Abrilumab

Tissue-directed therapies (TDTs) provide potential advantages, including improved tolerance, safety, and efficacy. This review provides a conceptual framework for understanding intestinal TDT and summarizes the current landscape of TDT in inflammatory bowel disease (IBD).

Vedolizumab, a mAb targeting the gut homing α4β7 integrin, served as revolutionary proof-of-principle for the power of advanced TDT in IBD. The development of other monoclonal antibodies targeting cell adhesion molecules followed including abrilumab (α4β7), etrolizumab (β7), and ontamalimab (MAdCAM-1). MORF-057, an oral small molecule inhibitor of α4β7, is now in development for ulcerative colitis. Efforts have also been made toward gut specific JAK inhibitors. Microbiome-based therapies, including engineered probiotics, bacteriophages, and postbiotics, are gaining interest. There are also a number of innovative drug delivery methods, including engineered yeast, hydrogels, and nanoparticles, and viral-based gene therapy.

Gut-targeted therapies range from novel variations on traditional drugs (i.e., mAbs and small molecules) to microbiome-based therapeutics and engineered delivery systems. They can be used alone or in combination with currently available therapies. Future directions should focus on the development of tried-and-true modalities (mAbs, small molecules) as well as the microbiome and more innovative delivery systems.

Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is a major cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab is a gut-selective anti-α4β7 integrin monoclonal antibody that reduces gut inflammation by inhibiting migration of GI-homing T lymphocytes. The efficacy and safety of vedolizumab added to standard GVHD prophylaxis (calcineurin inhibitor plus methotrexate/mycophenolate mofetil) was evaluated for prevention of lower-GI aGVHD after unrelated donor allo-HSCT in a randomized, double-blind, placebo-controlled phase 3 trial. Enrollment closed early during the COVID-19 pandemic with 343 patients randomized (n = 174 vedolizumab, n = 169 placebo), and 333 received ≥1 intravenous dose of 300 mg vedolizumab (n = 168) or placebo (n = 165) and underwent allo-HSCT. The primary end point was met; Kaplan–Meier (95% confidence interval) estimated rates of lower-GI aGVHD-free survival by day +180 after allo-HSCT were 85.5% (79.2–90.1) with vedolizumab versus 70.9% (63.2–77.2) with placebo (hazard ratio, 0.45; 95% confidence interval, 0.27–0.73; P < 0.001). For the 5 key secondary efficacy end points analyzed by day +180 after allo-HSCT, rates of lower-GI aGVHD-free and relapse-free survival and grade C–D aGVHD-free survival were significantly higher with vedolizumab versus placebo. No significant treatment differences were found for the other key secondary end points of non-relapse mortality, overall survival and grade B–D aGVHD-free survival, respectively. Incidence of treatment-related serious adverse events analyzed in patients receiving ≥1 dose of study treatment (n = 334) was 6.5% (n = 11 of 169) vedolizumab versus 8.5% (n = 14 of 165) placebo. When added to standard calcineurin inhibitor-based GVHD prevention, lower-GI aGVHD-free survival was significantly higher with vedolizumab versus placebo. ClinicalTrials.gov identifier: NCT03657160.