formulary review of 2 new biologic agents: tocilizumab for

402 Journal of Managed Care Pharmacy JMCP July/August 2010 Vol. 16, No. 6 www.amcp.org

•Biologics are an important component in the management ofmoderatetosevererheumatoidarthritis(RA)andpsoriasis.

•Tumor necrosis factor (TNF) antagonists have been found tobe effective in multiple autoinflammatory diseases includingRA, psoriasis, Crohn’s disease, and ulcerative colitis. However,patients may not experience adequate response with a TNFantagonistorlosethetherapeuticresponse.Newagentswithdif-ferentmechanismsofactionareneeded.

What is already known about this subject

Formulary Review of 2 New Biologic Agents: Tocilizumab for Rheumatoid Arthritis and Ustekinumab for Plaque Psoriasis

Jeremy A. Schafer, PharmD; Nicole K. Kjesbo, PharmD, BCPS; and Patrick P. Gleason, PharmD, BCPS, FCCP

ABSTRACT

BACKGROUND: Two autoimmune biologics were recently approved by the FDA: ustekinumab in September 2009 for the treatment of moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy and tocilizumab in January 2010 for adult patients with moderate to severe rheumatoid arthritis (RA) who have not responded adequately to 1 or more tumor necrosis factor (TNF) antagonist therapies. Both agents use new mechanisms of action and add to the growing group of autoimmune biologics.

OBJECTIVE: To critically review the phase 3 trials for ustekinumab and tocilizumab and provide managed care considerations in the context of the 9 other biologic agents on the market in the United States that are used to treat moderate to severe RA or psoriasis.

METHODS: A MEDLINE review was performed for articles published and available through January 2010 using keywords “ustekinumab” and “tocili-zumab” with an emphasis on phase 3 trials. The literature search was lim-ited to articles in English, clinical trials, randomized controlled trials, and research conducted in humans. Search results for ustekinumab included 8 articles of which 4 were excluded for not being psoriasis or psoriatic arthritis trials. Search results for tocilizumab included 16 articles of which 8 were excluded for not being RA trials or using biomarkers as primary endpoints. Additional information was obtained from the FDA website.

RESULTS: Three phase 3 trials are available for ustekinumab. Ustekinumab demonstrated superior efficacy to placebo in 2 trials for the treatment of psoriasis. In a 12-week trial, ustekinumab 45 milligrams (mg) and 90 mg demonstrated significantly higher rates of 75% improvement in the psoria-sis area and severity index (PASI 75) (67.5% and 73.8%, respectively) com-pared with etanercept (56.8%) in the first phase 3 comparative psoriasis trial between autoimmune biologics (P < 0.05 for both comparisons). In a phase 3 trial of RA patients who had failed prior TNF antagonist therapy, a 20% improvement in signs or symptoms according to the American College of Rheumatology criteria (ACR 20) at week 24 was achieved by signifi-cantly more study participants in the tocilizumab 8 mg per kilogram (kg) (50.0%) and 4 mg per kg (30.4%) groups than the placebo group (10.1%, P < 0.001 for both tocilizumab groups compared with placebo). Safety data for ustekinumab are limited to use for less than 2 years, and the prescrib-ing information contains warnings regarding infection and malignancy. Tocilizumab is associated with neutropenia, thrombocytopenia, and eleva-tions in lipids and liver function tests. Tocilizumab has unique adverse events when compared with other autoimmune biologics and requires labo-ratory testing and careful monitoring.

CONCLUSIONS: Ustekinumab and tocilizumab are new additions to the treatment of autoinflammatory disease. The majority of safety data for both agents are from trials lasting 3 to 6 months. Published long-term safety data for tocilizumab are limited to less than 143 patients treated longer than 5 years, and safety data for ustekinumab are scant beyond 2 years of use; therefore, clinicians should exercise caution prior to wide-spread adoption. The comparative efficacy and safety trial of etanercept

and ustekinumab brings important clinical information to decision makers. Tocilizumab is indicated after failure or intolerance to a TNF antagonist and has unique safety concerns. Managed care plans will consider the experi-ence and long-term data of these agents along with efficacy data and cost when establishing management programs such as prior authorization or step therapy.

J Manag Care Pharm. 2010;16(6):402-16

Copyright © 2010, Academy of Managed Care Pharmacy. All rights reserved.

FoRmul ARy mANAGemeNT

•Ustekinumabdemonstratedsuperiorefficacytoetanerceptinaninvestigator-blinded,phase3psoriasis trial.TheFDA-approvedindicationfortocilizumabissupportedbyclinicaldatademon-strating efficacy inRApatientswhohad failed1ormoreTNFantagonists.

•Long-term safety data are limited for ustekinumab and tocili-zumab. Both agents increase the risk of infection, and tocili-zumabhas adverse effects onneutrophils, platelets, lipids, andliverenzymes.

•Howustekinumabandtocilizumabwillbeusedinclinicalprac-ticeisunclearatthistime.Moredataandexperienceareneeded.Costcontinues tobean issuewithautoimmunebiologics,withincreases inpopulation-levelexpendituresdue to thecombina-tionofhigherutilizationandpriceinflation.

•Ustekinumabhashigherdrugcostatinitiationoftherapybecause2dosesareadministeredinthefirst30daysatweeks0and4,acurrent(2010)averagewholesaleprice(AWP)of$11,912,and$5,596every12weeksthereafter,yieldinganannualdrugcostofapproximately$33,576inthefirstyearfor6dosesand$22,384annuallythereafterfor4dosesperyear.Thecostoftocilizumabdependsonbodyweight,withdosingevery4weeksateither4mgor8mgperkg.Theinitialdoseis4mgperkg.Annualtocili-zumabdrugcostina70kgpersonrangesfrom$13,368at4mgperkgto$26,748at8mgperkgat12dosesperyear.

What this study adds

www.amcp.org Vol. 16, No. 6 July/August 2010 JMCP Journal of Managed Care Pharmacy 403


onmanagementoftreatmentfailuresandcomparativeefficacy.AUnitedKingdom (UK) database study found, in a registryof6,739patientswithRA,thatatotalof856patients(12.7%)switched to a secondTNF due to lack of efficacy or intoler-ance.13Patientswhoswitchedduetolackofefficacy(n=503)weremorelikelytofailasecondTNF(hazardratio[HR]=2.7,95% confidence interval [CI]=2.1-3.4).13 Additional studieshavefoundthatpatientsswitchingfrom1TNFantagonist toanotherhaveaprogressivelysmallerchanceoftreatmentsuc-cesswitheachswitch.14Choiceofautoimmunebiologicislim-itedbythelackofcomparativedatabetweendifferentagents.A2007reportsponsoredbytheAgencyforHealthcareResearchandQualitystatedthatthereisanurgentneedforcomparativedatafortheautoimmunebiologics.15

Ustekinumab, approved by the U.S. Food and DrugAdministration (FDA) in September 2009, and tocilizumab,approvedinJanuary2010,areautoimmunebiologicsindicatedforthetreatmentofpsoriasisandRA,respectively(Table1).16-19 Both agents have distinct mechanisms of action that differfrom those of previously available autoimmune biologics.Tocilizumab has demonstrated efficacy in patients failing atleast1TNFantagonist,andtheproductlabelspecifiesusein“adultpatientswithmoderately toseverelyactive rheumatoidarthritiswhohavehadaninadequateresponsetooneormoreTNFtherapies.”17Ustekinumabhasbeencomparedwithetan-erceptinthefirstphase3,double-blind,trialtocompareauto-immunebiologics.20Ustekinumab isapproved foruse in“thetreatmentofadultpatients(18yearsorolder)withmoderatetosevereplaquepsoriasiswhoarecandidatesforphototherapyorsystemictherapy.”16

Thepurposeofthisreviewistoprovideasummaryoftheclinicaldataforustekinumabandtocilizumabwithanempha-sisonthephase3clinicaltrials.Issueswiththeautoimmunebiologicsarediscussedinamanagedcarecontext,andinsightis provided for formulary decision makers on managementoptions.

■■ MethodsA MEDLINE review was performed for articles publishedandavailable through January2010,usingkeywords “usteki-numab” and “tocilizumab” with an emphasis on published,randomized,controlledtrials(Figure1).Theliteraturesearchwas limited to articles inEnglish, clinical trials, randomizedcontrolledtrials,andresearchconductedinhumans.Articlesthatwere reviewarticles,meta-analyses,ornot clinical trialswere excluded.Articles for disease states other thanRA andpsoriasiswere also excluded. Search results forustekinumabincluded8articlesofwhich4wereexcludedfornotbeingpso-riasisorpsoriaticarthritistrials.Searchresultsfortocilizumabincluded16articlesofwhich8wereexcludedfornotbeingRAtrials or using biomarkers as primary endpoints. AdditionalinformationwasobtainedfromtheFDAwebsite.

Rheumatoid arthritis (RA) is an autoimmune, chronic,multisystem, inflammatory joint disease characterizedbysynovitis,pain,andfatigue.RAaffectsanestimated

1.3millionAmericanadultsaged18yearsorolder,or0.6%ofthepopulationoftheUnitedStates.1ThecostsofRAtosocietyandindividualsareconsiderable.TheestimatedannualcostofRAintheUnitedStatesisbetween$26and$32.4billion.2AnanalysisofstudiesonthecostofRAestimatedtheannualmeandirectcostofRAperpatienttobe$5,425withannualindirectcostsof$9,744(1998dollars).2RApatientswithconcomitantcardiovascular disease or depression have even higher costs,more medication use, and more hospitalizations comparedwith patients with RA only.3 Patients with RA progressivelyaccumulatedisabilityleadingtounemploymentandincreasinghealthcareutilization.3-5

Psoriasisisacommonchronicautoimmuneconditionthatischaracterizedbyred,scaly,andinduratedskinlesions.6Theselesionsmore commonly occur on the scalp, elbows, umbili-cus,glutealcleft,genitalareas,andknees.Symptomsusuallyinclude itching, burning, and soreness of the lesions aswellas joint pains or true arthritis. The exact cause of psoriasisisunknown.Psoriasisaffectsbetween1%and3%oftheU.S.population,anestimated4.5-7.5millionAmericans.7Ofthesepersons, approximately one-third suffer from moderate toseverediseasethatcannotbecontrolledbytopicaltherapies.8 Totaldirectandindirecthealthcarecostsofpsoriasisarecal-culatedat$11.25billionannuallyintheUnitedStates.9Lossofworkaccountsfor40%ofthecostburden.9

Biologics are therapeutic agents derived from human oranimal sources ormanufacturedusing recombinant deoxyri-bonucleic acid (DNA) technology. Biologicsmay be proteins,monoclonal antibodies, recombinant receptors, or complexsugars.Biologicsareusedinavarietyofdiseasestatesincludingautoimmunedisease.Theintroductionoftheautoimmunebio-logicshashadasignificantimpactonthemanagementofauto-inflammatorydiseases.GuidelineshavepredominantlyplacedbiologictreatmentsassecondlinebehindconventionaltherapyforRAandpsoriasis.TheAmericanCollegeofRheumatology2008guidelinesrecommendmethotrexateasfirst-linetherapytobe followedbya tumornecrosis factor(TNF)antagonist ifthe response tomethotrexate is inadequate.10 Similar recom-mendations can be found in other guidance including theNational Institute for Health and Clinical Excellence (NICE)technology appraisal no. 130 (October 2007).11 AmericanAcademyofDermatologyguidelinesrecommendtopicalthera-piesforpatientswithlimiteddisease.12Biologicsareanoptionalong with ultraviolet light A or B/psoralen (UVB/PUVA) orother systemic therapies (acretin, methotrexate) for psoriasispatientswithextensivediseaseorthosewithlocaldiseasewhofailtopicaltherapy.12

Thereisasignificantamountofclinicaldataontheuseofbiologics inautoinflammatorydiseases,butquestionsremain

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669237/pdf/ar2666.pdf

http://www.effectivehealthcare.ahrq.gov/ehc/products/14/70/RheumArthritisExecSum.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125261s001lbl.pdf

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm197108.htm

http://www.gene.com/gene/products/information/actemra/pdf/pi.pdf


http://www3.interscience.wiley.com/cgi-bin/fulltext/119635887/PDFSTART

http://www.nice.org.uk/nicemedia/live/11867/37914/37914.pdf


EfficacyPHOENIX 1: Ustekinumab in psoriasis patients eligible for systemic treatment. The efficacy of ustekinumab in thetreatment of patients with moderate to severe psoriasis wasassessedinthe“PHOENIX1”study,aphase3,double-blind,placebo-controlled, randomized trial (Table 2).25 Patients eli-gibleforenrollmentwereat least18yearsofage,hadadiag-nosis of psoriasis for at least 6monthswith at least 10% ofthebodysurfaceaffected,andwerecandidatesforsystemicorphototherapy.Exclusioncriteria includednonplaqueformsofpsoriasis,historyorsymptomsofactivetuberculosis,arecentserioussystemicorlocalinfection,malignancy,treatmentwithany agent that specifically targeted IL-12 or IL-23, treatmentwith a biological or investigational agent received in previ-ous3months,treatmentwithconventionalsystemicpsoriasistherapyorphototherapyreceivedwithintheprevious4weeks,oratopicalpsoriasistreatmentreceivedwithintheprevious2weeks.

Thetrialhad3phases:aplacebo-controlledphasebetweenweeks0-12, aplacebo cross-over and active treatmentphasefrom weeks 12-40, and a randomized withdrawal phasebetweenweeks 40-76. Patientswere randomized to subcuta-neous injections of ustekinumab 45milligrams (mg; n=255;meanage44.8years,68.6%male),90mg(n=256;meanage46.2 years, 67.6%male), or placebo (n=255;mean age 44.8years,71.8%male)atweeks0,4,andevery12weeksthereaf-ter.Theprimaryendpointwasachievementofa75%improve-mentinthepsoriasisareaandseverityindex(PASI75)atweek12. Secondary endpoints included the proportion of patientsachieving a clear or minimal physician’s global assessment(PGA)scoreatweek12,andthetimetolossofPASI75duringthewithdrawalphase.

■■ ResultsPharmacologyUstekinumab. Interleukin (IL) IL-12 and IL-23 are involvedin innate and adaptive immune response and have beenimplicated in the pathogenesis of psoriasis. IL-12 stimulatesT-helper(TH)1cellimmuneresponsesleadingtothesecretionofinterferonandTcellrecruitment.IL-23inducesIL-17,regu-latesTmemorycells, andactivatesmacrophages tomaintainchronic autoimmune inflammation.21 Ustekinumab is a fullyhumanimmunoglobin(Ig)G1antibodythatbindstothep40subunit of IL-12 and IL-23 (Figure 2). The binding preventsinteractionwiththeIL-12Rbeta1receptor,neutralizingIL-12andIL-23mediatedcellimmuneresponses.22

Tocilizumab. IL-6 acts as a stimulator of B andT cell func-tions, including promoting the differentiation of B cells intoantibodyproducingplasmacells.23,24IL-6,whenboundtothesoluble IL-6 receptor,hasbeen shown to activate chemokineproductionandupregulateexpressionofadhesionmolecules,leadingtorecruitmentofleukocytesatinflammatorysites.23,24 TheseactionshaveimplicatedIL-6asanimportantcomponentof inflammatory diseases including RA. High levels of IL-6have been found in the serum and joints of RA patients.23,24 Additionally, IL-6 has been shown to induce proliferation ofosteoclasts,whichmaybeacomponentof thebonedegrada-tionseeninRA.23,24Tocilizumabisahumanized,monoclonalantibodythatcanbindtobothmembranousandsolubleIL-6receptors(Figure2).Theblockadepreventsthe interactionofIL-6 and IL-6 receptor, interrupting the actions of IL-6 thatcontributetothediseaseprocessesinRA.24


TABle 1 Approved Biologic Treatmentsa for Autoinflammatory Diseases

Drug Mechanism of ActionRoute of

Administration RAJuvenile

RAPsoriatic Arthritis AS Psoriasis UC CD

Adalimumab(Humira)47 TNFantagonist subcutaneous √ √ √ √ √ √ Etanercept(Enbrel)46 TNFantagonist subcutaneous √ √ √ √ √Infliximab(Remicade)38 TNFantagonist IVinfusion √ √ √ √ √ √ Certolizumab(Cimzia)48 TNFantagonist subcutaneous √ √ Alefacept(Amevive)49 ReduceThelpercell subcutaneous √Anakinra(Kineret)50 IL-1receptorantagonist subcutaneous √Abatacept(Orencia)53 BlocksCD28,inhibiting

TcellactivationIVinfusion √ √

Rituximab(Rituxan)51 BindsCD20receptorandreducesBcellcount

IVinfusion √b

Golimumab(Simponi)52 TNFantagonist subcutaneous √ √ √Ustekinumab(Stelara)16 IL-12and23antagonist subcutaneous √Tocilizumab(Actemra)17 IL-6receptorantagonist IVinfusion √b

aIndications approved by the U.S. Food and Drug Administration as of May 2010.bAfter failure or intolerance to a TNF antagonist.AS = ankylosing spondylitis; CD = Crohn’s disease; IL = interleukin; IV = intravenous; RA = rheumatoid arthritis; TNF = tumor necrosis factor; UC = ulcerative colitis.

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/125261s000_PharmR.pdf

http://www.rxabbott.com/pdf/humira.pdf

http://www.enbrel.com/documents/ENBREL-Prescribing-Information.pdf

http://www.remicade.com/remicade/assets/HCP_PPI.pdf

http://www.cimzia.com/pdf/Prescribing_Information.pdf





http://www.simponi.com/Prescribing-Information/Prescribing-Information.pdf




The study enrolled 766 patients. Baseline demographicand clinical characteristics were similar between treatmentgroups. Patients had an average 20-year history of psoriasis,andapproximately two-thirdsofpatients ineachgroupweremen.Mean involvedbodysurfacearea (BSA)atbaselinewas

between 25.2% and 27.7% for all groups. A total of 55.3%,55.1%,and55.7%intheustekinumab45mg,90mg,andpla-cebo groups, respectively, had tried psoralen plus ultravioletA(PUVA),methotrexate,acitretin,orcyclosporineinthepast.A total of 52.5%, 50.8%, and 50.2% in the 45 mg, 90 mg,and placebo groups, respectively, had tried an autoimmunebiologic—etanercept, alefacept, efalizumab, infliximab, oradalimumab—priortostudyinitiation.

APASI75 scorewasachievedby67.1%,66.4%,and3.1%of patients in the ustekinumab 45 mg, 90 mg, and placebogroups, respectively (P <0.001 for both strengths comparedwith placebo) at week 12. A PGA score of clear orminimalwas achieved by 60.4%, 61.7%, and 3.9%of patients treatedwith ustekinumab 45 mg, 90 mg, and placebo, respectively(P <0.001forbothstrengthscomparedwithplacebo),atweek12.Week28 resultsdemonstrateddurable results forusteki-numabwith71.2%and78.6%ofpatientstreatedwith45mgor90mgachievingormaintainingaPASI75score.Patientsmov-ingfromplacebotoustekinumab45mgor90mghadPASI75responseratesof65.9%and84.9%,respectively,atweek28.ThemediantimetolossofPASI75inpatientswithdrawnfromtherapywas15weeks.Patientssustainedonustekinumabdur-ingthewithdrawalphasedidnotloseresponse.

PHOENIX 2: Ustekinumab in psoriasis patients eligible for systemic treatment. “PHOENIX 2” compared ustekinumabwithplaceboforthetreatmentofmoderatetoseverepsoriasisin a studydesign similar toPHOENIX1 (Table2).26Patientswereatleast18yearsofage,hadadiagnosisofpsoriasisforat


FIGuRe 1 Flowchart of Literature Selection

Key word “ustekinumab” for publication through January 2010

65 articles identified

Key word “tocilizumab” for publication through January 2010

217 articles identified

Limits: English, “human,” “clinical trial,” or “randomized controlled trial”

Disease state other than psoriasis or psoriatic arthritis

Disease state other than RA or trial that did not use

clinical endpoint (e.g., biomarker studies

were excluded)

8 articles for review4 articles for review

21 articles excluded for not being in English or about humans

36 articles excluded for not being clinical trials or RCTs

8 articles remain

77 articles excluded for not being in English or about humans

124 articles excluded for not being clinical trials or RCTs

16 articles remain

RA = rheumatoid arthritis; RCT = randomized controlled trial.

TABle 2 Primary Endpoint Results from Phase 3 Trials of Ustekinumab

PHOENIX 125

DrugPASI 75 Response

at Week 12 (%) P Value Compared

with Placebo

Ustekinumab45mg(n=255) 67.1 < 0.001Ustekinumab90mg(n=256) 66.4 < 0.001Placebo(n=255) 3.1 —

PHOENIX 226



with Placebo

Ustekinumab45mg(n=409) 66.7 < 0.001Ustekinumab90mg(n=411) 75.7 < 0.001Placebo(n=410) 3.7 —

ACCEPT20



with Etanercept

Ustekinumab45mg(n=209) 67.5 0.012Ustekinumab90mg(n=347) 73.8 < 0.001Etanercept50mg(n=347) 56.8 —

mg = milligram; PASI 75 = 75% improvement in the psoriasis area and severity index.



least6monthswithatleast10%ofthebodysurfaceaffected,andwere candidates for systemic or phototherapy. ExclusioncriteriaweresimilartocriteriausedinPHOENIX1.

Thetrialhad3phases:aplacebo-controlledphasebetweenweeks0-12, aplacebo cross-over and active treatmentphasefromweeks 12 to 28, and a randomized dose-intensificationphase from weeks 28-52. Patients were randomly assignedtosubcutaneousustekinumab45mg(n=409;meanage45.1years, 69.2% male), 90 mg (n=411; mean age 46.6 years,66.7%male),orplacebo(n=410;meanage47.0years,69.0%male) atweeks0, 4, and every12weeks thereafter.Atweek12,patientstreatedwithplacebowerere-randomizedtoeitherustekinumab 45mg or 90mg every 12weeks. Atweek 28,patientsachievingapartialresponse(improvementofatleastPASI50butlessthanPASI75)werere-randomizedtousteki-numabdosedevery8or12weeks.Theprimaryendpointwasachievement of a PASI 75 score atweek 12. Secondary end-

pointsincludedtheproportionofpatientsachievingaclearorminimalPGAscoreatweek12,andtheproportionofpatientsachievingaPASI75scorebetweenweeks40and52duringthedose-intensificationphase.

The studyenrolled1,230patientsofwhomapproximatelytwo-thirds in each group were men. Groups were balancedwith regard to demographic and baseline characteristics.Average disease duration of psoriasis was approximately 20years.InvolvedBSAatbaselinewas25.9%,27.1%,and26.1%intheustekinumab45mg,90mg,andplacebogroups,respec-tively.Atotalof54.5%,54.5%,and58.8%inthe45mg,90mg,andplacebogroups,respectively,hadtriedPUVA,methotrex-ate,acitretin,orcyclosporinepriortostudyinitiation.Atotalof38.4%,36.5%,and38.8%inthe45mg,90mg,andplacebogroups,respectively,hadtriedanautoimmunebiologic—etan-ercept, alefacept, efalizumab, infliximab, or adalimumab—priortostudyinitiation.

FIGuRe 2 Pharmacology of Ustekinumab and Tocilizumaba

IL-12R

IL-23R

IL-23R

Macrophage Th1

Th17

MacrophageDendritic cell

Ustekinumab

Tocilizumab

Inflammatoryresponse

TNF antagonist

Tocilizumab

IL-23

IL-6, TNF

IL-6

IL-6R

IL-6

IL-6R

IL-12IFNγ

aAdapted from Iwakura Y and Ishigame H54 and other references.22,24

IFN = interferon; IL = interleukin; R = receptor; TNF = tumor necrosis factor; Th = T helper cell.

http://www.jci.org/articles/view/28508



monthsor5half-lives,whicheverwaslonger.Patients were randomized to receive either subcutaneous

ustekinumab 45mg (n=209) or 90mg (n=347) atweeks 0and4orsubcutaneousetanercept50mg(n=347)twiceweeklythroughweek12.Theprimaryendpointwastheproportionofpatientswho achieved a PASI 75 atweek12.The secondaryendpoints were the proportion of patients achieving a PGAscoreofclearedorminimalatweek12andtheproportionofpatientsachievingaPASI90scoreatweek12.Patientsintheetanercept group who did not demonstrate a PASI 75 scoreatweek12receivedustekinumab90mgatweeks16and20.Patients not achieving a PASI 75 score in the ustekinumabgroupatweek12gotanadditionaldoseofustekinumab.

Thestudyenrolled903patients.Baselinedemographicanddisease characteristicswere similar among treatment groups.Patientswere an average ageof 45 years andhad an averagedurationofpsoriasisof18.8years,withameaninvolvedBSAof25%.Atotalof61.7%,52.4%,and57.3%intheustekinumab45mgand90mgandetanerceptgroups,respectively,hadtriedPUVA,methotrexate, acitretin,or cyclosporineprior to studyinitiation.A total of 12.8%,10.4%, and11.8% in theusteki-numab45mgand90mgandetanerceptgroups,respectively,hadtriedanautoimmunebiologic—alefacept,efalizumab,in-fliximab,oradalimumab—priortostudyinitiation.

Atweek12,atotalof67.5%ofpatientstreatedwithusteki-numab45mgand73.8%treatedwith90mgachievedaPASI75scorecomparedwith56.8%ofpatients treatedwithetan-ercept (P =0.012 for ustekinumab 45 mg vs. etanercept andP <0.001forustekinumab90mgvs.etanercept).APGAscoreofclearedorminimalwasachievedby65.1%ofpatientstreatedwithustekinumab45mgand70.6%for90mgcomparedwith49.0%ofpatientstreatedwithetanerceptatweek12(P < 0.001 forbothustekinumabgroupsvs.placebo).APASI90scoreatweek12wasachievedby36.4%ofpatientstreatedwithusteki-numab 45mg and 44.7% for 90mg, compared with 23.1%ofpatients treatedwith etanercept (P <0.001 forbothusteki-numab groups vs. placebo). A total of 48.9% of patients notachievingaresponseintheetanerceptgroupachievedaPASI75 scorewhen treatedwith ustekinumab 90mg, and 23.4%had90%improvement.

RADIATE: Tocilizumab in RA patients with prior TNF fail-ure.TheefficacyoftocilizumabinthetreatmentofpatientswithmoderatetosevereRAwithpriorTNFfailurewasassessedina24-week,double-blind,randomized,placebo-controlledtrial(Table3).28Patientseligibleforenrollmentwereaged18yearsorolderandhadmoderatetosevereRAandfailedtorespondorwereintoleranttoprevioustreatmentwith1ormoreTNFantagonists inthepreviousyear.PatientshadactiveRAfor6months ormore anddiscontinued all prior therapies (exceptmethotrexate) prior to study initiation. Infliximab or adali-mumabhadtobediscontinued8weekspriorandetanercept2

APASI75scorewasachievedby66.7%,75.7%,and3.7%ofpatientsintheustekinumab45mg,90mg,andplacebogroups,respectively,atweek12(P <0.001forbothustekinumabregi-menscomparedwithplacebo).APGAscoreofclearedormini-malwasachievedby68%,73.5%,and4.9%ofpatientsintheustekinumab45mg,90mg,andplacebogroups,respectively,at week 12 (P <0.001 for both ustekinumab regimens com-paredwithplacebo).Atweek28, theproportionsofpatientswhowerepartialrespondersintheustekinumab45mgand90mggroupswere22.7%and15.8%,respectively.Increasingthedosingfrequencytoevery8weeksdidnotincreasethenumberofvisitswithaPASI75response(1.75visitsin8-weekgroupvs.1.56visitsin12-weekgroup,P =0.468).

Analysis of secondary endpoints in the PHOENIX-2 trialdeterminedtheeffectofustekinumabonanxietyanddepres-sion scales in patients with psoriasis.27 The analysis usedtheHospitalAnxiety andDepressionScale (HADS) to assesspatients’mentalhealthinthestudy.Ascoreof8orgreaterontheHADS scale indicated presence of depression or anxiety,respectively.Atbaseline,aHADS-Anxietyscoreof8orgreaterwas reported in 38.2%, 41.0%, and 41.6% of patients in theustekinumab45mg,90mg,andplacebogroups,respectively.AHADS-Depressionscoreof8orgreateratbaselinewasreportedin24.7%,31.1%,and24.2%ofpatientsintheustekinumab45mg,90mg,andplacebogroups,respectively.Atweek12,theproportionofpatientsreportingaHADS-Anxietyscoreof8orgreaterwas25.7%,27.1%,and43.0% in theustekinumab45mg,90mg,andplacebogroups,respectively(P <0.001forbothustekinumabgroupscomparedwithplacebo).Atweek12,theproportionofpatientsreportingaHADS-Depressionscoreof8orgreaterwas12.8%,12.5%,and34.4%intheustekinumab45mg,90mg,andplacebogroups,respectively(P <0.001forbothustekinumabgroupscomparedwithplacebo).27

ACCEPT: Comparative trial of ustekinumab and etan-ercept. The efficacy of ustekinumab in the treatment ofmoderatetosevereplaquepsoriasiswascomparedwithetan-erceptinaphase3,investigator-blinded,randomizedtrial.20 Patientswhowere at least 18 years of agewith a diagnosisofplaquepsoriasisforatleast6monthswithatleast10%ofBSA affected,were candidates for phototherapy or systemictherapy,andhadfailedtorespondto(orwereintolerantof)cyclosporine,methotrexate,orPUVA,wereeligibletoenroll.Noprevious treatmentwithustekinumabor etanerceptwasallowed.Otherexclusioncriteriaincludednonplaqueordrug-inducedformsofpsoriasis,arecentseriousinfectionorahis-tory of chronic or recurrent infectious disease, or a knownmalignant condition. Before enrollment, patients could nothavereceivedconventionalsystemictherapyorphototherapywithin 4 weeks before enrollment; topical psoriasis agentswithin 2 weeks; investigational drugs within 4 weeks or 5half-lives,whicheverwas longer;orbiologicagentswithin3



of at least6monthsduration andan inadequate response tomethotrexate.Patientshadtobetreatedwithmethotrexateforatleast12weekspriortothestudywithastabledoseof10mgto25mgweekly forat least8weeks.Patientswereexcludedif they had other autoimmune disorders, currently active orrecurrent infections, or had an inflammatory joint diseaseotherthanRA.

Patientswere randomized to either tocilizumab 8mg per

weekspriortothestartofthestudy.Exclusioncriteriaincludedprior treatmentwithcell-depletingagents (e.g.,azathioprine),uncontrolledmedicalconditions,historyofmalignancy,otherinflammatory diseases or recurrent infection, abnormal liverfunction,leukopenia,neutropenia,orthrombocytopenia.

Patientswererandomizedtotocilizumab8mgperkilogram(kg), tocilizumab 4 mg per kg, or placebo infusion every 4weeks. Infusionswereadministeredover1hour.Allpatientswere treated with a stable dose of methotrexate (10-25 mgweekly) and folate. Stableoral corticosteroids (prednisone10mgor lessorequivalent)andnonsteroidalanti-inflammatorydrugs (NSAIDs)werepermitted,butotherdisease-modifyingantirheumaticdrugs(DMARDs)werenotallowed.TheprimaryendpointwastheproportionofpatientsachievinganAmericanCollegeofRheumatologycriteria20%improvementinsignsorsymptomsofRA (ACR20) atweek24. Secondary endpointsincluded the proportion of patients achieving an ACR 50 orACR70,andpatientsachievingdiseaseremissiondefinedasadiseaseactivityscoreof28joints(DAS28)lessthan2.6.

The study enrolled 499 patients. Baseline characteristicswere similar between groups. Average disease duration priortothestudywas12.6,11.0,and11.4yearsinthetocilizumab8mgperkg,4mgperkg, andplacebogroups, respectively.A totalof50%,47%,and42%ofpatients in the tocilizumab8mgperkg,4mgperkg, andplacebogroups, respectively,hadtried1priorTNFagent.TwopriorTNFshadbeentriedin32%,41%,and42%,respectively,and3ormoreTNFshadbeentriedin18%,12%,and14%,respectively.Approximately95%ofpatientsdiscontinuedpriorTNFtherapyduetoinad-equate efficacy.AnACR20 atweek24was achievedby sig-nificantlymorestudyparticipantsinthetocilizumab8mgperkg(50.0%)and4mgperkg(30.4%)groupsthantheplacebogroup(10.1%,P <0.001forbothtocilizumabgroupscomparedwithplacebo).AnACR50wasachievedby28.8%and16.8%ofpatients in the tocilizumab8mgperkgand4mgperkggroups,respectively,comparedwith3.8%intheplacebogroup(P <0.001 for both tocilizumab groups compared with pla-cebo).AnACR70wasachievedby12.4%and5.0%ofpatientsinthetocilizumab8mgperkgand4mgperkggroups,respec-tively,comparedwith1.3%fortheplacebogroup.TheACR70responsewassignificantcomparedwithplaceboforthetocili-zumab8mgperkggroup(P =0.001)butnotthe4mgperkggroup(P =0.1).Diseaseremissionwasreportedatweek24in30.1%,7.6%,and1.6%ofpatientsinthetocilizumab8mgperkg,4mgperkg,andplacebogroups,respectively(P =0.001for8mgperkgcomparedwithplaceboandP =0.053for4mgperkgcomparedwithplacebo).

OPTION: Tocilizumab in RA patients with prior methotrex-ate failure.TheOPTIONtrialwasa24-week,phase3double-blind,randomized,placebo-controlledtrial(Table3).29PatientseligibleforenrollmentwereadultswithmoderatetosevereRA


TABle 3 Primary Endpoint Results from Phase 3 Trials of Tocilizumab

RADIATE28

DrugACR 20 Response

at Week 24 (%)P Value Compared

with Placebo

Tocilizumab4mgperkg+MTX(n=163)

30.4 < 0.001


50.0 < 0.001

Placebo+MTX(n=160) 10.1 —

OPTION29

DrugACR 20 Response


with Placebo


48.0 < 0.001


59.0 < 0.001

Placebo+MTX(n=204) 26.0 —

TOWARD31

DrugACR 20 Response at

Week 24 (%)P Value Compared

with Placebo

Tocilizumab8mgperkg+DMARD(n=802)

60.8 < 0.001

Placebo+DMARD(n=414) 24.5 —

SAMURAI32

DrugMean TSS Change at

Weeks 28 and 52P Value Compared

with Placebo

Tocilizumab8mgperkg(n=157)

1.9(95%CI=1.2-2.6)atweek28

2.3(95%CI=1.5-3.2)atweek52

<0.05

< 0.01

Placebo (n=145)

4.5(95%CI=3.1-6.0)atweek28

6.1(95%CI=4.2-8.0)atweek52

—

—

AMBITION33

DrugACR 20 Response


with MTX

Tocilizumab8mgperkg(n=265)

69.9 < 0.001

MTX(n=259) 52.5 —

ACR 20 = American College of Rheumatology criteria for 20% improvement in signs or symptoms of rheumatoid arthritis.CI = confidence interval; DMARD = disease-modifying antirheumatic drug; kg = kilogram; mg = milligram; MTX = methotrexate; TSS =total Sharp score.



4mgperkg,and8mgperkg+methotrexategroupcomparedwith41%inthemethotrexatemonotherapygroup(P <0.05forall comparisons to methotrexate monotherapy). An ACR 50scorewasachievedby53%ofpatientsinthetocilizumab8mgperkg+methotrexategroupcomparedwith29%inthemetho-trexatemonotherapygroup(P <0.05).AnACR70wasachievedby37%ofpatientsinthetocilizumab8mgperkg+methotrex-ategroupcomparedwith16%inthemethotrexatemonother-apygroup(P <0.05).RatesofachievementofACR50andACR70scoresdidnotdifferforanyoftheothertocilizumabgroupscomparedwithmethotrexatemonotherapy.

TOWARD: Treatment in RA patients in combination with DMARDs (except TNFs).TheTOWARDtrialwasa24-week,phase 3, double-blind, randomized, placebo-controlled trial(Table3).31Patientseligibleforenrollmentwereaged18yearsorolderandhadmoderatetosevereRAforatleast6monthsandwerecurrentlybeingtreatedwithaconventionalDMARDat a stable dose for 8 weeks or more prior to study entry.PermittedconventionalDMARDsincludedmethotrexate,chlo-roquine, hydroxychloroquine, parenteral gold, sulfasalazine,azathioprine, and leflunomide. Exclusion criteria includedprevioustreatmentandfailurewithaTNFantagonistorpriortreatmentwithacell-depletingagent.

Patientswererandomized2:1toeithertocilizumab8mgperkg or placebo once every 4weeks. Tocilizumab andplaceboinfusionswereadministeredover1hour.Allpatientscontin-uedtheirconventionalDMARDtherapyatastabledose.Oralcorticosteroids(<10mgprednisoneorequivalent)andNSAIDswerepermittedifthepatienthadreceivedastabledoseforatleast 6 weeks prior to the study. The primary endpoint wasachievementofanACR20scoreatweek24.Secondaryend-points included achievement of anACR50 score orACR70scoreandachievementofdiseaseremission(DAS28<2.6).

Thestudyenrolled1,220patientswithameanageof53.5years (82.5% female). Mean disease duration was 9.8 years.OneDMARDwas used in 77% and 75% in the tocilizumab8mg per kg and placebo groups, respectively. Two ormoreDMARDswereusedby22%and24%ofpatientsinthetocili-zumab8mgperkgandplacebogroups,respectively.ThemostcommonlyusedDMARDwasmethotrexate(meandose15mgweekly) in75.8%and73.9%ofpatients inthetocilizumab8mgperkgandplacebogroups,respectively.AnACR20scoreatweek24wasachievedby60.8%and24.5%inthetocilizumab8mgperkg andplacebogroups, respectively (P <0.001).AnACR50scoreatweek24wasachievedby37.6%and9.0%inthetocilizumab8mgperkgandplacebogroups,respectively(P <0.001).AnACR70scoreatweek24wasachievedby20.5%and2.9%ofpatientsinthetocilizumab8mgperkgandpla-cebo groups, respectively (P <0.001). Disease remission wasreachedby30.2%and3.4%ofpatientsinthetocilizumab8mgperkgandplacebogroups,respectively(P <0.001).

kg, 4mgper kg, or placebo infusion once every 4weeks asa 1-hour infusion for 24weeks. All patients continued theirbaselinestablemethotrexateregimen(10-25mgweekly).Oralcorticosteroids (prednisone 10mg or less or equivalent) andNSAIDs were permitted if the patient had received a stabledose for at least 6weeksprior to the study.DMARDs (otherthanmethotrexate)orbiologicswerediscontinuedpriortothebeginningofthestudy.TheprimaryendpointwasachievementofanACR20scoreatweek24.SecondaryendpointsincludedachievementofanACR50scoreorACR70scoreandachieve-mentofdiseaseremission(DAS28<2.6).

The study enrolled 622 patients with a mean age of 51years (71% female). Mean disease duration was 7.5 years.Concomitant use of corticosteroids or NSAIDs was similarbetweengroups.Meanmethotrexatedosewas14.5,14.7,and14.8mgweeklyinthetocilizumab8mgperkg,4mgperkg,andplacebogroups,respectively.AnACR20scoreatweek24wasachievedby59%,48%,and26%inthetocilizumab8mgperkg,4mgperkg,andplacebogroups,respectively(P < 0.001 forbothtocilizumabgroupscomparedwithplacebo).AnACR50 scoreatweek24wasachievedby44%,31%,and11% inthetocilizumab8mgperkg,4mgperkg,andplacebogroups,respectively (P <0.001 forboth tocilizumabgroupscomparedwithplacebo).AnACR70 scoreatweek24wasachievedby22%,12%,and2%ofpatientsinthetocilizumab8mgperkg,4mg per kg, and placebo groups, respectively (P <0.001 forboth groups comparedwith placebo).Disease remissionwasreachedby27%,13%,and0.8%ofpatientsinthetocilizumab8mgper kg, 4mgper kg, andplacebo groups, respectively(P <0.05forbothgroupscomparedwithplacebo).

Treatment in RA patients, comparison of methotrexate only, methotrexate plus tocilizumab, and tocilizumab only. AEuropeantrialreportedbyMainietal.(2006)enrolled350RA patients for a 20-week, double-blind, placebo-controlled,randomized trial.30 Patients with active RA despite previoustreatmentwithmethotrexateandonastabledoseforatleast4weekspriortorandomizationwereenrolled.Patientswereran-domizedto1of7groups:tocilizumab2mgperkg,4mgperkg,or8mgperkgplusplacebocapsule;tocilizumab2mgperkg,4mgperkg,or8mgperkgplusmethotrexate;orplaceboinfusionplusmethotrexate.TheprimaryendpointwasanACR20 score atweek 16. Secondary endpoints includedACR 50andACR70scoresatweek16.

AnACR20scoreatweek16wasachievedby31%,61%,and63%ofpatientsinthetocilizumab2mgperkg,4mgperkg,and8mgperkgmonotherapygroups,respectively,comparedwith 41% for methotrexate monotherapy (P <0.05 for 4 mgperkgand8mgperkgcomparedwithmethotrexate,P >0.05[exactP valuenot reported] for 2mgper kg comparedwithmethotrexate).AnACR20scoreatweek16wasachievedby64%,63%,and74%ofpatientsinthetocilizumab2mgperkg,




then tocilizumab 8 mg per kg every 4 weeks. Tocilizumaband placebo infusions were administered over 1 hour. Oralcorticosteroids (prednisone 10mg or less or equivalent) andNSAIDswerepermittedifthepatienthadreceivedastabledoseforat least6weeksprior tothestudy.Theprimaryendpointwas achievement of anACR20 score atweek24. SecondaryendpointsincludedachievementofanACR50scoreorACR70scoreandachievementofdiseaseremission(DAS28<2.6).Theprimary efficacy analysiswas a noninferiority comparison oftocilizumabandmethotrexateusingtheperprotocolpopula-tion.Ifnoninferiorityoftocilizumabwasmet,thensuperioritywasassessedintheintention-to-treat(ITT)group.

The study enrolled 673 patients with a mean age ofapproximately 50 years (81% female). Mean disease dura-tion was approximately 6.3 years. The majority of patients(approximately66% ineachgroup)weremethotrexatenaïve.Themean number of previousDMARDs/TNFswas 0.5, and40%ofpatientshadreceivedpriororalsteroids.AnACR20atweek24wasachievedby69.9%and52.5%inthetocilizumab8mgperkgandmethotrexategroups,respectively(weighteddifference0.21,95%CI=0.13-0.29),meetingtheendpointfornoninferiority.AnanalysisintheITTpopulationdemonstratedthe superiority of tocilizumab 8 mg per kg to methotrexate(weighted difference 0.19, 95% CI=0.34-0.52, P <0.001). AnACR50atweek24wasachievedby44.1%and33.5%inthetocilizumab8mgperkgandmethotrexategroups,respectively(weighted difference 0.12, 95%CI=0.04-0.20, P =0.002). AnACR70 score atweek24was achievedby28.0%and15.1%ofpatients in the tocilizumab8mgperkgandmethotrexategroups, respectively (weighteddifference0.14,95%CI=0.07-0.22, P <0.001).

SafetyUstekinumab.Infectionwasthemostcommonadverseeventinpatientstreatedwithustekinumabinclinicaltrials(Table4).Infectionswerereportedin73.3%and71.9%ofpatientsintheustekinumab45mgand90mggroups,respectively, through100weeksinthePHOENIX-2trial.34Duringthedouble-blindphaseofPHOENIX-2(12weeks)infectionsoccurredin21.5%,22.4%,and20.0%ofpatientsintheustekinumab45mg,90mg,andplacebogroups,respectively.34Nasopharyngitisandupperrespiratory tract infectionwere themost commonly reportedevents.34Duringthedouble-blindportionofthephase3trials,the incidence of infection was similar between ustekinumaband placebo. The incidence of serious infections during thedouble-blindportionofthephase3trialswas0.3%and0.4%intheustekinumabandplacebogroups,respectively.34

Patients treatedwithustekinumabmaybeatan increasedriskformalignancy.AnimalmodelshaveshownthatblockadeoftheIL-12/23subunitincreasestheriskofmalignancy.34,35 A totalof30malignancieswere reported in26patients treatedwithustekinumabover100weeksof thePHOENIX-2 trial.34

SAMURAI: Tocilizumab compared with DMARD in joint damage progression.Theefficacyoftocilizumabintheinhi-bition of progression of structural joint damage in RA wasassessed ina52-week,open label,x-rayreaderblinded,con-trolledtrial.32Adultpatientsaged20yearsorolderwithactiveRAandadiseasedurationbetween6monthsand5yearswereenrolled.All patients had an inadequate efficacy response toat least 1DMARDor immunosuppressant.Exclusion criteriaincluded medical history of a serious allergic reaction, sig-nificant underlying disease process other than RA, or activeinfection.

Patients were randomized to receive either tocilizumab 8mgperkgmonotherapyonce every4weeksor conventionalDMARD. DMARDs or immunosuppressants were discontin-ued in the tocilizumab group at the beginning of the study.Patients in the DMARD group were treated with a DMARD(exceptTNFs)or immunosuppressantat thediscretionof thetreatingphysician.Oralcorticosteroids(prednisone10mgorlessorequivalent)werepermittedifthepatienthadreceivedastabledoseforatleast2weekspriortothestudy.OralNSAIDswereallowedduringthetrial.TheprimaryendpointwasthechangeinthemeanmodifiedtotalSharpscore(TSS)atweeks28and52.

Thestudyenrolled306patients(meanage53years)withameandurationofdiseaseof2.3years.Demographicandbase-line characteristics did not differ between groups. A total of37%,30%,and22%ofpatientsintheDMARDgroupreceivedmethotrexate in combination with DMARDs, methotrexatemonotherapy,andDMARDsotherthanmethotrexate,respec-tively.Atbaseline,themean(standarddeviation)TSSwas30.6(42.0)and28.3(43.9)inthetocilizumabandDMARDgroups,respectively.MeanchangeintheTSSatweek28was1.9(95%CI=1.2-2.6) and 4.5 (95% CI=3.1-6.0) in the tocilizumabandDMARD groups, respectively (P <0.05).Mean change intheTSS atweek52was2.3 (95%CI=1.5-3.2) and6.1 (95%CI=4.2-8.0) in the tocilizumabandDMARDgroups, respec-tively(P <0.01).Thesedatademonstrate that tocilizumabsig-nificantlyinhibitedtheprogressionofstructuraljointdamagecomparedwithconventionalDMARDtherapy.

AMBITION: Tocilizumab monotherapy compared with methotrexate monotherapy. The AMBITION trial was a24-week, phase 3, double-blind, randomized, placebo-con-trolled trial.33 Patients eligible for enrollment were aged 18years or older and hadmoderate to severe RA for at least 3months. Exclusion criteria included treatment with metho-trexateinthe6monthspriortotrialinitiationoranydiscon-tinuationofpriormethotrexateand/orTNFantagonistduetointoleranceorlackofefficacy.

Patientswererandomized1:1:1toeithertocilizumab8mgperkgevery4weeks,methotrexate7.5mginitiallywithtitra-tionto20mgweeklybyweek8,orplacebofor8weeksand


http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/125261s000_MedR.pdf







experienced an absolute neutrophil count less than 500 permm3 and were withdrawn from the study.28 The 24-weekOPTIONtrialfoundhigherratesofgrade1(>1,500cellspermm3;18.8%vs.4.3%placebo),grade2(1,000-1,500cellspermm3; 11.6%vs. 0.5%placebo), andgrade3 (500-1,000 cellspermm3;3.7%vs.0%placebo)neutropeniainthetocilizumabgroupscomparedwithplacebo.29Thelong-termextensiontrialinvolving 5 years of follow-up (n=143) documented grade 2neutropenia in 17 (11.9%) patients and grade 3 in 9 (6.3%)patients.36Nopatientsdiscontinued tocilizumab in the long-termextensionduetoneutropenia.36Monitoringofneutrophilcountsisrecommendedevery4-8weeks,andpatientsexperi-encinganeutrophilcountlessthan500cellspermm3shoulddiscontinue tocilizumab.17 A connection between infectionsand tocilizumab-associatedneutropeniahasnotbeenproveninclinicaltrials;however,theriskofinfectioninneutropenicpatientshasbeenwelldocumentedinotherdiseasestates(e.g.,cancer).17

Infection was themost common adverse event associatedwithtocilizumabinclinicaltrials.AccordingtoanFDAanaly-sis,combinationtherapyoftocilizumab8mgperkgor4mgper kg and aDMARDhad infection rates of 133 events and127eventsper100patientyears,respectively,comparedwith112eventsper100patientyearsintheplaceboplusDMARDgroups.17 Serious infections occurredmore commonly in thetocilizumabmonotherapy cohort (3.6 events per 100 patientyears) comparedwithmethotrexatemonotherapy (1.5 eventsper100patientyears,Pvaluesnotreported).17A5-yearexten-sion trial involving 143 patients treated with tocilizumabmonotherapy (median duration of treatment 66.7 months)

Twelvepatientswerediagnosedwithsolidtumorsthatincludedprostate, bladder, pancreatic, breast, colon, and endometrialcancers.34 An evaluation of ustekinumab and cancer risk isseverelylimitedbythelackoflong-termdatainlargepopula-tions.Safetydatabeyond2yearsarenotcurrentlyavailable.

TheACCEPTtrialprovidesdataonthecomparativesafetybetween ustekinumab and etanercept; however, this triallasted only 12 weeks.20 Adverse events of any kind wereexperienced by 70.0%, 66.0%, and 69.2% of patients in theetanercept, ustekinumab 45 mg, and ustekinumab 90 mggroups, respectively, by week 12 (P values for comparisonswere not reported).20 Discontinuation due to adverse eventsoccurredin2.3%,1.9%,and1.2%ofpatientsintheetanercept,ustekinumab45mg,andustekinumab90mggroups,respec-tively.20Injectionsitereactions,predominantlymild,occurredin 24.8% of patients treated with etanercept compared with4.3%and3.7%ofpatientsintheustekinumab45mgand90mggroups,respectively.20Infectionratesweresimilarbetweengroups,occurring in29.1%,30.6%, and29.7%ofpatients intheetanercept,ustekinumab45mg,andustekinumab90mggroups,respectively.20Nocomparativedatabeyond12weekshavebeenreported.

Tocilizumab. Tocilizumab has been shown to increase theriskofneutropenia. In the24-weekRADIATEtrial, transientneutropenia (neutrophils <2,000 cells per cubic millimeter[mm3]) occurred in28.0%,20.3%, and<1.0%of patients inthetocilizumab8mgperkg,4mgperkg,andplacebogroups,respectively (Table 4).28 Four patients in the tocilizumab 8mgperkg(n=175)and1inthe4mgperkg(n=163)groups


TABle 4 Safety Warnings for Approved Autoimmune Biologics

Drug Black-Box Warnings Other Label Warnings

Adalimumab(Humira)47 Seriousinfections,malignancy HepatitisBreactivation,hematologicevents,hypersensitivity,demyelinatingsyndromes,heartfailure

Etanercept(Enbrel)46 Seriousinfections,malignancy HepatitisBreactivation,hematologicevents,demyelinatingsyndromesInfliximab(Remicade)38 Seriousinfections,malignancy,Tcelllymphoma HepatitisBreactivation,hepatotoxicity,hematologicevents,

hypersensitivity,demyelinatingsyndromes,heartfailureCertolizumab(Cimzia)48 Seriousinfections,malignancy HepatitisBreactivation,hematologicevents,hypersensitivity,

demyelinatingsyndromes,heartfailureAlefacept(Amevive)49 None Lymphopenia,seriousinfectionsAnakinra(Kineret)50 None Seriousinfections,usewithTNFantagonistsAbatacept(Orencia)53 None UsewithTNFantagonists,hypersensitivity,seriousinfections,increased

safetyriskinCOPDpatientsRituximab(Rituxan)51 Fatalinfusionreactions,tumorlysissyndrome,

severemucocutaneousreactions,progressivemultifocalleukoencephalopathy

HepatitisBreactivation,infections,cardiacarrhythmias,infusionreactions,renaldysfunction,bowelperforation

Golimumab(Simponi)52 Seriousinfections,malignancy HepatitisBreactivation,congestiveheartfailure,demyelinatingsyndromes,hematologicevents

Ustekinumab(Stelara)16 None Infections,malignancies,RPLSTocilizumab(Actemra)17 Seriousinfections Gastrointestinalperforations,neutropenia,thrombocytopenia,LFTand

lipidsincreases,hypersensitivity,demyelinatingsyndromes

COPD = chronic obstructive pulmonary disease; LFT = liver function test; RPLS = reversible posterior leukoencephalopathy syndrome; TNF =tumor necrosis factor.

http://ard.bmj.com/content/68/10/1580.full.pdf



















■■ Managed Care ConsiderationsUstekinumab and tocilizumab are new options in the treat-mentofautoinflammatorydiseasewithuniquemechanismsofaction.Theclinicaltrialdataforustekinumabincludethefirstresults from a phase 3 comparison to an active autoimmuneagent, showing superiority to etanercept for the treatment ofpsoriasis.20Tocilizumabhasdemonstratedefficacyinpatientswithaninadequateresponseto1ormoreTNFantagonists.28

Comparativeefficacytrialsandstudiesinpatientswithmulti-plepriorfailuresprovideusefuldatatocliniciansandmanagedcare decision makers. However, questions remain regarding(a)howbothagentswillbeusedinclinicalpractice,(b)short-and long-term safety, and (c) the additional valuebrought topatientsandpayers.

Long-termsafetydataaresparseforbothustekinumabandtocilizumab. There are 5-year data available for tocilizumabbutonlyfor143patients.36Safetydatabeyond2yearsofuseof ustekinumab are unknown. Biologics, like many drugs,require years of extensive use before the full adverse eventprofile isunderstood. Infliximabwasapproved in1998withfew warnings and precautions including hypersensitivity,autoimmunity,infection,andpossiblemalignancy.37Noboxedwarningswerepresentatapproval.37Theprescribinginforma-tionapproved in2009 for infliximabnow includeswarningsfor hepatotoxicity, avoidance in patients with heart failure,reactivationofhepatitisB,hematologictoxicity,andneurologicevents.38Additionally, infliximabhas black-boxwarnings for

foundseriousinfectionswerereportedin17.5%ofpatientsforarateof5.7eventsper100patientyears.36Thisrateishigherthan the 3.6 events calculated by the FDA using 6-monthclinicaltrialdata.Combinationtocilizumab8mgperkgor4mgperkgplusDMARDhadseriousinfectionratesof5.3and4.4eventsper100patientyears, respectively,comparedwith3.9eventsper100yearsintheplaceboplusDMARDgroup.17 Themostcommonseriousinfectionswerepneumonia,urinarytractinfection,andcellulitis.17Fatalinfectionswererare(0.13eventsper100patientyearsacrossallgroups).17Patientsshouldbecloselymonitoredforsignsandsymptomsofinfectionpriortoandduringtreatmentwithtocilizumab.

Malignancyisacommonconcernwithbiologicsforautoim-munedisease.AnFDAanalysisofthe6-monthtrialsoftocili-zumabreported15malignanciesinthetocilizumabgroupand8inthecontrolgroup.17Exposure-adjustedincidenceofmalig-nancywassimilarinthetocilizumabgroups(1.32eventsper100patientyears)andintheplaceboplusDMARDgroup(1.37eventsper100patientyears).17However,theriskofmalignancyiscomplicatedby the limited long-termdata for tocilizumab.A52-week study reported3malignancies in the tocilizumabgroup(2breastcancerand1coloncancer)comparedwithnomalignancies in the DMARD group.32 The 5-year extensiontrial found4malignancies (breast,bladder, colon, and intra-ductalcancers)inpatientstreatedwithtocilizumabforarateof0.7eventsper100patientyears.36


FIGuRe 3 PMPM Spending for Skin and Arthritis Medications Including Autoimmune Biologicsa

0.00

0.50

1.00

1.50

2.00

2.00

3.00

3.50

04 Q

104

Q2

04 Q

304

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Q2

06 Q

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Q4

07 Q

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07 Q

307

Q4

08 Q

108

Q2

08 Q

308

Q4

09 Q

109

Q2

09 Q

309

Q4

Tota

l Spe

ndin

g PM

PM ($

)

Calendar Quarter

aSpending is defined as allowed charge, the sum of plan and member cost, and includes ingredient cost and pharmacy dispensing fees, PMPM for pharmacy claims for approximately 8.7 million commercial plan members through 2009 Q4.43

PMPM = per member per month.


http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/inflcen082498lb.pdf











etanercept and comparable short-term safety. However, thedata are limited to 1 single-blind (investigator) trial in 903patients.18 The TNF antagonists have the advantage in yearsof experience and a well-defined safety and efficacy profile.CliniciansmaycontinueusingtheestablishedTNFantagonistsfirst,reservingustekinumabforpatientsfailingthesetherapies.Regardless,thephase3comparativetrialdataprovidevaluableinformationtodecisionmakerstryingtoevaluatetheclinicaladvantages between autoimmune biologics. For tocilizumab,theRADIATE trial andFDA indication for tocilizumabplacethistreatmentfirmlyafterTNFantagonistfailure.17,28

Autoimmunebiologicsaddressdifferentcomponentsoftheautoinflammatory disease process and frequently gain FDAindications in multiple conditions. Ustekinumab 63 mg atweeks 0 and4was comparedwithplacebo in the treatmentof psoriatic arthritis (n=146). Atweek 12, anACR 20 scorewasachievedby42%and14%ofpatientsintheustekinumab

increased risk of serious infections and for lymphoma andothermalignanciesinchildrenandadolescents.38Tocilizumabandustekinumabhaveuniquemechanismsofaction,andtheeffectsofwidespread,long-termuseareunknownatthistime.Tocilizumab’seffectsonneutrophils,platelets,andlipidlevelsareuniqueandconcerningamongsttheautoimmunebiologics,and the long-term implications areunknown.TheFDA, in areviewofustekinumab,statedthatpatientshadnotbeenfol-lowedforasufficientperiodoftime,andthattheriskofmalig-nancy should be communicated to prescribers.34 Extendedstudiesareneededtobetterdefineandunderstandthesafetyrisksofbothdrugs.

The ACCEPT trial introduces phase 3, comparative datato theautoimmunebiologics for the first timeandpresentsachallengeforhealthcareprofessionalsondefiningtheplaceintherapyofustekinumab.20Cliniciansandpatientsmaydefendustekinumabas a first-lineoptiondue to superior efficacy to


TABle 5 Cost of Autoimmune Biologics Available in 2010

Drug Maintenance Dosing in RA Costa in RA Maintenance Dosing in Psoriasis Costa in Psoriasis

Adalimumab(Humira)

40mgeveryotherweek $959.19per40mginjectionor$1,918monthly

40mgeveryotherweek $959.19per40mginjectionor$1,918monthly

Etanercept(Enbrel)

50mgweekly $498.71per50mginjectionor$1,995monthly

50mgweekly $498.71per50mginjectionor$1,995monthly

Infliximab(Remicade)

3-10mgperkgevery8weeks;maximumdose10mgperkgevery4weeks

Costfora70kgpersonrangesfrom$2,367every8weeks($1,184monthly)to$5,523every4weeksb

5mgperkgevery8weeks Costfora70kgpersonis$3,156every8weeks($1,578monthly)b

Certolizumab(Cimzia)

200mgeveryotherweek $1,841per200mgkit(2injections;1-monthsupply)

NA NA

Alefacept(Amevive)

NA NA 15mgweeklyfor12weeksc $1,190per15mginjectionor$4,760monthlyfor3months

Anakinra(Kineret)

100mgdaily $92.24per100mginjectionor$2,767monthly

NA NA

Abatacept(Orencia)

500-1,000mgevery4weeks $609.24per250mgvial(costpermonthrangesfrom$1,218to$2,437)

NA NA

Rituximab(Rituxan)

2X1,000mginfusionsevery24weeks

$3,404.50per500mgvialor$13,620perinfusionor$2,270monthly

NA NA

Golimumab(Simponi)

50mgevery4weeks $1,982.62per50mginjectionsmonthly

NA NA

Ustekinumab(Stelara)

NA NA 45or90mgevery12weeksd $5,595.60per45mgor90mginjectionor$1,865monthlye

Tocilizumab(Actemra)

4or8mgperkgevery4weeks

Costfora70kgpersonrangesfrom$1,114to$2,229permonthf

NA NA

aFor the autoimmune biologics available in the U.S. market as of May 2010. Cost is derived from the AWP in April 201055 and the maintenance dosing regimen shown in the table. The monthly cost estimates assume that a 4-week period is 1 month, and actual cost will also vary depending on discounts.bCost approximation assumes an AWP of $789 per 100 mg vial and wasting of remaining vial after use.cRegimen may be repeated for 1 more 12-week course at least 12 weeks after the initial course.dU.S. Food and Drug Administration dosing is 45 mg for patients up to 100 kg body weight and 90 mg for patients over 100 kg body weight.eUstekinumab is dosed at weeks 0 and 4 and then every 12 weeks thereafter. AWP cost for first month of therapy (doses 0 and 4 weeks) would be $11,192, no cost in month 2, and $5,596 in month 3 and every 12 weeks thereafter. Annual cost in the first year will be based on 6 doses and will therefore be higher than in subsequent years at approximately 4 doses per year.fThe tocilizumab starting dose is 4 mg per kg every 4 weeks, “followed by an increase to 8 mg per kg based on clinical response” according to the product label. Actual cost depends on body weight and will vary from $1,114 at 4 mg per kg or $2,229 at 8 mg per kg for a 70 kg person. Cost is estimated using an AWP of $79.60 per milliliter for the 20 mg per milliliter vial. Actual costs may be higher as vials are only available in 80 mg, 200 mg, and 400 mg strengths and wastage may occur.AWP = average wholesale price; kg = kilogram; mg = milligram; NA = not applicable; RA = rheumatoid arthritis.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm183851.htm





pensing of autoimmune biologics to the specified specialtypharmacy.Health plansmay also elect to place autoimmunebiologicsinaspecialtytierwithadditionalcostsharingforthemember.However, our research reportedpreviously suggeststhatpatientcopaymentsgreaterthan$100permonthforTNFblockerswereassociatedwithprescriptionabandonment.45

■■ ConclusionsUstekinumabandtocilizumabarethefirstbiologicstoinhibitIL-12/23andIL-6,respectively.Thepublicationofacompara-tivetrialandtreatmentinpatientsfailingmultipleTNFantago-nistswouldbetterdefinethevalueintroducedbyustekinumaband tocilizumab.Long-termsafetydataareneeded tounder-stand how differentmechanisms of actionmodify the safetyprofilecomparedwiththeTNFagents.Additionalstudieswillbetterdefinethesafetyrisksandestablishtheplaceintherapyfortheseagents.Costcontinuestobeaproblemfortheclassofbiologicals.Managedcaredecisionmakersshoulduseallavail-abletoolsincludingutilizationmanagementprograms,benefitdesign, and restricted distribution networks to provide themostcost-effectivepharmacybenefitmanagementforpatientsanddrugplansponsors.

andplacebogroups,respectively(P <0.001).39Tocilizumabwascompared with placebo in a double-blind, withdrawal studyin juvenile idiopathic arthritis (JIA) (n=56).40 At the end ofthewithdrawalperiod,80%and17%ofpatientstreatedwithtocilizumab8mgperkgandplacebo,respectively,maintainedan ACR 20.40 According to clinicaltrials.gov, ustekinumab isbeing studied in psoriatic arthritis and Crohn’s disease, andtocilizumabhastrialsongoingorrecruitinginJIAandRA.41,42 Cliniciansandmanagedcaredecisionmakersshouldbepre-paredforadditionaldataandexpandedusesofbothagents.

Biologic autoimmune agents used to treat RA and psoria-sis are expensive, ranging from$25,000-$50,000per yearoftherapy.AccordingtoPrimeTherapeutics’commercialbookofbusiness prescriptionmedication trend data on arthritis andskinagents,whichencompass theautoimmunebiologics, theannual growth rate in permember permonth (PMPM) costfor thiscategorywas21.1% from2007Q1 through2009Q4(Figure3).43Growthwasdrivenbyanaverageannualutiliza-tiongrowthrateof9.2%andanaverageannualpriceinflationrateof9.0%.43

Available information on the price of ustekinumab andtocilizumabindicatecomparablepricingbetweenthesethera-pies and existing autoimmune biologics (Table 5). However,administration fees, monitoring, and dose changes make anoverallcostcomparisondifficult.Ustekinumabhashighercostat the initiationof therapybecausedosesareadministeredatweeks0and4,foracombinedaveragewholesaleprice(AWP)drug cost at the current (2010) price of $11,912 in the first30days,or$16,788at16weeks.The first-yearustekinumabAWPcost is $33,576 for6doses, but the cost in subsequentyearswithdosingevery12weeksor4 timesperyearwouldbe approximately $22,384. The cost of tocilizumab dependson body weight and is dosed consistently every 4 weeks.TocilizumabAWPcostfora70kgpersonis$1,114atthedoseof4mgperkgor$2,229at8mgperkgoranannualcostthatranges from $13,368 to $26,748 if dosed 12 times per year.Managedcaredecisionmakersarechallengedtofindabalanceinproviding access tonewautoimmunebiologicals for thosewhoneedthemwhileencouragingthepreferreduseofprovencost-effectiveagentswithlong-termsafetyrecords.

Utilizationmanagementprogramsrequiringtrialandfailureofconventionalagentspriortotheuseofautoimmunebiolog-ics is one strategy. A conventional DMARD-first strategy issupportedbyananalysisbyFinckhetal.(2009)showingthatconventionalDMARDtreatmentinveryearlyRAiscosteffec-tive.44Theanalysisalso found thatautoimmunebiologicsarenotcosteffectiveas first-line therapyandshouldbe reservedforpatientsfailingconventionalDMARDs.44Selectingpreferredautoimmune biologics that cover the majority of indicationsandrequiringtrialandfailurepriortootherbiologicsisanotheroption.Pricevariabilitybetweenvendorsshouldbeminimizedby using a limited distribution channel and restricting dis-


JEREMY A. SCHAFER, PharmD, is Manager of Formulary Development; and NICOLE K. KJESBO, PharmD, BCPS, is Senior Clinical Pharmacist, Prime Therapeutics LLC, Eagan, Minnesota. PATRICK P. GLEASON, PharmD, BCPS, FCCP, is Director of Clinical Outcomes Assessment, Prime Therapeutics LLC, Eagan, Minnesota, and Adjunct Associate Professor, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.

AUTHOR CORRESPONDENCE: Jeremy A. Schafer, PharmD, Manager of Formulary Development, Prime Therapeutics, 1305 Corporate Center Dr., Eagan, MN 55121. Tel.: 612.777.5097; 612.777.5143; E-mail: [email protected].

Authors

DISCLOSURES

Therewasnoexternalfundingforthismanuscript.Theauthorsareemployeesof Prime Therapeutics, a pharmacy benefits management company whoseownership includes health plans. This manuscript was written primarilyfrom information that was prepared for and presented to a pharmacy andtherapeuticscommittee.

Schaferwasprimarilyresponsiblefortheconceptanddesignwithassis-tanceoftheother2authors.SchafercollectedthedatawithassistancefromKjesbo, andSchafer interpreted thedatawith the assistanceof theother2authors. Schafer wrote the manuscript with the assistance of the other 2authors,andSchaferandGleasonrevisedthemanuscript.

http://www.amcp.org/data/jmcp/648-658.pdf

http://www.clinicaltrials.gov/ct2/results?term=ustekinumab

http://www.clinicaltrials.gov/ct2/results?term=tocilizumab

http://www.annals.org/content/151/9/612.full.pdf+html


mailto:[email protected]



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formulary review of 2 new biologic agents: tocilizumab for

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