M4 Inhibitors
6 drugsAbout M4
The M4 receptor, a member of the muscarinic acetylcholine receptor family, modulates neuronal signaling. Its mechanism of action is complex, but it plays a role in various therapeutic areas.
Human genetic studies provide moderate support for M4 as a therapeutic target, with variants linked to hypertension (score 0.51) and schizophrenia (score 0.38). Activation of M4 is likely beneficial based on genetic evidence.
M4 is targeted by five FDA-approved small molecule drugs, including INCRUSE ELLIPTA, DARIFENACIN HYDROBROMIDE, and SPIRIVA RESPIMAT. These drugs are primarily used for respiratory diseases, with some applications in other therapeutic areas.
M4 Genetic Evidence Moderate
Genetic evidence provides moderate support for M4, with a maximum score of 0.51 for hypertension.
Moderate genetic support suggests further investigation into M4's role in hypertension may be warranted.
💡 Why activation?
- • Loss-of-function variants increase disease risk (OR > 1) — restoring function may help
- • 50% directional consistency across 2 traits
- • Strong signal in psychiatric disorder, nervous system disease pathways
Cross-Disease Effects
Trade-off: ModerateDirection of Effect
50% alignedEvidence Across Diseases
20 totalGWAS and other genetic studies link CHRM4 to 29 diseases.
Activating this target may be therapeutic
🔗 Colocalization Evidence 20 strong
max H4: 1.00eQTL/pQTL signals for CHRM4 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 M4 Drugs
Five companies have approved drugs targeting M4, including GSK, Alembic, and Boehringer Ingelheim.
The presence of multiple established players indicates a moderately competitive market.
| Drug | Company | Approved | Indications |
|---|---|---|---|
| SPIRIVA RESPIMAT | Boehringer Ingelheim | 2014 | 2 |
| TUDORZA PRESSAIR | AZURITY | 2012 | 1 |
| INCRUSE ELLIPTA | GSK | 2014 | 1 |
M4 Drug Modality Landscape
Modalities
Routes of Administration
M4 is druggable by small molecules, though no oral formulations are currently approved.
Exploring alternative modalities like antibodies or peptides could provide a competitive advantage.
M4 Clinical Trials 179 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on M4. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 19 | 17 | 1 | 1 | 94% |
| Phase 2 | 35 | 31 | 4 | 0 | 89% |
| Phase 3 | 69 | 66 | 2 | 1 | 97% |
| Phase 4 | 56 | 46 | 6 | 4 | 88% |
Top Sponsors
By Modality
Top Conditions
Top Drugs
M4 Drug Approval Timeline (2012 - 2023)
The first drug targeting M4 was approved in 2012, and the most recent in 2018, spanning 7 years.
The relatively short approval span suggests potential for further development and innovation in this area.
Pro Intelligence Preview
Deep insights for drug target analysis
Competitive Landscape
- • 6 companies competing
- • Market share by company
Full Drug Portfolio
- • All 6 approved drugs
- • Approval dates & indications
Genetic Validation
- • Full genetic evidence table
- • Effect sizes & directions
Approval Timeline
- • Full 6-drug timeline
- • First-of-modality markers
Clinical Trials Analysis
- • Sponsors: 51 (27 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 M4. A trial counts if an approved drug acting on M4 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.