Autoimmune R&D Series 03 | TL1A Is Already a Hot Target, but the Battleground Has Moved Beyond IBD
Originally published in Chinese on September 17, 2026. This commentary reflects information available as of September 17, 2026.
HKeyBio’s take. IBD defined the first phase of TL1A competition; the next phase will be driven by clinical validation across additional indications.
Over the past few years, TL1A has become one of the most closely watched targets in inflammatory bowel disease (IBD) drug development. Ulcerative colitis (UC) and Crohn’s disease (CD) pipelines are crowded, deal activity has been brisk, and multiple programs have advanced into late-stage clinical development. But for a biotech that already has a TL1A antibody, the next question may no longer be just “Can we still catch up in IBD?” It should also ask: “Beyond IBD, which other autoimmune diseases could create a second or even third source of value for this molecule?”
By September 2026, Merck & Co., Inc., known as MSD outside the United States and Canada, had reported positive phase 2 findings for its TL1A antibody tulisokibart (MK-7240) in moderate-to-severe hidradenitis suppurativa (HS). Meanwhile, MK-7240 was also being developed for indications beyond IBD, including axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and rheumatoid arthritis (RA).
This is not simply a matter of “adding a few more indications.” Merck is trying to answer a bigger question: Is TL1A an “IBD target,” or could it be a platform target for immune-mediated inflammation spanning the gut, skin, joints, and fibrotic diseases?
As of 2026, the evidence is diverging: tulisokibart has shown a positive clinical signal in a phase 2 HS study, whereas the phase 2 study in systemic sclerosis-associated interstitial lung disease (SSc-ILD) did not meet its primary endpoint. This contrast matters. Taking TL1A beyond IBD is worth exploring, but indication expansion is not a matter of simply replicating IBD success in other diseases. Disease selection, patient stratification, model selection, and the translational evidence chain will determine how far a TL1A asset can extend.
TL1A (tumor necrosis factor-like cytokine 1A), encoded by TNFSF15, participates in T-cell costimulation through its principal receptor, DR3 (TNFRSF25), and influences immune responses including Th1 and Th17. Chronic or aberrant TL1A–DR3 signaling has also been associated with tissue remodeling and fibrosis.
TL1A’s early success in IBD does not mean its biology is confined to the gut. More precisely, IBD had three well-developed lines of evidence:
· Genetic evidence is strong. The association between TNFSF15 risk variants and IBD is supported by a substantial body of research.
· Evidence in diseased tissue is strong. Abnormal activation of TL1A/DR3 in inflamed intestinal mucosa was validated relatively early.
· Clinical validation has progressed quickly. Multiple TL1A antibodies have entered late-stage clinical development for UC/CD, creating a relatively clear path for clinical validation.
The field therefore concentrated its resources on IBD first. The target product profiles (TPPs), efficacy assessments, clinical development pathways, and business development (BD) narratives for many TL1A programs have all been built around UC and CD.
But “IBD was the first indication to be validated” and “TL1A can only be used for IBD” are two very different statements.
Previous studies have reported altered TL1A expression or dysregulated TL1A–DR3 signaling in RA, psoriasis/PsA, spondyloarthritis, systemic sclerosis (SSc), and other diseases. What is changing now is that this disease-biology evidence is being formally brought into clinical development.
As of September 2026, tulisokibart’s clinical development program clearly extended beyond gastroenterology.
Table 1. Tulisokibart development across IBD and selected non-IBD indications
Indication | Development status and public findings | Significance for a TL1A asset |
Ulcerative colitis (UC) | Phase 3 development; positive late-stage clinical results reported | Core clinical validation setting |
Crohn’s disease (CD) | Phase 3 development | Core IBD market |
Hidradenitis suppurativa (HS) | Positive clinical signal in Phase 2 | An important indication for validation beyond IBD |
Rheumatoid arthritis (RA) | Phase 2 development | Expansion from the gut into joint inflammation |
Psoriatic arthritis (PsA) | Phase 2 development | A combined skin-and-joint disease setting |
Axial spondyloarthritis (axSpA) | Phase 2 development | Extension into spondyloarthritis |
SSc-ILD | Phase 2 study did not meet its primary endpoint; the study was to be discontinued | Success in one indication does not automatically translate to another |
More importantly, this is not an isolated effort by one company. Other TL1A programs are also beginning to explore immune-mediated inflammatory diseases beyond IBD. The second phase of TL1A competition may therefore be taking shape:
In the first phase, the question was who could demonstrate TL1A’s value in IBD.
In the second phase, the question may be who can first identify a disease beyond IBD in which targeting TL1A delivers meaningful clinical benefit.
This shift is especially important for biotech and biopharma companies that already own a TL1A antibody. If a molecule can expand from UC/CD into skin, joint, or even fibrotic diseases, its value will no longer be determined by the IBD market alone. It could open up new patient populations, lifecycle-management opportunities, and BD options.
HS is not simply “skin inflammation.” It involves chronic immune activation, Th17-associated inflammation, tissue destruction, sinus-tract formation, and fibrosis. The TL1A/DR3 axis may participate in both inflammation and tissue remodeling.
Clinical data provide the key evidence. The positive clinical signal observed with tulisokibart in a phase 2 HS study means TL1A in HS is no longer supported only by mechanistic rationale; it is beginning to gain clinical proof of concept. For companies whose TL1A development is currently focused on IBD, these findings provide a timely reason to evaluate the priority of HS within their indication strategy.
RA is not a newly emerging direction. Previous studies have found elevated TL1A levels in the serum and synovial fluid of patients with RA, with links to autoantibodies, Th17 responses, and local joint inflammation. TL1A has also been reported to aggravate arthritis and joint damage in collagen-induced arthritis models.
From a development perspective, multiple TL1A programs have entered clinical evaluation in RA. This makes RA an indication worth watching for TL1A asset owners: it has a human disease-biology rationale, standardized clinical endpoints, and established preclinical arthritis models that can support relatively early, integrated assessment of target engagement, efficacy, dose selection, and histopathology.
PsA is a particularly relevant development opportunity because it can involve multiple tissues. Patients may have psoriatic skin lesions, synovitis, enthesitis, and structural bone changes, with the IL-23/IL-17 axis playing an important role. Prior research linking TL1A to Th17-associated immune responses makes it an upstream immunomodulatory pathway worth testing.
It is too early to say that TL1A has been clinically validated in PsA. From an asset-development perspective, however, that is precisely why the indication merits early consideration: the mechanism is plausible, major clinical developers have begun testing it, and product standards and the competitive landscape are not yet fully established.
SSc may be the clearest example of why IBD experience cannot simply be copied. TL1A has a biological rationale related to inflammation and profibrotic activity, and previous human and experimental studies suggest that TL1A/DR3 signaling may contribute to tissue fibrosis and remodeling.
Clinical results, however, provide a more complex answer: the phase 2 study of tulisokibart in SSc-ILD did not meet its primary endpoint. These findings do not rule out a role for TL1A in SSc. They highlight the importance of aligning target biology with disease subtype, the stage of fibrosis, and the treatment window, and of selecting clinical endpoints that can capture the relevant pharmacological effects.
SSc should therefore be approached as a question to be re-examined through models, tissue biomarkers, and patient stratification.
Merck’s broader development program raises a practical question for companies with TL1A candidates: should HS, RA, PsA, and SSc be pursued in parallel, or should expansion be prioritized?
A coordinated expansion strategy should consider both the scientific rationale and the resources available for each indication. Indication expansion is fundamentally a portfolio decision: which disease can most quickly add new, evidence-backed value to an existing molecule at the lowest incremental development cost?
At least five factors should be evaluated together:
1. Is the human biology well supported? Is TL1A/DR3 dysregulated in the target tissue, and is it associated with disease activity, patient subtypes, or treatment response?
2. Can the molecule’s pharmacological profile support treatment in the proposed indication? Will the effective exposure, dosing frequency, and tissue distribution established in IBD remain appropriate in skin, synovium, or lung?
3. Is there a preclinical model that matches the disease mechanism? Model selection should reflect the mechanisms and tissue features relevant to each indication, with complementary models used where needed.
4. Are there biomarkers that can support clinical translation? Beyond disease activity scores, TL1A/DR3, inflammatory cytokines, histopathology, fibrosis, and PK/PD should be considered as parts of a connected body of evidence.
5. How quickly can clinical validation be achieved, and how crowded is the competitive landscape? For an asset already in clinical development or being positioned for partnering, time itself is value.
The core of indication expansion is therefore not “how many more diseases can we pursue?” but how to identify the asset’s maximum risk-adjusted value.
TL1A programs have historically concentrated on IBD. If the field expands toward HS, PsA, RA, and other diseases, preclinical development needs will change accordingly. Building on established TL1A-binding and functional characterization, the next task is to determine whether this pharmacology translates into a therapeutic effect in a different disease setting.
This is where disease models begin to create value.
HKeyBio has established a nonhuman primate (NHP) model of HS that supports efficacy assessment based on skin-lesion phenotypes, inflammatory histopathology, and relevant inflammatory markers. For a target such as TL1A, which is involved in both immune-mediated inflammation and tissue remodeling, an NHP disease model can help connect clinically relevant disease phenotypes, tissue pathology, inflammatory pathways, and pharmacokinetics/pharmacodynamics (PK/PD).
HKeyBio has established multiple mouse models of PsA, including induced models on different genetic backgrounds and models driven by IL-23-related pathways, allowing skin and joint phenotypes to be assessed in parallel. For TL1A programs, these models can assess changes in inflammatory markers alongside effects on skin inflammation, joint inflammation, and tissue pathology.
HKeyBio has technical expertise and capabilities in multiple rodent arthritis models and NHP arthritis models. C57BL/6-background systems can also facilitate integration with certain genetically engineered mouse programs. Given the evidence of elevated TL1A in RA synovial fluid and its links to Th17 responses and joint inflammation, these models can support a continuous chain of evidence from target biology to anti-arthritic efficacy, histopathology, and biomarkers.
HKeyBio has well-established models of SSc and related fibrotic diseases, including rodent and NHP models of SSc. These can be used to assess skin/tissue thickening, collagen deposition, histopathology, and relevant immune and fibrosis markers. The SSc-ILD findings provide an important basis for refining subsequent research. These models can help explore how target biology, disease subtype, tissue involvement, treatment window, and endpoint selection influence therapeutic responses.
The value of a model lies in helping teams prioritize indications and resolve key uncertainties before committing to larger, more costly clinical studies. Models support these decisions while clinical outcomes remain to be established.
TL1A is already a hot area. In IBD alone, several leading programs have reached late-stage clinical development, while long-acting antibodies, bispecific molecules, and next-generation products combining TL1A targeting with other inflammatory pathways continue to emerge.
As the UC/CD landscape becomes more competitive, a clear differentiation strategy is increasingly important for new TL1A antibodies. Could the same antibody establish clinical value first in a new indication where competition has not yet fully formed? This could offer another route to differentiation and asset growth.
Merck is looking for answers in HS, RA, PsA, and axSpA. Other companies are also trying to bring TL1A into new immune-mediated inflammatory diseases. More biotechs with TL1A assets are likely to face the same strategic choice.
Our view is this:
The first battle for TL1A took place in IBD.
The second battle will likely take place beyond IBD.
For companies with TL1A assets, this is an opportunity to revisit their indication strategy and consider skin diseases, joint diseases, axial spondyloarthritis, and fibrotic conditions. The goal is not simply to “add more indications,” but to recognize that a well-chosen expansion could redefine the value of the entire asset.
For a biotech that already has a TL1A antibody, what is the most important consideration when deciding whether to expand into an indication beyond IBD?
A. If TL1A works in IBD, the development strategy can be copied directly to other autoimmune diseases.
B. Prioritize the disease with the largest patient population; there is no need to revalidate the disease mechanism.
C. Confirm human disease biology, a disease-relevant model, tissue-level efficacy/PK-PD, and translatable biomarkers before deciding whether to proceed.
D. Enter clinical development immediately as long as there are few competitors.
Suggested answer: C. Indication expansion should bring together human disease biology, disease-relevant models, tissue pharmacology and PK/PD, and biomarkers that can support clinical translation.
[1] Merck. Product pipeline. Tulisokibart (MK-7240). 2026. Source
[2] Merck. Tulisokibart met primary and key secondary endpoints in the phase 3 ATLAS-UC induction-only study in patients with moderately to severely active UC. June 22, 2026. Source
[3] Merck. Second-quarter 2026 financial results and clinical development updates, including HS and SSc-ILD topline results. August 2026. Source
[4] ClinicalTrials.gov. Tulisokibart studies in HS (NCT06956235), PsA (NCT07486960), RA (NCT07176390), radiographic axSpA (NCT07133633), and SSc-ILD (NCT05270668). Source
[5] Sia J, Lee B, Oon HH. Unravelling the TL1A-DR3 axis in Hidradenitis suppurativa. Front Immunol. 2026. doi:10.3389/fimmu.2026.1837120. Source
[6] Xu W, et al. Elevated levels of TL1A are associated with disease activity in patients with systemic sclerosis. Clin Rheumatol. 2017;36(6):1317–1324. doi:10.1007/s10067-017-3612-y. Source
[7] Kitsou K, Kokkotis G, Bamias G. The Therapeutic Potential of Targeting TL1A in a Spectrum of Inflammatory Disorders. J Inflamm Res. 2026;19:546272. doi:10.2147/JIR.S546272. Source
[8] Roche. Afimkibart (RO7790121) development in immune-mediated diseases, including the phase 2 dRAvite RA study (NCT07137598). Source
[9] HKeyBio. Preclinical model information for hidradenitis suppurativa, psoriatic arthritis, rheumatoid arthritis, and systemic sclerosis. Source
