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Evaluating Complement Pathways for Paroxysmal Nocturnal Hemoglobinuria: Interprofessional Perspectives on Current and Emerging Approaches

  • Authors: Srikanth Nagalla, MD, MS; Catherine M. Broome, MD; Louise Arnold, RGN, BSc
  • CME / ABIM MOC / CE Released: 11/22/2022
  • Valid for credit through: 11/22/2023
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Target Audience and Goal Statement

This activity is intended for hematology/oncology specialists (including bone marrow failure [BMF] experts and fellows), physician assistants (PAs), nurses, and pharmacists.

The goal of this activity is for learners to be better able to understand the complement pathway within PNH and practical strategies for managing these patients as part of the interprofessional team.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Role of the therapies targeting the complement pathway for treating patients with PNH
    • Clinical trial data evaluating therapies used for the management of patients with PNH
  • Have greater competence related to
    • Managing potential adverse events associated with PNH therapies
  • Demonstrate greater confidence in their ability to
    • Coordinate with the interprofessional team to ensure optimal outcomes for patients with PNH


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  • Srikanth Nagalla, MD, MS

    Chief of Benign Hematology
    Miami Cancer Institute
    Miami, Florida, United States


    Srikanth Nagalla, MD, MS, has the following relevant financial relationships:
    Consultant or advisor for: Alexion; Alnylam; Apellis; Pharmacosmos; Rigel; Sanofi; SOBI
    Speaker or member of speakers bureau for: RIGEL; Sanofi

  • Catherine M. Broome, MD

    Associate Professor
    Department of Medicine
    MedStar Georgetown University Hospital
    Lombardi Comprehensive Cancer Center
    Columbia, Maryland, United States


    Catherine M. Broome, MD, has the following relevant financial relationships:
    Consultant or advisor for: Alexion; Argenx; Sanofi; Star Therapeutics
    Speaker or member of speakers bureau for: Alexion; Sanofi
    Research funding from: Alexion; Argenx; Incyte; Rigel; Sanofi

  • Louise Arnold, RGN, BSc

    Trainee Advanced Clinical Practitioner (Nurse)
    Department of Haematology
    St James' Institute of Oncology
    Leeds, United Kingdom


    Louise Arnold, RGN, BSc, has the following relevant financial relationships:
    Consultant or advisor for: Alexion UK; SOBI in UK
    Speaker or member of speakers bureau for: Alexion; SOBI


  • Deborah Middleton, MS

    Senior Medical Education Director, WebMD Global, LLC 


    Deborah Middleton, MS, has no relevant financial relationships.

  • Yoji Yamaguchi, MA, ELS

    Scientific Content Manager, WebMD Global, LLC 


    Yoji Yamaguchi, MA, ELS, has no relevant financial relationships.

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    Associate Director, Accreditation and Compliance, Medscape, LLC


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Evaluating Complement Pathways for Paroxysmal Nocturnal Hemoglobinuria: Interprofessional Perspectives on Current and Emerging Approaches

Authors: Srikanth Nagalla, MD, MS; Catherine M. Broome, MD; Louise Arnold, RGN, BScFaculty and Disclosures

CME / ABIM MOC / CE Released: 11/22/2022

Valid for credit through: 11/22/2023


Activity Transcript

Chapter 1: Overview of the Complement Pathway Within PNH

Srikanth Nagalla, MD, MS: Hello, everyone. Today we will be talking about "Evaluating Complement Pathways for PNH, Interprofessional Perspectives on Current and Emerging Approaches." I'm Sri Nagalla, I'm the Chief of Benign Hematology at the Miami Cancer Institute which is part of Baptist Health South Florida, and I have an interest in rare blood disorders. I will be presenting segment 1, "Overview of Complement Pathway Within PNH." Dr Catherine Broome will present segment 2, "Diving Into the Safety and Efficacy Profiles of Current and Emerging Strategies." Finally, Louise Arnold will present "Practical Considerations for Managing Patients With PNH."

So, let's dive into section 1. PNH, as you all know, stands for paroxysmal nocturnal hemoglobinuria. So let's start with pathogenesis. PNH is a result of an acquired mutation in the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene.

And this gene is responsible for initial synthesis of the glycosylphosphatidylinositol (GPI) anchors. More than 150 proteins are GPI-anchored proteins. If you take a cell there are multiple proteins that are anchored by GPI to this cell. If there are defects in the PIGA gene, as we just discussed, the GPI anchors are defective, so the tethering of these proteins are affected and you might be missing some proteins. There are a couple of proteins, CD55 and CD59, the decay-accelerating factor or membrane inhibitor of reactive lysis, which are breaks on the complement cascade or the regulators of the complement cascade. In PNH these go missing, which results in the pathophysiology later which I'm going to describe. PIGA mutations protect cells from immune-mediated destruction. So, you could have destruction of the other stem cells and other progenitor cells vs the cells that have the PIGA mutation, which have a selective advantage, in that they're not going to be destroyed by the T cells or the immune system.

So, there could be a proliferation of these clones that have the PIGA mutations. Now remember, there could be small PNH clones seen in patients with bone marrow failure (BMF) states like aplastic anemia or hypoplastic myelodysplastic syndrome (MDS). You don't have to treat these small PNH clones, you don't have to give them complement directed therapy. The treatment generally is required by patients with large PNH clones that put patients at risk of hemolysis, anemia and then thrombosis. Some BMF can also be seen in patients with de novo PNH, because if you're talking about this Coombs negative hemolytic anemia, you might be thinking, "Oh, maybe all that I see in PNH is this hemolytic anemia with a high lactate dehydrogenase (LDH) and low haptoglobin." But that's not the case. You could see some thrombocytopenia. You could see some leukopenia because there could be some BMF seen even in de novo PNH.

Let's briefly talk about the epidemiology of PNH. One to 10 cases per million is the usual incidence of PNH. So, if you're practicing in a large city, you could see quite a few PNH patients depending upon the population of that particular city. The median age of presentation is for patients to present usually in their thirties, but this is highly variable. There is no racial, ethnic, or gender predisposition to PNH.

Getting back to the GPI anchor biosynthesis, if you look at it, you can see this particular figure shows you the GPI anchor. You can see the inositol phospholipid part that is anchoring into the lipid bilayer of the plasma membrane. And at the top part of this figure you can see the entire composition of this anchor. You have the inositol phospholipid and then you have a glucosamine. You have 3 mannose molecules. And on top of that, there is ethanolamine phosphate.

For all these things to come together, you need multiple genes. The multiple genes include the PIGA, PIGC, PIGH, PIGP. But the first gene that's essential in the synthesis of GPI anchors is the PIGA gene. And PNH is a disease where mutations occur in the PIGA gene causing a defective GPI anchor. As I mentioned previously, you have defective GPI anchors. And because of that, some of the complement regulators like CD55 and 59 are missing from cell surfaces. This makes the cell very susceptible to complement-mediated attack. These are the cells that are lacking the GPI anchors or have defective GPI anchors and subsequently lacking CD55 and CD59. And because of that, you can have the complement system attacking these cells and causing the underlying PNH manifestations or the clinical presentation of PNH.

Let's delve into the complement system and what generally happens with this complement cascade. Most of you are aware that there's a classical pathway, lectin pathway, alternate pathway, and terminal complement pathway. In PNH, the most important thing that we are going to be talking about is the alternate pathway.

The alternate pathway is constantly activated through slow spontaneous hydrolysis of C3, forming the C3 tick-over. And this activated C3 pairs with factor B. So remember: because we're going to be talking about some complement inhibitors later on and factor B is will be important, factor D is will be important, C3 will be important. And then of course, C5, C5a will be important as we talk about the inhibitors of this complement cascade or the complement system. As I said, the activated C3 is pairing with factor B and then it generates the C3b. And the factor B is cleaved by factor D and it generates the fluid phase alternate pathway C3-convertase. That would be the C3b. Now, the latter catalyzes and cleaves additional C3 molecules to generate C3a and C3b.

And C3b binds factor B on cell surfaces, which is subsequently cleaved by factor D to generate a second surface phase alternative pathway C3-convertase. And this initiates the amplification loop. So, binding and cleavage of an additional C3 to C3-convertase form the APC C5-convertase that cleaves C5 into C5a and then C5b. Both C3 and C5aP convertases are stabilized by properdin or factor P, which also serves as a selective pattern recognition molecule for de novo C3aP convertase assembly. Now, there are other pathways and then the end of this is where you form the membrane attack complex (MAC), which is composed of C5b, C6, C7, C8 and C9. The MAC basically goes and destroys microorganisms or even the cells causing the intravascular hemolysis component of PNH. So in this particular thing, as we just went over, you see that there are some important molecules that could be targeted like factor B, factor D, C3, C5 and there are inhibitors that act on these various molecules of the alternate pathway that we're going to discuss later.

Similarly, you have a classical pathway. And in the classical pathway, the most important is the C1a protease that are also an inhibitor against the C1a protease, which is currently used in the treatment of cold agglutinin disease. And again, the C1s cleaves C4 and C2 leading to the formation of the classical pathway C3-convertase, which is C4bC2a. But for the discussion of PNH, we are going to be focusing mainly on the alternate pathway, and that finally forms the terminal complement in the MAC, which is the membrane attack complex.

Now, I told you about this clonal selection and expansion. So you have the normal hematopoietic stem cells (HSCs) and then you have the PIGA-mutant GPI anchor, the anchor proteins that are deficient in some of these HSCs because of the PIGA mutation.

Now, when there is an immune attack, the immune system can only recognize the normal HSCs that have all the proteins that the immune system can recognize and destroy, which means you're only destroying the normal HSCs. And the cells that have the PIGA mutation survive because they're not destroyed by the immune attack. And then subsequently in step 2, you have this clonal expansion and then you have this large clone of PNH cells that form. So that's what the clonal selection and expansion process leads to this larger clone in PNH.

Let's get to the clinical presentation in PNH. What are the main problems? What do patients really present with? Why do they have the symptoms and signs in PNH? It's mainly because of anemia, thrombosis, and smooth muscle dystonia. Like anemia, there are multiple causes, right? The classical things, if you're destroying the red cells, the complement system is destroying the red cells within the vascular system: that's intravascular hemolysis. But we also said there could be involvement of C3, which can cause extravascular hemolysis.

Patients also can have BMF, we discussed that. So, you could have an underproduction due to BMF. What happens when patients have intravascular hemolysis? They're unable to recapture the iron from these destroyed red cells because you have hemoglobinuria and the iron is being lost as hemoglobin. So you develop iron deficiency anemia. With this chronic damage to the kidneys that happens with hemoglobinuria and everything, you can have anemia of chronic kidney disease. There are multiple causes, but the key is the intravascular hemolysis, and then to some extent, the extravascular hemolysis.

Thrombosis. You see both venous and arterial clots, but venous is more common than arterial clots. You can get thrombosis in unusual locations. Like in PNH, the classical thing is the abdominal circulation or the abdominal venous system. You can have Budd-Chiari syndrome, you can have mesenteric vein thrombosis, you can have portal vein thrombosis. Those are the thrombi that you usually see in PNH.

These are unusual locations; normally, you don't have it unless there are some local precipitating factors like liver abscesses or inflammatory bowel disorders. You're not going to be having abdominal thrombosis just like that. So PNH is a condition you need to think of, especially in people with cytopenias when they present with abdominal thrombosis. The opposite could also be there, whereas you're having too many cells, red cells or platelets, that could produce or that could cause abdominal thrombosis, in which case you think about JAK2 positive myeloproliferative neoplasms. But in PNH, it's going to be cytopenia, hemolysis and then you have abdominal thrombosis. Sometimes you can get cerebral thrombosis, but you can also have regular pulmonary emboli. You can also have regular deep vein thrombosis (DVT). I'm just saying that you can see this unusual location thrombosis. So, don't say, "Oh, it cannot be PNH if the patient has a pulmonary embolism or a DVT." That could also be PNH.

Why does this thrombosis occur? Because of decreased nitric oxide. Nitric oxide is a potent vasodilator. And if you are taking away the nitric oxide, why does that happen? Because plasma-free hemoglobin soaks up all the nitric oxide. So now, the blood vessels are sensitive to the lack of nitric oxide and there is vasoconstriction. Normally, nitric oxide causes vasodilation, now it's the opposite. You have vasoconstriction and that causes thrombosis. You have procoagulant microparticles that are produced. You have decreased fibrinolytic proteins that can happen in PNH and then there could be increased cytokines because of the excess complement mediators that are in PNH. So all these things can be causing thrombosis. And of course, nitric oxide also is important for smooth muscle functioning. So decreased nitric oxide causes smooth muscle dystonia. You can have esophageal spasms, so people complain of something sitting in their chest. That's the esophageal spasms. Again, that's happening because of decreased nitric oxide.

Now, what is the role of nitric oxide? So you know how nitric oxide is synthesized, the nitric oxide synthase from arginine to citrulline, and then you have this nitric oxide that's formed. And it's important, when there is hemolysis, especially intravascular hemolysis, the plasma-free hemoglobin that comes out scavenges all the nitric oxide, and subsequently, the lack of nitric oxide is going to cause esophageal spasm, erectile dysfunction, thrombosis, abdominal pain and fatigue -- everything due to the lack of nitric oxide.

So, it's the PIGA mutation that is resulting in defective GPI anchors. And then because the GPI anchors are defective, CD55 and CD59, which can regulate or protect the cells from complement mediated attack, are now missing. And then whenever the complement system can get revved up, its attacking these cells. And if it's mainly the red cells, you get intravascular hemolysis. And the intravascular hemolysis is going to put out plasma-free hemoglobin that is basically going to scavenge the nitric oxide, resulting in thrombosis and vasoconstriction.

This slide puts together all the clinical manifestations that I spoke about. Again, you have the alternate pathway, which is the key, and then you have this classical pathway, which we briefly spoke about. And in between, there's the lectin pathway. But what's happening with this alternate pathway, again, we went over the various mechanisms, but you get intravascular hemolysis mainly because you're making the MAC, which destroys red cells. It can destroy other cells, but mainly the destruction of red cells causes intravascular hemolysis. With the C3 component, you can also have some extravascular hemolysis, but the intravascular hemolysis is the key towards a lot of these things we spoke about which is thrombosis. You can have a stroke, you can have cardiac ischemia, you can have pulmonary embolism, you can have Budd-Chiari syndrome, DVT. You can have renal insufficiency, the dark urine erectile dysfunction, the dark urine is the hemoglobinuria, abdominal pain, chest pain. You can have fatigue, dyspnea and then you have some BMF. So, it's the intravascular hemolysis along with BMF that can cause most of the clinical manifestations in PNH.

How do you diagnose PNH? You can get a flow cytometry for granulocytes and red blood cells (RBCs), looking for the deficient RBCs, granulocytes, or monocytes which are deficient in the GPI-anchored proteins like CD55 and 59. Now, in the flow cytometry, these antibodies are directed against various CD markers as well as fluorescent aerolysin (FLAER). It's a bacterial toxin aerolysin binding GPI anchor. And this makes the test more sensitive. Please remember 1 thing in PNH: you cannot just study the RBC population alone to look for the clone size because the RBCs, or the red blood cells, are getting destroyed due to intravascular hemolysis and extravascular hemolysis, which means these cells are going to be underestimated. So, if you get a clone size of 20%, that may not be true because a lot of them got destroyed by the intravascular hemolysis. That's the reason you need to be looking at granulocytes, monocytes, other cell lines. That's the key there.

Classification of PNH. PNH could be associated with BMFs like aplastic anemia or MDS, or you could have subclinical PNH where the clone size is less than 10% without any evidence of hemolysis, and it could be maybe found even in the general population, or you have this classical hemolytic PNH where the clone size is greater than 50%. There's active intravascular hemolysis and/or thrombosis. And there could be PNH, again initially I mentioned, associated with BMF and there the clone size could be 20, 30%. You can still have some hemolysis happening even with those clone sizes. So, these are the different categories of PNH that you can see in practice. Coming to the complement inhibitors, if you say, "How do I cure this? How do I take care of this once for all?" That would be a HSC transplant. But we're not going to do that in all the patients. So how do you help patients with PNH?

You can take away that complement system that is attacking these cells and causing the intravascular hemolysis, causing the extravascular hemolysis and then the intravascular hemolysis leading to thrombosis, anemia and all those things. And the extravascular hemolysis also leading to the anemia. So complement inhibition plays a very vital role in the management of PNH. So you can look at this particular figure and you can see what are the available things currently.

The first drug ever available was a C5 inhibitor, eculizumab. And then we have the longer acting formulation, which is done every 2 months, that's ravulizumab. Then you have other C5 inhibitors like crovalimab. So those are drugs which we are actively using.

And then there is C3 inhibitors. So again, we have the drug pegcetacoplan that is a C3 inhibitor, but you can see there are other drugs in development and other drugs that can come out in the future.

Remember I told you 2 other molecules in the complement system that activate the C3 form, the C3 convertase and then subsequently the C5 convertase. The first one is the factor B. So we have factor B inhibitors and we have now factor D inhibitors. So some of these are oral, these are oral agents like danicopan, and then we have ACH-5528, now it is called ALXN2050. So these are all factor D inhibitors and some of these are oral agents that can be used. And then I'm just showing you some of the other inhibitors in the complement system that could be used for other diseases also. But mainly currently we are focusing on, as you know, C5 inhibitors, which we have already been using, now you have the C3 inhibitor, and then you have factor D oral inhibitors against factor D, and you have factor B inhibitors and then some of the others that you can see on this particular figure.

What are the unmet needs? I mean yes, there are oral complement inhibitors, the factor D inhibitors, but again, most of them, it's either you do it 3 times a day, twice a day. So maybe longer acting oral complement inhibitors would help with compliance, with adherence. And then even if you miss a dose, maybe it's still safer if you're using it as monotherapy. So that's going to be a lot of things in the future that we need to look forward to see how this entire landscape evolves. Now, can you do proximal oral complement inhibitors? Because these are the proximal inhibitors, right? Anything C3 or they're all proximal because eculizumab and ravulizumab are terminal complement inhibitors. But then factor D inhibition, factor B inhibition, there are all proximal inhibitors. Can they replace C5 inhibitors or do you need both, ie, some degree of C5 inhibition? And then do you want to also have these oral complement inhibitors? Again, the cost, and then what are the risks? What is the safety profile? We don't know that. So that's something to wait for in the future. More data is needed to know if long-term proximal complement inhibition is safe from infection, autoimmune and cancer standpoint.

We don't have the data. We know about C5 inhibition, we've been doing it for a decade now, but we don't know about the proximal inhibition. So we need to wait more on that. Breakthrough hemolysis, which can happen even with proximal inhibition, is self-limited but can be massive because the clone size is big. More data is needed with these newer agents, the proximal agents, to see how the patients are going to do when there is this breakthrough hemolysis and how do we treat them. So, these are all going to be some of the unanswered questions that in the future, as we get more trials and more clinical experience, we're going to learn more about.

That brings my segment to an end. Thank you very much for your attention.

Chapter 2: Diving Into the Safety and Efficacy Profiles of Current and Emerging Strategies

Catherine M. Broome, MD: Hi. Welcome to segment 2, "Diving Into the Safety and Efficacy Profiles of Current and Emerging Therapies." I'm Catherine Broome, Associate Professor of Medicine, MedStar Health, Georgetown University, Washington, DC.

I'd like to begin by reminding us of an important aspect of PNH, which is the complement pathway. There are 3 ways that complement can be activated: the classical, the lectin, and the alternative pathway. We think about most of the hemolysis in PNH as being an alternative pathway activation. We know that this pathway constitutively is ongoing and it's generating not only C3, but then also generating C5, which leads to the intravascular hemolysis that we associate with PNH. Complement is a very important aspect of how these cells are humanized, and most of us are very familiar with the generation of the MAC, which is going to be responsible for the vast majority of the intravascular hemolysis.

Remember also, though, that in addition to generating the MAC activation of complement, either alternative classical or lectin pathway activation is going to also cause a generation of C3. If we are blocking the ability of the complement pathway to progress through C5, we're going to potentially have some buildup of C3, which is going to result in C3B deposition on the surface of those blood cells. That could result in extravascular hemolysis, meaning clearance not in the intravascular space.

We are all very familiar with C5 inhibition. C5 inhibition with eculizumab has been the cornerstone of therapeutic intervention for PNH for a number of years now. Here, you see the data that was first published in the New England Journal of Medicine in 2006, where we looked at eculizumab therapy, which is an inhibitor of C5, compared to placebo in patients that had PNH. You can see that the patients had a significant improvement in their LDH levels. They had a stabilization of the number of PNH cells, and then they had a significant improvement in their fatigue scores on eculizumab.

When we look at a safety profile of C5 inhibition with eculizumab, we know that C5 is very important in initiating the MAC formation, and that's important in helping us to deal with encapsulated organisms. Remember that all these patients are vaccinated against meningococcus. When we looked at placebo compared with eculizumab, there really were no significant safety signals that were noted in this trial.

The overall clinical portfolio that looks at eculizumab inhibition had 195 patients, consisted of a phase 2 pilot study, the data of which I just showed you, and then 2 additional phase 3 studies, TRIUMPH and SHEPHERD. All of these patients noted significant improvements in hemoglobin and in quality of life as measured by FACIT-Fatigue scores. One additional improvement with C5 inhibition is that these patients had a very significant decrease in the number of thromboembolic events while on C5 inhibition therapy.

When we look at what is the impact that C5 inhibition with eculizumab has had on PNH, we can see a pre-eculizumab survival graph looking at PNH patients as compared to age and sex match controls, and then we can see a post-eculizumab. I think what's really been gratifying about this program is that post-eculizumab, these patients with PNH now have a survival curve which basically mirrors that of age and sex match controls without PNH. This has been a huge improvement for our PNH patients.

Now, as we move into some newer therapeutic interventions, we're going to talk about ravulizumab. Ravulizumab is also a C5 inhibitor, but it has a much longer half-life than eculizumab, and if we look at the data that were presented in the clinical trials, almost 100 patients were on ravulizumab and almost 100 patients on the eculizumab group, and you can see that ravulizumab had noninferiority to eculizumab. And so, it too now has an FDA approval for the treatment of patients with PNH. We now have 2 options for C5 inhibition. We have eculizumab, which is a once-every-2-week intravenous (IV) infusion, and ravulizumab, a once-every-8-week IV infusion, both showing equal efficacy with regards to transfusion avoidance, improvements in hemoglobin, change in FACIT-Fatigue scores, and breakthrough hemolysis.

Now, one of the things that we know and we talked about a few moments before is that if we are blocking C5, and in PNH patients treated with C5 inhibition, there can be this phenomenon called tick-over hemolysis, where C3 builds up, and C3B is deposited on the red cells; that C3B can be recognized as an abstinent, and those red cells are phagocytosed by the monocyte macrophage system. Then, your patients are not having intravascular hemolysis because you're blocking it with C5, but they may be experiencing some clinically significant extravascular hemolysis due to the buildup of C3.

If we look at how can we consider taking advantage of what we now know with regards to PNH, the complement pathways, and what are going to be some of our abilities to interact with that alternative pathway, you can see here that we have a whole variety of different ways to potentially interact. We all know about interacting at C5: eculizumab and ravulizumab have been FDA approved. You can see that there's now a whole list of drugs that are in investigation as drugs that will interact with C5 at a different binding site. We've got ways to interact at C3, which are pegcetacoplan; we've got ways to interact with some of the enzymes that are responsible for forming the C3 convertase, which include factor B and factor D; we've also got ways of interacting with that C3 convertase directly, which include a variety of other experimental compounds.

Let's talk about some of the compounds that have gotten FDA approval. C3 inhibition with pegcetacoplan in PNH: this was published in 2021 in the New England Journal of Medicine. These were patients that were on eculizumab, but having evidence of ongoing extravascular hemolysis, so their hemoglobins were < 10 g/dL in spite of being on eculizumab therapy. Initially, the patients were treated with both drugs, and then they were randomized to either receive C3 inhibition alone or continue on C5 inhibition alone. If we look at the data, we can see that in general in these patients that were not well-controlled on eculizumab. Using a C3 inhibitor and blocking the ability to generate C3 as well as C5 was beneficial for these patients with regards to an improvement in their baseline hemoglobin and freedom from transfusion. They had a decrease in their reticulocyte count, as you might expect, and FACIT-Fatigue scores also improved.

When we look at 2 of the larger studies with regards to this, you can see the mean hemoglobin levels on the C3 inhibition definitely maintained on C3 inhibition alone, whereas back on the eculizumab alone, the hemoglobin levels definitely dropped. There's now been a pretty robust program with C3 inhibition, including PADDOCK and PALOMINO, which are 2 different trials, and you can see here the PADDOCK cohort, the PALOMINO cohort, and if we look at those data, we can see that whether or not you started out on C5 inhibition or you went directly to C3 inhibition, hemoglobin levels improved, LDH as a marker of hemolysis improved, reticulocyte counts improved, and bilirubin levels improved as well; FACIT-Fatigue scores were also improved. Did we see any safety signals by interacting with the complement system at a higher portion of the complement cascade? We did not, so about equal adverse events seen on the C3 inhibition as are seen on the C5 inhibition, and no concerning serious safety events.

Taking our attention to other drugs that have been looked at for PNH: there's crovalimab, which binds to C5, but it binds to a different portion than the eculizumab; it binds to this beta chain and prevents cleavage by the C5 convertase. Eculizumab and ravulizumab lack efficacy in patients that have inherited polymorphisms in the C5A subunit, which corresponds to their target epitope. These polymorphisms are present mostly in patients who are of Asian descent and have been reported in some patients with no known Asian ancestry. This drug is an attempt to allow a therapeutic intervention for patients that have this particular polymorphism.

If we look at the COMPOSER trial, which looked at crovalimab administered once every 4 weeks, you see that it provided complete and sustained terminal complement pathway inhibition, warranting further development, and there are phase 3 trials that are underway looking at this drug. Other ways to interact with the alternative pathway include inhibition of factors that are responsible for enzymatic activity, and those include factor D inhibition. There is a factor D inhibitor called danicopan. It was investigated in 2 open-label, single-arm phase 2 studies, and it's now under investigation as an add-on therapy in a phase 3 randomized trial of patients with PNH who are poor responders or having an inadequate response to C5 inhibition with eculizumab or ravulizumab.

If we look at factor B inhibition in PNH, we see that there was a phase 2 study to assess the safety in a factor B inhibitor in patients with PNH, who, again, were continuing to have this ongoing hemolysis in spite of C5 therapy. Iptacopan led to hemoglobin normalization in most patients with PNH who were poor responders, no safety concerns were noted, and this is an oral drug, so that is also something that is exciting. There is a phase 3 trial that is going to determine whether iptacopan alone may be advantageous to patients who have PNH.

How do we think about our patients right now? Well, we have patients who have PNH; they have mostly hemolysis or thrombosis; they're not meeting criteria for a plastic anemia or other underlying marrow failure disorders, so initially, I think we're still starting most patients on standard complement inhibition therapy. If they have a good response or better, then they continue on standard follow-up. If they're not responding, we have to think about are they not responding because they do or have progressed to BMF syndrome? Do they have residual intravascular or extravascular hemolysis? And then, should we consider placing them on investigational proximal complement pathway inhibitors, like some of the ones that we discussed?

I have here a pretty busy table, but it is just designed to show ravulizumab and pegcetacoplan, which are approved, and we definitely have data for them, crovalimab, which has a phase 1/2 multi-part study, which we do have some data for, and then the danicopan and the iptacopan studies, we have some early phase 1 and phase 2 data, but now those drugs have now progressed into phase 3 and phase 2 open-label trials.

I think there's going to be a lot of interesting progress with regards to how we approach these patients therapeutically as we move into the future. Thank you for listening, and please continue on to segment 3, where Louise Arnold will discuss practical considerations for managing patients with PNH.

Chapter 3: Practical Considerations for Managing Patients With PNH

Louise Arnold, RGN, BSc: Hello, welcome to segment 3. Today, we're going to be talking about "Practical Considerations for Management of Patients With PNH."

My name is Louise Arnold and I'm a hematology nurse with a specialist interest in BMFs, particularly PNH. I'm training to be an advanced clinical practitioner. I work in the PNH National Service at Leeds in Yorkshire, United Kingdom.

To give a background on PNH, I'm not going to talk about the disease itself, it's more about the impact of that on the patient. We know that the patients experience many different symptoms and each individual patient can experience different symptoms at different times. And even though a PNH clone size can be very similar for 2 similar patients, they may experience a very different stretch of disease symptoms.

Understanding how that impacts on the patient helps us understand how we manage that. We know patients experience anemia and hemoglobin at lower than a normal range and can live like that for many years. The anemia can also be coupled with fatigue. And the fatigue in PNH is often seen or experienced ongoing, even alongside therapies, and it is a concern of patients. But it's an understanding that the patient will experience this alongside management, although it is often very much improved by therapies.

You experience renal dysfunction due to the breakdown and the hemolysis of the blood cells. You have dysphasia, abdominal pain, and erectile dysfunction due to the nitric oxide being absorbed by the free hemoglobin in the system. So that gives problems with the muscles.

We see hemoglobinuria, which can often be very shocking to a patient they have the first time it happens to them. It can be before diagnosis or after diagnosis. A patient can have urine that is the color of cola and think about all the different things that have they have done before that and the experience that brings alongside it. When a diagnosis is made and that it's made very clear that it's the hemoglobin that's passing out in the urine, it can be one of the most calming factors for a patient.

We experience patients having thrombosis. This can be a presentation and once a patient has a thrombotic episode, they can then have ongoing thrombotic episodes and it can be the biggest concern from both the patient's experience but also the healthcare professionals.

One of the things that always I think to mention at the end is surprising for a patient is the jaundice. And this doesn't happen to all patients, just a small percentage, but can be one of the most obvious symptoms that a patient experiences with a diagnosis of PNH.

We put all of those together in 1 bag under the title of PNH and we know what's causing it by the problems and complications that we've heard about with PNH. But these can be lifelong and if we can manage these and support these, we can take this away. Treatment requirements in the UK are varied for the fact of the variation in the disease trajectory itself. Someone can have a PNH clone from 1% to 100% and that can bring different approaches to how that patient is managed.

So, the PNH clone size is very important but it's also a guide to how we manage patients because we also look at how they are symptomatically and how the rest of the picture fits together. Often, as we know, they can have an additional BMF and comorbidities alongside which can require treatment and support as well and it's very difficult to sometimes isolate those.

But there are certain criteria and things that we look at in the appropriateness of managing somebody with PNH. We use a set criteria here in the UK and we currently have 3 treatments which are available to us and there are some that are in clinical trial that are coming along that are changing the picture dramatically every few months. I think of having no treatment as we did when I first started working with people with a diagnosis of PNH and we used supportive care that involves things like blood transfusions, iron tablets, warfarin or anticoagulation to now being able to manage somebody effectively with a complement inhibitor. It all takes time and we do need to look at the wider picture and the holistic needs of the patient. From my experience that has been part of the vital positivity that we've seen in improvements in patients but also is something that we need to think about right from the start.

Who requires treatment for PNH? It's different slightly for the different treatments that we have. The experience that we've had from eculizumab which was licensed around 2008, although we had experience from clinical trials from 2002. So, we've known patients that have been on it for 20 years and then more recently in the last few years with ravulizumab, its cousin which is given every 8 weeks. So, the patients need to fulfill criteria here in our management as to why. And that the reasoning behind that was not so much in anything other than doing it appropriately and safely for the patients.

So, we look at whether the patient has had 1 or some of these issues to meet the criteria. This can be a thrombosis related to PNH, which are often in weird places. And as I just said, it can happen very quickly in repetitive cycles. Someone can have more than 1 thrombosis in a very short succession of time. There are complications from the hemolysis where the breakdown of the red blood starts, which can lead to renal failure. I've seen patients present with a fishy urine and are about to start dialysis and then started on complement inhibition and have not required dialysis. Pulmonary hypertension, which we generally see disappear once therapy is started.

Pregnancy is a slightly different issue. We use eculizumab for this because we have the experience in this. We do not have experience currently in ravulizumab. If a lady is pregnant, we sometimes start at a slightly lower clone level to support the pregnancy and keep mum well, keep baby well. And it's a discussion that is very much with the family, the partner, the obstetricians and everybody involved getting that appropriate for that individual. If someone is in our practice that is about to start treatment or in the switch over to ravulizumab more recently and is planning a family in the near future we tend to keep somebody to having eculizumab therapy so that they have the benefit of the experience that we've had with that in managing pregnancy.

Another reason for starting is hemolytic disease. So we monitor that very crudely by looking at an LDH level and if that's 1.5 times above the upper limit of normal or it's symptomatic with things like anemia > 90 g/dL, we used to say if somebody was transfused but now who don't wait until they've had 3 or 4 transfusions. It's just if they have a lower hemoglobin level or if there's an agreement with the specialist within the national service and the local hematologist that's appropriate to start that patient and they feel that that is something that would work for them. We have started patients particularly for things like fatigue and conversations around that, but it's not done without thorough discussion.

We then now have a third treatment, pegcetacoplan, for patients that are already established on a complement inhibitor ravulizumab or eculizumab for at least 3 months and they still had issues of unmet needs such as they're still anemic, so the hemoglobin is below normal range. You may see some extravascular hemolysis or C3 loading on the PNH clone. It's with agreement with the specialist within the service and the patient who see that that is an appropriate thing. It's also discussions I think from a nursing point of view about the change in administration and practical considerations with the patient: ie, are they willing to take on the responsibility and self-administer. Obviously, there is a split between people loving that idea to other patients being slightly nervous and being coached through it. But we've had successes in all ages and it works very well.

We also see new agents coming through and the new agents are quite exciting. You ask group of patients often what they would most like and obviously a cure but to see oral preparations and different things. We're starting to see that coming through but they're all met at the moment because of clinical trials with an eligibility criteria from the research itself.

In managing a patient through complement inhibition comes with some complexity as with any hematological condition. But there's a certain set of nuances that needed to be understand by the people involved. As long as there is that understanding and sharing of information, it's easy to do. But I think it also extends widely with the wider multidisciplinary team (MDT) and all involved. But identifying these potential adverse events alongside the therapies rather than disease itself comes with things such as the terminal complement being blocked.

There is an increased risk of serial infection, particularly meningococcal bug. So to manage this in the UK we give direct information and ongoing information sharing with the family, friends, and people involved. If someone's a student at university, we advise them to involve their housemates or somebody on their course, someone that's going to be nearby that's sensible to understand what's going on.

Obviously, not all patients want to do that and we have seen detrimental effects where somebody hasn't shared that information and struggled with an infection. Patient safety card has been a thing that we give to every patient for them to share the information when presenting it in an acute or a medical situation so they can be understood. But also emergency contact numbers. We have numbers for the local teams as well as say national service where a patient can get hold of somebody 24 hours a day, 7 days a week, whether it's Christmas or a holiday or any time so that they feel that they can have somebody in their corner to explain why there is a complication possible from the therapy they are on, not just the diagnosis they have.

We vaccinate against the risk of meningococcal infection. In the UK we give A, C, W, Y and more recently B, which is the most common strain. With these vaccinations we are here, we give them in advance and use a treatment dose of ciprofloxacin but it can be given in up to 14 days in advance.

We advocate that patients have prophylactic paracetamol or support around it because we have seen some reactions to that. And then vaccinations that are recommended, they're slightly different across the world between 3 and 5 yearly and depending on the age of the patient. Here we are lucky enough to work alongside public health and the meningococcal reference lab in Manchester where we are able to do blood titer monitoring of the levels of the zero groups in ACWY and we can revaccinate at a loss of response or give further information for someone that is a nonresponder to vaccination.

Next though, we are unable to take those blood titers and get a valuable result. So, we tend to vaccinate every 3 to 5 years. Our practice here is every 5 years and we also introduced in the last couple of years a prophylactic penicillin taken orally which is 500 mg twice a day or erythromycin 500 mg twice a day.

And during the COVID-19 pandemic, we have given a rescue antibiotic 2 doses which we increase to 10 doses which the patients are advised if there are signs of infection, particularly fever or headaches or changes in that way to take this and contact the center straight away. But this does not override medical advice. With complement block at C3, vaccination is recommended for pneumococci and Haemophilus influenzae to prevent possible infection there. This can tend to lead to a chest infections if it does happen.

Identification of meningococcal is always the focus but there are always those possible other things because in the context of managing a chronic disease and you're giving therapy to manage that disease, when this is challenged, the therapy is challenged. There can be complications of both the PNH as well. So in the same way as any patient, if they have sepsis, there is management around the sepsis but also the management of the PNH and the treatment.

They may require an extra dose of complement inhibition and they may experience some breakthrough hemolysis so their PNH symptoms may return and this may be acute and require complement inhibition straightaway. We always think about adherence and adherence to therapy timelines and that is very much about scheduling and timing and things like that, but also the patient's remembering and stresses on the body.

We talk about things like emotional stress but it's more if it's surgery or some other change in the system or the balance that maybe requires a little bit more intricate management and close liaison. Pregnancy, we've sort of discussed that a little bit, but we know that pregnancy brings an increased risk of thrombosis or clots. We try to keep mum well and we work very closely with the obstetrics teams to do that. And as I say, our experience has been with eculizumab and sometimes a patient may require increased dosing as they go through to the final stages of pregnancy or just slightly more input and blood monitoring.

Plasma products, if someone has an acute situation as bleeding, we don't want them not to stop bleeding so they can have plasma products but you might need slightly more increased dosing of the complement inhibition because there's complement in plasma.

Travel. We need to plan that. That is an adverse effect if someone misses a dose or gets delayed or stretches their holiday and then doesn't get home in time. So, it's just being mindful of that and managing that the best way we can. And missing a dose in the self-administration side of things is slightly a change in practice for us as healthcare professionals. We've had to retrain ourselves and know that patients could do that. But in the sense of working alongside that and being reassured and initially when we've started patients on self-administration, we hand over that but obviously work closely with just making sure there aren't any concerns around it. I often as a nurse advise a patient to put it in their phone or their diary to remind themselves because it's best will in the world some of us forget. And it's interesting how that has been taken and patients completely enjoyed that change in practice.

So how do we coordinate it as part of an interprofessional team for optimal outcomes and adherence? We need to be multidisciplinary. We need to work together. It's a long-term condition. We need holistic care. There are many people involved. There's pharmacy to administration as well as nurses and doctors, psychological support, different things. It can be quite difficult having a rare disease and having a long-term investment in an IV therapy, for example. Initial referral is so important to adherence and that vital investment of building that relationship, building that trust and finding a way to manage this appropriate for that person and sharing of information and giving information written online, verbal, whatever is appropriate for that patient. Some patients favor patient groups and other support groups. We have different organizations that may just find that perfect spot to get through but also just understand other patients, patient groups are not necessary and not required and not something they want to do and that's fine too. We are all different in that way.

We have an open-door policy to our nursing team. We're very lucky because we have dedicated nurses in a rare disease. My experience has been incredible to be able to offer that to patients and work alongside them. But I think even having a nurse that is there in a team somewhere that is able to be contacted makes a world of a difference to a long-term condition experiencer. Baseline investigations: We advocate that for long term success in the sense of coordinating it but also interprofessionally, we can do that across the different areas of countries. I mean it's very different. My colleague's in Australia, he has very much worked close links with different teams that are hundreds of miles away. We feel like when someone's an hour or so away here it's a challenge. So we all work differently in those ways and coordinating in that and working together makes such a difference.

Regular review is individual to the patient. We speculate when someone is stable and on therapy or have a small clone to be treated to be reviewed couple of times a year, 2 or 3 times a year. But there is more investment at times where it's needed. If someone's got an infection or a complication, we do invest more time on treatment as required by the UK criteria (that's our guide and I know it's different across the world). And also, patient choice and MDT decisions -- it's all one thing that comes together effectively. Supportive care needs to be considered. We very much work alongside local teams here in the UK and if someone needs a transfusion, we wouldn't drag them all the way to our national service. It would be locally and that works well. And that building of trust can really make a difference to that ongoing relationship.

Potential barriers and challenges in treating patients can be all related to this. Diagnosis is made before the complications come; that's OK. But sometimes the complications of the disease can be the diagnosis and sometimes you are dealing with the after-effect of that complication. If it's been a stroke or a different thing, there may be physical as well as mental complications. Travel to the centers I say can be different and is very good to have specialized care, but it also needs to work in combination with local teams and geographically challenged situations.

Adherence, we look at prescribing and scheduling, but we also have to remember that people have self-administration and their own responsibility for that and retrain ourselves. Many of the patients, like I say, are very keen to have an oral agent, but a patient that came to clinic this week said that they would stick to an 8-week IV. It was taken care of and they didn't need to forget and they're not going to worry about forgetting a medication or taking their drugs because they sometimes forget to take their anticoagulant. That was very honest, but it is something we need to consider as healthcare professionals.

The unmet needs continue to be something that we look at and we do manage that around. So if someone's still running a low hemoglobin, how we manage that or if there's things like fatigue, if there's things we can put in place, prevent disease complications and just manage the situation as it comes through. Funding and availability: obviously it's not the same for everyone, so it has to be something that is available for it to be successful. And we know that's not always the case and it's something to be mindful of. Communicating disease and treatment risks: we know how important it's about the meningococcal, but empowering or explaining that to somebody else can be difficult, which is where we use a telephone number so someone can ring a healthcare professional that can help them if they are in a situation of having to describe the risks or possible complications.

The key thing is that working together can create a much easier set of experiences for patients and take away some of these potential challenges.

Thoughts for success. We think if we get the process right, it will be fine, but we've got to work together with a common aim and simple things just kind of make a big difference. And working alongside the patients now in long-term conditions to give more ownership and control over that works very well in this setting. People are the experts of their disease and that's not everybody, but generally that works very, very well. We have a set of professional patients, so understanding and time, having regular reviews, making sure people are up to date with vaccinations, whether they're taking prophylactic antibiotics, how there are other conditions, if it's BMF is going and whether we can support that.

The family and friends very much involving that. Managing things like vaccinations, particularly in the era of COVID and flu. So we very much support that and give individual advice around what is appropriate. Not forgetting some with a small clone that might evolve into the big clone and managing therapies around that. And treatment is a lesser part of the pathway in many ways if it is present. We have got to do a bit of support around the long-term nature of it and the fatigue, but generally the patients are managed well and are the well sick for a better expression, as my friend often says when he's managing patients.

Thank you for listening today and please continue on to complete the CME posttest. Thank you.

This transcript has been edited for style and clarity.

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