Tofacitinib in ulcerative colitis: UEGW 2023 updates

At the United European Gastroenterology Week (UEGW) 2023 held in Copenhagen, Denmark, researchers presented latest findings on tofacitinib in ulcerative colitis (UC). Topics covered included identification of factors associated with tofacitinib treatment response and maintenance of response, histological outcomes following treatment, and long-term safety data from the global tofacitinib UC clinical programme.

Does induction week 8 symptomatic remission predict sustained week 52 remission?
A series of three phase III randomized controlled trials (RCTs) evaluated the efficacy and safety of tofacitinib in adults with moderately-to-severely active UC despite previous conventional therapy or treatment with an antitumour necrosis factor (TNF) agent. The two identical OCTAVE Induction 1 (n=598) and OCTAVE Induction 2 (n=541) trials involved induction therapy with tofacitinib 10 mg BID, which resulted in higher rates of remission at 8 weeks vs placebo (OCTAVE Induction 1: 18.5 percent vs 8.2 percent; p=0.007) (OCTAVE Induction 2: 16.6 percent vs 3.6 percent; p<0.001). In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomized to receive maintenance therapy with tofacitinib (5 mg BID or 10 mg BID) or placebo for 52 weeks. Significantly higher remission rates were achieved in the tofacitinib 5 mg BID (34.3 percent) and 10 mg BID (40.6 percent) arms vs the placebo arm (11.1 percent; p<0.001 for both comparisons with placebo). [N Engl J Med 2017;376:1723-1736]

A post hoc analysis of these trials was performed to:

1. Identify baseline factors associated with symptomatic remission (defined as a total Mayo score of ≤2 with no individual sub-score of >1, and both rectal bleeding and stool frequency subscores of 0) at the end of OCTAVE Induction trials;
2. Compare the efficacy of tofacitinib 5 mg BID and 10 mg BID at the end of the OCTAVE Sustain trial in patients who achieved symptomatic remission at maintenance baseline (ie, after 8 weeks of induction therapy) vs those who did not. [United European Gastroenterol J 2023;11(Suppl 8):957-958, abstract PP0759]

Prior TNF inhibitor exposure or failure was associated with lower odds of achieving symptomatic remission at week 8 of induction studies (prior exposure: odds ratio [OR], 0.44; 95 percent confidence interval [CI], 0.25–0.77) (prior failure: OR, 0.42; 95 percent CI, 0.23-0.75). In contrast, total Mayo score <9 (OR, 2.82; 95 percent CI, 1.63–4.88), lower stool frequency (0–2) (OR, 3.04; 95 percent CI, 1.63–5.65), endoscopic subscore of 2 at induction baseline (OR, 2.86; 95 percent CI, 1.65–4.97) and smoking status (current smokers) (OR, 3.98; 95 percent CI, 1.10–14.34) were associated with higher odds of achieving symptomatic remission at induction week 8. (Figure) [Desreumaux P, et al, UEGW 2023, poster PP0759]

At the end of the OCTAVE Sustain trial, a numerically higher proportion of maintenance baseline symptomatic remitters vs nonremitters achieved remission with both doses of tofacitinib. However, no differences were seen between maintenance baseline symptomatic remitters and nonremitters (all tofacitinib doses) in terms of achievement of corticosteroid-free remission (CSFR) and sustained CSFR at week 52. “Patients who did not achieve symptomatic remission after 8 weeks of induction treatment could still achieve efficacy endpoints with both tofacitinib maintenance doses at week 52 of OCTAVE Sustain,” the researchers noted. [United European Gastroenterol J 2023;11(Suppl 8):957-958, abstract PP0759]

Histological outcomes and gut immune landscape in tofacitinib-treated UC patients
A single-arm prospective cohort study was conducted in 40 patients with moderately-to-severely active UC to evaluate histological outcomes and immunological changes after 8 weeks of tofacitinib treatment. Colon biopsies were stained for Janus kinase (JAK) 1–3, tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription (STAT) 1–6 total protein expression using immunohistochemistry. [United European Gastroenterol J 2023;11(Suppl 8):1052-1053, abstract PP0891]

Tofacitinib treatment resulted in histological response (50 percent decrease in Robarts Histopathology Index [RHI] compared with baseline) and histological remission (RHI ≤3 points without mucosal neutrophils) in 85 percent and 58 percent of the patients, respectively. Significant decreases in total STAT1 (p<0.001), STAT3 (p=0.002) and STAT5 (p=0.026) expression were observed after 8 weeks of treatment in both responders and nonresponders. Furthermore, responders expressed significantly lower total STAT1 levels compared with nonresponders at 8 weeks (p<0.001). At baseline, responders tended to express lower JAK1, JAK2 and total STAT4 and higher total STAT6 levels. [van Gennep S, et al, UEGW 2023, poster PP0891]

Up to 9.2 years of safety data from global UC programme
Safety analysis was performed on data from six clinical trials involving 1,157 UC patients treated with tofacitinib for a maximum exposure of 9.2 years. Proportions and incidence rates (IRs) were evaluated for deaths and adverse events of special interest (AESIs; ie, serious infections, herpes zoster [HZ], opportunistic infections, malignancies [excluding nonmelanoma skin cancer (NMSC)], NMSC, major adverse cardiovascular events, deep vein thrombosis, pulmonary embolism, and gastrointestinal perforations). [United European Gastroenterol J 2023;11(Suppl 8):94-95, abstract OP098]

Except for HZ (nonserious and serious combined) and serious infections, IRs for AESIs were generally <1.0 case per 100 patient-years. Furthermore, IRs for AESIs remained stable over an extended period of time (≤9.2 years) with inclusion of data from the phase IIIb/IV RIVETING trial, and were consistent with prior overall cohort analyses (≤7.8 years). [Clin Gastroenterol Hepatol 2019;17:1541-1550; J Crohns Colitis 2023;17:338-351; Panes J, et al, UEGW 2023, poster OP098]