Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Efficacy and Safety of Abatacept Over 12 Months in Patients with Lupus Nephritis: Results From a Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II/III Study.

Furie1,  Richard, Nicholls2,  Kathy, Cheng3,  Tien-Tsai, Houssiau4,  Frederic, Burgos-Vargas5,  Ruben, Chen6,  Shun-Le, Aranda7,  Richard

North Shore-Long Island Jewish Health System, Lake Success, NY
Royal Melbourne Hospital, Victoria, Australia
Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
Cliniques Universitaires Saint-Luc, Brussels, Belgium
Hospital General de Mexico, Mexico City, Mexico
Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Ren Ji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Sh
Bristol-Myers Squibb [at time of study], Princeton, NJ
Bristol-Myers Squibb, Princeton, NJ
Oklahoma Medical Research Foundation, Oklahoma City, OK

Background/Purpose:

Abatacept (ABA), a selective T-cell costimulation modulator approved for rheumatoid arthritis, is being evaluated for lupus. Preclinical data in murine lupus and Phase II data in systemic lupus erythematosus (SLE) pts with arthritis, serositis or discoid lesions1 supported the development of ABA in lupus nephritis (LN).

Methods:

This was a 12-mth Phase II/III double-blind study in pts with active ISN/RPS Class III or IV LN, requiring: urinary protein/creatinine ratio (UPCR) >=0.44 mg/mg (50 mg/mmoL); active urinary sediment (>5 red blood cells [RBC]/high power field [hpf] or >8 white blood cells/hpf or cylindruria); and renal biopsy within 3 mths (if biopsy 3–12 mths, abnormal C3, C4 or anti-dsDNA also required). All pts received mycophenolate mofetil (MMF; target dose 1.5–3.0 g/day dependent on race) and up to 60 mg/day prednisone or equivalent (with response-guided taper after 28 days). Pts were randomized to placebo (PBO) or IV ABA (either 3 mths of ABA 30 mg/kg followed by 9 mths of 10 mg/kg [30/10], or 12 mths of 10 mg/kg [10/10]). The primary efficacy endpoint was time to Complete Renal Response (CRR: GFR within 10% of pre-flare/screening value; UPCR <0.26 mg/mg [30 mg/mmol]; inactive urinary sediment) confirmed at 30 days after the first response, compared using a Cox proportional hazards model. Secondary endpoints included time to Renal Improvement (RI) and Mth 12 rates of CRR and RI (RI: >=50% UPCR reduction, GFR >=50% improved if screening 15–59, otherwise >=90% of screening; no active sediment). Exploratory endpoints included 1) Patient Response (PR: UPCR <0.5 mg/mg [56.5 mg/mmol] or >=50% UPCR improvement to <1.0 mg/mg [113 mg/mmol] if baseline <=3.0 mg/mg [339 mg/mmol] or to 3.0 mg/mg if baseline >3.0; RBCs within reference range (<5–8/hpf) or >=50% reduction; serum creatinine normal or <=25% above baseline) and 2) Renal Response (RR: serum creatinine <=25% above baseline; >=50% UPCR improvement to <1.0 mg/mg if baseline <=3.0 or to <3.0 mg/mg if baseline >3.0). Safety was assessed.

Results:

Of 298 treated pts, 228 (76.5%) completed Mth 12 (78.0, 74.7, and 76.8% in PBO, ABA 10/10, and ABA 30/10). Time to CRR did not differ between groups (p=0.549 and 0.422) for ABA 10/10 and 30/10 vs PBO) nor did time to RI. Efficacy at Mth 12 is shown (Table). A subset analysis of 122 nephrotic pts (baseline UPCR >3.0 mg/mg) found ~20–30% greater reduction in UPCR in pts randomized to ABA vs PBO from Mth 6, maintained to Mth 12. Safety is reported (Table). Cause of death appeared to be underlying disease for 5 pts and infection for 7.

 Placebo N=10010/10 N=9930/10 N=99
CRR at Month 12, % (95% CI)3.0 (0.6, 8.5)3.0 (0.6, 8.6)5.1 (0.7, 9.4)
Estimate of difference vs placebo (95% CI)NA0.0 (-4.6, 4.7)2.4 (-2.4, 7.2)
RI at Month 12, %55.052.555.6
Hazard ratio estimate (95% CI)NA1.0 (0.69, 1.48)1.1 (0.76, 1.61)
PR at Month 12, % (95% CI)34.0 (24.7, 43.3)30.3 (21.3, 39.4)38.4 (28.8, 48.0)
Odds ratio (95% CI)NA0.88 (0.49, 1.59)1.21 (0.68, 2.13)
RR at Month 12, % (95% CI)   
Estimate of difference vs placebo33.0 (23.8, 42.2) NA39.4 (29.8, 49.0) 6.2 (-7.1, 19.0)45.5 (35.6, 35.3) 12.6 (-1.1, 26.2)
Deaths, n (%)7 (7.0)2 (2.0)5 (5.1)
SAEs, n (%)31 (31.0)28 (28.3)33 (33.3)
Serious infections, n (%)17 (17.0)18 (18.2)23 (23.2)
Most common:*3 (3.0)4 (4.0)4 (4.0)
Pneumonia06 (6.1)3 (3.0)
Herpes zoster2 (2.0)1 (1.0)5 (5.1)
Gastroenteritis2 (2.0)2 (2.0)0
Urinary tract infection   
*Reported in more than one pt in either abatacept group

Conclusion:

ABA, MMF and steroids exhibited a safety profile similar to MMF and steroids in pts with LN. Pre-specified efficacy endpoints did not demonstrate a benefit at 12 mths for ABA vs PBO. Among nephrotic pts, an exploratory analysis showed improvement in proteinuria with ABA, suggesting that additional exploration may be warranted to investigate potential biologic activity in this subset.

1Merrill, JT et al. A&R 2010;62:3077–87

To cite this abstract, please use the following information:
Furie, Richard, Nicholls, Kathy, Cheng, Tien-Tsai, Houssiau, Frederic, Burgos-Vargas, Ruben, Chen, Shun-Le, et al; Efficacy and Safety of Abatacept Over 12 Months in Patients with Lupus Nephritis: Results From a Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II/III Study. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2469
DOI:

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