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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 ~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. ClinicalTrials.gov numbers NCT00265122; NCT00771667; NCT01369329; NCT01369342; NCT01369355; NCT02407236.

Background & Aims The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn’s disease. Here, we report the final results of IM-UNITI LTE through 5 years. Methods Patients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued from the study after unblinding. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively. Results Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE. Conclusions Patients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

Background and Aims We assessed the effect of ustekinumab on health-related quality of life [HRQOL] in adults with Crohn's disease [CD]. Methods Patients with moderately to severely active CD and inadequate response or intolerance to tumour necrosis factor antagonists [UNITI-1, n = 741], or conventional therapy [UNITI-2, n = 627] were randomised to placebo, ustekinumab 130 mg, or 6 mg/kg intravenous induction therapy. At Week 8, ustekinumab-treated responders (Crohn's Disease Activity Index [CDAI] reduction ≥100 or CDAI

Background & Aims Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy. Methods We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis. Results Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 μg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations. Conclusions In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI).

Summary Background In Phase 3 studies of ustekinumab, a fully human monoclonal IL‐12/23p40 antibody approved for moderate‐to‐severe Crohn's disease, patients entered a long‐term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM‐UNITI maintenance are reported. Methods UNITI‐1 (TNF‐antagonist failures) and UNITI‐2 (conventional therapy failures) patients (N = 1281) entered IM‐UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose‐adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8–32). All Week 44 completers could enter the long‐term extension without further dose adjustment. Placebo patients discontinued following study unblinding. Results A total of 718 patients (all treated) entered the long‐term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient‐years) were similar among all placebo and ustekinumab patients (Week 0‐96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed. Conclusions Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

Background We studied the efficacy and safety of ustekinumab (UST) vs adalimumab (ADA) through 1 year in biologic-naïve patients (pts) with moderate-to-severe Crohn’s disease. Methods SEAVUE was a multicenter, randomized, blinded, parallel-group, active-controlled study in adults with CD Activity Index (CDAI) scores ≥220/≤450. Biologic-naïve pts failing/intolerant to conventional therapy with any size ulcer on baseline (BL) ileocolonoscopy were eligible. Pts were randomized 1:1 to UST (⁓6mg/kg IV at BL then 90mg SC every 8 weeks [Ws]) or ADA (160/80mg SC at BL/W2, then 40mg SC every 2 Ws) per US-approved regimens (no dose modifications). Primary endpoint was clinical remission at W52 (CDAI Results 386 pts were randomized to UST or ADA. BL demographics and disease characteristics were balanced between groups and indicative of pts with early, moderate-to-severe CD (median CD duration, 2.58 years; CDAI, 289.5; SES-CD, 8.0). At W52, 65% of UST-treated and 61% of ADA-treated pts achieved clinical remission (Δ=4.0%; 95% CI, -5.5%, 13.5%; p=0.417). Major secondary endpoints, including endoscopic remission, were similar between groups (Table 1), as were remission rates at assessment points through W52. Some other secondary endpoints showed numerical (not statistical) differences between UST and ADA (Table 1). Key safety events are summarized in Table 2. Among UST-treated and ADA-treated pts, 34.0% and 40.5% had infections, 2.6% and 7.2% had serious adverse events (AEs) of worsening CD, and 6.3% and 11.3% had AEs that led to discontinuation (DC) of study drug, respectively. One ADA-treated pt had active pulmonary TB. Injection-site reactions associated with active treatment occurred in 1.0% of UST-treated and 10.3% of ADA-treated pts. Overall, 15.2% of UST-treated and 23.6% of ADA-treated pts DC before W52. Reasons for DC were primarily lack of efficacy (UST, 2.1% vs ADA, 5.1%), AEs (UST, 5.7% vs ADA, 10.7%), and withdrawal of consent (UST, 5.8% vs ADA, 5.1%). Time to treatment DC was longer with UST vs ADA (post hoc analysis). Conclusion Both UST and ADA were highly effective in this population of biologic-naïve pts. Rates of clinical remission at W52 were not statistically significantly different between treatment groups. DC rates were numerically lower for UST. Safety results were consistent with prior experience for both treatments.

Background and Aims Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn’s disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported. Methods At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits. Results Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0–152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%]. Conclusions Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355.

BACKGROUND: Ustekinumab (UST) is well-established in psoriasis (PsO) & psoriatic arthritis (PsA) with up to 5 years safety data from psoriasis clinical trials with 3117 pts & 8998 patient years (PY). However, limited safety data have been presented in Crohn’s disease (CD). In CD, Phase 2/3 data show that UST is safe & effective. AIMS: Here we present CD safety data & compare it to safety from psoriatic diseases. METHODS: Safety data from 5 CD (2 Ph2/3Ph3) trials were analyzed with the previously reported PsO (1 Ph2/3Ph3) & PsA (1 Ph2/2 Ph3) trials. Psoriatic pts received UST 45 or 90mg SC; Ph3 CD pts received one IV UST dose (130mg or ~6 mg/kg) then 90mg SC q8w or q12w. Permitted concurrent treatments differed by indication: PsO – none; PsA – methotrexate; CD - immunosuppressives & corticosteroids. All pts who received ≥1 dose of UST were included. Outcomes are presented as events per 100 PY. RESULTS: In the PBO-control period, 3636 pts received UST (1582 PsO, 692 PsA & 1362 CD). Treated pts with ≥1 reported event PBO vs UST in pooled indications (events/100 PY): AEs 556.1 vs 594.3; SAEs 19.5 vs16.4; infections 135.8 vs138.1; serious infections 2.9 vs 3.3; MACE 0.26 vs 0.60; malignancies 0.26 vs 0.12; deaths 0 vs 0.12. Through 1 year, 5884 pts received UST (3117 PsO, 1018 PsA, & 1749 CD) over 4521 PY. Rates of AEs, SAEs, & infections were similar between UST & PBO (Table) across all groups. Event rates in the combined CD studies were also similar between groups with more frequent overall AEs, & infections in CD pts. CONCLUSIONS: UST has a favorable safety profile in CD with one IV induction dose up to 6mg/kg & SC maintenance up to 90mg q8wks. Evaluation of the CD experience did not alter the safety profile of UST established in pts with psoriatic disease treated up to 5 years. FUNDING AGENCIES: Janssen Research & Development, LLC

BACKGROUND: Tolerance to therapy is critical for pts to receive the maximal treatment benefit. In Phase 3 clinical trials for ustekinumab (UST) for moderate to severe Crohn’s disease (CD), UNITI-1 enrolled anti-TNF failures and UNITI-2 enrolled conventional therapy failures. In UNITI-1, 36.4% had previous intolerance (infusion-related reactions [IRR], delayed hypersensitivity reactions, or injection site reactions [ISR]) that led to discontinuation of the anti-TNF. UNITI-2 enrolled pts that were not intolerant to anti-TNFs, but some were intolerant to immunomodulators (39%) or corticosteroids (15%). AIMS: Here we assess tolerability as measured by IRR, delayed hypersensitivity, or ISR to UST in the Phase 3 CD trials. METHODS: All enrolled pts in UNITI-1 and UNITI-2 were given an intravenous (IV) induction infusion of UST 130mg, UST ~6 mg/kg, or placebo (PBO). The IM-UNITI maintenance study began 8 weeks after IV induction; UST IV responders were randomized to UST 90mg SC Q8W, UST 90mg SC Q12W, or PBO. Non-randomized patients, included non-responders to placebo who received 130mg IV UST, then continued to UST 90mg SC Q12W maintenance therapy; non-responders to IV UST who received UST 90 mg SC, then continued UST 90 mg SC Q8W in maintenance; and IV placebo responders who received placebo SC in maintenance. RESULTS: Overall, IRR were infrequent: 4.0 % and 1.9 % of all pts in UNITI 1 & 2, respectively, experienced infusion reactions to the single IV dose. There were no differences in IRR between PBO & UST, or between UST doses (UNITI 1 IRRs in 2.0%, PBO and 4.5% UST 130mg and 3.6%, UST ~6 mg/kg; UNITI 2 IRRs in 2.9%, PBO and 2.4% UST 130mg and 1.4%, UST ~6 mg/kg). During IM-UNITI, in non-randomized pts who were non-responders to placebo induction and received a 130mg IV injection, IRR to PBO and UST were similar and infrequent (2.5% and 1.8%, respectively). There were no anaphylactic or delayed hypersensitivity reactions to any IV dose. After SC administration, ISRs were infrequent and not different across groups. In the combined (randomized and non- randomized) population, ISRs were 1.7 % with PBO, and 3.0% with UST. No serious ISRs were reported. The most common ISR was erythema, reported in 1.1 % of PBO, and 1.7% of UST. There were no anaphylactic or delayed hypersensitivity reactions to any SC dose. Amongst randomized pts, ISRs were infrequent and consistent between groups. ISRs occurred in 3/418 (0.7 %) of all UST 90mg Q12W injections and in 12/599 (2.0 %) of all UST 90mg Q8W injections. One pt in the entire phase 3 program discontinued therapy due to ISR. CONCLUSIONS: In a broad population of pts with Crohn’s disease, many of whom were intolerant to previous therapies, UST had a tolerable profile. Rates of IRR and ISR were minimal, and were not different between groups, nor populations. FUNDING AGENCIES: Janssen Research & Development, LLC funded this study

AIMS: Ustekinumab (UST) has been shown to induce and maintain clinical response and remission in moderate-severe Crohn’s disease (CD) in 2 induction (UNITI-1 & 2) and 1 maintenance (IM-UNITI) randomized, PBO-controlled Phase 3 trials. We evaluated the efficacy of UST in 2 additional groups in IM-UNITI: patients (pts) who dose adjusted following loss of response (LOR) and pts who did not have a clinical response to IV UST during induction and had an additional subcutaneous (SC) dose. METHODS: Pts in clinical response [CR-100] (≥ 100 point decrease in CDAI) after single dose IV dose were randomized to SC PBO, UST 90mg q12w or q8w. Pts who met LOR criteria, defined as a CDAI score of ≥ 220 and a ≥ 100 point increase from the IM-UNITI baseline CDAI score, between wks8 and 32 of IM-UNITI could undergo a single dose adjustment as follows: PBO→q8w, q12w→q8w, and q8w→q8w (no adjustment) and were assessed for CR-100 and clinical remission (CDAI < 150) 16wks later. Separately, UST IV non-responders received SC UST 90mg, then continued SC UST 90mg q8w if in CR 8wks later. RESULTS: 51 (39%), 29 (23%), and 28 (22%) pts in the PBO, q12w and q8w groups, respectively, underwent dose adjustment after meeting LOR criteria. Among these pts, clinical remission and CR-100 were observed in 39% and 71% of pts adjusting PBO→q8w (a situation similar to a drug holiday), 41% and 55% in the q12w→q8w group, and 32% and 46% in the q8w→q8w group when assessed 16wks later (Table 1). Median change in CDAI after adjustment was -121, -141 and -78.5 in the PBO→q8w, q12w→q8w and q8w→q8w groups, respectively. Of 467 pts not in response to UST following IV induction in UNITI1&2, 50.5% and 28.9% were in clinical response and remission 8wks after one additional UST dose (90mg SC). Among the 251 of these pts continuing dosing at wk8 of maintenance, 68.1% were in CR-100 and 50.2% were in remission at wk44. No increases or changes in patterns of adverse events were seen among pts who dose adjusted. CONCLUSIONS: In pts who met LOR criteria, dose adjustment from UST 90mg q12w to 90mg q8w provided some additional clinical benefit compared to pts who remained on UST 90mg q8w. Additionally, pts who were initial induction non-responders can benefit from continued treatment with at least 1 SC UST dose 8wks after IV induction. FUNDING AGENCIES: Janssen Research & Development, LLC

Background & Aims We evaluated the ability of ustekinumab, a monoclonal antibody against the p40 subunit of interleukins 12 and 23, to induce endoscopic healing in patients with moderate to severe Crohn's disease (CD). Methods We performed an endoscopy substudy of 334 patients with moderate to severe CD participating in 3 randomized controlled phase 3 studies to determine the safety and efficacy of ustekinumab induction and maintenance therapy. All patients underwent colonoscopy at baseline and week 8 of the induction studies and at week 44 of the maintenance study; all colonoscopies were assessed by a blinded central reader. During the induction studies, patients were randomly assigned to groups given intravenous ustekinumab (130 mg or 6 mg/kg) or placebo. At the baseline time point of the maintenance study (week 8 of the induction studies), patients with a clinical response to ustekinumab were randomly assigned to groups given subcutaneous ustekinumab (90 mg every 12 weeks or 8 weeks) or placebo. Additional maintenance analysis populations were patients who did not respond to ustekinumab or placebo during the induction studies, and patients who responded to placebo during the induction studies; we performed a post-hoc pooled analysis of randomly assigned and non-randomly assigned patients of the maintenance study. We analyzed data from patients with an ulcer in at least 1 segment at baseline of the induction studies. The primary end point was change in the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), from baseline, at week 8. We also assessed the efficacy of maintenance therapy. Results Patients given ustekinumab had a greater reduction in SES-CD from the induction baseline time point until week 8 than placebo (reduction of 2.8 in patients given ustekinumab vs a reduction of 0.7 points in patients given placebo; P = .012). Results were similar among patients in different induction studies and patients given different doses of ustekinumab. At week 44, reductions in the SES-CD from the induction baseline were greater in patients given ustekinumab (for combined groups, a reduction of 2.5; P = .176 and for every 8 weeks, a reduction of 3.1; P = .107) than patients given placebo (reduction of 1.9 points). Maintenance results were similar for the larger pooled post-hoc analysis. Conclusions In an analysis of data from 3 trials of patients with moderate to severe CD, ustekinumab (intravenous induction and subcutaneous maintenance) reduces SES-CD compared with placebo. We observed significant reductions in endoscopic disease activity at week 8 of induction therapy with ustekinumab. (ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355).

BACKGROUND & AIMS: Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown. METHODS: We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs). RESULTS: At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline. CONCLUSIONS: In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355. ispartof: GASTROENTEROLOGY vol:157 issue:4 pages:1019-+ ispartof: location:United States status: published

Informative exposure-response modeling of clinical endpoints is important in drug development to identify optimum dose and dosing regimens. Despite much recent progress in mechanism-based longitudinal modeling of clinical data, challenges remain in clinical trials of diseases such as Crohn's disease, where a commonly used composite endpoint Crohn's Disease Activity Index (CDAI) has considerable variation in its administration and scoring between different assessors and complex study designs typically include maintenance phases with randomized withdrawal re-randomizations and other response driven dose adjustments. This manuscript illustrates the complexities of exposure-response modeling of such composite endpoint data through a latent-variable based Indirect Response model framework for CDAI scores using data from three phase III trials of ustekinumab in patients with moderate-to-severe Crohn's Disease. Visual predictive check was used to evaluate model performance. Potential impacts of the study design on model development and evaluation of the E-R relationship in the induction and maintenance phases of treatment are discussed. Certain biases appeared difficult to overcome, and an autocorrelated residual error model was found to provide improvement.

BACKGROUND: Ustekinumab(UST) has been shown to induce & maintain clinical response & remission in moderate-severe Crohn’s disease(CD) in 2 induction[(UNITI-1(anti-TNF failures) & UNITI-2(anti-TNF non-failures) & 1 maintenance(IM-UNITI)] randomized, PBO-controlled Ph3 trials. AIMS: We evaluated efficacy (response & remission) for all pts who received an IV induction dose of approximately 6mg/kg, including responders(CDAI decrease ≥100) & non-responders, 8wks after first UST maintenance dose of 90mg SC, i.e. 16wks from the IV induction dose. METHODS: Pts achieving clinical response 8wks after a single IV induction dose were randomized to SC PBO, UST 90mg q12wks or q8wks. UST pts not in clinical response 8wks after IV induction dose were given UST90mg SC & if in clinical response 8wks later were continued on 90mg SC q8w dosing. A total of 458pts were exposed to an IV induction dose of 6mg/kg(UNITI-1,N=249 & in UNITI-2 N=209) with a response rate at wk8 of 37.8% & 57.9% vs. PBO response rate of 20.2% & 32.1% respectively. The remission rate at wk8 in UNITI-1 & UNITI-2 was 20.9% & 40.7 vs. PBO of 7.3% & 19.6% respectively. For this evaluation, response & remission status of the entire population exposed to an IV induction dose of 6mg/kg of UST was evaluated 8wks after the first SC maintenance dose of UST. All pts who received 6mg/kg IV UST induction were included, including responders randomized to SC PBO (who did not receive SC UST at wk8). RESULTS: Of the 219 pts not in clinical response to a single UST IV induction dose in UNITI 1&2, 37.6% & 60.5% respectively were in clinical response 8wks after the first maintenance UST dose (90 mg SC). Evaluating all pts exposed to 6mg/kg IV UST induction, response rates 8wks after the first SC injection (16wks after the IV induction dose) for UNITI1&2 were 47.4% & 73.7% respectively. In the sub-population who were anti-TNF naïve upon enrolment into UNITI-2 (n=144), at 8 weeks after the first SC injection, 72.9% were in clinical response and 60.4% were in clinical remission. CONCLUSIONS: These numbers at wk16 are expected to reflect real world experience in pts who receive the induction dose & one additional maintenance dose 8wks later. The resulting rates of response & remission are higher than previously reported in induction studies across all populations (anti-TNF non-failures & anti-TNF failures). About 73% of anti-TNF non-failures attain clinical response & over half are in remission. The data support the clinical rationale for providing at least one SC maintenance dose of UST irrespective of clinical response 8wks after IV induction to assess UST benefit. FUNDING AGENCIES: Janssen Research & Development, LLC funded this study

BACKGROUND: Ustekinumab (UST), a monoclonal antibody to IL-12 and 23, was recently approved for the treatment of moderate-severe CD. AIMS: Here we report safety data with and without concomitant use of Immunomodulators(IMM) and corticosteroids(CS) in induction and maintenance in pts pooled from the Phase 2 and 3 CD studies. METHODS: Percentages of pts experiencing safety events (AEs, SAEs, infections, and deaths) were assessed with and without concomitant IMM or CS use at baseline after IV ustekinumab (UST) or placebo (PBO) induction (8 weeks) and were then also compared with SC UST or PBO maintenance (up to 44 weeks) from the Phase 2 and 3 CD clinical studies. Pts who received IV UST (doses included: 130mg flat dose and 1, 3, 4.5, & 6 mg/kg) during the PBO-controlled induction period (Week 0–8) were pooled from 2 Phase 2 (C0379T07 & CERTIFI) and 2 Phase 3 (UNITI-1 and 2) clinical studies (total n= 1,986). For maintenance, SC UST (combining 90mg q8w and q12w) and PBO were pooled and compared in the randomized responder populations (ie responders to IV UST induction) from the maintenance phase of the Phase 2 CERTIFI (Week 8 to Week 22) and Phase 3 IM-UNITI (Week 0 to Week 44) studies (total n= 541). RESULTS: No death occurred in either the induction or maintenance phases in any groups. Through 8 weeks of induction, the percentages of pts with AEs, SAEs, and infections were similar between UST and PBO both on and off IMM and CS: across all 4 subgroups, for UST, 58–63% had AEs, 4–7% had SAEs, and 19–23% had infections and for PBO, 56–66% had AEs, 5–9% had SAEs, and 21–26% had infections. In maintenance, proportions of pts experiencing AEs, SAEs, and infections were generally similar between UST and PBO groups both on and off IMM and CS,: across all 4 subgroups, for UST, 72–82% had AEs, 9–10% had SAEs, and 41–43% had infections and for PBO, 77–87% had AEs, 9–15% had SAEs, and 37–49% had infections. Proportions of pts on CS in both the UST and PBO groups experienced slightly higher rates of AEs compared with those not on CS (UST, 82% vs 74%, respectively; PBO, 87% vs 76%, respectively).Additionally, PBO pts on CS also experienced slightly higher rates of SAEs (15%) and infections (49%) than the other groups (9–12% with SAEs; 37–43% with infections). CONCLUSIONS: No differences in safety data were identified based on the use of concomitant IMMs or CSs in UST-treated pts with either IV induction or with SC maintenance compared to PBO. The concomitant use of IMM or CS during either IV induction or SC maintenance treatment with UST did not adversely impact the previously reported favorable safety profile of UST in moderate to severe CD pts, although concomitant CS did result in slightly higher rates of events during maintenance, particularly in the PBO group. FUNDING AGENCIES: Janssen Research & Development, LLC funded this study

BACKGROUND: Crohn’s disease Phase III maintenance clinical trials with biologics are typically randomized withdrawal trials, in which patients (pts) that responded after induction with a specific biologic are re-randomized to either maintenance therapy or placebo (PBO). Different response criteria have been used to qualify responders for these studies, such as CDAI70 at wk 2, 4 or 6 & CDAI 100 at wk8, but the influence of this criterion on remission results at year 1 has not been investigated. AIMS: In the IM-UNITI study, pts with a CDAI 100 response 8wks after ustekinumab (UST) induction were re-randomized to either PBO, UST 90mg Q12w or UST 90mg Q8w. Non-responders to UST induction, as well pts that received PBO for induction remained blinded in the trial. Non-responders to UST induction received UST 90mg SC Q8w at wk0 of IM-UNITI. Since both UST CDAI-100 responders & non-responders received 90mg Q8w, remission rates at 52wks of total treatment can be calculated for UST 90mg Q8w for pts with different induction response criteria. METHODS: Pre-specified analyses were conducted to evaluate the proportion of pts in remission & CDAI-100 response at 52wks of total treatment in the different arms of IM-UNITI for pts with a 70 point CDAI response to UST at wk6 of induction.70 point CDAI response to UST at wk3 of induction 100 point CDAI response to UST at wk8 of induction (original response criterion). The overall proportion of remitters & CDAI-100 responders at wk52 of total treatment were calculated for pts with a CDAI-70 response to UST respectively at wk3 or 6 of induction taking into account their relative distribution over the randomized or non-randomised arms receiving 90mg Q8w. RESULTS: Remission rates after 52wks of total treatment in pts receiving 90mg UST Q8w are summarized (see Table). Similarly, CDAI-100 response rates after 52wks of total treatment in pts receiving 90mg UST Q8w were calculated for the different induction response categories. Rates were 60.8%, 58.3% & 59.4% for CDAI-70 responders at wk3, 6, & CDAI-100 responders at wk8 respectively. CONCLUSIONS: The majority of pts with CDAI-70 response at either wk3 or 6 after induction also had a CDAI-100 response at wk8. Using different qualifiers for response to UST induction did not result in different response or remission rates after 1 year of treatment in pts treated with UST 90mg Q8w. FUNDING AGENCIES: Janssen Research & Development, LLC

AIMS: To evaluate endoscopic healing in the ustekinumab (UST) induction (UNITI-1&2) & maintenance (IM-UNITI) phase 3 studies. METHODS: Substudy patients (pts) had colonoscopies at baseline (UNITI Wk0), then 8 & 52 weeks later (IM-UNITI Wk44). Video-endoscopies were centrally read by a single blinded reader for ulcerations & SES-CD. In UNITI, pts received one IV dose (UST 130mg, UST ~6mg/kg, or PBO). Pts with clinical response [CR] (CDAI drop≥100) in UNITI were re-randomized to subcutaneous (SC) PBO or UST 90mg (q12w or q8w) [primary randomized IM-UNITI population]. Non-randomized pts were added to the pooled IM-UNITI population: UST IV non-responders - SC UST 90mg, then SC UST 90mg q8w if in CR 8wks later; PBO IV non-responders - UST IV 130mg, then SC UST 90mg q12w if in CR 8wks later; PBO induction responders - PBO throughout. Pts required SES-CD ≥3 at UNITI Wk0 to be included. Primary outcome: Change in SES-CD at UNITI Wk8 (combined UST vs PBO). IM-UNITI Wk44 efficacy was evaluated for both the IM-UNITI populations. RESULTS: At wk8, UST reduced SES-CD significantly more vs PBO. Results were similar across UST doses, studies, & other endpoints (Table 1a). At IM-UNITI Wk44, in the primary randomized IM-UNITI population trends favoured UST vs PBO maintenance (especially UST 90mg q8w) but small sample sizes (UST n=46; PBO n=24) limited conclusions. In the post-hoc pooled IM-UNITI population (Table 1b), trends supporting UST maintenance were favourable, especially 90mg q8w. CONCLUSIONS: The endoscopy substudy primary endpoint was met: One IV UST dose significantly reduced SES-CD vs PBO, as early as Wk8. More pts receiving UST maintenance achieved wk44 endpoints vs PBO. These data support efficacy of UST in inducing & maintaining endoscopic healing in CD. FUNDING AGENCIES: Janssen Research & Development, LLC

Background & Aims Among immunosuppressive- and biologic-naive patients with moderately-to-severely active Crohn’s disease (CD), a higher proportion of those treated with the combination of infliximab and azathioprine achieved corticosteroid-free remission at week 26 (CSFR26) than those given infliximab monotherapy; patients given the combination therapy also had higher serum concentrations of infliximab. Enhanced benefit of combination therapy may occur through synergistic modes of action or the influence of azathioprine on infliximab pharmacokinetics. Methods We analyzed data from 206 patients from whom week 30 serum samples were available: 97 received infliximab monotherapy (5 mg/kg, n = 97) and 109 received combination therapy (2.5 mg/kg/day; n = 109). Proportions of patients achieving CSFR26 and mucosal healing (absence of ulcers) at week 26 were calculated for each quartile of serum concentrations of infliximab, and exposure–response relationships were compared. Results Within quartiles of serum concentrations of infliximab, CSFR26 did not differ significantly between patients who received combination therapy vs monotherapy. However, among patients in the lowest quartile of serum concentration of infliximab, twice as many patients who received infliximab monotherapy achieved CSFR26 vs combination therapy. Anti-drug antibodies were detected only in the lowest quartile of serum concentrations of infliximab—in 35.9% of patients given monotherapy and 8.3% of patients given combination therapy. Conclusion Among patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. ClinicalTrials.gov , NCT00094458.