Background: Ulcerative colitis is one of the main entities of inflammatory bowel diseases. The clinical course of this immune-mediated disorder is marked by unpredictable exacerbations and asymptomatic remission, causing lifelong morbidity. Optimized anti-inflammatory treatment is a prerequisite to not only restore the quality of life of the affected patients but also halt progressive bowel damage and reduce the risk for colitis-associated neoplasia. Advances in understanding the underlying immunopathogenesis of ulcerative colitis have led to the advent of targeted therapies that selectively inhibit crucial molecular structures or signaling pathways that perpetuate the inflammatory reaction. Summary: We will delineate the mode of action and summarize efficacy and safety data of current and emerging targeted therapies in ulcerative colitis, which encompasses representatives of the drug classes of antibodies, small molecules, and oligonucleotides. These substances have already been approved for induction and maintenance treatment or are being tested in late-stage clinical trials in moderately-to-severely active ulcerative colitis patients. These advanced therapies have enabled us to define and achieve novel therapeutic outcomes, such as clinical and endoscopic remission, histological remission, mucosal healing, and recently, also barrier healing as an emerging outcome measure. Key Messages: Established and emerging targeted therapies and monitoring modalities broaden our therapeutic armamentarium and have enabled us to define novel therapeutic outcomes that have the potential to modify the individual disease course of patients with ulcerative colitis.

Ulcerative colitis represents one of the main entities of inflammatory bowel diseases (IBD). It affects the large intestine with typical inclusion of the rectum and continual proximal extension of mucosal inflammation. Clinically apparent are heightened stool frequency, bloody diarrhea, abdominal pain, urgency, general malaise, and fatigue. It is characterized by a relapsing and remitting disease course which is associated with marked morbidity, having a major impact on an individual’s quality of life and their ability to work, which highlights the need for optimized anti-inflammatory therapy. The complexity of the underlying pathophysiology is not yet entirely understood. However, it is known that genetic predisposition, environmental factors, and the gut microbiome conspire to initiate an immune-mediated inflammatory cascade that results in intestinal tissue damage and disease-related complications (e.g., structural tissue damage, heightened risk of colorectal cancer). Appropriate medical therapy depends on activity, severity and extent of disease. Furthermore, previous therapeutic exposure, existing extraintestinal manifestations, and comorbidities are considered. Anti-inflammatory therapy should only be introduced after objective evidence for inflammatory activity, such as biochemical markers (CRP, faecal Calprotectin), sonography, or endoscopic examination [1]. Moreover, it is recommended to introduce a long-term remission therapy after successful flare therapy. Patients with mild-to-moderate disease activity are primarily treated with aminosalicylates. In patients with mild-to-moderate proctitis, treatment with aminosalicylates in suppository form should be initiated. In case of failure, it is recommended to add topical corticosteroids. In patients with left-sided or extensive colitis, initial therapy should comprise combination therapy of an oral combined with a locally applied aminosalicylate. In refractory patients and patients with moderate-to-severe disease activity, systemic therapies are needed that include corticosteroids, biological therapies, and small molecules. Here, advanced therapies encompass the substance classes of anti-tumor necrosis factor (TNF) antibodies, anti-integrin antibodies, anti-interleukin (IL)-12/23 antibodies, Janus kinase (JAK) inhibitors, and recently also sphingosine 1-phosphate (S1P) receptor modulators. Colectomy should always be considered in therapy-refractory patients [2]. With increased understanding of the underlying immune pathophysiology, novel molecular targets have been identified with subsequent development of corresponding treatments with promising clinical study data. Many of these agents have entered the late-stage clinical trial phase and can potentially further enlarge the current therapeutic possibilities [3]. Likewise, with the described progress in available therapies, treatment goals are evolving simultaneously. Traditionally, treatment aimed mainly on symptom control, whereas nowadays biochemical remission, endoscopic remission, as well as restoration of quality of life are being strived for. Furthermore, novel endpoints that could potentially have an impact on the subsequent disease course such as histological remission and endoscopic barrier healing should be taken into account [4]. Interventional trials will offer further insight into positioning of these outcomes in clinical practice. The following review will give an overview on currently available and emerging therapies in ulcerative colitis.

Anti-TNF Antibodies: Infliximab, Adalimumab, Golimumab

Approval of the intravenously administered chimeric monoclonal IgG1 anti-TNF antibody infliximab in 2005 ushered in the era of biological treatments for ulcerative colitis. In the Active Ulcerative Colitis Trials (ACT) 1, clinical response at week 8 was achieved by 69% in the 5 mg/kg compared to 37% in the placebo group (p < 0.0001). In ACT 2, 64% of patients who received 5 mg/kg and 61% of patients who received 10 mg/kg of infliximab had a clinical response at week 8, as compared with 29% of those who received placebo (p < 0.001). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45% and 44%, respectively) than did those who received placebo (20%; p < 0.001). It has to be noted that all participating patients were biological naïve in these trials [5]. Subsequently, subcutaneous formulation of infliximab (CT-P13) has recently been shown to be as effective as intravenously administered infliximab after two doses of intravenous induction in a randomized trial [6]. The anti-TNF IgG1 monoclonal antibody adalimumab is subcutaneously administered, and induction of clinical remission at week 8 was 16.5% in the adalimumab and 9.3% in the placebo group (p = 0.019), while corresponding values for week 52 were 17.3% and 8.5% (p = 0.004) [7]. The human IgG1 anti-TNF antibody golimumab is also administered subcutaneously and demonstrated clinical response rates of 51.0% at week 6 in patients given 200 mg/100 mg golimumab versus 30.3% compared to placebo (p ≤ 0.0001). In the maintenance trial though week 54, 47% of patients receiving 50 mg golimumab and 49.7% of patients receiving 100 mg golimumab maintained clinical response compared to 31.2% of patients getting placebo (p = 0.010 and p < 0.001, respectively) [8, 9]. The anti-TNF agent certolizumab pegol has only been approved for treatment in Crohn’s disease but not ulcerative colitis [10]. Given the complexity of TNF signaling, the identification of the mechanism of action of anti-TNF therapy is challenging [11]. One of the main modes of action is that anti-TNF antibodies induce apoptosis in formerly apoptosis-resistant T cells indirectly by targeting the interaction of membrane TNF (mTNF)-expressing macrophages and TNFR2-expressing T cells (Fig. 1: 1) [12], which also build the basis to show that heightened mucosal mTNF expression could be used to predict subsequent response to anti-TNF therapy in a molecular endoscopy study [13, 14].

Fig. 1.

Signaling pathways in the pathogenesis of ulcerative colitis targeted by current and emerging advanced therapies. In ulcerative colitis, many cells, molecules, and pathways have been identified to be heavily involved in disease pathogenesis, leading to the development of advanced therapies. Already established anti-TNF antibodies target the soluble and membrane forms of TNF (1), while the anti-integrin antibody vedolizumab targets the alpha4beta7 integrin to inhibit lymphocyte trafficking into the gut (2), while ustekinumab inhibits the common p40 subunit of IL-12 and IL-23 (3), and anti-IL-23 antibodies selectively block the p19 subunit of IL-23 (6). The approved JAK inhibitors tofacitinib (pan JAK inhibitor) and filgotinib and upadacitinib (both selective JAK-1 inhibitors) target the important JAK-STAT signaling pathway (4), which is also inhibited by newly developed JAK inhibitors (9). The S1PR modulator ozanimod (5) and newly developed etrasimod (7) inhibit egress of lymphocytes from the lymphatic tissue. The TRL-9 agonist cobitolimod (8), the soluble gp130-Fc-fusion protein olamkicept (10), the miR-124 upregulator obefazimod, and the anti-TL1A antibody PRA023 are in late-stage clinical development (12). Image made with BioRender (License Atreya).

Fig. 1.

Signaling pathways in the pathogenesis of ulcerative colitis targeted by current and emerging advanced therapies. In ulcerative colitis, many cells, molecules, and pathways have been identified to be heavily involved in disease pathogenesis, leading to the development of advanced therapies. Already established anti-TNF antibodies target the soluble and membrane forms of TNF (1), while the anti-integrin antibody vedolizumab targets the alpha4beta7 integrin to inhibit lymphocyte trafficking into the gut (2), while ustekinumab inhibits the common p40 subunit of IL-12 and IL-23 (3), and anti-IL-23 antibodies selectively block the p19 subunit of IL-23 (6). The approved JAK inhibitors tofacitinib (pan JAK inhibitor) and filgotinib and upadacitinib (both selective JAK-1 inhibitors) target the important JAK-STAT signaling pathway (4), which is also inhibited by newly developed JAK inhibitors (9). The S1PR modulator ozanimod (5) and newly developed etrasimod (7) inhibit egress of lymphocytes from the lymphatic tissue. The TRL-9 agonist cobitolimod (8), the soluble gp130-Fc-fusion protein olamkicept (10), the miR-124 upregulator obefazimod, and the anti-TL1A antibody PRA023 are in late-stage clinical development (12). Image made with BioRender (License Atreya).

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Anti-Integrin Antibody: Vedolizumab

The humanized IgG1 anti-integrin antibody vedolizumab binds to alpha4beta7-expressing lymphocytes and thus inhibits trafficking to the intestine by inhibiting their interaction with MAdCAM1 expressed on endothelial cells (Fig. 1: 2). The primary outcome for induction therapy, clinical response at week 6, was reached by 47.1% receiving vedolizumab and 25.5% receiving placebo. At week 52, patients who were randomly assigned to continue receiving vedolizumab were more likely to have clinical remission than those who were randomly assigned to switch to placebo (41.8 and 44.8% of patients receiving vedolizumab every 8 or every 4 weeks, respectively, vs. 15.9% [p < 0.001]) [15]. Vedolizumab has a favorable safety profile with low incidence rates of serious infections over an extended treatment period [16].

Anti-IL12/23 Antibody: Ustekinumab

Ustekinumab is an IgG1 antibody that binds to the p40 subunit common to IL-12 and IL-23 and prevents their interaction with the IL-12 receptor β1 subunit of the IL-12 and IL-23 receptor complexes (Fig. 1: 3). These cytokines modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets [17]. At week 8, 56.5% patients receiving ustekinumab achieved a clinical response, compared to 31.3% with placebo (p < 0.001). The percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%; p = 0.002 and p < 0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo [18].

JAK Inhibitors: Tofacitinib, Filgotinib, Upadacitinib

Cytokines bind to corresponding receptors expressed on cell surfaces, triggering activation and initiation of intracellular signaling pathways. JAKs are a family of receptor-associated tyrosine kinases that have an essential role in cytokine signal transduction pathways. There are four members of the JAK family (JAK1, JAK2, JAK3, and TYK2). The JAK-signal transducers and activators of transcription (STAT) pathway often lead to the gene expression of many inflammatory pathways and are therefore an attractive target for the treatment of ulcerative colitis, as many cytokines implicated in disease pathogenesis use this pathway (Fig. 1: 4) [19]. Tofacitinib, an oral non-selective JAK inhibitor, was the first representative of the class of JAK inhibitors that has been approved for treatment of ulcerative colitis patients. In the OCTAVE Induction 1 and 2 trials, where patients received tofacitinib 10 mg BID, 18.5% versus 8.2% (p = 0.007) of patients and 16.6% versus 3.6% (p < 0.001) achieved clinical remission at 8 weeks in the tofacitinib compared to the placebo groups, respectively. In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% and in 40.6% of the patients in the 5 mg and 10 mg tofacitinib group, respectively, compared with 11.1% in the placebo group (p < 0.001) [20]. The once-daily, selective JAK-1 inhibitor filgotinib demonstrated at week 10, that a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A: 26.1 vs. 15.3%; p = 0.0157; induction study B: 11.5 vs. 4.2%; p = 0.0103). At week 58, 37.2% of patients given filgotinib 200 mg had clinical remission versus 11.2% in the respective placebo group (p < 0.0001) [21]. Statistically significantly more patients achieved clinical remission with the once-daily, selective JAK-1 inhibitor upadacitinib 45 mg (26% in UC1 and 34% in UC2) than in the placebo group (5% in UC1 and 4% in UC2, respectively, p < 0 0001). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg: 42%, 30 mg: 52%) than those receiving placebo (12%; p < 0.0001) [22]. In a recent randomized trial, called Oral Surveillance, rheumatoid arthritis patients aged >50 years with at least an additional cardiovascular risk factor at baseline, treated with tofacitinib experienced a higher proportion of major adverse cardiovascular events and cancer compared with the anti-TNF antibody (adalimumab or etanercept)-treated control group [23]. However, extrapolating these findings to ulcerative colitis patients may not be appropriate, as prevalence of risk factors is different across different indications and higher incidence of the described outcomes could yet not be seen in the ulcerative colitis patient population [24]. Selection of these agents, as with any other ones, should therefore always be based on patient profile and individual benefit-risk profile based on the risk factors.

S1P Receptor Modulator: Ozanimod

S1P is a bioactive lipid mediator that controls several cellular processes by binding with varying affinities to five S1P receptors (S1PR) expressed on various immune cells. There is a S1P gradient that is based on relatively low concentrations of S1P in lymphoid organs and a higher one in the lymph, which leads to the egress of lymphocytes from lymphoid tissue into the systemic circulation towards the inflamed intestinal tissue due to interaction between S1P and S1PR. S1PR agonists induce the internalization of the receptor and its subsequent degradation, leading to retention of lymphocytes within the lymph nodes and inhibition of lymphocyte trafficking to sites of inflammation (Fig. 1: 5) [25]. The S1P1 and S1P5 agonist ozanimod has already been approved for the treatment of ulcerative colitis patients. The incidence of clinical remission was significantly higher among patients who received 0.92 mg ozanimod than among those who received placebo during both induction (18.4 vs. 6.0%, p < 0.001) and maintenance (37.0 vs. 18.5%, p < 0.001) studies. The incidence of infection with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance [26].

Treatment of ulcerative colitis has greatly improved with the development of advanced therapies targeting an array of pivotal molecules or pathways that perpetuate the intestinal inflammatory reaction. Nevertheless, only a subgroup of patients respond to initiated treatment, and initial responders are often prone to lose response to therapy in the course of continued treatment, defining a large unmet clinical need for innovative therapeutic concepts. Furthermore, therapies are often associated with systemic side effects, such as increased susceptibility to serious infections or treatment-related complications. Novel therapeutic strategies are therefore needed, and greater understanding of the underlying immunopathogenic basis of ulcerative colitis has led to an exponential rise in the number of developed substances in late-stage clinical trial development. They should ideally be based on new-found mechanisms of action that are associated with higher efficacy rates and less risk of general immunosuppression. These agents should demonstrate efficacy not only in advanced therapy naive but also exposed patients [27]. Compatibility with potential combination strategies with other advanced therapies to either enhance efficacy in the treatment of ulcerative colitis or enable efficient and safe simultaneous treatment of different inflammatory disease entities (e.g., rheumatological or dermatological diseases) would also be welcomed. In the following, we will present promising new therapeutic approaches that are currently being tested in clinical trials in moderate-to-severe ulcerative colitis patients and may soon enrich our current therapeutic armamentarium.

Anti-IL-23p19 Inhibitors

IL-23p19 has been identified in preclinical studies to be mainly involved in the pathogenesis of IBD. It is a heterodimeric cytokine composed of a unique p19 subunit and a p40 subunit, which it shares with IL-12. It is predominantly produced by macrophages and antigen-presenting cells and is of great importance for the generation of pathogenic Th17 cells, that are characterized by the production of IL-17, IL-21, and IL-22, interferon (IFN)-γ and TNF. IL-23 also inhibits regulatory T-cell responses, further perpetuating the inflammatory reaction. Moreover, genome-wide association studies [GWAS] have identified genetic variants in the IL-23 receptor region that were associated with ulcerative colitis susceptibility, and enhanced IL-23 levels could be found in the mucosa of IBD patients with active inflammation [28]. While the anti-40 monoclonal antibody ustekinumab, which inhibits both IL-12 and IL-23, has already been approved for the treatment of ulcerative colitis, several specific IL-23p19 antibodies are in late-stage clinical development or have already completed it (Fig. 1: 6). The humanized monoclonal IgG4 antibody mirikizumab is the first IL-23p19 inhibitor that has already completed the randomized phase 3 induction and maintenance trials, and approval for therapy is expected in a short time. It was given 300 mg intravenously every 4 weeks in the induction study and 200 mg subcutaneously in the maintenance trial. The LUCENT-1 induction study showed a statistically significant rate of clinical remission at week 12 in favor of mirikizumab in comparison to placebo application (24.2 vs. 13.3%; p = 0.00006). Clinical response at week 12 was achieved by 63.5% in the mirikizumab and 42.2% in the placebo group (p < 0.0001). The subsequent LUCENT-2 maintenance phase 3 trial assigned clinical responders to mirikizumab induction treatment to either receive mirikizumab or placebo through week 40, for a total of 52 weeks of study treatment. The primary endpoint of clinical remission was achieved by 49.9% of the mirikizumab-treated patients versus 25.1% of the placebo-treated patients (p < 0.001). Mirikizumab not only showed efficacy in comparison to placebo in biological naïve patients (51.5 vs. 30.7%; p < 0.001) but also in patients with previous exposure to biological therapies (46.1 vs. 15.6%; p < 0.001) [29].

This heightened efficacy in biological exposed patients, who were predominantly exposed to prior anti-TNF therapy, fits well with recent data where an IL-23-induced molecular resistance to anti-TNF therapy could be shown in Crohn’s disease patients, suggesting that targeting IL-23 might be particularly effective in this IBD patient group [28]. All other prespecified outcome measures (e.g., endoscopic remission, histologic-endoscopic mucosal remission, urgency) were also met by mirikizumab with statistical significance when compared to placebo. The overall incidence of adverse events was comparable between the mirikizumab and placebo groups [29]. Three additional anti-IL-23p19 antibodies, guselkumab, risankizumab, and brazikumab, are being investigated in phase 2 trials. Here, guselkumab has proven its effectiveness in a concluded phase 2b randomized controlled trial as it was superior to placebo in achieving the primary endpoint of clinical response at week 12 (61.1% pooled for guselkumab 200 mg and 400 mg doses vs. 27.6% placebo; p < 0.001). There was comparable effectiveness of the 200 mg and 400 mg doses. Guselkumab was well tolerated in the study [30]. Further trial data are awaited. Therapeutic effectiveness of guselkumab was also further studied in a phase 2a trial as advanced combination therapy with the anti-TNF antibody golimumab in moderate-to-severe ulcerative colitis patients. Participating patients received either intravenous guselkumab 200 mg at weeks 0, 4, and 8 or golimumab 200 mg subcutaneously at week 0 and then 100 mg at weeks 2, 6, and 10, or a combination of these treatment regimens. Combination therapy of both substances was significantly more effective than either monotherapy groups for clinical remission (36.6% for combination treatment of guselkumab and golimumab, 21.1% for guselkumab monotherapy, and 22.2% for golimumab monotherapy) and endoscopic improvement (49.3% for combination treatment of guselkumab and golimumab, 29.6% for guselkumab monotherapy, and 25% for golimumab monotherapy) at week 12. There were no markable differences regarding safety between treatment groups, but long-term data on the potential risks of combination therapy are needed [31]. Long-term effectiveness and safety of guselkumab and golimumab combination therapy will be explored in the recently initiated DUET-CD and DUET-UC trials.

S1PR Modulators

Etrasimod is an orally once-daily selective S1P1, S1P4, and S1P5 agonist (Fig. 1: 7) that was recently tested in a randomized phase 3 trial that comprised a 12-week induction followed by a 40-week maintenance period with a treat-through design. The primary endpoint of clinical remission at weeks 12 and 52 was reached with statistical significance in favor of etrasimod 2 mg/day compared to placebo in the ELEVATE UC 52 trial (27 vs. 7%; p < 0.0001 at week 12 and 32% vs. 7% at week 52; p < 0.0001, respectively). Key secondary endpoints were also met with statistical significance by etrasimod. The conducted phase 3 trial also included patients with isolated ulcerative proctitis, where efficacy of etrasimod could also be shown. There were 9 etrasimod-associated events of bradycardia, and two patients discontinued the study due to symptomatic bradycardia [32].

Toll-Like Receptor 9 Agonist

The intracellular receptor Toll-like receptor 9 (TLR-9) recognizes bacterial DNA by serving as a ligand for its CG (CpG) motifs. These CpG sequence motifs composed of unmethylated CpG dinucleotides have been identified as the immunostimulatory component of bacterial and viral DNA. Cobitolimod is a single-stranded DNA-based synthetic oligonucleotide that contains an unmethylated CpG motif, that activates TLR-9 on target cells, such as lymphocytes or macrophages. Cobitolimod application resulted in suppression of pro-inflammatory mucosal Th17 cells and activation of anti-inflammatory Il-10-producing mucosal wound healing macrophages and regulatory T cells. The cobitolimod-mediated modulation of the Th17/Treg cell immune imbalance and activation of IL-10-producing macrophages and T cells represents a novel therapeutic mechanism (Fig. 1: 8) [33]. Effectiveness of cobitolimod applied as a rectal enema was tested in the randomized, phase 2b CONDUCT study in patients with moderate-to-severe, left-sided ulcerative colitis. Patients were randomized to receive rectal enemas of cobitolimod 31 mg, 125 mg, or 250 mg at weeks 0 and 3, cobitolimod 125 mg at weeks 0, 1, 2, and 3, or placebo. Significantly more patients achieved the primary endpoint of clinical remission at week 6, in the cobitolimod 250 mg group in comparison to placebo (21.4 vs. 6.8%; p = 0.0247). There was no statistically significant difference in clinical remission versus placebo in the other tested cobitolimod doses. There were similar adverse event rates across treatment groups including placebo, and no significant serious adverse events occurred with cobitolimod application [34]. There is a randomized phase 3 trial ongoing to further investigate the effectiveness of cobitolimod in left-sided ulcerative colitis patients.

JAK Inhibitors

Recently, ritlecitinib which inhibits JAK3, as well as the Tec kinase TEC, and brepocitinib which suppresses JAK1 and TYK2 have been tested in a phase 2b umbrella VIBRATO study (Fig. 1: 9). Here, ritlecitinib 20 mg, 70 mg, 200 mg and brepocitinib 10 mg, 30 mg, 60 mg, or placebo were tested. The placebo-adjusted mean total Mayo Score at week 8 were −2.0, −3.9, and −4.6 for ritlecitinib 20, 70, and 200 mg, respectively (p = 0.003, p < 0.001, p < 0.001), and −1.8, −2.3, and −3.2 for brepocitinib 10, 30, and 60 mg, respectively (p = 0.009, p = 0.001, p < 0.001). Proportions of patients with modified clinical remission at week 8 were 13.7%, 32.7%, and 36.0% for ritlecitinib 20, 70, and 200 mg, respectively, and 14.6%, 25.5%, and 25.5% for brepocitinib 10, 30, and 60 mg, respectively [35].

The JAK1 inhibitor ivarmacitinib 8 mg once daily, 4 mg twice daily, or 4 mg once daily was also tested in comparison to placebo in a recently conducted phase 2 study. The primary endpoint of clinical response at week 8 was met with statistical significance by ivarmacitinib 8 mg once daily (46.3%; p = 0.066), 4 mg twice daily (46.3%; p = 0.059), and 4 mg once daily (43.9%; p = 0.095) groups versus placebo (26.8%). During the initial 8-week period, treatment-emergent adverse events occurred in 43.9–48.8% of ivarmacitinib-treated patients and in 39.0% of the placebo group and were predominantly mild [36] (Fig. 1: 9).

Soluble IL-6 Receptor Inhibition

The pro-inflammatory cytokine Il-6 has been shown to be centrally involved in the pathogenesis of IBD. The complex of IL-6 and its soluble receptor (sIL-6R) has been previously shown to activate gp130-positive mucosal T cells lacking the membrane-bound IL-6R in IBD. This so-called trans-signaling process leads to augmented mucosal T-cell resistance against apoptosis, which results in unrestrained accumulation of activated T cells which perpetuate the inflammatory response (Fig. 1: 10) [37]. A recently published randomized phase 2 trial tested the efficacy of olamkicept, a soluble gp130-Fc-fusion protein, that selectively inhibits IL-6 trans-signaling by binding the soluble IL-6 receptor/IL-6 complex in active ulcerative colitis patients. Patients received biweekly intravenous administration of olamkicept 600 mg, 300 mg, or placebo for 12 weeks. Here, more patients receiving olamkicept 600 mg (58.6%; p = 0.03) or 300 mg (43.3%; p = 0.52) achieved clinical response than placebo (34.5%). The most common adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels in the olamkicept groups compared with placebo [38]. Further studies are warranted to investigate efficacy and safety of olamkicept in ulcerative colitis.

Micro-RNA-124 Upregulation

Micro-RNA-124 (miR-124) is a negative regulator of inflammation as it targets STAT3, which is one of the central regulators of inflammatory processes. Reduced miR-124 expression levels have been described in ulcerative colitis patients (Fig. 1: 11). Obefazimod, a miR-124 upregulator, has been tested in a randomized phase 2b induction study in patients with moderate-to-severe ulcerative colitis. Patients received orally once daily obefazimod 25 mg, 50 mg, 100 mg, or placebo. The primary endpoint, improvement of disease activity (Modified Mayo Score [MMS]) from baseline compared to placebo at week 8 was reached with statistical significance for all obefazimod dose groups. The least squares mean differences for disease activity from placebo were −1.2 for ABX464 25 mg, −1.3 for ABX464 50 mg, and −1.0 for ABX464 100 mg. While there was no apparent dose effect across the tested doses, adverse events were dose-dependent with headaches being the most common one [39]. Results of the currently ongoing phase 3 trial are awaited.

Anti-Tumor Necrosis Factor-Like Cytokine 1A Antibody

Tumor necrosis factor-like cytokine 1A (TL1A) is a TNF superfamily member of ligands expressed mainly on antigen-presenting cells under inflammatory stimulation. It binds to its functional receptor DR3, expressed primarily on lymphocytes, and thus modulates the mucosal immune response (Fig. 1: 12). In experimental colitis models, neutralization of TL1A attenuated inflammation and not only prevented but also reversed intestinal fibrosis. Very recently, results of the phase 2 study with the anti-TL1A monoclonal antibody PRA023 were presented. A significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission (26.5%) versus placebo (1.5%) at week 12 (p < 0.0001) [40]. Phase 3 study will be conducted to confirm these findings.

The therapeutic armamentarium is steadily increasing for ulcerative colitis and has already enabled us to define novel therapeutic outcomes that have the potential to modify the individual disease course of the patient. Therapies should ideally achieve rigorous clinical, biochemical, endoscopic, and histological endpoints and, in the future potentially also barrier healing to hopefully further benefit our treated patients [41]. Appropriate positioning of each targeted therapy in our treatment algorithms is challenging. Currently, therapies are chosen according to disease phenotype, extraintestinal manifestations, existing comorbidities, previous therapies, and, of course, patient preferences. There are only scarce head-to-head trials performed in ulcerative colitis. Here, vedolizumab was more efficacious than adalimumab in inducing clinical remission in ulcerative colitis patients (31.3 vs. 22.5%; p = 0.006) [42]. Newly developed therapies, like IL-23 inhibitors, TLR-9 agonists, sIL-6R inhibitors, and upregulators of micro-RNA, not only offer novel treatment approaches but also enable us to gather more insights into disease pathogenesis. Currently conducted cell-based therapy trials that investigate effectiveness of regulatory T-cell transfer might further expand our treatment approaches for the benefit of patients [43]. Combination or sequential use of advanced therapies warrants further investigation, as they might offer heightened efficacy, but long-term safety needs to be studied in these endeavors. The maximum benefit for therapies can be utilized only with personalized treatment strategies and development of validated biomarkers predicting individual response to prevent exposure of patients to ineffective and potentially harmful therapies [27, 44, 45].

R.P. has no conflicts to declare. T.R. served as a speaker for Pentax, AbbVie, Olympus, Medtronic, Takeda Pharma, Lilly, Janssen-Cilag, and Galapagos. M.F.N. reports research grants and/or personal fees from AbbVie, MSD, Takeda, Boehringer, Roche, Pfizer, Janssen, Pentax, and PPD. R.A. has served as a speaker or consultant or received research grants from AbbVie, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Cellgene, Celltrion Healthcare, DrFalk Pharma, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepsis, Takeda Pharma, and Viatris.

CRC1181 Project C02 (RA) and DFG-SFB/TRR241 Project No. C02 and IBDome (RA) are funded by the German Research Council DFG.

R.P., T.R., M.F.N., and R.A. wrote and critically revised the manuscript.

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