What drugs are in development for ulcerative colitis?

Overview of Ulcerative ColitisDefinitionon and Symptoms
Ulcerative colitis (UC) is a chronic, idiopathic inflammatory bowel disorder characterized by diffuse inflammation limited to the colonic mucosa and submucosa. Clinically, patients usually present with symptoms such as bloody diarrhea, abdominal pain and cramping, urgency, tenesmus, and weight loss. Other associated symptoms can include fatigue, fever, and in some cases, extra-intestinal manifestations such as arthritis, skin rashes, and eye inflammation. The disease follows a relapsing – remitting course; patients may experience periods of quiescence interspersed with acute flare-ups that cause severe mucosal ulceration and may eventually result in complications such as an increased risk of colon cancer or a need for colectomy if inflammation remains refractory over time.

The pathogenesis tends to involve a dysregulated immune response to the commensal microbiota in genetically predisposed individuals, which inflicts chronic mucosal inflammation and disruption of the barrier function in the colon. While the precise etiology is still not fully understood, a complex interplay of genetic predisposition, environmental influences, microbial dysbiosis, and immune dysregulation is generally accepted as the mechanistic basis for UC. This multifaceted pathology helps to explain why treatment outcomes may vary among patients and why there is an urgent need for increasingly personalized treatment options.

Current Treatment Options
For many years the mainstay of ulcerative colitis treatment has involved a “step-up” approach. Initial management for mild to moderately active UC typically includes aminosalicylates (such as mesalamine) to provide topical anti-inflammatory activity. Moderate or refractory cases are then treated with systemic corticosteroids for short-term control to induce remission. Frequently, imidazoles, immunomodulators like azathioprine, and 6-mercaptopurine are added to sustain remission over the longer term; however, their slow onset of action and long-term toxicities limit their appeal. In cases of severe or refractory disease, biological therapies—especially tumor necrosis factor-alpha (TNF-α) inhibitors (infliximab, adalimumab, golimumab), anti-integrin antibodies (vedolizumab), and interleukin-12/23 antagonists (ustekinumab)—have transformed patient management by producing higher rates of clinical remission, endoscopic healing and sustained corticosteroid-free response. More recently, advancements in oral small molecule inhibitors—including Janus kinase (JAK) inhibitors such as tofacitinib, upadacitinib, and filgotinib as well as sphingosine-1-phosphate (S1P) receptor modulators like ozanimod and etrasimod—have provided new mechanisms of action as alternative options. These drugs have not only broadened the therapeutic armamentarium but also sparked a robust research pipeline exploring novel molecules designed to overcome some of the limitations (such as immunogenicity and parenteral administration) of biologics.

Collectively, while many patients have benefited from these established options, the limitations associated with secondary loss of response, safety concerns over immunosuppression, and the fact that up to 30–40% of patients may not fully respond have spurred an active global pursuit of new UC therapies.

Drug Development Pipeline for Ulcerative Colitis

The current drug development pipeline for UC embraces both early- and late-stage compounds. As this field evolves, early-stage candidates (in preclinical and phase I/II studies) often explore novel targets and mechanisms, whereas late-stage compounds (phase II/III, and those nearing regulatory submission) are designed to offer improved efficacy, safety and convenience over existing treatments.

Early-Stage Drugs
Early-stage drug candidates for ulcerative colitis are typically in the initial phases of clinical testing or are in pre-clinical development. Several of these candidates target innovative mechanisms and may offer new benefits in terms of mucosal healing and reducing long-term complications. For example, some key early-phase drugs include:

• Novel immune modulators and receptor agonists. There is an emerging category of gut-selective modulators that aim to modulate immune cell trafficking within the colon. One such candidate is PL8177, a synthetic cyclic heptapeptide designed to act as an agonist at melanocortin receptor-1 (MC1r). It is being explored for its capacity to reduce inflammation by regulating local immune responses in pre-clinical studies and is already in early clinical evaluation stages for its anti-inflammatory action in UC.

• Other candidates include novel Toll-like receptor (TLR) agonists such as cobitolimod – a TLR9 agonist. Cobitolimod is designed to promote local anti-inflammatory responses when administered intrarectally, and clinical studies have demonstrated promising signs of efficacy in induction treatment for UC. Its unique mechanism of stimulating an innate immune response in a controlled way represents an early-phase innovation in UC drug development.

• Small molecules in the JAK inhibitor category are also represented in the early pipeline. Even though tofacitinib is already approved, improvements in selectivity and safety profiles have led to the development of next-generation JAK inhibitors. For instance, investigational compounds that might have enhanced JAK1 selectivity or even dual inhibition modes are in early studies to see if they can improve efficacy while reducing adverse effects. Such early-phase molecules are often studied as proof-of-concept candidates before the development is advanced to later phase trials.

Moreover, several pre-clinical studies are exploring natural product-based maneuvers and compounds derived from botanical sources. Some molecules combine anti-inflammatory activities with promotion of mucosal integrity. For example, novel hybrid compounds that incorporate hydrogen sulfide releasing moieties (H2S donors) with conventional non-steroidal anti-inflammatory structures are being tested in animal models and may eventually progress to early clinical testing. These molecules aim to reduce gastrointestinal toxicity while simultaneously exerting potent anti-inflammatory activities.

Late-Stage Drugs
Late-stage drugs in development for UC are those that have advanced beyond early proof-of-concept studies and are in advanced phase II/III or regulatory submission phases. These candidates have typically demonstrated promising efficacy and safety in earlier trials. Key examples include:

• Biologics and monoclonal antibodies targeting interleukin pathways have seen significant recognition. Eli Lilly’s mirikizumab is one such agent—a monoclonal antibody that targets IL-23—and is currently in phase III trials for ulcerative colitis. In clinical trials, mirikizumab has demonstrated robust improvements in clinical endpoints in both induction and maintenance settings. Its late-stage development suggests that it may soon become a valuable addition to the established arsenal of biologic therapies.

• Sphingosine-1-phosphate receptor modulators are also well represented among late-stage candidates. Pfizer’s VELSIPITY (etrasimod) has recently received approval in some regulatory territories in addition to being tested in extensive clinical trial programs. Etrasimod has shown significant improvement in clinical remission endpoints in large phase III programs such as the ELEVATE UC 52 and ELEVATE UC 12 trials, positioning it as one of the promising oral therapies for moderate-to-severe UC. Other S1P modulators like ozanimod have already been approved; however, additional compounds in this class with potentially improved safety/tolerability profiles are under late-stage evaluation.

• Another late-stage candidate is izencitinib, an oral, gut-selective pan-JAK inhibitor developed by Theravance Biopharma. Although its phase IIb trials did not meet the primary endpoint related to changes in the Mayo score at week eight, the molecule was well tolerated and garnered safety data consistent with gut-selectivity. These signals have spawned further investigations and potential reformulations that may eventually bring it forward as a late-stage candidate with an optimized therapeutic profile.

• There are also late-stage innovative compounds such as CBP-307, an oral S1P1 receptor modulator. Initial clinical data show that it is highly potent with significant T-cell modulation activity and good pharmacokinetic and pharmacodynamic profiles with once-daily dosing. These characteristics make it one of the promising late-stage candidates addressing inflammatory cell migration and local gut inflammation in UC.

• Some compounds are additionally designed to combine mechanisms; for example, bifunctional antibodies or molecules that target two pathways concurrently (for instance, cytokine inhibition and integrin blockade) may be in late-stage clinical trials aiming to overcome the therapeutic ceiling observed with monotherapy. While details of such dual-acting molecules are emerging, they represent an exciting trend in late-stage UC drug development that could result in improved clinical outcomes.

Collectively, the pipeline features both narrow-focused small molecules and large biologics that aim to capably address the heterogeneity observed in UC pathogenesis and treatment response.

Mechanisms of Action

Understanding the mechanisms by which novel agents work provides additional insight into how they might improve on current treatment profiles. Two major categories of new drugs in the UC development pipeline are biological therapies and small molecule agents.

Biological Therapies
Biologics develop by using engineered monoclonal antibodies or fusion proteins that target specific components of the immune cascade. Many of the current and emerging biologics for UC aim at selective inhibition of cytokines or immune cell trafficking molecules. For example:

• Interleukin-23 inhibitors such as mirikizumab work by binding to the p19 subunit of IL-23. This cytokine plays a key role in the differentiation of Th17 cells and amplification of inflammatory responses. By inhibiting IL-23, mirikizumab modulates the inflammatory cascade at an upstream level and has been shown to produce significant improvements in clinical remission and mucosal healing.

• Other monoclonal antibodies may target integrins, which are crucial for the adhesion and migration of immune cells to the site of inflammation within the gut mucosa. Vedolizumab, for instance, selectively prevents lymphocyte trafficking into intestinal tissues by binding to the α4β7 integrin. While vedolizumab is already approved, next-generation antibodies might further refine this mechanism with improved specificity or altered dosing profiles.

• There is also an interest in biologics that combine mechanisms or target multiple cytokine pathways simultaneously. Some dual-action antibodies are being designed to combine TNF-α inhibition with blockade of other inflammatory cytokines, aiming to achieve more durable control of the disease. Although these molecules are still in early to mid-stage clinical trials, they promise to overcome challenges such as primary non-response or immunogenic loss of efficacy observed with current monotherapies.

Biological agents tend to be administered parenterally; yet, researchers are continuously working on improving tolerability, reducing immunogenicity, and prolonging half-lives to ensure improved efficacy and patient adherence.

Small Molecules
Small molecule agents represent a significant area of innovation, driven by the advantage of oral administration, ease of dose adjustment, and elimination of immunogenicity seen with bulky protein therapeutics. These molecules work by interfering with key intracellular signaling pathways that propagate inflammation. Examples include:

• Janus kinase (JAK) inhibitors are among the most notable small molecules in the UC pipeline. Tofacitinib was the first oral JAK inhibitor approved for UC; however, its pan-JAK inhibition profile is associated with certain safety drawbacks. This has driven the development of next-generation compounds that are more selective for JAK1, such as upadacitinib and filgotinib. These drugs block the JAK-STAT signaling pathway that is critical for the action of multiple pro-inflammatory cytokines, thereby reducing inflammation and improving clinical outcomes.

• Sphingosine-1-phosphate receptor modulators represent another innovative class. Their mechanism relies upon sequestering lymphocytes within lymph nodes, thus reducing the number of inflammatory cells migrating to the gut mucosa. In addition to ozanimod—which is already approved—there are new candidates (for instance, CBP-307 and etrasimod) that are being developed with improved specificity for S1P receptor subtypes (such as S1P1). Their ability to modulate lymphocyte trafficking while minimizing systemic exposure is a promising approach to both safety and efficacy in UC treatment.

• There are also agents under investigation that target innate immune pathways. Cobitolimod, a TLR9 agonist, leverages the natural immune‐response by activating receptors that lead to a local anti-inflammatory state. This gut-restricted activation is intended to trigger mucosal healing by enhancing barrier integrity and modulating cytokine production without causing widespread systemic immunosuppression.

• Beyond these, several molecules are being evaluated for dual inhibition or multi-targeting. These small molecules may interdict multiple intracellular signaling routes simultaneously (for example, combining JAK inhibition with modulatory effects on other signaling proteins) to improve the overall therapeutic index. These multi-targeted strategies are being designed in response both to the heterogeneity of UC pathogenesis and to clinical evidence that monotherapy sometimes hits a “therapeutic ceiling”.

Small molecules are attractive because of their rapid onset of action and convenience, and they often have relatively simpler manufacturing processes compared to biologics. However, safety, particularly in terms of off-target effects and long-term impact on immune surveillance, is a key area under continuous evaluation.

Clinical Trials and Efficacy

Key Clinical Trial Results
Advanced clinical trials provide the backbone that validates the efficacy and safety profiles of new UC drugs. A series of large scale, randomized controlled trials (RCTs) have been conducted for several promising compounds:

• For biologic therapies, the phase III trials of mirikizumab in UC have reported significant clinical remission rates and good mucosal healing outcomes. In the LUCENT-1 trial, mirikizumab was tested in patients with moderate-to-severe UC, and the study demonstrated statistically significant improvement in primary endpoints compared with placebo. These results are coupled with favorable secondary endpoints such as reduced bowel urgency and endoscopic improvement.

• In the small molecule arena, etrasimod (VELSIPITY) has been evaluated in the ELEVATE UC 52 and ELEVATE UC 12 clinical programs. These trials enrolled hundreds of patients and demonstrated not only induction of clinical remission at week 12 but also sustained remission through week 52. The favorable benefit-risk profile shown by etrasimod in these trials underpins its recent market approval in Europe and possibly other regions in the near future.

• Another clinical trial of note is the phase IIb study of izencitinib. Although the primary endpoint (a change in the total Mayo score at eight weeks) was not met, the safety and tolerability profile of this gut-selective pan-JAK inhibitor was promising, prompting a re-evaluation of dosing or study design with the hope to refine its clinical use in subsequent trials.

• Additionally, several studies on TLR agonists (such as cobitolimod) have shown early promising data such as induction of anti-inflammatory cytokine profiles and improvements in clinical response rates in placebo controlled settings. These results support further investigation in larger phase III studies.

These trials also often assess patient-reported outcomes, quality of life measures, and surrogate markers such as fecal calprotectin or CRP, providing a comprehensive picture that goes beyond simple symptom relief. The robust design—often including both induction and maintenance phases—ensures that efficacy is measured over an extended period and reflects real-world therapeutic durability.

Comparative Efficacy of New Drugs
Comparative efficacy is a critical consideration given the increasing number of available options for UC treatment. Network meta-analyses (NMAs) have been conducted comparing biologics, small molecules, and even microbiome-based therapies. For example, NMAs indicate that highly selective JAK inhibitors (upadacitinib and filgotinib) and S1P receptor modulators (such as ozanimod and etrasimod) tend to rank favorably in terms of clinical remission and mucosal healing compared to some established anti-TNF agents.

When comparing biologics among themselves, studies have noted that while TNF-α inhibitors such as infliximab and adalimumab demonstrate robust efficacy, newer agents targeting different mechanisms like IL-23 or integrin pathways offer similar or better performance in certain refractory patient populations. Novel small molecules may have the additional advantage of oral dosing, which can translate into improved patient adherence and, ultimately, better clinical outcomes.

The differences in comparative efficacy can often be attributed to patient selection (biologic-naïve versus biologic-experienced), the specific immune pathways targeted, and differences in trial design; however, the overall trend in current data shows that new drugs can overcome some of the limitations of conventional treatments by inducing more durable and comprehensive mucosal healing, leading to lower rates of relapse over long-term follow-up.

Future Directions and Challenges

Emerging Therapies
Looking ahead, the future of drug development for ulcerative colitis in the next decade is likely to be shaped by several emerging trends and innovative therapeutic strategies. Some of the exciting emerging therapies include:

• Novel biologic agents – small molecules like the next-generation IL-23 inhibitors (for example, mirikizumab) and dual-targeted antibodies that blend TNF-α blockade with inhibition of other pro-inflammatory cytokines are expected to further personalize treatment. The goal is to identify patient subsets that respond optimally to specific mechanisms of action. Combined with the advent of biosimilars, this class will likely continue to evolve rapidly.

• Advanced small molecule drugs – further fine-tuning of JAK inhibitors, S1P modulators, TLR agonists and possibly inhibitors of other intracellular pathways (such as NF-κB or STAT3) that play a direct role in the inflammatory cascade. For example, molecules such as CBP-307 and further derivatives in the S1P modulator class are being refined to maximize gut selectivity and reduce systemic adverse events.

• Microbiome-based therapies – innovative approaches such as fecal microbiota transplantation (FMT) and microbial metabolite administration (without transferring live microbes) are being developed to modify gut dysbiosis. There is also work at identifying “next-generation probiotics” or rationally designed bacterial consortia that could restore intestinal homeostasis in a targeted manner. Early data suggest that these microbiome-based therapeutics might work best in combination with other anti-inflammatory drugs to reinforce mucosal healing.

• Nano-formulated approaches – advancements in nanotechnology are leading to the development of novel drug delivery systems. These include nanoparticles or microparticles that protect the active compound until it reaches the colon. This is especially useful for drugs that are otherwise degraded in the upper gastrointestinal tract. Emerging formulations might allow for enhanced targeting to the inflamed mucosa, thereby increasing local drug concentrations while reducing systemic exposure and side effects.

• Dual-mechanism agents – some of the future investigational strategies involve multivalent compounds or combination therapies that act on more than one target simultaneously. By dual-blocking pathways (for example, inhibiting both JAK-STAT and TNF-α), the therapeutic ceiling that has limited monotherapies may be broken, leading to improved remission and lower relapse rates in chronic disease.

Challenges in Drug Development
Despite these promising directions, several key challenges remain in UC drug development:

• Heterogeneity of the disease – UC is a heterogeneous disorder with variable presentation among patients. Genetic, immunologic, and microbial factors vary widely and likely contribute to differences in treatment responsiveness. This heterogeneity means that a “one-size-fits-all” drug will be difficult to develop, hence the emphasis on personalized or stratified medicine. Predictive biomarkers for treatment response remain scarce, and without them, clinical trials often have to enroll broad patient populations leading to variable results.

• Therapeutic ceiling – Even with advanced biologic and small molecule approaches, many current trials still achieve remission rates in only the 20–30% range in induction studies. This “therapeutic ceiling” is driven by the multifactorial and chronic nature of UC, where single-pathway inhibition may simply not be sufficient. As a result, there is ongoing research to develop combination therapies or drugs with dual mechanisms that can overcome this limitation.

• Long-term safety – Given that UC is a chronic condition often requiring lifelong therapy, long-term safety is a paramount concern. Although newer small molecule drugs provide ease of oral administration and cost benefits, they may have off-target effects that could accumulate over time. Biologics are also associated with risks such as infection and malignancy. Thus, any emerging therapy needs to demonstrate a robust long-term safety profile as well as efficacy.

• Regulatory hurdles and clinical trial design – The evolution in clinical trial design for UC has largely been driven by regulatory requirements and changing treatment populations. As historical trials enrolled mainly biologic-naïve patients, the modern refractory population is more difficult to treat. Additionally, comparator arms, endpoints (e.g., mucosal healing versus clinical remission), and surrogate markers of long-term efficacy are still under refinement. Novel endpoints such as barrier healing and quality-of-life measures are being introduced, but consensus on their standardization across trials is still a work in progress.

• Economic considerations and market competition – The cost of drug development remains high, and many of the innovative therapies are priced significantly higher than conventional treatments. Competition among major players and emerging biotech companies further complicates the market. In this setting, cost-effectiveness and real-world evidence will play increasing roles in determining which drugs are widely adopted.

• Patient adherence and convenience – Although oral small molecules promise better convenience, issues such as dosing frequency, side effects, and even the route of administration (oral versus injectable) can greatly impact adherence. Discrete choice experiments have highlighted that patients’ preferences may differ, with some placing greater value on symptom reduction and route of administration than on other factors. This behavioral component influences trial design as well as regulatory approvals.

Conclusion
In summary, the landscape of drug development for ulcerative colitis is expanding at an unprecedented pace. Starting from a comprehensive understanding of UC—its definition, heterogeneous clinical presentation, and current treatment limitations—the pipeline now includes both early- and late-stage candidates, which are being developed to address unmet needs in an increasingly refractory patient population. The development pipeline spans a range of mechanisms, including highly targeted biological therapies (such as IL-23 inhibitors and integrin blockers) and next-generation small molecules (including selective JAK inhibitors, S1P modulators, and TLR agonists), as well as emerging innovative strategies like microbiome-based therapies and nanotechnology-based drug delivery systems. Numerous clinical trials, such as those for mirikizumab, etrasimod (VELSIPITY), PL8177, and CBP-307, have already produced promising data on clinical remission, mucosal healing, and improved quality-of-life outcomes. NMAs have begun to show that these emerging therapies may offer comparable or superior efficacy to established treatments while also providing alternative routes of administration and potentially improved safety profiles.

Nevertheless, challenges remain. The heterogeneous nature of UC demands a more personalized approach, and the “therapeutic ceiling” seen in many trials underscores the necessity for combination or dual-mechanism therapies. Regulatory, safety, and economic considerations continue to pose hurdles, and future research must focus on identifying predictive biomarkers for response and long-term outcomes. In this context, the pipeline of both biologics and small molecules is poised to not only expand our therapeutic armamentarium but also shift the treatment paradigm toward a more individualized and durable approach.

In conclusion, a range of promising drugs are in development for ulcerative colitis across multiple therapeutic classes—from early-stage immune modulators and natural product-derived small molecules to late-stage advanced biologics and novel small molecule inhibitors. These drugs target various pathways such as cytokine signaling (JAK-STAT, IL-23), integrin-mediated cell trafficking, S1P receptor modulation, and innate immune activation via TLRs. The continued evolution in clinical trial design and the use of innovative delivery methods will likely enable these therapies to break through current efficacy barriers and meet unmet clinical needs, ultimately leading to more effective, personalized care for patients with ulcerative colitis. Future directions will undoubtedly emphasize combined and dual-targeting strategies, pragmatic approaches to address long-term safety, and the integration of predictive biomarkers to refine patient selection—all of which are critical to overcoming the challenges inherent in treating such a complex disease.