OP034 Efficacy and safety of abrilumab in subjects with moderate to severe ulcerative colitis: results of a phase 2b, randomised, double-blind, multiple-dose, placebo-controlled study

Background: α4β7 integrin is a validated target in IBD. We studied abrilumab (AMG181/MEDI7183), a fully human monoclonal antibody against α4β7 integrin, in subjects with ulcerative colitis (UC) and inadequate or loss of response to anti-tumor necrosis factors (TNFs) or immunomodulators. Methods: This phase 2b, multicentre, randomised, double-blind, placebo (PBO)-controlled, parallel-group, multi-dose study enrolled subjects with moderate to severe UC (total Mayo Score 6–12, rectosigmoidoscopy score ≥2). Subjects received PBO or abrilumab (7, 21, or 70 mg) subcutaneously (SC) on day 1, weeks 2 and 4, and every 4 weeks or abrilumab 210 mg SC on day 1, stratified by prior anti-TNF exposure and participation in a pharmacokinetic (PK) substudy. The primary endpoint was remission at week 8 (table); key secondary endpoints were response and mucosal healing at week 8. Endoscopy was centrally read. CD4+ T cell subsets were enumerated and α4β7 receptor occupancy was measured in a subset of subjects. Results: This study enrolled 354 subjects. The final allocation of 116, 21, 40, 98, and 79 in the PBO, 7, 21, 70, and 210 mg groups, respectively, was due to a systematic misalignment in investigational product; study blind and randomisation were intact. Remission rates were 4.4, 1.6, 2.9, 13.5, and 13.4% in the PBO, 7, 21, 70, and 210 mg groups, respectively; response and mucosal healing rates are listed in the table. Table 1. Rates of remission, response, and mucosal healing at week 8 in subjects who received abrilumab. Higher rates of remission, response, and mucosal healing in the prior anti-TNF failure subgroup 210-mg arm were observed: 13.9, 51.9, and 40.6%, respectively. Maximal reduction of free α4β7 on naïve CD4+ T cells in the peripheral blood was sustained through week 8, except for the 7-mg group. Abrilumab induced a significant post-dose increase in α4β7-high central memory CD4+ T cell (Tcm) counts from baseline to week 8. Exposure-response (E-R) modeling of PK data demonstrated that subjects in decile groups with mean trough levels >10 μg/mL showed maximal remission rates. Adverse events were balanced among groups through week 24, with no PML or deaths. No subject developed neutralising antibodies to abrilumab. Conclusions: Abrilumab demonstrated a favorable safety, immunogenicity, PK, pharmacodynamic, and efficacy profile, suitable for further testing in subjects with UC. Efficacy did not appear to correlate with peripheral target coverage or changes in α4β7-high Tcm. E-R modeling suggests that higher abrilumab exposure may result in higher remission and response rates. Disclosure: Amgen and AstraZeneca/MedImmune sponsored this study.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.