A recent phase 2b clinical trial (CARPO) indicates that zegocractin (Auxora), a calcium release-activated calcium (CRAC) channel inhibitor, may offer significant benefits for patients suffering from acute pancreatitis. The study, presented at the American College of Gastroenterology (ACG) 2024 Scientific Sessions, demonstrated that zegocractin could decrease the time to solid food tolerance and potentially reduce the risk of severe respiratory failure.
The multi-national team of investigators, led by Robert Sutton, BA, MBBS, DPhil, sought to evaluate the dose response of zegocractin on key outcomes for acute pancreatitis in patients with systemic inflammatory response syndrome (SIRS). The trial randomized 216 patients with acute pancreatitis and >2 criteria items for SIRS to one of four treatment arms: 0.5 mg/kg zegocractin, 1.0 mg/kg zegocractin, 2.0 mg/kg zegocractin, or placebo. The treatment was administered intravenously over 4 hours for 3 consecutive days.
The primary endpoint was the time to solid food tolerance, 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. A key secondary endpoint was severe respiratory failure, defined as any invasive mechanical ventilation or ≥48 hours of either high flow nasal cannula or noninvasive mechanical ventilation.
Key Findings from the CARPO Trial
The results showed that the median time to food tolerance was 66 hours in patients receiving 2.0 mg/kg zegocractin, 69 hours in patients receiving the 1.0 mg/kg dose, and 69 hours in patients receiving the 0.5 mg/kg dose. In comparison, the median time to food tolerance for patients receiving placebo was 112 hours. Patients with high hematocrit at baseline achieved earlier median food tolerance with the 1.0 and 2.0 mg/kg doses of zegocractin compared to the low dose or placebo.
Notably, 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.
Safety Profile
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.
Implications and Future Directions
According to Rachel Leheny, PhD, Chief Executive Officer of CalciMedica, "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."
The investigators concluded that higher doses of 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."
