Efficacy and safety of intravenous ustekinumab re-induction therapy in Crohn’s disease patients with secondary loss of response during ustekinumab maintenance therapy: week 16 results from the phase 3b POWER trial

Introduction After successful induction, a subset of patients (pts) with Crohn’s disease (CD) experience a secondary loss of response (LoR) to ustekinumab (UST) maintenance therapy. Dose intensification may assist in regaining response. Objectives The phase 3b randomized, double-blind, multicenter POWER study evaluated the efficacy and safety of a single intravenous (IV) re-induction UST dose vs continued UST subcutaneous (SC) treatment in CD pts with LoR to standard UST every 8 weeks (q8w) maintenance therapy. Methodology Adults with moderately–severely active CD who initially responded to UST IV induction therapy per label and subsequently experienced LoR were included. LoR for inclusion was defined as CDAI score of≥220 and≤450, in addition to elevated CRP (>3mg/L), fCal (>250mg/kg)/endoscopy performed≤3 months before W0 with evidence of active CD (≥1 ulcerations in ileum and/or colon). At baseline (W0), pts received either ~6mg/kg IV UST/SC placebo (IV arm) or IV placebo/SC UST 90mg (SC arm), followed by SC UST 90mg dosing in both groups at W8/16. Clinical and biomarker assessments were made at W0/8/16 and optional ileocolonoscopy at W0/16. Primary endpoint: clinical response (Cres;≥100 point decrease from W0/CDAI<150) at W16. Additional outcome measures included clinical, biomarker, endoscopic and quality of life endpoints assessed at W8/16. Outcome The analysis set comprised 215 pts at W0 (IV,108;SC,107). At W16, 92.6% and 86.0% completed treatment from IV and SC arms, respectively. In both arms (IV, 58.3%;SC, 57.9%) most pts experienced≥2 biologic failures before initiating UST ([ Table 1 ]). At W16, 49.1% in IV arm and 37.4% in SC arm achieved Cres (p=0.089). Percentages of pts with normalized fCal, normalized CRP and/or fCal, endoscopic remission and improvement, and improvement in IBDQ score were greater in IV vs SC arm ([ Table 2 ]). At W16, similar proportions of pts had≥1 adverse event (AE) (IV, 60.2%;SC, 61.7%) and serious AEs (IV, 5.6%;SC, 5.6%). The proportions of pts with infections were similar between arms (IV, 23.1%;SC, 21.5%), with only 1 serious infection in each arm. Table 1 Baseline characteristics (FAS) Full Analysis Set UST IV (N=108) UST SC (N=107) Age (years), mean (SD) 41.8 (13.6) 40.0 (13.1) Female sex, n (%) 62 (57.4) 62 (57.9) Prior biologic treatment failure a,b , n (%) 96 (88.9) 99 (92.5) 1 biologic (anti-TNF or VDZ) 33 (30.6) 37 (34.6) ≥2 biologics (anti-TNFs±VDZ) 63 (58.3) 62 (57.9) CDAI score, mean (SD) 288.6 (55.5) 289.9 (55.8) PRO-2 (without weighting) c , mean (SD) 49.3 (18.7) 49.1 (21.2) CRP (mg/L), mean (SD) 12.9 (17.9) 10.0 (12.1) fCal (mg/kg), mean (SD) 1346.5 (2962.9) 1882.0 (4261.2) SES-CD d , mean (SD), n 10.4 (6.8), 59 11.5 (7.0), 58 IBDQ e score, mean (SD) 118.4 (27.9) 122.8 (33.5) a Pts with a history of biologic treatment failure characterized by primary nonresponse, secondary nonresponse, or intolerance.; b The three anti-TNFs were adalimumab, infliximab and certolizumab pegol.; c Sum of the number of stools and the abdominal pain scores in the prior 7 days.; d Endoscopy was an optional procedure during the study.; e The IBDQ total scores were used, with a score range from 32 to 224.; CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; FAS, full analysis set; fCal, fecal calprotectin; IBDQ, inflammatory bowel disease questionnaire; IV, intravenous; PRO, patient-reported outcome; SES-CD, Simple Endoscopic Score in Crohn’s Disease; SC, subcutaneous; SD, standard deviation; TNF, tumor necrosis factor; UST, ustekinumab; VDZ, vedolizumab. Table 2 Key endpoint data. Full Analysis Set Week 8 Week 16 UST IV N=108) UST SC (N=107) Adjusted difference (%) (95% CI) a , p-value a UST IV N=108) UST SC (N=107) Adjusted difference (%) (95% CI) a , p-value a Clinical response b,c , n (%) [Primary endpoint] 56 (51.9) 48 (44.9) 7.1 53 (49.1) 40 (37.4) 11.5 (−6.0; 20.2), 0.300 (−1.5; 24.5), 0.089 Clinical remission b,d , n (%) 38 (35.2) 31 (29.0) 6.4 36 (33.3) 29 (27.1) 5.9 (−5.8;18.6), 0.314 (−6.0; 17.8), 0.338 Change from BL in CDAI e , mean (SD) −99.8 (101.0) −79.6 (94.1) N/A −99.3 (105.5) −80.4 (91.8) N/A (N/A) 0.112 (N/A) 0.113 Change from BL in PRO-2 (without weighting) e,f , mean (SD) −19.8 (19.7) −12.8 (20.9) N/A −19.2 (22.6) −12.5 (20.8) N/A (N/A) 0.004 (N/A) 0.017 fCal normalization b,g , n/N (%) 13/73 (17.8) 7/75 (9.3) 8.3 21/73 (28.8) 6/75 (8.0) 20.5 (−2.3; 19.0), 0.145 (8.7; 32.4), 0.001 CRP normalization b,g , n/N (%) 11/79 (13.9) 14/75 (18.7) −4.7 13/79 (16.5) 8/75 (10.7) 5.8 (−16; 6.7), 0.435 (−4.4; 16.1), 0.293 fCal and/or CRP normalization, n/N (%) 22/93 (23.7) 21/94 (22.3) 1.2 31/93 (33.3) 14/94 (14.9) 18.5 (−10.7; 13.2), 0.842 (6.8; 30.2), 0.004 ≥16−point improvement from BL in IBDQ score b , n (%) N/A N/A N/A 64 (59.3) 46 (43.0) 16.4 (3.4; 29.5) 0.017 Endoscopy Subset h Week 16 UST SC (N=58) UST IV (N=59) p−value a ≥25% improvement in SES-CD from BL b , n(%) 9 (15.5%) 24 (40.7%) 0.0037 Endoscopic response b,i , n (%) 6 (10.3) 12 (20.3) 0.1996 Endoscopic remission b,j , n (%) 3 (5.2) 11 (18.6) 0.0432 Change from baseline in SES-CD e , mean (SD) −0.8 (3.2) −2.3 (3.9) 0.004 Endoscopic improvement b,k , n(%) 11 (19.0) 24 (40.7) 0.0149 a The confidence intervals were based on the Wald statistic with Mantel-Haenszel weight. As primary endpoint was not met, all p-values should be considered nominal.; b Patients who had insufficient data at the designated analysis timepoint or a prohibited Crohn’s disease-related surgery, prohibited concomitant medication changes, or discontinued study agent due to lack of efficacy or due to an adverse event indicated to be of worsening Crohn’s disease prior to the designated analysis timepoint were not considered to have achieved clinical response/remission (regardless of CDAI score), biomarker response, IBDQ score improvement, endoscopic response/remission, SES-CD improvement and endoscopic improvement (regardless of SES-CD score).; c Clinical response is defined by CDAI<150 or decrease of≥100 points from W0.; d Clinical remission is defined by CDAI<150.; e Patients who had insufficient data at the designated analysis timepoint or who had a prohibited Crohn's disease-related surgery, discontinued due to lack of efficacy or due to an adverse event indicated to be of worsening Crohn's disease, or had prohibited concomitant medication changes prior to the designated analysis time point had their baseline sum value carried forward.; f Sum of the number of stools and the abdominal pain scores in the prior 7 days.; g Normalized CRP is defined as CRP value≤3 mg/L, and normalized fCal concentrations is defined as≤250 µg/g. When either the CRP or fCal value is abnormal (CRP>3 mg/L and fCal>250 µg/g) at baseline and the value of the same parameter normalizes at the designated analysis timepoint, patients are considered to be normalized.; h For SES-CD analysis, only patients with SES-CD score≥3 at baseline in FAS were included.; i Endoscopic response is defined as a reduction in SES-CD score by 50% from baseline or SES-CD score≤3 or SES-CD=0 for patients who enter the study with an SES-CD=3.; j Endoscopic remission is defined as an SES-CD score≤3 or SES-CD=0 for patients who enter the study with an SES-CD=3.; k Endoscopic improvement is a reduction in SES-CD score of≥3 points.; BL, baseline; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CRP, C-reactive protein; FAS, full analysis set; fCal, fecal calprotectin; IBDQ, Inflammatory Bowel Disease Questionnaire; IV, intravenous; N/A, not applicable; SES-CD; Simple Endoscopic Score in Crohn’s Disease; SC, subcutaneous; SD, standard deviation; TNF, tumor necrosis factor; UST, ustekinumab. Conclusion The CDAI-based primary endpoint at W16 was formally not met. However, pts in this heavily pre-treated population who received IV re-induction showed consistent, clinically meaningful improvements at W16 compared with those receiving SC, particularly for objective endpoints, including inflammatory biomarkers and endoscopic outcomes as well as pain/diarrhea scores. präsentiert in der Sitzung: CED – Teamwork worksSamstag, 16. September 2023, 10:15–11:45, Saal X01 Publication History Article published online: 28 August 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

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