Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study.

Abstract

BACKGROUND & AIMS:

An immune component of inflammatory bowel disease is up-regulated tumor necrosis factor-like ligand 1A (TL1A). Anti-TL1A antibodies such as PF-06480605, a fully human immunoglobulin G1 monoclonal antibody, may have therapeutic potential.

METHODS:

This Phase 2a, multicenter, single-arm, open-label study (TUSCANY) evaluated safety, tolerability, efficacy, pharmacokinetics, and immunogenicity in PF-06480605-treated participants with moderate to severe ulcerative colitis (UC). Participants received 500 mg intravenous PF-06480605 every 2 weeks, 7 doses total, with a 3-month follow-up period. Primary safety and efficacy endpoints were the incidence of adverse events (AEs) and week 14 endoscopic improvement (EI) (Mayo endoscopic subscore = 0 or 1), respectively. Secondary endpoints included total soluble TL1A (free/drug-bound) (sTL1A), incidence of anti-drug and neutralizing antibodies, PF-06480605 concentrations, and changes in fecal calprotectin and high-sensitivity C-reactive protein. Histology was assessed at week 14.

RESULTS:

The study enrolled 50 participants; 42 completed. Of 109 treatment-emergent AEs, 18 were treatment-related. The most common AEs were UC disease exacerbation and arthralgia (6 participants each). Four serious AEs, no deaths, and no malignancies were reported. Week 14 EI was observed in a statistically significant proportion of participants (38.2% [uniformly minimum-variance unbiased estimator, per protocol population]). Minimal histologic disease was observed after treatment (Robarts Histopathology Index ≤5: 33.3%; Geboes Index ≤3.2: 47.6%). sTL1A increase over time from baseline indicated sustained target engagement. Forty-one participants (82%) tested positive for anti-drug antibodies and 5 (10%) for neutralizing antibodies.

CONCLUSIONS:

PF-06480605 demonstrated an acceptable safety profile and statistically significant EI in participants with moderate to severe UC, warranting further study in a larger participant cohort. Tissue histopathology analyses support this conclusion.

TRIAL REGISTRATION NUMBER:

https://clinicaltrials.gov/NCT02840721.

• Authors: Silvio Danese, Maria Klopocka, Ellen J Scherl, Jacek Romatowski, Jessica R Allegretti, Elena Peeva, Michael S Vincent, Uwe Schoenbeck, Zhan Ye, Mina Hassan-Zahraee, Natalie Rath, Gang Li, Srividya Neelakantan, Christopher Banfield, Christopher Lepsy, Deepa E Chandra, Kenneth E Hung
• Journal: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association (Clin Gastroenterol Hepatol) Vol. 19 Issue 11 Pg. 2324-2332.e6 (11 2021) ISSN: 1542-7714 [Electronic] United States
• PMID: 34126262 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents, Immunological
• Tumor Necrosis Factor-alpha

Topics

• Antibodies, Monoclonal (adverse effects)
• Antineoplastic Agents, Immunological (therapeutic use)
• Colitis, Ulcerative (drug therapy)
• Humans
• Inflammatory Bowel Diseases
• Tumor Necrosis Factor-alpha (therapeutic use)