Empaveli (pegcetacoplan) for paroxysmal nocturnal hemoglobinuria

Last updated Feb. 24, 2023, by Teresa Carvalho, MS
Fact-checked by Joana Carvalho, PhD

What is Empaveli for PNH?

Empaveli (pegcetacoplan) is a complement inhibitor that’s approved for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). It’s given by subcutaneous (under-the-skin) injection and can be self-administered.

The therapy was developed by Apellis Pharmaceuticals and Sobi, and is marketed for PNH in Europe under the brand name Aspaveli.

Therapy snapshot

How does Empaveli work?

The complement system is a part of the immune system and helps the body fight off infections. It comprises a large number of different proteins that work together, creating a chain reaction known as the complement cascade.

A protein called C3 is a key point of the cascade, regulating its activation. This protein normally splits into two subunits: C3a and C3b. The C3b subunit is known to trigger the destruction of red blood cells outside blood vessels, usually inside the spleen or liver, a process called extravascular hemolysis.

This subunit also activates another complement protein called C5, which is the target of two other approved PNH therapies, Soliris (eculizumab) and Ultomiris (ravulizumab). C5 also splits into two subunits: C5a and C5b, with the latter being involved in intravascular hemolysis, or the destruction of red blood cells inside blood vessels.

By preventing C3 from splitting into C3a and C3b, Empaveli helps to stop both intravascular and extravascular hemolysis, both of which are considered hallmarks of PNH. It also was seen in clinical trials to ease both anemia and fatigue in participants.

Who can take Empaveli?

Empaveli was approved by the U.S. Food and Drug Administration in May 2021 for the treatment of adults with PNH. It can be used both for patients who have never been treated before (treatment naïve) and those switching from Soliris and/or Ultomiris.

Later in the same year, the therapy was approved in Europe for the treatment of adults with PNH who are anemic after having been treated with a C5 inhibitor for at least three months.

In the U.S., Empaveli is only available through a restricted access program under a Risk Evaluation and Mitigation Strategy (REMS) due to the risk of serious infections associated with the treatment. The access program is called Empaveli REMS.

Patients must be carefully monitored for signs of infections, in particular those caused by encapsulated bacteria, as these can become rapidly life-threatening or fatal if not detected and treated early. Specifically at issue are bacteria such as Streptococcus pneumoniae and certain types of Neisseria meningitidis and Haemophilus influenzae. The bacteria Neisseria meningitidis can cause a serious illness called meningococcal disease.

Who should not take Empaveli?

Empaveli should not be used for certain patients, including those:

• with known allergies to pegcetacoplan, Empaveli’s active ingredient, or any other of its components
• who are not vaccinated against certain encapsulated bacteria, including Neisseria meningitidis, unless the risks of delaying the treatment outweigh the risks of a possible serious infection
• with an unresolved serious infection caused by encapsulated bacteria encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae.

How is Empaveli administered?

Empaveli is given via a subcutaneous self-infusion, or one given under the skin. The recommended dose is 1,080 mg given twice weekly, using a commercially available pump.

The treatment does not require visits to an infusion center, as it can be self-administered following specialized instruction. Before self-infusion, a healthcare provider should show patients how to prepare and infuse the treatment.

Empaveli is administered with a small, thin needle that can be placed in either one or two sites on the abdomen, thighs, hips, or upper arms. Patients should rotate administration sites between infusions, and avoid regions where the skin is tender, bruised, red, or hard. Sites with tattoos, scars, or stretch marks also should be avoided.

Each infusion usually takes around 30 minutes if patients use two injection sites; it generally takes about 60 minutes, or one hour, if they use only one site.

The therapy is supplied in single-dose vials. Before use‚ Empaveli should reach room temperature for approximately 30 minutes. Until then, medication vials should be kept inside their carton and protected from light.

It is recommended that patients switching from C5 inhibitors do not discontinue these treatments abruptly when starting Empaveli so as to reduce the risk of hemolysis, or red blood cell destruction. Those  switching from Soliris are advised to discontinue this therapy only four weeks (one month) after starting treatment with Empaveli. Patients switching from Ultomiris are recommended to start Empaveli no more than four weeks after their last dose of Ultomiris.

Lactate dehydrogenase (LDH) is a marker of hemolysis. In patients in whom LDH levels are two times higher than the upper limit of normal, Empaveli’s dosing regimen should be adjusted for 1,080 mg given every three days.

Empaveli in clinical trials

The safety and efficacy of Empaveli in adults with PNH were evaluated in two Phase 3 clinical trials. One, called PEGASUS, enrolled patients previously treated with Soliris, while other, known as PRINCE, involved adults who had not been previously treated with a complement inhibitor.

PEGASUS trial

PEGASUS (NCT03500549), completed in 2020, assessed the efficacy and safety of Empaveli in 80 adults with PNH who were being treated with Soliris. To be eligible to participate in the study, patients had to have been on a stable dose of Soliris for at least three months before entering the trial. Additionally, their hemoglobin levels had to be lower than 10.5 g/dL; hemoglobin is the protein in red blood cells that’s responsible for oxygen transport.

Patients started by receiving both treatments for four weeks. After that, they were randomly assigned to receive either Empaveli or Soliris for 12 weeks, or about three months. Finally, patients were allowed to either continue or switch to Empaveli for an extension period of 32 or 28 weeks, respectively.

The trial’s primary goal was assessing changes in hemoglobin levels from the beginning of the study (baseline) until week 16. Further clinical and blood markers of hemolysis also were evaluated, as was treatment safety.

Results showed Empaveli outperformed Soliris in its ability to maintain or increase hemoglobin levels. In Empaveli-treated patients, hemoglobin levels rose by a mean of 2.37 g/dL over the course of 16 weeks, while in Soliris-treated patients they fell by a mean of 1.47 g/dL — a difference of 3.84 g/dL favoring Empaveli.

The majority of patients (85%) treated with Empaveli no longer needed blood transfusions — a procedure normally required to treat anemia due to hemolysis. In patients receiving Soliris, however, only 15% of patients no longer required blood transfusions. Empaveli also was found to ease fatigue.

Findings from the extension part of the trial also showed that hemoglobin levels remained sustainably higher in patients who remained on Empaveli over 48 weeks, or nearly one year.

PRINCE trial

PRINCE (NCT04085601) assessed the efficacy and safety of Empaveli in comparison to standard therapies in 53 adults with PNH who had not been previously treated with a complement inhibitor. To be eligible for this trial, patients must not have been treated with any complement inhibitor in the three months leading up to study entry. Additionally, their hemoglobin levels had to be below the lower limit of normal and LDH levels had to be above the upper limit of normal.

Participants were randomly divided into two groups and assessed for 26 weeks, or around six months. In one of the groups, patients were given Empaveli, while in the other group they continued receiving standard PNH supportive treatment (control group), which might include blood transfusions, corticosteroids, iron, folate, and vitamin B12 supplements.

The study’s main goals included assessing the proportion of patients achieving hemoglobin stabilization after 26 weeks of treatment, as well as evaluating changes in LDH levels over the same period of time.

Results showed most people in the Empaveli group achieved hemoglobin stabilization throughout the study period, while none of the patients in the control group did (85.7% vs. 0%). A higher reduction in mean LDH levels was observed within two weeks in the Empaveli group compared with the control group, which was sustained over the entire 26-week study period.

Ongoing trials

A Phase 2 trial (NCT04901936) is evaluating the safety and effectiveness of Empaveli in children and adolescents, ages 12-17, with PNH.

Participants are screened for four weeks and then treated for 16 weeks — for a total time period of about five months. Those switching from a C5 inhibitor will have an additional run-in period of four weeks between screening and treatment. At the end of the treatment period, participants will either enter in a long-term extension period or a follow-up period for two months. All participants will be given Empaveli, given by subcutaneous infusion twice weekly at home.

Primary outcome measures include assessing changes in blood levels of Empaveli, hemoglobin, and LDH over the 16-week period. Secondary goals include evaluating changes in several parameters over the extension part of the study, including C3 levels on red blood cells, incidence of blood clotting events and hemolysis, hemoglobin levels, quality of life, among others.

The trial is expected to conclude in October 2024.

Common side effects of Empaveli

The most common side effects related to Empaveli are:

• injection-site reactions
• infections
• diarrhea
• abdominal pain
• respiratory tract infection
• pain in the hands and feet
• low levels of potassium in the blood (hypokalemia)
• fatigue
• viral infection
• cough
• joint pain (arthralgia)
• dizziness
• headache
• rash.

Infections

The Empaveli label carries a boxed warning for serious meningococcal infections that can rapidly become life-threatening if not recognized and treated quickly.

Treatment with Empaveli may increase the risk of serious and life-threatening infections caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B.

To reduce this risk, all patients should be vaccinated against these bacteria — at least two weeks before starting treatment with Empaveli — according to the most updated Advisory Committee on Immunization Practices (ACIP) recommendations for patients with complement deficiencies. Those who are already vaccinated are recommended to receive a booster dose considering treatment duration.

If Empaveli has to be started immediately and vaccines are given less than two weeks before treatment initiation, patients are recommended to receive preventive antibacterial treatment for two weeks.

Patients should be closely monitored for early signs of infection and evaluated immediately if an infection is suspected. Therapy discontinuation should be considered if patients are being treated for serious infections.

Infusion-related reactions

People treated with Empaveli may develop infusion-related reactions, including hypersensitivity and potentially life-threatening reactions, known as anaphylaxis. If a severe hypersensitivity reaction occurs, Empaveli should be stopped and appropriate treatment initiated.

Use in pregnancy and breastfeeding

Studies on the use of Empaveli in pregnant women are still lacking. Studies in primates indicated the treatment may cause harm to the developing fetus. Patients who are pregnant or are planning to become pregnant should discuss this issue with their healthcare team.

It is not known whether Empaveli passes into human breast milk or if it affects milk production. However, traces of Empaveli were found in the breast milk of monkeys. As many compounds pass into human breast milk and potentially cause serious side effects in a nursing child, Empaveli’s label recommends breastfeeding should be stopped during treatment and for 40 days after the last dose.

PNH News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.