Brian G. Feagan, MD1, Bruce E. Sands, MD, MS, FACG2, Corey A. Siegel, MD, MS3, Marla C. Dubinsky, MD4, Randy Longman, MD, PhD5, João Sabino, MD, PhD6, Olivier Laurent, 7, Allison Luo, MD7, JD Lu, PhD7, Deanna D.. Nguyen, MD7, Fadi Towfic, 7, Aaron DuVall, MD8, Marek Woynarowski, MD, PhD9, Houssam Al Kharrat, MD10, Dermot McGovern, MD, PhD11 1Western University, London, ON, Canada; 2Icahn School of Medicine at Mount Sinai, New York, NY; 3Dartmouth-Hitchcock Inflammatory Bowel Disease Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH; 4Mount Sinai Kravis Children’s Hospital, New York, NY; 5Weill Cornell Medical College, New York, NY; 6University Hospitals Leuven, Leuven, Brussels Hoofdstedelijk Gewest, Belgium; 7Prometheus Biosciences, Inc., San Diego, CA; 8Tyler Research Institute, LLC, Tyler, TX; 9UJK Kielce, former IP CZD Warsaw, Kielce, Swietokrzyskie, Poland; 10West Texas Digestive Disease Center, Lubbock, TX; 11Cedars-Sinai Medical System, Los Angeles, CA
Introduction: Tumor necrosis factor–like cytokine 1A (TL1A) is regulator of inflammation and fibrosis. PRA023 is an anti-TL1A monoclonal antibody in development for inflammatory/fibrotic diseases with a companion genetic-based diagnostic test (Dx). This phase 2a, multicenter, open-label study aimed to assess the efficacy and safety of PRA023 as induction treatment in adults with moderately to severely active Crohn’s Disease (CD).
Methods: Key eligibility criteria included Crohn’s Disease Activity Index (CDAI) ≥220 and ≤450 with centrally read Simple Endoscopic Score (SES)-CD of ≥6 (≥4 isolated ileal disease) and a history of insufficient/loss of response and/or intolerance to conventional and/or approved biologic therapies. Eligible patients received intravenous PRA023 1000 mg on Day 1, 500 mg at weeks 2, 6, and 10. The primary endpoint was endoscopic response (reduction in SES-CD of ≥50%) at week 12. Historical placebo control rates were used as a reference for the null hypothesis. An exploratory efficacy assessment in a subpopulation identified by the Dx was included.
Results: Of the 55 patients enrolled, 53 (96.4%) completed the 12-week induction period. Patients had a high rate of prior biologic exposure (70.9%) and a mean (SD) disease duration of 10.3 (9.3) years (Table 1). A significantly greater proportion of patients receiving PRA023 achieved endoscopic response (26% PRA023 vs 12% historical placebo estimate, p=0.002) and clinical remission (CDAI < 150 points; 49% PRA023 vs 16% historical placebo estimate, p< 0.001). Efficacy was observed in biologic-exposed patients (33% endoscopic response and 38.5% clinical remission), while concurrent steroid or immunosuppressant use did not impact efficacy. Significant reductions from baseline in C-reactive protein and fecal calprotectin were observed at all time points (Figure 1). Although the pre-specified Dx algorithm provided only limited additional benefit in clinical responses, an alternative CD-specific algorithm demonstrated enhanced performance across both clinical (12/21 [57%] remission) and endoscopic (9/20 [45%] response) outcomes. No serious/severe adverse events were deemed as study drug–related.
Discussion: This phase 2a study demonstrated robust proof-of-concept for PRA023’s efficacy in moderately to severely active CD with favorable tolerability. Patient selection using prespecified genetic markers showed promising results. Placebo-controlled clinical trials will be conducted to confirm these findings.
Figure: Figure 1. Change Over Time in Geometric Mean Values ± SE for (A) High-Sensitivity C-Reactive Protein (hsCRP) and (B) Fecal Calprotectin Nominal p values, * p<0.05, ** p<0.01, ***p<0.001.
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