Glucosylceramide synthase Inhibitors
4 drugsAbout Glucosylceramide synthase
Glucosylceramide synthase (GCS) catalyzes the first committed step in glucosylceramide synthesis, a precursor to complex glycosphingolipids. These lipids are crucial for cell signaling, membrane structure, and cellular interactions.
Human genetic studies provide moderate support for GCS as a therapeutic target, with variants linked to second degree atrioventricular block (score 0.53) and visual impairment (score 0.51). Strong eQTL/pQTL signals (max H4: 0.99) further support the rationale.
Four FDA-approved small molecule drugs inhibit GCS, including MIGLUSTAT, CERDELGA, YARGESA, and ZAVESCA. These drugs are used to treat rare diseases, highlighting the potential of GCS inhibition.
Glucosylceramide synthase Genetic Evidence Moderate
Genetic evidence offers moderate support, with a max score of 0.53 linking GCS to second degree atrioventricular block.
Further investigation into the causal link between GCS and these genetically-supported diseases could expand therapeutic applications.
Evidence Across Diseases
11 totalGWAS and other genetic studies link UGCG to 11 diseases.
🔗 Colocalization Evidence 11 strong
max H4: 0.99eQTL/pQTL signals for UGCG 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 Glucosylceramide synthase Drugs
Four companies have approved GCS-targeting drugs, including NAVINTA LLC, Sanofi, EDENBRIDGE PHARMS, and ACTELION.
The presence of multiple players suggests a competitive market, requiring a differentiated approach for new entrants.
| Drug | Company | Approved | Indications |
|---|---|---|---|
| YARGESA | EDENBRIDGE PHARMS | 2020 | 1 |
Glucosylceramide synthase Drug Modality Landscape
Modalities
Routes of Administration
Glucosylceramide synthase is amenable to small molecule drugs, with oral options available for convenient dosing.
Exploring alternative modalities like antibodies or gene therapies could provide a competitive advantage and novel therapeutic options.
Glucosylceramide synthase Clinical Trials 31 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on Glucosylceramide synthase. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 12 | 10 | 1 | 1 | 91% |
| Phase 2 | 6 | 4 | 0 | 2 | 100% |
| Phase 3 | 11 | 7 | 1 | 3 | 88% |
| Phase 4 | 2 | 1 | 1 | 0 | 50% |
Top Sponsors
By Modality
Top Conditions
Phase 3 Readout Calendar Pro
1 Phase 3 trial testing approved Glucosylceramide synthase drugs across all sponsors.
Coverage: trials whose intervention is an approved drug targeting Glucosylceramide synthase. Pre-approval candidates with development codes (e.g. AZD0901, MK-7240) are not yet linked. Anchored on CT.gov primary completion date.
Glucosylceramide synthase Drug Approval Timeline (2003 - 2020)
The first GCS inhibitor was approved in 2003 (ZAVESCA), with the most recent approval in 2020 (YARGESA).
The approval timeline indicates a sustained interest in GCS inhibition, but potential saturation warrants careful market analysis.
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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: 14 (4 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 Glucosylceramide synthase. A trial counts if an approved drug acting on Glucosylceramide synthase 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.