certolizumab pegol therapy of rheumatoid arthritis: overview
TRANSCRIPT
DRUG DEVELOPMENT RESEARCH 72 : 603–614 (2011)
Clinical Research
Certolizumab Pegol Therapy of RheumatoidArthritis: Overview
Ines Zidi,1,2� Wissem Mnif,1 Aicha Bouaziz,1,3 and Nidhal Ben Amor1,2
1Laboratory of Biochemistry, Research Unit 02/UR/09-01, Higher Institute of Biotechnology, BP74, Avenue Tahar Haddad, Monastir 5000, Tunisia
2Department of Biology, Sciences College, King Faisal University, P.O. Box 1759, 31982 Al-Ahsa,Saudi Arabia
3Laboratory of Basic Health Group, 4002 Sousse, Tunisia
Strategy, Management and Health Policy
Enabling
Technology,
Genomics,
Proteomics
Preclinical
Research
Preclinical Development
Toxicology, Formulation
Drug Delivery,
Pharmacokinetics
Clinical Development
Phases I-III
Regulatory, Quality,
Manufacturing
Postmarketing
Phase IV
ABSTRACT First-line treatment for moderate to severe rheumatoid arthritis (RA) has been the use ofdisease-modifying anti-rheumatic drugs (DMARDs), e.g., methotrexate. Because of the cases of failurereported to respond to available treatments, newer RA drugs including tumor necrosis factor (TNF-a) blockershave emerged. Certolizumab pegol (CZP) is a unique polyethylene glycolated (PEG) humanized monoclonalantibody designed specifically to target TNF-a pro-inflammatory cytokine. Given that its properties closelyreflect its PEG fragment, CZP has demonstrated a clear efficiency. Pharmacokinetics and pharmacodynamicsof CZP are described together with Phase II and III CZP clinical studies focused on CZP efficiency and safety.We also discuss the future of CZP and new clinical studies that might help physicians in their choice of CZPamong available TNF-a blockers. Drug Dev Res 72:603–614, 2011. r 2011 Wiley Periodicals, Inc.
Key words: Certolizumab pegol; TNF-a; inhibitors; rheumatoid arthritis; autoimmune disease
INTRODUCTION
Rheumatoid arthritis (RA) is the most commoninflammatory arthritis affecting the small joints of thehands and feet [Lee and Weinblatt, 2001; Scott et al.,2010]. Without treatment, RA becomes more aggres-sive, leading to pronounced disability and a reductionof quality of life, as well as loss of work [Pincus andSokka, 2001]. The main societal consequence is thehigh economic burden [Kavanaugh et al., 2009].
The etiology of RA is unknown, but it is classiedas an autoimmune disease [Wordsworth and Holden,2005]. Accumulating evidence indicates that bothinnate and acquired immunity are involved in RA.Clinically, inflammatory immune cells including lym-phocytes and macrophages occur in the joints andother tissues [Bugatti et al., 2007; MaciejewskaRodrigues et al., 2009]. Moreover, the presence of
autoantibodies reactive with cyclic citrullinated pep-tides (CCP), vimentin, decorin, enolase, aldolaseA, and type II collagen has been demonstrated[Maciejewska Rodrigues et al., 2009; Scott et al., 2010].
There is consistent evidence that tumor necrosisfactor (TNF-a), a pro-inflammatory cytokine, isrelevant to the pathogenesis of RA. TNF-a is foundin high concentrations in the joints [Brennan et al.,1989]. Its effects are mediated, at least in part,by the synthesis of pro-inflammatory cytokines, theinterleukins IL-1 and IL-6, and growth factors, e.g.,
DDR
Published online in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/ddr.20470
�Correspondence to: Ines Zidi, Laboratory of Biochemistry,Research Unit 02/UR/09-01, Higher Institute of Biotechnology, BP74, Avenue Tahar Haddad, Monastir 5000, Tunisia.E-mail: [email protected]
�c 2011 Wiley Periodicals, Inc.
granulocyte-colony stimulating factor (GCS-F) andgranulocyte macrophage-colony stimulating factor(GM-CSF) [Barnes and Moots, 2007; Zidi et al.,2010; Scott et al., 2010]. TNF-a is involved in theoverproduction of prostaglandins, platelet activatingfactor, and nitric oxide [Food and Drug Administration,2009].
Several biochemical markers can be used topredict the stage of the disease, including markers forjoint disease (e.g., rheumatoid factor, anti-CCP anti-bodies), for bone turnover (bone formation or boneresorption), for cartilage turnover, and lastly, formarkers of synovitis and inflammation [Ehlers andLeary, 2008].
First-line treatment of RA involves the use bydisease-modifying antirheumatic drugs (DMARDs) incombination with corticosteroids and/or nonsteroidalanti-inflammatory drugs (NSAIDs) as an alternative tomonotherapy [Wilke and Clough, 1991]. Methotrexate(MTX) is the most commonly used DMARD for RAtreatment [Scott et al., 2010].
In addition, several biologic agents have beenproposed to treat RA that may target differentmediators of the disease. Abatacept (cytotoxicT-lymphocyte-associated antigen 4-immunoglobulin,Belatacept), a soluble recombinant protein, inhibitsT-cell function through CTLA-4 blockade that mimicsand competes with the co-stimulatory molecule CD28of regulatory T cells [Senolt et al., 2009; Boissier et al.,2010]. Rituximab (Mabthera, Rituxan), a chimeric anti-CD20 monoclonal antibody, can also be used in RAtherapy. It targets CD20 on B-cell lymphocytes,inducing their depletion [Yen, 2006; Senolt et al.,2009]. This impairs production of autoantibodies (e.g.,rheumatoid factor, anti-CCP antibodies), as well as theproduction of different growth and differentiationfactors that play key roles in the synovial microenvir-onment [Boissier et al., 2010].
Currently used biologic therapies for RAinclude IL-1 (Anakinra, Kineret) and IL-6 inhibitors(Tocilizumab, Actemra) [Senolt et al., 2009; Boissieret al., 2010]. Another class of biologic used to treat RAis the TNF-a blockers that include monoclonalantibodies and fusion proteins. TNF-a blockers areeffective in the treatment of moderate to severe activeRA, specifically inhibiting TNF-a in both its mem-brane-attached and soluble forms. TNF-a blockersinclude TNF-a antibodies, e.g., infliximab (Remicade),adalimumab (Humira), golimumab (Simponi), andcertolizumab pegol (CZP) (Cimzia). Decoy receptorsinclude etanercept (TNR-001, Enbrel).
Infliximab is the only chimeric antibody asso-ciated with high levels of reactive antibodies inclu-ding anti-drug antibodies (ADA; e.g., anti-infliximab
antibodies) and autoantibodies. However, TNF-ahumanized blockers are associated with decreasedproduction of the previously detected antibodies. Thisgroup of blockers also includes the polyethyleneglycolated antibody, CZP.
The focus of this review is on literature relating toCZP, including clinical trials reporting its efficiency,safety, and potential adverse events and comorbidities.The significant body of data identifying the propertiesof CZP associated with its polyethylene glycol (PEG)fragment is also reviewed. Furthermore, we discussand propose some ideas that may be useful in thedesign of future studies required for resolving thedebated side effects and associated complications ofCZP, and for exploiting its advantageous properties.
Pharmacology of Certolizumab Pegol
Description
CZP is a recombinant humanized monoclonalunivalent antibody with an approximate molecularweight of 91 KD [Food and Drug Administration,2009]. It is composed of the fragment antigen-bindingdomain (Fab0) that targets TNF-a conjugated via amaleimide linkage to a PEG fragment (2� 20 KD,PEG2MAL40K) [Barnes and Moots, 2007; Shealy andVisvanathan, 2008; Food and Drug Administration,2009] (Table 1).
TABLE 1. Certolizumab Pegol Characteristics
Commercialname Cimzias
Other names CDP 870Description Humanized polyethylene-glycolated (PEG) Fab0
fragment of anti-tumor necrosis factorProducer UCBTotal size (kDa) �91 kDaPEG fragment size(kDa)
40 kDa (2�20 kDa)
Initial dose 400 mg (two SC injections of 200 mg) at weeks 0,2, and 4; followed by 200 mg every other week
Maintenancedose
400 mg every 4 weeks
FDA approval May 2009 for RA therapy (treatment of adults withmoderately to severely active RA)April 2008 for CD therapy (treatment of adultswith moderately to severely active CD withinadequate response to other treatments)
EMG approval October 2009 for RA therapy (treatment of adultswith moderately to severe active RA when theresponse to DMARDs including methotrexate, hasbeen inadequate)
CD, Crohn’s disease; DMARDs, disease-modifying antirheumaticdrugs; EMG, European Medicines Agency; FDA, Food and DrugAdministration; RA, rheumatoid arthritis; SC, subcutaneous.
604 ZIDI ET AL.
Drug Dev. Res.
The Fab0 fragment manufactured in Escherichiacoli is composed of a light chain with 214 amino acids(AA) and a heavy chain with 229 AA [Food and DrugAdministration, 2009]. The PEG fragment, a hydro-philic polymer, consists of repeated ethylene glycolsubunits [Alexis et al., 2008].
The lack of toxicity of CZP led to its approval bythe FDA [Monfardini and Veronese, 1998] for thetreatment of adults suffering from moderate to severeactive RA, and also for the treatment Crohn’s disease.Nevertheless, the European Medicines Agency has sofar approved its use only for RA (Table 1).
CZP is used by the subcutaneous route (s.c.) andhas similar effects intravenously (i.v.) [Kaushik andMoots, 2005; Barnes and Moots, 2007]. CZP can beadministrated as monotherapy or in combination withMTX to improve disease outcomes [Furst et al., 2011].The recommended dose for patients with RA is 400 mgat weeks 0, 2, and 4; followed by 200 mg every otherweek (Table 1) (see other recommendations of CZP use[Ding et al., 2010]). The maintenance dose was 400 mgevery 4 weeks [Food and Drug Administration, 2009].Using a pharmacodynamic-Markov mixed-effectsmodel of simulation of the American College ofRheumatology (ACR) 20 measure, Lacroix et al.[2009] supported CZP dosing, while reporting analternative maintenance regimen of 400 mg once amonth. In the study conducted by Kaushik et al.[2005], the optimal IV dose of CZP in RA patients was5 mg/kg/month [Kaushik and Moots, 2005; Shealy andVisvanathan, 2008]. The peak plasma CZP concentra-tion, linear with dosing, occurs at the end of theinfusion and declined thereafter [Choy et al., 2002;Shealy and Visvanathan, 2008].
The PEG fragment role has been extensivelyinvestigated and has been found to be effective inreducing immunogenicity in DZP. PEGylation alsoincreases the half-life of CZP to 13–14 days. WithoutPEG, the biological half-life is 0.3–0.8 days [Chameset al., 2009]. This decreases the distribution volumeand injection frequency (single s.c. injection once amonth) [Barnes and Moots, 2007; Pisal, Kosloski andBalu-Iyer, 2010]. PEGylation also decreases urinaryclearance and proteolysis by trypsin and chymotrypsin[Lu et al., 2008; Pisal et al., 2010; Singh, 2011] andenhances the solubility and stability of proteins bymasking their hydrophobic sites involved in aggrega-tion, nonfunctionality, and immunogenicity [Lu et al.,2008; Pisal et al., 2010; Singh, 2011].
Pharmacodynamics
CZP, like other TNF-ablockers, specifically tar-gets TNF-a, inhibiting its function. CZP can inhibitboth membrane-associated and soluble TNF-a. CZP
does not bind TNF-b (lymphotoxin a). TNF-a inhibi-tion by CZP proves that the crystallizable fragment(Fc) is not essential for this function [Scott and Cope,2009]. Fossati and Nesbitt [2011a] demonstratedin vitro that CZP 90% inhibitory concentration (IC90)neutralization activity is observed at 2.5 ng/ml. This isclose to the IC90 of etanercept (0.3 ng/ml) and belowthe IC90 values of infliximab and adalimumab (20 ng/mland 15 ng/ml, respectively). CZP was the most potentinhibitor of LPS-driven IL-1b secretion as comparedwith all reported TNF antibodies. However, no knownfunction has been ascribed to the latter observation[Fossati and Nesbitt, 2011a].
Administration of intact and large antibodies(constituted from two Fab fragments and one Fcfragment) is associated with frequent disadvantagesthat include immunogenicity, difficulty of diffusion, aswell as poor tissue penetration [Elbakri et al., 2010].The reduced size of CZP is thus advantageous,exhibiting better penetration into arthritic tissues andreduced immunogenicity [Taylor, 2010; Nesbitt et al.,2008]. Indeed, CZP does not contain the Fc fragmentinvolved in complement activation and in antibody-dependent cell-mediated cytotoxicity in vitro [Foodand Drug Administration, 2009].
The univalent structure of CZP is also advanta-geous because of the small immune complexes formedwith TNF-a, low passage through the placenta, and lessaccumulation in milk as compared with other IgG1anti-TNF-a antibodies [Nesbitt et al., 2008]. Moreover,CZP does not stimulate apoptosis in vitro in monocytesor lymphocytes [Fossati and Nesbitt, 2011a] and doesnot cause neutrophil necrosis [Fossati and Nesbitt,2011a].
CZP has reduced opsonization properties [Alexiset al., 2008], especially a reduced mononuclearphagocyte system rate [Li and Huang, 2008]. CZP isthe only TNF-a blocker that does not induceneutrophil degranulation in vitro [Food and DrugAdministration, 2009]. Indeed, Fossati and Nesbitt[2011b] found that the PEG fragment associated withFab0 in CZP inhibited Ca21 flux in cellular systems(IC50 �10 mg/ml) explaining the very low incidence ofCZP injection site pain in clinical studies.
Pharmacokinetics
The pharmacokinetic properties of CZP closelyrelate to its PEG fragment. Increased vascular perme-ability and retention are examples of the biologicalrelevance of PEGylation [Palframan et al., 2009]. Usingbiofluorescence imaging, CZP has enhanced penetra-tion in inflamed arthritic paws as compared with theTNF-a blockers adalimumab and infliximab [Palframanet al., 2009]. The steady-state volume of distribution
605CERTOLIZUMAB IN RHEUMATOID ARTHRITIS
Drug Dev. Res.
was estimated at 6-8L in RA patients [Food and DrugAdministration, 2009]. In addition, this antibodyremains for prolonged periods in inflamed tissuesversus normal ones, and accumulates to higher tissuelevels as compared with adalimumab and infliximab[Palframan et al., 2009].
In addition to its lack of toxicity, low immuno-genicity, and reduced clearance, the PEG fragment isassociated with favorable excretion kinetics withoutfurther metabolism [Monfardini and Veronese, 1998;Food and Drug Administration, 2009]. Followingsubcutaneous injection of CZP in RA patients theclearance rate is estimated at 21 mL/h (with 30.8%inter-subject variability and 16% inter-occasion varia-bility) [Food and Drug Administration, 2009].
Clinical Studies Using Certolizumab Pegol
The efficacy of CZP has been demonstrated invarious studies (Table 2). Multiple changes in inflamedjoints quantified by different measures and scores havebeen reported. In fact, RA patient outcomes can bedetermined by several tests: the core data set (moresuitable for clinical use), composite disease activityindices (the European index: Disease Activity Score,DAS), and the ACR response criteria [Scott andKingsley, 2007]. In clinical trials relating to CZP,DAS28 (Table 3) and ACR20, ACR50, and ACR70(Table 2) were most often used.
Efficacy
Disease Activity Score 28 (DAS28)The Disease Activity Score (DAS 28) score tests
28-joint counts for both tenderness and swelling [Scottand Kingsley, 2007]. It is based on changes in jointcounts, global responses, and erythrocyte sedimenta-tion rate (ESR) or C-reactive protein [Tebib andMiossec, 2006; Rovensky et al., 2008]. When this scoreis o3.2, disease activity is considered low, between 3.2and 5.1 to be of intermediate activity, and 45.1 to be ofhigh activity [Tebib and Miossec, 2006; Rovensky et al.,2008]. In clinical trials of CZP, both treatment withCZP alone [Choy et al., 2002; Fleischmann et al., 2009]or in combination with MTX [Keystone et al., 2008;Smolen et al., 2009] were associated with greaterimprovement of DAS28 at study end (Table 3). Theresponse to CZP at 12 weeks was predictive of a lowdisease activity after 1 year [Keystone, 2009].
American College of Rheumatology (ACR) measureImprovement of ACR composite disease measure
involves improvements in tender joint count andswollen joint count, as well as a change in threeparameters reported by patients and physicians (i.e.,global assessment of disease activity, pain, either ESR
or CRP as inflammation markers), and a functionalstatus measure such as the health assessment ques-tionnaire (HAQ) [Scott and Kingsley, 2007; Rovenskyet al., 2008]. (For more details about the ACR20improvement, see [Klippel et al., 2010].) The ACRmeasure can be divided into three levels of improve-ments at 20% (ACR20 indicates that monitored criteriahave been improved by at least 20% in both tenderjoint count and swollen joint count, and in at least threeof the five core set measures of the ACR score[National Institute for Health and Clinical Excellence,2010]), at 50% (ACR50), and at 70% (ACR70) [Scottand Kingsley, 2007].
A meta-analysis performed by UCB reported thatpatients receiving CZP plus MTX were five times aslikely to achieve an ACR20 at week 24 compared withplacebo plus MTX [National Institute for Health andClinical Excellence, 2010]. With the combination ofCZP with MTX, both Keystone et al. [2008] and Smolenet al. [2009] demonstrated similar ACR20, ACR50, andACR70 in patients treated with 200 mg CZP or with400 mg CZP every 2 weeks. The use of MTX incombination with CZP enhanced the ACR measuresimprovement in comparison with clinical studies usingCZP alone. Indeed, without MTX, the phase III studyof Fleischmann et al. [2009] reported reduced ACRvalues compared with previous studies of CZP with MT.This finding is in favor of MTX use along with CZP aspreviously reported for other anti-TNF-a blockers suchas golimumab [Zidi et al., 2010]. The phase II study ofChoy et al. [2002] reported different values becausethey tested the efficiency of CZP with different doses(1 mg/kg, 5 mg/kg, and 20 mg/kg). The ACR20 andACR50 increased linearly with CZP dosing (Table 2).An unpublished study (C87014) reported improvementof 46% ACR20, 18% ACR50, and 0% ACR70 inpatients treated with CZP (400 mg monthly) plus MTXthat were clearly improved in comparison with valuesobtained in patients treated with placebo plus MTX(23% ACR20, 6% ACR50, and 2% ACR70) [NationalInstitute for Health and Clinical Excellence, 2010].
Other measuresCZP clinical efficacy has been checked via
endpoints that were not homogeneous. Only twostudies (out of four cited in Table 2) have comparedthe radiographic progression of hands and feet withbaseline scores [Keystone et al., 2008; Smolen et al.,2009; Furst et al., 2011]. At week 52, Keystone et al.[2008] noted that the mean change from baseline in themodified total Sharp score was significantly smaller inpatients treated with CZP and MTX (0.4 Sharp unitsand 0.2 Sharp units, respectively, for patients treatedwith 200 mg and 400 mg CZP every 2 weeks) compared
606 ZIDI ET AL.
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608 ZIDI ET AL.
Drug Dev. Res.
with patients treated with placebo (2.8 Sharp units).Having reported only the means of change frombaseline, Smolen et al. [2009] showed that the placeboplus MTX patient group had more disease progressioncompared with the CZP plus MTX groups (with bothdoses either 200 mg or 400 mg every 2 weeks). Post hocanalysis revealed a difference between placebo plusMTX groups and the CZP plus MTX groups [Keystoneet al., 2008; Smolen et al., 2009].
The improved HAQ disability index (DI), report-ing physical function response, was clinically importantwhen compared with patients treated with placebo[Choy et al., 2002; Keystone et al., 2008; Fleischmannet al., 2009; Scott and Cope, 2009; Smolen et al.,2009].
Safety
Many studies have proved the safety of CZP forthe treatment of RA patients. In 1999, the first phase Istudies reported good tolerance of CZP with no sideeffects [Barnes and Moots, 2007]. However, it was laterdemonstrated that CZP, similar to other TNF-ablockers, was associated with active to severe infectiousdiseases [National Institute for Health and ClinicalExcellence, 2010] (Table 2). CZP is associated withexacerbated tuberculosis risk [Furst et al., 2011], aswell as sepsis, invasive fungal infections, and bacterial,viral, and other opportunistic infections [Food andDrug Administration, 2009].
In spite of the very low incidence of injection sitereactions associated with CZP [Furst et al., 2011], othersevere morbidities can occur after CZP administration[Food and Drug Administration, 2009]. Indeed, casesof malignancies were reported in studies of CZP(Table 2). CZP was not associated with enhanced solidmalignancies, but was associated with lymphoma (50%of malignancies with the two types of Hodgkin’s and
non-Hodgkin’s lymphomas) [Food and Drug Adminis-tration, 2009; Furst et al., 2011]. This later malignancywas reported in children and adolescents [Food andDrug Administration, 2009]. However, these cases havenot substantially increased the risk of malignancy ascompared with DMARDs [Nam et al., 2010].
Some cases of severe heart failure have beenreported after CZP administration [National Institutefor Health and Clinical Excellence, 2010].The FDA hastherefore recommended carefully following and mon-itoring patients with cardiac complications [Food andDrug Administration, 2009].
Concerning autoimmunity, CZP has beenreported as an inducer of low percentages of auto-antibodies. Further studies are undoubtedly needed inorder to monitor these antibodies systematically inpatients treated with CZP. In the studies reportedin Table 2, low percentages of ADA were detected.Indeed, anti-CZP antibodies were reported in twostudies [Choy et al., 2002; Fleischmann et al., 2009].Similarly, anti-nuclear antibodies were noted in pre-vious studies that were slightly unchanged comparedwith placebo. The study of Choy et al., 2002] hasscreened for changes in anti-DNA and anti-cardiolipinantibodies without positive results (Table 2).
Future of Certolizumab Pegol
Patients with RA are at risk of losing theirmobility and quality of life. Physicians have a choicebetween many drugs, including DMARDs such asMTX, and the biologic agents [Papagoras et al., 2010].The latter may target different cytokines (e.g., IL-1,IL-6, TNF-a) [Senolt et al., 2009; Zidi et al., 2010].TNF-a inhibitors are among the most promisingbiological RA drugs [Harris and Keane, 2010; Vliegheet al., 2010]. They currently include infliximab,adalimumab, etanercept, golimumab, and CZP, which
TABLE 3. DAS28 Scores at Study End in Clinical Trials Using Certolizumab Pegol for Rheumatoid Arthritis
Choy [2002] Keystone [2008] Smolen [2009] Fleischmann [2009]
(wk 8) (wk 52) (wk 24) (wk 24)
Placebo Mean change in DAS28 from baseline NR �2.4 �0.5 �0.6(Reduction in DAS28, median) (0.31) (NR) (NR) (NR)
CZP 200 mg Mean change in DAS28 from baseline — �3.3 �2.3 —(Reduction in DAS28, median) (NR) (NR)
CZP 400 mg Mean change in DAS28 from baseline — �3.4 �2.5 �1.5(Reduction in DAS28, median) (NR) (NR) (NR)
CZP 1 mg/kg Mean change in DAS28 from baseline NR — — —(Reduction in DAS28, median) (0.09)
CZP 5 mg/kg Mean change in DAS28 from baseline NR — — —(Reduction in DAS28, median) (2.09)
CZP 20 mg/kg Mean change in DAS28 from baseline NR — — —(Reduction in DAS28, median) (1.76)
CZP, Certolizumab pegol; DAS28, disease activity score 28-joint assessement; NR, Not reported.
609CERTOLIZUMAB IN RHEUMATOID ARTHRITIS
Drug Dev. Res.
TA
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tati
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610 ZIDI ET AL.
Drug Dev. Res.
have been designated as efficient and safe. Improvedpatient quality of life has been recorded in severalclinical trials. Evidence to date has not specified thebest TNF-a blocker that should be used to treat RA,nor the most effective agent in RA therapy [Furst et al.,2011]. This makes the choice of the therapy difficult foreither the first line or switch after failure [Papagoraset al., 2010; Atzeni et al., 2011]. Here, head-to-headstudies are needed to compare composite endpoints,adverse events, and comorbidities under the sameconditions [Deighton, 2010], and to clarify thedifferences in clinical effectiveness between TNF-ablockers [National Institute for Health and ClinicalExcellence, 2010]. Temporal quality control (e.g.,radiographic progression [Russell et al., 2010; Atzeniet al., 2011] and ACR hybrid [van Vollenhoven et al.,2011]) of inflamed joints should be monitored longterm to ascertain the efficacy of TNF-a blocker. A fewstudies have included these endpoints in their initialdesign (Table 4).
Fossati and Nesbitt [2011a] demonstrated theadvantages of CZP compared with other TNF-ablockers. Moreover, using a multiple treatment Baye-sian meta-analysis, Launois et al. [2011] showed thatthe ACR20 of CZP was superior to that of infliximab,adalimumab, and anakinra and similar to golimumab,etanercept, and tocilizumab (an anti-IL-6 receptorantibody).
Apart from its efficacy and safety forRA treatment, like that of other TNF-a blockers[Massarotti, 2009; National Institute for Health andClinical Excellence, 2010; Furst et al., 2011], CZP hasdifferent properties attributable to its PEG fragment(see above). Its reduced cost (due to the restrictedstructure of the Fab0 fragment, instead of the totalantibody with the other TNF-a blockers) makes ita superior choice as compared with older TNF-ablockers. Studies on the cost-effectiveness of TNF-ablockers are still required to aid rheumatologists indrug selection [O’Dell, 2010]. To achieve this goal,studies should be performed with real-life practice orbased on clinical trial data [Moots, 2009]. However,cost should not be the only criteria for drug choice dueto conflicting methods of cost estimates [NationalInstitute for Health and Clinical Excellence, 2010].Some investigators consider only the inhibitor manu-facturing costs, whereas others consider its clinical costafter dose escalation, or inclusion of laboratory tests tomonitor disease progress [Moots, 2009].
The most cost-effective TNF-a blocker is likely tobe the most sensible choice [Scott and Cope, 2009].The NICE committee concluded that CZP could beconsidered a cost-effective option for RA treatment at£20,000 every quality-adjusted life year (QALY) gainedN
CT01147341
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cite
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611CERTOLIZUMAB IN RHEUMATOID ARTHRITIS
Drug Dev. Res.
[National Institute for Health and Clinical Excellence,2010]. This committee reported that CZP plus MTXwas the least costly TNF-a with a more enhancedQALY when compared with adalimumab and inflix-imab. The opposite was observed for CZP comparedwith etanercept [National Institute for Health andClinical Excellence, 2010].
CZP has demonstrated a considerable indirectcost gain, as it has shown improved productivity andsocial activities in RA patients [Kavanaugh et al., 2009].These results were consolidated by Strand et al. [2009],who reported that the treatment of RA patients withCZP plus MTX was associated with significantimprovements in health-related quality of life (HRQoL)and in physical function at the first week, as well asreductions in fatigue, disease activity, and pain.
Because of its smaller structure CZP has reducedimmunogenicity. Indeed, some clinical trials havereported low anti-CZP antibodies (Table 2). Eventualimmunogenicity might be ascribed to other factors,including product-related factors, patient-relatedfactors, and treatment-related factors [Singh, 2011].
The rationale for the use of PEG fragment indrugs is well established. PEG is also a part ofpegsunercept, a soluble TNF receptor type I antibody[Furst et al., 2005]. Both CZP and pegsunercept havedemonstrated efficacy in RA [Furst et al., 2005;Bingham, 2008]. However, care must be taken withPEGylated drugs [Constantinou et al., 2010]. Anti-bodies against the PEG fragment moiety have beenfound after CZP treatment [Veronese and Pasut, 2008].Additionally, PEG fragments accumulate in rat kidney[Bendele et al., 1998; Singh, 2011]. Some reduction ofthe intended drug–target activity has also been noted[Pisal et al., 2010] and explained by an alteration in thebalance between the pharmacodynamic and pharma-cokinetic properties of CZP [Fishburn, 2008]. Con-cerns about the safety of PEG fragment-containingdrugs must be resolved with further studies.
Targeting TNF-a continues to be a major ther-apeutic opportunity in RA. Having demonstrated itsefficacy and safety as favorable properties deriving fromPEGylation, CZP is a new treatment option for RA.Recent advances and current clinical studies (Table 4)provide additional data on CZP for rheumatologists.
CONFLICT OF INTEREST
The authors declare having no conflict of interest.
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