Douglas Jacobstein

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohns disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohns Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohns disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).

Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy

In Phase 3 studies of ustekinumab, a fully human monoclonal IL‐12/23p40 antibody approved for moderate‐to‐severe Crohns 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.

Long-Term Efficacy and Safety of Ustekinumab for Crohn’s Disease: Results From Im-Uniti Long-Term Extension Through two Years

Introduction Ustekinumab (UST) is a fully human mAB to IL–12/23 p40 approved for treatment of moderate-severe active Crohn’s disease (CD). The IM-UNITI long-term extension (LTE) evaluates efficacy and safety of subcutaneous (SC) UST through approximately 5 years of treatment, with wk96 results reported herein. Method 1281 patients (pts) entered the maintenance study, including 397 UST induction responders in the primary IM-UNITI population. PBO induction responders continued on PBO, PBO induction non-responders received UST 130 mg IV then UST 90 mg SC q12w if in clinical response at wk8, and UST induction non-responders received UST 90 mg SC and if in clinical response at wk8 continued on UST 90 mg q8w. All pts completing wk44 were eligible to enter LTE continuing their treatment regimen, including 567 UST pts. Results Table 1 presents analyses for randomised pts where pts missing data/discontinued are assumed not to be in response/remission at wk92, with 72.6% of q12w pts and 74.4% of q8w pts achieving remission at wk92. Baased on observed data analyses, among randomised pts who continued to receive UST through wk96, 79.2% of q12w and 87.1% of q8w pts were in remission and 90.9%–94.3% were in response at wk92, respectively. Among all UST treated pts who continued to receive UST through wk96, remission and response rates at wk92 were 70.7%–84.7%. Safety events were not higher among UST treated pts vs PBO through wk96, including overall AE’s (82.9 vs 91), SAE’s (14.16 vs 18.2), and serious infections (3.73 vs 4.33). Among UST treated pts, there were 2 deaths (sudden death, asphyxia). Two non-NMSC malignancies were reported, a seminoma (UST) and a papillary thyroid cancer (PBO only). Conclusion SC UST maintained clinical response and remission through two years. No new safety signals were observed. Disclosure of Interest None Declared

The Effects of Ustekinumab on Health-related Quality of Life in Patients With Moderate to Severe Crohn’s Disease

Background and Aims We assessed the effect of ustekinumab on health-related quality of life [HRQOL] in adults with Crohns 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 (Crohns Disease Activity Index [CDAI] reduction ≥100 or CDAI <150 points) were re-randomised to subcutaneous maintenance therapy [IM-UNITI, n = 388] with placebo, ustekinumab 90 mg every 12 weeks [q12w], or ustekinumab 90 mg every 8 weeks [q8w], for 44 additional weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and 36-item Short Form Health Survey [SF-36] physical component summary [PCS] and mental component summary [MCS] scores were completed at induction baseline and Week 8, and at maintenance Weeks 20 and 44. Clinically meaningful improvement in IBDQ and PCS and MCS scores were evaluated. For all HRQOL outcomes, each ustekinumab dose and placebo were compared. Results Induction baseline mean values of IBDQ, PCS, and MCS were similar across groups, but impaired relative to general population norms. At Week 8, ustekinumab induced greater improvement than placebo in both HRQOL scores. Significantly greater proportions of patients receiving ustekinumab 6 mg/kg or 130 mg had clinically meaningful IBDQ improvement [UNITI-1: 54.8%, 46.9% versus 36.5%, respectively; UNITI-2: 68.1%, 58.7% versus 41.1%, respectively; p <0.05, all comparisons]. Similarly, greater proportions of ustekinumab-treated patients in both studies had clinically meaningful improvements in PCS and MCS as compared with placebo. At Week 44, improvements in IBDQ, PCS, and MCS scores were maintained with ustekinumab. Conclusions Ustekinumab improved HRQOL in patients with moderately to severely active CD.

DOP046 Genome-wide association study of baseline disease characteristics and response to Ustekinumab in moderate to severe Crohn's disease

Background: Both genetic & environmental risk factors contribute to Crohns disease (CD) susceptibility, & genetic biomarkers may allow for the characterization of disease activity & severity as well as response to therapeutic agents. Here, we evaluated the association of genetic polymorphisms with

OC-045 Efficacy & safety of dose adjustment & delayed response to ustekinumab in moderate–severe crohn’s disease patients: results from im-uniti maintenance study

Introduction Ustekinumab (UST) induced/maintained clinical response (CR) and remission (CRM) in mod-severe Crohn’s disease (CD) as shown in 2 induction (UNITI-1 and 2) and 1 maintenance (IM-UNITI) RCT, placebo (PBO) controlled phIII trials. We evaluated UST efficacy in 2 more grps in IM-UNITI: pts undergoing dose adjustment after loss of response (LOR) and pts without a CR to IV UST during induction and had an additional SC dose. Method Pts achieving CR after single dose IV induction randomised to SC PBO, UST 90 mg/q12w or q8w. Pts meeting LOR criteria (i.e. CDAI ≥220 and a≥100 point ←from baseline maintenance CDAI score, between wks 8–32 of IM-UNITI trial) underwent a single dose adjustment as follows: PBO→q8w, q12w→q8w, and q8w→q8w (no dose adjustment) and assessed for CR (≥100 point ↓in CDAI) and CRM (CDAI <150) 16 wks later. Separately, UST pts not in CR 8 wks after IV dose given SC UST 90 mg and if CR 8 wks later stayed on q8w. Results 51 (39%), 29 (23%), and 28 (22%) pts in PBO, q12w and q8w grps, respectively, had dose adjustment after meeting LOR criteria. We observed CRM and CR in 39% and 71% of pts adjusting PBO→q8w (situation similar to drug holiday), 41%–55% in q12w→q8w grp and 32%–46% in q8w→q8w grp assessed 16 wks later respectively (Table 1). Median CDAI change after adjustment was −121,–141 and −78.5 in PBO→q8w, q12w→q8w and q8w→q8w grs, respectively. UST 467 pts not in response after IV dose,50.5%–28.9% had CR and CRM 8 wks after 1 extra UST dose (90 mg SC). Of 251 of these pts continued dosing at wk 8 of maintenance, 68.1% had CR and 50.2% CRM at wk 44. No ←or changes in AEs seen among dose adjustment pts. Conclusion Pts meeting LOR criteria, dose adjustment from UST 90 mg/q12w to q8w had some additional clinical benefit vs pts remaining on UST 90 mg/q8w. Initial induction non-responders pts can benefit from continued treatment with at least 1 SC UST dose 8 wks after IV induction. Disclosure of Interest B. Sands: None Declared, C. Gasink Conflict with: Janssen R and D, LLC, D. Jacobstein Conflict with: Janssen R and D, LLC, L. Gao Conflict with: Janssen R and D, LLC, J. Johanns Conflict with: Janssen R and D, LLC, P. Szapary Conflict with: Janssen R and D, LLC, J. Colombel: None Declared, S. Targan: None Declared, S. Ghosh: None Declared, W. Sandborn: None Declared

Efficacy of Ustekinumab for Induction and Maintenance of Histological Healing in patient's with Crohn’s Disease

Introduction Ustekinumab (UST) has been shown to induce and maintain clinical response and remission and to produce clinically meaningful endoscopic improvement in patients with moderate-severe Crohn’s disease (CD). Effects of UST on histologic CD activity were evaluated in a substudy of the induction (UNITI-1 and 2) and maintenance (IM-UNITI) Phase 3 studies. Method Biopsies were taken at induction baseline(I-Wk0), Wk8(I-Wk8), and maintenance Wk44(M-Wk44) from 3 sites (ileum, splenic flexure, rectum) and blindly scored by an expert GI pathologist (GDH) using the Global Histology Activity Score (GHAS1). At I-Wk0, pts received a single IV dose (UST 130 mg, UST~6 mg/kg, or PBO). At I-Wk8, UST induction responders were re-randomised to subcutaneous (SC) PBO, UST 90 mg q12w or UST 90 mg q8w. Histology data from 251 substudy pts with simple endoscopic score for CD (SES-CD)≥3 at I-Wk0 were eligible for analysis. The relationship between GHAS and SES-CD was evaluated by Spearman correlation. Histologic improvements were assessed within groups (UST, PBO) and between groups (UST vs. PBO, at I-Wk0, I-Wk8 and M-Wk44). Results Regional and overall GHAS were moderately correlated with SES-CD at all timepoints (r~0.6, p Conclusion Histologic and endoscopic disease activities were moderately correlated. Consistent with previously reported results, statistically significant histologic improvements were observed in pts induced with UST, but not PBO. Trends for greater and continued histologic improvement were observed in pts who received UST 90 mg q8w maintenance. Disclosure of Interest K Li Conflict with: Janssen R and D, D Chan Conflict with: Janssen R and D, P Pollack Conflict with: Janssen R and D, D Jacobstein Conflict with: Janssen R and D, C Brodmerkel Conflict with: Janssen R and D, C Gasink Conflict with: Janssen R and D, B Feagan: None Declared, W Sandborn: None Declared, P Rutgeerts: None Declared, G De Hertogh: None Declared

OC-057 A PH3 Randomised, Multicenter, Double-Blind, Placebo (PBO)-Controlled Study of Ustekinumab (UST) Maintenance Therapy in Moderate–Severe Crohn’s Disease (CD) PTS: Results from IM-UNITI

Introduction Single dose intravenous (IV) UST induced response and remission in CD pts refractory to TNF antagonists (UNITI-1) and failing conventional therapies (UNITI-2). The objective of this study (IM-UNITI) was to evaluate safety and efficacy of 2 subcutaneous (SC) UST regimens as maintenance therapy. Methods Moderate-severe CD pts (n = 388 for primary study population) who achieved clinical response at Wk8 in 1 of 2 UST IV induction studies were randomly assigned to receive SC injections of PBO or UST 90 mg every 8 wks (q8w) or every 12 wks (q12w). The primary endpoint was clinical remission at Wk44. Results A significantly greater proportion of pts in the UST grps were in clinical remission at Wk44 compared with PBO (53.1% & 48.8% in the q8w & q12w grps vs 35.9% PBO; p = 0.005 & p = 0.040, respectively). The treatment effect difference for q8w vs PBO (17.2%, [95%CI: 5.32%, 29.71%]) was numerically higher than the q12w grp (13.0%, [95%CI: 1.05%, 24.87%]. Primary, major, and other secondary endpoints in notable subsets are in Table 1 below. Similar proportions of pts with AEs were seen across treatment grps (81.7% & 80.3% for q8w & q12w vs 83.5% PBO). The proportions of pts with SAEs were 9.9%, 12.2%, and 15.0% among q8w, q12w, and PBO grps. Serious infections occurred in 2.3%, 5.3%, and 2.3% of pts in q8w, q12w, and PBO grps. Among the primary population, no deaths or major adverse cardiovascular events were reported, and 2 pts reported malignancies (1 basal cell carcinoma each in PBO and q8w grps).Abstract OC-057 Table 1 Maintenance of Clinical Response and Remission in IM-UNIT I at Week 44 Conclusion UST 90 mg q8w and q12w maintained clinical response and remission among pts with moderate-severe CD induced into clinical response with IV UST, with a favourable safety profile through Wk44. The q8w regimen more consistently demonstrated efficacy than the q12w regimen across the range of endpoints. Disclosure of Interest W. Sandborn Grant/research support from: Receptos, Exact Sciences, Amgen, the American College of Gastroenterology, Broad Foundation, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, and Nutrition Science Partners, Conflict with: Personal fees from Receptos, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, Nutrition Science Partners, Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc., Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc., Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx Inc., Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen, and the University of Western Ontario (owner of Robarts Clinical Trials); non-financial support from Receptos, B. Feagan Grant/research support from: Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, UCB Pharma, Consultant for: Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner-Chilcott, Wyeth, Zealand, Zyngenia, Speaker bureau with: Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma, Conflict with: Patent holder; Member Scientific Advisory board, Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma; Member, Board of Directors Officer – Robarts Clinical Trials Inc, C. Gasink Shareholder of: Janssen, Employee of: Janssen, D. Jacobstein Employee of: Janssen, L.-L. Gao Shareholder of: Janssen, Employee of: Janssen, J. Johanns Shareholder of: Janssen, Employee of: Janssen, B. Sands Grant/research support from: Janssen, Consultant for: Janssen, S. Hanauer Grant/research support from: Janssen, Consultant for: Janssen, Conflict with: Lecturer for Janssen, S. Targan Grant/research support from: Cedars-Sinai Medical Centre, Consultant for: Janssen, NuMedii, Inc., Conflict with: Advisory Board for Seaver Foundation; Scientific Advisory Board Member Symbiotix, S. Ghosh Grant/research support from: Abbvie, Conflict with: International Steering Committees: Janssen, Abbvie, Pfizer, Receptos, BMS, Aerpio; Advisory Committees: Takeda, Abbvie, Janssen, Pfizer, Allergan, W. de Villiers Conflict with: member of steering committee, active participant as investigator, J.-F. Colombel Consultant for: Pfizer, Takeda, Protagonist Therapies, Celgene, Genentech, Second Genome, Vertex, Amgen, Merck Sharp Dohme, Janssen, Nestle, AbbVie, Tigenix, Receptos, Conflict with: Speaker for AbbVie, Ferring, Shire, Takeda, S. Lee Grant/research support from: AbbVie Pharmaceuticals UCB Pharma Janssen Pharmaceuticals, Inc. Salix Pharmaceuticals Takeda Pharmaceuticals, Inc. Celgene Pharmaceuticals, Inc. Amgen Pharmaceuticals, Inc. Pfizer Pharmaceuticals, Inc., Consultant for: UCB Pharma Robarts Mesoblast Cornerstones Janssen Pharmaceuticals, Inc. Takeda Pharmaceuticals, Inc., L. Dieleman Grant/research support from: Canadian Institutes of Health and Research (CIHR) and Alberta Innovates Biosolutions, Consultant for: Janssen, Abbvie and Shire, S. Katz Grant/research support from: Abbott, Amgen, BMS, Centocor, Hutchison, Millennium, Pfizer, Receptos, Salix, Sanofi, Speaker bureau with: Abbvie, UCB, Actavis, P. Rutgeerts Grant/research support from: J&J, Merck, UCB, AbbVie, Consultant for: J&J, Merck, UCB, AbbVie, Millenium/Takeda, Genentech/Hoffman LaRoche, Medimmune/AstraZeneca/Amgen, Merck/Serono, Bristol-Myers Squibb, Robarts, Tillots Pharma, Conflict with: Lectures for J&J, Merck, AbbVie