Right. Well, thanks so much. Welcome back to the Citizens Life Sciences Conference. My name is Silvan Tuerkcan, and I cover precision medicines. Now it's my pleasure to host Terns Pharmaceuticals. I got with me Amy Burroughs, CEO. Thank you so much for joining us. We got Scott Harris, Chief Development Officer. Thank you so much. Good to be here. Maybe start off, people not so familiar with this story, can you just tell us or give us your thoughts on the company and specifically, 701 and CML? Sure. First of all, thank you so much, Silvan, to you and the Citizens team for having us today, for everyone who's in the room. We will be making forward-looking statements, and I would refer you to our filings and our website. Terns an exciting company. We were founded in 2017. We've discovered all of our own molecules, including TERN-701. We have a history of great development, and we are focused on precision oncology and focused on small molecule TERN-701 for chronic myeloid leukemia. We presented data in December that was really unprecedented, showing, you know, 2x-3 x the efficacy that we've seen with other agents and also a differentiated safety profile, which is very important in a chronic disease. We also don't have a food effect, which is important for people who may have to take a therapy every day, and there's a huge unmet need in chronic myeloid leukemia. Yeah. Can you maybe set the stage in, you know, you kind of did, but the unmet need in CML for TERN-701, which is, you know, next generation TKI here? Yeah, absolutely. On the efficacy front, no matter what line the patient is in, there are a substantial number of patients who do not get to the major molecular response rate. In the third line plus setting where we are currently studying TERN-701, it's actually a second-line plus trial, but most of our patients are third line plus. The best TKI out there has seen 25%, so 75% of patients do not respond and become refractory. There's also cytopenias, pancreatic toxicity. You know, one of the second generations causes a 30% rate of pleural effusion. That's why safety and tolerability is such a big unmet need. Maybe talking about the frontline here, when we talk to doctors, you know, it's either imatinib, but it seems like asciminib is making some inroads, also there. What's kinda like your explanation of why that's picking up and some of the benefits maybe newer molecules can bring to patients? Traditionally, you know, imatinib really changed CML. It's an amazing drug, and it changed CML from a fatal disease to a chronic disease, and that was all people had for a while, and it's a good drug. However, more than half of patients become refractory to imatinib, primarily due to efficacy. The second-generation TKIs were developed, which have better efficacy, but pretty meaningful safety trade-offs. As asciminib has come in, they've very quickly gotten 25% market share about in the frontline. We expect them to go to closer to 50%, taking share both from the second gen TKIs and from imatinib. Used to be even in the presence of generic imatinib, 2G-TKI's got about half the market. You know, today, a lot of that asciminib share does seem to be coming out of imatinib because you don't need to give them imatinib to have a safer drug. Asciminib was shown to be safer and more tolerable in the frontline than imatinib. To me, what's striking is obviously imatinib is generic, and then we've got a branded drug and that is still growing despite all that. There seems to be some real tangible benefits here. Maybe talking about the reason people switch. You mentioned progression, but are there. Is that the primary reason for switching or is there also some tolerability issues or some other dynamics that drive patients cycling through these different. Yeah Drugs? Particularly in the first and second generation agents, tolerability can be an equal driver of switching as safety and efficacy. Efficacy is also the interesting thing a lot of people, investors ask us is this primarily due to resistance mutations? Mm-hmm. It is not. It's many patients become refractory due to efficacy, particularly on imatinib. For 2G-TKI's, it's both efficacy and tolerability, but more often tolerability. Then for asciminib in the frontline trial, we see about equal efficacy and safety tolerability. Great. Maybe I want to go back to last year. At the end of last year, obviously, you had an abstract at ASH. The stock reacted positively. There was very exciting data in there. At ASH, in my opinion, you made a splash, and it got even significantly better. We got the whole profile. Can you just maybe walk us through some of the highlights and details around the data that you presented there? Sure. You know, I think that the headline number was a 75% MMR achievement. Mm-hmm At the go-forward doses of 320 mg and above. We also saw deep molecular response rates of over 30% in that same patient population. Something that is trending, you know, 2x to 3 x higher than what we've seen from asciminib in their phase I and phase III program in this similar population. In addition to that, the overall safety profile looks very clean. We've really yet to identify a safety signal. We're seeing low rates of cytopenias, which are commonly expected adverse events in this patient population. Importantly, differentiating it from asciminib, we have not seen any signal related to some of the known adverse events of asciminib such as hypertension or pancreatic toxicity. Overall, the profile that's emerging from the CARDINAL study really does look to be a best-in-disease profile. I'll say, Silvan, that one of the big questions investors had between the abstract and ASH was what's your response? Are you able to treat asciminib-refractory patients? Yeah. Because that's really a proxy for efficacy and having a better drug, and we're the only ones who've shown efficacy in asciminib-refractory patients. Also, I would say the deep molecular response rate that Scott mentioned, this is deep molecular response achievement, and it's important when looking at CML, there are overall or cumulative response rates, which means that includes patients who came into the study in deep molecular response and maintained it, but more important, can you deepen responses? We saw a 36% deep molecular response achievement rate. Right. You mentioned already the responses post asciminib but also post ponatinib. What's interesting about post-ponatinib? Ponatinib is reserved for late line therapy. Typically if you're seeing a patient that has already been on ponatinib and is refractory or has come off for tolerability reasons, these are extremely tough patients. Probably some of the toughest patients to treat. Seeing responses in these patients that are potentially, you know, third, fourth, fifth line patients is pretty impressive. Great. Maybe at this point, what can we infer about durability from this data set that we saw at ASH? I guess what I can say is that, in our study, patients that achieve MMR have not lost MMR. When we presented the data in December, we had a median follow-up of about 6.1 months. I think to date, the important aspect that we're looking at is the fact that patients that come into the study not in MMR that achieve an MMR are still maintaining those MMRs over time. Great. Then I think if I remember correctly during the presentation you also kind of emphasized these confidence intervals that you generated and what's the right way of thinking about that when comparing to asciminib data? Yeah. 95% confidence interval basically means that if when you look at you know you can look at the point estimate and that factors into to the confidence interval as well. When you look at comparing drugs the important aspect when we look at our data compared to asciminib is that the lower bound of our confidence interval does not overlap with the upper bound of the asciminib confidence intervals. What you can say with fairly high certainty is that these drugs do produce different numbers. Mm-hmm As far as response rates goes, and you can have confidence in the fact that these are accurate, and these will be reproducible. Investors are asking us all the time, you know, 75%, that's high, you know, is that going to degrade? You know, to Scott's point, when we were coming into this, really the bar was can you get more than 40%. Mm-hmm In this highly refractory patient population, as Scott said. You know, more than 1/3 were treated already with asciminib. It's quite impressive to have 40% or more. We don't know where it's going to end up. We've got an ongoing study, but we're confident that it's going to be somewhere between that 52 lower bound and that 90 upper bound. Yeah. No, I immediately focus, of course, as an Analyst on the lower bound, right? How bad can it possibly be? It's your job. You're trained for that. You're trained for that. But, but, uh- Yeah You know, it was remarkably high. Remarkably high. Even the lower bound of that confidence interval is still over 2x the response rates of asciminib. Yeah. It really gives us confidence that this is going to be a best-in-disease drug and, you know, asciminib did not show a statistically significant difference in efficacy from 2G-TKIs in the front line. We believe a lot of that's being driven by good efficacy, but its superior safety profile to 2G-TKIs, and we really have an opportunity here to demonstrate superior efficacy. Great. Maybe thinking about, you know, you're evaluating two doses, 320 mg and 500 mg going forward. What matters most in picking that dose? Would it be MMR rates, deeper molecular responses, maybe the dynamics of it? Like the safety profile? I think the answer is all of the above. You know, we mentioned in December of last year, when we did the ASH presentation, at that point in time, we'd enrolled over 85 patients in the study. Typically to satisfy the Project Optimus requirements with the FDA, you really want to have about 20 patients treated at each dose level with about six months of follow-up. We'd enrolled enough patients at that point in time, to ultimately generate the data, and it's really just waiting for the passage of time for those patients to get to six months. What you do is you will do a safety exposure safety analysis, and hopefully you see that there's no exposure-related increase in any sort of adverse event. You do an exposure efficacy analysis. You're not just looking at whether with one of the doses is the MMR achievement rate higher than the other? As you mentioned, we'll be looking at the kinetics of the responses. Is there one dose that produces faster responses? We'll also take all of the patients, even those that don't achieve MMR, and see if there's a difference in just categorical shifts of those patients. Even though they haven't reached an MMR yet, are their transcript levels still going down, and does that happen more frequently with one dose versus the other? Great. Then, maybe my last question on this data set. There was, you know, the 2x-3 x outperformance in response versus or MMR rates versus asciminib. This was in a later line patient population. What does that mean for, you know, a potential front line setting where you know, these patients are much healthier. Like Yeah. Would that go up? The rule of thumb is that a newly presenting frontline patients are easier to treat, and so you can expect that the MMR achievement rate in those patients will be higher. If you look at the historical precedent, for example, with asciminib, in a third line plus population, they showed a 25% MMR achievement rate. When they ultimately moved to the frontline setting, that number went from 25% up to about 67.5%. I don't think you can, you know. We're not gonna see 150. We're not gonna see a 150% response, but I think that we have high confidence seeing how these numbers translate from later line to frontline, that we can expect a pretty high MMR achievement rate in that frontline setting. I'll also say that people ask us frequently about going up against asciminib, and if you look at the data that continues to come out about asciminib in the frontline, they continue to show little separation between 2G-TKIs and asciminib on efficacy. There's another study called the ASC4START study. The pivotal was the ASC4FIRST study, where you see both 2G-TKIs and asciminib around 60%. Mm-hmm. If you think about sort of that confidence interval where they are with frontline, you know, we're already seeing more than that in third-line-plus patients, so that's what gives us confidence that we could really see strong frontline MMR. Right. Obviously with this data on hand, can you just kind of tell us how you view this fitting into the landscape? I think we, you know, we've covered some of the points, but also in terms of your development, late-stage development plans. Yeah. I'm gonna answer the first part of the question first and then let Scott answer the development plan. We really see this as a frontline drug. Mm-hmm. We see this as a drug that's really sort of for the first time in CML bringing, you know, best in disease on all three of these fronts that I mentioned, efficacy, safety, and lack of food effect. We see that when a branded allosteric is gonna be chosen in the frontline for the patient who wants the best drug, for a high-risk patient- Mm-hmm Particularly for a younger patient who may be on this TKI for decades, or a patient who's really looking for treatment-free remission, which is a functional cure in CML. If you can get fast and deep responses quickly in CML, there is a better chance of getting patients down to practically undetectable levels, so deep molecular response in CML and trying to take them off drug. For some patients today, sort of 15%-20% get that functional cure because their BCR-ABL levels don't come back. With a better drug, can we get more patients to that point? That would really be a dream. Yeah. As far as the development path, I think we have a number of important milestones ahead of us this year. We mentioned the dose selection, so we expect to have the data that we need to do the analysis to support either the 320 mg or 500 mg dose, take that to the FDA at an end-of-phase II meeting sometime midyear. At that meeting, we would get buy-in from the agency on what the design of our first registrational study would look like, and that would be a second line plus population, going up against a control arm that's a 2G-TKI. We'll also use that meeting as an opportunity to present the key aspects of our frontline study as well. Typically, a barrier to getting into a frontline study in an indication where there are already approved therapies is having an adequate safety database. I think, you know, you can see in the data we presented in December that the safety, overall safety profile of TERN-701 appears to be very clean. Our proposal would be that there shouldn't be, you know, really a barrier to launching a frontline study. We would aim to start that frontline study as quickly as possible after the second line plus study initiates. Great. They will be maybe separated by what would you estimate like? We've been saying within the 6- to 12-month range, but it could be quicker. Mm-hmm. Obviously it would run a little bit longer too in the frontline, right? Yeah, the typical time to enroll the study, they're about the same length of time to enroll, but obviously the endpoints are different. In the second line plus study, the accelerated approval endpoint is MMR achievement at 24 weeks. Mm-hmm. In the frontline setting, it's MMR achievement at 48 weeks. It's about 6 months longer. Great. This food effect thing, if you could just, you know, people always say that it rolls off the tongue very easily, but what does that mean for a patient having to fast? I think, you know, some of them are BID drugs, and now you don't have it. How many hours of fasting do you- Yeah Do away with that? Generally for a lot of drugs. Mm It's one hour before and two hours after eating. Mm-hmm. with BID, that's really challenging. If you look at studies, there was an ASH abstract. There's also a pretty good patient survey that's been published by Novartis that shows you that about 1/2 of patients say they really have trouble. Mm-hmm with the food effect. It could impact efficacy significantly. On asciminib, a lot of patients don't realize it, and Scott was just on a hike last week with the CML Foundation. There was a patient who didn't realize how important that is. Mm-hmm With asciminib, they see a 60% reduction in AUC. Patients struggle with that. They may not be fully informed about that, and more than half of them say that that would be a driver for them for switching. Mm-hmm. You presented data on drug-drug interactions or the absence of it. Mm-hmm. What are kind of the key interactions that some of the competition has that- Yeah. So they vary. Sometimes you have to switch people to different statins that they're already on. There are a number of other sort of, you know, these patients typically have a lot of comorbidities, and so they're on a lot of other medications. Having a limited drug-drug interaction profile is really important for patients, but also for physicians not having to scramble to try and find other drugs for these patients to take. Right. Then there's a few, let's call them third-generation active site inhibitors, in the works. At least in the clinic. Can you just comment about how those could fit into the treatment landscape and could they offer something as similar to 701 or not so much? Yeah. Technically third- generation's actually ponatinib. Oh. 'Cause ponatinib offers a significant efficacy advantage over the other drugs. It just has this safety profile. There are other active sites. Yeah. There's several active sites out there in development really looking to offer a better safety profile than ponatinib with comparable efficacy. You know, we think we talked a lot about the unmet need for CML up front, so I think there's a need particularly for these later line patients. Mm-hmm who may become refractory to an allosteric TKI to have better options. There's this mutant population as well. Do you have plans for that population? Do we have any data on them? We do. We've actually just recently added a mutation-specific cohort to the CARDINAL study. Right now it's about a 20-patient signal-seeking cohort. We open that up to patients that have T315I as well as a range of other mutations. Depending on what we see from that cohort, we could expand that and ultimately use the data generated from that in labeling discussions to get labeling related to specific mutations in the label. That's exactly what Novartis did with asciminib. Mm-hmm. You always study these patients separately. You wanna have them, we have them at our highest dose. Mm-hmm. Um, and- Ask about that. Yeah. Yeah. that's really what we see in our preclinical and our cell-based assays. You really see better coverage at 500 mg. We see better coverage. We presented this at EHA last year over many of the mutations versus asciminib. We should see good efficacy on the most common active site mutation T315I. Then in our data in December, you saw that we had an F317L patient who was on asciminib. Mm-hmm They went to double the dose of asciminib because they were progressing. That did not stop the progression. They then, as they were switching off asciminib, were identified with this mutation. They went on to the ENLIVEN trial. They also failed on the ENLIVEN trial. Then coming into the TERN-701 trial, we've gotten some questions about this. They were 100% mutated still for the F317L and had a very rapid response on TERN-701. As we're studying mutations, these other, you know, examples and signals that the preclinical data that we saw translates into clinical results. Mm-hmm. Asciminib has a much higher dose, if I remember correctly, in that mutant patient population. They're 400 mg. Yeah Specifically for the T315I. Yeah. For you chose- We're evaluating a broader range of mutations in our study. That's what explains the 500 mg dose. Yeah. The reason we didn't include a lot of these mutations in the randomized dose expansion, which is between 320 mg and 500 mg, is, although we have good coverage at 320 mg for many of these mutations, the possibility that a patient could get randomized to 320 mg instead of 500 mg not necessarily ethical, so that's why we created the separate cohort at the highest dose level, at 500 mg where we have better coverage amongst most of these mutations. Great. Yeah, maybe, you know, thinking about this year, what are some of the key updates, you know, you expect over the next 12 months? Or I guess it's not even that many more months left in this year, but. Mm-hmm Let's say over the next 12 months, what can we expect and what are the updates from the CARDINAL and what would you advise investors to really look for in the next update? I think obviously the most immediate step ahead of us is dose selection. To select that go forward dose into a registrational study. That key FDA interaction midyear where we'll get the buy-in on that dose, and the design of the first registrational study. Also launching that study. We expect to be able to launch that second line plus study sometime in the second half of this year, or early 2027. We'll also have another, you know, I would say substantial data update in the second half of this year from the CARDINAL study that would include, not only, you know, additional number of patients, longer duration of follow-up, but also the justification data that went into that dose selection. Mm-hmm. Great. Obviously we have the FDA interaction midyear and I'm sure I don't know if you'll educate The Street what the outcomes are, but, you know, the trial design, what are your thoughts obviously on the second-line setting? What will be the construction of the control arm? Also maybe thinking forward about the frontline, what would you use in that control arm? For the second line plus study, the comparator arm would be a physician's choice 2G-TKI. Mm-hmm. For the frontline study, we do have some optionality. We could run a study that's very similar to what Novartis did with ASC4FIRST, where we could have TERN-701 versus a control arm of imatinib or an investigator selected 2G-TKI. I'd say that based on the strength of the data that we are seeing emerge from the CARDINAL study, we are strongly leaning into adding asciminib into that arm as well. Mm-hmm. Where you would include asciminib is in the 2G-TKI strata. The reason you can do that is because in the ASC4FIRST study, although asciminib showed superiority to the overall group of imatinib in 2G-TKI, as far as efficacy goes, they did not show statistically significantly superior efficacy to the 2G-TKI strata alone. Mm-hmm. We haven't made a decision on that yet. We'd like to see head-to-head data with asciminib. If we don't elect to include it in the registrational study, we do have other mechanisms of generating that data, whether it be an investigator-sponsored trial or a meta-analysis type study. Mm-hmm. Of course, that would have huge implications, right, on the commercial aspect of things. Yes. Yeah, obviously you raised some money in conjunction with the, Some ... with the data. A little bit. Does that fund, you know, your late-stage development or how is your timeline? Actually, Silvan, we're in the rare position where this money gets us to commercialization and launch. Mm-hmm. Nice. of the second line plus. You know, we view that as putting us in a valuable position to really take this to market. We appreciate the investors who have supported us. Mm-hmm. Great. No, very enviable position and, yeah, great outlook and allows you to execute really. Well, thanks so much for joining us today. It's really a pleasure to host you. Thank you. Thanks. Thank you.