ORENCIA Approved For Treatment Of Polyarticular Juvenile Idiopathic Arthritis

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FDA has approved Bristol-Myers Squibb's ORENCIA (abatacept) for reducing signs and symptoms in pediatric patients six years and older with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA). ORENCIA may be used as monotherapy or concomitantly with methotrexate (MTX). ORENCIA should not be administered concomitantly with tumor 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 ORENCIA provides significant evidence of its durable efficacy and long-term safety in pediatric patients, including those initiating biologic therapy for the first time. The safety and efficacy of ORENCIA in JIA were assessed in a three-part study through one year. The approval of ORENCIA in JIA represents the ongoing commitment of Bristol-Myers Squibb in this therapeutic area.

"In a JIA clinical trial, ORENCIA provided meaningful and sustained improvements in this patient population across three major sub-types of JIA through one year," said Edward H. Giannini, M.Sc., Dr.P.H., Professor of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, OH.

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 ORENCIA (abatacept) in patients six to 17 years of age with moderately to severely active polyarticular JIA who had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs), such as MTX or TNF antagonists.

"Juvenile idiopathic arthritis is the most prevalent form of arthritis in children(3)," said Elliott Sigal, M.D., Ph.D., executive vice president, chief scientific officer and president, Research and Development, Bristol-Myers Squibb. "This new indication for ORENCIA offers another treatment option to help improve signs and symptoms of this serious disease in pediatric and adolescent patients."

In addition to the approval for JIA, Bristol-Myers Squibb has added a post-marketing safety section to the package insert. This section states that the post-marketing 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 one DMARD before initiating therapy with ORENCIA. The new indication statement is: ORENCIA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active RA. ORENCIA may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists. ORENCIA should not be administered concomitantly with TNF antagonists and is not recommended for use concomitantly with other biologic RA therapy, such as anakinra. The revised adult indication means that ORENCIA is an appropriate option for patients with moderate-to-severe RA, regardless of prior treatment received.

ORENCIA JIA Study (AWAKEN Trial)

The AWAKEN trial was a three-part study which included patients with subtypes of JIA that at disease onset included Oligoarticular JIA (16 percent), Polyarticular JIA (64 percent; 20 percent were rheumatoid factor (RF) positive) and Systemic JIA with polyarticular course (20 percent) who had not responded adequately to other JIA therapies. In the first phase of this study (Period A), a total of 190 patients aged six to 17 years, with disease duration of approximately four years with moderately to severely active disease at study entry, were enrolled in this open-label, four-month, lead-in phase of the study. The majority (70 percent) of these study patients were new to biologic treatments. Nearly 30 percent of patients had previously had an inadequate response to a TNF antagonist or anakinra. Patients received ORENCIA (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 30 definition of improvement, defined as greater than or equal to 30 percent improvement in at least three of the six JIA core set variables and greater than or equal to 30 percent worsening in not more than one of the JIA core set variables.

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In Period A of the study, ORENCIA demonstrated consistent improvement in ACR Pedi 30 with similar responses across all JIA subtypes (Oligoarticular extended, 59.3 percent; Polyarticular-RF positive, 68.4 percent; Polyarticular-RF negative 64.3 percent; and Systemic JIA with polyarticular course, 64.9 percent). In patients who were inadequate responders to DMARDs including MTX and were new to biologic treatment, ORENCIA demonstrated meaningful ACR Pedi response rates with 76 percent of patients achieving an ACR Pedi 30 response rate, 60 percent achieving an ACR Pedi 50 response rate, 36 percent achieving an ACR Pedi 70 response rate and 17 percent achieving an ACR Pedi 90 response rate. In patients who received prior biological treatment, 38.6 percent achieved an ACR Pedi 30 response rate, 24.6 percent achieved an ACR Pedi 50 response rate, 10.5 percent achieved an ACR Pedi 70 response rate and 1.8 percent achieved an ACR Pedi 90 response rate.

In Period B of the study, patients who completed Period A and achieved an ACR Pedi 30 response were eligible to enter this six-month, double-blind phase. Patients entering Period B (n=122) were randomized to remain on ORENCIA (n=60) or receive placebo (n=62) for six months.

The primary endpoint of the study was time to occurrence of disease flare. Disease flare was defined as a greater than or equal to 30 percent worsening in at least three of the six JIA core set variables with greater than or equal to 30 percent improvement in not more than one of the six JIA core set variables; greater than or equal to two centimeters of worsening of the Physician or Parent Global Assessment was necessary if used as one of the three JIA core set variables used to define flare, and worsening in greater than or equal to two joints was necessary if the number of active joints or joints with limitation of motion was used as one of the three 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 ORENCIA (abatacept) (p-value equals 0.0002).

-- Patients treated with ORENCIA experienced significantly fewer disease flares compared to placebo-treated patients (20 percent vs. 53 percent, respectively, p-value less than 0.001).

-- The risk of disease flare among patients continuing on ORENCIA was less than one-third than that for patients who withdrew from ORENCIA treatment [Hazard Ratio: 0.31, 95 percent CI (0.16, 0.59)].

In patients receiving ORENCIA 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 one year.

In both the open-label, lead-in (Period A) and double-blind (Period B) phases of the study, the adverse reactions in pediatric 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.

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