Phase 1 study on the safety and efficacy of E6011, antifractalkine antibody, in patients with Crohn's disease

Katsuyoshi Matsuoka, Makoto Naganuma, Toshifumi Hibi, Hirohito Tsubouchi, Kiyoshi Oketani, Toshinori Katsurabara, Seiichiro Hojo, Osamu Takenaka, Tetsu Kawano, Toshio Imai, Takanori Kanai, Katsuyoshi Matsuoka, Makoto Naganuma, Toshifumi Hibi, Hirohito Tsubouchi, Kiyoshi Oketani, Toshinori Katsurabara, Seiichiro Hojo, Osamu Takenaka, Tetsu Kawano, Toshio Imai, Takanori Kanai

Abstract

Background and aim: E6011 is a humanized monoclonal antibody targeting fractalkine (FKN), a CX3C chemokine, which regulates leukocyte trafficking during inflammation. We evaluated the safety and pharmacokinetic profile of E6011 in patients with Crohn's disease (CD) and also performed preliminary pharmacodynamic (PD) and efficacy assessments.

Methods: This study included a 12-week multiple ascending dose (MAD) phase (2, 5, 10, and 15 mg/kg intravenously every 2 weeks, n = 6, 8, 7, and 7, respectively) and a 40-week Extension phase (n = 12) at the same dose as the MAD phase. Serum E6011, serum total FKN (free soluble FKN and E6011-FKN complex) as a PD marker and CD activity index were evaluated. The primary outcome was safety assessment in the MAD phase.

Results: Twenty-seven (96%) of 28 patients had previously been treated with anti-tumor necrosis factor α agents. During the MAD phase, adverse events (AEs) occurred in 18 (64%). The most common AE was nasopharyngitis (five patients, 18%). No severe AEs occurred. Serious AEs occurred in three patients, progression of CD in two, and anemia in one. Serum E6011 concentrations increased dose-dependently after infusion and reached a plateau around 4-6 weeks. Serum total FKN rose simultaneously. Five (18%) patients developed anti-E6011 antibodies during the study. Overall, clinical response and clinical remission were observed at Week 12 in 40% (10/25) and 16% (4/25) of active CD patients, respectively.

Conclusion: E6011 was well-tolerated and might be effective in CD patients. These findings need to be clarified in a randomized controlled study.

Keywords: Crohn's disease; E6011; fractalkine; leukocyte trafficking.

© 2021 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Figures

FIGURE 1
FIGURE 1
Serum E6011 and total fractalkine concentrations after repeated administrations of E6011 in patients with Crohn's disease. (a) Serum E6011 concentration; (b), serum total fractalkine concentration. Data represent mean ± standard deviations. Each dose in Cohorts 1–4 is presented in Table 1. , Cohort 1 (n = 3–5); , Cohort 2 (n = 6–7); , Cohort 3 (n = 5–7); , Cohort 4 (n = 4–6). FKN, fractalkine. [Color figure can be viewed at wileyonlinelibrary.com].

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