Welcome to this next session. My name is Paul Jiang. I'm a member of the biotech research team at Guggenheim, and I'm very pleased to welcome TScan Therapeutics as our next presenting company. With us today is Gavin MacBeath, CEO. Welcome, Gavin. Great. Thank you for having us. Of course. Perhaps for some of you who are maybe newer to the story, could you start by providing a brief overview of the company and your TCR-T cell therapy platform? Sure. Thank you. TScan was founded in 2018 and founded based on a technology that enables us to figure out the target of any T-cell. What we've been doing with that technology is trying to understand how anti-cancer T-cells function, what they're recognizing, and then with that information, build a pipeline of therapeutic TCRs that we can use to genetically engineer a patient's T-cells. Over the years, we've built two main clinical programs. Our lead program is in heme malignancies, where we're treating patients with AML and MDS that are undergoing allogeneic bone marrow transplants. The goal in that program is to treat residual disease following the transplant so that you can prevent relapse in those patients. That's our lead program, and we're moving that program into a pivotal trial starting in Q2 of next year. We'll have updated data at ASH this year. So far, the data have been very promising. We've seen about a 50% reduction in relapse rates in patients treated with our therapy relative to patients that are undergoing standard of care transplants alone. Our second program is in solid tumors, where the goal of this program is to treat patients with more than one TCR-T at a time. We've had an ongoing phase I clinical trial in which we've been testing a variety of different TCR-Ts as well as TCR-Ts in combination. We recently treated our first patient with multiplex therapy. However, we've made the strategic decision recently to pause further enrollment on that trial and really pivot to an in vivo engineering platform. We've seen a lot of advantages, a lot of early data recently with in vivo engineering of CAR T-cells. It's a promising new area, provides an off-the-shelf way to deliver engineered T-cell therapy. We're moving our solid tumor program to an in vivo engineering platform. Finally, we have target discovery work going on in autoimmunity. We've recently reported some early results at ACR this year, in which we've discovered the targets of T-cells in ankylosing spondylitis, in scleroderma, in bird shot uveitis, and in ulcerative colitis. We have an ongoing collaboration with Amgen to discover the targets of T-cells in Crohn's disease. Overall, a fully integrated company with a lead clinical program in heme, and then preclinical and discovery efforts in solid tumors and autoimmunity. All right. A lot of activity across a lot of indications. I wanted to start on the lead asset in the heme malignancies segment, but maybe just pulling back, could you first provide a little context on what the unmet need here is for, for instance, AML and MDS patients undergoing allogeneic transplants? What proportion of patients actually undergo transplants? What proportion experience relapse? What are you trying to do to improve those rates? Great. Thank you. If you look at AML and MDS, it's about 35,000 patients a year get diagnosed with those diseases. Of those, about 7,500 of them will ultimately go to allogeneic transplant. Transplant is really the only curative therapy for patients with AML and MDS. There's no available CAR T therapies for myeloid malignancies. For patients undergoing transplant, you can really get two types of conditioning therapy, either myeloablative conditioning, which is really only accessible to young, very healthy people that can tolerate that, or reduced intensity conditioning. Among those that are getting reduced intensity conditioning, which is about 60% of transplants, the relapse rate is quite high. About 40% of patients will relapse following an allogeneic transplant with reduced intensity conditioning. If they relapse, the prognosis is very poor. About 80% will die within two years of relapse. The real unmet need in this area is to make allogeneic transplant more effective, particularly for patients undergoing transplant with reduced intensity conditioning. If we can drop the relapse rates in that patient population, we can really have a profound effect and really lead to a curative therapy for many patients. Okay. Now might be a good time to walk through the engineering and rationale behind your therapy. You had a couple of options that you were evaluating at ASH last year. You have moved forward with TSC-101. Can you quickly sort of review the data from ASH? What led to your prioritizing of 101 as the go-forward asset? Yeah. Historically, we had two different TCRTs in this program, TSC-101 and TSC-100. They both work with the same mechanism of action. They target antigens that are present on the patient's blood cells, but not the donor's blood cells. The idea here is that when you undergo a transplant, the goal of the transplant is to replace the patient's blood cells with blood cells from the donor. Any relapse that could occur is coming from any residual patient-derived cells, either malignant cells or premalignant cells. As I said, we originally had two assets, one targeting an antigen called HA1, the other targeting an antigen called HA2. In some respects, they had overlapping patient populations. Ultimately, TSC-101, which targets the antigen HA2, really addresses pretty much any patient that we could have treated with TSC-100. Ninety-seven percent of patients that have the HLA type A0201 are HA2 positive. Just the asset TSC-101 enables us to address 97% of patients that have the HLA type A0201. That is the asset that we're moving forward. That is the TCR-T that we're taking into pivotal trials. Yeah, what did you show with TSC-101 in terms of reduced relapse rates last year? Yeah. Actually, I can speak to the updated data since the abstract came out for ASH earlier, last week on Monday. In our updated ASH abstract from this year, what we're showing now is that 82% of patients remain relapse-free treated with TSC-101 compared to 64% of patients on our control arm. We have a biological control arm in our phase I study. We're seeing a 50% reduction in relapse rates associated with patients treated with our product relative to transplant alone. We've also seen long and durable responses. Three patients that were treated initially are now past two years remaining relapse-free, and four additional patients are past one year. We're seeing long and durable responses with our product. Finally, we also note in the abstract that in one case, we had a patient this year that did undergo relapse. We then retreated that patient with TSC-101, and within a couple of weeks, that patient had a complete response. At the time, they had 10% blasts in their bone marrow, and within a couple of weeks, at their next bone marrow biopsy, had no detectable disease and remained in remission for the next five months. This is direct evidence that the product targets remaining residual patient cells, including malignant cells, as well as 50% reduction in relapse rates associated with the product. How should we think about other, I guess, possible surrogate endpoints for showing the activity of your product, such as MRD negativity? Yeah. There are two main assays that we use to track early response to our product. One is MRD tests. That is looking in bone marrow biopsies to see if there is any minimal residual disease. If there is no detectable disease, that patient has a much greater chance of being cured or remaining relapse-free than those that are MRD positive. What we have seen with our product so far is that every patient treated with TSC-101 has become MRD negative within their first follow-up biopsy at 60 days. The other assay that we use is what is called donor chimerism. The goal of a transplant is to remove all of the patient's blood cells and replace them with donor. If they have 100% donor chimerism, that means that all of their patient-derived cells have disappeared. There are no detectable patient cells. 100% of the cells are donor-derived. If they have mixed chimerism, there's still some detectable patient cells left. We track donor chimerism again with the goal of having 100% complete chimerism in the patients. With every patient that we've treated with TSC-101, we've seen conversion to complete donor chimerism, contrasting with the control arm in which we don't see that. OK. Great. On top of the ASH abstract that came out last week, you also updated some alignment with the FDA on the design of your pivotal study, specifically on the control arm. Could you walk through some of the key takeaways from that update? Yeah. We had a very productive meeting with the FDA, with our end of phase I meeting to plan for our pivotal trial. In that meeting, we presented to them a design for our pivotal trial. Previously, we had been talking to the FDA about using an external control arm for this trial, in which we would construct a control arm using patients in the CIBMTR registry. This is a database that includes all patients that undergo transplant in the U.S. As we came up to that meeting with the FDA, in working with our colleagues at CIBMTR, what we learned is that there are some challenges associated with an external control arm. In particular, we felt there was an underreporting of relapses in the control arm, which would obviously negatively impact our study. Going into the meeting with the FDA, we pivoted to a design that actually just directly mirrors our phase I clinical trial, in which we're using an internal control arm. Patients are assigned to the control arm based on their HLA type. If the patient is A0201 positive, they would qualify for TSC-101. Those go into the treatment arm. Any patient that's A0201 negative, or for which we can't find an appropriately mismatched donor, will go to the control arm. It is a biologically assigned control arm, but one in which we can directly monitor relapse rates and have central review of relapse in the study. It is a better controlled study that mirrors our phase I design. Okay. So with that guidance now in place, how are you thinking about the timing of the initiation of the pivotal study, possible timing for the primary endpoint readout, and sort of visibility into a filing? Yeah. So one other thing that came out of the meeting is we discussed a recommended dose range for our pivotal trial. The FDA recommended that we treat five additional patients at the high end of our recommended dose range prior to launching the pivotal study. We are currently enrolling patients to meet that obligation. With the timing of that, we anticipate launching the pivotal trial in Q2 of next year, which means we would have a top-line readout about 2 and a half later or end of 2028. We anticipate filing within six months of that. Mid-2029 would be when we anticipate filing on this. OK. There's also a few updates that you've implemented this year regarding the fixed dosing versus weight-based dosing, as well as an updated manufacturing process. Can you walk us through those findings and rationale that supported some of those changes? Yeah. As we prepared for the pivotal trial, one thing that we introduced this year is a fixed dosing schedule rather than weight-based dosing. Fixed dosing is much easier to implement in the commercial setting. That way, you fill bags with just the same number of cells for every patient. Our PK/PD data supported the use of fixed dosing. We introduced a fourth dose level with fixed dose, in which patients receive 0.8 billion cells at their first infusion and 1.6 billion cells at their second infusion. The other thing that we did is designed a commercial-ready manufacturing process. This manufacturing process is significantly less expensive than our early phase I process. More importantly, it also reduces the manufacturing time significantly. It takes us from a 17-day process down to a 12-day process. What we've learned in the field of CAR T therapy is that shorter manufacturing times lead to more persistent cells, cells that are better able to expand in vivo in the patient. We believe a potentially better product with a shortened manufacturing process. The other thing we observed this year, more learnings from our phase I study, is that in looking at the manufacturing from patients in our phase I study that either had complete remissions and stayed relapse-free versus those that had mixed donor chimerism or relapse, what we observed is that the patients that had the mixed chimerism or relapse, their T cells underwent higher levels of T cell expansion ex vivo during the manufacturing process than those that had complete donor chimerism and stayed relapse-free. Again, consistent with what we know in the field of engineered T cell manufacturing, in which more expansion ex vivo leads to more exhausted T cells, cells that are less able to persist in the patient long term. Our commercial-ready manufacturing process really addresses this issue as well. We see less need for ex vivo T cell expansion with our commercial-ready process. We're excited about treating patients now with this commercial-ready process. We filed an IND amendment to move to that process now. The additional patients that we're enrolling to meet that recommended dose range will also be treated using that commercial-ready manufacturing process. Okay. Then how do you think about the market opportunity for TSC-101 when considering the various qualifying characteristics, eligible patients based on donor types and conditioning regimens? Yeah. As I mentioned earlier, about 7,000-7,500 patients with AML or MDS get allotransplants every year. To qualify for our therapy, you would need to qualify for allotransplant with reduced intensity conditioning, which is about 60% of those transplants. In addition, to qualify for TSC-101, you need to have the HLA type A0201. In the United States, about 42% of people are A0201 positive. In Europe, it is about 47%. Looking at just the US market, this means that about 2,000 patients a year are addressable based on that label. The patients do have to be paired with a donor that is negative for that HLA type. We have observed about 80% success rate in identifying donors that are A0201 negative. A fairly large addressable patient population, around 2,000 in the US. At an anticipated pricing range that's consistent with what we've seen recently with products like Amtagvi or Tecelra, we anticipate this to be a greater than $1 billion addressable market opportunity in the US just with TSC-101. OK. Super. I wanted to spend a little bit of time on the non-heme opportunities, including the solid tumor. There was an update, as you mentioned, that you're pausing the current phase I study and pivoting towards a lentiviral-based in vivo T cell engineering approach. First of all, what were the factors that led to this decision, and why was this shift to the in vivo an attractive opportunity for you? Yeah. So there's really two things that drove this. One, in our phase I study, we've encountered many of the same challenges that other companies have encountered with respect to autologous T cell therapy for solid tumors, just challenges in terms of clinically, patients have to be able to undergo washout, apheresis, and then wait for a product that has a vein-to-vein time of about four weeks. A lot of those patients will clinically progress during that period, as well as the challenges in manufacturing when you're dealing with T cells from patients that have undergone multiple rounds of T cell toxic chemotherapy. One, I would say just the challenges of autologous T cell therapy in solid tumors is what drove this decision. More importantly, I would say it's really the opportunity to have an off-the-shelf product using this in vivo engineering platform. What we have seen recently is several companies develop in vivo engineering approaches for CAR T therapy. We have seen incredible clinical data, albeit with a relatively small number of patients at this stage. I think there has been a shift in the whole field of engineered T cell therapy towards in vivo approaches. We wanted to be ahead of the game and really go all in in developing an in vivo engineering platform, and then pivoting our entire ImmunoBank of therapeutic TCRs into this in vivo platform. All right. I believe you'll still be reporting some data from the ex vivo Plexi-T study next year. Any key takeaways that should help inform how the next-gen approach could work? Yeah. At this point, what we announced last week is that we've treated two patients with multiplex therapy, as well as seven additional patients at dose level three or higher, which is what we consider to be an efficacious dose of this product. We will report data from the phase I study in Q1 of next year. I think that data will be informative because it provides us with direct clinical evidence that the TCRTs that we're developing work in patients. It would be those same T cells, sorry, those same TCRs that we would move into the in vivo engineering platform. Really building off the momentum of the Plexi-T trial towards this in vivo engineering approach. Perfect. You earlier alluded to the potential for your platform in indications outside of oncology, such as autoimmune. Remind us of the ongoing activities in the space and why you think that your platform is well positioned there. Yeah. The core value of our discovery platform is this target identification technology. It is actually called TScan, which is where the name of the company comes from. It is essentially a high-throughput screen that enables us to figure out the target of any TCR in a single day. A single screen reveals what the target of these T cells are. There are a subset of autoimmune diseases that appear to be very much driven by T cells. I would say sort of the textbook example of that is ankylosing spondylitis, in which there is a very strong association with your HLA type. 95% of patients with AS have the HLA type B2705, so clearly a T cell-driven disease. What we have been doing is using our platform to isolate T cells from patients with T cell-driven autoimmune disease and then figure out what their T cells are recognizing. What that provides is a way to have a much more directed therapy for autoimmunity. Right now, the therapies in autoimmunity are relatively blunt tools. They basically tamp down the patient's immune system to relieve them of symptoms. That comes at the risk of increased infection and other risks associated with a compromised immune system. Whereas if you can take a target-directed approach and really just target the T cells or antibodies that are driving the disease, you have a much more directed way of treating autoimmunity. As mentioned earlier, we've recently used this platform and have discovered targets in basically five different diseases: ankylosing spondylitis, scleroderma, bird shot uveitis, and ulcerative colitis. Those are all internal programs at TScan. We've also been discovering targets in Crohn's disease, which we have a partnership with Amgen, which has been going on for a couple of years now. What's the possible timeline to the first IND we could see? We have not disclosed sort of a timeline on therapeutic programs with the autoimmunity. We are developing a platform internally to treat autoimmune disease based on the targets that we are identifying. Right now, our focus has been on really identifying targets, which we think is the most valuable aspect of our work in autoimmunity, to identify the targets. Just as an example, with ankylosing spondylitis, it has been decades where it has been an unsolved problem as to what the targets are. We believe we have identified the targets that actually drive origination of the disease, as well as the pathogenic targets that lead to the symptoms of the patient. All right. Perfect. Maybe just to wrap up, I think you just had earnings this morning. Can you remind us of your cash runway and review some of the major catalysts that you're expecting next year? Yeah. We announced last week, as well as strategic structuring of the program, we had a reduction in force. As a result of that, we've now extended our runway into the second half of 2027. The key milestones that we have coming up, obviously presenting data on our TSC-101 program in heme malignancies, the data should be presented at ASH this year. The other key milestone is launching our pivotal trial, which we anticipate in Q2 of next year. We are also going to present data on the solid tumor program in Q1 of next year. Finally, sorry, backtracking to the heme program, we also intend to file two additional INDs on the heme program. We are extending that program to other HLA types as well. TSC-101 targets just a single HLA type, which addresses about 42% of patients in the U.S. With the addition of three other TCRs for three additional HLA types, we can extend that to about 80% of patients in the U.S., about 80% of patients in Europe, and about 50% of patients in Asian countries. Overall, plan to really extend the heme program to address the vast majority of patients that are undergoing transplant with reduced intensity conditioning. All right. Super. With that, I think we'll wrap up. Thanks so much, Gavin, for joining us. Great. Thank you for having me.