Effective Date

Date of Origin 

01-01-2026            

10-01-2021

Empaveli®

(pegcetacoplan)

Injection for subcutaneous use

Treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH)

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

1

Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, life-threatening, rare, multi-systemic disease developing as a result of a somatic mutation of hematopoietic stem cells, and characterized by clonal, complement-mediated intravascular hemolysis. A mutation in the X-linked gene phosphatidylinositol glycan class A (PIGA) results in a deficiency in the glycosylphosphatidylinositol (GPI) protein, which is responsible for anchoring proteins to the surface of red blood cells.(3) This lack of anchoring leads to hemolysis and complications such as hemolytic anemia and thrombosis.(3) PNH is mainly a disease of adults with a median age of onset in the thirties. High precision flow cytometry is the most useful and accepted diagnostic test to confirm the diagnosis of PNH. Flow cytometry is performed by incubating the patient’s peripheral blood cells with fluorescently-labeled monoclonal antibodies that bind to GPI anchored proteins, which are reduced or absent on blood cells in PNH. Since different blood cell lineages display different combinations of GPI-linked proteins, and some proteins bind to cell surfaces via both GPI-linked and GPI-independent mechanisms, it is recommended that at least two independent flow cytometry reagents be used on at least two cell lineages (e.g., red blood cells [RBCs] and white blood cells [WBCs]) to establish a diagnosis of PNH.(2)

The lack of the complement inhibitor CD59 on RBCs surface is mostly responsible for the clinical manifestations of PNH. These patients manifest with chronic intravascular hemolysis, paroxysmal flares of hemolysis, and a propensity for thrombosis. Intravascular hemolysis leads to release of free hemoglobin (Hb) into the blood. Free Hb, in turn, can cause various toxic effects, including hypercoagulability, changes in vascular tone from reduction of circulating nitric oxide, and renal damage.(3)

Extravascular hemolysis also occurs in patients with PNH because C3 fragments that are not destroyed by the membrane attack complex (MAC) intravascularly can accumulate on the GPI-negative RBCs (lacking CD55) surface and these fragments opsonize the RBCs, causing reticuloendothelial destruction in the liver and spleen.(3)

The main clinical situations or diseases that should be considered in the differential diagnosis of PNH are:(3)

• Coombs-negative hemolytic anemia (e.g., hemoglobinopathies, hereditary spherocytosis), microangiopathic hemolytic anemias, drug- or toxin-induced hemolysis/anemias, disseminated intravascular coagulation, and autoimmune hemolysis
• Venous thrombosis in atypical sites, including myeloproliferative disorders; solid tumors associated with hypercoagulability; extrinsic compression of vessels, and; inherited/acquired thrombophilias
• Anemia and/or other cytopenias related to bone marrow failure syndrome (e.g., aplastic anemia, myelodysplastic syndrome [MDS])

PNH is classified into three different categories:(3)

• Classic PNH (PNH with clinical and laboratory findings of intravascular hemolysis without any evidence of bone marrow deficiency)
• PNH in the setting of another specified bone marrow disorder (evidence of hemolysis, as well as another specified bone marrow disorder [e.g., aplastic anemia, MDS])
• Subclinical PNH (patients with a small population of PNH cells and no clinical or laboratory evidence of hemolysis or thrombosis)

Historically, patients with PNH had a median survival of ten years after diagnosis however, since the development of complement inhibitors survival rates have improved to approximately 75%.(4) The approach to therapy depends on the severity of symptoms and the degree of hemolysis. The treatment options for PNH are supportive care (e.g., iron supplementation, transfusions, anticoagulation), allogenic hematopoietic stem cell transplantation (HSCT), and complement blockade.(2,3)

Complement 3 Glomerulopathy

Complement 3 glomerulopathy (C3G) is a progressive and ultra-rare (5 cases per 1,000,000 in the United States) kidney disease that is characterized by dysregulation of the alternative complement pathway.(5) The disease can be divided into two major subgroups, dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). While these two subgroups have unique characteristics that can be differentiated with a kidney biopsy and electron microscopy, they both cause excessive activation of the alternative complement pathway.(6) It is estimated that within 10 years of diagnosis, almost 50% of patients with C3G will progress to end-stage kidney disease.(7) The clinical presentation of C3G can be highly variable. Most patients will present with proteinuria and/or hematuria, hypertension, complement abnormalities (low serum C3 levels), and kidney function decline. The onset of disease can also be variable affecting both pediatric and adult patients. The mean age at diagnosis is 9 and 39 years.(7) Kidney biopsy is required to confirm the diagnosis of C3G.(8) Guidelines recommend treating patients with C3G who have proteinuria greater than 1 g/d.(8) Proteinuria of 1 g/d is approximately equivalent to a urine protein to creatinine ratio (UPCR) of 0.88 g/g.(9) Historically, treatment options for C3G have been limited and have focused more on supportive measures (e.g., blood pressure management, lifestyle modification, diet). Therapeutic decisions are driven by disease severity and several off-label therapies have shown mixed results.(6) Most experts recommend renin angiotensin system inhibitor (RASi) therapy, and in some patients immunosuppressants are used as first-line agents. Furthermore, the recommendation to use immunosuppressants (corticosteroids and mycophenolate based regimens) is largely based on a few retrospective studies and well controlled studies are unavailable.(6,7,8)

Immune-complex  membranoproliferative glomerulonephritis

Immune-complex membranoproliferative glomerulonephritis (IC-MPGN) is a rare kidney disease that shares many similarities with C3G. The two diseases are differentiated by glomerular deposits of C3 in the presence or absence of immune complexes as seen on kidney biopsy.(10) ICGN is characterized by the deposition of immune complexes which is most commonly a secondary result of infections (e.g., hepatitis B & C, bacterial, protozoal) or an autoimmune disorder (e.g., systemic lupus erythematosus, Sjogren’s syndrome, rheumatoid arthritis). The clinical presentation of IC-MPGN is similar to C3G with most patients presenting with proteinuria and/or hematuria, hypertension, and kidney function decline.(10,11) Kidney biopsy is required to confirm the diagnosis of IC-MPGN and therapeutic decisions are driven by disease severity. KDIGO guidelines recommend supportive care (e.g., renin angiotensin system inhibitor [RASi]) for all patients as renoprotective benefit has been demonstrated across a number of active glomerular diseases. The use of immunosuppressants should be carefully considered and may only be appropriate for patients with active inflammation.(8,11)

Efficacy

The efficacy and safety of Empaveli in patients with PNH were assessed in two open-label, randomized-controlled Phase 3 studies (NCT03500549 and NCT04085601). The first study (NCT03500549) enrolled patients with PNH who had been treated with a stable dose of eculizumab for at least the previous 3 months and with Hb levels less than 10.5 g/dL. Eligible patients entered a 4-week run-in period during which they received Empaveli 1,080 mg subcutaneously twice weekly in addition to their current dose of eculizumab. Patients were then randomized in a 1:1 ratio to receive either 1,080 mg of Empaveli twice weekly or their current dose of eculizumab through the duration of the 16-week randomized controlled period. If required due to a lactate dehydrogenase (LDH) greater than 2 X the upper limit of normal (ULN), the dose of Empaveli could be adjusted to 1,080 mg every three days.(1)

The primary efficacy endpoint was change from baseline to week 16 (during randomized controlled period) in Hb level. Baseline was defined as the average of measurements recorded prior to taking the first dose of Empaveli. Secondary efficacy endpoints included transfusion avoidance, defined as the proportion of patients who did not require a transfusion during the randomized controlled period, and change from baseline to week 16 in absolute reticulocyte count (ARC).(1)

Empaveli was superior to eculizumab for the change from baseline in Hb level at week 16 (P<0.0001). The adjusted mean change from baseline in Hb level was 2.37 g/dL in the group treated with Empaveli versus -1.47 g/dL in the eculizumab group, demonstrating an adjusted mean increase of 3.84 g/dL with Empaveli compared to eculizumab at week 16 (95% CI, 2.33-5.34). Non-inferiority was demonstrated in the endpoints of transfusion avoidance and change from baseline in ARC.(1)

The second study (NCT04085601) enrolled patients with PNH who had not been treated with any complement inhibitor within 3 months prior to enrollment and with Hb levels less than the lower limit of normal. Eligible patients were randomized in a 2:1 ratio to receive Empaveli or supportive care (control arm) (excluding complement inhibitors [e.g., transfusions, corticosteroids, supplements such as iron, folate, and vitamin B12]) through the duration of the 26-week treatment period. The primary efficacy endpoints were the percentage of patients achieving Hb stabilization, defined as avoidance of a > 1 g/dL decrease in Hb levels from baseline in the absence of transfusion, and the change from baseline in LDH level. Secondary efficacy endpoints included change from baseline in ARC, change from baseline in Hb, and transfusion avoidance, defined as the proportion of patients who did not require a transfusion through week 26. Baseline was defined as the average of measurements recorded prior to taking the first dose of Empaveli or prior to randomization to the control arm treatment group. Efficacy results are shown below.(1)

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. This was a randomized, double-blind, placebo-controlled study that included 124 adult and pediatric patients aged 12 years and older (weighing at least 30 kg). Eligible patients had biopsy-proven, eGFR greater than or equal to 30 mL/min/1.73 m2, and proteinuria greater than or equal to 1 g/day. Patients were required to be on stable and optimized doses of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) and/or sodium-glucose cotransporter-2 (SGLT2) inhibitors for at least 12 weeks before randomization and throughout the 26 week treatment period. Patients were randomized (1:1) to Empaveli or placebo, administered twice weekly as a subcutaneous infusion. 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) in the Empaveli group and 1.03 (95% CI: 0.91, 1.16) in the placebo group. This resulted in a 68% reduction in UPCR from baseline for the treatment group versus placebo (p<0.0001).(1)

There is no evidence to support concomitant use of Empaveli with another complement inhibitor (e.g., eculizumab [Soliris, biosimilars], Ultomiris [ravulizumab-cwvz], Piasky [crovalimab-akkz], Fabhalta [iptacopan]).

Safety

Empaveli contains the following boxed warnings:(1)

• Empaveli increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B. Life-threatening and fatal infections have occurred and these infections may become rapidly life-threatening or fatal if not recognized and treated early.

• Vaccinate patients against encapsulated bacteria as recommended at least 2 weeks prior to administering the first dose of Empaveli unless risks of delaying Empaveli therapy 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
• Patients receiving Empaveli are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected

Empaveli is contraindicated in the following:(1)

• Patients with a hypersensitivity to pegcetacoplan or any of the excipients
• Initiation in patients with unresolved serious infection caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B

Empaveli is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Empaveli REMS.(1)

1

Empaveli prescribing information. Apellis Pharmaceuticals, Inc. July 2025.

2

Sahin F, Akay OM, Ayer M, et al. Pesg PNH diagnosis, follow-up and treatment guidelines. PubMed Central (PMC). Published 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981648/

3

Cançado RD, Da Silva Araújo A, Sandes AF, et al. Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Hematology, Transfusion and Cell Therapy. 2021;43(3):341-348. doi:10.1016/j.htct.2020.06.006

4

Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. StatPearls - NCBI Bookshelf. Published July 31, 2023. https://www.ncbi.nlm.nih.gov/books/NBK562292/

5

Cattran DC, Sethi S. Slowly unraveling the mysteries of C3G. American Journal of Kidney Diseases. 2021;77(5):670-672. doi:10.1053/j.ajkd.2020.12.009.

6

Smith RJH, Appel GB, Blom AM, et al. C3 glomerulopathy — understanding a rare complement-driven renal disease. Nature Reviews Nephrology. 2019;15(3):129-143. doi:10.1038/s41581-018-0107-2.

7

Magliulo EK, Ravipati P. C3 Glomerulopathy: A Current perspective in an evolving landscape. Glomerular Diseases. 2024;4(1):200-210. doi:10.1159/000542354.

8

Rovin BH, Adler SG, Barratt J, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney International. 2021;100(4):S1-S276. doi:10.1016/j.kint.2021.05.021.

9

Pitcher D, Braddon F, Hendry B, et al. Long-Term outcomes in IGA nephropathy. Clinical Journal of the American Society of Nephrology. 2023;18(6):727-738. doi:10.2215/cjn.0000000000000135.

10

Bomback AS, Charu V, Fakhouri F. Challenges in the Diagnosis and Management of Immune Complex-Mediated Membranoproliferative Glomerulonephritis and Complement 3 Glomerulopathy. Kidney Int Rep. 2024 Sep 21;10(1):17-28. doi: 10.1016/j.ekir.2024.09.017.

11

Noris M, Remuzzi G. C3G and Ig-MPGN-treatment standard. Nephrol Dial Transplant. 2024;39(2):202-214. doi:10.1093/ndt/gfad182.

Empaveli

pegcetacoplan subcutaneous soln

1080 MG/20ML

M ; N ; O ; Y

N

Empaveli

Pegcetacoplan Subcutaneous Soln

1080 MG/20ML

8

Vials

28

DAYS

Empaveli

pegcetacoplan subcutaneous soln

1080 MG/20ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance

Empaveli

Pegcetacoplan Subcutaneous Soln

1080 MG/20ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The patient has a diagnosis of Paroxysmal Nocturnal Hemoglobinuria (PNH) AND ALL of the following:
      1. The diagnosis was confirmed by flow cytometry with at least 2 independent flow cytometry reagents on at least 2 cell lineages (e.g., RBCs and WBCs) demonstrating that the patient’s peripheral blood cells are deficient in glycosylphosphatidylinositol (GPI) – linked proteins (lab tests required) AND
      2. The patient will NOT be using the requested agent in combination with Soliris (eculizumab), Bkemv (eculizumab-aeeb), or Epysqli (eculizumab-aagh) (NOTE: if the patient is switching from Soliris, Bkemv, or Epysqli then Soliris, Bkemv, or Epysqli should be continued for the first 4 weeks after starting the requested agent and then Soliris, Bkemv, or Epysqli should be discontinued) AND
      3. The patient will NOT be using the requested agent in combination with Fabhalta (iptacopan), Ultomiris (ravulizumab-cwvz), or Piasky (crovalimab-akkz) OR
   2. The patient has a diagnosis of complement 3 glomerulopathy (C3G) confirmed by kidney biopsy AND ALL of the following:
      1. ONE of the following:
         1. The patient has a urine protein-to-creatinine ratio (UPCR) greater than 0.88 g/g OR
         2. The patient has proteinuria greater than 1.0 g/day AND
      2. The patient’s eGFR is greater than or equal to 30 mL/min/1.73 m^2 AND
      3. ONE of the following:
         1. BOTH of the following:
            1. The patient is currently treated with a maximally tolerated angiotensin-converting-enzyme inhibitor (ACEi, e.g., benazepril, lisinopril) or angiotensin II blocker (ARB, e.g., losartan), or a combination medication containing an ACEi or ARB for at least a 90-day duration of therapy AND
            2. The patient will continue maximally tolerated ACEi, or ARB, or a combination medication containing an ACEi or ARB therapy in combination with the requested agent OR
         2. The patient has an intolerance, hypersensitivity, or FDA labeled contraindication to ALL ACEi, ARB, and combination medications containing an ACEi or ARB AND
      4. The patient will NOT be using the requested agent in combination with Fabhalta (iptacopan) OR
   3. The patient has a diagnosis of Immune-complex membranoproliferative glomerulonephritis (IC-MPGN) confirmed by kidney biopsy AND ALL of the following:
      1. ONE of the following:
         1. The patient has a urine protein-to-creatinine ratio (UPCR) greater than 0.88 g/g OR
         2. The patient has proteinuria greater than 1.0 g/day AND
      2. The patient’s eGFR is greater than or equal to 30 mL/min/1.73 m^2 AND
      3. ONE of the following:
         1. BOTH of the following:
            1. The patient is currently treated with a maximally tolerated angiotensin-converting-enzyme inhibitor (ACEi, e.g., benazepril, lisinopril) or angiotensin II blocker (ARB, e.g., losartan), or a combination medication containing an ACEi or ARB for at least a 90-day duration of therapy AND
            2. The patient will continue maximally tolerated ACEi, or ARB, or a combination medication containing an ACEi or ARB therapy in combination with the requested agent OR
         2. The patient has an intolerance, hypersensitivity, or FDA labeled contraindication to ALL ACEi, ARB, and combination medications containing an ACEi or ARB OR
   4. The patient has another FDA labeled indication for the requested agent and route of administration AND
2. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hematologist, nephrologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent 

Length of Approval: 6 months for C3G & IC-MPGN; 12 months for all other indications

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process (Note: patients not previously approved for the requested agent will require initial evaluation review) AND
2. ONE of the following:
   1. The patient has a diagnosis Paroxysmal Nocturnal Hemoglobinuria (PNH) AND BOTH of the following:
      1. The patient has had improvements or stabilization with the requested agent (e.g., decreased requirement of RBC transfusions, stabilization/improvement of hemoglobin, reduction of lactate dehydrogenase [LDH], stabilization/improvement of symptoms) (medical records required) AND
      2. The patient will NOT be using the requested agent in combination with Fabhalta (iptacopan), Soliris (eculizumab), Bkemv (eculizumab-aeeb), Epysqli (eculizumab-aagh), Ultomiris (ravulizumab-cwvz), or Piasky (crovalimab-akkz) OR 
   2. The patient has a diagnosis of complement 3 glomerulopathy (C3G) AND ALL of the following:
      1. The patient has had improvements or stabilization with the requested agent as indicated by ONE of the following: 
         1. Decrease from baseline (prior to treatment with the requested agent) of urine protein-to-creatinine (UPCR) ratio OR
         2. Decrease from baseline (prior to treatment with the requested agent) in proteinuria AND
      2. ONE of the following:
         1. BOTH of the following:
            1. The patient is currently treated with a maximally tolerated angiotensin-converting-enzyme inhibitor (ACEi, e.g., benazepril, lisinopril) or angiotensin II blocker (ARB, e.g., losartan), or a combination medication containing an ACEi or ARB within the past 90 days AND
            2. The patient will continue maximally tolerated ACEi, or ARB, or a combination medication containing an ACEi or ARB therapy in combination with the requested agent OR
         2. The patient has an intolerance, hypersensitivity, or FDA labeled contraindication to ALL ACEi, ARB, and combination medications containing an ACEi or ARB AND
      3. The patient will NOT be using the requested agent in combination with Fabhalta (iptacopan) OR
   3. The patient has a diagnosis of Immune-complex membranoproliferative glomerulonephritis (IC-MPGN) AND BOTH of the following:
      1. The patient has had improvements or stabilization with the requested agent as indicated by ONE of the following: 
         1. Decrease from baseline (prior to treatment with the requested agent) of urine protein-to-creatinine (UPCR) ratio OR
         2. Decrease from baseline (prior to treatment with the requested agent) in proteinuria AND
      2. ONE of the following:
         1. BOTH of the following:
            1. The patient is currently treated with a maximally tolerated angiotensin-converting-enzyme inhibitor (ACEi, e.g., benazepril, lisinopril) or angiotensin II blocker (ARB, e.g., losartan), or a combination medication containing an ACEi or ARB within the past 90 days AND
            2. The patient will continue maximally tolerated ACEi, or ARB, or a combination medication containing an ACEi or ARB therapy in combination with the requested agent OR
         2. The patient has an intolerance, hypersensitivity, or FDA labeled contraindication to ALL ACEi, ARB, and combination medications containing an ACEi or ARB AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hematologist, nephrologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent 

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

QL with PA

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The patient has a diagnosis of Paroxysmal Nocturnal Hemoglobinuria (PNH) and BOTH of the following:
   1. The requested quantity (dose) exceeds the program quantity limit AND
   2. ONE of the following:
      1. The patient has a lactate dehydrogenase (LDH) level greater than 2X the upper limit of normal (lab test required) OR
      2. ALL of the following: (medical records required)
         1. The patient had a prior LDH greater than 2X the upper limit of normal and required a dose increase AND
         2. The patient is currently using the requested quantity (dose) AND
         3. The requested quantity (dose) does NOT exceed 1,080 mg every three days

Length of Approval: up to 12 months NOTE: If approving for every three days dosing approve a quantity of 10 vials/30 days for 12 months