Alirocumab 75mg/1ml solution for injection pre-filled disposable devices

Background and Objectives: The proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab are recently developed promising drugs used for treatment of familial hypercholesterolemia (FH). This systematic review and meta-analysis aimed to thoroughly evaluate the efficacy and safety of evolocumab and alirocumab among pediatric patients with FH. Materials and Methods: A comprehensive search was conducted in PubMed, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov from inception through July 2024 to identify primary interventional studies among pediatric patients with FH. Meta-analyses were performed if appropriate. Statistics were analyzed using Review Manager version 5.4 and Stata version 16.0. Results: Fourteen articles reporting nine unique studies were included. There were three randomized controlled trials (RCTs) assessing evolocumab or alirocumab involving a total of 320 pediatric patients, one cross-over trial and five single-arm or observational studies. Pooled results showed significant efficacy of evolocumab/alirocumab in reducing low-density lipoprotein cholesterol (LDL-C) (weighted mean difference [WMD]: −37.92%, 95% confidence interval [CI]: −43.06% to −32.78%; I2 = 0.0%, p = 0.60), apolipoprotein B (WMD: −33.67%, 95% CI: −38.12% to −29.22%; I2 = 0.0%, p = 0.71), and also lipoprotein(a) (WMD: −16.94%, 95% CI: −26.20% to −7.69%; I2 = 0.0%, p = 0.71) among pediatric patients with FH. The efficacies of evolocumab/alirocumab on LDL-C reduction within pediatric patients with heterozygous FH (HeFH) were consistent between studies, whereas in patients with homozygous FH (HoFH), it varied dramatically. Pediatric patients with the null/null variant may respond to the treatment. PCSK9 inhibitors were generally well tolerated within most pediatric patients, in line with previous studies among adult populations. Conclusions: The PCSK9 inhibitors evolocumab/alirocumab significantly reduced LDL-C and some other lipid parameters, such as apolipoprotein B, in pediatric patients with HeFH. These drugs may be appropriate as a potential therapy for pediatric patients with HoFH who cannot achieve LDL-C targets with other treatments. Evolocumab/alirocumab was generally well tolerated in the pediatric population.

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INTRODUCTION: The PCSK9 enzyme is present mainly in the liver and is responsible for the degradation of LDL-C receptors. Currently, there are some drugs that inhibit this enzyme, such as alirocumab and evolocumab. Consequently, these drugs reduce serum LDL-C levels. Therefore, a systematic review and a meta-analysis were carried out in order to compare alirocumab against evolocumab in reducing cardiovascular outcomes. METHODS: This systematic review was carried out in accordance with PRISMA and was registered in PROSPERO (CRD42024573217). The following databases were searched on July, 9, 2024: PubMed, Web of Science and Scopus. Randomized clinical trials with a control group were included and meta-analyses were performed to assess relative risk (RR). The random effects model was used in heterogeneous samples. The articles were distributed into 2 subgroups: use of alirocumab and evolocumab. RESULTS: Initially, 2,213 articles were found, of which 6 were included. In total, 62,119 patients participated. The RR values were significant for alirocumab in the following outcomes: myocardial infarction (MI) 0.85 (95% CI 0.77-0.93), stroke 0.75 (95% CI 0.60-0.94) and hospitalization for unstable angina 0.58 (95% CI 0.39-0.86), while for evolocumab they were significant for MI 0.75 (95% CI 0.68-0.83) and coronary revascularization 0.81 (95 CI % 0.75-0.88). There was a statistically significant difference between the drugs for hospitalization for unstable angina (p=0.02). DISCUSSION: This study highlights the benefits of PCSK9 inhibitors, especially alirocumab, in reducing major cardiovascular events. Alirocumab significantly lowered hospitalizations for unstable angina, with a 42% reduction, and showed favorable outcomes in reducing myocardial infarction, coronary revascularization, and stroke. These reductions are clinically meaningful, as they lower morbidity, improve patient quality of life, and reduce healthcare costs. Both alirocumab and evolocumab are effective and safe, offering important therapeutic options for high-risk cardiovascular patients. CONCLUSION: The use of alirocumab is preferable if the focus is to avoid hospitalizations for unstable angina or stroke, while evolocumab may be an option if one wants to avoid coronary revascularization. Both drugs are effective in reducing cardiovascular outcomes, but alirocumab was superior to evolocumab.

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Background: Direct comparisons between the drugs are limited, and the dosing remains debatable. Therefore, the study aims to indirectly compare the efficacy and safety of inclisiran, alirocumab, evolocumab, and evinacumab in lipid-lowering through a network meta-analysis. Methods: Databases including PubMed, EMBASE, Web of Science, and the Cochrane Library were utilized to retrieve randomized controlled trials (RCTs). The search was conducted up to July 1, 2023. The Cochrane risk of bias tool was employed to appraise the quality of included studies. R software was used to conduct the Bayesian network meta-analysis. Results: Twenty-one RCTs with 10,835 patients were included. The network meta-analysis indicated that Evolocumab [mean difference (MD) = -60, 95% credibility interval (CrI) (-72, -49)] was the most effective (87%) in reducing low-density lipoprotein cholesterol (LDL-C), followed by alirocumab (71.4%) and inclisiran (47.2%), with placebo being the least effective (0.01%). In increasing high-density lipoprotein cholesterol (HDL-C), evolocumab [MD = 6.5, 95% CrI (3.2, 10)] ranked first (81.8%), followed by alirocumab (68.2%), with placebo again at the bottom (0.03%). In lowering total cholesterol, evolocumab [MD = -36, 95% CrI (-54, -19)] performed the best (86%), followed by alirocumab (64%), and placebo remained the least effective (0.04%). Regarding adverse events (AEs), evinacumab [odds ratio (OR) = 2, 95% CrI (1.17, 3.44)] ranked the highest (98.9%), followed by inclisiran (59.6%) and evolocumab (15.2%). Conclusions: Evolocumab appears to be the most effective in increasing HDL-C and reducing LDL-C and total cholesterol. Evinacumab shows the best safety profile with the lowest incidence of AEs. The PROSPERO registration: CRD42024570445, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=570445.

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Background: A meta-analysis was conducted to determine whether the cardiovascular mortality and lipid-lowering effects of alirocumab and evolocumab are influenced by various baseline low-density lipoprotein cholesterol (LDL-C) levels. Methods: We searched for literature published before June 2023. Eligible randomized controlled trials (RCTs) included adults treated with alirocumab or evolocumab and reported LDL-C changes and cardiovascular deaths. The primary endpoints were cardiovascular mortality and percent changes in LDL-C from baseline. Results: Forty-one RCTs were included in the meta-analysis. Evolocumab did not significantly affect the outcome of cardiovascular mortality whether the baseline data were greater than 100 mg/dL or less than 100 mg/dL. However, the stratified result showed that alirocumab decreased the risk of cardiovascular mortality in patients with a baseline LDL-C level of ≥100 mg/dL (relative risk (RR) 0.45; 95% CI: 0.22 to 0.92; p = 0.03). In terms of lipid-lowering efficacy, alirocumab (mean difference (MD) –56.62%; 95% CI: –60.70% to –52.54%; p < 0.001) and evolocumab (MD –68.10%; 95% CI: –74.85% to –61.36%; p < 0.001) yielded the highest percentage reduction in LDL-C level when baseline levels were 70–100 mg/dL, while the smallest reduction in alirocumab (MD –37.26%; 95% CI: –44.06% to –30.46%; p < 0.001) and evolocumab (MD –37.55%; 95% CI: –40.47% to –34.63%; p < 0.001) occurred with baseline LDL-C levels of ≥160 mg/dL. Conclusions: Alirocumab and evolocumab presented a better lipid-lowering effect when the baseline LDL-C levels were <100 mg/dL. Alirocumab was associated with a significant reduction in cardiovascular mortality at baseline LDL-C levels of ≥100 mg/dL. This finding can have significant implications for the development of personalized drug therapy. The PROSPERO Registration: CRD42023446723, https://www.crd.york.ac.uk/PROSPERO/view/CRD42023446723.

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Importance: Many pediatric patients with heterozygous familial hypercholesterolemia (HeFH) cannot reach recommended low-density lipoprotein cholesterol (LDL-C) concentrations on statins alone and require adjunct lipid-lowering therapy (LLT); the use of alirocumab in pediatric patients requires evaluation. Objective: To assess the efficacy of alirocumab in pediatric patients with inadequately controlled HeFH. Design, Setting, and Participants: This was a phase 3, randomized clinical trial conducted between May 2018 and August 2022 at 43 centers in 24 countries. Pediatric patients aged 8 to 17 years with HeFH, LDL-C 130 mg/dL or greater, and receiving statins or other LLTs were included. Following consecutive enrollment into dosing cohorts, 25 of 99 patients screened for dosing every 2 weeks (Q2W) failed screening; 25 of 104 patients screened for dosing every 4 weeks (Q4W) failed screening. A total of 70 of 74 Q2W patients (95%) and 75 of 79 Q4W patients (95%) completed the double-blind period. Interventions: Patients were randomized 2:1 to subcutaneous alirocumab or placebo and Q2W or Q4W. Dosage was based on weight (40 mg for Q2W or 150 mg for Q4W if <50 kg; 75 mg for Q2W or 300 mg for Q4W if ≥50 kg) and adjusted at week 12 if LDL-C was 110 mg/dL or greater at week 8. After the 24-week double-blind period, patients could receive alirocumab in an 80-week open-label period. Main Outcomes and Measures: The primary end point was percent change in LDL-C from baseline to week 24 in each cohort. Results: Among 153 patients randomized to receive alirocumab or placebo (mean [range] age, 12.9 [8-17] years; 87 [56.9%] female), alirocumab showed statistically significant reductions in LDL-C vs placebo in both cohorts at week 24. Least squares mean difference in percentage change from baseline was -43.3% (97.5% CI, -56.0 to -30.7; P < .001) Q2W and -33.8% (97.5% CI, -46.4 to -21.2; P < .001) Q4W. Hierarchical analysis of secondary efficacy end points demonstrated significant improvements in other lipid parameters at weeks 12 and 24 with alirocumab. Two patients receiving alirocumab Q4W experienced adverse events leading to discontinuation. No significant difference in adverse event incidence was observed between treatment groups. Open-label period findings were consistent with the double-blind period. Conclusions and Relevance: The findings in this study indicate that alirocumab Q2W or Q4W significantly may be useful for reducing LDL-C and other lipid parameters and be well tolerated in pediatric patients with HeFH inadequately controlled with statins. Trial Registration: ClinicalTrials.gov Identifier: NCT03510884.

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