ACR Boston 2014 | Daily Highlights

Efficacy and Safety Study of a Sequential Therapy of Tocilizumab and, If Initially Inadequately Responded to Tocilizumab, Followed By Rituximab in Patients with Rheumatoid Arthritis and Inadequate Response to Traditional Disease Modifying Anti-Rheumatic Drugs

Abstract: 497
Presenter: Thomas Dörner
Co-Authors: Hans-Peter Tony, Gerd Burmester, Hendrik Schulze-Koops, Jörg Kaufmann, Peter Kästner, Herbert Kellner, Reiner Kurthen, Sylke Wagner, Marvin A. Peters and Christoph Iking-Konert

Background:
The MIRAI study evaluated a sequential exposure to 2 defined biologics under rigorous study conditions within a homogeneous population of biological naive patients (pts) with moderate/severe active RA who inadequately responded to traditional DMARDs. This study investigated the early response to the IL-6 inhibitor tocilizumab (TCZ); non-responders to TCZ subsequently received 1 cycle of rituximab (RTX; anti-CD20 therapy).

Methods:
We report the results of the final analysis (first-pat-in: MAR-2011; last-pat-out: FEB-2014) of MIRAI (NCT01332994), a German, multicenter, two-arm, open-label, phase-III-study. All pts received 4 TCZ infusions (8 mg/kg, q4w; 1st treatment period) until week 16. Partial responders (ΔDAS28>1.2 or DAS28≥2.6 and ≤3.2) received further 4 TCZ infusions (8 mg/kg, q4w); non-responders (ΔDAS28≤1.2 and DAS28>3.2) received subsequent RTX treatment (1g each at weeks 16 and 18). All pts with a 2nd treatment period (TCZ or RTX) completed study at week 32. Primary endpoint: pts in remission (DAS28 <2.6) at week 16 (expected 45%). Secondary endpoints: DAS28/ACR response at week 32, patient-reported outcomes, B-cells, adverse events (AE).

Results:
519 pts (ITT-Main/Safety; mean age: 56 years, females 67.8%) received TCZ in the 1st treatment period. 504 pts received concomitant DMARDs (mostly MTX, 365 pts). At week 8, a clinically relevant DAS28 reduction (>1.2) from baseline was seen in 81.5% of pts. At week 16, 222 pts (42.8%) were in remission and completed study, 213 pts received a 2nd TCZ period (ITT-TCZ2), only 27 non-responder initiated subsequent RTX (ITT-RTX). At week 32, 117 of 213 pts achieved remission under continued TCZ therapy, and 10 of 27 pts showed a clinically relevant DAS28 reduction from week 16 after 1 cycle RTX.

Total incidence of drug related AEs/SAEs: 38.3%/4.4%. Drug-related serious infections occurred in 10 pts (1.9%). One death possibly related to TCZ was reported (fall plus craniocerebral injury). No RTX related SAEs were reported.

Conclusions:
Early response to TCZ was demonstrated by a rapid improvement of RA symptoms until week 16. Initially partial responders to TCZ benefited from a continued TCZ therapy. Notably, the proportion of TCZ non-responders was low (27 of 519 pts); about 1/3 of these pts clearly benefited from subsequent RTX therapy with lasting effects until week 66.

Disclosure of Interest:
T. Dörner, Roche Pharmaceuticals, Chugai, 5, Roche Pharmaceuticals, Chugai, 9; H. P. Tony, Roche Pharmaceuticals, 5; G. Burmester, Roche Pharmaceuticals, Abbott, Pfizer, UCB, Merck Sharp and Dohme, Bristol-Myers Squibb, 2, Roche Pharmaceuticals, Chugai, Pfizer, UCB, Bristol-Myers Squibb, 5, Roche Pharmaceuticals, Pfizer, Merck Sharp and Dohme, Abbott, Bristol-Myers Squibb, 8; H. Schulze-Koops, Roche Pharmaceuticals, 5, Roche Pharmaceuticals, 8; J. Kaufmann, None; P. Kästner, None; H. Kellner, None; R. Kurthen, None; S. Wagner, None; M. A. Peters, Roche Pharmaceuticals, 3; C. Iking-Konert, Roche Pharmaceuticals, Chugai Pharma, 5.

Comment:
The MIRAI study is a open label study evaluating a sequential biotherapy approach in RA patients. All patients started with Tocilizumab (TCZ), which was continued further only in patients demonstrating a response at 4 months, the other patients were switched to Rituximab (RTX). Initially partial responders to TCZ benefited from a continued TCZ therapy. Among the fairly small proportion of TCZ non-responders, about 1/3 clearly benefited from subsequent RTX therapy. This study illustrates the current treatment paradigm of swift treatment switches in case of non-response and the benefit of changing mode of action in non-responders.

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