Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: Bristol-Myers Squibb Pharma EEIG, Uxbridge Business Park, Sanderson Road, Uxbridge UB8 1DH, United Kingdom
Pharmacotherapeutic group: selective immunosuppressants
ATC code: L04AA24
Abatacept is a fusion protein that consists of the extracellular domain of human cytotoxic Tlymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in Chinese hamster ovary cells.
Abatacept selectively modulates a key costimulatory signal required for full activation of T lymphocytes expressing CD28. Full activation of T lymphocytes requires two signals provided by antigen presenting cells: recognition of a specific antigen by a T cell receptor (signal 1) and a second, costimulatory signal. A major costimulatory pathway involves the binding of CD80 and CD86 molecules on the surface of antigen presenting cells to the CD28 receptor on T lymphocytes (signal 2). Abatacept selectively inhibits this costimulatory pathway by specifically binding to CD80 and CD86. Studies indicate that naive T lymphocyte responses are more affected by abatacept than memory T lymphocyte responses.
Studies in vitro and in animal models demonstrate that abatacept modulates T lymphocyte-dependent antibody responses and inflammation. In vitro, abatacept attenuates human T lymphocyte activation as measured by decreased proliferation and cytokine production. Abatacept decreases antigen specific TNFα, interferon-γ, and interleukin-2 production by T lymphocytes.
Dose-dependent reductions were observed with abatacept in serum levels of soluble interleukin2 receptor, a marker of T lymphocyte activation; serum interleukin-6, a product of activated synovial macrophages and fibroblast-like synoviocytes in rheumatoid arthritis; rheumatoid factor, an autoantibody produced by plasma cells; and C-reactive protein, an acute phase reactant of inflammation. In addition, serum levels of matrix metalloproteinase-3, which produces cartilage destruction and tissue remodelling, were decreased. Reductions in serum TNFα were also observed.
The efficacy and safety of intravenous abatacept were assessed in randomised, double-blind, placebocontrolled clinical trials in adult patients with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, V, and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study IV did not require any specific number of tender or swollen joints. Study SC-I was a randomized, double-blind, double-dummy noninferiority study administered to patients stratified by body weight (<60 kg, 60 to 100 kg, >100 kg) that compared the efficacy and safety of abatacept administered subcutaneously and intravenously in subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX), and experiencing an inadequate response to MTX (MTX-IR).
In Studies I, II, and V the efficacy and safety of abatacept compared to placebo were assessed in patients with an inadequate response to methotrexate and who continued on their stable dose of methotrexate. In addition, Study V investigated the safety and efficacy of abatacept or infliximab relative to placebo. In Study III the efficacy and safety of abatacept were assessed in patients with an inadequate response to a TNF-inhibitor, with the TNF-inhibitor discontinued prior to randomization; other DMARDs were permitted. Study IV primarily assessed safety in patients with active rheumatoid arthritis requiring additional intervention in spite of current therapy with non-biological and/or biological DMARDs; all DMARDs used at enrollment were continued. In Study VI, the efficacy and safety of abatacept were assessed in methotrexate-naive, Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide 2 (Anti-CCP2)-positive patients with early, erosive rheumatoid arthritis (≤2 years disease duration) who were randomized to receive abatacept plus methotrexate or methotrexate plus placebo. In Study SC-I, the goal was to demonstrate non-inferiority of the efficacy and comparability of the safety of abatacept subcutaneous relative to intravenous administration in subjects with moderate to severely active RA and experiencing inadequate response to MTX. Study SC-II investigated the relative efficacy and safety of abatacept and adalimumab, both given subcutaneously without an intravenous loading dose and with background MTX, in patients with moderate to severely active RA and an inadequate response to previous MTX therapy. In study SC-III, abatacept SC was evaluated in combination with methotrexate, or as abatacept monotherapy, and compared to MTX monotherapy in induction of remission following 12 months of treatment, and the possible maintenance of drug-free remission after complete drug withdrawal, in adult MTX-naive patients with highly active early rheumatoid arthritis (mean DAS28-CRP of 5.4; mean symptom duration less than 6.7 months) with poor prognostic factors for rapidly progressive disease (e.g. anticitrullinated protein antibodies [ACPA+], as measured by anti-CCP2 assay, and/or RF+, baseline joint erosions).
Study I patients were randomized to receive abatacept 2 or 10 mg/kg or placebo for 12 months. Study II, III, IV, and VI patients were randomized to receive a fixed dose approximating 10 mg/kg of abatacept or placebo for 12 (Studies II, IV, and VI) or 6 months (Study III). The dose of abatacept was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg. In Study SC-I, abatacept was given subcutaneously to patients after a single loading dose of intravenous abatacept and then every week thereafter. Subjects continued taking their current dose of MTX from the day of randomization. Study V patients were randomized to receive this same fixed dose of abatacept or 3 mg/kg infliximab or placebo for 6 months. Study V continued for an additional 6 months with the abatacept and infliximab groups only.
Studies I, II, III, IV, V, VI, SC-I, SC-II, and SC-III evaluated 339, 638, 389, 1441, 431, 509 1371, 646, and 351 adult patients, respectively.
The percent of abatacept-treated patients achieving ACR 20, 50, and 70 responses in Study II (patients with inadequate response to methotrexate), Study III (patients with inadequate response to TNFinhibitor), Study VI (methotrexate-naive patients), and Study SC-I (subcutaneous abatacept) are shown in Table 2.
In abatacept-treated patients in Studies II and III, statistically significant improvement in the ACR 20 response versus placebo was observed after administration of the first dose (day 15), and this improvement remained significant for the duration of the studies. In Study VI, statistically significant improvement in the ACR 20 response in abatacept plus methotrexate-treated patients versus methotrexate plus placebo-treated patients was observed at 29 days, and was maintained through the duration of the study. In Study II, 43% of the patients who had not achieved an ACR 20 response at 6 months developed an ACR 20 response at 12 months.
In Study SC-I, abatacept administered subcutaneously (SC) was non-inferior relative to intravenous (IV) infusions of abatacept with respect to ACR 20 responses up to 6 months of treatment. Patients treated with abatacept subcutaneously also achieved similar ACR 50 and 70 responses as those patients receiving abatacept intravenously at 6 months. No difference in clinical response between subcutaneous and intravenous abatacept was seen across the 3 weight groups. In SC-1, the ACR 20 response rates at Day 169 for subcutaneous and intravenous abatacept were respectively 78.3% (472/603 SC) and 76.0% (456/600 IV) in patients <65 years, versus 61.1% (55/90 SC) and 74.4% (58/78 IV) for patients ≥65 years.
Table 2. Clinical Responses in Controlled Trials:
| Percent of Patients | ||||||||
|---|---|---|---|---|---|---|---|---|
| Intravenous administration | Subcutaneous administration | |||||||
| MTX-Naive | Inadequate Response to MTX | Inadequate Response to TNF Inhibitor | Inadequate Response to MTX | |||||
| Study VI | Study II | Study III | Study SC-I | |||||
| Response Rate | Abatacepta+MTX n=256 | Placebo+MTX n=253 | Abatacepta+MTX n=424 | Placebo+MTX n=214 | Abatacepta+DMARDsb n=256 | Placebo+DMARDsb n=133 | Abataceptf SC+MTX n=693 | Abataceptf IV+MTX n=678 |
| ACR 20 | ||||||||
| Day 15 | 24% | 18% | 23%* | 14% | 18%** | 5% | 25% | 25% |
| Month 3 | 64%†† | 53% | 62%*** | 37% | 46%*** | 18% | 68% | 69% |
| Month 6 | 75%† | 62% | 68%*** | 40% | 50%*** | 20% | 76%§ | 76% |
| Month 12 | 76%‡ | 62% | 73%*** | 40% | NAd | NAd | NA | NA |
| ACR 50 | ||||||||
| Month 3 | 40%‡ | 23% | 32%*** | 8% | 18%** | 6% | 33% | 39% |
| Month 6 | 53%‡ | 38% | 40%*** | 17% | 20%*** | 4% | 52% | 50% |
| Month 12 | 57%‡ | 42% | 48%*** | 18% | NAd | NAd | NA | NA |
| ACR 70 | ||||||||
| Month 3 | 19%† | 10% | 13%*** | 3% | 6%†† | 1% | 13% | 16% |
| Month 6 | 32%† | 20% | 20%*** | 7% | 10%** | 2% | 26% | 25% |
| Month 12 | 43%‡ | 27% | 29%*** | 6% | NAd | NAd | NA | NA |
| Major Clinical Responsec | ||||||||
| 27%‡ | 12% | 14%*** | 2% | NAd | NAd | NA | NA | |
| DAS28-CRP Remissione | ||||||||
| Month 6 | 28%‡ | 15% | NA | NA | NA | NA | 24%§§ | 25% |
| Month 12 | 41%‡ | 23% | NA | NA | NA | NA | NA | NA |
* p<0.05, abatacept vs. placebo.
** p<0.01, abatacept vs. placebo.
*** p<0.001, abatacept vs. placebo.
† p<0.01, abatacept plus MTX vs. MTX plus placebo
‡ p<0.001, abatacept plus MTX vs. MTX plus placebo
†† p<0.05, abatacept plus MTX vs. MTX plus placebo
§ 95% CI: −4.2, 4.8 (based on prespecified margin for non-inferiority of −7.5%)
§§ ITT data is presented in table
a Fixed dose approximating 10 mg/kg (see section 4.2).
b Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, gold, and anakinra.
c Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.
d After 6 months, patients were given the opportunity to enter an open-label study.
e DAS28-CRP Remission is defined as a DAS28-CRP score <2.6.
f Per protocol data is presented in table. For ITT; n=736, 721 for subcutaneous (SC) and intravenous (IV) abatacept, respectively.
In the open-label extension of Studies I, II, III, VI, and SC-I durable and sustained ACR 20, 50, and 70 responses have been observed through 7 years, 5 years, 5 years, 2 years, and 5years, respectively, of abatacept treatment. In study I, ACR responses were assessed at 7 years in 43 patients with 72% ACR 20 responses, 58% ACR 50 responses, and 44% ACR 70 responses. In study II, ACR responses were assessed at 5 years in 270 patients with 84% ACR 20 responses, 61% ACR 50 responses, and 40% ACR 70 responses. In study III, ACR responses were assessed at 5 years in 91 patients with 74% ACR 20 responses, 51% ACR 50 responses, and 23% ACR 70 responses. In study VI, ACR responses were assessed at 2 years in 232 patients with 85% ACR 20 responses, 74% ACR 50 responses, and 54% ACR 70 responses. In study SC-I, ACR responses were assessed at 5 years with 85% (356/421) ACR 20 responses, 66% (277/423) ACR 50 responses, and 45% (191/425) ACR 70 responses.
Greater improvements were seen with abatacept than with placebo in other measures of rheumatoid arthritis disease activity not included in the ACR response criteria, such as morning stiffness.
Disease activity was also assessed using the Disease Activity Score 28. There was a significant improvement of DAS in Studies II, III, V, and VI as compared to placebo or comparator.
In study VI, which only included adults, a significantly higher proportion of patients in the abatacept plus methotrexate group (41%) achieved DAS28 (CRP)-defined remission (score <2.6) versus the methotrexate plus placebo group (23%) at year 1. The response at year 1 in the abatacept group was maintained through year 2.
A randomized, double-blind study was conducted to assess the safety and efficacy of intravenous abatacept or infliximab versus placebo in patients with an inadequate response to methotrexate (Study V). The primary outcome was the mean change in disease activity in abatacept- treated patients compared to placebo-treated patients at 6 months with a subsequent double-blind assessment of safety and efficacy of abatacept and infliximab at 12 months. Greater improvement (p<0.001) in DAS28 was observed with abatacept and with infliximab compared to placebo at six months in the placebo-controlled portion of the trial; the results between the abatacept and infliximab groups were similar. The ACR responses in Study V were consistent with the DAS28 score. Further improvement was observed at 12 months with abatacept. At 6 months, the incidence of AE of infections were 48.1% (75), 52.1% (86), and 51.8% (57) and the incidence of serious AE of infections were 1.3% (2), 4.2% (7), and 2.7% (3) for abatacept, infliximab and placebo groups, respectively. At 12 months, the incidence of AE of infections were 59.6% (93), 68.5% (113), and the incidence of serious AE of infections were 1.9% (3) and 8.5% (14) for abatacept and infliximab groups, respectively. The open label period of the study provided an assessment of the ability of abatacept to maintain efficacy for subjects originally randomized to abatacept and the efficacy response of those subjects who were switched to abatacept following treatment with infliximab. The reduction from baseline in mean DAS28 score at day 365 (-3.06) was maintained through day 729 (-3.34) in those patients who continued with abatacept. In those patients who initially received infliximab and then switched to abatacept, the reduction in the mean DAS28 score from baseline were 3.29 at day 729 and 2.48 at day 365.
A randomized, single(investigator)-blinded, non-inferiority study was conducted to assess the safety and efficacy of weekly subcutaneous (SC) abatacept without an abatacept intravenous (IV) loading dose versus every-other-weekly subcutaneous adalimumab, both with background MTX, in patients with an inadequate response to methotrexate (Study SC-II). The primary endpoint showed noninferiority (predefined margin of 12%) of ACR20 response after 12 months of treatment, 64.8% (206/318) for the abatacept SC group and 63.4% (208/328) for the adalimumab SC group; treatment difference was 1.8% [95% confidence interval (CI): -5.6, 9.2], with comparable responses throughout the 24-month period. The respective values for ACR 20 at 24 months were 59.7% (190/318) for the abatacept SC group and 60.1% (197/328) for the adalimumab SC group. The respective values for ACR 50 and ACR 70 at 12 months and 24 months were consistent and similar for abatacept and adalimumab. The adjusted mean changes (standard error; SE) from baseline in DAS28-CRP were -2.35 (SE 0.08) [95% CI: -2.51, -2.19] and -2.33 (SE 0.08) [95% CI: -2.50, -2.17] in the SC abatacept group and the adalimumab group, respectively, at 24 months, with similar changes over time. At 24 months, 50.6% (127/251) [95% CI: 44.4, 56.8] of patients in abatacept and 53.3% (130/244) [95% CI: 47.0, 59.5] of patients in adalimumab groups achieved DAS 28 <2.6. Improvement from baseline as measured by HAQ-DI at 24 months and over time was also similar between abatacept SC and adalimumab SC.
Safety and structural damage assessments were conducted at one and two years. The overall safety profile with respect to adverse events was similar between the two groups over the 24-month period. After 24 months, adverse reactions were reported in 41.5% (132/318) and 50% (164/328) of abatacept and adalimumab-treated patients. Serious adverse reactions were reported in 3.5% (11/318) and 6.1% (20/328) of the respective group. At 24 months, 20.8% (66/318) of patients on abatacept and 25.3% (83/328) on adalimumab had discontinued. In SC-II, serious infections were reported in 3.8% (12/318) of patients treated with abatacept SC weekly, none of which led to discontinuation and in 5.8% (19/328) of patients treated with adalimumab SC every-other-week, leading to 9 discontinuations in the 24-month period. The frequency of local injection site reactions was 3.8% (12/318) and 9.1% (30/328) at 12 months (p=0.006) and 4.1% (13/318) and 10.4% (34/328) at 24 months for abatacept SC and adalimumab SC, respectively. Over the 2 year study period, 3.8% (12/318) and 1.5% (5/328) patients treated with abatacept SC and adalimumab SC respectively reported autoimmune disorders mild to moderate in severity (e.g., psoriasis, Raynaud’s phenomenon, erythema nodosum).
A randomized and double-blinded study evaluated abatacept SC in combination with methotrexate (abatacept + MTX), abatacept SC monotherapy, or methotrexate monotherapy (MTX group) in induction of remission following 12 months of treatment, and maintenance of drug-free remission after complete drug withdrawal in MTX-naive adult patients with highly active early rheumatoid arthritis with poor prognostic factors. Complete drug withdrawal led to loss of remission (return to disease activity) in all three treatment arms (abatacept with methotrexate, abatacept or methotrexate alone) in a majority of patients (Table 3).
Table 3. Remission Rates at End of Drug Treatment and Drug Withdrawal Phases in Study SC-III:
| Number of Patients | Abatacept SC+MTX n=119 | MTX n=116 | Abatacept SC n=116 |
|---|---|---|---|
| Proportion of Randomized Patients with Induction of Remission after 12 Months of Treatment | |||
| DAS28-Remissiona | 60.9% | 45.2% | 42.5% |
| Odds Ratio (95% CI) vs. MTX | 2.01 (1.18, 3.43) | N/A | 0.92 (0.55, 1.57) |
| P value | 0.010 | N/A | N/A |
| SDAI Clinical Remissionb | 42.0% | 25.0% | 29.3% |
| Estimate of Difference (95% CI) vs. MTX | 17.02 (4.30, 29.73) | N/A | 4.31 (-7.98, 16.61) |
| Boolean Clinical Remission | 37.0% | 22.4% | 26.7% |
| Estimate of Difference (95% CI) vs. MTX | 14.56 (2.19, 26.94) | N/A | 4.31 (-7.62, 16.24) |
| Proportion of Randomized Patients in Remission at 12 Months and at 18 Months (6 Months of Complete Drug Withdrawal) | |||
| DAS28-Remissiona | 14.8% | 7.8% | 12.4% |
| Odds Ratio (95% CI) vs. MTX | 2.51 (1.02, 6.18) | N/A | 2.04 (0.81, 5.14) |
| P value | 0.045 | N/A | N/A |
a DAS28-defined remission (DAS28-CRP <2.6)
b SDAI criterion (SDAI ≤ 3.3)
In SC-III the safety profiles of the three treatment groups (abatacept + MTX, abatacept monotherapy, MTX group) were overall similar. During the 12-month treatment period, adverse reactions were reported in 44.5% (53/119), 41.4% (48/116), and 44.0% (51/116) and serious adverse reactions were reported in 2.5% (3/119), 2.6% (3/116) and 0.9% (1/116) of patients treated in the three treatment groups, respectively. Serious infections were reported in 0.8% (1/119), 3.4% (4/116) and 0% (0/116) patients.
Structural joint damage was assessed radiographically over a two-year period in Studies II, VI, and SC-II. The results were measured using the Genant-modified total Sharp score (TSS) and its components, the erosion score and joint space narrowing (JSN) score.
In Study II, the baseline median TSS was 31.7 in abatacept-treated patients and 33.4 in placebo-treated patients. Abatacept/methotrexate reduced the rate of progression of structural damage compared to placebo/methotrexate after 12 months of treatment as shown in Table 4. The rate of progression of structural damage in year 2 was significantly lower than that in year 1 for patients randomized to abatacept (p<0.0001). Subjects entering the long term extension after 1 year of double blind treatment all received abatacept treatment and radiographic progression was investigated through year 5. Data were analyzed in an as-observed analysis using mean change in total score from the previous annual visit. The mean change was, 0.41 and 0.74 from year 1 to year 2 (n=290, 130), 0.37 and 0.68 from year 2 to year 3 (n=293, 130), 0.34 and 0.43 year from 3 to year 4 (n=290, 128) and the change was 0.26 and 0.29 (n=233, 114) from year 4 to year 5 for patients originally randomized to abatacept plus MTX and placebo plus MTX respectively.
Table 4. Mean Radiographic Changes Over 12 Months in Study II:
| Parameter | Abatacept/MTX n=391 | Placebo/MTX n=195 | P-valuea |
|---|---|---|---|
| Total Sharp score | 1.21 | 2.32 | 0.012 |
| Erosion score | 0.63 | 1.14 | 0.029 |
| JSN score | 0.58 | 1.18 | 0.009 |
a Based on non-parametric analysis.
In Study VI, the mean change in TSS at 12 months was significantly lower in patients treated with abatacept plus methotrexate compared to those treated with methotrexate plus placebo. At 12 months 61% (148/242) of the patients treated with abatacept plus methotrexate and 53% (128/242) of the patients treated with methotrexate plus placebo had no progression (TSS ≤0). The progression of structural damage was lower in patients receiving continuous abatacept plus methotrexate treatment (for 24 months) compared to patients who initially received methotrexate plus placebo (for 12 months) and were switched to abatacept plus methotrexate for the next 12 months. Among the patients who entered the open-label 12 month period, 59% (125/213) of patients receiving continuous abatacept plus methotrexate treatment and 48% (92/192) of patients who initially received methotrexate and switched to combination with abatacept had no progression.
In Study SC-II, structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde-modified Total Sharp Score (mTSS) and its components. Similar inhibition was observed in both treatment groups up to 24 months (mTSS (mean ± standard deviation [SD] = 0.89 ± 4.13 vs 1.13 ±8.66), erosion score (0.41 ± 2.57 vs 0.41 ±5.04), and JSN score (0.48 ±2.18 vs 0.72 ±3.81)) for the abatacept (n=257) and adalimumab (n=260) groups, respectively.
In Study SC-III, structural joint damage was assessed by MRI. The abatacept + MTX group had less progression in structural damage compared with MTX group as reflected by mean treatment difference of the abatacept + MTX group versus MTX group (Table 5).
Table 5. Structural and Inflammatory MRI Assessment in Study SC-III:
| Mean Treatment Difference between Abatacept SC+MTX vs. MTX at 12 Months (95% CI)* | |
|---|---|
| MRI Erosion Score | -1.22 (-2.20, -0.25) |
| MRI Osteitis/Bone Oedema Score | -1.43 (-2.68, -0.18) |
| MRI Synovitis Score | -1.60, (-2.42, -0.78) |
* n=119 for Abatacept SC + MTX; n=116 for MTX
Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) in Studies II, III, IV, V, and VI and the modified HAQ-DI in Study I. In Study SC-I, 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, III, and VI are shown in Table 6.
Table 6. Improvement in Physical Function in Controlled Trials:
| Methotrexate-Naive | Inadequate Response to Methotrexate | Inadequate Response to TNF Inhibitor | ||||
|---|---|---|---|---|---|---|
| Study VI | Study II | Study III | ||||
| HAQc Disability Index | Abatacepta+MTX | Placebo+MTX | Abatacepta+MTX | Placebo+MTX | Abatacepta+DMARDsb | Placebo+DMARDsb |
| Baseline (Mean) | 1.7 (n=254) | 1.7 (n=251) | 1.69 (n=422) | 1.69 (n=212) | 1.83 (n=249) | 1.82 (n=130) |
| Mean Improvement from Baseline | ||||||
| Month 6 | 0.85 (n=250) | 0.68 (n=249) | 0.59*** (n=420) | 0.40 (n=211) | 0.45*** (n=249) | 0.11 (n=130) |
| Month 12 | 0.96 (n=254) | 0.76 (n=251) | 0.66*** (n=422) | 0.37 (n=212) | NAe | NAe |
| Proportion of patients with a clinically meaningful improvementd | ||||||
| Month 6 | 72%† | 63% | 61%*** | 45% | 47%*** | 23% |
| Month 12 | 72%† | 62% | 64%*** | 39% | NAe | NAe |
*** p<0.001, abatacept vs. placebo.
† p<0.05, abatacept plus MTX vs MTX plus placebo
a Fixed dose approximating 10 mg/kg (see section 4.2).
b Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, gold, and anakinra.
c Health Assessment Questionnaire; 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
d Reduction in HAQ-DI of ≥ 0.3 units from baseline.
e After 6 months, patients were given the opportunity to enter into an open-label study.
In Study II, among patients with clinically meaningful improvement at month 12, 88% retained the response at month 18, and 85% retained the response at month 24. During the open-label periods of Studies I, II, III, and VI the improvement in physical function has been maintained through 7 years, 5 years, 5 years, and 2 years, respectively.
In Study SC-III, the proportion of subjects with a HAQ response as a measure of clinically meaningful improvement in physical function (reduction from baseline in HAQ-D1 score of ≥0.3) was greater for the abatacept+ MTX group vs. the MTX group at Month 12 (65.5% vs 44.0%, respectively; treatment difference vs. MTX group of 21.6% [95% CI: 8.3, 34.9]).
Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies I, II, and III and at 12 months in Studies I and II. In these studies, clinically and statistically significant improvement was observed in the abatacept group as compared with the placebo group in all 8 domains of the SF-36 (4 physical domains: physical function, role physical, bodily pain, general health; and 4 mental domains: vitality, social function, role emotional, mental health), as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS). In Study VI, improvement was observed at 12 months in abatacept plus methotrexate group as compared with the methotrexate plus placebo group in both PCS and MCS, and was maintained through 2 years.
A study of open-label intravenous abatacept on a background of nonbiologic DMARDs was conducted in patients with active RA who had an inadequate response to previous (washout for at least 2 months; n=449) or current (no washout period; n=597) TNF-inhibitor therapy (Study VII). The primary outcome, incidence of AEs, SAEs, and discontinuations due to AEs during 6 months of treatment, was similar between those who were previous and current TNF-inhibitor users at enrollment, as was the frequency of serious infections.
The efficacy and safety of abatacept were assessed in two randomized, double-blind, placebocontrolled trials (Studies PsA-I and PsA-II) in adult patients, age 18 years and older. Patients had active PsA (≥3 swollen joints and ≥3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin lesion of at least 2 cm in diameter.
In study PsA-I, 170 patients received placebo or abatacept intravenously (IV) on Day 1, 15, 29, and then every 28 days thereafter in a double blind manner for 24 weeks, followed by open-label abatacept 10 mg/kg IV every 28 days. Patients were randomized to receive placebo or abatacept 3 mg/kg, 10 mg/kg, or two doses of 30 mg/kg followed by 10 mg/kg, without escape for 24 weeks, followed by open label abatacept 10 mg/kg monthly IV every month. Patients were allowed to receive stable doses of concomitant methotrexate, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial.
In study PsA-II, 424 patients were randomized 1:1 to receive in a double-blind manner weekly doses of subcutaneous (SC) placebo or abatacept 125 mg without a loading dose for 24 weeks, followed by open-label abatacept 125 mg SC weekly. Patients were allowed to receive stable doses of concomitant methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial. Patients who had not achieved at least a 20% improvement from baseline in their swollen and tender joint counts by Week 16 escaped to open-label abatacept 125 mg SC weekly.
The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response at Week 24 (Day 169).
The percent of patients achieving ACR 20, 50, or 70 responses at the recommended abatacept dose in Studies PsA-I (10 mg/kg IV) and PsA-II (125 mg SC) are presented in Table 7 below.
Table 7. Proportion of Patients With ACR Responses at Week 24 in Studies PsA-I and PsA-II:
| PsA-Ia | PsA-IIb,c | |||||
|---|---|---|---|---|---|---|
| Abatacept 10 mg/kg IV N=40 | Placebo N=42 | Estimate of difference (95% CI) | Abatacept 125 mg SC N=213 | Placebo N=211 | Estimate of difference (95% CI) | |
| ACR 20 | 47.5%* | 19.0% | 28.7 (9.4, 48.0) | 39.4%* | 22.3% | 17.2 (8.7, 25.6) |
| ACR 50 | 25.0% | 2.4% | 22.7 (8.6, 36.9) | 19.2% | 12.3% | 6.9 (0.1, 13.7) |
| ACR 70 | 12.5% | 0% | 12.5 (2.3, 22.7) | 10.3% | 6.6% | 3.7 (-1.5, 8.9) |
* p<0.05 vs placebo, p values not assessed for ACR 50 and ACR 70.
a 37% of patients were previously treated with TNF inhibitor.
b 61% of patients were previously treated with TNF inhibitor.
c Patients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and were considered non-responders.
A significantly higher proportion of patients achieved an ACR 20 response after treatment with abatacept 10 mg/kg IV in PsA-I or 125 mg SC in PsA-II compared to placebo at Week 24 in the overall study populations. Higher ACR 20 responses were observed with abatacept vs placebo regardless of prior TNF-inhibitor treatment in both studies. In the smaller study PsA-I, the ACR 20 responses with abatacept 10 mg/kg IV vs placebo in patients who were TNF inhibitor-naive were 55.6% vs 20.0%, respectively, and in patients who were TNF inhibitor-experienced were 30.8% vs 16.7%, respectively. In study PsA-II, the ACR 20 responses with abatacept 125 mg SC vs placebo in patients who were TNF inhibitor-naive were 44.0% vs 22.2%, respectively (21.9 [8.3, 35.6], estimate of difference [95% CI]), and in patients who were TNF inhibitor-experienced were 36.4% vs 22.3%, respectively (14.0 [3.3, 24.8], estimate of difference [95% CI]).
Higher ACR 20 responses in study PsA-II were seen with abatacept 125 mg SC vs. placebo irrespective of concomitant non-biological DMARD treatment. The ACR 20 responses with abatacept 125 mg SC vs placebo in patients who did not use non-biological DMARDs were 27.3% vs 12.1%, respectively, (15.15 [1.83, 28.47], estimate of difference [95% CI]), and in patients who had used nonbiological DMARDs were 44.9% vs 26.9%, respectively, (18.00 [7.20, 28.81], estimate of difference [95% CI]). Clinical responses were maintained or continued to improve up to one year in studies PsA-I and PsA-II.
In study PsA-II, the proportion of radiographic non-progressors (≤0 change from baseline) in total PsA-modified SHS on x-rays at Week 24 was greater with abatacept 125 mg SC (42.7%) than placebo (32.7%) (10.0 [1.0, 19.1] estimate of difference [95% CI]).
In study PsA-I, the proportion of patients with ≥0.30 decrease from baseline in HAQ-DI score was 45.0% with IV abatacept vs 19.0% with placebo (26.1 [6.8, 45.5], estimate of difference [95% CI]) at Week 24. In study PsA-II, the proportion of patients with at least ≥0.35 decrease from baseline in HAQ-DI was 31.0% with abatacept vs. 23.7% with placebo (7.2 [-1.1, 15.6], estimate of difference [95% CI]). Improvement in HAQ-DI scores was maintained or improved for up to 1 year with continuing abatacept treatment in both PsA-I and PsA-II studies. No significant changes in PASI scores with abatacept treatment were seen over the 24-week doubleblind period. Patients entering the two PsA studies had mild to moderate psoriasis with median PASI scores of 8.6 in PsA-I and 4.5 in PsA-II. In study PsA-I, the proportions of patients achieving PASI 50 response was 28.6% with abatacept vs. 14.3% with placebo (14.3 [-15.3, 43.9], estimate of difference [95% CI]), and the proportion of patients who achieved PASI 75 response was 14.3% with abatacept vs. 4.8% with placebo (9.5 [-13.0, 32.0], estimate of difference [95% CI]). In study PsA-II, the proportion of patients who achieved PASI 50 response was 26.7% with abatacept vs. 19.6% with placebo (7.3 [-2.2, 16.7], estimate of difference [95% CI]), and the proportion of patients who achieved PASI 75 response was 16.4% with abatacept vs. 10.1% with placebo (6.4 [-1.3, 14.1], estimate of difference [95% CI]).
The European Medicines Agency has deferred the obligation to submit the results of studies with ORENCIA subcutaneous in one or more subsets of the paediatric population in chronic idiopathic arthritis (including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis) (see section 4.2 for information on paediatric use).
The geometric mean estimate (90% confidence interval) for the bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6% (64.7%, 95.6%). 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. 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.
A single study was conducted to determine the effect of monotherapy use of abatacept 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. The efficacy response over time in this study appeared consistent with studies that included an intravenous loading dose, however, the effect of no intravenous load on the onset of efficacy has not been formally studied.
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 MTX, NSAIDs, corticosteroids, and TNF-inhibitors did not influence abatacept apparent clearance.
In PsA-I, patients were randomized to receive IV placebo or abatacept 3 mg/kg (3/3 mg/kg), 10 mg/kg (10/10 mg/kg), or two doses of 30 mg/kg followed by 10 mg/kg (30/10 mg/kg), on Day 1, 15, 29, and then every 28 days thereafter. In this study, the steady-state concentrations of abatacept were doserelated. The geometric mean (CV%) Cmin at Day 169 were 7.8 mcg/mL (56.3%) for the 3/3 mg/kg, 24.3 mcg/mL (40.8%) for 10/10 mg/kg, and 26.6 mcg/mL (39.0%) for the 30/10 mg/kg regimens. In study PsA-II following weekly SC administration of abatacept at 125 mg, steady-state of abatacept was reached at Day 57 with the geometric mean (CV%) Cmin ranging from 22.3 (54.2%) to 25.6 (47.7%) mcg/mL on Days 57 to 169, respectively.
Consistent with the results observed earlier in RA patients, population pharmacokinetic analyses for abatacept in PsA patients revealed that there was a trend toward higher clearance (L/h) of abatacept with increasing body weight.
No mutagenicity or clastogenicity was observed with abatacept in a battery of in vitro studies. In a mouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary gland tumours (in females) occurred. The increased incidence of lymphomas and mammary tumours observed in mice treated with abatacept may have been associated with decreased control of murine leukaemia virus and mouse mammary tumour virus, respectively, in the presence of long-term immunomodulation. In a one-year toxicity study in cynomolgus monkeys, abatacept was not associated with any significant toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centres in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphological changes was observed, despite the presence of a virus, lymphocryptovirus, which is known to cause such lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of abatacept is unknown.
In rats, abatacept had no undesirable effects on male or female fertility. Embryo-foetal development studies were conducted with abatacept in mice, rats, and rabbits at doses up to 20 to 30 times a human 10 mg/kg dose and no undesirable effects were observed in the offspring. In rats and rabbits, abatacept exposure was up to 29-fold a human 10 mg/kg exposure based on AUC. Abatacept was shown to cross the placenta in rats and rabbits. In a pre- and postnatal development study with abatacept in rats, no undesirable effects were observed in pups of dams given abatacept at doses up to 45 mg/kg, representing 3-fold a human 10 mg/kg exposure based on AUC. At a dose of 200 mg/kg, representing 11-fold a human exposure at 10 mg/kg based on AUC, limited changes in immune function (a 9-fold increase in the mean T-cell-dependent antibody response in female pups and inflammation of the thyroid of 1 female pup out of 10 male and 10 female pups evaluated at this dose) were observed.
Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (juvenile rats). In addition, inflammation of the thyroid and pancreas was frequently seen in both juvenile and adult rats exposed to abatacept. Juvenile rats seemed to be more sensitive to lymphocytic inflammation of thyroid. Studies in adult mice and monkeys have not demonstrated similar findings. It is likely that the increased susceptibility to opportunistic infections observed in juvenile rats is associated with the exposure to abatacept before development of memory responses. The relevance of these results to humans greater than 6 years of age is unknown.
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