Good morning, welcome to the Actinium Pharmaceuticals KOL Call with Dr. Sergio Giralt. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Actinium website following the conclusion of the event. I'd now like to turn the call over to PJ Kelleher from LifeSci Advisors. Please go ahead, PJ.
Thanks, Tara. Good morning, everyone. Welcome to Actinium Pharmaceuticals KOL Call with Dr. Sergio Giralt. Before we begin, I'd like to cover a brief agenda before turning the call over to Dr. Sergio Giralt. Dr. Giralt will give a presentation of the pivotal Phase 3 SIERRA trial results. Then we'll transition to a moderator-led KOL Q&A session before opening the call to a live Q&A with the audience. At this time, I'd like to turn it over to your presenter, Dr. Sergio Giralt.
Thank you so very much, PJ, and hello to everybody. I'm Sergio Giralt. I'm currently the Deputy Division Head of the Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center. I'm an attending physician on adult BMT service. As you can see in the slide, I've been in the field now for 30 years. My clinical research activities have been focused on bone marrow transplant for patients with blood disorders, and I've pioneered the use of reduced-intensity conditioning regimen for older and more debilitated patients. It is a true pleasure today to present to you the results of the SIERRA trial, a multi-center, pivotal Phase 3 study of Iomab-B prior to allogeneic hematopoietic cell transplantation versus conventional care in older patients with active relapsed or refractory acute myeloid leukemia. I'm presenting this on behalf of all the co-investigators that you see. This is a truly global multi-center trial.
Here are all the centers that were represented in this trial. Patients with active relapsed refractory AML have a dismal prognosis, particularly with increasing age. They are generally not offered allogeneic transplant because of the fact that patients with active disease going to transplant either tolerate very poorly myeloablative regimens or have a huge risk of relapse. SIERRA was designed to offer these patients who are considered transplant ineligible in many transplant centers, and many times will receive only palliative care to have a potentially curative transplant. Iomab-B Iodine-131 apamistamab is an anti CD45 antibody conjugated to radioactive iodine. It is designed to deliver targeted myeloablative radiation to hematopoietic cells along with reduced-intensity conditioning prior to allogeneic transplant.
The SIERRA trial is a prospective randomized control Phase 3 study in patients over the age of 55, comparing rates of durable complete remissions as defined as complete remissions that lasted more than six months after the initial complete remission between two arms. Iomab-B, followed by transplant with a reduced-intensity conditioning regimens of fludarabine and low-dose TBI, or a physician-choice conventional care followed by transplant according to the physician's choice. Just so you can see, it is approximately 21,000 patients are diagnosed with AML annually. It is the largest indication for allogeneic transplant. The median age at diagnosis is 68, with more than 70% of patients over the age of 55. Outcome for older patients remain poor. More than 50% of AML patients develop relapse refractory disease. Without a transplant, these patients will un-inevitably die from their disease.
Although the number of allogeneic transplants continue to grow and the percentage of patients over the 65 continue to increase, it is still an unmet need, as you will see in the end of my presentation. What are the factors that prevent patients from going to transplant? Many transplant centers will not take a patient with active disease because of the fact that the results are very poor, either because they cannot tolerate intensive chemotherapy to induce a complete remission, or they cannot tolerate a myeloablative conditioning needed to achieve long-term disease control. In essence, what happens is with older patients with active disease, you're left with the quagmire of, do I just give this patient palliative care, or do I try to induce a complete remission so they will accept the patient to transplant?
SIERRA actually changes this paradigm because it provides a way of taking or bridging the patient to a reduced-intensity conditioning transplant, which we know is well-tolerated, and by taking the patient with a lower tumor burden and therefore increasing the chances of achieving a durable complete remission as opposed to the conventional strategies that we have today. These are the different conditioning regimens that we have from ablative to reduced intensity. It's important to note that myeloablative conditioning regimens are rarely, if ever, performed in patients over the age of 65 or in patients with high comorbidity scores, which is very common in older patients with refractory relapse of acute myeloid leukemia. What can Iomab-B do? Iomab-B can provide disease control with myeloablative conditioning in one agent. Allow that patient to be successfully bridged to reduced-intensity conditioning regimen.
As you can see here in the schema, Iomab-B is a monoclonal antibody against CD45, which is actually present in the majority of leukemic cells. It is conjugated with a radioisotope actinium, and therefore it can deliver very high amounts of radiation to acute myelogenous leukemia cells, not only in the bone marrow but in other extramedullary sites, which can serve as potential sentries to traditional chemotherapy-based conditioning regimens. This way, you have an induction regimen that can successfully bridge a patient to a reduced intensity conditioning regimen. This can be applicable not only in hematologic malignancies, but potentially in non-hematologic disorders. This was the design of the SIERRA trial. The SIERRA trial, patients over the age of 55 who had active acute myelogenous leukemia, as defined by a bone marrow blast count greater than 5% or the presence of circulating blasts.
Patients had to have an eight out of eight matched related or unrelated donor. They could have not had a previous transplant and had to be candidates for reduced intensity conditioning with fludarabine and low-dose TBI based on their Karnofsky score and other organ functions. Patients were randomized one to one to either Iomab-B or conventional care. Conventional care were a wide range of different options at physician's discretion, including many targeted therapies. Patients in the Iomab-B arm would proceed to transplant with fludarabine and low-dose TBI. Those achieving a complete remission a month after transplant would continue to be followed for the pre-specified primary endpoint, which was a durable complete remission six months after that initial remission. Secondary endpoints were overall survival and event-free survival. Patients randomized to the conventional care arm were done on...
If they achieved a complete remission, would proceed to an allogeneic transplant at physician's discretion with the conditioning regimen chosen by the physician at that time. Patients were also achieving a complete remission who the physician decided not to go to transplant would continue with standard of care. Patients achieving a complete remission would be eligible for the primary endpoint and be followed to see if they had a durable complete remission that lasted six months. Of note, and very important, patients in the conventional care arm who did not achieve a complete remission were allowed to cross over to the Iomab-B arm. This is the way Iomab-B was delivered. On day - 19, a dosimetric dose of 20 millicuries was given to the patient. Through imaging and just.
With our nuclear medicine specialist, a therapeutic dose was calculated to deliver an upper limit of 24 Gray to the liver and essentially a median of 16 Gray to the bone marrow. On day -4, patient would start their conditioning regimen with the reduced intensity conditioning regimen of fludarabine and low-dose TBI. Graft-versus-host disease prevention was done with a calcineurin inhibitor and mycophenolate mofetil. This is the consent diary. 103 53 patients were randomized, 76 to the Iomab-B arm, 77 to the conventional arm. Amongst the 76 patients that were randomized to the Iomab-B arm, 66 of these patients received the therapeutic dose and underwent an allogeneic transplant. Only 59 are being analyzed per protocol because seven of these patients either did not have the adequate assessments or received non-protocol therapy before the primary endpoint.
It is notable that I will provide the intent to treat analysis of all 66 patients as well as the per protocol analysis. In the conventional care arm, 62 patients failed to achieve a complete remission, of which 44 went on to cross over to Iomab-B, of which 40 underwent transplant. 38 of these patients will be analyzed per protocol. Of the 14 patients that achieved a complete remission, 14 underwent an allogeneic transplant and 11 will be analyzed per protocol. Again, per protocol analysis was pre-specified in the protocol and they only include patients who, a, got all the adequate assessments and did not get non-protocol therapy. Again, we will present the data for intent to treat and per protocol analysis. These are the patient's characteristics.
As you can see from both the Iomab-B arm and the conventional care arm, the main patient characteristics are well balanced. Average age of 64 versus 66. 35% of the patients with intermediate risk acute leukemia versus 40% and 56% of the patients in the Iomab-B group with adverse or poor risk genetics versus 55% in the conventional care group. More importantly, similar number of patients had primary induction failures and 21% of these patients in the Iomab-B arm, as well as 19% in the conventional care arm, were either relapse refractory or beyond second relapse. It is important to note that these are patients that would not qualify for the ASAP trial that was recently presented by the German group in the ASH annually session. Median number line of prior therapies was three.
47, 60% of the patients received prior targeted therapy in both groups. The Karnofsky score was less than 90 in 60% of the patients in the I-MM group versus 56% of the patients in the conventional care arm. Note that the median percentage of blast in the bone marrow in the I-MM group was 30%, the median percentage of blast in the conventional care group was 20%. It is important to note that many of these patients, because of their high tumor burden, would never have been considered for any conventional transplant unless a significant reduction in tumor burden were able to be achieved. These are the conditioning transplant characteristics. The median infused activity in the Iomab-B group was 664.4 millicuries that gave a median dose to the bone marrow of 16 Gray.
The median time from randomization to transplant was 29 days versus 66 days for the standard transplant arm. Engraftment kinetics were similar for both neutrophil and platelets, with a slightly lower platelet recovery in the Iomab-B group than in the conventional transplant group of 14 patients. Comorbidity indexes were similar in both groups. I will not go into the details of the crossover patients, but they were similar to the patients who were treated on Iomab-B. Here is the results of the primary endpoint. Per protocol analysis, with 59 patients on the Iomab-B group and 64 patients on the conventional care group. 74% of the patients in the Iomab-B group achieved complete remission, of which 22 achieved the primary endpoint of a durable complete remission greater than 180 days after that first initial complete remission.
This is in contrast to only 6% of patients in the conventional chemotherapy arm who actually achieved a complete remission, and none of them were durable or none of them lasted more than six months. In the crossover arm, 91% of the patients achieving transplants, 52% achieved a complete remission, of which 13% were durable beyond six months. Maintenance was only allowed in with a TKI in the Iomab-B group for platelets where FLT3 mutated or BCR-ABL1 mutated, while patients on the conventional chemotherapy arm could get any type of maintenance therapy. That is important to note. Here you see the overall survival for all patients. What you can see is that for patients in the Iomab-B group, the median overall survival was 6.4%.
For patients in conventional chemotherapy group who did not cross over, that's a total of 33 patients, overall, median overall survival was three months. That's doubling survival with the Iomab-B group. 1-year survival was also twice as likely in the Iomab-B group versus the conventional chemotherapy group. 26 months versus 13 months. As you can see, the crossover groups in blue seem to have durable survivals compared as to like the Iomab-B group, suggesting that it was very important to get Iomab-B either early or later in the course of your disease journey. This is interesting because one says, "Well, are these the best results? Like, can we maintain?" The answer is no, because remember, per protocol, these patients could not receive any form of maintenance until at least six months for transplant.
We now know that there are many different maintenance options that these patients could really get earlier, actually between 60 and 90 days post-transplant, which is what many maintenance protocol recommended. Iomab-B enables access to transplant for patients who would not otherwise be eligible for transplant or would not be considered for transplant in many transplant centers across the United States. Iomab-B resulted in a durable complete remission in many more patients than those who received conventional chemotherapy. This is true across all risk categories, and event-free survival was also significantly better with Iomab-B. Remember here, an event is defined as an induction treatment failure, crossover to Iomab-B, a relapse after induction treatment success or death. Remember that patients who had either induction treatment failure, who crossed over or who did not receive a transplant were scored as having an event on day of randomization.
That way these curves look like this. If you look at the event-free survival at six months, 28% for the Iomab-B group versus less than 1% for the conventional chemotherapy group with a very important significant statistical difference in a hazard ratio of 0.22. An 80% reduction in the bad events. Are durable remissions truly durable? As you can see on this slide again, in all patients who achieved a complete remission or who had that primary endpoint of achieving a durable, complete remission, 60% of them remained in remission two years down the road. Is Iomab-B well-tolerated? The answer is definitely yes. There was significantly less septic events, 6% versus 26%. Fever of neutropenia was similar, 43% versus 50%. Mucositis seemed to be numerically less, 15% versus 21%.
The risk of acute graft-versus-host disease was similar in both groups. How difficult is it to start IOMAB-B or to deliver IOMAB-B? SIERRA trial was conducted in 22 leading U.S. transplant centers, and more than 100 patients were treated with IOMAB-B. The nuclear medicine and radiation safety officers established procedures and protocols for patient care that will facilitate commercial efforts. MSKCC utilized actinium shielding solutions for the majority of patients and did not use lead-lined rooms, although they were available. IOMAB-B can administer any corner hospital room utilizing shielding solutions, as you can see in the picture. Daily blood draws from central venous access devices were feasible with minimal radiation exposure risk to caregivers and staff. Sites were trained and equipped in conjunction with radiation safety officers to address any emergency situation with no interruption to clinical care.
Average exposure of personnel on study was 0.09 mSv. That is significantly less than the public dose limit of one mSv. Coordination with nuclear medicine and radiation colleague is in line with other radiotherapeutics and was essential for the success of this trial. What did we learn? There is definitely positive efficacy and safety results that were demonstrated by Iomab-B in older relapsed refractory AML patients with active disease. SIERRA met the primary endpoint of durable complete remission greater or equal to 100 of days with high statistical significance. Durable complete remission is a very appropriate endpoint in this study actually was designed and required by FDA guidance. Company intends to file a BLA for Iomab-B in the second quarter or the second half of 2023. Company plans to launch an early access program to make Iomab-B available prior to potential approval.
A lot of questions have come up is, well, these results look worse than the ASAP trial that was recently presented at ASH. Once again, I remind everybody that cross-trial comparisons are very dangerous. The key difference here is that patients in the SIERRA arm, many of them would not have been eligible for the ASAP trial. They were beyond second relapse. Many of them were considered to be unfit for myeloablative conditioning. The ASAP trial really only enrolled patients who were fit transplant-eligible patients, different than what we saw in the SIERRA trial. Thus, Iomab-B is truly paradigm changing as it enables unfit transplant-ineligible patients with advanced refractory relapsed AML, who many of them receive palliative care, give them access to transplant and to benefit from the treatment. What is the current status?
Many patients, because they're not in remission or because they're not fit for a myeloablative conditioning regimen, would not go on to receive transplant. The ASAP trial, interestingly enough, showed that taking patients straight to transplant makes a difference, and the results are similar than if you try to reinduce with chemotherapy. These patients are fit, many of them were only at first relapse or primary induction failure. What was interesting is that many of these patients were treated in the same transplant center. There was really no need. The communications between the referring physician and the transplanters were immediate. Iomab-B has a unique impact. It will be offered to older patients with refractory disease and many of them who would be considered unfit for a myeloablative conditioning regimen.
In conclusion, the SIERRA trial results demonstrate the viability of successfully transplanting relapsed refractory AML patients who are currently offered palliative care and improving their outcomes, thereby paving the way for Iomab-B to become a new standard of care. Iomab-B achieved the SIERRA trial's primary endpoint of durable complete remission with high statistical significance. It doubled the median overall survival and the 1-year survival. Event-free survival was also significantly improved with Iomab-B. Iomab-B was well-tolerated with a low rate of serious events. Further exploration of Iomab-B in other indications and with different condition regimens and donor types is planned. Let me once again underscore why is this important. As you can see, the fraction of patients over the age of 65 that are undergoing allogeneic transplant has increased significantly over time. Remember, the median age of AML patients is 68 years old.
Still, we have an enormous unmet need, as you can see here from different studies. The best one done by Dr. Roboz using the Connect MDS/AML registry trial suggests that only one in five patients with AML or MDS over the age of 65 are actually getting transplanted. Here is another study showing the huge practice variation. There is a 8-fold less chance of being transplanted if you are 60 years or above. Some of this is we need to educate our referring physicians. Only 30% of them in a recent survey actually thought that patients aged over 60 with AML could benefit from transplant, many of them because they're saying that the patients at this age do not achieve a complete remission, and taking the patient to transplant with active disease is not beneficial.
Iomab-B should change that paradigm and should change that thought. Thank you very much for your attention. I will now take questions from the moderator and stop sharing the slides.
Thank you, Dr. Giralt. We've received a number of questions leading up to today's e-event, we thought it would be appropriate to present some of these to Dr. Giralt before opening the call to live Q&A from today's audience. First, Dr. Giralt, how were the SIERRA results received at the TCT conference last weekend? What was the medical community's reaction?
The SIERRA results were received very enthusiastically. The comments of, you know, we now have something that we can offer patients with active disease. This looks like a great bridge to a reduced-intensity conditioning transplant. You know, really, you know, one of the big comments was, well, when are you going to do this for mismatched donors or looking at different GVHD prevention strategies? Said those studies are currently being planned. I think the most important comments was one made by one of my colleagues in one of the transplant centers who was participating in part of the SIERRA trial, who said, "Look, I was able to take patients to transplant because of the SIERRA trial and because of the crossover design that we would have rejected because they had poor disease control.
We did not think they would be good candidates for a myeloablative conditioning regimen." This opens a whole new door for a variety of patients who up to now many times were being rejected for a curative transplant.
Awesome. Thank you, Dr. Giralt. I guess on a second question here, how do the recently approved targeted agents impact the treatment patient population or treatable patient population for Iomab-B?
I think we're very excited about all the targeted therapies. Remember, the targeted therapies are good in reducing leukemic burden, but they do not achieve long-term disease control, and these patients are destined to relapse. What we believe is that this will actually make the Iomab-B trials even more relevant because you can now take a patient to Iomab-B with a lower tumor burden, but even though they still have low levels of active disease, Iomab-B will get these patients in remission and will hopefully achieve durable complete remissions, but even better than the SIERRA results, because we can now use these targeted therapies as maintenance strategies which we were unable to do in the SIERRA trial.
Great. I guess a third question here that has come in a few times is that, can you explain why the statistical analysis for overall survival is confounded by the crossover arm?
Oh, yeah, sure. Remember that 40 patients in the conventional care arm went on to crossover to Iomab-B, and these patients actually did as well as those that were randomized to Iomab-B alone. Had we not had the crossover design, we probably would not have been able to approve. Having the crossover design, you now confound the overall survival because many of the patients who crossed over achieved durable complete remissions, and many of those complete remissions have lasted more than two years. That affects the survival curve. That's why you see such a difference between the patients with conventional care who did not crossover versus those who crossed over. Significantly different. Those who crossed over did as well as those who were originally randomized to Iomab-B.
Great. Thank you. I guess an extension on the, on the crossover arm here. What do you think about the crossover results overall? You know, how do you interpret them?
Well, I think it's excellent that the patients who were crossed over did as well as those who were randomized to Iomab-B. Does that mean that, A, you should wait until get to give somebody? No. I think what it means is that if you have a patient with active disease, and you were unable to get them in remission because you didn't, that you wanted to try, that patient should be referred immediately once it becomes commercially available to an Iomab-B center that can induce, treat those patients with Iomab-B and rapidly take them to a reduced-intensity conditioning regimen to increase their chances of achieving a durable complete remission and long-term disease control.
Great. Thank you again. I guess another, you know, two questions here that we've got in the queue, what additional indications do you think Iomab-B could be used in?
We're very excited of exploring Iomab-B in myelodysplastic syndromes, which is rapidly becoming one of the most common indications for allo transplants in older patients. Obviously, one can consider using Iomab-B in other CD45 positive malignancies or even as just a strategy to deliver myeloablative radiation to the marrow for other non-CD45 positive diseases. Those have to be studied in, you know, in obviously prospective, well-designed clinical trials.
Great. Thank you. I guess finally here is there anything in development for bone marrow transplant conditioning that would potentially impact Iomab-B?
I could say in the, in the near future, there is a lot of talk of what we call non-genotoxic conditioning regimens with monoclonal antibodies. I mean, there was data presented with Jasper and Magenta, but these are not ready for prime time. I mean, they've never shown the results that we're seeing with the Iomab-B results we've seen today. I mean, in the early horizon, I can say I don't think there's anything yet there.
Great. Thank you, Dr. Giralt, and for your presentation earlier. At this time, I'd like to turn the call back over to the operator or to open the call for a live Q&A. Thank you again.
Great. Thank you, PJ. Please hold for a brief moment while we pull for questions. Our first question comes from Jason McCarthy from Maxim. Please go ahead, Jason. Jason, you might be on mute.
You might not be.
Jason, unfortunately, we can't hear you. All right, we'll go with the next question, and we'll hopefully help Jason with his audio. Our next question comes from Rick Miller from Cantor Fitzgerald. Please go ahead, Rick.
Hi. Thank you. This is Rick on for Kristen Kluska today. Thanks for taking our questions. This question's for the company and maybe Dr. Giralt as well, if you have anything to add. Are you able to offer any details potentially on what an early access program for Iomab-B could look like? Would you be looking at working with the same sites as the SIERRA trial, or could you look to expand to other potential sites for early access?
Yeah. What we've said is. First, thank you for the question. What we said is we will message about the early access program in terms of details towards the middle of the year. What I will say at this point is we expect to be in several more sites in addition to the SIERRA trial use that as, you know, a preparation in order for site expansion, assuming that the drug gets approved. In terms of further details on, you know, the trial itself, we will be back to you in a few months.
Great. If I could maybe just add one more, and maybe Dr. Giralt could add some perspective here. Thinking about the, the radiation dose actually delivered, you went over the dosimetric dose and therapeutic dose, the IOMAB dosing. In terms of dose level, how does this compare to dose levels typically delivered, for other indications in the radiotherapy clinic? To ask this another way, how used to this level of radiation dosing are the centers typically?
That's a great question, Rick, and thank you for asking. Just put into perspective that total body radiation is limited to about 12 Gray, and that's not 12 Gray delivered to marrow spaces. For myeloma, for example, you need five Gray to be able to cure a plasmacytoma. Here the median radiation delivered to the marrow was 16 Gray. Now the dose is capped at 24 Gray to the liver. This is done by our nuclear medicine specialists who do all the dosimetry. It truly is, one, a personalized dosing, giving the maximum amount of radiation to the marrow where the disease lives, but it also allows us to deliver radiation to extramedullary sites. Regarding how the sites feel, I think all the SIERRA sites feel very comfortable. They deliver radioiodine.
They, you know, this is very similar to when we used to do Zevalin and Bexxar for radioimmunotherapy. The nuclear medicine staff is very accustomed to giving these type of radiopharmaceuticals.
Let me just add to that, Rick. You know, you wanna be thinking about, obviously, you know, you're trying to wipe out the bone marrow here. If you're trying to do something in the brain, that's a different dose, right? You have to think about it in that context. The relevant metric also for people administering the dose is what is that radiation exposure? I think, you know, Dr. Giralt alluded to that in some of his slides. It's very, very low compared to acceptable radiation dose exposure limits annually. It's about one-tenth of that dose.
Great. Thank you very much.
Great. Thank you for the questions, Rick.
Okay. Can you hear me now?
Yes, we can hear you now, Jason.
Fantastic. Sorry for the confusion. Just a question, Dr. Giralt, on the primary endpoint, the use of the six-month DCR. I understand the survival data is of course confounded by the crossovers, but when you look at kind of the totality of the impact on six-month DCR, what you see in trends on the survival, in terms of approvability by FDA, can you compare that to what has been approved for targeted therapies in relapse refractory settings and kind of explain how this is so much better?
I think that's a great question, and thank you for asking. Let's just go with the first endpoint, right? 70% of patients who received Iomab-B at 30 days post-transplant had achieved a complete remission. Complete remission is the single most important surrogate for not only long-term disease control, but overall survival. Mind you, if you think about all the targeted therapies, those complete remission rates fall somewhere between 30%-40%. Unfortunately, many of the patients who receive targeted therapy, even if they achieve a complete remission, end up relapsing very early on. As you can see in the control group in SIERRA, very few people actually had none of them had remissions that lasted more than six months.
In the Iomab-B group, there was 22% of the patients achieved a complete remission that lasted I mean, 13% of the patients achieved a complete remission that lasted more than six months. When you add the crossover group and you look at all those patients who achieved that durable complete remission and see what happened to them two years later, two-thirds of those patients are still in complete remission. I think, one, this is a clinically relevant endpoint, a very good clinical significance and clinical benefit. Can we work upon that? Can we make it better? As I said in my talk, I think we can definitely make it better by adding post-transplant therapies that the protocol did not allow. I definitely think this is a very important primary endpoint of clinical significance and clinical benefit for these patients.
Great. One more question. Just from a very broad perspective, considering that this is the sickest of the sick or just one of the most challenging settings in AML that you can have, and you look at the DCR and the one-year survival, but can you talk a little bit more about the event-free survival, which was so much more tilted towards the Iomab-B arm, and how that will translate with maintenance therapies and extended quality of life for patients as well as pharmacoeconomic benefit for payers and hospitals potentially?
That's an excellent question and a complex one to answer. Let's just go for the 1st, the event-free survival. And I'm not gonna go into the details of what we defined as events. I think the important thing is that event-free survival was significantly better for patients on Iomab-B versus conventional chemotherapy. The way I think you have to look at it, or the way I look at it as a physician, is a patient's in the community, has acute myelogenous leukemia. The patient decided not to get transplanted in 1st complete remission and relapses, which is what frequently happens. An older patient fails to respond to induction therapy.
In these patients, traditionally, many transplant centers have said, "We will not take them unless they're in a complete remission." Now you have a strategy that will allow you to bridge these patients successfully into a reduced-intensity conditioning regimen. I think one of the things that we talked about the ASAP trial, but one of the things the ASAP trial shows us is, look, if you have a patient who does not respond to induction therapy or a patient who's relapsed, rather than trying to get them in remission, particularly if they had a short first remission, this Iomab-B becomes the optimal bridging strategy to a reduced-intensity conditioning regimen. It should allow us to transplant many more patients above the age of 65. As I showed you, now, only one in five of those patients are actually being considered for transplant.
Great. Thank you for taking the questions.
Thank you.
Thanks, Jason. Our next question comes from Joe Pantginis from H.C. Wainwright. Please go ahead, Joe.
Great. Thank you. Can you hear me?
Yes, we can.
Fantastic. Thank you for hosting the call, today and all the details. Dr. Giralt, I hate to belabor this because it just seems like a foolhardy exercise for something that's been in the ether, but I really appreciate your comparisons with SIERRA and the ASAP study. That comparison is the one that seems to be a theme that's been out there that, like I said, has been quite foolhardy in our belief, in our assessment. I just wanted to ask about the actual conditioning regimen that's been used in ASAP. Is that actually used in real world, and to what extent with regard to cytarabine and mitoxantrone?
I would say that the ASAP regimen, the ASAP study was a study that was performed in Germany in centers that are committed to doing this type of studies. The things we don't know about the ASAP study is who wasn't randomized. It wasn't all comers, right? It was basically patients in which the physicians felt equally comfortable giving just mitoxantrone or cytarabine at low doses versus mitoxantrone and cytarabine at a dose to try to induce a remission. What's interestingly enough is all those patients got transplanted, the conditioning regimen used for transplant was each individual transplant center decided. I think very few of those patients got fludarabine and low-dose cyclophosphamide, which is the best tolerated of the reduced-intensity conditioning regimens.
Our transplant-related mortality on SIERRA was extremely low. I don't think you really can compare ASAP to SIERRA, as you just alluded to, Joe, because the patient population was totally different. SIERRA population was 66 years of age versus 64. Remember, a significant proportion of patients in SIERRA were beyond first relapse, and these patients were not allowed in ASAP.
Got it. Thank you. That's very, very helpful. My, my next question is really a macro question with regard to potential real-world use for Iomab-B. I appreciate your comments about, you know, the specialty centers like you guys and the radiation shielding in the room and what have you. Can you put into perspective, you know, over the last several years, there's been a lot more interest by pharma and acquisitions of companies with radiopharmaceuticals and why, you know, real-world use might be more accepted than, say, you know, 10, 15 or more years ago of the Bexxars and the Zevalins of the past?
Well, I think, you know, I think the example is prostate cancer, right? You now have a radiopharmaceutical in prostate cancer, which has been rapidly adopted by the prostate cancer community. Because, one, it's safe and it's effective, and we now have, I would say, a critical mass of nuclear medicine specialists who know how to deliver these drugs and a critical mass of oncology specialists who know the values of these drugs. I think this is a similar situation. We now have a critical mass of nuclear medicine physicians who can deliver Iomab-B safely, and we have a critical mass of transplant centers who can make that connection with their nuclear medicine colleagues to make sure that they're bridged successfully to transplant. The other thing that's happened now that does not a decade ago is in the transplant arena with post-transplant cyclophosphamide, everybody has a donor.
We're no longer... I mean, as long as the transplant center gets involved early in the care of the patient, we will find a donor for that patient, and we can take that patient successfully to transplant.
Got it. Thank you very much for the color.
Joe, I just want to add one more thing. You know, one of our advisors that we work with actually launched Zevalin out of sharing many, many moons ago. You know, they were going up against Rituxan, which at that time was the world's best-selling drug.
Sure.
The oncologist who was the treating, you know, healthcare provider, was giving these patients Rituxan outside the clinic. You had a demand that was met, very well met. Here there is, you know, unmet medical need. I think that really is the key differentiator as well, right? Not to be forgotten.
No, you bet. Thank you.
Great. Thank you for the questions, Joe. Our next question comes from Yuan Zhi from B. Riley. Please go ahead, Yuan.
Yeah. Thank you for taking our questions. Dr. Giralt, maybe you have covered this, but in your view, does the benefit observed from the SIERRA trial, such as higher engraftment and overall survival justify the Iomab-B conditioning process and bone marrow transplant, knowing that this process involves radioactive materials?
Well, I mean, I think this is a question that, I mean, it was really addressed throughout the TCT, where everybody who approached this said, "Look, this is a valuable new agent that will allow patients who otherwise had no options but palliative care to undergo a transplant with a curative potential of around, you know, 15% to 20%." you know, I think definitely this is of clinical value and clinical benefit. The way I always look at it, look, the SIERRA trial was probably our lowest bar. We're only going to get better because we're gonna learn how to use these drugs much more effectively and probably learn how to use them in earlier phases of disease where the benefit's actually gonna be even more.
I think the two ways to look at it is Iomab-B looks as the best way to bridge a patient to transplant if they're older and they're not in remission. Can Iomab-B work better in other situations? Those are clinical trials that are currently being planned, but the answer is probably yes, and it is a paradigm shift in the treatment of AML of the elderly patient.
Got it. Thank you for that insight. Can you talk about the baseline characteristics of those patients who had complete remission and stayed live for more than two years?
One, that is an excellent question, and I can tell you we are doing those analysis now. When we did the forest plots that I showed there, Yeah, Iomab-B benefited all patients of categories that were pre-specified. We are now going back into the data to see if we can try to parse out which patients had the best benefit. For now, from what we have from the 66 patients that were treated, it seems to benefit all patients across all disease categories. Further analysis of the data is currently being planned.
Got it. Got it. As you can see, there's ongoing debate on the trial design and the clinical benefit we observed here. If you were to design this phase three trial of Iomab-B in AML bone marrow transplant setting, how would you design it to show the benefit more clearly and the additional thoughts on potential endpoint selection there?
One, let me tell you that the study was designed together with the FDA. The reality is when you ask me, "How would you design it?" I'll design it whichever way the FDA wants me to design it to get the drug approved. That's how it was designed.
Got it. That's all my questions. Thank you.
Great. Thank you for the question, Yuan. Our next question comes from Justin Walsh from JonesTrading. Justin, you may go ahead.
Hi. Yes. Can you hear me?
Yes, we can.
Thanks. You've touched on these questions, in one form or another, I wanted to ask directly and maybe dig a little deeper into starting with the expected reception of Iomab-B versus Bexxar and Zevalin. Do you think community physicians will be at all hesitant to refer out patients for treatment with Iomab-B from both a clinical and a business perspective?
That's an excellent question, Justin. Let me tell you about three initiatives that are currently being done nationally. Let's just... I'm gonna put Iomab-B in the picture in a minute. One, both the National Marrow Donor Program and the transplant centers and the American Society for Transplantation and Cellular Therapy have really worked enormously over the last couple of years to make sure that we increase our transplantation rates. Currently, in the United States, only 30%-40% of patients with acute leukemia or MDS who could potentially be cured with a transplant are actually getting transplant. We have a huge gap to fulfill. Now, one of the gaps is the lack of communication between the treating physician and the transplant centers.
You know, Be The Match and has actually started a trial, a study that we asked the Be The Match goes and gets patients HLA typed earlier. ASTCT is working to make sure that all the community physicians have good connections with their transplant centers. Now to the question of Iomab-B. Once you have that connection between the person that is treating the leukemia patient and the transplant center that's going to do the transplant, it makes a logical connection that if a patient is a primary induction failure or the patient's relapse, with the SIERRA data you can now say, "Get me that patient early. That patient's already been HLA typed. We already have a donor identified, and we have the best strategy to bridge this patient to transplant if they're over the age of 55, and that would be Iomab-B.
Got it. Maybe expanding on this, clearly, most of the major centers are able to handle Iodine-131 without problem, particularly the ones that are involved in SIERRA. Maybe you can just give us a sense of how many transplant centers that were not involved in SIERRA have experience working with radiopharmaceuticals, and/or are capable of easily adopting Iomab-B.
That's a difficult question to answer. There's 150 large transplant centers across the country. 22 were involved in SIERRA. I, you know, I think the company can tell you how many more they're thinking for the expanded access protocol. I mean, in any place where there is a large nuclear medicine facility, they probably can handle Iomab-B if there's a transplant center involved with it.
Justin, let me put this in perspective here, right? Transplant is done in very large hospitals that have transplant centers of excellence.
Show me even a relatively medium-sized hospital that doesn't have the ability to use radiation in terms of diagnostics. That implies they have radiation safety officers. That implies they have a nuclear medicine department, right? We actually polled all of the 156 transplant centers when we were starting the trial. Maybe there's a few more or less, I'm not sure at this point. We have a pretty good idea of, you know, who is capable. We also have a very good idea through publicly available data of the number of transplants these centers do. When we do our strategic plan for commercialization, you know, what we've said consistently is the first phase will be expanding from 22 sites in the United States to about 50. The early access program will cover some or all of those, depending.
We are looking at, you know, based on our guidance for BLA and approval in the second half of next year. It takes, in my opinion and my experience, you know, six months to a year to get a site up and running. Those efforts are underway already. In terms of, you know, the ability of a large quaternary care cancer center to handle radiation, I think that's a complete non-issue.
Got it. Thanks.
Mm-hmm.
One more question from me here. You mentioned that the trial design was made in collaboration and consultation with the FDA. I think it's worth just sort of double-checking on this because we saw companies' neuroblastoma radiopharmaceutical drug receive a CRL at the end of last year due to insufficient evidence that it improved survival. Just wanted to double-check in that context if Sergio Giralt, if you really have any concern at all that the FDA might be worried that there isn't conclusive survival results due to the crossover, or if you really think that that'll be a non-issue from a regulatory perspective.
I think when the SIERRA trial was designed, the Board of Scientific Advisors as well as the company, when we went to the FDA, we advised them that there was no way that this trial was going to be able to accrue adequately unless there was a crossover. Now, the crossover actually worked much better than we ever thought of, right? Remember, one is we had 40 people crossover from conventional chemotherapy to the apamistamab. That's more than 50% of the control arm. The other thing that happens is the crossover happened relatively early. These patients were getting transplanted within 60 days of randomization.
You know what usually happens when you have crossover designs is that if the crossover happens later on in the journey, you can see a survival benefit for the experimental arm because a lot of people are not able to cross over because they fail very early and die. Here, we didn't see that. We saw that these people failed, they were able to cross over successfully, and they had the benefit of getting the Iomab-B. I think the survival data is actually compelling, and it speaks to the benefit of the drug by the fact that the group that crossed over did so much better than the group that didn't cross over, despite the fact that they actually achieved a durable complete remission.
Got it. Thanks for taking the questions.
You know, for those of you who are, you know, interested, there's a JAMA article on, you know, cancer trials and, you know, the structural artifacts that are necessary in cancer trials with respect to a crossover, given that you are treating late-line patients that have no treatment options. This is actually very, very common. The JAMA article lists about 50 drugs, some of which are household names that had a similar issue to SIERRA. You know, you can go look up that article. It's very informative. Thank you.