Background: Etrolizumab, an anti-β7 mAb targeting α4β7 and αEβ7 integrins, showed efficacy and safety vs placebo (PBO) during 10 weeks of induction in patients with moderate-to-severe UC in the phase 2 trial, EUCALYPTUS. Because a reduction in histological inflammation has been linked with improved long-term clinical outcome (Bryant et al. Gut 2016), and the FDA recommends using both histological assessments and endoscopy to evaluate efficacy, we assessed the effect of etrolizumab on histological inflammation in mucosal biopsies from EUCALYPTUS patients using the Robarts histopathology index (RHI).
Methods: Patients were randomly assigned (1:1:1) to subcutaneous etrolizumab (100 mg at weeks 0, 4 and 8, with PBO at week 2, or 420-mg loading dose at week 0, followed by 300 mg at weeks 2, 4 and 8), or matching PBO. Biopsies were taken using flexible sigmoidoscopy/full colonoscopy from the most inflamed colonic area within 10–40 cm from the anal verge at baseline (BL) and at week 10. Batched H&E stained slides were scored by a single pathologist using the Geboes scale and converted to RHI (Mosli et al. Gut 2015). At week 10, mean change from BL RHI score and mean difference between pooled etrolizumab and PBO were calculated. Subanalyses explored histological improvement (defined as categorical reductions in RHI of ≥6 points or ≥50% improvement from BL RHI score) and the relationship with endoscopic improvement.
Results: Analysis included 89 (of 119 efficacy-evaluable) patients with BL histological data and BL RHI >1. Mean week 10 RHI reduction was greater for etrolizumab- compared with PBO-treated patients regardless of previous aTNF experience, and a greater proportion of patients receiving etrolizumab achieved histological improvement compared with PBO. Of patients with an endoscopic subscore (ES) ≤1 at week 10, 89% experienced histological improvement. Mean (SD) RHI change was −14.2 (5.5) in patients with an ES ≤1 at week 10 versus −2.5 (9.5) in patients with an ES >1.
Conclusions: RHI-measured histological activity improved after 10 weeks of etrolizumab treatment. Consistent with the clinical remission rates observed in EUCALYPTUS, the magnitude of histological improvement was greater in the aTNF-naive vs aTNF-IR subgroup. RHI reductions are associated with improved ES at week 10.