Listen to expert hematologists provide an up-to-date clinical overview of paroxysmal nocturnal hemoglobinuria (PNH), exploring its pathogenesis, clinical manifestations, and the evolution of complement-based therapies.
In this educational podcast discussion, Carlos M. De Castro, MD, and David Dingli, MD, PhD, FRCP, FRCPEd, FACP, FRCPath, explore paroxysmal nocturnal hemoglobinuria (PNH). They trace the evolution of treatment from early complement inhibitors to today’s expanding therapeutic options, emphasizing how these advances have transformed patient outcomes and quality of life. The conversation blends clinical insights with practical considerations for therapy selection and patient care, including:
Presenters:
Carlos M. De Castro, MD
Professor of Medicine, DUMC
Division of Malignant Hematology and Cellular Therapy
Department of Medicine
Duke University
Duke Cancer Institute
Durham, North Carolina
David Dingli, MD, PhD, FRCP, FRCPEd, FACP, FRCPath
Consultant Hematologist and Director of Bone Marrow Transplant Program
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine and Science
Rochester, Minnesota
Link to full program:
https://bit.ly/3Jtjqgr
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. De Castro: All right. Welcome, everybody. This is a podcast about paroxysmal nocturnal hemoglobinuria or PNH. I am joined by my colleague, Dr. David Dingli from the Mayo Clinic. I am Carlos De Castro, at Duke University. We are talking about PNH, which is this rare and very unusual disease that affects the blood. Patients with PNH can present in a lot of different ways, but the classic way is by having hemolysis of their red cells intravascularly, and presenting with dark urine and a lot of symptoms, including abdominal pain, fatigue, etc.
PNH has gotten much more exciting over the past 10-20 years with the development of complement inhibition, which has really revolutionized our treatment for this disease. There are even more agents being developed that we are going to be talking about.
I am going to turn it over to Dr. Dingli to talk about PNH and its background and pathogenesis.
Dr. Dingli: Thank you, Dr. De Castro, and thank you all for joining us today. As Dr. De Castro mentioned, the disease is rare, a few patients per million, but the prevalence is increasing because patients now are living much longer with this disease. In fact, I think this is a very important point, that now the patient with PNH who is properly treated can expect a normal life expectancy.
There are many features that have to occur for this disease to manifest. There is a mutation in a gene called PIG-A, which is fundamental for the synthesis of the GPI anchor, which is required for a number of complement regulatory proteins to be expressed on the surface of cells. However, this is not enough for PNH to manifest itself. The clone that this mutation that arises in the hematopoietic stem cell, must expand, and there are various mechanisms of how this happens, some of which are understood better than others. Again, this is not enough to explain the disease. The reason red cells are destroyed is because, whereas white cells and platelets have other mechanisms to protect them from complement activation, red cells do not. Specifically, they do not express CD46 and complement receptor 1, which also regulate complement activation.
In our body, complement is continuously active at a very low level through the alternative complement pathway. There is continuous hydrolysis of C3, which is amplified through the interaction of C3 with factor B and factor D. Finally, we need to remember that complement factor 3 is attached on the surface of cells. It is this combination of features that results in the disease.
As Dr. De Castro mentioned, the fundamental feature is intravascular hemolysis, typically in the patient who is not on therapy, and this can manifest itself as anemia with symptoms, such as shortness of breath, fatigue. The patient can have hemoglobinuria, so they may have dark urine classically in the morning, but this is not essential for the diagnosis, because there is free hemoglobin in the blood, it depletes nitric oxide, and this results in smooth muscle spasm.
The patient can have abdominal pain and muscle cramps, esophageal spasm. The combination of these features also increases the risk of thrombosis, which traditionally was the main reason for that in patients with untreated PNH. Thrombosis can be in usual sites or unusual sites, in particular the splanchnic circulation, so the portal vein, the superior mesenteric vein, etc., but patients can also have arterial thrombosis.
Dr. De Castro: Thanks, David. About 20 years ago, we entered a new era of having a complement inhibitor. It was developed by some investigators at Yale who wanted to inhibit the complement system to try to block myocardial damage during a heart attack or a myocardial infarction.
They chose C5 as the target, the C5 component of complement, in part because children who are deficient in C5 get a meningococcal infection. They do not get other types of infection.
They developed a monoclonal antibody against C5, and they started clinical trials from this. Pete Hilleman in England heard about this and said this would be a wonderful new treatment for PNH. Do you mind if I try this? Eventually, he was able to convince them to try it in a small pilot study of 11 patients, and it was pretty impressive that blocking complement C5 stopped hemolysis within a week or two, and patients felt much better.
That was the drug we now call eculizumab. It was given as a loading dose weekly for four weeks and then every two weeks. It was very well tolerated. All patients had to be vaccinated against meningococcus before getting the drug, and they had to be educated to be aware of the risks of meningitis and the symptoms so they could get immediate treatment. Eculizumab blocked hemolysis in marked ways, and later we learned that it also seemed to markedly decrease the rates of thrombosis in these patients, which was the major cause of death in many of these patients. Not only were patients feeling better, but they were actually living longer with complement inhibition.
Later, ravulizumab came out. Ravulizumab is a modification of the same monoclonal antibody. It allows it to stay in the circulation longer, so you can achieve higher levels for longer periods of time. It is given as two loading doses two weeks apart, and then you go on ravulizumab every eight weeks. It was a much more convenient drug, in addition to having somewhat higher levels.
Now, the studies that were done with it were non-inferior studies. We really cannot claim one is better than the other, but most patients in this country were switched to ravulizumab just because it was so much more convenient. Ravulizumab also seems to lower the rate of thrombotic episodes. Really, these two drugs became the standard of care in the country for many years.
Now, there are some problems with C5 inhibition that we learned about. The biggest one is probably the development of extravascular hemolysis. With these two drugs, it is pretty uncommon for hemoglobin levels to go in the normal range. LDH levels stay just above normal, but not normal. As time went on, we learned that, because we are blocking C5, all the PNH red cells are getting coated with C3. They have no way to remove C3 fragments from their surface.
In some patients, this was leading to uptake in the spleen and the liver, and leading to extravascular hemolysis. In some patients, it was pretty significant. They had really suboptimal responses to C5 inhibition. This led us to a new age of trying other parts of the complement system for inhibition
Dr. Dingli: Some patients with PNH would continue to require transfusions. As Dr. De Castro mentioned, many patients do not normalize their hemoglobin, even though their fatigue improves. The phenomenon of extravascular hemolysis was actually identified fairly soon after the availability of eculizumab, where patients were found to be Coombs-positive, whereas classically, the untreated patients with PNH will have Coombs-negative hemolytic anemia.
The first drug that was developed to address this problem was pegcetacoplan. It is a cyclic peptide that blocks C3, and therefore C3 does not accumulate on the surface of red blood cells. The idea here is that it will prevent both intravascular hemolysis as well as extravascular hemolysis by preventing coating of red cells with C3 that opsonizes red cells for the reticuloendothelial system.
Pegcetacoplan was studied in two clinical trials. One was called PRINCE, one was called PEGASUS, and one of these was in the treatment-naive population. The other study was in patients who were already on a C5 inhibitor. At that time, most of these patients were on eculizumab. PEGASUS took patients with persistent anemia, and they were randomized to either pegcetacoplan or continuing on the same therapeutic approach.
All patients initially received pegcetacoplan in combination with eculizumab, and the hemoglobin improved in these patients by two grams or more. Then, based on the randomization, patients could continue on pegcetacoplan alone or switch to their C5 inhibitor. As expected, the patients were switched back to the C5 inhibitor. The hemoglobin dropped to their baseline. This study clearly showed that proximal inhibition can improve hemoglobin, in many patients lead to transfusion avoidance, and again, the quality of life improves based on several scoring systems.
Pegcetacoplan needs to be given at least twice a week at home. It is a self-administered dose, using a pump, but it is a bit inconvenient for some patients, although patients have benefited from this approach. Soon after, iptacopan started being studied. This was again a major step forward because it is an oral agent that inhibits factor B. Factor B is a crucial component in the amplification loop for the generation of C3 through the alternative pathway. The idea here is that by going even more proximal, preventing the amplification loop from generating C3 activation, we can prevent both intravascular and extravascular hemolysis.
Iptacopan was studied also in two trials, the APPLY and the APPOINT, and subsequently it was studied in the APPPULSE clinical trial. The data suggests that both in patients who have been previously on a C5 inhibitor, or even treatment-naive, have an improvement in hemoglobin because hemolysis is very well controlled, the LDH, essentially returns to normal, the reticulocyte count returns to normal, and the vast majority of patients who are on iptacopan would expect a hemoglobin above 12. Quite a few will have a normal hemoglobin, and transfusion avoidance is extremely high.
Quality of life metrics showed significant improvement, with the FACIT-Fatigue score, for example, being similar to that of the general population when matched for age.
Patients who start treatment, if they do not respond well, the etiology for that response has to be looked at, but if it turns out it is either extravascular hemolysis or a different problem, if you are on a C5 inhibitor, then there is no reason you cannot switch to oral iptacopan or one of the proximal inhibitors. Similarly, if you are on a proximal inhibitor and you are having problems with either recurrent breakthrough hemolysis, or other issues, we can switch to a different proximal inhibitor, such as oral iptacopan or one of the other ones, without too much problem, and see if they can tolerate that better and have less side effects or less problems with breakthrough hemolysis.
One of the AEs that we learned about with iptacopan was a rise in lipids that occurred in about 6% of patients. Some required a statin or a treatment, but they were able to just watch and use diet measures.
Sometimes, with iptacopan, patients complain about a bit of a headache, but I do not think that it is something specific for this drug. If one looks at the literature, headache seems to be a very common symptom in PNH. Even in the original eculizumab trials, patients reported some headaches, and generally these get better with time.
With iptacopan now, there is nothing predictive that they are going to get a side effect. There does not seem to be a steady time course. I will say the headaches usually occur early with the treatment. Patients are monitored with initiation of the treatment every month or so to make sure they are doing okay on it. After that, they can be seen every three months or every six months. We talk to them about their symptoms, we talked to them about how they are feeling, and then we go into their labs and see if there is anything going on there, if there is something that it needs to be investigated.
Usually, most patients have not had any problems with that, remarkably enough, so it becomes a very easy visit once you see they are doing well and do not have any complaints, and their labs look good.
The additional drug that has been studied was danicopan. Danicopan is also an oral agent. It has to be taken three times a day, and it is only approved in patients who are already on a C5 inhibitor with a suboptimal improvement in hemoglobin.
The idea here is that the danicopan, which will inhibit factor D, will prevent C3 activation and accumulation on the surface of red cells, while also the presence of the complement 5 inhibitor would prevent intravascular hemolysis. This was studied in the ALPHA trial, and again, many patients had improvement in hemoglobin by over two grams, many patients normalizing their hemoglobin, and the high incidence of transfusion avoidance. The other good piece of news with all these proximal inhibitors is that the risk of infections does not appear to be increased compared to C5 inhibitor therapy alone.
We can move to the C5 inhibitor crovalimab.
Dr. De Castro: Crovalimab was developed using something called SMART technology, so it lasts in the circulation longer. Therefore, it can be given in smaller doses subcutaneously until achieved levels of C5 inhibition.
It was tried in three trials called COMMODORE 1, 2, and 3, both in naive patients and those with treatment on a C5 inhibitor, and it showed that it was certainly as good as eculizumab and ravulizumab. The hope was it could be given at home, given that it's small volume subcutaneously and given every four weeks.
It is a more convenient drug. It does block C5. It still has problems with extravascular hemolysis. You still have to vaccinate all these patients against meningococcus. We are now starting to recommend vaccination against pneumococcus and other encapsulated organisms while patients are on these drugs.
Crovalimab adds another choice to our armamentarium, so we now have six FDA-approved drugs for treating PNH, and there are several others now undergoing clinical trials. Choosing amongst these treatments is not an easy thing, and it takes a good discussion with a provider who knows the treatment and the choices, and the patient to make a decision about what to do. Some of these drugs block at C5, some are proximal inhibitors, some are oral, so that makes it more convenient, but you have to make sure the patient is compliant. You have issues with insurance companies and what they will cover. You have issues with IV access. You have issues with making sure that the patient is not having any other symptoms that need to be investigated. All of this is a long discussion with the patient. There is no right or wrong answer. They all seem to be very effective, even upfront.
In terms of treating patients, the only one that I will say we have to give with a C5 inhibitor is danicopan, so it cannot be upfront. Otherwise, all the others can be given upfront as the initial treatment, or we can give C5 inhibitors since we have more experience with them, and if they have a suboptimal response, we can consider switching them to one of these newer agents.
Dr. Dingli: Pozelimab is an anti-C5 antibody. It is being studied in combination with an siRNA that blocks C5 synthesis. The idea is that the combination would result in good control of C5 expression and activation in principle being effective against intravascular hemolysis mainly. The issue with C5 inhibition is always going to be the same. No matter how much we block C5, the possibility of extravascular hemolysis persists because C5 inhibition will replace the effect of CD59, but we are not replacing the loss of CD55, which is there to block C3 accumulation on the surface of red blood cells.
The other component that is also relevant with some of these newer C5 inhibitors that I think we should discuss is that there is a polymorphism in C5 that is present in a small proportion of the population, usually people from Asia that are resistant to ravulizumab and eculizumab. These patients can respond to more novel C5 inhibitors such as crovalimab.
Dr. De Castro: Tesidolumab is a novel anti-C5 antibody that has mostly been tested in Japan and Asia because they have a problem with a polymorphism in C5 that leaves them unresponsive or poorly responsive to eculizumab and ravulizumab. This binds a whole new epitope on C5. There is a Phase II study that was published in a letter to the editor that showed it to be very effective in patients with PNH. Even in those who might have the polymorphism. It is a treatment that will probably be more used in Asia than in the U.S., only because we already have C5 inhibitors that work well, and that polymorphism rarely occurs in the U.S.
Dr. Dingli: Vensobafusp is an antibody targeting C5 that is also fused with a protein that inhibits complement factor H. The result here is that they both block C5 generation on red cells and also block the accumulation of C3. The result being that this is a parental compound that should be able to control both intravascular and prevent extravascular hemolysis. These studies are still ongoing, but the preliminary results are also quite promising.
Dr. De Castro: There are several other agents that are being investigated. Some of these are oral factor B inhibitors. Really, we have a whole bunch that are coming down the line that are all exciting. I think the biggest issue now is with all these choices, is one even better than the other? How do we know what the biggest adverse events are? I will say that one of the key issues that we have been focusing on is breakthrough hemolysis.
If a patient has a complement-activating event, sometimes the levels of complement can get so high that they overwhelm the inhibitor, and you end up with a flare in intravascular hemolysis that can be quite serious. So far, we are looking at all these agents, and maybe some are a little bit better than others, but I think we are going to need more time to see if that is true. I think these newer agents are also focusing on that, saying, can we find a perfect drug that really does not have much breakthrough hemolysis, and then we will have to wait and see.
Other adverse events with these drugs are all very well tolerated. They all seem to improve thrombotic rates down to very low levels, not completely gone, but to very low levels. They all have little quirks about them. For example, pegcetacoplan has to be given subcutaneously; you can end up with skin reactions. Some of them have a little bit of mild diarrhea with them. For the most part, the side effect profiles of all these drugs so far have been pretty incredible, and they have been well tolerated.
Dr. Dingli: Yes. I think one of the main lessons that we have learned with complement inhibition in PNH is that, despite the initial concerns about the risk of infections, actually, complement inhibition is, overall, I would say, quite a safe approach to treat quite a number of diseases. PNH has been leading the charge in complement inhibition for many diseases. It opened the field of complement-modifying therapies for other diseases where complement plays a significant pathogenic role, including kidney diseases, ocular diseases, etc.
I am not saying that there is no risk, but certainly, the concern related to meningitis or overwhelming infection with proper vaccination does not seem to be a major concern. the main thing is related to education of the patient, that the patient must take the drug, and if they have anything suggestive of a complement-amplifying condition, any vaccine, any recent infection, potential surgery, it is very important that they keep taking the drug. Actually, I have had quite a few patients now on this drug who had such complement-amplifying conditions, including surgery, COVID, which is a well-known complement-amplifying infection. As long as they take the drug regularly, the risk of breakthrough hemolysis, in my experience, has been essentially zero, including patients who have had quite extensive surgical procedures while taking the medication. I think now that the disease can be well controlled, in my view at least, the focus should be on improving quality of life. I want these patients to be as normal as possible, and being normal means that the patient can live with minimal to no symptoms related to the disease, and can enjoy life like anybody else.
With these novel therapies, I think we can now aim to personalize the therapy, because one therapeutic approach may be applicable for one patient, and a different approach may be applicable to a different patient. I do not think we are going to have a one-size-fits-all approach, but certainly, it is very exciting to have so many different treatment options for our patients.
Dr. De Castro: I think they raised great points that quality of life should really be a high focus. These patients are doing well in terms of controlling their blood count levels and controlling complement and feeling much better, but really, we should focus on how well are they living, are they able to do what they want to do, etc. He is right, infections have not really been a problem despite us moving into the proximal inhibitor as targets. It really has changed things quite dramatically for us. Hopefully, we can continue to improve with these therapies and really until we eventually get a cure for this disease. Right now, we are at a very good place where treatments have really made a marked difference in the lives of patients with PNH.
Dr. De Castro: The only other thing I will mention, just briefly, is the issue of pregnancy in these patients because right now, none of them have FDA approval for pregnancy, but we have a lot of case series that was put together by Richard Kelly showing that eculizumab seems to be fairly safe and improve outcomes during pregnancy. All the other ones, there is a little bit of data, but not enough to feel comfortable yet to use these drugs during pregnancy. Right now, we are using eculizumab as our treatment standard for pregnant females with PNH. The others, we will have to wait and see.