Cinqair (reslizumab injection for intravenous use)

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1 Cinqair (reslizumab injection for intravenous use) Policy Number: Last Review: 04/2018 Origination: 04/2016 Next Review: 04/2019 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Cinqair (reslizumab) when it is determined to be medically necessary because the following criteria have been met. When Policy Topic is covered FDA-Approved Indications 1. Asthma in Patients with Severe Disease and an Eosinophilic Phenotype. A) Initial Therapy. Approve for 6 months if the patient meets the following criteria (i, ii, iii, iv and v): i. Patient is 18 of age; AND ii. Cinqair is prescribed by or in consultation with an allergist, immunologist, or pulmonologist; AND iii. Patient has a peripheral blood eosinophil count of 400 cells per microliter within the iv. previous 4 weeks (prior to treatment with Cinqair); AND Patient has received at least 3 consecutive months of combination therapy with BOTH of the following (a and b): a) An inhaled corticosteroid (ICS) [e.g. Flovent HFA {fluticasone inhalation aerosol}, Flovent Diskus {fluticasone inhalation powder}, Arnuity Ellipta {fluticasone furoate inhalation powder}, Asmanex Twisthaler {mometasone inhalation powder}, Asmanex HFA {mometasone inhalation aerosol}, Aersopan {flunisolide HFA inhalation aerosol}, Alvesco {ciclesonide inhalation aerosol}, Pulmicort Flexhaler {budesonide inhalation powder}, QVAR {beclomethasone HFA inhalation aerosol}]; AND b) At least ONE of the following (1, 2, 3 or 4): (1) Inhaled long-acting beta-agonist (LABA) [e.g., Serevent Diskus {salmeterol xinafoate inhalation powder}]; OR NOTE: Use of a combination inhaler containing both an ICS and a LABA would fulfil the requirement for both criteria a and b (e.g., Advair Diskus/HFA [fluticasone propionate and salmeterol inhalation powder/aerosol], Symbicort [budesonide and formoterol fumarate inhalation aerosol], Breo Ellipta [fluticasone furoate and vilanterol inhalation powder], and Dulera [mometasone furoate and formoterol fumarate inhalation aerosol]) (2) Inhaled long-acting muscarinic antagonist (LAMA) [e.g., Spiriva Respimat {tiotropium bromide inhalation spray}]; OR (3) Leukotriene receptor antagonist (LTRA) [e.g. montelukast tablets/granules {Singulair, generics}, Accolate {zafirlukast tablets}]; OR (4) Theophylline (Theo-24, Uniphyl, TheoChron ER, generics); AND v. Patient s asthma continues to be uncontrolled as defined by ONE of the following (a, b, c, d or e): a) The patient experienced two or more asthma exacerbations requiring treatment with systemic corticosteroids in the previous year; OR b) The patient experienced one or more asthma exacerbation requiring hospitalization or an Emergency Department (ED) visit in the previous year; OR

2 c) Patient has a forced expiratory volume in 1 second (FEV 1 ) < 80% predicted; OR d) Patient has an FEV 1 /forced vital capacity (FVC) < 0.80; OR e) The patient s asthma worsens upon tapering of oral corticosteroid therapy. B) Patients Continuing Cinqair Therapy. Approve for 1 year if the patient meets the following criteria (i, ii, iii and iv): i. Patient is 18 years of age; AND ii. Cinqair is prescribed by or in consultation with an allergist, immunologist, or iii. pulmonologist; AND Patient continues to receive therapy with BOTH of the following (a and b): a) An inhaled corticosteroid (ICS) [e.g. Flovent HFA {fluticasone inhalation aerosol}, Flovent Diskus {fluticasone inhalation powder}, Arnuity Ellipta {fluticasone furoate inhalation powder}, Asmanex Twisthaler {mometasone inhalation powder}, Asmanex HFA {mometasone inhalation aerosol}, Aersopan {flunisolide HFA inhalation aerosol}, Alvesco {ciclesonide inhalation aerosol}, Pulmicort Flexhaler {budesonide inhalation powder}, QVAR {beclomethasone HFA inhalation aerosol}]; AND b) At least ONE of the following (1, 2, 3 or 4): (1) Inhaled long-acting beta-agonist (LABA) [e.g., Serevent Diskus {salmeterol xinafoate inhalation powder}]; OR NOTE: Use of a combination inhaler containing both an ICS and a LABA would fulfil the requirement for both criteria a and b (e.g., Advair Diskus/HFA [fluticasone propionate and salmeterol inhalation powder/aerosol], Symbicort [budesonide and formoterol fumarate inhalation aerosol], Breo Ellipta [fluticasone furoate and vilanterol inhalation powder], and Dulera [mometasone furoate and formoterol fumarate inhalation aerosol]) (2) Inhaled long-acting muscarinic antagonist (LAMA) [e.g., Spiriva Respimat {tiotropium bromide inhalation spray}]; OR (3) Leukotriene receptor antagonist (LTRA) [e.g. montelukast tablets/granules {Singulair, generics}, Accolate {zafirlukast tablets}]; OR (4) Theophylline (Theo-24, Uniphyl, TheoChron ER, generics); AND iv. The patient has responded to Cinqair therapy as determined by the prescribing physician (e.g., decreased asthma exacerbations; decreased asthma symptoms; decreased hospitalizations, emergency department (ED)/urgent care, or physician visits due to asthma; decreased requirement for oral corticosteroid therapy). Cinqair is indicated for add-on maintenance treatment of patients with severe asthma aged 18 years who have an eosinophilic phenotype. 1 According to the 2014 ERS/ATS guidelines, severe asthma is defined as asthma which requires treatment with a high-dose ICS in addition to a second controller medication (and/or systemic corticosteroids) to prevent it from becoming uncontrolled, or asthma which remains uncontrolled despite this therapy. 10 Uncontrolled asthma is defined as asthma that meets one of the following four criteria: poor symptom control; frequent severe exacerbations (two or more requiring systemic corticosteroids per year); serious exacerbations (one hospitalization in the previous year); or airflow limitation (FEV 1 < 80% of predicted in the setting of reduced FEV 1 /FVC). Additionally, patients may also have severe asthma if their asthma worsens upon tapering of corticosteroids (highdose ICSs or systemic corticosteroids). Cinqair has been studied in patients with asthma uncontrolled by moderate-dose ICSs (or more potent) alone or in combination with maintenance oral corticosteroids or an additional controller medication. 7,11-12 However, in the asthma exacerbation studies, > 80% of patients were using an ICS in combination with a LABA at baseline and 12% to 19% of patients also required daily maintenance treatment with an oral corticosteroid. 7 Current guidelines confirm that ICS therapy remains the mainstay of therapy even in the setting of difficult-to-treat, severe asthma For patients with persistent symptoms or exacerbations despite correct inhaler technique and good adherence to high-dose ICS therapy and a second controller medication (e.g., a LABA), referring the patient to a specialist with expertise in the management of severe asthma to investigate and consider additional treatments is recommended. 9 Finally, in three of the four pivotal trials of Cinqair, patients were required to demonstrate evidence of eosinophilic inflammation. 7,11-12 In these studies that

3 selected patients based on baseline eosinophil levels 400 cells/microliter, Cinqair demonstrated reduced exacerbation rates and improved FEV 1 values when compared with placebo. In the study in which patients were unselected for eosinophil levels, there was not a statistically significant increase in FEV 1 values with Cinqair vs. placebo. However, in a subgroup of patients with baseline eosinophil levels 400 cells/microliter, the improvement in FEV 1 with Cinqair was significantly greater than with placebo [treatment difference: +270 ml; P = 0.04]. 12 In the opinion of expert physicians reviewing the data we have adopted the eosinophil criteria and criteria for uncontrolled asthma. When Policy Topic is not covered Conditions Not Recommended for Approval Cinqair has not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions. Rationale for noncoverage for these specific conditions is provided below. (Note: This is not an exhaustive list of Conditions Not Recommended for Approval.) 1. Concurrent use of Cinqair with Xolair (omalizumab injection for subcutaneous use). Xolair is a recombinant humanized immunoglobulin G (IgG)1κ monoclonal antibody indicated for use in adults and adolescents (aged 12 years) with moderate to severe persistent asthma and who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with ICSs. 8 The efficacy and safety of Cinqair in combination with Xolair have not been established. 2. Concurrent use of Cinqair with Nucala (mepolizumab injection for subcutaneous use). Nucala is a recombinant IgG1κ monoclonal antibody indicated for add-on maintenance treatment of patients with severe asthma aged 12 years who have an eosinophilic phenotype. 6 The efficacy and safety of Cinqair in combination with Nucala have not been established. 3. Eosinophilic Esophagitis (EoE) or Eosinophilic Gastroenteritis. One pilot study (available as abstract) [n = 4] examined the effects of Cinqair on peripheral blood and gastrointestinal eosinophils in patients with eosinophilic gastroenteritis. 3 Following one IV infusion of Cinqair 1 mg/kg, blood eosinophil counts declined quickly in all patients, but symptom scores were not improved. One additional randomized, double-blind, placebo controlled study (published) [n =226] evaluated the efficacy of Cinqair in pediatric and adolescent patients with EoE. 2 In this study, patients were randomly assigned to receive Cinqair IV infusions of 1 mg/kg, 2 mg/kg, or 3 mg/kg, or placebo at Weeks 0, 4, 8, and 12. At Week 15, peak esophageal eosinophil counts were reduced by a median 24%, 59%, 67%, and 64%, with placebo, Cinqair 1 mg/kg, 2 mg/kg, 3 mg/kg, respectively; all reductions with Cinqair were significant compared with placebo (P < 0.001). Improvements in physician s global assessment scores were also observed in all groups (including placebo), but the difference between Cinqair and placebo was not statistically significant. Additional, well-controlled trials are needed to determine the role of Cinqair in the treatment of EoE and eosinophilic gastroenteritis. 4. Hypereosinophilic Syndrome (HES), Idiopathic. One small pilot study (published) [n = 4] evaluated the safety and efficacy of Cinqair in patients with HES who were refractory to or intolerant of treatment with conventional therapy. 4 A single 1 mg/kg dose of Cinqair resulted in a response in 2 of 4 patients. In the two responders, blood eosinophil counts dropped to within the normal range within 48 hours of the Cinqair infusion and this was accompanied by an improvement in clinical signs and symptoms. Additional, well-controlled trials are needed to determine the role of Cinqair in the treatment of HES. 5. Nasal Polyps. Cinqair was studied in one double-blind, placebo-controlled, randomized safety and pharmacokinetic study (published) [n = 24] in patients with nasal polyps. 5 Patients received a single infusion of either Cinqair 3 mg/kg, Cinqair 1 mg/kg, or placebo. It was reported that blood eosinophil counts and concentrations of eosinophil cation protein were reduced for up to 8 weeks following the Cinqair infusion. Nasal polyp scores improved for approximately 4 weeks in one-half

4 of patients receiving active treatment. Additionally, a pooled subgroup analysis from the two pivotal Cinqair asthma exacerbation trials found that in patients with inadequately controlled asthma and chronic sinusitis with nasal polyps (n = 150) Cinqair demonstrated enhanced efficacy. Patients in this subgroup experienced an 83% reduction the clinical asthma exacerbation (CAE) rate with Cinqair vs. placebo (rate ratio [RR] 0.17; P = ). 14 The magnitude of this reduction was greater than that observed with the overall study population. However, additional, well-controlled trials are needed to determine the role of Cinqair in the treatment of patients with nasal polyps who do not have asthma. 7,14 6. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available. Considerations Prior authorization is recommended for prescription benefit coverage of Cinqair. Because of the specialized skills required for evaluation and diagnosis of patients treated with Cinqair as well as the monitoring required for adverse events and long-term efficacy, approval requires Cinqair to be prescribed by or in consultation with a physician who specializes in the condition being treated. Description of Procedure or Service Cinqair, an interleukin (IL)-5 antagonist immunoglobulin G (IgG)4κ monoclonal antibody, is indicated for add-on maintenance treatment of patients with severe asthma aged 18 years who have an eosinophilic phenotype. 1 Limitations of Use: Cinqair is not indicated for the treatment of other eosinophilic conditions or for the relief of acute bronchospasm/status asthmaticus. Cinqair is a human IL-5 antagonist; IL-5 is the main cytokine involved in the growth, differentiation, recruitment, activation, and survival of eosinophils. The most important factor in the pathogenesis of asthma is inflammation, which involves multiple mediators and cell types, including eosinophils. By inhibiting the signaling of IL- 5, Cinqair decreases the production and survival of eosinophils. However, the exact mechanism of action of Cinqair in asthma has not been established. Cinqair should be administered as a 3 mg/kg intravenous (IV) infusion once every 4 weeks by a healthcare professional. Rationale Summary of Cinqair Pivotal Trial Data in Patients with Asthma The efficacy of Cinqair was established in four randomized, double-blind, placebo-controlled, multicenter pivotal studies. 7,11-13 The studies included patients 12 years of age with moderate to severe asthma; three of the four studies (all except Study 4) also required patients to have blood eosinophil levels 400 cells/microliter despite medium to high dose inhaled corticosteroid (ICS) therapy. In all studies, patients received either Cinqair 3 mg/kg IV or placebo administered once every 4 weeks. Study 1 and Study 2 were identical, 52-week studies; the primary endpoint was the annual frequency of clinical asthma exacerbations (CAEs) with Cinqair vs. placebo. 7 In Study 1 (n = 489) [published], the rate of CAEs per patient per year was 0.9 with Cinqair and 1.8 with placebo (50% reduction vs. placebo; P < ). In Study 2 (n = 464) [published], the rate of CAEs per patient per year was 0.86 with Cinqair and 2.11 with placebo (59% reduction vs. placebo; P < ). Study 3 and Study 4 were 16-week lung-function studies; the primary endpoint was the improvement in forced expiratory volume in 1 second (FEV 1 ) with Cinqair vs. placebo In Study 3 (n = 311) [available as an abstract only], Cinqair significantly increased FEV 1 from baseline to Week 16 compared with placebo (treatment difference: +160 ml [P = ]). In Study 4 (n = 492) [available as an abstract only], Cinqair did not significantly increase FEV 1 from baseline to Week 16 compared with placebo (treatment difference: +76 ml [P = non-siginificant {NS}]). However, in a subgroup of patients with a baseline eosinophil level 400 cells/microliter, the improvement in FEV 1 with Cinqair (n = 69) was significantly greater than with placebo (n = 13) [treatment difference: +270 ml; P = 0.04].

5 Guidelines The 2015 Global Initiative for Asthma (GINA) Global Strategy for Asthma Management and Prevention addresses asthma treatment using a step-wise approach. 9 For patients with persistent symptoms or exacerbations despite correct inhaler technique and good adherence to high-dose ICS therapy and a second controller medication, referring the patient to a specialist with expertise in the management of severe asthma to investigate and consider additional treatments is recommended. It is noted that very few patients are completely resistant to corticosteroids; ICSs remain the mainstay of therapy even in the setting of difficult-to-treat, severe asthma. Optimizing the ICS/LABA dose is also important, as some patients may respond to doses of ICSs that are higher than doses routinely recommended for general use. If this strategy is utilized, the risk of systemic AEs increases and dose reduction should be considered at 3 to 6 month intervals. Some patients with severe asthma may also require low-dose oral corticosteroid maintenance treatment; however, long-term AEs need to be considered and patients should be monitored for osteoporosis. Other add-on therapies may be considered, including theophylline and leukotriene receptor antagonists (LTRAs), although data to support their use is limited and the benefits demonstrated were minimal in patients with severe asthma. The addition of Spiriva Respimat (tiotropium bromide inhalation spray), a long-acting muscarinic antagonist (LAMA), to moderate to high dose ICS/LABA has also demonstrated improved lung function and reduced time to first exacerbation. Phenotyping of asthma is also addressed in the GINA guidelines. 9 Patients with severe asthma may benefit from phenotyping into disease categories such as severe allergic, aspirin-exacerbated, or eosinophilic asthma. Overall it is noted that more research is needed to fully understand the clinical utility of phenotypic classification. Anti-immunoglobulin E (IgE) therapy (Xolair [omalizumab injection for subcutaneous use]) may be beneficial in patients with severe allergic asthma with elevated IgE levels. LTRAs may be useful in patients found to be aspirin-sensitive. Sputum-guided treatment may allow corticosteroid dose and/or exacerbation frequency to be reduced as treatment can be adjusted on the basis of sputum eosinophils; however, this requires a center with expertise in inducing and analyzing sputum. The GINA guidelines state that in rare cases of steroid-resistant asthma with eosinophilia, an anti-il-5 antibody can reduce asthma exacerbations, although Cinqair is not referenced specifically. Non-pharmacological interventions are discussed as well with the consensus that more studies are needed to determine the value of these treatments. The 2014 International European Respiratory Society (ERS)/American Thoracic Society (ATS) Guidelines on Definition, Evaluation, and Treatment of Severe Asthma are generally in-line with the GINA recommendations The ERS/ATS guidelines state that no specific asthma phenotypes have been broadly agreed upon, although several have been identified. 10 Identification of eosinophilic inflammation may be helpful when considering both non-specific (corticosteroids) and targeted therapies. It is noted that in adult patients with severe asthma, treatment should be guided by clinical criteria as well as sputum eosinophil counts performed in centers that are experienced with this technique, rather than clinical criteria alone. The ERS/ATS guidelines do not specifically address the use of blood eosinophil levels to guide therapy; however, they do note that blood eosinophils are biomarkers of T-helper cell inflammation. The clinical utility of blood eosinophils, as well as more specific biomarkers, requires confirmation. Blood and sputum eosinophils are often elevated in patients with severe allergic asthma, eosinophilic asthma, and patients experiencing recurrent exacerbations. The ERS/ATS guidelines also recommend a trial of Xolair in patients with severe allergic asthma 6 years old with an elevated IgE level despite optimal pharmacological and non-pharmacological management. Cinqair is mentioned as a possible new targeted severe asthma therapy; in patients with severe asthma and persistent sputum eosinophilia, Cinqair was found to decrease exacerbation and improve asthma symptoms and lung function.

6 References 1. Cinqair injection for intravenous use [prescribing information]. Frazer, PA: Teva Respiratory, LLC; March Spergel JM, Rothenberg ME, Collins MH, et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2012;129(2): Prussin C, James SP, Huber MM, et al. Pilot study of anti-il-5 in eosinophilic gastroenteritis. J Allergy Clin Immunol. 2003;111:S Klion AD, Law MA, Noel P, et al. Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome. Blood. 2004;103(8): Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine the response to anti-il-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118(5): Nucala injection for subcutaneous use [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; November Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicenter, parallel, double-blind, randomized, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3: Xolair subcutaneous injection [prescribing information]. South San Francisco, CA and East Hanover, NJ: Genentech, Inc. and Novartis Pharmaceuticals Corporation; September Global Initiative for Asthma. Global strategy for asthma management and prevention. Updated August Available at: Accessed on March 15, Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43: Bjermer L, Lemiere C, Maspero J, et al. A randomized phase 3 study of the efficacy and safety of reslizumab in subjects with asthma with elevated eosinophils. Eur Respir J. 2014;44(Suppl58):P Corren J, Weinstein S, Janka L, et al. A randomized phase 3 study of reslizumab efficacy in relation to blood eosinophil levels in patients with moderate to severe asthma. Eur Respir J. 2014;44(Suppl58): Teva Pharmaceuticals. Reslizumab. Briefing document for the Food and Drug Administration Pulmonary and Allergy Drug Advisory Committee. Meeting Date: December 9, Available at: AllergyDrugsAdvisoryCommittee/ucm htm. Accessed on March 13, Weinstein SF, Germinaro M, Bardin P, et al. Efficacy of reslizumab with asthma, chronic sinusitis with nasal polyps elevated blood eosinophils [abstract 283]. J Allergy Clin Immunol. 2016;137:AB Billing Coding/Physician Documentation Information Medical benefit; specialty 100mg/10mL solution in single-use vials J2786 Injection, reslizumab, 1 mg (effective 1/1/2017) Additional Policy Key Words Policy Implementation/Update Information 04/2016 New policy 04/2017 Added J2786 Injection, reslizumab, 1 mg (effective 1/1/2017)

7 State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.