Study result

Jun 6, 2022

Hello everyone. Thank you for joining the Medexus webcast this afternoon. Today we are joined by Filippo Milano, a physician and scientist whose research is focused on the use of umbilical cord blood as a source of stem cells for transplantation to treat various blood cancers. He is an associate professor in the clinical research division at Fred Hutch, and also a director on the cord blood transplant program in the clinical research division at Fred Hutch. Just a reminder for everyone, if I could please refer you to the forward-looking disclaimer in the press release Medexus issued this morning titled, "Treosulfan Pivotal Study Results Published." With that, I'm going to turn it over to Filippo. At the end, we'll be back and we can answer Q&A. Thanks, Filippo. Over to you. Thank you. Thank you, Victoria, and thank you everyone for the opportunity to be here with you and actually sharing some exciting news that have been recently released. One thing that I would like to add in terms of my area of expertise, yes, I'm the director of cord blood transplant, but as many of you know, at Fred Hutch, we pretty much treat any type of transplant types. I also have protocols in using haploidentical donors, unrelated donors, and related donors. As I said, I'm very excited because it's been now over 2 years that we were waiting for this data to come up after the first study that was published in 2020 by Dylan and colleagues. At that point, the first study was including 476 patients, and mostly was a non-inferiority study where they were comparing the non-myeloablative or reduced intensity, as we want to prefer to name it, busulfan fludarabine approach versus a Treosulfan fludarabine approach. It was the first result that were reported, actually ended up in the plenary session at the TCT meeting, showed non-inferiority of Treosulfan compared to busulfan. That was the initial study, and everyone was very excited because it's already proven in a randomized fashion that Treosulfan could be comparable to busulfan. Thanks to the leading authors and to the other center participating in Europe in this study, they decided to move forward in trying to change the aspect of this study from a non-inferiority to evaluate actually superiority of Treosulfan. That's actually what we are here today to speak about is the updated results, which now include not 476 patients, but 570 patients. Of this 570, we have 280 patients that were randomized in the Treo/Flu arm versus 290 that were randomized in the busulfan flu arm. I would say that the primary endpoint of the study was evaluating event-free survival, and event-free survival was defined by the authors as any type of disease progression, graft failure, or any type of death, which is the most meaningful endpoint related to a randomized study. What the others found was that the significantly better event-free survival in the group of patients receiving Treosulfan when compared to the patients receiving busulfan, with a difference of 59% versus 49%, bringing to an observation of 0.64, which basically means a 36% reduction in risk of any type of event correlated to survival in the group receiving Treosulfan. The others then moved towards analyzing secondary endpoints. The secondary endpoints, and what they found out is that overall survival was, once again, favorable to patients receiving Treosulfan when compared to ones receiving busulfan, was a difference of 67% versus 56%, but once again, with a 36% reduction in risk of overall mortality among patients receiving Treosulfan. There was no difference in terms of relapse. Cumulative incidence for relapse for both groups was pretty much the same. The difference they were noting in this study was mainly for non-relapse mortality, which is significantly lower in the group receiving treosulfan. Those are the main points of the study, but as a investigator and as Victoria said, my last name kind of give me away. Milano, it tells you that I'm Italian. I worked in Italy as a transplant doctor at University of Rome, then I moved in Seattle in 2008. It's been 14 years for me being in United States. When I came to United States, one of the things that I was surprised is that treosulfan was not approved yet, while in Europe I was already utilizing this drug, and I'm talking about 2007, 2006. It's been around long enough in Europe, and this study testifies why European colleagues, they use it as one of the main drugs for conditioning regimen. I said all that because I think another thing that, in this study, was really appealing to me as a transplant physician is the fact that also some of the secondary endpoints are very interesting. First of all, in the group receiving Treosulfan, patients achieved a more stable and more sustained chimerism at day 28. It's a very important point, which leads to another endpoint, which is GRFS or graft-versus-host disease-free, relapse-free survival, which is now another endpoint of main interest for transplant physicians. GRFS at 2 years was significantly higher for patients receiving Treosulfan when compared to the one receiving busulfan. The announcement of this study is very recent. I tried to make up my mind of trying to understand this difference. I do think that the fact that chimerism happens in a more robust way in patients receiving Treosulfan, it might also help in terms of tolerance in these patients, because the GVHD prophylaxis was the same for both groups. as a matter of fact, patients receiving Treosulfan had less extensive chronic graft-versus-host disease when compared to patients receiving busulfan. I forgot to say one thing that's very important. Again, too many things to share in a very short period of time. this study was only for patients with AML and MDS, only for adult patients who was 18-70 years old, and median age was 60 years old with a median comorbidity score of few. I think these are very important demographic data because they might come up in the discussion later on. As you know, transplant population is increasing over the years. The approach of using conditioning regimen of reduced intensity or non-myeloablative, again, as you prefer to call it, is very important because this is the main population that we treat these days. I think I will stop it here. I tried to summarize, and I'm very happy to answer questions, if anything, from the audience. Thank you. Okay. Thanks, Filippo. I'm just going to add a few more participants, so we can have a bit of a broader discussion, and then if there's any Q&A from the audience, I just want to remind you to type it into the Q&A box at the bottom of the screen, and we can get to that. Just one more participant to add. Okay, perfect. Hi, Michael and Ken. Hey there, everybody. Hey there, Mark. Hey. Just a couple of quick comments. Thank you very much to Professor Dr. Milano for his review of the top-line information from our phase III clinical study. As you saw in the press release, the manuscript of the results of this study have been accepted for publication by the American Journal of Hematology. The print edition is still forthcoming, but the journal has made the results available on their website as of last week, and we've included the URL to the online version in this morning's press release. Joining us from Medexus, you know Ken d'Entremont, our CEO, and also Mark Fozdar, Director of Scientific Communications, who incidentally used to work at the same institution as Professor Milano. Thanks for joining us, and we'd love to open up the floor to questions from the participants in the audience. We do have one question that's come in so far. Is there any potential for any off-label use for any other patients? You want me to answer these questions or I think I will leave this one maybe to Medexus, because for me, I can tell you one thing. Okay, let's put this way, maybe I can set the stage. As I said to you, as a European, I've been using this drug in Europe, before coming here, and it's a very popular drug in Europe, and it's becoming the one that we use the most among our colleagues in Europe. In the United States, we're a little bit different. Fred Hutch actually has been very lucky to have available this drug for a long time for our collaboration with Medac. We have been treating more than 500 patients using Treosulfan. I'm very happy to share this data with you and tell you some of those are already published, and I can tell you our experience at Fred Hutch. Going to the question to set the stage, one of the studies that we've been doing is, for example, using Treosulfan in patients with cord blood transplant. I was actually the PI of that study, and we enrolled over 100 patients with the overall survival was approaching 70%, and everyone knows that cord blood is not an easy transplant to do. It's not really an off-label. It's just a different stem cell source used. We do have other investigators at Fred Hutch which are using Treosulfan with very good success. Some of them have been already presented for non-malignancies. It's becoming another area of interest where to use this drug. I'll stop here, and I don't know if Medexus wants to add anything else on top of this. To your point, Dr. Milani, you mentioned the fact that there's many factors, many different types of donors, many different types of graft-versus-host disease prophylaxis, and we are pursuing. They're not really off-label per se, but they are different sources of, let's see. I think, Dr. Milani, you're doing this as well with the haploidentical transplants and GVHD prophylaxis using post-transplant cyclophosphamide, which is becoming more common. It's not just MDS and AML. It's also different combinations of GVHD prophylaxis as well. As Dr. Milani mentioned, non-malignant diseases is another area of interest that has also been in Europe as well. That's actually in the indication too, Mark, the non-malignant. We expect the label to reflect adult and pediatric use in conditioning before a hematopoietic stem cell transplant for both AML and MDS patients. Okay. A second question. Nice data so far. Given that the Treosulfan data is superior to busulfan, can you envision anything on the clinical side that would prevent physicians switching to Treosulfan use if it were available? Short answer, absolutely not. I don't see any point why our colleagues should not switch. I'm telling you that actually, again, as I said, we are very lucky here in Seattle because we had the chance of using this drug. I have many colleagues of mine in the United States that are asking me to participate to my trials or how they can access to it. Unfortunately, the drug is not approved yet here. They can be associated with my studies, but the interest is extremely high, especially because they know the results in Europe. The practice in Europe is very similar to the practice in the United States. We would like to do exactly the same here. A follow-up question to that, is busulfan still used in Europe or has it been replaced by Treosulfan? Very good question and will be a very logical question. I can tell you that it's still used. Some of the reason behind it is because some of the centers might acquire only busulfan, not necessarily, especially the one that's small. The majority of the big centers that I know and that I collaborate with, they have switched to Treosulfan, not only based on this data, based on their experience. In regards to the study, a question, why does event-free survival of Treosulfan decrease further at three years versus two years by more than the decrease for busulfan? Yeah. It's a good point. I don't think that the data allow us to kind of tease out yet the reason of that less decrease. I would say, though, that the percentage of patients alive at two years is pretty high for such population. I think that's why I think we see maybe a bigger decrease in the Treosulfan arm. I can tell that here in Seattle, we're actually now analyzing the data. We have data from 2009. We're talking about 12 years of data and trying to analyze if there is anything specific related to Treosulfan. So far we have not found any signal. I would say that this is just something that needs to be better investigated, but I don't see it as a detrimental effect, honestly. Is data being collected for event-free survival past the three-year point on Treosulfan? From my side, yes. As I said, I have plenty of data. I cannot speak for these others, but I suppose they are. Okay. Once Medexus' response to the CRL is considered complete by the FDA, when would Medexus expect to launch Treosulfan, assuming FDA approval? I'll jump in on that one, Victoria. The study, of course, is the basis for the New Drug Application that's currently with FDA, and the basis of our plans for communication. We're looking forward to it being approved. We do expect there to be up to 6 months from the time of complete resubmission to FDA approval, and we are working on tightening up supply chains and timelines as much as possible to minimize the delay, but it will take us a few months. Okay. I just want to remind everyone that if they have a question, they could type it in the Q&A at the bottom of the screen. Those were all of the questions that we've had come in so far, so I'm not sure if there's any general or closing comments that anyone here would like to make. I tried to summarize the paper, if I may. As an expert in the field, I really think that, as I said, I was very surprised when I came in 2008 in Seattle with my broken English that Treosulfan was not approved in the United States. I was using in Europe already, and I knew the results. It's been a little bit of struggle to understand why this drug is not on the market yet, because it's definitely a drug that we love as a transplant physician. I'm telling you why we love it. We love it because it's associated with less liver toxicity. That's where it really comes down, and that's why the studies are showing at the end of it, the difference is non-relapse mortality. The reason why is because this complication is called, in the past it was called VOD, veno-occlusive disease, which is a mortal complications after transplant, happens in the first few weeks post-transplant. Busulfan drug is metabolized in the liver, so it affects the liver and create toxicity in the liver. Treosulfan has two different molecules. There are two hydroxyl groups in its molecule, which bypass the liver, and bypassing the liver doesn't bring the toxicity. As a matter of fact, again, as I said to you, we've been treating now over 500 patients, and I don't even think we can count on one hand patients having complications like the one I'm describing. Why? When you use busulfan, it is a complication that we need to always be aware. Unfortunately, there's not that many drugs. Only one on the market. It doesn't work all the time, and patients end up dying after conditioning regimen. That's why I really would like to have this drug available, not only for me, I have it right now on clinical study, but for all my colleagues. I would also add another thing that is important. I said it before, but the majority of our patients now are older patients. Having a drug that allows what is a non-myeloablative regimen is what we are looking for. We want to create a regimen that is not toxic for our patients, that make establish engraftment so that we can have the desired outcomes. The study is only on AML and MDS. Sorry that I'm talking very much, but because, again, the experience we had in Seattle has been outstanding so far. We also tried Treosulfan in patient with Acute Lymphoblastic Leukemia, and the effect seems to stand also there for that disease. Okay. Yeah. Thank you so much for that. Two other questions that come in. These are more geared toward Medexus. Are you able to clarify what additional data the FDA has requested, and why it wasn't sent originally? I'll take that, Victoria. We sent our press release that the FDA was reviewing the resubmission, that a question came up that couldn't be answered within the timeframe that we had available, which was 30 days. That really caused the delay that we're experiencing now. It's a very straightforward data collection, but it has to come from the institution. We do feel like it can be accomplished, and certainly within the timeframe that we have available prior to the one year anniversary of the CRL, which is July 30. We do believe that we will, or Medac will, have the resubmission submitted prior to that deadline. The last question. The data that was presented in the study that was just released, has this been included in the application? Yes. I think that's why it's important to have this discussion with Dr. Milano and hear his experience and his interpretation of the data, because this is the data that the FDA is reviewing. This will be the data from which Michael and his team will promote Treosulfan. We think it really important that investors understand that what's been presented here today is the information that the FDA is reviewing and will form the basis of our label upon approval, assuming approval is granted. Okay. Well, that's it for the questions. Thank you everyone for joining today. Thank you, Dr. Milano, so much for coming on here and giving your opinion. With that, unless there's any more comments from any of you, I will end the call. Just want to thank Dr. Milano for sharing his vast experience. It's very much appreciated. My pleasure. Thank you so much for having me. Okay. Thank you, everyone. Bye now.