One‐year outcomes with ustekinumab therapy in infliximab‐refractory paediatric ulcerative colitis: a multicentre prospective study

Abstract

Summary Background The phase 3 (UNIFI) trial of ustekinumab (anti‐interleukin 12/23) demonstrated efficacy even after prior biologic failure in adult ulcerative colitis (UC), but paediatric data are lacking. Aim To prospectively monitor efficacy and serum concentrations of ustekinumab given to children with UC refractory to other biologics. Methods Children with anti‐TNF refractory UC initiating ustekinumab intravenously at sites of the Canadian Children IBD Network prior to 12/2019 are included. The primary endpoint was steroid‐free clinical remission with subcutaneous ustekinumab at 52 weeks (Paediatric Ulcerative Colitis Activity Index <10, no steroids ≥4 weeks). Ustekinumab levels were measured after week 20. Endoscopic improvement was defined as Mayo endoscopic subscore ≤1, or faecal calprotectin (FCP) <250 μg/g if not re‐colonoscoped. Results At six sites between 01/2018 and 11/2019, 25 children (median [IQR] age 14.8 years [12.3‐16.2], 72% female) with UC duration 2.3 years (1.1‐4.2) received intravenous ustekinumab (median dose/kg of 6.4 [5.5‐7.5] mg). All patients had failed prior infliximab therapy, and 12 (48%) also vedolizumab. Five patients discontinued ustekinumab after IV induction (four undergoing colectomy). On intent to treat basis, 44% achieved the primary endpoint of steroid‐free remission at week 52, including nine (69%) of 13 who previously treated with anti‐TNF only vs two (17%) of 12 who previously failed also by vedolizumab (P = 0.008). Seven of 11 remitters met the criteria for endoscopic improvement. The median (IQR) trough levels (μg/mL) were greater with q4 vs q8 weekly dosing (8.7 [4.6‐9.9] vs 3.8 [12.7‐4.8]) P = 0.02, but greater exposure was not associated with a superior rate of clinical remission. No adverse events were associated with therapy. Conclusion Ustekinumab demonstrated efficacy in this paediatric cohort with otherwise treatment‐refractory UC. Treatment failure was not due to inadequate drug exposure.

New Insights and Advances in Pathogenesis and Treatment of Very Early Onset Inflammatory Bowel Disease

“…Ustekinumab, a therapeutic human IgG1 monoclonal antibody (mAb) targeting the interleukin (IL)-12/IL-23 shared p40 subunit, is approved in adolescents (12 years of age and older) for the treatment of moderate and severe psoriasis, as well as for the treatment of adult celiac disease and UC (91)while celiac disease currently has gluten-free diet as the only therapy. In a multicenter prospective cohort of children, the effectiveness of ustekinumab in treating refractory UC was demonstrated (92), which is similar to the results of a retrospective study of pediatric IBD, suggesting that ustekinumab is effective and safe in children with IBD (93). Some case reports suggest that 50% of children with IBD have a clinical response to ustekinumab (94,95).…”

Significant advantages for first line treatment with TNF-alpha inhibitors in pediatric patients with inflammatory bowel disease – Data from the multicenter CEDATA-GPGE registry study

“…In a retrospective multicenter study, approximately 54% of pediatric patients with IBD who were treated with vedolizumab achieved remission after 14 weeks, even after treatment failure with anti-TNF-α drugs ( 11 ). In another small multicenter sample, ustekinumab led to endoscopic improvement in children with UC who were refractory to therapy with infliximab and vedolizumab ( 12 ). Similarly, golimumab was an effective treatment for IBD in children and adolescents because it induced clinical remission, as measured by clinical scores ( 13 ).…”

Targeting IL12/23 in ulcerative colitis: update on the role of ustekinumab

“… 16 – 18 Currently, few real-life data have been reported on the effectiveness of ustekinumab for UC treatment and, as it usually happens with new drugs, most of these studies included patients with prior exposure/failure to multiple biological drugs. 19 – 22 …”