Smoothened Inhibitors
3 drugsAbout Smoothened
Smoothened (SMO) is a transmembrane protein and a key component of the Hedgehog (Hh) signaling pathway, crucial for embryonic development and tissue maintenance. It functions as a signal transducer, activating downstream targets upon Hh ligand binding to the PTCH1 receptor. This activation promotes cell growth, differentiation, and survival.
Human genetic studies provide strong validation for SMO as a therapeutic target (max score 0.86). Variants are linked to congenital hypothalamic hamartoma syndrome (score 0.86), osteoarthritis (0.78), and Hirschsprung disease (0.61). Activation of SMO is likely beneficial based on genetic evidence.
SMO is targeted by three FDA-approved small molecule drugs: ERIVEDGE, ODOMZO, and DAURISMO. ERIVEDGE has two indications, while ODOMZO and DAURISMO each have one. One drug is used in oncology, while the other two target other therapeutic areas.
Strategic Insights
ℹ️ How we calculate- White space opportunity in Advanced Lymphoma with only 2 trials.
- phase2 represents biological uncertainty with 57% completion.
Human Genetic Evidence Strong
SMO has strong genetic support with a maximum score of 0.86 across 8 diseases.
The strong genetic support suggests a higher probability of clinical success for SMO-targeting drugs.
💡 Why activation?
- • Loss-of-function variants increase disease risk (OR > 1) — restoring function may help
- • 100% directional consistency across 1 traits
- • Strong signal in endocrine system disease, genetic, familial or congenital disease, musculoskeletal or connective tissue disease pathways
Cross-Disease Effects
Trade-off: LowDirection of Effect
100% alignedEvidence Across Diseases
8 totalGWAS and other genetic studies link SMO to 8 diseases.
Loss-of-function causes disease; activation may help
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
Three companies, Sun Pharma, Pfizer and Roche, have approved drugs targeting SMO.
The limited number of companies suggests relatively high barriers to entry in the SMO-targeting drug market.
Drug Modality Landscape
Modalities
Routes of Administration
Smoothened is amenable to small molecule drugs, with oral options available for convenient dosing.
The exclusive use of small molecules indicates a potential whitespace opportunity for alternative modalities like antibodies.
Clinical Trials 116 trials
Completion by Phase
| Phase | Total | Completed | Failed | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 43 | 32 | 7 | 4 | 82% |
| Phase 2 | 60 | 31 | 14 | 15 | 69% |
| Phase 3 | 8 | 7 | 1 | 0 | 88% |
| Phase 4 | 5 | 4 | 1 | 0 | 80% |
Top Sponsors
By Modality
Top Conditions
Drug Approval Timeline (2012 - 2018)
The first SMO-targeting drug was approved in 2012, with the most recent approval in 2018.
The approval timeline indicates a potentially maturing market with fewer near-term opportunities for novel SMO-targeting drugs.
Pro Intelligence Preview
Deep insights for drug target analysis
Competitive Landscape
- • 3 companies competing
- • Market share by company
Full Drug Portfolio
- • All 3 approved drugs
- • Approval dates & indications
Genetic Validation
- • Full genetic evidence table
- • Effect sizes & directions
Approval Timeline
- • Full 3-drug timeline
- • First-of-modality markers
Clinical Trials Analysis
- • Competition: High (15 sponsors)
- • White space: 10 underexplored indications
- • 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 61 clinical trials targeting Smoothened.
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