Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2022041
Category:	Pharmacy
Initiated:	December 2022
Last Review:	November 2024

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).

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 November 6, 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)

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.

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 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)

>10% PNH type III red cells OR
>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:

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

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

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

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

Stabilization of hemoglobin levels; OR
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)

CPT/HCPCS:

References:

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

Hillmen P, Szer J, Weitz I, et al.(2021) Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2021 Mar 18;384(11):1028-1037. PMID: 33730455. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2029073 Accessed on April 18, 2021.

Parker CJ, Omine M, Richards S, et al.(2005) Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106(12):3699-3709

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2025 American Medical Association.