353 An Open-Label, Dose-Response Study of CM4620-Injectable Emulsion in Emergency Department Patients With Acute Pancreatitis

Abstract

Hyperactivation of Calcium Release-Activated Calcium (CRAC) channels results in excessive Ca2+ influx in acinar cells and plays a pivotal role in cellular injury and the progression of acute pancreatitis. Our purpose was to evaluate the efficacy of CM4620-IE, a potent selective CRAC channel inhibitor, to improve outcomes in ED patients with acute pancreatitis. This was a 2 phase, open-label, multicenter, placebo controlled dose-response pilot study enrolling patients with acute pancreatitis (AP), who met SIRS criteria, and who had a room air SpO2 <96% (NCT03401190). Patients were randomized in a 3:1 fashion to CM4620-IE or placebo, in all phases. In phase 1, patients received 1.0 mg/kg on day 1 and 1.4 mg/kg on Days 2-4. In phase 2, females had the same dose of CM4620-IE as in the 1st phase, and males received 2.08 mg/kg of CM4620-IE on Days 1-2, and 1.6 mg/kg on Days 3-4. Patients were discharged after meeting local criteria, potentially before completion of study drug. All patients had pancreatic CT imaging before randomization and again at the earliest of days 5-7 or discharge. CTs, read by a central reader blinded to therapy, were graded as severe AP (SAP), moderately SAP (MSAP), or mild AP (MAP) using the CT severity index (CTSI) scoring system. All patients had daily dietary assessments, and tolerating a solid diet was defined as eating >50% of a solid meal. Of 21 patients, 14 received CM4620-IE and 7 placebo. Five females and 3 males received low dose and 6 males received the high dose CM4620-IE. In both phases, all CM4620-IE patients received a median of 3 doses. The median age, baseline SpO2, number of patients with >2 SIRS criteria, and percent of patients with MSAP or SAP on the initial CT were comparable between CM4620-IE and placebo. The results are presented in Table 1. No serious adverse events were reported as being drug-related. CM4620-IE was well tolerated, was not associated with an increase in serious adverse events and had multiple efficacy signals that warrant further clinical development and a larger Phase 2b/3 study.Table 1Main ResultsCM4620-IE, N=14SOC, N=7Age, median (IQR)50.5 (26, 66)54 (40, 72)Screening SpO2, median (IQR)94% (93, 95)94% (93, 95)Screening HR, median (IQR)105 (100, 109)105 (102, 116)Screening SBP mmHg, median (IQR)156 (143, 172)129 (124, 145)Baseline Median Pain Score (0-10) (IQR)8 (5, 9)8 (6, 8)Patients with ≥3 SIRS criteria at screening, n (%, 95% CI)4 (28.6%, 11.7-54.6%)2 (28.6%, 8.2-64.1%)Baseline moderate or severe pancreatitis by CTSI score, n (%, 95% CI)9 (64.3%, 38.8-83.7%)4 (57.1%, 25.0-84.2%)Baseline Pain Score (0-10) (IQR)8 (5, 9)8 (6, 8)Tolerating solid diet at 72 hours, n (%, 95% CI)8 (57.1%, 32.6-78.6%)1 (14.3%, 2.6-51.3%)Tolerating solid diet at discharge, n (%, 95% CI)12 (85.7%, 36.5-75.5%)3 (42.9%, 15.8-75.0%)Baseline moderate or severe pancreatitis converting to mild, n (%, 95% CI)5 (37.5%, 16.3-61.2%)0 (0%, 0.0-35.4%)SIRS persisting ≥48 hours, n (%, 95% CI)5 (35.7%, 16.3-61.2%)5 (71.4%, 35.9-91.8%)Development of de-novo acute kidney injury, n (%, 95% CI)1 (8.3%, 1.3-31.5%)1 (20%, 2.6-51.3%)Length of stay for all patients, median days (IQR)3.7 (2.5, 8.4)6.0 (2.5, 7.3)Length of stay for moderate or severe pancreatitis, median days (IQR)4.3 (1.9, 12.3)7.3 (6.6, 18.7) Open table in a new tab