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Expert Opinion on Biological Therapy Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/iebt20

Subcutaneous abatacept in rheumatoid arthritis: current update a

b

Edward Keystone , Abdulaziz Alkhalaf & Mosaab Makkawy

c

a 1

Mount Sinai Hospital, Toronto, Ontario, Canada

b 2

King Saud University Medicine, Riyadh, Saudi Arabia

c 3

Prince Mohammed bin Abdulaziz Medicine, Riyadh, Saudi Arabia Published online: 09 Jul 2015.

Click for updates To cite this article: Edward Keystone, Abdulaziz Alkhalaf & Mosaab Makkawy (2015) Subcutaneous abatacept in rheumatoid arthritis: current update, Expert Opinion on Biological Therapy, 15:8, 1221-1230, DOI: 10.1517/14712598.2015.1065248 To link to this article: http://dx.doi.org/10.1517/14712598.2015.1065248

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Drug Evaluation

Subcutaneous abatacept in rheumatoid arthritis: current update 1.

Introduction

2.

Mechanism of action

3.

Route and recommended

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dose 4.

Pharmacokinetics

5.

Efficacy of subcutaneous abatacept

6.

Subcutaneous abatacept safety

7.

Pregnancy and nursing

8.

Immunization

9.

Immunogenicity

10.

Outcome of interest

11.

Conclusion

12.

Expert opinion

Edward Keystone†, Abdulaziz Alkhalaf & Mosaab Makkawy †

Mount Sinai Hospital, Toronto, Ontario, Canada

Introduction: A number of biologic agents have been approved for the treatment of rheumatoid arthritis (RA). They have changed the landscape of therapy and demonstrate substantial efficacy with a good safety record. One of these agents is intravenous (i.v.) abatacept (ABA), which has a novel mechanism of action by selectively inhibiting the interaction between T- and antigen-presenting cells. Recently, ABA administered by subcutaneous (s.c.) injection has also been approved for use in RA. In this review, will focus in recent data published in this agent. Areas covered: This paper reviews Phase III clinical trials (ACQUIRE, ACCOMPANY, ALLOW, ATTUNE, AMPLE and AVERT) in terms of clinical efficacy including long-term efficacy, radiographic progression, safety and immunogenicity. Expert opinion: Given the current trend in biologic therapy to s.c. administration, the availability of both i.v. and s.c. ABA provides considerable advantage both to patients and physicians in this competitive environment. The clinical trials have shown comparable efficacy and safety of s.c. ABA to i.v. ABA and others biologics. Keywords: abatacept, biologic therapy, rheumatoid arthritis, subcutaneous Expert Opin. Biol. Ther. (2015) 15(8):1221-1230

1.

Introduction

Rheumatoid arthritis (RA) is a chronic multisystem autoimmune inflammatory disease, with a 1% prevalence worldwide [1]. Early use of disease-modifying antirheumatic drugs (DMARDs) including methotrexate (MTX) and other biologic treatments leads to significant improvement in symptoms, function and inhibition of structural damage in patients with RA [2,3]. Different biological strategies have been implemented in patients with RA who have had an inadequate response to conventional DMARDs, and these strategies have shown significant efficiency in terms of reduction in sign and symptoms, improved function and reduced structural damage [4]. These strategies include TNF-a agents, IL (IL-1, IL-6) inhibition, B-cell depletion and T-cell targeting therapy represented by abatacept (ABA) (Box 1). 2.

Mechanism of action

Hematopoietic stem cells in the bone marrow are the original source of all T cells, which play a central role in immunity. The activation of T cells stimulates a variety of cellular activities, for example, macrophage activation, generation of proinflammatory cytokines and antibody producing B cells [5-8]. T cells require two signals to be activated: the first signal results from binding of the antigen-specific receptor on T cells in association with the major histocompatibility complex on the antigen-presenting cell (APC). The second signal known as 10.1517/14712598.2015.1065248 © 2015 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted

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4.

Box 1. Drug summary. Drug name Phase Indication Pharmacology description/mechanism of action Rout of administration Chemical structure

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Pivotal trails

Abatacept Launched Moderate-to-severe active RA Biologic agent inhibits T-cell (T lymphocyte) activation by blocking interaction between CD80/CD86 and CD28 Intravenous infusion Subcutaneous injection A recombinant fusion protein of the extracellular domain of human CTLA4 and a fragment of the Fc domain of IgG1 Phase III trials include: ACQUIRE, ACCOMPANY, ALLOW, ATTUNE, AMPLE and AVERT [16-19,24-27,33]

APC

CD80/CD86

MHC T cell receptor

Abatacept CD28 T cell

Figure 1. Abatacept inhibits T-cell activation by binding to CD80 and CD86 and preventing interaction between these and CD28.

the costimulatory signal is represented by interaction between the T cells surface receptors and APC [9,10]. ABA is a human fusion protein that selectively inhibits T-cell activation by binding to CD80/CD86, leading to a block of engagement with CD28 on APC’s known as the costimulatory signal (second signal) (Figure 1) [11-13]. 3.

Route and recommended dose

ABA primarily is used in combination with MTX or other DMARDs. Alternatively, it can be used alone as monotherapy. ABA is available in two forms: i.v. or s.c. Unlike i.v. ABA, which is dose-dependent on body weight (10 mg/kg/ month), s.c. ABA (self-injectable formulation) was approved as a fixed dose (125 mg/week) by FDA in 2011 and can be given with or without an i.v. loading dose (10 mg/kg). 1222

Pharmacokinetics

Intravenous and subcutaneous administration have a comparable half-life (14.3 days). After 85 days of treatment, the mean for Cmin at steady state was 32.5 mcg/ml (6.6 -- 113.8 mcg/ml) and Cmax at steady state was 48.1 mcg/ml (9.8 -- 132.4 mcg/ ml) [14,15]. Based on i.v. data, clearance of ABA increases with body weight and is not affected by age or gender. No clinical data is available on the pharmacokinetics effects on hepatic or renal impaired patients [15]. 5.

Efficacy of subcutaneous abatacept

Based on prior research and published clinical data, this review addresses six studies of s.c. ABA. The ACQUIRE study (Abatacept Comparison of Subcutaneous vs Intravenous in Inadequate Responders to Methotrexate) was a Phase III, 6-month randomized double-blind (1:1), non-inferiority study comparing efficacy and safety of i.v. and s.c. ABA in 1457 patients. Patients received either s.c. injection (125 mg) weekly, including an i.v. ABA infusion (~ 10 mg/kg) on day 1 only or i.v. infusion (~ 10 mg/kg) on days 1, 15 and 29, and every 4 weeks thereafter (up to day 162 for the s.c. ABA group, and up to day 141 for the i.v. ABA group. An open-label long-term extension (LTE) followed, in which all 1372 eligible patients received s.c. ABA 125 mg weekly. The ACR 20, 50 and 70 responses at 6 months were comparable in all three groups (Table 1; Figure 2). On day 169, DAS28 low disease activity (DAS28 LDAS) was achieved in 39.9% of patients with DAS28 remission achieved in 24.2% of patients in the s.c. group. In the i.v. group, DAS28 LDAS was achieved in 41.7% of patients and DAS28 remission was achieved in 25% of patients. On day 981 of the LTE, DAS28 remission was achieved in 38.5% of patients in s.c. ABA and in 34.5% of patients in the i.v. ABA group [16,17]. The results demonstrate comparable efficacy of i.v. versus s.c. ABA both in terms of the therapeutic response and target outcomes achieved with similar safety profiles. However, interpretation of the LTE was limited by the use of as observed data. ACCOMPANY study (Abatacept in Subjects with Rheumatoid Arthritis Administered Plus or Minus Background Methotrexate Subcutaneously) was a Phase III, multi-center, parallel-arm, open-label study. The study assessed immunogenicity, efficacy and safety of s.c. ABA with or without methotrexate based on MTX use prior to the study start in 90 patients. The study had two periods: a short-term period for 4 months and 18 months LTE. At 18 months, DAS28 LDAS was achieved in 57.5% patients and DAS28 remission was achieved in 42.5% of the combination group. In the monotherapy group, DAS28 LDAS was achieved in 69.4% with DAS28 remission achieved in 58.3%, and although the ACCOMPANY study

Expert Opin. Biol. Ther. (2015) 15(8)

25%

-2.55 (-2.65, -2.45)

80.00% 52.80% 26.70%

24.20%

-2.57 (-2.67, -2.47)

80.20% 53.40% 27.70%

NR

41.70%

39.90%

6 month*

Open-label

51

s.c. Abatacept + MTX

-2.86 (-3.46, -2.27)

58.30%

NR NR NR NR

-1.84 (-2.33, -1.34)

42.50%

4 months short term 18 months LTE † 69.40% 57.50%

49

s.c. Abatacept

ACCOMPANY [33] s.c. Abatacept + MTX (withdraw/ reintroduction)

-2.22 (-2.50, -1.94)

51.30%

69.20%

NR NR NR NR

-2.32 (-2.56, -2.09)

63.50%

79.70%

40 80 Phase I: Open-label Phase II: Double blind Phase III: Open-label 9 months

s.c. Abatacept + MTX (continuous)

ALLOW [18,19]

-0.24 (NR)

43.50%

58%

71

NR NR NR NR

52

-0.07 (NR)

34.10%

40.90%

12 months

Open-label

s.c. Abatacept (anti-TNF IR)

ATTUNE [24] s.c. Abatacept (MTX-IR)

Trial

59.70% 44.70% 31.10% 0.58 (3.22)

-2.35 (-2.51, -2.19)

50.60%

53.30%

68%

60.10% 46.60% 29.30% 0.38 (5)

-2.33 (-2.50, -2.17)

24 months

328

Adalimumab + MTX

Double blind

65.30%

318

s.c. Abatacept + MTX

AMPLE [25,26]

75% 63.00% 52.10%

s.c. Abatacept

65.50% 53.40% 38.80% NR

-0.26 (-0.11, -0.48)

42.50%

†

NA

12 months

116 Double blind

-0.52 (-0.74, -0.30)

60.90%

NA

119

s.c. Abatacept + MTX

AVERT [27]

*All result on day 169. Result at 18 months. z Unless otherwise stated. ACR: American college of rheumatology; CRP: C-reactive protein; DAS 28: Disease activity score in 28 joints; LDAS: Low disease activity score; NR: Not reported; SD: Stander deviation; TSS: Total sharp score [16-19,24-27,33].

Study duration DAS28 LDAS DAS28 Remission DAS28-CRP mean change from baseline (95% CI)z %ACR 20 %ACR 50 %ACR 70 Radiographic progression (mean TSS change± SD)

736

No. patient Study design

i.v. Abatacept + MTX

721 Double blind

s.c. Abatacept + MTX

Therapy:

ACQUIRE [16,17]

Table 1. Efficacy of abatacept iin rheumatoid arthritis trials.

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63.80% 46.60% 34.50%

-

45.20%

NA

116

MTX

E. Keystone et al.

100

80 80.0% n = 670

Patients (%)

80.2% n = 686

81.9% n = 652

60 53.4% n = 689

52.8% n = 672

58.5% n = 653

57% n = 663

84.8% n = 310

63.5% n = 310

84.7% n = 301

63.2% n = 302

40

20

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81.8% n = 661

27.7% n = 690

26.7% n = 671

39.5% n = 309

33.6% n = 666

33% n = 655

39.2% n = 301

ACR20 ACR50 ACR70

0 s.c. ABA

i.v. ABA Day 169

s.c. ABA

i.v. ABA Day 365

s.c. ABA

i.v. ABA Day 981

Figure 2. Proportion of subcutaneous (s.c.) or intravenous abatacept-treated patients in the ACQUIRE study achieving ACR-20, -50 or -70 responses for patients who entered the long-term extension (all patients received s.c. abatacept + methotrexate, n = 1372; as-observed analysis) [16,17]. ABA: Abatacept; ACR: American college of rheumatology.

had a relatively small sample size, the data supports the use of s.c. ABA as monotherapy. In the Phase IIIb ALLOW study (Evaluation of Abatacept Administrated Subcutaneously in Adults with Active Reintroduction on Immunogenicity, Efficacy and Safety), 167 patients were enrolled in period I, an open-label study for 12 weeks (i.v. ABA loading dose ~ 10 mg/kg and weekly fixed dose of ABA 125 mg s.c.). This was followed by period II, a randomized double-blind 12-week trial of 120 patients treated with s.c. placebo or s.c. ABA. Subsequently, 119 patients entered period III, a 12-week open-label study where the placebo group received s.c. ABA and the other group continued on same s.c. ABA dose. The response of DAS28-CRP at the initial and re-introduction period were comparable at 9 months, the DAS28 LDAS was achieved in 69.2% and DAS28 remission in 51.3% of the subcutaneous continuous group. In the withdraw and reintroduction group, DAS28 LDAS was achieved in 79.7% and DAS28 remission in 63.5% [18,19]. The results give credence to the concept of s.c. ABA’s low immunogenicity consistent with its molecular structure of a CD 28 fusion protein and not a monoclonal antibody. ATTUNE study (Abatacept in subjects who switch from intravenous to subcutaneous therapy) (Figure 3) was a Phase III b, 12-month open-label single-arm study of 123 patients with active RA previously refractory to either MTX or anti-TNFs who had received ‡ 4 years of i.v. ABA in AIM (Abatacept in Inadequate responders to Methotrexate 1224

study) or ATTAIN (Abatacept Trial in Treatment of AntiTNF inadequate responders) [20-23]. In the ACR 20, 50 and 70 responses, the ABA plus MTX group was superior to the groups, which is expected. However, monotherapy was slightly better in ACR responses in comparison to MTX. Throughout the 12 months, efficacy was maintained in the switching group where DAS28 LDAS was achieved in 51.3% (43.4% at the baseline) and DAS28 remission in 39.8% (32% at baseline) [24]. Despite a small sample size and short trial duration with a fixed treatment regimen, the results of the AMPLE trial suggest that switching from i.v. and s.c. ABA can be accomplished without loss of efficacy. AMPLE study (Abatacept vs Adalimumab Comparison in Biologic-Naı¨ve rheumatoid arthritis Subjects With background Methotrexate) was a Phase IIIb, 2-year head-to-head study in 646 patients with active RA who received 125 mg s.c. ABA weekly or 40 mg s.c. adalimumab (ADA) biweekly, both given in combination with MTX. The result showed that ACR 20, 50 and 70 responses were comparable at 24 months (Table 1). Also, DAS28 LDAS was achieved in 65.3% and DAS28 remission in 50.6% of the s.c. ABA group. In the ADA group, DAS28 LDAS was achieved in 68% and DAS28 remission in 53.3% [25,26]. Overall the results demonstrated comparable efficacy of ABA to ADA both clinically and radiographically. AVERT study (Assessing Very Early RA Treatment) was a Phase IIIb trial in 232 patients with early active RA who were randomized to double-blind (1:1:1) weekly, s.c. ABA 125 mg plus MTX, ABA 125 mg monotherapy, or MTX for

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Abatacept

A. LDAS

Proportion of patients in LDAS (%)

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100

64.3%

80

58.0% 54.6%

60

51.3%

40.8%

40.9%

40

20

Proportion of patients in remission (%)

B. Remission

100

80 48.6%

60

43.5% 39.8%

38.7% 34.1%

40

24.5%

20

0

0 Month 3

Month 6

Month 12

Month 3

Month 6

Month 12

Anti-TNF inadequate responders Overall MTX inadequate responders

Figure 3. Maintenance of clinical efficacy (A) Proportion of patients sustaining DAS28 LDAS; error bars represent 95% CI. (B) Proportion of patients sustaining remission; error bars represent 95% CI. LDAS is defined as DAS28 (CRP) £3.2 and remission as DAS28 (CRP) < 2.6. CRP: C-reactive protein; LDAS: Low disease activity score; s.c.: Subcutaneous.

12 months. The study population included patients with active clinical synovitis of ‡ 2 joints for ‡ 8 weeks, and persistent symptoms for £ 2 years. In the ACR 20, 50 and 70 responses, the ABA plus MTX group was superior to the groups which is expected. However, monotherapy was slightly better in ACR responses in comparison to MTX (Table 1). At 12 months, DAS28 remission was achieved in 60.9% of the ABA plus MTX group, 45.2% of the MTX monotherapy group and 42.5% of the ABA monotherapy group [27]. The results showed that despite early aggressive therapy with the MTX/ABA combination, few patient achieve drug free remission. This data suggests that early use of s.c. ABA is more efficacious than use later in disease, suggesting the role of ABA in treatment of early RA patients. The results are consistent with studies of IV ABA [28,29].

pooled analysis [30,31] which compared efficacy and safety between s.c. ABA and i.v. ABA from five clinical trials (Phase II, ACQUIRE, ACCOMPANY, ALLOW, ATTUNE) over 4.5 years, the safety was reported as the incident rate (IR) in events per 100 patient-years. The IR of death with s.c. ABA was similar to i.v. ABA, 0.55 and 0.6, respectively. There were four cases of infection, two cases of malignancy (peritoneal and lung cancer) and one case of multiple organ failure who died in the s.c. ABT group. Indirect comparison of intravenous ABA to other biologics reported in a Cochrane review [32] showed a better safety profile mainly in relation to the total serious adverse events and serious infection. The incidence of malignancies was comparable to other biologic therapies.

Radiographic progression Radiographic progression reflects the long term damage and disability in RA. The AMPLE study compared radiographic progression between s.c. ABA and s.c. ADA. Comparable progression was observed in both groups through 2 years of treatment with similar change from baseline in the total Van De Heijde sharp score at all 4 months (Figure 4) [25,26].

6.1

5.1

6.

Subcutaneous abatacept safety

The most frequently reported adverse effects of s.c. ABA were pneumonia, urinary tract infection and gastroenteritis. In the

Infection In the pooled analysis [30], the most common serious infections reported, which were also the most common adverse effects, were pneumonia (IR 0.36), urinary tract infection (IR 0.14) and gastroenteritis (IR 0.10). In these clinical trials, the IR of opportunistic infections was 0.31, and the IR of Herpes Zoster was 0.7. Among the s.c. ABA group, there were four cases of tuberculosis (TB). Two cases of pulmonary TB, one case of peritoneal TB and one case of TB with no dissemination. Over a cumulative period, there were no more cases of TB reported.

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Change from baseline ≤ SDC (%)

100 88.6% 84.8% 87.8%

80

83.8%

60

s.c. Abatacept Adalimumab

0 Baseline

Year 1

Year 2

s.c. Abatacept (n = 295)

s.c. Abatacept (n = 257)

Adalimumab (n = 297)

Adalimumab (n = 260)

Time point Figure 4. Radiographic outcomes in patients treated with s.c. abatacept or adalimumab over 2 years: change from baseline # SDC (%). s.c.: Subcutaneous; SDC: Smallest detectable change.

Overall, the IR of serious infections with long-term exposure (5 years) to s.c. ABA was 3.31, which was relatively stable. The IR of Herpes Zoster was 0.7. In the AVERT trial [27], the rate of infection and serious infection were higher on the s.c. ABA plus MTX group (3.4%) in comparison to (0.8%) s.c. ABA monotherapy, with no event with MTX monotherapy. In the AQUIRE trial [16,17], the risk of serious infection i.v. ABA was 0.7 -- 1.4% for the s.c. ABA. The rate of serious infections were higher in the AMPLE trial [28], in the ADA 5.8 versus 3.8% in the s.c. ABA group. Discontinuation due to a serious infection was higher with ADA (n = 5) versus s.c. ABA (n = 0).

Injection site reaction The IR of injection site reaction (ISR) reported in the pooled analysis was 2.2. In the ACCOMPANY trial [33], the most common reaction was pruritus. The rate of the reaction of s.c. ABA plus MTX versus s.c. ABA monotherapy was 5.9 and 8.2%, respectively. In the long-term 20 month extension period, the rate of the reactions was not reported in the all 90 patients included. In the ALLOW trial [18,19], two events (pruritus and hematoma) were reported in the introduction period (s.c. ABA with i.v. ABA loading dose). In period II (withdrawal Phase) and period III (re-introduction phase), there were no reaction events reported. 6.2

1226

In the AMPLE trial [25,26], the ISRs with ADA group were much higher, with an IR of 10.4% with ADA versus 3.8% with s.c. ABA. The rate of discontinuation due to ISR was more common with ADA than the s.c. ABA groups. Malignancy The overall rate of malignancy did not increase with cumulative period of exposure to s.c. ABA in the pooled analysis [30]. The IR of total malignancies excluding non-melanoma skin cancer was 0.71. The basal cell carcinoma IR was 0.45, and 0.21 for squamous cell cancer. Lymphoma in particular was not reported in any case of both i.v. and ABA groups. In the AQUIRE trial [17], LTE the IR of all malignancies was 1.19 which is in the same range of RA-patients treated with DMARD therapy [34]. The rate of malignancy was not different between the s.c. and i.v. ABA groups. In the AVERT trial [27], the rate of malignancy was 0.8, 1.7 and 0.9% for ABA plus MTX, ABA monotherapy and MTX, respectively. In the AMPLE trial [25,26], there were seven cases of malignancy each in the s.c. ABA and ADA groups. Two cases of squamous cell carcinoma, one case of acute myeloid leukemia, one case of diffuse large B cell lymphoma, one case of squamous cell carcinoma of lung, one case of prostate cancer and once case of uterine cancer, were reported on s.c. ABA group. In the ADA group, two basal cell carcinomas, two transitional cell carcinomas, one breast cancer, one malignant melanoma and one small cell lung cancer were reported. 6.3

Expert Opin. Biol. Ther. (2015) 15(8)

Abatacept

Table 2. The main safety profile of subcutaneous abatacept as reported in the clinical trials profile. Clinical trial

ACQUIRE [16,17]

ACCOMPANY*

Treatment group

S/C Abatacept + MTX i.v. Abatacept + MTX All S/C Abatacept

No. patients

No. serious adverse effects (%)

No. serious infections (%)

No. malignancies (%)

No. deaths (%)

736

31 (4.2)

5 (0.7)

3 (0.4)

2 (0.3)

721

35 (4.9)

10 (0.6)

5 (0.7)

5 (0.7)

90

13 (17.4)

4 (4.4)

1 (1.1)

0

40 80 71

0 2 (2.25) 8 (11.3)

5 (12.5) 7 (8.8) 1 (0.7)

0 0 0

0 0 0

52

8 (9.6)

0

2 (3.8)

0

318

44(13.8)

12 (3.8)

7 (2.2)

1 (0.3)

328 119

54 (16.5) 8 (6.7)

19 (5.8) 1 (0.8)

7 (2.1) 1 (0.8)

1 (0.3) 0

116 116

14 (12.1) 9 (7.8)

4 (3.4) 0

2 (1.7) 1 (0.9)

0 0

[33]

ALLOW† [18,19]

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ATTUNE [24]

AMPLEz [25,26]

AVERT [27]

s.c. abatacept s.c. placebo S/C Abatacept (MTX-IR) S/C Abatacept (anti-TNF IR) S/C Abatacept + MTX Adalimumab + MTX S/C Abatacept + MTX S/C Abatacept MTX

*Long-term extension up to 20 months, 47 patients on s.c. abatacept plus methotrexate and 43 patients on s.c. abatacept onotherapy. † The date presented her is from the withdrawal Phase (period II). z Two-year analysis [16,17,33,18,19,24-27]. MTX: Methotrexate; s.c.: Subcutaneous.

Autoimmune events The most common autoimmune events reported in the pooled analysis were psoriasis with an IR of 0.33, sjogren’s syndrome (IR 0.24) and erythema nodosum (IR 0.12). In the ATTUNE trial [24], of 123 patients continuing on s.c. ABT, there was one case of sarcoidosis and one of erythema nodosum. In the ACCOMPANY trial [33], there was one case of autoimmune thyroiditis. In the 2-year analysis of AMPLE trial [25,26], the rate of autoimmune events was 1.8% in ADA group and 3.8% in s.c. ABA group. The rate of ANA seroconversion was 6.3% in the s.c. ABA versus 14.7% with ADA group. In the ADA group, 12.2% were anti-dsDNA test positive, compare to none of the s.c. ABA group. The main safety profile of all clinical trials is summarized in Table 2. 6.4

7.

Pregnancy and nursing

There is not enough data to show whether s.c. ABA can be used safely in pregnant or nursing mothers. It has been shown that ABA can cross the placenta of animals. FDA classifies ABA as class C in pregnancy, and it should be used only if the potential benefit to the mother justifies the potential risk to the fetus [15]. ABA is also excreted in rat milk, but it is not known if it is excreted in human milk. It is prudent to advise the patient to either discontinue nursing or ABA.

8.

Immunization

It is recommended to not receive live vaccines while a patient is receiving ABA. It should be considered 3 months prior to start of therapy. Pneumococcal vaccine, one of the most recommended vaccines, should be given for RA patients on biologic therapy. It was shown that ABA reduced the antibody response on i.v. ABA.

9.

Immunogenicity

The presence of antibodies can lead to decrease in the concentration of the drug and hence efficacy. Anti-abatacept or CLTA4 antibody is detected by either ELISA (enzyme linked immunosorbent assay) and ELS (electroluminescence). ELISA detects the whole ABA or CLTA-4 portion, while ELS is similar to but more sensitive than the ELISA [35-37]. In the pooled analysis, there were no serious adverse effects related to the immunogenicity: s.c. ABA had similar immunogenicity to i.v. ABA. Switching from i.v. ABA to s.c. ABA was addressed in ATTUNE trial, the rate was 6.6% by ELISA and no antibodies detected by ECL at 3 months. None of the ELISA-positive patients discontinued the study due to a serious adverse event. The re-introduction phase (after a 3-month withdrawal of s.c. ABA and entry into the open-label phase) in the ALLOW trial showed no difference in efficacy or safety in patients, whether they withdrew or continued s.c. ABA.

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In the ACCOMPANY trial during a 16-month period, antibodies did not lead to serious adverse effects in the ABA monotherapy group. In fact, there were more antibodies detected in the combined group (ABA plus MTX) compared to ABA monotherapy. However, 73.9% of patients on s.c. ABA were able to maintain the antibody response at day 28 after in two clinical trials [16,17,24] after standard 23-valent pneumococcal polysaccharide vaccine.

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10.

Outcome of interest

There were two cases of systemic vasculitis and one case of leucocytoclastic vasculitis reported in all clinical trials [28]. There is recent data showing the safety of ABA use in RA patients with or without pulmonary complications. Interestingly, some patients improved after ABA therapy [38]. 11.

12.1 Position of s.c. abatacept in the current therapeutic algorithm

Conclusion

The data presented demonstrate the efficacy and safety of s.c. ABA is comparable to i.v. ABA. The efficacy of s.c. ABA is similar to that of ADA with the possibility of a better safety profile with regards of serious infection. 12.

Expert opinion

The need for more options in the administration of biologic therapy is important for both, clinicians and patients. Having i.v. and s.c. therapy for RA patients is an advantage. Some patients having difficulty for easy access to infusion center to get their medication for many different reasons; busy job schedules, different life-style, long-distance stay and difficult transportation or disability. s.c. ABA in the clinical trials showed similar efficacy and safety profile in comparison to i.v. ABA. The data also showed that patients can be switched from i.v. to s.c. ABA without loss of efficacy, without a change or increase adverse events [24]. The issue of giving i.v. loading dose prior to s.c. ABA was addressed [38,39]. The data showed patients had a similar result whether he/she received the loading dose. However, there are a number of caveats regarding the data presented in several trials that need to be addressed. Although the data in the ATTUNE study suggests the ability to switch from i.v. to s. c. ABA in patients that have achieved low disease state or remission after several years of i.v. therapy a relatively small number of patients were studied in an open-label fashion using as observed data. The patients had a fixed s.c. treatment regimen for 3 months and then were allowed DMARD and NSAID changes in the extension period. Although limited, the data suggest that at least in the short-term, patients continue to do well by switching from i.v. to s.c. ABA. A longer study with a larger population would be needed to validate the findings. Whether patients treated with i.v. ABA for a 1228

significantly shorter period of time would maintain the similar disease state remains unclear. The ACCOMPANY trial data showed similar efficacy, safety and tolerability whether s.c. ABA is combined with MTX or not. Although the data does provide some support for the use of ABA as monotherapy, the trial was open-label and sample size of the study was small. A larger double blind study would have been more convincing. The AVERT trial tested the hypothesis that treatment with ABA in patients with very early RA would enable a substantial proportion of patients would achieve drug free remission. However, the results showed that only a minority of patients achieved drug-free remission. Unfortunately, an opportunity was lost to evaluate the sustainability of ABA-free remission with maintenance of methotrexate. Similar studies of other biologics have yielded similar results.

The place of s.c. ABA in the current biologic armamentarium is predictable. The comparable efficacy and safety of s.c. ABA to i.v. ABA with similar efficacy to ADA, its low immunogenicity, some evidence as a monotherapy, as well as ability to switch from i.v. to s.c. therapy makes ABA particularly appealing with the likelihood of a more rapid uptake than its i.v. formulation. The availability of two formulations is clearly advantageous. Here patient, and possibly in the USA payer, preference may determine its use. Given s.c. ABA current dossier, it will be used earlier in RA than its i.v. counterpart. More data on its efficacy as a monotherapy as well as a demonstration of dose reduction or even ABA-free remission in target responders will help cement its position within the algorithm. Although there is a paucity of data in TNFi inadequate responders with s.c. ABA, the efficacy of i.v. ABA in the ATTAIN trial, coupled with similar outcomes of the s.c. and i.v. formulation to date make it likely to perform in a similar fashion. Taken together, the data presented in this review demonstrate that ABA is an important and welcome addition to the therapeutic armamentarium in RA.

Acknowledgments Sources of Funding for Research: Abbvie Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, F. Hoffmann-La Roche Inc, Janssen Inc, Novartis Pharmaceuticals, Sanofi-Aventis, UCB. Consulting Agreements/Advisory Board Membership: Abbott Laboratories, AstraZeneca Pharma, Bristol-Myers Squibb Company, F. Hoffmann-La Roche Inc, Genentech Inc, Janssen Inc, UCB. Speaker Honoraria Agreements: Abbvie Laboratories, Astrazeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., UCB, Amgen.

Expert Opin. Biol. Ther. (2015) 15(8)

Abatacept

Declaration of interest E Keystone has received research funding speaker honoraria, consultancy fees and participated in advisory boards for Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with

any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation

Edward Keystone†1, Abdulaziz Alkhalaf2 & Mosaab Makkawy3 † Author for correspondence 1 Mount Sinai Hospital, Toronto, Ontario, Canada E-mail: [email protected] 2 King Saud University Medicine, Riyadh, Saudi Arabia 3 Prince Mohammed bin Abdulaziz Medicine, Riyadh, Saudi Arabia