Background

Empaveli is a C3 complement inhibitor indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults. It is the first treatment for PNH that binds to complement protein C3 and acts proximally in the complement cascade to control both C3b-mediated extravascular hemolysis and terminal complement-mediated intravascular hemolysis. It should be dosed as 1,080 mg by subcutaneous infusion twice weekly via a commercially available infusion pump with a reservoir of at least 20 mL or via a single-use, disposable on body injector. Other treatments available for PNH include the C5 complement inhibitors Soliris, Ultomiris, and PiaSky; the Factor B inhibitor Fabhalta; and the Factor D inhibitor Voydeya. It should be noted that Empaveli was demonstrated to be superior to Soliris in clinical trials and also has the advantage of easier administration.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

PNH is an acquired hematopoietic stem cell disorder associated with an acquired somatic mutation of the phosphatidylinositol glycan class A (PIGA) gene. Mutations disrupt the first step in glycophosphatidylinositol (GPI) synthesis, which causes an absence of the GPI anchor and a deficiency of GPI proteins. The absence of GPI proteins on erythrocytes makes them susceptible to attack by complement and intravascular hemolysis. Intravascular hemolysis associated with PNH leads to release of free hemoglobin, leading to anemia, hemoglobinuria, thrombosis, dysphagia, abdominal pain, pulmonary hypertension, renal impairment, and erectile dysfunction. The prevalence of PNH is estimated to be between 0.5-1.5 per million people in the general population, with an approximately equal male to female distribution. Although PNH can affect any age group, the median age at diagnosis is during the fourth decade of life. The primary clinical finding is hemolysis of red blood cells by complement, which leads to hemoglobinuria that is most prominent in the morning. Those with PNH are also susceptible to repeated, potentially life-threatening thromboses. Underlying bone marrow dysfunction may also be present and those who are severely affected may have pancytopenia. Many patients also have acquired aplastic anemia. Although less common, some patients have concomitant myelodysplasia. For unknown reasons, PNH may rarely develop into acute leukemia.

Signs and symptoms of PNH may vary, with some patients exhibiting mild and stable disease for many years while other patients have severe symptoms that rapidly progress to life-threatening. However, chronic hemolysis is central to all of the symptoms and physical findings associated with PNH. Fatigue, rapid heartbeat, headaches, and chest pain and difficulty breathing while exercising can result from mild hemolysis. With severe hemolysis, disabling fatigue, dysphagia, and painful contractions of the abdomen and esophagus may occur. It is estimated that 15-30% of patients with PNH develop blood clots, particularly venous thrombosis. Diagnosis of PNH is suspected in those with unexplained hemoglobinuria or abnormally high serum lactate dehydrogenase (LDH) levels. However, flow cytometry is the main diagnostic test for the identification of PNH cells.

There are no formal guidelines for treatment of PNH. However, there is an expert opinion for management of PNH published in a journal supported by the American Society of Hematology. Diagnosis of PNH is straightforward based on flow cytometry and specific treatment is recommended based on classification by the PNH interest group. Soliris is recommended for patients with classic PNH characterized by >50% of GPI-AP-deficient PMNs as well as patients with PNH in the setting of another bone marrow failure syndrome with large PNH clones. No specific PNH therapy is recommended for patients with subclinical PNH with no clinical or biochemical evidence of intravascular hemolysis. This review was published before the approval of Ultomiris, Empaveli, Fabhalta, PiaSky, and Voydeya.

Policy (Criteria)

Coverage of these drugs is provided when the criteria below is met and for non-preferred products there has been a trial and failure of preferred therapy (if applicable).

Pegcetacoplan may be considered MEDICALLY NECESSARY for the following condition(s):

Paroxysmal nocturnal hemoglobinuria (PNH)

1. Submission of medical records (e.g., chart notes, laboratory values, etc.) documenting the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) as confirmed by both of the following:
   • Flow cytometry analysis confirming presence of PNH clones
   • Laboratory results, signs, and/or symptoms attributed to PNH (e.g., abdominal pain, anemia, dyspnea, extreme fatigue, smooth muscle dystonia, unexplained/unusual thrombosis, hemolysis/hemoglobinuria, kidney disease, pulmonary hypertension, etc.)
2. Member is not receiving Empaveli in combination with another complement inhibitor used for the treatment of PNH (e.g., Soliris, Ultomiris) OR One of the following:

• Member is currently receiving Soliris (eculizumab) which will be discontinued after an initial 4 week overlap period with Empaveli
• Member is currently receiving Ultomiris (ravulizumab-cwvz) which will be stopped and Empaveli will be initiated no more than 4 weeks after the last dose

3. Prescribed by, or in consultation with one of the following:

• Hematologist
• Oncologist

Authorization duration: 6 months

Complement 3 Glomerulopathy or Primary Immune-Complex Membranoproliferative Glomerulonephritis

1. Used to reduce proteinuria.
2. Member meets FDA approved age requirement
3. Member is currently being treated with a maximally tolerated dose of one of the following for at least 12 weeks prior to initiating treatment:
   • Angiotensin-converting enzyme inhibitors (e.g., benazepril, lisinopril)
   • Angiotensin receptor blockers (e.g., losartan, valsartan)
   • Sodium-glucose cotransporter-2 (SGLT2) inhibitors (e.g., Farxiga [dapagliflozin], Jardiance [empagliflozin])
4. Prescribed by nephrologist
5. For Primary Immune-Complex Membranoproliferative Glomerulonephritis, member has not had a kidney transplant

Authorization duration: 6 months

Continuation of therapy is considered MEDICALLY NECESSARY when the following criteria are met:

1. Documentation of positive clinical response to therapy (e.g., reduction in UPCR, stable or improved eGFR compared to baseline)
2. Member continues to be treated with a maximally tolerated dose of one of the following:
   • Angiotensin-converting enzyme inhibitors (e.g., benazepril, lisinopril)
   • Angiotensin receptor blockers (e.g., losartan, valsartan)
   • Sodium-glucose cotransporter-2 (SGLT2) inhibitors (e.g., Farxiga [dapagliflozin], Jardiance [empagliflozin])
3. For Primary Immune-Complex Membranoproliferative Glomerulonephritis, member has not had a kidney transplant

Authorization duration: 12 months

Continuation of therapy is considered MEDICALLY NECESSARY when the following criteria are met:

Documentation of positive clinical response to therapy (e.g., improvement in hemoglobin level, hemoglobin stabilization, decrease in the number of red blood cell transfusions)

Authorization duration: 12 months

References

1. Empaveli [package insert]. Apellis Pharmaceuticals, Inc. Waltham, MA. Updated February 2024.
2. Empaveli Drug Evaluation. Express Scripts. Updated May 2021.
3.  Wong RSM, Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol. 2022; 13.
4. Empaveli [package insert]. Waltham, MA: Apellis Pharmaceuticals, Inc.; May 2021.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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