S18 © 2019 by the Crohn’s & Colitis Foundation and the AGA Institute. Controlled Clinical Trials in Humans P036 LONG-TERM SAFETY AND EFFICACY OF THE ANTI-MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1 (MADCAM-1) ANTIBODY SHP647 IN ULCERATIVE COLITIS: AN OPEN-LABEL EXTENSION STUDY (TURANDOT II) Walter Reinisch, William J. Sandborn, Silvio Danese, Xavier Hébuterne, Bruce Salzberg, Maria Klopocka, Dino Tarabar, Tomáš Vanásek, Miloš Greguš, Paul Hellstern, Joo Sum Kim, Miles Sparrow, Kenneth J. Gorelick, Martina Goetsch, Caleb Bliss, Fabio Cataldi, Séverine Vermeire Introduction: SHP647, a fully human IgG 2 monoclonal antibody, binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to reduce lymphocyte homing to the gastrointestinal tract. SHP647 was well tolerated in a randomized, double-blind phase 2 trial (TURANDOT I; NCT01620255) in patients with ulcerative colitis (UC) over 12 weeks. Methods: This phase 2, multicenter, 2-part, open-label (OL) extension study (TURANDOT II; NCT01771809) assessed long-term safety and tolerability of SHP647 in patients with moderate-to-severe UC who completed TURANDOT I on placebo or SHP647 7.5, 22.5, 75 or 225mg s.c. every 4 weeks and discontinued immuno- suppressants. At TURANDOT II baseline, patients were randomized to SHP647 75 or 225mg s.c. every 4 weeks for 72 weeks (OL part 1). Dose escalation from 75 to 225mg was permitted at the investigator’s discretion for patients with relapse or no response by week 8. In OL part 2, all patients received 75mg every 4 weeks for another 72 weeks and were followed up for safety 12 and 24 weeks after treatment cessation. Primary endpoints were adverse events (AEs), serious AEs (SAEs) and AEs leading to withdrawal. Mucosal healing (Mayo endoscopic subscore 0 or 1, cen- trally read endoscopy), clinical remission (total Mayo score ≤2 with no individual subscore >1, rectal bleed subscore 0 or 1) and response (based on total Mayo score) were assessed at week 16. Serum trough concentrations and soluble MAdCAM-1 concentrations were also assessed. Results: In total, 330 patients were randomized and treated (Figure 1). Of these, 132 (40.0%) were women, and the mean patient age was 40.8 years (standard devi- ation [SD]: 13.2 years). Mean duration of disease was 8.1 years (SD: 7.2 years) and 186 patients (56.4%) had previously used an anti-TNF. Table 1 shows incidence of AEs. One woman (26 years, 75mg escalated to 225mg) died of pulmonary embolism, unrelated to SHP647. No progressive multifocal leukoencephalopathy or lymphop- roliferative disorders occurred. Serious infections were infrequent (n=18, 5.5%). The most common AE was gastroenteritis (n=3, 0.9%; 1 drug-related case) and the most common SAE was UC (10.0%). The most common AE causing treatment withdrawal was UC (7.0%). At week 16, the following rates of clinical response (56.1% and 57.2%), clinical remission (18.3% and 22.3%) and mucosal healing (27.4% and 29.5%) were observed in the 75 and 225mg groups, respectively. For patients achieving clinical response in TURANDOT I (n=154), rates of clinical response (79.7% and 77.3%), clini- cal remission (30.4% and 40.0%) and mucosal healing (43.0% and 50.7%) were mark- edly higher. Discussion: SHP647 was well tolerated for up to 144 weeks in patients with mod- erate-to-severe UC. Continued clinical beneft, observed in both treatment arms, supports the efcacy of SHP647. Figure 1. Patient fow. OL, open-label. Percentages shown in parentheses are calculated as n number divided by the num- ber of patients in that treatment subgroup, unless otherwise specifed. *Calculated as n number divided by the number of patients who received any amount of study drug (safety analysis set, n=330). **Calculated as n number divided by the number of patients who entered OL part 2 (n=156). In total, 21 patients discontinued treatment after completing OL part 1 and entered the follow-up period without entering OL part 2. P037 LONG-TERM SAFETY, EFFICACY AND PHARMACOKINETICS OF THE ANTI- MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1 (MADCAM-1) MONOCLONAL ANTIBODY SHP647 IN CROHN’S DISEASE: THE OPERA II STUDY Geert D’Haens, Walter Reinisch, Scott D Lee, Dino Tarabar, Edouard Louis, Maria Klopocka, Jochen Klaus, Stefan Schreiber, Dong-Il Park, Xavier Hébuterne, Fabio Cataldi, Steven W Martin, Satyaprakash Nayak, Anindita Banerjee, Kenneth J. Gorelick, William J. Sandborn Introduction: The endothelial adhesion protein mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a promising novel drug target. The fully human IgG 2 anti-MAdCAM-1 monoclonal antibody SHP647 is in development for the treatment of Crohn’s disease (CD). Methods: OPERA II, a multicenter, open-label, phase 2 extension study (NCT01298492), assessed the long-term safety and efficacy of SHP647 in mod- erate-to-severe CD. Included patients completed 12 wks’ induction treatment (placebo or SHP647 22.5, 75 or 225mg sc) in OPERA (NCT01276509) or had a clin- ical response (≥3-point Harvey-Bradshaw Index [HBI] score decrease) to SHP647 225mg in TOSCA (NCT01387594). In OPERA II, patients received SHP647 (75mg sc) every 4 wks from wk 0–72 and were followed up monthly for safety for a further 24 wks. Dose reduction to 22.5mg owing to intolerance/adverse events (AEs), or escalation to 225mg owing to clinical deterioration/poor response, was allowed from wk 8 as judged by the investigator. Primary endpoints were AEs, AEs leading to withdrawal and serious AEs (SAEs). Secondary endpoints were serum SHP647, high-sensitivity C-reactive protein (hsCRP) and fecal calprotectin (FC) levels. Changes in HBI score and the pharmacodynamics of SHP647 were also assessed. Results: Overall, 268 patients entered the study and 149 completed. Of those who entered the study, 151 (56.3%) were women and the mean age was 36.5 yrs (stan- dard deviation [SD]: 11.7 years). Mean baseline HBI score was 4.9 (SD: 3.0). Table 1 shows primary safety outcomes. The most common treatment-related AEs were arthralgia (n=16, 6.0%), nasopharyngitis (n=15, 5.6%) and headache (n=14, 5.2%). During treatment, one woman (30 yrs, 75mg) died of multiple organ failure after postoperative aspiration following terminal ileum resection; one man (36 yrs old, 225mg) died of metastatic adenocarcinoma of unknown primary during follow-up. Neither death was considered drug-related. No dose reductions occurred; 157 patients dose escalated (median 28 wks). Serum trough SHP647 levels averaged Table 1. Primary safety endpoints across OL parts 1 and 2, and follow-up. AEs SHP647 75mg (n=164) SHP647 225mg (n=166) SHP647 overall (n=330) On-treatment AEs, n (%) 146 (89.0) 147 (88.6) 293 (88.8) SAEs, n (%) 34 (20.7) 40 (24.1) 74 (22.4) AEs related to study drug, n (%) 58 (35.4) 61 (36.7) 119 (36.1) AEs leading to withdrawals, n (%) 12 (7.3) 23 (13.9) 35 (10.6) AE, adverse event; OL, open-label; SAE, serious adverse event. The 75mg treat- ment group includes patients who escalated from SHP647 75 mg to SHP647 225mg (n=94), as well as those who did not escalate (n=70). The 225mg treatment group includes only patients who were assigned to receive SHP647 225mg at the beginning of OL part 1 (n=166). The incidences of AEs are based on initial treatment assign- ment and do not necessarily refect the dose at the time of AE onset. Downloaded from https://academic.oup.com/ibdjournal/article/25/Supplement_1/S18/5308214 by guest on 16 December 2021