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Orencia (Abatacept) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ORENCIA (abatacept) is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons.

ORENCIA is supplied as a sterile, white, preservative-free, lyophilized powder for parenteral administration. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the solution of ORENCIA is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of ORENCIA provides 250 mg abatacept, 500 mg maltose, 17.2 mg monobasic sodium phosphate, and 14.6 mg sodium chloride for administration.

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 costimulatorysignal 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

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
a  Multiple intravenous infusions were administered at days 1, 15, 30, and monthly thereafter.
Peak Concentration (Cmax) [mcg/mL]292 (175-427)295 (171-398)
Terminal half-life (t1/2) [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)

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 (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 MTX, 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 (57 to 700) and 11.9 (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 (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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a mouse carcinogenicity study, weekly subcutaneous injections of 20, 65, or 200 mg/kg of abatacept administered for up to 84 weeks in males and 88 weeks in females were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors (intermediate- and high-dose in females). The mice from this study were infected with murine leukemia virus and mouse mammary tumor virus. These viruses are associated with an increased incidence of lymphomas and mammary gland tumors, respectively, in immunosuppressed mice. The doses used in these studies produced exposures 0.8, 2.0, and 3.0 times higher, respectively, than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). The relevance of these findings to the clinical use of ORENCIA is unknown.

In a one-year toxicity study in cynomolgus monkeys, abatacept was administered intravenously once weekly at doses up to 50 mg/kg (producing 9 times the MRHD exposure based on AUC). Abatacept was not associated with any significant drug-related toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed, despite the presence of a virus (lymphocryptovirus) known to cause these lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of ORENCIA is unknown.

No mutagenic potential of abatacept was observed in the in vitro bacterial reverse mutation (Ames) or Chinese hamster ovary/hypoxanthine guanine phosphoribosyl-transferase (CHO/HGPRT) forward point mutation assays with or without metabolic activation, and no chromosomal aberrations were observed in human lymphocytes treated with abatacept with or without metabolic activation.

Abatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg/kg every three days (11 times the MRHD exposure based on AUC).

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 were assessed in five randomized, double-blind, placebo-controlled studies in patients ≥18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, and IV 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.

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 MTX and who were continued on their stable dose of MTX. 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.

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, and V patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III and V) 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.

Clinical Response

The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, and IV 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. In Studies II and III, 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.

Table 4: ACR Responses in Placebo-Controlled Trials
Percent of Patients
  Inadequate Response to
DMARDs
Inadequate Response to
MTX
Inadequate Response to
TNF Blocking Agent
  Study I Study III Study IV
*      p<0.05, ORENCIA vs placebo.
**    p<0.01, ORENCIA vs placebo.
***  p<0.001, ORENCIA vs placebo.
a      10 mg/kg.
b      Dosing 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.
Response RateORENCIAa
n=32
Placebo
n=32
ORENCIAb
+MTX
n=424
Placebo
+MTX
n=214
ORENCIAb
+DMARDs
n=256
Placebo
+DMARDs
n=133
ACR 20    
     Month 353%31%62%***37%46%***18%
     Month 6NANA68%***40%50%***20%
     Month 12NANA73%***40%NANA
ACR 50    
     Month 316%6%32%***8%18%**6%
     Month 6NANA40%***17%20%***4%
     Month 12NANA48%***18%NANA
ACR 70    
     Month 36%013%***3%6%*1%
     Month 6NANA20%***7%10%**2%
     Month 12NANA29%***6%NANA
Major Clinical
Responsec
NANA14%***2%NANA

The results of the components of the ACR response criteria for Studies III and IV are shown in Table 5. 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 Response at 6 Months
  Inadequate Response to MTX Inadequate Response to TNF Blocking
Agent
Study III Study IV
**   p<0.01, ORENCIA vs placebo, based on mean percent change from baseline.
*** p<0.001, ORENCIA vs placebo, based on mean percent change from baseline.
a     Visual analog scale: 0 = best, 100 = worst.
b     Health Assessment Questionnaire2: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
 ORENCIA
+MTX
n=424
Placebo
+MTX
n=214
ORENCIA
+DMARDs
n=256
Placebo
+DMARDs
n=133
Component (median)BaselineMonth 6BaselineMonth 6BaselineMonth 6BaselineMonth 6
Number of
tender joints
(0-68)
287***31143013***3124
Number of
swollen joints
(0-66)
195***20112110***2014
Paina6727***70507343**7464
Patient global
assessmenta
6629***64487144***7363
Disability
indexb
1.751.13***1.751.381.881.38***2.001.75
Physician
global assessmenta
6921***68407132***6954
CRP (mg/dL)2.20.9***2.11.83.41.3***2.82.3

The time course of ACR 50 response for Study III is shown in Figure 1. The time course for Study IV was similar.

ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness.

Radiographic Response

In Study III, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score3 (TSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/MTX slowed the progression of structural damage compared to placebo/MTX after 12 months of treatment as shown in Table 6.

Table 6: Mean Radiographic Changes in Study IIIa
Parameter ORENCIA/MTXb Placebo/MTXc Differences P-valued
a  Based on radiographic reads following 2 years of treatment.
b  Patients received 2 years of treatment with ORENCIA/MTX.
c  Patients received 1 year of placebo/MTX followed by 1 year of ORENCIA/MTX.
d  Based on ANCOVA model with treatment and site as factors and baseline score as covariate.
First Year
     TSS1.072.431.36<0.01
     ES0.611.470.86<0.01
     JSN score0.460.970.51<0.01
Second Year
     TSS0.480.74--
     ES0.230.22--
     JSN score0.250.51--

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

Following 2 years of treatment with ORENCIA/MTX, 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/MTX-treated patients had no progression during the first year compared to 45% of placebo/MTX-treated patients. In their second year of treatment with ORENCIA/MTX, 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).2,4 In Studies II-V, ORENCIA demonstrated greater improvement from baseline than placebo in the HAQ-DI. The results from Studies II and III are shown in Table 7. Similar results were observed in Study V. 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)
  Inadequate Response to Methotrexate
  Study II Study III
*** p<0.001, ORENCIA vs placebo.
a     10 mg/kg.
b     Dosing based on weight range [see Dosage and Administration ].
c     Modified Health Assessment Questionnaire4: 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
d     Health Assessment Questionnaire2: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.


HAQ Disability Index
ORENCIAa
+MTX
(n=115)
Placebo
+MTX
(n=119)
ORENCIAb
+MTX
(n=422)
Placebo
+MTX
(n=212)
Baseline (Mean)0.98c0.97c1.69d1.69d
Mean Improvement
     Year 1

0.40c,***

0.15c

0.66d,***

0.37d

Health-related quality of life was assessed by the SF-36 questionnaire5 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 MTX 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 MTX (mean dose, 13.2 mg/m2 per week) and remained on a stable dose of MTX (those not receiving MTX did not initiate MTX 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,6 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.

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