Ulcerative colitis treatment
Treatment goals in UC
Key treatment goals in UC
Gastroenterologist Dr Tim Raine, from Cambridge University Hospitals in the UK, rounds up treatment goals and targets that have the most impact on people with ulcerative colitis (UC).
Treatment goals and targets for management of ulcerative colitis
A key focus of UC treatment is to induce and maintain remission1-5. Across European and US guidelines, there is general agreement that symptomatic remission and endoscopic/mucosal healing are required or preferred treatment goals for medical therapy in UC1-3,6. The STRIDE-II consensus grouped treatment goals into short-, intermediate- and long-term goals to guide treatment, aiming for the long-term goals of restored quality of life and absence of disability5. Key treatment goals in UC are summarised in Figure 1.
Figure 1. Overview of key treatment goals recommended by European and US guidelines for the management of ulcerative colitis and the STRIDE-II consensus1-3,5,6. CRP, C-reactive protein; FC, faecal calprotectin; QoL, quality of life.
Short-, intermediate- and long-term UC treatment goals
In the short and intermediate term, key treatment goals across guidelines are centred around attaining symptomatic relief2,5,6, including clinical response and then clinical remission1,3,5, although thresholds for endoscopic response and clinical remission can vary5
The STRIDE-II consensus also suggests normalisation of serum and faecal markers of mucosal inflammation, including C-reactive protein (CRP) and faecal calprotectin (FC), as short-term targets in UC5, as significant mucosal inflammation has been observed in people with inflammatory bowel disease (IBD) who are in complete clinical remission5.
In the long term, endoscopic/mucosal healing is prioritised as a key treatment goal in British3 and US guidelines1,6. The terms endoscopic and mucosal healing are generally used interchangeably in guidelines when referring to the resolution of inflammatory changes on endoscopic evaluation, defined by a Mayo Endoscopic Subscore (MES) of 0 or 11,3,6,7. Although the STRIDE-II consensus only defines endoscopic healing as a MES of 05, Rubin and colleagues have noted that both endoscopic improvement (MES 0 or 1) and complete healing (MES 0) are associated with similar outcomes1. Overall, the achievement of endoscopic/mucosal healing is considered to increase the likelihood of sustained steroid-free remission and prevent hospitalisation and surgery1. In combination with symptomatic remission, it also has prognostic significance for future relapses1,2.
Other long-term or ‘ultimate’ treatment goals in UC are focused on maintaining, normalising or restoring the patient’s health-related quality of life, and avoiding disability2,5
Although it is not considered a formal treatment goal, histological healing/remission may be used as an adjunct to endoscopic/mucosal healing to represent a deeper level of healing5. However, the definition of histological healing/remission can vary between studies3,5, and has been referred to as histological normalisation1,5. There is not yet sufficient evidence to support its utility as a treatment target1,5, and the clinical significance of histological healing must be balanced against the cost and risks of extended treatment required to achieve this potential goal in the long term5.
Treatment goals and therapeutic decisions in UC
Treatment goals can be used to inform the therapeutic approach to management of UC1, in consultation with local guidelines.
Strategies for the management of UC should take into account both the patient and healthcare professional’s goals, and the chronic nature of the disease1
The STRIDE-II consensus recommends reconsidering the treatment approach if longer-term UC treatment goals have not been achieved5.
Treatment targets and goals can also be considered in a ‘treat-to-target’ clinical management strategy5, which involves regularly assessing disease activity, using objective and clinical outcome measures, and adjusting treatments as required to improve the chance of achieving the relevant treatment goals1.
However, selection of appropriate treatment for people with UC should be informed by disease extent, severity and prognosis1, as well as their needs and preferences1,3,8.
UC treatments options
Expert commentary on treatments for UC
Dr Tim Raine highlights the benefits and limitations of short- and long-term corticosteroid use in UC-related mucosal inflammation, and the potential of other treatment options in the management of UC.
The benefits and limitations of using corticosteroids for managing ulcerative colitis
Dr Raine discusses the role of small molecules and biologics in the treatment of UC, while also taking a closer look at the clinical trials that supported regulatory approval of these treatments.
The role of targeted small molecules and biologics in the treatment of ulcerative colitis
Chapter 1: Targeted small molecules and biologics in UC. Chapter 2: Clinical trials in UC: Design and key endpoints.ofessor Stephen Hanauer (Northwestern University, USA) covers the key endpoints in the clinical trials supporting the approval of small molecules and biologic treatments for UC, with a focus on how evolving therapeutic goals are impacting clinical trial design and trial endpoints.
Targeted small molecule treatment key clinical findings
Chapter 1: UC trial endpoints for targeted small molecules. Chapter 2: UC trial endpoints for biologics.
The role of targeted small molecules and biologics in UC
Professor Hanauer summarises the differences between the regulatory approvals of targeted small molecules for moderate-to-severe UC in the USA and the UK.
Approved indications for UC treatments
Approved biologics in UC
Tumour necrosis factor alpha (TNF-α) inhibitors, anti-integrin agents and interleukin inhibitors with approved indications for UC treatment in the USA and Europe are summarised in Table 1 and Table 2.
Table 1. EMA- and/or FDA-approved indications for TNF-α inhibitors in ulcerative colitis9-14. 6-MP, 6-mercaptopurine; ASA, aminosalicylate; AZA, azathioprine; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; TNF-α, tumour necrosis factor alpha; UC, ulcerative colitis.
| Treatment | Approved indication |
| Infliximab | EMA • Moderate-to-severe UC in adults, or for severely active UC in children or adolescents aged 6–17 years • If inadequate response, intolerance or contraindication to conventional therapy including corticosteroids and 6-MP or AZA FDA • Moderate-to-severe UC in adult and paediatric patients (≥6 years of age) • If inadequate response to conventional therapy • To reduce signs and symptoms, induce and maintain clinical remission • To induce and maintain mucosal healing, and eliminate corticosteroid use (in adults only) |
| Adalimumab | EMA • Moderate-to-severe UC in adult and paediatric patients (≥6 years of age) • If inadequate response, intolerance or medical contraindication to conventional therapy including corticosteroids and 6-MP or AZA FDA • Moderate-to-severe UC in adult and paediatric patients (≥5 years of age) • Limitations of use: Effectiveness not established in patients who have lost response, or were intolerant, to TNF-α inhibitors |
| Golimumab | EMA • Moderate-to-severe UC in adults • If inadequate response, intolerance or contraindication to conventional therapy including corticosteroids and 6-MP or AZA FDA • Moderate-to-severe UC in adults • If demonstrated corticosteroid dependence, or if inadequate response/intolerance to oral ASAs, oral corticosteroids, AZA or 6-MP • For inducing and maintaining clinical response, improving endoscopic appearance of the mucosa during induction, inducing clinical remission, achieving and sustaining clinical remission in induction responders |
Table 2. EMA- and/or FDA-approved indications for anti-integrin agent and interleukin inhibitors in ulcerative colitis15-19. EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; IL, interleukin; TNF-α, tumour necrosis factor alpha; UC, ulcerative colitis.
| Treatment | Approved indication |
| Vedolizumab (anti-integrin agent) |
EMA • Moderate-to-severe UC in adults • If inadequate response, loss of response or intolerance to either conventional therapy or a TNF-α inhibitor FDA • Moderate-to-severe UC in adults |
| Ustekinumab (IL-12/23 antagonist) |
EMA • Moderate-to-severe active UC in adults • If inadequate response, loss of response, intolerance or contraindication to either conventional therapy or a biologic FDA • Moderate-to-severe UC in adults |
| Mirikizumab (IL-23 antagonist) |
EMA • Moderate-to-severe UC in adults • If inadequate response, loss of response or intolerance to either conventional therapy or a biologic FDA • Not approved |
Approved indications vary across treatments for UC according to disease severity, patient characteristics and previous treatment experience, consistent with clinical trial evidence9-27. While biologics and targeted small molecules approved by the EMA and FDA are indicated for adults with moderate-to-severe UC, only infliximab and adalimumab are indicated for use in paediatric patients with UC9-19,22-27.
Approved indications for TNF-α inhibitors require an inadequate response (± intolerance or contraindication) to conventional therapies only9-14; however, the required treatment experience for other biologics15-19 and targeted small molecules22-25,27 can vary between treatments and across regions. Some indications require an inadequate response/intolerance to conventional therapies or a biologic, while others require this to be demonstrated for TNF-α inhibitors only9-19,22-27.
Approved targeted small molecules in UC
Targeted small molecules that are EMA- and/or FDA-approved for the treatment of adults with moderate-to-severe UC include three JAK inhibitors, and the sphingosine-1-phosphate receptor (S1PR) modulator ozanimod (Table 3).
Table 3. Treatments with EMA-and/or FDA-approved indications for targeted small molecules in ulcerative colitis22-25,27. Note measures/restrictions/cautions apply to the use of JAK inhibitors in chronic inflammatory disorders including UC, per advice from the EMA and FDA28,29. AZA, azathioprine; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; JAK, Janus kinase; S1PR, sphingosine-1-phosphate receptor; TNF-α, tumour necrosis factor alpha; UC, ulcerative colitis.
| Treatment | Approved indication |
| Tofacitinib (JAK inhibitor) |
EMA • Moderate-to-severe active UC in adults • If inadequate response, loss of response, intolerance to either conventional therapy or a biologic FDA • Moderate-to-severe active UC in adults • If inadequate response or intolerance to ≥1 TNF-α inhibitors |
| Upadacitinib (JAK inhibitor) |
EMA • Moderate-to-severe UC in adults • If inadequate response, loss of response, intolerance to either conventional therapy or a biologic FDA • Moderate-to-severe active UC in adults • If inadequate response or intolerance to ≥1 TNF-α inhibitors • Limitations of use: Not recommended for use in combination with other JAK inhibitors, biologics for UC, or potent immunosuppressants (e.g. AZA and cyclosporine) |
| Filgotinib (JAK inhibitor) |
EMA • Moderate-to-severe active UC in adults • If inadequate response, loss of response, intolerance to either conventional therapy or a biologic FDA • Not approved |
| Ozanimod (S1PR modulator) |
EMA • Moderate-to-severe active UC in adults • If inadequate response, loss of response, intolerance to either conventional therapy or a biologic FDA • Moderate-to-severe active UC in adults |
Place in therapy for UC treatments
Overall, the management of UC requires a multidisciplinary approach that includes medication and lifestyle modifications, with surgery usually reserved for certain severe, acute and treatment-refractory cases1-4. Although some treatments are appropriate for both induction and maintenance treatment, others are considered appropriate for induction only (e.g., corticosteroids)1-3,30. The type of UC treatment used for induction can also influence the choice of maintenance therapy1-3,11-15.
The place in therapy for UC treatment options according to disease severity is summarised in Table 4, based on recommendations in European (ECCO2), British (BSG3) and US (ACG1 and AGA4) guidelines for the management of UC.
Table 4. Place in therapy for treatment options in ulcerative colitis, according to European, UK and US guidelines*1-4,8. Note: filgotinib, mirikizumab, ozanimod and upadacitinib are not included in guideline recommendations because they were not approved by the EMA or FDA for use in UC at the time these guidelines were released. 5-ASA, 5-aminosalicylate; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; MMX, multimatrix; TNF-α, tumour necrosis factor alpha; UC, ulcerative colitis.
| UC guidelines | Recommended place in therapy according to UC severity |
| Mild-to-moderate UC | |
| Europe/UK US |
Standard therapy to induce and maintain remission (including patients with extensive disease): 5-ASAs To induce remission, in cases of 5-ASAs failure or intolerance: Corticosteroids • Options include systemic (e.g. prednisone) or non-systemic (e.g. colonic release such as budesonide MMX, or topical) corticosteroids To maintain remission in steroid-dependent UC or those intolerant to 5-ASAs: Thiopurines |
| Moderate-to-severe UC |
|
| Europe/UK | To induce remission in active disease: Oral corticosteroids If inadequate response/intolerance to conventional therapy: • TNF-α inhibitors (infliximab, adalimumab and golimumab), vedolizumab or tofacitinib are recommended to induce remission • If the patient has responded to induction therapy with a TNF-α inhibitor, vedolizumab or tofacitinib; the same drug can be used to maintain remission |
| USA | To induce remission, recommended options include: • Oral corticosteroids • TNF-α inhibitors (infliximab, adalimumab and golimumab) • Vedolizumab • Tofacitinib To maintain remission • If in remission after induction therapy with TNF-α, vedolizumab or tofacitinib; the same drug is recommended to maintain remission • If in remission after induction with corticosteroids, thiopurines are suggested to maintain remission |
Generally, treatments for UC that are effective for inducing remission are continued for maintenance of remission2,4,8, except for corticosteroids, which are not recommended or considered effective for maintaining remission in UC1-3,30.
However, the place in therapy of treatments for UC must be considered in the context of the regulatory-approved indications in your local region.
Mechanisms of action for UC treatments
The growing number of biologic and targeted small molecules available for people with UC target various inflammatory pathways implicated in UC pathophysiology (Figure 2)20,21,31.
Figure 2. Mechanism of action for biologics and targeted small molecules in ulcerative colitis 17,21,24,25,27 (Adapted21). Image licensed under Creative Commons CC-BY 4.0. IL, interleukin; JAK/STAT, Janus kinase/signal transducers and activators of transcription; S1PR, sphingosine-1-phosphate receptor; TGFβ, transforming growth factor beta; TNF-α, tumour necrosis factor alpha.
A summary of mechanisms of action across conventional, biologic and targeted small molecules in UC is provided in Table 5.
Table 5. Mechanisms of action of treatments for ulcerative colitis 9,11,14-17,20,22,24,27,31-36. 5-ASA, 5-aminosalicylic acid; IFN, interferon; IL, interleukin; JAK, Janus kinase; MAdCAM-1, mucosal address in cell adhesion molecule-1; NF-κB, nuclear factor kappa B; NK, natural killer; S1PR, sphingosine-1-phosphate receptor; TNF-α, tumour necrosis factor alpha; UC, ulcerative colitis.
| Treatment | Mechanism of action in UC |
| Conventional therapies | |
| Aminosalicylates • Sulfasalazine • Other types of 5-ASA drugs (e.g. mesalamine) |
Pro-apoptotic, anti-proliferative and anti-inflammatory effects • Inhibits lipoxygenase and cyclooxygenase • Inhibits production of cytokines including IL-1, IL-2 and TNF-α • Inhibits NF-κB activity • Antioxidant and free-radical scavenger effect |
| Corticosteroids • Oral corticosteroids • Second-generation oral corticosteroids (e.g. budesonide) • Systemic corticosteroids |
• Inhibits transcription of pro-inflammatory genes (including cytokines) • Inhibits pro-inflammatory transcription factors such as NF-κB • Upregulates expression of anti-inflammatory genes • Inhibits cytokine release, reduces lymphocyte recruitment, lowers vascular permeability, inhibits cytokine-mediated tissue necrosis |
| Thiopurine immunomodulators • Azathioprine • 6-mercaptopurine |
• Controls intestinal inflammation by inhibiting T lymphocyte proliferation and activation • Inhibits survival and function of T lymphocytes |
| Cyclosporin | • Calcineurin inhibitor • Inhibits T cell activation and production of IL-2 by T-helper lymphocytes • Blocks production of IFN-γ and B-cell-activating factors |
| Biologics (all monoclonal antibodies) | |
| TNF-α inhibitors • Infliximab • Adalimumab • Golimumab |
Bind to TNF-α, neutralising its biological functions by blocking its interaction with TNF receptors |
| Vedolizumab (anti-integrin agent) | Specifically inhibits the binding of α4β7 integrin to MAdCAM-1, preventing lymphocyte migration to the intestinal tissue, and thereby alleviating local intestinal inflammation |
| Ustekinumab (IL-12/23 antagonist) | Binds to the shared p40 subunit of IL-12 and IL-23, inhibiting their binding to the IL-12 receptor on T cells and NK cells, thereby inhibiting intestinal inflammation |
| Mirikizumab (IL-23 antagonist) | Selectively binds to p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor |
| JAK inhibitors | |
| Tofacitinib | • An oral small-molecule JAK inhibitor • Inhibit all JAKs, preferentially JAK1 and JAK3, which modulate the immune and inflammatory response |
| Upadacitinib | A selective JAK1 inhibitor that modulates signalling of JAK-dependent cytokines |
| Filgotinib | An inhibitor of JAK 1–3, preferentially inhibits JAK1 |
| S1PR modulator | |
| Ozanimod | • An oral and selective S1PR modulator that acts on S1PR-1 and S1PR-5 • Induces peripheral blood lymphocytes to isolate in the lymph nodes, thereby reducing the number of activated lymphocytes circulating to the inflammatory sites |
Key evidence for recently approved treatments in UC
Biologics and targeted small molecules that have been recently approved for ulcerative colitis (UC) include:
- The interleukin inhibitor mirikizumab (in 2023 by the European Medicines Agency [EMA])37
- The Janus kinase (JAK) inhibitors upadacitinib (in 2022 by the EMA and U.S. Food and Drug Administration [FDA])38,39 and filgotinib (in 2021 by the EMA)40
- The sphingosine-1-phosphate receptor (S1PR) modulator ozanimod (in 2021 by the EMA and FDA)37-39
Mirikizumab in UC
Key results from the two phase 3 clinical trials that led to EMA approval of mirikizumab for moderate-to-severe UC, LUCENT-1 and LUCENT-2 (Table 6), showed a significantly higher proportion of patients achieved remission with mirikizumab, compared with placebo, after up to 40 weeks of treatment41. Herpes zoster infection, hepatic enzyme elevations and infusion-/injection-site reactions were more common in those treated with mirikizumab than those who received placebo41.
Table 6. Key evidence from phase 3 clinical trials supporting the EMA approval of mirikizumab in moderate-to-severe ulcerative colitis41-43. *Opportunistic infections included candidiasis, cytomegalovirus, herpes zoster infection and tuberculosis41. †Both cancers were adenocarcinoma of the colon41. ‡One patient with non-melanoma skin cancer in the placebo group, and one with gastric cancer in the mirikizumab group41. AESI, adverse events of special interest; CS, corticosteroids; DB, double-blind; IM, immunomodulator; MACE, major adverse cardiovascular event; MC, multicentre; PC, placebo-controlled; RCT, randomised controlled trial; SAE, serious adverse event; SC, subcutaneous.
| Trial/treatment/population | Efficacy and safety |
| LUCENT-1 (N=1,281) RCT – MC, PC, DB SC mirikizumab (200 mg) vs placebo, every 4 weeks up to 12 weeks Patients had previous inadequate response, loss of response or intolerance to CS or IM, biologic or JAK inhibitor |
Efficacy: At week 12, clinical remission for mirikizumab vs placebo was 24.2% vs 13.3%, respectively (P<0.001) Safety: For mirikizumab vs placebo • SAEs in 2.8% vs 5.3% • Serious infections in 0.7% vs 0.6% • AESIs o Opportunistic infection in 0.5% vs 0.3%* o Adjudicated cerebrocardiovascular events in 0.1% vs 0.6% o Cancer in 0.2% vs 0%† o Immediate hypersensitivity reaction in 1.0% vs 0.3% o No instances of MACE |
| LUCENT-2 (N=544) RCT – MC, PC, DB SC mirikizumab (200 mg) vs placebo, every 4 weeks up to 40 weeks If clinical response to mirikizumab induction therapy at week 12 in LUCENT-1 |
Efficacy: For mirikizumab vs placebo, respectively, rates of clinical remission at week 40 of maintenance therapy were 49.9% vs 25.1% (P<0.001) Safety: For mirikizumab vs placebo • SAEs in 3.3% vs 7.8% • Serious infections in 0.8% vs 1.6% • AESIs o Opportunistic infection in 1.3% (4 of which were herpes zoster) vs 0%* o Adjudicated cerebrocardiovascular events in 0% vs 0.5% o Cancer reported in 1 patient in each group‡ o Immediate hypersensitivity reaction in 1.8% vs 1.0% o Hepatic-related events in 3.1% vs 2.1% o Infusion- or injection-site reactions in 8.7% vs 4.2% o One instance of MACE in placebo group |
Janus kinase inhibitors in UC
Upadacitinib in UC
The key phase 3 evidence supporting EMA and FDA approval of upadacitinib in UC was derived from two replicate induction studies (U-ACHIEVE induction and U-ACCOMPLISH) and one maintenance study (U-ACHIEVE maintenance)44 (Table 7). In these trials, significantly more patients achieved clinical remission in the induction and maintenance studies on upadacitinib compared with placebo44.
Regarding safety, similar rates of serious infections were reported overall across both groups; however, more patients on upadacitinib reported herpes zoster infections than those who received placebo (4% vs 0%, respectively)44. There was also a higher rate of hepatic disorders (7% vs 2%), neutropenia (3% vs 1%) and creatine phosphokinase elevation (6% vs 2%) with upadacitinib versus placebo44. Overall, upadacitinib was considered to have a positive efficacy and acceptable safety profile44.
Table 7. Phase 3 clinical trial evidence supporting the EMA and FDA approval of upadacitinib in moderate-to-severe ulcerative colitis44. *Included oral aminosalicylates, corticosteroid, immunosuppressant or the following biologic therapies: infliximab, adalimumab, golimumab, vedolizumab or ustekinumab44. AESI, adverse events of special interest; DB, double-blind; MACE, major adverse cardiovascular event; MC, multicentre; NMSC, non-melanoma skin cancer; PC, placebo-controlled; RCT, randomised controlled trial; SAE, serious adverse event; VTE, venous thromboembolism.
| Trial/treatment/population | Efficacy and safety |
| U-ACHIEVE induction (N=474) RCT – MC, PC, DB Previous inadequate response, loss of response, or intolerance to ≥1 conventional treatment or biologic* |
Efficacy: Clinical remission rates at week 8 were 26% for upadacitinib vs 5% for placebo (P<0.0001) Safety: For upadacitinib vs placebo: • SAEs in 3% vs 6% • Serious infections in 2% vs 1% Other AESIs: No NMSC, adjudicated MACE, or adjudicated VTE |
| U-ACCOMPLISH (N=522) RCT – MC, PC, DB Previous inadequate response, loss of response, or intolerance to ≥1 conventional treatment or biologic* |
Efficacy: Clinical remission rates at week 8 were 33% for upadacitinib vs 4% for placebo (P<0.0001) Safety: For upadacitinib vs placebo: • SAEs in 3% vs 5% • Serious infections in 1% (in each group) Other AESIs: • No NMSC or adjudicated MACE • 1 patient with adjudicated VTE in placebo group (none in upadacitinib group) |
| U-ACHIEVE maintenance (N=451) RCT – MC, PC, DB If achieved a clinical response after 8 weeks of upadacitinib induction treatment |
Efficacy: Clinical remission rates at week 52 for upadacitinib were 42% (15 mg), 52% (30 mg) vs 12% in the placebo group (P<0.0001) Safety: • SAEs were reported with upadacitinib in 7% (15 mg), 6% (30 mg), vs 13% placebo • Serious infections were reported with upadacitinib in 3% (15 mg and 30 mg), vs 4% in placebo Other AESIs: • In the 30 mg upadacitinib group, NMSC and adjudicated VTE were each reported in 2 patients (none in the 15 mg group or placebo group) • Adjudicated MACE was reported for 1 patient in placebo group (none in the upadacitinib groups) |
Filgotinib in UC
The key phase 2b/3 trial supporting EMA approval of filgotinib in UC, SELECTION, included an analysis of clinical remission in biologic-naive and biologic-experienced patients during the induction phase45. At week 10, a significantly higher rate of remission was achieved in both groups of patients treated with filgotinib 200 mg, compared with those who received placebo, and at week 52 in patients who received 100 mg or 200 mg doses of filgotinib, compared with placebo45.
Regarding the safety profile, filgotinib was considered well tolerated45. The incidence of serious adverse events and serious infections was largely similar between groups, and adverse events of special interest, such as non-melanoma skin cancer, herpes zoster and pulmonary embolism, occurred at low rates45. Key results of this trial are summarised in Table 8.
Table 8. Results from key phase 2b/3 clinical trial supporting the EMA approval of filgotinib in moderate-to-severe ulcerative colitis45. AESI, adverse events of special interest; DB, double-blind; MC, multicentre; NMSC, non-melanoma skin cancer; PC, placebo-controlled; RCT, randomised controlled trial; SAE, serious adverse event.
| Trial/treatment/population | Efficacy and safety |
| SELECTION (n=659 for biologic-naive patients [induction study A]; n=689 for biologic-experienced patients [induction study B]) Phase 2b/3 RCT – MC, PC, DB |
Efficacy: Rates of clinical remission at week 10: • Biologic-naive: 19.1% (100 mg), 36.1% (200 mg) for filgotinib, vs 15.3% in placebo (P value not significant and P=0.0157, respectively) • Biologic-experienced: 9.5% (100 mg), 11.5% (200 mg) for filgotinib, vs 4.2% in placebo (P value not significant and P=0.0103, respectively) Rates of remission at week 52 were: • 23.8% for filgotinib 100 mg vs 13.5% in placebo (P=0.0420) • 37.2% for filgotinib 200 mg, vs 11.2% in placebo (P<0.0001) Safety: For filgotinib (100 mg/200 mg) vs placebo: • SAEs in 5.0%, 4.3% vs 4.7% • Serious infections in 1.1%, 0.6% vs 1.1% • AESIs o Herpes zoster in 1, 3 and 0 patients o NMSC in 0, 2 and 1 patients o Pulmonary embolism in 1 patient on filgotinib 200 mg o 1 cerebrovascular event in 1 patient on placebo |
Safety profile of JAK inhibitors – recommendations from EMA and FDA
In 2021–2022, the FDA and EMA issued recommendations to minimise the risk of serious side effects with JAK inhibitors, which apply to tofacitinib, filgotinib and upadacitinib in UC28,29.
In Europe, an EMA review concluded that JAK inhibitors are linked to a higher risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignancy, serious infections and all-cause mortality compared with tumour necrosis factor alpha (TNF-α) inhibitors28. Although these findings were based on clinical data for tofacitinib and another JAK inhibitor, baricitinib, in rheumatoid arthritis, the EMA concluded these risks apply to all JAK inhibitors approved for treatment of chronic inflammatory disorders, including UC28. The EMA has therefore recommended cautions/restrictions for use of JAK inhibitors in28:
- Patients aged 65years and older
- Current or past long-time smokers
- Those with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors
- Those with malignancy risk factors
- Those with other known risk factors for VTE, other than those described above
For more information, refer to the EMA guidance and/or FDA guidance, and the relevant summary of product characteristics/product information for each JAK inhibitor.
Ozanimod in UC
Key clinical trial results from the True North trial, which led to regulatory approval of ozanimod (Table 9)46,47, demonstrated ozanimod was significantly more effective than placebo for induction and maintenance of remission in moderate-to-severe UC48.
The safety profile of ozanimod in the True North trial was considered consistent with that demonstrated in other indications, such as multiple sclerosis48. There was a higher incidence of infection of any severity, and elevated alanine aminotransferase levels with ozanimod, compared with placebo48. Rates of serious infection remained low48.
Table 9. Key evidence from the phase 3 clinical trial supporting the EMA and FDA approval of ozanimod in moderate-to-severe ulcerative colitis48. *Excluding patients who had primary non-response to ≥2 approved treatments for UC (e.g., TNF-α inhibitors or vedolizumab)48. AESI, adverse events of special interest; DB, double-blind; MC, multicentre; PC, placebo-controlled; RCT, randomised controlled trial; SAE, serious adverse event; TNF-α, tumour necrosis factor alpha; UC, ulcerative colitis.
| Trial/population | Efficacy and safety |
| True North (N=645) RCT – MC, PC, DB (Cohort 1 only) Previous treatment with conventional therapies, biologics or small molecule inhibitors was permitted* |
Efficacy: For ozanimod vs placebo, rates of clinical remission were: • 18.4% vs 6.0% at 10 weeks (P<0.001) • 37.0% vs 18.5% at 52 weeks (P<0.001) Safety: For ozanimod vs placebo in the induction period: • SAEs in 4.0% vs 3.2% • Serious infections in 0.9% vs 0.5% • AESIs o Hypertension was reported in 6 vs 0 patients o Bradycardia was reported in 2 vs 0 patients o Hypertensive crisis and macular oedema were each reported in 1 vs 0 patients For ozanimod vs placebo in the maintenance period: • SAEs in 49.1% vs 36.6% • Serious infections in 0.9% vs 1.8% • AESIs o Hypertension was reported in 4 vs 3 patients o No instances of bradycardia were reported o Hypertensive crisis in 1 patient in each group o Macular oedema in 1 vs 0 patients |
Investigational treatments for UC
Despite the availability of multiple approved treatments for ulcerative colitis (UC), high rates of primary and secondary response failure rates remain a significant challenge in treatment49, and clinical remission is still not achieved in a considerable proportion of patients50-52.
Remission rates are 30−40% with most biologics and evidence indicates rates of colectomy are not decreasing despite availability of these treatments31,32
To help address these unmet needs for UC, several investigational treatments are in clinical development for moderate-to-severe UC52-54. Several recent phase 3 clinical trials are summarised in Figure 3.
Figure 3. Investigational treatments in phase 3 clinical trials for moderate-to-severe ulcerative colitis32,55-66. *Only patients with active, moderate UC are eligible for the phase 3 trial of AJM30055. Last updated on 8 April 2024. JAK, Janus kinase; MAdCAM-1, mucosal vascular addressin cell adhesion molecule 1; miRNA, micro RNA; TLR9, toll-like receptor 9.
Clinical guidelines for UC management
Several clinical practice guidelines exist for the management of ulcerative colitis (UC) across Europe, the UK and the USA, as summarised below.
European and UK guidelines
- The 2022 European Crohn’s and Colitis Organisation (ECCO) guidelines on medical treatment2, with a separate guideline on surgical treatment67 for UC
- 2019 British Society of Gastroenterology Guidelines (BSG) on the management of inflammatory bowel disease (IBD) in adults3
- The 2023 European Crohn’s and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation68, which specifically addresses the treatment of IBDs during pregnancy and lactation
US guidelines
- The 2021 American Society of Colon and Rectal Surgeons (ASCRS)6, which covers surgical management of UC
- The 2020 American Gastroenterological Association Guidelines (AGA)8 on the management of moderate-to-severe UC
- The 2019 American College of Gastroenterology Guidelines (ACG)1, which focuses on the management of UC in adults
Global
- The 2021 World Society of Emergency Surgery and the American Association for the Surgery of Trauma (WSES-AAST)69, which focuses on IBD management in emergency settings
References
- Rubin, 2019. ACG Clinical Guideline: Ulcerative Colitis in Adults. <link: https://www.doi.org/10.14309/ajg.0000000000000152 >
- Raine, 2022. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. <link: https://www.doi.org/10.1093/ecco-jcc/jjab178 >
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