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Published on: September 15, 2018
Pediatric experience with mipomersen as adjunctive therapy for homozygous familial hypercholesterolemia
Frederick J Raal1, Marjet J Braamskamp2, Sheryl L Selvey3
1Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Insights
Mipomersen effectively lowered LDL-C and apo B in pediatric patients with homozygous familial hypercholesterolemia (HoFH). Long-term treatment showed efficacy but highlighted compliance challenges in this HoFH population.
Area of Science:
- Cardiovascular Medicine
- Genetics and Inherited Diseases
- Pharmacology and Therapeutics
Background:
- Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder causing extremely high LDL-C levels and premature cardiovascular disease.
- Current treatments for HoFH are limited, especially for pediatric populations, necessitating exploration of novel therapeutic options.
- Mipomersen, an antisense oligonucleotide targeting apolipoprotein B synthesis, has shown promise in reducing LDL-C in adult HoFH patients.
Purpose of the Study:
- To evaluate the efficacy and safety of mipomersen in pediatric patients with HoFH.
- To assess long-term outcomes of mipomersen treatment in a pediatric cohort through an open-label extension study.
- To identify potential challenges, such as compliance, associated with mipomersen therapy in adolescents.
Main Methods:
- A phase 3 randomized controlled trial (RCT) involving seven pediatric patients (aged 12-18 years) randomized to mipomersen or placebo for 26 weeks.
- Subsequent open-label extension (OLE) study where all participants received mipomersen for 52 or 104 weeks.
- Assessment of plasma LDL-C and apolipoprotein B (apo B) concentrations, along with adverse events, throughout the study duration.
Main Results:
- Pediatric patients receiving mipomersen in the RCT showed significant reductions in LDL-C (42.7%) and apo B (46.1%).
- Placebo-treated patients who switched to mipomersen in the OLE also experienced substantial LDL-C reductions (26.5%-42.1%).
- While efficacy was demonstrated, three patients discontinued treatment due to adverse events, and lipid level fluctuations suggested compliance issues in some participants.
Conclusions:
- Long-term mipomersen treatment demonstrated efficacy in managing lipid levels for pediatric HoFH patients.
- The safety profile of mipomersen in this pediatric cohort was consistent with findings from previous adult trials.
- Adherence to long-term mipomersen therapy is crucial for sustained efficacy, and strategies to support patient compliance should be implemented.
Background:
Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited condition resulting in severely elevated low-density lipoprotein cholesterol levels (LDL-C) leading to premature cardiovascular disease and, often, death. Mipomersen is an antisense oligonucleotide that inhibits apolipoprotein B (apo B) synthesis, lowering LDL-C levels. Mipomersen has demonstrated efficacy in adult HoFH patients, possibly providing a therapeutic option for pediatric patients. Study objectives were to summarize mipomersen efficacy and safety in the pediatric cohort of a phase 3 randomized controlled trial (RCT) and subsequent open-label extension study (OLE).
Methods:
Seven patients aged 12-18 years were randomized to 200-mg mipomersen or placebo weekly (26 weeks) and received mipomersen in the OLE (52 or 104 weeks). Plasma LDL-C and apo B concentrations and adverse events were assessed.
Results:
All pediatric patients completed the RCT and entered OLE. The 3 mipomersen patients in the RCT experienced mean reductions from baseline to RCT end of 42.7% and 46.1% for LDL-C and apo B, respectively. Of the 4 placebo patients, 3 responded well to mipomersen during OLE, with reductions in LDL-C of 26.5%-42.1%. Three patients completed OLE treatment, and 4 patients discontinued therapy due to adverse events. Lipid level fluctuations were observed and were likely due to poor compliance.
Conclusions:
Long-term mipomersen treatment was successful regarding efficacy parameters for pediatric HoFH patients. The safety profile was consistent with other phase 3 clinical trials. Long-term compliance was an issue. Measures supporting adherence should be encouraged.
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