PNH care faces a turnaround, but the new drug’s reimbursement remains an issue

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease that affects a small number of patients but is difficult to treat and has a high economic burden.

Current standard of care, C5 inhibitors, have played an important role in prolonging the lives of PNH patients, but anemia and transfusion dependency due to extravascular hemolysis (EVH) remain unmet needs.

Recently, the PNH treatment has taken another leap forward with the emergence of “proximal inhibitors” that compensate for the limitations of existing C5 inhibitors. In particular, the B-factor inhibitor Fabhalta (iptacopan) is expected to improve the mechanistic limitations of the existing C5 inhibitors and the cumbersome administration method.

Korea Biomedical Review interviewed Professor Silvia Park of the Department of Hematology at the Catholic University of Korea Seoul St. Mary's Hospital to learn more about the pathophysiology of PNH and the limitations of existing C5 inhibitors, as well as the clinical value of the new drug Fabhalta and the improvement of the PNH treatment environment in Korea.

Question: What is PNH, and how large is the patient population in Korea?

Answer: PNH is a rare disease caused by an acquired genetic mutation, specifically a mutation in the PIGA gene. The PIGA gene plays an important role in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. Mutations in the PIGA gene impair the production of GPI anchors, preventing CD55 and CD59 proteins from attaching to the surface of red blood cells, which protect them from attack by the complement system.

Globally, 1 to 1.5 per million people are newly diagnosed annually, and 10 to 40 per million people are thought to have PNH. In Korea, the number of PNH patients is reported to be around 500 out of a population of 50 million. Overseas reports indicate up to 40 patients per million people, which indicates that there are many undiagnosed patients in Korea.

Q: What causes PNH? Are there certain groups of patients who are more susceptible to PNH?

A: PNH is not a genetic deficiency inherited from your parents. It is caused by an acquired gene mutation that occurs suddenly at some point in life. In the general population, it's unknown that some people are more susceptible than others. However, it is known that 40 to 50 percent of people with aplastic anemia, a bone marrow failure disorder, have a PNH clone, so patients with this unusual blood disorder are more likely to have a PNH clone.

Q: How are patients diagnosed with PNH?

A: If multiple hematologic indicators of hemolysis in a blood vessel, the first step is to test immunologic causes. If the tests show that non-immune mechanisms destroy red blood cells, PNH is a possible cause. To confirm that hemolysis is due to PNH, flow cytometry is performed to determine the presence of red blood cells that do not express CD55 and CD59. In addition to red blood cells, white blood cells also have several proteins that require GPI to adhere, and the percentage of white blood cells lacking these proteins is also determined.

Intravascular hemolysis can lead to jaundice, elevated liver values, and blood test abnormalities, so it's not uncommon for a patient to come to a gastroenterologist thinking they have bad liver values, only to be referred to a hematologist when it turns out they don't, and PNH is diagnosed.

Q: What is the treatment after PNH is diagnosed?

A: Generally, once PNH is diagnosed, treatment with a “complement inhibitor” is recommended. Historically, the standard of care has been using C5 inhibitors and complement inhibitors. Patients diagnosed with PNH should be treated with complement inhibitors. However, prescription is limited in Korea due to the high cost of C5 inhibitors and the difficulty of obtaining insurance coverage. This is because the mere diagnosis of PNH is not enough to qualify for insurance coverage of C5 inhibitors. To be reimbursed, it must be proven that very serious complications have occurred because of intravascular hemolysis (IVH). For example, a patient must have thrombosis, kidney failure, dialysis, severe shortness of breath due to pulmonary arterial hypertension, severe abdominal or chest pain that requires narcotic painkillers, or a history of multiple hospitalizations.

There are an estimated 500 people with PNH in Korea, but only about 150 of them receive complement inhibitor treatment through insurance benefits or clinical trials. This is because the annual cost of complement inhibitor treatment is about 400 million won ($277,100) per patient, which puts a heavy burden on health insurance finances to provide coverage for all patients. Therefore, the country limits coverage to patients with severe, life-threatening complications. While these financial constraints are understandable, the lack of access to treatments that can prevent complications creates challenges at the point of care for healthcare providers and patients. Furthermore, serious complications themselves contribute to increased healthcare costs.

Due to the high cost of C5 inhibitors, there was a system in the past that allowed the drug to be used only for patients, which was approved in advance through a prior review committee based on a physician's opinion. However, after Nov. 1, 2024, the prior review system was eliminated, and the drug became subject to post-insurance evaluation like other drugs, resulting in a problem. Concern arose that the drug may be subject to a large benefit cut after prescription. If a complement inhibitor is discontinued due to cuts, the patient could be faced with a life-threatening medical situation due to rebound complement activation. These concerns have made it difficult for clinicians to prescribe the drug for now, further limiting access to care.

Q: We have heard that there is an unmet medical need for C5 inhibitors themselves.

A: PNH treatment is divided into pre- and post-C5 inhibitors. While C5 inhibitors have improved treatment outcomes by effectively controlling intravascular hemolysis (IVH), anemia and the need for transfusions remain. This is due primarily to extravasation hemolysis (EVH) and breakthrough hemolysis (BTH). BTH is caused by complement activation triggered by infections and other factors, and it is difficult to avoid these factors in daily life. EVH, on the other hand, can be controlled, depending on which part of the complement pathway the drug inhibits. C5 inhibitors inhibit C5, the downstream end of the complement pathway, but do not affect the upstream pathway and, therefore, do not wholly inhibit EVH. As a result, red blood cells opsonized by C3 complement are destroyed in the liver and spleen, resulting in persistent anemia and the need for blood transfusions. Although C5 inhibitor treatment effectively controls IVH, there are still unmet medical needs, including anemia and transfusion requirements due to EVH.

Q: What is the share of patients whose disease is not well controlled with C5 inhibitors?

A: Based on whether hemoglobin levels reach the normal range, 80 percent of patients do not. In addition, about 40 percent of patients do not reach a hemoglobin level of “10 or higher.” While a hemoglobin level below 10 does not necessarily require a transfusion, additional measures should be taken for patients who remain transfusion dependent with a hemoglobin level below 10 during treatment.

Q: Are there indicators that you monitor regularly and carefully when treating patients with C5 inhibitors?

A: The first thing to consider is whether IVH is well controlled. Lactate dehydrogenase (LDH) is a clinically relevant marker to check for this, and we look at hemoglobin levels, transfusion requirements, and others to see if anemia is a well-controlled secondary marker. Also, the development of subsequent complications that can result from hemolysis is an important indicator. For example, the recurrence of thrombosis or kidney failure is monitored.

Q: In August last year, the first B-factor inhibitor, iptacopan, was approved in Korea. What kind of treatment is it?

A: The complement pathway includes the Lectin Pathway, Classical Pathway, and Alternative Pathway, and the first factor that converges these three pathways is “C3.” One of the factors involved in the synthesis of C3 is Factor B, and the drug that inhibits it is the Factor B inhibitor, iptacopan. By inhibiting factor B, C3 is inhibited at the top of the complement pathway and C5 at the bottom. Therefore, it is known as a treatment that can control IVH, which is the most important, and EVH secondarily.

Because it inhibits factor B at the top of the pathway, experts predicted that it would be effective in controlling EVH but might be less effective in controlling IVH than existing agents. However, in clinical trials, it was found to be effective in controlling IVH overall, and in addition, it controlled EVH well, resulting in a significant improvement in hemoglobin levels and a reduction in transfusion requirements.

Regarding adverse events, there is a concern about “infections.” The complement is not just for red blood cells but also the body's natural defense against invading bacteria, so suppressing it too far upstream could weaken the defense and increase the risk of infection. This is why the clinical studies were conducted in patients who had already been vaccinated against the expected infections. Fortunately, there were no serious infections of concern in clinical studies.

Q: We’re curious if there are any head- to-head studies comparing iptacopan to C5 inhibitors.

A: There are two clinical trials of iptacopan, one for first-line treatment and one for second-line treatment. However, there are no head-to-head comparisons in first-line treatment. The first-line trial of iptacopan was a single-arm design, looking at efficacy and safety with no placebo or control group. The single-arm design was chosen because it is not ethical to use a placebo in patients for research purposes when there are already medications available to treat PNH.

In second-line treatment, a trial directly compares iptacopan to a C5 inhibitor. Patients who were treated with a C5 inhibitor and switched to iptacopan were compared to patients who remained on C5 inhibitor treatment. This included patients who were anemic despite being on a C5 inhibitor, and switching to iptacopan resulted in superior outcomes compared to remaining on the C5 inhibitor on endpoints, such as improved hemoglobin levels and reduced transfusion requirements.

Q: Iptacopan is known as an “oral” drug. There may be a difference here.

A: Oral treatments are more convenient than injections, but patients may have different preferences. For example, you must take it twice a day. The C5 inhibitor, eculizumab (Soliris in trademark), requires a clinic visit every two weeks to receive an intravenous infusion. In comparison, ravulizumab (Ultomiris in trademark) requires a clinic visit once every eight weeks to receive an intravenous infusion. Some patients prefer to visit the clinic every two months for injections, while others prefer to take the medication daily to avoid injections.

When taking oral medications, one thing to watch out for is missing a dose. The consensus is that missed doses can significantly impact treatment with oral therapy.

Q: Iptacopan has applied for insurance coverage, and it is unclear whether the government will cover first- and second-line treatment or only second-line treatment. Do you have a treatment strategy for this?

A: If both agents are available for first-line treatment, it would be a happy medium for clinicians. However, no one can say for sure whether C5 inhibitors or B factor inhibitors are better for first-line PNH worldwide. C5 inhibitors have the advantage of a relatively long history of prescribing experience, and their clinical utility is well established, as they have been shown to improve survival. B factor inhibitors have shown excellent data in clinical trials as first-line therapy, so much so that experts worldwide are split down the middle on the selection criteria.

In other words, if iptacopan becomes available in the country for first-line treatment, clinician experience, and patient preference will be important factors when choosing options. As we move from first-line to second-line treatment, we may consider changing the treatment or adding a new agent to the existing treatment. The clinical data is good, so at the end of the day, we will listen to the patient's preferences and choose the option that will allow the patient to maintain good adherence.

Q: Although PNH is a rare disease, treatment is evolving, with the recent development of many treatment options, including C3 inhibitors, factor B inhibitors, and factor D inhibitors, as a clinician, that must be exciting.

A: Yes, it is. PNH is a very rare disease. However, thanks to the researchers who have been working hard on this disease, we have many treatment options, and we are very happy that the survival rate of PNH patients has improved significantly. I'm happy and encouraged by the development of C5 inhibitors and even another proximal that may improve the subsequent problems. The more options we have, the better. While we are happy to have multiple options and must think about the best treatment for the patient, there is still a lot of work to do regarding which treatment sequence, strategy, and other things to use.

Meanwhile, the current state of PNH practice is unfortunate. As mentioned earlier, all PNH treatments are expensive, and many patients are not covered by insurance, even though they should be. First, it is necessary to treat the disease before it progresses further and complications arise, but under the current reimbursement standards, it is necessary to prove that complications have occurred before insurance coverage is granted. This is a big disappointment. Patients who are not covered by insurance cannot receive effective treatment, and their quality of life suffers greatly, often causing them to quit their jobs. As a clinician, I often think about how to solve this problem. Nothing is more frustrating than not being able to use effective medicines for patients. Korean doctors who treat PNH patients face this situation every day.

Q: What can we do to increase the diagnosis rate of PNH patients who have yet to be diagnosed?

A: The role of medical professionals is more important than the patient. First, doctors should be able to see it and suspect PNH at the screening stage. Only a few doctors in the country are familiar with PNH, so it is difficult for them to suspect PNH in patients with abnormal findings at the initial screening stage. There is a need for a campaign to raise awareness among doctors about what PNH is and when to suspect PNH.