Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual

Policy #:

2022041

Category:

Pharmacy

Initiated:

December 2022

Last Review:

November 2025

Pegcetacoplan (e.g., Empaveli)

Description:

Pegcetacoplan (e.g., Empaveli) is an inhibitor of the complement protein C3 and the activation fragment

C3b. Binding of C3 prevents intravascular hemolysis by regulating the downstream membrane attack

complex while C3b inhibition prevents extravascular hemolysis.

Regulatory Status

On May 14, 2021, the U.S. Food and Drug Administration (FDA) approved Pegcetacoplan (e.g. Empaveli) subcutaneous infusion for the treatment of adult individuals with paroxysmal nocturnal hemoglobinuria (PNH).

Pegcetacoplan (e.g. Empaveli) was approved by the U.S. Food and Drug Administration (FDA) on July 28, 2025, for the treatment of adult and pediatric patients aged 12 years and older with C3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), to reduce proteinuria, and proposed modification to the approved Empaveli REMS.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Pegcetacoplan (e.g., Empaveli) is not covered under the medical benefit. Please check the member’s pharmacy benefit for coverage. This policy applies to members whose plan utilizes AR BCBS pharmacy and have pegcetacoplan as a formulary option. (Please see Coverage Policy 2020005, Self-Administered Medication).

Effective January 15, 2026

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Pegcetacoplan (e.g., Empaveli) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:

Paroxysmal Nocturnal Hemoglobinuria (PNH)

INITIAL APPROVAL:

1. Individual is 18 years of age or older; AND

2. Individual has a diagnosis of PNH confirmed by flow cytometry (Parker, 2016):

a. Greater than or equal to 10% PNH type III red cells; OR

b. Greater than or equal to 40% Glycosyl phosphatidylinositol–anchored proteins GPI-AP–deficient polymorphonuclear cells (PMNs); AND

3. Individual does not have an unresolved serious infection caused by encapsulated bacteria (Empaveli, 2024); AND

4. Either of the following criteria are met:

a. Individual is switching from treatment with C5 inhibitor (eculizumab or ravulizumab); AND

i. Individual is currently receiving eculizumab (e.g., Soliris) which will be discontinued after an initial 4 week overlap period with pegcetacoplan; OR

ii. Individual is currently receiving ravulizumab (e.g., Ultomiris) which will be stopped and pegcetacoplan will be initiated no more than 4 weeks after the last dose; OR

b. Individual is C5 Inhibitor naive (not switching from eculizumab or ravulizumab); AND

i. Individual has documented persistent anemia as defined by the following:

1. Hemoglobin less than 10.5 g/dL within the last 60 days (Hillmen 2021); AND

2. Individual has history of at least 1 transfusion in the last year with documentation (Hillmen 2021); AND

ii. Individual has lactate dehydrogenase (LDH) greater than or equal to 1.5 times the upper limit of normal, and documentation is provided (Wong, 2023); AND

4. Individual will not receive pegcetacoplan in combination with another complement inhibitor or biologic agent (e.g., iptacopan, danicopan, eculizumab, or ravulizumab) used for the treatment of PNH outside of the initial overlap as described in transition of therapy.

CONTINUATION OF THERAPY:

1. Individual has experienced a clinical response as documented by one of the following (Hillmen 2021):

a. Stabilization of hemoglobin levels; OR

b. Reduction in number of transfusions required;(e.g., 6 months); OR

c. Improvement in hemolysis (i.e., normalization or decrease of LDH levels) (Wong, 2023); AND

2. Pegcetacoplan (e.g., Empaveli) is not being used in combination with another complement inhibitor or biologic agent used for the treatment of PNH.

C3 GLOMERULOPATHY (C3G) OR PRIMARY IMMUNE-COMPLEX MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (IC-MPGN)

INITIAL APPROVAL:

1. Individual is aged 12 years and older (Empaveli, 2025); AND

2. Individual weighs at least 30 kg or more (NCT05067127); AND

3. Individual has a diagnosis of one of the following:

a. C3 glomerulopathy (C3G); OR

b. Primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN) to reduce proteinuria; AND

4. Evidence of active renal disease or advance glomerulosclerosis/interstitial fibrosis as assessed by baseline renal biopsy per policy guidelines; AND

5. Individual has at least 1 g/day of proteinuria on a screening 24-hour urine collection and a urine protein-to-creatinine ratio (uPCR) of at least 1000 mg/g in at least 2 first-morning spot urine samples; AND

6. eGFR greater than or equal to 30 mL/min/1.73 square meters; AND

7. Individual is on stable regimen for C3G/IC-MPGN treatment, as described below:

a. Angiotensin-converting enzyme (ACE) inhibitor/, angiotensin receptor blocker (ARB), and/or sodium-glucose cotransporter-2 inhibitor therapy that is stable and optimized for at least 12 weeks prior initiation of treatment; AND

b. Stable doses of other medications that can affect proteinuria (e.g., steroids, mycophenolate mofetil, and/or other allowed immunosuppressants that the individual is receiving for treatment of C3G or IC-MPGN) for at least 8-12 weeks prior to the baseline renal biopsy; AND

8. If individual is on prednisone (or other systemic corticosteroid) for C3G or IC-MPGN treatment, the dosage is stable and no higher than 20 mg/day (or equivalent dosage of a corticosteroid other than prednisone) for at least 12 weeks prior; AND

9. Diagnosis of primary immune-complex membranoproliferative glomerulonephritis (ICMPGN) is NOT secondary to another condition (including but not limited to infection, malignancy, monoclonal gammopathy, a systemic autoimmune disease such as systemic lupus erythematosus, chronic antibody-mediated rejection, or a medication is excluded; AND

10. Individual does not have any of the following:

a. Previous exposure to Pegcetacoplan (e.g., Empaveli); OR

b. An absolute neutrophil count less than 1000 cells per microliter of blood.

CONTINUATION OF THERAPY:

1. Documentation is provided that individual will be taking Pegcetacoplan (e.g., Empaveli) in combination with an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and/or sodium-glucose cotransporter-2 inhibitor therapy unless contraindicated or not tolerated; AND

2. Individual has experienced a clinical response as documented by significant reduction in proteinuria.

Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria

Pegcetacoplan (e.g., Empaveli), for any indication or circumstance not described above, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.

For members with contracts without Primary Coverage Criteria, Pegcetacoplan (e.g., Empaveli), for any indication or circumstance not described above, is considered not Medically Necessary or is investigational and is not covered. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

POLICY GUIDELINES

Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of Pegcetacoplan (e.g., Empaveli), unless the risks of delaying Pegcetacoplan (e.g., Empaveli) outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in individuals receiving a complement inhibitor.

Prescribing provider is responsible for ensuring individual has received vaccinations against S pneumoniae, N meningitidis (types A, C, W, Y, and B), and H influenzae (type B) within 5 years prior treatment.

Prescribing provider is responsible for ensuring individual does not have current or previous diagnosis of human immunodeficiency virus (HIC) hepatitis B (HBV), or hepatitis C (HCV) infection or positive serology.

Active renal disease or advance glomerulosclerosis/interstitial fibrosis as assessed by baseline renal biopsy, based on one or more of the following:

1. In adults or adolescents with a baseline renal biopsy (either one collected during screening or a historic biopsy collected within 28 weeks of initiation of therapy), at least 2+ C3c staining on the baseline renal biopsy; OR

2. In adolescents not providing a baseline renal biopsy, at least one of the following:

a. Plasma sC5b-9 level above the upper limit of normal during screening; OR

b. Serum C3 below the LLN; OR

c. Presence of an active urine sediment, as evidenced by hematuria with at least 5 red blood cells (RBCs) per high-power field (HPF) and/or red blood cell casts on local or central microscopic analysis of urine; OR

d. Presence of 3 nephritic factor within 6 months, based on central laboratory results or medical history.

DOSAGE AND ADMINISTRATION

For FDA labeled indications, Pegcetacoplan (e.g., Empaveli) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.

PNH

The recommended dose of Pegcetacoplan (e.g., Empaveli) is 1,080 mg by subcutaneous infusion twice weekly via a commercially available infusion pump with a reservoir of at least 20 mL.

C3G or Primary IC-MPGN

Adults: The recommended dose of Pegcetacoplan (e.g., Empaveli) is 1,080 mg administered subcutaneously twice weekly.
Pediatric: The recommended dose of Pegcetacoplan (e.g., Empaveli) is dependent upon individual weight.
- 50 kg or higher body weight:
  - First dose: 1,080 mg
  - Second dose: 1,080 mg
  - Maintenance dose: 1,080 mg twice weekly
- 35 kg to less than 50 kg body weight:
  - First dose: 648 mg
  - Second dose: 810 mg
  - Maintenance dose: 810 mg twice weekly
- Less than 35 kg body weight:
  - First dose: 540 mg
  - Second dose: 540 mg
  - Maintenance dose: 648 mg twice weekly

Pegcetacoplan (e.g., Empaveli), is available as a 1,080 mg/20 mL single-dose vial.

Pegcetacoplan (e.g., Empaveli), is for subcutaneous infusion using an infusion pump. Pegcetacoplan is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous infusion, an individual may self-administer, or the individual’s caregiver may administer pegcetacoplan, if a healthcare provider determines that it is appropriate.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Effective February 5, 2025 to January 14, 2025

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Pegcetacoplan meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for an individual with paroxysmal nocturnal hemoglobinuria (PNH) when ALL the following criteria are met:

1. Individual is 18 years of age or older; AND

2. Individual has a diagnosis of PNH confirmed by flow cytometry (Parker, 2016):

a. Greater than or equal to 10% PNH type III red cells; OR

b. Greater than or equal to 40% Glycosyl phosphatidylinositol–anchored proteins GPI-AP–deficient polymorphonuclear cells (PMNs); AND

3. Individual does not have an unresolved serious infection caused by encapsulated bacteria (Empaveli, 2024); AND

4. Individual has been immunized against encapsulated bacteria (including streptococcus pneumoniae, Neisseria meningitidis (serogroups A, C, W, Y, and B), and Haemophilus influenzae type B) at least 2 weeks prior to administration of the first dose of pegcetacoplan unless the clinical record documentation the risks of administration are outweighed by benefit; AND

5. Either of the following criteria are met:

a. Individual is switching from treatment with C5 inhibitor (eculizumab or ravulizumab); AND

i. Individual is currently receiving eculizumab (e.g., Soliris) which will be discontinued after an initial 4 week overlap period with pegcetacoplan; OR

ii. Individual is currently receiving ravulizumab (e.g., Ultomiris) which will be stopped and pegcetacoplan will be initiated no more than 4 weeks after the last dose; OR

b. Individual is C5 Inhibitor naive (not switching from eculizumab or ravulizumab); AND

i. Individual has documented persistent anemia as defined by the following:

1. Hemoglobin less than 10.5 g/dL within the last 60 days (Hillmen 2021); AND

2. Individual has history of at least 1 transfusion in the last year with documentation (Hillmen 2021); AND

ii. Individual has lactate dehydrogenase (LDH) greater than or equal to 1.5 times the upper limit of normal, and documentation is provided (Wong, 2023); AND

6. Individual will not receive pegcetacoplan in combination with another complement inhibitor or biologic agent (e.g., iptacopan, danicopan, eculizumab, or ravulizumab) used for the treatment of PNH outside of the initial overlap as described in transition of therapy; AND

7. Must be dosed in accordance with the FDA label.

CONTINUATION for up to 12 months:

1. Individual has completed or updated immunization against encapsulated bacteria (including streptococcus pneumoniae, Neisseria meningitidis(serogroups A, C, W, Y, and B), and Haemophilus influenzae type B); AND

2. Individual has experienced a clinical response as documented by one of the following (Hillmen 2021):

a. Stabilization of hemoglobin levels; OR

b. Reduction in number of transfusions required;(e.g., 6 months); OR

c. Improvement in hemolysis (i.e., normalization or decrease of LDH levels) (Wong, 2023); AND

3. Pegcetacoplan is not being used in combination with another complement inhibitor or biologic agent used for the treatment of PNH.

Policy Guidelines

Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of Pegcetacoplan (e.g., Empaveli) , unless the risks of delaying Pegcetacoplan (e.g., Empaveli) outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in individuals receiving a complement inhibitor.

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose of Pegcetacoplan is 1,080 mg by subcutaneous infusion twice weekly via a commercially available infusion pump with a reservoir of at least 20 mL.

Pegcetacoplan is available as a 1,080 mg/20 mL single-dose vial.

Pegcetacoplan is for subcutaneous infusion using an infusion pump. Pegcetacoplan is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous infusion, an individual may self-administer, or the individual’s caregiver may administer pegcetacoplan, if a healthcare provider determines that it is appropriate.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Pegcetacoplan, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, pegcetacoplan, pegcetacoplan, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective November 6, 2024 to February 4, 2025

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

Paroxysmal Nocturnal Hemoglobinuria (PNH)

1. Individual is 18 years of age or older; AND

2. Individual has a diagnosis of PNH confirmed by flow cytometry (Parker, 2016):

a. Greater than or equal to 10% PNH type III red cells; OR

b. Greater than or equal to 40% Glycosyl phosphatidylinositol–anchored proteins GPI-AP–deficient polymorphonuclear cells (PMNs); AND

3. Individual does not have an unresolved serious infection caused by encapsulated bacteria (Empaveli, 2024); AND

4. Individual has been immunized against encapsulated bacteria (including streptococcus pneumoniae, Neisseria meningitidis (serogroups A, C, W, Y, and B), and Haemophilus influenzae type B) at least 2 weeks prior to administration of the first dose of pegcetacoplan unless the clinical record documentation the risks of administration are outweighed by benefit; AND

5. Either of the following criteria are met:

a. Individual is switching from treatment with C5 inhibitor (eculizumab or ravulizumab); AND

i. Individual is currently receiving eculizumab (e.g., Soliris) which will be discontinued after an initial 4 week overlap period with pegcetacoplan; OR

ii. Individual is currently receiving ravulizumab (e.g., Ultomiris) which will be stopped and pegcetacoplan will be initiated no more than 4 weeks after the last dose; OR

b. Individual is C5 Inhibitor naive (not switching from eculizumab or ravulizumab); AND

i. Individual has documented persistent anemia as defined by the following:

1. Hemoglobin less than 10.5 g/dL within the last 60 days (Hillmen 2021); AND

2. Individual has history of at least 1 transfusion in the last year with documentation (Hillmen 2021); AND

ii. Individual has lactate dehydrogenase (LDH) greater than or equal to 1.5 times the upper limit of normal, and documentation is provided (Wong, 2023); AND

6. Individual will not receive pegcetacoplan in combination with another complement inhibitor or biologic agent (e.g., iptacopan, danicopan, eculizumab, or ravulizumab) used for the treatment of PNH outside of the initial overlap as described in transition of therapy; AND

7. Must be dosed in accordance with the FDA label.

CONTINUATION for up to 12 months:

1. Individual has completed or updated immunization against encapsulated bacteria (including streptococcus pneumoniae, Neisseria meningitidis(serogroups A, C, W, Y, and B), and Haemophilus influenzae type B); AND

2. Individual has experienced a clinical response as documented by one of the following (Hillmen 2021):

a. Stabilization of hemoglobin levels; OR

b. Reduction in number of transfusions required;(e.g., 6 months); OR

c. Improvement in hemolysis (i.e., normalization or decrease of LDH levels) (Wong, 2023); AND

3. Pegcetacoplan is not being used in combination with another complement inhibitor or biologic agent used for the treatment of PNH.

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose of Pegcetacoplan is 1,080 mg by subcutaneous infusion twice weekly via a commercially available infusion pump with a reservoir of at least 20 mL.

Pegcetacoplan is available as a 1,080 mg/20 mL single-dose vial.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective November 2023 to November 5, 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Individual is ≥ 18 years of age; AND

2. Individual has a diagnosis of PNH confirmed by flow cytometry (Parker, 2016):

a. >10% PNH type III red cells; OR

b. >40% Glycosyl phosphatidylinositol–anchored proteins GPI-AP–deficient polymorphonuclear cells (PMNs); AND

3. Individual has been immunized against encapsulated bacteria (including Step pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B) at least 2 weeks prior to administration of the first dose of pegcetacoplan unless the clinical record documentation the risks of administration are outweighed by benefit; AND

4. Either of the following criteria are met:

a. Individual is switching from treatment with C5 inhibitor (eculizumab or ravulizumab); AND

i. Individual is currently receiving eculizumab (e.g., Soliris) which will be discontinued after an initial 4 week overlap period with pegcetacoplan; OR

ii. Individual is currently receiving ravulizumab (e.g., Ultomiris) which will be stopped and pegcetacoplan will be initiated no more than 4 weeks after the last dose; OR

b. Individual is C5 Inhibitor naive and have documented persistent anemia as defined by the following:

i. Hemoglobin < 10.5 g/dL within the last 60 days (Hillmen 2021); AND

ii. Individual has history of at least 1 transfusion in the last year with documentation (Hillmen 2021); AND

5. Individual will not receive pegcetacoplan in combination with another complement inhibitor or biologic agent used for the treatment of PNH outside of the initial overlap as described in transition of therapy; AND

6. Must be dosed in accordance with the FDA label.

CONTINUATION for up to 12 months:

Continuation of therapy for PNH meets primary coverage criteria when:

Individual has experienced a clinical response as documented by one of the following (Hillmen 2021):

a. Stabilization of hemoglobin levels; OR

b. Reduction in number of transfusions required;(e.g., 6 months) AND

2. Pegcetacoplan is not being used in combination with another complement inhibitor or biologic agent used for the treatment of PNH.

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose of Pegcetacoplan is 1,080 mg by subcutaneous infusion twice weekly via a commercially available infusion pump with a reservoir of at least 20 mL

Pegcetacoplan is available as a 1,080 mg/20 mL single-dose vial.

Pegcetacoplan is for subcutaneous infusion using an infusion pump. Pegcetacoplan is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous infusion, a patient may self-administer, or the patient’s caregiver may administer pegcetacoplan, if a healthcare provider determines that it is appropriate.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective December 14, 2022 to October 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Pegcetacoplan meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for an individual with paroxysmal nocturnal hemoglobinuria (PNH) when ALL the following criteria are met:

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

Individual is ≥18 years of age
Individual has a diagnosis of PNH confirmed by flow cytometry (Parker, 2016)
1. >10% PNH type III red cells OR
2. >40% Glycosyl phosphatidylinositol–anchored proteins GPI-AP–deficient polymorphonuclear cells (PMNs)
Individual has been immunized against encapsulated bacteria (including Step pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B) at least 2 weeks prior to administration of the first dose of pegcetacoplan unless the clinical record documentation the risks of administration are outweighed by benefit.
Either of the following criteria are met:
1. Individual is switching from treatment with C5 inhibitor (eculizumab or ravulizumab) AND
  1. Individual is currently receiving eculizumab (e.g., Soliris) which will be discontinued after an initial 4 week overlap period with pegcetacoplan OR
  2. Individual is currently receiving ravulizumab (e.g., Ultomiris) which will be stopped and pegcetacoplan will be initiated no more than 4 weeks after the last dose OR
2. Individual is C5 Inhibitor naive and have documented persistent anemia as defined by the following:
  1. Hemoglobin <10.5 g/dL within the last 60 days (Hillmen 2021); AND
  2. Individual has history of at least 1 transfusion in the last year with documentation (Hillmen 2021)
Individual will not receive pegcetacoplan in combination with another complement inhibitor or biologic agent used for the treatment of PNH outside of the initial overlap as described in transition of therapy.
Must be dosed in accordance with the FDA label.

CONTINUATION for up to 12 months:

Continuation of therapy for PNH meets primary coverage criteria when:

Individual has experienced a clinical response as documented by one of the following (Hillmen 2021):
1. Stabilization of hemoglobin levels; OR
2. Reduction in number of transfusions required;(e.g., 6 months) AND
Pegcetacoplan is not being used in combination with another complement inhibitor or biologic agent used for the treatment of PNH.

Dosage and Administration

The recommended dose of Pegcetacoplan is 1,080 mg by subcutaneous infusion twice weekly via a commercially available infusion pump with a reservoir of at least 20 mL

Pegcetacoplan is available as a 1,080 mg/20 mL single-dose vial.

Pegcetacoplan is for subcutaneous infusion using an infusion pump. Pegcetacoplan is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous infusion, a patient may self-administer, or the patient’s caregiver may administer pegcetacoplan, if a healthcare provider determines that it is appropriate.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

For members with contracts without primary coverage criteria, pegcetacoplan, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Prince trial is an ongoing, 26-week, multicenter, randomized, open-label, Phase III trial in adults with PNH who have not been treated with a complement inhibitor within 3 months. Patients are randomized to Empaveli 1,080 mg SC twice weekly or standard of care (excluding complement inhibitors). The primary endpoints are Hb stabilization and reduction in LDH at

week 26. Results are not yet available. A long-term extension trial is also ongoing and no data is currently available. The extension is a multicenter, nonrandomized, open-label study in patients with PNH who completed a Empaveli trial and experienced a clinical benefit. Enrollment of 160 patients is planned and the primary endpoint is safety at 2 years.

PEGASUS trial: the efficacy and safety of pegcetacoplan was compared to eculizumab in a randomized, open-label, 16-

week study. Patients with PNH stabilized on eculizumab for at least 3 months with a hemoglobin of less than 10.5 g/dL were included. There was a 4-week period where patients received eculizumab and pegcetacoplan 1080 mg subcutaneously twice weekly before continuing pegcetacoplan as a single agent. There were 80 patients enrolled in the trial. The primary endpoint was the change from baseline to week 16 in hemoglobin level which was significantly improved with pegcetacoplan treatment as compared with eculizumab with an adjusted mean increase of 3.84 g/dL (2.37 vs -1.47 g/dL; 95% CI, 2.33

to 5.34 g/dL). Secondary endpoints achieving noninferiority included transfusion avoidance (85% pegcetacoplan vs 15% eculizumab), change from baseline in mean absolute reticulocyte count (-136 vs 28 x 10 cells/L). The change from baseline in LDH did not reach noninferiority (-15 vs -10 U/L), but there was a higher proportion of patients receiving pegcetacoplan who achieved normalization of LDH at the end of week 16 as compared to eculizumab (71% vs 15%). Numerical improvements on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale (ranges from 0-52, with a higher score indicating less fatigue) occurred in the group treated with pegcetacoplan (9.2 improvement from baseline). Two additional uncontrolled studies in patients with PNH not receiving a complement inhibitor have been conducted over a 1-year period also resulted in an increase in hemoglobin. Adverse reactions that occurred in patients treated with pegcetacoplan as compared with eculizumab included injection-site reactions (39% vs 5%), infections (29% vs 26%), diarrhea (22% vs 3%), abdominal pain (20% vs 10%), respiratory tract infection (15% vs 13%), viral infection (12% vs 8%), and fatigue (12% vs 23%), breakthrough hemolysis (10% vs 23%), headache (7% vs 23%), and chest pain (7% vs 3%).

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.

2024 Update

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targerted therapy approved for adults with PNH (United States), adults with PNH with inadequate response or intolerance to a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for > 3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate the efficacy and safety of pegcetacoplan vs control (supportive care only; e.g., blood transfusions, corticosteroids, and supplements) in complement inhibitor-naïve patients with PNH. Eligible adults receiving supportive care only for PNH were randomly assigned and stratified based on their number of transfusions (< 4 or > 4) 12 months before screening. Patients revived pegcetacoplan 10180 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary end points were hemoglobin stabilization (avoidance of > 1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients receive pegcetacoplan (n=35) or control (n=18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0); difference, 73.1%; 95% confidence interval [CI], 57.2-89.0; P<0.0001) and change from baseline in LDH (least square mean change: pegcetacoplan, -1870.5 U/L; control, -400.1 U/L; difference, -1470.4 U/L; 95% CI, -2113.4 to -827.3; P<0.0001). Pegcetacoplan was well tolerated. No pegcetacoplan related adverse events were serious, and no new safety signals were observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor-naïve patients and had a favorable safety profile. (Wong, 2023)

2025 Update

The efficacy of EMPAVELI in reducing proteinuria in adult and pediatric patients aged 12 years and older with native kidney C3G, native kidney IC-MPGN, or recurrent C3G following kidney transplant was demonstrated in Study APL2-C3G-310. Safety and effectiveness of EMPVAELI in patients with recurrent IC-MPGN following kidney transplant have not been established.

APL2-C3G-310 is a randomized, double-blind, placebo-controlled study that included 124 adult and pediatric patients aged 12 years and older and weighing at least 30 kg with biopsy-proven, native kidney or post-transplant recurrent C3G, or native kidney primary IC-MPGN, eGFR ≥30 mL/min/1.73 m2, proteinuria ≥1 g/day, and urine protein-to-creatinine ratio (UPCR) ≥1 g/g (NTC 05067127). For at least 12 weeks before randomization and throughout the 26-week placebo-controlled period, patients were required to be on stable and optimized doses of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and/or sodium-glucose cotransporter-2 (SGLT2) inhibitors. Immunosuppressant medication doses (e.g., steroids no higher than 20 mg daily, mycophenolate mofetil, tacrolimus) had to be stable for at least 12 weeks before randomization and throughout the 26-week placebo-controlled period.

Patients were randomized (1:1) to EMPAVELI or placebo, administered twice weekly as a subcutaneous (SC) infusion for 26 weeks. Randomization was stratified by post-transplant recurrence and by kidney biopsy obtained within 28 weeks of screening. Adults and pediatric patients weighing 50 kg or more received EMPAVELI 1,080 mg (20 mL) twice weekly. Pediatric patients weighing 35 kg to less than 50 kg received 648 mg (12 mL) for the first infusion and 810 mg (15 mL) for each infusion thereafter. Pediatric patients weighing 30 kg to less than 35 kg received EMPAVELI 540 mg (10 mL) for the first 2 infusions and 648 mg (12 mL) twice weekly thereafter.

Patients were vaccinated against Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B (Hib) at least 14 days prior to randomization, unless documented evidence existed that participants received the recommended vaccinations or were non-responders to vaccination.

At baseline, the mean age was 26 years (range 12 to 74 years); 57% were female, 73% White, 15% Asian, 1% Black or African American, and 11% others. The study population included 55 pediatric patients 12 years to less than 18 years of age; mean age 14.7 years (28 randomized to EMPAVELI and 27 to placebo). Disease type was reasonably balanced between the treatment groups. Overall, 88 patients (71%) had native kidney C3G, 27 patients (22%) had native kidney primary IC-MPGN, and 8 patients (6%) had post kidney transplant recurrent C3G. At baseline, mean UPCR from triplicate first morning urine (FMU) collections was 3.1 g/g and 2.5 g/g in the pegcetacoplan and placebo groups, respectively; mean eGFR (mL/min/1.73 m2) was 79 and 87 in the pegcetacoplan and placebo groups, respectively; and mean baseline serum albumin was approximately 3.4 g/dL in both treatment groups.

Approximately 91% of patients were treated with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB), 72% with immunosuppressants (e.g., mycophenolate mofetil, tacrolimus), 40% with systemic corticosteroids, and 11% with sodium-glucose co-transporter 2 (SGLT2) inhibitors. Use of each of these medications was balanced between the treatment groups.

The primary efficacy endpoint was the log-transformed ratio of UPCR (sampled from first morning urine collections) at Week 26 compared to baseline. At Week 26, the geometric mean UPCR ratio relative to baseline was 0.33 (95% CI: 0.25, 0.43) and 1.03 (95% CI: 0.91, 1.16) in the EMPAVELI and placebo groups, resulting in a 68% reduction in UPCR from baseline in the EMPAVELI group compared to placebo (p<0.0001). the treatment effect was consistent across all subgroups including disease type, age, transplant status (C3G), sex, race, baseline disease characteristics (eGFR and UPCR), and immunosuppressant use.

During the 26-week placebo-controlled period, 49% of patients in the EMPAVELI group achieved a composite renal endpoint defined as a ≥50% reduction in UPCR and stable eGFR (≤15% reduction from baseline) compared with 3% of patients in the placebo group. Sixty percent of patients in the EMPAVELI group achieved a 50% or greater reduction in UPCR from baseline to Week 26 compared with 5% in the placebo arm, and 68% of patients in the EMPAVELI group had a stable eGFR (≤15% reduction from baseline to Week 26) compared with 59% in the placebo group. Over the first 6 months of treatment, EMPAVELI reduced the loss of kidney function compared to placebo. The efficacy of EMPAVELI in pediatric patients 12 years of age and older was similar to adults. (Empaveli, 2025)

CPT/HCPCS:

References:

ACIP(2025) Advisory Committee on Immunization Practices (ACIP). Centers for Disease Control and Prevention www.cdc.gov/acip/index.html

Apellis Pharmaceuticals, Inc.(2021) Empaveli [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215014s000lbl.pdf

Empaveli(2022) Package insert Waltham, MA; Apellis Pharmaceuticals, Inc.; 2022.

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Wong RSM, Navarro-Cabrera JR, Comia NS, Goh YT, Idrobo H, Kongkabpan D, Gomez-Almaguer D, Al-Adhami M, Ajayi T, Alvarenga P, Savage J, Deschatelets P, Francois C, Grossi F, Dumagay T.(2023) Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria. Blood Adv. 2023 Jun 13;7(11):2468-2478. doi: 10.1182/bloodadvances.2022009129. PMID: 36848639; PMCID: PMC10241857.

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