P0849Dose escalation in participants with primary/secondary loss of response to conventional dosing of ustekinumab in paediatric Crohn’s Disease (UNITI Jr study)

Abstract Background Limited data exist on the safety and efficacy of shortening ustekinumab maintenance intervals in paediatric patients with Crohn’s disease who experience an initial lack of response or subsequent loss of response. This analysis examines ustekinumab efficacy, safety, and pharmacokinetics in paediatric participants from the UNITI Jr (NCT04673357) exposure optimization study (EOS). Methods Participants (N = 101; ≥2 – 18 years; Paediatric Crohn’s Disease Activity Index (PCDAI) 30; inadequate response/intolerant to prior treatment or corticosteroid-dependent) received 1 open-label IV dose of ustekinumab and were randomized 1:1 at Week (W)8 to blinded maintenance subcutaneous ustekinumab every 8 weeks (Q8W) or Q12W for 44-weeks. Those who had low steady-state trough ustekinumab concentrations (1.4μg/mL) and who either were W16 induction non-responders or lost response after W16 were eligible for entry to an optional 16-week EOS with Q4W dosing. Results Of randomized participants in the main study (N = 97), 26 (26.8%) enrolled in the EOS with median age (IQR) 14.0 (12.0; 16.0) years; 21/26 (80.8%) had prior biologic failure; 14/26 (53.8%) had PCDAI 40 at baseline of the EOS. While 21 (80.8%) completed ≥16-weeks of EOS treatment, 20 completed the sPCDAI assessment at W16 of the EOS. 10/20 (50.0%) and 19/20 (95.0%) achieved clinical remission and response, respectively; at W16 of the EOS and the median/mean (range) sPCDAI score was 10.0/12.5 (0; 45); change-from-baseline was −40.0/−37.5 (−70; 5) (Figure 1). Laboratory parameters of inflammation and fecal lactoferrin improved from EOS baseline to W16 and were similar to W52 of the main study (Table 1). Median (IQR) ustekinumab concentration increased from 0.71μg/mL (0.37; 1.02) at the start of the EOS to 3.92μg/mL (2.08; 4.74) at W16, falling within the observed W16 range in adults with CD receiving a Q8W regimen (median 2.05μg/mL 1.00; 3.70). Adverse events were recorded in 73.1% of participants (of those, 38.5% were GI-related) and 11.5% had serious adverse events. Safety was generally consistent with the main UNITI Jr study; no new safety issues were identified. Conclusion Paediatric participants who were non-responders or who lost response to ustekinumab in the UNITI Jr study responded favorably to switching to Q4W dosing with an increased proportion of participants achieving clinical response and remission, plus improvements in inflammatory markers after 16 weeks. Q4W dosing resulted in higher serum concentrations that were within the exposure range observed in adult CD ustekinumab studies. The safety profile of ustekinumab in these participants was similar to that in the overall UNITI Jr study and the known profile in adults. Conflict of interest: Prof. Russell, Richard K.: Received consultation fees, research grant, royalties, or honorarium from Johnson & Johnson, Pfizer, Ferring, Celltrion, Lilly, & AlfaSigma, received medical writing support from Johnson & Johnson De Greef, Elisabeth: Advisory Board J&J, received medical writing support from Johnson & Johnson Turner, Dan: Consultation fee, research grant, royalties, or honorarium from Johnson & Johnson, Pfizer, Shaare Zedek Medical Center, Hospital for Sick Children, Ferring, Abbvie, Takeda, Prometheus Biosciences, Lilly, SorrisoPharma, Boehringer Ingelheim, Galapagos, BMS, AlfaSigma, and Merck, received medical writing support from Johnson & Johnson Hyams, Jeffrey: Serves/served on advisory board for Johnson & Johnson, Lilly was/is a consultant for Takeda, Roche, Genentech, and Boehringer Ingelheim, received medical writing support from Johnson & Johnson Griffiths, Anne: Received consultation fee, research grant, royalties or honorarium from Abbvie, Alfasigma, Johnson & Johnson, Lilly, Merck, Pfizer, Shaare Zedek Medical Centre, SickKids Hospital, Takeda, received medical writing support from Johnson & Johnson Cohen, Stanley: Consultant for Johnson & Johnson, received medical writing support from Johnson & Johnson Rosh, Joel: Served/serves as an advisor and consultant for Abbvie serves/served as an advisor, consultant, and medical monitor for Johnson& Johnson, received medical writing support from Johnson & Johnson Kierkuś, Jarosław: Received a grant from Nestle for the study research conducted, received medical writing support from Johnson & Johnson Korczowski, Bartosz: Received grant from Johnson & Johnson for the study research conducted, received medical writing support from Johnson & Johnson Meglicka, Monika: Received consultation fees, royalties from Sandoz and Ferring, received medical writing support from Johnson & Johnson Cheng, Edaire: Employee of Janssen Pharmaceuticals and hold stock or stock options in Johnson & Johnson, received medical writing support from Johnson & Johnson Strauss, Richard: Employee of Johnson & Johnson and may hold stock or stock options in Johnson & Johnson, received medical writing support from Johnson & Johnson Van Limbergen, Els: Employee of Johnson & Johnson and may hold stock or stock options in Johnson & Johnson, received medical writing support from Johnson & Johnson Conklin, Laurie: I am an employee of Johnson and Johnson and I hold stock options in the company, received medical writing support from Johnson & Johnson Adedokun, Omoniyi: Employee Johnson & Johnson and may hold stock or stock options in Johnson & Johnson, received medical writing support from Johnson & Johnson Kim, Lilianne: I’m an employee of Johnson and Johnson Innovative Medicine and I hold stocks in the company, received medical writing support from Johnson & Johnson Volger, Sheri: Employee of Johnson & Johnson and may hold stock or stock options in Johnson & Johnson, received medical writing support from Johnson & Johnson