European Commission Approves ORENCIA® (abatacept) in Combination with Methotrexate for Children with Moderate to Severe Polyarticular Juvenile Idiopathic Arthritis (pJIA)

Bristol-Myers Squibb Company (NYSE: BMY) today announced that on 20 January 2010, the European Commission approved ORENCIA^® (abatacept) in combination with methotrexate for the treatment of moderate to severe active polyarticular juvenile idiopathic arthritis (pJIA) in paediatric patients six years of age and older who have had an insufficient response to other DMARDS, including at least one TNF inhibitor.¹

Disease-modifying treatment options for children with pJIA have been extremely limited to date. ORENCIA, in combination with methotrexate (MTX), offers another treatment option for children six years of age and older with pJIA, filling an unmet need. ORENCIA has not been studied in children under six years old. ORENCIA is designed to act early in the immune cascade by selectively modulating T-cells to reduce downstream inflammatory responses.^2,3

The AWAKEN Study

The approval of ORENCIA in pJIA is based on findings from the double-blind, randomised controlled study AWAKEN (Abatacept Withdrawal study to Assess efficacy and safety in Key Endpoints in juvenile idiopathic arthritis Not responding to current treatment) which evaluated the efficacy and safety of ORENCIA in patients six to 17 years of age with moderate to severe active pJIA who had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs), such as MTX or tumour necrosis factor (TNF) antagonists.⁴

AWAKEN studied ORENCIA in pJIA in three phases – the first (Period A) was an open-label, lead-in period where patients received active treatment with ORENCIA; the second (Period B) was the double-blind period where patients who had demonstrated an ACR Paediatric (Pedi) 30 response were randomised to either ORENCIA or placebo treatment; and the third (Period C) was the open-label extension period open to those patients experiencing flare or completing Period B as well as non-responders from Period A.

The following results constituted the basis for the regulatory approval of ORENCIA in pJIA:

• In Period A, ORENCIA demonstrated meaningful ACR Pedi response rates, with 65%, 49% and 28% of patients achieving an ACR Paediatric 30, 50 and 70, respectively
• ACR Pedi responses throughout the study (Period A, Period B and Period C) remained consistent for one year and were higher in biologic naïve patients compared with those previously receiving biologic therapy
• In Period B, patients on ORENCIA experienced significantly fewer disease flares versus placebo (20% vs. 53%, respectively, p=0.0003). 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% CI (0.16, 0.59)]
• In the lead-in open-label period (Period A), during which all patients were given ORENCIA, the overall frequency of adverse events was 70%; infections occurred at a frequency of 36%. The infections had a typical course and resolved with treatment. No opportunistic infections were recorded
• During the double-blind period (Period B), the frequency of adverse events did not significantly differ between the treatment group (62%) and placebo (55%) (p=0.47); three serious adverse events were reported for two patients, both in the placebo group (p=0.50). 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.

In addition, an improvement in quality of life was shown in a study where treatment with ORENCIA allowed children to miss fewer school days and parents to get back to usual activities.⁵

About Juvenile Idiopathic Arthritis (JIA)

JIA is the most common form of arthritis affecting children and an important cause of short-term and long-term disability in children.⁶ Studies in developed countries have reported that JIA may affect between 16–150 in every 100,000 children and the disease usually begins before the age of 16.⁶ Like adult rheumatoid arthritis (RA), JIA is an autoimmune disease, where the body’s immune system mistakenly attacks healthy joint tissues causing chronic pain, stiffness and swelling of the joints, which if not treated early may ultimately lead to joint damage and deformities.^7,8 T-cells are thought to play a major part in the development of JIA.

About Rheumatoid Arthritis

RA is a systemic, chronic, autoimmune disease characterised by inflammation in the lining of joints (or synovium), causing joint damage with chronic pain, stiffness and swelling. RA causes limited range of motion and decreased function as a result of affected joints losing their shape and alignment. RA may affect up to 7 million people in Europe.^9,10

About ORENCIA

ORENCIA is a selective co-stimulation modulator of T-cell activation. ORENCIA is designed to prevent full T-cell activation and inhibit the release of chemicals leading to joint inflammation and destruction as observed in RA¹¹ and pJIA.⁴

ORENCIA is the first biologic discovered and developed in Bristol-Myers Squibb research centres and was first approved for adult RA in May 2007 by the European Commission.

ORENCIA in combination with MTX is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have had an insufficient response or intolerance to other disease-modifying anti-rheumatic drugs including at least one TNF inhibitor. A reduction in the progression of joint damage and improvement of physical function have been demonstrated during combination treatment with ORENCIA and MTX.

ORENCIA, in combination with MTX, is also indicated for the treatment of moderate to severe active pJIA in paediatric patients six years of age and older who have had an insufficient response or who are intolerant to other DMARDS, including at least one TNF inhibitor. ORENCIA has not been studied in children under six years old.

The safety profile of ORENCIA has been studied through more than 10,000 patient-years of exposure and has demonstrated a consistent safety profile to seven years.¹²

Medicinal products, including ORENCIA, which affect the immune system, may affect host defences against infections and malignancies. Serious infections, at least possibly related to treatment, were reported in 1.8% of patients with ORENCIA and in 1.0% of patients not treated by ORENCIA (receiving placebo). There is a need to evaluate and monitor patients regarding the risk of infection prior to and during treatment. In the placebo-controlled clinical trials, the frequency of malignancies with ORENCIA was 1.4% and with placebo 1.1%. These rates are similar to that observed in the general RA population.¹³

ORENCIA, like other biologics, is contraindicated in patients with severe and uncontrolled infections such as sepsis and opportunistic infections and in patients with hypersensitivity to the active substance or to any of the excipients. Allergic reactions have been reported uncommonly with ORENCIA in clinical trials, where patients were not required to be pretreated to prevent allergic reactions. In the case of any serious allergic/anaphylactic reaction, ORENCIA should be discontinued.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases.

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ORENCIA^® (abatacept) is a trademark of Bristol-Myers Squibb Company.

For information regarding ORENCIA, please consult the Summary of Product Characteristics.

References

1. ORENCIA EU Summary of Product Characteristics, 2010.

2. Davis P, et al. Gene Profiling Studies Reveal that Abatacept Does Not Directly Induce Transcriptional Changes in Antigen-presenting Cells. Abstract submitted to ACR/ARHP Meeting 2008, San Francisco Oct 24-29th 2008;08-A-2321-ACR.

3. European Medicines Agency (EMEA). ORENCIA Scientific Discussion. 2007:1-36.

4. Ruperto N, et al. Abatacept In Children With Juvenile Idiopathic Arthritis: A Randomised, Double-Blind, Placebo-Controlled Withdrawal Trial. The Lancet 2008;372(9636):383-91.

5. Li T, et al. Reduction in Missed School Days and Improvement in Parent Activity Participation in Children with Juvenile Idiopathic Arthritis Treated with Abatacept. ACR 2008, abstract no. 2019.

6. Ravelli A. Juvenile Idiopathic Arthritis. The Lancet 2007:369:767-78.

7. Medline Plus. Juvenile Rheumatoid Arthritis. US National Library of Medicine, National Institute of Health. Available at: http://www.nlm.nih.gov/medlineplus/juvenilerheumatoidarthritis.html. Accessed November 24 2009.

8. Zeginni E. Association of HLA-DRB1*13 with Susceptibility to Uveitis In Juvenile Idiopathic Arthritis In Two Independent Data Sets. Rheumatology 2006;45:972-74.

9. United Nations. 2008 Revision Population Database. Available at: http://esa.un.org/unpp/. Accessed November 24 2009.

10. Symons D, et al. The Global Burden of Rheumatoid Arthritis in the Year 2000. Available at: www.who.int/healthinfo/statistics/bod_rheumatoidarthritis.pdf. Accessed November 24 2009.

11. Kremer JM, et al. Treatment of Rheumatoid Arthritis by Selective Inhibition of T-Cell Activation with Fusion Protein CTLA4Ig. N Engl J Med 2003;349:1907-15.

12. Smitten A, et al. Descriptive Analysis of Serious Infections, Hospitalized Infections and Malignancies Over Time in the Abatacept Clinical Development Program: A Safety Update with >10,000 Person-Years of Exposure. EULAR 2008, abstract no. 1065.

13. Simon T, et al. Ann Rheum Dis 2006;65(Suppl II):489.