PNH treatment and support

 

Treatments for paroxysmal nocturnal hemoglobinuria (PNH) aim to reduce the destruction of blood cells that drive its symptoms. Supportive therapies also may be given to manage specific disease manifestations.

In PNH, blood cells lack certain surface proteins, and as a result, become more susceptible to being attacked and destroyed by the complement cascade, a group of immune proteins in the blood. Activation of the complement system works a bit like a Rube Goldberg machine or a series of dominoes falling down — when one protein becomes activated, it activates the next, which in turn activates other complement proteins, and so forth.

There are six medications approved by the U.S. Food and Drug Administration (FDA) to treat PNH: Soliris, Ultomiris, PiaSky, Empaveli, Fabhalta, and Voydeya. These therapies work by blocking steps in the complement cascade, preventing complement-mediated blood cell destruction.

Since all of these therapies block the complement system, which normally helps defend the body against infectious invaders, all four of these therapies may increase a person’s risk of developing infections, including serious meningococcal infections. For this reason, these therapies are only available in the U.S. through a restricted access program under a Risk Evaluation and Mitigation Strategy (REMS).

Soliris

Soliris (eculizumab) was the first therapy to be approved by the FDA for the treatment of PNH in 2007. It is a monoclonal antibody that blocks complement activation by binding and preventing the cleavage of a complement protein called C5. The therapy was originally developed by Alexion Pharmaceuticals, which was acquired by AstraZeneca in 2021.

Clinical trials in PNH have shown Soliris can reduce blood cell destruction, ease common disease symptoms like fatigue, and improve patients’ quality of life.

Soliris is administered via infusions into the bloodstream, which usually take a bit longer than half an hour for adults. The first five infusions are given once weekly, and subsequent infusions are administered every other week.

Ultomiris

Ultomiris (ravulizumab-cwvz) was approved by the FDA in 2018 to treat adults with PNH. In 2021, its approval was extended to children 1 month and older with the disease.

Its mechanism of action is virtually identical to that of Soliris. The key difference between Ultomiris and Soliris is in how the two therapies are administered.

Ultomiris may be administered by into-the-vein infusion like Soliris, but because Ultomiris lasts longer in the body, infusions don’t need to be given as frequently. After initial loading doses, maintenance infusions of Ultomiris are given every eight weeks for adults, and every four or eight weeks for children, depending on body weight.

Ultomiris can also be administered by subcutaneous (under-the-skin) injection once weekly. This mode of administration is approved for maintenance dosing in adult patients only.

Like Soliris, Ultomiris was originally developed by Alexion, which is now a part of AstraZeneca.

PiaSky

PiaSky (crovalimab-akkz) was approved by the FDA to treat adults and children, ages 13 and older and weighing at least 40 kilograms (about 88 pounds), in 2024.

Like Soliris and Ultomiris, PiaSky also blocks complement activation by binding and preventing the cleavage of the C5 protein. The therapy was originally created by  Chugai Pharmaceutical and it is being marketed in the U.S. by Genentech.

PiaSky is given by subcutaneous injection every four weeks, after an initial intravenous loading dose and four subcutaneous doses given once weekly.

Clinical trial data showed PiaSky is as efficient as Soliris at preventing red blood cell destruction and enabling patients to remain free of blood transfusions.

Empaveli

Empaveli (pegcetacoplan) was approved by the FDA to treat adults with PNH in 2021. The therapy also is approved in Europe, where it’s marketed under the brand name Aspaveli. The treatment, which is administered via a subcutaneous self-infusion twice weekly, was co-developed by Sobi and Apellis.

Unlike Soliris and Ultomiris that target C5, Empaveli targets another complement protein called C3, which is slightly upstream of C5 in the domino-like process of complement activation.

Clinical trial data showed Empaveli is able to maintain or increase the levels of hemoglobin — the protein in red blood cells responsible for oxygen transport — and to reduce red blood cell destruction.

Fabhalta

Fabhalta (iptacopan) was approved by the FDA to treat adults with PNH in 2023, becoming the first oral monotherapy to be approved for that indication.

The therapy, which was developed by Novartis, is supplied in the form of oral capsules containing 200 mg of the active ingredient. Fabhalta is recommended to be given at a dose of 200 mg twice daily, with or without food.

Fabhalta is designed to inhibit factor B, a complement protein that acts upstream of C5 in the complement cascade. By specifically targeting this earlier step of complement activation, Fabhalta is thought to be able to prevent red blood cell destruction occurring both inside and outside of blood vessels.

Clinical trial data showed Fabhalta outperformed previously-approved C5 inhibitors in its ability to boost hemoglobin levels in PNH adults who had residual anemia despite being treated with C5 inhibitors. The proportion of patients who remained free of blood transfusions was also higher among those treated with Fabhalta compared with those given C5 inhibitors.

Fabhalta also was found to have a favorable effect on boosting hemoglobin levels in patients who had never been treated with complement inhibitors.

Voydeya

Voydeya (danicopan) was approved by the FDA as an add-on treatment to Ultomiris or Soliris to treat extravascular hemolysis, or red blood cell destruction occurring outside blood vessels, in adults with PNH in 2024.

The therapy, which is marketed by Alexion, AstraZeneca Rare Disease, is supplied in the form of film-coated oral tablets containing 50 or 100 mg of the therapy’s active ingredient, which can be taken with or without food. Voydeya is recommended to be given at a starting dose of 150 mg three times per day, which can be increased to 200 mg three times per day if needed.

Voydeya is designed to inhibit a complement protein called factor D, which also acts upstream of C5 in the cascade of complement activation, much like factor B. By inhibiting factor D, Voydeya is expected to help prevent extravascular hemolysis, without interfering with the ability of Ultomiris and Soliris to control red blood cell destruction occurring inside blood vessels.

Clinical trial data showed that when given as an add-on treatment to Ultomiris or Soliris, Voydeya significantly outperformed a placebo in its ability to boost hemoglobin levels in PNH adults who had clinically significant extravascular hemolysis.

Hematopoietic stem cell transplantation (HSCT)

Hematopoietic stem cells, or HSCs, are cells in the bone marrow that are responsible for giving rise to new blood cells, including red blood cells that carry oxygen through the body, white blood cells that fight off infections, and platelets that play a key role in blood clotting.

In most cases, PNH is caused by an acquired mutation in the PIGA gene in HSCs that causes blood cells to lack certain proteins on their surface. This causes the immune system to mistake them for an infectious threat, ultimately leading to their destruction.

HSC transplantation (HSCT), sometimes also referred to as a stem cell transplant or a bone marrow transplant, is a procedure that basically aims to “reset” the HSCs in a person’s bone marrow.

Simplistically, the procedure involves first collecting healthy HSCs from a healthy donor. Then, potent cell-killing treatments like radiation or chemotherapy are used to wipe out the faulty HSCs in the patient’s bone marrow. Healthy HSCs are then transplanted into the patient to repopulate the bone marrow and give rise to new healthy blood cells.

Because it directly tackles the underlying cause of the disease, HSCT is considered the only truly curative treatment for PNH. However, HSCT is an intense and invasive procedure that usually requires a long hospital stay and is associated with a high risk of side effects and complications that can be fatal in some cases.

Due to these risks, HSCT is usually not adopted as an initial treatment for people with PNH in regions where complement-targeting therapies are available. HSCT may be used in patients with severe disease who don’t respond well to complement inhibitors and in those who don’t have access to complement-blocking treatments.

HSCT may also be considered as a treatment for PNH patients who have other co-occurring bone marrow disorders, such as aplastic anemia or myelodysplastic syndromes.

Supportive treatments

In addition to targeted therapies, there are a number of supportive treatments that can help manage PNH.

Anticoagulation

Thrombosis, which occurs when blood clots form and block blood flow in veins or arteries, has historically been the leading cause of fatal complications in PNH. Anticoagulants, such as heparin and warfarin, are therapies that act to prevent blood clotting.

Prior to the development of complement-targeting therapies, people with PNH were often placed on prophylactic (preventive) regimens of anticoagulant therapies. Now, however, these therapies are not usually given prophylactically unless the patient has a known history of dangerous blood clots, lacks access, or is not eligible to be treated with complement-blocking therapies. In patients who do experience thrombosis, prompt treatment with anticoagulants is recommended.

Blood transfusions

Blood transfusions are used to transfer healthy blood cells into the body, which can help ease PNH symptoms caused by low blood cell counts, such as fatigue.

Historically, regular blood transfusions were a part of standard care for PNH. With modern complement-blocking therapies, most patients do not require regular transfusions. Even so, it has been estimated that around a fourth of patients may still need regular transfusions even while on therapies like Soliris.

Regardless of underlying treatment, blood transfusions also may be given to replenish blood cells if patients experience a PNH attack.

Folic acid supplements

Folic acid is an artificial form of a vitamin that HSCs require in order to make new blood cells. While most people get a sufficient amount of folate — the natural form of the vitamin — in their diet, people with PNH commonly have low levels of this vitamin because HSCs are overactive as they attempt to replace the blood cells that get destroyed by the disease. As such, it’s generally recommended that PNH patients take folic acid supplements.

Iron supplements and iron chelation

Hemoglobin is the iron-rich protein that red blood cells use to ferry oxygen through the bloodstream. In PNH, red blood cells get destroyed, causing hemoglobin to be released into the bloodstream and ultimately eliminated in the urine.

The loss of iron-rich hemoglobin can lead to iron deficiency. As such, iron supplements may be recommended as part of treatment for PNH patients with low iron levels.

Conversely, some patients with PNH — especially those who are on complement-blocking therapies, but still need regular blood transfusions — can be at risk of iron overload, which happens when there’s too much iron in the body. In these cases, iron chelation therapies — medications that help remove extra iron from the body — are commonly used to reduce iron levels.

Continuous renal replacement therapy (CRRT)

In some people with PNH, the disease can lead to kidney damage. Management of kidney injury in PNH commonly involves continuous renal replacement therapy, or CRRT. This is a form of continuous, 24-hour dialysis that uses a machine to filter blood, mimicking the natural function of the kidneys in patients with kidney injury.

Does treatment increase life expectancy?

Before the development of complement-blocking treatments like Soliris, Ultomiris, and Empaveli, the expected survival for someone with PNH was about 10 to 22 years after disease onset. However, because these modern treatments can substantially lower the risk of life-threatening complications, particularly blood clotting problems, people with PNH who are treated in the modern era have a life expectancy that’s comparable to the general population.

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PHN 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.