Ulcerative colitis research moved faster between 2021 and 2025 than in the prior decade combined — with five new drug approvals across three mechanistically distinct classes. The S1P receptor modulators (ozanimod, etrasimod) introduced the first genuinely new mechanism in UC in years. JAK inhibitors — upadacitinib in particular — produce the highest induction remission rates ever seen in a UC Phase 3 trial, with all the cardiovascular risk conversation that comes with them. And selective IL-23p19 inhibitors (mirikizumab, risankizumab) are showing strong efficacy in biologic-experienced patients, the population that had the least to work with before. The 2026 trial landscape is largely about what happens after all of this: combination therapy, positioning these agents earlier in the disease course, and the FMT work that could eventually offer a route to remission without immunosuppression.
This article is for informational purposes only and does not constitute medical advice. Clinical trial eligibility and availability vary. Always consult a qualified healthcare professional before making any medical decisions or considering participation in a clinical trial.
Summary
Ulcerative colitis treatment has expanded dramatically from its corticosteroid and aminosalicylate origins. In 2026, multiple new drug classes have reached approval: S1P receptor modulators (ozanimod, etrasimod), selective JAK1 inhibitors (upadacitinib), IL-23p19 inhibitors (mirikizumab, risankizumab), and gut-selective biologics (vedolizumab, now with biosimilar competition). The central research challenge has shifted from finding drugs that work to understanding optimal sequencing, combination strategies for partial responders, and whether earlier use of advanced therapies can prevent the cumulative colonic damage that drives colorectal cancer risk.
S1P Modulators: What the Long-Term Ozanimod Data Shows
Sphingosine-1-phosphate (S1P) receptor modulators reduce gut inflammation by trapping lymphocytes in lymph nodes — preventing their migration to the inflamed intestinal mucosa. The mechanism is fundamentally different from biologics or JAK inhibitors, with no direct anti-cytokine effect. This matters clinically because patients who fail biologics on the basis of secondary loss of response (antibody formation, pharmacokinetic failure) may still respond to S1P modulators, which operate via a non-overlapping mechanism.
Ozanimod (Zeposia, Bristol Myers Squibb) was approved for moderate-to-severe UC in May 2021. The TRUE NORTH Phase 3 trial showed clinical remission in 18.4% at 10 weeks (induction) and 37% at 52 weeks (maintenance), with endoscopic improvement in 45.7% of patients at one year. Long-term extension data now available at three years show sustained remission rates with durable tolerability. Unlike first-generation S1P modulators (fingolimod), ozanimod has minimal heart rate effects — the first-dose cardiac monitoring required for fingolimod is not required with ozanimod. Current trials are evaluating ozanimod in combination with biologic therapy for partial responders and in pediatric UC.
Etrasimod (Velsipity, Pfizer) received FDA approval in October 2023. The ELEVATE UC 52 and ELEVATE UC 12 trials showed clinical remission in 32.1% at 52 weeks and 24.8% at 12 weeks in biologic-naive patients — higher than ozanimod's 52-week rate in a similarly defined population, though cross-trial comparisons are unreliable. Etrasimod selectively targets S1P1, S1P4, and S1P5 receptors. The S1P4 and S1P5 selectivity may influence immunological effects beyond gut-specific lymphocyte trafficking. Active trials include adolescent UC and etrasimod in biologic-experienced UC, addressing a gap in the ELEVATE program's enrollment.
Upadacitinib: Highest Remission Rates, Most Important Safety Conversation
Upadacitinib (Rinvoq, AbbVie) is a selective JAK1 inhibitor — designed to spare JAK2, JAK3, and TYK2 to reduce off-target hematologic and thrombotic effects relative to tofacitinib. The U-ACHIEVE induction trials reported clinical remission in 26.1% at 8 weeks for the 45 mg dose in biologic-naive patients, and 19.5% in biologic-experienced patients — higher induction rates than any previously tested UC drug, including anti-TNF agents and vedolizumab. The U-ACHIEVE maintenance trial showed 42% clinical remission at 52 weeks with 15 mg maintenance dosing after 45 mg induction. Endoscopic remission and histologic normalization rates at one year exceeded prior Phase 3 benchmarks.
The context that cannot be separated from these efficacy data: upadacitinib carries an FDA boxed warning for serious cardiovascular events, malignancy (particularly lymphoma and non-melanoma skin cancer), and venous thromboembolism — the same class effect warning applied to all JAK inhibitors based on the ORAL Surveillance tofacitinib data. The risk profile is concentration- and duration-dependent, and significantly higher in patients over 65 with cardiovascular risk factors or a history of smoking. For younger UC patients without cardiovascular comorbidities, the absolute risk increment appears small; for older patients with risk factors, the calculus is genuinely complex and requires explicit shared decision-making. Trials in 2026 are generating long-term real-world safety data and specifically examining the 15 mg maintenance dose risk profile in younger, low-risk populations.
IL-23 Inhibitors: Mirikizumab, Risankizumab, and the Biologic-Experienced Gap
The selective IL-23p19 inhibitors (blocking the p19 subunit of IL-23 without affecting IL-12) are arguably the most important class advance for biologic-experienced UC patients, where prior options were limited and response rates lower. IL-23 is a master regulator of intestinal Th17 inflammation; unlike IL-6 (a general inflammatory cytokine with systemic effects), IL-23p19 inhibition is more gut-relevant.
Mirikizumab (Omvoh, Eli Lilly) received FDA approval for moderately to severely active UC in June 2023. The LUCENT-1 induction trial showed clinical remission in 24.2% at 12 weeks; the LUCENT-2 maintenance trial showed remission in 49.9% at 52 weeks. The most clinically important finding: in biologic-experienced patients (who had failed at least one biologic prior to enrollment), mirikizumab showed clinical remission rates of 14.3% at induction and 40.4% at maintenance — meaningful rates in a population historically difficult to treat.
Risankizumab (Skyrizi, AbbVie), already approved for Crohn's disease and psoriasis, completed Phase 3 for UC (INSPIRE induction and COMMAND maintenance trials) with primary endpoint results reported in 2024–2025, showing comparable clinical profiles to mirikizumab in both biologic-naive and biologic-experienced populations. The FDA submission for UC is pending. Head-to-head comparison trials between mirikizumab and risankizumab are under discussion — likely necessary to differentiate positioning in an increasingly crowded IL-23 inhibitor landscape.
FDA Approvals for Ulcerative Colitis: 2024, 2025 and 2026
The pace of FDA approvals for ulcerative colitis drugs has accelerated significantly since 2021. Here is a timeline of major UC approvals and regulatory activity from 2024 through 2026:
| Year | Drug | Action | Notes |
|---|---|---|---|
| 2023 | Etrasimod (Velsipity) | FDA approved | Oral S1P receptor modulator; 2nd oral non-JAK advanced therapy for UC |
| 2023 | Mirikizumab (Omvoh) | FDA approved | First selective anti-IL-23 approved for UC; strong data in biologic-experienced patients |
| 2024 | Risankizumab (Skyrizi) | Phase 3 data — UC | INSPIRE and COMMAND trials reported; sNDA submission anticipated for UC indication |
| 2024 | Biosimilars to Vedolizumab | FDA approvals | Multiple vedolizumab biosimilars entering US market; cost reduction for gut-selective therapy |
| 2025–2026 | Next-gen IL-23 inhibitors | Phase 3 recruiting | Brazikumab, tulisokibart and other IL-23-targeting agents in late-stage UC trials |
The trajectory is significant: patients who exhausted options five years ago — failed anti-TNF followed by vedolizumab failure — now have mechanistically distinct oral and biologic options with Phase 3 evidence across multiple drug classes. The active 2026 trial landscape is predominantly studying combination strategies (biologic plus small molecule), earlier positioning of advanced therapies before anti-TNF exposure, and optimization of the induction-to-maintenance transition to maximize endoscopic and histologic remission rates that predict long-term outcomes.
FMT for UC: Where the Evidence Actually Stands
Fecal microbiota transplantation for UC operates on solid theoretical grounding — UC patients have demonstrably reduced microbial diversity and altered microbiome composition, with loss of specific bacterial taxa (particularly Faecalibacterium prausnitzii and other butyrate producers) that maintain epithelial barrier function. The translational question is whether restoring those communities can meaningfully reduce mucosal inflammation.
The controlled trial data is more interesting than the clinical adoption rate suggests. The FOCUS and TOPF trials, using colonoscopic delivery of pooled multi-donor FMT preparations, showed clinical remission in 32–35% of patients with active UC versus 9–10% for water enema placebo. The effect is real. The problem is reproducibility: "super-donor" characteristics that predict FMT success are not yet consistently defined, donor preparation varies between centers, and the delivery method (colonoscopic pooled FMT appears superior to enema-based approaches) matters substantially.
The clinical development trajectory has been challenging. SER-287 (Seres Therapeutics' capsule-based FMT) failed Phase 2b. Next-generation products targeting specific bacterial communities — Vedanta Biosciences VE303, a defined consortium of 8 commensal Clostridia species — are in Phase 2 trials for UC and other indications. These are distinct from donor FMT: manufactured, characterized products whose composition can be controlled and reproduced. The path from "FMT works in trials" to "FMT becomes standard therapy" requires these manufactured approaches to succeed.
Key Takeaways
- Ozanimod (37% remission at 52 weeks, TRUE NORTH) and etrasimod (32.1% at ELEVATE UC 52) offer oral alternatives with non-overlapping mechanisms compared to biologics — important for patients with secondary biologic loss of response.
- Upadacitinib has the highest induction remission rate of any UC drug (26.1% at 8 weeks, biologic-naive) but carries important cardiovascular and malignancy warnings — shared decision-making is essential, particularly for patients over 65 with cardiovascular risk factors.
- Mirikizumab and risankizumab show strong efficacy in biologic-experienced patients (mirikizumab: 40.4% maintenance remission) — the population most underserved by prior drug development.
- Colonoscopic multi-donor FMT achieves ~32–35% clinical remission in controlled trials, with donor selection appearing critical. Manufactured bacterial consortium products are in Phase 2 and represent the most plausible path to reproducible FMT therapy.
- The 2026 trial focus has shifted to combination therapy (biologic plus small molecule), earlier advanced therapy initiation, and whether endoscopic-histologic remission targets can be achieved at rates that meaningfully reduce long-term colorectal cancer risk.