Phenylalanine Hydroxylase Inhibitors
5 drugsAbout Phenylalanine Hydroxylase
Phenylalanine Hydroxylase (PAH) is an enzyme responsible for breaking down phenylalanine, an essential amino acid, and its dysfunction leads to metabolic disorders.
PAH is a strong therapeutic target, supported by genetic evidence linking it to phenylketonuria (score 0.99) and hyperphenylalaninemia (score 0.90). Loss-of-function variants increase disease risk, suggesting activation may be beneficial.
Four FDA-approved drugs target PAH: SAPROPTERIN DIHYDROCHLORIDE, KUVAN, PALYNZIQ, and ZELVYSIA. These include small molecules (3 drugs) and other biologics (1 drug), developed by Aurobindo Pharma, BIOMARIN PHARM, and AUCTA.
Phenylalanine Hydroxylase Genetic Evidence Strong
PAH has strong genetic support with a max score of 0.99 linking it to phenylketonuria.
Strong genetic support increases the probability of clinical success for PAH-targeting drugs.
💡 Why activation?
- • Loss-of-function variants increase disease risk (OR > 1) — restoring function may help
- • 67% directional consistency across 3 traits
- • Strong signal in nutritional or metabolic disease, genetic, familial or congenital disease pathways
Cross-Disease Effects
Trade-off: ModerateDirection of Effect
67% alignedEvidence Across Diseases
20 totalGWAS and other genetic studies link PAH to 47 diseases.
Activating this target may be therapeutic
Loss-of-function causes disease; activation may help
🔗 Colocalization Evidence 20 strong
max H4: 0.99eQTL/pQTL signals for PAH 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 Phenylalanine Hydroxylase Drugs
Three companies, including Aurobindo Pharma and BIOMARIN PHARM, have approved drugs targeting PAH.
The concentrated market may present entry barriers for new companies.
| Drug | Company | Approved | Indications |
|---|---|---|---|
| SAPROPTERIN DIHYDROCHLORIDE | PH HEALTH | 2019 | 2 |
| ZELVYSIA | AUCTA | 2025 | 2 |
Phenylalanine Hydroxylase Drug Modality Landscape
Modalities
Routes of Administration
Phenylalanine Hydroxylase is druggable by both biologics (1) and small molecules (4), indicating broad therapeutic accessibility.
The dominance of small molecules suggests an opportunity for novel biologic modalities.
📈 Modality Evolution
Small molecules pioneered Phenylalanine Hydroxylase targeting (2007), with other biologics entering more recently (2018).
Phenylalanine Hydroxylase Clinical Trials 28 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on Phenylalanine Hydroxylase. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 7 | 6 | 0 | 1 | 100% |
| Phase 2 | 8 | 4 | 4 | 0 | 50% |
| Phase 3 | 7 | 5 | 0 | 2 | 100% |
| Phase 4 | 6 | 4 | 1 | 1 | 80% |
Top Sponsors
By Modality
Top Conditions
Phenylalanine Hydroxylase Drug Approval Timeline (2007 - 2025)
The first drug targeting PAH was approved in 2007, with the most recent in 2025.
The recent approval suggests continued innovation and market potential in this area.
Pro Intelligence Preview
Deep insights for drug target analysis
Competitive Landscape
- • 4 companies competing
- • Market share by company
Full Drug Portfolio
- • All 5 approved drugs
- • Approval dates & indications
Genetic Validation
- • Full genetic evidence table
- • Effect sizes & directions
Approval Timeline
- • Full 5-drug timeline
- • First-of-modality markers
Clinical Trials Analysis
- • Sponsors: 16 (3 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 Phenylalanine Hydroxylase. A trial counts if an approved drug acting on Phenylalanine Hydroxylase 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.