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- [00:02]
A
Welcome to the American Society of Hematology Conversations with Blood Authors podcast. This episode is hosted by Dr. Laura Michaels. She discusses long term efficacy and safety results of betabeglogine autotemcell gene therapy for transfusion dependent beta thalassemia with Dr. Alexis Thompson.
- [00:24]
B
Hello, I am Laura Michaels. Welcome to the Blood podcast. I am here with former ASH president Alexis Thompson of Children's Hospital of Philadelphia and the University of Pennsylvania. She's here to discuss their study on the long term efficacy and safety results of beta. I'm going to ask her how to pronounce this. Beta Balogene autosem cell gene therapy for transfusion dependent beta thalassemia. This report includes pooled results from both the early phase and the registrational studies of gene therapy for this germline condition. Thompson and her co authors describe the rates of trans transfusion independence, the reduction of iron overload and changes in quality of life for individuals treated with this. Thank you for joining us Dr. Thompson. Perhaps you could start by just correcting my pronunciation of this gene therapy.
- [01:18]
C
How about that name? It's Betty Beglo Gene autotemcel. During the clinical trials we called it Bety Cel and in its commercial form it's called Zenteglo.
- [01:28]
B
Okay, great. So Beticel. I'll use that. As we have broad listenership for this, I wonder if you might start out by discussing a little bit about beta thalassemia and what are the most important health related consequences of this condition, at least for those affected enough to qualify for this trial.
- [01:46]
C
Beta thalassemia is an inherited condition that typically affects the beta globin gene, which is one of the principal building blocks of hemoglobin. And it's by and large an autosomal recessive disorder. So you inherit one abnormal copy from each parent and it's not one disease, it is caused by a series of mutations. We think that there hundreds of mutations that cause beta thalassemia and in its most severe form it results in the body not being able to make beta globin at all. And so if you can imagine missing one of the fundamental building blocks to adult hemoglobin, they survive on fetal hemoglobin for the most part, which is not what we would normally have beyond infancy. And so many will become anemic shortly after birth and if they were not treated would succumb primarily from anemia. It affects people globally. We believe that there's over a million people worldwide who have thalassemia. They tend to be individuals who are from Asia, from southern Mediterranean, from Africa, and the Middle East. In the United States, many, many children are now picked up by newborn screening. But I dare say it is still almost every year that we identify children who come in with severe anemia, with families who had no ide idea that they were at risk for having a child with thalassemia.
- [03:10]
B
The health related consequences must include long term transfusional support, iron overload, as you guys described. So gene therapy, it's been a dream for a long time, but it was only maybe in the last decade that it's become a reality in certain conditions. Can you describe the developmental path for this particular agent? And I'm curious about how the modified cells differ from wild type beta globin.
- [03:37]
C
The path forward up until gene therapy. I will certainly mention that transplantation allogeneic transplants were found to be effective decades ago. The challenge is, is that they require tremendous numbers of resources and the best outcomes are for children who are fortunate enough to have a sibling donor who is an HLA match. And that just does not happen for the majority of children who have thalassemia. And so it's always limited the applic of allogeneic stem cell transplant. We have made some progress with having iron chelating agents. Now the most common ones are given orally. That's helped in terms of the iron overload because iron overload is associated with some of the complications that can be life threatening in thalassemia. Otherwise these are individuals who are having to be transfused every two to four weeks for a lifetime, which in and of itself is a tremendous burden. And you are absolutely right. I do think that many of us, when we think about monogenic disorders that are accessible because it is the hematopoietic stem cell that's accessible from the bone marrow that is abnormal. Theoretically this should have been one of the conditions that we approach. The strategy that's taken up in this set of studies for bety cell is actually extracting hematopoietic stem cells from the bone marrow or mobilizing them into the peripher and then having them collected by apheresis. Then in the laboratory, they're transduced with a lentiviral vector that contains beta globin. The sequences of human beta globin under the control of the beta locus control region. So the normal regulatory sequences in our red blood cells, and with a small minor change that's called T87Q, which we can come back to, has less implications for thalassemia than for sickle cell. But once their cells are transduced with this lentiviral vector that payload, the beta globin is actually integrated into their own chromosomes. The lentiviral vector is destroyed. It is not retained for the most part. And then once it's integrated, our hope is, is that these long, long lasting stem cells, so the repopulating CD34 cells are then returned to the marrow. Hopefully they then begin reproducing. Instead of producing the beta globin that contained the thalassemia defect, they instead will Produce Beta A T87Q. By that, Beta A will combine with alpha globin in the usual way and make hemoglobin. It requires chemotherapy in order to do myeloablation. That continues to be an essential part of gene therapy for hemoglobin disorders. It does two things. It makes space in the bone marrow. The bone marrow otherwise in people with thalassemia is hypercellular. It's quite packed out with all of these defective red blood cells and stem cells. It also allows the transduced stem cells to have less competition. There is not a survival advantage at the stem cell level for these modified stem cells. And so if we did not cyto reduce the marrow, they would be out competed by the patient's defective stem cells. And so the myeloablation is an essential component. Unfortunately, it is also the source of many of the complications so far of gene therapy. And those complications include the short term ones with cytopenias, so low red blood cells, platelets and white blood cells, but also mild sores and the fevers that come along with it, just really feeling pretty ill for a period of time. It also is associated with risk of lung toxicity, liver problems and fertility issues. Busulfan, which is the agent that primarily is being used, has a very small risk of malignancies that are associated with it as a chemotherapeutic agent. So certainly the busulfan or the continued need for myeloablation is an essential component, but is also a source of some of the risk.
- [07:46]
B
Of course, this is a combined report looking at your phase one two studies as well as the phase three. And I understand that there was an alteration in the vector copy number that was in the phase three. I'm not sure if I have that right. Did that demonstrate itself in the outcomes of transfusion independence or need for iron chelation?
- [08:11]
C
Yes, the modifications in the manufacturing process that took place and were applied in the phase three are now the processes that are used in the commercial setting for beticel now in commercial use. We found in the initial trial that there was absolutely a relationship between the efficiency with which the cells were transduced. So what we call vector copy number and the amount of the therapeutic globin that was being produced, we knew that there was a threshold value that you had to achieve a certain vector copy number to expect to make a certain amount of hemoglobin that would be effective. And so we found that there was this lower limit that had to be achieved and that anything less than that was not likely to be effective. And therefore we would do something different if, in fact, at the first cycle, we didn't see that we were achie even prior to even giving it back to the patient. Fast forward to the phase three. Once understanding how to more efficiently transduce cells and to optimize the transduction process, we were able to get the vector copy number higher, we were able to get the hemoglobin higher. So that is an example, and you've already pointed it out. In the phase 12 trial, about 2/3 of the patients, 68% of them, achieved transfusion independence, which was the primary efficacy endpoint for the trial, whereas in the phase trial, over 90% achieved that. Their total hemoglobins were also different. In the phase 12 trials, the mean weighted average hemoglobin was about 10, whereas in the phase 3 trial it was over 11. And ability to control iron was certainly better in the phase 3 trial compared to the phase 1 2, at least in part related to the ongoing anemia. And when we have ongoing anemia, the body senses that it, ironically, it senses that it needs more iron, even though these are patients who have iron overload. And so the persistence of anemia probably is one of the contributors to the difference in outcome in terms of the iron status of those individuals.
- [10:22]
B
One of the questions I think will be important for our audience is when is a beta thalassemia patient the right patient to consider this kind of therapy?
- [10:32]
C
I think that that's really an important question, and it was one that was considered in this clinical trial. So early on, we wanted to be sure that we took patients that were slightly lower risk. And so the very first patients had a variant of beta thalassemia called hemoglobin E. Beta thalassemia, hemoglobin E is another hemoglobin disorder. But we knew that even though they have severe thalassemia, that the hemoglobin E is one that does carry oxygen. And so the very first patients were ethals. Having said that, we moved, forged ahead right after that and then continued doing thalassemia. Patients of a certain age who had to be severe enough to be transfusion dependent. And in the early study, we actually treated patients who had the full spectrum. So patients who had made some beta globin and therefore were considered beta zero beta plus versus those who are beta zero beta zero, the most severe form, really having really almost no ability to make normal adult hemoglobin. We found that, not surprisingly, it was easier to get the best outcomes with patients who had something other than beta 0 beta 0. However, with the improvements that occurred in the phase 3 studies, they were all the same. And so it certainly was possible to achieve really outstanding results whether you were beta zero beta zero or beta zero beta plus. And that, I think, has been very rewarding. It's also been interesting in that the results seem to be fairly similar across the entire age spectrum of the people who were treated. So down to age 4 and up to age 37, those limitations were built into the study. There's very little reason to think that a child who's younger than 4 might still benefit and that a well managed patient over the age of 37 probably could as well. But certainly, looking at the study that we've published, those were the parameters that were part of the eligibility criteria.
- [12:33]
B
That's fascinating. So thank you so much for this fascinating work and for all that you and your team did to pull it together and for taking the time to be on the podcast today. Thanks, Dr. Thompson.
- [12:42]
C
I really appreciate the invitation. Thanks again.
- [12:47]
A
Thank you for listening to this episode of Conversations with Blood Authors. To read the articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.