Pivotal results of etrolizumab for CD partly disappointing

Only the maintenance results of the pivotal cohort of the BERGAMOT trial met their co-primary endpoint, whereas the outcomes of induction failed statistical significance at week 14 in patients with Crohn’s Disease (CD). Although the effect size was as anticipated, very high placebo rates impacted the difference between groups.

Etrolizumab is an anti-integrin with dual action that targets both α4β7 and αEβ7 selectively. “So, you have a mode of action where you prevent the cells from trafficking into the gut, but you also have an impact on the inflammatory lymphocytes that already reside within the GI tract,” Prof. Séverine Vermeire (University Hospital Leuven, Belgium) described [1]. The phase 3 BERGAMOT trial (NCT02394028) consisted of 3 induction and maintenance cohorts, to assess the safety and efficacy of etrolizumab treatment in patients with moderately to severely active CD. Prof. Vermeire reported on the pivotal cohort 3.

In this cohort, 385 participants were initially randomised 3:3:2 to a 14-week induction with subcutaneous etrolizumab 105 or 210 mg, or placebo. Thereafter, etrolizumab responders, i.e. patients with a drop in Crohn’s Disease Activity Index (CDAI) of ≥70 points, were re-randomised 1:1 to the lower dose of etrolizumab or placebo. The co-primary endpoints in the induction phase at week 14 were clinical remission and endoscopic improvement (etrolizumab 210 mg versus placebo). The maintenance study had the same co-primary endpoints at week 66, comparing those on etrolizumab 105 mg with the group that received an induction with the study drug and then continued on placebo until week 66.

The groups were balanced on their baseline characteristics. Between 36.6% and 42.4% of participants used corticosteroids, 24.7% to 32.7% used immuno-suppressants, and between 40.6% and 49.7% were anti-TNF-naïve. The co-primary endpoint of the induction trial was not met at week 14. “If we look at the effect size for etrolizumab, it’s within the expected range: 33% for clinical remission, 27% for endoscopic improvement, but what is immediately clear is that the placebo response rates for remission and endoscopic improvement were very high,” Prof. Vermeire commented, referring to the 29.2% and 21.6% of participants in the placebo arms also reaching these endpoints.

In contrast, the maintenance study was positive in both components of the co-primary endpoint. Clinical remission was reached by 35.0% on etrolizumab 105 mg and 24.0% on placebo (P=0.0088). Endoscopic improvement was attained by 23.6% in the study drug arm and 12.2% in the placebo arm (P=0.0026). “So, induction: primary endpoint not met, maintenance: primary endpoint met,” Prof. Vermeire underlined. The key secondary induction endpoints were also not statistically significant. These outcomes were partly negative for maintenance with only some significant nominal P-values for endoscopic remission and steroid-free clinical remission.

In terms of adverse events, etrolizumab was overall well tolerated. “No real safety signal was observed, also no safety signal with respect to infections or serious infections,” Prof. Vermeire highlighted.

1. Sandborn WJ, et al. Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn’s disease: results from the phase 3 BERGAMOT study. OP127, UEG Week 2022, 8–11 October, Vienna, Austria.

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Posted on 1 December, 2022