Abatacept: The first T-lymphocyte co-stimulation modulator; for use in rheumatoid arthritis

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Abatacept (Orencia, Bristol-Myers Squibb) is the first T-lymphocyte co-stimulation modulator to be approved by FDA. The agent is indicated for use in patients with moderate-to-severe, active rheumatoid arthritis who have not had an adequate response to methotrexate, tumor necrosis factor (TNF) inhibitors, or other disease-modifying anti-rheumatic drugs (DMARDs).

Abstract

Abatacept (Orencia, Bristol-Myers Squibb) is the first T-lymphocyte co-stimulation modulator to be approved by FDA. The agent is indicated for use in patients with moderate-to-severe, active rheumatoid arthritis who have not had an adequate response to methotrexate, tumor necrosis factor (TNF) inhibitors, or other disease-modifying anti-rheumatic drugs (DMARDs). Abatacept inhibits the immune and inflammatory response by blocking the activation of helper T-cells. Abatacept 10 mg/kg intravenously at Weeks 0, 2, and 4, and then every 4 weeks thereafter, decreases inflammation and pain in 2 to 4 weeks. The agent may be used as the only DMARD or in combination with other DMARDs except TNF-alpha inhibitors. The most common adverse effects associated with abatacept are headache, upper respiratory symptoms or infection, and gastrointestinal disturbance. (Formulary. 2006;41:322–326.)

Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disease that affects 0.5% to 1.0% of the US population. It is associated with joint destruction in at least 60% of those with the disease and increases in vital organ dysfunction and cardiovascular mortality in those with more severe, progressive disease.1,2 The treatment of RA has changed markedly over the last 5 years following the approval of specific biologic therapies that target specific components of the immune response, such as inhibitors of tumor necrosis factor (TNF)-alpha, interleukin-1, and calcineurin/interleukin-2. Inhibitors of TNF-alpha are generally well tolerated, show long-term responses in over 50% of patients, diminish the destructive nature of rheumatoid arthritis, and may improve overall survival.3 Rituximab (Rituxan, Genentech/Biogen Idec), a chimeric human-murine monoclonal antibody directed against the CD20 antigen on B-lymphocytes, is effective and was recently approved to be used in combination with methotrexate in the treatment of disease-modifying anti-rheumatic drug (DMARD)-resistant rheumatoid arthritis.4 A recent trial has indicated a relatively low rate of long-term responsiveness to anakinra, an inhibitor of interleukin-1.5 However, additional therapies are needed for those who have inadequate response or tolerability.

CHEMISTRY AND PHARMACOLOGY

Abatacept is a soluble protein of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) fused with the Fc portion of IgG1.6 This is a large molecule with an apparent molecular weight of 92,000 daltons. Abatacept is the product of recombinant DNA technology utilizing a mammalian cell line. The product formulation is a preservative- free, lyophilized powder that needs to be reconstituted with 10 mL of sterile water prior to intravenous injection.

PHARMACOKINETICS

The pharmacokinetics of abatacept following a single dose of 10 mg/kg intravenously to normal subjects include a mean peak concentration of 292 mg/L (range 175–427 mg/L), elimination half-life of 16.7 hours (range 12–23 h), total clearance of 0.23 mL/h/kg (range 0.16–0.30 mL/h/kg), and volume of distribution at steady state of 0.09 L/kg (range 0.06–0.13 L/kg).6 Multiple doses of abatacept 10 mg/kg intravenously monthly in patients with RA revealed similar pharmacokinetics, with a mean peak concentration of 295 mg/L (range 171–398 mg/L), mean trough concentration of 24 mg/L (range 1–66 mg/L), elimination half-life of 13.1 hours (range 8–25 h), total clearance of 0.22 mL/h/kg (range 0.13–0.47 mL/h/kg), and volume of distribution at steady state of 0.07 L/kg (range 0.02–0.13 L/kg). Peak concentrations and area under the plasma concentration-time curve are reportedly proportional to dose between 2 and 10 mg/kg. Clearance increased with increased weight, but was not altered by age, gender, nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, or TNF-alpha inhibitors.

PHARMACODYNAMICS

Abatacept inhibits the activation of helper T-lymphocytes by macrophages. The human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) portion of abatacept binds to CD80 and CD86 on macrophages.6 The binding of abatacept to CD80 and CD86 blocks the binding with CD28 on T-lymphocytes and subsequently blocks the co-stimulating signal needed to fully activate T-lymphocytes. As a result, abatacept inhibits T-lymphocyte proliferation, secretion of tumor necrosis factor-alpha, interferon-gamma, interleukin-2, soluble interleukin-2 receptor, interleukin-6, matrix metalloproteinase 3, and production of rheumatoid factor and other autoantigens. In a rat model of collagen-induced arthritis, abatacept decreased production of anticollagen antibodies, cytokines, chemokines, swelling, and bone destruction.7,8

CLINICAL TRIALS

Studies in RA involve the analysis of global response terms ACR20, ACR50, ACR 70, and remission. ACR20 responses (ACR50 and ACR70 responses) are defined as having at least a 20% decrease (50% and 70% response, respectively) in the number of tender joints, number of swollen joints, and in at least 3 of the following: patient's global assessment of disease, patient's assessment of pain, patient's assessment of physical function, physician's global assessment of disease, and C-reactive protein (CRP).

Remission is defined as a Disease Activity Score in 28 joints (DAS28) less than 2.6, with a range in this score from 2 to 10. A low-level disease activity is defined as a DAS28 <3.2. The components of this score include the number of swollen joints, number of tender joints, CRP, and patient's global assessment on a visual analog scale.9

In the following studies, abatacept was administered intravenously at 0, 2, and 4 weeks and then every 4 weeks. Patients in these studies were allowed to continue therapy with NSAIDs and low-dose oral corticosteroids.

Abatacept as the only DMARD. Abatacept 0.5 mg/kg (n=26), 2 mg/kg (n=32), and 10 mg/kg (n=32) were compared with placebo (n=32) in a 3-month, double-blind, placebo-controlled study involving patients with RA who had been treated unsuccessfully with previous DMARDs.10 DMARDs were stopped at least 4 weeks prior to starting the study. Abatacept was administered over 2 months and then patients were evaluated 1 month later. This 3-month study was completed by 62% of patients in the placebo group and 78% of patients in the abatacept groups. Withdrawals for lack of efficacy were seen in 31% of those receiving placebo and 22% of those receiving abatacept. Tender joint counts, swollen joint counts, and morning stiffness improved by 40% to 54% on average in those receiving abatacept 2 or 10 mg/kg compared with a 3% improvement in morning stiffness and 29% to 32% improvement in tender and swollen joint counts for patients receiving placebo. At 85 days, ACR20 response rates were seen in approximately 32% of those receiving placebo compared with approximately 23% of those on abatacept 0.5 mg/kg, 43% of those on abatacept 2 mg/kg, and 53% of those on abatacept 10 mg/kg. ACR50 and ACR70 responses at 85 days, respectively, were seen in 6% and 0% of those on placebo, 0% and 0% of those on abatacept 0.5 mg/kg, 19% and 12% on abatacept 2 mg/kg, and 16% and 6% of those on abatacept 10 mg/kg.

Abatacept added to methotrexate. Abatacept 2 mg/kg (n=105), abatacept 10 mg/kg (n=115), and placebo (n=119) were compared in patients with RA treated with concomitant methotrexate in a 6-month prospective, parallel, double-blind, placebo-controlled, phase 2b study.11 Patients had active disease at study entry despite chronic, stable therapy with methotrexate. This 6-month study was completed by 65.5% of patients in the placebo group, 78.1% in the abatacept 2 mg/kg group, and 86.1% in the abatacept 10 mg/kg group. Withdrawals for lack of efficacy were seen in 24.3% of those receiving placebo plus methotrexate compared with 12.4% of those receiving abatacept 2 mg/kg plus methotrexate and 10.4% of those receiving abatacept 10 mg/kg plus methotrexate (P<.05 for each abatacept group vs placebo). After 6 months, ACR20 response rates were seen in 35.3% of those receiving placebo plus methotrexate, compared with 41.9% of those receiving abatacept 2 mg/kg plus methotrexate (P=.31 vs placebo) and 60% of those on abatacept 10 mg/kg plus methotrexate (P<.001 from Months 2 through 6 vs placebo). ACR50 and ACR70 responses at 6 months were seen in 11.8% and 1.7%, respectively, of those receiving placebo plus methotrexate, compared with 22.9% and 10.5% of those receiving abatacept 2 mg/kg plus methotrexate and 36.5% and 16.5% of those receiving abatacept 10 mg/kg plus methotrexate (P<.05 for each abatacept group vs placebo).

The 12-month results were reported for the previously mentioned study comparing abatacept 2 and 10 mg/kg to placebo when added to concomitant methotrexate in patients with arthritis.12 The 12 months of this study were completed by 59.7% of patients in the placebo group, 70.5% in the abatacept 2 mg/kg group, and 78.3% in the abatacept 10 mg/kg group (P<.01 abatacept 10 mg/kg vs placebo). Withdrawals for lack of efficacy were seen in 25.2% of those receiving placebo plus methotrexate compared with 16.2% on abatacept 2 mg/kg plus methotrexate and 11.3% on abatacept 10 mg/kg plus methotrexate (P<.05 for each abatacept group vs placebo). After 12 months, ACR20 response rates were seen in 36.1% of those on placebo plus methotrexate compared with 62.6% of those on abatacept 10 mg/kg plus methotrexate (P<.01 from Months 2 through 12 vs placebo). ACR50 and ACR70 responses at 12 months were seen in 20.2% and 7.6%, respectively, of those on placebo plus methotrexate compared with 41.7% and 20.9% of those on abatacept 10 mg/kg plus methotrexate (P<.003 vs placebo). Improvement in physical function, as reported on a health questionnaire, was 10.3% for placebo plus methotrexate versus 42.3% for abatacept 10 mg/kg plus methotrexate (P<.001), with a statistically significant difference seen as early as 30 days after beginning the study. For those on abatacept 10 mg/kg plus methotrexate, the low level of disease activity (as defined above) was seen in 29.6% at 3 months, 40% at 6 months, and 49.6% at 12 months, compared with 18.5%, 19.3%, and 21.9% in the placebo plus methotrexate group (P<.05 at all time points vs abatacept 10 mg/kg). Remission was seen in 10.1% of patients in the placebo group and 34.8% of patients in the abatacept 10 mg/kg group (P<.001).7,12

Abatacept (10 mg/kg per dose, n=433) or placebo (n=219) were added to methotrexate for 1 year in another randomized, double-blind, multi-center study in patients with active RA despite therapy with methotrexate.13 Withdrawals were seen in 57 (26%) of those receiving placebo, including 40 (18%) for lack of efficacy and 4 (2%) for adverse events, and in 48 (11%) of those assigned to abatacept, with 13 (3%) for lack of efficacy and 18 (4%) for adverse events. The ACR20, ACR50, and ACR70 responses at 1 year were seen, respectively, in 39.7%, 18.2%, and 6.1% of patients receiving placebo compared to 73.1%, 48.3%, and 28.8% of patients receiving abatacept (P<.001 for all comparisons). Abatacept slowed progression of joint destruction by approximately 50% compared to placebo after 1 year (P<.05). At 1 year, a low level of disease activity, as defined previously, was seen in 9.9% of patients receiving placebo and 42.5% of those receiving abatacept (P<.001). Remission, as defined previously, was observed in 1.9% of patients receiving placebo and 23.8% of patients receiving abatacept (P<.001). In all measures, there were differences between placebo and abatacept at 6 months and those differences increased at 12 months.

Abatacept plus at least 1 other DMARD. Abatacept 10 mg/kg (n=258) and placebo (n=133) were compared in patients with RA who had an inadequate response to TNF-alpha inhibitors in this parallel, randomized, double-blind, placebo-controlled 6-month study (called the ATTAIN study).14 Patients stopped TNF-alpha inhibitors prior to initiation of the study, but were allowed concomitant therapy with oral DMARDs: methotrexate (n=304), hydroxychloroquine (n=35) or chloroquine (n=1), leflunomide (n=34), sulfasalazine (n=31), azathioprine (n=10), gold (n=1), and penicillamine (n=1), and the interleukin-1 inhibitor anakinra (n=10). Abatacept was dosed at approximately 10 mg/kg per dose, with those weighing <60 kg receiving 500 mg, those weighing 60 to 100 kg receiving 750 mg, and those weighing >100 kg receiving 1,000 mg. This study was completed by 74.4% of patients in the placebo group and 86.4% in the abatacept group. Withdrawals for lack of efficacy were seen in 20.3% of those in the placebo group compared with 5.4% in the abatacept group (P<.001). After 6 months, ACR20 response rates were seen in 19.5% of those in the placebo group and 50.4% in the abatacept group (P<.001), with statistically significant differences occurring at 2 weeks into the trial. ACR50 and ACR70 responses at 12 months were seen in 3.8% and 1.5%, respectively, of those receiving placebo compared with 20.3% and 10.2% of those receiving abatacept (P<.001 and P=.003, respectively). Improvements in physical function and health-related quality of life were higher with abatacept than placebo (P<.001). A low-level of disease activity was seen in 3.1% of those receiving placebo and 17.1% of those receiving abatacept (P<.001). Remission was seen in 0.8% of those receiving placebo and 10.0% of those receiving abatacept (P<.001).

Quality of life was more intensively evaluated in patients from the previously mentioned study using a number of measurements, including the SF-36 survey, health assessment questionnaire (HAQ), visual analog fatigue scale, and the disease activity score 28 (DAS28).15 As expected from the clinical evidence provided above, abatacept improved the quality of life. By Week 4, abatacept was superior to placebo for improvements in mental health and fatigue. By Week 12, improvements with abatacept over placebo were seen in general health, bodily pain, vitality, social functioning, and the physical and mental component scores. By Week 24, abatacept was superior in physical functioning, the overall HAQ, and all other measures reported. Subanalyses of these data found that more patients receiving abatacept improved and fewer became worse compared with the placebo group.

ADVERSE EVENTS

DRUG INTERACTIONS

DOSAGE AND ADMINISTRATION

Abatacept is administered intravenously at a dose of approximately 10 mg/kg at 0, 2, and 4 weeks and then every 4 weeks. Patients weighing <60 kg receive 500 mg per dose, those weighing 60 to 100 kg receive 750 mg per dose, and those weighing >100 kg receive 1,000 mg per dose. The drug is provided in vials containing 250 mg of abatacept as sterile powder that must be reconstituted with sterile water prior to administration.

Dr Boyce is the assistant dean for assessment and a professor of pharmacy at the School of Pharmacy, Wingate University, Wingate, NC. He can be reached at eboyce@wingate.edu
.

Disclosure Information: The author has no disclosures to report as related to products discussed in this article.

REFERENCES

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6. Orencia [package insert]. New York, NY: Bristol-Myers Squibb; 2005.

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8. Kliwinski C, Kukral D, Postelnek J, et al. Prophylactic administration of abatacept (CTLA4-Ig; BMS-18886677) prevents disease induction and bone destruction in a rat model of collagen-induced arthritis. Arthritis Res Ther. 2005;7(Suppl 1):P4.

9. Disease Activity Score in Rheumatology. Available at: http:// http://www.das-score.nl/www.das-score. nl/index.html. Accessed June 26, 2006.

10. Moreland LW, Alten R, Van den Bosch F, et al. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum. 2002;46:1470–1479.

11. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003;309:1907–1915.

12. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a Phase IIb, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:2263–2271.

13. Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2006;1 44:865-876.

14. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353:1114–1123.

15. Westhovens R, Cole JC, Li T, et al. Improved health-related quality of life for rheumatoid arthritis patients treated with abatacept who have inadequate response to anti-TNF therapy in a double-blind, placebo-controlled, multicentre randomized clinical trial. Rheumatology (Oxford). 2006 Mar 27; [Epub ahead of print].

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