4-hydroxyphenyl-pyruvate dioxygenase Inhibitors
4 drugsAbout 4-hydroxyphenyl-pyruvate dioxygenase
4-Hydroxyphenyl-pyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate, a crucial step in tyrosine catabolism. This enzyme's role in tyrosine metabolism makes it relevant to various metabolic disorders.
Human genetic studies provide strong validation for HPPD as a therapeutic target, with variants linked to hawkinsinuria (score 0.93) and tyrosinemia (scores 0.91, 0.89). Loss-of-function variants are associated with increased disease risk, suggesting activation may be beneficial.
HPPD is targeted by three FDA-approved small molecule drugs: NITISINONE, NITYR, and ORFADIN. These drugs are currently classified under "Other" therapeutic areas, demonstrating the feasibility of modulating HPPD activity.
4-hydroxyphenyl-pyruvate dioxygenase Genetic Evidence Strong
HPPD has strong genetic support with a maximum score of 0.93 across 12 diseases.
Strong genetic support suggests HPPD-targeting therapies have a higher probability of clinical success.
💡 Why activation?
- • Loss-of-function variants increase disease risk (OR > 1) — restoring function may help
- • 100% directional consistency across 3 traits
- • Strong signal in nutritional or metabolic disease, genetic, familial or congenital disease pathways
Cross-Disease Effects
Trade-off: LowDirection of Effect
100% alignedEvidence Across Diseases
12 totalGWAS and other genetic studies link HPD to 12 diseases.
Loss-of-function causes disease; activation may help
Loss-of-function causes disease; activation may help
🔗 Colocalization Evidence 20 strong
max H4: 1.00eQTL/pQTL signals for HPD 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 4-hydroxyphenyl-pyruvate dioxygenase Drugs
The competitive landscape includes three companies with approved drugs: MEDUNIK, CYCLE, and SWEDISH ORPHAN.
The small number of companies indicates relatively low market concentration and potentially lower entry barriers.
4-hydroxyphenyl-pyruvate dioxygenase Drug Modality Landscape
Modalities
Routes of Administration
4-hydroxyphenyl-pyruvate dioxygenase is amenable to small molecule drugs, with oral options available for convenient dosing.
The exclusive use of small molecules suggests an opportunity to explore other modalities like antibodies or biologics.
4-hydroxyphenyl-pyruvate dioxygenase Clinical Trials 11 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on 4-hydroxyphenyl-pyruvate dioxygenase. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 8 | 8 | 0 | 0 | 100% |
| Phase 2 | 2 | 2 | 0 | 0 | 100% |
| Phase 3 | 1 | 1 | 0 | 0 | 100% |
Top Sponsors
By Modality
Top Conditions
Top Drugs
4-hydroxyphenyl-pyruvate dioxygenase Drug Approval Timeline (2002 - 2019)
The first HPPD-targeting drug was approved in 2002, with the most recent approval in 2019, spanning 18 years.
The approval timeline suggests a sustained interest in HPPD as a drug target, but may be approaching saturation.
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Competitive Landscape
- • 3 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: 5 (2 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 4-hydroxyphenyl-pyruvate dioxygenase. A trial counts if an approved drug acting on 4-hydroxyphenyl-pyruvate dioxygenase 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.