Gasink, C

Abstract Background Ustekinumab (UST) is an approved treatment for adults with inflammatory bowel disease (IBD: Crohn’s disease [CD] and ulcerative colitis [UC]), psoriasis (PsO), and psoriatic arthritis (PsA). Here, we present pooled safety analyses in these approved indications of patients (pts) with active tuberculosis (TB) and opportunistic infections (OIs) through 5 years (yrs) of UST treatment. Methods Pooled data included 13 Phase 2/3 UST studies through 5 yrs of CD and PsO, 2 yrs of UC, and 1 yr of PsA. OIs were identified by clinician review. Herpes zoster (HZ) was evaluated separately. Event rates per 100 pt yrs (PYs) are presented. Concomitant immunomodulators/corticosteroids were permitted in IBD and PsA pts. All pts who received ≥1 UST dose were included. In IBD, placebo (PBO) pts included data up to the first UST dose for pts initially treated with PBO, or >16 weeks after the last UST dose for UST pts who switched to PBO. Results Across all approved indications, 19 OIs including TB were reported, with rates in PBO of 0.40 and UST of 0.10 through 5 yrs in 13807 PYs of follow-up (Table 1); rates of HZ were 1.21 and 0.63, respectively. Of 19 OIs, 18 were in IBD pts and 1 in a PsO pt. Overall, 14/16 pts (12/13 UST) with OIs excluding TB were also receiving confounding concomitant medications. A total of 3 active TB cases (2 pts with CD and 1 pt with UC) were reported in PBO (n=2; 1 in a Hungarian CD pt 10 months after receiving last UST dose) and UST (n=1) pts (Table 1). One active TB case was reported in an asymptomatic South African CD pt treated with UST who had a positive QuantiFERON®-TB Gold test on routine screening and bronchial brushings positive for M. tuberculosis. Both CD pts completed TB treatment with disease resolution. The most common OIs were esophageal candidiasis (UST n=3; PBO n=2) and cytomegalovirus colitis (UST n=3; PBO n=1). Conclusion Rates of OIs, including active TB, in UST-treated pts were low across approved indications through up to 5 yrs with 13807 PYs of follow-up and not higher in UST pts vs PBO pts, suggesting no increased risk of OI with long-term UST treatment.

INTRODUCTION: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD). METHODS: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation. RESULTS: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49–0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48–0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients. DISCUSSION: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response.

Abstract Background Perianal fistulas are common and cause significant quality of life impairment in patients (pts) with Crohn’s disease (CD). In previous phase 2/3 studies, ustekinumab (UST) showed some evidence of efficacy on fistula resolution, with no clear dose-response relationship. Additional studies are needed to evaluate the role of UST in perianal fistula treatment. Here, we report fistula data from two recent studies of UST in CD, SEAVUE and STARDUST. Methods In SEAVUE, biologic-naïve pts with moderate-to-severe CD were randomized to receive blinded UST (⁓6mg/kg IV at baseline then 90mg SC q8w) or adalimumab (ADA; 160/80mg SC at baseline/W2, then 40mg SC q2w). In STARDUST, biologic-naïve and biologic-failure pts with moderate-to-severe CD received open-label UST ⁓6mg/kg IV at baseline and UST 90mg SC at W8. At W16, pts were randomized to maintenance treatment under standard of care (90mg SC q12w or q8w) or treat-to-target (90mg SC q12w or q8w with potential adjustment to q4w) regimens. In both trials, the number of open and draining perianal fistulas was evaluated at baseline and the end of maintenance (SEAVUE W52, STARDUST W48). Fistula resolution was defined as closure of all fistulas. Pts with missing data at W52/W48 were considered to not have been in fistula resolution. In SEAVUE, pts who had a prohibited CD-related surgery, discontinued for lack of efficacy or an adverse event of worsening CD, or had prohibited concomitant medication changes before W52 were considered not to be in fistula resolution. Results In SEAVUE, 7 of 13 pts (53.8%) with active perianal fistulas at baseline in the UST group had complete fistula resolution at W52, and 6 of 16 patients (37.5%) in the ADA group had fistula resolution. In STARDUST, 9 of 19 pts (47.4%) with active perianal fistulas at baseline had complete fistula resolution at W48. Of the 9 pts in fistula resolution, 2 were receiving q12w at W48, 6 were receiving q8w, and 1 was receiving q4w. Of the 10 pts without fistula resolution, 2 were receiving q12w at W48, 3 were receiving q8w, 1 was receiving q4w and 4 discontinued before W48. In both studies, among pts with evaluable samples for pharmacokinetic analysis, fistula closure at W52/48 was not associated with higher serum drug concentrations at either the early time point of W16 or at the end of maintenance (Figure). This result was consistent for UST in both studies as well as ADA in SEAVUE. Conclusion Of pts with perianal fistulas at baseline in SEAVUE and STARDUST who received UST (32 pts in total), half were in fistula resolution after ~1 year of maintenance treatment. No relationship was observed between fistula resolution and serum drug concentrations, but no definite conclusions can be drawn given the relatively small sample size.