Neprilysin Inhibitors
3 drugsAbout Neprilysin
Neprilysin, also known as neutral endopeptidase (NEP), is a zinc-dependent metalloprotease that degrades various endogenous peptides, including natriuretic peptides. By degrading these peptides, neprilysin impacts vasodilation and sodium excretion.
Human genetic studies provide strong validation for neprilysin as a therapeutic target (max score 0.92). Loss-of-function variants are associated with diseases like Charcot-Marie-Tooth disease axonal type 2T (score 0.92) and spinocerebellar ataxia 43 (score 0.80), suggesting activation may be beneficial.
Neprilysin is targeted by three FDA-approved small molecule drugs, including SACUBITRIL AND VALSARTAN (ENTRESTO). These drugs, developed by Novartis and TORRENT, are approved for cardiovascular indications.
Neprilysin Genetic Evidence Strong
Neprilysin has strong genetic support with a maximum score of 0.92 across 26 diseases.
Strong genetic support suggests a higher probability of clinical success for neprilysin-targeting drugs.
💡 Why activation?
- • Loss-of-function variants increase disease risk (OR > 1) — restoring function may help
- • 100% directional consistency across 2 traits
- • Strong signal in nervous system disease, phenotype, genetic, familial or congenital disease pathways
Cross-Disease Effects
Trade-off: LowDirection of Effect
100% alignedEvidence Across Diseases
20 totalGWAS and other genetic studies link MME to 26 diseases.
Loss-of-function causes disease; activation may help
🔗 Colocalization Evidence 20 strong
max H4: 1.00eQTL/pQTL signals for MME 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 Neprilysin Drugs
The competitive landscape is dominated by Novartis and TORRENT, with approved drugs.
The presence of only two companies suggests relatively high barriers to entry in this market.
Neprilysin Drug Modality Landscape
Modalities
Routes of Administration
Neprilysin is amenable to small molecule drugs, with oral options available for convenient dosing.
The modality landscape suggests an opportunity to explore alternative modalities like antibodies or peptides.
Neprilysin Clinical Trials 135 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on Neprilysin. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 17 | 12 | 0 | 5 | 100% |
| Phase 2 | 29 | 19 | 6 | 4 | 76% |
| Phase 3 | 32 | 19 | 6 | 7 | 76% |
| Phase 4 | 57 | 37 | 9 | 11 | 80% |
Top Sponsors
By Modality
Top Conditions
Top Drugs
Neprilysin Drug Approval Timeline (2015 - 2024)
The first drug targeting neprilysin was approved in 2015, with the most recent approval in 2024.
The recent approval indicates continued interest and potential for further development in this area.
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Competitive Landscape
- • 2 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: 90 (18 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 Neprilysin. A trial counts if an approved drug acting on Neprilysin 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.