Safety, pharmacokinetics and efficacy of E6011, an anti-fractalkine monoclonal antibody, in a first-in-patient phase 1/2 study in rheumatoid arthritis

Background: 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. Accumulating evidence is telling that FKN-CX3CR1 axis plays a pivotal role in leukocyte/lymphocyte accumulation in inflamed tissues in RA1. We developed E6011, a novel humanized anti-FKN monoclonal antibody. Objectives: To evaluate safety, pharmacokinetics and efficacy of E6011 in a Phase 1/2, open-label, multiple ascending dose study in RA patients for the first time (NCT02196558). Methods: Active RA patients with inadequate response to MTX or TNF inhibitors were received 7 consecutive doses (subcutaneous: SC) of E6011 at week 0, 1, 2 and thereafter every 2 weeks up to week 10. A hundred and 200 mg of E6011 were chosen for the study as putatively appropriate doses for patients by the PK/PD modeling previously obtained in the Ph1 healthy volunteer study of E6011. Results: Twelve subjects were enrolled in the cohort of 100 mg and subsequently 15 subjects were enrolled in the 200 mg cohort, in total, 27 subjects received repeated subcutaneous administrations of E6011. As a result, repeated dose of E6011 was found safe and well tolerated. The incidence of AE, treatment-related AE and SAE was 59.3%, 29.6% and 7.4%, respectively. There were no severe AE or deaths, and no significant differences were observed in the incidence or severity of AE between the 100 mg and 200 mg cohorts. After starting multiple SC injection of E6011, serum E6011 concentration reached steady-state at week 2, and its level was maintained up to week 12. Mean trough E6011 concentrations from week 2 through week 12 were 11.6 - 15.7 ug/mL and 29.2 - 38.8 ug/mL after dosing of 100 and 200 mg, respectively. Clinical outcome was also available in the study in which response rates of ACR20, 50 and 70 at week 12 were 75.0%, 33.3%, 8.3% and 80.0%, 26.7%, 20.0% in the cohort of 100 and 200 mg, respectively. At week 12, 33.3% of subjects achieved DAS28-CRP remission in both cohorts, 16.7% and 20.0% for SDAI remission and 8.3% and 26.7% for Boolean remission were observed in the 100 and 200 mg cohorts, respectively. Conclusions: E6011 was safe and well tolerated, and demonstrated a promising efficacy in active RA patients with MTX or TNFi-IR. While further clinical studies are required, the results obtained indicate that a novel biological DMARD targeting FKN/CX3CR1 interaction will be clinically beneficial for active RA patients.