Impact of Age on the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia.
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ABSTRACT:
SUBMITTER: Ginsberg HN
PROVIDER: S-EPMC6433806 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
Publications
Impact of Age on the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia.
Ginsberg Henry N HN Tuomilehto Jaakko J Hovingh G Kees GK Cariou Bertrand B Santos Raul D RD Brown Alan S AS Sanganalmath Santosh K SK Koren Andrew A Thompson Desmond D Raal Frederick J FJ
Cardiovascular drugs and therapy 20190201 1
<h4>Purpose</h4>This post-hoc analysis examined whether age modified the efficacy and safety of alirocumab, a PCSK9 inhibitor, in patients with heterozygous familial hypercholesterolemia (HeFH), using pooled data from four 78-week placebo-controlled phase 3 trials (ODYSSEY FH I, FH II, LONG TERM, and HIGH FH).<h4>Methods</h4>Data from 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies were analyzed by an alirocumab dose regimen and by age subgroups (18 to < 45 ...[more]
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Project description:Even with statins and other lipid-lowering therapy (LLT), many patients with heterozygous familial hypercholesterolemia (heFH) continue to have elevated low-density lipoprotein cholesterol (LDL-C) levels. ODYSSEY HIGH FH (NCT01617655) assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 monoclonal antibody, versus placebo in patients with heFH and LDL-C ? 160 mg/dl despite maximally tolerated statin ± other LLT.Patients were randomized to subcutaneous alirocumab 150 mg or placebo every 2 weeks (Q2W) for 78 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24.Mean baseline LDL-C levels were 196.3 mg/dl in the alirocumab (n = 71) and 201.0 mg/dl in the placebo groups (n = 35). Significant mean (standard error [SE]) reductions in LDL-C from baseline to week 24 were observed with alirocumab (-45.7 [3.5] %) versus placebo (-6.6 [4.9] %), a difference of -39.1 (6.0) % (P < 0.0001). Absolute mean (SE) LDL-C levels were reduced from baseline by 90.8 (6.7) mg/dl with alirocumab at week 24, with reductions maintained to week 78. Treatment-emergent adverse events were generally comparable between groups. Injection-site reactions were more frequent in the alirocumab group (8.3 %) versus placebo (5.7 %); most were mild in severity and did not result in study medication discontinuation.In patients with heFH and very high LDL-C baseline levels despite maximally tolerated statin ± other LLT, alirocumab 150 mg Q2W demonstrated significant reductions in LDL-C levels with 41 % of patients achieving predefined LDL-C goals. Alirocumab was generally well tolerated.
| S-EPMC5055560 | biostudies-literature
Project description:BackgroundIndividuals with heterozygous familial hypercholesterolemia (heFH) have higher levels of low-density lipoprotein cholesterol (LDL-C) and are predisposed to premature cardiovascular disease. Alirocumab is a fully-human, monoclonal antibody targeted to proprotein convertase subtilisin/kexin type 9 currently in Phase 3 development for the treatment of hypercholesterolemia. Described here are three ODYSSEY Phase 3 trials, FH I (NCT01623115), FH II (NCT01709500) and HIGH FH (patients with heFH and LDL-C levels ≥160 mg/dL) (NCT01617655), in which alirocumab is further evaluated in the heFH population.MethodsMulticenter, multinational, randomized, double-blind, placebo-controlled studies have been designed to evaluate efficacy and safety of alirocumab in more than 800 patients with heFH who are not adequately controlled with a maximally-tolerated stable daily dose of statin for ≥4 weeks prior to the screening visit, with or without other lipid-lowering therapy. Patients are randomized (2:1) to receive alirocumab or placebo via a 1-mL subcutaneous auto-injection every 2 weeks (Q2W) for 78 weeks. In studies FH I and II, if their Week 8 LDL-C level is ≥70 mg/dL, patients will undergo a dose uptitration from 75 to 150 mg alirocumab Q2W at Week 12. In HIGH FH, patients will receive alirocumab 150 mg Q2W throughout the entire treatment period. The primary efficacy endpoint in all three studies is the percent change in calculated LDL-C from baseline to Week 24.ConclusionsThe ODYSSEY FH studies are three Phase 3 studies aiming to further evaluate the efficacy and long-term safety of alirocumab as an effective therapeutic option for patients with heFH.
| S-EPMC4074463 | biostudies-literature
Project description:BackgroundAlirocumab reduces low-density lipoprotein cholesterol (LDL-C) levels by up to 61%. The ODYSSEY Open-Label Extension study investigated the effect of alirocumab in patients with heterozygous familial hypercholesterolaemia (HeFH) over 144 weeks.MethodsEligible patients with HeFH had completed an earlier double-blind, randomised, placebo-controlled parent study. Patients were initiated on 75 mg alirocumab Q2W subcutaneous (SC) unless baseline LDL-C was > 8.9 mmol/l, in which case they received 150 mg alirocumab Q2W. Dose titration to 150 mg Q2W was at the investigator's discretion.ResultsThe study enrolled 167 patients and the parent study mean (± SD) baseline LDL-C level was 3.65 ± 1.9 mmol/l. Mean LDL-C level was reduced by 48.7% at week 144; mean on-treatment LDL-C was 2.30 ± 1.24 mmol/l. Eight patients reported injection-site reactions, with one treatment discontinuation. Treatment emergent anti-drug antibodies were identified in five patients but these did not affect the efficacy.ConclusionsAlirocumab effectively and safely reduced LDL-C in these patients.
| S-EPMC8802375 | biostudies-literature
Project description:AimTo evaluate the effect of alirocumab on frequency of standard apheresis treatments [weekly or every 2 weeks (Q2W)] in heterozygous familial hypercholesterolaemia (HeFH).Methods and resultsODYSSEY ESCAPE (NCT02326220) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis. Patients were randomly assigned (2:1, respectively) to receive alirocumab 150 mg (n = 41) or placebo (n = 21) Q2W subcutaneously for 18 weeks. From day 1 to week 6, apheresis rate was fixed according to the patient's established schedule; from weeks 7 to 18, apheresis rate was adjusted based on the patient's low-density lipoprotein cholesterol (LDL-C) response in a blinded fashion. Apheresis was not performed when the LDL-C value was ≥30% lower than the baseline (pre-apheresis) value. The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks (weeks 7-18), standardized to number of planned treatments. In the alirocumab group the least square (LS) mean ± SE (95% confidence interval [CI]) per cent change in pre-apheresis LDL-C from baseline at week 6 was -53.7 ± 2.3 (-58.2 to - 49.2) compared with 1.6 ± 3.1 (-4.7 to 7.9) in the placebo group. The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab (Hodges-Lehmann median estimate of treatment difference: 0.75; 95% CI 0.67-0.83; P < 0.0001). Therefore, alirocumab-treated patients had a 0.75 (75%) additional reduction in the standardized rate of apheresis treatments vs. placebo-treated patients. During this period, 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments. Adverse event rates were similar (75.6% of patients on alirocumab vs. 76.2% on placebo).ConclusionsLipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis, and the rate was at least halved in 92.7% of patients. Alirocumab was generally safe and well tolerated.
| S-EPMC5233802 | biostudies-literature
Project description:Background/aimsEfficacy and safety data of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), is not yet well established in the Korean population. We assessed them in ODYSSEY-KT through the pre-specified Korean subanalysis.MethodsIn the ODYSSEY-KT study, South Korean and Taiwanese patients with hypercholesterolemia and high cardiovascular risks were randomized (1:1) to alirocumab or placebo. Alirocumab was self-administered subcutaneously at 75 mg every 2 weeks with a maximally tolerated statin dose with or without other lipid-modifying therapies. Alirocumab dose was increased to 150 mg every 2 weeks at week 12 if low density lipoprotein cholesterol (LDL-C) ? 70 mg/dL at week 8. Primary endpoint was percent change in LDL-C from baseline to week 24. Results from Korean cohort (n = 83: 40 for alirocumab and 43 for placebo, respectively) analyses are reported here.ResultsIn alirocumab group, the least square of mean change percent in LDL-C levels was -65.7% (placebo: 11.1%; p < 0.0001) and 92.0% of them achieved LDL-C < 70 mg/dL (placebo: 12.7%; p < 0.0001) at week 24. Alirocumab also showed significantly greater improvements in high density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol, lipoprotein(a), and apolipoprotein B than placebo (p < 0.05). Two consecutive calculated LDL-C values < 25 mg/dL were observed in 37.5% of alirocumab-treated patients. Overall, 45.0% alirocumab-treated and 51.2% placebo-treated patients experienced treatment-emergent adverse events (TEAEs) without discontinuation of treatment due to TEAEs.ConclusionAlirocumab has demonstrated to be effective in improvement of LDL-C and related lipid profiles in Korean cohort. Alirocumab was generally well tolerated with no significant safety signals.
| S-EPMC6823573 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is a common inherited disorder that results in premature atherosclerosis. Diagnosis of FH is suspected on the basis of clinical criteria, but confirmation requires genetic testing. In the era of statins, early diagnosis and initiation of treatment can modify disease progression and outcomes. Therefore, cascade screening with a combination of lipid concentration measurements and DNA testing should be used to identify relatives of index cases with a clinical diagnosis of FH. Autosomal dominant FH is related to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Genetic screening of the LDLR gene is challenging to achieve at a feasible cost, especially in people who do not have a founder effect. Nucleotide sequencing of all exons and flanking splicing regions in combination with multiplex ligation probe amplification to detect large insertions or deletions is considered the gold-standard approach to screen for LDLR mutations. Alternatively, the cDNA can be sequenced; however, this procedure is not suitable for use in large populations, because of the need of RNA extraction. Multiplex analysis can be appropriate for population with founder effects or a low number of different mutations. Finally, there are many techniques for a mutation scanning approach, which have some benefits over sequencing, and also with the potential for detecting known and novel mutations. Familial defective Apo B is amenable to genetic diagnosis by screening for a few mutations. Recently, gain-of-function mutations in PCSK9 gene have been demonstrated to cause FH phenotype. Strategies for population screening, cost-effectiveness of genetic screening, ethical aspects, and insurance policies are discussed and need implementation worldwide.
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Project description:Hypercholesterolemia and statins are risk factors for aortic stenosis (AS) and vascular calcification, respectively. Whether heterozygous subjects with familial hypercholesterolemia (HeFH) treated with statins are at risk of AS is unknown. We study the prevalence of AS, aortic valve calcification (AoVC), and aortic sclerosis (ASc) in elderly subjects with HeFH in a prolonged statin treatment. Case-control study, cases were adults ?65 years of age with a genetic diagnosis of HeFH, LDLc >220 mg/dl, and statin treatment ?5 years. Controls were relatives of HeFH patients, with LDLc <190 mg/dl. Participants underwent a cardiac ultrasound for aortic valve analysis. We studied 205 subjects, 112 HeFH and 93 controls, with mean age 71.8(6.5) years and 70.0(7.3) years, respectively. HeHF, with respect to controls, presented greater gradients of aortic transvalvular pressure, 7.4(7.3) mmHg versus 5.0(2.8) mmHg, and maximum aortic velocity, 1.7(0.7) m/s versus 1.5(0.4) m/s, and lower aortic valve opening area, 2.0(0.7) cm2 versus 2.4(0.6) cm2 (all p < 0.05). AoVC and ASc were also more prevalent in HeFH (p < 0.05 between groups). Moderate/severe AS prevalence was higher among HeFH: 7.1% versus 1.1% (age- and sex-adjusted odds ratio (OR) 8.33, p = 0.03). Independent risk factors for aortic valve disease in HeFH were age and LDLc before treatment. The number of years under statin treatment was not associated with any aortic valve measurement. Subjects ?65 years with HeFH in prolonged statin treatment show more aortic valvular disease and higher frequency of AS than controls. Life-long elevated LDLc exposure, rather than time of exposure to statins, explains this higher risk.
| S-EPMC6947617 | biostudies-literature
Project description:BackgroundDeterminants of coronary artery calcification (CAC) prevalence and severity in heterozygous familial hypercholesterolemia (HeFH) remain understudied. The objective of this cross-sectional study was to investigate correlates of CAC in patients with HeFH.MethodsA CAC score was calculated by a noncontrast computed tomography scan in women (n = 68) and men (n = 78) with genetically defined HeFH. We classified CAC prevalence and severity using 3 categories: CAC score = 0 Agatston Unit (AU), CAC score = 1-100 AU, and CAC score > 100 AU. Information on potential correlates of CAC including familial and personal health history, cardiovascular risk factors, lipid-lowering medication, and lifestyle habits was collected.ResultsA total of 95 patients had prevalent CAC. Independent correlates of CAC prevalence and severity included age (odds ratio [OR] per 10 years: 5.06, 95% confidence interval [CI]: 3.19, 7.93, P < 0.0001), family history of premature cardiovascular disease (OR: 3.88, 95% CI: 1.71, 8.81, P = 0.001), male sex (OR: 3.40, 95% CI: 1.49, 7.78, P = 0.004), statin use (OR: 15.5, 95% CI: 1.89, 126, P = 0.01), diet quality assessed with the Alternative Healthy Eating Index score (OR per 1 standard deviation: 0.59, 95% CI: 0.39, 0.90, P = 0.01), ever smoking (OR: 3.06, 95% CI: 1.20, 7.81, P = 0.02), receptor-negative genotype (OR: 3.17, 95% CI: 1.16, 8.66, P = 0.02), lipoprotein(a) year-score (OR per 1 standard deviation of log-transformed year-score: 1.53, 95% CI: 0.99, 2.36, P = 0.05).ConclusionsIn individuals with HeFH, age, family history of premature cardiovascular disease, sex, statin use, diet quality, smoking status, the LDLR genotype, and lipoprotein(a) concentrations were independently associated with CAC prevalence and severity.
| S-EPMC7801218 | biostudies-literature
Project description:Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder that affects about 1 in 500 people, with a higher prevalence in certain subpopulations such as people of Quebecois, Christian Lebanese and Dutch South Afrikaner extraction. HeFH is characterized by cholesterol deposits affecting the corneas, eyelids and extensor tendons; elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol; and accelerated vascular disease, especially coronary artery disease (CAD). Although HeFH is genetically heterogeneous, it is most often caused by heterozygous mutations in the LDLR gene encoding the LDL receptor. We describe a man who was diagnosed with HeFH after he had a myocardial infarction at 33 years of age. By DNA sequence analysis, he was found to have a heterozygous splicing mutation in his LDLR gene. This discovery expanded the growing mutational spectrum in patients with HeFH in Ontario. Given that HeFH is a treatable cause of early vascular disease, it is important that this condition be recognized, diagnosed and treated in affected patients; but as yet, there is no consensus on the best approach. Diagnostic criteria based on family history and clinical presentation have been proposed for patients with suspected HeFH. Biochemical or molecular screening might be considered to detect new cases of HeFH in populations with a relatively high HeFH prevalence and a relatively small number of possible causative mutations. So far, however, the most cost-effective and efficient systematic strategy to detect previously undiagnosed cases of HeFH is still cascade testing: clinical and biochemical screening of close relatives of the proband patient diagnosed with HeFH. Pharmacologic treatment of HeFH is cost-effective.
| S-EPMC1421462 | biostudies-literature
Project description:BackgroundThe PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low-density lipoprotein-cholesterol (LDL-C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin-associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone.Methods and resultsPatients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL-C target levels were not met. The primary efficacy endpoint was LDL-C percentage change from baseline to W24. Mean baseline LDL-C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n=59), 154.5 mg/dL (alirocumab 75 mg Q2W, n=116), and 158.5 mg/dL (placebo, n=58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least-squares mean LDL-C changes from baseline to W24 were -51.7% and -53.5%, respectively (placebo [+4.7%]; both groups P<0.0001 versus placebo). In total, 63.9% and 70.3% of alirocumab-treated patients achieved their LDL-C targets at W24. Treatment-emergent adverse events occurred in 77.6% (alirocumab 150 mg Q4W), 73.0% (alirocumab 75 mg Q2W), and 63.8% (placebo) of patients, with injection-site reactions among the most common treatment-emergent adverse events.ConclusionsAlirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL-C.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT02023879.
| S-EPMC5079013 | biostudies-literature