Background Certolizumab pegol (CZP) has demonstrated rapid and sustained improvements in disease activity in Japanese patients (pts) with active rheumatoid arthritis (RA), both with methotrexate (J-RAPID; NCT00791999) and with or without DMARDs other than methotrexate (HIKARI; NCT00791921) in placebo-controlled double-blind (DB) randomized trials.1,2 Although previous analysis suggested that the loading dose (LD) of CZP (400mg at Weeks (Wks) 0, 2 and 4) improves the clinical response of CZP for the first 24 wks3, the impact of the initial LD on the long-term outcomes remains unknown.
Objectives To compare the safety, efficacy and immunogenicity 1 year (yr) after initiation of CZP with and without the LD.
Methods Data from the Japanese clinical trials1,2 and the respective open-label extensions (OLEs) (J-RAPID OLE: NCT00851318; HIKARI OLE: NCT00850343)4,5 were used for this analysis. Pts randomized to receive CZP 200mg every 2 wks (Q2W) with the LD were defined as LD groups (J-RAPID: n=82; HIKARI: n=116), whereas pts randomized to receive placebo in the DB trials who entered the respective OLEs and initiated CZP 200mg Q2W without LD were defined as No-LD groups (J-RAPID: n=61; HIKARI: n=99). The ACR response rates, achievement of DAS28 LDA, safety assessments, plasma CZP levels and rates of anti-CZP antibodies (Abs) were analyzed up to 1yr after initiating CZP. DB baseline for the LD groups and at OLE entry for the No-LD groups were used as the baselines.
Results The ACR20/50/70 responses of the LD vs No-LD groups in J-RAPID were 74.4%/62.2%/32.9% vs 76.8%/60.7%/26.8%, and in HIKARI were 69.0%/50.9%/31.9% vs 62.1%/43.2%/23.2%, respectively, at 1yr (Figure). The LD groups had higher proportion of pts in DAS28 LDA (J-RAPID: 48.8% vs 42.6%; HIKARI: 42.2% vs 26.3%). Frequency of anti-CZP Abs was lower in the LD groups than in the No-LD groups (J-RAPID: n=2/82 [2.4%] vs n=4/61 [6.6%]; HIKARI: n=30/116 [25.9%] vs n=32/99 [32.3%]). Pts who developed anti-CZP Abs had lower plasma CZP levels and lower clinical responses than Ab-negative pts. Safety profiles were similar between the groups.
Conclusions While this post-hoc analysis has limitations including the comparison of DB vs OLE data, the results suggest that the benefits potentially due to the initial loading dose are sustained until at least 1yr without additional risk of adverse events.
Yamamoto K. et al. Mod Rheum 2013; epub.
Yamamoto K. et al. Mod Rheum 2013; epub. 3.
Takeuchi T. et al. Arthritis Rheum 2013;65(Suppl.10):S989.
Tanaka Y. et al. Mod Rheum; in press.
Tanaka Y. et al. Mod Rheum; epub.
Acknowledgements The authors acknowledge Costello Medical Consulting for editorial assistance which was funded by UCB Pharma.
Disclosure of Interest : T. Takeuchi Grant/research support: Abbott Japan, Astellas Pharma, Bristol–Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Janssen, Mitsubishi Tanabe, Pfizer Japan, Sanofi–Aventis, Santen, Takeda, Teijin Pharma, Abbvie, Asahikasei, Taisho-Toyama, Consultant for: Astra Zeneca, Eli Lilly Japan, Novartis, Mitsubishi Tanabe, Asahi Kasei Medical, Abbvie, Daiichi Sankyo, Speakers bureau: Abbott Japan, Bristol–Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Pfizer Japan, Takeda, Astellas Pharma, Diaichi Sankyo, K. Yamamoto Grant/research support: UCB Pharma, Pfizer, Abbott, Santen, Mitsubishi-Tanabe, Eisai, Consultant for: UCB Pharma, Pfizer, Abbott, BMS, Roche, Chugai, Mitsubishi-Tanabe, Eisai, H. Yamanaka Grant/research support: AbbVie, Asahikasei Pharma, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, MSD, Nippon Kayaku, Pfizer, Santen, Taisho-Toyama, Takeda, Teijin Pharma, Speakers bureau: AbbVie, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Pfizer, Takeda, Teijin Pharma, N. Ishiguro Grant/research support: Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken and Pfizer, Daiichi Sankyo, Speakers bureau: Daiichi Sankyo, Takeda, Hisamitsu, Otsuka, Taisho-Toyama, Kaken, Eisai, Janssen, Bristol-Myers Squibb, Abbott Japan, Chugai, Mitsubishi Tanabe, UCB Japan, Astellas Pharma, Pfizer Japan, Y. Tanaka Grant/research support: Bristol-Myers Squibb, Mitsubishi-Tanabe, Abbvie, MSD, Chugai, Astellas, Daiichi-Sankyo, Consultant for: Mitsubishi-Tanabe, Eisai, Chugai, Abbott Japan, Astellas, Daiichi-Sankyo, Abbvie, Janssen, Pfizer, Takeda, Astra-Zeneca, Eli Lilly Japan, GlaxoSmithKline, Quintiles, MSD, Asahi-Kasei, Speakers bureau: Mitsubishi-Tanabe, Eisai, Chugai, Abbott Japan, Astellas, Daiichi-Sankyo, Abbvie, Janssen, Pfizer, Takeda, Astra-Zeneca, Eli Lilly Japan, GlaxoSmithKline, Quintiles, MSD, Asahi-Kasei, K. Eguchi Consultant for: UCB Pharma, A. Watanabe Grant/research support: Daiichi-Sankyo, Kyorin, Shionogi, Taisho, Dainippon-Sumitomo, Taiho, Toyama Chemical and Meiji Seika, Speakers bureau: MSD, GSK, Shionogi, Daiichi-Sankyo, Taisho-Toyama, Dainippon-Sumitomo, Mitsubishi-Tanabe, Pfizer, H. Origasa Consultant for: UCB Pharma and Astellas, M. Kobayashi Employee of: UCB Pharma, T. Shoji Employee of: UCB Pharma, O. Togo Employee of: UCB Pharma, N. Miyasaka Grant/research support: Pfizer, Takeda, Mitsubishi-Tanabe, Chugai, Abbott, Eisai and Astellas, T. Koike Speakers bureau: UCB Pharma, Pfizer, Chugai, Abbott, Mitsubishi-Tanabe, Takeda, Eisai, Santen, Astellas, Taisho-Toyama, BMS, Teijin Pharma, Daiichi-Sankyo