UTAH MEDICAID DUR REPORT FEBRUARY 2019

BRODALUMAB AND FOR THE TREATMENT OF MODERATE TO SEVERE PLAQUE

Brodalumab (Siliq) Guselkumab (Tremfya)

Report finalized: January 2019

Drug Regimen Review Center

Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Jacob Crook, MStat, Data and Statistical Analyst Joanne LaFleur, PharmD, MSPH, Associate Professor

University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2019 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

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Contents

Introduction ...... 2 Table 1. FDA-Approved Antagonists for Moderate to Severe Plaque Psoriasis .. 2 Methods ...... 2 Disease Overview ...... 3 Table 2. Examples of Psoriasis Severity Assessment Tools ...... 4 Table 3. Proposed Definitions for Psoriasis Severity and Treatment Options in Plaque Psoriasis...... 5 Treatment Strategies and Guideline Recommendations ...... 6 Table 4. Available Treatment Options for the Management of Psoriasis ...... 7 Table 5. Clinical Guideline Recommendations for the Treatment of Psoriasis ...... 8 Table 6. American Academy of Dermatology Algorithms for the Treatment of Plaque Psoriasis Without Psoriatic Arthritis ...... 9 Brodalumab and Guselkumab for Moderate to Severe Plaque Psoriasis ...... 10 Table 7. Prescribing Information for Brodalumab and Guselkumab ...... 10 Safety ...... 10 Table 8. Adverse Reactions, Warnings, and Contraindications for Brodalumab and Guselkumab ...... 11 Evidence ...... 12 Utah Medicaid Utilization Data ...... 15 Discussion Topics and Potential Prior Authorization Criteria ...... 16 Summary ...... 18 References ...... 19 Appendix A: Literature Search Strategies ...... 22 Appendix B: Key Findings in Published Clinical Trials ...... 23

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Introduction

Brodalumab and guselkumab are interleukin antagonist agents approved in 2017 by the U.S. Food and Drug Administration (FDA) for the “treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.”1,2 In addition, the labeled indication of brodalumab limits the use of this agent to patients who “have failed to respond or have lost response to other systemic therapies.”1

Both agents are monoclonal antibodies produced by recombinant DNA technology and are available as injectable formulations for subcutaneous administration.1,2 Brodalumab and guselkumab target cytokines, particularly , which play an important role in the development of psoriasis.3 Other interleukin antagonist agents are currently approved in the United States (US) for the same indication as brodalumab and guselkumab. Table 1 includes FDA-approved interleukin antagonists for the management of moderate to severe psoriasis.

Table 1. FDA-Approved Interleukin Antagonists for Moderate to Severe Plaque Psoriasis Agent (Brand name) FDA Approval Date MoA (Stelara)4 September 2009 IL-12 and IL-23 inhibitor (Cosentyx)5 January 2015 IL-17A inhibitor (Talzt)6 March 2016 IL-17A inhibitor Brodalumab (Siliq)1 February 2017 IL-17 receptor A inhibitor Guselkumab (Tremfya)2 July 2017 IL-23 inhibitor -asmn (Ilumya)7 March 2018 IL-23 inhibitor Abbreviations: FDA, Food and Drug Administration; IL, interleukin; MoA, mechanism of action

Among the interleukin antagonists included in Table 1, tildrakizumab-asmn (Ilumya) is the only agent with Utah Medicaid prior authorization criteria in place.8 The purpose of this review is to provide evidence to assist the Medicaid Drug Utilization Review (DUR) Board in assuring appropriate use of brodalumab and guselkumab in patient populations most likely to benefit. Methods

A literature search for systematic reviews addressing the efficacy and safety of brodalumab and guselkumab was conducted in the Cochrane Library and Ovid Medline. References of relevant search results were screened. Search strategies are provided in Appendix A.

Information concerning product labeling and FDA clinical review documents was obtained from the FDA website. Additional information was found in Micromedex, Lexicomp, Up To Date, and the National Psoriasis Foundation (NPF). Treatment guidelines for the management of psoriasis were identified by searching the American Academy of Dermatology (AAD) and the National Institute for Health and Care Excellence (NICE) websites, and checking the reference lists of relevant systematic reviews.

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Disease Overview Psoriasis is a chronic, immune-mediated, inflammatory disease primarily characterized by skin and joint symptoms.9 Typical skin manifestations include “scaly, erythematous patches, papules, and plaques” that may cause pain, itch, burning sensation, and bleeding.9-11 These signs mainly appear on the scalp, trunk, buttocks, elbows, and knees.9 Psoriasis can cause visible disfiguration that usually affects the patient’s psychological quality of life.9,10 Epidemiology, Risk Factors, and Co-morbidities The National Psoriasis Foundation (NPF) estimates that approximately 2% of Americans live with psoriasis and 10 to 30% of people with psoriasis also experience psoriatic arthritis.10,12 Psoriasis is more common in adults compared to children.13,14 The exact cause of psoriasis is unknown; however, , genetic, and environmental factors play an important role in the development of psoriasis.9,15 T helper cells (eg, IL-17A-secreting T helper cell) have been associated with psoriatic skin inflammation because they release cytokines that cause skin cell growth and redness due to angiogenesis in the psoriatic plaque.16,17 A family history of psoriasis has been identified in approximately 40% of people with psoriasis and psoriatic arthritis.14 Many immune-related genes have been strongly associated with psoriasis.9 Of them, PSORS1, a psoriasis-susceptibility locus on chromosome 6p21, is considered the major genetic risk factor for early-onset psoriasis.9,14 Other triggering factors associated with the development or exacerbation of psoriasis include trauma, obesity, infection (eg, Streptococcal infections), stress, (eg, beta-blockers, lithium, and some antibiotics), smoking, and alcohol consumption.11 Medical comorbidities commonly occurring in patients with psoriasis may include psoriatic arthritis, cardiovascular disease, metabolic syndrome, depression, anxiety, suicide, obesity, and inflammatory bowel syndrome.9,11 Classification of Psoriasis Psoriasis can be classified in different categories based on morphologic descriptions.9 However, based on clinical findings, patients can fall into more than 1 category.9 These major morphological categories include: 1) plaque psoriasis (also called psoriasis vulgaris), 2) inverse psoriasis (ie, intertriginous/flexural psoriasis), 3) erythrodermic psoriasis, 4) pustular psoriasis (eg, palmoplantar pustulosis and generalized pustular psoriasis), 5) guttate psoriasis, 6) nail psoriasis, and 7) psoriatic arthritis.9,11 Plaque psoriasis is the most common type of psoriasis, accounting for approximately 80% to 90% of cases.9,10 It is characterized by “monomorphic, sharply demarcated erythematous plaques covered by silvery lamellar scales” that can affect small parts of the body, large parts of the body, or the entire body surface (also called erythroderma, a potentially life-threatening complication of psoriasis).10 Frequent locations of plaque psoriasis are knee, elbows, scalp, peri-umbilical, perianal, and retro-auricular regions.10 The scalp is generally affected in 75 to 90% of the patients.10 Diagnosis Diagnosis of psoriasis is usually based on family history and physical examination of several body regions such as scalp, nails, and anogenital region.10,11,14 In addition, patient’s new and infections should be evaluated for a potential contribution to psoriasis.10,14 Skin biopsy is rarely performed.10 Psoriasis Severity Severity of the psoriasis and efficacy of psoriasis treatment can be assessed with different tools such as the Psoriasis Area and Severity Index (PASI).9 PASI evaluates the severity (thickness, redness, and scaling) 3

of skin lesions and extent of body surface area (BSA) affected.18 PASI is frequently used in clinical trials; however, it is rarely utilized in clinical practice.9 The percentage of BSA involved and Physician’s global assessment (PGA) are other frequently utilized assessment tools to evaluate psoriasis severity.9 PGA is an easier-to-use tool developed for clinical practice.9-11 Impact of psoriasis on quality of life can be measured with several instruments such as the Short-Form 36 Health Survey (SF-36), Psoriasis Quality of Life (PQOL), or Dermatology Life Quality Index (DLQI).9,19 Table 2 includes further information regarding some of the psoriasis severity assessment tools.

Table 2. Examples of Psoriasis Severity Assessment Tools11,18,20 PASI11,18,20 IGA18,20 DLQI18,20 • Severity signs of psoriatic lesions, including (1) Severity signs of psoriatic • 10 questions associated with thickness, (2) redness, and (3) scaling are lesions (thickness, the impact of skin disorders on evaluated in 4 body regions: the head, trunk, redness, and scaling) are daily life during the prior week and upper and lower extremities. Scores for rated by the investigator are responded by the patient each sign in each body part range from 0 at a specific time point on • Questions include “symptoms (none) to 4 (very severe) a scale of 0-4 : and feelings, daily activities, • PASI score is the sum of the 3 signs’ scores for • 0: cleared leisure, work or school each body part multiplied by the proportion • 1: minimal performance, personal of BSA involved and BSA involvement score • 2: mild relationships, and treatment”20 • Total score ranges from 0 to 72 • 3: moderate • Score ranges from 0 to 30 • 4: severe Abbreviations: BSA, body surface area; DLQI, Dermatology Life Quality Index; IGA, Investigator Global Assessment; PASI, Psoriasis Area and Severity Index

According to the severity of disease, psoriasis is commonly classified into 3 categories as mild, moderate, and severe or into 2 categories (for treatment purposes) as mild psoriasis (“limited disease” that is managed with topical therapies) and moderate to severe psoriasis (“extensive disease” that is managed with phototherapy or systemic therapy).15,21,22 Disease classification by severity is challenging due to the variety of objective features that should be considered (eg, severity of lesions, areas affected, extension of the area affected, and symptoms) and the subjective impact of psoriasis in each person.11,23 Specific definitions of disease severity vary in the literature; there are no formal definitions.23-25 Clinicians should evaluate psoriatic patients individually.25 The Medical Advisory Board of the NPF and the American Academy of Dermatology (AAD) propose definitions for the 3 disease categories based on the affected BSA, location of areas involved, and impact on quality of life.23,26 The NPF does not support the use of BSA alone to evaluate the severity of psoriasis because there may be patients with small BSA affected who have severe psoriasis or patients with large BSA affected who have mild psoriasis.23 Both the NPF and the AAD are currently developing new treatment guidelines for psoriasis;25 these guidelines are expected to be released by the first quarter of 2019.27 Table 3 includes definitions for mild, moderate, and severe psoriasis proposed by the NPF, the AAD, a European consensus, and the North American Psoriasis Guidelines. In addition, treatment options for each disease state are included. In clinical trials, psoriasis classification criteria are usually very rigid (including numerical cutoff values) and less subjective than in clinical practice.18 For example, severe psoriasis has been defined in clinical trials as a PASI score ≥12 and BSA ≥10.25 However, these criteria are often not feasible in clinical practice because they do not represent patients’ real burden of psoriasis.18,21 PASI is difficult to use and therefore, is rarely used in clinical practice.25 BSA, location and thickness of lesions, symptoms, and quality of life are often considered in the clinical setting.9,11

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Table 3. Proposed Definitions for Psoriasis Severity and Treatment Options in Plaque Psoriasis Definitions by a Disease Definitions by the Definitions by the North American Definitions by the NPF23 European Treatment Options9 Severity AAD26 Psoriasis Guideline18a Consensus28 BSA ≤10 and PASI Topicals (as monotherapy - QoL is not altered ≤10 and DLQI ≤10 - Minimal impact on the or in combination)26 - Patient may not require BSA <5% (usually Mild (If DLQI >10, patient’s QoL treatment not affecting the plaque psoriasis can be - Symptomatic control by If patients do not respond - Treatment has no known face, hands, psoriasis considered as routine skin care measures to topical therapy, serious risks to patients genitals, or feet) moderate to and/or topical therapy phototherapy or systemic - Affected BSA is generally <5% severe) agents may be needed29 - QoL is altered - QoL is significantly altered BSA: 5%-<10% or - Patient expects that treatment because of the extent of the involvement of will improve quality of life disease, physical distress, or Moderate small crucial areas - Affected BSA: 2 to 20% location (eg, face, hands, feet, plaque (eg, hands, feet, - Treatment options have low or genitals) psoriasis face, or genitals), risks; however, they may be - Disease is not controlled to an which may reduce - Topical agents as inconvenient, expensive, and acceptable degree by routine quality of life adjunct therapy time-consuming skin care measures - Phototherapy (eg, - QoL is altered BSA >10 or PASI >10 narrow-band UVB) - Affected BSA is generally >10% and DLQI >10 - Photochemotherapy - Disease does not respond to (If DLQI <10, with PUVA treatment with low risks BSA ≥10% or psoriasis can be - Traditional systemic - Patients are willing to accept involvement of considered as mild) - Severe reduction of the agents (Oral) Severe more aggressive therapies to small crucial areas patients QoL - Biologic agents plaque improve the disease (eg, hands, feet, - Disease is not satisfactorily (Injectable) psoriasis - Other factors to consider: face, or genitals), controlled by topical therapy disease location (face, feet, which may reduce hands, etc.), symptoms (pain, quality of life intense itching, bleeding, etc.), or presence of arthralgias/arthritis Abbreviations: AAD, American Academy of Dermatology; AE, adverse events; BSA, body surface area; DLQI, dermatology life quality index; NPF, National Psoriasis Foundation; PASI, psoriasis area and severity index; PUVA, psoralen plus UVA; QoL, quality of life; UVA, ultraviolet A; UVB, ultraviolet B a Canadian Guidelines updated by the NPF

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Treatment Strategies and Guideline Recommendations

Psoriasis is a chronic disease with no cure; however, several treatment strategies are available for the management of psoriasis.10 Selection of agents for the treatment of psoriasis should be individualized based on disease type, extent of lesions, response to prior treatments, quality of life concerns, side effects, patient preferences, and comorbidities (eg, cardiovascular disease, metabolic syndrome, and psychological or psychiatric disorders).9,10,26 According to the AAD guidelines on psoriasis, mild disease or “limited disease” should be treated with topical medications.26,30 The most commonly used are topical corticosteroids.11,30 Approximately 70% to 80% of patients experience mild to moderate psoriasis and are adequately treated with topical medication.10,30 Moderate to severe disease or “extensive disease” should be managed with phototherapy (ie, use of ultraviolet radiation) and/or systemic agents (traditional oral systemic agents or biologic agents).26 Topical products can additionally be used in combination with phototherapy and systemic agents in patients with moderate to severe disease.11,31 Systemic agents have positive results in psoriasis; however, treatment effect may decrease over time and many patients with severe and unremitting psoriasis typically require switching to another systemic agent.32 The 2011 AAD guideline on psoriasis (section 6) does not provide a preference for one systemic agent over another.26 Traditional or biologic agents for patients with moderate to severe psoriasis are listed as first-line options when phototherapy is not available.26 This guideline states that “biological agents are now routinely used when one or more traditional systemic agents fail to produce an adequate response, are not tolerated because of adverse effects, or are unsuitable because of the presence of comorbidities.”26 The NPF highlights that biologic agents are usually prescribed in patients with moderate to severe psoriasis who do not respond to other treatments.33 Table 4 describes treatment options for the management of psoriasis. Table 5 and Table 6 summarize guideline recommendations for the management of psoriasis. “Treat to Target” Strategy In 2017, specific treatment goals to promote patient care in psoriasis were published by the NPF’s Medical Board, which is composed of 25 experts in the management of psoriasis disease.34 These treatment goals, also known as “Treat to Target”, define time points at which specific treatment benefits should be achieved.34 Although scores on multiple clinical measures (eg, BSA, PASI, PGA, and DLQI) have been considered to evaluate treatment success or failure in countries outside the US, the percentage of BSA affected was the most preferred psoriasis assessment for clinicians and patients in the United States.34 An affected BSA of 1% is equivalent to the entire patient´s hand (the palm, fingers, and thumb together).31 The following treatment goals that should be achieved in patients with psoriasis were agreed by consensus based on BSA affected34: 1. At month 3 following treatment (initial evaluation), BSA equal or less than 1% was considered the target response. An acceptable response was considered as an affected BSA of 3% or less or a 75% or greater improvement from baseline in the BSA at month 334 2. At month 6 after treatment (maintenance evaluation), BSA equal or less than 1% was considered as the target response34 However, these definitions of treatment success have some limitations such as the exclusion of patients’ quality of life considerations or other assessment tools (eg, PASI and PGA) to evaluate psoriasis improvement.34

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Table 4. Available Treatment Options for the Management of Psoriasis Treatment Treatment Class Agents31,35,36 Advantages9,11,36 Disadvantages9,11,32,36 - Anthralin - Reduced adverse - Strength lower than - Vitamin D derivatives: events systemic therapies calcipotriene, calcipotriene and - Lower cost - Slow absorption betamethasone, calcitriol - Non-invasive - Time consuming Topicals - Vitamin A derivatives: tazarotene medication - Inconvenience - Topical steroids - Poor adherence - OTC products containing salicylic acid and coal tar. Moisturizers, bath solutions, keratolytics, etc. - Effective in extensive - For short-term control disease of the disease Phototherapy (eg, narrow-band UVB) - Lower long-term - Time consuming (2-3 photocarcinogenic times weekly visits) risk than PUVA - Effective in extensive - For short-term control Phototherapy disease (slightly more of the disease effective than UVB), - Time consuming (2-3 Photo- with PUVA but it is rarely used times weekly visits) - Increased skin cancer risk with long-term use - Accelerate photoaging - Traditional systemic medications: - Effective for - More AEs than topicals Acitretin, apremilast, moderate to severe - Organ toxic effects and cyclosporine, methotrexate patients drug-drug interactions Systemic Oral - Systemic steroids Therapies - Off-label systemic agents: Hydrea (hydroxyurea), isotretinoin, mycophenolate mofetil, sulfasalazine, 6-thioguanine - TNF-alpha inhibitors: - Effective for - More AEs than topicals , etanercept, moderate to severe (eg, risk of serious , patients infections such as TB, Biologics - IL-12/23 inhibitors: ustekinumab - No cumulative organ neutropenia, (Injectable - IL-17 inhibitors: secukinumab, toxicity exacerbation of Crohn’s formulations) brodalumab, ixekizumab disease - IL-23 inhibitors: guselkumab, - Expensive tildrakizumab-asmn Abbreviations: AE, adverse events; IL, interleukin; MoA, mechanism of action; OTC, over-the-counter; PDE4, phosphodiesterase 4; PUVA, ultraviolet A plus psoralen; TB, tuberculosis; TNF, tumor necrosis factor; UVB, ultraviolet B

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Table 5. Clinical Guideline Recommendations for the Treatment of Psoriasis Guideline; Sponsoring Recommendation Organization, Year Management of mild psoriasis: - Topicals (as monotherapy or in combination) Management of moderate to severe psoriasis: Guidelines of care for the - Topical agents as adjunct therapy management of psoriasis - Phototherapy (eg, narrow-band UVB) and psoriatic arthritis: - Photochemotherapy with PUVA section 1, 3, 4, 5, and 6; - Traditional systemic agents (Oral): ciclosporin, methotrexate, and acitretin AAD, 2008-20119,26,30,37,38 - Biologic agents (Injectable): TNF inhibitors, interleukin antagonists, biologic agents targeting T cells, combination therapy * See Table 6 for further information concerning AAD recommendations in different subpopulations - First-line therapy: topical therapies Psoriasis: assessment and - Second-line therapy: phototherapy (UVB and PUVA) and systemic non- management; NICE, 2012 biological agents (eg, cyclosporine, methotrexate, and acitretin) (revised in June 2017)39 - Third-line therapy: systemic biological therapies (TNF antagonists and monoclonal antibodies that block interleukins) Management of mild psoriasis: - Topical agents (eg, corticosteroids-most widely used, vitamin D3 analogues, retinoids, anthralin and tars, combination therapy of topical agents) Management of moderate to severe psoriasis: North American Psoriasis - Topical agents as adjuvants Guidelines: National - Phototherapy and photochemotherapy Psoriasis Foundation Update - Systemic therapy with traditional and biologic agents. of Canadian Traditional systemic agents (eg, cyclosporine, methotrexate, and Guidelines for the o acitretin) “remain mainstays of treatment for plaque psoriasis”; Management of Plaque however, their safety profile limits their use Psoriasis; NPF, 201218 o Biologic agents (eg, TNF inhibitors, interleukin antagonists, biologic agents targeting T cells) are available for psoriasis. They are not associated with organ toxicity as the traditional agent. “There is no clinical reason, therefore, to reserve the biologics for second-line use” Abbreviations: AAD, America Academy of Dermatology; NICE, National Institute for Health and Care Excellence; NPF, National Psoriasis Foundation; PUVA, ultraviolet A plus psoralen; UVB, ultraviolet B

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Table 6. American Academy of Dermatology Algorithms for the Treatment of Plaque Psoriasis Without Psoriatic Arthritis26 Healthy adult males with chronic Women of childbearing potential Women trying to conceive Pediatric patients (<18 Population plaque psoriasis using appropriate contraception with chronic plaque years) with chronic plaque psoriasis psoriasis Treatment options for First line: topical First line: topical limited disease (mild First line: topical treatment First line: topical treatment treatment treatment disease: BSA <5%)30 Topical treatment as monotherapy Topical treatment as monotherapy Topical treatment as Topical treatment as for extensive disease is not usually for extensive disease is not usually monotherapy for extensive monotherapy for recommended30 recommended30 disease is not usually extensive disease is recommended30 not usually First line options if UV is available: First line options if UV is available: recommended30 - UVB Phototherapy (NB or BB) - UVB Phototherapy (NB or BB) First line options if UV is Alone Alone available: First line options if UV - UVB Phototherapy + Acitretin - UVB + Isotretinoin - Topical is available: - PUVA - UVB + MTX calcipotriene/calcitriol - UVB - UVB Phototherapy + MTX First line options if UV is - Topical corticosteroids Phototherapy (NB First line options if UV is unavailable: unavailable: traditional systemic - UVB Phototherapy or BB) as traditional or biologic systemic agents, PUVA, or biologics: (NB or BB) monotherapy Treatment options for agents: - Adalimumab First line options if UV is - UVB extensive disease - Acitretin - Alefacept unavailable: traditional Phototherapy + (moderate to severe - Adalimumab - Cyclosporine systemic agents, PUVA, or MTX disease: BSA ≥5%)26 - Alefacept - Etanercept biologics: First line options if UV - Cyclosporine - Infliximab - Adalimumab is unavailable: - Etanercept - Methotrexate - Alefacept traditional systemic - Infliximab - PUVA - Cyclosporine agents, PUVA, or - Methotrexate - Ustekinumab - Etanercept biologics: - Ustekinumab Second line options: combinations - Infliximab - Adalimumab Second line options: combinations of of agents - PUVA - Cyclosporine agents - Biologic + UVB - Ustekinumab - Etanercept - Acitretin + Biologic - Isotretinoin + Biologic - Infliximab - CsA + Biologic - MTX + Biologic - Methotrexate - CsA + MTX - MTX + CsA - PUVA - MTX + Biologic - UVB + Biologic Abbreviations: BB, broadband; BSA, body surface area; CsA, cyclosporine; MTX, methotrexate; NB, narrowband; PsA, psoriatic arthritis; PUVA, ultraviolet A plus psoralen; UV, ultraviolet; UVB, ultraviolet B

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Brodalumab and Guselkumab for Moderate to Severe Plaque Psoriasis Interleukins (ILs) are a group of cytokines that play an important role in the inflammatory and immune response processes in psoriasis. ILs are known to be elevated in psoriasis. Brodalumab and guselkumab are human immunoglobulin G monoclonal antibodies that inhibit interleukin pathway.3 Brodalumab binds to the IL-17 receptor inhibiting its interaction with several types of interleukins.1 Guselkumab binds to the p19 subunit of IL-23 inhibiting the interaction of IL-23 with its receptor.1,2 The ultimate effect is the blockage of cytokine-induced responses such as the release of inflammatory cytokines and chemokines.1-3

Information from the FDA-approved brodalumab and guselkumab labels is summarized in Table 7.

Table 7. Prescribing Information for Brodalumab and Guselkumab Generic Name Preparations & & Description Administration MoA Indication & Dosage Brand Name Route (Approval Date)

Brodalumab Human 210 mg/1.5 mL IL-17 Treatment of moderate to severe plaque monoclonal solution in a receptor A psoriasis in adult patients who are IgG2κ single-dose antagonist candidates for systemic therapy or antibody prefilled syringe phototherapy and have failed to respond expressed in a or have lost response to other systemic Siliq1 CHO cell line therapies SC injection (February 2017) - Administer 210 mg at weeks 0, 1, and 2, then every 2 weeks thereafter

Guselkumab Human 100 mg/mL IL-23 Treatment of moderate-to-severe plaque monoclonal solution in a antagonist psoriasis in adult patients who are IgG1λ single-dose candidates for systemic therapy or antibody prefilled syringe phototherapy 2 Tremfya produced in a - Administer 100 mg at week 0, and 4, (July 2017) mammalian SC injection then every 8 weeks thereafter cell line Abbreviations: CHO, Chinese Hamster Ovary; IgG, immunoglobulin G; IL, interleukin; MoA, mechanism of action; SC, subcutaneous

Safety Brodalumab carries a black box warning concerning the risk of suicidal ideation and behavior with the use of this agent. Four completed suicides were reported in psoriasis clinical trials with brodalumab.32 This medicine is only available through the Siliq Risk Evaluation and Mitigation Strategy (REMS) program.1,32 REMS requirements include the following: a) prescribers must become certified with the program via the siliqrems.com website, b) patients must sign a Patient-Prescriber Agreement Form which informs the patient of the black box warning and collects their attestation for steps they agree to take if they experience signs of the adverse effect, and 3) dispensing pharmacies must be certified with the program in order to dispense the medication to patients.1,32,40

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No black box warning or REMS is applied for guselkumab prescribing.2

Brodalumab and guselkumab may increase the risk of infections and patients should be evaluated for tuberculosis (TB) infection before initiating treatment with these agents.1,2,32 Live vaccines should be avoided in patients receiving either agent.1,2,32 In addition, brodalumab may increase the risk of developing Crohn’s disease and it is contraindicated in patients with Crohn’s disease.1

The most common adverse events with brodalumab include joint and muscle pain, headache, fatigue, diarrhea, oropharyngeal pain, nausea, injection site reactions, influenza, neutropenia and tinea infections.1 With guselkumab, the most common adverse events were upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections.2 The development of antibodies against brodalumab and guselkumab has been reported in a low number of patients.1,2 None of the antibodies against brodalumab were classified as neutralizing antibodies.1 With guselkumab therapy, some patients developed neutralizing antibodies and one patient experienced loss of efficacy after the formation of antibodies against guselkumab.2 Table 8 includes warnings, contraindications, and common adverse events.

Table 8. Adverse Reactions, Warnings, and Contraindications for Brodalumab and Guselkumab Generic Name & Warnings Contraindications Common Adverse Reactions Brand Name Black box warning: Crohn’s disease Serious adverse reactions: Brodalumab Suicidal ideation/behavior and - Suicidal ideation

completed suicides have been - Infections

reported - Crohn’s disease

Other warnings: Common adverse reactions

- Increased risk for infections. (frequency ≥1%): arthralgia (4.7%), Siliq1 Serious infections have occurred headache (4.3%), fatigue (2.6%), - TB: Do not use in patients with diarrhea (2.2%), oropharyngeal pain active TB (Evaluate patients for (2.1%), nausea (1.9%), myalgia TB infection before starting Siliq) (1.7%), injection site reactions - Crohn’s disease may occur (1.5%), influenza (1.3%), neutropenia during treatment (1%), and tinea infections (1%) - Immunizations: Do not use live Immunogenicity: antibody vaccines with Siliq development to brodalumab (3%) No black box warning Common adverse reactions Guselkumab No labeled Other warnings: (frequency ≥1%): upper respiratory contraindications - Increased risk for infections infections (14.3%), headache (4.6%),

- TB: Do not use in patients with injection site reactions (4.5%),

active TB. Evaluate patients for increased liver enzymes (3%), Tremfya2 TB infection before starting arthralgia (2.7%), diarrhea (1.6%), Tremfya. Monitor patients for TB gastroenteritis (1.3%), tinea signs and symptoms during and infections (1.1%), and herpes after treatment simplex infections (1.1%) - Immunizations: Do not use live Immunogenicity: antibody vaccines with Tremfya development to guselkumab (6%) Abbreviations: IL, interleukin; MoA, mechanism of action; SC, subcutaneous; TB, tuberculosis

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Clinical Trial Evidence

Appendix B outlines the efficacy results from clinical trials evaluating brodalumab and guselkumab agents. A. Brodalumab Pivotal Clinical Trials

The efficacy of brodalumab has been demonstrated in 3 multicenter, phase III randomized controlled trials (RCTs) (AMAGINE-1, AMAGINE-2, and AMAGINE-3) including adult patients with moderate to severe plaque psoriasis.1,32 AMAGINE-1 compared brodalumab (BRO) 140 mg and BRO 210 mg at weeks 0, 1, and 2, then every 2 weeks versus placebo. AMAGINE-2 and AMAGINE-3 included 4 arms: BRO 210 mg at weeks 0, 1, and 2, then every 2 weeks, BRO 140 mg at weeks 0, 1, and 2, then every 2 weeks, ustekinumab (USTE) 45 mg or 90 mg depending on the weight (at weeks 0, 4, and 16, then every 12 weeks), and placebo.32 The following criteria were required for patients to enter these trials32:

1. Patients ≥ 18 years old1; AND 2. “Patients with at least a 6-month history of moderate to severe plaque psoriasis, defined as a) minimum affected body surface area (BSA) of 10%, b) a Psoriasis Area and Severity Index (PASI) score ≥12, and c) a static Physician’s Global Assessment (sPGA) score ≥3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 5”1; AND 3. Patients were eligible for systemic therapy or phototherapy1

Regarding baseline demographic and disease characteristics, mean age was 45 years old, median baseline PASI score was 17.4 (ranges of 12 to 72), and median baseline BSA was 21% (ranges of 10 to 97%).32 The percentage of patients with baseline sPGA scores of 3 (moderate), 4 (severe), and 5 (very severe) was 58%, 37%, and 5%, respectively.32 Around 30% of patients had been previously treated with a biologic therapy and 12% had failed prior biologic therapy.1,32

Two co-primary efficacy endpoints for the comparison of brodalumab vs. placebo were evaluated in all 3 trials32:

1. Change from baseline to week 12 in the percentage of patients achieving at least 75% improvement in the PASI score (PASI 75)1 2. Change from baseline to week 12 in the percentage of patients with an “sPGA score of 0 (clear) or 1 (almost clear) and at least 2-point improvement from baseline”1

In addition, AMAGINE-2 and AMAGINE-3 trials evaluated the change from baseline to week 12 in the PASI 100 (ie, percentage of patients achieving 100% improvement in the PASI score) as the primary endpoint for the comparison of BRO vs. USTE.1,32

Efficacy results from phase III RCTs of brodalumab for moderate to severe plaque psoriasis are summarized as follows32:

1. AMAGINE-1 results

• Co-primary endpoints (PASI 75 and sPGA success) showed significant differences for both doses of BRO compared to placebo at week 12 (PASI 75 responders: 83%, 60%, and 3% for

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BRO 210 mg, BRO 140 mg, and placebo, respectively; sPGA 0 to 1 responders: 76%, 54%, and 1% for BRO 210 mg, BRO 140 mg, and placebo, respectively)

• Statistically significant results were reported in favor of BRO 210 mg (FDA-approved dose) regarding health-related quality of life improvements at week 12

• Results at week 52 showed maintenance of effect in terms of PASI 75 and percentage of patients achieving sPGA of 0 or 1 with brodalumab 210 mg

2. AMAGINE-2 and AMAGINE-3 results

• BRO 210 mg was superior to placebo at week 12 for the 2 co-primary endpoints (PASI 75 and sPGA success)

• BRO 210 mg was superior to USTE for the primary endpoint of PASI 100 at week 12.32 Quality of life seemed improved at week 12; however, statistical significance was not evaluated

• Maintenance of sPGA response and quality of life improvements was observed at week 52; however, statistical significance was not evaluated 32

The following results were reported at week 12 for each trial regarding PASI 75, PASI 100, and sPGA success32:

AMAGINE-2:

• Around 86% of patients in the BRO 210 mg arm and 70% of patients in the USTE arm achieved PASI 75 compared to 8% in the placebo group32

• PASI 100 was achieved in 44%, 22%, and 1% of patients in the BRO 210 mg, USTE, and placebo groups, respectively1,32

• The percentage of patients with sPGA of 0 or 1 was 79%, 61%, and 4% in the BRO 210 mg, USTE, and placebo groups, respectively1,32

AMAGINE-3:

• Around 85% in the BRO 210 mg arm and 69% of patients in the USTE arm achieved PASI 75 compared to 6% of patients in the placebo group1,32

• Results for PASI 100 were 37%, 19%, and <1% in the BRO 210 mg, USTE, and placebo groups, respectively32

• Percentage of patients with sPGA of 0 or 1 was 80%, 57%, and 4%, in the BRO 210 mg, USTE, and placebo groups, respectively1,32

3. In post-hoc analyses of patients who failed prior biologic therapies, the percentage of patients treated with BRO who achieved PASI 75 was 82%.32

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B. Guselkumab Pivotal Clinical Trials

The efficacy of guselkumab has been shown in 3 multicenter, phase III RCTs (VOYAGE 1, VOYAGE 2, and NAVIGATE) including adult patients with moderate to severe plaque psoriasis.2,41 The following criteria were required for patients to enter VOYAGE 1 and VOYAGE 2 studies2,41:

1. Patients ≥ 18 years old2 2. Patients have moderate to severe psoriasis, defined as “Investigator’s Global Assessment (IGA) score of ≥3 (“moderate”) on a 5-point scale of overall disease severity, a PASI score ≥12, and a minimum affected BSA of 10”2 3. Patients were candidates for systemic therapy or phototherapy2

Regarding baseline demographic and disease characteristics, mean age was 44 years old, median baseline PASI score was 19, and median affected BSA was 21% (ranges of 10 to 90%).2,41 Around 76% of patients had an IGA score of 3 (moderate), 24% of patients had an IGA score of 4 (severe), and 23% of patients had been previously treated with a biologic systemic therapy.2,41

1. VOYAGE 1 and VOYAGE 2 studies VOYAGE 1 and VOYAGE 2 were 48-week phase III RCTs in patients with moderate to severe plaque psoriasis. Patients were randomized to guselkumab (GUSE) 100 mg at week 0, 1, 4, and every 8 weeks afterwards, placebo, or FDA-approved adalimumab (80 mg at week 0, 40 mg at week 1, then every 2 weeks). At week 16, patients receiving placebo switched to GUSE. Both trials evaluated responses of GUSE versus placebo for the following co-primary efficacy endpoints at week 1641:

1. Change from baseline to week 16 in the percentage of patients achieving at least 90% improvement in the PASI score (PASI 90)2 2. Change from baseline to week 16 in the percentage of patients with an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (minimal)2

In addition, secondary endpoints for the comparison of GUSE versus adalimumab included (1) PASI 90, PASI 75, and the percentage of patients achieving IGA score of 0 or 1 at week 16, and (2) PASI 90 and percentage of patients achieving IGA score of 0 or 1 at week 24 and 48.

The following clinical results were reported:

• GUSE vs. placebo: At week 16, VOYAGE-1 and VOYAGE-2 trials demonstrated superiority of GUSE compared to placebo for both co-primary endpoints (PASI 90 and IGA score of 0 or 1).41 In VOYAGE 1, the percentage of patients achieving PASI 90 was 73% with GUSE vs. 3% with placebo, and the percentage of patients with IGA of 0 or 1 was 85% with GUSE vs. 7% with placebo.20,41 In VOYAGE-2, the percentage of patients achieving PASI 90 was 70% vs. 2% and the percentage of patients with IGA of 0 or 1 was 84% vs. 8%.42 GUSE was additionally superior to placebo at week 16 in terms of patient-reported outcomes (ie, DLQI and Psoriasis Symptoms and Signs Diary [PSSD])41

• GUSE vs. adalimumab: GUSE was superior to adalimumab at weeks 16 and 24 for all secondary endpoints in both trials (PASI 75, PASI 90, and IGA 0/1 at week 16 and PASI 90 and IGA 0/1 at week 24).20,41,42 GUSE was additionally superior to adalimumab at week 24 regarding the percentage of patients with PSSD symptom score of 041

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• Regarding maintenance of effect through week 48, GUSE showed significantly better improvements in psoriasis severity in terms of PASI 75, PASI 90, PASI 100, and IGA 0/1 compared to adalimumab at week 48 (VOYAGE-1).20 In the VOYAGE 2 study, patients who had a PASI 90 response to 28 weeks of GUSE were re-randomized to continue GUSE or discontinue GUSE (placebo arm).2,41 Maintenance of PASI 90 response was reported at week 48 in 89% of patients who continued GUSE therapy compared to 37% of patients who were withdrawn from GUSE2,41,42

2. NAVIGATE study This study was a 24-week phase III RCT in patients with moderate to severe plaque psoriasis who failed USTE treatment (ie, patients who had IGA ≥2 at Week 16 following treatment with USTE).2 In patients not responding to USTE, 31% of patients who switched to GUSE and 14% of patients who continued with USTE achieved an IGA score of 0 or 1 with at least 2-point improvement at week 28.2

Utah Medicaid Utilization Data

The Utah Medicaid Utilization Data documented less than 5 patients receiving guselkumab in 2018. No utilization data was documented for brodalumab.

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Discussion Topics and Potential Prior Authorization Criteria

The following prior authorization (PA) criteria may be considered for brodalumab and guselkumab:

- Patient is 18 years or older

- Documentation for diagnosis of moderate to severe plaque psoriasis:

o There are several definitions for psoriasis severity proposed by different organizations; however, no formal definitions are available. The 2011 AAD guideline on the management of psoriasis and psoriatic arthritis defines psoriasis severity based on BSA, location of lesions, and quality of life.26 Affected BSA < 5% is considered mild psoriasis, BSA ≥ 5% - < 10% is moderate psoriasis and BSA ≥ 10% is severe psoriasis; however, involvement of smaller BSA (eg, hands, feet, facial, or genital regions) that have a high impact on activities of daily life should also be considered for the classification of psoriasis severity.26 Other authors consider PASI, BSA, and DLQI cutoffs28 or quality of life and response to treatment to classify patients by disease severity18

o Clinical trials with brodalumab and guselkumab included patients with moderate to severe plaque psoriasis, defined as having all the following criteria met:

. Body surface area > 10%

. Psoriasis Area and Severity Index (PASI) score ≥ 12

. Physician global assessment score ≥3

- Patient is eligible for systemic therapy or phototherapy

- The labeled indication for brodalumab is slightly different to guselkumab indication. Brodalumab is indicated for the “treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies.“1 Brodalumab may increase the risk for suicidal ideation and behavior and a REMS program is required by the FDA.1 According to the FDA summary review, the labeled indication of brodalumab limits the use of this agent to “patients who have failed to respond or have lost response to other systemic therapies” as an additional risk mitigation approach32

- If a requirement of trial and failure of a certain number of agents is considered before prescribing guselkumab or brodalumab, the following points may be taken into consideration:

o The 2011 AAD guideline on the management of psoriasis and psoriatic arthritis recommends phototherapy alone or phototherapy in combination with traditional systemic agents (if phototherapy is available) as first-line options for the treatment of moderate to severe plaque psoriasis. If phototherapy is not available, either traditional systemic agents (eg, acitretin, apremilast, cyclosporine, or methotrexate) or biologic agents (eg, TNF-alpha inhibitors such as adalimumab, etanercept, and infliximab, IL-12/23 inhibitors such as ustekinumab, IL-17 inhibitors such as secukinumab, ixekizumab, and brodalumab, and IL-23 inhibitors such as guselkumab and tildrakizumab-asmn) are recommended as first line options.26 This guideline do not specify a preference for one biologic agent over another26

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o In clinical trials, guselkumab and brodalumab showed superior efficacy over adalidumab and ustekinumab, respectively

- Patient has been tested for TB infection before starting treatment with brodalumab or guselkumab. According to brodalumab and guselkuman prescribing information, these agents should not be used in patients with active TB infection. If latent TB is diagnosed, patients should start TB prophylaxis before initiating treatment with brodalumab or guselkumab due to the potential risk for latent TB reactivation1,2

- Specific safety considerations for brodalumab:

• Do not use brodalumab in patients with Crohn’s disease (labeled contraindication).1 New cases or exacerbation of Crohn’s disease were reported in clinical trials1

• Brodalumab label carries a black box warning regarding the risk for suicidal ideation and behavior. Prescribers should evaluate the benefits of prescribing brodalumab versus the potential risks in patients with “a history of depression and/or suicidal ideation or behavior”1

Re-authorization criteria:

- Re-authorization approval for tildrakizumab (Ilumya), a biological product approved in March 2018 by the FDA for moderate to severe plaque psoriasis, currently requires a confirmation of a “positive clinical response and reduction in baseline PASI”8

- According to the National Psoriasis Foundation (NPF), treatment success is defined as follows34:

• For initial evaluation, BSA ≤ 1% is considered as the target response at month 3 following treatment initiation. BSA ≤ 3% or BSA improvement from baseline ≥ 75% is considered as an acceptable response at month 3 following treatment initiation

• For maintenance evaluation, BSA ≤ 1% is considered as the target response for every 6-month assessment during maintenance therapy

However, these definitions of treatment success have some limitations such as the exclusion of patients’ quality of life considerations or other assessment tools (eg, PASI and sPGA) to evaluate psoriasis improvement.

Alternatively, you may wish to consider keeping the definition of treatment success open to the provider (or lesser degrees of success) to accommodate scenarios where remaining on the agent despite not having met strict cut-off values may be the best option for the patient

- Prescribing information for brodalumab recommends reassessing brodalumab response after 12 to 16 weeks. If no adequate response is achieved, therapy discontinuation should be considered.1,32

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Summary Brodalumab and guselkumab are monoclonal antibodies targeting against interleukin pathways. Both agents have been recently approved as subcutaneous injections for the “treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.” In addition, the labeled indication of brodalumab limits the use of this agent to “patients who have failed to respond or have lost response to other systemic therapies” due to safety concerns (ie, an increased risk for suicidal ideation and behavior). Plaque psoriasis can be classified as mild, moderate, or severe; however, specific definitions of disease severity vary in the literature. Some authors consider PASI, BSA, and DLQI cutoffs to classify patients by disease severity; other authors only evaluate BSA or quality of life and response to treatment. In clinical practice, BSA assessment, location and thickness of lesions, symptoms, and quality of life are often evaluated by physicians. Clinicians should evaluate psoriatic patients on a case-by-case basis. For the treatment of mild plaque psoriasis (or limited disease), topical agents are the mainstay of psoriasis therapy. For the treatment of moderate to severe plaque psoriasis (or extensive disease), current treatment options include phototherapy, photochemotherapy and/or systemic agents. Systemic agents comprise traditional oral agents (ie, acitretin, apremilast, cyclosporine, and methotrexate), and biologic injectable products (eg, TNF-alpha inhibitors such as adalimumab, etanercept, and infliximab, IL-12/23 inhibitors such as ustekinumab, IL-17 inhibitors such as secukinumab, ixekizumab, and brodalumab, and IL-23 inhibitors such as guselkumab and tildrakizumab-asmn). Systemic agents have positive results in psoriasis; however, treatment effect may decrease over time and many patients with severe and unremitting psoriasis typically require switching to another systemic agent. Guidelines do not state a preference for one systemic agent over another. However, in clinical practice it seems that biologic agents are often prescribed in patients with moderate to severe psoriasis who do not respond, have intolerable adverse effects, or have contraindications to traditional systemic agents. In clinical trials including patients with moderate to severe psoriasis, a significantly higher percentage of patients treated with brodalumab or guselkumab compared to placebo achieved sPGA or IGA success (ie, an sPGA score of 0 [clear] or 1 [almost clear] with ≥ 2-point improvement from baseline), a PASI 75 response (for brodalumab), or a PASI 90 response (for guselkumab). Trials comparing brodalumab with placebo demonstrated that around 75% of patients achieved sPGA success and 80% of patients reached PASI 75 at week 12. Trials comparing guselkumab versus placebo showed that around 85% of patients achieved IGA success and 70% of patients reached PASI 90 at week 16. In addition, patients treated with brodalumab or guselkumab experienced significant improvements on their quality of life compared to placebo at weeks 12 and 16, respectively. Comparisons of brodalumab and guselkumab versus older biologic agents (eg, ustekinumab or adalimumab) showed significantly better results in terms of improvements in psoriasis severity with the newer biologic agents. Treatment effect was maintained for 52 weeks with brodalumab therapy and 48 weeks with guselkumab therapy. The Utah Medicaid Utilization Data documented less than 5 patients receiving guselkumab in 2018. No utilization data was documented for brodalumab. Prior authorization criteria may include FDA approved indication and dosage, failure to respond or loss of response to other systemic agents (labeled indication for brodalumab only), confirmation for diagnosis of moderate to severe plaque psoriasis, TB infection test prior to therapy, warnings (eg, an increased risk for suicide ideation and behavior with brodalumab), and contraindications (eg, avoid using brodalumab in patients with Crohn´s disease).

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20. Blauvelt A, Papp KA, Griffiths CE, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 , compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. Journal of the American Academy of Dermatology. 2017;76(3):405-417. 21. Pariser DM, Bagel J, Gelfand JM, et al. National Psoriasis Foundation clinical consensus on disease severity. Archives of dermatology. 2007;143(2):239-242. 22. Feldman SR et al. Treatment of psoriasis in adults. UpToDate 2018. Accessed December 6, 2018. 23. Krueger GG, Feldman SR, Camisa C, et al. Two considerations for patients with psoriasis and their clinicians: what defines mild, moderate, and severe psoriasis? What constitutes a clinically significant improvement when treating psoriasis? Journal of the American Academy of Dermatology. 2000;43(2 Pt 1):281-285. 24. Hsu S, Papp KA, Lebwohl MG, et al. Consensus guidelines for the management of plaque psoriasis. Archives of dermatology. 2012;148(1):95-102. 25. Singh JA, Guyatt G, Ogdie A, et al. 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis. Arthritis care & research. 2018. 26. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. Journal of the American Academy of Dermatology. 2011;65(1):137-174. 27. American Academy of Dermatology. Clinical Guidelines. https://www.aad.org/practicecenter/quality/clinical-guidelines. Accessed January 03, 2019. 28. Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Archives of dermatological research. 2011;303(1):1-10. 29. Callen JP, Krueger GG, Lebwohl M, et al. AAD consensus statement on psoriasis therapies. Journal of the American Academy of Dermatology. 2003;49(5):897-899. 30. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. Journal of the American Academy of Dermatology. 2009;60(4):643-659. 31. National Psoriasis Foundation. Systemic treatments. Biologics and oral treatments; 2018. https://www.psoriasis.org/sites/default/files/systemic_treatments_-_biologics_and_oral_tx.pdf. Accessed December 5, 2018. 32. Kendall A. Marcus. Center for Drug Evaluation and Research. Application number: 761032Orig1s000. Summary Review. Siliq (brodalumab). February 2017. 33. National Psoriasis Foundation. Psoriasis treatments; 2018. https://www.psoriasis.org/about- psoriasis/treatments. Accessed December 12, 2018. 34. Armstrong AW, Siegel MP, Bagel J, et al. From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis. Journal of the American Academy of Dermatology. 2017;76(2):290-298. 35. National Psoriasis Foundation. Topical tretments for psoriasis; 2016. https://www.psoriasis.org/sites/default/files/topicals_booklet.pdf. Accessed December 5, 2018. 36. National Psoriasis Foundation. Phototherapy; 2018. https://www.psoriasis.org/sites/default/files/light_therapy_1.pdf. Accessed December 12, 2018. 37. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy. Journal of the American Academy of Dermatology. 2010;62(1):114- 135.

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38. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. Journal of the American Academy of Dermatology. 2009;61(3):451-485. 39. National Clinical Guideline C. National Institute for Health and Clinical Excellence: Guidance. In: Psoriasis: Assessment and Management of Psoriasis. London: Royal College of Physicians (UK) Copyright (c) National Clinical Guideline Centre - October 2012.; 2012. 40. Siliq REMS program. https://siliqrems.com/SiliqUI/home.u. Accessed January 8, 2019. 41. Duan R. and Hill, B. Center for Drug Evaluation and Research. Application number: 761061Orig1s000. Multi-discipline Review. Guselkumab. April 2017. 42. Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. Journal of the American Academy of Dermatology. 2017;76(3):418-431. 43. Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo- controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. The British journal of dermatology. 2016;175(2):273-286. 44. Lebwohl M, Strober B, Menter A, et al. Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis. The New England journal of medicine. 2015;373(14):1318-1328.

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Appendix A: Literature Search Strategies

Table 1. Cochrane Library Search Strategy Search Date: January 14, 2019 #1 (brodalumab):ti,ab,kw (Word variations have been searched) 78 #2 (guselkumab):ti,ab,kw (Word variations have been searched) 66 #3 MeSH descriptor: [Psoriasis] this term only 2565 #4 (Psoriasis):ti,ab,kw (Word variations have been searched) 5607 #5 #1 OR #2 138 #6 #3 OR #4 5607 #7 #5 AND #6 105 (1 network meta-analysis and 104 clinical trials)

Table 2. Ovid Medline Literature Search Strategy for Systematic Reviews Database: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to January 11, 2019> Search Strategy: ------1 brodalumab.mp. (198) 2 guselkumab.mp. (100) 3 brodalumab.ti,ab,kw,kf. (179) 4 guselkumab.ti,ab,kw,kf. (88) 5 psoriasis.mp. or PSORIASIS/ (44024) 6 psoriasis.ti,ab,kw,kf. (36995) 7 Meta-Analysis/ (96078) 8 (metaanaly$ or meta-analy$).ti,ab,kw,kf. (141966) 9 (cochrane$ or systematic review?).jw. (16182) 10 (systematic adj3 review).ti,ab,kw,kf. (130013) 11 (MEDLINE or systematic review).tw. or meta analysis.pt.a (229822) 12 1 or 2 or 3 or 4 (265) 13 5 or 6 (44024) 14 7 or 8 or 9 or 10 or 11 (277897) 15 12 and 13 and 14 (21) - Total number of potential systematic reviews a Search filter for “Reviews” (Maximizes specificity) in Ovid Medline from McMaster University (https://hiru.mcmaster.ca/hiru/hiru_hedges_medline_strategies.aspx)

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Appendix B: Key Findings in Published Clinical Trials

Table 1. Main Clinical Trials Including Brodalumab and Guselkumab Reference/ Study Design/ Participants Results for Primary Endpoint Clinical Study Intervention Brodalumab Phase 3 RCT 661 patients Co-primary endpoints (PASI 75 and sPGA) at with moderate week 12: • BRO 140 mg to severe % of patients achieving PASI 75 at week 12: Q2W plaque psoriasis • BRO 140 mg Q2W: 60% • BRO 210 mg • BRO 210 mg Q2W: 83% Papp, 201643 Q2W • PLA: 3% • PLA AMAGINE-1 % of patients achieving sPGA 0 or 1: • BRO 140 mg Q2W: 54% • BRO 210 mg Q2W: 76% • PLA: 1% (There were significant differences between BRO and PLA) Phase 3 RCT 1,831 patients Primary endpoints: with moderate % of patients achieving PASI 75 at week 12: Arms: to severe • BRO 140 mg Q2W: 67% • BRO 140 mg plaque psoriasis • BRO 210 mg Q2W: 86% Q2W • PLA: 8% • BRO 210 mg (There were significant differences between BRO Q2W and PLA) Lebwohl, 201544 • USTE every 12 weeks % of patients achieving sPGA 0 or 1: AMAGINE-2 • PLA Rates for BRO 210 mg (79%) and BRO 140 mg (58%) were significantly greater vs. PLA (4%) Induction phase: 12 weeks % of patients achieving PASI 100: Maintenance • BRO 210 mg vs. USTE: BRO (44%) vs. USTE phase: 40 weeks (22%) (significant differences in favor of BRO) • BRO 140 mg vs. USTE: no significant differences Phase 3 RCT 1,881 patients % of patients achieving PASI 75 at week 12: with moderate • BRO 140 mg Q2W: 69% Arms: to severe • BRO 210 mg Q2W: 85% • BRO 140 mg plaque psoriasis • PLA: 1% Q2W • BRO 210 mg % of patients achieving sPGA 0 or 1: Lebwohl, 201544 Q2W Rates for BRO 210 mg (80%) and BRO 140 mg

• USTE every 12 (60%) were significantly greater vs. PLA (4%) AMAGINE-3 weeks • PLA % of patients achieving PASI 100: (same design as • BRO 210 mg vs. USTE: BRO (37%) vs. USTE AMAGINE-2) (19%) (significant differences in favor of BRO) • BRO 140 mg vs. USTE (significant differences in favor of BRO)

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Table 1. Main Clinical Trials Including Brodalumab and Guselkumab Reference/ Study Design/ Participants Results for Primary Endpoint Clinical Study Intervention Guselkumab Phase 3 RCT 837 randomized GUSE vs. PLA: GUSE was superior to PLA for all co- patients with primary endpoints Arms: moderate to % of patients achieving PASI 90 at week 16 • GUSE 100 mg severe plaque compared to PLA: at week 0, 4 psoriasis and every 8 • GUSE (73%) vs. PLA (3%); p < 0.001 weeks % of patients achieving IGA 0 or 1 at week 16 thereafter compared to PLA: • ADA 80 mg at • Blauvelt, 201720 week 0, GUSE (85.1%) vs. PLA (7%); p< 0.001 followed by GUSE vs. ADA: GUSE was superior to ADA for all 40 mg at week VOYAGE-1 secondary endpoints at week 16 and 24 1, then Q2W

• PLA Results at week 16:

• IGA 0/1: GUSE 85.1% vs ADA 65.9%; p < 0.001 Study duration: 1 • PASI 90: GUSE 73.3% vs ADA 49.7%; p< 0.001 year (48 weeks) • PASI 75: GUSE 91.2% vs ADA 73.1%; p< 0.001 Results at week 24: • IGA 0/1: GUSE 84% vs ADA 61%; p < 0.001 • PASI 90: GUSE 80% vs ADA 53%; p< 0.001 • IGA 0 (clear): GUSE 53% vs ADA 29%; p< 0.001 Responses were maintained though week 48 Phase 3 RCT 992 randomized GUSE vs. PLA: GUSE was superior to PLA for all co- patients with primary endpoints Arms: moderate to % of patients achieving PASI 90 at week 16: • GUSE 100 mg severe plaque at week 0, 4 psoriasis • GUSE (70%) vs. PLA (2.4%); p< 0.001 and every 8 % of patients achieving IGA 0 or 1: weeks thereafter • GUSE (84.1%) vs. PLA (8%); p< 0.001 42 • ADA 80 mg at Reich, 2017 GUSE vs. ADA: GUSE was superior to ADA for all week 0, secondary endpoints at week 16 and 24 followed by VOYAGE-2 40 mg at week Results at week 16: 1, then Q2W • IGA 0/1: GUSE 84.1% vs ADA 67.7%; p< 0.001 • PLA • PASI 90: GUSE 70% vs ADA 46.8%; p< 0.001

• PASI 75: GUSE 86.3% vs ADA 68.5%; p< 0.001 Study duration: 1 Results at week 24: year (48 weeks) • IGA 0/1: GUSE 83% vs ADA 65%; p < 0.001 • PASI 90: GUSE 75% vs ADA 55%; p< 0.001 • IGA 0 (clear): GUSE 52% vs ADA 31%; p< 0.001 Abbreviation: ADA, adalimumab; BRO, brodalumab; GUSE, guselkumab; IGA; Investigator’s Global Assessment; PLA, placebo; Q2W, every 2 weeks; USTE, ustekinumab

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