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Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three
Frederick J Raal1, Robert A Hegele2, Andrea Ruzza3
1Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.).
Insights
Evolocumab is well-tolerated in pediatric patients with homozygous familial hypercholesterolemia (HoFH), showing no new safety concerns. However, LDL-C reduction varied significantly among patients, supporting PCSK9 inhibitor trials regardless of residual LDLR function.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Pharmacology
Background:
- Pediatric patients with homozygous familial hypercholesterolemia (HoFH) face high risks of atherosclerotic cardiovascular disease.
- Achieving target low-density lipoprotein cholesterol (LDL-C) levels is challenging for these young patients.
- Evolocumab, a PCSK9 inhibitor, is a potential treatment option for managing HoFH.
Purpose of the Study:
- To evaluate the pooled safety and efficacy of evolocumab in pediatric patients with HoFH.
- To assess treatment-emergent adverse events and lipid-lowering effects of evolocumab.
- To determine if residual LDL receptor (LDLR) activity influences treatment response.
Main Methods:
- Pooled safety and efficacy data from 3 clinical studies (TAUSSIG, RAMAN, HAUSER-OLE) of pediatric HoFH patients.
- Patients aged 10-17 years received evolocumab (420 mg monthly or biweekly) with background statins +/- ezetimibe.
- Primary endpoint: treatment-emergent adverse events; Secondary endpoints: changes in lipids and PCSK9 levels.
Main Results:
- Evolocumab was well-tolerated in 39 pediatric HoFH patients with a median exposure of 18.2 months.
- Common adverse events included upper respiratory tract infection, influenza, and acne.
- Significant variability in LDL-C reduction was observed; 42.9% achieved ≥15% reduction, but residual LDLR activity did not correlate with response.
Conclusions:
- Evolocumab demonstrated a favorable safety profile in pediatric HoFH patients, consistent with prior studies.
- No new safety signals were identified, reinforcing its tolerability.
- The variable LDL-C response supports initiating PCSK9 inhibitor therapy irrespective of estimated residual LDLR function.
Background:
Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab.
Methods:
Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9.
Results:
Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C.
Conclusions:
In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.
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