01The science

Targeting pathologic CRAC channel signaling.

CRAC channel signaling is mediated by Orai1 channels activated by STIM1, a calcium sensor in the endoplasmic reticulum. In disease, persistent CRAC channel signaling can contribute to inflammatory activation, direct tissue injury, microvascular dysfunction, and vascular and ventricular remodeling.

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02Normal signaling

How normal CRAC channel signaling works.

In healthy cells, CRAC channels open when internal calcium stores run low, producing a localized calcium signal that is tightly regulated and self-limited.

01
Calcium sensing
STIM1 detects calcium depletion within the endoplasmic reticulum.
02
Channel activation
STIM1 engages Orai1 at the plasma membrane, opening the CRAC channel and permitting calcium entry.
03
Cellular response
Calcium entry replenishes stores within the endoplasmic reticulum and supports tightly regulated programs including activation, secretion, migration, repair, and gene regulation.

FIG. 1 — STORE-OPERATED CALCIUM ENTRYORAI1 / STIM1

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Resting state

Calcium stores are maintained and Orai1 remains closed.

Adapted from Roos et al., J Cell Biol. 2005; Zhang et al., Nature. 2005; Zhang et al., PNAS. 2006.

03Disease biology

Persistent CRAC channel signaling in disease.

Persistent receptor activation and cellular stress can sustain Orai1-mediated calcium influx, engaging downstream pathways associated with inflammation, tissue injury, microvascular dysfunction, and remodeling.

Disease context

Persistent receptor activation and cellular stress can sustain CRAC channel opening.

Sustained calcium influx

Continued Orai1-mediated calcium entry creates a persistent intracellular calcium signal.

Downstream response

Excess calcium activates calcineurin/NFAT and NF-κB signaling, promotes mitochondrial stress, and alters pathways controlling vascular integrity and tissue remodeling.

Downstream consequences

Inflammatory activation

Persistent signaling can amplify cytokine production and immune-cell activation.

Direct tissue injury

Sustained calcium signaling can contribute to direct injury in organ tissues.

Barrier and microvascular dysfunction

CRAC channel signaling can disrupt endothelial barrier function and microvascular integrity.

Vascular and ventricular remodeling

Chronic signaling can contribute to pathologic remodeling in the vasculature and heart.

Therapeutic approach

CalciMedica's compounds are designed to inhibit persistent Orai1-mediated calcium entry upstream of these disease-associated cellular responses.

04Drug candidates

Two candidates spanning hospital-based and chronic treatment settings.

Auxora is a clinical-stage intravenous candidate for hospital-based use. CM5480 is an oral candidate in preclinical and IND-enabling development for chronic treatment.

Auxora

zegocractin

Clinical-stage · IV

4-hour infusion · 3–5 days per course

Clinical experience

Evaluated in multiple Phase 2 studies across acute pancreatitis, severe COVID-19 pneumonia, and acute kidney injury
More than 350 patients exposed across the clinical program

Translational evidence

Clinical biomarker analyses showed normalization of IL-6, TNF-α, and IL-17
Improvements observed in markers of endothelial injury and microcoagulation, including D-dimer, Ang-1, and Ang-2

Development status

PAH Phase 1b IND submission anticipated 2H 2026; data anticipated mid-2027
FDA-aligned design for a planned Phase 2b study in acute pancreatitis; initiation subject to additional funding

CM5480

selective, potent oral CRAC channel inhibitor

Preclinical · Oral

IND-enabling · designed for chronic dosing

Preclinical evidence

Improved pulmonary vascular and right-ventricular measures in preclinical PAH models
Preclinical activity observed in models of rheumatoid arthritis, ulcerative colitis, asthma, and chronic pancreatitis

Pharmacology

Anti-inflammatory, tissue-protective, and antiproliferative activity in preclinical studies
Pharmacokinetics, dosing, and toxicology evaluated in three species (unpublished)

Development status

Preclinical, formulation, and IND-enabling studies ongoing in pulmonary hypertension
IND submission anticipated mid-2027

05Selected research

Research supporting CRAC channel biology and therapeutic development.

Selected peer-reviewed studies span foundational Orai1/STIM1 biology, pulmonary vascular and ventricular remodeling, and disease-relevant preclinical models.

Preclinical2025