Of what's going to happen in CML, given the great data from Scemblix, Novartis' fourth-generation allosteric inhibitor, and our assumption would be it would have ultimately come up into earlier lines of therapy. And as patients developed resistance to that allosteric mechanism, they would go back to an ATP- pocket inhibitor, which is known to work, treat CML very well, but there are problems with the old-generation ATP- pocket inhibitors, namely they're limited by their off-target kinase activity. So we sort of made this bet that treatment would change over the next 5 to 10 years and has done so today. And we had sort of the insights in how to make a selective activated form inhibitor, which we have now done and are developing for the treatment of chronic CML in late-line setting. Got it. Yeah, that's a great overview of 01. And you've reported some data earlier this year as well from your phase I-A study, and you're guiding to having a big data update next year as well. Maybe talk a little bit about the data that you reported and just expectations for the event next year. Yeah, certainly. We've had two, actually, data releases this year for the 001 program, both from the dose escalation portion of our phase I study, which is in late-line CML, actually for patients that have no remaining available TKIs known to be effective for their CML. So these are very heavily pretreated patients. And so far we've presented. Our goal has been, can we generate a data set that looks similar to what Novartis had generated in late-line CML and then ultimately in early-line CML with their allosteric mechanism, Scemblix, because that is known to have a wider safety margin to fully optimize target coverage to give not only the best efficacy but good tolerability. And those properties have led to significant differentiation compared to the approved five other approved ATP- pocket inhibitors, which, again, as I mentioned, are limited by their off-target safety profile. So going into this, we wanted to see if we could attain the same level of target coverage or inhibition, but at very well-tolerated safe doses, and then see late-line efficacy largely in line to Scemblix, which then was superior to those other ATP- pocket inhibitors. It's always difficult to compare phase I data sets, single-arm, open-label studies, but so far the results have been trending very, very well from a comparison standpoint and then always compare at least as good or favorable even to Scemblix in this late-line heavily pretreated patient population. Got it. Anything more you can say about comparing and contrasting just based on the patient baseline characteristics and you're seeing deepening of MMR response in patients who were in MMR at baseline, too? Maybe talk about the meaningfulness of that. Yeah, definitely, so all of our patients have seen at least two prior TKIs. The vast majority have seen far more than that. In fact, over 25% of our patients have had greater than or equal to five prior lines of therapy, and over 50% of our patients had had prior Scemblix. So this patient population has seen pretty much all the available therapies, as is indicated in the inclusion criteria for the study, and so in that setting, we know second-gen TKIs have pretty close to zero major molecular response rates. Scemblix, depending again on the baseline status of the patient and what they had previously, is more like 15%-30% response rate in terms of achieved MMRs. And then you have to take into account, as you mentioned, those patients that come in at baseline MMR, why did they come on your study and how did they perform? So there's lots of different features, and in our corporate deck, you'll see we break it out and try to make the fair comparison to the relevant benchmark. But so far across all those categories, I think we've been, I think it's our opinion that we're trending pretty significantly better than prior-generation ATP pocket inhibitors and in line with Scemblix, even though we have more heavily pretreated patients. Got it. And for the phase I-B that you're enrolling currently, can you talk about the baseline characteristics and how do those compare to the phase I-A patients with regard to prior number of treatments and proportion of late-line CML patients already in MMR as well? Yeah, so a couple of points there, and I think maybe I glossed over part of the question in terms of patients that entered the study in baseline MMR. So I'll get to that question. Remind me if I don't answer this. So we did have a number of patients, as did Novartis on the phase I study, that enrolled on the study already achieving a major molecular response, which I think just to kind of calibrate the audience here, major molecular response is used as a regulatory endpoint, primarily in front-line studies because there's a known benchmark with imatinib, but major molecular response is a relevant treatment goal in all lines of therapies because if, as a patient, you achieve and maintain major molecular response, you have a near 100% chance that CML will not kill you, right? So that's why CML is well-managed. The general population, sorry, for a newly diagnosed CML patient, you have the same life expectancy as the age-matched general population. That's what's so unique about this disease indication. So in our late-line setting, we've had a number of patients that had come in in baseline MMR. In our case, most of those patients had actually been resistant to their last prior TKI, which was either a Scemblix or Ponatinib, the most potent available TKIs. So as a late-line patient, if you lose even deeper than major molecular responses, so your BCR-ABL transcript levels start to come back up, even if you're in a deep response, if you've already been resistant to prior-generation, particularly second-generation TKIs, your next option is a bone marrow transplant. And that's the case for most of the patients that came in in baseline MMR. You don't wait for that transcript level to rise to the point where the disease state starts to change, you develop blasts, and then it becomes very, very urgent. And so for us, it's actually quite meaningful that we've been able to take these patients that lost response on a Scemblix or Ponatinib and then kept them in that major molecular response. In multiple cases, we've had deepening of responses. One of those patients actually was a patient that had developed deep response on Scemblix in a front-line setting, developed one of the key emergent resistant mutations, lost that response, was also resistant, meaning transcripts were not controlled with Ponatinib, came on our study over a year ago and is now in a complete molecular response, no detectable disease over a year later. So that's one maintained response, but that's obviously pretty transformational efficacy. It's important to sort of look at the patient-level details, which we do provide on the patients that come in in baseline MMR, but it does and can to some extent skew the cumulative MMR, which is why we also break out the percent of patients that had not been in major molecular response that then achieved that. That number is very comparable to the Scemblix phase I as well. In terms of where we're going with the phase I-b update, the patient population we're enrolling is very similar, late-line patients. We'll get more in each of these categories just as we expand and continue to enroll patients, which should make it easier to go back and continue making these comparisons with smaller subgroup analyses. We're not seeing anything too different in terms of the composition. I'm not exactly sure what proportion will be in MMR and not in MMR because we don't select based on that. We take any patient that meets our criteria for that study. Got it. Okay, and for the update next year, just based on the data that you showed in the phase I-A, I guess how are you setting expectations around what you could show in the phase I-B? Yeah, exactly. So our kind of key goal for next year is to obviously continue generating data that we can strengthen our view on and positioning for the molecule. But most importantly, it's to generate enough data to take to regulatory authorities to begin to map out our phase III study, which I think we'll probably talk about in a moment. So what we're guiding to is at least 60 to 100. We give that broad range because the lower end of that range, we hope to have very significant follow-up. By that, we mean kind of roughly six months or more. So actually, enrollment's going extremely well. We're on track to meet all those enrollment goals. And I think what will be most important is actually the safety and tolerability data from a regulatory standpoint. That's what's going to pretty much ungate how early of line patient can we enroll in our ultimate phase III is largely going to be safety-dependent because, again, as I mentioned, this is disease that you're not likely to die from anymore, so kind of do no harm. And from an efficacy standpoint, there's very little risk for patients. From a futility standpoint, we've already achieved all of that. So really what we're looking is just to continue to build out that safety tolerability profile, which so far has been probably the best attribute of 01. And then, of course, we want to look at efficacy and just sort of make sure we're trending in the same direction. But there's no sort of new efficacy goal we have. If the data looks similar, continue to evolve where we see patients staying on drug, same sort of ratios in terms of those achieving responses, those maintaining responses, getting good clinical benefit, we're going to be very, very happy. Got it. And I don't know how much more you could say on proportions, but for the post-Scemblix patients, is it going to be around 50% of the patients as well, or? Yeah, so far, if anything, it might be higher. It's hard to predict because kind of two things are happening. We're getting sort of the same patients, but investigators are quite excited about this profile. So we're also getting patients that are either younger, meaning they've had fewer prior therapies or have switched through those prior therapies faster. But we're also getting patients that are the patients that aren't responding to everything. When we've had that mix in our phase I, a lot of patients have seen Scemblix. I mean, it's an exciting drug option, as I'm sure you guys have watched. It's doing outstandingly well from its first launch standpoint. So we know a lot of patients are switching out of their therapies onto Scemblix, and then, of course, some of them have issues or resistance to Scemblix, so then they come onto our study. I think it's going to be similar, but it does seem like we're getting a lot of post-Scemblix patients. Got it. And you said for the initial patients, you'd have about six months follow-up. For earlier or for later patients that enrolled into the study, would you have about three months follow-up for them? Yeah. I mean, so you can look at so potentially. I mean, we haven't actually decided when in the year, but you could imagine it could be mid-year or later in the year, probably not an earlier update. I think that we'll likely have probably the lower end of that range at minimum to be able to do a six-month analysis, but as you guys know, many of our patients are staying on. We have a significant number of patients now out over a year, and so those will also be included in the analysis. Got it. Okay. And you mentioned a patient vignette, but in September, in your slide deck, you showed one patient in particular. It was the F359V patient. I don't know if that's the same patient or a different one versus what you just mentioned prior, but. Oh, that was a different patient, yeah. Different one. And so maybe talk about the F359V patient, the significance of that, and how much weight should investors give to this case example of what your drug could do? Yeah. So we included that in our corporate deck, and as we mentioned, that patient had an atypical transcript, so it wasn't evaluable for efficacy in the main presentation. But given that we had the treatment history for that patient and how they did on their prior TKIs from the investigator, we thought that was a nice case study to show. We've always assumed, or not assumed, predicted that we'd have similar activity in F359 patients as we achieve in patients with just the native wild-type fusion protein, BCR-ABL, based on our preclinical modeling. And that's really also leveraging what we know about Ponatinib and its activity, and to some extent, Scemblix and its activity in F359V patients. One challenge we've had in picking a dose for F359 on our current study is that all of the patients we've enrolled to date that have the F359V mutation have already had Ponatinib and Scemblix. And if you look at a Scemblix's response rate in Ponatinib pretreated patients, it's incredibly low. So their almost entire signal comes from Ponatinib naive patients. And we know doctors don't like to give Ponatinib at the high dose because it comes with enhanced cardiovascular risk, a significant safety risk. And even for patients with F359V, that's a big risk to take as long as you can manage the disease. And so what was nice about that with a patient that you're referencing is a very difficult patient, had already been resistant to Ponatinib and to Scemblix and a combination of Scemblix and Ponatinib, and we got a best-ever response. It's not an international scale, but it would be equivalent to something like an MR4 response in that patient. It's just a good indication that our drug is working the way we think it should work. In fact, based on that data and some other data, we'll likely continue to explore the dose we believe will be our dose for the naïve population in this because we think that could be a competitive advantage compared to Scemblix, which requires 10 times the dose, the dose exposure, I should say. Got it. And for F359 in particular, how many of those patients could you have in the update next year? And yeah, maybe talk more about that. Yeah, I'm not sure. So that's sort of on its own parallel path. We're going to continue to pursue it, and there's high interest. It's a relatively small patient population, maybe 5% of second-line plus. So we're much more interested in just going for the broader patient population. That's where the focus has been. That's the much more attractive market and frankly is going to be the more meaningful registrational path because we're going to generate head-to-head data. So I actually don't know. We are continuing to enroll F359V, but the more important part of the update is just the broader late-line setting, which will roll into our phase III trial design. And actually, the more interesting mutants are going to be those with the myristoyl pocket mutations because we believe that's going to be the larger patient population in the future with Scemblix coming up front. Got it. Makes sense. And I think that's a good segue into what next steps could look like for a registrational path. Maybe talk about how the phase I study is informing that and what that could look like. Yeah. So far, in terms of target coverage and late-line efficacy as measured by decline in BCR-ABL transcripts, the phase I data is already quite informative. And frankly, we'll be picking our dose based on PK and trying to align target coverage with what Novartis selected for Scemblix at its 80 milligram dose. Similar to Scemblix, 01 has a wide safety margin. We have not reached a maximum tolerated dose, and it's even well tolerated, very well tolerated at the highest dose exposures we've evaluated in patients. So we know we don't need that safety margin. We don't need to keep going up for optimal efficacy. And we can design our phase III study both in a late-line setting, leveraging ASCEMBL, which was Novartis' phase III study, and making assumptions about the magnitude of benefit on the major molecular response endpoint at 24 weeks for Scemblix for second-gen TKI. There's also some of that data in the ASC4FIRST study, which was Scemblix's or Novartis' front-line study for Scemblix versus both imatinib and the combined comparator arm, including second-gen TKIs, and in particular, the time-to-MMR advantage that Scemblix had over the second-gen TKIs. So we already have that information, and largely it's going to be a PK leveraging a mechanistic model. In fact, that's the briefing document we recently submitted to the FDA and have aligned on them from the beginning in terms of selecting our dose. So really with the regulatory authorities, the conversation will be what line of therapy can we begin our head-to-head study. We would like to do a comparative study, so a head-to-head study comparing 01 to imatinib and second-gen TKIs. How we stratify that will sort of depend on the line of therapy and those assumed efficacy, magnitude, and benefit assumptions we're making based on Scemblix, and we can be conservative in that estimate, of course, but we're not talking about a huge study. ASC4FIRST was only 400 patients. We will likely do this in a second-line or later study, and we're hoping to get a broader second-line label from that. I think the key question will be, are there going to be restrictions on what those patients had to have previously? We know many of them will have two, three, four priors, similar to ASCEMBL, which was the phase III study for, again, for Novartis, for Scemblix. But we are hoping to get at least some patients that have only had imatinib or a second-gen in the front-line setting because that will lead to a broader label, and we can, of course, promote on that. And that'll be key in designing our phase III study. So these are the questions we'll be asking the FDA, and I think a large part of it's going to just be dependent on safety and how much follow-up we have at the time of those conversations and when we want to start the phase III study. Got it. Can you say more about just timing for when you want to meet with FDA next about this? Yeah. There'll likely be multiple interactions, as I mentioned. Step one is aligning on dose. We'll use that as an opportunity to also start to ask questions about what dataset we can come back with to inform on that phase III study design, but our goal is by the end of next year to have a pretty clearly articulated plan we can disclose and start talking about whether or not we still need a little bit more data or time before we start that study. We'll be TBD, but we're hopeful we'll have pretty good clarity by the end of next year on both what the study will be and when we can start it, and hopefully, it would be shortly after that. Can you say, and it sounds like for primary endpoint, it would be 24 weeks MMR, is that right? And maybe talk about just how much confidence you have that that could be the endpoint. Yeah. I'm very confident that that will be the endpoint. I think the one question would be, do we get to include patients that have only had prior imatinib? I don't think that's a must-have. It's still a very broad patient population. If you include all patients that have had at least one non-imatinib, it would sort of be the alternative. Right now, the precedent is in that setting for an accelerated approval, 24-week endpoint of a major molecular response with full approval coming from that same study with 96-week follow-up. But the caveat is there might be just one sort of slice of patients that it's unclear. There hasn't been a study done, a randomized study done in that patient population before. Got it. And are there potential accelerated approval paths too that you can? Yeah. So that 24-week endpoint would be the accelerated. You mean single-arm? Single-arm, right. Yeah, so traditionally, in fact, all the other drugs, with the exception of Scemblix, had been approved on cytogenetic response at 48 weeks. Cytogenetic response on the international scale today is equivalent to BCR-ABL 1%. That's another important efficacy benchmark. Once we get enough patients at 48 weeks, we can start to compare MR2 or 1% to the prior precedent, and there's a pretty well-established precedent for second-gen TKIs in that setting. That's actually what ARIAD used or Takeda used for Ponatinib's broad approval in third-line plus. It was a single-arm design, but the second-gens were also approved on that endpoint as well. We're less interested in that because while it could lead to potentially a faster approval timeline, it wouldn't be that much faster. More importantly, what we want is the comparative data that we can promote on to second and first-gen TKIs, not just efficacy, but the safety comparison. That's going to be most important for use. As we've seen with Scemblix, and its tremendous launch, it had that comparative data they can promote on that, and it's what's leading to very rapid switching through to get to that better treatment option. Got it. All makes sense. And maybe briefly talk about Scemblix and with the run rate that they've had so far, $782 million in third-line plus CML. So what does that mean for your opportunity for 01 and what that could look like? Yeah. It's been great for us just as evidence that there is still an unmet need, despite the fact that none of these drugs have any difference in expected overall survival. So really, this has been driven by not giving up efficacy, but having better safety and tolerability. Of course, efficacy is important for those regulatory endpoints, but there's a pretty clear path and math equation to get there. So really, this is used and driven by that comparative data that proved tolerability, safety profile with better early efficacy as well. So that number that you just quoted, over 7, that's close to $730 million in annualized revenues coming from about 25% of third-line plus CML. They just two weeks ago got broad accelerated approval for any patient with CML, and that's without generating any true comparative superiority data to the main second-gen TKI. So it just, again, shows what can be done in this indication in a relatively short period of time and the acceptance of new agents. So we're really enthused by that, especially given that Scemblix now is approved for, again, front-line and any patient with CML will likely come up front. I think it really sets the stage for 01 to fill that gap. Again, we know that the existing drugs are suboptimal. Scemblix just proved that. And so far, 01 has at least as good of a profile as Scemblix moving forward in that late-line setting. So we're really excited about that and the potential to get to market and start getting that use. Got it. And so pretty much out of time, but maybe Ben, if you want to talk about cash runway and what that looks like. And then Sam, if you want to close. One other thing I'd just say about the Scemblix news that just came out is also that including the label, they also included time-to-MMR so they can promote on that. That's a key differentiating factor there. In their front-line trial, their time-to-MMR was 24 weeks versus the comparator arm of 36. So as we think about our potential endpoints, that's also a good feature that we hope to show.