Sigma-1 receptor Inhibitors
3 drugsAbout Sigma-1 receptor
The Sigma-1 receptor (σ1R) is an endoplasmic reticulum chaperone protein that modulates calcium signaling, protein folding, and receptor trafficking. Its diverse functions make it a compelling target for drug development.
Human genetic studies provide strong validation for SIGMAR1 as a therapeutic target (max score 0.84), with variants linked to familial amyotrophic lateral sclerosis and other motor neuron diseases. Loss-of-function variants are associated with increased disease risk, suggesting activation may be beneficial.
Three FDA-approved drugs target Sigma-1 receptor: dextromethorphan hydrobromide and quinidine sulfate (NUEDEXTA) and AUVELITY, all small molecules. These drugs span CNS and other therapeutic areas.
Sigma-1 receptor Genetic Evidence Strong
SIGMAR1 has strong genetic support with a max score of 0.84 linking it to familial amyotrophic lateral sclerosis.
The strong genetic support suggests a higher probability of clinical success for SIGMAR1-targeting drugs.
💡 Why activation?
- • Loss-of-function variants increase disease risk (OR > 1) — restoring function may help
- • 100% directional consistency across 3 traits
- • Strong signal in nervous system disease, genetic, familial or congenital disease, phenotype pathways
Cross-Disease Effects
Trade-off: LowDirection of Effect
100% alignedEvidence Across Diseases
7 totalGWAS and other genetic studies link SIGMAR1 to 7 diseases.
Loss-of-function causes disease; activation may help
Loss-of-function causes disease; activation may help
🔗 Colocalization Evidence 9 strong
max H4: 0.99eQTL/pQTL signals for SIGMAR1 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 Sigma-1 receptor Drugs
Three companies, including HETERO LABS LTD III, AVANIR PHARMS, and AXSOME, have approved drugs targeting Sigma-1 receptor.
The limited number of players suggests relatively low barriers to entry in this market.
Sigma-1 receptor Drug Modality Landscape
Modalities
Routes of Administration
Sigma-1 receptor is amenable to small molecule drugs, with oral options available for convenient dosing.
Exploring alternative modalities like antibodies or peptides could offer a competitive advantage.
Sigma-1 receptor Clinical Trials 161 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on Sigma-1 receptor. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 73 | 63 | 3 | 7 | 95% |
| Phase 2 | 31 | 25 | 4 | 2 | 86% |
| Phase 3 | 20 | 12 | 3 | 5 | 80% |
| Phase 4 | 37 | 23 | 11 | 3 | 68% |
Top Sponsors
By Modality
Top Conditions
Top Drugs
Sigma-1 receptor Drug Approval Timeline (2010 - 2022)
Pseudobulbar Affect
The first drug was approved in 2010 (NUEDEXTA), and the most recent in 2022 (AUVELITY), spanning 13 years.
The recent approval suggests renewed interest and potential for further development in this area.
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Competitive Landscape
- • 3 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: 100 (37 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 Sigma-1 receptor. A trial counts if an approved drug acting on Sigma-1 receptor 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.