JAKs

Janus kinase (JAK) inhibitors reduce inflammation by preventing intracellular signaling that would otherwise activate inflammatory genes.¹ By targeting different JAK proteins, therapies may have different levels of efficacy, preferred patient populations, and safety profiles. Three JAK inhibitors are approved for the treatment of IBD: upadacitinib is approved for both CD and UC, whereas tofacitinib and filgotinib are approved only for UC, and filgotinib has yet to receive approval from the US Food and Drug Administration for the treatment of patients with IBD.

JAK inhibitors provide oral, once-daily options that are fast acting and highly efficacious for both biologic-naive and biologic-experienced patients with UC and CD (such as upadacitinib). MACE events seen in rheumatoid arthritis trials were not observed at increased risk in IBD trials. The rapid onset of action of JAKs may afford opportunities to treat acute severe UC, including in hospitalized patients.

– Stephen B. Hanauer, MD

The phase 3 OCTAVE Sustain trial investigated twice-daily tofacitinib 5 mg and tofacitinib 10 mg vs placebo in patients with UC who had failed prior therapy.² The study enrolled 593 patients who had demonstrated a clinical response to induction therapy in the OCTAVE Induction 1 and 2 trials for randomization into the 3 arms (Figure 2). At week 52, the proportion of patients in remission was 11.1% in the placebo arm, 34.3% in the tofacitinib 5 mg arm (P<.001), and 40.6% in the tofacitinib 10 mg arm (P<.001), thus achieving the primary endpoint. Both doses of tofacitinib were significantly superior to placebo based on numerous other endpoints, including response, remission, sustained mucosal healing, and sustained steroid-free remission. The ORAL Surveillance study investigated safety events associated with administration of tofacitinib, with a specific focus on major adverse cardiovascular events (MACE) and malignancy, excluding nonmelanoma skin cancer, in patients over 50 years of age with rheumatoid arthritis.³ Patients were randomized to tofacitinib 5 mg or tofacitinib 10 mg, administered twice daily, vs anti-TNF therapy. The study demonstrated a higher incidence of MACE with the combined tofacitinib arms vs the anti-TNF arm (3.4% vs 2.5%; HR, 1.33; 95% CI, 0.91-1.94), as well as an increase in malignancy (4.2% vs 2.9%; HR, 1.48; 95% CI, 1.04-2.09). Subsequent analyses suggested that patients who did not smoke and were less than 65 years of age did not have an increased risk of MACE or malignancy.

Figure 2.

Clinical response and remission at 52 weeks in patients with ulcerative colitis from the OCTAVE Sustain trial.

^aDecrease in total Mayo score of ≥3 points and ≥30%, with decrease in RBS of ≥1 or absolute RBS ≤1.

^bTotal Mayo score of ≤2, with no subscore >1 and RBS of 0.

^cMayo endoscopic subscore of ≤1 at both 24 and 52 weeks.

^dCorticosteroid-free defined as not requiring corticosteroids for ≥4 weeks before each visit. BID, twice daily; RBS, rectal bleeding subscore.

Adapted from Loftus et al. JAKs. Presented at the Advances in Inflammatory Bowel Disease Conference; Orlando, Florida; December 14-16, 2023.¹

Upadacitinib was investigated in patients with UC in the phase 3 U-ACHIEVE and U-ACCOMPLISH studies.^4,5 A total of 474 patients with moderately to severely active UC were randomized to receive daily upadacitinib 45 mg vs placebo for 8 weeks of induction therapy. Patients with a response were then randomized to daily upadacitinib 15 mg, upadacitinib 30 mg, or placebo for the maintenance portion of the study. Based on the ability to induce or maintain clinical remission, upadacitinib was superior to placebo in the induction trials (P<.001) and in the maintenance trial (P<.001). Upadacitinib induced responses in patients as early as week 2 of therapy, with improvements observed as early as day 1.^6,7 Based on the common adverse events (AEs) of anemia and leukopenia, a complete blood count and hepatic enzymes should be evaluated every 3 months for patients receiving JAK inhibitor therapy for UC.

Daily upadacitinib 45 mg was also investigated as induction therapy in the U-EXCEL trial, which enrolled patients with CD with an inadequate response or intolerance to conventional or biologic therapy.⁸ A notable finding of the study was the superior rate of steroid-free clinical remission at week 12 with upadacitinib vs placebo (22.2% vs 50.7%; P<.0001). The trial also showed a significantly higher rate of early responses and clinical remissions, including steroid-free remissions, with upadacitinib vs placebo. Rates of any AE, severe AEs, and serious AEs were similar between upadacitinib and placebo. However, placebo treatment was associated with a greater likelihood of worsening of CD symptoms (10.2% vs 3.7%). Anemia was more common with upadacitinib therapy vs placebo (6.3% vs 4.5%), as was acne (6.9% vs 0.6%). Herpes zoster was more common with upadacitinib vs placebo (2.9% vs 0%) and can be prevented with vaccination. Patients who achieved a clinical response at week 24 were randomized to U-ENDURE maintenance therapy with upadacitinib vs placebo. This trial achieved both primary endpoints, demonstrating a superior rate of clinical remission and endoscopic response with the JAK inhibitor, administered at 15 mg or 30 mg daily, compared with placebo (P<.0001 for all comparisons vs placebo). Rates of any AE, severe AEs, and serious AEs were numerically higher in the placebo arm vs either upadacitinib arm. Upadacitinib 30 mg daily is the preferred dose; however, the dose can be reduced to 15 mg in patients with anemia, leukopenia, or liver function abnormalities.

ABSTRACT SUMMARY Efficacy of Upadacitinib in Patients With One or More Prior Surgical Procedures for Crohn’s Disease: A Post Hoc Analysis of U-EXCEL, U-EXCEED, and U-ENDURE Phase 3 Trials.

A post hoc analysis of data from the U-EXCEL and U-EXCEED induction trials and the U-ENDURE maintenance trial to assess the efficacy of upadacitinib vs placebo in patients with CD who had undergone at least 1 surgical procedure for their CD (Abstract S7). In the induction cohort, the rate of CDAI clinical remission was similar with upadacitinib (45 mg) vs placebo (P<.05), but upadacitinib was superior to placebo based on the rate of steroid-free/ abdominal pain score remission (P<.05), endoscopic response (P=.0001), and endoscopic remission (P<.01). In the maintenance cohort, the higher dose of upadacitinib (30 mg) but not the lower dose (15 mg) yielded a superior rate of CDAI clinical remission (P<.05), steroid-free/abdominal pain score clinical remission (P<.05), and endoscopic remission (P<.01) vs placebo, whereas endoscopic remission rates were similar with either dose of upadacitinib vs placebo. No new safety signals were observed.

Filgotinib has been investigated in patients with UC in the phase 2b/3 SELECTION trial.⁹ The higher dose of 200 mg yielded significantly better outcomes vs placebo, demonstrating a superior rate of clinical remission at week 10 of induction therapy in biologic-naive patients (26.1% vs 15.3%; P=.0157) and in biologic-experienced patients (11.5% vs 4.2%; P=.0103). Filgotinib 200 mg also yielded a significantly higher rate of clinical remission at week 58 of maintenance therapy (37.2% vs 11.2%; P<.0001). Filgotinib has an acceptable safety profile. Rates of any AE and serious AEs were similar between the placebo and filgotinib arms.