Post–Hoc Analysis Showing Better Clinical Response With The Loading Dose Of Certolizumab Pegol In Japanese Patients With Active Rheumatoid Arthritis

Tsutomu Takeuchi¹, Kazuhiko Yamamoto^2,3, Hisashi Yamanaka⁴, Naoki Ishiguro⁵, Yoshiya Tanaka⁶, Katsumi Eguchi⁷, Akira Watanabe⁸, Hideki Origasa⁹, Mariko Kobayashi¹⁰, Toshiharu Shoji¹⁰, Nobuyuki Miyasaka¹¹ and Takao Koike¹², ¹Department of Rheumatology, Keio University, Tokyo, Japan, ²Department of Allergy and Rhaumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, ³University of Tokyo, Tokyo, Japan, ⁴Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, ⁵Orthopaedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Japan, ⁶The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan, ⁷Sasebo City General Hospital, Sasebo, Nagasaki, Japan, ⁸Tohoku University, Sendai, Japan, ⁹Division of Biostatistics and Clinical Epidemiology, University of Toyama School of Medicine, Toyama, Toyama, Japan, ¹⁰UCB Pharma, Tokyo, Japan, ¹¹Tokyo Medical and Dental University, Tokyo, Japan, ¹²Rheumatology, NTT Sapporo Medical Center, Sapporo, Japan

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: anti-TNF therapy, certolizumab pegol and rheumatoid arthritis (RA), Japanese

Session Information

Title: Rheumatoid Arthritis Treatment - Small Molecules, Biologics and Gene Therapy III

Session Type: Abstract Submissions (ACR)

Background/Purpose: Certolizumab pegol (CZP) with MTX (J-RAPID; NCT00791999) and without MTX (HIKARI; NCT00791921) has demonstrated rapid and sustained improvements in disease activity in Japanese patients (pts) with active rheumatoid arthritis (RA) in placebo-controlled, double-blind (DB), randomized studies^1,2. Based on these and previous studies, the recommended dose of CZP includes subcutaneous initial loading dose (LD) of 400mg at Weeks (wks) 0, 2 and 4 followed by 200mg every 2 wks (Q2W). Nevertheless, benefits of LD have never been directly demonstrated in a clinical study. We hereby report safety and efficacy of CZP, with and without LD, from two Japanese studies.

Methods: Data from J-RAPID and HIKARI were used for this analysis; pts eligible to enter open-label extension (OLE) studies at Wk16 or Wk24 received CZP 200mg Q2W or CZP 400mg Q4W without LD (label dose). In J-RAPID DB study, 316 pts were randomized to CZP 100, 200 or 400mg + MTX with initial LD or placebo + MTX Q2W for 24 wks. In HIKARI DB study, 230 pts were randomized to CZP 200mg with LD or placebo Q2W for 24 wks.

Safety and efficacy in pts who received CZP 200mg Q2W with LD during DB phases (LD group: n=82 J-RAPID; n=116 HIKARI) and pts who received CZP 200mg Q2W without LD during OLE phases after being assigned to placebo in DB phase (No-LD group: n=61 in J-RAPID; n=99 in HIKARI) were directly compared. Mean DAS28(ESR) in No-LD groups at OLE baseline were slightly lower than DB baseline (5.8 vs 6.5 J-RAPID; 6.2 vs 6.3 HIKARI). ACR response rates, DAS responses and development of anti-CZP antibodies (Abs) were assessed during 24 wks after initiating CZP. ACR responses were determined using non-responder imputation. Safety population consisted of 1) all pts who received CZP in DB (n=239), 2) LD group and 3) No-LD group. Adverse events were reported both within DB and OLE.

Results: No-LD group showed delayed initial kinetics of ACR20/50/70 responses and sustained lower response to Wk24 (ACR50/70) compared to LD group (Figure). Development of anti-CZP Abs was observed more frequently in No-LD group than LD group (J-RAPID: n=4 [6.6%] vs n=1 [1.2%]; HIKARI: n=27 [27.3%] vs n=18 [15.5%]). Similar safety profiles were reported between No-LD and LD groups during CZP administration period (incidence rates per 100 pt-years; any AEs: 299.2 vs 310.5 J-RAPID, 312.9 vs 308.6 HIKARI; any serious AEs: 17.9 vs 13.4 J-RAPID, 23.0 vs 21.5 HIKARI).

Conclusion: While comparison of DB and OLE data has limitations, administration of CZP loading dose over the first 24 wks is associated with more rapid onset of efficacy, development of lower Ab levels and sustained response compared with initiating CZP without loading dose. These results suggest administration of CZP loading dose improves clinical response in active RA pts with similar safety profile.

References:

1. Yamamoto K. Arthritis Rheum 2011;63(Suppl10):S474; 2. Yamamoto K. Arthritis Rheum 2011;63(Suppl10):S476

Disclosure:

T. Takeuchi,

AstraZeneca, Eli Lilly, Novartis, Mitsubishi-Tanabe and Asahi Kasei,

Abott, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Janssen, Mitsubishi-Tanabe, Nippon Shinyaku, Otsuka, Pfizer, Sanofi-Aventis, Santen, Takeda and Teijin,

UCB Pharma, Abbott, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda,

K. Yamamoto,

UCB Pharma, Pfizer, Abbott, BMS, Roche, Chugai, Mitsubishi-Tanabe and Eisai,

UCB Pharma, Pfizer, Abbott, Santen, Mitsubishi-Tanabe and Eisai,

H. Yamanaka,

UCB Pharma, Abbott, Astellas, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda,

N. Ishiguro,

Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken and Pfizer,

Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken, Pfizer, Taisho-Toyama and Otsuka,

Y. Tanaka,

BMS, MSD, Chugai, Mitsubishi-Tanabe, Astellas, Abbvie, Daiichi-Sankyo,

UCB, Mitsubishi-Tanabe, Abbott, Abbvie, Eisai, Chugai, Janssen, Pfizer, Takeda, Astellas, Daiichi-Sankyo, GSK, AstraZeneca, Eli Lilly, Quintiles, MSD, Asahi Kasei,

K. Eguchi,

UCB Pharma,

A. Watanabe,

Daiichi-Sankyo, Kyorin, Shionogi, Taisho, Dainippon-Sumitomo, Taiho, Toyama Chemical and Meiji Seika,

MSD, GSK, Shionogi, Daiichi-Sankyo, Taisho-Toyama, Dainippon-Sumitomo, Mitsubishi-Tanabe, Pfizer,

H. Origasa,

UCB Pharma and Astellas,

M. Kobayashi,

UCB Pharma,

T. Shoji,

UCB Pharma,

N. Miyasaka,

Pfizer, Takeda, Mitsubishi-Tanabe, Chugai, Abbott, Eisai and Astellas,

T. Koike,

UCB Pharma, Pfizer, Chugai, Abbott, Mitsubishi-Tanabe, Takeda, Eisai, Santen, Astellas, Taisho-Toyama, BMS, Teijin and Daiichi-Sankyo,

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