Introduction

The treatment landscape for ulcerative colitis (UC) and Crohn's disease (CD) has evolved over the past 2 decades with the introduction of biologics and nonbiologic small molecule agents.^[1,2] The biologic era began with the anti-tumor necrosis factor (TNF) therapies, followed by the anti-integrin agents natalizumab (CD) and vedolizumab (UC and CD), and the anti-interleukin (IL)-12/23 agent ustekinumab (UC and CD). Tofacitinib became the first oral Janus kinase (JAK) inhibitor to be approved for UC.^[3,4] Although these therapies have significantly improved outcomes, 10% to 30% of patients with inflammatory bowel disease (IBD) are primary nonresponders to anti-TNF agents and 23% to 46% develop secondary loss of response.^[5] Loss of response, along with adverse events (AEs), prompted the development of novel therapies.^[3,4,6] Among the recently approved IBD agents are a selective anti-IL‐23 monoclonal antibody (risankizumab), a selective JAK1‐inhibitor (upadacitinib), and a sphingosine-1-phosphate receptor (S1PR) modulator (ozanimod) (Figure 1).^[4] Several other agents from these classes are in late-stage clinical development.

Figure 1. Mucosal Inflammation in Inflammatory Bowel Disease and Targets for Novel Therapies*^[4]

*Therapies are grouped by categories according to their main mechanism of action.

JAK Inhibitors

JAKs are a family of 4 intracellular tyrosine kinases: JAK1, JAK2, JAK3, and tyrosine-protein kinase 2.^[4,7] JAKs phosphorylate activated cytokine receptors, allowing signal transducer and activator of transcription (STAT) proteins to bind the receptors and induce gene transcription. The JAK-STAT pathway regulates the expression of multiple downstream proinflammatory mediators, including interferon (IFN)-γ, IL-2, IL-5 to IL-7, IL-12-13, IL-15, and IL-21 to 23, which are involved in IBD pathogenesis.^[4,8] JAK inhibitors block the JAK-STAT inflammatory pathway.

Tofacitinib

Tofacitinib is an oral pan-JAK inhibitor of JAKs 1 to 3.^[4] It received initial FDA approval in 2018 for the treatment of moderate to severe UC in patients without restrictions but is now indicated for patients who had an inadequate response or developed intolerance to ≥ 1 TNF inhibitors.^[9] Tofacitinib is also indicated for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis.^[9]

Upadacitinib

Upadacitinib is an oral selective JAK1 inhibitor.^[4] It was FDA approved in March 2022 for moderate to severe active UC, and in May 2023 for moderately to severely active CD after loss of response or intolerance to TNF inhibitors.^[10] Upadacitinib is also approved for RA, PsA, ankylosing spondylitis, and atopic dermatitis.^[10] The efficacy and safety of upadacitinib in UC were demonstrated in two parallel phase 3 studies induction studies (U-ACHIEVE induction and U-ACCOMPLISH), and a maintenance study (U-ACHIEVE Maintenance).^[11] The primary endpoint of clinical remission was achieved in 26% of patients in U-ACHIEVE induction and in 34% in U-ACCOMPLISH after 8 weeks of treatment with upadacitinib 45 mg once daily. By comparison, clinical remission in the placebo groups were 5% and 4% in the 2 trials, respectively (P < .001). In U-ACHIEVE Maintenance, patients who had clinical remission in the induction trials received upadacitinib 15 mg or 30 mg once daily or placebo for 52 weeks. Clinical remission was seen in 42% and 52% of patients who received upadacitinib vs 12% who got placebo (P < .001). In all 3 studies, secondary endpoints were all significantly improved with upadacitinib vs placebo (Figure 2).

Figure 2. Key Secondary Endpoints in U-ACHIEVE Induction, U-ACCOMPLISH, and U-ACHIEVE Maintenance^[11]

Across the 3 trials, the most common AEs occurring more frequently with upadacitinib than placebo were nasopharyngitis, creatine phosphokinase elevation, acne, worsening of UC, creatine phosphokinase elevation, and upper respiratory tract infection. Malignancies, adjudicated major adverse cardiac events (MACE), or venous thromboembolism were reported infrequently, and there were no treatment-related deaths.^[11]

The efficacy and safety of upadacitinib in CD was established in two phase 3 induction trials (U-EXCEL and U-EXCEED) and a maintenance study (U-ENDURE).^[12] Significantly more patients treated with upadacitinib 45 mg once daily vs placebo achieved clinical remission (50% vs 29% in U-EXCEL; 39% vs 21% in U-EXCEED); in U-ENDURE, remission was attained by 37% with upadacitinib 15 mg, 48% with upadacitinib 30 mg, and 15% for placebo (P < .001 for both comparisons). Endoscopic response was 46% vs 13% in U-EXCEL; 35% vs 4% in U-EXCEED; and in U-ENDURE was 28% with 15 mg, 40% with 30 mg, and 7% (P < .001). All secondary endpoints were also met (including endoscopic remission and glucocorticoid-free clinical remission). The most common AEs were acne, anemia, nasopharyngitis, headache, worsening of CD, and upper respiratory tract infections. Herpes zoster activation occurred more frequently with upadacitinib than placebo. There were no cases of active tuberculosis or adjudicated MACE. Cancer and death were infrequent.

The product labeling for upadacitinib and tofacitinib includes a boxed warning for the potential of an increased risk of MACE, certain malignancies, thrombosis, and all-cause mortality (including sudden cardiovascular [CV] death).^[9,10] This labeling was based on a post-approval, noninferiority trial of tofacitinib in RA (ORAL Surveillance).^[13] Patients in this trial were aged 50 years and older and had at least 1 CV risk factor.^[13] These findings were not seen in IBD studies, which generally included younger patients.

Treatment with upadacitinib or tofacitinib can lead to changes in lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids.^[9,10] Laboratory monitoring is recommended before and during treatment. These agents may also cause fetal harm based on animal studies. Female patients should be advised of the potential for fetal harm and to use an effective contraception during treatment and for 4 weeks after treatment completion.^[10]

Other JAK Inhibitors

Several other JAK inhibitors are in clinical development for IBD, including izencitinib, peficitinib, ritlecitinib, and beprocitinib.^[6] Filgotinib, an oral JAK-1 inhibitor, is approved for UC in the European Union, Great Britain, and Japan, primarily based on results from a phase 2b/3 study (SELECTION).^[14] However, it is no longer under development for UC or CD in the United States following concerns about testicular toxicity from animal studies, which were later allayed in phase 2 studies (MANTA and MANTA-RAy),^[15] and after failing to meet its primary endpoint in a phase 3 trial in CD (DIVERSITY).^[16]

Selective IL-23 Inhibitors

IL-12 and IL-23 mediate distinct inflammatory responses in IBD.^[4,6] IL-12 promotes Th1 response and associated IFN-γ and TNF production, while IL-23 induces Th17 differentiation, upregulates IL-17, recruits neutrophils, macrophages, and dendritic cells, and drives intestinal inflammation. IL-12 and IL-23 share subunit p40, whereas subunit p35 is unique to IL-12, and subunit p19 is unique to IL-23. Agents that target subunit p40 are nonselective, as they modulate both the IL-12 and IL-23 inflammatory pathways. Ustekinumab, a monoclonal antibody that targets subunit p40, was FDA approved for CD in 2016 and for UC in 2019.^[17] Because targeting the p19 subunit demonstrated greater efficacy in psoriasis than targeting p40,^[18,19] selective IL-23 inhibitors targeting p19 are approved (risankizumab) or being evaluated in IBD (mirikizumab, guselkumab).^[6]

Risankizumab

Risankizumab, a selective IL-23 inhibitor of subunit p19, was approved for the treatment of moderate to severe CD in 2022.^[20] It is also approved for plaque psoriasis and PsA.^[20] The efficacy and safety of risankizumab in CD were evaluated in two phase 3 induction studies (ADVANCE, MOTIVATE)^[21] and a maintenance study (FORTIFY).^[22]

The ADVANCE trial included patients with intolerance or inadequate response to conventional therapies (non-bio-failure) or biologic therapies (bio-failure), or both, while in MOTIVATE all enrolled patients with CD were bio-failures.^[21] In ADVANCE, the coprimary endpoints of clinical remission and endoscopic response were significantly higher with IV risankizumab 600 mg and 1200 mg vs placebo (Crohn's Disease Activity Index [CDAI] remission, 45% and 42% vs 25%; endoscopic response, 40% and 32% vs 12%; P < .0001 for both). Clinical remission was higher in patients without prior biologic failure (49% for 600 mg IV) than in those with prior biologic failure (43%) but was significant for both (P < .0001).^[21] In MOTIVATE, clinical remission and endoscopic response were significantly higher with risankizumab 600 mg and 1200 mg vs placebo (CDAI remission, 42% and 40% vs 20%; endoscopic response, 29% and 34% vs 11%; P < .0001 for both).

In both induction trials, all clinical and endoscopic secondary outcomes were achieved (Figure 3). Risankizumab was well tolerated, with rates of serious and severe AEs numerically higher with placebo. Headache and nasopharyngitis were most frequently reported.

In FORTIFY, patients who had a response in the ADVANCE or MOTIVATE studies received risankizumab 360 mg or 180 by subcutaneous (SC) injection, or placebo.^[22] Clinical remission and endoscopic response were significantly higher with risankizumab 360 mg and 180 mg vs placebo (CDAI remission, 52% and 55% vs 41%, P < .001; endoscopic response, 47% and 47% vs 22%; P < .0001). Secondary endpoints are shown in (Figure 3). Worsening CD, arthralgia, and headache were the most frequently reported AEs in all treatment groups, with serious AEs similar among groups.

Figure 3. Key Secondary Endpoints in ADVANCE, MOTIVATE, and FORTIFY^[21,22]

Risankizumab is also being evaluated for UC. A phase 3 induction study (INSPIRE) in patients who had intolerance or an inadequate response to conventional therapies and/or advanced therapies, including biologics, JAK inhibitors, and S1PR modulators, met its primary endpoint.^[23] Clinical remission was 20% for patients receiving risankizumab vs 6% for placebo. Secondary endpoints were also significantly improved with risankizumab. Adjudicated MACE, anaphylactic reactions, or malignancy were not reported with risankizumab. There was 1 death in the risankizumab arm due to COVID-19 pneumonia.

Mirikizumab

Mirikizumab, an IgG4 monoclonal antibody, is under FDA review for moderate to severe UC based on results from two phase 3 studies: LUCENT‐1 (induction) and LUCENT‐2 (maintenance).^[24,25] In LUCENT-1, mirikizumab 300 mg IV produced significantly higher clinical remission vs placebo (24% vs 13% P = .00006), clinical response (64% vs 42%, P < .00001), endoscopic remission (36% vs 21%, P < .00001), and histologic-endoscopic mucosal improvement (HEMI) (27% vs 14%, P < .00001) at week 12.^[24] AEs with mirikizumab were comparable to or lower than in the placebo group. In LUCENT‐2, patients who received a maintenance regimen of mirikizumab 200 mg SC had a significantly higher rate of clinical remission at week 40 vs placebo (50% vs 25%, P < .001).^[25] All key secondary endpoints were significant higher with mirikizumab (P < .001 for all comparisons vs placebo). Serious AEs were numerically lower than with placebo. A phase 3 study (VIVID-1) and an open-label extension (OLE) study (VIVID-2) in CD are ongoing.

Guselkumab

Guselkumab, a fully human anti-IgG1 monoclonal antibody, is in phase 3 trials for UC. Results from a phase 3 induction trial (QUASAR) have been presented.^[26] In QUASAR, patients with moderate to severe UC who had an inadequate response/intolerance to conventional and/or advanced therapies received guselkumab 200 mg IV or placebo. A significantly greater proportion of guselkumab-treated patients achieved clinical remission vs placebo (23% vs 8%, P < .001). Significant improvements were seen in all key secondary endpoints, including clinical response, endoscopic improvement, and HEMI. AEs were similar to placebo. Guselkumab was also evaluated in a phase 2 induction study (GALAXI-1) in moderately to severely active CD.^[27] At week 12, significantly greater reductions in CDAI from baseline and higher clinical remission rates were seen with guselkumab 200 mg, 600 mg, and 1200 mg vs placebo.

S1PR Modulators

S1PRs are a family of 5 receptors, S1PR1-5 involved in multiple cellular processes, including inflammation.^[28] S1PR modulators bind to and internalize the S1PRs, thereby preventing lymphocytes from exiting the lymph nodes into the circulation and the intestines.

Ozanimod

Ozanimod, an oral S1PR modulator that selectively targets S1PR1 and S1PR5 was FDA approved in 2021 for moderate to severe active UC.^[29] It is also indicated for relapsing forms of multiple sclerosis.

A phase 3 trial, TRUE NORTH (induction and maintenance), established the efficacy and safety of ozanimod in UC.^[30] After 10 weeks of induction treatment, 18% of patients treated with oral ozanimod 1 mg achieved clinical remission (primary endpoint) vs 6% who received placebo (P = .001). In the maintenance period, 37% of patients maintained clinical remission at 52 weeks vs 19% in the placebo arm (P < .001). All key secondary endpoints in both periods were significantly improved with ozanimod (Figure 4). The incidence of infection with ozanimod was similar to placebo during induction and higher than placebo during maintenance. Serious infections occurred in < 2%. Elevated liver aminotransferase levels were more common with ozanimod.

Figure 4. Key Secondary Endpoints in TRUE North^[30]

Because of the risk of infection and liver injury, a complete blood count and liver function tests are recommended before and during treatment with ozanimod.^[29] Transient decreases in heart rate may occur with ozanimod; an electrocardiogram is therefore recommended before treatment. Ophthalmic evaluation is recommended before and during treatment in patients with an increased risk of macular edema, such as those with diabetes mellitus or uveitis. Vaccination against herpes zoster is also recommended.^[4] Women of childbearing potential should use effective contraception during treatment and for 3 months after discontinuing treatment.^[29] Ozanimod is being evaluated in a phase 3 trial in CD (YELLOWSTONE).^[31]

Etrasimod

Etrasimod is an oral S1PR modulator with selectivity for S1PR1, S1PR4, and S1PR5.^[4] It was evaluated in two phase 3 studies, ELEVATE UC 52 and ELEVATE UC 12, in moderate to severe UC in patients with inadequate or loss of response or intolerance to at least 1 UC therapy.^[32] ELEVATE UC 52 was an induction and maintenance trial while ELEVATE UC 12 was a separate induction trial. In ELEVATE UC 52, clinical remission was achieved in 27% of patients who received etrasimod vs 7% with placebo (P < .0001) in the induction period, and in 32% vs 7% in the maintenance period (P < .0001). In ELEVATE UC 12, clinical remission was 25% vs 15% (P = .026). All secondary endpoints in both trials, including endoscopic improvement, symptomatic remission, and endoscopic improvement–histological remission, were achieved in etrasimod-treated patients. Most frequently reported AEs included anemia, headache, and worsening of UC or UC flare. All infections, serious infections, and opportunistic infections were similar between the treatment groups. There were no deaths or malignancies. A phase 2/3 study in patients refractory/intolerant to ≥ 1 current therapies for CD is ongoing.

Concluding Remarks

With the rapidly expanding treatment armamentarium in CD and UC, clinicians have more choices than ever for their patients. Thoughtful patient selection for the novel targeted therapies is critical for optimizing patient outcomes while minimizing the risk for AEs. Decisions regarding treatment selection should take into consideration the IBD phenotype and disease behavior, previous exposure to biologics and/or nonbiologic small molecules and patient response to these agents, potential adverse effects, comorbidities that may place patients at a higher risk for certain AEs, fertility plans, patient preference for mode of drug delivery, and any coexisting autoimmune conditions that may benefit from targeted therapies. Since many of the novel therapies have multiple indications in autoimmune diseases, patients may benefit from agents that target multiple conditions simultaneously. Combinations of targeted therapies are also being investigated. Clinicians treating IBD patients must become familiar with the nuances of these novel therapies, as there are important differences in their mechanisms of action that may impact efficacy and safety in certain patients.