BioDrugs (2014) 28 (Suppl 1):S25–S37 DOI 10.1007/s40259-013-0065-y

REVIEW ARTICLE

Efficacy and Safety of Certolizumab Pegol in Rheumatoid Arthritis: Meeting Rheumatologists’ Requirements in Routine Clinical Practice Leonardo Punzi • Giovanni Lapadula Alessandro Mathieu

•

Ó Springer International Publishing Switzerland 2014

Abstract Certolizumab pegol, a pegylated Fab0 antitumour necrosis factor (TNF)-a agent, has shown efficacy in patients with rheumatoid arthritis (RA) unresponsive to previous treatment. In key randomised controlled trials involving patients with moderate to severe RA and an inadequate response to methotrexate or one or more disease-modifying antirheumatic drug (DMARD), the efficacy of certolizumab pegol, as monotherapy or with methotrexate, was similar to that reported in other anti-TNF clinical studies, with 60 % or fewer of patients achieving American College of Rheumatology 20 % improvement in RA. Rapid clinical response was also seen, with significant differences evident at week 1, and efficacy maintained at study end and in open-label extensions. Adding certolizumab pegol to non-biological DMARDs is efficacious in other RA populations. In the CERTAIN study, certolizumab increased remission rates, prevented disease worsening and improved work productivity and daily activity in patients with low to moderate RA. In the REALISTIC study, rapid and consistent clinical responses were observed in a diverse group of anti-TNF-eligible RA patients representing those seen in clinical practice. In the RAPID studies, rapid and sustained reduction in RA signs

L. Punzi (&) Rheumatology Unit, Department of Medicine DIMED, University of Padova, 35128 Padua, Italy e-mail: [email protected] G. Lapadula Rheumatology Unit of Interdisciplinary Department of Medicine (DIM), University of Bari, Bari, Italy A. Mathieu Rheumatology Unit, Department of Medical Sciences, University of Cagliari, Cagliari, Italy

and symptoms, inhibition of structural joint damage progression, and improved physical function were seen with certolizumab pegol plus methotrexate versus methotrexate alone in RA patients with an incomplete response to methotrexate. Certolizumab pegol was generally well-tolerated in clinical trials, although long-term observational data are not yet available. Current data suggest that certolizumab pegol suits a ‘treat to target’ approach, providing rapid and sustained improvements in RA signs and symptoms, and beneficial effects on workplace and home productivity in patients with RA.

1 Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with significant morbidity and mortality that is estimated to affect between 0.5 and 1.0 % of adults in developed countries. Its prevalence increases with age, and it is threefold more common in women than men [1, 2]. Tumour necrosis factor (TNF)-a is a key cytokine involved in the inflammation-induced joint damage in RA, and the availability of TNF-a inhibitors has revolutionised the treatment of RA [3]. However, the lack of response and tolerability issues with existing agents suggests the need for TNF-a inhibitors with improved efficacy and tolerability profiles. Certolizumab pegol is the only pegylated Fab0 anti-TNF agent, and it is currently approved for use in combination with methotrexate in patients with moderate to severe RA who have inadequate response to treatment, or as monotherapy in methotrexate-intolerant patients [4, 5]. This paper reviews the efficacy and safety of certolizumab pegol in clinical trials of patients with RA, and

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discusses its potential role as part of a ‘treating to target’ management strategy in these patients.

2 Clinical Efficacy in Different Settings Several randomised, double-blind, placebo-controlled clinical trials have evaluated the efficacy of certolizumab pegol in patients with RA (Table 1): RAPID (Rheumatoid Arthritis PreventIon of structural Damage) 1; RAPID 2; FAST4WARD (eFficAcy and Safety of cerTolizumab pegol-4-Weekly dosAge in RheumatoiD arthritis); REALISTIC (RA EvALuation In Subjects receiving TNF-a Inhibitor Certolizumab pegol); CERTAIN (CERTolizumab pegol in the treatment of RA: remission INduction and maintenance in patients with low disease activity); and C87014 (the Efficacy and Safety of Certolizumab Pegol 400 mg in Combination with Methotrexate Compared to Methotrexate Alone in the Treatment of the Signs and Symptoms of Patients with Rheumatoid Arthritis who are Partial Responders to Methotrexate Study) [6–11]. In phase III trials, patients had moderate to severe RA and inadequate response to methotrexate (RAPID 1 [7] and RAPID 2 [9]), or had failed to respond to one or more previous disease-modifying antirheumatic drugs [DMARDs] (FAST4WARD) [6]. In phase IIIb trials, patients had active inadequately controlled RA with varying disease durations, co-morbidities, and a variety of previous and current DMARDs (including almost 40 % who had previously been treated with a TNF-a inhibitor; REALISTIC) [11] or had low to moderate disease activity (CERTAIN) [8]. The primary efficacy measure in the majority of clinical trials of certolizumab pegol was the American College of Rheumatology (ACR) 20 % definition of improvement in RA (ACR20) [12]. Response is defined as a 20 % or greater improvement in both tender and swollen joint counts, as well as an improvement of 20 % or greater in three of the five other measures (patient’s and physician’s global assessment of disease activity, patient’s assessments of pain and physical function, and an acute-phase reactant [either C-reactive protein or erythrocyte sedimentation rate]) [12]. The primary efficacy endpoint in the CERTAIN trial was remission, defined by the Clinical Disease Activity Index (CDAI), a composite index for assessing disease activity [13].

L. Punzi et al.

In both RAPID 1 and RAPID 2, ACR20 responder rates at the end of the study were significantly higher in patients treated with certolizumab pegol than placebo (Table 2). Certolizumab pegol also significantly inhibited the progression of structural damage and improved physical functioning in RA, as evidenced by changes in the modified total Sharp score (mTSS; a radiographic measure of structural joint damage) [15] and a reduction in the Health Assessment Questionnaire–Disability Index (HAQ-DI) [7, 9]. Other secondary clinical endpoints, including ACR 50 % and 70 % definition of improvement in RA (ACR50 and ACR70), and the mean change in the Disease Activity Score in 28 joints (DAS28), were also significantly improved in patients who received either dose of certolizumab pegol compared with placebo (Table 2). 2.1.1 Early Response and Clinical Outcomes In RAPID 1, significant differences in ACR20 response rates were evident at week 1, peaked at week 12, and were maintained at week 52 (p \ 0.001) [7]. A post hoc analysis of RAPID 1 showed rapid clinical responses evaluated using European League Against Rheumatism (EULAR), DAS28 of C1.2 and ACR20 responses [16]. Furthermore, the rapid attainment of clinical response (i.e. by week 6) was associated with more meaningful and sustained improvements in clinical and patient-derived outcomes at week 52 than those achieving a response at week 12 [16]. Early response by week 12 (i.e. DAS28 improvement from baseline of C1.2 points) also predicted the likelihood of achieving low disease activity (DAS28 B3.2): among certolizumab pegol-treated patients with versus without an early response, 37 versus 6 % had low disease activity at 1 year [17]. Additional analysis demonstrated that a nonresponse at week 12 was shown to predict failure to achieve low disease activity at 52 weeks; fewer patients with a DAS28 improvement less than 0.6 at week 12 had low disease activity at week 52 than patients with a DAS28 improvement less than 1.2 [18]. Similarly, in a post hoc analysis from the RAPID 2 trial, more patients with improvements in pain at week 6 than week 12 had lower disease activity at week 24 [19]. Pain responders at week 12 also had better clinical outcomes at week 24 than non-responders [19]. 2.1.2 Patient-Reported Outcomes

2.1 Efficacy in Combination with Methotrexate RAPID 1 and RAPID 2 were 52- and 24-week studies, respectively, in which patients received subcutaneous certolizumab pegol 400 mg at weeks 0, 2 and 4, followed by either certolizumab pegol 200 or 400 mg, or placebo, every 2 weeks in addition to methotrexate [7, 9].

Overall, patients treated with certolizumab pegol in addition to methotrexate in RAPID 1 and RAPID 2 had rapid and clinically meaningful improvements in all patientreported outcomes, including pain, patient’s global assessment of disease activity, physical function, fatigue, and health-related quality of life [19, 20].

To investigate the efficacy and safety of CZP monotherapy in patients with RA previously nonresponsive to at least one DMARD

Diagnosis of inflammatory arthritis other than RA; history of life-threatening, serious or chronic infection; current infection; test suggestive of TB (chest X-ray or positive Mantoux); history of TB; use of biological RA treatments within 6 months prior to study; previous treatment with any anti-TNF agent

Age 18–75 years; adult-onset RA for C6 months; C9 tender joints, C9 swollen joints and either C45 mins morning stiffness, ESR C28 mm/h or CRP [10 mg/L

Age C18 years; adult-onset RA for C6 months; C9 tender joints, C9 swollen joints and either ESR C30 mm/h or CRP [15 mg/L

Patients nonresponsive to C1 previous DMARD (220)

Patients with active RA despite the use of MTX (982)

FAST4WARD (mc, r, db, pc; 24) [6]

RAPID 1 (mc, r, db, pc; 52) [7]

Diagnosis of inflammatory or noninflammatory secondary arthritis, other than RA; high risk of infection; history of malignancy, demyelinating disease, blood dyscrasias; test suggestive of active or latent TB (chest X-ray or positive Mantoux); history of TB; severe, progressive and/or uncontrolled hepatic, hematologic, renal, gastrointestinal, cardiac, cerebral, endocrine, pulmonary or neurological disease; use of biological RA treatments within 6 months prior to study, or etanercept and/or akinra within 3 months; a previous severe allergic reaction to biological therapy; previous non-response to any anti-TNF agent

Comparing the efficacy and safety of CZP ? MTX versus PL ? MTX in patients non-responsive to MTX

Diagnosis of inflammatory arthritis other than RA; history of life-threatening, serious or chronic infection; current infection; test suggestive of TB (chest X-ray or positive Mantoux); history of TB; history of infected joint prosthesis; use of corticosteroids or hyaluronic acid within 4 weeks prior to study; previous treatment with any anti-TNF agent

Age 18–75 years; adult-onset RA for C6 months; C9 tender joints, C9 swollen joints and either C45 min morning stiffness, ESR C28 mm/h or CRP [10 mg/L; receipt of MTX for C6 months, plus a stable dosage of 15–25 mg/week for C8 weeks prior to study

Patients with active RA despite the use of MTX (247)

Choy et al. (mc, r, db, pc; 24) [10]

To investigate the efficacy and safety of CZP (200 or 400 mg) ? MTX versus PL ? MTX in patients non-responsive to MTX

To determine the efficacy and safety of CZP, including effects on work productivity and daily activity

Not stated

Not stated

Patients with low to moderate disease activity (194)

CERTAIN (mc, r, db, pc; 52) [8]

Aim(s)

Exclusion criteria

Inclusion criteria

Study population (n)

Clinical trial (study design; duration, weeks)

Table 1 Study design details of the main certolizumab clinical trials (n [ 150)

Primary endpoint: ACR20 response at week 24 and the mTSS at week 52. Secondary endpoint: ACR50 and ACR70 response at weeks 24 and 52; ACR20 response at week 52; change from BL in HAQ-DI at weeks 24 and 52 and in the mTSS at week 24

Primary endpoint: ACR20 response at week 24. Secondary endpoint: ACR50 and ACR70 response; ACR component measures; VAS, DAS28 (ESR)3, HAQDI, HR-QOL, SF-36, mBPI, FAS

Primary endpoint: ACR20 response at week 24. Secondary endpoint: ACR50 and ACR70 response; ACR component measures; VAS, HAQ-DI, HR-QOL, SF36

Primary endpoint: percentage of patients in remission (CDAI B2.8) at weeks 20 and 24

Outcome measurements

Efficacy and Safety of Certolizumab Pegol in Rheumatoid Arthritis S27

Patients with active RA despite the use of MTX (619)

Patients nonresponsive to C1 previous DMARD (1,063)

RAPID 2 (mc, r, db, pc; 24) [9]

REALISTIC (mc, r, db, pc; 12) [11]

Aim(s)

To investigate the efficacy and safety of CZP (200 or 400 mg) ? MTX versus PL ? MTX in patients non-responsive to MTX

To investigate the safety and efficacy of CZP in a broad population of patients with RA

Exclusion criteria

Use of biological RA treatments within 6 months prior to study, or etanercept and/ or akinra within 3 months; a previous severe allergic reaction to biological therapy; previous initial non-response to any anti-TNF agent; test suggestive of TB; history of TB

History of life-threatening, serious or chronic infection; current infection; history of or currently active TB; evidence suggesting latent TB (skin test or close contact with TB-infected individuals); previous treatment with [2 anti-TNF agents, rituximab or abatacept; use of cyclosporine, CYC, MMF, chlorambucil or penicillamine within 3 months of study BL

Age C18 years; adult-onset RA for C6 months but \15 years; active disease at screening and BL; receipt of MTX for C6 months, plus a stable dosage of C10 mg/week for C2 months prior to study

Age C18 years; adult-onset RA for C3 months; a demonstrated lack of response or intolerance to C1 DMARD; C5 tender joints, C4 swollen joints and either ESR C28 mm/h or CRP [10 mg/L

Inclusion criteria

Primary endpoint: ACR20 response at week 12. Secondary endpoint: ACR50 and ACR70 response; ACR component measures; DAS28 (CRP) ACR20 stratified by previous MTX and anti-TNF use, and disease duration

Primary endpoint: ACR20 response at week 24 plus C20 % improvement in C3 of patient’s and physician’s global assessment of disease activity (assessed using the DAS28 (ESR)4), patient’s assessment of arthritic pain, HAQ-DI and CRP or ESR. Secondary endpoint: ACR50 and ACR70 response, mean change from BL in mTSS, SF-36 and individual ACR core set variables, at week 24

Outcome measurements

ACR American College of Rheumatology, ACRx ACR definition of x % improvement in rheumatoid arthritis, BL baseline, CDAI clinical disease activity index, CRP C-reactive protein, CYC cyclophosphamide, CZP certolizumab pegol, DAS28 Disease Activity Score in 28 joints, DAS28 (ESR)3 3-variable DAS28 using t28 (number of painful joints), ESR and SJC28, DAS28 (ESR)4 4-variable DAS28 using t28 (number of painful joints), ESR, SJC28 and patient’s global assessment of disease activity on a 100 mm VAS, db double-blind, DMARD disease-modifying antirheumatic drug, ESR erythrocyte sedimentation rate, FAS fatigue assessment scale, HAQ-DI Health Assessment Questionnaire–Disability Index, HR-QOL health-related quality of life, mBPI modified brief pain inventory, mc multicentre, MMF mycophenylate mofetil, mTSS modified total Sharp score, MTX methotrexate, pc placebo-controlled, PL placebo, r randomised, RA rheumatoid arthritis, SF-36 short-form 36-item health survey, SJC28 swollen joint count out of 28 joints, TB tuberculosis, TNF tumour necrosis factor-a, VAS visual analogue scale

Study population (n)

Clinical trial (study design; duration, weeks)

Table 1 continued

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Efficacy and Safety of Certolizumab Pegol in Rheumatoid Arthritis

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Table 2 Principal results from randomised, double-blind, placebo-controlled clinical trials of certolizumab pegol in patients with rheumatoid arthritis Study

RAPID 1 [7, 14]

RAPID 2 [9]

Drug and dosage

Primary endpoints (at end of study)

Secondary endpoints (at end of study)

ACR20a response rates (%)

Mean change in mTSSb (Sharp units)

ACR50 response rates (%)

ACR70 response rates (%)

Mean change in HAQ-DIb

Mean change in DAS28

390

58.8*

0.2*

39.9*

23.2*

0.63*

2.8*

CZP 400 mg at weeks 0, 2 and 4 then 200 mg q4w (?MTX)

393

60.8*

0.4*

38.0*

21.2*

0.60*

2.6*

PL

199

13.6

2.8

7.6

3.5

0.18

0.7

246

57.6*

0.4**

33.1*

10.6*

0.5*

2.5*

246

57.3*

0.2**

32.5*

15.9*

0.5*

2.3*

0.8

0.14

0.5

0.36*

1.5*

0.13

0.6

CZP 400 mg at weeks 0, 2 and 4 then 400 mg q4w (?MTX)

CZP 400 mg at weeks 0, 2 and 4 then 400 mg q4w (?MTX)

Study duration

52 weeks

24 weeks

CZP 400 mg at weeks 0, 2 and 4 then 200 mg q4w (?MTX) PL FAST4WARD [6]

CZP 400 mg at weeks 0, 2 and 4 then 400 mg q4w

24 weeks

PL

No. of patients

127

8.7

1.2

3.1

111

45.5*

NR

22.7*

109

9.3

NR

3.7

5.5 

0.0

ACRx American College of Rheumatology definition of x % improvement in rheumatoid arthritis, CZP certolizumab pegol, DAS28 Disease Activity Score in 28 joints, HAQ-DI Health Assessment Questionnaire–Disability Index, mTSS modified total Sharp score, MTX methotrexate, NR not reported, PL placebo, q4w every 4 weeks * p \ 0.001, ** p \ 0.01,   p \ 0.05 versus PL a

At week 24

b

Reduction from baseline

Significant improvements from baseline in pain (measured using a 0–100 mm visual analogue scale [VAS]) and fatigue (measured using the fatigue assessment scale) [21] were observed as early as week 1 and sustained until the end of study in both studies (all p \ 0.001 for certolizumab pegol compared with placebo) [19, 20]. Improvements from baseline that were equal to or greater than the Minimal Clinically Important Difference (MCID) in the short form 36-item health survey (SF-36), a measure of functional health and well-being [22], were also observed in significantly more patients treated with certolizumab pegol plus methotrexate than methotrexate monotherapy at the end of both studies (both p \ 0.05) [19, 20]. 2.1.3 Work Productivity RA-dependent productivity at work and in the home was measured every 4 weeks in the RAPID trials using the

Work Productivity Survey, a validated questionnaire that evaluates the impact of RA on productivity in the home and workplace, as well as participation in family, social and leisure activities. Consisting of nine questions and administered by an interviewer, the survey is based on self-report over a period of 1 month [23, 24]. In RAPID 1, patients who received certolizumab pegol 200 mg plus methotrexate gained an annual average of 52.1 full days of household activities and 42.0 workdays compared with the placebo group. Results were similar for patients treated with certolizumab pegol 400 mg plus methotrexate, and in the RAPID 2 trial [23]. In the CERTAIN trial, certolizumab pegol (400 mg at weeks 0, 2 and 4 followed by certolizumab pegol 200 mg every other week) in addition to current treatment was associated with presenteeism, and with greater reductions in absenteeism, overall work impairment and daily activity impairment than placebo [8].

S30 Fig. 1 Sustainability of a DAS28 and b HAQ-DI scores over 3 years (LOCF) in RAPID 2 patients who completed 24 weeks of double-blind treatment with certolizumab pegol every other week plus methotrexate then entered an open-label extension period (reproduced with permission from Smolen et al. [26]; (poster presented at ACR [American College of Rheumatology] 2010, Atlanta, Georgia, USA). CZP certolizumab pegol, DAS28 Disease Activity Score in 28 joints, EOW every other week, HAQ-DI Health Assessment Questionnaire– Disability Index, LOCF last observation carried forward, MTX methotrexate, OLE openlabel extension, SD standard deviation

L. Punzi et al.

A

B

2.1.4 Long-Term Response and Patient-Reported Outcomes Two-year open-label extension results from the RAPID 1 trial demonstrate that the combination of certolizumab pegol and methotrexate produced sustained improvements in RA and inhibition of radiographic progression. At 100 weeks, ACR20/50/70 rates were 68.2, 55.2 and 35.6 %, respectively, while 46.7 % of patients achieved low disease activity. Improvements in DAS28 and HAQ-DI were sustained throughout the extension phase. Radiographic progression (change from baseline in mTSS of B0.5) was not observed in 77.3 % of patients in the certolizumab pegol 400 mg group, compared to 72.4 and 51.5 % of the 200 mg and placebo groups, respectively [25]. The sustainability of improvements in RA signs and symptoms and inhibition of joint damage progression was evaluated in RAPID 2 patients who completed 24 weeks of double-blind treatment then entered an open-label extension period (n = 342). ACR responses and improvements in DAS28, HAQ-DI and pain VAS from baseline were

sustained up to 3 years (Fig. 1). Radiographic progression did not increase as the level of inhibition was maintained from the 24-week phase until the last X-ray at 2.5 years. Overall, 73 % of patients on the 200 mg dose and 75 % on the 400 mg dose were non-progressors (change from baseline in mTSS B0.5) [26]. 2.2 Efficacy as Monotherapy FAST4WARD was a 24-week trial evaluating the efficacy of subcutaneous certolizumab pegol 400 mg every 4 weeks in patients with RA who had previously failed treatment with more than one DMARD [6]. At week 24, patients treated with certolizumab pegol showed significantly superior ACR20, ACR50 and ACR70 responses compared with placebo (all p \ 0.001, except for ACR70 p B 0.05). Significant differences in ACR20 were evident as early as week 1 through to week 24 (p \ 0.001). Similarly, improvements in ACR50, the components of ACR, DAS28 and all patient-reported outcomes were also seen early with certolizumab pegol and were sustained throughout the study (Table 2) [6].

Efficacy and Safety of Certolizumab Pegol in Rheumatoid Arthritis

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Table 3 Principal results from randomised, double-blind, placebo-controlled clinical trials of certolizumab pegol in patients with rheumatoid arthritis with incomplete (CERTAIN) or inadequate (REALISTIC) response to one or more disease-modifying antirheumatic drug Study

CERTAIN [8]

Drug and dosage

CZP 400 mg at weeks 0, 2 and 4 then 200 mg eow (? existing DMARD)

Study duration

No. of patients (CZP)

Primary endpoints % of patients in CDAI remission at week 20 and 24

ACR20 response rates (%)

ACR50a response rates (%)

24 weeks, then 28-week extension

96

18.8**

36.5 

20.8à

98

6.1

16.3 51.1*

PL (? existing DMARD) REALISTIC [11]

CZP 400 mg at weeks 0, 2 and 4 then 200 mg eow (? existing DMARD)

12 weeks, then 16-week open-label extension

PL (? existing DMARD)

851c

NR

Secondary endpoints a

ACR70a response rates (%)

Mean change in HAQDIb

Mean change in DAS28b

9.4

0.25 

1.12

8.2

3.1

0.06

0.07

26.6*

12.9*

0.43*

1.64d,* 1.73e,*

212c

NR

25.9

9.9

2.8

0.20

0.78

ACRx American College of Rheumatology definition of x % improvement in rheumatoid arthritis, CDAI clinical disease activity index, CRP C-reactive protein, CZP certolizumab pegol, DAS28 Disease Activity Score in 28 joints, DMARD disease-modifying antirheumatic drug, eow every other week, HAQ-DI Health Assessment Questionnaire–Disability Index, NR not reported, PL placebo, TNF tumour necrosis factor-a * p \ 0.001, ** p = 0.013,   p \ 0.01, à p \ 0.05 versus PL a

At week 24 in CERTAIN and week 12 in REALISTIC

b

Mean reduction from baseline to 24 weeks (CERTAIN) or 12 weeks (REALISTIC)

c

Intention-to-treat population

d

DAS28-CRP in patients with previous TNF-a inhibitor use

e

DAS28-CRP in patients with no previous TNF-a inhibitor use

Mean changes in patients’ assessment of pain (using VAS) and physical function (using HAQ-DI) from baseline were also significantly higher in the certolizumab pegol group at both week 1 and week 24 (all p \ 0.001 vs. placebo) [6]. In addition, preliminary results from an open-label extension showed a sustained response to week 112 in 69 patients who continued treatment, with ACR20 and ACR50 responses evident in 70.3 and 34.4 % of patients at week 112 [27]. In the HIKARI study, among a subset of Japanese patients who received certolizumab pegol monotherapy for 24 weeks, ACR20 and ACR50 responses were significantly greater in the active group than placebo, with significant differences evident from week 1 and sustained until week 24 (p \ 0.001). Certolizumab pegol monotherapy also significantly inhibited radiographic progression (p = 0.0087) compared with placebo [28]. 2.3 Efficacy in the REALISTIC Clinical Trial Typical patient populations in clinical trials of RA represent only a small proportion of the patients seen in clinical

practice [29]. Therefore, the REALISTIC study evaluated certolizumab pegol treatment (a 400 mg loading dose followed by 200 mg every 2 weeks for 12 weeks) as either monotherapy, or in combination with a DMARD, in patients with active inadequately controlled RA with varying disease durations (range 0.2–52.0 years), various co-morbidities, and a variety of previous and current DMARDs; almost 40 % had previously been treated with a TNF-a inhibitor [11]. Efficacy results from REALISTIC are shown in Table 3. At week 12, almost twice as many patients who received certolizumab pegol responded to treatment (as shown by the primary endpoint, ACR20) compared with controls, and this difference was seen as early as week 2 (31.8 vs. 8.5 %, p \ 0.001). The 12-week ACR20 response rate was similar in groups who received certolizumab pegol as monotherapy (46 vs. 21 % of controls) or in combination with other DMARDs (52 vs. 27 %), and was similar regardless of concomitant DMARD therapy (52 % for methotrexate, 56 % for leflunomide and 57 % for sulfasalazine) [11]. Secondary endpoints, including ACR50 and ACR70 responder rates at week 12 and change in DAS28 and HAQ-DI scores at week 12 from baseline, were also

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Fig. 2 ACR20, ACR50 and ACR70 responder rates at week 12 in patients enrolled in the REALISTIC study, treated with certolizumab pegol or placebo (controls), stratified according to previous tumour necrosis factor inhibitor use (intent-totreat population, non-responder imputation) [11]. ACRx American College of Rheumatology definition of x % improvement in rheumatoid arthritis, CZP certolizumab pegol, PL placebo, TNF tumour necrosis factor-a. *p \ 0.05, **p \ 0.01, ***p \ 0.001 versus placebo

Table 4 Stratification analyses from the REALISTIC trial: ACR20 response rates at week 12 [11]

Previous anti-TNF use

Certolizumab pegol (n = 851)

Placebo (n = 212)

47.2*

27.5

No previous anti-TNF use

53.5**

25.0

MTX use at baseline

52.5**

28.0

No MTX use at baseline

48.1**

21.7

Disease duration \2 years

50.0 

30.0

Disease duration C2 years

51.5**

24.7

ACR20 American College of Rheumatology definition of 20 % improvement in rheumatoid arthritis, MTX methotrexate, TNF tumour necrosis factor-a * p \ 0.01, ** p \ 0.001,   p \ 0.05 versus placebo

significantly better in the certolizumab pegol than the control group (Table 3) [11]. From week 2, significant differences existed between placebo and certolizumab for improvements in DAS28 (C-reactive protein), DAS28 (erythrocyte sedimentation rate) and physical functioning [11]. At 12 weeks certolizumab pegol was associated with significant and meaningful improvements from baseline compared with controls in fatigue (-1.3 vs. -0.5; p \ 0.001) and sleep problems (-7.6 vs. -4.2; p \ 0.01), and significantly reduced the patient-reported outcomes pain (59.0 vs. 42.0 %; p \ 0.001) and patients’ global assessment of disease activity (59.5 vs. 42.5 %; p \ 0.001) [30]. 2.3.1 Stratification Analyses Stratification analyses showed that ACR20 response rates were significantly higher in patients with previous TNF-a

inhibitor use who were treated with certolizumab pegol than in controls, and in patients without previous TNF-a inhibitor use than in controls (Fig. 2) [11]. A similar treatment effect was seen for patients with or without methotrexate use at baseline, and with disease duration of less than 2 years or 2 years or greater (Table 4). Post hoc analyses also showed higher ACR50 and ACR70 response rates in patients receiving certolizumab pegol (both in patients receiving monotherapy and those receiving concomitant DMARDs) than in placebo groups (Fig. 2) [11]. 2.4 Efficacy in Patients with Low to Moderate Disease Activity The CERTAIN trial investigated the efficacy of certolizumab pegol in combination with DMARDs in 194 RA patients with low to moderate disease activity (CDAI [6 and B16). During an initial 24-week period, patients received either certolizumab pegol (400 mg at weeks 0, 2 and 4, then 200 mg every other week) or placebo in addition to an existing DMARD [8]. At both week 20 and week 24, significantly more patients who received certolizumab pegol achieved CDAI remission than with placebo (18.8 vs. 6.1 %; p = 0.013). More patients in the certolizumab group also showed CDAI remission/low disease activity at week 24 (63.1 vs. 29.7 %; p value not available). Furthermore, fewer certolizumab pegol-treated patients had moderate or high disease activity at 24 weeks compared with placebo (37.0 vs. 70.4 %; p \ 0.001), and mean CDAI, simplified disease activity index and DAS28 scores worsened (increased compared with baseline) in the placebo group while disease activity improved in patients treated with certolizumab [8]. Similar to what was

Efficacy and Safety of Certolizumab Pegol in Rheumatoid Arthritis

observed in other studies of certolizumab pegol, ACR20, ACR50 and ACR70 responses at week 24 were higher in patients who received certolizumab pegol than placebo (Table 3).

3 Safety Profile of Certolizumab Pegol Overall, the safety profile of certolizumab pegol appears similar to that reported for other anti-TNF agents. Certolizumab pegol was generally well-tolerated in clinical trials; the majority of events were mild to moderate in severity. In the 12-week REALISTIC study, commonly reported adverse events included nausea, upper respiratory infections, RA flare and headaches; the most commonly reported serious adverse events were infections (most frequently lower respiratory tract infections and lung infections) [11]. A similar adverse event profile was seen in the 24-week FAST4WARD study, with headache, nasopharyngitis, sinusitis, upper respiratory tract infections and diarrhoea reported in at least 5 % of patients receiving certolizumab, while serious adverse events reported included RA flare, bacterial arthritis, benign parathyroid tumour and ischaemic stroke [6]. No tuberculosis was reported in either study; in REALISTIC there were four cases of malignancy, while in FAST4WARD two tumours were detected that were both benign [6, 11]. In studies in which patients received certolizumab or placebo plus methotrexate (RAPID 1 and 2), commonly reported adverse events included urinary tract infection, upper respiratory tract infections, headache and nasopharyngitis [7, 9]. Serious infections seen in the RAPID studies included tuberculosis, but investigators attributed this to insufficient screening standards and/or enrolling patients from European countries with a high incidence of tuberculosis in the population [7, 9]. The rate of malignancy was generally low in the RAPID studies. Investigators in all studies considered the adverse event profile to be consistent with that of previous reports, either of certolizumab or other anti- agents. While the RAPID 1 study was 52 weeks in duration, longer-term data for certolizumab are scarce. A 52-week open-label extension phase of the RAPID 1 study revealed no new safety signals compared to the double-blind phase of RAPID 1, with the number of deaths, malignancies and serious infections remaining stable over time. Malignancy rates at 2 years were similar across treatment groups, and were consistent with expected rates in the general population [25]. Similar consistency in the long-term safety profile was seen in a cumulative analysis of the safety and efficacy of tocilizumab over 4.6 years of exposure [31]. In addition to national and international registries, which provide important data regarding the short- and long-term

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safety of biological agents, the clinical safety of biological agents has been evaluated in one large Cochrane analysis [32]. The meta-analysis included 163 randomised clinical trials (n = 50,010) and 46 extension studies (n = 11,954) and evaluated adverse effects in patients treated with biological agents for any indication [32]. Overall, the rate of serious adverse events, serious infections, lymphoma and congestive heart failure was not significantly increased with biological agents compared with controls; however, in the short-term, biological agents were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and tuberculosis reactivation [32]. In the Cochrane analysis, certolizumab pegol had a significantly greater risk of serious infections compared with controls (odds ratio 3.51, 95 % CI 1.59–7.79; number needed to harm 17, 95 % CI 7–68). However, no consistency was observed across adverse outcomes, and the authors reported that while long-term comparative data regarding the safety of biological agents are lacking, these short-term results (over a median of 6–13 months) should be interpreted with caution. Furthermore, the authors acknowledged that these results were limited by a number of factors in the analysis, including study design and a high drop-out rate (observable adverse event rates are affected by differential exposure time and placebo recipients were followed for shorter periods than certolizumab pegol-treated patients), a zero event rate in the control groups of certolizumab studies (which may result in a higher risk score for active treatment), and differences in the background risk of infection or adverse event across and within different disease conditions [32]. A systematic review conducted by the Canadian Agency for Drugs and Technologies in Health also found an increased risk of serious adverse events with certolizumab pegol compared with placebo, which was not evident for other biological agents [33]. However, this finding may have been due to bias caused by large differences in withdrawal rates among included studies. Exposure-adjusted analyses revealed a similar incidence of serious adverse events between certolizumab pegol and placebo [33], indicating the importance of adjusting for exposure when there is differential exposure time between placebo and active treatment arms (in studies that allow for early escape of non-responders). A safety analysis involving 3,397 RA patients (8,658 patient-years of exposure at 31 October 2010) treated with certolizumab pegol in clinical trials and open-label extensions demonstrated that the rates of infection and serious infection with certolizumab were consistent with rates observed with other anti- treatments in clinical trials [34]. The most frequent adverse events (by system organ class) leading to withdrawal were infections and infestations

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(1.83 cases/100 patient-years, occurring in 4.7 % of certolizumab pegol-treated patients). The most commonly occurring adverse events were infections and infestations (63.7 % of patients; 57.97/100 patient-years), of which nasopharyngitis (6.96 cases/100 patient-years), upper respiratory tract infection (6.35 cases/100 patient-years) and urinary tract infections (5.41 cases/100 patient-years) were the most common. Lower respiratory tract and lung infections occurred in 3.0 % of patients (1.2 cases/100 patient-years). Serious infections occurred in 10.8 % of patients (4.5 cases/100 patient-years). The most common serious infections were pneumonia (0.83 cases/100 patientyears), cellulitis (0.33 cases/100 patient-years) and pulmonary tuberculosis (0.22 cases/100 patient-years). A total of 487 serious infections and 76 opportunistic infections occurred, including tuberculosis (52 cases; 0.5 cases/100 patient-years), herpes (11 cases), legionellosis (2 cases), salmonellosis (2 cases), aspergillosis (2 cases) and histoplasmosis (2 cases) [34]. There remains some uncertainty regarding the relationship between anti- agents and malignancy rates in patients with RA. As described previously, the clinical trial programme for certolizumab has shown that recipients of certolizumab do not have a significantly higher malignancy rate than those receiving placebo, but conflicting data still exist in the literature for anti- agents as a whole. A meta-analysis of 63 randomised controlled trials of 29,423 patients with RA receiving anti- agents (including adalimumab, certolizumab, etanercept, golimumab and infliximab) was recently published and showed that in trials of at least 6 months’ duration, therapy with anti- agents in patients with RA was not associated with an increased malignancy rate compared with placebo or other DMARDs [35]. 3.1 Use in Patients with Hepatitis B Virus TNF-a blockade had been associated with hepatitis B virus (HBV) reactivation and it has recently been suggested that, with appropriate antiviral prophylaxis, anti-TNF agents can safely be administered to patients with chronic HBV infection [36]. However, the risk of HBV reactivation appears to vary according to the serological status of the patient before the initiation of treatment with anti-TNF agents; therefore, it has been suggested that serological markers are evaluated in all patients with HBV who require anti-TNF therapy (including measurement of viral load in HBV surface antigen-positive patients) [37].

4 Dosage and Administration In Europe, certolizumab pegol is indicated for the treatment of adults with moderate to severe active RA in

L. Punzi et al.

combination with methotrexate, when the response to DMARDs (including methotrexate) has been inadequate, and as monotherapy in patients with methotrexate intolerance or when continued methotrexate administration is inappropriate [4, 5]. Certolizumab pegol, in combination with methotrexate, can also be used to reduce the rate of joint damage progression and improve physical function. Before starting treatment with certolizumab pegol, it is recommended that all patients should be assessed for possible active or latent tuberculosis infection [4, 5]. The recommended starting dosage of certolizumab pegol is 400 mg (given as two 200 mg injections) subcutaneously at weeks 0, 2 and 4, followed by a maintenance dosage of 200 mg every 2 weeks [4, 5]. Certolizumab pegol should not be used concurrently with biological DMARDs or other anti-TNF agents [5].

5 Treating to a Target: Tight Control of Symptoms with Certolizumab Pegol Consistent evidence supports the benefits of treating to a target in RA (i.e. using specific parameters to decide whether to modify treatment in order to meet treatment goals) [38–40]. Evidence-based guidelines recommend early treatment of RA according to a target of disease activity or patient function, with the ultimate goal being clinical remission [41], as achieving remission, or low disease activity, results in better structural and functional outcomes than allowing residual disease activity [40–43]. EULAR guidelines recommend achievement of the treatment target within 6 months, but preferably within 3 months [41]. This recommendation was based on the use of a 1- to 3-month period for switching treatments in trials [39, 40, 44], and on data showing that disease activity in RA during the first 3 months of treatment is significantly associated with disease activity at 1 year [45]. Furthermore, response criteria (i.e. a good or major response) after only 6 weeks’ treatment predict the likelihood that patients will continue treatment with an anti-TNF agent [46]. A Markov mixed-effects model determined the effect of exposure to certolizumab pegol on the ACR20 score in 2,380 RA patients enrolled in the five pivotal studies of certolizumab pegol. The studies ranged in duration from 12 weeks to 1 year: i.e. 24,519 observation-versus-time records [47]. Increasing exposure to certolizumab pegol significantly increased the likelihood of becoming a responder, while significantly decreasing the likelihood of reversion to nonresponse [47]. Covariates associated with an increased probability of response were high versus low baseline C-reactive protein level (273.0 vs. 0.2 mg/L), older versus younger age (83 vs. 18 years) and living in North America.

Efficacy and Safety of Certolizumab Pegol in Rheumatoid Arthritis

Covariates associated with a reduced probability of response were high versus low (n = 68 vs. n = 2) tender joint count at baseline, and maximum versus minimum (100 vs. 0 mm) VAS pain assessment at baseline [47]. Using the patient population from the RAPID 1 study, Curtis et al. [48] developed a simple classification and regression tree model based on clinical and laboratory data during the first 12 weeks of therapy that was able to predict response to certolizumab pegol at 1 year. The model was able to predict at week 12, using DAS28 scores, whether or not a patient would achieve low disease activity status at year 1 for approximately 88 % of RAPID 1 patients with established RA. For the remaining patients, treatment for longer than 12 weeks may be required before the likelihood of a treatment response, defined as DAS28 low disease activity, can be made with a degree of certainty. In a further analysis of DAS28 changes during RAPID 1, the extent and speed of DAS28 changes during the first 12 weeks of treatment were more strongly predictive of low disease activity status at years 1 and 2 (following a 1-year open-label extension period) [18]. Taken together, these data indicate that a treatment response at week 12 is highly predictive of longer-term response to treatment. Equally important, the data allow the identification of patients at week 12 who have a very low probability of achieving low disease activity and for whom alternative treatment options should be considered. Because the response to certolizumab pegol at 12 weeks from treatment initiation appears to predict long-term outcome, continued treatment should be reconsidered if no response is achieved within this time period [5]. Early improvement in disease activity also correlates with reduced long-term radiographic progression: patients with a DAS28 score less than 1.2 at week 12 had less radiographic progression than those who were non-responders [16]. It should be noted that the effect of certolizumab pegol on early and rapid improvements in disease activity and radiographic progression and long-term functional outcomes have yet to be elucidated. Treating to a target can be achieved with DMARD monotherapy, combinations of DMARDs or DMARD–biological combinations [49]. A strong body of evidence has demonstrated the efficacy of anti-TNF agents in the treatment of RA, usually in combination with methotrexate [50]. However, in order to meet higher targets of treatment, with the ultimate goal of remission, there is still a need for alternative treatment options, especially as patients may also lose their initial response to treatment over time [51]. Furthermore, while the concept of treating to a target in RA appears to be gaining broader acceptance in practice, clinicians should be aware that optimal patient care still requires individually tailored treatment approaches and continuing, open discussion between the clinician and patient [52].

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Certolizumab pegol is one of two newer anti-TNF agents and has shown efficacy in patients who have not responded to another treatment. The efficacy of certolizumab pegol in RAPID 1, RAPID 2 and FAST4WARD, and their open-label extensions, is similar to that observed with other anti-TNF agents, with up to 60 % of patients achieving ACR20 [6, 7]. Rapid clinical response was also seen in those trials, with significant differences evident at week 1. Importantly, clinical efficacy was maintained at the end of the trial periods and in the open-label extensions [6, 7, 9, 17, 27]. Moreover, adding certolizumab pegol to a non-biological DMARD has also shown efficacy in other populations of RA patients, increasing rates of remission, preventing disease worsening, and improving work productivity and daily activity in patients with low to moderate disease activity in the CERTAIN study [8], and showing rapid and consistent clinical responses in a diverse group of antiTNF-eligible RA patients who reflect those seen in routine clinical practice in the REALISTIC study [11]. Cost is also an important consideration when selecting an anti-TNF agent for initial treatment; thus, issues of overall administration costs and utility gains obtained from treatment are important. Biological agents have the greatest potential to decrease the long-term medical and social costs associated with RA, especially if such agents are used early in the disease course, when joint damage is minimal [49]. In clinical trials, certolizumab pegol demonstrated rapid and significant effects on home and workplace productivity in addition to improving functional outcomes, suggesting that considerable cost gains may also be possible with certolizumab pegol treatment [23].

6 Conclusions Certolizumab pegol fits into a ‘treating to target’ approach, providing rapid and sustained improvements in the signs and symptoms of RA, as well as beneficial effects on workplace and home productivity in patients with RA. As such, it holds promise in the treatment of RA. Acknowledgments The authors acknowledge Jane Caple, David Murdoch and Mary Hines of inScience Communications, Springer Healthcare, for medical writing and editorial assistance. Assistance with post-submission requirements was provided by Sheridan Henness, PhD, inScience Communications, Springer Healthcare. This assistance was funded by UCB Pharma, Milan, Italy. This article was published in a supplement sponsored by UCB Pharma SpA, Italy. The supplement was guest edited by Daniel Aletaha and peer reviewed by Leonard H. Calabrese who both received a small honorarium from Springer Healthcare to cover out-of-pocket expenses. D.A. has received honoraria and research grants from UCB, and honoraria from Abbvie, Gru¨nenthal, Janssen, Merck, Medac, Mitsubishi Tanabe, Pfizer, AstraZeneca, Eli Lilly, Novo Nordisk, and Sanofi/Regeneron. L.H.C. has consulted for UCB, Roche, Janssen, Pfizer and BMS.

S36 Conflict of interest The authors have no conflict of interest to declare.

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