Cigna Drug and Biologic Coverage Policy

Cigna Drug and Biologic Coverage Policy Subject Alpha1-Proteinase Inhibitors Table of Contents Coverage Policy... 1 General Background... 3 Coding/Billing Information... 5 References... 6 Effective Date... 3/15/2018 Next Review Date... 3/15/2019 Coverage Policy Number... 4037 Related Coverage Resources INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Coverage Policy Cigna covers intravenous alpha 1-proteinase inhibitor (human) (Aralast NP, Glassia, Prolastin -C, Zemaira ) as medically necessary for the treatment of congenital alpha 1-proteinase inhibitor deficiencyassociated lung disease when all of the following criteria are met: Alpha 1 -antitrypsin (AAT) concentration less than 80 milligrams per deciliter (mg/dl) [or less than11 micromolar (μm)] Presence of obstructive lung disease as defined by a forced expiratory volume in one second (FEV 1 ) of 30 65% of predicted or a rapid decline in lung function defined as a change in FEV 1 of greater than 120 ml/year Current non-smoker Cigna does not cover alpha 1-proteinase inhibitor (human) for any other indication including the following because it is considered experimental, investigational, or unproven (this list may not be all inclusive): Isolated alpha1-proteinase inhibitor deficiency-associated liver disease in the absence of obstructive lung disease Cystic fibrosis Diabetes mellitus Graft-Versus-Host Disease Page 1 of 6

Cigna does not cover the inhalation form of alpha 1-proteinase inhibitor (human) because it is considered experimental, investigational, or unproven. When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to Alpha 1- Proteinase Inhibitors (Human) (Aralast NP, Glassia, Prolastin-C, Zemaira). Note: Receipt of sample product does not satisfy any criteria requirements for coverage. FDA Approved Indications Brand Name Aralast NP Approved Indication Aralast NP is indicated for chronic augmentation therapy in adults with clinically evident emphysema due to severe congenital deficiency of alpha1-proteinase inhibitor (alpha1-pi) (alpha1-antitrypsin deficiency). Aralast NP increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining fluid levels of alpha1-pi. The effect of augmentation therapy with any alpha1-pi, including Aralast NP, on pulmonary exacerbations and on the progression of emphysema in alpha1-antitrypsin deficiency has not been conclusively demonstrated in randomized, controlled clinical trials. Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy with Aralast NP or Aralast are not available. Glassia Prolastin-C Aralast NP is not indicated as therapy for lung disease in patients in whom severe congenital alpha1-pi deficiency has not been established. Glassia, is an Alpha1-Proteinase Inhibitor (Human), indicated for chronic augmentation and maintenance therapy in individuals with clinically evident emphysema due to severe hereditary deficiency of Alpha1- PI, also known as alpha1-antitrypsin (AAT) deficiency. Glassia increases antigenic and functional (antineutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining fluid levels of Alpha1-PI. Limitations of Use: The effect of augmentation therapy with Glassia or any Alpha1-PI product on pulmonary exacerbations and on the progression of emphysema in Alpha1-PI deficiency has not been conclusively demonstrated in randomized, controlled clinical trials. Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy of individuals with Glassia are not available. Glassia is not indicated as therapy for lung disease in patients in whom severe Alpha1-PI deficiency has not been established. Prolastin-C is an Alpha1-Proteinase Inhibitor (Human) (Alpha1-PI) indicated for chronic augmentation and maintenance therapy in adults with clinical evidence of emphysema due to severe hereditary deficiency of Alpha1-PI (alpha1-antitrypsin deficiency). Prolastin-C increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining fluid levels of Alpha1-PI. Limitations of Use: The effect of augmentation therapy with any Alpha1-PI, including Prolastin-C, on pulmonary exacerbations and on the progression of emphysema in Alpha1-PI deficiency has not been conclusively demonstrated in randomized, controlled clinical trials. Clinical data demonstrating the long-term effects of chronic augmentation or maintenance therapy with Prolastin-C are not available Prolastin-C is not indicated as therapy for lung disease in patients in whom severe Alpha1-PI deficiency has not been established. Page 2 of 6

Brand Name Zemaira Approved Indication Zemaira is an alpha1-proteinase inhibitor (A1-PI) indicated for chronic augmentation and maintenance therapy in adults with A1-PI deficiency and clinical evidence of emphysema. Zemaira increases antigenic and functional (anti-neutrophil elastase capacity [ANEC]) serum levels and lung epithelial lining fluid (ELF) levels of A1-PI Clinical data demonstrating the long-term effects of chronic augmentation therapy of individuals with Zemaira are not available. The effect of augmentation therapy with Zemaira or any A1-PI product on pulmonary exacerbations and on the progression of emphysema in A1-PI deficiency has not been demonstrated in randomized, controlled clinical studies. Zemaira is not indicated as therapy for lung disease patients in whom severe A1-PI deficiency has not been established. FDA Recommended Dosing Brand Name Aralast NP Glassia Prolastin-C Zemaira Drug Availability Recommended Dosing The recommended dosage of Aralast NP is 60 mg/kg body weight administered once weekly by intravenous infusion. Dose ranging studies using efficacy endpoints have not been performed. Administer Aralast NP at a rate not to exceed 0.2 ml per kg body weight per minute, and as determined by the response and comfort of the patient. The recommended dosage of Glassia is 60 mg/kg body weight administered once weekly by intravenous infusion. Dose ranging studies using efficacy endpoints have not been performed. Administer Glassia at a rate not greater than 0.2 ml/kg body weight per minute. The recommended dosage of 60 mg/kg takes approximately 15 minutes to infuse. The recommended dose of Prolastin-C is 60 mg/kg body weight administered once weekly intravenously. Dose ranging studies using efficacy endpoints have not been performed with any alpha1-pi product. Prolastin-C should be given intravenously at a rate of approximately 0.08 ml/kg/min as determined by the response and comfort of the patient. The recommended dosage of 60 mg/kg takes approximately 15 minutes to infuse. The recommended dose of Zemaira is 60 mg/kg body weight administered once weekly intravenously. Dose ranging studies using efficacy endpoints have not been performed with Zemaira or any alpha1-pi product. Zemaira may be administered intravenously at a rate of approximately 0.08 ml/kg/min as determined by the response and comfort of the patient. The recommended dosage of 60 mg/kg body weight will take approximately 15 minutes to infuse. Brand Name Drug Availability Aralast NP Aralast NP is supplied as a lyophilized powder in single-dose vials of 0.5 gram and 1 gram of functional Alpha1-PI. Glassia Glassia is available as a single-use vial containing approximately 1 gram of functional alpha1-pi in 50 ml of ready to use solution. Each vial of Glassia has the functional activity stated on the label. Prolastin-C Prolastin-C is supplied in 1,000 mg single-use vials with a separate 20 ml vial of Sterile Water for Injection, USP. The total alpha1-pi functional activity, in milligrams, is stated on the label of each vial. Zemaira Zemaira is supplied in a single use vial containing approximately 1,000 mg of functionally active Alpha1-PI as lyophilized powder for reconstitution with 20 ml of Sterile Water for Injection, USP. The amount of functional Alpha1-PI is printed on the vial label and carton. General Background Disease Overview Congenital alpha1-pi deficiency, commonly known as alpha1-antitrypsin deficiency (AATD), is an autosomal recessive disorder with several variants. Patients with specific mutations in the alpha1-antitrypsin (AAT) gene have reduced or absent secretion of alpha1-pi and are at higher risk for developing early onset emphysema or chronic obstructive pulmonary disease (COPD). Mutations causing AATD occur in about 10% of Caucasians with COPD in the United States. The primary role of alpha1-pi is to prevent tissue damage caused by neutrophil elastase and other serine proteases. In the lungs, these enzymes degrade many proteins in their microenvironment including elastin. Elastin is an extracellular matrix protein that allows for much of the elastic expansion and contraction in the alveoli. When the neutrophil elastase-antiproteinase relationship becomes Page 3 of 6

unbalanced, elastin is excessively catabolized, causing emphysematous changes and the progression of COPD. Pharmacology Alpha1-PI is a naturally occurring inhibitor of serine proteases, enzymes that aid in proteolytic destruction of the alveolar walls and connective tissue framework of the lung parenchyma. Exogenous administration of alpha1-pi (human) in patients with congenital alpha1-pi deficiency provides another source of enzyme inhibitor that protects lung tissues from proteolytic destruction. Guidelines The American Thoracic Society and the European Respiratory Society (ATS/ERS) issued standards for the diagnosis and management of individuals with AATD in 2003. These standards recommend augmentation therapy with alpha1-pi (human) for patients who are deficient in AAT (i.e., defined as serum concentration < 11 micromoles) with obstructive lung disease defined by a forced expiratory volume in one second (FEV1) of 30 65% of predicted or a rapid decline in lung function defined as a change in FEV1 of > 120 ml/year. In addition the guidelines recommend that patients with very poor lung function already receiving treatment continue on therapy. The ATS/ERS state that alpha1-pi (human) does not confer benefit in, and is not recommended for, patients who have alpha1-proteinase inhibitor deficiency-associated liver disease. Likewise, alpha1-pi (human) is not indicated as treatment for patients with lung disease in whom congenital alpha1-pi deficiency has not been established. Clinical Efficacy The effect of augmentation therapy with any alpha1-pi product on pulmonary exacerbations and on the progression of emphysema in AATD has not been demonstrated in adequately powered, randomized, controlled, clinical trials. Clinical data demonstrating the long-term effects of chronic augmentation therapy are not available. Safety and effectiveness in pediatric patients have not been established. Clinical and biochemical studies have demonstrated that the administration of alpha1-pi (human) increases plasma levels of alpha1-pi, and that levels of functionally active alpha1-pi in the lung epithelial lining fluid are increased proportionately. Estimates of the sample size required of this rare disorder and the slow, progressive nature of the clinical course have been considered impediments in the ability to conduct such trials. The FDA has required that studies of randomized, controlled, parallel, masked design be conducted to determine the effect of regular administration of alpha1-pi (human) on one or more clinically meaningful endpoints (e.g., pulmonary exacerbations, serial pulmonary functions, and serial quantitative computerized axial tomographic [CT] lung scans). Intravenous administration of alpha1-pi (human) can increase lung concentrations of alpha1-pi, but there is limited data describing improved clinical outcomes. Most trials address surrogate outcomes such as lung function tests or lung volume. An observational report of 1,129 patients with AATD shows better survival rates for patients receiving alpha1-pi (human) therapy than those who did not receive treatment (RR 0.64, 95% CI 0.43, 0.94, p = 0.02). This report outlined the greatest benefit for patients with an initial FEV1 of 35 49% of predicted (RR 0.21, 95% CI 0.09 0.5, p < 0.001). Another observational report of German patients with AATD shows that the rate of FEV1 decline in patients with an initial FEV1 of 30 65% of predicted is much less with treatment than without (64 ml/year vs. ~100 ml/year for historical controls, P=not reported). A meta-analysis of 5 trials found that the decline in FEV1 was slowed by 23% in patients who received alpha1-pi and reduced by 26% in patients with a baseline FEV1 of 30-65% of predicted. There were not statistically significant trends for patients with a baseline FEV1 less than 30% or greater than 65% (Chapman, 2009). A Cochrane review evaluated 2 placebo-controlled trials of alpha1-pi that were conducted for 2 or 3 years using either FEV1 as the primary endpoint or lung density measured by CT scans. The authors concluded that alpha1- PI could not be recommended due to a lack of evidence of clinical benefit and the high cost of treatment (Gøtzsche, 2010). While there are few efficacy data, patients with an initial FEV1 of 30 65% seem to benefit the most from augmentation therapy, with improved survival rates and a slower decline in FEV1. No data are available regarding switching between brands of alpha1-pi (human) products. Page 4 of 6

The prescribing information for Aralast NP describes a clinical trial comparing Aralast (predecessor product) and Prolastin in 28 patients with congenital alpha1-pi deficiency and emphysema. Patients received either Aralast or Prolastin 60 mg/kg intravenously once weekly for 10 weeks. After week 10 patients receiving Prolastin switched to Aralast and patients on Aralast continued therapy. Serum antigenic and functional alpha1-pi trough levels were measured prior to infusions during weeks 8-11. The authors concluded that Aralast and Prolastin similarily maintained target serum alpha1-pi trough levels and increased antigenic levels of alpha1-pi in the epithelial lining fluid. Forty-four (44) patients with alpha1-pi deficiency and emphysema were randomized to either Zemaira or Prolastin for 10 weeks with a primary objective of demonstrating bioequivalence of the products. After the initial 10 weeks, patients on Prolastin were switched to Zemaira for the remaining 14 weeks of the trial. The difference in steady-state trough serum alpha1-pi levels was 1.45 µm with the lower limit of the 90% confidence interval being -2.77 µm. This demonstrated bioequivalence of Zemaira and Prolastin as the values were within 3 µm. In addition, there were no serious or severe adverse events and no differences were found between the treatment groups (Stocks, 2006). In a double-blind, randomized, controlled study comparing Glassia to Prolastin, 50 patients with alpha1- antitrypsin deficiency and evidence of lung disease (defined as either an FEV1 < 80% predicted; decline in FEV1 over 1 year of at least 35 ml; or evidence of emphysema by computed tomography) were randomized to receive either Glassia (n = 33) or Prolastin (n = 17) at a dose of 60 mg/kg IV once weekly for 12 weeks. The primary objective was to assess alpha1-pi trough antigenic and functional levels over weeks 7 12 of the study and the results established that Glassia was non-inferior to Prolastin. The safety profile was also similar between the products (Sandhaus, 2014). No clinical endpoints were assessed. Experimental, Investigational, Unproven Uses Use of alpha1-pi is under investigation for use in the treatment of new onset type 1 diabetes mellitus and acute graft-versus-host disease (GVHD). Inhaled alpha1-pi has been investigated for use in emphysema and cystic fibrosis. At this time, however, there is insufficient published data in terms of safety and efficacy to support the use of alpha1-pi products for these indications. A randomized, double-blind, crossover study evaluated the safety and pharmacokinetics of 120 mg/kg IV once weekly and 60 mg/kg IV once weekly of Prolastin-C. Thirty (30) subjects with COPD and a documented diagnosis of AATD (defined as a genotype associated with severe deficiency and a serum AAT level < 11 µm) received either the 120 mg/kg dose or the 60 mg/kg dose for 8 weeks, followed by 8 weeks of the alternate regimen. In the 60 mg/kg dose group, 76.7% of subjects had 69 treatment emergent adverse events (TEAEs), and in the 120 mg/kg dose group, 60% of subjects had 43 TEAEs. Mean steady-state and trough concentrations were higher with the 120 mg/kg dose compared with the 60 mg/kg dose. (Campos, 2013) This trial did not evaluate clinical endpoints. Coding/Billing Information Note: 1) This list of codes may not be all-inclusive. 2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement Covered when medically necessary: HCPCS Codes J0256 J0257 Description Injection, alpha 1 proteinase inhibitor (human), not otherwise specified, 10 mg Injection, alpha 1 proteinase inhibitor (human), (glassia), 10 mg Experimental/Investigational/Unproven/Not Covered when used to report the inhalation form of alpha 1- proteinase inhibitor (human): Page 5 of 6

HCPCS Codes J7699 Description NOC drugs, inhalation solution administered through DME References 1. American Thoracic Society/European Respiratory Society. American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency. Am J Respir Crit Care Med. Oct 1 2003;168(7):818-900. 2. Aralast NP [alpha1-proteinase inhibitor (human)] Prescribing Information. Baxter Healthcare Corporation, Westlake Village, CA: September 2017. 3. Campos MA, Kueppers F, Stocks JM, et al. Safety and pharmacokinetics of 120 mg/kg versus 60 mg/kg weekly intravenous infusions of alpha-1 proteinase inhibitor in alpha-1 antitrypsin deficiency: a multicenter, randomized, double-blind, crossover study (SPARK). COPD 2013; 10: 687-95. 4. Chapman KR, Stockley RA, Dawkins C et al. Augmentation therapy for α-1 antitrypsin deficiency: a metaanalysis. COPD 2009; 6: 177-84. 5. Glassia [alpha1-proteinase inhibitor (human)] Prescribing Information. Baxter Healthcare Corporation, Westlake Village, CA: June 2017. 6. Gøtzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD007851. DOI: 10.1002/14651858.CD007851.pub2. 7. McEvoy GK, ed. AHFS 2017 Drug Information. Bethesda, MD: American Society of Health-Systems Pharmacists, Inc; 2017. 8. Prolastin-C (alpha1-proteinase inhibitor [human]) Prescribing Information. Grifols Therapeutics Inc., Research Triangle Park, NC: September 2017. 9. Sandhaus RA, Stocks J, Rouhani FN et al. Biochemical efficacy and safety of a new, ready-to-use, liquid alpha-1-proteinase inhibitor, GLASSIA (alpha1-proteinase inhibitor (human), intravenous). COPD 2014; 11: 17-25. 10. Stocks JM, Brantly M, Pollock D et al. Multi-center study: the biochemical efficacy, safety and tolerability of a new α1-proteinase inhibitor, Zemaira. COPD 2006; 3: 17-23. 11. Zemaira [alpha1-proteinase inhibitor (human)] Prescribing Information. CSL Behring LLC., Kankakee, IL: September 2015. Cigna Companies refers to operating subsidiaries of Cigna Corporation. All products and services are provided exclusively by or through such operating subsidiaries, including Cigna Health and Life Insurance Company, Connecticut General Life Insurance Company, Cigna Behavioral Health, Inc., Cigna Health Management, Inc., QualCare, Inc., and HMO or service company subsidiaries of Cigna Health Corporation. The Cigna name, logo, and other Cigna marks are owned by Cigna Intellectual Property, Inc. 2018 Cigna. Page 6 of 6