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Review
1.
Background
2.
Mechanism of action
3.
Pharmacokinetics
4.
Approval of tocilizumab
5.
Efficacy and safety of intravenous tocilizumab
6.
Safety of subcutaneous tocilizumab
7.
Head-to-head trial of intravenous versus subcutaneous tocilizumab
8.
Summary of main safety information
9.
Expert opinion
Safety of subcutaneous versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis € or’s† Maeve McLaughlin & Andrew Ost€ †
Cambridge University, School of Clinical Medicine, Cambridge, UK
Introduction: Tocilizumab (TCZ), a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody, has demonstrated efficacy and tolerability in several large randomized, controlled trials for the treatment of rheumatoid arthritis (RA). Areas covered: This article compares the safety profile of the newer, subcutaneous (SC) formulation of TCZ with the original intravenous (IV) formulation, in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in patients with RA. Several pivotal clinical trials are included, highlighting data from: i) trials of TCZ-IV; ii) trials of TCZ-SC; and iii) trials comparing IV to SC TCZ. TCZ use in pediatric populations is beyond the scope of this review. Expert opinion: The efficacy and safety of TCZ-IV in the treatment of RA has been demonstrated in multiple clinical trials, both as monotherapy and in combination with traditional DMARDs. The data for TCZ-SC is similar, albeit with a higher frequency of injection site reactions (ISRs). With careful patient selection, the benefit: risk ratio is favorable, offering patients a rapid and sustained reduction in disease activity, improved function and reduced structural damage. Given that most patients prefer SC to IV medication, TCZ-SC will likely become a mainstay, along with other biologic agents, for the treatment of RA patients who have failed traditional non-biologic DMARDs. Keywords: humanized anti-IL-6 receptor (IL-6R) antibody, immunotherapy, rheumatoid arthritis, safety, tocilizumab Expert Opin. Drug Saf. [Early Online]
1.
Background
Rheumatoid arthritis (RA) is a chronic systemic autoimmune condition associated with inflammatory manifestations in synovial joints and other organs. The condition has a prevalence in most industrialized countries of between 0.3 and 1% [1], with an incidence in populations of northern European origin of 20 -- 300 per 100,000 per year [2]; however the disease is present worldwide [3]. The natural history of RA involves progressive joint deformity leading to loss of function. Extra-articular manifestations are common, affecting the cardiovascular, pulmonary, ocular, neurological and hematological systems. The disorder is also associated with significantly reduced quality of life and longevity, reduction in work capacity and increased use of healthcare services [4]. Patients with long-standing active disease have a substantially increased risk of premature mortality [5]. The underlying pathophysiology of RA is complex and not fully understood, although immune system dysfunction is critical to the development of the disease. 10.1517/14740338.2015.998198 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Article highlights. .
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Tocilizumab, a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody can be used with confidence to treat patients with RA. Tocilizumab is NICE-approved in the UK for use in adults with moderate to severe RA if the disease has responded inadequately to * DMARDs * DMARDs and a TNF inhibitor treatment, in patients with a contraindication to rituximab * one or more TNF inhibitor treatment and to rituximab. The main safety concerns relate to infections (including reactivation of tuberculosis), neutropenia, thrombocytopenia, hyperlipidemia, transaminitis, and gastrointestinal perforation. The newer subcutaneous formulation appears to share a similar safety and efficacy profile with the IV formulation of tocilizumab, albeit with increased incidence of injection site reactions.
This box summarizes key points contained in the article.
The inflammatory response seen in RA stems from multifarious interactions between cells of the immune system resulting in the production of pro-inflammatory cytokines as well as auto-antibodies. Many of these molecular mediators of inflammation have been singled out as the target of pharmacotherapy with newer biological agents such as anti-TNF antagonists [6]. To date, no single agent has been shown to successfully treat all patients suffering from this disease due to its heterogeneous nature [7]. However, the impact of early intensive intervention, aiming to achieve remission in the long term, has had a dramatic impact on the course of the illness [8]. Given the variety of therapeutic options now available, it has become possible for clinicians to individualize treatment to a degree, attempting to utilize the most appropriate agent for the patient. Although many of these decisions are based on the side effect profile of the drug in relation to the patient’s comorbidities, there are also practical issues to consider. For some patients, the availability of a drug as a subcutaneous (SC) injection confers freedom, flexibility and independence [9]. Time that would otherwise have been spent travelling to and from the hospital for regular infusions may be devoted to more useful pursuits such as work or family responsibilities. For other patients, such as those who are needle-phobic, who suffer from hand deformities and disability, or where issues of adherence exist, intravenous (IV) infusions are preferable to self-administered SC injections. The overall aim of this article is to clarify whether there is parity between the safety profiles of IV and SC injections of Tocilizumab (TCZ), in order to allow the clinician and the patient to make an informed choice regarding their treatment. 2.
Mechanism of action
3.
Pharmacokinetics
In a large randomized controlled study (SUMMACTA) the pharmacokinetic profiles of TCZ administered via both IV and SC routes were compared [12]. Serum trough TCZ levels (Ctrough) increased more rapidly in the TCZ-SC group than in the TCZ-IV group; however the trough levels in both groups plateaued with subsequent dosing by week 12. The observed steady-state Ctrough (± SD) at week 24 was higher following TCZ-SC dosing, at 42 (± 27.4) µg/ ml than following TCZ-IV dosing (18 (± 14.2) µg/ml). Despite higher trough levels for TCZ-SC, the mean area under the curve and maximum plasma concentration (Cmax) of TCZ at steady state were higher for TCZ-IV. CRP levels decreased in both groups after the first dose of TCZ and remained below the upper limit of normal (ULN; 0.99 mg/dl) to week 24. The time course for the reduction in CRP following TCZ-SC was comparable to that for TCZ-IV, with a tendency towards slightly lower CRP levels in the SC group. This may reflect the higher trough levels for TCZ-SC. Similar results were observed for the ESR. In vivo pharmacokinetic analysis was also performed as part of another randomized controlled study in Japan (MUSASHI), allowing comparison between the IV and SC routes of administration [13]. Serum samples were processed by enzyme-linked immunosorbent assay to detect the amount of TCZ not bound by the IL-6 receptor (free TCZ). The serum trough concentration in the TCZ-SC monotherapy and TCZ-IV monotherapy groups was similar over time, despite a smaller dose-per-kilogram being administered in the TCZ-SC arm compared with TCZ-IV. From week 4 onward, the Ctrough were comparable between the TCZ-SC and TCZ-IV groups, with > 80% of patients maintaining concentrations > 1 µg/ml in the TCZSC monotherapy group. This timecourse was also reflected in the time to clinical improvement, with the effectiveness of TCZ-SC becoming approximately equal to that of TCZ-IV from week 4 onward. 4.
IL-6 is a pro-inflammatory cytokine, which has multiple physiological and pathological actions. The production of 2
IL-6 is induced promptly upon tissue damage or inflammation and ceases when homeostasis is restored. IL-6 contributes to the host defense through the stimulation of acute-phase immune reactions. The dysregulation of the synthesis of IL-6 has been implicated in the development of immune-mediated diseases and cancer [10]. Indeed, studies have shown that in RA patients, levels of IL-6 are increased in synovial fluid and tissue, and correlate with C-reactive protein (CRP) and disease activity [11]. TCZ is a recombinant humanized anti-IL-6 receptor (IL-6R) monoclonal antibody that blocks IL-6 from binding to the soluble and membrane-bound IL-6R.
Approval of tocilizumab
The IV formulation of TCZ was approved by the EMA as a treatment for moderate to severe RA in January 2009. The
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Safety of SC versus intravenous TCZ in combination with traditional DMARDs in patients with rheumatoid arthritis
drug also received FDA approval for use in the USA in January 2010. TCZ may be used both as a single-agent therapy and in combination with methotrexate (MTX) or other non-biologic disease-modifying antirheumatic drug (DMARDs). The SC formulation of TCZ was approved by the FDA for the same indication in October 2013 and by the EMA in April 2014. In August 2010, the UK’s National Institute for Health and Care Excellence (NICE), which analyses the costeffectiveness of therapies, recommended the use of TCZ in RA in patients with moderate to severe disease, who have responded inadequately to one or more TNF inhibitors, and who are unsuitable for rituximab, or following failure of rituximab [14]. These guidelines were revised and replaced by TA247, published in February 2012, in which TCZ was also approved as a first-line biological agent [15].
Efficacy and safety of intravenous tocilizumab
5.
5.1
The radiate study The RADIATE study was a Phase III, randomized, doubleblind, placebo-controlled, parallel group study conducted throughout North America and Western Europe, in which 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg TCZ or placebo (control) IV every 4 weeks with stable MTX for 24 weeks [18]. Efficacy: the proportion of patients achieving ACR20 by week 24 was significantly higher in both TCZ groups compared with the placebo group (50.0, 30.4 and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 < 2.6) rates at week 24 were achieved by 30.1, 7.6 and 1.6% of 8 mg/kg, 4 mg/kg and control groups respectively (< p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Safety: most AEs in this study were classified as mild or moderate. The most common AEs with higher incidence in TCZ groups were infections, gastrointestinal symptoms, rash and headache. The incidence of SAEs was higher in controls (11.3%) than in the TCZ 8 (6.3) or 4 mg/kg (7.4%) groups. 5.1.3
Clinical trials The option study
5.1.1
The OPTION study was a double-blind randomized, placebo-controlled, parallel-group Phase III study to investigate the safety and efficacy of TCZ in combination with MTX in 623 patients with moderate to severe RA, who had responded inadequately to MTX [16]. Efficacy: significant improvements were found in American College of Rheumatology scores (ACR20, ACR50 and ACR 70) at week 24 with TCZ (at either of the two dosing regimens, i.e., 4 or 8 mg/kg) in combination with MTX, compared with placebo (59% in the 8 mg/kg group [odds ratio 4.0 compared with placebo], 48% in the 4 mg/kg group [odds ratio 2.6 compared with placebo] and 26% in the placebo group. Additionally, significantly more patients in the treatment arms achieved disease remission, as measured by disease activity score in 28 joints (DAS28) scores, when compared with placebo. Starting with a mean baseline DAS28 of 6.8 for each of the treatment groups, the percentage of patients who achieved a reduction to a DAS28 score of < 2.6, was 21/156 (13%) in the 8 mg/kg group, 47/171 (27%) in the 4 mg/kg group and 1/121 (0.8%) in the placebo group. Safety: the incidence of serious adverse events (SAEs) including infectious complications was the same in each of the three groups in the option study (6%), although the frequency of non-serious infections was higher in the 8 mg/kg group (3%) than in the 4 mg/kg and placebo groups (at 1% each group). The toward study The TOWARD study was a 24-week Phase III, randomized, double-blind, placebo-controlled, international, multicentre study conducted in 18 countries on 1216 patients with active RA and an inadequate response to DMARDs [17]. Patients 5.1.2
were randomized in a 2:1 ratio to receive either TCZ or placebo combined with stable DMARD therapy. Efficacy: compared with placebo, TCZ 8 mg/kg combined with DMARD therapy, significantly improved ACR20 (61 vs 25%), ACR50 (38 vs 9%) and ACR70 (21 vs 3%). Rates of remission responses (DAS28 < 2.6) were also higher in the TCZ group versus the control group, with 30% of patients and 3% of patients, respectively, achieving clinical remission at week 24 (p < 0.0001). By week 24, mean changes from baseline were greater in the TCZ group than in the control group (-3.17 and -1.16, respectively; p < 0.0001). Safety: the overall incidence of adverse events (AEs) was higher in the TCZ group compared with the control group (73 vs 61%). More than 90% of AEs in each group were of mild or moderate intensity. Serious AEs (6.7 vs 4.3%), AEs leading to withdrawal (3.9 vs 1.9%), and AEs leading to dose modification (13.8 vs 7.2%) occurred more frequently in the TCZ group than in the control group.
The ambition study The AMBITION study was designed to compare TCZ monotherapy versus MTX monotherapy in patients with moderate to severe RA [19]. This 24-week, double-blind, double-dummy, parallel-group study, randomized 673 patients to either TCZ 8 mg/kg every 4 weeks, or MTX, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by TCZ 8 mg/kg. Efficacy: the intention-to-treat analysis demonstrated that TCZ was better than MTX treatment with a higher ACR20 response (69.9 vs 52.5%; p < 0.001), and 28-joint DAS28 < 2.6 rate (33.6 vs 12.1%) at week 24. 5.1.4
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Safety: the incidence of SAEs with TCZ was 3.8 vs 2.8% with MTX (p = 0.50), and of serious infections, 1.4 vs 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1 vs 0.4%), increased total cholesterol ‡ 240 mg/dl (13.2 vs 0.4%), and lower incidence of alanine aminotransferase elevations of 3 to 5 times the upper limit of normal (1.0 vs 2.5%), with TCZ use compared with MTX treatment respectively. The authors concluded that TCZ monotherapy was better than MTX monotherapy, showing rapid improvement in RA signs and symptoms, and a favorable benefit--risk ratio, in patients for whom treatment with MTX or biological agents has not previously failed. The ADACTA study The ADACTA study compared the safety and efficacy of TCZ monotherapy with that of adalimumab monotherapy [20]. The study was a randomized, double-blind, parallel-group, Phase IV superiority trial undertaken in 76 centers in 15 countries in North and South America, Australasia, and Europe. Three hundred and twenty-six patients were enrolled who had severe RA for 6 months or more, and were intolerant to MTX or were inappropriate for continued MTX treatment. Patients were randomly assigned (1:1; block size of four) to receive TCZ 8 mg per kg bodyweight IV every 4 weeks plus placebo SC every 2 weeks or adalimumab 40 mg SC every 2 weeks plus placebo IV every 4 weeks for 24 weeks. The intention-to-treat population contained 325 patients (163 assigned to TCZ, 162 assigned to adalimumab). Efficacy: at week 24 the mean change from baseline in DAS28 was significantly greater in the TCZ group (-- 3·3) than in the adalimumab group (-- 1·8) patients (difference --1·5, 95% CI: --1·8 to --1·1; p < 0·0001). Safety: SAEs were reported in 16 of 162 (10%) patients in the adalimumab group versus 19 of 162 (12%) in the TCZ group with the majority of SAEs related to infection. More patients in the TCZ group than in the adalimumab group had increased LDL-cholesterol, increased alanine aminotransferase concentrations, and reduced platelet and neutrophil counts. The authors concluded that TCZ monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of RA in patients for whom MTX was deemed inappropriate. The AE profiles of TCZ and adalimumab were consistent with previous findings. 5.1.5
5.2
Registry data The REGATE registry (France)
5.2.1
The REGATE registry is a French cohort study designed by the French Society of Rheumatology to collect safety information on the use of TCZ in RA [21]. The registry started in 2010 and aimed to include 1500 patients, with a prospective follow-up period of 5 years. The tolerability data from the 1 year of the study was published in 2014 [22], looking at 1503 patients from 78 French centers, who had been treated with TCZ initiated after January 1st 2010 and who had been 4
recruited to the registry between January 13th 2011 and June 19th 2013. Twenty percent of the patients were receiving TCZ as a first-line biologic and 40% as monotherapy. Safety: after 1.3 years, the drug had been stopped in 71 patients (36%) for safety reasons. There were 55 severe infections (mostly soft tissues and respiratory tract infections, 32 and 27% respectively) reported in 49 patients, corresponding to a rate of 5.2 severe infections per 100 patients years. The other SAEs were three lymphomas (0.3/100 PY), seven cancers (0.65/100 PY), eight thromboembolic events (0.7/100 PY), eight infusion reactions with definitive withdrawal of TCZ (0.7/100 PY) and one cardiovascular event (0.1/100 PY). Six bowel perforations were observed (0.6/100 PY) and five out of these six patients had been treated with concomitant steroids. Three deaths were recorded: one septic shock, one pneumocystosis, and one hypertrophic cardiopathy. The DANBIO registry (Denmark) The nationwide DANBIO registry was started in 2000 and approved as a clinical quality registry by the Danish National Board of Health in 2006 [23]. Registration in DANBIO is mandatory for all Danish departments involved in biological treatment of RA, and > 90% of adult patients with RA are followed prospectively who are treated with biological drugs in Denmark [24]. Safety: the SAEs reported for TCZ were urticaria and chest pain (n = 1); skin cancer (n = 1); raised liver enzymes and jaundice (n = 1); general allergic reaction with palpitations (n = 1). AEs were acute polyarthritis, dizziness and chest pain (n = 1); skin rash, raised cholesterol and elevated blood pressure (n = 1); sensitivity loss (n = 1); worsening of existing infection (n = 1). In four cases, where AEs were reported as the reason for withdrawal, the AE was not described further. 5.2.2
The ICHIBAN study (Germany) The non-interventional ICHIBAN study evaluated the efficacy and safety of TCZ in German patients with RA in clinical practice over a 2 year period [25], starting in February 2010. By the reference date of 18th December 2011, 1036 patients had baseline data and 343 of those patients had observation periods of at least 52 weeks (or discontinuation or change in treatment was documented). Safety: 781 AEs were reported (in 339 of the 1036 patients; 85.8/100 patient years). Of these, 147 events were infections (16.2/100 patient years). There were 160 reports of SAEs (in 95 patients; 17.6/100 patient years), 110 of which included at least improbable causal relationship with TCZ (12.1/100 patient years). 5.2.3
6.
Safety of subcutaneous tocilizumab
The BREVACTA study The BREVACTA study evaluated the safety and efficacy of TCZ-SC versus placebo [26]. In total 656 patients with RA 6.1
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Safety of SC versus intravenous TCZ in combination with traditional DMARDs in patients with rheumatoid arthritis
and an inadequate response to DMARDs were randomized 2:1 to receive TCZ-SC 162 mg every other week (q2w) or placebo-SC q2w for 24 weeks. Escape therapy with TCZSC 162 mg weekly was offered from week 12 for inadequate response (i.e., for patients who had < 20% improvement from baseline in both SJC and TJC between weeks 12 and 48). Efficacy: the results showed that TCZ-SC was superior to placebo-SC for the primary endpoint of an ACR20 response at week 24 (60.9 vs 31.5%; p < 0.0001). All secondary endpoints showed TCZ-SC to be superior to placebo-SC: ACR50 and ACR70 (40 vs 12 and 20 vs 5%; both p < 0.0001) and DAS28 remission (DAS28 < 2.6: 32 vs 4% p < 0001). Safety: with respect to the safety profile of TCZ-SC, AEs and SAEs were comparable between the TCZ-SC and placebo-SC groups: 4.6 and 3.7% had at least one SAE, and infectious complications were the most common SAE, in 2.1 and 1.8% respectively. More injection-site reactions occurred with TCZ-SC versus placebo-SC (7.1 vs 4.1%). No anaphylaxis or serious hypersensitivity reactions occurred. There were three deaths in the TCZ-SC group (two due to sepsis and one due to a respiratory tract infection) and none in the placebo-SC group. Twenty-six patients withdrew from the study before week 24 and 71 patients received escape therapy of TCZ-SC qw. Open-label extension: at week 24 patients were rerandomized 1:1, to TCZ-SC every 2 weeks via pre-filled syringe or autoinjector. By week 48, 11% of patients had achieved a major clinical response (defined as maintaining an ACR70 response for ‡ 24 weeks). Efficacy was maintained or improved between 24 and 48 weeks, with sustained reduction in radiographic progression of structural joint damage and maintenance of the improvement in DAS28 and physical function (measured by HAQ-DI). Similarly the safety profile was maintained during the extension period. By week 48, 21 patients had withdrawn from TCZ-SC treatment due to AEs, most commonly infections or elevated liver enzyme levels. Between weeks 24 and 48, 20 patients withdrew from the study and six patients received escape therapy of TCZ qw; thus of the 438 patients randomized at baseline to the TCZ arm, 315 (72%) completed to week 48.
Head-to-head trial of intravenous versus subcutaneous tocilizumab
7.
The SUMMACTA study The SUMMACTA study was a 2-year, randomized, doubleblind, parallel-group Phase III study of the safety and efficacy of TCZ-SC versus TCZ-IV in combination with traditional DMARDs in 1262 patients with moderate to severe RA and an inadequate response to DMARDs. Efficacy: the primary outcome was achieved showing that TCZ-SC was not inferior to TCZ-IV with respect to the proportion of patients in each group achieving an 7.1
ACR20 response at week 24, using a 12% non-inferiority margin (69.4 vs 73.4% respectively). Safety: rates of AEs, SAEs and discontinuations due to AE were comparable between groups. Infection was the most common AE, with a frequency of 36% in the TCZ-SC group and 39.1% in the TCZ-IV group. The most common AE was upper respiratory tract infection (7.3 TCZ-SC and 11.6% TCZ-IV) and the most common SAE was infection (1.4% in both groups). Overall, the safety profiles of the two preparations were similar, except for a higher incidence of ISRs in the TCZSC group (10.1%) than the group, which received TCZ-IV with placebo-SC (2.4%). Open-label extension: the week 49 cumulative safety profiles of patients on TCZ-SC were consistent with the 24 week data, with the rate of ISRs remaining higher in the TCZ-SC group (12%) compared with 2.4% in the TCZ-IV group [27].
The MUSASHI Study The MUSASHI study was a Phase III study of the efficacy and safety of SC versus IV TCZ monotherapy in patients with RA undertaken in Japan. The study had a double-blind, parallelgroup, double-dummy, comparative Phase III design and patients were randomized to receive TCZ-SC 162 mg every 2 weeks or TCZ-IV 8 mg/kg every 4 weeks. No DMARDs were allowed during the study. The non-inferiority margin was set at 18%, as determined using the difference between the ACR20 results of SATORI (Study of Active Controlled TCZ Monotherapy for Rheumatoid Arthrits Paitents with an Inadequate Response to MTX) [28]. Efficacy: non-inferiority of TCZ-SC to TCZ-IV was demonstrated at week 24. ACR20 response was achieved in 79.2% (95% confidence interval [95% CI] 72.9, 85.5) of the TCZSC group and in 88.5% (95% CI: 83.4, 93.5) of the TCZ-IV group. The weighted difference was -9.4% (95% CI: -17.6, 1.2), confirming the non-inferiority of TCZ-SC to TCZ-IV. Remission rates of the DAS28 using the ESR and the Clinical Disease Activity Index at week 24 were 49.7 and 16.4% in the TCZ-SC group and 62.2 and 23.1% in the TCZ-IV group, respectively. Safety: incidences of all AEs and SAEs were 89.0 and 7.5% in the TCZ-SC group and 90.8 and 5.8% in the TCZ-IV group, respectively. Anti-TCZ antibodies were detected in 3.5% (6 of 173 patients) of the TCZ-SC group and 0% of the TCZ-IV group. None of the patients who developed anti-TCZ antibodies experiences ISRs, SIRs or lack of efficacy after developing the antibodies. Overall, the safety data was comparable between the IV and SC groups and the authors concluded that TCZ-SC could provide an alternative therapeutic option for RA patients. They also found that the rate of anti-drug antibody development was numerically no higher than rates reported for other agents used to treat RA [29-32]. 7.2
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8.
Summary of main safety information
Overall, from the clinical trial data, it would appear that TCZ has an acceptable safety profile and is reasonably well tolerated by the vast majority of patients. TCZ therefore provides an important therapeutic option for the management of patients with RA. However, a number of well-established potential side effects exist and although these are often mild to moderate and transient, awareness is critical in order to ensure the safe monitoring and management of patients. The British Society for Rheumatology has developed guidelines for the treatment of RA with TCZ-IV focusing on the monitoring required [33]. These may also be used to monitor TCZ-SC. These guidelines offer key recommendations for the monitoring and management of the main safety considerations, including lipid profile, neutropenia and liver function tests. Advice is also provided for how to manage special circumstances such as surgery, pregnancy and breastfeeding, vaccination and gastrointestinal perforation. In summary, the safety profile of TCZ-SC is similar to that of TCZ-IV with no specific differences having been identified to date. Clinicians should have confidence in using TCZ-SC, which is certainly a welcome addition to the management of the complex and crippling condition of RA. 9.
Expert opinion
With the increasing number of treatment options currently available for the management of RA, the challenge now is to decide the optimum order of drugs to use. TCZ has been shown in clinical trials and in routine practice to be efficacious in RA patients who fail to respond to conventional DMARDs and TNF antagonists. However, in addition to efficacy, multiple other factors influence the treatment choice, at individual, local and governmental levels. Safety, it goes without saying, is paramount. Additionally, an obligation exists to offer treatment that is both acceptable to the individual and cost-effective to society. Whereas the future of RA treatment is unclear with new biologics and small molecules offering exciting prospects, for now it appears that TCZ has an important role to play in the management of the condition. The efficacy of TCZ has been demonstrated in clinical trials, as well as in longer-term registry data and clinical practice. The benefits include reduction in disease activity (as measured by ACR scores, DAS28, swollen and tender joint counts and inflammatory markers), as well as functional improvements (evidenced by HAQ-DI) and reduction of radiographic evidence of structural joint damage. The AMBITION study demonstrated the superiority of TCZ monotherapy versus MTX monotherapy, the first and only RCT to show the superiority of a biologic agent given as monotherapy over MTX monotherapy. The ADACTA trial has shown that in a head-to-head comparison with adalimumab monotherapy, TCZ monotherapy offers superior efficacy in patients who cannot take MTX. 6
The most serious safety concerns relating to TCZ include the risk of infection and gastrointestinal perforation. Six cases of tuberculosis were reported in the worldwide TCZ RA clinical trials database based on > 10 000 PYs of exposure [34]. In a long-term follow-up study > 3.6 years, with a total treatment exposure of 12,293 patient years, the overall rate of serious infection was 4.6/100 patient years [35]. In the same analysis, 29 patients experienced gastrointestinal perforation (0.24/100 PYs), 17 (59%) of which were colonic diverticular perforations. For this reason, TCZ should be used cautiously in those patients with diverticular disease or a history of intestinal ulceration [36]. Greater frequencies of neutropenia, thrombocytopenia, hyperlipidemia, and transaminitis have been observed with TCZ compared with placebo [37]. Rates of cardiovascular disease and stroke with TCZ have been consistent with those expected in an RA population [29]. Overall, the safety of TCZ-SC is comparable to that of TCZ-IV and offers an acceptable benefit: risk ratio for the majority of patients in whom it is indicated. For patients living with a long-term condition such as RA, it is vital that we have the ability to offer treatment options that they find acceptable. For most patients, the route of administration is an important factor when making a choice between different therapeutic options. Most patients prefer SC injections rather than IV or intramuscular injections (52.5% compared with 17.5 and 30%, respectively, of biologic-naive patients according to one study) [9]. Similarly there is a preference to be treated at home (62.5% of those already on anti-TNF and 52% of biologic-naive patients) rather than in hospital. The development of the SC formulation of TCZ is thus a welcome advance in the era of patientfocused medicine. In the UK, NICE found TCZ-IV to be cost-effective for the treatment of RA as a first- or second-line biologic agent [14]. NICE decided in July 2011 that TCZ SC, for moderate-to-severe RA in combination with DMARDs, would not progress as a technology appraisal, given that it would be used to treat the same target populations as the previously approved TCZ-IV [38]. In a letter from NICE to the manufacturer, it was explained that given the positive appraisal for TCZ-IV, and assuming the clinical equivalence of the IV and SC preparations, the expected cost-savings would support a switch to TCZ-SC, without the need for revised guidelines. Thus, in the UK, it is now possible to prescribe NHS patients TCZ-SC as an alternative to TCZ-IV. Whereas SC injections are cheaper and offer patients a greater degree of flexibility and freedom compared with IV infusions, it is important to remember that most patients would prefer to avoid the need for regular injections altogether. The biologics in current use are derived from proteins and are thus unsuitable for oral administration due to the presence of proteases in the digestive tract. However, the discovery of new classes of small molecule anti-inflammatory compounds offers the potential for further orally administered anti-rheumatic drugs [39]. These agents work at an
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Safety of SC versus intravenous TCZ in combination with traditional DMARDs in patients with rheumatoid arthritis
intracellular level, offering targeted therapy against specific signal transduction molecules, such as tyrosine kinases. Their shorter half-life compared with biologics may be advantageous in circumstances such as infection or surgery, when a faster elimination time is beneficial. They may also be cheaper and easier to manufacture. These drugs have now been licensed for use in RA in many countries including the USA; however, the EMA requested further safety and efficacy data prior to granting a license for use in Europe. In conclusion, the efficacy and safety of TCZ in the treatment of RA have been shown in multiple RCTs, both as monotherapy and in combination with traditional DMARDs. The efficacy and safety data for TCZ-SC is similar to the IV form, albeit with a higher frequency of ISRs. TCZ offers patients a rapid and sustained reduction in disease activity, improved function and reduced structural damage. Given Bibliography
that patients overall prefer SC to IV medication, it is likely that TCZ-SC will become a mainstay of RA treatment, along with other SC biologic agents, for years to come.
Declaration of interest € or’s has received support from (including attendance at A Ost€ conferences), undertaken clinical trials and acted as a consultant to Roche, Lilly, Chugai, Merck Sharp & Dohme, Abbvie, Pfizer, Novartis, Napp and Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
7.
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Safety of SC versus intravenous TCZ in combination with traditional DMARDs in patients with rheumatoid arthritis
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Affiliation Maeve McLaughlin1 MBBS (Lond) MA (Cantab) MRCP & € or’s†2 MA MB BS FRACP FRCP Andrew Ost€ FRCP (Edin) † Author for correspondence 1 Rheumatology Clinical Research Fellow, Addenbrooke’s Hospital, Rheumatology Research Unit, Box 204, Cambridge Biomedical Campus, Hills Road, Cambridge, UK 2 Rheumatology Consultant, Associate Lecturer, Director of the Cambridge Rheumatology Research Unit, Cambridge University, School of Clinical Medicine, Cambridge, UK Tel: +44 1223 245 151 E-mail: [email protected]
Expert Opin. Drug Saf. (2014) 14(3)
9
Review
1.
Background
2.
Mechanism of action
3.
Pharmacokinetics
4.
Approval of tocilizumab
5.
Efficacy and safety of intravenous tocilizumab
6.
Safety of subcutaneous tocilizumab
7.
Head-to-head trial of intravenous versus subcutaneous tocilizumab
8.
Summary of main safety information
9.
Expert opinion
Safety of subcutaneous versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis € or’s† Maeve McLaughlin & Andrew Ost€ †
Cambridge University, School of Clinical Medicine, Cambridge, UK
Introduction: Tocilizumab (TCZ), a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody, has demonstrated efficacy and tolerability in several large randomized, controlled trials for the treatment of rheumatoid arthritis (RA). Areas covered: This article compares the safety profile of the newer, subcutaneous (SC) formulation of TCZ with the original intravenous (IV) formulation, in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in patients with RA. Several pivotal clinical trials are included, highlighting data from: i) trials of TCZ-IV; ii) trials of TCZ-SC; and iii) trials comparing IV to SC TCZ. TCZ use in pediatric populations is beyond the scope of this review. Expert opinion: The efficacy and safety of TCZ-IV in the treatment of RA has been demonstrated in multiple clinical trials, both as monotherapy and in combination with traditional DMARDs. The data for TCZ-SC is similar, albeit with a higher frequency of injection site reactions (ISRs). With careful patient selection, the benefit: risk ratio is favorable, offering patients a rapid and sustained reduction in disease activity, improved function and reduced structural damage. Given that most patients prefer SC to IV medication, TCZ-SC will likely become a mainstay, along with other biologic agents, for the treatment of RA patients who have failed traditional non-biologic DMARDs. Keywords: humanized anti-IL-6 receptor (IL-6R) antibody, immunotherapy, rheumatoid arthritis, safety, tocilizumab Expert Opin. Drug Saf. [Early Online]
1.
Background
Rheumatoid arthritis (RA) is a chronic systemic autoimmune condition associated with inflammatory manifestations in synovial joints and other organs. The condition has a prevalence in most industrialized countries of between 0.3 and 1% [1], with an incidence in populations of northern European origin of 20 -- 300 per 100,000 per year [2]; however the disease is present worldwide [3]. The natural history of RA involves progressive joint deformity leading to loss of function. Extra-articular manifestations are common, affecting the cardiovascular, pulmonary, ocular, neurological and hematological systems. The disorder is also associated with significantly reduced quality of life and longevity, reduction in work capacity and increased use of healthcare services [4]. Patients with long-standing active disease have a substantially increased risk of premature mortality [5]. The underlying pathophysiology of RA is complex and not fully understood, although immune system dysfunction is critical to the development of the disease. 10.1517/14740338.2015.998198 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Article highlights. .
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Tocilizumab, a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody can be used with confidence to treat patients with RA. Tocilizumab is NICE-approved in the UK for use in adults with moderate to severe RA if the disease has responded inadequately to * DMARDs * DMARDs and a TNF inhibitor treatment, in patients with a contraindication to rituximab * one or more TNF inhibitor treatment and to rituximab. The main safety concerns relate to infections (including reactivation of tuberculosis), neutropenia, thrombocytopenia, hyperlipidemia, transaminitis, and gastrointestinal perforation. The newer subcutaneous formulation appears to share a similar safety and efficacy profile with the IV formulation of tocilizumab, albeit with increased incidence of injection site reactions.
This box summarizes key points contained in the article.
The inflammatory response seen in RA stems from multifarious interactions between cells of the immune system resulting in the production of pro-inflammatory cytokines as well as auto-antibodies. Many of these molecular mediators of inflammation have been singled out as the target of pharmacotherapy with newer biological agents such as anti-TNF antagonists [6]. To date, no single agent has been shown to successfully treat all patients suffering from this disease due to its heterogeneous nature [7]. However, the impact of early intensive intervention, aiming to achieve remission in the long term, has had a dramatic impact on the course of the illness [8]. Given the variety of therapeutic options now available, it has become possible for clinicians to individualize treatment to a degree, attempting to utilize the most appropriate agent for the patient. Although many of these decisions are based on the side effect profile of the drug in relation to the patient’s comorbidities, there are also practical issues to consider. For some patients, the availability of a drug as a subcutaneous (SC) injection confers freedom, flexibility and independence [9]. Time that would otherwise have been spent travelling to and from the hospital for regular infusions may be devoted to more useful pursuits such as work or family responsibilities. For other patients, such as those who are needle-phobic, who suffer from hand deformities and disability, or where issues of adherence exist, intravenous (IV) infusions are preferable to self-administered SC injections. The overall aim of this article is to clarify whether there is parity between the safety profiles of IV and SC injections of Tocilizumab (TCZ), in order to allow the clinician and the patient to make an informed choice regarding their treatment. 2.
Mechanism of action
3.
Pharmacokinetics
In a large randomized controlled study (SUMMACTA) the pharmacokinetic profiles of TCZ administered via both IV and SC routes were compared [12]. Serum trough TCZ levels (Ctrough) increased more rapidly in the TCZ-SC group than in the TCZ-IV group; however the trough levels in both groups plateaued with subsequent dosing by week 12. The observed steady-state Ctrough (± SD) at week 24 was higher following TCZ-SC dosing, at 42 (± 27.4) µg/ ml than following TCZ-IV dosing (18 (± 14.2) µg/ml). Despite higher trough levels for TCZ-SC, the mean area under the curve and maximum plasma concentration (Cmax) of TCZ at steady state were higher for TCZ-IV. CRP levels decreased in both groups after the first dose of TCZ and remained below the upper limit of normal (ULN; 0.99 mg/dl) to week 24. The time course for the reduction in CRP following TCZ-SC was comparable to that for TCZ-IV, with a tendency towards slightly lower CRP levels in the SC group. This may reflect the higher trough levels for TCZ-SC. Similar results were observed for the ESR. In vivo pharmacokinetic analysis was also performed as part of another randomized controlled study in Japan (MUSASHI), allowing comparison between the IV and SC routes of administration [13]. Serum samples were processed by enzyme-linked immunosorbent assay to detect the amount of TCZ not bound by the IL-6 receptor (free TCZ). The serum trough concentration in the TCZ-SC monotherapy and TCZ-IV monotherapy groups was similar over time, despite a smaller dose-per-kilogram being administered in the TCZ-SC arm compared with TCZ-IV. From week 4 onward, the Ctrough were comparable between the TCZ-SC and TCZ-IV groups, with > 80% of patients maintaining concentrations > 1 µg/ml in the TCZSC monotherapy group. This timecourse was also reflected in the time to clinical improvement, with the effectiveness of TCZ-SC becoming approximately equal to that of TCZ-IV from week 4 onward. 4.
IL-6 is a pro-inflammatory cytokine, which has multiple physiological and pathological actions. The production of 2
IL-6 is induced promptly upon tissue damage or inflammation and ceases when homeostasis is restored. IL-6 contributes to the host defense through the stimulation of acute-phase immune reactions. The dysregulation of the synthesis of IL-6 has been implicated in the development of immune-mediated diseases and cancer [10]. Indeed, studies have shown that in RA patients, levels of IL-6 are increased in synovial fluid and tissue, and correlate with C-reactive protein (CRP) and disease activity [11]. TCZ is a recombinant humanized anti-IL-6 receptor (IL-6R) monoclonal antibody that blocks IL-6 from binding to the soluble and membrane-bound IL-6R.
Approval of tocilizumab
The IV formulation of TCZ was approved by the EMA as a treatment for moderate to severe RA in January 2009. The
Expert Opin. Drug Saf. (2014) 14(3)
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Safety of SC versus intravenous TCZ in combination with traditional DMARDs in patients with rheumatoid arthritis
drug also received FDA approval for use in the USA in January 2010. TCZ may be used both as a single-agent therapy and in combination with methotrexate (MTX) or other non-biologic disease-modifying antirheumatic drug (DMARDs). The SC formulation of TCZ was approved by the FDA for the same indication in October 2013 and by the EMA in April 2014. In August 2010, the UK’s National Institute for Health and Care Excellence (NICE), which analyses the costeffectiveness of therapies, recommended the use of TCZ in RA in patients with moderate to severe disease, who have responded inadequately to one or more TNF inhibitors, and who are unsuitable for rituximab, or following failure of rituximab [14]. These guidelines were revised and replaced by TA247, published in February 2012, in which TCZ was also approved as a first-line biological agent [15].
Efficacy and safety of intravenous tocilizumab
5.
5.1
The radiate study The RADIATE study was a Phase III, randomized, doubleblind, placebo-controlled, parallel group study conducted throughout North America and Western Europe, in which 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg TCZ or placebo (control) IV every 4 weeks with stable MTX for 24 weeks [18]. Efficacy: the proportion of patients achieving ACR20 by week 24 was significantly higher in both TCZ groups compared with the placebo group (50.0, 30.4 and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 < 2.6) rates at week 24 were achieved by 30.1, 7.6 and 1.6% of 8 mg/kg, 4 mg/kg and control groups respectively (< p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Safety: most AEs in this study were classified as mild or moderate. The most common AEs with higher incidence in TCZ groups were infections, gastrointestinal symptoms, rash and headache. The incidence of SAEs was higher in controls (11.3%) than in the TCZ 8 (6.3) or 4 mg/kg (7.4%) groups. 5.1.3
Clinical trials The option study
5.1.1
The OPTION study was a double-blind randomized, placebo-controlled, parallel-group Phase III study to investigate the safety and efficacy of TCZ in combination with MTX in 623 patients with moderate to severe RA, who had responded inadequately to MTX [16]. Efficacy: significant improvements were found in American College of Rheumatology scores (ACR20, ACR50 and ACR 70) at week 24 with TCZ (at either of the two dosing regimens, i.e., 4 or 8 mg/kg) in combination with MTX, compared with placebo (59% in the 8 mg/kg group [odds ratio 4.0 compared with placebo], 48% in the 4 mg/kg group [odds ratio 2.6 compared with placebo] and 26% in the placebo group. Additionally, significantly more patients in the treatment arms achieved disease remission, as measured by disease activity score in 28 joints (DAS28) scores, when compared with placebo. Starting with a mean baseline DAS28 of 6.8 for each of the treatment groups, the percentage of patients who achieved a reduction to a DAS28 score of < 2.6, was 21/156 (13%) in the 8 mg/kg group, 47/171 (27%) in the 4 mg/kg group and 1/121 (0.8%) in the placebo group. Safety: the incidence of serious adverse events (SAEs) including infectious complications was the same in each of the three groups in the option study (6%), although the frequency of non-serious infections was higher in the 8 mg/kg group (3%) than in the 4 mg/kg and placebo groups (at 1% each group). The toward study The TOWARD study was a 24-week Phase III, randomized, double-blind, placebo-controlled, international, multicentre study conducted in 18 countries on 1216 patients with active RA and an inadequate response to DMARDs [17]. Patients 5.1.2
were randomized in a 2:1 ratio to receive either TCZ or placebo combined with stable DMARD therapy. Efficacy: compared with placebo, TCZ 8 mg/kg combined with DMARD therapy, significantly improved ACR20 (61 vs 25%), ACR50 (38 vs 9%) and ACR70 (21 vs 3%). Rates of remission responses (DAS28 < 2.6) were also higher in the TCZ group versus the control group, with 30% of patients and 3% of patients, respectively, achieving clinical remission at week 24 (p < 0.0001). By week 24, mean changes from baseline were greater in the TCZ group than in the control group (-3.17 and -1.16, respectively; p < 0.0001). Safety: the overall incidence of adverse events (AEs) was higher in the TCZ group compared with the control group (73 vs 61%). More than 90% of AEs in each group were of mild or moderate intensity. Serious AEs (6.7 vs 4.3%), AEs leading to withdrawal (3.9 vs 1.9%), and AEs leading to dose modification (13.8 vs 7.2%) occurred more frequently in the TCZ group than in the control group.
The ambition study The AMBITION study was designed to compare TCZ monotherapy versus MTX monotherapy in patients with moderate to severe RA [19]. This 24-week, double-blind, double-dummy, parallel-group study, randomized 673 patients to either TCZ 8 mg/kg every 4 weeks, or MTX, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by TCZ 8 mg/kg. Efficacy: the intention-to-treat analysis demonstrated that TCZ was better than MTX treatment with a higher ACR20 response (69.9 vs 52.5%; p < 0.001), and 28-joint DAS28 < 2.6 rate (33.6 vs 12.1%) at week 24. 5.1.4
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€ o € r’s M. McLaughlin & A. Ost
Safety: the incidence of SAEs with TCZ was 3.8 vs 2.8% with MTX (p = 0.50), and of serious infections, 1.4 vs 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1 vs 0.4%), increased total cholesterol ‡ 240 mg/dl (13.2 vs 0.4%), and lower incidence of alanine aminotransferase elevations of 3 to 5 times the upper limit of normal (1.0 vs 2.5%), with TCZ use compared with MTX treatment respectively. The authors concluded that TCZ monotherapy was better than MTX monotherapy, showing rapid improvement in RA signs and symptoms, and a favorable benefit--risk ratio, in patients for whom treatment with MTX or biological agents has not previously failed. The ADACTA study The ADACTA study compared the safety and efficacy of TCZ monotherapy with that of adalimumab monotherapy [20]. The study was a randomized, double-blind, parallel-group, Phase IV superiority trial undertaken in 76 centers in 15 countries in North and South America, Australasia, and Europe. Three hundred and twenty-six patients were enrolled who had severe RA for 6 months or more, and were intolerant to MTX or were inappropriate for continued MTX treatment. Patients were randomly assigned (1:1; block size of four) to receive TCZ 8 mg per kg bodyweight IV every 4 weeks plus placebo SC every 2 weeks or adalimumab 40 mg SC every 2 weeks plus placebo IV every 4 weeks for 24 weeks. The intention-to-treat population contained 325 patients (163 assigned to TCZ, 162 assigned to adalimumab). Efficacy: at week 24 the mean change from baseline in DAS28 was significantly greater in the TCZ group (-- 3·3) than in the adalimumab group (-- 1·8) patients (difference --1·5, 95% CI: --1·8 to --1·1; p < 0·0001). Safety: SAEs were reported in 16 of 162 (10%) patients in the adalimumab group versus 19 of 162 (12%) in the TCZ group with the majority of SAEs related to infection. More patients in the TCZ group than in the adalimumab group had increased LDL-cholesterol, increased alanine aminotransferase concentrations, and reduced platelet and neutrophil counts. The authors concluded that TCZ monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of RA in patients for whom MTX was deemed inappropriate. The AE profiles of TCZ and adalimumab were consistent with previous findings. 5.1.5
5.2
Registry data The REGATE registry (France)
5.2.1
The REGATE registry is a French cohort study designed by the French Society of Rheumatology to collect safety information on the use of TCZ in RA [21]. The registry started in 2010 and aimed to include 1500 patients, with a prospective follow-up period of 5 years. The tolerability data from the 1 year of the study was published in 2014 [22], looking at 1503 patients from 78 French centers, who had been treated with TCZ initiated after January 1st 2010 and who had been 4
recruited to the registry between January 13th 2011 and June 19th 2013. Twenty percent of the patients were receiving TCZ as a first-line biologic and 40% as monotherapy. Safety: after 1.3 years, the drug had been stopped in 71 patients (36%) for safety reasons. There were 55 severe infections (mostly soft tissues and respiratory tract infections, 32 and 27% respectively) reported in 49 patients, corresponding to a rate of 5.2 severe infections per 100 patients years. The other SAEs were three lymphomas (0.3/100 PY), seven cancers (0.65/100 PY), eight thromboembolic events (0.7/100 PY), eight infusion reactions with definitive withdrawal of TCZ (0.7/100 PY) and one cardiovascular event (0.1/100 PY). Six bowel perforations were observed (0.6/100 PY) and five out of these six patients had been treated with concomitant steroids. Three deaths were recorded: one septic shock, one pneumocystosis, and one hypertrophic cardiopathy. The DANBIO registry (Denmark) The nationwide DANBIO registry was started in 2000 and approved as a clinical quality registry by the Danish National Board of Health in 2006 [23]. Registration in DANBIO is mandatory for all Danish departments involved in biological treatment of RA, and > 90% of adult patients with RA are followed prospectively who are treated with biological drugs in Denmark [24]. Safety: the SAEs reported for TCZ were urticaria and chest pain (n = 1); skin cancer (n = 1); raised liver enzymes and jaundice (n = 1); general allergic reaction with palpitations (n = 1). AEs were acute polyarthritis, dizziness and chest pain (n = 1); skin rash, raised cholesterol and elevated blood pressure (n = 1); sensitivity loss (n = 1); worsening of existing infection (n = 1). In four cases, where AEs were reported as the reason for withdrawal, the AE was not described further. 5.2.2
The ICHIBAN study (Germany) The non-interventional ICHIBAN study evaluated the efficacy and safety of TCZ in German patients with RA in clinical practice over a 2 year period [25], starting in February 2010. By the reference date of 18th December 2011, 1036 patients had baseline data and 343 of those patients had observation periods of at least 52 weeks (or discontinuation or change in treatment was documented). Safety: 781 AEs were reported (in 339 of the 1036 patients; 85.8/100 patient years). Of these, 147 events were infections (16.2/100 patient years). There were 160 reports of SAEs (in 95 patients; 17.6/100 patient years), 110 of which included at least improbable causal relationship with TCZ (12.1/100 patient years). 5.2.3
6.
Safety of subcutaneous tocilizumab
The BREVACTA study The BREVACTA study evaluated the safety and efficacy of TCZ-SC versus placebo [26]. In total 656 patients with RA 6.1
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Safety of SC versus intravenous TCZ in combination with traditional DMARDs in patients with rheumatoid arthritis
and an inadequate response to DMARDs were randomized 2:1 to receive TCZ-SC 162 mg every other week (q2w) or placebo-SC q2w for 24 weeks. Escape therapy with TCZSC 162 mg weekly was offered from week 12 for inadequate response (i.e., for patients who had < 20% improvement from baseline in both SJC and TJC between weeks 12 and 48). Efficacy: the results showed that TCZ-SC was superior to placebo-SC for the primary endpoint of an ACR20 response at week 24 (60.9 vs 31.5%; p < 0.0001). All secondary endpoints showed TCZ-SC to be superior to placebo-SC: ACR50 and ACR70 (40 vs 12 and 20 vs 5%; both p < 0.0001) and DAS28 remission (DAS28 < 2.6: 32 vs 4% p < 0001). Safety: with respect to the safety profile of TCZ-SC, AEs and SAEs were comparable between the TCZ-SC and placebo-SC groups: 4.6 and 3.7% had at least one SAE, and infectious complications were the most common SAE, in 2.1 and 1.8% respectively. More injection-site reactions occurred with TCZ-SC versus placebo-SC (7.1 vs 4.1%). No anaphylaxis or serious hypersensitivity reactions occurred. There were three deaths in the TCZ-SC group (two due to sepsis and one due to a respiratory tract infection) and none in the placebo-SC group. Twenty-six patients withdrew from the study before week 24 and 71 patients received escape therapy of TCZ-SC qw. Open-label extension: at week 24 patients were rerandomized 1:1, to TCZ-SC every 2 weeks via pre-filled syringe or autoinjector. By week 48, 11% of patients had achieved a major clinical response (defined as maintaining an ACR70 response for ‡ 24 weeks). Efficacy was maintained or improved between 24 and 48 weeks, with sustained reduction in radiographic progression of structural joint damage and maintenance of the improvement in DAS28 and physical function (measured by HAQ-DI). Similarly the safety profile was maintained during the extension period. By week 48, 21 patients had withdrawn from TCZ-SC treatment due to AEs, most commonly infections or elevated liver enzyme levels. Between weeks 24 and 48, 20 patients withdrew from the study and six patients received escape therapy of TCZ qw; thus of the 438 patients randomized at baseline to the TCZ arm, 315 (72%) completed to week 48.
Head-to-head trial of intravenous versus subcutaneous tocilizumab
7.
The SUMMACTA study The SUMMACTA study was a 2-year, randomized, doubleblind, parallel-group Phase III study of the safety and efficacy of TCZ-SC versus TCZ-IV in combination with traditional DMARDs in 1262 patients with moderate to severe RA and an inadequate response to DMARDs. Efficacy: the primary outcome was achieved showing that TCZ-SC was not inferior to TCZ-IV with respect to the proportion of patients in each group achieving an 7.1
ACR20 response at week 24, using a 12% non-inferiority margin (69.4 vs 73.4% respectively). Safety: rates of AEs, SAEs and discontinuations due to AE were comparable between groups. Infection was the most common AE, with a frequency of 36% in the TCZ-SC group and 39.1% in the TCZ-IV group. The most common AE was upper respiratory tract infection (7.3 TCZ-SC and 11.6% TCZ-IV) and the most common SAE was infection (1.4% in both groups). Overall, the safety profiles of the two preparations were similar, except for a higher incidence of ISRs in the TCZSC group (10.1%) than the group, which received TCZ-IV with placebo-SC (2.4%). Open-label extension: the week 49 cumulative safety profiles of patients on TCZ-SC were consistent with the 24 week data, with the rate of ISRs remaining higher in the TCZ-SC group (12%) compared with 2.4% in the TCZ-IV group [27].
The MUSASHI Study The MUSASHI study was a Phase III study of the efficacy and safety of SC versus IV TCZ monotherapy in patients with RA undertaken in Japan. The study had a double-blind, parallelgroup, double-dummy, comparative Phase III design and patients were randomized to receive TCZ-SC 162 mg every 2 weeks or TCZ-IV 8 mg/kg every 4 weeks. No DMARDs were allowed during the study. The non-inferiority margin was set at 18%, as determined using the difference between the ACR20 results of SATORI (Study of Active Controlled TCZ Monotherapy for Rheumatoid Arthrits Paitents with an Inadequate Response to MTX) [28]. Efficacy: non-inferiority of TCZ-SC to TCZ-IV was demonstrated at week 24. ACR20 response was achieved in 79.2% (95% confidence interval [95% CI] 72.9, 85.5) of the TCZSC group and in 88.5% (95% CI: 83.4, 93.5) of the TCZ-IV group. The weighted difference was -9.4% (95% CI: -17.6, 1.2), confirming the non-inferiority of TCZ-SC to TCZ-IV. Remission rates of the DAS28 using the ESR and the Clinical Disease Activity Index at week 24 were 49.7 and 16.4% in the TCZ-SC group and 62.2 and 23.1% in the TCZ-IV group, respectively. Safety: incidences of all AEs and SAEs were 89.0 and 7.5% in the TCZ-SC group and 90.8 and 5.8% in the TCZ-IV group, respectively. Anti-TCZ antibodies were detected in 3.5% (6 of 173 patients) of the TCZ-SC group and 0% of the TCZ-IV group. None of the patients who developed anti-TCZ antibodies experiences ISRs, SIRs or lack of efficacy after developing the antibodies. Overall, the safety data was comparable between the IV and SC groups and the authors concluded that TCZ-SC could provide an alternative therapeutic option for RA patients. They also found that the rate of anti-drug antibody development was numerically no higher than rates reported for other agents used to treat RA [29-32]. 7.2
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8.
Summary of main safety information
Overall, from the clinical trial data, it would appear that TCZ has an acceptable safety profile and is reasonably well tolerated by the vast majority of patients. TCZ therefore provides an important therapeutic option for the management of patients with RA. However, a number of well-established potential side effects exist and although these are often mild to moderate and transient, awareness is critical in order to ensure the safe monitoring and management of patients. The British Society for Rheumatology has developed guidelines for the treatment of RA with TCZ-IV focusing on the monitoring required [33]. These may also be used to monitor TCZ-SC. These guidelines offer key recommendations for the monitoring and management of the main safety considerations, including lipid profile, neutropenia and liver function tests. Advice is also provided for how to manage special circumstances such as surgery, pregnancy and breastfeeding, vaccination and gastrointestinal perforation. In summary, the safety profile of TCZ-SC is similar to that of TCZ-IV with no specific differences having been identified to date. Clinicians should have confidence in using TCZ-SC, which is certainly a welcome addition to the management of the complex and crippling condition of RA. 9.
Expert opinion
With the increasing number of treatment options currently available for the management of RA, the challenge now is to decide the optimum order of drugs to use. TCZ has been shown in clinical trials and in routine practice to be efficacious in RA patients who fail to respond to conventional DMARDs and TNF antagonists. However, in addition to efficacy, multiple other factors influence the treatment choice, at individual, local and governmental levels. Safety, it goes without saying, is paramount. Additionally, an obligation exists to offer treatment that is both acceptable to the individual and cost-effective to society. Whereas the future of RA treatment is unclear with new biologics and small molecules offering exciting prospects, for now it appears that TCZ has an important role to play in the management of the condition. The efficacy of TCZ has been demonstrated in clinical trials, as well as in longer-term registry data and clinical practice. The benefits include reduction in disease activity (as measured by ACR scores, DAS28, swollen and tender joint counts and inflammatory markers), as well as functional improvements (evidenced by HAQ-DI) and reduction of radiographic evidence of structural joint damage. The AMBITION study demonstrated the superiority of TCZ monotherapy versus MTX monotherapy, the first and only RCT to show the superiority of a biologic agent given as monotherapy over MTX monotherapy. The ADACTA trial has shown that in a head-to-head comparison with adalimumab monotherapy, TCZ monotherapy offers superior efficacy in patients who cannot take MTX. 6
The most serious safety concerns relating to TCZ include the risk of infection and gastrointestinal perforation. Six cases of tuberculosis were reported in the worldwide TCZ RA clinical trials database based on > 10 000 PYs of exposure [34]. In a long-term follow-up study > 3.6 years, with a total treatment exposure of 12,293 patient years, the overall rate of serious infection was 4.6/100 patient years [35]. In the same analysis, 29 patients experienced gastrointestinal perforation (0.24/100 PYs), 17 (59%) of which were colonic diverticular perforations. For this reason, TCZ should be used cautiously in those patients with diverticular disease or a history of intestinal ulceration [36]. Greater frequencies of neutropenia, thrombocytopenia, hyperlipidemia, and transaminitis have been observed with TCZ compared with placebo [37]. Rates of cardiovascular disease and stroke with TCZ have been consistent with those expected in an RA population [29]. Overall, the safety of TCZ-SC is comparable to that of TCZ-IV and offers an acceptable benefit: risk ratio for the majority of patients in whom it is indicated. For patients living with a long-term condition such as RA, it is vital that we have the ability to offer treatment options that they find acceptable. For most patients, the route of administration is an important factor when making a choice between different therapeutic options. Most patients prefer SC injections rather than IV or intramuscular injections (52.5% compared with 17.5 and 30%, respectively, of biologic-naive patients according to one study) [9]. Similarly there is a preference to be treated at home (62.5% of those already on anti-TNF and 52% of biologic-naive patients) rather than in hospital. The development of the SC formulation of TCZ is thus a welcome advance in the era of patientfocused medicine. In the UK, NICE found TCZ-IV to be cost-effective for the treatment of RA as a first- or second-line biologic agent [14]. NICE decided in July 2011 that TCZ SC, for moderate-to-severe RA in combination with DMARDs, would not progress as a technology appraisal, given that it would be used to treat the same target populations as the previously approved TCZ-IV [38]. In a letter from NICE to the manufacturer, it was explained that given the positive appraisal for TCZ-IV, and assuming the clinical equivalence of the IV and SC preparations, the expected cost-savings would support a switch to TCZ-SC, without the need for revised guidelines. Thus, in the UK, it is now possible to prescribe NHS patients TCZ-SC as an alternative to TCZ-IV. Whereas SC injections are cheaper and offer patients a greater degree of flexibility and freedom compared with IV infusions, it is important to remember that most patients would prefer to avoid the need for regular injections altogether. The biologics in current use are derived from proteins and are thus unsuitable for oral administration due to the presence of proteases in the digestive tract. However, the discovery of new classes of small molecule anti-inflammatory compounds offers the potential for further orally administered anti-rheumatic drugs [39]. These agents work at an
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Safety of SC versus intravenous TCZ in combination with traditional DMARDs in patients with rheumatoid arthritis
intracellular level, offering targeted therapy against specific signal transduction molecules, such as tyrosine kinases. Their shorter half-life compared with biologics may be advantageous in circumstances such as infection or surgery, when a faster elimination time is beneficial. They may also be cheaper and easier to manufacture. These drugs have now been licensed for use in RA in many countries including the USA; however, the EMA requested further safety and efficacy data prior to granting a license for use in Europe. In conclusion, the efficacy and safety of TCZ in the treatment of RA have been shown in multiple RCTs, both as monotherapy and in combination with traditional DMARDs. The efficacy and safety data for TCZ-SC is similar to the IV form, albeit with a higher frequency of ISRs. TCZ offers patients a rapid and sustained reduction in disease activity, improved function and reduced structural damage. Given Bibliography
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Declaration of interest € or’s has received support from (including attendance at A Ost€ conferences), undertaken clinical trials and acted as a consultant to Roche, Lilly, Chugai, Merck Sharp & Dohme, Abbvie, Pfizer, Novartis, Napp and Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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Affiliation Maeve McLaughlin1 MBBS (Lond) MA (Cantab) MRCP & € or’s†2 MA MB BS FRACP FRCP Andrew Ost€ FRCP (Edin) † Author for correspondence 1 Rheumatology Clinical Research Fellow, Addenbrooke’s Hospital, Rheumatology Research Unit, Box 204, Cambridge Biomedical Campus, Hills Road, Cambridge, UK 2 Rheumatology Consultant, Associate Lecturer, Director of the Cambridge Rheumatology Research Unit, Cambridge University, School of Clinical Medicine, Cambridge, UK Tel: +44 1223 245 151 E-mail: [email protected]
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