Cigna Drug and Biologic Coverage Policy

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1 Cigna Drug and Biologic Coverage Policy Subject Eculizumab Table of Contents Coverage Policy... 1 General Background... 4 Coding/Billing Information... 5 References... 6 Effective Date... 8/15/2018 Next Review Date... 7/15/2019 Coverage Policy Number Related Coverage Resources Medication Administration Site of Care (1605) Routine Immunizations - (9001) 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 eculizumab (Soliris ) as medically necessary for ANY of the following indications: confirmed diagnosis of complement-mediated hemolytic uremic syndrome (atypical hemolytic uremic syndrome) as evidenced by BOTH of the following: o Diagnosis of thrombocytopenic purpura (TTP) has been excluded (for example, normal ADAMTS 13 activity) OR a trial of plasma exchange did not result in clinical improvement o Absence of Shiga toxin-producing escherichia coli (E. coli) infection Initial authorization, for complement-mediated atypical hemolytic uremic syndrome (atypical hemolytic uremic syndrome) will be for up to 6 months. Reauthorization requires meeting initial criteria AND documentation of a positive clinical response. paroxysmal nocturnal hemoglobinuria (PNH) when BOTH of the following have been met: o Flow cytometry demonstrates one of the following: At least 10% PNH type III red cells OR Greater than 50% of glycosylphosphatidylinositol-anchored proteins (GPI-AP)- deficient polymorphonuclear cells (PMNs) AND o At least one transfusion related to anemia secondary to PNH OR occurrence of a thromboembolic event Initial authorization, for paroxysmal nocturnal hemoglobinuria (PNH)) will be for up to 6 months. Reauthorization requires meeting initial criteria AND documentation of a positive clinical response. Page 1 of 7

2 generalized Myasthenia Gravis (gmg), that is non-ocular and persistent, in adults when ALL of the following criteria are met: o Positive serologic test for anti-acetylcholine receptor (AChR) antibody o Individual has not had a thymectomy in the previous 12 months o Individual has failed* treatment over 1 year or more with ONE of the following: Treatment with at least two immunosuppressive agents (for example, azathioprine, prednisone) Treatment with at least one immunosuppressive agent and required chronic plasma exchange or intravenous immunoglobulin (IVIg) *Note: Failure is defined as one of the following: o Difficulty breathing or swallowing o Functional disability responsible for discontinuation of physical activity Initial authorization, for generalized Myasthenia Gravis (gmg), will be for 3 months Reauthorization, generalized Myasthenia Gravis (gmg), will be for up to 6 months Reauthorization requires meeting initial criteria AND documentation of a positive clinical response. Cigna does NOT cover the use of eculizumab (Soliris) for any other indication including the following because it is considered experimental, investigational or unproven (this list may not be all-inclusive): acute antibody mediated rejection chronic antibody-mediated rejection in recipients with persistently high B flow crossmatch after positive crossmatch kidney transplantation geographic atrophy in age-related macular degeneration relapsing neuromyelitis optica prevention of delayed graft function systemic lupus erythematosus stem cell transplant-associated thrombotic microangiopathy typical hemolytic uremic syndrome (HUS) 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 eculizumab (Soliris) therapy. Note: Receipt of sample product does not satisfy any criteria requirements for coverage FDA Approved Indication Paroxysmal Nocturnal Hemoglobinuria (PNH) Soliris is indicated for the treatment of patients with PNH to reduce hemolysis. Atypical Hemolytic Uremic Syndrome (ahus) Soliris is indicated for the treatment of patients with ahus to inhibit complement-mediated thrombotic microangiopathy Limitation of use: Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). Generalized Myasthenia Gravis (gmg) Soliris is indicated for the treatment of adult patients with gmg who are anti-acetylcholine receptor (AchR) antibody positive. FDA Recommended Dosing Patients must be administered a meningococcal vaccine at least two weeks prior to initiation of Soliris therapy and revaccinated according to current medical guidelines for vaccine use. Complement-mediated hemolytic uremic syndrome Page 2 of 7

3 For patients 18 years of age and older, Soliris therapy consists of 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every 2 weeks thereafter. Soliris should be administered at the recommended dosage regimen time points, or within two days of these time points. For patients less than 18 years of age, administer Soliris based upon body weight in the following table: Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly x 4 doses 1200 mg at week 5; then 1200 mg every 2 weeks 30 kg to less than 40 kg 600 mg weekly x 2 doses 900 mg at week 3; then 900 mg every 2 weeks 20 kg to less than 30 kg 600 mg weekly x 2 doses 600 mg at week 3; then 600 mg every 2 weeks 10 kg to less than 20 kg 600 mg weekly x 1 dose 300 mg at week 2; then 300 mg every 2 weeks 5 kg to less than 10 kg 300 mg weekly x 1 dose 300 mg at week 2; then 300 mg every 3 weeks PNH For patients 18 years of age and older, Soliris therapy consists of 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Soliris should be administered at the recommended dosage regimen time points, or within two days of these time points. gmg Soliris therapy consists of 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every 2 weeks thereafter. Soliris should be administered at the recommended dosage regimen time points, or within two days of these time points. For adult and pediatric patients with ahus and adult patients with gmg, supplemental dosing of Soliris is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI). Supplemental Dose of Soliris after PE/PI Type of Plasma Intervention Plasmapheresis or plasma exchange Fresh frozen plasma infusion Most Recent Soliris Dose 300 mg 600 mg 300 mg Supplemental Soliris Dose With Each Plasma Intervention 300 mg per each plasmapheresis or plasma exchange session 600 mg per each plasmapheresis or plasma exchange session 300 mg per infusion of fresh frozen plasma Timing of Supplemental Soliris Dose Within 60 minutes after each plasmapheresis or plasma exchange 60 minutes prior to each infusion of fresh frozen plasma Drug Availability Soliris is supplied as 300 mg single-use vials containing 30 ml of 10 mg/ml solution per vial. Because of the risk of meningococcal infections, Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program. Prescribers must counsel patients about the risk of meningococcal infection, provide the patients with the REMS educational materials, and ensure patients are vaccinated with a meningococcal vaccine. Page 3 of 7

4 General Background Pharmacology Eculizumab is a recombinant humanized IgG monoclonal antibody. The drug binds specifically and with high affinity to the complement protein C5, preventing activation of terminal complement components. Eculizumab prevents the cleavage of complement protein C5 into C5a and C5b, thereby blocking subsequent formation of the C5b-C9 terminal complement complex (also referred to as the membrane attack complex). Eculizumab is an option for patients whose current hemolysis prevention therapy is limited by medication toxicity or inconsistent efficacy. (McEvoy, 2017) Guidelines American Society of Hematology (ASH) - PNH Although ASH has not published any formal practice guidelines for the treatment of PNH, the organization provides a framework for individualizing treatment based on disease classification. Eculizumab for the treatment of PNH is a well-tolerated long-term (> 8 years) therapy that shows improvement in PNH associated symptoms, a reduction in transfusion requirements and a higher proportion of transfusion independent patients than previously seen in other therapies. There is a significant reduction in the development of thromboembolism on eculizumab therapy and most importantly, some patients have been able to stop primary prophylaxis with warfarin without any thrombotic complications. (ASH, 2010) ASH Complement-mediated hemolytic uremic syndrome There are no published guidelines or framework available for ahus. However, ASH has published documents relating to the correct diagnosis of the disease. Typical HUS and STEC-HUS are caused by external factors (bacteria, virus, etc.) and are accompanied by the presence of bloody diarrhea. A confirmed positive Shiga toxin test will confirm a diagnosis of STEC-HUS. The clinical context, predominant symptoms, and basic laboratory data at presentation may allow differentiation into thrombotic thrombocytopenic purpura (TTP). The presence of an ADAMTS 13 deficiency allows a tentative diagnosis of TTP in some patients. ADAMTS 13 is a protein secreted in the blood that helps regulate clotting by cutting through von Willebrand factor. If a patient has less than 5% of normal ADAMTS13 levels, then TTP is the likely disease. ahus should be considered when TTP or typical HUS seem less likely, when no other disease can be identified that would account for the presenting signs and symptoms, when the ADAMTS 13 levels are greater than 5%, and when the systemic C3 complement level is low. (ASH, 2010) American Academy of Neurology (AAN) gmg The AAN, International consensus guidance for management of myasthenia gravis, states that pyridostigmine should be part of the initial treatment in most patients with MG. Corticosteroids or immunosuppressive therapy should be used in all patients with MG who have not met treatment goals after an adequate trial of pyridostigmine. The following therapies may be used in refractory MG: Cyclophosphamide, Chronic IVIg and chronic plasma exchange (PLEX). Evidence of efficacy for rituximab is building, but a formal consensus could not be reached. The statement does not address the use of eculizumab in myasthenia gravis. (Sanders, 2016) Clinical Efficacy PNH Clinical experience with eculizumab is limited to three case reports, an open-label pilot study, a 52-week extension of the pilot study, and one randomized, double-blind, placebo-controlled, multicenter trial. Eculizumab was well tolerated and increased quality of life in all of these studies. In the 26-week experimental trial, stabilization of hemoglobin concentrations was established in 49% of eculizumab patients compared to no patients in the placebo group, and the median number of units of RBCs transfused was zero units in the eculizumab group versus 10 units in the placebo group. (Hillmen, 2006) Flow cytometry is an important point of differentiation in the three categories of clinical PNH. In diagnosing classic PNH, flow cytometry reveals greater than 50% GPI-AP deficient PMNs. This is in contrast to PNH in the setting of other syndromes where bone marrow is dysfunctional, such as aplastic anemia (AA) or low-risk myelodysplastic syndrome (MDS). In cases of AA or low-risk MDS, analysis by flow cytometry demonstrates generally less than 10% GPI-AP deficient PMNs. (Hillmen, 2006) Page 4 of 7

5 Complement-mediated hemolytic uremic syndrome A diagnosis of ahus includes a confirmation of TMA signs and symptoms as evidenced by hemolysis, impaired renal function, and/or thrombocytopenia. Data published from two pivotal trials shows Soliris substantially inhibits systemic complement-mediated TMA, decreases the need for TMA-related intervention, results in significant and sustained improvement in platelet count, increasingly improves renal function across patient groups over time, and is associated with substantial kidney recovery in patients with ahus. In addition, chronic Soliris treatment leads to reversal of vital organ damage and significant improvements in health-related quality of life. The study data also indicate that earlier intervention with Soliris improves clinical outcomes. (Legendre, 2013) The two prospective phase 2 trials studied 37 (17 in trial 1 and 20 in trial 2) patients 12 years of age or older who received eculizumab for 26 weeks and during long-term extension phases. Inclusion criteria included low platelet counts and renal damage in trial 1 and renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion in trial 2. The primary end points included a change in the platelet count in trial 1 and TMA event free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) in trial 2. Eculizumab resulted in increases in the platelet count in trial 1. In trial 2, 80% of the patients had TMA event free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). (Legendre, 2013) gmg Clinical experience with eculizumab is limited to a phase 3, 26 week randomized, double-blind, placebocontrolled trial. In the REGAIN trial, 125 adult individuals, with a diagnosis of myasthenia gravis received either eculizumab or placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group) and gender. Approximately 50% of each group had been previously treated with at least 3 immunosuppressive therapies (ISTs). The primary efficacy endpoint was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score at Week 26. A statistically significant difference favoring Soliris was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4.2 points in the Soliris treated group compared with -2.3 points in the placebo-treated group. A key secondary endpoint in the REGAIN trial was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. A statistically significant difference favoring Soliris was observed in the mean change from baseline to Week 26 in QMG total scores [-4.6 points in the Soliris-treated group compared with -1.6 points in the placebo-treated group. (Alexion, 2018) Experimental Investigational, Unproven Uses Results of the Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year study demonstrated eculizumab treatment does not prevent chronic antibody-mediated rejection in recipients with persistently high B flow crossmatch after positive crossmatch kidney transplantation. (Cornell, 2015) Results of the Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study, failed to demonstrate any treatment effect in this condition. (Yehoshua, 2014) Case series, randomized controlled trials, systematic reviews, and/or meta-analysis have investigated eculizumab for numerous conditions/indications, including the following: relapsing neuromyelitis optica (Pittock, 2013), prevention of delayed graft function (Alexion, 2015), acute antibody mediated rejection (Sadaka, 2013), systemic lupus erythematosus (El-Husseini, 2015) and stem cell transplant-associated thrombotic microangiopathy (de Fontbrune, 2015) Coding/Billing Information Note: 1) This list of codes may not be all-inclusive. Page 5 of 7

6 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 J1300 Description Injection, eculizumab, 10 mg References 1. ACIP Recommendations. Use of Serogroup B Meningococcal (MenB) Vaccines in Persons Aged 10 Years at Increased Risk for Serogroup B Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices, Accessed May 30, Available at: 2. Alexion Pharmaceuticals Inc. Soliris (eculizumab) [package insert]. Cheshire, CT: Alexion Pharmaceuticals. February Alexion Pharmaceuticals Inc. Prevention of Delayed Graft Function Using Eculizumab Therapy (PROTECT Study). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2015 Jun 9]. Available from NLM Identifier:NCT Alexion Pharmaceuticals Inc. A Double Blind Trial To Evaluate The Safety And Efficacy Of Eculizumab In Relapsing NMO Patients (PREVENT Study). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2015 Jun 9]. Available from NLM Identifier: NCT American Society of Hematology (ASH) annual meeting and exposition, Dec Accessed 5/21/2018. Available at: 6. Cornell LD, Schinstock CA, Gandhi MJ, et al. Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. Am J Transplant May; 15(5): de Fontbrune FS, Galambrun C, Sirvent A, et al. Use of Eculizumab in Patients With Allogeneic Stem Cell Transplant-Associated Thrombotic Microangiopathy: A Study From the SFGM-TC. Transplantation Sep;99(9): El-Husseini A, Hannan S, Awad A. Thrombotic microangiopathy in systemic lupus erythematosus: efficacy of eculizumab. Am J Kidney Dis Jan;65(1): Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. Sep ; 355(12): Howard Jr JF, Barohn RJ, Cutter GR, et al. A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle & Nerve.Mar ; 48: Kim M, Martin ST, Townsend KR et al. Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options. Pharmacotherapy 2014; 34(7): Legendre, et.al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med Jun 6; 368(23): McEvoy GK, Pharm.D., ed AHFS Drug Information - 59th Ed. Bethesda, MD. American Society of Health-System Pharmacists 14. Pittock SJ, Lennon VA, McKeon A, et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol Apr ; 12: Sadaka B, Alloway RR, Woodle ES. Management of antibody-mediated rejection in transplantation. Surgical Clinics of North America 2013; 93(6): Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology Jul 26;87(4): Accessed 6/4/2018. Page 6 of 7

7 17. Yehoshua Z, de Amorim C, Nunes R, et al. Systemic complement inhibition with eculisumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthamology 2014 Mar; 121(3): 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 Cigna. Page 7 of 7