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

The endothelial adhesion protein mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a promising novel drug target. The fully human IgG2 anti-MAdCAM-1 monoclonal antibody SHP647 is in development for the treatment of Crohn’s disease (CD). OPERA II, a multicenter, open-label, phase 2 extension study (NCT01298492), assessed the long-term safety and efficacy of SHP647 in moderate-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 clinical 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. 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 (standard 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 7629ng/mL at week 4 and remained constant over time in patients remaining on 75mg; steady-state level was 7567 ng/mL at wk 72. Patients who escalated achieved a new steady-state level of 18608ng/mL 12 weeks after dose escalation. Concentrations of hsCRP decreased over time in patients who remained on 75mg and in those who dose escalated, but patients who escalated had slightly higher hsCRP concentrations at baseline (Figure). Concentrations of FC also decreased over time in both patient subgroups, but this decrease was less rapid than that for hsCRP. FC levels were slightly higher at baseline in patients who dose-escalated than in those who remained on 75mg. SHP647 75mg (with possible dose escalation to 225mg) was generally well-tolerated in patients with CD over 72 wks, adding to evidence for the long-term safety of SHP647.Table 1All-cause and treatment-related AEs in the treatment and follow-up periods.Number of patients, n (%)Treatment period: all-causeTreatment period: treatment-relatedFollow up period: all-causeFollow-up period: treatment-relatedAEs249 (92.9)124 (46.3)133 (68.8)31 (16.0)SAEs80 (29.9)10 (3.7)57 (29.4)1 (0.5)Discontinued study owing to AEs53 (19.8)15 (5.6)1 (0.5)0 (0.0)AE, adverse event; SAE, serious adverse event. Open table in a new tab AE, adverse event; SAE, serious adverse event.