Zegocractin for acute pancreatitis with systemic inflammatory response syndrome: a randomized, controlled, dose-ranging, phase 2b trial.

Background: Acute pancreatitis (AP) is without specific drug therapy. We conducted a phase 2b trial of the calcium release-activated calcium channel inhibitor zegocractin, previously found to accelerate recovery of food intake in AP, to determine dose-response, target population, endpoints, safety and tolerability in AP with systemic inflammatory response syndrome. Methods: This double-blind, randomised, placebo-controlled, phase 2b trial enrolled adults (aged ≥18 years) with AP and systemic inflammatory response syndrome at 37 centres in the US and India. Patients were randomly assigned (1:1:1:1) to receive placebo or 0.5 (low), 1.0 (medium) or 2.0 (high) mg per kilogramme intravenous zegocractin once daily for 3 days. The primary outcome was time to solid food tolerance, and all outcomes were specified a priori. This trial is registered with ClinicalTrials.gov (NCT04681066) and is complete. Findings: Between 30th March, 2021 and 16th April, 2024, 216 patients were assigned to placebo (N = 53), low (N = 53), medium (N = 56) or high (N = 54) dose zegocractin. The primary outcome of median time to solid food tolerance was 66, 78, 64, and 67 h in these groups respectively (n.s.). Dose-response was observed in patients with a high haematocrit (n = 92), the median times being 113.5, 78, 64 and 67 h, and in those with Balthazar D or E computed tomography at presentation (n = 145), at 112, 68.5, 68.5, and 66 h respectively. Overall, there were dose-dependent responses for the secondary outcomes new-onset severe respiratory failure (4, 4, 0, and 0 patients), new-onset necrotising pancreatitis (17, 17, 20 and 11 patients) and time to medically indicated discharge (104, 109.5, 104.5 and 89 median hours), reflected in an exploratory win ratio for high dose zegocractin compared to placebo of 1.640 (95% CI 1.030-2.612; p = 0.04). Interpretation: This trial was negative for the primary endpoint of time to solid food tolerance in the whole trial population but improvement with zegocractin was seen in patients with a high haematocrit or Balthazar score. Multiple secondary endpoints improved consistently with zegocractin compared to placebo, most notably in preventing new-onset severe respiratory failure. These findings identified a suitable dose, a potential patient population, and endpoints for a phase 3 trial. Funding: CalciMedica.