PRINCETON, N.J.–(BUSINESS WIRE)–Bristol-Myers Squibb Company (NYSE: BMY) today announced new data from the randomized Phase IIIb Assessing Very Early Rheumatoid arthritis Treatment (AVERT)-2 trial exploring de-escalation of therapy in early, seropositive rheumatoid arthritis (RA) patients who achieved sustained Simplified Disease Activity Index (SDAI) remission following induction with ORENCIA® (abatacept) and methotrexate (MTX). The study showed that, across all ORENCIA treatment arms, patients achieved maintenance of remission and inhibition of structural damage progression at week 48 after de-escalation. These results will be featured in a late-breaking oral presentation at the 2019 American College of Rheumatology and Association of Rheumatology Professionals (ACR/ARP) Annual Meeting, November 8-13, 2019, in Atlanta. Results to be presented from a second study, CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions), a prospective cohort study of adult patients with RA recruited from the Corrona® registry, demonstrate that in a sample of 138 ORENCIA-treated patients, higher anti-citrullinated protein antibody (ACPA) concentrations at baseline were associated with improvement in patient-reported outcomes (PROs) in adjusted and unadjusted models, Clinical Disease Activity Index (CDAI) score in the adjusted model and CDAI score in the unadjusted model after six months.2 This association was not observed in a similar sample size of patients treated with other common therapies, TNF inhibitors (TNFi).2
“The AVERT-2 and Corrona CERTAIN abstracts presented at the 2019 ACR/ARP Meeting reinforce the potential benefit of ORENCIA in patients with biomarkers indicating a more severe disease course, and the consistent maintenance of disease response following de-escalation treatment,1,2” said Brian Gavin, Ph.D., development lead, ORENCIA, Bristol-Myers Squibb. “More and more, our research suggests that the presence of certain biomarkers such as ACPA may prove useful when selecting a treatment regimen in early rheumatoid arthritis. Bristol-Myers Squibb remains committed to advancing biomarker science in support of expanding the treatment options for patients with immune–mediated diseases.”
AVERT-2 data demonstrate maintenance of remission at 48 weeks following de-escalation in early RA ACPA-positive patients treated with ORENCIA
In AVERT-2, ACPA-positive patients with early (ACR/EULAR 2010 criteria; disease duration <6 months), active RA (SDAI > 11) were randomized 3:2 to blinded subcutaneous (SC) ORENCIA (125 mg QW) + methotrexate (MTX) or placebo (PBO) + MTX induction treatment for 56 weeks. The SDAI assesses disease activity in RA. Generally, remission is considered achieved if the score is between 0 and 3.3 included. Patients who completed induction with ORENCIA + MTX and had sustained SDAI remission (≤3.3 at Weeks 40 and 52) were re-randomized 1:1:1 to ORENCIA QW + MTX for 48 weeks, ORENCIA every other week (EOW) + MTX for 24 weeks followed by ORENCIA PBO + MTX for 24 weeks, or ORENCIA QW + MTX PBO for 48 weeks in the de-escalation (DE) period. Methotrexate and oral corticosteroid doses in the DE period were stable. Patients with sustained SDAI remission who received ORENCIA PBO + MTX during induction were not re-randomized and continued this treatment in the DE period in a blinded fashion; no comparisons between this arm and the ORENCIA arms were made. Endpoints were proportion of patients in SDAI remission, adjusted mean change from DE Day 1 in SDAI score, safety to DE Week 48 and radiographic progression at DE Week 48.
Results demonstrated that combination therapy (ORENCIA QW + MTX) resulted in the best maintenance of remission, yet remission maintenance was observed across the study arms:
- ORENCIA QW + MTX regimen: 74% of patients maintained remission at DE week 48.1
- ORENCIA QW + MTX PBO regimen: after an initial drop in remission rates to 64%, rates stabilized from DE Week 12.1
- ORENCIA EOW + MTX regimen: after halving the ORENCIA dose upon entry to the DE period, remission decreased from 88% at DE Week 0 to 74% at DE Week 24, and then further decreased to 48% at DE Week 48 after ORENCIA was fully withdrawn at DE Week 24.1
- ORENCIA PBO + MTX regimen: at DE Week 48, 59% of patients who received ORENCIA PBO + MTX during induction maintained remission with this treatment.1
Adjusted mean change in SDAI score in the ORENCIA arms in the DE period was numerically low, but varied between arms and increased (patients’ disease activity worsened) following ORENCIA withdrawal from the ORENCIA EOW + MTX arm at DE Week 24.1 Sustained inhibition of structural damage was seen in all ORENCIA arms.1 Safety was similar across treatments with no new signals.1
“Although the American College of Rheumatology and European League Against Rheumatism guidelines suggest tapering of biologic therapy following a period of sustained remission in rheumatoid arthritis patients,3,4 additional research has been needed to identify appropriate de-escalation regimens for individual therapies,” said Paul Emery, M.D., Director of the Leeds NIHR Biomedical Research Centre, Leeds Teaching Hospitals Trust. “The findings from the AVERT-2 study are important because they reveal the potential for maintenance of clinical remission and inhibition of structural damage with ORENCIA in early, moderate-to-severe rheumatoid arthritis positive for anti-citrullinated protein antibody, a population that historically has faced a poor prognosis and a more severe disease course,1,5,6 and provide important scientific information related to de-escalation of ORENCIA therapy.”
Corrona CERTAIN analysis finds greater improvement in PROs and CDAI at six months in ORENCIA-treated early RA, ACPA-positive patients
Previous ORENCIA clinical trial research demonstrated that RA patients who test positive for higher ACPA concentrations show a better response to treatment with ORENCIA than those with lower concentrations.7 With the Corrona CERTAIN analysis, researchers assessed the association between baseline ACPA concentration and six-month treatment responses to ORENCIA or TNFis in a real-world setting.2 The Corrona RA Registry is the largest RA real-world prospective cohort study in the world.8
The study found significant differences between ACPA quartiles at baseline in mean CDAI, SJC28, CRP, DAS28 (CRP), RF, mHAQ and physician global assessment, and in mean RF, mHAQ and PtGA among TNFi initiators.2 Among ORENCIA initiators, but not TNFi initiators, a greater improvement at six months in CDAI and all PROs was observed with increasing ACPA quartile. 2 In the adjusted analysis, among ORENCIA initiators, there was a numerically greater improvement in CDAI (p=0.208) and statistically significantly greater improvements in all PROs (p<0.05) with increasing ACPA quartile. 2
“Because rheumatoid arthritis can impact patients in different ways,6 responses we see in clinical trials do not always translate to routine clinical practice,” said Leslie R. Harrold, M.D., M.P.H., associate professor of medicine, UMass Medical School and chief scientific officer, Corrona, LLC. “The data from this particular sample, showing improvement in CDAI, a measure of disease activity, and patient-reported outcomes in patients positive for anti-citrullinated protein antibody taking ORENCIA,2 are important for physicians to consider because they replicate, in a real-world setting, what previous clinical research has shown: that this specific treatment may have benefit for this particular patient population.”
Safety was not assessed in this observational study.
Bristol-Myers Squibb will present research from across its Immunology portfolio at 2019 ACR/ARP Annual Meeting
In total, Bristol-Myers Squibb is sponsoring 38 abstracts at the 2019 ACR/ARP Annual Meeting. The breadth of research to be presented includes clinical and real–world ORENCIA data supporting our focuses on furthering precision medicine in RA and addressing unmet patient needs in other conditions, such as moderate-to-severe juvenile idiopathic arthritis. Findings on new modes of action being explored as part of Bristol–Myers Squibb’s early Immunology program also will be shared. A full list of abstract titles and authors can be accessed online here.
About the AVERT-2 Study
In total, 147 ORENCIA + MTX–treated pts were re-randomized in the DE period (ORENCIA QW + MTX, n=50; ORENCIA EOW + MTX, n=50; ORENCIA QW + MTX PBO, n=47); 37 patients with sustained remission who received ORENCIA PBO + MTX during induction continued in the DE period. Across the re-randomized arms, mean DAS28 (CRP), SDAI and HAQ-DI scores ranged from 1.63–1.79, 1.87–2.52 and 0.18–0.30, respectively, at DE Day 1.
About the Corrona CERTAIN Study
CERTAIN is a prospective cohort study of adult patients with RA recruited from the Corrona network.2 Patients had at least moderate disease activity (CDAI >10) and either started therapy with or switched to a TNFi or non-TNF biologic.2 Patients were followed for 12 months or until they switched/discontinued biologic therapy.2
This analysis included patients from CERTAIN who initiated ORENCIA or any TNFi, were ACPA-positive (>20 U/mL), had CDAI >10 at baseline and had serum samples at baseline and at six months.2 Eligible patients also had known baseline ACPA concentration and serostatus (–, ≤10 U/mL; +, >10 U/mL) and prior biologic exposure.2 TNFi initiators were matched to ORENCIA initiators based on CDAI by line of therapy.2 Baseline demographics, patient and disease characteristics were compared within treatment groups using descriptive statistics.2 Treatment response by baseline ACPA quartile in ACPA-positive patients, assessed by change from baseline at six months in CDAI and patient-reported outcomes (PROs: modified [m]HAQ, pain, fatigue and patient global assessment [PtGA]), was evaluated separately in the ORENCIA and TNFi groups using a linear regression model adjusted for age, sex, CDAI or PROs at initiation, co-morbidity index and current MTX use.2
In total, 151 matched biologic-experienced ORENCIA and TNFi initiators were included (13 and 14 were ACPA negative and 138 and 137 were ACPA-positive, respectively).2 At baseline, median age was 57–60 years, 74–75% were female, median duration of RA was 10–12 years and mean BMI was 29.2–29.8.2
About Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a destructive immune-mediated disease characterized by inflammation in the lining of joints (or synovium), causing joint damage with chronic pain, stiffness, and swelling.9,10 RA causes limited range of motion and decreased joint function.9,10 The condition is more common in women than in men, who account for 75 percent of patients diagnosed with RA.9
ORENCIA® is an immunomodulator that disrupts the continuous cycle of T–cell activation that characterizes RA.
U.S. Indications/Usage and Important Safety Information for ORENCIA® (abatacept)
Indication and Usage
Adult Rheumatoid Arthritis (RA): ORENCIA® (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® (abatacept) is indicated for reducing signs and symptoms in patients 2 years of age and older with moderately to severely active polyarticular JIA. ORENCIA may be used as monotherapy or concomitantly with methotrexate (MTX).
Adult Psoriatic Arthritis (PsA): ORENCIA® (abatacept) is indicated for the treatment of adult patients with active PsA.
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 for ORENCIA® (abatacept)
Concomitant Use with TNF Antagonists: Concurrent therapy with ORENCIA and a TNF antagonist is not recommended. In controlled clinical trials, adult RA 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. There were 2 cases (<0.1%; n=2688) of anaphylaxis or anaphylactoid reactions in clinical trials with adult RA patients treated with intravenous ORENCIA. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in <0.9% of patients. 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 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. The efficacy of vaccination in patients receiving ORENCIA is not known. ORENCIA 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, including COPD exacerbations, cough, rhonchi, and dyspnea. In adult RA studies, 97% of COPD patients treated with ORENCIA developed adverse reactions versus 88% treated with placebo and respiratory disorders occurred more frequently in patients treated with ORENCIA compared to those on placebo (43% vs 24%, respectively), including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of adult RA 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 pyrroloquinoline quinone (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.
Pregnancy: There are no adequate and well-controlled studies of ORENCIA use in pregnant women and the data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to ORENCIA during pregnancy. Healthcare professionals are encouraged to register patients by calling 1-877-311-8972.
Lactation: There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed with abatacept.
Most Serious Adverse Reactions: Serious infections (3% ORENCIA vs 1.9% placebo) and malignancies (1.3% ORENCIA vs 1.1% placebo).
Malignancies: The overall frequency of malignancies was similar between adult RA patients treated with ORENCIA or placebo. However, more cases of lung cancer were observed in RA 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. Other events reported in ≥5% of JIA patients were diarrhea, cough, pyrexia, and abdominal pain. In general, the adverse events in JIA and adult PsA patients were similar in frequency and type to those seen in adult RA patients.
Note concerning ORENCIA administration options: Intravenous dosing has not been studied in patients younger than 6 years of age. The safety and efficacy of ORENCIA ClickJect™ Autoinjector for subcutaneous injection has not been studied in patients under 18 years of age.
Please see Full Prescribing Information at http://packageinserts.bms.com/pi/pi_orencia.pdf.
ORENCIA® (abatacept) is a registered trademark of Bristol-Myers Squibb Company.
About Bristol-Myers Squibb Immunology
With a robust pipeline of immunomodulatory therapies, Bristol–Myers Squibb is committed to the discovery and development of transformational medicines that could lead to long-term remission in patients with immune-mediated diseases. As we discover more about the immune system in such diseases with substantial unmet medical needs, the potential for developing novel therapies and biomarkers of response that target specific pathways in the immune system continues to drive our research efforts.
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 us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook, and Instagram.
Cautionary Statement Regarding Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results will be consistent with the results to date, that ORENCIA, alone or in combination with methotrexate, may not achieve its primary study endpoints or receive regulatory approval for the additional indications described in this release in the currently anticipated timeline or at all and, if approved, whether such product candidate or combination treatment for such additional indications described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol-Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2018, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol-Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.
- Emery P, Tanaka Y, Bykerk V, et al. Maintenance of Remission Following Dose De-Escalation of Abatacept in Early, MTX-Naïve, ACPA-Positive Patients With RA: Results From a Randomized Phase IIIb Study. ACR 2019. Abstract.
- Harrold L, Bryson J, Lehman T, et al. Association Between Baseline Anti-CCP2 Antibody Concentration and Clinical Response After 6 Months of Treatment With Abatacept or a TNF Inhibitor in Biologic-Experienced Patients With RA: Results From a US National Observational Study. ACR 2019. Abstract.
- Singh JA, Saag KG, Bridges, Jr. SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res. 2016 Jan; 68(1):1-25.
- Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Annals of the Rheumatic Diseases. 2017;76:960-977.
- Catrina A, Svensson C, Malmstrom V, et al. Mechanisms leading from systemic autoimmunity to joint–specific disease in rheumatoid arthritis. Nat Rev Rheumatol. 2017;13: 79-86.
- Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: Rheumatoid factors and anticitrullinated protein antibodies. Q J Med. 2010; 103:139-146.
- Sokolove J, et al. Impact of baseline anti-cyclic citrullinated peptide-2antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial. Ann Rheum Dis. 2016; 75:709–14.
- Corrona. RA Registry. https://www.corrona.org/registry/rheumatoid-arthritis. Accessed October 1, 2019.
- American College of Rheumatology. Rheumatoid Arthritis. https://www.rheumatology.org/i-am-a/patient-caregiver/diseases-conditions/rheumatoid-arthritis. Accessed October 1, 2019.
- Centers for Disease Control and Prevention. Rheumatoid Arthritis Fact Sheet. https://www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html. Accessed October 1, 2019.