M2 Inhibitors
6 drugsAbout M2
The M2 receptor (CHRM2) is a muscarinic acetylcholine receptor involved in physiological processes like smooth muscle contraction. As a G protein-coupled receptor, it mediates the effects of acetylcholine in various tissues. Its activation impacts functions ranging from heart rate to glandular secretion.
Human genetics provide moderate support for M2 as a drug target, with a max genetic score of 0.56 linked to risk-taking behaviour. Variants in CHRM2 are associated with 35 diseases, including hypertrophic cardiomyopathy (0.52) and rheumatoid arthritis (0.48). Strong eQTL/pQTL signals further support its role in disease.
M2 is targeted by 5 FDA-approved drugs, all of which are small molecules, including INCRUSE ELLIPTA, SPIRIVA RESPIMAT and YUPELRI. Four drugs are for respiratory conditions, while one (DARIFENACIN HYDROBROMIDE) addresses other therapeutic areas. GSK and Boehringer Ingelheim are key players.
M2 Genetic Evidence Moderate
Genetic evidence offers moderate support for M2, with a maximum score of 0.56.
Further research is needed to validate M2 as a target for genetically-supported indications.
Evidence Across Diseases
20 totalGWAS and other genetic studies link CHRM2 to 35 diseases.
🔗 Colocalization Evidence 5 strong
max H4: 1.00eQTL/pQTL signals for CHRM2 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 M2 Drugs
Five companies have approved drugs targeting M2, including GSK and Boehringer Ingelheim.
The presence of multiple players suggests moderate competition, requiring strong IP to succeed.
| Drug | Company | Approved | Indications |
|---|---|---|---|
| SPIRIVA RESPIMAT | Boehringer Ingelheim | 2014 | 2 |
| TUDORZA PRESSAIR | AZURITY | 2012 | 1 |
| INCRUSE ELLIPTA | GSK | 2014 | 1 |
M2 Drug Modality Landscape
Modalities
Routes of Administration
M2 is druggable by small molecules, though no oral formulations are currently approved.
Exploring alternative modalities like antibodies or peptides could provide differentiation.
M2 Clinical Trials 179 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on M2. 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
M2 Drug Approval Timeline (2012 - 2023)
The approval timeline spans 7 years, from 2012 (TUDORZA PRESSAIR) to 2018 (YUPELRI).
The recent approval of YUPELRI suggests continued interest in M2, but market saturation may be a concern.
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 M2. A trial counts if an approved drug acting on M2 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.