Targeting pulmonary vascular disease and right-ventricular dysfunction.
CalciMedica is investigating CRAC channel inhibition to address pulmonary vascular disease and preserve right-ventricular function. Intravenous Auxora is advancing toward clinical proof-of-concept in PAH, while oral CM5480 is in development for PAH and CpcPH-HFpEF.
High pressure persists. The right ventricle remains at risk.
Existing therapies focus on lowering pulmonary pressure, yet pressure can remain elevated even with combination treatment. The right ventricle’s ability to withstand this load is a major determinant of prognosis.
The unmet need
Our initial focus: pulmonary arterial hypertension (PAH) and combined post- and pre-capillary PH in heart failure with preserved ejection fraction (CpcPH-HFpEF).
Lower the pressure. Protect the right ventricle.
CRAC channel inhibition has the potential to do both: reduce pulmonary pressure and directly protect RV function.
Lower pulmonary pressure
Reduced pulmonary vascular resistance, pressure, and remodeling in preclinical models.
Directly protect RV function
Improved RV function and reduced remodeling in preclinical models where pressure overload is maintained.
A distinct pathway. Potential for added benefit.
Pathway studies support CRAC channel signaling as distinct from the pathways targeted by existing PAH therapies, providing a rationale for additive benefit alongside those treatments.
CRAC channel components are upregulated in human pulmonary vascular and cardiac disease.
Human tissue studies show upregulation in the pulmonary arteries and veins, right ventricle, and left ventricle.
Pulmonary arteries (PAH)
Orai1 is upregulated in pulmonary arteries from patients with pulmonary arterial hypertension.
Pulmonary veins (PVOD)
Orai1 is upregulated in pulmonary veins from patients with pulmonary veno-occlusive disease.
Right ventricle (PAH)
STIM1L, a CRAC channel regulator, is upregulated in right-ventricular tissue from patients with PAH.
Left ventricle (heart failure)
Orai1 is upregulated in left-ventricular fibroblasts from patients with heart failure.
Evidence across the pulmonary vasculature and the heart.
Five complementary models examine CRAC channel inhibition in pulmonary vascular disease and in the heart under pressure overload.
Positive results across five complementary models
- Monocrotaline (MCT)
- Sugen/hypoxia
- Chronic hypoxia
- Pulmonary artery banding (PAB)
- Transverse aortic constriction (TAC)
MCT and PAB studies evaluated CM5480; Sugen/hypoxia, chronic hypoxia, and TAC studies used Orai1 tool compounds. PAB and TAC isolate cardiac pressure overload.
Direct RV pressure overload
Direct RV effects beyond pulmonary vasodilation.
In a pulmonary artery banding model that isolates right-ventricular pressure overload from pulmonary vascular disease, CM5480 improved RV systolic and diastolic function and reduced hypertrophy and fibrosis. These findings support the potential for direct cardiac protection, independent of pulmonary vascular effects.
Integrated pulmonary vascular and cardiac effects.
In the MCT rat PAH model, CM5480 reduced pulmonary vascular resistance and remodeling, improved cardiac output, and reduced right-ventricular remodeling.
Reduced PVR
CM5480 reduced pulmonary vascular resistance.
Reduced vascular remodeling
CM5480 reduced muscularization and remodeling of pulmonary vessels.
Improved cardiac output
CM5480 improved cardiac output.
Reduced RV remodeling
CM5480 reduced right-ventricular hypertrophy and remodeling.
Additive with standard-of-care vasodilators
Preserving left-ventricular function under pressure overload.
The Orai1 tool compound JPIII preserved left-ventricular systolic function and reduced fibrotic gene expression in mice subjected to pressure overload. These findings extend the cardiac rationale to the left ventricle and support further investigation in PH associated with left-heart disease.
- LV ejection fraction
- 71.2% vs. 56.9%
- JPIII vs. vehicle · p=0.001
- LV end-systolic volume
- 0.044 vs. 0.089 mL
- JPIII vs. vehicle · p=0.003
Between-group comparisons at eight weeks, after five weeks of pressure overload and three weeks of treatment; five mice per TAC group.
Published sources: Saint-Martin Willer et al., JCI Insight (2025) (opens in a new tab); Masson et al., Circulation Research (2022) (opens in a new tab); Bartoli et al., Circulation (2020) (opens in a new tab).
Pulmonary artery banding data: INSERM (Antigny & Sabourin), unpublished and shared with permission.
Auxora Phase 1b data expected in mid-2027.
The planned Auxora Phase 1b study will evaluate CRAC channel inhibition in PAH and inform development of oral CM5480 for chronic treatment in PAH and CpcPH-HFpEF.
- 2H 2026
Auxora PAH Phase 1b IND submission
IND submission anticipated for the planned Auxora Phase 1b proof-of-concept study in PAH.
- Mid-2027
Auxora PAH Phase 1b data
- Approximately 10 patients with functional class II–III PAH
- Five-day intravenous treatment course
- Right- and left-ventricular hemodynamics assessed through right heart catheterization (RHC), echocardiography, cardiac MRI, and biomarkers
- Mid-2027
CM5480 IND submission
IND submission anticipated for CM5480, a next-generation oral CRAC channel inhibitor designed for chronic treatment.
- Potential follow-on
Auxora in hospitalized pulmonary hypertension
Potential follow-on development in hospitalized PH populations, including CpcPH-HFpEF.
Strategic objectives
- Generate initial human proof-of-concept for CRAC channel inhibition in PAH
- Inform clinical development of CM5480 in PAH and other PH groups
- Evaluate Auxora as a potential IV therapy in hospitalized PH populations