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. Last year, we presented an interim report (up to 200 mg cohort) of Phase 1/2 study of E6011, a novel humanized anti-FKN monoclonal antibody, for active Japanese RA patients2.
Objectives To evaluate safety, pharmacokinetics and efficacy of E6011 with the dosage up to 400 mg in a Phase 1/2, open-label, multiple ascending dose study in RA patients (NCT02196558).
Methods Active RA patients with inadequate response (IR) to MTX or TNF inhibitors (TNFi) were received 7 consecutive doses (subcutaneous) of E6011 at week 0, 1, 2 and thereafter every 2 weeks up to week 10. The safety, pharmacokinetics and efficacy up to week 12 were evaluated.
Results Twelve, 15 and 10 subjects were enrolled in the cohort of 100, 200 and 400 mg dosage, respectively, in total 37 subjects received repeated subcutaneous (SC) administrations of E6011. As a result, repeated dose of E6011 was found safe and well tolerated. The incidence of adverse event (AE), treatment-related AE and serious AE were 56.8%, 29.7% and 5.4%, respectively. AEs occurring in ≥2 subjects were nasopharyngitis, Injection site erythema, headache and oropharyngeal pain, among which there were no severe AEs, serious infections and deaths. No significant differences were observed in the incidence or severity of AEs across the 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 in all cohorts. Clinical outcome was also available in the study in which response rates of ACR20, 50 and 70 at week 12 calculated using the non-responder imputation (NRI) were 75.0%, 33.3%, 8.3% in 100 mg cohort, 66.7%, 20.0%, 13.3% in 200 mg cohort and 60.0%, 30.0%, 20.0% in 400 mg cohort, respectively. The percentage of patients categorized “good response” with the EULAR response criteria at week 12 (NRI) were 16.7% in 100 mg cohort, 20% in 200 mg cohort and 40% in 400 mg cohort.
Conclusions E6011 was safe and well tolerated, and the study demonstrated a promising efficacy of E6011 in active RA patients with MTX- or TNFi-IR. The results obtained suggest that a novel approach to target FKN/CX3CR1 interaction will be clinically beneficial for RA, and support to conduct phase 2 clinical trials in which the efficacy and safety should be confirmed in a placebo controled double-blind manner.
Nanki T. Arthritis Rheum. 2002; 46(11):2878–83.
Tanaka Y, et al., EULAR Congress 2016, Poster Number FRI0236.
Acknowledgements The authors wish to thank the study investigators.
Disclosure of Interest Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, Eisai, Speakers bureau: Abbvie, Chugai, Daiichi-Sankyo, Bristol-Myers, Mitsubishi-Tanabe, Astellas, Takeda, Pfizer, Teijin, Asahi-kasei, YL Biologics, Sanofi, Janssen, Eli Lilly, GlaxoSmithKline, T. Takeuchi Grant/research support from: Astellas, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, AYUMI, Takeda, Teijin, AbbVie, Asahikasei, Taisho-Toyama, Consultant for: Astra Zeneca, Eli Lilly, Novartis, Mitsubishi-Tanabe, Asahi-Kasei, AbbVie, Daiichi-Sankyo, Bristol-Myers, Nipponkayaku, Janssen, Merck Serono, Takeda, Astellas, Pfizer, Speakers bureau: AbbVie, Bristol-Myers, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer, Takeda, Astellas, Daiichi-Sankyo, Celtrion, Nipponkayaku, H. Umehara: None declared, T. Nanki Grant/research support from: Chugai, Eisai, Takeda, Teijin, Eli Lilly, Bristol-Myers, AbbVie, Ono, Novartis, Asahi-Kasei, Consultant for: UCB, Eisai, Chugai, Speakers bureau: Mitsubishi-Tanabe, Chugai, Eisai, Takeda, Astellas, Janssen, Eli Lilly, Ayumi, Pfizer, Ono, AbbVie, N. Yasuda Shareholder of: EISAI, Employee of: EISAI, F. Tago Employee of: EISAI, Y. Kitahara Shareholder of: EISAI, Employee of: EISAI, M. Kawakubo Shareholder of: EISAI, Employee of: EISAI, S. Hojo Employee of: EISAI, T. Kawano Employee of: KAN Research Institute, T. Imai Employee of: KAN Research Institute