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Orencia

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Orencia

CLINICAL PHARMACOLOGY

Mechanism Of Action

Abatacept, a selective costimulation modulator, inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of RA and are found in the synovium of patients with RA.

In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its effects in RA is unknown.

Pharmacodynamics

In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNFα. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its effects in RA is unknown.

Pharmacokinetics

Healthy Adults and Adult RA - Intravenous Administration

The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions (see Table 3).

Table 3: Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/kg Intravenous Infusion(s)

PK Parameter Healthy Subjects (After 10 mg/kg Single Dose)
n=13
RA Patients (After 10 mg/kg Multiple Dosesa)
n=14
Peak Concentration (Cmax) [mcg/mL] 292 (175-427) 295 (171-398)
Terminal half-life (t½) [days] 16.7 (12-23) 13.1 (8-25)
Systemic clearance (CL) [mL/h/kg] 0.23 (0.16-0.30) 0.22 (0.13-0.47)
Volume of distribution (Vss) [L/kg] 0.09 (0.06-0.13) 0.07 (0.02-0.13)
aMultiple intravenous infusions were administered at days 1, 15, 30, and monthly thereafter.

The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady-state by day 60 with a mean (range) trough concentration of 24 mcg/mL (1 to 66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients.

Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF blocking agents did not influence abatacept clearance.

No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept.

Juvenile Idiopathic Arthritis

In patients 6 to 17 years of age, the mean (range) steady-state serum peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 11.9 mcg/mL (0.15 to 44.6 mcg/mL). Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increased with baseline body weight. The estimated mean (range) clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of body weight, the clearance of abatacept was not related to age and gender. Concomitant methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept clearance.

Adult RA - Subcutaneous Administration

Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration.

Study SC-2 was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load. When the intravenous loading dose was not administered, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing.

Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance.

Animal Toxicology And/Or Pharmacology

A juvenile animal study was conducted in rats dosed with abatacept from 4 to 94 days of age in which an increase in the incidence of infections leading to death occurred at all doses compared with controls. Altered T-cell subsets including increased T-helper cells and reduced T-regulatory cells were observed. In addition, inhibition of T-cell-dependent antibody responses (TDAR) was observed. Upon following these animals into adulthood, lymphocytic inflammation of the thyroid and pancreatic islets was observed.

In studies of adult mice and monkeys, inhibition of TDAR was apparent. However, infection and mortality, altered T-helper cells, and inflammation of thyroid and pancreas were not observed.

Clinical Studies

Adult Rheumatoid Arthritis

The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥ 18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study V did not require any specific number of tender or swollen joints. ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in intravenous Studies I, II, III, IV, and VI. The safety and efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1, which was a randomized, double-blind, double-dummy, non-inferiority study that compared abatacept administered subcutaneously and intravenously in 1457 subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR).

Study I evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept. In Study II and Study III, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to methotrexate and who were continued on their stable dose of methotrexate. In Study IV, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to a TNF blocking agent, with the TNF blocking agent discontinued prior to randomization; other DMARDs were permitted. Study V primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions. In Study VI, the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo. In Study SC-1, the goal was to demonstrate the efficacy and safety of ORENCIA subcutaneous relative to ORENCIA intravenous administration in subjects with moderate to severely active RA and experiencing inadequate response to methotrexate, using a non-inferiority study design.

Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of ORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg. In Study SC-1, patients were randomized with stratification by body weight ( < 60 kg, 60 to 100 kg, > 100 kg) to receive ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of methotrexate from the day of randomization.

Clinical Response

The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 4. ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients. Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III.

In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus methotrexate in Study VI. In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients. ACR responses were maintained up to three years in the open-label extension of Study II. In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness.

In Study VI, a greater proportion of patients treated with ORENCIA plus methotrexate achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with methotrexate plus placebo (Table 4). Of patients treated with ORENCIA plus methotrexate who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both.

In Study SC-1, the main outcome measure was ACR 20 at 6 months. The pre-specified non-inferiority margin was a treatment difference of -7.5%. As shown in Table 4, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment. ACR 50 and 70 responses are also shown in Table 4. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown).

Table 4: Clinical Responses in Controlled Trials

  Percent of Patients
Intravenous Administration Subcutaneous Administration
Inadequate Response to DMARDs Inadequate Response to Methotrexate (MTX) Inadequate Response to TNF Blocking Agent MTX-Naive Inadequate Response to MTX
Study I Study III Study IV Study VI Study SC-1
Response Rate ORNa
n=32
PBO
n=32
ORNb +MTX
n=424
PBO +MTX
n=214
ORNb + DMARDs
n=256
PBO + DMARDs
n=133
ORNb +MTX
n=256
PBO +MTX
n=253
ORNe SC +MTX
n=693
ORNe IV +MTX
n=678
ACR 20
Month 3 53% 31% 62%‡ 37% 46%‡ 18% 64%* 53% 68% 69%
Month 6 NA NA 68%‡ 40% 50%‡ 20% 75%† 62% 76%§ 76%
Month 12 NA NA 73%‡ 40% NA NA 76%‡ 62% NA NA
ACR 50
Month 3 16% 6% 32%‡ 8% 18%† 6% 40%‡ 23% 33% 39%
Month 6 NA NA 40%‡ 17% 20%‡ 4% 53%‡ 38% 52% 50%
Month 12 NA NA 48%‡ 18% NA NA 57%‡ 42% NA NA
ACR 70
Month 3 6% 0 13%‡ 3% 6%* 1% 19%† 10% 13% 16%
Month 6 NA NA 20%‡ 7% 10%† 2% 32%† 20% 26% 25%
Month 12 NA NA 29%‡ 6% NA NA 43%‡ 27% NA NA
Major Clinical Responsec NA NA 14%‡ 2% NA NA 27%‡ 12% NA NA
DAS28CRP < 2.6d
Month 12 NA NA NA NA NA NA 41%‡ 23% NA NA
* p < 0.05, ORENCIA (ORN) vs placebo (PBO) or MTX.
† p < 0.01, ORENCIA vs placebo or MTX.
‡ p < 0.001, ORENCIA vs placebo or MTX.
§ 95% CI: -4.2, 4.8 (based on prespecified margin for non-inferiority of -7.5%).
a10 mg/kg.
bDosing based on weight range [see DOSAGE AND ADMINISTRATION].
c Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.
d Refer to text for additional description of remaining joint activity.
ePer protocol data is presented in table. For ITT; n=736, 721 for SC and IV ORENCIA, respectively.

The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 5 (results at Baseline [BL] and 6 months [6 M]). In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients.

Table 5: Components of ACR Responses at 6 Months

  Intravenous Administration Subcutaneous Administration
Inadequate Response to Methotrexate (MTX) Inadequate Response to TNF Blocking Agent Inadequate Response to MTX
Study III Study IV Study SC-1c
ORN +MTX
n=424
PBO +MTX
n=214
ORN +DMARDs
n=256
PBO +DMARDs
n=133
ORN SC +MTX
n=693
ORN IV +MTX
n=678
Component (median) BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M
Number of tender joints (0-68) 28 7‡ 31 14 30 13‡ 31 24 27 5 27 6
Number of swollen joints (0-66) 19 5‡ 20 11 21 10‡ 20 14 18 4 18 3
Paina 67 27‡ 70 50 73 43† 74 64 71 25 70 28
Patient global assessmenta 66 29‡ 64 48 71 44‡ 73 63 70 26 68 27
Disability indexb 1.75 1.13‡ 1.75 1.38 1.88 1.38‡ 2.00 1.75 1.88 1.00 1.75 1.00
Physician global assessmenta 69 21‡ 68 40 71 32‡ 69 54 65 16 65 15
CRP (mg/dL) 2.2 0.9‡ 2.1 1.8 3.4 1.3‡ 2.8 2.3 1.6 0.7 1.8 0.7
† p < 0.01, ORENCIA (ORN) vs placebo (PBO), based on mean percent change from baseline.
‡ p < 0.001, ORENCIA vs placebo, based on mean percent change from baseline.
aVisual analog scale: 0 = best, 100 = worst.
b Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
c SC-1 is a non-inferiority study. Per protocol data is presented in table.

The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1. The time course for the ORENCIA group in Study VI was similar to that in Study III.

Figure 1: Percent of Patients Achieving ACR 50 Response by Visit* (Study III)

Percent of Patients Achieving ACR 50 Response by Visit - Illustration

The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15—SC 3%, IV 5%; Day 29—SC 11%, IV 14%; Day 57—SC 24%, IV 30%; Day 85— SC 33%, IV 38%; Day 113—SC 39%, IV 41%; Day 141—SC 46%, IV 47%; Day 169—SC 51%, IV 50%.

Radiographic Response

In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/methotrexate slowed the progression of structural damage compared to placebo/methotrexate after 12 months of treatment as shown in Table 6.

Table 6: Mean Radiographic Changes in Study IIIa and Study VIb

Parameter ORENCIA/MTX Placebo/MTX Differences P-valued
Study III
First Year
  TSS 1.07 2.43 1.36 < 0.01
  ES 0.61 1.47 0.86 < 0.01
  JSN score 0.46 0.97 0.51 < 0.01
Second Year
  TSS 0.48 0.74c - -
  ES 0.23 0.22c - -
  JSN score 0.25 0.51c - -
Study VI
First Year
  TSS 0.6 1.1 0.5 0.04
aPatients with an inadequate response to MTX.
bMTX-naive patients.
c Patients received 1 year of placebo/MTX followed by 1 year of ORENCIA/MTX.
dBased on a nonparametric ANCOVA model.

In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/methotrexate and 65% of patients initially randomized to placebo/methotrexate were evaluated radiographically at Year 2. As shown in Table 6, progression of structural damage in ORENCIA/methotrexate-treated patients was further reduced in the second year of treatment.

Following 2 years of treatment with ORENCIA/methotrexate, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline. Fifty-six percent (56%) of ORENCIA/methotrexate-treated patients had no progression during the first year compared to 45% of placebo/methotrexate-treated patients. In their second year of treatment with ORENCIA/methotrexate, more patients had no progression than in the first year (65% vs 56%).

Physical Function Response and Health-Related Outcomes

Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus methotrexate in Study VI. In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous administration. The results from Studies II and III are shown in Table 7. Similar results were observed in Study V compared to placebo and in Study VI compared to methotrexate. During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years.

Table 7: Mean Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)

HAQ Disability Index Inadequate Response to Methotrexate
Study II Study III
ORENCIAa +MTX
(n=115)
Placebo +MTX
(n=119)
ORENCIAb +MTX
(n=422)
Placebo +MTX
(n=212)
Baseline (Mean) 0.98c 0.97c 1.69d 1.69d
Mean Improvement Year 1 0.40c,*** 0.15c 0.66d,*** 0.37d
*** p < 0.001, ORENCIA vs placebo.
a 10 mg/kg.
bDosing based on weight range [see DOSAGE AND ADMINISTRATION].
c Modified Health Assessment Questionnaire: 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
dHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS).

Juvenile Idiopathic Arthritis

The safety and efficacy of ORENCIA were assessed in a three-part study including an open-label extension in children with polyarticular juvenile idiopathic arthritis (JIA). Patients 6 to 17 years of age (n=190) with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as methotrexate or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). The patients enrolled had subtypes of JIA that at disease onset included Oligoarticular (16%), Polyarticular (64%; 20% were rheumatoid factor positive), and Systemic (20%). At study entry, 74% of patients were receiving methotrexate (mean dose, 13.2 mg/m² per week) and remained on a stable dose of methotrexate (those not receiving methotrexate did not initiate methotrexate treatment during the study).

In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥ 30% improvement in at least 3 of the 6 JIA core set variables and ≥ 30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare. Disease flare was defined as a ≥ 30% worsening in at least 3 of the 6 JIA core set variables with ≥ 30% improvement in not more than 1 of the 6 JIA core set variables; ≥ 2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥ 2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare.

At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied.

During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on ORENCIA was less than one-third than that for patients withdrawn from ORENCIA treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year.

Last reviewed on RxList: 1/6/2014
This monograph has been modified to include the generic and brand name in many instances.

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