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The results show a placebo-controlled trial is warranted in the future.
A team, led by Brian G. Feagan, Department of Medicine, Division of Gastroenterology, Western University, tested the emerging medication in a specific subset of patients that have largely been exposed to biologics in the past.
Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals that has shown promise as a potential treatment for patients with IBD and other inflammatory diseases. It may also lead to better hopes for precision medicine with treatments like PRA023.
In the phase 2a, multi-center, open-label study, the investigators assessed the efficacy and safety of PRA023 as an induction treatment for 55 adults with moderately to severely active Crohn’s disease, 96.4% (n = 53) of which completed the 12 week Induction period.
What was specific about this particular patient population is that 70.9% were previously exposed to biologics and there was a mean disease duration of 10.3 years.
In the study, the investigators implemented an eligibility criteria that included Crohn’s disease activity index ≥220 and ≤450 with centrally read [with adjudication] Simple Endoscopic Score (SES)-CD score of ≥6 (≥4 isolated ileal disease) and a history of insufficient/loss of response and/or intolerance to conventional and/or approved biologic therapies (≤4 biologic agents from ≤3 classes).
Patients included in the study were treated with intravenous PRA023 1000 mg at day 1, followed by 500 mg at weeks 2, 6, and 10.
The investigators sought a primary endpoint of endoscopic response, defined as a reduction in SES-CD scores of at least 50% at week 12 and exploratory endpoints of efficacy assessments in a subpopulation identified by genetics-based companion diagnostic tests.
The results show there was a significantly greater proportion of patients in the PRA023 group that 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).
Moreover, patients that were previously exposed to biologics (33% endoscopic response and 38.5% clinical remission) in the PRA023 had higher levels of efficacy, while concurrent steroid or immunosuppressant use did not impact efficacy in this patient population.
The results also show significant reductions from baseline in C-reactive protein and fecal calprotectin in all timepoints.
The investigators also developed an alternative Crohn’s disease-specific algorithm using the same genetic markers that showed enhanced performance across both clinical (n = 12; 57% remission) and endoscopic (n = 9; 45% response) outcomes.
For safety, there were no serious or severe adverse events deemed related to the study drug.
“This Phase 2a study demonstrated robust proof-of-concept for PRA023’s efficacy in moderately to severely active CD with favorable tolerability,” the authors wrote. “Patient selection using prespecified genetic markers showed promising results. Placebo-controlled clinical trials will be conducted to confirm these findings.”
B G Feagan, B Sands, C A Siegel, M Dubinsky, R Longman, J Sabinho, O Laurent, A Luo, J D Lu, D Nguyen, F Towfic, A DuVall, M Woyranowski, H Al Kharrat, D P B McGovern, DOP87 The Anti-TL1A Antibody PRA023 Demonstrated Proof-of-Concept in Crohn’s Disease: Phase 2a APOLLO-CD Study Results, Journal of Crohn's and Colitis, Volume 17, Issue Supplement_1, February 2023, Pages i162–i164, https://doi.org/10.1093/ecco-jcc/jjac190.0127