Long-term Safety and Efficacy of the Anti-MAdCAM-1 Monoclonal Antibody Ontamalimab [SHP647] for the Treatment of Ulcerative Colitis: The Open-label Study TURANDOT II

Abstract

Background and Aims Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM1, induced remission in patients with moderate-to-severe ulcerative colitis (UC) in TURANDOT. We assessed long-term safety, tolerability and efficacy of ontamalimab in TURANDOT II. Methods TURANDOT II was a phase 2, multicentre, open-label (OL) study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab. Patients were randomized to 75mg or 225mg ontamalimab every 4 weeks for 72 weeks (OL1). Dosage could be increased to 225mg from week 8 at the investigator’s discretion. All patients then received 75mg every 4 weeks for 72 weeks (OL2), followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events (AEs), serious AEs (SAEs) and AEs leading to withdrawal. Mucosal healing (MH; centrally read endoscopy) was assessed. Results Of 330 patients, 180 completed OL1; 94 escalated to 225mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE (10.0%) was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis (0.9%). One death and four cancers (all unrelated to ontamalimab) occurred. No PML/lymphoproliferative disorders occurred. Geometric mean hsCRP and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned placebo in TURANDOT achieving MH increased from 8.8% (6/68) at baseline to 35.3% at week 16 (24/68; non-responder imputation). The corresponding increase in the ontamalimab group was from 23.3% (61/262) to 26.7% (70/262). Conclusions Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

Review article: emerging drug therapies in inflammatory bowel disease

“…There were no significant differences between ontamalimab and placebo in adverse events, no dose‐related increase in adverse effects and no serious infections or PML 44 . In the OLE, patients were randomised to receive ontamalimab 75 or 225 mg every 4 weeks for 72 weeks 45 . In this group, 36.1% had drug‐related AEs, the most common being worsening UC (10.0% and serious infection (5.5%).…”

“…There were 1 death and 4 cancers, but all were deemed unrelated to the study drug. Patients who initially received placebo and then received study drug in the OLE had mucosal healing rates increase from 8.8% at baseline to 35.3% at week 16 45 …”

“…Patients who initially received placebo and then received study drug in the OLE had mucosal healing rates increase from 8.8% at baseline to 35.3% at week 16. 45 OPERA was a phase 2 study assessing ontamalimab in patients with moderate-to-severe CD. 46 Two hundred and sixty-five patients were eligible for the study.…”

Small Molecule Drugs in Inflammatory Bowel Diseases

“…Patients who completed the 12 weeks of treatment were subsequently included in the ongoing, 144-week open-label extension trial TURANDOT II to assess the long-term safety of PF-00547659. Conversely, PF-00547659 failed to demonstrate efficacy in CD [ 107 ]. The OPERA trial, a randomized, double-blind, placebo-controlled phase II study, included moderate to severe CD patients (CDAI range: 220–450) who failed immunosuppressive drugs or anti-TNF-α [ 44 ].…”

Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives

“…An open-label dose escalation extension of the TURANDOT trial demonstrated acceptable drug tolerance, with 36.1% of patients experiencing drug-related adverse events (AEs), with the most common serious AE being worsening or ongoing UC, followed by serious infection. 80 Ontamalimab was originally developed by Pfizer, which licensed it out to Shire back in 2016. Takeda later acquired Shire in 2019.…”