Expert Review of Pharmacoeconomics & Outcomes Research Downloaded from informahealthcare.com by University of Queensland on 03/14/15 For personal use only.
Drug Profile
Cost–effectiveness of abatacept for moderate-tosevere rheumatoid arthritis Expert Rev. Pharmacoecon. Outcomes Res. 14(1), 9–18 (2014)
Nicole W Tsao1, Kam Shojania2 and Carlo A Marra*1 1 Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, Canada V6T 1Z3 2 Division of Rheumatology, Faculty of Medicine, University of British Columbia, Vancouver, Canada *Author for correspondence: [email protected]
Abatacept, a selective T-cell costimulation modulator, has become a valuable treatment option for those with moderately to severely active rheumatoid arthritis. Given new clinical evidence, for the first time guidelines from the American College of Rheumatology and Canadian Rheumatology Association are promoting the consideration of abatacept as the first biologic added to initial traditional disease-modifying antirheumatic drugs once an inadequate response to disease-modifying antirheumatic drug monotherapy has been established, putting abatacept at the same line of treatment options as TNF-a inhibitors or rituximab. Since the advent of the subcutaneous formulation of abatacept, positive results from its clinical trials have further increased its appeal. In light of these changes, a review of the literature was conducted on the cost–effectiveness of abatacept for moderate-to-severe rheumatoid arthritis. Here we discuss current evidence, gaps in the literature and abatacept’s future outlook. KEYWORDS: abatacept • biologic response modifiers • cost–effectiveness • health economics • rheumatoid arthritis
Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis, with an estimated prevalence of 1% of the adult population [1]. RA is found to affect women approximately two- to three-times more often than men [1,2]. The onset of RA can occur at any age; however, the age-specific incidence rates of RA varies considerably according to sex, with a 4:1 ratio of women to men in the age group of 35–44 compared with a ratio of 1.1:1 in the age group of 75–84 [3]. RA is a systemic and chronic autoimmune inflammatory disease characterized by joint damage, functional disability, reduced quality of life and premature mortality [1,4–7]. Individuals with RA often report symptoms including pain, stiffness and swelling of the peripheral joints [7]. Individuals with RA also experience higher levels of fatigue, functional impairment, weight loss and depression [7,8], leading to substantial negative effects on quality of life [9,10]. Due to the progressive nature of RA and associated long-term disability, there exists considerable economic burden to patients and society. Individuals with RA have been shown to incur disproportionately high resource use, and indirect costs including lost productivity, compared with other major chronic
www.expert-reviews.com
10.1586/14737167.2014.861742
illnesses [11]. A significantly higher risk of mortality is seen in RA patients, particularly in those with more severe forms of the disease [12,13] compared with the general population. RA has standardized mortality ratio ranging from 1.28 to 2.98 reported in the literature [13–16]. The largest contributor to mortality risk has been attributed to comorbid cardiovascular disease [12,17,18]. The etiology of RA is thought to be multifactorial with both environmental and genetic elements [19]. Aspects of the genetic risks are not fully understood; however, the most important association appears to be with the HLA DRB1 gene locus, an established genetic determinant of risk for the disease [20]. A range of environmental factors have also been identified as possible risk factors for the development of RA these include tobacco smoking, infection and lifestyle factors [21–23]. The molecular pathogenesis of RA involves inflammatory cytokines such as TNF-a and IL-1 [24,25]. These factors are potent stimulators of synovial tissue proliferation, metalloproteinase expression, adhesion molecule expression and secretion of other cytokines resulting in an amplification of inflammatory pathways leading to eventual joint destruction [24,25]. The activation of T and B
2014 Informa UK Ltd
ISSN 1473-7167
9
Drug Profile
Tsao, Shojania & Marra
Expert Review of Pharmacoeconomics & Outcomes Research Downloaded from informahealthcare.com by University of Queensland on 03/14/15 For personal use only.
Table 1. Currently approved treatments for moderate-to-severe rheumatoid arthritis. Traditional DMARDs
Biologic response modifiers
Methotrexate Hydroxychloroquine Sulfasalazine Leflunomide
TNF-a inhibitors – Etanercept (ENBREL; Immunex Corporation, Thousand Oaks, CA, USA) – Infliximab (REMICADE; Janssen Biotech Inc., Horsham, PN, USA) – Adalimumab (HUMIRA; Abbott Laboratories Ltd.; North Chicago, IL, USA) – Certolizumab pegol (CIMZIA; UCB Inc., Brussels, Belgium) – Golimumab (SIMPONI; Janssen Biotech Inc., Horsham, PN, USA) T-cell costimulation modulator – Abatacept (ORENCIA; Bristol-Myers Squibb, New York City, NY, USA) B-cell depletory – Rituximab (RITUXAN; Hoffman-La Roche Ltd., Basel, Switzerland) Interleukin-6 inhibitor – Tocilizumab (ACTEMRA; Hoffman-La Roche Ltd., Basel, Switzerland) Interleukin-1 inhibitor – Anakinra (KINERET; Swedish Orphan Biovitrum AB, Stockholm, Sweden)
DMARDs: Disease-modifying antirheumatic drugs; TNF: Tumor necrosis factor.
lymphocytes resulting in the production of autoantibodies also play important roles in RA pathogenesis [26]. In 1987, the American College of Rheumatology (ACR) revised criteria for RA [27] was developed and has been widely used as the RA classification criteria in clinical trials for disease-modifying antirheumatic drugs (DMARDs) and biologic response modifiers (BRMs). The 1987 ACR revised criteria require that a patient exhibit four of the seven criteria for a diagnosis of RA to be made; four of the criteria must have been present for at least 6 weeks: morning stiffness, arthritis of three or more joint areas, arthritis of the hands and symmetric arthritis [27]. The other three criteria were presence of rheumatoid nodules, radiographic erosive changes and rheumatoid factor [27]. Due to the criticisms of the 1987 criteria’s insensitivity in identifying some patients with early disease, revised classification criteria were developed by ACR and the European League Against Rheumatism (EULAR) in 2010 [28]. Several instruments have been developed in order to assess disease activity in RA patients [29]. These include the Disease Activity Score in 28 joints assessment tool (DAS28), Simplified Disease Activity Index and the Clinical Disease Activity Index [29]. These assessment tools allow calculation of a score for disease activity in which the scores have been classified into remission and low, moderate and high levels of disease activity, reflecting different RA severities [29]. The ACR 20/50/70 criteria along with the health assessment questionnaire (HAQ) are other measures that have been used extensively in clinical trials to assess response to treatment [30,31]. There are also a number of clinical signs that have been associated with poorer outcomes in RA. These include the presence of extra-articular manifestations, marked functional limitation, radiographic evidence of erosions, rheumatoid factor or anticyclic citrullinated peptide antibodies [32]. Diminished functionality and quality of life experienced by RA patients result in substantial economic burden from both a payer and a societal perspective [33]. However, large variations in cost of illness estimates were found in systematic reviews in RA [34,35]. A recent study by Lundkvist et al. in 2008 estimated the direct and indirect costs of RA in several countries based 10
on a cost model populated with data found in literature [10]. The total annual costs per RA patient were calculated at $13,133 in Canada, $19,465 in UK, $21,538 in Western Europe and $26,455 in the USA, all reported in 2006 US dollars [10]. It was also estimated that drug costs represented up to 43% of the direct costs, and up to 39% of the total economic burden was attributed to indirect costs [10]. A study by Birnbaum et al. in 2009 using large administrative databases in the USA estimated that direct costs of RA were on the order of US$8.4 billion [36]. Societal costs were found to range from US $19.3 billion to US$39.2 billion, depending on the assumptions used in the calculations (reported in 2005 US dollars) [36]. Given the excess economic burden of RA, the mainstay of initial management strategy has been early aggressive treatment with traditional DMARDs [32,37]. The most widely used traditional DMARD has been methotrexate (MTX); others include hydroxychloroquine, sulfasalazine and leflunomide [32]. Traditional DMARDs have demonstrated cost–effectiveness; however, a proportion of moderate-to-severe RA patients experience an inadequate response to monotherapy or combination therapy with these agents [38]. Newer therapeutic options have become available in the last decade, these are the BRMs that include TNF-a inhibitors – etanercept, infliximab, adalimumab, golimumab and certolizumab pegol; and others including rituximab, tocilizumab and abatacept (TABLE 1) [38,39]. However, the BRMs are considerably more expensive than traditional DMARDs, and their cost–effectiveness claims have been under scrutiny [40]. The aim of this article is to review and discuss the clinical and economic evidence of abatacept for the management of moderate-to-severe RA. BRMs for moderate-to-severe RA
Until the 1980s, treatments for RA have largely been centered on the relief of symptoms rather than on the modification of disease processes. Today the treatment of RA aims to target remission, often defined as DAS28
Drug Profile
Cost–effectiveness of abatacept for moderate-tosevere rheumatoid arthritis Expert Rev. Pharmacoecon. Outcomes Res. 14(1), 9–18 (2014)
Nicole W Tsao1, Kam Shojania2 and Carlo A Marra*1 1 Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, Canada V6T 1Z3 2 Division of Rheumatology, Faculty of Medicine, University of British Columbia, Vancouver, Canada *Author for correspondence: [email protected]
Abatacept, a selective T-cell costimulation modulator, has become a valuable treatment option for those with moderately to severely active rheumatoid arthritis. Given new clinical evidence, for the first time guidelines from the American College of Rheumatology and Canadian Rheumatology Association are promoting the consideration of abatacept as the first biologic added to initial traditional disease-modifying antirheumatic drugs once an inadequate response to disease-modifying antirheumatic drug monotherapy has been established, putting abatacept at the same line of treatment options as TNF-a inhibitors or rituximab. Since the advent of the subcutaneous formulation of abatacept, positive results from its clinical trials have further increased its appeal. In light of these changes, a review of the literature was conducted on the cost–effectiveness of abatacept for moderate-to-severe rheumatoid arthritis. Here we discuss current evidence, gaps in the literature and abatacept’s future outlook. KEYWORDS: abatacept • biologic response modifiers • cost–effectiveness • health economics • rheumatoid arthritis
Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis, with an estimated prevalence of 1% of the adult population [1]. RA is found to affect women approximately two- to three-times more often than men [1,2]. The onset of RA can occur at any age; however, the age-specific incidence rates of RA varies considerably according to sex, with a 4:1 ratio of women to men in the age group of 35–44 compared with a ratio of 1.1:1 in the age group of 75–84 [3]. RA is a systemic and chronic autoimmune inflammatory disease characterized by joint damage, functional disability, reduced quality of life and premature mortality [1,4–7]. Individuals with RA often report symptoms including pain, stiffness and swelling of the peripheral joints [7]. Individuals with RA also experience higher levels of fatigue, functional impairment, weight loss and depression [7,8], leading to substantial negative effects on quality of life [9,10]. Due to the progressive nature of RA and associated long-term disability, there exists considerable economic burden to patients and society. Individuals with RA have been shown to incur disproportionately high resource use, and indirect costs including lost productivity, compared with other major chronic
www.expert-reviews.com
10.1586/14737167.2014.861742
illnesses [11]. A significantly higher risk of mortality is seen in RA patients, particularly in those with more severe forms of the disease [12,13] compared with the general population. RA has standardized mortality ratio ranging from 1.28 to 2.98 reported in the literature [13–16]. The largest contributor to mortality risk has been attributed to comorbid cardiovascular disease [12,17,18]. The etiology of RA is thought to be multifactorial with both environmental and genetic elements [19]. Aspects of the genetic risks are not fully understood; however, the most important association appears to be with the HLA DRB1 gene locus, an established genetic determinant of risk for the disease [20]. A range of environmental factors have also been identified as possible risk factors for the development of RA these include tobacco smoking, infection and lifestyle factors [21–23]. The molecular pathogenesis of RA involves inflammatory cytokines such as TNF-a and IL-1 [24,25]. These factors are potent stimulators of synovial tissue proliferation, metalloproteinase expression, adhesion molecule expression and secretion of other cytokines resulting in an amplification of inflammatory pathways leading to eventual joint destruction [24,25]. The activation of T and B
2014 Informa UK Ltd
ISSN 1473-7167
9
Drug Profile
Tsao, Shojania & Marra
Expert Review of Pharmacoeconomics & Outcomes Research Downloaded from informahealthcare.com by University of Queensland on 03/14/15 For personal use only.
Table 1. Currently approved treatments for moderate-to-severe rheumatoid arthritis. Traditional DMARDs
Biologic response modifiers
Methotrexate Hydroxychloroquine Sulfasalazine Leflunomide
TNF-a inhibitors – Etanercept (ENBREL; Immunex Corporation, Thousand Oaks, CA, USA) – Infliximab (REMICADE; Janssen Biotech Inc., Horsham, PN, USA) – Adalimumab (HUMIRA; Abbott Laboratories Ltd.; North Chicago, IL, USA) – Certolizumab pegol (CIMZIA; UCB Inc., Brussels, Belgium) – Golimumab (SIMPONI; Janssen Biotech Inc., Horsham, PN, USA) T-cell costimulation modulator – Abatacept (ORENCIA; Bristol-Myers Squibb, New York City, NY, USA) B-cell depletory – Rituximab (RITUXAN; Hoffman-La Roche Ltd., Basel, Switzerland) Interleukin-6 inhibitor – Tocilizumab (ACTEMRA; Hoffman-La Roche Ltd., Basel, Switzerland) Interleukin-1 inhibitor – Anakinra (KINERET; Swedish Orphan Biovitrum AB, Stockholm, Sweden)
DMARDs: Disease-modifying antirheumatic drugs; TNF: Tumor necrosis factor.
lymphocytes resulting in the production of autoantibodies also play important roles in RA pathogenesis [26]. In 1987, the American College of Rheumatology (ACR) revised criteria for RA [27] was developed and has been widely used as the RA classification criteria in clinical trials for disease-modifying antirheumatic drugs (DMARDs) and biologic response modifiers (BRMs). The 1987 ACR revised criteria require that a patient exhibit four of the seven criteria for a diagnosis of RA to be made; four of the criteria must have been present for at least 6 weeks: morning stiffness, arthritis of three or more joint areas, arthritis of the hands and symmetric arthritis [27]. The other three criteria were presence of rheumatoid nodules, radiographic erosive changes and rheumatoid factor [27]. Due to the criticisms of the 1987 criteria’s insensitivity in identifying some patients with early disease, revised classification criteria were developed by ACR and the European League Against Rheumatism (EULAR) in 2010 [28]. Several instruments have been developed in order to assess disease activity in RA patients [29]. These include the Disease Activity Score in 28 joints assessment tool (DAS28), Simplified Disease Activity Index and the Clinical Disease Activity Index [29]. These assessment tools allow calculation of a score for disease activity in which the scores have been classified into remission and low, moderate and high levels of disease activity, reflecting different RA severities [29]. The ACR 20/50/70 criteria along with the health assessment questionnaire (HAQ) are other measures that have been used extensively in clinical trials to assess response to treatment [30,31]. There are also a number of clinical signs that have been associated with poorer outcomes in RA. These include the presence of extra-articular manifestations, marked functional limitation, radiographic evidence of erosions, rheumatoid factor or anticyclic citrullinated peptide antibodies [32]. Diminished functionality and quality of life experienced by RA patients result in substantial economic burden from both a payer and a societal perspective [33]. However, large variations in cost of illness estimates were found in systematic reviews in RA [34,35]. A recent study by Lundkvist et al. in 2008 estimated the direct and indirect costs of RA in several countries based 10
on a cost model populated with data found in literature [10]. The total annual costs per RA patient were calculated at $13,133 in Canada, $19,465 in UK, $21,538 in Western Europe and $26,455 in the USA, all reported in 2006 US dollars [10]. It was also estimated that drug costs represented up to 43% of the direct costs, and up to 39% of the total economic burden was attributed to indirect costs [10]. A study by Birnbaum et al. in 2009 using large administrative databases in the USA estimated that direct costs of RA were on the order of US$8.4 billion [36]. Societal costs were found to range from US $19.3 billion to US$39.2 billion, depending on the assumptions used in the calculations (reported in 2005 US dollars) [36]. Given the excess economic burden of RA, the mainstay of initial management strategy has been early aggressive treatment with traditional DMARDs [32,37]. The most widely used traditional DMARD has been methotrexate (MTX); others include hydroxychloroquine, sulfasalazine and leflunomide [32]. Traditional DMARDs have demonstrated cost–effectiveness; however, a proportion of moderate-to-severe RA patients experience an inadequate response to monotherapy or combination therapy with these agents [38]. Newer therapeutic options have become available in the last decade, these are the BRMs that include TNF-a inhibitors – etanercept, infliximab, adalimumab, golimumab and certolizumab pegol; and others including rituximab, tocilizumab and abatacept (TABLE 1) [38,39]. However, the BRMs are considerably more expensive than traditional DMARDs, and their cost–effectiveness claims have been under scrutiny [40]. The aim of this article is to review and discuss the clinical and economic evidence of abatacept for the management of moderate-to-severe RA. BRMs for moderate-to-severe RA
Until the 1980s, treatments for RA have largely been centered on the relief of symptoms rather than on the modification of disease processes. Today the treatment of RA aims to target remission, often defined as DAS28
