NET Inhibitors
7 drugsAbout NET
The norepinephrine transporter (NET), encoded by the SLC6A2 gene, regulates norepinephrine levels in the synapse by reuptaking it, effectively terminating its signaling. This protein plays a vital role in neurotransmission within the central nervous system.
NET is a drug target with moderate genetic support (max score 0.64) linking it to six diseases, including orthostatic intolerance. Loss-of-function variants are associated with increased risk of orthostatic intolerance, suggesting activation of NET may be beneficial.
Seven FDA-approved small molecule drugs target NET, including VENLAFAXINE HYDROCHLORIDE (Effexor XR), Pristiq, Fetzima, and Sunosi. These drugs are primarily used for CNS disorders, with some applications in pain management.
NET Genetic Evidence Moderate
Genetic evidence provides moderate support for NET's role in diseases like orthostatic intolerance (score 0.64).
Further investigation into activating NET may offer therapeutic opportunities for orthostatic intolerance.
💡 Why activation?
- • Loss-of-function variants increase disease risk (OR > 1) — restoring function may help
- • 100% directional consistency across 1 traits
- • Strong signal in cardiovascular disease, genetic, familial or congenital disease, nervous system disease pathways
Cross-Disease Effects
Trade-off: LowDirection of Effect
100% alignedEvidence Across Diseases
6 totalGWAS and other genetic studies link SLC6A2 to 6 diseases.
Loss-of-function causes disease; activation may help
🔗 Colocalization Evidence 3 strong
max H4: 0.99eQTL/pQTL signals for SLC6A2 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 NET Drugs
Seven companies have approved drugs targeting NET, including MEDICAP LABS and UPJOHN.
The presence of multiple players suggests a competitive market, requiring strong differentiation for new entrants.
| Drug | Company | Approved | Indications |
|---|---|---|---|
| VENLAFAXINE HYDROCHLORIDE | ORBION PHARMS | 2006 | 4 |
| LEVOMILNACIPRAN HYDROCHLORIDE | AMNEAL PHARMS | 2019 | 1 |
| FETZIMA | AbbVie | 2013 | 1 |
| PRISTIQ | PF PRISM CV | 2008 | 1 |
NET Drug Modality Landscape
Modalities
Routes of Administration
NET is amenable to small molecule drugs, with oral options available for convenient dosing.
Exploring alternative modalities like antibodies or gene therapies could provide differentiation in the NET-targeting space.
NET Clinical Trials 106 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on NET. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 13 | 13 | 0 | 0 | 100% |
| Phase 2 | 21 | 14 | 4 | 3 | 78% |
| Phase 3 | 34 | 23 | 2 | 9 | 92% |
| Phase 4 | 38 | 29 | 7 | 2 | 81% |
Top Sponsors
By Modality
Top Conditions
Top Drugs
NET Drug Approval Timeline (1997 - 2019)
The first NET-targeting drug was approved in 1997, with the most recent approval in 2019, spanning 23 years.
The relatively long approval span indicates sustained interest in NET as a target, but also potential saturation.
Pro Intelligence Preview
Deep insights for drug target analysis
Competitive Landscape
- • 7 companies competing
- • Market share by company
Full Drug Portfolio
- • All 7 approved drugs
- • Approval dates & indications
Genetic Validation
- • Full genetic evidence table
- • Effect sizes & directions
Approval Timeline
- • Full 7-drug timeline
- • First-of-modality markers
Clinical Trials Analysis
- • Sponsors: 64 (19 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 NET. A trial counts if an approved drug acting on NET 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.