Afimkibart in ulcerative colitis: Biological insights from the phase 2b TUSCANY-2 study

touchIMMUNOLOGY coverage of DDW 2026

What is the mechanism of action of afimkibart, and what is the rationale for investigating it in UC?

Afimkibart is a fully human monoclonal antibody that specifically targets the functional, trimeric, form of the TL1A protein. It prevents TL1A from binding to the DR3 receptor, which acts as a key amplifier of inflammatory pathways and tissue remodelling in immune-mediated diseases. Inhibiting the TL1A pathway has the potential to address the key features of IBD by targeting both the inflammatory and fibrotic aspects of the disease.

Could you describe the aims and design of the phase 2b TUSCANY-2 study?

TUSCANY-2 was a multicentre, double-blind, treat-through, multi-dose, randomized, placebo-controlled, phase 2b study designed to evaluate the safety, efficacy, and pharmacokinetics of multiple doses of afimkibart in patients with moderately-to-severely active ulcerative colitis.

How was high-sensitivity serum proteomics used to evaluate the biologic effects of afimkibart?

We conducted translational analyses on serum samples from the high dose and placebo arms of the TUSCANY-2 study measuring the screening, Week 4, and Week 14 timepoints. These results were compared with 30 age- and gender-matched healthy controls. The highly sensitive proteomics platform, NULISA, was selected to measure protein levels in the serum because its detection limit is in the low femtograms per milliliter (fg/mL) range. This sensitivity is approximately 100 to 1,000 times higher than traditional ELISA or proximity ligation assays (PLA), making NULISA particularly effective for detecting low-abundance cytokines that are often “invisible” to other proteomic platforms.

What were the key findings of the study?

The results showed that samples from afimkibart-treated patients had greater changes than placebo for 45 of the 250 measured proteins at Week 14. Afimkibart reduced inflammatory pathway markers, including receptors for both TNF (TNFR1 and 2) and IL-12/23 (IL-12R1), indicating that TL1A inhibition has a broad biological impact across inflammatory networks.

Beyond inflammation, afimkibart also modulated stromal and tissue-remodeling processes, as seen for several mediators linked to fibroblast collagen production (AREG), extracellular matrix remodeling (MMP8 and MMP12), and accumulated fibrosis (HGF). Afimkibart also reduced OSM, a marker that remains elevated in the subset of IBD patients who do not respond to many different biologics, including anti-TNFs, and is associated with the persistence of inflammatory fibroblasts.

Taken together, this large-scale serum proteomic profiling from TUSCANY-2 confirms and broadens previous mechanistic observations of TL1A pathway inhibition with afimkibart. Treatment not only suppressed inflammatory and fibrotic mediators, but also shifted multiple disease-associated proteins toward levels seen in healthy individuals.

How do these findings build on previous data regarding afimkibart?

These results suggest that blocking TL1A with afimkibart may rebalance immune and stromal activity in UC, supporting its potential as a differentiated therapeutic approach targeting TL1A-driven disease biology in IBD.