The 9 Hottest Clinical Trials in IBD — and What We've Already Learned

The IBD pipeline has never looked more promising. Yet distinguishing truly practice-changing trials from incremental advances requires careful analysis.

• Which studies will fundamentally alter how we approach IBD management?

• Which represent genuine paradigm shifts versus refinements of existing strategies?

Today we are focusing on the pivotal trials that are reshaping our field — those that challenge established treatment algorithms, expand our therapeutic targets beyond traditional inflammation, and even explore whether we can intercept IBD before clinical onset.

What Makes a Practice-Changing Trial?

It's not just about statistical significance. The trials that reshape IBD care share three characteristics:

1. They challenge dogma — whether it's treatment sequencing, remission targets, or the very pathophysiology of disease

2. They solve real clinical dilemmas — the daily decisions we face about failing therapies, combination strategies, and risk-benefit trade-offs

3. They open new therapeutic horizons — not just "me-too" drugs but fundamentally different approaches

With that lens, let's examine the trials that have already moved the needle and those poised to do so next.

Part 1: The Game-Changers We've Already Learned From

VARSITY: When Gut-Selective Beat Systemic

The first true head-to-head biologic trial in IBD pitted vedolizumab against adalimumab in moderate-to-severe UC.

The result? Vedolizumab's superior clinical and endoscopic remission rates legitimised gut-selective therapy and pushed it earlier in treatment algorithms.

SEQUENCE: IL-23 Takes the Crown in Crohn's

When risankizumab went head-to-head with ustekinumab in bio-experienced Crohn's disease, it won decisively across all ranked endpoints. This wasn't just about one drug beating another — it validated selective IL-23p19 blockade as potentially superior to dual IL-12/23 inhibition.

The ripple effect: SEQUENCE is already influencing guidelines and will positions IL-23 inhibitors as the go-to class for moderate-to-severe Crohn's, especially in patients who've failed anti-TNF therapy.

GALAXI and GRAVITI: All-Subcutaneous IL-23 Arrives

Guselkumab's phase 3 program demonstrated robust efficacy in both bio-naïve and bio-experienced Crohn's patients, with one key differentiator: fully subcutaneous dosing from induction through maintenance.

Clinical impact: No more scheduling infusion suites for induction. For patients seeking convenience without sacrificing efficacy, guselkumab becomes a compelling option in both Crohn’s disease and UC.

CALM: The Strategy Trial That Changed Everything

By using biomarkers (CRP and faecal calprotectin) rather than symptoms alone to guide treatment escalation, CALM achieved dramatically better outcomes. This wasn't about a new drug — it was about using our existing arsenal more intelligently.

The legacy: Treat-to-target is now standard of care. Every IBD clinic that checks regular calprotectin levels owes a debt to CALM.

Part 2: The Next Wave — 8 Trials to Watch Closely

1. TL1A Inhibition: the next drug class for IBD

TL1A (tumour necrosis factor-like cytokine 1A) represents the most exciting new target in IBD because it looks like it drives both inflammation AND fibrosis.

Multiple companies are racing to market:

• Tulisokibart (MK-7240, Merck): positive phase 2 data in ARTEMIS-UC and APOLLO-CD already published; Phase 3 ATLAS-UC and ARES-CD trials ongoing with >1,200 patients in UC and CD.

• Duvakitug (TEV-48574, Teva/Sanofi): Phase 2b (RELIEVE UCCD) showed ~48% remission in UC and strong CD results; Phase 3 program planned for H2 2025 in both indications.

• FG-M701 (AbbVie/FutureGen): Preclinical next-gen anti-TL1A mAb engineered for extended dosing (interval tbc); licensed in 2024 for IBD development.

• Afimkibart (RG6631/RO7790121, Roche): Formerly PF-06480605/RVT-3101; Phase 3 ongoing in UC (treat-through design), Phase 2 in CD.

• SPY002 (Spyre): Extended half-life mAb from modular platform; positive Phase 1 interim data in June 2025 showing safety and PK; Phase 2 in UC planned late 2025.

• XmAb942 (Xencor): High-potency, extended half-life anti-TL1A; positive Phase 1 interim results in April 2025 in healthy volunteers; Phase 2 planning for IBD in late 2025.

• ABS-101 (Absci): AI-designed anti-TL1A with high affinity and potential quarterly dosing; Phase 1 trial dosed first participants in May 2025; interim data expected H2 2025.

Why this matters: If TL1A inhibitors can prevent or reverse fibrosis, they'll fundamentally change how we approach Crohn's disease. Phase 2 data are looking robust in UC and CD.

Hot questions: Just how good will these drugs be? Who will be first to market? Who will be best in class? How does TL1A look in combination? Does the biomarker stack-up?

2. DUET: Rational Combination Therapy Arrives?

This phase 2b program tests dual biologic therapy — guselkumab (IL-23) plus golimumab (TNF) — in both UC and CD. Early UC data showed impressive results, with combination therapy outperforming either monotherapy.

The paradigm shift: If DUET succeeds, it opens the floodgates for combination biologics in IBD, something rheumatology embraced years ago.

But if it fails? Where does that leave combo strategies?

3. Obefazimod: A Completely Novel Mechanism

This oral, once-daily small molecule upregulates microRNA-124 to dampen inflammation through an entirely new pathway. The phase 3 ABTECT trials in UC are fully enrolled with results expected soon.

What's exciting: After years of cytokine and integrin blockers, obefazimod represents genuine mechanistic innovation — definitely one to watch.

4. VICTRIVA: Vedolizumab + Upadacitinib in CD

This phase 3b trial combines gut-selective anti-integrin therapy with JAK inhibition in Crohn's disease, comparing the combination to vedolizumab alone.

Clinical relevance: Many patients partially respond to vedolizumab but need "something more" for induction. VICTRIVA tests whether adding a JAK inhibitor provides that boost without compromising safety.

5. VECTORS: Making Transmural Healing the New Target

This pragmatic trial uses intestinal ultrasound to guide treatment escalation until patients achieve transmural (full-thickness) healing, not just mucosal healing.

Why it's revolutionary: If VECTORS proves transmural healing prevents complications, it could make ultrasound as important as endoscopy in IBD management.

6. REVAMP UC: the first in a new wave of head-to-heads

Risankizumab versus vedolizumab in moderate to severe UC (NCT06880744). Primary outcomes is endoscopic improvement at week 48.

Impact on drug sequencing: p19’s offer the same safety advantage as vedolizumab; but which drugs are more efficacious? Time to find out!

7. The SPYRE Platform: Modular Innovation

Spyre Therapeutics is building a fascinating pipeline of extended half-life antibodies that can be combined:

• SPY001 (anti-α4β7)

• SPY002 (anti-TL1A)

• SPY003 (anti-IL-23)

• Combinations: SPY120 (α4β7+TL1A), SPY130 (α4β7+IL-23), SPY230 (TL1A+IL-23)

The innovation: Imagine prescribing two mechanisms of action in a single injection - given once or twice a year. SPYRE's modular approach could revolutionise how we think about combination therapy.

8. INTERCEPT: Can We Prevent Crohn's Disease?

This ambitious European consortium will follow 8,000 first-degree relatives of Crohn's patients, using biomarker scores to predict disease onset and intervene before the first symptom appears.

The moonshot: While still early, INTERCEPT represents the holy grail — stopping IBD before it starts.

Part 3: New Strategy Trials — CALM for the AI Era

Two ongoing trials are modernising treat-to-target:

VERDICT tests three strategies in UC:

• Symptom-based targets (traditional)

• Endoscopic remission (current gold standard)

• Histologic remission (the future?)

With 738 patients and cost-effectiveness as a co-primary endpoint, VERDICT could hard-wire histology into routine practice.

QUOTIENT asks a provocative question: Should we proactively switch therapies in patients who feel well but have ongoing endoscopic inflammation? This pragmatic trial randomises such patients to switch drug class versus continue current therapy.

The Digital Trial We Still Need

Imagine combining:

• Weekly home calprotectin tests

• Continuous symptom tracking via apps

• Wearable data (sleep, stress, activity)

• AI algorithms predicting flares 2-4 weeks early

• Automated dose optimisation suggestions

This isn't science fiction — the technology exists. We just need someone brave enough to build the tool and test it in a rigorous trial.

Key Takeaways for Clinical Practice

1. Combination therapy is coming: DUET and VICTRIVA are testing the waters. Start thinking about which patients might benefit from dual mechanisms.

2. Deeper remission targets keep emerging: From clinical to endoscopic to histologic to transmural — the bar keeps rising. VECTORS and VERDICT will tell us if chasing perfection improves outcomes.

3. TL1A are the next class and could change everything: If these antibodies deliver on anti-fibrotic promises, they'll become must-use agents in Crohn's disease.

4. Head to heads are getting interesting: revamp-UC leads the way for a new wave of head-to-head studies to guide drug positioning. Great science versus clinical gain versus industry competition in an increasingly crowded therapeutic landscape? Let’s see where we land!

5. Prevention is on the horizon: INTERCEPT may seem ambitious, but identifying and intercepting pre-clinical IBD could transform our field. And it will probably work … in first-degree relatives at least. The problem is that most new IBD patients have no family history. What then???

The Bottom Line

We're at an inflection point in IBD therapeutics. The trials reading out over the next 24 months won't just add new drugs to our formulary — they'll challenge how we sequence therapies, define treatment goals, and perhaps even prevent disease altogether.

Stay tuned to Atomic IBD as we break down each pivotal readout, cutting through the hype to deliver what actually matters for your practice and your patients.

What trials are you most excited about? Which do you think are overhyped? Drop a comment below.