PCSK9 Inhibitors
4 drugsAbout PCSK9
PCSK9 is a protein convertase that regulates LDL receptor levels, influencing cholesterol homeostasis. By binding to the LDL receptor, PCSK9 promotes its degradation, leading to higher circulating LDL cholesterol.
PCSK9 is a validated drug target with strong genetic support (max score 0.94) from 41 diseases. Loss-of-function variants in PCSK9 protect against hypercholesterolemia, coronary artery disease, and metabolic disease, supporting inhibition as a therapeutic strategy.
Four PCSK9-targeting drugs are FDA-approved, including PRALUENT, REPATHA, LEQVIO, and LEROCHOL. These include antibody (PRALUENT, REPATHA), siRNA (LEQVIO), and other biologic modalities, addressing metabolic and other therapeutic areas.
PCSK9 Genetic Evidence Strong
PCSK9 has strong genetic support with a max score of 0.94 across 41 diseases.
The strong genetic support suggests a higher probability of clinical success for PCSK9-targeting therapies.
💡 Why inhibition?
- • Loss-of-function variants reduce disease risk (OR < 1)
- • 100% directional consistency across 3 traits
- • Strong signal in phenotype, cardiovascular disease, nutritional or metabolic disease pathways
- • 2/2 diseases show protective effect sizes
Cross-Disease Effects
Trade-off: LowDirection of Effect
100% alignedEvidence Across Diseases
20 totalGWAS and other genetic studies link PCSK9 to 41 diseases.
Inhibiting this target may be therapeutic
Inhibiting this target may be therapeutic
Effect Sizes
Genetic effect on disease risk. OR<1 or β<0 = loss-of-function is protective (inhibiting target may help).
🔗 Colocalization Evidence 20 strong
max H4: 1.00eQTL/pQTL signals for PCSK9 colocalize with these GWAS traits, providing causal evidence that gene expression changes drive disease risk.
Understanding these scores
Association Score (0-1): Combines all evidence types (genetic, literature, drugs, animal models). Higher = more evidence linking target to disease. This is a ranking heuristic, not a confidence score.
L2G Score: Open Targets uses a machine learning model (Locus-to-Gene) to predict which gene is causal at each GWAS locus. L2G=0.5 means ~50% probability of being the causal gene. Only associations with L2G > 0.05 are included.
Odds Ratio (OR): From gene burden studies (UK Biobank, AstraZeneca PheWAS). Measures how loss-of-function variants affect disease risk. OR<1 = protective (inhibiting target may help), OR>1 = risk (losing function causes disease).
Beta (β): Effect size for continuous traits. β<0 = protective, β>0 = risk.
Clinical Translation (~1.8x): Based on Nelson et al. 2015: drug targets with genetic evidence have ~2x higher success rates in clinical trials. We estimate: Strong support (score ≥0.7) → ~1.8x, Moderate (0.3-0.7) → ~1.3x, Weak → baseline.
Colocalization (H4): Tests whether a GWAS signal and an eQTL/pQTL signal share the same causal variant. H4 is the posterior probability that both traits are associated AND share a causal variant. H4 > 0.8 = strong evidence that gene expression/protein levels drive disease risk. This links genetic variation → gene expression → disease, supporting the target-disease connection.
Top PCSK9 Drugs
Four companies have approved PCSK9-targeting drugs, including Regeneron, Amgen, Novartis and LIB THERAPEUTICS, INC.
The presence of multiple players indicates a competitive market, requiring differentiation for new entrants.
| Drug | Company | Approved | Indications |
|---|---|---|---|
| LEROCHOL | LIB THERAPEUTICS, INC. | 2025 | 2 |
PCSK9 Drug Modality Landscape
Modalities
Routes of Administration
PCSK9 is exclusively targeted by antibodies, suggesting it may be a cell-surface or secreted protein.
The presence of siRNA modalities suggests an opportunity for novel delivery methods or combination therapies.
📈 Modality Evolution
Antibodies pioneered PCSK9 targeting (2015), with other biologics entering more recently (2025).
PCSK9 Clinical Trials 208 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on PCSK9. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 20 | 18 | 1 | 1 | 95% |
| Phase 2 | 38 | 27 | 4 | 7 | 87% |
| Phase 3 | 96 | 77 | 2 | 17 | 97% |
| Phase 4 | 54 | 21 | 12 | 21 | 64% |
Top Sponsors
By Modality
Top Conditions
PCSK9 Drug Approval Timeline (2015 - 2025)
The first PCSK9 inhibitor was approved in 2015, with the most recent approval in 2025.
The recent approval suggests continued interest and potential for further innovation in PCSK9-targeting therapies.
Pro Intelligence Preview
Deep insights for drug target analysis
Competitive Landscape
- • 4 companies competing
- • Market share by company
Full Drug Portfolio
- • All 4 approved drugs
- • Approval dates & indications
Genetic Validation
- • Full genetic evidence table
- • Effect sizes & directions
Approval Timeline
- • Full 4-drug timeline
- • First-of-modality markers
Clinical Trials Analysis
- • Sponsors: 76 (15 companies)
- • Completion rates by condition
Full summary • All drugs • Genetic evidence • Trials • Timeline
How We Count Trials
- Trials: phase 1-4 interventional trials on ClinicalTrials.gov that started in 2008 or later and test an FDA-approved drug acting on PCSK9. A trial counts if an approved drug acting on PCSK9 is in any arm, including as a comparator, and a trial that tests two such drugs counts once. Trials that test only unapproved drugs are not counted. A trial listed as phase 1/2 counts as phase 1, and phase 2/3 as phase 2.
- Active: recruiting, not yet recruiting, enrolling by invitation, or active and no longer recruiting.
- Completion rate: of the trials that have ended, the share marked Completed rather than Terminated or Withdrawn. Completed means the trial ended as planned; it does not mean the drug worked. Suspended trials are not counted as ended.
- Stopped: terminated or withdrawn. Trials stop for many reasons, including slow enrolment and business decisions, not only safety or efficacy.
- Sponsors: the lead sponsor of each trial. Companies are the sponsors ClinicalTrials.gov classes as industry; the rest are universities, hospitals, cooperative groups, government bodies and individuals.