Background/Purpose: Fractalkine (CX3CL1, designated as FKN hereafter) is the sole member of the CX3C-chemokine which leads to dual actions, chemotaxis and cell adhesion for leukocytes expressing the cognate receptor, CX3CR1, during their migration. We have conducted clinical trials of E6011, a novel humanized anti-FKN monoclonal antibody, for patients with rheumatoid arthritis (RA) in Japan¹. This is the report of a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study of E6011 in RA patients inadequately responding to biologics (NCT02960490).

Methods: During the 24-week double-blind period, patients with moderately to severely active RA of inadequate response to biologics were randomly assigned to E6011 400 mg or placebo groups at a 1:1 ratio. Patients who continued the study beyond Week 12 were further allocated to E6011 200 mg or 400 mg at a 1:1 ratio within the initially assigned group. Patients received either E6011 400 mg or placebo at Weeks 0, 1, 2, and every 2 weeks subsequently until Week 10 and then E6011 200 mg or 400 mg every 2 weeks between Weeks 12 and 22 in a double-blind manner.

Results: A total of 64 subjects (33 in the placebo group and 31 in the E6011 400 mg group) received study drug. Of the 64 subjects, 55 completed and 9 discontinued study treatment prematurely during the 12-week placebo controlled double-blind period. The ACR20 response rate at Week 12 (non-responder imputation), the primary endpoint, was 27.3% (9/33 subjects) in the placebo group and 22.6% (7/31 subjects) in the E6011 group. ACR50 and ACR70 response rate at Week 12 were 3.0%, 0% in the placebo group and 9.7%, 3.2% in the E6011 group, respectively. No statistically significant differences were found in any of the ACR components between the placebo and E6011 groups.

After completion of Week 12, 55 subjects were re-randomized and treated with E6011 200 mg or 400 mg (15 subjects for placebo/200 mg, 14 subjects for placebo/400 mg, 14 subjects for 400/200 mg, 12 subjects for 400/400 mg). Of the 55 subjects, 48 completed the planned treatment regimen and 7 discontinued study treatment prematurely between Week 12 and Week 24. During the Weeks 12-24, no apparent differences were found in any of the efficacy endpoints between the each groups during the Weeks 12–24 (after re-randomization). ACR20 response rate at Week 24 was 46.7% (7/15 subjects)  in the placebo/200 mg group, 28.6% (4/14 subjects) in the placebo/400 mg group, 21.4% (3/14 subjects) in the 400/200 mg group and 33.3% (4/12 subjects) in the 400/400 mg group.ACR50 and ACR70 response rate at Week 24 were 20.0%, 0% in the placebo/200 mg group, 0%, 0% in the placebo/400 mg group, 7.1%, 0% in the 400/200 mg group and 16.7%, 0% in the 400/400 mg group respectively.

During the Weeks 0-24, Adverse events that occurred in at least 2 subjects in the 400/200 mg group or 400/400 mg group were injection site erythema and nasopharyngitis. 

Conclusion: E6011 was well tolerated with no notable safety concerns, but did not show clear efficacy when administered subcutaneously for up to 24 weeks in RA patients with inadequately responding to biologics. Further investigation to seek an optimal clinical dose and evaluation period of E6011 are warranted.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-2-study-of-e6011-an-anti-fractalkine-monoclonal-antibody-%e3%8f%8c-patients-with-rheumatoid-arthritis-inadequately-responding-to-biologics/