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Analyses from Phase IIIb Study Provide Additional Data in Earlier Use of Orencia (abatacept) Plus Methotrexate (MTX) in Citrullinated Protein (CCP)-Positive Adult Patients with Early Rheumatoid Arthritis (RA)

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Bristol-Myers Squibb Company (NYSE:BMY) today announced results of several new sub-analyses of the Phase IIIb AVERT (Assessing Very Early Rheumatoid arthritis Treatment) trial that investigated the use of Orencia plus methotrexate (MTX) in biologic and MTX-na”ive citrullinated protein (CCP)-positive early moderate to severe rheumatoid arthritis (RA) patients. These data were presented this week at the American College of Rheumatology (ACR) 2014 annual meeting.

Orencia is currently indicated in adults for moderate to severe RA. Orencia should not be administered with tumor necrosis factor antagonists and should not be used with other biologic RA drugs.

One of the analyses looked at anti-CCP antibodies, which are a marker of RA and may contribute to disease progression. The analysis assessed the development of anti-CCP antibodies in patients with early rapidly progressing RA by measuring isotypes (related antibody classes) and the number of epitopes (a specific area of an antigen to which an antibody binds) recognized after treatment with Orencia plus MTX, Orencia alone, or MTX alone. Results demonstrated Orencia plus MTX numerically reduced the concentrations of all CCP isotypes and the average number of epitopes recognized over one year of treatment more than Orencia alone or MTX alone.

“Important results were seen in CCP-positive patients,” said T.W.J. Huizinga, MD, PhD, Leiden University Medical Center, Leiden Netherlands. “The results of our analysis demonstrate that patients who start treatment with a combination of Orencia plus methotrexate in early rheumatoid arthritis may potentially slow disease progression.”

Over 12 months of treatment, 6.7 percent, 12.1 percent, and 7.8 percent of patients on Orencia plus MTX, Orencia alone, and MTX alone, respectively, experienced a serious adverse event and 1.7 percent, 4.3 percent and 2.6 percent led to discontinuation. Serious infections were observed in 0.8 percent of patients in the combination arm and 3.4 percent in the Orencia monotherapy arm. None of the patients in the MTX alone arm experienced a serious infection. Malignancies were reported in 0.8 percent, 1.7 percent, and 0 percent of patients in the Orencia + MTX, Orencia, and MTX arms, respectively.

Additional AVERT Sub-Analyses Findings

Additionally at ACR, investigators presented 12-month efficacy data from AVERT, including new results assessing the effect of Orencia on more clinically stringent remission criteria than DAS-defined (DAS28 CRP <2.6) remission, as well as new MRI data.

Significantly more patients on Orencia plus MTX achieved the stringent clinical endpoint of Boolean-defined remission at 12 months (37 percent Orencia plus MTX; 26.7 percent Orencia alone; 22.4 percent MTX alone; P<0.05). Higher remission rates as compared to MTX or Orencia alone were consistent across other clinically stringent measures, including CDAI remission (42 percent Orencia plus MTX; 31 percent Orencia alone; 27.6 percent MTX alone; P<0.05) and SDAI remission (42 percent Orencia plus MTX; 29.3 percent Orencia alone; 25 percent MTX alone; P<0.05). A small but significantly higher number of patients treated with Orencia plus MTX were able to maintain drug-free remission up to month 18 and six months after drug withdrawal, according to the remission threshold of DAS28-CRP <2.4 (13 percent Orencia plus MTX; vs. 3.5 percent MTX alone; P=0.002).

Sustained improvements on MRI endpoints were also observed at six months after stopping combination therapy with Orencia plus MTX vs. MTX alone, including improved measurements of both joint inflammation and joint erosion. At 18 months of this post-hoc analysis, the adjusted mean change from baseline in total synovitis score was -1.34 for Orencia plus MTX vs. -0.49 for MTX alone; -2.03 for Orencia plus MTX vs. 0.34 for MTX alone in total osteitis score; and 0.13 for Orencia plus MTX vs. 2.00 for MTX alone in total erosion score (p<0.05 for all three measures).

“The new AVERT findings presented at ACR reinforce Bristol-Myers Squibb’s commitment to understanding the disease pathology of RA and the results associated with earlier treatment with a combination of Orencia plus methotrexate,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “Collectively, the efficacy, safety and real-world data presented at ACR will provide clinicians with valuable insights into treatment response and outcomes in patients with early rheumatoid arthritis.”

Patient-Reported Outcomes

Orencia plus MTX improved patient-reported outcomes for fatigue, pain, physical functioning and participation in daily activities compared to MTX. At 12 months, the Orencia plus MTX treatment arm reported a significant improvement in fatigue (-34.9) vs. MTX alone (-26.7; P<0.05); and in health-related quality of life score, 13.9 for Orencia plus MTX vs. 10.9 for MTX alone; (P<0.05). Recent EULAR recommendations reinforce the need to assess a treatment’s impact on the patient’s daily activities and overall quality of life.

About the AVERT Trial

The AVERT trial includes 351 adult patients with symptoms of moderate to severe RA for less than two years, positive for anti-CCP antibodies, DAS28 CRP >3.2 and na”ive to treatment with methotrexate and biologic therapies for RA. The patients were randomly assigned to 12 months of weekly treatment in one of three groups: Orencia 125 mg subcutaneous plus MTX; Orencia 125 mg subcutaneous alone; or MTX alone.

Indications/Usage and Important Safety Information for ORENCIA(R) (abatacept)

Indications/Usage

Adult Rheumatoid Arthritis (RA): ORENCIA(R) (abatacept) 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 disease-modifying, anti-rheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists.

Juvenile Idiopathic Arthritis (JIA): ORENCIA is also indicated for reducing signs and symptoms in pediatric patients aged 6 years and older with moderately to severely active polyarticular JIA. ORENCIA may be used as monotherapy or concomitantly with methotrexate (MTX).

Important Limitations of Use: ORENCIA should not be administered concomitantly with TNF antagonists, and is not recommended for use concomitantly with other biologic RA therapy, such as anakinra.

Important Safety Information

Concomitant Use with TNF Antagonists: Concurrent therapy with ORENCIA and a biologic DMARD is not recommended. In controlled clinical trials, adult patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively), without an important enhancement of efficacy.

Hypersensitivity: Anaphylaxis or anaphylactoid reactions can occur during or after an infusion and can be life-threatening. In controlled, double-blind and open-label clinical trials, anaphylaxis and anaphylactoid reactions were reported in <0.1% of adult patients dosed with intravenous ORENCIA. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, that occurred within 24 hours of ORENCIA infusion, were uncommon (<1% each). There was one case of a hypersensitivity reaction with ORENCIA in JIA clinical trials (0.5%; n=190). In postmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA was reported. Appropriate medical support measures for treating hypersensitivity reactions should be available for immediate use. If an anaphylactic or other serious allergic reaction occurs, administration of ORENCIA should be stopped immediately and permanently discontinued, with appropriate therapy instituted.

Infections: Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infection. Caution should be exercised in patients with a history of infection or underlying conditions which may predispose them to infections. Treatment with ORENCIA (abatacept) should be discontinued if a patient develops a serious infection. Patients should be screened for tuberculosis, and viral hepatitis in accordance with published guidelines, and if positive, treated according to standard medical practice prior to therapy with ORENCIA.

Immunizations: Live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation as it may blunt the effectiveness of some immunizations. It is recommended that JIA patients be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating therapy with ORENCIA.

Use in Patients with Chronic Obstructive Pulmonary Disease (COPD): Adult COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in patients treated with ORENCIA compared to those on placebo (43% vs 24%, respectively), including COPD exacerbations, cough, rhonchi, and dyspnea. A greater percentage of patients treated with ORENCIA developed a serious adverse event compared to those on placebo (27% vs 6%), including COPD exacerbation [3 of 37 patients (8%)] and pneumonia [1 of 37 patients (3%)]. Use of ORENCIA in patients with RA and COPD should be undertaken with caution, and such patients monitored for worsening of their respiratory status.

Blood Glucose Testing: ORENCIA for intravenous administration contains maltose, which may result in falsely elevated blood glucose readings on the day of infusion when using blood glucose monitors with test strips utilizing glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). Consider using monitors and advising patients to use monitors that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods. ORENCIA for subcutaneous (SC) administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.

Pregnant and Nursing Mothers: ORENCIA should be used during pregnancy only if clearly needed. The risk for development of autoimmune diseases in humans exposed in utero to abatacept has not been determined. Nursing mothers should be informed of the risk/benefit of continued breast-feeding or discontinuation of the drug. A pregnancy registry has been established to monitor fetal outcomes. Healthcare professionals are encouraged to register pregnant patients exposed to ORENCIA by calling 1-877-311-8972.

Most Serious Adverse Reactions: Serious infections (3% ORENCIA vs 1.9% placebo) and malignancies (1.3% ORENCIA vs 1.1% placebo). In general, adverse events in pediatric and adolescent patients were similar in frequency and type to those seen in adult patients.

Malignancies: The overall frequency of malignancies was similar between adult patients treated with ORENCIA or placebo. However, more cases of lung cancer were observed in patients treated with ORENCIA (0.2%) than those on placebo (0%). A higher rate of lymphoma was seen compared to the general population; however, patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of ORENCIA in the development of malignancies in humans is unknown.

Most Frequent Adverse Events (>=10%): Headache, upper respiratory tract infection, nasopharyngitis, and nausea were the most commonly reported adverse events in the adult RA clinical studies.

Note concerning SC ORENCIA: The safety and efficacy of SC ORENCIA has not been studied in patients under 18 years of age.

Please see Full Prescribing Information.

About Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic, chronic, autoimmune disease characterized 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 joint function. The condition is more common in women than in men, who account for 75 percent of patients diagnosed with RA.

About Orencia

Orencia SC and IV 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 rheumatoid arthritis. Orencia may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists.

Orencia IV is indicated for reducing signs and symptoms in pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. Orencia IV may be used as monotherapy or concomitantly with methotrexate (MTX). The safety and efficacy of Orencia SC has not been studied in patients under 18 years of age.

Orencia should not be administered concomitantly with TNF antagonists.

Orencia is not recommended for use concomitantly with other biologic rheumatoid arthritis (RA) therapy, such as anakinra.

Orencia is intended for use under the guidance of a physician or healthcare practitioner.

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.

For more information about Bristol-Myers Squibb, visit http://www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews

Orencia is a registered trademark of Bristol-Myers Squibb Company.

About Bristol-Myers Squibb Immunoscience

The immune system is the body’s natural defense against disease. These processes come into play in almost every human disease. That is why Bristol-Myers Squibb is focused on exploring ways to harness the body’s own immune system to treat immune-related diseases with high unmet medical needs, including RA – a chronic, systemic, inflammatory autoimmune disorder that affects the joints.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2013 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

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