BioDrugs DOI 10.1007/s40259-013-0076-8

ADIS DRUG EVALUATION

Intravenous Tocilizumab: A Review of Its Use in Adults with Rheumatoid Arthritis Sohita Dhillon

 Springer International Publishing Switzerland 2013

Abstract Tocilizumab (Actemra, RoActemra) is a humanized monoclonal antibody that acts as an interleukin6 receptor antagonist. Intravenous tocilizumab as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs) is indicated for the treatment of adult patients with moderate to severe active rheumatoid arthritis (RA) who had an inadequate response to one or more DMARDs or tumor necrosis factor (TNF) a antagonists (the specific indication varies between countries); it may also be used as monotherapy in patients for whom continued methotrexate use is inappropriate. This article reviews the efficacy and tolerability of tocilizumab in these patients and briefly summarizes its pharmacology. Several large well-designed clinical trials and routine clinical practice studies showed that tocilizumab was an effective and generally well tolerated biologic for the treatment of adults with RA, including those with an inadequate response to DMARDs or TNFa antagonists. In these studies, tocilizumab as monotherapy or in combination with DMARDs (including methotrexate) had beneficial effects on the signs and symptoms of disease, health-related quality of life/

The manuscript was reviewed by: R. Alten, Internal Medicine II, Rheumatology, Clinical Immunology, Schlosspark-Klinik, Charite´University Medicine Berlin, Berlin, Germany; M. Bergman, Division of Rheumatology, Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, USA; N. Miyasaka, Tokyo Medical and Dental University, Tokyo, Japan; K. Puolakka, Department of Medicine, Lappeenranta Central Hospital, Lappeenranta, Finland; Y. Tanaka, The First Department of Internal Medicine, University of Occupational & Environmental Health, Kitakyushu, Japan. S. Dhillon (&) Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand e-mail: [email protected]

physical function, and/or radiologic disease progression. In addition, tocilizumab monotherapy was more effective than adalimumab monotherapy in improving the signs and symptoms of disease in patients for whom continued methotrexate use was inappropriate. As with other biologic DMARDS, infections were the most common adverse event associated with tocilizumab therapy. Pooled and metaanalyses demonstrated that the efficacy and tolerability profile of tocilizumab was sustained during long-term (up to 9 years) therapy. Although additional comparative data are needed to position tocilizumab more definitively with respect to other biologic DMARDs, current evidence indicates that tocilizumab is effective as a first- or subsequentline biologic in patients with moderate to severe RA. Intravenous tocilizumab in adults with moderate to severe active rheumatoid arthritis: a summary Inhibits binding of interleukin (IL)-6 to its receptors, thereby blocking IL-6 signaling Monotherapy or combination therapy with methotrexate or disease-modifying anti-rheumatic drugs (DMARDs) is effective in patients with an inadequate response to DMARDs Combination therapy with methotrexate is effective in patients with an inadequate response to tumor necrosis factor a antagonists Monotherapy is effective in patients with no previous failures and is more is effective than adalimumab monotherapy in patients for whom continued methotrexate use is inappropriate Clinical benefits are sustained during long-term therapy Generally well tolerated, with infections being the most common adverse event

S. Dhillon

1 Introduction Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by swelling and tenderness in the joints and persistent synovitis that results in severe disability and premature mortality [1–3]. According to a systematic review conducted in 2005, the worldwide prevalence of RA was estimated to vary between 0.2 and 1.2 %, and its annual incidence in North America and Northern Europe was 20–50 cases per 100,000 population [4, 5]. RA is a multifactorial disease involving a complex interplay between personal, lifestyle, environmental, and genetic factors [2, 6]. Although the etiology of RA is not fully understood, proinflammatory cytokines, such as tumor necrosis factor (TNF) a and interleukin (IL)-6, are thought to play a central role in the pathogenesis of the disease [6, 7]. IL-6 is a pleiotropic cytokine with diverse activities that contribute to both local and systemic symptoms [8, 9]. Its local effects, such as activation of endothelial cell production and stimulation of synoviocyte proliferation and osteoclast activation, result in local inflammation, synovial pannus formation, and joint and cartilage damage [8]. The systemic effects of IL-6, such as the induction of acute-phase response, B cell differentiation, T cell activation and differentiation, and macrophage differentiation, result in elevated levels of C-reactive protein (CRP) and other acute-phase proteins, secondary amyloidosis, and anemia [8]. In patients with RA, elevated levels of IL-6 and soluble IL6 receptor (IL-6R) seen in the serum [10] and synovial fluid of affected joints [11, 12] correlated with surrogate markers of disease activity (e.g. rheumatoid factor and erythrocyte

sedimentation rate [ESR]) and clinical manifestations of the disease (e.g. morning stiffness and the number of inflamed joints) [8, 10, 12–14]. It was suggested that blocking IL-6 signaling may be beneficial in patients with RA [3, 8]. Tocilizumab (Actemra, RoActemra) is a humanized monoclonal antibody that acts as an IL-6R antagonist [15, 16]. It is approved in several countries, including the USA [17] and EU [18], for the treatment of moderate to severe RA (Sect. 6). This article reviews the efficacy and tolerability of intravenous tocilizumab in adults with moderate to severe RA and briefly summarizes its pharmacology; see the end of Sect. 7 for data selection details. Trial acronyms, where available, are defined in Table 1. 2 Pharmacodynamic Properties This section briefly summarizes the pharmacodynamic properties of tocilizumab, which have been reviewed previously [19]. Tocilizumab binds to membrane-bound (dissociation constant 2.54 nmol/L) and soluble (dissociation constant not available) IL-6Rs, thereby inhibiting the binding of IL-6 and resulting in the blockade of IL-6 signaling [15]. Tocilizumab does not block signaling of other IL-6 family cytokines [15]. Possible mechanisms by which tocilizumab exerts its beneficial clinical effects (via IL-6 inhibition) include the induction/expansion of B-regulatory cells [20] and inhibition of mitogen-activated protein kinases (e.g. c-Jun N-terminal kinase) [21]. In patients with RA (n = 15), treatment with intravenous tocilizumab 2, 4, or 8 mg/kg (administered every 4 weeks) for 24 weeks was associated with significant (p \ 0.05)

Table 1 Acronyms of clinical studies of tocilizumab Acronym

Definition

ACT-RAY

2-year randomized controlled strategy trial in rheumatoid arthritis

ADACTA

ADalimumab ACTemrA

AMBITION

Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy

CHARISMA

Chugai Humanized Anti-Human Recombinant Interleukin-6 Monoclonal Antibody

DREAM

Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy

LITHE

tociLIzumab safety and THE prevention of structural joint damage

OPTION

tOcilizumab Pivotal Trial in methotrexate Inadequate respONders

RADIATE

Research on Actemra Determining efficacy after Anti-TNF failurEs

REACTION

Retrospective Actemra Investigation for Optimal Needs of RA Patients

RESTORE

Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence

ROSE SAMURAI

Rapid Onset and Systemic Efficacy Study of Active controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 inhibitor

SATORI

Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate

SURPRISE

Success of tocilizumab in rheumatoid arthritis patients with remission induction and sustained efficacy after discontinuation

TAMARA

Tocilizumab And DMARDs: Achievements in Rheumatoid Arthritis

TOWARD

Tocilizumab in cOmbination With traditional DMARD therapy

Tocilizumab: A Review

reductions from baseline in the levels of the inflammatory markers CRP and ESR, with CRP levels being normalized as early as week 2 of treatment in the 8 mg/kg group [22]. Among patients who had detectable concentrations of serum tocilizumab throughout the treatment period (12 of 15 patients), CRP, ESR, and serum amyloid A levels were normalized by week 6 of treatment [22]. In addition, neutrophil and leukocyte counts were decreased, while hemoglobin levels were increased from baseline with tocilizumab treatment [22]. In healthy volunteers (n = 26) receiving single ascending doses of tocilizumab 2–28 mg/kg, the absolute neutrophil count (ANC) decreased to a nadir at 3–5 days after tocilizumab administration, with a dosedependent recovery in ANC being observed thereafter [17, 18, 23]. Other key pharmacodynamic effects of tocilizumab are summarized in Table 2 and its effects in large clinical studies are discussed in Sects. 4 and 5. Studies have suggested several biomarkers that may predict clinical response to tocilizumab in patients with RA [31, 42–49]. For example, pre- and post-treatment serum levels of IL-6 and baseline levels of soluble IL-6R were found to be predictive of clinical response to tocilizumab at 4 weeks [42] and 24 weeks [43], respectively. However, a biomarker analysis of data from five large, controlled clinical trials (AMBITION, LITHE, OPTION, RADIATE, TOWARD; see Sect. 4 for study details) showed that although higher baseline serum levels of IL-6 were significantly (p \ 0.0001) associated with better clinical response with tocilizumab (relative to placebo), this association was found to be weak (a 3-fold difference in baseline IL-6 levels corresponded to a 0.17 unit change from baseline in Disease Activity Score using 28 joints [DAS28]-ESR) [50]. No correlations between treatment response (as assessed by the change from baseline in DAS28) and baseline serum levels of soluble IL-6R, or IL-6 and IL-6R polymorphisms were observed in this analysis [50]. Pre-treatment CRP levels also correlated with clinical response at week 24 in patients receiving tocilizumab according to an analysis of data from three pivotal studies [46] (OPTION, LITHE, TOWARD; see Sect. 4 for study details); however, the utility of CRP as a biomarker for clinical response is limited because of the small effect size and large intra-individual variability observed during treatment. Other studies showed that a decrease from baseline in matrix metalloproteinase-3 (MMP-3; a marker of synovitis) levels in the blood [44], macrophage migration inhibitory factor (MIF; cytokine involved in the regulation of immune and inflammatory processes) levels in the serum [31], and neutrophil counts [45] following 1 month to 3 years of treatment with tocilizumab were positively correlated with clinical response. In addition, a glycosylation profiling study showed differential peripheral blood gene expression and an increase in the degree of galactosylation of IgG N-glycans in

Table 2 Key pharmacodynamic effects of tocilizumab in patients with rheumatoid arthritis Immunologic effects Down-regulated the expression of cytokine and chemokine genes (e.g. IL-6, IL-7, CCL8) and up-regulated genes associated with healing in synovial biopsy samples [24] Reduced serum levels of T cell-related cytokines (e.g. IL-2, IL-12, TNF) [25] and IL-21 production by memory/activated CD4? cells [26] Increased the number of regulatory T cells and seemed to restore NK cell cytotoxicity (known to be impaired in RA) [27] Reduced the frequency of memory B cells (indicating probable effect on B cell hyperactivity) [28], and serum levels of Ig [29] and IgG4-specific anti-CCP autoantibodies [26] Reduced circulating myeloid dendritic cells and monocytes (in responders) [30], and serum macrophage MIF levels [31] Reduced serum sodium nitrite levels (which plays a central role in inflammatory joint diseases) [32] Effects on joints and bone Induced dose-dependent reductions in the levels of serum MMP-3 (a marker of synovitis), bone resorption (e.g. CTX-1) and cartilage degradation (e.g. PIIANP, C2M) markers, and increases in bone formation markers (e.g. osteocalcin, PINP) [33, 34] Increased the expression of osteoprotegerin (which probably blocks RANKL-RANK signaling and inhibits bone resorption) [35] Facilitated partial repair of existing bone erosion [36] Cardiovascular and metabolic effects Increased serum lipid levels (e.g. total cholesterol, HDL-C) [37], body mass index, and waist circumference [38], and improved insulin resistance (which is common in RA) [39]; did not change atherogenic indices to a significant extent [37] Reduced arterial stiffness [40] and serum levels of PAI-1 (potentially reducing cardiovascular risk) [38] and reactive oxygen species (oxidative stress marker) [41] Anti-CCP anti-cyclic citrullinated peptide; C2M MMP-degraded type II collagen, CCL8 CC ligand chemokine 8, CTX-I C-terminal crosslinking telopeptide of type I collagen, HDL-C high-density lipoprotein cholesterol, Ig immunoglobulin, IL interleukin, MIF macrophage inhibitory factor, MMP matrix metalloproteinase, NK natural killer, PAI plasminogen activator inhibitor, PINP N-terminal propeptide of type I collagen, PIIANP N-terminal propeptide of type IIA collagen, RA rheumatoid arthritis, TNF tumor necrosis factor

patients who responded to tocilizumab therapy versus those who did not respond to treatment [51]. However, additional studies are required to assess and confirm the clinical usefulness, if any, of biomarkers and glycosylation profiling in patients with RA. As IL-6 is known to play an essential role in the differentiation of B cells to antibody producing plasma cells, there were concerns regarding the effect of tocilizumab on immune responses generated by vaccines. However, in two studies in patients with RA, the immune responses elicited by influenza vaccine [52] or the 23-valent pneumococcal polysaccharide vaccine [53] were not altered to a clinically relevant extent by tocilizumab monotherapy. Although

S. Dhillon

methotrexate had a negative impact on vaccine-induced immune responses [52, 53], patients receiving tocilizumab plus methotrexate achieved adequate antibody responses against all influenza strains (postvaccination seroprotection rates of [70 %) [52]; therefore, influenza vaccination was considered effective in protecting patients who received tocilizumab with or without methotrexate [52]. Protective antibody levels against invasive pneumococcal disease in adults have not been clearly defined; therefore, it was concluded that the antibody response elicited by pneumococcal polysaccharide vaccine may be reduced in patients receiving tocilizumab plus methotrexate [53]. In healthy subjects, therapeutic (10 mg/kg) or supratherapeutic (20 mg/kg) doses of tocilizumab were not associated with a prolongation of corrected QT interval [54], indicating that tocilizumab is not likely to be associated with adverse events such as torsades de pointes.

3 Pharmacokinetic Properties This section briefly summarizes the pharmacokinetics of intravenous tocilizumab, which have been reviewed previously [19]. Discussion focuses on a population pharmacokinetic analysis [55] of 1,793 patients with moderate to severe RA who received intravenous tocilizumab 4 or 8 mg/ kg every 4 weeks for 24 weeks in four phase III clinical trials (AMBITION, OPTION, RADIATE, TOWARD; see Sect. 4 for details of individual studies). These data are supplemented with those from the manufacturer’s prescribing information [17, 18]. Data from healthy subjects and patients with RA suggest that the pharmacokinetics of tocilizumab are similar between the two populations [17]. Table 3 summarizes the pharmacokinetic properties of intravenous tocilizumab in patients with moderate to severe RA [17, 18, 55]. Following administration of tocilizumab 4 or 8 mg/kg every 4 weeks, the maximum serum concentration (Cmax) of tocilizumab increased dose-proportionally, while the area under the serum concentration-time curve (AUC) and the minimum serum concentration (Cmin) of tocilizumab increased to a greater than dose proportional extent [17, 18]. At steady-state, the estimated AUC and Cmin of tocilizumab were 2.7- and 6.5-fold higher, respectively, with tocilizumab 8 mg/kg than with tocilizumab 4 mg/kg [17]; the observed Cmin was sustained over time during 104 weeks’ treatment. For the tocilizumab 4 mg/kg dose, AUC and Cmax steady states were reached after the first dose of the drug and Cmin steady state was reached after 16 weeks [17]. For the tocilizumab 8 mg/kg dose, steady-state Cmax, AUC, and Cmin were reached after the first dose, 8 weeks, and 20 weeks respectively [17, 18]. In patients with bodyweight C100 kg, the estimated AUC, Cmax, and Cmin were higher than the mean exposure values for

Table 3 Pharmacokinetics of intravenous tocilizumab administered every 4 weeks in patients with moderate to severe rheumatoid arthritis [17, 18, 55] Dose

Cmin lg/mL

AUC lgh/mL

Cmax lg/mL

4 mg/kg

13,000

88

8 mg/kg

35,000

183

9.7

8 mg/kg (BW C100 kg)

55,500

269

19.0

4 mg/kg

1.1

1.0

2.0

8 mg/kg

1.2

1.1

2.4

Steady statea 1.5

Accumulation ratiosa

AUC area under the serum concentration-time curve, BW bodyweight, Cmax maximum serum concentration, Cmin minimum serum concentration a

Simulated mean values and accumulation ratios following 48 weeks of treatment

the overall population (Table 3) [17, 18]. At high exposure, smaller efficacy gains are observed for each incremental increase in tocilizumab concentration, with no clinically meaningful increases in efficacy being seen in patients receiving [800 mg of tocilizumab [18]; therefore, doses of [800 mg per infusion are not recommended (Sect. 6) [17, 18]. In patients with RA, the central volume of distribution of tocilizumab was 3.5 L and its peripheral volume of distribution was 2.9 L, resulting in a steady-state volume of distribution of 6.4 L [18]. Intravenous tocilizumab undergoes biphasic elimination from the circulation [17, 18]. The total clearance of tocilizumab was concentration dependent and was the sum of linear (estimated 12.5 mL/h) and non-linear clearance. At low tocilizumab concentrations, concentration-dependent non-linear clearance plays a major role; at higher tocilizumab concentrations, because of saturation of the non-linear pathway, clearance is mainly determined by the linear component [17]. The half-life (t‘) of tocilizumab was concentration-dependent; after administration of tocilizumab 8 mg/kg every 4 weeks, the effective t‘ of tocilizumab at steady state decreased with decreasing concentrations within a dosing interval (from 14 days to 8 days) [17, 18]. The apparent t‘ of tocilizumab at steady state is B11 days for a 4 mg/kg dose and B13 days for an 8 mg/kg dose administered every 4 weeks [17]. 3.1 Special Populations and Drug Interactions Age, gender, and ethnicity did not affect the pharmacokinetics of tocilizumab, according to population pharmacokinetics analyses [17, 18]. The pharmacokinetics of tocilizumab have not been assessed in patients with hepatic or renal impairment. Most patients in the pharmacokinetic analysis had normal renal function and in those who had

Tocilizumab: A Review

mild renal impairment (Cockcroft-Gault creatinine clearance \80 and C50 mL/min), the pharmacokinetics of tocilizumab were not affected to a clinically relevant extent. Therefore, no dosage adjustments are required in patients with mild renal impairment [17, 18]. Coadministration of a single dose of tocilizumab 10 mg/ kg with methotrexate 10–25 mg once weekly in patients with RA did not affect methotrexate exposure to a clinically significant extent [17, 18, 56]. Tocilizumab clearance was also not affected by coadministration of methotrexate, NSAIDs, or corticosteroids, according to population pharmacokinetics analyses [17, 18]. Cytokines, such as IL-6, that stimulate inflammation suppress the expression of cytochrome P450 (CYP) enzymes [17, 18]. Potent cytokine inhibitory therapy (e.g. tocilizumab) may reverse CYP expression, resulting in increased metabolism of drugs that are CYP substrates [17, 18]. In vitro studies showed that tocilizumab normalized the expression of CYP1A2, CYP2C9, CYP2C19, and CYP3A4 that had been suppressed by IL-6 in cultured human hepatocytes [17, 18]. The effect of tocilizumab on CYP2C8 and transporters (e.g. P-glycoprotein) is unknown [17]. Because of the effect of tocilizumab on the expression of CYP enzymes, patients receiving drugs that are individually adjusted, and are metabolized via CYP3A4, CYP1A2, or CYP2C9 (e.g. atorvastatin, calcium-channel antagonists, warfarin, benzodiazepines) should be closely monitored when starting or stopping tocilizumab treatment, as their doses may need to be increased to maintain therapeutic benefit [17, 18]. For example, the exposure to simvastatin (CYP3A4 and OATP1B1 substrate) and its metabolite simvastatin acid, dextromethorphan (CYP2D6 and CYP3A4 substrate) and its metabolite dextrorphan (CYP3A4 substrate), and omeprazole (CYP2C19 and CYP3A4 substrate) was decreased 1 week after administration of a single infusion of tocilizumab in patients with RA [17, 57, 58]. It should be noted that the effect of tocilizumab on CYP activity may persist for several weeks because of the long t‘ of tocilizumab [17, 18].

4 Therapeutic Efficacy This section focuses on pivotal, large (n [ 100), clinical trials evaluating the efficacy of tocilizumab as monotherapy (Sect. 4.1) or combination therapy (Sect. 4.2) in adults with moderate to severe RA. Also discussed are studies comparing the efficacy of the addition of tocilizumab (to methotrexate) with that of switching to tocilizumab (Sect. 4.3), pooled/meta-analyses (Sect. 4.4), and large (n [ 200) clinical practice studies (Sect. 4.5). Discussion focuses on results relevant to the approved dosages of tocilizumab (4 or 8 mg/kg; Sect. 6).

In general, patients (aged C18 years) enrolled in the randomized, controlled trials [59–71] were required to have RA for C6 months (or C3 months [59]); most patients in these studies were women (79–83 % across the studies) [61–70]. Tocilizumab was administered as a 1-h intravenous infusion once every 4 weeks either as monotherapy or in combination with disease-modifying anti-rheumatic drugs (DMARDs). In studies of tocilizumab monotherapy, patients randomized to receive tocilizumab or active comparator were required to discontinue treatment with DMARDs prior to or at study initiation. Patients who were to receive combination therapy with tocilizumab continued with stabledose DMARDs. Most studies permitted the concomitant use of stable-dose oral corticosteroids and/or NSAIDs. 4.1 As Monotherapy 4.1.1 In Patients with No Previous Treatment Failures The randomized, double-blind, multicenter AMBITION study compared the efficacy of tocilizumab 8 mg/kg monotherapy with that of methotrexate in adults with moderate to severe RA who had not experienced any prior treatment failures with methotrexate or biologic agents [59]. Eligible patients had active RA, defined by the presence of C6 swollen joints, C8 tender joints, and a CRP level of C1 mg/dL or ESR of C28 mm/h. The majority (&66 %) of patients enrolled in the study were methotrexate naı¨ve [59] and[40 % of patients had RA for\2 years [17]. Tocilizumab 8 mg/kg monotherapy was noninferior to methotrexate in terms of improving the clinical signs and symptoms of RA, as assessed by the proportion of patients in the per-protocol population who achieved an improvement of C20 % in the American College of Rheumatology standard criteria (ACR20) at week 24 (primary endpoint; Table 4) [59]. A subsequent superiority analysis in the intent-to-treat population showed that the ACR20 response rate was significantly higher in tocilizumab than methotrexate recipients (Table 4), with statistically significant between-group differences observed as early as week 2 of therapy and increasing over time [59]. Patients receiving tocilizumab also had higher ACR50 and ACR70 response rates than methotrexate recipients at week 24 (Table 4). The proportion of patients achieving remission at week 24, as assessed by a DAS28 (ESR) of \2.6, was almost 3-fold higher in patients receiving tocilizumab than those receiving methotrexate (Table 4), with tocilizumab recipients five times more likely to achieve remission by week 24 than methotrexate recipients (odds ratio [OR] 5.83 [95 % CI 3.27–10.4]) [59]. The adjusted mean change from baseline in DAS28 (ESR) was -3.31 in tocilizumab recipients compared with -2.05 in methotrexate recipients. A European League Against Rheumatism (EULAR)

S. Dhillon

difference was greater than zero indicating superiority). Mean CRP levels were within the normal range as early as week 2 of tocilizumab treatment, with [90 % of patients having normal levels from weeks 12 to 24. In addition, the adjusted mean hemoglobin levels increased by 1.2 g/dL in tocilizumab recipients compared with an increase of 0.1 g/ dL in methotrexate recipients (baseline levels &13.3 g/dL; value estimated from a graph) [59]. The efficacy of tocilizumab as monotherapy was sustained during long-term (240 week) therapy, according to a post hoc exploratory analysis of data from patients who

response of ‘good or moderate’ was seen in 82 % of patients receiving tocilizumab compared with 65 % of patients receiving methotrexate, with tocilizumab recipients four times more likely to achieve at least a ‘moderate’ EULAR response by week 24 than methotrexate recipients (OR 4.24 [95 % CI 2.92–6.14]). With the exception of patient’s global (-34.5 vs. -30.7) and pain (-31.9 vs. -29.9) visual analog scale scores, individual ACR core components improved from baseline to a greater extent with tocilizumab than with methotrexate (the lower limit of the 95 % CI of the between-group

Table 4 Efficacy of tocilizumab monotherapy in adults with moderate to severe rheumatoid arthritis in randomized, double-blind (or X-ray reader blind [64]), multicenter clinical trials. Tocilizumab was administered intravenously once every 4 weeks Study

Duration of RAb (years)

Prior therapy

Treatment duration (weeks)

Treatmenta (TCZ mg/kg)

No. of ptsc

24

TCZ 8

Response rates (% of pts) ACR20

ACR50

ACR70

Remission rated (% of pts)

286

70   e

44  

28   

34

MTX

284

53

34

15

12

TCZ 8

163

65  

47   

33  

40   

ADA 40

162

49

28

18

11

In pts with no prior treatment failures &6

AMBITION [59]

Not failed MTX/BA

In pts for whom MTX is inappropriate &7.5

ADACTA [60]

MTX-IA

24

In treatment-refractory pts Nishimoto et al. [61]f

CHARISMAh [62]

7.6

&10

SATORI [63]f

8.6

SAMURAI [64]f

2.3

DMARD-IR

MTX-IR

MTX-IR DMARD-IR

12

16

24 52

TCZ 4

54

57*g

26*

20*

NR

TCZ 8

55

78*§g

40*

16*

NR

g

PL

53

11

2

0

NR

TCZ 2

53

31g

6

2

NR

TCZ 4 TCZ 8

54 52

61 g 63 g

28 41

6 16

NR 17

MTX

49

41g

29

16

8

TCZ 8

61

80   g

49

30

43   

MTX

64

g

25

11

6

2

TCZ 8

157

78   

64   

44   

59   

DMARD

145

34

13

6

3

ACR20, 50, or 70 improvement of C20, 50, or 70 % in the American College of Rheumatology standard criteria, ADA40 subcutaneous adalimumab 40 mg administered once every 2 weeks, BA biologic agents, DAS28 Disease Activity Score, DMARD disease-modifying antirheumatic drug, DMARD-IR inadequate response to DMARDs, MTX methotrexate, MTX-IA MTX was deemed inappropriate, MTX-IR inadequate response to MTX, NR not reported, PL placebo, pt(s) patients, RA rheumatoid arthritis, TCZ tocilizumab * p B 0.002 vs. PL,

§

p \ 0.05 vs. TCZ 4,

 

p \ 0.05,

  

p \ 0.01,

   

p \ 0.001 vs. active comparator

a

MTX 8 mg/week [63], 7.5–20 mg/week (escalating dose regimen) [59], or 10–25 mg/week [62]

b

Mean values except for median values in one study [61]

c

Pt numbers are the intent-to-treat [59, 60, 63, 64], full-analysis-set [61], or randomized [62] population; where reported, results are for the intent-to-treat population [59, 60, 62–64] d

Proportion of patients with 28-joint count DAS28 \2.6; DAS28 was calculated using the erythrocyte sedimentation rate, where specified [59, 60, 62] e

Superiority of TCZ vs. MTX (weighted between-group difference 0.19 [95 % CI 0.11–0.27]) was demonstrated after noninferiority between the groups (primary analysis) was established in the per-protocol population (n = 265 and 259; ACR20 response rate 71 vs. 52 %; weighted between-group difference 0.21 [95 % CI 0.13–0.29]), based on the null hypothesis that the proportion of TCZ recipients with an ACR20 response would be [12 % lower than the proportion of MTX recipients

f

Studies involving Japanese pts

g

Primary endpoint

h

CHARISMA also assessed the efficacy of TCZ in combination with MTX, results for which are presented in Table 5

Tocilizumab: A Review

remained on tocilizumab monotherapy in an ongoing extension of AMBITION (abstract presentation) [72]. Of the 243 patients who entered the extension, 139 (57 %) remained on monotherapy, with the remainder adding a DMARD either prior to (n = 24) or after (n = 80) entry into the extension. In tocilizumab monotherapy recipients, DAS28 (ESR) remission rates and clinical disease activity index (CDAI) remission rates (CDAI score of B2.8) increased from 40 and 17 %, respectively, at week 24 (entry into the extension) to 67 and 41 % at week 240. The proportion of patients with low disease activity according to DAS28 (ESR) criteria (i.e. score of B3.2) and CDAI criteria (i.e. score of B10) also increased from 52 and 48 %, respectively, at week 24 to 78 and 80 % at week 240. Similar improvements were also observed in the swollen and tender joint count scores during long-term therapy [72]. 4.1.2 In Patients for whom Methotrexate is Inappropriate The randomized, double-blind, multicenter ADACTA study compared the efficacy of intravenous tocilizumab 8 mg/kg monotherapy versus subcutaneous adalimumab 40 mg (a fully human monoclonal antibody against TNFa) monotherapy in adults with severe active RA who were intolerant of methotrexate or for whom continued methotrexate was inappropriate [60]. Patients included had active RA, defined by the presence of C6 swollen joints, C8 tender joints, and a CRP level of C1 mg/dL or ESR of C28 mm/h [60]. This superiority study showed that tocilizumab monotherapy was more effective than adalimumab monotherapy in improving signs and symptoms of disease in patients for whom methotrexate was inappropriate [60]. At week 24, the mean change from baseline in the DAS28 (ESR) [primary endpoint] was significantly (p \ 0.0001) greater in tocilizumab than adalimumab recipients (-3.3 vs. -1.8; baseline values 6.7 and 6.8, respectively). Sensitivity analyses of the primary endpoint using different populations and imputation methods supported the findings of the primary analysis, with results significantly (p \ 0.0001) favoring tocilizumab over adalimumab. ACR response and DAS28 (ESR) remission rates at week 24 were also significantly higher in tocilizumab than adalimumab recipients (Table 4). In addition, significantly (p \ 0.0001) more tocilizumab recipients had DAS28 (ESR) low disease activity (52 vs. 20 %) and EULAR ‘good’ (52 vs. 20 %) or ‘good or moderate’ (78 vs. 55 %) responses than adalimumab recipients at week 24 [60]. Health-related quality of life (HR-QOL) generally improved from baseline in both treatment groups, with no significant differences observed between tocilizumab and adalimumab recipients in the Health Assessment Questionnaire (HAQ) scores (mean change -0.7 vs. -0.5; baseline value 0.6 in both groups). There were also no significant differences between the two groups in the improvements in

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores (adjusted mean change 11.4 vs. 8.9 in adalimumab recipients; baseline values not available) and the proportion of patients experiencing a decrease of C0.22 units in HAQ scores (56 vs. 51 %) [60]. Short Form-36 health survey (SF-36) mental component summary scores improved from baseline to a significantly (p = 0.0497) greater extent with tocilizumab than adalimumab (adjusted mean change 7.9 vs. 5.0), but the two groups did not differ significantly in terms of the improvement in physical component summary scores (9.2 vs. 7.6) [baseline values not available] [60]. 4.1.3 In Treatment-Refractory Patients Four randomized, double-blind (or X-ray reader blind [64]), multicenter trials assessed the efficacy of tocilizumab monotherapy in patients with moderate to severe active RA who had an inadequate response to methotrexate or DMARDs (Table 4) [61–64]. Eligible patients had active RA, defined by the presence of C6 swollen joints, C6 tender joints [61–64], and a CRP level of C1 [61–63] or C2 [64] mg/dL or ESR of C28 [62] or C30 [61, 63, 64] mm/h. Patients had a disease duration of \5 years [64] or &8–10 years [61–63]; three of the studies (Nishimoto et al., SATORI and SAMURAI) were conducted in Japan [61, 63, 64] and one study was conducted in Europe [62]. Where specified, DAS28 was calculated using ESR [62]. The primary endpoint is specified where reported. 4.1.3.1 Versus Placebo Tocilizumab (4 or 8 mg/kg) as monotherapy was effective in improving the clinical signs and symptoms of disease in patients with moderate to severe RA who had an inadequate response to at least one DMARD or immunosuppressant in a Japanese trial [61]. After 12 weeks of treatment, ACR 20 (primary endpoint), ACR50, and ACR70 response rates were significantly higher in tocilizumab 4 or 8 mg/kg recipients than placebo recipients (Table 4). In addition, significantly (p B 0.001) more patients in the tocilizumab 8 mg/kg than the placebo group achieved DAS28 ‘good’ (18 vs. 0 %) or ‘good or moderate’ (91 vs. 19 %) responses; tocilizumab 4 mg/kg recipients also had a significantly (p \ 0.001) higher DAS28 ‘good or moderate’ response rate than placebo recipients (72 vs. 19 %) [61]. Comparing the two tocilizumab groups, significantly (p \ 0.05) more patients in the 8 mg/kg group achieved an ACR20 response (Table 4) or a DAS28 ‘good’ or ‘good or moderate’ response at week 12 than patients in the 4 mg/kg group [61]; however, no significant between-group differences were observed for the ACR50 or ACR70 response rates. By week 12, CRP levels were normalized in 26 and 76 % of patients in the tocilizumab 4 and 8 mg/kg groups compared with 2 % of patients in the placebo group [61]. A significant (p \ 0.05) increase from baseline in hemoglobin levels was also observed in the tocilizumab 4 and 8 mg/kg

S. Dhillon

groups but not in the placebo group (week 12 levels were 12.8 and 12.2 vs. 11.2 g/dL; baseline levels 11.3 g/dL) [61]. The efficacy of tocilizumab monotherapy was sustained in a long-term (5-year), open-label extension (STREAM [73]) of this study [61], with ACR response rates increasing during the first year of treatment and being maintained thereafter until 5 years. Of the patients who participated in the initial double-blind study, 143 entered the extension trial and received tocilizumab 8 mg/kg once every 4 weeks for the first 12 weeks; thereafter, dose reductions and changes in treatment interval (minimum of 2 weeks) were permitted. Of the patients who entered the extension, 76 % had completed 3 years and 66 % had completed 5 years of treatment as of March 2007 (median treatment duration 66.7 months); analyses were based on data from patients who remained in the study and had completed visit reports. The ACR20, ACR50, and ACR70 response rates at 5 years were 84, 69, and 44 %, respectively (no imputation used for missing data), and the DAS28 remission rate was 55 % [73]. 4.1.3.2 Versus Conventional Disease Modifying AntiRheumatic Drugs The CHARISMA [62] and SATORI [63] trials compared the efficacy of tocilizumab with that of methotrexate and showed that tocilizumab was significantly more effective than methotrexate in improving the clinical signs and symptoms of disease in patients refractory to prior treatment with methotrexate (Table 4). Tocilizumab 8 mg/ kg monotherapy recipients had significantly higher ACR20 response rates (primary endpoint) than methotrexate recipients after 16 (CHARISMA) or 24 (SATORI) weeks of treatment (Table 4). Tocilizumab 4 mg/kg monotherapy, assessed in CHARISMA, was also associated with significantly higher ACR20 response rates than methotrexate at week 16 [62]. DAS28 remission rates were significantly higher (SATORI) or &2-fold higher (CHARISMA; no p-value reported) with tocilizumab 8 mg/kg monotherapy than with methotrexate (Table 4), and DAS28 was reduced from baseline to a significantly (p \ 0.001) greater extent with tocilizumab than with methotrexate, with significant between-group differences in DAS28 observed as early as week 4 of treatment [62, 63]. The SAMURAI study compared the efficacy of tocilizumab monotherapy with conventional DMARDs in patients with moderate to severe RA who had an inadequate response to at least one DMARD or immunosuppressant [64]. Patients had active RA as indicated by a DAS28 of 6.5 and a CRP level of 4.8 mg/dL at baseline. In addition, patients had a very high total Sharp score of 29.4 at baseline, despite the relatively short duration of disease (mean &2 years) [64]. Results showed that tocilizumab 8 mg/kg was more effective than conventional DMARDs in improving the clinical signs and symptoms of disease [64]. At week 52, patients receiving tocilizumab had significantly

higher ACR response and DAS28 remission rates than patients receiving DMARDs (Table 4). DAS28 improved from baseline to a significantly (p \ 0.001) greater extent with tocilizumab than with DMARDs (week 52 scores 2.3 vs. 5.4 [values estimated from a graph]; baseline values 6.4 and 6.5), with significant between-groups differences observed from week 12 onwards (all p \ 0.001) [64]. HR-QOL also improved with tocilizumab 8 mg/kg, with modified HAQ scores reduced from baseline to a significantly (p \ 0.001) greater extent with tocilizumab than with DMARDs (week 52 scores 0.35 vs. 0.75; baseline scores 0.8 and 0.9; values estimated from a graph). Significant betweengroup differences in these scores were observed from week 12 onwards (all p \ 0.001) [64]. In addition, at week 52, significantly (p \ 0.001) more tocilizumab than DMARD recipients experienced a decrease of [0.22 units (indicating significant clinical improvement and minimum clinically important difference) in HAQ scores (68 vs. 40 %) [64]. Moreover, patients receiving tocilizumab 8 mg/kg experienced significantly less radiographic damage than those receiving DMARDs [64]. At week 52, a significantly (p \ 0.01) greater proportion of tocilizumab than DMARD recipients had no radiographic progression (i.e. change from baseline in total Sharp score of B0.5; 56 vs. 39 %). In addition, the modified total Sharp, erosion, and joint-space narrowing scores increased from baseline to a significantly smaller extent with tocilizumab than with DMARDs (Fig. 1) [64]. The efficacy of tocilizumab monotherapy was sustained during longer-term therapy in a 3-year open-label extension of SAMURAI, which enrolled 241 patients who had completed the earlier double-blind study (128 patients previously treated with tocilizumab and 113 patients previously treated with DMARDs) [74]. All patient in the extension study received tocilizumab 8 mg/kg monotherapy. At 3 years, the ACR70 response rate was 45 %, and 57 % of patients had achieved DAS28 remission. Radiographic progression was also strongly suppressed with tocilizumab treatment during the extension phase. The yearly progression rate (as assessed by total Sharp scores) in the 2 years since the end of the SAMURAI study was numerically lower than the rates during the first year (i.e. in the SAMURAI study) in patients who had previously received tocilizumab (1.25 vs. 4.93) or DMARDs (2.47 vs. 11.38). Similar results were seen for the yearly progression rates of erosion and joint-space narrowing scores. Over 3 years of treatment, patients previously treated with tocilizumab had significantly lower mean changes from baseline in total Sharp (7.42 vs. 16.32), erosion (2.23 vs. 7.72), and joint-space narrowing (5.38 vs. 8.58) scores than patients previously treated with DMARDs (no p-values reported) [74]. A sub-group analysis of SAMURAI assessed the efficacy of tocilizumab in patients at high risk for structural damage [75]. Patients were stratified according to four independent markers of progressive joint damage at baseline: urinary

Tocilizumab: A Review TCZ 8 mg/kg (n = 157) DMARDs (n = 143)

**

Total Sharp score

***

Erosion score

Joint-space narrowing score

*

0

1

2

3

4

5

6

7

8

Mean change from baseline Fig. 1 Effect of intravenous tocilizumab on radiographic progression of structural joint damage in the SAMURAI trial in patients with moderate to severe rheumatoid arthritis who had an inadequate response to prior treatment with DMARDs [64]. Mean change from baseline in modified total Sharp (baseline scores of 30.6 in tocilizumab vs. 28.3 in DMARD recipients), erosion (13.9 vs. 13.8), and joint-space narrowing (16.7 vs. 14.5) scores at week 52. TCZ tocilizumab, DMARDs disease-modifying anti-rheumatic drugs. *p \ 0.05, **p \ 0.01, ***p \ 0.001 vs. DMARDs

C-terminal crosslinking telopeptide of type II collagen (uCTX-II) \500 or C500 ng/mmol/creatinine; urinary pyridinoline/deoxypyridinoline (uPYD/DPD) ratio\6.8 or C6.8; body mass index (BMI)\18.5, C18.5 to\25, or C25 kg/m2; joint-space narrowing score 0 or[0. In patients at high risk of progression of erosion (as indicated by high uCTX-II, uPYD/ DPD, or low BMI) or at high risk of progression of joint-space narrowing (as indicated by low BMI or high joint-space narrowing score), mean changes from baseline in erosion and joint-space narrowing scores at week 52 were significantly (p \ 0.05) smaller in tocilizumab 8 mg/kg than DMARD recipients, indicating slower progression of disease. By contrast, in low-risk patients, the between-group differences were not significant. These results suggest that patients at high risk for progression of joint damage may benefit more from tocilizumab therapy [75]. 4.1.4 Other Monotherapy Studies The open-label, single arm, multicenter DREAM study assessed the duration of DAS28 (ESR) remission and low disease activity after cessation of prior tocilizumab monotherapy [76]. Patients (n = 187) who had participated in previous long-term tocilizumab monotherapy clinical studies in Japan were eligible for inclusion. At the time of entry into the initial studies, patients had active RA and an inadequate response to at least one DMARD, including methotrexate or immunosuppressants. At baseline of DREAM, the median disease duration was 7.8 years, 88 % of patients were women,

preceding tocilizumab treatment period was 4.0 (range 1.9–8.6) years, median DAS28 (ESR) was 1.5, and 90 % of patients had DAS28 (ESR) remission. The primary endpoint was the rate of DAS28 (ESR) remission or low disease activity at 52 weeks after cessation of tocilizumab treatment [76]. Tocilizumab monotherapy induced biologics-free remission or low disease activity in a small proportion of patients who discontinued tocilizumab treatment [76]. At week 52, the rate of continued low disease activity without concomitant use of conventional DMARDs was 13 %, according to a Kaplan–Meier estimate. DAS28 (ESR) remission was maintained in 17 (9 %) patients and 19 (10 %) patients were completely drug-free (i.e. no concomitant corticosteroids or NSAIDS) at week 52; the mean DAS28 (ESR) of the drugfree patients was 2.2 at week 52. However, the majority of patients (n = 161) withdrew from the DREAM study (i.e. within 52 weeks), largely because of loss of efficacy (determined by DAS28 [ESR] [3.2 at two consecutive visits, initiation of additional RA treatments, increase in oral corticosteroid dose, patient’s request for retreatment, or investigator’s judgment) [76, 77]. These patients were subsequently enrolled in the RESTORE trial, which was undertaken to evaluate the efficacy of retreatment with tocilizumab on recurrence of disease activity after tocilizumab discontinuation in DREAM [77]. RESTORE also included three patients who had experienced loss of efficacy after completion of the DREAM study (an interval of[52 weeks) [77]. Patients in RESTORE were treated with tocilizumab (with or without DMARDs; n = 157) or other DMARDs (including methotrexate and/or infliximab; n = 7) for 12 weeks and disease activity was assessed using DAS28 (ESR) [77]. Results suggested that re-treatment with tocilizumab was beneficial in patients who experienced recurrence of disease activity after cessation of tocilizumab therapy [77]. In tocilizumab-treated patients, the mean DAS28 (ESR) decreased from 4.4 at baseline (at the start of RESTORE) to 1.8 at 12 weeks. In patients treated with DMARDs with or without infliximab, the mean DAS28 (ESR) reduced from 4.2 at baseline to 3.3 at 12 weeks. DAS28 (ESR) low disease activity rates in tocilizumab-treated and DMARD-treated patients were 96 versus 29 % and the DAS28 (ESR) remission rates in the respective groups were 89 versus 14 %. Within the tocilizumab group, the DAS28 (ESR) remission rate in patients who received tocilizumab monotherapy was 88 % compared with 90 % in those who received tocilizumab in combination with conventional DMARDs [77]. 4.2 As Combination Therapy 4.2.1 Short-Term Treatment The efficacy of up to 24 weeks’ treatment with tocilizumab in combination with conventional DMARDs, including

S. Dhillon

methotrexate, was assessed in five randomized, doubleblind, multicenter trials in adults with moderate to severe RA. Eligible patients had active RA, defined by the presence of C6 swollen joints [62, 66–69], C6 [62, 68] or C8 [66, 67, 69] tender joints, and a CRP level of C1 mg/dL or ESR of C28 mm/h [62, 66–69]. Where specified, DAS28 was calculated using ESR [62, 69]. The primary endpoint, where specified, was the proportion of patients with an ACR20 response [62, 66, 67, 69]. In most studies, patients who did not achieve C20 % improvement from baseline in swollen joint counts and tender joint counts by week 16 were eligible for rescue therapy with: tocilizumab 8 mg/kg and steroids (if needed) [66]; tocilizumab 8 mg/kg plus methotrexate [67]; two courses of tocilizumab 8 mg/kg [68]; or adjustment of background DMARD dosage and/or a different DMARD and/or corticosteroids [69]. 4.2.1.1 Clinical Outcomes Tocilizumab (4 or 8 mg/kg) in combination with methotrexate [62, 66, 67] or DMARDs [68, 69] (i.e. methotrexate/DMARDs) was more effective than methotrexate/DMARDs alone in improving the clinical signs and symptoms of disease in patients who had an inadequate response to prior treatment with methotrexate (CHARISMA, OPTION), DMARDs (ROSE, TOWARD), or TNFa antagonists (RADIATE) (Table 5). Significantly higher ACR response rates were seen with tocilizumab 8 mg/kg plus methotrexate/DMARDs than with methotrexate/DMARDs alone in all the studies [62, 66–69] (Table 5). DAS28 remission rates were significantly higher with tocilizumab 8 mg/kg combination therapy than with methotrexate/DMARDs alone in all studies that reported statistical data, and in CHARISMA these rates were &4-fold higher with combination therapy than with methotrexate/DMARDs alone (no p-value reported) [62] (Table 5). The lower dose of tocilizumab (4 mg/kg) in combination with methotrexate/DMARDs was also associated with significantly higher ACR20 [62, 66, 67], ACR50 [66, 67], and ACR70 [66] response rates and DAS28 remission rates [66] than methotrexate alone in some studies (Table 5). The proportions of patients with DAS28 low disease activity in tocilizumab 4 or 8 mg/kg plus methotrexate recipients were 15 and 51 % compared with 5 % in methotrexate recipients (RADIATE) [67], and the proportion of patients with low disease activity in tocilizumab 8 mg/kg plus DMARD recipients was 45 % compared with 6 % in DMARD alone recipients (TOWARD) [69]. The improvements in DAS28 observed with tocilizumab combination therapy were rapid, with patients receiving tocilizumab 4 or 8 mg/kg plus methotrexate in OPTION experiencing a mean improvement corresponding to at least a ‘moderate’ EULAR response as early as week 2 of treatment and improving during the course of the study [66]. In TOWARD, at week 2, a ‘good or moderate’

EULAR response was achieved by 64 % of patients receiving tocilizumab 8 mg/kg plus DMARD (vs. 18 % of DMARD alone recipients) [69], while in ROSE, a ‘good’ EULAR response was achieved by significantly (p \ 0.0001) more patients in the tocilizumab 8 mg/kg plus DMARD group than in the DMARD alone group from week 4 onwards (13 vs. 2 % at week 4) [68]. By week 24, EULAR ‘good or moderate’ responses were achieved by significantly (p \ 0.001) more patients in the tocilizumab 4 or 8 mg/kg plus methotrexate groups than in the methotrexate alone groups in OPTION (62 and 79 vs. 35 %) and RADIATE (47 and 68 vs. 17 %), and in the tocilizumab 8 mg/kg plus DMARD groups than in the DMARD alone groups in TOWARD (80 vs. 38 %) and ROSE (33 vs. 6 %) [66–69]. Where reported, swollen and tender joint counts were reduced from baseline to a significantly (p \ 0.001) greater extent with tocilizumab 4 or 8 mg/kg plus methotrexate/ DMARDs relative to methotrexate/DMARDs alone [66, 67, 69]. In terms of the effect of tocilizumab on markers of inflammation, mean CRP levels and ESR had normalized following 24 weeks’ treatment with tocilizumab 8 mg/kg plus methotrexate in RADIATE and OPTION [66, 67]. Improvements in CRP levels and ESR were also observed with tocilizumab 8 mg/kg plus DMARDs, with significantly (p \ 0.0001) lower mean CRP levels and ESR observed in the combination therapy group than in the DMARD group from week 4 onwards until study end (ROSE) or at week 24 (TOWARD) [68, 69]. Combination treatment with the lower dose of tocilizumab (4 mg/kg) plus methotrexate was not associated with consistent improvements in, or normalization of, CRP levels and ESR in RADIATE and OPTION [66, 67]. Tocilizumab combination therapy was also associated with improvements in hemoglobin levels. At week 24, the mean change from baseline in hemoglobin levels was significantly (p \ 0.0001) greater with tocilizumab 4 or 8 mg/kg plus methotrexate than with methotrexate alone in OPTION (0.92 and 1.24 vs. -0.03 g/dL) [66], and hemoglobin levels at this timepoint were significantly (p \ 0.05) higher in the respective tocilizumab groups than in the methotrexate group in RADIATE (13.9 and 14.7 vs. 13.3 g/dL; values estimated from a graph) [67]. A significant (p \ 0.0001) increase from baseline in hemoglobin levels was also observed with tocilizumab 8 mg/kg plus DMARDs relative to DMARDs alone at week 24 in TOWARD (mean change 0.98 vs. -0.13 g/L) [69]. Baseline values, where available, were approximately 13.5–13.6 g/dL [66, 67, 69]. 4.2.1.2 Health-Related Quality of Life Tocilizumab plus methotrexate/DMARD combination therapy was associated with improvements in measures of HR-QOL [66–69]. The mean decrease from baseline to week 24 in HAQ-disability index (HAQ-DI) scores was significantly (p \ 0.03) greater

Tocilizumab: A Review Table 5 Efficacy of tocilizumab combination therapy in adults with moderate to severe, treatment-refractory rheumatoid arthritis in randomized, double-blind (or open-label [71]), multicenter clinical trials. Tocilizumab was administered intravenously once every 4 weeks Study

Duration of RAb (years)

Prior therapy

Treatment duration (weeks)

Treatmenta (TCZ mg/kg)

MTX-IR

16

TCZ 2 ? MTX

No. of ptsc

Response rates (% of pts) ACR20

ACR50

ACR70

Remission rated (% of pts)

52

64 e

32

14

NR

TCZ 4 ? MTX

49

63 e

37

12

NR

TCZ 8 ? MTX

50

74  e

53 

37 

34

MTX

49

41e

29

16

8

TCZ 4 ? MTX

399

48f

29f

16f

30 

TCZ 8 ? MTX

398

56   f

38   f

20   f

47   

MTX

393

25

f

f

10

4

TCZ 4 ? MTX

213

48   e

31   

12   

205

59

   e

   

44

22

   

26

e

11

2

1

  e

17

5

8

29  

12  

30  

As combination therapy CHARISMA [62]

LITHE [65]

&10

9

MTX-IR

&7.6

OPTION [66]

MTX-IR

52

24

TCZ 8 ? MTX MTX RADIATE [67]

&11.7

&8.5

ROSE [68] TOWARD [69]

AntiTNF-IR

DMARD-IR

9.8

DMARD-IR

24

24 24

204

  

f

8 13   27   

TCZ 4 ? MTX

161

30

TCZ 8 ? MTX

170

50  e

MTX TCZ 8 ? DMARD

158 409

e

10 45   f

4 30   e

1 15   f

2 38   

DMARD

207

25f

11e

1f

1f

TCZ 8 ? DMARD

803

61   e

38   

21   

30   

DMARD

413

25

e

9

3

3

TCZ 8

277

70

40

25

35e

TCZ 8 ? MTX

276

72

46

25

40eg

TCZ8

115

67

53

36

58

TCZ8 ? MTX

118

64

49

28

71§i

Adding versus switching to TCZ ACT-RAY [70] h

SURPRISE [71, 78]

&8.3

MTX-IR

&3.9

MTX-IR

24 24

ACR20, 50, or 70 improvement of C20, 50, or 70 % in the American College of Rheumatology standard criteria, AntiTNF-IR inadequate response to tumor necrosis factor antagonists, DAS28 Disease Activity Score, DMARD disease-modifying anti-rheumatic drug, DMARD-IR inadequate response to DMARDs, MTX methotrexate, MTX-IR inadequate response to MTX, NR not reported, pts patients, RA rheumatoid arthritis, TCZ tocilizumab  

p \ 0.05,

  

a

MTX 2.5 mg/week [70], or 10–25 [62, 65–67] mg/week

b

Mean values

p B 0.001,

   

p \ 0.0001 vs. MTX or DMARD,

§

p \ 0.05 vs. TCZ8

c

Pt numbers are the intent-to-treat [65–70], full analysis set [71], or randomized [62] population; results are for the intent-to-treat [62, 65–70] population or the full analysis set [71] d Proportion of patients with 28-joint count DAS28 \2.6; DAS28 was calculated using the erythrocyte sedimentation rate, where specified [62, 65, 69–71] e

Primary endpoint

f

Values estimated from graphs

g

Add-on TCZ was not superior to switching to TCZ for this parameter, as the absolute difference in DAS28 remission rates (5.65 % [95 % CI 2.41 to 13.71]) was less than the superiority margin of 12.5 %

h

Study in Japanese patients (available as an abstract)

i

Noninferiority between the TCZ 8 (n = 109 per-protocol) and the TCZ 8 ? MTX (n = 106 per-protocol) groups was demonstrated as the between-group difference in DAS28 remission rates (59.4 vs. 71.6 %; 12.1 % [95 % CI -1.3 to 25.2]) in the per-protocol population (primary endpoint) met the predefined noninferiority margin of 10 %

with tocilizumab 4 or 8 mg/kg plus methotrexate than with methotrexate alone in OPTION (-0.52 and -0.55 vs. -0.34) [66] and RADIATE (-0.31 and -0.39 vs. -0.05) [67, 79], indicating an improvement in physical functioning. A clinically meaningful improvement in HAQ-DI scores

(decrease of C0.3 points from baseline) was achieved by 61, 59, and 47 % of patients in the tocilizumab 4 or 8 mg/kg plus methotrexate and methotrexate groups, respectively, in OPTION [66]. Similarly, in TOWARD, HAQ-DI scores improved from baseline to a significantly (p \ 0.0001)

S. Dhillon

greater extent with tocilizumab 8 mg/kg plus DMARDs than with DMARDs alone at week 24 (mean change -0.5 vs. -0.2) [69]; 60 % compared with 34 % of patients in the respective groups had a clinically meaningful improvement in these scores. HAQ-DI scores at baseline in these studies were 1.5–1.7 [66, 67, 69, 79]. Physical function as assessed by SF-36 was also improved with tocilizumab combination therapy at week 24, with physical component summary scores increasing from baseline to a significantly (p B 0.002) greater extent with tocilizumab 4 or 8 mg/kg plus methotrexate than with methotrexate alone in OPTION (mean change 9.7 and 9.5 vs. 5.0 [baseline &32]) [66] and RADIATE (adjusted least-square mean change 7.1 and 8 vs. 2.2 [baseline &29]) [79]. SF-36 mental component summary scores at week 24 improved significantly (p \ 0.04) from baseline with tocilizumab 4 or 8 mg/kg plus methotrexate relative to methotrexate alone in OPTION (mean change 5.7 and 7.3 vs. 2.7 [baseline &40]) [66], but no significant between-group differences were seen in RADIATE (mean change 4.5 and 4.1 vs. 4.1 [baseline &41]) [79]. In TOWARD, tocilizumab 8 mg/kg in combination with DMARDs was associated with significantly (p \ 0.0001) greater improvements from baseline in both the SF-36 physical (mean change 8.9 vs. 4.1) and mental (mean change 5.3 vs. 2.3) component summary scores than with DMARDs alone (baseline values not available) [69]. Tocilizumab combination therapy improved FACIT-F scores, with the mean change from baseline being significantly greater with tocilizumab 4 or 8 mg plus methotrexate than with methotrexate alone at week 24 in OPTION (7.3 and 8.6 vs. 4.0 [baseline &27]) and RADIATE (6.7 and 8.8 vs. 4.2 [baseline &23]) [79]. Moreover, the improvement in these scores was greater than the minimum clinically important difference of a C4 point increase from baseline [79]. Significant (p \ 0.02) improvements from baseline to week 24 in FACIT-F scores were also seen in tocilizumab 8 mg/kg plus DMARD recipients relative to DMARD recipients in ROSE (mean change 8.4 vs. 5.9) and TOWARD (mean change 8.0 vs. 3.6) (baseline values not available) [68, 69]. 4.2.2 Long-Term Treatment The 2-year randomized, double-blind, multicenter LITHE study [65, 80] and its 3-year extension phase assessed the long-term efficacy of tocilizumab plus methotrexate in patients with moderate to severe RA who had an inadequate response to prior treatment with methotrexate. Results for the long-term extension are available only as an abstract and poster presentation [81]. Patients eligible for the double-blind study had active RA, defined by the presence of C6 swollen joints, C8 tender joints, a CRP level of C1 mg/dL or ESR of C28 mm/h, and C1 radiologically confirmed joint erosion [65].

Study design details are summarized in Fig. 2. Briefly, patients were randomized to receive double-blind tocilizumab 4 or 8 mg/kg plus methotrexate or methotrexate alone for 52 weeks [65], with rescue therapy available from week 16 for patients who did not achieve C20 % improvement from baseline in the swollen joint and tender joint counts [65]. At week 52, patients who had attained a C70 % improvement from baseline in the swollen joint and tender joint counts at two consecutive visits during year 1 were permitted to continue their initially randomized treatment at the discretion of the patient or the investigator [80]. All other patients were switched to open-label treatment with tocilizumab 8 mg/kg plus methotrexate [80]. Patients who chose to continue double-blind treatment could switch to open-label treatment with tocilizumab 8 mg/kg plus methotrexate at any time during year 2 [65, 80]. Over 5 years of treatment, at least one dose of tocilizumab was administered to 1,149 patients (referred to as the ‘all tocilizumab’ population) with 4,379.6 patient-years of exposure [81]. Co-primary endpoints at weeks 52 and 104 were the change from baseline in Genant-modified total Sharp scores and the change in physical function as assessed by the area under the curve (AUC) for the change from baseline in HAQ-DI scores. Primary endpoint analyses were conducted in the intent-totreat population (n = 1,190) [65, 80]. Missing radiographic data were imputed using linear extrapolation (post-escape and post-withdrawal data were censored at week 104); for patients with missing HAQ-DI scores, the AUC of the change from baseline in these scores was standardized using the latest timepoint available for the calculation of AUC [65, 80]. The long-term extension analysis included patients who had at least baseline, week 104, and post-week 104 radiographs (post-withdrawal and post-rescue data were included and missing 260 week data were imputed using linear extrapolation) [81]; data for signs and symptoms in this analysis were pooled for all patients who had received at least one dose of tocilizumab (the ‘all tocilizumab’ group). Of the patients initially randomized, 86 % completed 52 weeks of treatment, including 29 % who required rescue therapy [65]. At week 52, the majority of patients remaining in the study began open-label tocilizumab 8 mg/kg plus methotrexate treatment, including 62, 63, and 68 % of those initially randomized to receive tocilizumab 8 mg/kg plus methotrexate, tocilizumab 4 mg plus methotrexate, or methotrexate alone (23, 22, and 15 % of patients in these groups, respectively, continued double-blind treatment) [80]. Of the patients initially randomized to these treatments, 78, 78, and 73 % of patients, respectively, completed 104 weeks’ treatment, of whom 49, 38, and 22 patients were still receiving the treatment to which they were initially randomized [80]. Overall, 59 % of patients completed 260 weeks of treatment, of whom 244, 241, and 219 patients had been initially randomized to receive tocilizumab 8 mg/

Tocilizumab: A Review

Rescue 1 (week 16)

Rescue 2 (week 28)

Randomization

TCZ 8 mg/kg + MTX (n = 399)

TCZ 8 mg/kg + MTX

TCZ 4 mg/kg + MTX (n = 399)

TCZ 4 mg/kg + MTX

PL + MTX (n = 392)

PL + MTX

Year 1 Double-blind treatment Rescue 1 (available from week 16) and rescue 2 (available from week 28 to 52) if improvement in TJC and SJC was