Paroxysmal Nocturnal Hemoglobinuria (PNH)

Empaveli® is a drug indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH),1 a rare disease of the blood caused by the clonal expansion of mutated hematopoietic stem cells (HSCs).2 Stress triggered by infection or exertion can lead to complement activation and the complement-mediated lysis of red blood cells and platelets. Hemolysis and thrombosis are features of PNH.2 

Empaveli was approved by the US Food and Drug Administration (FDA) in 2021 for the treatment of PNH. Although not the first complement inhibitor treatment approved for PNH treatment, it has a different mechanism of action and is the first to inhibit the complement protein C3, which is further up the complement cascade from C5.3

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Mechanism of Action 

In individuals with PNH, a mutation of the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene, which encodes a protein involved in the synthesis of glycosyl phosphatidylinositol (GPI) anchors, results in HSC abnormalities. GPI anchors allow various proteins to be linked to the cell membrane, contributing to cellular viability.1 

A lack of CD55 and CD59 in HSC membranes in individuals with PNH exposes the cells to complement-mediated hemolysis. CD55 inhibits complement activation via complement component 3 (C3) and limits the formation of C5 convertases; CD59 inhibits complement activation via preventing the incorporation of C9 into the membrane attack complex (MAC).2 In patients with PNH, extravascular hemolysis is mediated by C3b and intravascular hemolysis is mediated by the MAC.1

The active ingredient in Empaveli is pegcetacoplan, a pegylated peptide that is a complement inhibitor. It inhibits complement activation by binding to the precursury C3 and its activation fragment C3b. This binding controls extravascular hemolysis as mediated by C3b. This then also controls intravascular hemolysis as mediated by the MAC.1 

Read more about PNH pathophysiology


The recommended dose of Empaveli is 1080 mg, administered as a subcutaneous infusion 2 times a week. The infusion pump has a reservoir of at least 20 mL, and patients can be taught by healthcare professionals to self-administer their medication.1

Adverse Effects

The most frequently reported side effects (affecting more than 10% of patients) were injection-site reactions, infections, abdominal pain, diarrhea, and fatigue.1

Read more about PNH complications

Warnings and Precautions

Empaveli is associated with a risk for serious, life-threatening infections caused by bacteria such as Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B (Hib). Patients receiving Empaveli must be vaccinated against these agents at least 2 weeks before the first dose is administered.1 Infusion-related reactions may occur, such as facial swelling, rash, and urticaria.1

Read more about PNH prognosis

Safety and Efficacy in Trials

Empaveli was approved following the results of PEGASUS (NCT03500549), a randomized, multicenter, open-label, active-comparator controlled phase 3 clinical trial designed to determine the safety and efficacy of Empaveli in patients with PNH.4 Recruited patients had PNH with a hemoglobin level below 10.5 g/dL and had previously been treated with a stable dose of Soliris® (eculizumab) for at least 3 months. In the first phase of the trial, patients received Empaveli twice a week for 4 weeks, in addition to their dose of Soliris, after which 80 patients were randomized to receive either Empaveli or Soliris.1

The primary endpoint of this clinical trial was mean change in the hemoglobin level from baseline to week 16. Other clinical and hematologic markers of hemolysis and safety were also assessed.5 The results indicated that Empaveli was superior to Soliris at increasing hemoglobin levels from baseline to week 16 in adult patients who had PNH with a hemoglobin level lower than 10.5 g/dL. A total of 35 of the 41 patients (85%) who received Empaveli no longer required transfusions, whereas 6 of the 39 patients (15%) who received their dose of Soliris no longer required transfusions.5

The most common adverse reactions reported during the trial after the administration of Empaveli and Soliris were injection site reactions, diarrhea, breakthrough hemolysis, headache, and fatigue.5

Two other clinical trials, a phase 1 study (NCT02588833) and a phase 2 study (NCT03593200), supported the results reported by PEGASUS.6,7 A total of 24 patients who had not previously received Soliris were enrolled in these trials and were treated with Empaveli for approximately 1 year. The results showed an increase in the hemoglobin level.1,2

The safety and efficacy of Empaveli were also evaluated in the phase 3 clinical trial PRINCE (NCT04085601).8 In this randomized, open-label, multinational trial that enrolled 53 patients with treatment-naïve PNH, hemoglobin stabilization at week 26 was observed in significantly more of the patients who received Empaveli than of those who received standard of care. Additionally, the mean lactate dehydrogenase level was reported to be within normal range at week 26 in the patients who received Empaveli.2,8

Read more about PNH clinical trials


1. EMPAVELI (pegcetacoplan). Highlights of prescribing information. Apellis Pharmaceuticals; revised 05/2021. Accessed November 17, 2022.

2. Hoy SM. Pegcetacoplan: first approval. Drugs. 2021;81(12):1423-1430. doi:10.1007/s40265-021-01560-8

3. Paroxysmal nocturnal hemoglobinuria. NORD (National Organization for Rare Disorders). Accessed November 17, 2022.

4. Study to evaluate the efficacy and safety of APL-2 in patients With paroxysmal nocturnal hemoglobinuria (PNH). June 14, 2018. Updated March 25, 2022. Accessed November 17, 2022

5. Hillmen P, Szer J, Weitz I, Röth A, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028-1037. doi:10.1056/NEJMoa2029073

6. A phase IIa study to assess the safety, efficacy, and pharmacokinetics of subcutaneously administered pegcetacoplan (APL-2) in subjects with PNH. August 16, 2018. Updated December 22, 2020. Accessed November 17, 2022.

7. Pilot study to assess safety, preliminary efficacy and pharmacokinetics of S.C. pegcetacoplan (APL-2) in PNH subjects (PADDOCK). December 1, 2015. Updated January 11, 2021. Accessed November 17, 2022.

8. A study to evaluate the efficacy and safety of pegcetacoplan in patients with PNH. August 27, 2019. Updated October 21, 2022. Accessed November 17, 2022.

Reviewed by Harshi Dhingra, MD, on 11/19/2022.