FDA Approves Omisirge to Treat Patients with Severe Aplastic Anemia

Leigh Clark:    00:03    Hi, everyone. Welcome to Podcasts 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, Senior Director of Patient Programs, and I have the pleasure today of speaking with Dr. Richard Childs, who's the scientific Director of the National Heart, Blood and Lung Institute at the National Institutes of Health. Dr. Childs also serves as the principal investigator for 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… for patients diagnosed with aplastic anemia. Before we get started, I'd also like to thank our Diamond Level sponsors, Alexion, Apellis, and Novartis, as well as our patients families and caregivers, who without their support, this podcast would not be possible. Welcome, Dr. Childs. Thank you so much for joining me today.

Richard Childs:    01:00    Good morning. Good to talk to you this morning.

Leigh Clark:    01:02    So, before we get started, tell me a little bit about, what is aplastic anemia?

Richard Childs:    01:08    Well, Leigh, aplastic anemia is a very rare, but very devastating,  disease that affects the bone marrow bone marrow: The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow. , where there's a diminished number of hematopoietic precursor 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. And in most cases, we think it's an autoimmune disease autoimmune disease: Any condition that happens when the immune system attacks the body's own normal tissues by mistake. . And because of the lack of these hematopoietic stem cells, patients develop cytopenias, they develop anemia anemia: (uh-NEE-mee-uh) A condition in which there is a shortage of red blood cells in the bloodstream. This causes a low red blood cell count. Symptoms of anemia are fatigue and tiredness. , their platelet platelet: The smallest type of blood cell. Platelets help the blood to clot and stop bleeding. Also called a thrombocyte. counts are low, and their white blood cell white blood cell: Cells in the body that fight disease and infection by attacking and killing germs. There are several types of white blood cells including neutrophils, eosinophils, basophils, lymphocytes and monocytes. Each type of cell fights a different kind of germ. Also called WBC, leukocyte. count is low, and they're susceptible to infection, bleeding, and to severe anemia, and if untreated, uh, the disease is uniformly fatal.

Leigh Clark:    01:49    Dr. Childs, what are the current treatment options available for patients?

Richard Childs:    01:54    There's two principal modalities to treat patients with aplastic anemia. One is immunosuppressive therapy immunosuppressive therapy: Immunosuppressive drug therapy lowers your body's immune response. This prevents your immune system from attacking your bone marrow, allowing bone marrow stem cells to grow, which raises blood counts. For older patients with acquired aplastic anemia, immunosuppressive drug therapy is the… to try to turn off the immune cells that are suppressing the bone marrow to allow them to grow back. Then there's bone marrow transplantation, where we take a donor that is, tissue matched or HLA HLA: See human leukocyte antigen. compatible, and we collect their stem cells, either through bone marrow harvest or through a procedure where we collect the stem cells from the blood. And we give them immunosuppressive therapy and then infuse those stem cells back. That type of bone marrow transplantation could use brothers or sisters that are, tissue compatible. You can also use matched unrelated donors. And now more recently, there's an option to use family members that are only partially matched. Cord blood transplantation historically, has had sort of mediocre results for aplastic anemia.
    02:54    The problem with cord blood transplantation is the stem cell numbers are very small, and because of that, when you use cord blood, it usually takes about a month before the blood counts start to recover. And the longer it takes, the higher the risk of the transplant procedure in terms of getting infections or having bleeding complications. That's why up until recently, cord blood transplantation is really, sort of moved out of favor as a transplant option for aplastic patients.

Leigh Clark:    03:30    What led to the investigation of Omisirge?

Richard Childs:    03:36    Well, I and my team have been exploring ways to try to improve the results of cord blood transplantation for aplastic anemia for about 20 years now. And our last trial before the Omisirge trial had used a combination of a single cord blood unit and haploidentical stem cells combined, and that resulted in... in pretty good results. We had about 84% of patients that were cured with that approach, but it was complex. It involved two stem cell sources. Logistically, difficult to pull off, and not something, you know, that any transplant center could do because of the logistical challenges. So, we were very interested in trying to find a way to use a single cord blood unit, to improve the results, to move away from two stem cell sources.
    04:32    Omisirge, also known as Omidubicel, had been, developed by the Gamida Corporation, and they had some very interesting, uh, technology where they could take a cord unit, put it into the laboratory, and then, in vitro expand up the stem cells over about a three-week period using, a combination of, growth factors growth factors: Growth factors are naturally occurring hormones in your body that signal your bone marrow to make more of certain types of blood cells. Man-made growth factors may be given to some people with bone marrow failure diseases to help increase red blood cell, white blood cell or platelet counts. Red… and other chemicals to keep the stem cells, from differentiating. And they had shown that, um, this expanded cord blood product when given to patients with acute my- myelogenous leukemia that were undergoing cord blood transplantation very good results, where they had very rapid recovery of the hematopoietic system, and where their neutropenia neutropenia: (noo-truh-PEE-nee-uh) A condition in which there is a shortage of neutrophils in the bloodstream. Neutrophils are a type of white blood cell. This results in a low white blood cell count. or low neutrophil neutrophil: (NOO-truh-fil) The most numerous of the white blood cells, important for helping the body fight infections (particularly bacterial and fungal infections. count, recovered in only 12 days, which is much faster than the typical 25 to 30 days with the cord unit.
    05:33    And based on those data, Omidubicel was FDA approved, for treating patients that had hematologic malignancies over the age of 12 that were undergoing cord blood transplantation. So, we got very interested when we saw that data that was published in around 2021, that this could be a strategy to improve the results of cord blood transplantation for patients with aplastic anemia. The goal to use an expanded cord blood unit, was that... the thought was at least that if we had a lot more stem cells in the expanded cord unit, that that would not only improve or shorten the time for neutrophil recovery, that that, would translate it to less risk of infections associated with the transplant, but also would reduce the risk of the transplant being rejected because there's very clear data that the higher number of stem cells that you transplant, the better the transplant outcome and the lower the risk of rejection.
    06:36    So, our hypothesis was that if we applied Omisirge as a transplant component in patients, getting cord blood transplantation with aplastic anemia, that the transplant results would improve. And then the other thing that's interesting about cord blood transplant cord blood transplant: A procedure where umbillical cord stem cells are given to the patient through an intravenous (IV) line. Stem cells are collected from an umbilical cord right after the birth of a baby. They are kept frozen until needed. In time, donated stem cells given to the patient begin making new, healthy… , a real attraction, is that you don't have to have a perfectly matched cord unit to have great results, you only need to have a partially matched cord unit. And for patients that don't have HLA-matched donors or even, you know, half-matched, family donors that can serve as a stem cell donor, this really opens up  a large pool of potential donors, that could utilize cord blood transplantation as a donor stem cell source. So, for all those reasons, we decided that we would move into 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… to explore whether Omisirge could have good results in patients with aplastic anemia that was really severe.
    07:40    Because it was the, the first in-human trial for aplastic anemia, we restricted the study to patients that had aplastic anemia, that were transfusion dependent, and they also had to have failed immunosuppressive therapy. And those are patients that have higher risks of transplant, they have higher risk of rejection, they have survival rates. So we wanted for our initial trial, restrict it to patients. Since we didn't know much information as to whether it would work in a population that was higher risk that would justify that big unknown of the trial.

Leigh Clark:    09:15     And what were the results of the trial?

Richard Childs:    09:21    So, we have so far transplanted 20 patients, and the results have been far better than anything that we expected or anticipated, given the high risk of the population that went, into the study. And when I say, you know, high risk all 20 of these patients had failed immunosuppressive therapy. They were very heavily transfused. They were iron overloaded from those transfusions. And that's known to increase the risk of a transplant. Basically, you know, what happened was that we were able to expand the cord unit for all 20 of these patients. The stem cell numbers that were contained in those cord units were substantially higher than what was in the non-expanded cord unit, about a 38-fold expansion of the stem cell, component.
    10:21    Remarkably, because of having that higher stem cell number, we saw really, great engraftment engraftment: Refers to how well a graft (donor cells) is accepted by the host (the patient) after a bone marrow or stem cell transplant. Several factors contribute to better engraftment - physical condition of the patient, how severe the disease is, type of donor available, age of patient. Successful… , results. 19 of the 20 patients had engraftment, and that engraftment time, was very, very, rapid, occurred at a median 11 days, again, which is much, much quicker than you would get with, a non-expanded cord. And, 19 of the 20 patients that survive are transfusion independent. Patients that had platelet recovery that occurred about a month after the transplant that's also pretty quick after a cord unit. It's more typically in the 45 to 60 day with a non-expanded cord unit.
    11:09    When we looked at something called chimerism where we can look and see what is the origin of the hematopoietic stem cells in the circulation after the transplant, we found that the immune system from the cord unit in terms of T cells engrafted very, very quickly, with the patients becoming 95% or higher donor T cell T cell: see lymphocyte chimeric errors by, only 21 days post-transplant. So, you know, rapid engraftment, sustained engraftment, transfusion independence transfusion independence: No longer needing any type of blood transfusion. achieved in those patients. And then really, the two other remarkable things were that we didn't see any severe graft versus host disease, which is a known complication of bone marrow transplantation.
    12:00    When we graded from grade one to four we only saw about 16% of patients that had grade one or two, which is the minor GVHD, but we saw no patients that had the severe GVHD, grade three or four. And the other remarkable thing was we had no patients who developed chronic GVHD, which usually occurs in somewhere between 20 to 35% of patients. The other thing that was remarkable was the immune system recovered very, very quickly in these patients. And when I say quickly I mean that the CD4 counts, which we look at and everybody that gets a transplant, it came back, much quicker than we see with any of the transplant modalities,  that we've studied at the NIH. Also came back quicker than historical published data with cord blood units that don't involve expanded cord, and came back quicker than what is published historically with patients undergoing, half-matched or half-blood transplants.
    13:17    We also saw some other interesting immune cells that came back quicker, like natural killer cells natural killer cells: a type of cell that lacks B-cell and T-cell receptors and attacks mutant and virus-infected cells . They really recovered super quick early on. We know those natural killer cells are produced from the stem cell population, so we think lots of stem cells produce lots of natural killer cells. We think those natural killer cells protected patients from infection, and also help to ensure that the transplant engrafted, had sustained engraftment and, prevented any late graft rejection. So, I have to say, the results far exceeded anything that we anticipated.
    14:01    And because, we were seeing such great results in high-risk patients, the company that produces the cord unit, Gamida, went to the FDA and said, "Hey, could you take a look at these interesting data coming from the NIH and see if you think that,  this is sufficient to warrant a label change on the product?" And the FDA came, reviewed our data and then granted a label change and FDA approval for the product in December of 2025.

Leigh Clark:    14:38    And how does this new approval change transplant options for patients?

Richard Childs:    14:45    So, it adds an additional option for patients that don't have an HLA-matched donor. Sort of the algorithm that we follow when we do, bone marrow transplants or stem cell transplants for patients with aplastic anemia is we, you know... we... we... You know, it's great if you could find an HLA-identical sibling or an identical twin. You know, almost nobody has identical twins with aplastic anemia. It's very rare. Um, but an HLA-identical sibling, we find, you know, in the range of 20, 25% of patients with aplastic anemia matched unrelated donors, are another good option, but a significant amount of patients don't have matched unrelated donors, particularly, minority populations.
    15:46    And then once you get to the point where a transplant would be indicated could help you, but you don't have a donor, that's where Omisirge could be a potential benefit to patients because it is now an option to take a look, get the tissue, typing, the HLA data and look: is there a potential cord unit that could be used, that could be expanded up and used as a stem cell source for patients with aplastic anemia? So, it adds another therapeutic transplant stem cell source option to patients that don't have HLA-identical donors.

Leigh Clark:    16:28    Are there any additional benefits or risks that you would like patients to know about?
Richard Childs:    16:35    Yeah, I think that the data that we have right now is extremely encouraging, um, but I would say the, the disclaimer is that we've only transplanted 20 patients. Granted, they were a high risk and transfusion dependent, and many of them had very severe neutropenia, and had HLA antibodies which increase the risk of rejection, but despite having those HLA antibodies, and in our case, 75% of the patients had HLA antibodies, we didn't see any rejection. But if somebody has those HLA antibodies when you're picking a cord unit, you have to work around those antibodies and pick a unit where that antibody is not going to be a problem. And you also have to pick a cord unit that has a sufficient number of starting stem cells in it.
    17:32    So, there is an art, you know, to picking that cord unit. In some cases, when we do a preliminary search, we may find that there are many, many potential cord units that we could use, but you do need to have an HLA expert. Most transplant centers will have these HLA experts that can look and say, "Okay, the  prerequisite to having a cord unit that could be expanded is that it has to have a sufficient starting number of stem cells and that there are no HLA antibodies that would cause a problem." And then you say, "Okay, that's a potential option. Now let's see how many of those we have and which ones are the best match." So there is an algorithm that goes into trying to pick the best unit.
    18:22    In terms of other things that I would tell patients considering different transplant approaches is that the data looks fantastic so far but, again, it's a small study and we'll have to see how these results look when we start to get larger and larger numbers of patients that are enrolled. And the last thing is it does take about six weeks from the time that somebody gets referred to us to when we can do a transplant. We're not able to immediately jump into a transplant, because we have to identify a cord unit. That cord unit has to be shipped to a facility where it's expanded and then shipped back. That whole process is about a six week process.
    19:07    So, for patients that really have a super emergent indication for transplant, sometimes you'll have patients with active fungal infections where, you know, you just want to transplant them immediately and get the neutrophil count to recover. In that kind of a case, this may not be the best transplant option. For the majority of patients though that don't have that urgency, I think that this expanded cord unit approach with Omisirge is a viable therapeutic option that needs to be considered when a patient sits down and talks with their transplant physician.

Leigh Clark:    19:47    Is there anything else that you'd like patients to know?

Richard Childs:    19:52    I anticipate in the future that there probably will be a trial that may compare a transplant that uses Omisirge with a more conventional transplant approach.  Right now, I would say that if you were to do a head-to-head comparison, what would be the approach that you would compare it to, it probably would be to the half-match haplotransplant approach. There was a recent trial that compared non-expanded cord units to haplotransplants in patients with hematologic malignancies, and the cord unit patients did worse and they had lower survival. Now, with the ability to expand those stem cells off, to shorten that time to having neutrophil recovery, to improve engraftment rates, I think it makes people interested again in saying, "Hey, you know, maybe this is the way to make cord transplantation a viable option."
    20:55    So, I think people are gonna become very interested in comparing an expanded court unit approach with the more conventional transplant approaches. And when those trials  open, I would encourage patients, if given the opportunity, to participate in those trials because we don't have an answer as to which is better. The results from our single study look great, but historically, single institution studies where there's a lot of expertise, you know, in transplantation, the data from those studies tend to be very, very good, but when you go to a randomized trial, the results are not quite as good as in the single institution study. So, I would tell patients, "You know, discuss this as an option with your doctor if you don't have a perfectly matched donor," and if given the option to participate in... in a clinical trial, to strongly, consider that because I think that Omisirge is a definite, viable option with extremely encouraging data coming out of the gate from this, first in-human study.

Leigh Clark:    22:03    Thank you so much, Dr. Childs, for sharing your time and your expertise with all of us today. And if you'd like to learn more about aplastic anemia and all the current treatment options that are available, please visit our website, which is aamds.org, or give us a call at 800-747-2820. We're happy to answer all of your questions that you may have about aplastic anemia and the treatment options that are available to patients. Thank you again, Dr. Childs, so much for spending your time with us today and answering all of these questions.

Richard Childs:    22:41    Thank you very much, Leigh. And, uh, I would also tell patients that, you know, we have multiple clinical trials at the NIH for aplastic anemia, and this trial is still open. That's something to consider as well. Thank you.

Leigh Clark:    22:55    Wonderful. Thank you so much and have a great day.

Richard Childs:    22:59    Thank you. You too.