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Updated: Jul 4, 2025
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
PCSK9-directed therapies: an update
Julius L Katzmann1, Ulrich Laufs
1Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany.
Purpose Of Review:
Two large cardiovascular outcomes trials of monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) demonstrated that therapeutic inhibition of extracellular PCSK9 markedly reduces LDL cholesterol concentration and cardiovascular risk. Several novel strategies to inhibit PCSK9 function are in development. Different mechanisms of action may determine specific properties with potential relevance for patient care.
Recent Findings:
For the monoclonal antibodies evolocumab und alirocumab as first-generation PCSK9 inhibitors, follow-up data of up to 8 years of exposure complement the information on efficacy and safety available from outcome trials. For the small-interfering RNA inclisiran as second-generation PCSK9 inhibitor, several phase III trials have been published and a cardiovascular outcome trial has completed recruitment and is ongoing. Third-generation PCSK9 inhibitors encompass, among others, orally available drugs such as MK-0616 and the fusion protein lerodalcibep. Additional strategies to inhibit PCSK9 include vaccination and gene editing.
Summary:
Long-term inhibition of PCSK9 with monoclonal antibodies is safe and conveys sustained cardiovascular benefit. Novel strategies to inhibit PCSK9 function such as orally available drugs, RNA targeting, and one-time treatment with gene editing may further enhance the therapeutic armamentarium and enable novel preventive strategies.
Insights
Novel strategies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) offer sustained cardiovascular benefits. These advancements in PCSK9 inhibition, including new drugs and gene editing, promise enhanced patient care and prevention.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Biotechnology
Background:
- Monoclonal antibodies targeting PCSK9 significantly lower LDL cholesterol and cardiovascular risk.
- PCSK9 inhibition is a validated therapeutic strategy for cardiovascular disease prevention.
Purpose of the Study:
- To review current and emerging strategies for inhibiting PCSK9.
- To discuss the potential clinical relevance of novel PCSK9 inhibitors.
Main Methods:
- Review of cardiovascular outcomes trials for first-generation PCSK9 inhibitors (evolocumab, alirocumab).
- Analysis of phase III trial data for second-generation PCSK9 inhibitors (inclisiran).
- Overview of emerging third-generation PCSK9 inhibitors and other strategies (oral drugs, RNA targeting, gene editing, vaccination).
Main Results:
- Long-term data confirm the safety and sustained cardiovascular benefits of monoclonal antibody PCSK9 inhibition.
- Second-generation PCSK9 inhibitors show promise with ongoing outcome trials.
- Novel approaches like oral PCSK9 inhibitors, RNA targeting, and gene editing are under development.
Conclusions:
- Long-term PCSK9 inhibition with monoclonal antibodies is safe and effective for cardiovascular risk reduction.
- Emerging PCSK9 inhibition strategies, including oral agents and gene editing, may expand therapeutic options and preventive capabilities.
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