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 MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess 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 (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator's discretion. All patients then received 75 mg 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 225 mg; 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 [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to 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.

Keywords: MAdCAM-1; Ulcerative colitis; phase 2.

Figure 1.

Patient flow. Of 180 patients who completed OL1, 21 did not enter OL2 and proceeded to follow-up, owing to the timing of a protocol amendment which stipulated that OL2 be added to the study design to further evaluate the long-term safety of ontamalimab. An additional three patients completed OL1 and intended to progress to OL2; however, they proceeded directly to follow-up. OL1, open-label treatment period 1; OL2, open-label treatment period 2. *Calculated as n divided by the number of patients who received any amount of study drug [safety analysis set, n = 330]. ^†Calculated as n divided by the number of patients who entered OL2 [n = 156].

Figure 2.

Proportion [90% CI] of patients in the safety analysis set with mucosal healing at Week 16 compared with baseline [Week 12 of TURANDOT]: [A] overall; [B] in patients who received placebo in TURANDOT; [C] in patients who received ontamalimab in TURANDOT. 90% CIs calculated using Wilson score test. Patients who were missing results for the endpoint were imputed as not meeting the endpoint. Treatment groups based on initial randomisation assignment. CI, confidence interval.

Figure 3.

Proportion [90% CI] of patients in the long-term efficacy set* with endoscopic mucosal healing at baseline [Week 12 of TURANDOT], Week 16, and Weeks 40–72 of TURANDOT II. 90% CIs calculated using Wilson score test. Treatment groups based on initial randomisation assignment. CI, confidence interval. *The long-term efficacy set was defined as the subgroup of patients who had a second endoscopy between Week 40 and Week 72.

Figure 4.

Proportion [90% CI] of patients [A] in remission and [B] with response to ontamalimab at baseline [Week 12 of TURANDOT] and Week 16, based on total Mayo score. 90% CIs calculated using Wilson score test. Patients who were missing results for the endpoint were imputed as not meeting the endpoint. Treatment groups based on initial randomisation assignment. CI, confidence interval.

Figure 5.

Geometric mean [90% CI] concentrations of [A] hsCRP and [B] FC from baseline [Week 12 of TURANDOT] to Week 72. Treatment groups based on initial randomisation assignment. CI, confidence interval; FC, faecal calprotectin; hsCRP, high-sensitivity C-reactive protein.