Merck posts ‘encouraging’ Phase 3 ulcerative colitis data but Roche challenge looms

Merck's Tulisokibart Meets Primary Endpoint in Phase 3 Ulcerative Colitis Study

Merck's investigational antibody, tulisokibart, an intravenous TL1A inhibitor, successfully met its primary endpoint of clinical remission at 12 weeks in a late-stage study for ulcerative colitis. It also met key secondary outcomes, though specific data was not disclosed. Analysts remain cautious due to the lack of detailed findings and the competitive landscape, particularly Roche's subcutaneously administered afimkibart. Despite this, some analysts are optimistic, projecting peak sales over $5 billion. Merck plans to release more detailed findings at an upcoming medical congress and is developing a subcutaneous formulation for maintenance treatment.

• Merck's tulisokibart, an intravenous TL1A inhibitor, achieved its primary endpoint of clinical remission at 12 weeks in a Phase 3 study for ulcerative colitis, along with meeting key secondary outcomes. However, specific quantitative data for these results were not disclosed, leading to analyst caution regarding its competitive positioning.
• The market for ulcerative colitis treatments is highly competitive, with Roche's afimkibart, an anti-TL1A antibody, posing a significant challenge due to its subcutaneous administration option. Analysts suggest tulisokibart's efficacy would need to be substantially superior to afimkibart to overcome its intravenous route in the induction setting, although Merck is developing a subcutaneous formulation for maintenance.
• While some analysts expressed disappointment over the lack of detailed data, others, like Guggenheim Partners, maintained an optimistic outlook, supporting above-consensus estimates for tulisokibart with peak sales potentially exceeding $5 billion by the late 2030s, compared to a consensus of around $4 billion.

Merck's Tulisokibart Meets Primary Endpoint in Ulcerative Colitis Phase 3

Three recent clinical studies offer meaningful updates on the therapeutic landscape for ulcerative colitis (UC). The TUSCANY-2 trial (NCT04090411), a multicentre, double-blind, randomised, placebo-controlled Phase 2b trial conducted across 114 centres in 23 countries, evaluated afimkibart — a TL1A-directed monoclonal antibody — at subcutaneous doses of 50 mg, 150 mg, or 450 mg every four weeks in 245 treated patients. Although the primary endpoint of clinical remission at week 14 by total Mayo score was not statistically significant versus placebo (26%, 23%, and 24% across dose groups versus 12% for placebo), secondary endpoint analyses using the modified Mayo score demonstrated remission rates of 30–35% across active arms versus 12% for placebo, suggesting a clinically meaningful signal. The safety profile was acceptable, with treatment-emergent adverse events reported in 48% of patients during induction; the most common included nausea, urinary tract infection, anaemia, fatigue, headache, and pyrexia. No deaths occurred during the study period.

The LUCENT Phase 3 programme (NCT03518086, NCT03524092, and NCT03519945) assessed mirikizumab, an anti-interleukin-23 p19 antibody, with disease clearance — defined as concurrent symptomatic, endoscopic, and histologic remission — as the primary outcome. Clearance rates progressed from 16.0% at week 12 to 36.4% at week 52 and 51.3% at week 104, with early clearance at week 12 associated with significantly better outcomes at subsequent time points across most endpoints. Complementing this, the real-world INSIGHT study — a multicenter retrospective cohort of 85 patients with moderate-to-severe UC across 12 Japanese centres — reported clinical remission rates of 62.4% at week 12 and 55.3% at week 52, with effectiveness maintained irrespective of prior biologic or JAK inhibitor exposure. Notably, 27.3% of initial non-responders achieved remission by week 24 with extended induction. The safety profile was favourable, with adverse events in 17.6% of patients and no serious infections or hospitalisations reported.

A large-scale individual patient-level data meta-analysis pooling 10 randomised controlled trials examined the impact of age on the efficacy and safety of advanced therapies — including TNF antagonists (infliximab, adalimumab, golimumab), vedolizumab, ustekinumab, and tofacitinib — in 6,192 patients with moderate-to-severe UC, of whom 634 (10.2%) were aged ≥60 years. Efficacy across all agents was comparable between older and younger adults, with no significant treatment effect modification observed for induction of clinical remission (TNF antagonists: RRR 0.94, 95% CI 0.41–2.15; non-TNF-targeting agents: RRR 1.26, 95% CI 0.60–2.62). However, older adults were significantly more likely to experience infections when treated with advanced therapies versus placebo, with relative risk ratios of 1.52 (95% CI 1.12–2.05) for TNF antagonists and 2.04 (95% CI 1.45–2.87) for non-TNF-targeting agents, underscoring the importance of infection risk stratification in older UC populations.

Tulisokibart's Position in the TL1A Ulcerative Colitis Landscape

Two other anti-TL1A monoclonal antibodies — Afimkibart and Duvakitug — are currently under clinical investigation for inflammatory bowel disease (IBD), sharing tulisokibart's mechanism of inhibiting the TL1A–DR3 signaling axis. Across Phase 2 trials, all three agents demonstrated clinical remission/response rates of 26–66% in patients with moderate-to-severe IBD at 12–14 weeks, with favorable safety profiles. Specific intervention model data for Afimkibart and Duvakitug were not available in the source literature; tulisokibart's trial designs are detailed below.

Expanding Tulisokibart's Potential Beyond Ulcerative Colitis

Tulisokibart is being investigated across multiple inflammatory indications beyond ulcerative colitis, reflecting the broad pathophysiological relevance of TL1A/DR3 axis inhibition. Current clinical development encompasses both gastrointestinal and dermatological disease areas, with distinct trial designs characterising each programme.

• Crohn's Disease (APOLLO-CD; NCT05013905): Tulisokibart was evaluated in a phase 2a, multicentre, open-label, single-arm study in adults aged ≥18 years with moderately to severely active Crohn's disease (CDAI 220–450; SES-CD ≥6 for ileocolonic or colonic disease, or ≥4 for isolated ileal disease) who had a history of insufficient response, loss of response, or intolerance to conventional or approved biological therapies. The dosing regimen comprised intravenous tulisokibart 1000 mg on Day 1, followed by 500 mg at weeks 2, 6, and 10. Of 101 participants screened, 55 were enrolled; the cohort had a mean age of 39.1 years (SD 15.7), was 62% male, and 71% had prior biological therapy exposure. Co-primary endpoints were safety and endoscopic response at week 12 (defined as ≥50% reduction in SES-CD from baseline). Endoscopic response was achieved in 13 of 50 participants (26.0%; 95% CI 15.9–39.6) in the per-protocol analysis set. Adverse events occurred in 43 (78%) participants, with most being mild to moderate in severity; the most frequently reported events (≥5%) were COVID-19 (11%), urinary tract infection (9%), Crohn's disease exacerbation (9%), anaemia (7%), nasopharyngitis (5%), and fatigue (5%). Serious adverse events were reported in 8 (15%) participants, none of which were considered related to the study drug, and no deaths occurred. The trial is closed for recruitment, with an open-label extension ongoing and a double-blind, placebo-controlled phase 3 trial currently underway.

• Hidradenitis Suppurativa (NCT06956235): Tulisokibart is being assessed in a phase 2b trial in participants with moderate-to-severe hidradenitis suppurativa (HS), a chronic inflammatory disorder characterised by cutaneous manifestations, extracutaneous comorbidities, and frequent treatment failure with existing options including antibiotics and biologics. The therapeutic rationale centres on inhibition of the TL1A/DR3 signalling axis, which drives immune cell activation and fibrosis implicated in HS pathogenesis. Participant recruitment for this trial was reported as completed as of 1 December 2025.

• Mechanistic Breadth Across Indications: The expansion of tulisokibart's development into both luminal gastrointestinal disease (Crohn's disease) and inflammatory dermatology (hidradenitis suppurativa) underscores the pleiotropic role of TL1A signalling in driving chronic inflammation and fibrosis across tissue compartments, supporting a mechanism-first development strategy that extends well beyond its originating indication in ulcerative colitis.

Tulisokibart's UC Success: A New Chapter for TL1A in IBD

Merck's recent announcement regarding tulisokibart, its investigational TL1A inhibitor, marks a significant milestone in the ongoing quest to improve treatment for ulcerative colitis. The successful achievement of its primary endpoint of clinical remission in a late-stage study, coupled with positive key secondary outcomes, underscores the potential of this novel therapeutic class.

Inflammatory bowel diseases like ulcerative colitis continue to present substantial challenges, with many patients experiencing inadequate responses or developing intolerance to current therapies. The TL1A pathway is gaining prominence as a target due to its dual role in driving both inflammation and fibrosis, addressing critical unmet needs that existing treatments often fall short of. Tulisokibart's development, notably incorporating a genetic diagnostic test, exemplifies a precision medicine approach aimed at identifying patients most likely to benefit, potentially optimizing treatment outcomes and resource allocation.

However, the competitive landscape for IBD therapies is robust, with other TL1A inhibitors also in development. While the initial results are promising, the absence of detailed efficacy and safety data from the late-stage study means a full comparative assessment is not yet possible. Future disclosures at medical congresses will be crucial for understanding tulisokibart's specific profile and differentiation. Furthermore, the chronic nature of ulcerative colitis demands confirmation of long-term safety and sustained efficacy in ongoing or future Phase III trials. The planned subcutaneous formulation for maintenance treatment, alongside the potential for extended dosing intervals, will be vital for patient convenience and adherence, which are key factors for successful long-term management. If these aspects are successfully navigated, tulisokibart could emerge as a cornerstone therapy, significantly advancing the treatment paradigm for ulcerative colitis and potentially other immune-mediated diseases.