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Ustekinumab (STELARA) in Psoriatic ArthritisNational Drug MonographApril 2016VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist ExecutivesThe purpose of VA PBM Services drug monographs is to provide a focused drug review for making formulary decisions. Updateswill be made when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive sectionwhen the information is deemed to be no longer current.FDA Approval InformationUstekinumab is a human IgG1k monoclonal antibody that binds to the p40 subunit ofDescription/MechanismIL-12 and IL-23, thereby inhibiting their binding to receptors on T-cells, natural killerof Actioncells and antigen presenting cells. IL-23 plays a key role in stimulating production ofIL-17, a cytokine involved in immune regulation and joint injury. IL-23 alsostimulates release of IL-22, a pro-inflammatory cytokine that targets keratinocytesand has been linked to new bone formation in an animal model of enthesitis.Ustekinumab is FDA-approved for the treatment of adult patients 18 years or olderwith Moderate to severe plaque psoriasis who are candidates for phototherapy orsystemic therapy. Active psoriatic arthritis, alone or in combination with methotrexate.Treatment of adult patients (18 years or older) with active psoriatic arthritis.Indication(s) UnderUstekinumab can be used alone or in combination with methotrexate (MTX).Review in ThisDocumentInjection:Dosage Form(s) UnderReview 45 mg/0.5 mL in a single-use prefilled syringe 90 mg/mL in a single-use prefilled syringe 45 mg/0.5 mL in a single-use vial 90 mg/mL in a single-use vialREMSREMSNo REMSPostmarketing RequirementsSee Other Considerations for additional REMS informationCategory BPregnancy RatingExecutive SummaryEfficacy Safety Other Considerations Ustekinumab has a small effect size in achieving ACR20 response in patientswith psoriatic arthritis (PsA) who have received prior therapy with NSAIDs,conventional synthetic DMARDs or tumor necrosis factor inhibitors (TNFIs).Ustekinumab significantly improves function, dactylitis, enthesitis andspondylitis, and was shown to significantly inhibit radiographic progression andis therefore a DMARD, although the effect of ustekinumab on radiographicprogression in TNFI-experienced patients was not adequately studied and has notbeen established.Based on indirect comparisons, ustekinumab seems to be less likely to achieveACR20 response relative to four TNFIs (etanercept, infliximab, adalimumab andgolimumab) and secukinumab; however, ustekinumab seems to be more likely toobtain an ACR20 response than apremilast. These findings are inconclusive.Ustekinumab is one of only three or four agents shown to be efficacious fordactylitis.The safety profile of ustekinumab in PsA studies was similar to that seen inpsoriasis studies.Potential advantages of ustekinumab over TNFIs include the following:o A different mechanism of actiono Less frequent and fewer injections

Ustekinumab in Psoriatic Arthritis, MonographoooProjected Place inTherapy BackgroundPurpose for ReviewOther TherapeuticOptionsLower incidence of injection site reactions (versus etanercept)Lack of cytopeniasLack of TNFI complications or contraindications such as heart failure,demyelinating disease and lupus-like syndromeBased on the evidence from clinical trials and current practice guidelines,ustekinumab would be useful as an alternative to TNFIs when TNFIs areinappropriate in patients with active psoriatic arthritis despite treatment with atleast one csDMARD OR for switching biologic mechanism in patients withactive disease despite induction treatment with one or more TNFIs.Studies directly comparing ustekinumab with other agents are lacking.The presence of dactylitis might be a reason to use infliximab, certolizumab,ustekinumab or perhaps golimumab.High risks for infection and tuberculosis are patient factors that may influence adecision to use ustekinumab, apremilast (if there is no joint erosion) or perhapsetanercept over other biologic agents as first-line therapy in PsA.To review the comparative safety and efficacy of ustekinumab in psoriatic arthritis(PsA) to inform an update to the VA PBM-MAP-VPE criteria for use of biologicsin psoriasis and PsA. Ustekinumab currently remains nonformulary.Issues to be determined: Does ustekinumab offer efficacy or safety advantages over other drug options? Are there subgroup response predictors for efficacy or safety?Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) suchas methotrexate and leflunomide are generally considered for moderate to severePsA or as second-line therapies after nonsteroidal antiinflammatory drugs(NSAIDs) for mild PsA. Other therapeutic options at approximately the same lineof therapy as ustekinumab are shown in the tables below.Formulary AlternativesNoneOther ConsiderationsClinical GuidanceNonformulary AlternativesTumor Necrosis limumabInfliximabOther ConsiderationsEffectiveness is establishedin PsA.Administeredsubcutaneously exceptinfliximab is emilastOrally administered.Disease-modifyingcapability is uncertain.Anti-IL-17A MonoclonalAntibodySecukinumabApproved for PsA in1/2016. Administeredsubcutaneously.Inhibits radiographicprogression.1Clinical GuidanceGenerally used forinadequate responders tocsDMARDs for moderateto severe PsA or may beused first-line in severePsA; generally givenconcomitantly with acsDMARD.1PBM Criteria for Use inPsA are available.Place in therapy isunclear.PBM Criteria for Use inPsA are available.European League AgainstRheumatism (EULAR)guideline for PsA statesthat secukinumab may beconsidered in patients withperipheral arthritis and aninadequate response to atleast one csDMARD andfor whom TNFIs are2inappropriate.Updated version may be found at www.pbm.va.gov or PBM INTRAnet2

Ustekinumab in Psoriatic Arthritis, MonographEfficacy (FDA Approved Indications)Literature Search SummaryA literature search was performed on PubMed/Medline (1966 to January 2016) using the search terms ustekinumaband psoriatic arthritis. The search was limited to studies performed in humans and published in the Englishlanguage. Reference lists of review articles and the manufacturer’s AMCP dossier were searched for relevantclinical trials. All randomized controlled trials and long-term studies ( 1 year) published in peer-reviewed journalswere included. An FDA Medical Review on psoriatic arthritis trials was not available.Review of EfficacyMajor Efficacy-Safety Trials In two multicenter, double-blind, placebo-controlled Phase 3 RCTs (PSUMMIT 1 and PSUMMIT 2),ustekinumab 90 mg and 45 mg were significantly better than placebo in achieving at least 20% improvement inAmerican College of Rheumatology scores (ACR20). Results were consistent across the trials.o In PSUMMIT 1 (N 615, mean age 48 years, 53.6% men, 4 years with PsA, 13 years withpsoriasis), patients had active PsA despite 4 weeks of NSAID therapy or 3 months of csDMARDtherapy (without TNFI). About half (48.1%) of the patients were taking methotrexate (mean, 16mg/week). ACR20 responder rates at Week 24 were 50%, 42% and 23% for ustekinumab 90 mg, 45mg and placebo, respectively.3 NNTs were 4 and 6 for the 90-mg and 45-mg dose, reflecting small tonear-moderate effect sizes.4 Response rates showed significant treatment differences versus placebostarting at Week 8, peaked at Week 28 and were maintained at Week 52. ACR20 response was similarbetween subgroups who did and did not receive concomitant methotrexate therapy (44.5% and 47.4%,respectively, for ustekinumab (pooled 90 mg and 45 mg) versus 26.0% and 20.0%, respectively, forplacebo.6o In PSUMMIT 2 (N 312, mean age 48 years, 52.6% men, 5 years with PsA, 12 years withpsoriasis), patients had active PsA despite use of either csDMARDs or 8 weeks of TNFI therapy(except 14 weeks for infliximab) or shorter periods in case of intolerance. About half (49.7%) of thepatients were taking methotrexate (mean, 17 mg/week). Of the planned 300 randomized patients, 150to 180 (50% to 60%) were required to have prior TNFI treatment regardless of the reason therapy wasdiscontinued. ACR20 responder rates at Week 24 were 44%, 44% and 20% for ustekinumab 90 mg, 45mg and placebo, respectively.5 NNT was 5 (small effect size) for both the 90-mg and 45-mg doses.4ACR20 responder rates in the subgroup of patients who previously used TNFIs were 36% forustekinumab (pooled 90 mg and 45 mg) and 15% for placebo (p 0011).6o Statistically significant and clinically relevant improvement in function (Health AssessmentQuestionnaire-Disability Index [HAQ-DI] increase of at least 0.3) occurred in 48%, 48% and 28% ofthe 90-mg, 45-mg and placebo groups at Week 24 of PSUMMIT 1. HAQ-DI change was –0.25, –0.25and 0.00 in the 90-mg, 45-mg and placebo groups, respectively, in PSUMMIT 1, and thecorresponding values were –0.25, –0.13 and 0.00 in PSUMMIT 2.o Ustekinumab significantly improved psoriasis in both PSUMMIT trials, showing a large effect size.NNTs for 75% improvement in Psoriasis Area and Severity Index (PASI75) relative to placebo were1.9–2.0 and 2.0–2.2 for 90 mg and 45 mg, respectively, in PSUMMIT 1 and PSUMMIT 2.4o In PSUMMIT 1, ustekinumab (pooled 90 mg and 45 mg), as compared with placebo, resulted in asignificantly lower percentage of patients with residual dactylitis (56.2% and 76.1%; p 0.0013) andenthesitis (64.6% and 81.0%; p 0.0006) at Week 24. Dactylitis and enthesitis scores also showedsignificantly greater improvements from baseline with ustekinumab than placebo. In the 2-year studydata, the median percent improvement in dactylitis and enthesitis was 100% at Week 100. 7o Ustekinumab therapy also showed significant benefit in terms of exploratory axial disease /“spondylitis” outcome measures at Week 24. In PSUMMIT 1, a significantly greater percentage ofpatients with axial and peripheral PsA on ustekinumab (pooled 45 and 90 mg) than patients on placebo(27.9% vs. 13.1%; p 0.0232) achieved at least 50 percent reduction on the Bath ankylosingspondylitis disease activity index (BASDAI50). Significant differences were also found for BASDAI20 and 70. Improvement was maintained at Week 100.8 In PSUMMIT 2, BASDAI50 responder rateswere also significantly greater with ustekinumab (pooled 45 mg and 90 mg) than placebo (32.6% vs.Updated version may be found at www.pbm.va.gov or PBM INTRAnet3