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Homozygous familial hypercholesterolemia: what treatments are on the horizon?
1Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Insights
Homozygous familial hypercholesterolemia (HoFH) treatments are challenging, but new therapies like PCSK9 and ANGPTL3 inhibitors show promise. Gene therapy offers a potential one-time treatment for HoFH patients to lower LDL-C levels.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Pharmacology
Background:
- Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder causing severe LDL receptor (LDLR) pathway dysfunction.
- This leads to early atherosclerotic disease, with high morbidity and mortality despite current treatments.
- Existing therapies often fail to achieve target LDL-C levels in HoFH patients.
Purpose of the Study:
- To review current and emerging therapies for HoFH.
- To discuss the potential of novel treatments, including gene therapy, for managing HoFH.
- To highlight the challenges and advancements in lowering LDL-C in HoFH.
Main Methods:
- Review of recent real-world studies on HoFH treatments.
- Analysis of clinical trial data for emerging therapies targeting PCSK9 and ANGPTL3.
- Evaluation of preclinical and early clinical data for gene therapy and gene editing techniques.
Main Results:
- Lomitapide is effective as an adjunct therapy for HoFH.
- PCSK9 inhibitor monoclonal antibodies provide an additional 24% average LDL-C reduction.
- Evinacumab demonstrated a 49% average LDL-C reduction, independent of LDLR activity.
Conclusions:
- Lowering LDL-C in HoFH remains challenging, necessitating novel therapeutic approaches.
- Emerging therapies targeting PCSK9 and ANGPTL3 offer additional LDL-C reduction potential.
- Gene therapy and gene editing represent promising, potentially curative, one-time treatment options for HoFH.
Purpose Of Review:
Homozygous familial hypercholesterolemia (HoFH) is a rare disorder associated with early atherosclerotic disease due to impairment of the LDL receptor (LDLR) pathway. Because of their molecular defect, current treatment options have limited success in bringing HoFH patient to LDL-C target and morbidity and mortality remain high. We review current and upcoming therapies directed at HoFH, including gene therapy.
Recent Findings:
Recent real-world studies have confirmed the strength in lomitapide as a treatment adjunct to statins and other lipid-lowering therapies in HoFH patients. The approval of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies has also been a welcome addition to the treatment armamentarium offering an additional average reduction in LDL-C levels of 24% when added to background lipid-lowering therapies in this population. Although achieving adequate LDL-C levels in this population is difficult, there are several therapies on the horizon that may help more patients reach goal. Evinacumab, a monoclonal antibody against ANGPTL3, has been shown to substantially reduce LDL-C of an average of 49%, independently of residual LDLR activity. RNA interference targeting PCSK9 and ANGPTL3 shows promise in clinical trials. Adeno-associated virus-mediated gene transfer and gene editing techniques are in early clinical and preclinical development.
Summary:
LDL-C lowering in HoFH patients remains very challenging. However, novel treatment options are emerging. Upcoming therapies directed at PCSK9 and ANPTL3 may offer additional LDL-C reduction, to help patients achieve adequate LDL-C levels. Gene therapy and gene editing techniques, if proven effective, may offer a unique opportunity to treat patients with a one-time treatment.
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