Long-Term Safety and Efficacy of the Anti-Mucosal Addressin Cell Adhesion Molecule-1 Monoclonal Antibody Ontamalimab (SHP647) for the Treatment of Crohn's Disease: The OPERA II Study

Abstract

Background: Patients with Crohn's disease (CD) experience intestinal inflammation. Ontamalimab (SHP647), a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1, is a potential novel CD treatment. OPERA II, a multicenter, open-label, phase 2 extension study, assessed the long-term safety and efficacy of ontamalimab in patients with moderate-to-severe CD.

Methods: Patients had completed 12 weeks of blinded treatment (placebo or ontamalimab at 22.5, 75, or 225 mg subcutaneously) in OPERA (NCT01276509) or had a clinical response to ontamalimab 225 mg in TOSCA (NCT01387594). Participants received ontamalimab at 75 mg every 4 weeks (weeks 0-72), then were followed up every 4 weeks for 24 weeks. One-time dose reduction to 22.5 mg or escalation to 225 mg was permitted at the investigator's discretion. The primary end points were safety and tolerability outcomes. Secondary end points included changes in serum drug and biomarker concentrations. Efficacy end points were exploratory, and used non-responder imputation methods.

Results: Overall, 149/268 patients completed the study. The most common adverse event leading to study discontinuation was CD flare (19.8%). Two patients died; neither death was considered to be drug related. No dose reductions occurred; 157 patients had their dose escalated. Inflammatory biomarker concentrations decreased. Serum ontamalimab levels were consistent with known pharmacokinetics. Remission rates (Harvey-Bradshaw Index [HBI] ≤ 5; baseline, 48.1%; week 72, 37.3%) and response rates (baseline [decrease in Crohn's Disease Activity Index ≥ 70 points], 63.1%; week 72 [decrease in HBI ≥ 3], 42.5%) decreased gradually.

Conclusions: Ontamalimab was well tolerated; treatment responses appeared to be sustained over 72 weeks.ClinicalTrials.gov ID: NCT01298492.

Keywords: Crohn’s disease; clinical trial; mucosal addressin cell adhesion molecule-1; ontamalimab.

© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.

Figures

Figure 1.

Ontamalimab treatment schedule and patient disposition during OPERA II. A single ontamalimab dose change (increase or decrease) was permitted at any study visit from week 8 onwards. *Usually characterized by an HBI score increase of ≥3 to a value of ≥8 in those with acceptable disease control at baseline (after ruling out other potential causes: eg, infection) or continued inadequate disease control (usually an HBI score ≥8) in those not controlled at baseline. †Usually characterized by an HBI score reduction of <3 or an HBI score ≥8 after at least 8 weeks at the higher dose. ‡Dose could not be reduced in these patients. §HBI score increased by ≥3 from the lowest value following a response, to a value of ≥8. Abbreviations: AE, adverse event; HBI, Harvey-Bradshaw Index; s.c., subcutaneously.

Figure 2.

Concentrations of (A) hsCRP and (B) FC over time in patients who continued to receive ontamalimab at 75 mg versus those who escalated to 225 mg, grouped by the final dose received. Data show means ± 95% CIs. Abbreviations: CI, confidence interval; FC, fecal calprotectin; hsCRP, high-sensitivity C-reactive protein.

Figure 3.

Overall proportions of patients in HBI score–defined (A) clinical remission* and (B) clinical response† from baseline to week 72, calculated using a non-responder imputation approach. Data show means ± 90% CIs. Numbers on figures show numbers of patients in (A) remission* and (B) response† at each time point. *Clinical remission was defined as an HBI score <5. †Clinical response was defined as an HBI score that decreased by ≥3 from the baseline value in the feeder study. Abbreviations: CI, confidence interval; HBI, Harvey-Bradshaw Index.

Figure 4.

Kaplan-Meier graph showing (A) time to remission* in the subgroup of patients not in remission at baseline and (B) time to response† in the subgroup of patients with no response at baseline. *Clinical remission was defined as an HBI score <5. †Clinical response was defined as an HBI score that decreased by ≥3 from the baseline value in the feeder study. Abbreviation: HBI, Harvey-Bradshaw Index.