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Abstract Number: 884

Treatment Of Lupus Nephritis With Abatacept Plus Low-Dose Pulse Cyclophosphamide Followed By Azathioprine (the Euro-Lupus Regimen): Twenty-Four Week Data From a Double-Blind Controlled Trial

David Wofsy1, Anca Askanase2, Patricia C. Cagnoli3, W. Winn Chatham4, Gabriel Contreras5, Maria Dall'era6, Mary Anne Dooley7, Hilda Fragoso-Loyo8, David R. Karp9, Meenakshi Jolly10, Kenneth Kalunian11, Diane L. Kamen12, Iris Lee13, Marc C. Levesque14, S. Sam Lim15, Meggan Mackay16, Cesar Ramos-Remus17, Brad H. Rovin18, Tammy O. Utset19, Swamy Venuturupalli20, Robert Winchester21, Linna Ding22, Wendy Gao22, Lynette Keyes-Elstein23 and Patti Tosta24, 1Rheumatology/Immunology, University of California San Francisco and NIAID Autoimmunity Centers of Excellence, San Francisco, CA, 2NYU School of Medicine, New York, NY, 3Int Med/Div of Rheum, University of Michigan Health, Ann Arbor, MI, 4University of Alabama at Birmingham, Birmingham, AL, 5University of Miami, Miami, FL, 6Medicine/Rheumatology, University of California, San Francisco, San Francisco, CA, 7University of North Carolina at Chapel Hill, Chapel Hill, NC, 8Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico, Mexico, 9Rheumatic Diseases Division, UT Southwestern Medical Center, Dallas, TX, 10Rheumatology, Rush University Medical Center, Chicago, IL, 11UCSD School of Medicine, La Jolla, CA, 12Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC, 13Nephrology, Temple University, Philadelphia, PA, 14Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, 15Emory University School of Medicine, Division of Rheumatology, Atlanta, GA, 16Autoimmune & Musculoskeletal Disease, Feinstein Institute for Medical Research, Manhasset, NY, 17Unidad de Investigacion en Enfermedades Cronico-Degenerativas, Guadalajara, Mexico, 18Division of Nephrology, Ohio State University Medical Center, Columbus, OH, 19Rheumatology, University of Chicago Medical Center, Chicago, IL, 20Cedars-Sinai Medical Center, West Hollywood, CA, 21Dept of Medicine & Pathology, Columbia University, New York, NY, 22NIAID, Bethesda, MD, 23Rho Federal Systems, Inc., Chapel Hill, NC, 24Immune Tolerance Network, San Francisco, CA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Abatacept, clinical trials, cyclophosphamide, lupus nephritis and systemic lupus erythematosus (SLE)

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Session Information

Session Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment: Lupus Nephritis and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Studies in murine models for SLE have shown that CTLA4Ig can ameliorate murine lupus nephritis.  Moreover, the combination of CTLA4Ig plus intravenous cyclophosphamide (IVC) acts synergistically in mice to reverse lupus nephritis.  The purpose of this study (the ACCESS Trial) was to determine whether these observations in mice could be translated into an effective treatment for lupus nephritis in people.

Methods: Subjects with biopsy-proven class III or IV lupus nephritis (with or without class V) and urine protein:creatinine ratio (UPCR) >1 were enrolled in the trial.  All subjects received low-dose IVC (500 mg q 2 wks x 6) followed by azathioprine (2 mg/kg/d up to a maximum of 200 mg/dose), per the Euro-Lupus nephritis (ELN) regimen.  Subjects were randomized 1:1 to receive either saline (n=68) or abatacept (ABA) (n=66) intravenously at weeks 0, 2, 4, and then every four weeks.  ABA was dosed based on weight: <60 kg, 500 mg; 60-100 kg, 750 mg; >100 kg, 1 gm.  In addition, subjects received oral prednisone beginning at 60 mg/d and tapered to 10 mg/d within 12 weeks.  The primary outcome measure was complete response (CR) at 24 weeks, defined as: (i) UPCR <0.5; (ii) serum creatinine normal or, if abnormal, within 25% of baseline; and (iii) adherence to the steroid regimen.  Partial response required a >50% improvement in UPCR and otherwise mirrored the CR criteria.

Results: A racially and ethnically diverse population of North American subjects was enrolled (39% African American and 40% Hispanic/Mestizo).  The groups were well matched for baseline characteristics, including race, ethnicity, severity of nephritis, and biopsy class.  At 24 weeks, the CR rate in the ABA group was 22/66 (33%) compared to 21/68 (31%) in the control group (p=0.85).  Total response (CR+PR) was 59% in both groups (39/66 vs 40/68).  Among African American subjects, 33% (9/27) of subjects in the ABA group achieved CR, compared to 16% (4/25) in the control group (p=0.20).  Twice as many subjects in the ABA group experienced disappearance of anti-dsDNA Ab (24% vs 11%), but the difference was not statistically significant (p=0.22).  Patient global assessment improved by 74% in the ABA group compared to 38% in the control group (p=0.051).  There was no difference between the groups at week 24 in mean UPCR, anti-dsDNA and complement levels, BILAG score, SF-36 (physical and mental), frequency of serious adverse events (SAEs), or withdrawals (total or lupus-related).   The rate of infectious SAEs was 0.3/yr in the ABA group compared to 0.2/yr in the control group (NS). 

Conclusion: The ACCESS trial did not achieve its primary goal of demonstrating a benefit for ABA plus ELN compared to ELN alone at 24 weeks.  However, it achieved an important secondary objective by providing the first systematic examination of the ELN regimen in a racially and ethnically diverse North American population.  The response rate of >30% CR within 24 weeks in the ELN control group is higher than has been reported in prior lupus nephritis trials (including studies of mycophenolate mofetil and high-dose IVC), suggesting that the ELN regimen may have broad applicability.  Subjects in the ACCESS trial are still undergoing blinded evaluation to examine outcome at later time points.


Disclosure:

D. Wofsy,

Bristol-Myers Squibb,

5,

Genentech and Biogen IDEC Inc.,

5,

GlaxoSmithKline,

5;

A. Askanase,
None;

P. C. Cagnoli,
None;

W. W. Chatham,
None;

G. Contreras,
None;

M. Dall’era,
None;

M. A. Dooley,
None;

H. Fragoso-Loyo,
None;

D. R. Karp,

Bristol-Myers Squibb,

2;

M. Jolly,
None;

K. Kalunian,

Bristol-Myers Squibb,

5;

D. L. Kamen,
None;

I. Lee,
None;

M. C. Levesque,
None;

S. S. Lim,

Bristol-Myers Squibb,

2;

M. Mackay,
None;

C. Ramos-Remus,
None;

B. H. Rovin,

Onyx,

5,

Biogen Idec,

5,

Astellas,

5,

Lilly,

5,

Celtic,

5,

Questcor,

2;

T. O. Utset,

Genentech and Biogen IDEC Inc.,

5,

Anthera Pharmaceuticals,

5,

GlaxoSmithKline,

5;

S. Venuturupalli,
None;

R. Winchester,
None;

L. Ding,
None;

W. Gao,
None;

L. Keyes-Elstein,
None;

P. Tosta,
None.

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