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.
Smoothened 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 Smoothened 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.
Smoothened 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.
Smoothened Clinical Trials 95 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on Smoothened. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 32 | 23 | 6 | 2 | 79% |
| Phase 2 | 56 | 28 | 13 | 15 | 68% |
| Phase 3 | 4 | 3 | 1 | 0 | 75% |
| Phase 4 | 3 | 3 | 0 | 0 | 100% |
Top Sponsors
By Modality
Top Conditions
Smoothened 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
- • Sponsors: 45 (5 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 Smoothened. A trial counts if an approved drug acting on Smoothened 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.