, lipid-lowering therapies; LDLR, low-density lipoprotein receptor; TC, total cholesterol; q.d., once daily Cuchel M, et al. Lancet 2013;381:40-6
Patients had a broad range of Baseline LDL-C levels, mmol/l n (%) LDL-C at baseline Mean age, years (range) Apheresis, n (%) 3.9 5.2 4 (14) 29 (18 55) 3 (75) >5.2 7.6 7 (24) 33 (21 54) 3 (43) >7.6 10.3 8 (28) 33 (22 45) 7 (88) >10.3 10 (34) 28 (18 41) 5 (50) Apheresis n (%) Mean age, years (range) Mean baseline LDL-C, mmol/l (range) Yes 18 (62) 30 (18 54) 8.4 (3.9 13.0) No 11 (38) 31 (19 55) 9.2 (4.3 14.6) 38% of patients had treated LDL-C levels at or below 7.6mmol/L (the traditional treated LDL-C cutoff of >8mmol/L is now considered obsolete 1 ) Mean age and mean baseline LDL-C levels were similar in subgroups of patients receiving/not receiving apheresis 1. Cuchel M, et al. Eur Heart J 2014;35:2146-57
Most patients were compound heterozygotes and had residual receptor functionality Genotype (n=29) n (%) LDLR homozygous 8 (28%) LDLR compound heterozygous 20 (69%) ARH (homozygous recessive) 1 (3%) LDL-R functional status (n=28)* Defective/any 21 (75%) Defective/Defective 8 (38%) Defective/Negative 4 (19%) Defective/ Unclassified 9 (43%) Negative/Negative 4 (14%) Unclassified/Unclassified 3 (11%) *The remaining patient had LDLRAP1 mutations Cuchel M, et aj Lancet 2013; 381(9860):40-6 Aegerion Data on File
LDL-C, mmol/l Results: baseline LDL-C levels, apheresis and mutation status 16 Apheresis 14 Yes No 12 Highest LDL-C levels were not even in the most severe mutations 10 8 6 4 2 0 Mutation status Negative/ negative Negative/ defective Defective/ defective Defective/ unclassified Unclassified/ unclassified Individual patients LDLRAP1 Defective, >5% functionality Negative <5% functionality LDLRAP1, LDL-R adapter protein-1 A wide range of LDL-C values, and varied mutation patterns
LDL-C, mmol/l Results: LDL-C levels according to patient age 16 14 12 10 8 6 4 2 R² = 0,0012 for the LDL-C/age comparison 0 0 10 20 30 40 50 60 Age, years Receiving apheresis Not receiving apheresis There was no relationship between age or (p=0.509 for LDL-C) apheresis status and LDL-C levels R 2, linear regression
Conclusions Treated LDL-C levels ranged from 3.9 to 14.6mmol/L and did not appear to correlate with receptor function status 8/29 patients were homozygous for mutations to the LDLR, 20/29 were compound heterozygotes for LDLR mutations, and one carried the LDLRAP1 mutation HoFH, while a homozygous condition, has wide genotypic and phenotypic variability LDL-C levels vary markedly despite residual receptor functionality in some patients Diagnosis of HoFH should not be excluded in patients with treated LDL-C levels <8mmol/L (<300mg/dL), and other clinical and genetic evidence should be examined to ensure that HoFH patients are directed towards the correct treatment pathway
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LDL-C, mmol/l Results: baseline LDL-C levels, apheresis * and mutation status 16 14 12 10 8 6 4 2 LDLR mutation type Defective/Defective Defective/Negative Defective/Unclass. Negative/Negative Unclass./Unclass. LDLRAP1 0 Individual patients *Striped bars represent patients receiving apheresis; solid bars represent patients not receiving apheresis A wide range of LDL-C values, and varied mutation patterns Defective, >5% functionality; Negative <5% functionality Unclass., unclassified; LDLRAP1, LDL-R adapter protein-1
Results: baseline LDL-C levels and mutation status (1) Subject Baseline LDL-C, mmol/l Mutation type Receptor activity 23-002 3.9 LDLR Unc/Def 02-001 4.1 LDLR Unc/Def 32-002 4.3 LDLR Def/Def 31-001 4.7 LDLR Unc/Def 35-001 5.6 LDLR Def/Def 12-001 5.9 LDLR Def/Neg 13-002 6.0 LDLR Def/Neg 11-001 6.2 LDLR Neg/Neg 12-004 6.4 LDLR Def/Neg 22-003 6.7 LDLR Def/Unc 11-004 7.2 LDLR Def/Def 13-001 7.9 LDLR Def/Unc 01-006 7.9 LDLR Neg/Neg 11-003 8.5 LDLR Def/Unc 32-001 9.2 ARH ARH 01-003 9.8 LDLR Neg/Neg 12-003 9.9 LDLR Def/Def Baseline LDL-C levels were as low as 3.9mmol/L Def, defective; Neg, negative; Unc, unclassified
Results: baseline LDL-C levels and mutation status (2) Subject Baseline LDL-C, mmol/l Mutation type Receptor activity 01-001 10.0 LDLR Unc/Unc 31-002 10.2 LDLR Def/Def 02-002 10.6 LDLR Def/Unc 23-003 10.7 LDLR Unc/Unc 11-002 10.7 LDLR Neg/Neg 01-002 11.0 LDLR Def/Def 12-006 11.3 LDLR Def/Def 12-005 11.6 LDLR Def/Neg 33-001 12.3 LDLR Def/Unc 23-001 12.4 LDLR Def/Unc 01-004 12.9 LDLR Unc/Unc 22-004 14.6 LDLR Def/Def A wide range of mutation types were evident Def, defective; Neg, negative; Unc, unclassified
LDL-C, mmol/l 25 20 15 Results: baseline LDL-C levels in subjects treated with LLT LDLR mutation type Negative/Negative Defective/Negative Defective/Unclass. Defective/Defective Unclass./Unclass. LDLRAP1 10 5 0 Prior to LLT Sjouke et al, 2014 1 After LLT Lomitapide study baseline levels (LLT-treated*) *Non-lomitapide 1. Sjouke B, et al. Eur Heart J 2014, Feb 28 (epub ahead of print doi:10.1093/eurheartj/ehu058)