Zegocractin Significantly Improves Acute Pancreatitis Symptoms in Phase 2 CARPO

Robert Sutton, BA, MBBS, DPhil

Credit: LinkedIn

Calcium release-activated calcium (CRAC) channel inhibitor zegocractin (Auxora) may decrease the time to solid food tolerate, along with other symptom relief, in patients with acute pancreatitis, according to new data presented at the American College of Gastroenterology (ACG) 2024 Scientific Sessions in Philadelphia, PA, this weekend.¹

In a late-breaking abstract presented at ACG 2024, a multinational team of investigators reported that various assessed doses of zegocractin provided earlier median hours to food tolerance in patients with acute pancreatitis, whereas higher doses of the CRAC channel inhibitor from CalciMedica resulted in no new cases of severe respiratory failure. The findings from the dose-ranging phase 2b CARPO trial may support further late-stage assessment for zegocractin.

Investigators led by Robert Sutton, BA, MBBS, DPhil, of the Liverpool Pancreatitis Research Group, University of Liverpool, sought to evaluate dose response with zegocractin on key outcomes for acute pancreatitis in patients with systemic inflammatory response syndrome (SIRS). As they explained, overactive CRAC channels contribute to acute pancreatitis, a condition predominately driven by gallstones and excessive alcohol consumption. The multi-pathway targeting capability of zegocractin could make it a viable option for affected patients.

“CARPO has added significantly to the body of evidence showing Auxora's potential as an effective treatment for critically ill patients with acute inflammatory disease and warrants advancing our drug in both (acute pancreatitis) and acute kidney injury," Rachel Leheny, PhD, Chief Executive Officer of CalciMedica, recently said in a press release.²

Sutton and colleagues randomized 216 patients with acute pancreatitis and >2 criteria items for SIRS to 1 of 4 treatment arms:

• 0.5 mg/kg zegocractin
• 1.0 mg/kg zegocractin
• 2.0 mg/kg zegocractin
• Placebo¹

Treatment was administered intravenously over 4 hours for 3 consecutive days. Investigators sought a primary endpoint of time to solid food tolerance, which they defined as individuals eating ≥50% of a ≥500 calorie, low fat, solid food meal without any increases in abdominal pain or emesis within 2 hours of eating.

They additionally sought a key secondary endpoint of severe respiratory failure as per any invasive mechanical ventilation or ≥48 hours of either high flow nasal cannula or noninvasive mechanical ventilation.

The final patient population (n = 214) included 70% US participants and 30% India participants. Median patient age was 43 years old; medial time from abdominal pain onset to randomization was 3 days. Approximately 4 in 10 (39%) patients were female, and alcohol etiology was 43%.

Another 43% of patients had a high hematocrit, and 94% of patients provided follow-up at 30 days. Approximately two-thirds (68%) of patients had a Balthazar score of D or E at enrollment.

Median time to food tolerance was 66 hours in patients receiving 2.0 mg/kg zegocractin (IQR, 26 – 120), 69 hours in patients receiving the 1.0 mg/kg dose (IQR, 20 – 134), and 69 hours in the patients receiving the 0.5 mg/kg dose (IQR, 27 – 181). Comparatively, median time to food tolerance for patients receiving placebo was 112 hours (IQR, 45 – 120).

Patients with high hematocrit at baseline achieved earlier median food tolerance with the 1.0 and 2.0 mg/kg doses of zegocractin compared the low dose or placebo.

Patients on the 1.0 and 2.0 mg/kg doses (n = 102) reported no new cases of severe respiratory failure onset, versus 4 (8.3%) in the low-dose group and 4 (8.5%) in the placebo group. Additionally, the high-dose zegocractin group had only a 30% necrotizing pancreatitis rate at 30 days, versus the 1.0 mg/kg (41%), 0.5 mg/kg (39%) and placebo (37%) groups.

Regarding safety, a lesser rate of patients receiving high-dose zegocractin (43%) reported a treatment-emergent adverse event than the placebo arm (47%); no serious adverse reactions were observed in the treatment.

Investigators concluded that higher doses fo zegocractin decreased the time to solid food tolerance, as well as the risk of respiratory failure and necrotizing pancreatitis in patients with acute pancreatitis and SIRS.

“Zegocractin, a selective CRAC channel inhibitor, provides a novel mechanism of action that inhibits multiple inflammatory pathways in acute pancreatitis,” Sutton and colleagues wrote. “The phase 2b trials results demonstrate zegocractin’s potential to reduce mortality and morbidity in acute pancreatitis with SIRS, and provide savings to the healthcare system.”

References

1. ^{Sutton R, Garg PK, Wu B, Hebbar S, et al. A Randomized, Double-Blind, Placebo Controlled Dose Ranging Study of Auxora in Patients with Acute Pancreatitis (AP) and Accompanying Systemic Inflammatory Response Syndrome (SIRS) - CARPO. Abstract presented at: American College of Gastroenterology (ACG) 2024 Scientific Sessions. Philadelphia, PA. October 25 – 30, 2024.}
2. ^{CalciMedica. CalciMedica Announces Positive Topline Data from Phase 2b CARPO Trial of Auxora™ in Acute Pancreatitis (AP). Press release. Published June 27, 2024. https://ir.calcimedica.com/news-releases/news-release-details/calcimedica-announces-positive-topline-data-phase-2b-carpo-trial}