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Title: FDA Approves Abatacept for the Treatment of Polyarticular Juvenile Idiopathic Arthritis

"FDA Approves Abatacept for the Treatment of Polyarticular Juvenile Idiopathic Arthritis"

PRINCETON, N.J. -- April 8, 2008 -- The US Food and Drug Administration (FDA) has approved abatacept (Orencia) for reducing signs and symptoms in paediatric patients aged 6 years and older with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA). Abatacept, which may be used as monotherapy or concomitantly with methotrexate, is a first-in-class biologic treatment option for use in paediatric patients with JIA. (1,2). Orencia should not be administered concomitantly with tumour necrosis factor (TNF) antagonists and is not recommended for use concomitantly with other biologic rheumatoid arthritis (RA) therapy, such as anakinra. This new indication for abatacept provides significant evidence of its durable efficacy and long-term safety in paediatric patients, including those initiating biologic therapy for the first time. The safety and efficacy of abatacept in JIA were assessed in a 3-part study through 1 year. "In a JIA clinical trial, [abatacept] provided meaningful and sustained improvements in this patient population across 3 major sub-types of JIA through 1 year," said Edward H. Giannini, MSc, DrPH, Professor of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. The approval is based on the AWAKEN (Abatacept Withdrawal study to Assess Efficacy and Safety in Key Endpoints in Juvenile Idiopathic Arthritis Not Responding to Current Treatment) trial, which evaluated the efficacy and safety of abatacept in patients aged 6 to 17 years with moderately to severely active polyarticular JIA who had an inadequate response to 1 or more disease-modifying antirheumatic drugs (DMARDs), such as methotrexate or TNF antagonists. The 3-part AWAKEN trial included patients with subtypes of JIA that at disease onset included oligoarticular JIA (16%), polyarticular JIA (64%; 20% were rheumatoid factor [RF] positive), and systemic JIA with polyarticular course (20%) who had not responded adequately to other JIA therapies. The first phase of this study (Period A), an open-label, 4-month, lead-in phase, enrolled 190 patients with disease duration of approximately 4 years with moderately to severely active disease at study entry. The majority (70%) of these study patients were new to biologic treatments. Nearly 30% of patients had previously had an inadequate response to a TNF antagonist or anakinra. Patients received abatacept intravenously (10 mg/kg; maximum 1,000 mg) on days 1, 15, 29, and every month thereafter. Response was assessed utilizing the ACR Pediatric (ACR Pedi) 30 definition of improvement, defined as greater than or equal to 30% improvement in at least 3 of the 6 JIA core set variables and greater than or equal to 30% worsening in not more than 1 of the JIA core set variables. In Period A of the study, abatacept demonstrated consistent improvement in ACR Pedi 30 with similar responses across all JIA subtypes (oligoarticular extended, 59.3%; polyarticular-RF positive, 68.4%; polyarticular-RF negative, 64.3%; and systemic JIA with polyarticular course, 64.9%). In patients who were inadequate responders to DMARDs including methotrexate and were new to biologic treatment, abatacept demonstrated meaningful ACR Pedi response rates with 76% of patients achieving an ACR Pedi 30 response rate, 60% achieving an ACR Pedi 50 response rate, 36% achieving an ACR Pedi 70 response rate, and 17% achieving an ACR Pedi 90 response rate. In patients who had received prior biological treatment, 38.6% achieved an ACR Pedi 30 response rate, 24.6% achieved an ACR Pedi 50 response rate, 10.5% achieved an ACR Pedi 70 response rate, and 1.8% achieved an ACR Pedi 90 response rate. Patients who completed Period A and achieved an ACR Pedi 30 response were eligible to enter this 6-month, double-blind phase (Period B). Patients entering Period B (n =122) were randomised to remain on abatacept (n = 60) or receive placebo (n = 62) for 6 months. The primary endpoint of the study was time to occurrence of disease flare, defined as a greater than or equal to 30% worsening in at least 3 of the 6 JIA core set variables with greater than or equal to 30% improvement in not more than 1 of the 6 JIA core set variables; greater than or equal to two cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in greater than or equal to 2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare. Efficacy results included: · Time difference to occurrence of disease flare was statistically significant based on the log-rank test in patients treated with placebo compared with abatacept ([P = .0002).

· Patients treated with abatacept experienced significantly fewer disease flares compared with placebo-treated patients (20% vs 53%, respectively, P < .001).

· The risk of disease flare among patients continuing on abatacept was less than one-third than that for patients who withdrew from abatacept treatment (HR: 0.31, 95% CI: 0.16, 0.59).

In patients receiving abatacept treatment throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of ACR Pedi 30, 50 and 70 responders remained consistent through 1 year.

In both the open-label, lead-in (Period A) and double-blind (Period B) phases of the study, the adverse reactions in paediatric patients were similar in type and frequency to those seen in adult patients. This was also seen in patients who participated in the open-label (Period C) extension period.

The overall frequency of adverse events in Period A was 70%; infections occurred at a frequency of 36%. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient paediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhoea, cough, pyrexia, and abdominal pain. A total of 6 serious adverse events (acute lymphocytic leukaemia, ovarian cyst, varicella infection, disease flare and joint wear) were reported during the initial 4 months of treatment with ORENCIA.(2) There was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related events occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults. Upon continued treatment in the open-label extension period, the types of adverse events were similar except for a single patient diagnosed with multiple sclerosis while on open-label treatment.

In addition to the approval for JIA, Bristol-Myers Squibb, maker of abatacept, has added a postmarketing safety section to the package insert. This section states that the postmarketing adverse event profile that was observed in adult RA patients did not differ from that seen in the clinical trials of adult RA patients. The FDA also has revised the adult indication to remove the requirement that patients must first fail at least 1 DMARD before initiating therapy with abatacept.

References

1. FDA Website. Approval History: sBLA 125057/114. Available at: http://www.fda.gov/cder/foi/appletter/2008/125057s114ltr.pdf. Accessed March 10, 2008.

2. FDA Website. Approval History: sBLA 103795/1001. Available at: http://www.fda.gov/cder/foi/appletter/1999/etanimm052799L.htm. Accessed March 10, 2008.

SOURCE: Bristol-Myers Squibb Company

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