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In moderate to severe rheumatoid arthritis (RA)
See ORENCIA in a different light
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Overview of Registrational Trial in MTX-naïve* Patients1
The AGREE Registrational Trial was a 12-month,
AGREE: Study design and co-primary endpoints
IV, intravenous; MTX, methotrexate.
*Or prior exposure to MTX ≤10 mg/week for ≤3 weeks with none administered for 3 months prior to enrollment.
In a broad population of MTX-IR patients with moderate to severe RA
ORENCIA was studied
head-to-head in a noninferiority trial vs adalimumab2
The AMPLE 2-Year Trial was a randomized, Phase IIIb, head-to-head noninferiority trial of adult MTX-IR patients, and is not contained within the Full Prescribing Information. It is a supportive trial to AGREE, which was studied in MTX-naïve patients and had a different comparator. Patients were randomized to ORENCIA SC + MTX (n=318) or adalimumab SC + MTX (n=328).1,2
Comparable efficacy vs adalimumab2
ACR, American College of Rheumatology; CRP, C-reactive protein; DAS28, Disease Activity Score in 28 joints; MTX-IR, inadequate response to methotrexate; SC, subcutaneous.
Over half of patients had ≥1 comorbid condition3
Primary Endpoint2
Noninferiority measured by ACR 20 at 1 year
- ORENCIA SC + MTX – 64.8% (59.5% to 70.0%)
- adalimumab SC + MTX – 63.4% (58.2% to 68.6%)
Selected Secondary Endpoint2
Remission rates* vs adalimumab (DAS28-CRP <2.6 at 2 years)
- ORENCIA SC + MTX – 50.6% (44.0% to 56.8%
- adalimumab SC + MTX – 53.3% (47.0% to 59.5%)
*Remission is defined as DAS28-CRP <2.6.4 Clinical remission does not mean drug-free remission or complete absence of disease activity.
Comparable efficacy vs adalimumab2
ACR, American College of Rheumatology; CRP, C-reactive protein; DAS28, Disease Activity Score in 28 joints; MTX-IR, inadequate response to methotrexate; SC, subcutaneous.
Baseline Characteristics3
Study reports did not always include detailed patient characteristic data for all individual patients. In patients for whom detailed characteristic data were available, 62% of patients in the ORENCIA group (n=310) had at least one comorbid condition, with the most frequent being high blood pressure (42%) and high cholesterol (26%).
In the adalimumab group, 315 patients had detailed patient characteristic data. At least one comorbid condition was identified in 55% of patients, with the most frequent being high blood pressure (38%) and high cholesterol (26%).
Study Design2
Primary Endpoint2
Noninferiority of ORENCIA SC + MTX vs adalimumab SC + MTX, assessed by ACR 20 at 1 year
Selected Secondary Endpoint2
Proportion achieving remission* (DAS28-CRP <2.6)
- 86.2% of patients using ORENCIA and 82% of those using adalimumab completed Year 1 of the study
- 79.2% of patients using ORENCIA and 74.7% of those using adalimumab completed the study at Year 2
Primary Endpoint2
Noninferiority of ORENCIA SC + MTX vs adalimumab SC + MTX, assessed by ACR 20 at 1 year
Selected Secondary Endpoint2
Proportion achieving remission* (DAS28-CRP <2.6)
*Remission is defined as DAS28-CRP <2.6.4 Clinical remission does not mean drug-free remission or complete absence of disease activity.
Key Limitations of the Study2
Double-blinding for the study drugs was not feasible due to the difficulty masking the adalimumab administration. Patients were not blinded with regard to study drug. To mitigate this limitation, the study used clinical assessors and radiographic readers, who were blinded with regard to each patient’s treatment.
Key Inclusion Criteria2,4
- ≥18 years of age with moderate to severe active RA with a confirmed diagnosis for ≤5 years
- Inadequate response to MTX and biologic naïve
- ≥3.2 DAS28-CRP and a history of ≥1 of the following:
- Seropositivity for anti-CCP or RF
- Elevated ESR or CRP level
Key Exclusion Criteria5
- Previous treatment with an investigational or approved biologic RA therapy
- History of active or chronic hepatitis B
- Subjects with any other rheumatic disease or with active vasculitis of a major organ
anti-CCP, anti-cyclic citrullinated peptide; ESR, erythrocyte sedimentation rate;
RF, rheumatoid factor.
AMPLE 2-year included a broad patient population, with over half having poor prognostic factors2,3
Baseline Characteristics2,3
- Average age: 51.4 for ORENCIA-treated patients, 51 years for adalimumab-treated patients
- Study reports did not always include detailed patient characteristic data for all individual patients. In patients for whom detailed characteristic data were available:
- ORENCIA group (n=310): 62% had at least one comorbid condition, the most frequent being high blood pressure (42%) and high cholesterol (26%)
- Adalimumab group (n=315): 55% had at least one comorbid condition, the most frequent being high blood pressure (38%)and high cholesterol (26%)
BMI, body mass index.
*Anti-CCP status was reported by patient’s medical history for 488 of the 646 patients at baseline.5
†In a post hoc analysis of serum collected for 508 of 646 patients at baseline, 74% of ORENCIA-treated patients and 79% of adalimumab-treated patients were anti-CCP+.6
‡Seropositive for RF antibodies as reported by patient’s medical history.2
§Radiographic evidence of joint erosions.2
¶Study reports did not always include detailed patient characteristic data for all individual patients.
#Comorbid conditions included high BMI, advancing age (65 or older), cardiovascular disease, high cholesterol, high blood pressure, and diabetes.3
Selected Important Safety Information
Increased Risk of Infection with Concomitant Use with TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors:
Concurrent therapy with ORENCIA and a TNF antagonist is not recommended. In controlled clinical trials, adult moderate to severe rheumatoid arthritis (RA) patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63% vs 43%) and serious infections (4.4% vs 0.8%) compared to patients treated with only TNF antagonists, without an important enhancement of efficacy. Additionally, concomitant use of ORENCIA with other biologic RA/PsA therapy or JAK inhibitors is not recommended.
In moderate to severe, treatment-naïve, early RA patients with poor prognostic factors
ORENCIA was studied among 3 biologics vs active conventional therapy (ACT)7
NORD-STAR (N=795) was a 48-week, multicenter, randomized, blinded-assessor study in patients with early RA and seropositivity (RF+ or anti-CCP+) or CRP ≥10 mg/L and DAS28-CRP >3.2.7
Co-primary Endpoints7
- CDAI remission: CDAI ≤2.8 at 48 weeks
- Change in radiographic score at 48 weeks
Selected Secondary Endpoint7
- DAS remission: DAS28-CRP <2.6 at 48 weeks
Co-primary Endpoints7
Van der Heijde-modified Sharp Score (vdHSS)
ACT: 0.45 (0.31 to 0.59)
CTZ: 0.47 (0.33 to 0.61)
ORENCIA: 0.62 (0.48 to 0.76)
TCL: 0.50 (0.36 to 0.64)
Remission rates for 3 biologics vs ACT at 48 weeks (ITT)7*†
Co-primary Endpoints7
Van der Heijde-modified Sharp Score (vdHSS)
ACT: 0.45 (0.31 to 0.59)
CTZ: 0.47 (0.33 to 0.61)
ORENCIA: 0.62 (0.48 to 0.76)
TCL: 0.50 (0.36 to 0.64)
CDAI, Clinical Disease Activity Index; CI, confidence interval; ITT, intent to treat.
*Clinical remission does not mean drug-free remission or complete absence of disease activity.4
†Oral prednisolone (tapered from 20 mg/day to 5 mg/day in 9 weeks and discontinuation after 9 months) or enterotablets sulfasalazine (2 g/day), hydroxychloroquine (35 mg/kg/week or 200 mg/day) and intra-articular triamcinolone hexacetonide injection (or equivalent) in all swollen joints at each visit (maximally 4 joints and 80 mg/visit).7
ORENCIA was studied in treatment-naïve, early RA patients with poor prognostic factors7
Patients were randomized into 4 treatment arms7
- ACT: prednisolone or triple therapy (MTX + csDMARDs) + glucocorticoids (n=200)*
- CTZ: certolizumab pegol SC 200 mg (400 mg at 0, 2, 4 weeks) (n=203)
- ORENCIA SC: 125 mg (n=204)
- TCL: tocilizumab IV 8 mg/kg/4 weeks or SC 162 mg/weekly (n=188)†
All patients received MTX starting on Day 1 (escalated to 25 mg/week within 4 weeks). MTX dose could be reduced in all treatment arms due to toxicity/intolerability, and subsequently re-escalated up to 20 mg/week.7
Key Inclusion Criteria7
- 18 years or older
- Symptom duration of <24 months
- Poor prognostic factors:
- Moderate-to-severe disease activity with DAS28-CRP >3.2
- ≥2 (of 66) swollen and ≥2 (of 68) tender joints
- RF+ or anti-CCP+ or CRP of ≥10 mg/L
Key Exclusion Criteria7
- Previous treatment with a DMARD
- Women nursing or pregnant
- Inflammatory diseases other than RA
Limitations7
- The ACT arm comprised 2 different treatment strategies based on national recommendations for conventional RA therapy in the individual countries
- Analyses were adjusted for country effects, whereas the study was not powered for subgroup analyses
- The open-label design may influence certain subjective outcomes
csDMARDs, conventional synthetic DMARDs; DMARD, disease-modifying antirheumatic drug.
*Oral prednisolone (tapered from 20 mg/day to 5 mg/day in 9 weeks and discontinuation after 9 months) or enterotablets sulfasalazine (2 g/day), hydroxychloroquine (35 mg/kg/week or 200 mg/day), and intra-articular triamcinolone hexacetonide injection (or equivalent) in all swollen joints at each visit (maximally 4 joints and 80 mg/visit).7
†17 Finnish patients randomized to arm 4 (tocilizumab + MTX) but not receiving it due to unavailability are not included. They were excluded from the ITT population to allow a fair analysis of the efficacy of tocilizumab. Robustness analyses showed comparable results.7
SD, standard deviation.
Selected Important Safety Information
Hypersensitivity Reactions: There were 2 cases (<0.1%; n=2688) of anaphylaxis 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 pJIA clinical trials (0.5%; n=190).In postmarketing experience, fatal anaphylaxis following the first infusion of ORENCIA and life-threatening cases of angioedema have been reported. Angioedema has occurred as early as after the first dose of ORENCIA, but also has occurred with subsequent doses. Angioedema reactions have occurred within hours of administration and in some instances had a delayed onset (i.e., days). 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 intravenous or subcutaneous ORENCIA should be stopped immediately and permanently discontinued, with appropriate therapy instituted.
In moderate to severe MTX-naïve* RA patients with almost half having comorbid conditions
Remission and radiographic progression were studied in a registrational trial1
AGREE was a 12-month, multinational, placebo-controlled, randomized, double-blind, Phase IIIb study of MTX-naïve patients (n=509). Adult patients were randomized to ORENCIA IV + MTX (n=256) or placebo + MTX (n=253).1
49% of ORENCIA patients and 43% of placebo patients had ≥1 comorbid condition8†
Significantly improved remission rates‡ and radiographic progression in treatment-naïve patients1
Co-primary endpoints at 1 year1
Co-primary Endpoints1
- Proportion of patients achieving remission (DAS28-CRP <2.6) at 12 months
- Radiographic progression measured by Genant-modified TSS at 12 months
Selected Secondary Endpoint1
- ACR 50 response at 12 months
Selected Endpoint at 12 Months1
- ACR 20/70 responses
Comorbid conditions8
In the ORENCIA arm, 49% had ≥1 comorbid condition, the most common being hypertension (33%). In the placebo arm, 43% had ≥1 comorbid condition, hypertension again being the most common (32%). 9% of ORENCIA patients and 11% in the placebo arm had high cholesterol.
Significantly improved remission rates‡ and radiographic progression in treatment-naïve patients1
Co-primary endpoints at 1 year1
Selected endpoints: ORENCIA IV + MTX significantly
improved ACR 20, 50 and 70 responses at 1 year1,9
Selected endpoints: ORENCIA IV + MTX significantly
improved ACR 20, 50 and 70 responses at 1 year1,9
TSS, Total Sharp Score.
*Or prior exposure to MTX ≤10 mg/week for ≤3 weeks with none administered for 3 months prior to enrollment.1
†This study was not powered to detect differences in response based oncomorbid conditions.
‡Remission is defined as DAS28-CRP <2.6.1 Clinical remission does not mean drug-free remission or complete absence of disease activity.
§Missing data for the as-observed population at 6 months were imputed by linear extrapolation at 1 year.1
¶Day 29 was an exploratory endpoint.9
Study Design7
Patients were randomly assigned to treatment groups. ORENCIA IV (~10 mg/kg based on patient weight) plus MTX and placebo given with MTX were administered on Days 1, 15, and 29, and every 4 weeks thereafter. MTX was initially dosed at 7.5 mg/week and subsequently increased to 15 mg at Week 4 and to 20 mg at Week 8. Dose reduction was permitted to a minimum of 15 mg/week due to toxicity or intolerability.1
Baseline Characteristics1
- 89% of patients were anti-CCP+
- 96.5% were RF+
- Mean disease duration: 6.5 months
- Mean DAS28-CRP: 6.3
Key Exclusion Criteria1
- Early (≤2 years) and active RA according to ACR criteria
- ≥18 years of age
- MTX-naïve or prior exposure of ≤10 mg/week for ≤3 weeks with none administered for 3 months
- ≥12 tender and ≥10 swollen joints, CRP ≥0.45 mg/dL
- RF and/or anti-CCP seropositivity
- Radiographic evidence of bone erosion of the hands, wrist, and feet
AGREE is one of the 6 registrational trials for ORENCIA; the safety experience of these patients at 1 year was consistent with that of the other 5 trials.1,10
Please refer to the Pooled Safety and Full Prescribing Information.
ORENCIA IV + DMARDs in TNFi-IR patients with moderate to severe RA
Patients with long disease duration and previous treatment failure saw improved symptom relief and physical function with ORENCIA11,12
ATTAIN was a 6-month, randomized, double-blind, Phase III, placebo-controlled trial of ORENCIA in patients with inadequate response to ≥3 months of TNFi therapy. 55% of patients had ≥1 comorbid condition.
Co-primary endpoint:
Symptom improvement at 6 months11
∆ 30.9% (P<0.001)
Co-primary endpoint: Improved physical function at 6 months11
Patients with a ≥0.3 HAQ-DI improvement
(P<0.001)
Safety: ATTAIN is one of the 6 registrational trials for ORENCIA; the safety experience of these patients at 6 months was consistent with that of the other 5 trials.10,11
Please refer to the Pooled Safety and Full Prescribing Information.
Co-primary endpoint: Improved physical function at 6 months11
Patients with a ≥0.3 HAQ-DI improvement
(P<0.001)
DMARDs, disease-modifying antirheumatic drug; TNFi, tumor necrosis factor inhibitor; TNFi-IR, inadequate response to TNFi therapy; HAQ-DI, Health Assessment
Questionnaire-Disability Index.
*Of these 258 patients, 1 did not meet the inclusion criteria and 1 withdrew for other reasons, leaving 256 patients in the ORENCIA IV + nonbiologic DMARD arm.11
ORENCIA was studied in TNFi-IR patients11
391 patients were randomized 2:1 to receive ORENCIA IV 10 mg/kg + DMARDs (n=258)* or placebo + DMARDs (n=133).† ORENCIA or placebo was given on Days 1, 15, and 29 and every 4 weeks thereafter, up to and including Day 141.1
Inclusion Criteria10
- ≥18 years of age with active RA for ≥1 year
- Inadequate response to anti-TNFα therapy (etanercept, infliximab, or both at approved dose)‡ after ≥3 months of treatment and discontinued before randomization
- ≥12 tender and ≥10 swollen joints, CRP ≥1 mg/dL at randomization
- Had been taking oral DMARD or anakinra for ≥3 months, with stable dose for ≥28 days
Baseline Characteristics11,12
- Disease duration: ORENCIA 12.2 years; placebo 11.4 years
- Mean DAS28-CRP: 6.5
- 73.3% of ORENCIA patients and 72.9% of placebo patients were RF+
- 55% of patients had ≥1 comorbid condition
- High blood pressure was the most common comorbid condition in both treatment arms (ORENCIA, 38%; placebo, 31%)
- 12% of ORENCIA patients and 10% in the placebo arm had high cholesterol
*Of these 258 patients, 1 did not meet the inclusion criteria and 1 withdrew for other reasons, leaving 256 patients in the ORENCIA IV + nonbiologic DMARD arm.11
† 75.6% and 82.0% of patients continued on MTX in the ORENCIA IV and placebo arms, respectively. Other DMARDs used in ≥5% of patients in both treatment arms included hydroxychloroquine, leflunomide, and sulfasalazine.11
‡ Some patients received adalimumab.11
Selected Important Safety Information
Infections: Serious infections, including sepsis and pneumonia, were reported in 3% and 1.9% of RA patients treated with intravenous ORENCIA and placebo, respectively. 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.
The efficacy of ORENCIA was consistent regardless of BMI13
ACTION was a 2-year,* non-interventional, international, prospective study that evaluated ORENCIA retention rates in both biologic-naïve and csDMARD-IR patients. In this subgroup analysis, the effect of BMI on the clinical efficacy and retention rate of ORENCIA was evaluated at 6 months in biologic-naïve patients according to their baseline BMI.
csDMARD-IR, inadequate response to conventional synthetic disease-modifying antirheumatic drug; EULAR, European Alliance of Associations for Rheumatology.
*2-year study included 2359 patients, with 672 patients identified as biologic naïve. Of these patients, BMI data were available for 643 patients.13
†Moderate response: DAS28-CRP >3.2 and ≤5.1; reduction >0.6 to ≤1.2.14
‡Good response: DAS28-CRP ≤3.2; reduction of >1.2.14
~80% of patients had a moderate† or good‡ EULAR response at 6 months13
Study Design13
The Abatacept in Routine Clinical Practice (ACTION) study was a non-interventional, 2-year, international (Europe and Canada), prospective study in patients who started treatment with ORENCIA IV during routine clinical practice from May 2008 to December 2013. This study evaluated the clinical efficacy and retention for ORENCIA IV as a first-line biologic at 6 months according to patients’ baseline BMI using EULAR response criteria (DAS28-CRP at 6 months). Retention rates were estimated by Kaplan-Meier survival analysis.
Inclusion Criteria13
- Biologic-naïve
- BMI measured at baseline
- All patients were aged ≥18 years
- Had an established diagnosis of moderate to severe disease according to the 1987 ACR criteria
- Were not already participating in an interventional clinical trial for RA
Limitations13
- Observational in nature
- Lack of active comparator
- Subgroup analysis of a larger study
- Potential for referral and channeling bias
- The obese subgroup had higher disease activity at baseline, which is a potential limitation of the results
csDMARD-IR, inadequate response to conventional synthetic disease-modifying antirheumatic drug; EULAR, European Alliance of Associations for Rheumatology.
*2-year study included 2359 patients, with 672 patients identified as biologic naïve. Of these patients, BMI data were available for 643 patients.13
†Moderate response: DAS28-CRP >3.2 and ≤5.1; reduction >0.6 to ≤1.2.14
‡Good response: DAS28-CRP ≤3.2; reduction of >1.2.14