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.


Serious Infections with Ocrelizumab in Rheumatoid Arthritis: Pooled Results from Double-Blind periods of the Ocrelizumab phase III RA program.

Emery1,  P, Rigby2,  W, Tak3,  PP, Dorner4,  T, Genovese6,  MC, Ferracioli7,  G, Martin-Mola8,  E

Univ of Leeds, Leeds, United Kingdom
Roche, Welwyn Garden City, United Kingdom
Genentech, South San Francisco, CA
Dartmouth, Lebanon, NH
Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands
Charité Univ Hospital, Berlin, Germany
Standford Univ, Palo Alto, CA
Catholic Univ, Rome, Italy
La Paz Univ Hospital, Madrid, Spain
Hopital Cochin, Paris, France

Purpose:

Ocrelizumab (OCR), a novel humanized monoclonal antibody that selectively targets CD20+ B cells, has been studied in 4 phase III randomized clinical trials in different patient (pt) populations with active rheumatoid arthritis (RA). Here, we report safety data from the double-blind, placebo (PBO)-controlled (DBPC) periods in phase III studies.

Methods:

The OCR RA program includes 4 randomized, DBPC globally conducted trials assessing the safety and efficacy of OCR given as 2 infusions of 200 mg or 500 mg (400 mg × 1 in FEATURE) every 6 months in combination with methotrexate (MTX) or leflunomide (LEF). STAGE studied OCR in combination with MTX vs MTX alone in pts with an inadequate response (IR) to MTX. SCRIPT included pts with an IR to at least one TNF inhibitor and was conducted in combination with either MTX or LEF. FEATURE investigated a single infusion regimen (400 mg) in pts who failed MTX and/or biologic DMARDs. FILM included pts who were MTX-naïve. Pooled safety data was analyzed for the DBPC periods of the RA phase III trials (48 wks in STAGE and SCRIPT, 52 wks in FILM, and 24 wks in FEATURE). Frequencies and rates (events per 100 pt-yrs) of serious infection events (SIEs) were assessed by dose and region. Pts who received either 200 mg × 2 or 400 mg × 1 were grouped together in pooled analyses.

Results:

SIE rates in each treatment group of each study are shown in Table. Increased SIE rates were predominantly seen with OCR 500 mg × 2. Following pooling of the 4 studies by treatment group, the weighted difference from PBO in the number of pts with at least one SIE was calculated to be 0.6 (95% CI: -1.3 to 2.4) for OCR 200 mg × 2 and 2.4 (95% CI: 0.3 to 4.5) for OCR 500 mg × 2. Thus, statistically significant increases in the number of pts experiencing an SIE were only seen in the 500 mg group. In a sub-analysis of SIE rates in one year trials, pooled by dose and region (Asia vs Other), OCR pts in Asia had relatively higher rates compared to rates seen in pts from non-Asian (Other) regions (Table), although the imbalance was also seen in non-Asian regions vs PBO. There were 9 opportunistic infections in 9 pts in OCR-treated pts comprised of 2 de novo pulmonary tuberculosis, 1 Pneumocystis jiroveci suspected, 1 hepatitis B, 1 Mycobacterium kansasii infection, 1 esophageal candidiasis, 1 Varicella pneumonia, 1 histoplasmosis, 1 fungal pneumonia and there was one 1 Mycobacterium abscessus reported on PBO. None of these events resulted in death. No cases of PML were observed. 2 fatal infections (both pneumonias) occurred in the OCR 500-mg group in STAGE.

Conclusions:

The pooled SIE rates were increased for OCR 500, but not OCR 200 compared to the PBO group in the DBPC periods with the imbalance primarily driven by rates in Asia. A detailed evaluation of risk factors for SIEs is underway. The same infection-related safety signal seen in the OCR high-dose has not been observed with rituximab.

Table 1. Summary of serious infection event rates

No. pts with SIE/No. pts in treatment group (%)PlaceboOCR 200 mg × 2 or OCR 400 mg × 1OCR 500 mg × 2
STAGE10/320 (3.1%)11/343 (3.2%)21/343 (6.1%)
  SIE rate/100 pt-yrs 95% CI3.5 (1.7–6.4)3.5 (1.8–6.3)8.7 (5.7–12.6)
SCRIPT7/277 (2.5%)14/277 (5.1%)12/282 (4.3%)
  SIE rate/100 pt-yrs 95% CI3.7 (1.7–6.9)6.9 (4.0–11.0)6.3 (3.6–10.2)
FEATURE2/64 (3.1%)5/248 (2.0%)NA
  SIE rate/100 pt-yrs 95% CI7.0 (0.8–25.2)4.4 (1.4–10.3)NA
FILM6/207 (2.9%)5/196 (2.6%)10/202 (5.0%)
  SIE rate/100 pt-yrs 95% CI3.0 (1.1–6.5)2.6 (0.9–6.1)7.1 (3.9–11.9)
*Pooled weighted Difference OCR minus PBO (95% CI) 0.6 (-1.3–2.4)2.4 (0.3–4.5)
 PlaceboOCR 200 mg × 2OCR 500 mg × 2
Region†AsiaOtherAsiaOtherAsiaOther
STAGE (No. pts in subgroup)N=24N=296N=35N=308N=37N=306
  SIE rate/100 pt-yrs 95% CI4.5 0.1–25.23.4 1.6–6.50 0–11.44.0 2.0–7.115.0 4.9–35.07.9 5.0–12.0
SCRIPT (No. pts in subgroup)N=37N=240N=36N=241N=38N=244
  SIE rate/100 pt-yrs 95% CI0 0–11.04.2 1.9–8.115.1 4.9–35.25.6 2.9–9.814.3 4.6–33.35.0 2.5–9.0
FILM (No. pts in subgroup)n=21N=186N=17N=179N=20N=182
  SIE rate/100 pt-yrs 95% CI4.8 0.1–26.62.8 0.9–6.50 0–22.02.9 0.9–6.730.1 11.0–65.54.5 2.0–8.9
**PooledN=82N=722N=88N-728N=95N=732
  No. SIEs2235281641
  Total pt-yrs exposure76.77657.5382.24666.6888.47675.13
  SIE rate/100 pt-yrs 95% CI2.6 0.3–9.43.5 2.2–5.36.1 2.0–14.24.2 2.8–6.118.1 10.3–29.46.1 4.4–8.2
*Patients with at least one serious infection adverse event   
**Includes STAGE, SCRIPT and FILM only. Naive pooling, not weighted by study size.   
†Asia includes China, Hong Kong, Indonesia, Malaysia, Philippines, Republic of Korea, Singapore, Taiwan, Thailand, and Japan; Other includes North and South America, Europe, and South Africa. CI=confidence interval; NA=not applicable   

To cite this abstract, please use the following information:
Emery, P, Rigby, W, Tak, PP, Dorner, T, Genovese, MC, Ferracioli, G, et al; Serious Infections with Ocrelizumab in Rheumatoid Arthritis: Pooled Results from Double-Blind periods of the Ocrelizumab phase III RA program. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :414
DOI: 10.1002/art.28183

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