Advances in Treating PNH (Paroxysmal Nocturnal Hemoglobinuria) with Dr. Allyson Pishko - 2022

Leigh Clark:    00:00    Hi, everyone. This is Podcast for Patients with the Aplastic Anemia Aplastic Anemia: (ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells - red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most… and MDS International Foundation. I'm Leigh Clark, director of patient programs, and I'll be moderating the podcast today. Our podcast series is brought to you, and I'd like to give special thanks to our corporate sponsors and our patients' families and caregivers for supporting the podcast series.
Leigh Clark:    00:26    Today, we're talking about advances in treating PNH with Dr. Allyson Pishko, who is an assistant professor in hematology oncology at the University of Pennsylvania. Welcome, Dr. Pishko.
Allyson Pishko,...:    00:41    Thank you. It's so great to be here.
Leigh Clark:    00:46    Thank you for joining us. Let's start out. What is PNH?
Allyson Pishko,...:    00:51    So PNH is a rare disorder, with two hallmark features being the breakdown of red cells, or lysis, and tendency to clot in atypical places. The name paroxysmal nocturnal hemoglobinuria paroxysmal nocturnal hemoglobinuria: (par-uk-SIZ-muhl nok-TURN-uhl hee-muh-gloe-buh-NYOOR-ee-uh) A rare and serious blood disease that causes red blood cells to break apart. Paroxysmal means sudden and irregular. Nocturnal means at night. Hemoglobinuria means hemoglobin in the urine. Hemoglobin is the red part of red blood cells. A… comes from the fact that the onset of symptoms are paroxysmal, or sudden; nocturnal, as the symptoms often increase at night, and hemoglobinuria hemoglobinuria: (hee-muh-gloe-buh-NYOOR-ee-uh) The presence of hemoglobin in the urine. , which is the presence of free hemoglobin hemoglobin: A protein in the red blood cells. Hemoglobin picks up oxygen in the lungs and brings it to cells in all parts of the body. , which is usually found inside intact red cells, being present in the urine, leading to a dark color.
Allyson Pishko,...:    01:29    In PNH, what causes the red cells to lyse is really a loss of two markers on the red cell surface, um, that's CD55 and CD59, and these markers on the red cell surface usually are there to signal the body's immune system not to attack the cell. When these markers are not on the red cell surface, the immune system is missing this do not attack signal, and thus will destroy the red cells, specifically by comp-, by complement depositing on the red cell membrane.
Allyson Pishko,...:    02:03    What causes this loss of this important cell surface markers are acquired mutations, which occur in the stem cells stem cells: Cells in the body that develop into other cells. There are two main sources of stem cells. Embryonic stem cells come from human embryos and are used in medical research. Adult stem cells in the body repair and maintain the organ or tissue in which they are found. Blood-forming (hemapoietic) stem… in the bone marrow bone marrow: The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow. where the red cells are produced and mature. Uh, we generally say acquired as it's not something that's inherited from your mother or father, but rather develops after birth. This mutation mutation: Any change or alteration in a gene. A mutation may cause disease or may be a normal variation. Paroxysmal nocturnal hemoglobinuria (PNH) occurs because of a mutation in the PIG-A gene of a single stem cell in the bone marrow. in the stem cells is specifically in the PIGA gene, and it's unclear why some patients develop this mutation. Um, we don't have clear risk factors for developing it, although we do know that patients with other bone marrow disorders, conditions like aplastic anemia, are more likely to have this and to have PNH.
Leigh Clark:    02:47    Thank you so much. Uh, what are the current treatments available for PNH?
Allyson Pishko,...:    02:53    Yeah, so fortunately, we have expanded, uh, treatments for PNH. Um, like we talked about, PNH is the loss of these cell surface markers on the red cells, which leads to too much of complement activation by the immune system. So the approach to treatment is really turning off this complement system complement system: A group of proteins that move freely in the bloodstream. These proteins support (complement) the work of white blood cells by fighting infections. .
Allyson Pishko,...:    03:16    In the complement system, it's a cascade where one thing activates another, activates another to form this attack complex which ultimately can lead to lysis of what's supposed to lyse, which is bacteria. But in this case, it can lead to lysis, or breakdown, of the red cell. So complement inhibitors were developed to treat this and other disorders which involve overactivation of the complement system.
Allyson Pishko,...:    03:45     Eculizumab Eculizumab: Eculizumab (Soliris ®) is given as an IV into a vein at the doctor’s office or at a special center. The procedure usually takes about 35 minutes. You will probably get an IV once a week for the first 4 weeks. Starting in the 5th week, you will get a slightly higher dose of Soliris every 2 weeks. … was the first complement inhibitor FDA approved in this space and inhibits the complement protein C5. This medication is intravenous and dosed every two weeks. The second complement inhibitor to be developed was ravulizumab, which has a similar mechanism which also inhibits C5, and this is dosed every eight weeks.
Allyson Pishko,...:    04:11    And now, we have the newest complement inhibitor on, on the block, which is pegcetacoplan pegcetacoplan: EMPAVELI® is the first PNH treatment that binds to complement protein C3. It was approved by the Food and Drug Administration in May 2021 for treating adult patients with paroxysmal nocturnal hemoglobinuria (PNH). EMPAVELI is given skin (subcutaneously) by using the Empaveli injector or with an… , which is a subcutaneously-infused medication via an infusion pump. This medication also targets the complement system, but a little bit higher up, or proximal, in the complement cascade. It inhibits something called C3. Thus, this medication has been shown to inhibit the red cell lysis that not only occurs in the blood vessel, which we call intravascular, but also extravascular hemolysis hemolysis: (hi-MOL-uh-suss) The destruction of red blood cells. , that red cell breakdown that can occur in the liver and the spleen.
Allyson Pishko,...:    04:51    Additionally, patients may not just need complement inhibitors, because another component of this disorder can be thrombosis thrombosis: (throm-BOE-suss) A blood clot (thrombus) that develops and attaches to a blood vessel. , or clotting. Uh, the clotting can occur in the leg, where we call it deep vein thrombosis. It can be in the abdomen or near the liver like a portal vein thrombosis. And those patients with, with clots may also need anticoagulation, or blood thinners. This is, uh, typically been with, uh, either warfarin warfarin: It is used to prevent blood clots from forming. Warfarin is a tablet that is taken by mouth. or enoxaparin enoxaparin: Enoxaparin is in a class of medications called low molecular weight heparins. It works by stopping the formation of substances that cause clots. It is also used in combination with warfarin to treat blood clots in the leg.  , but newer medications, um, called the direct oral anticoagulants like apixaban, uh, rivaroxaban are now also being used for the clotting component of this disorder.
Leigh Clark:    05:38    Thank you so much for that answer. What should patients consider when selecting a treatment for PNH?
Allyson Pishko,...:    05:46    A, a great question. Um, first, I, I just wanna start off by mentioning that the good news is that medications for PNH are generally very effective at, at halting the, the red cell breakdown and are, are pretty well tolerated. Um, the medications that we generally used in the, the first line are the eculizumab or the ravulizumab, which were those, uh, C5 inhibitors. The major risk of these medications that patients and providers need to be aware of is this increased risk of meningitis, 'cause you really need your complement system to fight off, uh, that type of infection. So it's very important that patients are vaccinated against meningitis before or, or after, shortly after starting therapy and really keep up with these, with these vaccinations.
Allyson Pishko,...:    06:39    As far as, um, the choice between, the two medications, um, the ravulizumab does have a longer half-life, so it can be dosed every eight weeks versus every two weeks for the eculizumab. And so that is a, a major advantage for some, for some patients,  it is IV, so they don't have to infuse it as, as frequently. So that may affect the decision of which medication to use.
Allyson Pishko,...:    07:09    As far as the newer medication, the one that is subcutaneous, or, you know, given under the skin, that's pegcetacoplan, um, that may be advantageous, advantageous to patients who are still having significant red cell breakdown despite ravulizumab or eculizumab. So patients may be switched to that medication if we're still seeing that they're having a lot of red cell turnover, perhaps still needing, um, red blood cell red blood cell: The most numerous type of blood cell in healthy people. Red blood cells contain hemoglobin, a protein that picks up oxygen in the lungs and brings it to cells in all parts of the body. Also called erythrocyte, RBC. transfusions, because that medication not only targets the intravascular hemolysis, or that red cell breakdown that's happening in the blood vessel, but it also targets the, the hemolysis that is happening in the liver and the spleen. So that is generally some- something, at this time, that patients would be switched to if they weren't having, uh, as good of a response to the... those other two agents.
Leigh Clark:    08:06    What's on the horizon for treating PNH?
Allyson Pishko,...:    08:10    Another really... a really good question. So I'm happy to say that there are, um, lots of, different agents in development. Um, there are oral, um, inhibitors of complement that are under investigation. So even though, um, we can decrease the frequency of infusion, um, with the ravulizumab, it can be burdensome to, to have to infuse, um, this medication via, via IV. So an oral medication, I think, would be a, a big, uh, advance, uh, potentially, and there are some under development.
Allyson Pishko,...:    08:45    There are also other approaches to blocking, um, complement activation, um, ongoing with some other monoclonal antibodies, which means, um, things that can kind of block or inhibit the complement from depositing on, on the red cells. And so there, there is, more to be done in PNH and, and trials, uh, ongoing, so hopefully the, the list of medications that patients are offered in the future will be much longer. We're also learning more about how, uh, best to manage patients, um, which therapies should be used, you know, first and second line, and learning about which anticoagulation strategy is best as well.
Leigh Clark:    09:34    Thank you. And last question, Dr. Pishko. You mentioned about clinical trials clinical trials: Clinical research is at the heart of all medical advances, identifying new ways to prevent, detect or treat disease. If you have a bone marrow failure disease, you may want to consider taking part in a clinical trial, also called a research study. Understanding Clinical Trials Clinical… . If somebody was interested in looking for clinical trials, where would someone find, uh, listings for clinical trials?
Allyson Pishko,...:    09:48    Well, um, they can always, uh, speak to, to their provider. Uh, they also can go on, um, clinicaltrials.gov. If you type in, paroxysmal nocturnal hemoglobinuria, uh, it should, it should list any ongoing trials if you click those that are, are currently enrolling.
Allyson Pishko,...:    10:08    And Leigh, I should've asked you. Is there anything on the, um, aplastic anemia website about clinical trials?
Leigh Clark:    10:15    Absolutely.
Leigh Clark:    12:53    Thanks, Dr. Pishko. How would someone go about finding a clinical trial clinical trial: A type of research study that tests how a drug, medical device, or treatment approach works in people. There are several types of clinical trials. Treatment trials test new treatment options. Diagnostic trials test new ways to diagnose a disease. Screening trials test the best way to detect a… for PNH?
Allyson Pishko,...:    12:59    That's a really important question, and we always encourage our patients to enroll in clinical trials so that we can improve therapies for patients with PNH. I suggest, you know, they start off by talking to, to their clinician about, uh, trials they may be aware of, and then they can also search the www.aamds.org website. If  you click on Clinical Trials, you can actually type in some of your criteria that, um, you, that you have and look and find out watch... which clinical trials you would be eligible for. Another resource, which is a, which i- is available to patients, the clinicaltrials.gov website, which also can be, um, searched directly by typing in, PNH.
Leigh Clark:    13:56    Well, thank you so much, Dr. Pishko, for sharing your time and your expertise with all of us today. And you can find out more about PNH and other bone marrow failure bone marrow failure: A condition that occurs when the bone marrow stops making enough healthy blood cells. The most common of these rare diseases are aplastic anemia, myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Bone marrow failure can be acquired (begin any time in life) or can be… diseases on our website at aamds.org. You can also follow us on Facebook, Instagram and Twitter, or give us a call at our helpline, which is 800-747-2820. This concludes our podcast.