Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Efficacy and Safety of Ocrelizumab in Patients with Active Rheumatoid Arthritis Who Have an Inadequate Response to at Least One TNF Inhibitor: Results from the Phase III SCRIPT Trial.

Tak1,  Paul P., Mease7,  Philip J., Genovese8,  Mark C., Kremer9,  Joel M., Haraoui4,  Boulos, Tanaka10,  Yoshiya, Bingham5,  Clifton O.

Academic Med Ctr/Univ of Amsterdam, Amsterdam, The Netherlands
U Occupa & Environ Hlth, Kitakyushu, Japan
Genentech, San Francisco, CA
Genentech
Institut de Rhumatologie, Montreal, QC, Canada
Johns Hopkins University, Baltimore, MD
Roche
Seattle Rheumatology Associate, Seattle, WA
Stanford Univ, Sunnyvale, CA
The Center for Rheumatology, Albany, NY

Purpose:

Treatment with rituximab has demonstrated clinical benefit in patients (pts) with rheumatoid arthritis (RA). This phase III study evaluated efficacy and safety of Ocrelizumab (OCR, a humanized anti-CD20 antibody) plus methotrexate (MTX) or leflunomide (LEF), in pts with active RA who had an inadequate response to >=1 TNF inhibitor.

Methods:

SCRIPT was a randomized, double-blind and placebo (PBO)-controlled (DBPC) study. 840 pts with active RA (1987 ACR criteria; SJC >=4, TJC >=4, CRP >=0.6 mg/dL and RF+ and/or anti-CCP+) and on stable MTX (7.5–25 mg/wk) or LEF (10–20 mg/day), were randomized (1:1:1; 277 PBO, 278 OCR 2 × 200 mg, 285 OCR 2 × 500 mg). Pt baseline (BL) characteristics were well balanced between treatment groups (mean: age ~54 yrs, SJC ~17, TJC ~26, CRP ~2.8, DAS28 ~6.5 and RA duration 11.8 to 12.7 yrs). The DBPC period (48 wks) was comprised of 2 courses of 2 treatments each (Days 1, 15 and Wks 24, 26). All pts received 100 mg IV methylprednisolone premedication. Co-primary endpoints were ACR20 responses at Wks 24 and 48. Secondary endpoints included the change from BL in the total modified (van der Heijde) Sharp score (mTSS) at 48 wks and ACR50/70 responses at 24 and 48 wks.

Results:

Key efficacy and safety data are shown in Table 1. Both OCR doses showed statistically significant (p<0.0001) improvements (vs PBO) in ACR20/50/70 at Wks 24 and 48. At Wk 48, statistically significant slowing of progression of joint damage (PJD) (change from BL in mTSS) was seen in OCR 500 mg dose group (62% inhibition, p=0.0020) but not in OCR 200 mg dose group (30% inhibition, p= 0.2153) vs PBO. Frequencies of AEs, SAEs, and overall infections were comparable among the 3 treatment arms. Serious infections (SIEs) were observed more frequently in OCR dose groups (5.1% and 4.3%) compared to PBO (2.5%). SIE rates were similar in both OCR and PBO groups outside Japan. Most common SIEs included pneumonias, cellulitis and urinary tract infections. Opportunistic infections in OCR-treated groups included 1 suspected Pneumocystis jiroveci, 2 de novo pulmonary tuberculosis, and 1 hepatitis B reactivation and none in PBO. There were no fatal infections during the DBPC period in any treatment groups.

Table 1. Efficacy, radiologic, and safety summary

 Placebo (n=277)OCR 2 × 200 mg (n=277)OCR 2 × 500 mg (n=282)
Week 24a   
**ACR2024.543.0*48.2*
**ACR509.021.3*25.2*
**ACR702.97.6***10.3**
Week 48a   
**ACR2021.749.5*50.7*
**ACR5010.129.2*30.9*
**ACR705.111.2***18.1*
X-ray radiographicb   
Mean change in mTSS Score, 24 wks1.301.110.67
Mean change in mTSS Score, 48 wks2.611.831.00*
Safety, %   
AEs227 (81.9)232 (83.8)238 (84.4)
SAEs32 (11.6)40 (14.4)32 (11.3)
Infections143 (51.6)150 (54.2)164 (58.2)
Serious infections (SIEs)7 (2.5)14 (5.1)12 (4.3)
Infusion-related reactions, %   
**1st infusion5.113.018.4
**2nd infusion5.84.14.0
**3rd infusion2.36.46.7
**4th infusion2.33.31.6
Serious AE disorder   
Musculoskeletal12 (4.3)7 (2.5)7 (2.5)
Cardiac4 (1.4)5 (1.8)3 (1.1)
Injury6 (2.2)4 (1.4)1 (0.4)
GI1 (0.4)5 (1.8)2 (0.7)
Neoplasms4 (1.4)2 (0.7)1 (0.4)
Blood/lymphatic3 (1.1)1 (0.4)1 (0.4)
Serious infection rates   
Total patient-years246.03247.63254.92
Infections91716
Infections/100 pt-yrs3.666.876.28
95% CI1.67–6.944.00–10.993.59–10.19
Safety sub-analysisPlacebo (n=37/240)OCR 200 mg (n=36/241)OCR 500 mg (n=38/244)
Total patient-yearsAsia†/RoW33.67/212.36Asia†/RoW33.16/214.47Asia†/RoW35.10/219.82
Serious Infections0/95/125/11
Serious Infections/100 pt-yrs0/4.2415.08/5.6014.25/5.00
95% CI0–10.96/1.94–8.054.90–35.19/2.89–9.774.63–33.25/2.50–8.95
* p<0.0001;
** p<0.005;
*** p<0.05 vs PBO.
Notes:
aCochran-Mantel-Haenszel, stratified for DMARD (MTX/LEF) and region (US/RoW).
Missing data set to Non Responder.
bVan Elteren test, stratified for DMARD (MTX/LEF) and region (US/RoW). mITT (pts 1 BL and at least 1 post BL X-ray) n=265 for PBO, n=261 for OCR 2 × 200 mg.
and n=266 for OCR 2 × 500 mg groups. Missing data was extrapolated/interpolated.
†Asian pts mostly recruited in Japan.
CI=confidence interval, RoW=rest of world

Conclusions:

Both OCR doses met the clinical primary efficacy endpoints. The reduction in PJD was statistically significant for 500 mg dose but not for 200 mg dose at 48 wks. The rate of SIEs was higher in both OCR doses compared to PBO; the increased rates appeared to be primarily driven by pts in Japan.

To cite this abstract, please use the following information:
Tak, Paul P., Mease, Philip J., Genovese, Mark C., Kremer, Joel M., Haraoui, Boulos, Tanaka, Yoshiya, et al; Efficacy and Safety of Ocrelizumab in Patients with Active Rheumatoid Arthritis Who Have an Inadequate Response to at Least One TNF Inhibitor: Results from the Phase III SCRIPT Trial. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2169
DOI: 10.1002/art.29933

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