Complement Inhibitors

POLICY NUMBER

L.5.01.544

Piasky (crovalimab-akkz)

Soliris (eculizumab)

Ultomiris (ravulizumab-cwvz)

Zilbrysq (zilucoplan)

Please perform a formulary drug search on your patient’s member ID to ensure the prescription drug is covered under their benefit plan. The medication(s) in this medical policy may not be covered under a specific member’s benefit plan.

DESCRIPTION

The complement system is a major component of innate immunity and a “complement” to antibody-triggered responses. The complement system is made up of nearly 60 plasma and membrane proteins that form three activating pathways, a terminal lytic cascade, and a network of regulators and receptors. The three major functions of complement include identification of foreign materials and damaged self, elimination of these targets, and promotion of inflammatory and immune responses to these targets. Due to the broad functional reach of complement, dysregulation contributes to a wide range of diseases. Inappropriate, uncontrolled, and/or chronic complement activation can induce inflammatory or autoimmune conditions. Treatments aimed at harnessing complement inhibition aim to prevent undesirable activation.

Eculizumab, ravulizumab, crovalimab, and zilucoplan are is monoclonal antibodies that specifically bind to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement components. Ravulizumab was engineered from eculizumab to have an extended half-life and longer duration of action.

FDA APPROVED INDICATIONS

Soliris (eculizumab) is indicated for the treatment of adult patients (>18 years of age) with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis, for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy, for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive, and for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

Ultomiris (ravulizumab-cwvz) is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH) for the 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), for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive, and for the treatment of adult patients with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaphorin-4 (AQP4) antibody positive.

Piasky (crovalimab-akkz) is indicated for the treatment of adult and pediatric patients 13 years and older with paroxysmal nocturnal hemoglobinuria (PNH) and body weight of at least 40 kg.

Zilbrysq (zilucoplan) is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.

Related medical policies - 

• Rituximab Non-Oncology

• Immunoglobulin Therapy

POLICY

Prior authorization is required.

The use of samples by an individual will not be considered current or stable therapy to satisfy Medical Policy requirements. 

Initial Criteria

Soliris (eculizumab) and Ultomiris (ravulizumab-cwvz) may be considered medically necessary when ALL of the following criteria are met:

1. There is no evidence of an active meningococcal infection;

2. ONE of the following:

   1. The individual has been immunized with a meningococcal vaccine at least two weeks prior to administration of the first dose of the requested agent;

      OR

   2. The individual has received two weeks of antibacterial drug prophylaxis prior to administration of the first dose if the requested agent must be initiated immediately or if vaccines are administered less than 2 weeks before starting the requested agent;

3. ONE of the following:

   1. The individual has a documented diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) and ALL of the following:

      1. Clinical documentation supporting the diagnosis includes BOTH of the following:

         1. Flow cytometry confirmation of at least 2 different glycosylphosphatidylinositol (GPI)-linked protein deficiencies (e.g., CD55, CD59, etc.) within at least 2 different cell lines (e.g., granulocytes, monocytes, erythrocytes); AND

         2. Laboratory results, signs, and or/symptoms attributed to PNH (e.g., anemia, extreme fatigue, dyspnea, transfusion dependence, episodic hemοglοbinuria, thrombosis, pain, and/or organ dysfunction);

      2. ONE of the following:

         1. The request is for Ultomiris (ravulizumab-cwvz) and the individual is at least 1 month of age; OR

         2. The request is for Soliris (eculizumab) and ALL of the following:

            1. The individual is at least 18 years of age; AND

            2. The individual has an inadequate response (see Policy Guidelines), FDA-labeled contraindication, or intolerance to Ultomiris (ravulizumab-cwvz); AND

      3. The requested agent will not be used in combination with another complement protein C5 inhibitor, a complement protein C3 inhibitor, or a complement factor B inhibitor;

   2. The individual has a documented diagnoses of atypical Hemolytic Uremic Syndrome (aHUS) and ALL of the following:

      1. The diagnosis has been confirmed by ONE of the following:

         1. Genetic mutation (e.g., CFH, CD46, CFI, C3, CFB, THBD, CFHR1, CFHR3, CFHR5);

         2. Antibodies to complement factors; OR

         3. A differential diagnosis of complement-mediated HUS has been demonstrated (i.e., screening for Shiga toxin-producing E. coli [STEC] for STEC-HUS, pneumococcal culture of blood/sputum/cerebrospinal or pleural fluid for pneumococcal associated HUS, ADAMTS13 less than 10% activity for thrombotic thrombocytopenic purpura [TTP], screening for defective cobalamin metabolism);

      2. The individual is negative for Shiga toxin-producing E. coli (STEC);

      3. ONE of the following:

         1. The request is for Ultomiris (ravulizumab-cwvz), and the individual is 1 month of age or older; OR

         2. The request is for Soliris (eculizumab) and ALL of the following:

            1. The individual is 2 months of age or older; AND

            2. The individual has an inadequate response (see Policy Guidelines), FDA-labeled contraindication, or intolerance to Ultomiris (ravulizumab-cwvz); AND

      4. The requested agent will not be used in combination with another complement inhibitor for the treatment of aHUS;

   3. The individual has a documented diagnosis of generalized Myasthenia Gravis (gMG) and ALL of the following:

      1. The individual has a positive anti-AChR antibody;

      2. The individual has a Myasthenia Gravis Foundation of America (MFGA) clinical classification class of II-IV;

      3. The individual has a MG-Activities of Daily Living total score of greater than or equal to 6;

      4. ONE of the following:

         1. The individual has tried and had an inadequate response (see Policy Guidelines) to an acetylcholinesterase inhibitor (e.g., pyridostigmine, neostigmine) AND an inadequate response to at least two or more immunosuppressive therapies over a 12-month period (e.g., glucocorticoids, azathioprine, cyclosporine, methotrexate, mycophenolate, tacrolimus, cyclophosphamide) either in combination or as monotherapy;

         2. The individual has an FDA-labeled contraindication to ALL conventional agents used for the treatment of myasthenia gravis (i.e., pyridostigmine, corticosteroids, azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide); OR

         3. The individual has required chronic IVIG or plasmapheresis/plasma exchange (i.e., at least every 3 months over 12 months without symptom control); AND

      5. ONE of the following:

         1. The request is for Ultomiris (ravulizumab-cwvz), and the individual is 18 years of age or older; OR

         2. The request is for Soliris (eculizumab) and ALL of the following:

            1. The individual is 18 years of age or older; AND

            2. The individual has an inadequate response (see Policy Guidelines), FDA-labeled contraindication, or intolerance to Ultomiris (ravulizumab-cwvz); AND

      6. The requested agent will not be used in combination with another complement inhibitor or neonatal Fc receptor blocker; OR

   4. The individual has a documented diagnosis of neuromyelitis optica spectrum disorder (NMOSD) and ALL of the following:

      1. The individual is anti-aquaporin-4 (AQP4) antibody positive;

      2. The diagnosis was confirmed by at least ONE of the following:

         1. Optic neuritis;

         2. Acute myelitis;

         3. Area postrema syndrome (episode of otherwise unexplained hiccups or nausea and vomiting);

         4. Acute brainstem syndrome;

         5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions; OR

         6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions;

      3. The individual has had at least one discrete clinical attack of CNS symptoms;

      4. Alternative diagnoses (i.e., multiple sclerosis, ischemic optic neuropathy) have been ruled out;

      5. The individual has tried and had an inadequate response, FDA- labeled contraindication, or intolerance to rituximab therapy (see Policy Guidelines);

      6. ONE of the following:

         1. The request is for Ultomiris (ravulizumab-cwvz), and the individual is 18 years of age or older; OR

         2. The request is for Soliris (eculizumab) and ALL of the following:

            1. The individual is 18 years of age or older; AND

            2. The individual has an inadequate response (see Policy Guidelines), FDA-labeled contraindication, or intolerance to Ultomiris (ravulizumab-cwvz); AND

      7. The requested agent will not be used in combination with other biologics for the treatment of NMOSD;

4. The prescriber is a specialist in the area of the individual’s diagnosis or has consulted with a specialist in the area of the individual’s diagnosis (e.g., neurologist, hematologist/oncologist, nephrologist);

5. The prescriber is enrolled in the ULTOMIRIS and SOLIRIS Risk Evaluation and Mitigation Strategy (REMS) program;

6. The individual does not have any FDA-labeled contraindication(s) to therapy with the requested agent; AND

7. The prescribed dosage is within the program quantity limits based on FDA approved labeled dosage.

Length of Approval: 6 months  

Renewal Criteria

Soliris (eculizumab) and Ultomiris (ravulizumab-cwvz) may be approved for RENEWAL when ALL of the following criteria are met:

1. The individual has been previously approved for the requested agent through the BCBSMS PA process;

2. The individual has documented clinical response/improvement (i.e., slowing of disease progression, stabilization of disease, decrease in symptom severity and/or frequency, etc.) as demonstrated by ONE of the following; 

   1. PNH: stabilization/improvement of hemoglobin levels from pretreatment baseline, decrease in serum LDH from pretreatment baseline, decrease in packed RBC transfusion requirement, etc.;

   2. aHUS: increased platelet count, reduced hemolysis, reduction of plasma exchanges, etc.;

   3. gMG: reductions in exacerbations, improvements in activities of daily living (speech, swallowing, mobility, respiratory function) reflected by greater than or equal to 3-point improvement in the MG-ADL from baseline, etc., OR

   4. NMOSD: no evidence of relapse or documented reduction in relapses;

3. The prescriber is a specialist in the area of the individual’s diagnosis or has consulted with a specialist in the area of the individual’s diagnosis (e.g., neurologist, hematologist/oncologist, nephrologist);

4. The individual does not have any FDA-labeled contraindication(s) to therapy with the requested agent;

5. The requested agent is not used in combination with another complement inhibitor/neonatal Fc receptor blocker/biologic agent for treatment of the individual’s condition, as outlined above; AND

6. The prescribed dosage is within the program quantity limits based on FDA approved labeled dosage.

Length of Approval: 12 months

Soliris (eculizumab) and Ultomiris (ravulizumab-cwvz) are considered investigational for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

Zilbrysq (zilucoplan) and Piasky (crovalimab-akkz) are considered not medically necessary as there are other alternatives covered by the Plan for the treatment of generalized myasthenia gravis and paroxysmal nocturnal hemoglobinuria.

POLICY EXCEPTIONS

State Health Plan (State and School Employees) Participants

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

1. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

2. appropriate with regard to standards of good medical practice; and

3. not solely for the convenience of the Member, his or her Provider; and

4. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [ie, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

Medication Failure

Medication failure is defined as disease progression at generally accepted doses (for ≥3 months use) as appropriate for the disease state being treated. Dosages below the recommended dose for the specific condition being treated and/or experience of common side effects of medication will not be considered medication failure or lack of response for the purpose of this review.

BCBSMS determines patient medication trial and adherence by a review of pharmacy claims data over the preceding twelve months. Additional information may be requested on a case-by-case basis to allow for proper review. If member is new to BCBSMS and pharmacy records are needed to confirm medication trials and adherence, it is the responsibility of the member and/or requesting provider to obtain said records and to submit them to BCBSMS upon request. Medical records from the provider that list previously prescribed medications will not be sufficient to show medication trials or adherence.

POLICY HISTORY

03/02/2020: New policy added.

10/19/2020: Minor edit made to medically necessary statement for Ultomiris. Second policy statement for Ultomiris updated to change "continuation of therapy" to "RENEWAL." Revised policy statement to state that Ultomiris is considered investigational, and therefore not covered, for any other indication. Medically necessary statement for Soliris updated to add "Member has failed rituximab (i.e., Rituxan, Ruxience, Truxima, etc.)" as a requirement. Second policy statement for Soliris updated to change "continuation of therapy" to "RENEWAL." Code Reference section updated to add HCPCS codes J1300, J1303, and ICD-10 diagnosis codes D59.3, D59.5, G36.0, G70.00, and G70.01.

09/19/2022: Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders." Code Reference section updated to add new ICD-10 diagnosis codes D59.30, D59.31, D59.32, and D59.39, effective 10/01/2022.

02/01/2023: Policy Exceptions updated to add the following: State Health Plan (State and School Employees): The prescription drug(s) in this medical policy may be covered under a prescription drug benefit plan administered by the State Health Plan’s Pharmacy Benefit Manager. Please perform a formulary drug search at https://www.dfa.ms.gov/cvs-caremark and submit any required Prior Authorization Requests for coverage determination to the Plan’s Pharmacy Benefit Manager. Services related to delivery and/or administration of a medication determined to be not medically necessary will also be considered not medically necessary. Services related to delivery and/or administration of a self-administered drug are not covered.

07/01/2023: Policy Exceptions updated regarding State Health Plan (State and School Employees) Participants.

02/14/2025: Combined the Initial and Renewal Criteria for Soliris and Ultomiris. Policy description updated to add indications for Piasky (crovalimab-akkz) and Zilbrysq (zilucoplan). Policy statement updated to state that the use of samples by an individual will not be considered current or stable therapy to satisfy Medical Policy requirements. Policy section updated to remove weight/dose tables. Initial and Renewal criteria extensively revised for Soliris (eculizumab) and Ultomiris (ravulizumab-cwvz). Added the following statements: 1) Soliris (eculizumab) and Ultomiris (ravulizumab-cwvz) are considered investigational for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 2) Zilbrysq (zilucoplan) and Piasky (crovalimab-akkz) are considered not medically necessary as there are other alternatives covered by the Plan for the treatment of generalized myasthenia gravis and paroxysmal nocturnal hemoglobinuria. Policy Guidelines updated to define medication failure. Sources updated. Code Reference section updated to add HCPCS code J1307 to the Investigational Codes table. Removed deleted ICD-10 diagnosis code D59.3.

04/01/2025: Code Reference section updated to add new HCPCS code J1299, effective 04/01/2025.

SOURCE(S)

1. Bird SJ. Chronic immunotherapy for myasthenia gravis. UpToDate, Connor RF (Ed), Wolters Kluwer. https://www.uptodate.com/contents/chronic-immunotherapy-for-myasthenia-gravis

2. Brodsky RA. Paroxysmal nocturnal hemoglobinuria: Treatment and prognosis. UpToDate, Connor RF (Ed), Wolters Kluwer. https://www.uptodate.com/contents/paroxysmal-nocturnal-hemoglobinuria-treatment-and-prognosis

3. Kümpfel T, Giglhuber K, Aktas O, et al. Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management [published correction appears in J Neurol. 2024 Jun;271(6):3702-3707. doi: 10.1007/s00415-024-12288-2]. J Neurol. 2024;271(1):141-176. doi:10.1007/s00415-023-11910-z

4. Liszewski MK. Overview and clinical assessment of the complement system. UpToDate, Connor RF (Ed), Wolters Kluwer. https://www.uptodate.com/contents/overview-and-clinical-assessment-of-the-complement-system

5. Oliver M, Patriquin CJ. Paroxysmal Nocturnal Hemoglobinuria: Current Management, Unmet Needs, and Recommendations. J Blood Med. 2023 Dec 6;14:613-628. doi: 10.2147/JBM.S431493. PMID: 38084255; PMCID: PMC10710797.

6. Piasky prescribing information. Genentech, Inc. June 2024. Last accessed February 2025.

7. Raina R, Vijayvargiya N, Khooblall A, Melachuri M, Deshpande S, Sharma D, Mathur K, Arora M, Sethi SK, Sandhu S. Pediatric Atypical Hemolytic Uremic Syndrome Advances. Cells. 2021 Dec 18;10(12):3580. doi: 10.3390/cells10123580. PMID: 34944087; PMCID: PMC8700093.

8. Soliris prescribing information. Alexion Pharmaceuticals Inc. September 2024. Last accessed January 2025.

9. Ultomiris prescribing information. Alexion Pharmaceuticals Inc. September 2024. Last accessed January 2025.

10. Vu T, Wiendl H, Katsuno M, Reddel SW, Howard JF Jr. Ravulizumab in Myasthenia Gravis: A Review of the Current Evidence. Neuropsychiatr Dis Treat. 2023 Dec 1;19:2639-2655. doi: 10.2147/NDT.S374694. PMID: 38059203; PMCID: PMC10697093.

11. West EE, Woodruff T, Fremeaux-Bacchi V, Kemper C. Complement in human disease: approved and up-and-coming therapeutics. Lancet. 2024 Jan 27;403(10424):392-405. doi: 10.1016/S0140-6736(23)01524-6. Epub 2023 Nov 15. PMID: 37979593; PMCID: PMC10872502.

12. Zilbrysq prescribing information. UCB, Inc. September 2024. Last accessed January 2025.

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.