Great. Hi, everyone. My name is Tara. I'm one of the senior biotech analysts at TD Cowen, and I want to welcome you to TD Cowen's 46th Annual Healthcare Conference. For our next session, we have a presentation from TScan, and it's my pleasure to introduce Gavin MacBeath, the CEO. Without further ado, whenever you're ready, take it away.
Thank you, Tara, thank you to the organizers for inviting us to the conference. For those unfamiliar, we are a publicly traded company, and so I will be making forward-looking statements. Just as a broad overview of TScan, we're a clinical stage, next-generation TCR T-cell therapy company, with our lead asset in heme malignancies. Our lead clinical program, we are using a cell therapy product to target residual disease and prevent relapse in patients undergoing allogeneic hematopoietic cell transplantation. We have very promising data.
We most recently updated data at the ASH meeting in December of last year, in which we showed that patients in our phase I study that included a control arm, that those patients had a hazard ratio of 0.5 for relapse-free survival relative to the control arm. We also showed long-term follow-up data on those patients that three out of three patients that were on study for over two years were continuing on study relative to only one out of four patients on the control arm. Based on the strength of these data, we have now met with the FDA in our end of phase meeting. We have agreement on a pivotal trial design, and we intend to launch that pivotal trial in the second quarter of this year.
We have also recently expanded this program by filing and clearing INDs on two additional products that enables us to expand into additional patients in this patient population, which will ultimately double the addressable market with this heme program. Beyond the heme program, we have a program in solid tumors in which we have recently pivoted to an in vivo engineering platform. This program is now in pre-clinical development with a promising way to do off-the-shelf TCR T-cell therapy with in vivo engineering. Finally, our target discovery platform is a first-in-class platform for discovering the targets of any T-cell receptor, and we are using that platform to discover the targets of pathogenic T-cells in patients with autoimmune disorders, and so continuing work in that direction.
For today's presentation, I'm going to focus exclusively on the heme program. An updated look at our pipeline. Our ongoing study is called the ALLOHA Study. It's our Phase I study of TSC-101, which is our product that is intended to treat residual disease and prevent relapse in patients undergoing transplant therapy. As you can see, the recent additions to our pipeline, two new TCRs cleared for clinical trials, which we intend to launch in the second half of this year. Gonna start with a sort of broad overview of the program, but really focus on the potential market opportunity for this program.
Just to summarize the program, right now, the lead product, TSC-101, is intended for patients with AML and MDS that are undergoing allogeneic transplant. Right now, bone marrow transplants, is really the only curative therapy for patients with AML and MDS. In fact, a lot of patients are cured by getting a transplant. Unfortunately, there's about a 40% relapse rate for patients that are undergoing transplant with reduced intensity conditioning. If you relapse, the prognosis is very poor. In fact, 80% of patients that relapse will die within the next two years. The unmet need here is to make transplant fully curative, to prevent relapse, and really, you know, have patients fully cured by that transplant.
Just to show you how this product works, our product actually, you know, integrates seamlessly into the current standard of care transplant journey. For a start, if you're diagnosed with AML or MDS, typically in the community setting, your treating oncologist will refer you to a transplant center. There's only 120 transplant centers in the U.S. that conduct allogeneic transplants. Very concentrated market. We don't need to go looking for those patients. They're already being referred to those transplant centers. When a patient arrives, in order to get a transplant, they're going to get HLA typed, and their prospective donors will also get HLA typed. In fact, that's part of standard of care, so we don't need to be developing a companion diagnostic for HLA typing.
That's just part of standard of care, transplant therapy. To qualify for our therapy, the patient has to be HA2 positive, and any patient that has the HLA type HLA-A*02:01 will generally be HA2 positive. They simply need to be paired with a donor that doesn't have that HLA type. They're A2 negative. Once that donor has been identified, then we apheresis the donor to collect their T-cells, and we start our manufacturing process. The donor then undergoes a second apheresis to collect their stem cells, and the patient in the hospital has their regular standard of care transplant. The patient needs to recover from the transplant before they can receive our therapy, and that typically takes about three weeks for their white blood cell count to recover.
The patient is still in the hospital, just had their white blood cell count recover, at which point they get their first infusion of our engineered T-cells. It all is seamlessly integrated into that standard of care. The patient is then typically discharged, and they have just a second administration of our product 40 days later, which these days we're typically doing in the outpatient setting. Overall, very little impact to either the patient or the donor, in terms of those that are receiving our therapy. By the time we launch this product, and we anticipate launching the product in 2029, we estimate that about 6,200 patients a year in the United States, with AML and MDS will undergo an allogeneic transplant.
To qualify for TSC-101, you need to have the HLA type HLA-A*02:01, and about 42% of people in the U.S. are HLA-A*02:01 positive. As I said, you need to pair them with a donor that's HLA-A*02:01 negative. Our current experience, we're finding that about 80% of the time, we can identify an appropriate donor. This is how we come up with an addressable patient population of 2,100 patients per year. We have done initial work with payers, including Medicare and private payers, and right now, we estimate that we'd be able to price this product in the range of other cell therapy products.
The calculation shown here is based on a price of $675,000, which is, you know, sort of in the middle of our general pricing corridor. This means that just in the U.S. alone, this first product, TSC-101, has a, you know, peak revenue of little more than $1.4 billion. This is TSC-101. As I said, 2,100 patients addressable in the U.S. If you look at Europe, there's slightly higher incidence of AO 201 in Europe, about 3,900 patients, lower incidence in APAC countries, about 1,500 patients per year, for a total of 7,700 patients a year.
As I said earlier, we are expanding this program by introducing additional products very similar to TSC-101 that address other HLA types as well. Our strategy is to develop three additional products for the HLA types HLA-A*01:01, HLA-A*03:01, and HLA-A*24:02. Just last week, the FDA cleared two of our INDs for TSC-102-A03 and TSC-102-A01. Those are the first two HLA types for expansion. We do have another TCR in late stage discovery for HLA-A*24:02 and anticipate filing an IND for that product down the road. Right now, we have two cleared INDs to further expand this program.
You can see across the numbers that ultimately, if all four of these products get approved worldwide, we'd have about 15,000 patients a year addressable with these products. Backing off to TSC-101, the worldwide addressable market is about 7,500 patients a year. If we include these other products for HLA expansion, it gets us to about 15,000 a year. There are other expansion opportunities beyond this, including other areas in oncology, other disease types, as well as non-oncology indications that would ultimately enable us to address about 20,000 patients a year.
All right, stepping back now to our clinical development program, we have, over the last three years, been running a phase I study of TSC-101, as I mentioned earlier, included a control arm in that study. Before I launch into the study, just wanna walk you through the mechanism of action of this product. TSC-101, as I said, is intended for patients that are HA2 positive who have a donor that's HA2 negative. In these diagrams, the patient's blood cells are represented in pink, and the donor blood cells are represented in blue. Of course, the donor blood cells are HA2 negative.
If a patient comes along with an HA2 negative donor and undergoes a transplant, then post-transplant, all of the new healthy blood cells that get regenerated from those stem cells are all donor-derived and are HA2 negative. That's why they're colored in blue. However, that patient may have some residual disease, some residual cancer. Any residual cancer, of course, comes from the patient and is HA2 positive, which is why it's colored in pink. We wanna get rid of those residual cancer cells. What we do is, as I said, while the patient's undergoing the transplant, we take T cells from the donor, and those T cells are HA2 negative, and we engineer them with a T-cell receptor that recognizes HA2.
Now, once the patient has recovered from the transplant, we give them their infusion of those engineered T cells, and those T cells will only target HA2 positive cells. They'll target the residual cancer in the patient, but they won't touch any of the new healthy donor-derived cells because they are all HA2 negative. It's a really clean way to mop up any residual cancer and prevent relapse in those patients. As I said, we've been conducting a Phase I study that included a control arm. What I'm showing here is the patient characteristics for the patients that were included in this study at ASH last December. We had a total of 23 patients in the treatment arm and 19 patients in the control arm.
Overall, we saw a very good balance between the treatment and the control arm, in terms of these patient characteristics. If anything, the treatment arm had slightly higher-risk patients than the control arm. I think that's highlighted in particular by patients that had P53 mutations. P53 is a very prognostically bad mutation to have. 32% of our patients in the treatment arm had P53 mutations, compared to only 11% in the control arm. This product is extremely well-tolerated. Obviously, patients undergoing transplant have various adverse events associated with the transplant. In terms of any AEs associated with the product itself, it's been very well-tolerated.
We've only seen two cases of grade one CRS, one case of grade two CRS that were attributable to the product, and then one case of ICANS that resolved immediately following treatment. Very well-tolerated product in this trial. This is a summary of the patients in the treatment and control arm in this swimmer plot representation. In this plot, the squares represent bone marrow biopsies, and if there's any minimal residual disease that's detectable, the square is colored pink. If there's MRD negative in that biopsy, it's colored in blue. If you first focus to the left, you can see that prior to transplant, about 50% of the patients in both the treatment and control arm were MRD positive going into the transplant.
As you look to the right, post-transplant, those green vertical lines that are barely visible in the treatment arm patients, those represent when they got their infusion of engineered T cells. You can see that in the treatment arm, almost every patient converted to MRD negative following that first infusion, and many stayed MRD negative at every reading thereafter. Overall, you can see in the bottom right that the RFS hazard ratio in this trial, as reported last December, was 0.5 for relapse-free survival and 0.6 for overall survival. We've also been tracking what we call donor chimerism. Donor chimerism is a measure of how well you have replaced all the patient's blood cells with donor cells. Complete donor chimerism is the goal.
That means that all of the patient's blood cells are donor-derived. If there's mixed chimerism, that means that there's still some patient-derived cells detectable. In these diagrams, the blue checks indicate complete donor chimerism. The red X's indicate incomplete chimerism. You can see just visually, kind of from a stepping back, that there's a lot more blue checks on the left, the treatment arm patients, relative to the right, the control arm patients. You know, that's obviously very promising for their long-term prognosis. I do wanna highlight one patient in the treatment arm here. This is a patient that actually had a delay in getting their second infusion. They had GvHD, and so were being treated with steroids at the time.
This patient ultimately relapsed, as indicated by that pink triangle around day 161. We did have some extra cells in our freezer. Not a lot, just 370 million cells, but they received a third infusion. What we found is that this is showing the relapsing cells, so this is the recipient chimerism that had risen up to 20% by that point, immediately upon receiving that infusion. At that time, that patient was not receiving any other therapy. They immediately converted to complete donor chimerism and stayed in complete remission for five months, until ultimately relapsing after five months. Again, just direct evidence of mechanism of action, that the product does target residual patient cells.
I'm just gonna highlight one result that we presented at the Tandem Meetings in February, and that is that if you look at all the patients in our study, this is both treatment and control arm patients, what we found is that chimerism at two months is an accurate predictor of long-term outcome. This is dividing the patients that had complete donor chimerism in pink, with those that had incomplete chimerism in the teal color, and you can see that the probability of relapse is much higher if you have mixed chimerism at two months than if you don't. Based on this, we feel like we have a very good predictor of, you know, what's going on in the patient if you look at them at that two-month mark.
Overall, just in summary, a very attractive safety profile for this product, very meaningful relapse-free survival benefit, and evidence of long-term persistence of our product. In fact, every patient that we've tested at every reading has shown detectable engineered T cells in their blood. This product is persistent in these patients. Just wanna shift in the last three minutes here, to where we are now, with this program. One thing we highlighted at ASH in December, is that we have now developed a commercial-ready manufacturing process. As we launched the phase I trial, we had what we call a phase I manufacturing process, but now we need something that's sort of more efficient and more commercial-ready. This new process is actually a lot more efficient than the original process.
In fact, it's a shorter manufacturing time, so we can now manufacture the product in 12 days as opposed to 17 days. We also think that there's a potentially an improvement with this product. What we're highlighting here on the right is that we took the patients in our study and divided them into those that had complete donor chimerism with no relapse on the left-With those that had incomplete chimerism or relapse to the right. What we found is that the patients that had incomplete chimerism or relapse, their T cells had been expanded more in the manufacturing process than the patients that had complete donor chimerism. This is consistent with everything that's known in the field, right?
The longer the manufacturing process, the more cells expand, the more exhausted they get, the less proliferative potential they have. It's not surprising that we saw this result. The good news is that our new commercial-ready manufacturing process is much more efficient and it re-requires much less expansion of the cells during the manufacturing process. What we're doing now is we're enrolling 10 patients into what we call Cohort C of the study, and all 10 of those patients will be treated using the commercial-ready manufacturing process. What we announced last week is that we've completed enrolling over 10 patients in that Cohort. They're all in the process of getting transplanted and treated.
We intend to share data, pharmacokinetic data, but also chimerism data on those patients in the second quarter of this year prior to launching the pivotal study. We believe this is gonna give us confidence that the commercial-ready manufacturing process is working, that patients are responding appropriately prior to launching the study. We did share just one data point back in January, and that is that the first patient we treated with the commercial-ready manufacturing process immediately converted to complete donor chimerism within three weeks of getting their first infusion. We will share data on those 10+ patients in the second quarter of this year. Finally, I'm gonna end with this last slide, and that is the pivotal trial design.
We have agreement with the FDA on how to run our pivotal trial. The study population will include patients with AML and MDS. Then the investigational arm patients will receive transplant plus TSC-101, and the control arm, transplant alone. It is a randomized trial, but it's what is referred to as genetic randomization. Patients will be assigned to the treatment arm if they have the HLA type AO 201. They will go to the control arm if they don't qualify for our product. Either they're AO 201 negative or they're AO 201 positive, but we couldn't find an A2 negative donor for that patient. Patients will be biologically assigned to treatment and control arm, based on their HLA type, which we've shown, does not have an association with outcome in the transplant field.
Our intention is to launch this study in Q2. We estimate the study will take about 2.5 years to get to a top-line readout. By the end of 2028, we should have a top-line readout on our pivotal study. With this, I'm going to end and move to the Q&A session of this fireside chat or whatever it is. Presentation, fireside chat. There we go.
No. Great. Thanks so much for that presentation, Gavin. It was a wonderful overview. I think where a good place to start is a couple of things that you said on the last couple of slides. One being the manufacturing process and the 10-plus patients that you now have treated with that and an update coming for them in Q2. Maybe you could just set expectations for that. I know we've seen the one patient that had a fantastic result. Should that be the expectation for all of these? In that, maybe discuss how long a follow-up these patients could possibly have. Like, are we gonna have some that we could see some durability with? Some will be too early.
Yeah. Just timing-wise, right? As I said, we've enrolled actually over 10 patients into that cohort. They are in various stages, right? Some of those patients have not yet had their transplant. Some have been transplanted but not yet dosed, right? Some have been dosed already. When we share data in Q2, it'll be a range, right? Some patients will have longer follow-up than others. Hopefully, as a collective, it will have a meaningful look at patients. That's why I set expectations around this two-month mark for chimerism. If we can get chimerism at two months for, you know, most of those 10 patients, I think that would provide the most confidence as to what the product is looking like.
We'll also have, you know, pharmacokinetic data, so that we'll, you know, see how that compares to our Phase I process. Just to clarify from a regulatory perspective, we have shown that our commercial-ready manufacturing process is comparable to our Phase I process, right? That's a regulatory requirement for, you know, moving that product into the pivotal trial, and we've already done that work with the FDA.
Okay. While we're on the topic of the pivotal trial, maybe you could give us some context for what the bar for success is there and, you know, with the background and the phase I data that you have, in what ways do you believe that de-risks the results for that trial?
Yeah. As I said, we've seen a hazard ratio of 0.5 for relapse-free survival at this point. Based on that, we're currently looking at, you know, how best to size the trial. We do wanna see data on these 10 patients because, if you look at the data from the trial, really up until we got to dose level four, we had seen very promising data. And really, if you just look at the last six patients on the study, where we were struggling to get to the dosing for dose level four, that's where we saw most of that, you know, extensive expansion of the cells during the manufacturing process. We feel that's gone away with the commercial-ready manufacturing process.
If we see, you know, really encouraging data from this, Cohort C, we could get a little more aggressive on the powering for the study. Right now we've been indicating generally that there will be about 140 patients per arm, which would translate to a hazard ratio of about 0.55 for relapse-free survival. But until we see those data, we won't finalize the numbers on how big the pivotal trial will be.
Okay, great. We will look forward to that. Maybe, you know, in your presentation, I know you went through patient numbers that could possibly be addressable with this, but how are you thinking about your peak penetration estimates in each of those for 101 and then how can 102 add to that?
Yeah. That's a great question. In order to receive our therapy, patients need to be undergoing allogeneic transplant with reduced intensity conditioning. In our protocol, we specify a range of different reduced intensity conditioning regimens. They must be paired with an A2 negative donor, which would come from that donor being either a haploidentical donor or a mismatched unrelated donor. If you look at the transplant space, there's quite a wide range of clinical practice. Some sites prefer to use haploidentical donors. For example, Johns Hopkins University invented haploidentical transplants, they have a very strong preference for haplo donors. Whereas other sites have more of a preference for matched unrelated donors.
Really, I think our penetration into that market will really depend on the data, right? If we have very strong data, I think we could expect very high penetration because it will change clinical practice, right? If we drop the relapse rates by more than 50%, then you would have a better outcome getting a haploidentical donor with our product than using a matched unrelated donor that doesn't allow use of our product. We would expect to see a shift in the use of haploidentical donors or mismatched unrelated donors in order for patients to get our product. Similarly, with the conditioning regimen, right now, two-thirds of transplants use reduced intensity conditioning.
If your outcome is better with reduced intensity conditioning paired with our product than getting myeloablative conditioning, you would much prefer to get reduced intensity conditioning and two easy infusions of engineered T cells than to go through the harsh conditioning regimen of myeloablative conditioning, which actually has a 16% mortality rate associated with just the conditioning.
Okay, great. Maybe just a little bit on solid tumors. I know this was a big investor focus with really high upside potential. We remain interested. I know that you've prioritized the heme program, but maybe you could give us a general explanation of the rationale for that decision and any updates you could provide there.
Sure. Just to catch everyone up. Our solid tumor program, very excited about it, right? It's a way to treat patients with heterogeneous solid tumors, where we think the best strategy is to actually give them more than one TCR-T cell therapy at a time, or what we call multiplex therapy. We did run a phase I study called the PLEXI-T Study, in which we got to the point of actually treating patients with multiplex therapy. We elected to terminate that program for two reasons. This occurred back in October of last year. One was because got agreement with the FDA on the heme program and really wanted to prioritize clinical development of heme.
you know, was finding the solid tumor program challenging to make dose, engineering, you know, from patient-derived T cells in late-line patients where they've had multiple rounds of chemotherapy. From that perspective, just, you know, a very challenging setting. The second reason that we decided to pivot in that program is because we've been seeing very exciting data coming out of the in vivo engineering field, right? Multiple companies have now reported clinical data on patients in which their T cells have been engineered in vivo using lentivirus. This is so much easier than ex vivo manufacturing. It's an off-the-shelf product. The patient doesn't need to go through lymphodepletion. There's no vein-to-vein time. It costs a fraction of ex vivo engineered product.
For that positive reason, we felt now is the time to get in early on that trend, start generating an in vivo engineered product, for solid tumors, and hopefully reenter the clinic, in a year or two, with that program. It's really a pivot based on the exciting new data that's coming out of the in vivo engineering field.
Okay, great. One last question is what do you believe is just most underappreciated about TScan?
I would say, just how different our heme cell therapy product is from other cell therapy products, right? The fact that you don't have to go looking for the patient, they're already there. Highly concentrated, market in 120 transplant centers in the U.S. By the way, we currently have 21 clinical sites. These are the biggest transplant centers in the U.S. running our study already. The physicians already know our product, right? Two, that there is no rush on the manufacturing product process, right? We're not racing the time because we're making the product while the patient's undergoing transplant. Three, that we're gonna have much higher consistency in manufacturing because the heme program, unlike the solid tumor program, is an allogeneic product, right? We are engineering the donor's T cells, not the patient's T cells.
The donors are all healthy, right? They're all young, right? You're taking T cells from young, healthy donors to do the manufacturing. Much easier prospect than manufacturing using T cells from, you know, patients that have had multiple lines of chemotherapy. I think this is a very different cell therapy product from what we've been seeing with other programs, and I think that's the most underappreciated aspect.
Couldn't agree more. Gavin, sorry, we're up on time. I wish we could keep talking about this, but I appreciate your time, your insights, everything, and thanks everyone for listening.
Thank you.