Biologic Therapy, Abatacept, Shows Promise in the Treatment of Children with Severe, Treatment Resistant Juvenile Idiopathic Arthritis

Newswise — Abatacept, a biologic therapy used to treat adults with moderate to severe rheumatoid arthritis, may be a well-tolerated treatment for juvenile arthritis, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Boston, Mass.

Juvenile idiopathic arthritis, also known as juvenile rheumatoid arthritis, is the most common form of arthritis in children. There are several different types of JIA. All cause joint inflammation and begin before the age of 16, but otherwise are often associated with distinct symptoms and complications and may require different approaches to treatment.

Abatacept (Orencia) selectively inhibits T-cell activation, which is important in causing JIA symptoms. Trials in adults with rheumatoid arthritis have shown that abatacept induces significant improvement in disease and health-related quality of life, and inhibits progression of structural damage in patients who did not respond to other disease-modifying antirheumatic drugs including anti-TNF therapies.

Researchers recently evaluated the effectiveness and safety of abatacept in children and adolescents with active, treatment-resistant polyarticular JIA (with a focus on the safety of the treatment) in a phase III, double-blind, randomized, placebo controlled withdrawal trial.

This is the first trial to allow patients who had failed prior anti-TNF therapy biologic therapy to enroll, At the end of four months of open label treatment, 123 (65 percent) of the 190 patients enrolled were considered "responders," as they met the ACR Pediatric 30 (a validated, standardized definition of response). In those who had previously failed prior anti-TNF therapy, 39 percent met the ACR Pediatric 30.

Responders entered the blinded phase of the study and were randomized to either continue abatacept or receive placebo for up to six months, or until they met standardized definition for disease flare. Patients randomized to the placebo group compared to the abatacept group demonstrated disease flare much more frequently (53 percent vs. 20 percent, respectively) and quickly. An ACR Pediatric 90 response (representing excellent disease control) was seen in 40 percent of those who received abatacept for the 10 months of the study.

During the open-label lead-in, six patients reported serious adverse events, of which three were related to underlying disease. In the double-blind period, no SAEs were reported in the abatacept group and three SAEs were reported in two patients in the placebo group.

The overall frequencies of all adverse events were similar in the two treatment groups. Infusion reactions were reported in 1.7 percent versus 3.2 percent of the abatacept and placebo groups, respectively; all were mild/moderate (none serious) in intensity. No serious infections, autoimmune disorders or anaphylaxis episodes were reported in any period. No consistent patterns of abnormal liver/kidney function tests or hematological parameters emerged. "The results of this randomized double blind trial of abatacept were very encouraging for both efficacy and safety in these children with severe polyarticular JIA. Abatacept was effective for many of the children who had already failed anti-TNF therapy. Because of its unique mechanism of action, abatacept is an important new treatment approach for children with JIA," said Daniel J. Lovell, MD, MPH, professor of pediatrics at Cincinnati Childrens Hospital Medical Center and a lead investigator in the study. The participating clinical investigators in this international collaborative effort were from the Pediatric Rheumatology Collaborative Study Group and the Pediatric Rheumatology International Trials Organization.

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see http://www.rheumatology.org/annual.

Editor's Notes: Dr. Lovell will present this research during the ACR Annual Scientific Meeting at the Boston Convention and Exhibition Center from 2:30 " 4:00 pm ET on Thursday, November 8, 2007, in Room 253. Dr. Lovell will be available for media questions and briefing at 1:30 pm ET on Saturday, November 10 in the on-site press conference room, Room 251.

Presentation Number: 680

Abatacept Treatment of Juvenile Idiopathic Arthritis (JIA): Safety Report

D. J. Lovell1, N. Ruperto2, A. M. Prieur2, E. Paz2, N. Rubio-Perez2, C. A. Silva2, C. Abud2, R. Burgos-Vargas2, V. Gerloni2, J. A. Melo-Gomes2, C. Saad Magalhaes2, F. Sztajnbok2, C. Goldenstein-Schainberg2, M. Scheinberg2, P. Hashkes1, C. Hom1, L. H. Sigal3, A. J. Block3, A. Covucci3, P. L. N Cornet3, L. Pagliaro3, E. H. Giannini1, A. Martini2. 1Cincinnati Children's Hospital Medical Center, PRCSG, Cincinnati, OH; 2IRCCS Istituto G Gaslini-PRINTO, University of Genoa, Genoa, Italy; 3Global Clinical Research - Immunology, Bristol-Myers Squibb, Princeton, NJ

Purpose: Report of safety experience in a double-blind (DB), randomized withdrawal study, with an open-label (OL) extension in patients with JIA/JRA treated with abatacept (ABA).

Methods: Patients who met the ACR Pediatric (Pedi) 30 definition of improvement following a 4-month OL lead-in period were randomized 1:1 to DB therapy with ABA or placebo (PBO) every 28 days for up to 6 months. Safety is presented for the OL lead-in and DB periods.

Results: 190 patients were enrolled and 170 completed the OL lead-in period; 123 patients achieved an ACR Pedi 30 response and 122 elected to enter the DB withdrawal period. During the OL lead-in, 6 patients reported serious AEs (SAEs): 3 related to underlying disease (flare [2 cases]; joint replacement [1 case]) and 1 case each of varicella, ovarian cyst and acute lymphocytic leukemia. The leukemia was diagnosed at Day 89 in a patient who was anemic at enrollment - with progressive decreasing hemoglobin from Day 1 (relationship to study medication was unlikely). 70% of patients reported AEs; the most common were headache (13.2%), nausea (10.0%), cough (8.9%), diarrhea (8.9%), upper respiratory tract infection (URTI; 7.4%) and pyrexia (6.3%). Other than URTI, there were few infectious AEs (all had a typical course and resolved with treatment) and no opportunistic infections. Eight (4.2%) patients experienced acute infusional AEs: all but 1 were mild in intensity; none were serious; most were single events in 1 patient each; headache and dizziness occurred in 4 and 2 patients, respectively, with no recurrences. In the DB period, no SAEs were reported in the ABA group; 3 SAEs were reported for 2 PBO-treated patients (hematoma in 1; varicella and encephalitis in the other); all resolved and none resulted in discontinuation. AEs were reported by 61.7% vs 54.8% in the ABA vs PBO groups; the most common events were influenza (5 [8.3%] vs 4 [6.5%]), bacteriuria (4 [6.7%] vs 0 [0%]), nasopharyngitis (4 [6.7%] vs 3 [4.8%]), URTI (4 [6.7%] vs 5 [8.1%]) and pyrexia (4 [6.7%] vs 5 [8.1%]). Other AEs occurred with similar frequencies in both groups. Acute infusional AEs were reported in 1.7% vs 3.2% of ABA vs PBO groups; all were mild/moderate (none serious) in intensity. No serious infections, autoimmune disorders or anaphylaxis episodes were reported in any period. No consistent patterns of abnormal liver/kidney function tests or hematological parameters emerged.

Conclusion: Abatacept appeared to be well tolerated in patients with JIA through the OL lead-in and DB periods of this study.

Disclosure Block: D.J. Lovell, Abbott, 5; Amgen, 5; Bristol-Myers Squibb, 5; Centocor, 5; Hoffmann-La Roche, 5; Novartis, 5; Pfizer, 5; Regeneron, 5; Xoma, 5; Editorial Board, Clinical and Experimental Rheumatology; Associate Editor, Arthritis Care and Research, 9; N. Ruperto, Bristol-Myers Squibb, 2; A.M. Prieur, None; E. Paz, None; N. Rubio-Perez, None; C.A. Silva, None; C. Abud, None; R. Burgos-Vargas, None; V. Gerloni, None; J.A. Melo-Gomes, None; C. Saad Magalhaes, None; F. Sztajnbok, The Rheumatology unit receives a grant corresponding to the patients' monthly infusions and medical visits from Bristol-Myers Squibb, 9; Investigator at a clinical site in the Bristrol-Myers Squibb sponsored JIA trial, 9; C. Goldenstein-Schainberg, None; M. Scheinberg, None; P. Hashkes, None; C. Hom, Investigator at a clinical site in the Bristol-Myers Squibb sponsored JIA trial, 9; L.H. Sigal, Bristol-Myers Squibb, 3; A.J. Block, Bristol-Myers Squibb, 1; Bristol-Myers Squibb, 3; A. Covucci, Bristol-Myers Squibb, 3; P.L. Cornet, Bristol-Myers Squibb, 3; L. Pagliaro, Bristol-Myers Squibb, 3; E.H. Giannini, Bristol-Myers Squibb, 2; A. Martini, Bristol-Myers Squibb, 2.