Good. Okay. Hi, everyone. My name is Maury Raycroft, one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome the Enliven team. We've got Sam Kintz, the CEO, and Ben Hohl, the CFO. Thanks so much for joining us today. Thanks for having us. Yes, thank you. We're going to do fireside chat format. Maybe for those who are new to this story, if you want to give a one-minute intro to EnLiven. Yeah, very briefly. We at EnLiven were developing an ATP-competitive, highly selective BCR-ABL inhibitor for the treatment of patients with chronic myeloid leukemia. It's an indication where there's been a long history of TKI use. It's changed the disease from once a very scary diagnosis to now we are able to effectively control the disease such that newly diagnosed patients with CML are expected to live as long as the age-matched general population, which has led to now, 20 years later, several new agents that are really aimed to differentiate based on tolerability, convenience, as well as efficacy. Truly a chronic condition, which leads to, I think, interesting new treatment goals. Got it. Yeah, it's a great intro. Maybe talk a little bit more about your mechanism and how it differentiates versus SCEMBLIX and TERN-701. Yeah, absolutely. I think mechanism, and when we talk about mechanism, it is both binding mode and where you bind on the fusion protein itself. I think it is really important in the context of a disease where you have got multiple TKIs that are used as the primary treatment option for patients with this disease. Unlike other cancers that have different chemotherapies, different mechanisms, different modalities, patients with CML really only are treated with BCR-ABL TKIs. When we founded the company in 2019, it was based on the hypothesis that early lines of therapy would be largely addressed by the introduction of novel allosteric TKIs. Novartis has a drug, asciminib, marketed as SCEMBLIX, which is highly effective for the treatment of CML. What is unique about that drug is it binds, as I mentioned, to the allosteric pocket, and that allows them to achieve great kinome selectivity. A lot of the pre-existing agents have been limited in their utility because of off-target kinase selectivity issues leading to suboptimal tolerability, which therefore impacts efficacy. Novartis was able to solve that issue with the allosteric TKI. We made the assumption at that point in time that this was going to change standard of care. Patients would see this allosteric mechanism earlier in their treatment journey. We had insights from the work we had done early in our career about how to make highly selective orthosteric or ATP-competitive inhibitors, which we would expect and now have confirmed would have great activity in patients that develop primary resistance to allosteric inhibitors. We sort of anticipated a future unmet need with the assumption that a lot of patients that had been turned over and began to initiate treatment on allosteric inhibitors would then unfortunately have resistance and become potentially a patient population we could address with 001. Got it. That makes sense. I think it provides a good backdrop as well. You also reported some data at EHI earlier this year in June, where you showed 32% achievement of MMR in heavily pretreated late-line patients. Maybe recap some of the key takes from the data and how the efficacy and safety compare and contrast versus SCEMBLIX in late-line CML. Yeah, absolutely. Yeah, we're thrilled with our early data. The data that continues to emerge looks even better than the data we have reported previously. It's, of course, hard to make cross-trial comparisons. For us, we wanted to see clear clinical evidence that we could be superior to our class of molecule, ATP-competitive molecules. Really benchmarking against SCEMBLIX or asciminib's phase I data to kind of give us that certainty because, of course, for those of you that don't know, that drug went on to show superiority, both in efficacy and tolerability to these prior-generation ATP-competitive inhibitors. The response rates we've shown and the subgroup analyses that we've broken out, frankly, look quite similar to SCEMBLIX, albeit in a heavier pretreated patient population. For context there, of our evaluable patients, over half of them had been previously treated with asciminib, and 70% of those were either refractory or resistant to asciminib. Again, very difficult-to-treat patient population. We also had a much higher prior TKI use of ponatinib, which is, at the time, the late-line drug. Again, more heavily pretreated patients. Even though these are early numbers, phase I study, treatment dynamics have changed. Our data held up really well with that context and continues to look really good. That gives us a ton of confidence as we move into phase III next year. Got it. One of the other allosteric drugs that we mentioned, TURN, they had some data that they reported recently in an ASH abstract. A lot of discussion around it right now, where they showed 64% achievement of MMR. What are your thoughts on the potential differences and similarities in patient enrollment and selection based on the available information? What are you looking out for in the full data set that they show at ASH? Yeah, absolutely. I think we were, frankly, surprised at how positive their data was, at least the top-line numbers, and impressed by that data. I think if we take the numbers at face value, we'll get into some of the nuances there and what could be driving differences. If we just take the data at face value, it could potentially represent a superior option to asciminib or SCEMBLIX. I personally believe, and physicians we speak to believe, that in order to compete for use with SCEMBLIX in the earlier lines of therapy, they will have to show a statistically significant superior MMR rate. Because remember, Novartis is, they're going to have a 15-year head start. They're already broadly approved. There's already 10 years of safety data. It was a pretty big hurdle to start to prescribe SCEMBLIX over imatinib, which had 25 years' worth of safety data, a drug that works very well. Remember, we're not going to see differences in overall survival across any of these TKIs, even the very first one that was approved. I think to see adoption of TERN's asset in earlier lines, great for patients if this holds up and they are able to show that superiority. I think in that case, 001 will be then the preferred use in the direct setting after that asset. Again, that's an allosteric mechanism more similar to SCEMBLIX, very, very similar in terms of the binding mode and the key chemical features of the molecule. We would expect resistance to look very, very similar. There are other allosteric inhibitors in the clinic, and those that have been evaluated using our preclinical tools, not ours, but the community's and through peer-reviewed publication, have 100% overlap in the resistance mechanisms. You are still going to need an ATP-competitive inhibitor following an allosteric. It does change the dynamic a little bit. Is 001 going to follow a summative, or is TERN's going to be able to effectively compete upfront? I think our position is that no matter what happens, because of our differentiated and different mechanism and binding mode, we are going to be able to address primary resistance, which we believe will be the main reason patients discontinue an allosteric in the real world. Got it. Yeah, what are your thoughts on tolerability to patients switching from an allosteric based on tolerability? Yeah, absolutely. I think tolerability has become, and tolerability to some extent falls under the bucket of quality of life, are extremely important treatment goals. It is very, very different now where, frankly, you are not going to see a difference, like I mentioned, in PFS OS. As long as you take your drug and can sustain that dose intensity, you are expected to live as long as a patient with CML, as long as the age-matched general population. That raises the bar on the level of discomfort you are willing to live with. Grade 1 nausea, diarrhea, rash, all of these can result in switching behavior. In the case for SCEMBLIX, it is a remarkably safe drug. There are not these off-target kinase-driven AEs that are resulting in treatment switch decisions. Like any small molecule, there are drug-related adverse events. Often those are associated with what I would characterize as off-target effects. In this case, for SCEMBLIX, I think a lot of it has to do with how the drug is metabolized, potential reactive metabolites leading to allergic reaction, maybe liver enzyme elevation, rash, et cetera. They are very, very infrequent and generally low grade, but they do result in switch decisions. In that case, there is not a fundamental change in the underlying biology. Those patients should potentially respond very well to another allosteric and may not have the same AEs. I think certainly in that case, I will note though that is a very small percentage of patients. I think there is this more broader ambiguous bucket of, well, what about just those patients that are suboptimally dosed in terms of their exposures? That is a lot harder to characterize. I will note that I believe, and I think there's evidence for that, a huge chunk of those are just uncharacterized resistance. We don't know the exact allosteric mutations or resistance mechanisms. You need to know what you're looking for in the patients that discontinued and sequence for that to see it. I think a lot of them are just not getting characterized. The other thing I'll mention is in the real world, outside of a clinical trial study, SCEMBLIX is approved at a higher dose, a much higher dose, including 10 x higher C trough concentrations at its 200 BID dose. It is approved at 80 or 40 BID. You can go higher. There are studies ongoing allowing patients to dose escalate. A couple of things I'll note from those studies is you don't see a dramatic increase in molecular response rates upon additional dose increases with SCEMBLIX. Is that really going to make a difference in terms of going earlier with a higher dose? Patients will have the option to dose escalate before they switch. I think that's just going to further drive a higher proportion of patients that switch due to primary resistance and therefore will necessitate switching to an ATP-competitive inhibitor. I'd also note that this is an area where it's completely unfolding now as we're living it. At ESH CML a couple of months ago, there's a presentation noting that there are 18 new emerging resistant mutations to asciminib and allosteric class. That bucket of mutations is going to continue to grow as we learn more and more about allosterics. Got it. That is going to be a key driver of growth for you guys as those resistance mutations get identified, those patients would eventually switch over to something different. Yeah. I think so. I think we already have strong data to support. Here is where preclinical translation has really mapped to clinical performance. In those patients that we have evaluated on our study that have had these allosteric mutations or mutations that disrupt the allosteric mutation, we have got extremely good performance. We have not had one that did not respond is another way to look at it. You would predict that based on our binding mode. We are actually more active against some of these activating mutations given the way we bind and preferentially bind to the BCR-ABL fusion protein. I do think it is going to be important. The other thing I'll mention is that it's not common broadly to sequence patients. When there's suspected primary resistance, the instinct is either to dose increase, which is often done if there's a safety margin, there's not a tolerability issue, or to switch class of drug. When you look at the NCCN guidelines, Ben just mentioned these contraindicated mutations, there's literally going to be a paragraph of mutations that confer resistance to the allosteric mechanism associated with SCEMBLIX. You're a local HemOnc, you've got a patient that's not responding or stopped responding to SCEMBLIX, you're going to look at the NCCN guidelines and see the same paragraph of contraindicated mutations for allosterics. Whether or not that patient could benefit from a higher dose, I don't think that's going to be the default behavior. You're going to go to the one that doesn't have the same overlapping list of mutations. I think, again, in the real world, it's going to be different than clinical study. You will see this behavior change and evolve as the community adjusts to these new treatment options. Yeah, makes sense. I'm kind of jumping around in our question list a little bit too. Along these lines, I guess, would you consider doing some sort of an exploratory combo study then, combining the two mechanisms? Would love to do that. I can't tell you how many times at conferences investigators have pulled our team and Novartis' team together. You guys need to do this. For those of you that are CML historians, that's actually what Novartis developed asciminib to do initially. It was to use it in combination with orthosteric or ATP-competitive inhibitors with the idea of potentially getting to treatment-free remission outcomes for patients. That would be kind of the next frontier from an efficacy standpoint, meaning real differences. If you can get to a point where you can stop therapy altogether, then you're not a cancer patient anymore. That would be the ultimate goal. I think preclinically, Novartis has done a lot of work, some pretty high-profile scientific publications. They've had really encouraging, interesting clinical data in combination. The issue historically has been, though, you're still kind of strapped with the baggage of the first- and second-generation ATP-competitive tolerability profile. That's not going away. It can only possibly get worse if you're adding something to it. That trade-off has never been worth it. If you're not going to, if this isn't going to make a difference in my survival outcome, why do I care about these higher molecular or deeper molecular response rates? Even if I could get off therapy, I'm not going to suffer through this treatment. They've sort of dropped that, and the monotherapy has looked really good. In theory, with 001, we've got a remarkable tolerability profile, very wide safety margin, not limited by off-target kinases. The same is true for SCEMBLIX and probably for TERN's as well. With any allosteric, 001 should combine. I think if we want to do something truly transformational, I said, go to a front line, and you could imagine doing a study where you've got asciminib or SCEMBLIX in one arm plus the combination in the other arm. That could potentially be game-changing for patients. Absolutely, it's something that we're highly interested in. We really focus on establishing our dose first and getting the second-line plus study going. That's going to be most important to get our second-line plus label, get onto the market so we can be an option for patients with CML that require an ATP-competitive inhibitor. We're absolutely going to be looking into combinations, and I think it could be really fun and interesting to do that. Maybe sometime next year, you'd be able to talk more about concrete plans there. I think definitely in terms of the plans, I would actually like to start to initiate studies. We'll need some cooperation on those studies unless we want to go pay for a really expensive drug. I suspect there's going to be an appetite to do combo. Okay. Interesting. I think that just generally kind of, if you take a step back, that just speaks to we're going after a complementary mechanism to allosterics. And allosteric versus allosteric, that's competitive. In our general position, we are very complementary too. I think that's just an important takeaway. Yeah. Yeah. Makes sense. Going back to TERN, just with the debate there around patients being different between your studies, I guess, can you just comment and compare and contrast on how those patients look versus your study versus SCEMBLIX's assembled study? Yeah. It's hard to compare to the randomized study. There are different contexts in there. You've got a randomization to bosutinib. Probably more appropriate to compare back to the phase I, but that was 10 years ago for SCEMBLIX. I will focus first just on comparing our patient population. These are trials that are largely enrolling in real time together. There has been a lot of overlap in terms of the investigators we're working with, speaking with, and even the sites we're operating in. I think the main most obvious difference is that on the TERN's phase I, there were fewer patients that had prior SCEMBLIX use and fewer patients that had prior ponatinib use. And pretty substantially different in terms of the relative percentage of those patients. Earlier in this talk, I mentioned how many of our patients that had prior SCEMBLIX were actually resistant to that drug. Those patients really represent our latest line patients. They had failed multiple. Most of those patients had been multiply resistant to all the pre-existing TKIs and therefore represent the most difficult-to-treat patient population. In fact, our response rate is incredibly low in that patient population, the multiply resistant patients. If you reduce the number of those patients in the denominator, you're going to have a significantly higher response rate. Those are driving it. The inclusion criteria were different. We started with a last-line inclusion criteria. It was a first-in-human study for us. TERN's had the benefit of filing their IND with safety data from their ongoing China study. They had a second-line plus inclusion criteria. That allowed for earlier line patients to be considered for that phase I study. At least initially, and I understand this has changed now, but they excluded patients that were previously resistant or refractory to asciminib. Right off the bat, I think it set the tone that, hey, this is an allosteric mechanism. We're not sure if it's going to be viable in patients that didn't work or had resistance to prior SCEMBLIX. I think there's a compounding effect too where, again, we're out at the same sites enrolling at the same time. There are physicians that understand what patients are expected to do well on an allosteric inhibitor and those that they don't expect or have already had a bad experience or resistance to an allosteric. You can imagine where are they going to funnel their patients? Those that had a difficult time or lost a response on an allosteric inhibitor are going to come to the new next-generation ATP-competitive inhibitor. Those that are maybe earlier in line, do not have access to SCEMBLIX, are going to go to the allosteric trial. I do think there are these things. It is a remarkably high response rate. I do not want to diminish that. I think that is incredibly encouraging, and they should pursue that to the fullest. I just think it is really difficult given these dynamics, the inclusion criteria, the fact that, again, there is sort of a natural bias in terms of what studies enroll, what types of patients, that make these studies really, really hard to compare. Frankly, our threshold is different. To believe in 001, you just need to believe that we are better than a second-gen TKI. If we take that's driven by safety margin and better target coverage, we can just use the summative assumptions because we're matching and exceeding that. I think to believe there's the opportunity to differentiate in efficacy to a summative, a very safe, well-tolerated allosteric inhibitor, you have to get something more. Where's that coming from? What's driving that? I just don't think we have enough data to understand that yet. Got it. You commented a little bit earlier about target coverage. Maybe just talk a little bit more about what's known there with the correlation between target coverage and MMR and what gives you confidence based on your data set that increased target coverage is unlikely to lead to greater efficacy. Yeah. So when you think about, so with respect to MMR, the mechanistic models that we've evaluated and looked at really focus on front line 48 MMR achievement rates. I think there, it's very, very hard to see a scenario where higher target coverage is going to lead to a higher proportion of patients achieving MMR by 48 weeks. I think that there's probably more potential for deeper molecular response rates at higher exposure, but that's not a regulatory endpoint. So we've been really focused on MMR achieve rates. In a later line setting, it's really hard to know. We can compare directly, and we have done so compared to asciminib. We have not compared directly to TERN-701, but no reason not to distrust. I believe their data and what they've said relative to that. Whether or not you can show based on these time-based milestones, molecular milestones, a statistically significant difference, I don't know. I mean, I think you'd have to believe that Novartis truly is suboptimally dosing patients, which means if you think of a sigmoidal exposure efficacy relationship, Novartis is somewhere in the middle of that curve, which I find hard to believe. They've got 10 years of data. They're able to dose higher. There's tons of data that's not published. They've been compassionate use programs at higher doses. They're allowing dose escalation on multiple studies. If there was some big difference that's just exposure-based, do you really think Novartis would leave themselves vulnerable to somebody beating them head-to-head on just a target coverage game when they have the safety margin? I kind of get stuck on first principles there. It doesn't mean it's not true, though. I think no one's done that direct comparison. It comes back to, okay, what efficacy is meaningful and what line of therapy are you going to do that? Again, I feel very confident that Novartis has proved clinically in randomized clinical studies that you can show superiority leveraging this target coverage difference to the pre-existing ATP-competitive inhibitors. I think going that step further to say, in a head-to-head study compared to SCEMBLIX, is there room with the regulatory endpoints we have today? I find it really hard to believe. I mean, Novartis has looked at that. You'd have to bet that Novartis isn't going to react to that and do a higher dose cohort maybe compared to a lower dose cohort. We'll see. We'll let the allosterics battle it out for that front line use. I think our main play there, we can get broadly indicated using the same trial designs that exist, something we're going to look at. I think there's the front line combo play, which is whether it's with TERN-701 or another allosteric or asciminib, I think it's a great thing to try for patients. I think they're also running the ASC2ESCALATE study, Novartis in the second line. I think it allows patients to dose escalate as they move through different time points in the trial. It has been hard to show that they have materially improved outcomes there. Right. Yeah. Makes sense. Yeah, we've talked a lot about data you've shown about TERN's. You guys are going to be starting this phase III study next year. Maybe provide an update on the latest there and what that study is going to look like. Yeah, absolutely. Our plan is to go to regulatory authorities with a second-line plus trial design. The proportion of patients in that second line will likely have a minimum and potentially a maximum we enroll. That will basically dictate how we power the study, how large it will be. We are looking at somewhere between 400-500 patients for that head-to-head study. We will need to have at least two main points of regulatory engagement. First, we have to define our dose and then go and talk about that trial design. We feel like we are in good shape operationally and timeline-wise to be in position to get that done and be enrolling patients next year on that study. Got it. You are planning on having another data update next year as well. I think you said either middle of next year or second half. Maybe just set some expectations for what that could look like. Yeah. I mean, we have the rest of our phase I to present on, the phase I B cohorts where I think we'd expect potentially even better data given it's enriched for higher exposures. We have not seen a difference in terms of efficacy across those randomized cohorts. That is also influencing my bias and beliefs that target coverage only gets you so far. I think just data there and larger patient numbers to show everything's holding up, safety profile continues to look good. We'll be able to share that update next year. We haven't picked the exact time. To some extent, it'll depend on when we have those regulatory engagements. Will you break out patients by line of therapy, like the second-line population? Yeah. I think we definitely, whether it's in this first update along the way, I think an ongoing story for our phase I will be, how does it look in earlier lines? I can tell you right now, it looks better in earlier lines of therapy. I think mostly that should just shore up even higher probability of technical success as we get into our phase III. Got it. You have talked about your pipeline in the past, provided some tidbits there. I guess, is there any new assets that could be disclosed in 2026? I hope so. Yeah. We've been working really hard on a couple of non-oncology indications. I have one that I'm particularly really excited about. We're holding that bar really high. If and when we announce it, it'll mean that we're going into the clinic. I do think it's possible next year. Got it. Okay. So we're out of time. Maybe in closing, Ben, if you just want to comment on cash position and runway. Yes. Our runway is into the first half of 2029, which, as we talked about that pivotal trial, hopefully should get us well through the top line data for that pivotal. We did that raise this year to make sure that that was the case. We ended last quarter with roughly $480 million of cash. Got it. Okay. Thanks, Sam. Thanks, Ben. Thanks so much. Really appreciate it.