Topoisomerase I Inhibitors
6 drugsAbout Topoisomerase I
Topoisomerase I (TOP1) is an enzyme that relieves torsional stress during DNA replication and transcription by cutting and rejoining single DNA strands. Inhibiting TOP1 disrupts DNA metabolism, especially in rapidly dividing cells, making it a target for oncology drugs.
Human genetics provide moderate support for TOP1 as a therapeutic target, with variants linked to hypercholesterolemia (score 0.67) and autism spectrum disorder (score 0.55). Strong eQTL/pQTL signals further support TOP1's role in disease.
Six FDA-approved drugs target TOP1, including ENHERTU, IRINOTECAN HYDROCHLORIDE, and DATROWAY. These drugs are split between small molecules and ADCs, with applications in oncology and other therapeutic areas.
Strategic Insights
ℹ️ How we calculate- Validated target with strong trial activity and 83% attractiveness score.
Human Genetic Evidence Moderate
Genetic evidence shows moderate support for Topoisomerase I as a drug target.
Further research into the genes regulated by TOP1 could reveal novel therapeutic opportunities.
Evidence Across Diseases
14 totalGWAS and other genetic studies link TOP1 to 14 diseases.
🔗 Colocalization Evidence 20 strong
max H4: 1.00eQTL/pQTL signals for TOP1 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 Drugs
Six companies have approved drugs targeting Topoisomerase I, including QILU PHARM HAINAN and DAIICHI SANKYO.
The presence of multiple players suggests a competitive market, requiring a strong value proposition for new entrants.
Drug Modality Landscape
Modalities
Routes of Administration
Topoisomerase I is druggable by both biologics (3) and small molecules (3), indicating broad therapeutic accessibility.
Consider novel modalities to differentiate from existing Topoisomerase I-targeting therapies.
📈 Modality Evolution
Small molecules pioneered Topoisomerase I targeting (1996), with adcs entering more recently (2019).
Clinical Trials 1,282 trials
Completion by Phase
| Phase | Total | Completed | Failed | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 402 | 185 | 73 | 141 | 72% |
| Phase 2 | 606 | 218 | 111 | 272 | 66% |
| Phase 3 | 250 | 87 | 15 | 148 | 85% |
| Phase 4 | 24 | 9 | 1 | 13 | 90% |
Top Sponsors
By Modality
Top Conditions
Phase 3 Readout Calendar Pro
8 Phase 3 trials testing approved Topoisomerase I drugs across all sponsors.
Coverage: trials whose intervention is an approved drug targeting Topoisomerase I. Pre-approval candidates with development codes (e.g. AZD0901, MK-7240) are not yet linked. Anchored on CT.gov primary completion date.
Drug Approval Timeline (1996 - 2025)
Unresectable or metastatic HER2-positive breast cancer
Unresectable locally advanced or metastatic triple-negati...
The first Topoisomerase I-targeting drug was approved in 1996, with the most recent in 2025.
The continued approval of new drugs indicates sustained interest in Topoisomerase I as a target.
Pro Intelligence Preview
Deep insights for drug target analysis
Competitive Landscape
- • 6 companies competing
- • Market share by company
Full Drug Portfolio
- • All 6 approved drugs
- • Approval dates & indications
Genetic Validation
- • Full genetic evidence table
- • Effect sizes & directions
Approval Timeline
- • Full 6-drug timeline
- • First-of-modality markers
Clinical Trials Analysis
- • Competition: High (15 sponsors)
- • Success rates by condition
Full summary • All drugs • Genetic evidence • Trials • Timeline
How We Calculate These Metrics
Target Attractiveness Score
A 0-100 score based on trial activity, sponsor diversity, and completion rates. Calculated from 871 clinical trials targeting Topoisomerase I.
Completion rate: Percentage of trials that reached their planned endpoint. Trials terminated early, withdrawn, or suspended are not counted—these often indicate safety issues, lack of efficacy, or strategic pivots.
- Highly Attractive (80+): High trial activity, many sponsors, strong completion rates
- Attractive (60-79): Good trial activity and validation
- Moderate (40-59): Moderate interest from sponsors
- Low (under 40): Limited trial activity or validation concerns
Strategic Insights
Auto-generated insights based on trial analytics including competition intensity, white space opportunities, modality shifts, and failure patterns. We analyze trial sponsors, phases, indications, and outcomes.
Risk Signals
- High Competition: Many sponsors competing for this target (may reduce market opportunity)
- High Failure Risk: Low trial completion rates suggest development challenges
- Low Validation: Limited trial activity or poor outcomes indicate uncertain viability
- White Space Available: Underexplored indications present opportunities