A CRAC channel inhibitor in acute kidney injury: the KOURAGE mortality imbalance

What was tried

CalciMedica ran KOURAGE (NCT06374797), a randomized, quadruple-masked, placebo-controlled Phase 2 trial of Auxora, the intravenous formulation of zegocractin, in adults with Stage 2 or Stage 3 acute kidney injury and concurrent acute hypoxemic respiratory failure. Eligibility required a PaO2/FiO2 ratio at or below 300 in the prior 24 hours not explained by cardiogenic pulmonary edema or volume overload, plus active respiratory support at randomization. The primary endpoint was days alive, ventilator-free and kidney-replacement-therapy-free through Day 30, analyzed by the win ratio and Finkelstein-Schoenfeld methods.

The trial opened on 1 July 2024 and reached an actual enrollment of 122 against a planned 150 reported by Fierce Biotech. ClinicalTrials.gov records completion on 6 April 2026 and gives the reason for stopping as "The study was stopped due to imbalance in randomization stratification of severe patients." CalciMedica announced the discontinuation on 28 January 2026 following a recommendation from the independent data monitoring committee.

The biological hypothesis

ORAI1 (ENSG00000276045) encodes the pore-forming subunit of the calcium release-activated calcium channel, the dominant route for store-operated calcium entry in lymphocytes, neutrophils and epithelial cells. Open Targets classifies it within the Ca2+ release-activated Ca2+ channel family and flags a high-quality small-molecule ligand under its tractability assessment, which matches zegocractin (CHEMBL4753998, small molecule, maximum phase 2, also known as CM4620).

The preclinical case for blocking this channel in critical illness is real and multi-organ. Orai1 drives lymphocyte IL-17 expression and progressive kidney injury in mouse models (Mehrotra et al., J Clin Invest, 2019). Neutrophil-specific ORAI1 inhibition reduces pancreatitis-associated acute lung injury (Function, 2024). Selective Orai1 blockade resolves inflammation and clears bacteria in a pneumonia model (Am J Respir Crit Care Med, 2024). The lung-kidney "crosstalk" framing in the KOURAGE title follows directly from that body of work.

The human anchoring is thinner. Open Targets returns an overall ORAI1 to acute kidney injury association score of 0.0157 for MONDO_0002492, from a literature datatype score of 0.129 and no genetic evidence datatype.

What actually happened

CalciMedica disclosed that the IDMC identified a safety concern that warranted reevaluation of the study design, particularly the enrollment criteria. In its 3 March 2026 annual results the company characterized the finding as a mortality imbalance and stated that "The IDMC did not identify evidence of drug-related toxicity, and the Company's comprehensive review, performed in conjunction with external experts, reached the same conclusion." The company added that "imbalances in the patients' severity of disease at baseline may have contributed to the observed safety concern."

The January release stated that there were no deaths in the trial assessed by investigators or by CalciMedica as related to study drug, and that no serious adverse events met FDA expedited reporting criteria. No arm-level mortality counts, endpoint estimates, win ratios or confidence intervals have been released. The stock closed at $1.25on28January2026againstapriorcloseof$5.12. Cash stood at $13.0 million at the end of 2025, sufficient into the fourth quarter of 2026.

Failure mechanism, best guess

The archetype here is a safety signal, and the most defensible reading is that the signal was generated by population construction rather than by pharmacology.

Zegocractin's one clean efficacy readout came from CARPO, a 216-patient Phase 2b trial in acute pancreatitis reported on 27 June 2024. Benefit was confined to a hyper-inflammation subgroup of roughly 43 percent of participants, where median time to solid food tolerance improved by 1.5, 2.1 and 1.9 days at the 0.5, 1.0 and 2.0 mg/kg doses against a placebo median of 4.7 days. CalciMedica reported no measurable benefit in non-hyper-inflamed patients. That subgroup contained about 92 randomized patients across four arms.

KOURAGE did not carry that enrichment forward. It enrolled all-comers meeting a severity and oxygenation floor. Applying the CARPO hyper-inflammation prevalence of 43 percent to KOURAGE's 122 randomized patients gives roughly 52 patients with the phenotype in which the drug had previously shown an effect, or about 26 per arm before any stratification. Inputs: 122 actual enrollment from ClinicalTrials.gov and 43 percent from the CARPO topline release. A trial that small, in a population with high background mortality and wide baseline severity, is one in which a chance imbalance in baseline severity across arms can produce a mortality difference large enough to stop it. Both the sponsor's own conclusion and the ClinicalTrials.gov stop reason point in exactly that direction.

How to prevent this next time

No endpoint-level data has been released, so a quantitative reanalysis is not possible and none is attempted here. The qualitative levers are the ones that apply.

Biomarker enrichment is the first. The CARPO result was a subgroup result, and a subgroup result is a hypothesis about who to enroll, not a license to enroll everyone. An explicit hyper-inflammation entry criterion would have concentrated the treatment effect and narrowed the severity spread that later confounded the safety review.

Base-rate adjustment is the second. Critical care trials in Stage 2 to 3 AKI with respiratory failure run against high and heterogeneous mortality. At 122 patients, KOURAGE had enough events to trigger a monitoring signal and not enough to interpret one. Sizing and stratification should be set against the observed baseline severity distribution rather than a nominal target.

A red-team review is the third. A pre-specified plan for adjudicating a mortality imbalance under a hierarchical win-ratio endpoint would have let the IDMC separate a severity artifact from a drug effect while the trial was still running, rather than leaving that question to an unblinded post-hoc review.

The single highest leverage change would have been to carry the CARPO hyper-inflammation entry criterion into KOURAGE as a randomization-gating biomarker rather than as an exploratory subgroup.

What this means for similar programs

Store-operated calcium entry remains a drug-like target class, and the tractability assessment supports that. The caution is directional rather than about the channel. Programs inhibiting a broadly expressed immune signaling node in critical illness inherit a base-rate problem: the same channel that drives injurious inflammation also supports host defense, and at least one report finds that Orai1 overexpression improves sepsis-induced T-lymphocyte immunosuppression and organ dysfunction (doi:10.1016/j.heliyon.2022.e12082). Directional ambiguity of that kind is a reason to enrich, not to broaden.

The Claidex Mechanism Risk Score for ORAI1 in acute kidney injury is 38 out of 100, in the yellow band. The score is driven mainly by weak genetic anchoring rather than by an accumulated failure record: this is the first ORAI1 program in the Claidex graph.

Open questions

What was the mortality split by arm, and did it survive adjustment for baseline severity? Was randomization stratified by severity as designed, and if so where did the stratification break? Did any KOURAGE participants meet the CARPO hyper-inflammation definition, and did they behave differently?

Sources

1. ClinicalTrials.gov, NCT06374797, KOURAGE, Phase 2, terminated. https://clinicaltrials.gov/study/NCT06374797.

2. CalciMedica, "Announces Discontinuation of Phase 2 KOURAGE Trial in AKI Following Independent Data Monitoring Committee Recommendation," 28 January 2026.

3. CalciMedica, "Reports 2025 Financial Results and Provides Clinical Updates," 3 March 2026.

4. CalciMedica, "Announces Positive Topline Data from Phase 2b CARPO Trial," 27 June 2024.

5. Fierce Biotech, "CalciMedica stock craters as calcium channel inhibitor trial stopped over safety concern," 28 January 2026.

6. Clinical Trials Arena, "CalciMedica's stock drops 75% on acute kidney injury trial termination," January 2026.

7. Open Targets Platform API v4, target ENSG00000276045, disease MONDO_0002492, accessed 2 September 2026.

8. ChEMBL, zegocractin, CHEMBL4753998.

9. Mehrotra P, et al. Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury. J Clin Invest. 2019.

10. Niu M, et al. Neutrophil-specific ORAI1 calcium channel inhibition reduces pancreatitis-associated acute lung injury. Function (Oxf). 2024.

11. Peng S, et al. ORAI1 CRAC channel in immune cells is a therapeutic target for pancreatitis-associated acute lung injury. Function (Oxf). 2024.

12. Ahmad S, et al. Specific inhibition of Orai1-mediated calcium signalling resolves inflammation and clears bacteria. Am J Respir Crit Care Med. 2024.

13. Chen L, et al. Orai1 overexpression improves sepsis-induced T-lymphocyte immunosuppression and acute organ dysfunction. Heliyon. 2022.