Drug and Biologic Coverage Policy

Effective Date ...... 1/1/2021 Next Review Date… ...... 1/1/2022 Coverage Policy Number ...... 1103

Complement Inhibitors

Table of Contents Related Coverage Resources

Overview ...... 1 CP 1605 Medication Administration Site of Care Coverage Policy ...... 1 CP 9001 Routine Immunizations Background ...... 5 Coding/ Billing Information ...... 9 References ...... 10

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.

Overview

This policy supports medical necessity review of eculizumab (Soliris®) and ravulizumab (Ultomiris™).

Complement Inhibitors includes the following products: • Eculizumab (Soliris®) • Ravulizumab (UltomirisTM)

Coverage Policy

Eculizumab (Soliris)

Eculizumab (Soliris) is considered medically necessary when ANY of the following criteria are met: 1. Confirmed diagnosis of Complement-mediated hemolytic uremic syndrome (atypical hemolytic uremic syndrome) as evidenced by ALL of the following: A) 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 B) Absence of Shiga toxin-producing escherichia coli (E. coli) infection C) Eculizumab is prescribed by, or in consultation, with a hematologist and/or a nephrologist

Page 1 of 10 Coverage Policy Number: 1103 D) Individual has been vaccinated against meningococcal infection (at least 2 weeks prior to treatment, if not previously vaccinated), where and when clinically appropriate

Initial authorization is up to 6 months.

Eculizumab is considered medically necessary for continued use when the initial criteria are met AND there is documentation of a positive clinical response (for example, reduced hemolysis, improved thrombocytopenia or renal function).

Reauthorization for up to 12 months.

2. Generalized Myasthenia Gravis (gMG), that is non-ocular and persistent, in adults when ALL of the following criteria are met: A) 18 years of age and older B) Positive serologic test for anti-acetylcholine receptor (AChR) antibody C) Individual has not had a thymectomy in the previous 12 months D) Individual has failed* treatment over 1 year or more with ONE of the following: i. Treatment with at least two immunosuppressive agents (for example, azathioprine, prednisone) ii. Treatment with at least one immunosuppressive agent and required chronic plasma exchange or intravenous immunoglobulin (IVIg)

*Note: Failed is defined as one of the following: • Persistent symptoms of generalized myasthenia (for example, difficulty breathing or swallowing) • Reduced physical activity due to generalized symptoms of myasthenia (for example, double vision, talking, impairment of mobility)

E) Eculizumab is prescribed by, or in, consultation with a neurologist F) Individual has been vaccinated against meningococcal infection (at least 2 weeks prior to treatment, if not previously vaccinated) where and when clinically appropriate

Initial authorization is up to 3 months.

Eculizumab is considered medically necessary for continued use in gMG when the initial criteria are met AND there is documentation of a positive clinical response (for example, reductions in exacerbations of MG; improvements in speech, swallowing, mobility, and respiratory function, improvement in MG ADL or QMG scores).

Reauthorization for up to 6 months.

3. Neuromyelitis Optica Spectrum Disorder (NMOSD) when ALL of the following have been met: A) Neuromyelitis optica spectrum disorder diagnosis confirmed by blood serum test for anti- aquaporin-4 antibody positive B) Individual is 18 years of age or older C) Documentation of failure or inadequate response [history of at least one relapse (acute attack from neuromyelitis spectrum disorder) in the last 12 months, or two relapses in the last 2 years] to ONE of the following systemic therapies; OR a Contraindication per FDA label or significant intolerance to ALL of the following systemic therapies: i. Azathioprine ii. Mycophenolate mofetil iii. *Rituximab

*Note: May require prior authorization

Page 2 of 10 Coverage Policy Number: 1103 Note: An exception to the requirement of systemic therapy can be made if the individual has already failed or had an inadequate response Enspryng (satralizumab) or Uplizna (inebilizumab) for neuromyelitis optica spectrum disorder.

D) Eculizumab is prescribed by, or in, consultation with a neurologist E) Individual has been vaccinated against meningococcal infection (at least 2 weeks prior to treatment, if not previously vaccinated) where and when clinically appropriate

Initial authorization is up to 12 months

Eculizumab (Soliris) is considered medically necessary for continued use in NMOSD when the initial criteria are met AND there is documentation of beneficial response.

Note: Examples of clinical benefit include: reduction in relapse rate, reduction in symptoms (for example, pain, fatigue, motor function), or a slowing progression in symptoms.

Reauthorization for up to 12 months.

4. Paroxysmal nocturnal hemoglobinuria (PNH) when ALL of the following have been met: A) Flow cytometry demonstrates one of the following: i. At least 10% PNH type III red cells OR ii. Greater than 50% of glycosylphosphatidylinositol-anchored proteins (GPI-AP)- deficient polymorphonuclear cells (PMNs) AND B) At least one transfusion related to anemia secondary to PNH OR occurrence of a thromboembolic event C) Eculizumab prescribed by, or in consultation, with a hematologist D) Individual has been vaccinated against meningococcal infection (at least 2 weeks prior to treatment, if not previously vaccinated) where and when clinically appropriate

Initial authorization is up to 6 months.

Eculizumab is considered medically necessary for continued use when the initial criteria are met AND there is documentation of a positive clinical response (for example, stabilization of hemoglobin levels, decreased transfusion requirements or transfusion independence, reductions in hemolysis).

Reauthorization for up to 12 months.

Conditions Not Covered

Eculizumab is considered experimental, investigational or unproven for ANY other use including the following: • Acute antibody mediated rejection • Chronic antibody-mediated rejection in recipients with persistently high B flow crossmatch after positive crossmatch kidney transplantation • Concomitant use with a rituximab product, Enspryng™ (satralizumab-mwge), or Uplizna™ (inebilizumab- cdon injection). • Geographic atrophy in age-related macular degeneration • Prevention of delayed graft function • Systemic lupus erythematosus • Stem cell transplant-associated thrombotic microangiopathy • Typical hemolytic uremic syndrome (HUS)

Page 3 of 10 Coverage Policy Number: 1103 Ravulizumab (Ultomiris)

Ravulizumab (Ultomiris) is considered medically necessary when EITHER of the following criteria are met: 1. Confirmed diagnosis of complement-mediated hemolytic uremic syndrome (atypical hemolytic uremic syndrome) as evidenced by ALL of the following: A) 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 B) Absence of Shiga toxin-producing escherichia coli (E. coli) infection C) Ravulizumab is prescribed by, or in consultation, with a hematologist and/or a nephrologist D) Individual has been vaccinated against meningococcal infection (at least 2 weeks prior to treatment, if not previously vaccinated) where and when clinically appropriate

Initial authorization is up to 6 months.

Ravulizumab is considered medically necessary for continued use when the initial criteria are met AND there is documentation of a positive clinical response.

Reauthorization for up to 12 months.

2. Paroxysmal nocturnal hemoglobinuria (PNH) when ALL of the following have been met: A) Flow cytometry demonstrates one of the following: i. At least 10% PNH type III red cells OR ii. Greater than 50% of glycosylphosphatidylinositol-anchored proteins (GPI-AP)- deficient polymorphonuclear cells (PMNs) AND B) At least one transfusion related to anemia secondary to PNH OR occurrence of a thromboembolic event C) Ravulizumab prescribed by, or in consultation, with a hematologist D) Individual has been vaccinated against meningococcal infection (at least 2 weeks prior to treatment, if not previously vaccinated) where and when clinically appropriate

Initial authorization is up to 6 months.

Ravulizumab is considered medically necessary for continued use when the initial criteria are met AND there is documentation of a positive clinical response (for example, stabilization of hemoglobin levels, decreased transfusion requirements or transfusion independence, reductions in hemolysis).

Reauthorization for up to 12 months.

Conditions Not Covered

Ravulizumab is considered experimental, investigational or unproven for ANY other use.

Soliris / Ultomiris

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 therapy.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage.

Documentation: When documentation is required, the prescriber must provide written documentation supporting the trials of these other agents. Documentation may include, but is not limited to, chart notes, prescription claims records, and/or prescription receipts.

Page 4 of 10 Coverage Policy Number: 1103 Background

Overview

I. Soliris Soliris, a complement inhibitor, is indicated for the following uses:1 • Atypical hemolytic uremic syndrome (aHUS), to inhibit complement-mediated thrombotic microangiopathy. • Generalized myasthenia gravis (gMG), in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. • Neuromyelitis optica spectrum disorder (NMOSD), in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. • Paroxysmal nocturnal hemoglobinuria (PNH), to reduce hemolysis.

Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome. The safety and effectiveness of Soliris for the treatment of PNH, gMG, and NMOSD in pediatric patients have not been established. The safety and effectiveness of Soliris in pediatric patients for aHUS is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of Soliris for the treatment of aHUS. (Soliris FDA PI, 2019)

II. Ultomiris Ultomiris, a complement inhibitor, is for the following uses: • Treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). • Treatment of adults and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

The safety and effectiveness of Ultomiris for the treatment of PNH in pediatric patients have not been established. PNH is a clinical diagnosis that should be confirmed with peripheral blood flow cytometry to detect the absence or severe deficiency of GPI-anchored proteins on at least two lineages. The recommended dosing regimen for adults with PNH consists of a weight-based loading dose (dosage range: 2,400 mg to 3,000 mg) followed by maintenance dosing (dosage range: 3,000 mg to 3,600 mg), administered by intravenous (IV) infusion. Starting 2 weeks after the loading dose administration, begin maintenance doses at a once every 8-week interval. The recommended dosing regimen for patients with aHUS consists of a weight-based loading dose (dosage range: 600 mg to 3,000 mg) followed by maintenance dosing (dosage range: 300 mg to 3,600 mg), administered by intravenous (IV) infusion. Starting 2 weeks after the loading dose administration, begin maintenance doses at a once every 4-week interval for patients ≥ 5 kg to < 20 kg or at a once every 8-week interval for patients ≥ 20 kg. For both PNH and aHUS the dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (with the exception of the first maintenance dose) but the subsequent dose should be administered according to the original schedule. (Ultomiris FDA PI, 2019; Brodsky, 2014)

Ultomiris has a Boxed Warning regarding life-threatening and fatal meningococcal infections. Meningococcal infections have occurred in patients receiving Ultomiris and may become rapidly life- threatening or fatal if not recognized and treated early. Ultomiris is contraindicated in patients with unresolved serious Neisseria meningitides infection. Ultomiris has a Risk Evaluation and Mitigation Strategy (REMS) program to mitigate the occurrence and morbidity associated with meningococcal infections. The REMS program also educates healthcare professionals and patients regarding the increased risk of meningococcal infections with Ultomiris, the early signs of invasive meningococcal infections, and the need for immediate medical evaluation of signs and symptoms consistent with possible meningococcal infections. (Ultomiris FDA PI, 2019)

FDA Recommended Dosing Patients must be administered a meningococcal vaccine at least two weeks prior to initiation of complement inhibitor therapy and revaccinated according to current medical guidelines for vaccine use.

Page 5 of 10 Coverage Policy Number: 1103 I. Eculizumab (Soliris) • PNH For patients 18 years of age and older, Soliris therapy consists of: o 600 mg weekly for the first 4 weeks, followed by o 900 mg for the fifth dose 1 week later, then o 900 mg every 2 weeks thereafter Administer Soliris at the recommended dosage regimen time points, or within two days of these time points.

• aHUS For patients 18 years of age and older, Soliris therapy consists of: o 900 mg weekly for the first 4 weeks, followed by o 1200 mg for the fifth dose 1 week later, then o 1200 mg every 2 weeks thereafter.

For patients less than 18 years of age, administer Soliris based upon body weight, according to the following schedule (Table 1): Table 1: Dosing Recommendations in Patients Less Than 18 Years of Age Patient Body Weight Induction Maintenance 1200 mg at week 5; 40 kg and over 900 mg weekly x 4 doses then 1200 mg every 2 weeks 900 mg at week 3; then 900 30 kg to less than 40 kg 600 mg weekly x 2 doses mg every 2 weeks 600 mg at week 3; then 600 20 kg to less than 30 kg 600 mg weekly x 2 doses mg every 2 weeks 300 mg at week 2; then 300 10 kg to less than 20 kg 600 mg weekly x 1 dose mg every 2 weeks 300 mg at week 2; then 300 5 kg to less than 10 kg 300 mg weekly x 1 dose mg every 3 weeks

Administer Soliris at the recommended dosage regimen time points, or within two days of these time points.

• gMG and NMOSD For patients with generalized myasthenia gravis or neuromyelitis optica spectrum disorder, Soliris therapy consists of: o 900 mg weekly for the first 4 weeks, followed by o 1200 mg for the fifth dose 1 week later, then o 1200 mg every 2 weeks thereafter.

Administer Soliris at the recommended dosage regimen time points, or within two days of these time points.

• Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion 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) (Table 2).

Table 2: Supplemental Dose of Soliris after PE/PI Type of Plasma Most Recent Soliris Supplemental Soliris Timing of Intervention Dose Dose With Each Supplemental Soliris Plasma Intervention Dose Plasmapheresis or 300 mg per each Within 60 minutes 300 mg plasma exchange plasmapheresis or after each

Page 6 of 10 Coverage Policy Number: 1103 Type of Plasma Most Recent Soliris Supplemental Soliris Timing of Intervention Dose Dose With Each Supplemental Soliris Plasma Intervention Dose plasma exchange plasmapheresis or session plasma exchange 600 mg per each plasmapheresis or ≥600 mg plasma exchange session 60 minutes prior to Fresh frozen plasma 300 mg per infusion of ≥300 mg each infusion of fresh infusion fresh frozen plasma frozen plasma

II. Ravulizumab (Ultomiris) • PNH The recommended dosing regimen in adult patients with PNH weighing 40 kg or greater, consists of a loading dose followed by maintenance dosing, administered by intravenous infusion. Administer the doses based on the patient’s body weight, as shown in Table 1. Starting 2 weeks after the loading dose administration, begin maintenance doses at a once every 8-week interval.

The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of Ultomiris); but the subsequent doses should be administered according to the original schedule.

Table 1: Ultomiris Weight-Based Dosing Regimen Body Weight Range (kg) Loading Dose (mg) Maintenance Dose (mg) and Dosing Interval 40 to less than 60 2,400 3,000 60 to less than 100 2,700 3,300 Every 8 weeks 100 or greater 3,000 3,600

• aHUS The recommended dosing regimen in adult and pediatric patients one month of age and older with aHUS weighing 5 kg or greater, consists of a loading dose followed by maintenance dosing, administered by intravenous infusion. Administer the doses based on the patient’s body weight, as shown in Table 2. Starting 2 weeks after the loading dose administration, begin maintenance doses once every 8 weeks or every 4 weeks (depending on body weight).

The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but the subsequent doses should be administered according to the original schedule.

Table 4: Ultomiris Weight-Based Dosing Regimen Body Weight Range Loading Dose (mg) Maintenance Dose (mg) and Dosing (kg) Interval 5 to less than 10 600 300 Every 4 weeks 10 to less than 20 600 600 20 to less than 30 900 2,100 30 to less than 40 1,200 2,700 40 to less than 60 2,400 3,000 Every 8 weeks 60 to less than 100 2,700 3,300 100 or greater 3,000 3,600

Page 7 of 10 Coverage Policy Number: 1103 Drug Availability Because of the risk of meningococcal infections, complement inhibitors are available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris and Ultomiris 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.

I. Eculizumab (Soliris) Supplied as 300 mg single-use vials containing 30 mL of 10 mg/mL solution per vial.

II. Ravulizumab (Ultomiris) • Ultomiris 100 mg/mL: . Injection: 300 mg/3 mL (100 mg/mL) and 1,100 mg/11 mL (100 mg/mL) as a translucent, clear to yellowish color solution in a single-dose vial. • Ultomiris 10 mg/mL . Injection: 300 mg/30 mL (10 mg/mL) as a clear to translucent, slight whitish color solution in a single-dose vial.

Disease Overview

Myasthenia Gravis Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease that causes weakness in the skeletal muscles, which are responsible for breathing and moving parts of the body, including the arms and legs. The hallmark of myasthenia gravis is muscle weakness that worsens after periods of activity and improves after periods of rest. Certain muscles such as those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are often involved in the disorder; however, the muscles that control breathing and neck and limb movements may also be affected. Acquired MG results from the binding of autoantibodies to components of the neuromuscular junction, most commonly the AChR. (NINDS, 2020; Sanders, 2016)

Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder involving bone marrow failure that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias. Due to the absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, uncontrolled complement activation leads to hemolysis and other PNH manifestations. GPI anchor protein deficiency is often due to mutations in phosphatidylinositol glycan class A (PIGA), a gene involved in the first step of GPI anchor biosynthesis. Prior to the availability of Soliris® (eculizumab injection for IV) [a complement inhibitor]3, there was no specific therapy for PNH with only supportive management in terms of the cytopenias and control of thrombotic risk. Supportive measures used include platelet transfusion, immune suppressive therapy for patients with bone marrow failure, use of erythropoietin for anemias, and aggressive anticoagulation. Soliris is the treatment of choice for patients with severe manifestations of PNH. Bone marrow transplantation is the only cure for PNH but should be reserved for patients with a suboptimal response to medication. (Brodsky, 2014)

Hemolytic Uremic Syndrome Hemolytic uremic syndrome (HUS) is defined as the triad of non-immune hemolytic anemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). The TMA process that characterizes HUS can be caused by a variety of things. Atypical HUS (aHUS) is a sub-type of HUS in which TMA are the consequence of endothelial damage in the microvasculature of the kidneys and other organs due to a dysregulation of the activity of the complement system. Various aHUS- related mutations have been identified in genes of the complement system, which can explain approximately 60% of the aHUS cases, and a number of mutations and polymorphisms have been functionally characterized. aHUS should be distinguished from a more common condition referred to as typical HUS. The two disorders have different causes and different signs and symptoms. Unlike aHUS, the typical form is caused by infection with certain strains of Escherichia coli (E. coli) bacteria that produce toxic substances called Shiga-like toxins. The typical form is characterized by severe diarrhea and most often affects children < 10 years of age, and it is less likely than aHUS to involve recurrent attacks of kidney damage that lead to end stage renal disease

Page 8 of 10 Coverage Policy Number: 1103 (ESRD). The incidence of aHUS is estimated to be 1:500,000 people/year in the US; aHUS is approximately 10 times less common than typical HUS. (Campistol, 2015)

Neuromyelitis Optica Spectrum Disorder NMOSD is a rare, relapsing, autoimmune disorder of the brain and spinal cord with optic neuritis and/or myelitis as predominate characteristic symptoms. NMOSD often causes significant, permanent damage to vision and/or spinal cord function causing blindness or impaired mobility.3 Patients may experience pain, paralysis, loss of bowel and bladder control, loss of visual acuity, uncontrolled motor functions, and complications can cause death. Uplizna™ (inebilizumab-cdon injection for intravenous infusion) and Enspryng™ (satralizumab-mwge for subcutaneous injection) are two other FDA-approved medications for treatment of NMOSD in adults who are anti-AQP4 antibody-positive. For acute attacks, typical treatment is high-dose intravenous corticosteroids. Plasma exchange may be effective in patients who suffer acute severe attacks that do not response to intravenous corticosteroids. For long-term control of the disease a variety of immunosuppressive drugs are utilized as first-line therapy. While all are considered off-label use, corticosteroids, azathioprine, mycophenolate mofetil, and rituximab are treatments prescribed as preventative therapy. (NORD, 2020; NIH, 2020)

Guidelines An international consensus guidance for the management of MG was published in 2016 and do not address Soliris. The guidelines recommend pyridostigmine for the initial treatment in most patients with MG. The ability to discontinue pyridostigmine can indicate that the patient has met treatment goals and may guide the tapering of other therapies. Corticosteroids or immunosuppressant therapy should be used in all patients with MG who have not met treatment goals after an adequate trial of pyridostigmine. Nonsteroidal immunosuppressant agents include azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, and tacrolimus. It is usually necessary to maintain some immunosuppression for many years, sometimes for life. Plasma exchange and intravenous immunoglobulin can be used as short-term treatments in certain patients. The guidelines note that few physicians treat enough patients with MG to be comfortable with all available treatments. (Sanders, 2016)

Conditions Not Covered Results of the Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond one 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. 2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement.

Considered Medically Necessary when criteria in the applicable policy statements listed above are met:

HCPCS Description Codes C9052 Injection, ravulizumab-cwvz, 10 mg (Code effective 07/01/2019) (Code deleted 09/30/2019)

Page 9 of 10 Coverage Policy Number: 1103 HCPCS Description Codes J1303 Injection, ravulizumab-cwvz, 10 mg J1300 Injection, eculizumab, 10 mg

*Current Procedural Terminology (CPT®) ©2019 American Medical Association: Chicago, IL.

References 1. Alexion Pharmaceuticals Inc. Prevention of Delayed Graft Function Using Eculizumab Therapy (PROTECT Study). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2015 Jun 9]. Available from http://clinicaltrials.gov/show/NCT02145182 NLM Identifier:NCT02145182. 2. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804–2811 3. Campistol JM, Arias M, Ariceta G, et al. An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. Nefrologia. 2015;35:421–447. 4. Cornell LD, Schinstock CA, Gandhi MJ, et al. Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. Am J Transplant. 2015 May; 15(5):1293-302. 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. 2015 Sep;99(9):1953-9. 6. El-Husseini A, Hannan S, Awad A. Thrombotic microangiopathy in systemic lupus erythematosus: efficacy of eculizumab. Am J Kidney Dis. 2015 Jan;65(1):127-30. 7. Genetics Home Reference. Atypical hemolytic-uremic syndrome. National Institutes of Health (NIH). Available at: https://ghr.nlm.nih.gov/condition/atypical-hemolytic-uremic-syndrome#sourcesforpage. Accessed on May 19, 2020. 8. Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016;31(1):15-39. 9. National Institute of Health, U.S. National Library of Medicine. Genetics Home Reference. Neuromyelitis optica. Available at: https://ghr.nlm.nih.gov/condition/neuromyelitis-optica#genes. Accessed May 19, 2020. 10. National Institute of Neurological Disorders and Stroke (NINDS). Myasthenia Gravis Fact Sheet. National Institutes of Health (NIH) Publication No. 17-768. Publication last updated: April 27, 2020. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Myasthenia-Gravis-Fact- Sheet. Accessed on May 19, 2020. 11. National Organization for Rare Disorders. Neuromyelitis Optica Spectrum Disorder. Available at: https://rarediseases.org/rare-diseases/neuromyelitis-optica/. Accessed May 19, 2020. 12. 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 26 2013; 12:554-62. 13. Sadaka B, Alloway RR, Woodle ES. Management of antibody-mediated rejection in transplantation. Surgical Clinics of North America 2013; 93(6):1451-66. 14. Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis. Neurology. 2016;87:419–425. 15. Soliris® injection [prescribing information]. New Haven, CT: Alexion Pharmaceuticals, Inc.; June 2019. 16. Taylor CM, Machin S, Wigmore SJ, et al. Clinical Practice Guidelines for the management of atypical Haemolytic Uraemic Syndrome in the United Kingdom. Br J Haematol. 2010;148(1):37-47. 17. Ultomiris™ injection [prescribing information]. New Haven, CT: Alexion Pharmaceuticals, Inc.; October 2019. 18. 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. Ophthalmology 2014 Mar; 121(3):693- 701.

“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. © 2021 Cigna.

Page 10 of 10 Coverage Policy Number: 1103