Introduction: The Phase 3 QUASAR induction study evaluated efficacy and safety of guselkumab (GUS), an IL-23p19 subunit antagonist, in patients (pts) with moderately to severely active UC. At Week (Wk) 12, GUS 200mg IV was more effective than placebo (PBO) in inducing clinical remission and clinical response. Pts not in clinical response at Wk12 received GUS through Wk24. Here, we report GUS cumulative efficacy and safety. Methods: Pts with a modified Mayo score of 5-9 and a centrally reviewed Mayo endoscopy subscore ≥2 at baseline (BL) were randomized 3:2 to receive GUS 200mg IV or PBO at Wks0, 4, and 8. Pts not in clinical response at Wk12 received GUS at Wks12, 16, and 20 (GUS 200mg IV→GUS 200mg SC; PBO→GUS 200mg IV) and were evaluated at Wk24. Matching IV or SC PBO were used to maintain study blinding. Final safety assessments were conducted through Wk 32 (ie, 12 wks after last dose of GUS). Results: The primary analysis population consisted of 701 pts. BL demographics were similar among treatment groups, and approximately 50% had a history of inadequate response/intolerance to advanced therapy (ADT-IR). At Wk12, clinical response was achieved by a higher percentage of GUS- vs PBO-treated pts (61.5% vs 27.9%, respectively; adjusted Δ [95% CI]: 33.8% [26.9%, 40.7%]; P< 0.001; Figure 1). Of GUS-treated pts who were not in clinical response at Wk12 and received additional GUS treatment (GUS IV→GUS SC), 55% (66/120) achieved clinical response at Wk24. Cumulative clinical response at Wk12 or 24 was achieved by 77.2% of pts randomized to GUS at BL. Pts with and without history of ADT-IR benefitted from continued treatment with GUS SC through Wk24 (51.4% and 60.9% achieved clinical response at Wk24, respectively). Of PBO-treated pts who were not in clinical response at Wk12 and received GUS treatment (PBO IV→GUS IV), clinical response rate at Wk24 (69.7%) was similar to that at Wk12 for pts randomized to GUS at BL (61.5%). Safety findings through the final safety visit were consistent with Wk12 results; no new safety signals were identified (Table 1). The most frequent adverse events among GUS-treated pts (n=586) were COVID-19 (7.2%), anemia (5.1%), and worsening UC (4.6%). Conclusion: Among pts randomized to GUS IV who did not achieve clinical response at Wk12, continued treatment with GUS SC allowed 55% to achieve clinical response at Wk24. Overall, more than three-quarters of pts randomized to GUS IV achieved clinical response at Wk12 or 24. No new safety signals for GUS were identified.Figure 1.: Cumulative clinical response through Week 24. Table 1. - Safety summary through final safety visit IV Induction Cross-over Combined PBO IVa GUS 200mg IVa PBO IV → GUS 200mg IVb GUS 200mg IV → GUS 200mg SCb All GUSc Safety analysis set, N 280 421 165 125 586 Average duration of follow-up (weeks) 12.1 12.3 13.9 14.6 15.9 Average exposure (number of administrations) 2.9 2.9 2.9 2.8 3.5 Deathsd 2 (0.7%) 1 (0.2%) 0 0 1 (0.2%) Patients with one or more: Adverse events 138 (49.3%) 208 (49.4%) 65 (39.4%) 56 (44.8%) 292 (49.8%) Serious adverse events 20 (7.1%) 12 (2.9%) 3 (1.8%) 3 (2.4%) 18 (3.1%) Adverse events leading to discontinuation of study agent 11 (3.9%) 7 (1.7%) 7 (4.2%) 5 (4.0%) 19 (3.2%) Infectionse 43 (15.4%) 67 (15.9%) 26 (15.8%) 18 (14.4%) 104 (17.7%) Serious infectionse 1 (0.4%) 3 (0.7%) 1 (0.6%) 2 (1.6%) 6 (1.0%) Adverse events within 1 hour of infusionf 1 (0.4%) 6 (1.4%) 1 (0.6%) 3 (2.4%) 10 (1.7%) Note: Includes only pts with modified Mayo score 5-9 at induction baseline.aIncludes data up to Week 12 for subjects who received treatment at Week 12. Includes all data through final safety visit (12 weeks after the last dose of study intervention) for subjects who did not receive treatment at Week 12.bIncludes data from Week 12 onward.cFrom the first guselkumab dose onward.dAll reported deaths were cardiovascular in nature and the patient in GUS arm had substantial cardiovascular risk factors.eInfections were defined as any adverse event which was coded to the MedDRA system organ class 'Infections and infestations.’fNo AEs within 1 hour of infusion were serious or resulted in treatment discontinuation.

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.

Background and Aims: Tesnatilimab, a monoclonal antibody targeting NKG2D, was evaluated in Crohn's disease [CD] patients who had failed or were intolerant to biologic or conventional therapy. Methods: TRIDENT was a phase 2b, two-part, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study. In Part 1 [proof of concept], 145 patients who were biologic intolerant or refractory [Bio-IR] or had not failed biologic therapy [Bio-NF] were randomised in a 1:1 ratio to placebo subcutaneously [SC] or tesnatilimab 400 mg SC. In Part 2 [dose ranging], 243 Bio-IR and Bio-NF patients were randomised in a 1:1:1:1:1 ratio to placebo, tesnatilimab [50 mg, 150 mg, 400 mg], or intravenous infusion of ustekinumab similar to 6 mg/kg at Week 0 and 90 mg SC at Weeks 8 and 16. The primary endpoint was mean change from baseline in Crohn's Disease Activity Index [CDAI] at Week 8 [Part 1] and Week 12 [Part 2]. Clinical and endoscopic remission/response were evaluated. Efficacy analyses were also assessed by NKG2D and MICB single nucleotide polymorphism [SNP] status [SNP-positive means positive in at least one of two SNPs]. Safety events were summarised. Results: In Part 1, mean change from baseline in CDAI score was significantly greater with tesnatilimab vs placebo at Week 8 [-103.6 vs -60.0; p < 0.01]. In Part 2, no dose-response signal was detected. Mean changes from baseline in CDAI at Week 12 were -93.2, -72.2, and -84.3 for low, middle, and high doses of tesnatilimab, respectively, vs -59.2 for placebo and -148.8 for ustekinumab. Similar reductions from baseline in CDAI score were observed in patients receiving tesnatilimab, regardless of SNP status. Clinical remission rates were greater with tesnatilimab than placebo in Parts 1 and 2, whereas endoscopic response rates were greater with tesnatilimab only in Part 1. No unexpected safety events occurred. Conclusions: Tesnatilimab was well tolerated. The efficacy of tesnatilimab in patients with CD was significant for the primary endpoint in Part 1; however, no dose-response signal was detected for the primary endpoint in Part 2. Based on these inconsistent findings, tesnatilimab was not considered an effective treatment for patients with CD and no further development is planned.

Introduction: The POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction ustekinumab (UST) dose vs placebo on a background of continued UST subcutaneous (SC) treatment in Crohn’s disease (CD) patients (pts) with secondary loss of response (LoR) to standard q8w UST maintenance therapy. This subgroup analysis reports primary and major secondary endpoints up to week (W)16 in pts with/without a history of inadequate response or intolerance to prior biologics. Methods: Adults with moderately–severely active CD who initially responded to UST IV induction therapy per label and later experienced LoR were included. LoR was defined as CD Activity Index (CDAI) score of ≥220 and ≤450, plus either elevated C-reactive protein (CRP; >3mg/L), fecal calprotectin (fCal; >250mg/kg), or endoscopy performed ≤3 months before W0 with evidence of active CD. At W0 randomized pts received ∼6mg/kg IV UST/SC placebo (IV arm) or IV placebo/SC UST 90mg (SC arm) followed by 90mg SC UST at W8/16. Clinical/biomarker assessments occurred at W0/8/16. Primary endpoint: W16 clinical response (CRes; decrease of ≥100 points from W0 or CDAI < 150). Secondary endpoints: CRes; clinical remission (CRem); normalization of CRP and/or fCal at W8/16. Results: The full analysis set comprised 215 pts at W0 (SC, n=107; IV, n=108). At W16, 86.0% (SC) and 92.6% (IV) of pts completed treatment. Most pts (SC, 92.5%; IV, 88.9%) had a history of inadequate response/intolerance to prior biologics. At W16, while CRes did not statistically differentiate between arms, secondary outcomes indicated a difference in the IV vs SC arm. In this analysis, differences were seen in bionaïve pts and those with inadequate response/intolerance to < 3 biologics. A numerically greater proportion of pts achieved CRes in the IV vs SC arms in all groups except pts with ≥3 prior biologics, with a nominal difference in pts with 1 prior biologic (P=0.043; Table 1). A similar trend was observed for pts achieving W16 CRem, albeit the nominal threshold was not reached. A numerically greater proportion of pts in the IV vs SC arm achieved normalization of CRP and/or fCal at W16, except those with ≥3 prior biologics, and with a nominal difference in pts with 1 prior biologic (P< 0.001). Conclusion: POWER is the first trial to assess the efficacy and safety of UST IV re-induction in pts with secondary LoR. This analysis suggests that both naïve pts and those with prior inadequate response or intolerance to biologics may benefit from UST re-induction therapy. Table 1. - Primary and major secondary endpoints at W8 and W16 for patients with or without a history of inadequate response or intolerance to prior biologic(s) (Full analysis set) Overall population No history of prior biologic* inadequate response or intolerance History of inadequate response or intolerance to 1 prior biologic* History of inadequate response or intolerance to 2 prior biologics* History of inadequate response or intolerance to ≥3 prior biologics* UST SC n=107 UST IVn=108 UST SCn=8 UST IVn=12 UST SCn=37 UST IVn=33 UST SCn=35 UST IVn=35 UST SCn=27 UST IVn=28 Clinical response†‡ at W16 (primary endpoint) 40 (37.4) 53 (49.1)Δ 11.5 (-1.5; 24.5) P=0.089 1 (12.5) 5 (41.7)Δ 29.2 P=0.325 15 (40.5) 21 (63.6)Δ 24.4 (2.0; 46.8) P=0.043 13 (37.1) 18 (51.4)Δ 16.2 (-6.2; 38.7) P=0.177 11 (40.7) 9 (32.1)Δ -8.4 (-33.2; 16.3) P=0.535 Clinical remission‡§ at W16 29 (27.1) 36 (33.3)Δ 5.9 (-6.0; 17.8) P=0.338 0 4 (33.3)Δ 33.3 P=0.117 12 (32.4) 15 (45.5)Δ 11.8 (-9.9; 33.4) P=0.313 8 (22.9) 12 (34.3)Δ 10.6 (-10.7; 31.9) P=0.334 9 (33.3) 5 (17.9)Δ -11.0 (-33.3; 11.2) P=0.359 Patients with normalized CRP and/or fCall‡ ||¶** at W16 14/94 (14.9) 31/93 (33.3)Δ 18.5 (6.8; 30.2) P=0.004 1/8 (12.5) 2/8 (25.0)Δ 12.5 P=1.00 2/31 (6.5) 12/28 (42.9)Δ 37.6 (17.9; 57.4) P< 0.001 6/30 (20.0) 12/32 (37.5)Δ 17.8 (-3.1; 38.7) P=0.131 5/25 (20.0) 5/25 (20.0)Δ 3.8 (-18.8; 26.4) P=0.743 Clinical response†‡ at W8 48 (44.9) 56 (51.9)Δ 7.1 (-6.0; 20.2) P=0.300 3 (37.5) 4 (33.3)Δ -4.2 P=1.00 21 (56.8) 20 (60.6)Δ 4.7 (-18.4; 27.7) P=0.696 12 (34.3) 19 (54.3)Δ 22.0 (-0.2; 44.3) P=0.067 12 (44.4) 13 (46.4)Δ -2.7 (-29.1; 23.6) P=0.844 Clinical remission‡§ at W8 31 (29.0) 38 (35.2)Δ 6.4 (-5.8; 18.6) P=0.314 3 (37.5) 4 (33.3)Δ -4.2 P=1.00 15 (40.5) 14 (42.4)Δ -0.2 (-22.3; 21.8) P=0.985 6 (17.1) 14 (40.0)Δ 21.5 (1.3; 41.6) P=0.049 7 (25.9) 6 (21.4)Δ -2.0 (-24.3; 20.2) P=0.864 Data are presented as n (%) Δ (95% CI) P-value P<0.05 was the threshold for significance; P-values should be considered nominal as primary endpoint was not met.*Tumor necrosis factor inhibitors or vedolizumab.†Clinical response is defined as a decrease of ≥100 points from W0 or CDAI score of <150 points.‡Patients who had insufficient data at the designated analysis timepoint or a prohibited CD-related surgery, prohibited concomitant medication changes, or discontinued study agent due to lack of efficacy or due to an adverse event indicated to be caused by worsening CD prior to the designated analysis timepoint were not considered to have achieved the endpoint.§Clinical remission is defined as CDAI <150 points.||Abnormal CRP is defined as CRP value >3 mg/L and abnormal fCal concentrations is defined as >250 µg/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 at baseline and the value of the same parameter normalizes at W16, patients are considered to be normalized at the designated analysis timepoint.**Patients who had insufficient data at the designated analysis timepoint had their last value carried forward.Δ, difference; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CRP, C-reactive protein; fCal, fecal calprotectin; IV, intravenous; SC, subcutaneous; UST, ustekinumab; W, week.

Introduction: The 36-week (W) POWER trial evaluated the efficacy and safety of a single intravenous (IV) re-induction ustekinumab (UST) dose vs continued UST subcutaneous (SC) treatment in Crohn’s disease (CD) patients with secondary loss of response (LoR) to standard UST maintenance therapy. Here, we report subgroup analysis of the primary endpoint by baseline characteristics. Methods: Adults with moderately–severely active CD who initially responded to UST IV induction therapy per label and later experienced LoR were included. LoR has been previously defined1. At baseline (W0), randomized patients received ∼6mg/kg IV UST/SC placebo (IV arm) or IV placebo/SC UST 90mg (SC arm), followed by SC UST 90mg dosing at W8/16. Descriptive statistics were used to summarize baseline characteristics. Clinical assessments occurred at W0/8/16. Primary endpoint: clinical response (CRes; decrease of ≥100 points from W0 in CD activity index [CDAI] or CDAI < 150) at W16. Odds ratios (ORs), confidence intervals (CIs) and P-values were estimated with a logistic regression model. Results: The full analysis set comprised 215 patients at W0 (SC, n=107; IV, n=108). At W16, 86.0% (SC) and 92.6% (IV) of patients completed treatment. At W16, 37.4% (SC) and 49.1% (IV) of patients achieved CRes (P=0.089). Of all baseline characteristics, disease location and duration, inflammatory biomarkers and prior biologic failures were of particular interest (Table 1). A greater proportion of patients from the IV vs SC arm achieved CRes at W16 (OR 3.6; 95%CI 1.6–8.1; P=0.002) of those with ileum and colon involvement. Patients with disease duration of < 5 years in the IV (n=22) vs SC (n=20) arm were more likely to achieve W16 CRes (OR 4.5; 95%CI 1.2–17.4; P=0.029). A greater proportion of patients in the IV vs SC arm with elevated baseline C-reactive protein (OR 2.1; 95%CI 1.1–4.0; P=0.029) or fecal calprotectin (OR 2.0; 95%CI 1.0–4.0; P=0.045) achieved W16 CRes as did patients with 1 prior biologic failure (OR 2.8; 95%CI 1.0–7.6; P=0.042). Conclusion: POWER assessed the efficacy and safety of UST IV re-induction in patients with LoR during UST maintenance therapy. This analysis suggests that patients with fewer prior biologic exposures and shorter disease duration but a higher disease burden at baseline including greater disease extent involving ileum and colon, or elevated inflammatory biomarkers, are more likely to benefit from UST IV re-induction therapy. 1. S.W. Schreiber, et al. J Crohns Colitis. 2023;17(Suppl 1):571 (Abstract P436). Table 1. - Proportion of patients who achieved clinical response*† at Week 16 by baseline characteristics (Full analysis set). As the primary endpoint was not met, all P-values should be considered nominal Baseline and clinical disease characteristics UST SC (n=107), n/N (%) UST IV (n=108), n/N (%) OR‡ (95%CI); P-value Age (median years) ≤40 22/62 (35.5) 28/52 (53.8) 2.1 (1.0; 4.4); P=0.060 >40 18/45 (40.0) 25/56 (44.6) 1.3 (0.6; 2.8); P=0.58 CDAI Score ≤300 24/68 (35.3) 30/68 (44.1) 1.4 (0.7; 2.9); P=0.312 >300 16/39 (41.0) 23/40 (57.5) 2.0 (0.8; 4.8); P=0.138 Prior CD-related surgery history Total or subtotal colectomy 4/9 (44.4) 7/17 (41.2) NE Partial bowel resection 12/28 (42.9) 21/39 (53.8) 1.5 (0.5; 4.0); P=0.472 Current draining fistula 2/10 (20.0) 4/11 (36.4) NE Prior perianal surgery 4/21 (19.0) 14/23 (60.9) 5.8 (1.5; 23.3); P=0.013 Involved gastrointestinal areas Ileum only 13/28 (46.4) 10/29 (34.5) 0.6 (0.2; 2.0); P=0.434 Colon only 11/22 (50.0) 10/24 (41.7) 0.7 (0.2; 2.3); P=0.505 Ileum and colon 16/55 (29.1) 33/55 (60.0) 3.6 (1.6; 8.1); P=0.002 Disease duration (years) < 5 5/20 (25.0) 13/22 (59.1) 4.5 (1.2; 17.4); P=0.029 ≥5 35/87 (40.2) 40/86 (46.5) 1.3 (0.7; 2.4); P=0.395 Prior failed biologics 0 1/8 (12.5) 5/12 (41.7) NE 1 15/37 (40.5) 21/33 (63.6) 2.8 (1.0; 7.6); P=0.042 2 13/35 (37.1) 18/35 (51.4) 2.0 (0.7; 5.3); P=0.173 3 10/25 (40.0) 6/23 (26.1) 0.6 (0.2, 2.0); P=0.363 4 1/2 (50.0) 3/5 (60.0) NE Baseline biomarker levels CRP ≤3 mg/L 12/32 (37.5) 10/29 (34.5) 0.9 (0.3; 2.5); P=0.780 CRP >3 mg/L 28/75 (37.3) 43/79 (54.4) 2.1 (1.1; 4.0); P=0.029 fCal ≤250 mg/kg 16/32 (50.0) 18/35 (51.4) 1.1 (0.4; 2.8); P=0.920 fCal >250 mg/kg 24/75 (32.0) 35/73 (47.9) 2.0 (1.0; 4.0); P=0.045 *Clinical response is defined as a decrease of ≥100 points from Week 0 or CDAI score of < 150 points.†Patients who had insufficient data at the designated analysis timepoint or a prohibited CD-related surgery, prohibited concomitant medication changes, or discontinued study agent due to lack of efficacy or due to an adverse event indicated to be caused by worsening CD prior to the designated analysis timepoint were not considered to have achieved clinical response, regardless of their CDAI score.‡OR, 95%CI for OR, and P-values were based on logistic regression.CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CRP, C-reactive protein; fCal, fecal calprotectin; IV, intravenous; NE, not evaluated; OR, odds ratio; SC, subcutaneous; UST, ustekinumab.

Introduction: The POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction ustekinumab (UST) dose vs continued UST subcutaneous (SC) treatment in Crohn’s disease (CD) patients (pts) with secondary loss of response (LoR) to standard UST maintenance therapy. Here, we present Week (W) 16 pharmacokinetics, exposure–response relationships, and immunogenicity analysis. Methods: Adult pts with moderately–severely active CD who initially responded to UST IV induction therapy per label and later experienced LoR were included. LoR was defined as CD Activity Index (CDAI) score ≥220–≤450, plus elevated C-reactive protein ( >3mg/L)/fecal calprotectin ( >250mg/kg), or endoscopy performed ≤3 months before baseline (W0) with active CD. At W0, randomized pts received ∼6mg/kg IV UST, or SC UST 90mg, followed by SC UST 90mg dosing at W8/16. Clinical assessments occurred at W0/8/16. Serum samples evaluated UST concentration (conc) and anti-drug antibodies (ADAs) at W0/8/16 using validated assays. Clinical response (CRes) and endoscopic remission (ERem) were evaluated based on CDAI and centrally read endoscopy, respectively, at W0/8/16. Efficacy outcomes were analyzed by W0 trough conc groups (undetectable, 0.17–< 0.8, 0.8–< 1.3, and ≥1.3µg/mL) and conc quartile groups (QGs) at W16 using a proprietary immunoassay. Results: Serum UST conc data were obtained from 215 pts (SC, n=107; IV, n=108) with ≥1 blood sample collected. Similar at W0, median serum UST concs at W0 (1-hour post-dose)/8/16 were higher in the IV vs SC arm (Table 1). Based on W16 trough concs, 63.9% (69/108) of pts were in the ≥1.3µg/mL group in the IV arm, vs 41.1% (44/107) in the SC arm. The proportion of pts with W16 CRes in the ≥1.3µg/mL group was similar between arms; more pts were in W16 ERem in the IV vs SC arm. By W16 quartile analysis, CRes was numerically higher in the IV vs SC arm in QG1 and 4. More IV arm pts achieved ERem in QG4 vs QG1; a small number of pts in SC arm achieved ERem independent of QGs. Incidence of UST ADAs through W16 was low (SC, n=2; IV, n=0; 0.93% overall). Conclusion: Although, IV re-induction resulted in higher serum concs and proportions of pts with high (≥1.3µg/mL) trough conc at W16; there did not appear to be an exposure-response relationship for CRes. However, quartile analysis showed a relationship between increased exposure in the IV arm and differences in ERem. This observation is consistent with the notion that pts with secondary LoR may benefit from single-dose re-induction. Table 1. - Summary of serum UST concentrations and the proportion of patients in clinical response and endoscopic remission at W16 by UST trough concentrations and trough concentration quartile groups at W16 (full analysis set) Serum concentrations µg/mL (median, IQR) SC arm (N=107) IV arm (N=108) W0 pre-dose 1.26 (0.58; 2.53) 1.30 (0.62; 2.79) W0 post-dose* 1.47 (0.70; 2.62) 105.62 (82.94; 128.13) W8 1.38 (0.85; 2.61) 8.45 (4.25; 10.49) W16 1.41 (0.81; 2.17) 2.99 (1.20; 4.78) W16 outcomes by UST trough concentrations at W16 (µg/mL), n/N (%) Undetectable 0.17–< 0.8 0.8–< 1.3 ≥1.3 Undetectable 0.17–< 0.8 0.8–< 1.3 ≥1.3 Clinical response†‡ at W16 0/1 5/18 (27.8) 8/16 (50.0) 24/44 (54.5) 0/2 8/15 (53.3) 3/7 (42.9) 39/69 (56.5) Endoscopic remission‡§|| at W16 0/1 0/9 1/7 (14.3) /24 (8.3) 0/1 1/6 (16.7) 0/4 10/42 (23.8) W16 outcomes by UST trough concentration quartile groups¶ at W16, n/N (%) QG1 (≤q1) QG2 ( >q1 and ≤q2) QG3 ( >q2 and ≤q3) QG4 ( >q3) QG1 (≤q1) QG2 ( >q1 and ≤q2) QG3 ( >q2 and ≤q3) QG4 ( >q3) Clinical response†‡ by QG 5/20 (25.0) 11/20 (55.0) 12/20 (60.0) 9/19 (47.4) 11/24 (45.8) 11/23 (47.8) 13/23 (56.5) 15/23 (65.2) Endoscopic remission‡§|| by QG 0/10 1/11 (9.1) 0/9 2/11 (18.2) 1/11 (9.1) 2/10 (20.0) 3/14 (21.4) 5/18 (27.8 *The post-dose sample was collected within 24 hours of UST administration.†Clinical response is defined by CDAI <150 or decrease of ≥100 points from W0.‡Patients who had insufficient data to calculate CDAI or SES-CD, a prohibited CD-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 CD prior to the designated analysis timepoint are considered not to be in clinical response or endoscopic remission.§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.||Endoscopy was an optional procedure in the study; only 58 (SC arm) and 59 (IV arm) patients were included in the endoscopic analysis.¶Quartiles are based on patients in each treatment group: SC arm, q1=0.81 µg/mL, q2=1.41 µg/mL, q3=2.17 µg/mL; IV arm, q1=1.20 µg/mL, q2=2.99 µg/mL, q3=4.78 µg/mL. CD, Crohn’s Disease; CDAI, Crohn’s Disease Activity Index; IQR, interquartile range; IV, intravenous; q, quartile; QG, quartile group; SC, subcutaneous; SES-CD; Simple Endoscopic Score in Crohn’s Disease; UST, ustekinumab; W, week.

Abstract Background After successful induction, a subset of patients with Crohn’s disease (CD) experience a secondary loss of response (LoR) to ustekinumab (UST) maintenance therapy. Dose intensification may assist in regaining response. The phase 3b randomised, double-blind, multicentre POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction UST dose vs continued UST subcutaneous (SC) treatment in CD patients with LoR to standard UST every 8 weeks (q8w) maintenance therapy. Methods 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) or endoscopy performed ≤3 months before W0 with evidence of active CD (≥1 ulcerations in the ileum and/or colon). At baseline (W0), randomised patients 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; decrease of ≥100 points from W0/CDAI <150) at W16. Additional outcome measures included clinical, biomarker, endoscopic and quality of life endpoints assessed at W8/16. Results The analysis set comprised 215 patients at W0 (IV, n=108; SC, n=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 patients experienced ≥2 biologic failures before initiating UST (Table 1). At W16, 49.1% in the IV arm and 37.4% in the SC arm achieved CRes (p=0.089). Percentages of patients with normalisation of fCal, normalisation of CRP and/or fCal, endoscopic remission and improvement, and improvement in IBDQ score were greater in the IV vs SC arm (Table 2). At W16, similar proportions of patients had ≥1 adverse event (AE) (IV, 60.2%; SC, 61.7%) and serious AEs (IV, 5.6%; SC, 5.6%). The proportions of patients with infections were similar between arms (IV, 23.1%; SC, 21.5%), with only 1 serious infection in each arm. Conclusion POWER is the first randomised, controlled, double-blind trial to assess the efficacy and safety of UST IV re-induction in patients with LoR during UST maintenance therapy. The CDAI-based primary endpoint at W16 was not met. However, patients in this heavily pre-treated population who received IV re-induction showed clinically meaningful improvements at W16 compared with those receiving SC, particularly for objective endpoints, including inflammatory biomarkers and endoscopic outcomes.

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. 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. 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). 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: Ustekinumab (UST) is a well-established therapy and was approved for treatment of adults with psoriasis (PsO) in 2009, psoriatic arthritis (PsA) in 2013, Crohn’s disease (CD) in 2016, and ulcerative colitis (UC) in 2019. An integrated analysis of safety data through 1 year1 and the more recently presented 2020 IBD Pooled Safety Dataset showed a favorable safety profile for UST across indications that was generally similar to placebo (PBO). Here, we present an integrated analysis of the pooled safety data incorporating phase 2/3 long-term safety data from IBD studies through up to 5 years in CD and 2 years in UC and psoriatic disease studies through up to 5 years in PsO and 1 year in PsA. Methods: Data from 13 phase 2/3 studies in approved indications were pooled. Concomitant immunomodulators and corticosteroids were permitted for IBD and PsA pts, but not PsO pts. All pts who received ≥1 dose of UST were included in this analysis. Safety outcomes are presented as events per 100 patient-years (PY) of follow-up and 95% confidence interval (CIs). Of note, the PBO-controlled period in most PsO studies was 12 wks, and 16 wks in PSA. Results: Across all indications, 2501 pts were treated with PBO with 1244 PYs of follow-up and 6710 pts were treated with UST with 13807 PYs of follow-up. Rates of key events per 100 PYs and corresponding 95% CIs were generally similar between UST and PBO groups (Table 1). In pooled indications in the PBO and UST groups, respectively, the most frequent adverse events (AEs; excluding preferred terms of CD and UC) were nasopharyngitis (20.83 vs 20.87), upper respiratory tract infection (13.51 vs 14.53), arthralgia (13.99 vs 7.01), abdominal pain (10.77 vs 4.01), and diarrhea (6.67 vs 3.88). Anal abscess (PBO 0.72 vs UST 0.17), pneumonia (PBO 0.32 vs UST 0.14), and cellulitis (PBO 0.16 vs UST 0.11) were the most frequently reported serious infections. Events of malignancy and death were less frequently reported, particularly in the PBO group and as such, CIs were wide. Conclusion: The safety profile of UST across pooled indications was favorable through up to 5 yrs, confirming the well-established safety profile of UST in psoriatic and IBD indications.Table 1.: Key Safety Events in CD, UC, PsO, and PsA Studies Through Up to 5 Years

Background: Ustekinumab is currently approved globally in Crohn's disease (CD) and psoriatic diseases. Recent phase 3 data demonstrate safety/efficacy in ulcerative colitis (UC). Crohn's disease and UC phase 3 programs had similar study designs, facilitating integrated safety analyses. Methods: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year. Patients received 1 placebo or ustekinumab (generally 130 mg or similar to 6 mg/kg) intravenous induction, then subcutaneous (90 mg) maintenance every 8/12 weeks. Analyses incorporated all patients who received >= 1 ustekinumab dose. Safety outcomes are presented as percentages of patients (induction) and as number of patients with events per 100 patient-years of follow-up (through 1 year). For key safety events, 95% confidence intervals (CIs) are provided, as appropriate. Hazard ratios with 95% CIs from time-to-event analyses for serious adverse events and serious infections were also performed. Results: Through 1 year, 2574 patients received ustekinumab (1733 patient-years of follow-up). The number of patients with adverse events per 100 patient-years (placebo 165.99 [95% CI, 155.81-176.67] vs ustekinumab 118.32 [95% CI, 113.25-123.55]), serious AEs (27.50 [95% CI, 23.45-32.04] vs 21.23 [95% CI, 19.12-23.51]), infections (80.31 [95% CI, 73.28-87.84] vs 64.32 [95% CI, 60.60-68.21]), serious infections (5.53 [95% CI, 3.81-7.77] vs 5.02 [95% CI, 4.02-6.19]), and malignancies excluding nonmelanoma skin cancer (0.17 [95% CI, 0.00-0.93] vs 0.40 [95% CI, 0.16-0.83]) were similar between placebo and ustekinumab. Conclusions: The safety profile of ustekinumab across the pooled inflammatory bowel disease population through 1 year was favorable and generally comparable to placebo. These data are consistent with the established safety profile of ustekinumab across indications.

The UNIFI randomized-withdrawal maintenance study evaluated the safety and efficacy of subcutaneous (SC) ustekinumab in patients with moderately-to-severely active ulcerative colitis (UC) who had responded to intravenous (IV) ustekinumab during induction. In this analysis, durability of remission through maintenance Week44 is described.

INTRODUCTION: The UNIFI induction study evaluated the efficacy and safety of ustekinumab (UST) in patients with moderately to severely active ulcerative colitis (UC) after a single intravenous infusion. In this analysis, we evaluated the rapidity of the onset of the treatment effect. METHODS: Eligible patients were randomly assigned to placebo (PBO) or UST 130 mg or ∼6 mg/kg. Patients recorded stool frequency and categorized rectal bleeding daily for the 7 days before each visit. Partial Mayo scores were calculated at baseline and Week 2 using the average of the stool frequency and rectal bleeding scores from the most recent consecutive 3-day period before the visit and the physician's global assessment score recorded at the visit. C-reactive protein (CRP) and fecal biomarkers were measured at baseline and Day 14. RESULTS: At baseline, the mean 3-day average daily stool frequency was 7.0 in the PBO group, 6.9 in the UST 130-mg group, and 7.0 in the UST ∼6-mg/kg group. Patients receiving UST showed greater reductions in the daily number of stools compared with PBO as soon as the first assessment time point at Day 7. Mean changes from baseline in daily stool frequency were -0.7 for PBO, -1.0 for UST 130-mg ( P = 0.098), and -1.2 for UST ∼6-mg/kg group ( P = 0.018) by Day 7, respectively, and -0.9, -1.6 ( P < 0.001), and -1.9 ( P < 0.001) by Day 13, respectively (Figure 1). Rectal bleeding scores at baseline and Week 2 are summarized in Figure 2. Patients receiving UST showed significantly greater improvement from baseline to Day 14 in partial Mayo score and CRP (Table, P < 0.001 for all comparisons of UST vs PBO). Differences between the UST and PBO treatment groups in mean changes from baseline to Day 14 in fecal calprotectin did not reach significance (PBO -33.96 mg/kg, UST 130 mg 79.12 mg/kg [ P = 0.875], UST ∼6 mg/kg -412.68 mg/kg [ P = 0.152]). However, patients receiving UST showed significantly greater improvement in fecal calprotectin at Week 4 (mean changes from baseline: PBO -226.78 mg/kg, UST 130 mg -881.22 mg/kg [ P = 0.013], UST ∼6 mg/kg -802.75 mg/kg [ P < 0.001]). Similar results were observed for fecal lactoferrin. CONCLUSION: The effect of UST began rapidly after induction, with symptomatic improvement and reduction of systemic inflammation seen as early as the first assessments at Days 7 and 14, respectively.