Thank you for standing by, and welcome to the ELVN-001 Initial Proof of Concept Data and the Evolving CML Landscape event. Currently, all participants are in a listen-only mode. As a reminder, today's program will be recorded. After the speaker's presentation, there will be a question and answer session. If you have a question, please use the Ask a Question tab at the top right of the webcast player. Questions can be submitted at any time during the program. Now I'd like to turn the call over to Sam Kintz, Co-founder and CEO of Enliven Therapeutics. Please go ahead. Thank you all for joining us today. We are excited to share an update on our ELVN-001 program. We will begin with a brief introduction of the company and the speakers for today's presentation. We will then provide an overview of the evolving CML landscape and ELVN-001's preclinical profile. Next, we will review what clinical benefit in CML means, including efficacy and tolerability. Then we will provide an update on our ongoing 001 phase I-A trial and share initial proof of concept data. After that, we will have a discussion with leading CML investigator and key opinion leaders about today's treatment landscape, the remaining unmet need in CML, and impressions regarding the 001 phase I-A data. Finally, we will open it up to the broader audience for a live Q&A. Enliven is a clinical-stage precision oncology company led by an experienced leadership team, including the inventors of multiple approved cancer therapies. Our primary focus is pursuing well-validated biology with differentiated chemistry that we believe has the potential to address new and emerging unmet needs. We have two early clinical-stage parallel lead programs that are both targeting validated targets and aimed at large and attractive oncology markets. Thanks to our recent PIPE financing, we are well-capitalized through multiple clinical milestones, with runway into late 2026. Here is a snapshot of our pipeline. Both of our lead development programs have nearly completed their respective first-in-human phase I-A dose escalation trials. ELVN-001, which will be our main focus today, is a highly selective, active-site BCR::ABL1 kinase inhibitor with activity against multiple clinically relevant resistance mutations for the treatment of CML. ELVN-002 is a potent CNS-penetrant, selective, and irreversible HER2 and pan-HER2 mutant kinase inhibitor for the treatment of HER2-driven tumor types. Our ELVN-002 monotherapy dose escalation study in late-line patients with any HER2-altered cancer has progressed rapidly, and our next step is to establish proof of concept in combination therapy for HER2-positive cancers, particularly metastatic breast and colorectal cancer, which we believe represent the largest opportunities for this program. We recently initiated an additional phase I-A trial in pursuit of this opportunity, and we expect to share additional clinical data in 2025. Additionally, we believe our ongoing discovery efforts will continue to fuel our pipeline, and our current emphasis is on both novel approaches and targets. On today's call, for management, I am Sam Kintz, CEO and Co-founder of Enliven. With me is Helen Collins, our Chief Medical Officer, and Damiette Smit, our Vice President of Clinical Development. We are privileged to be joined today by leading CML investigators and key opinion leaders, Professors Fabian Lang and Michael Mauro. The treatment of chronic myeloid leukemia, or CML, represents one of the greatest success stories in precision medicine. In fact, since the first approval of Gleevec, or imatinib, over 20 years ago, the median overall survival for newly diagnosed patients with CML has not been reached. Despite the relatively low incidence of CML, it has become one of the largest TKI markets of all time, driven by the fact that these drugs have turned the disease into a chronic condition requiring up to decades of daily therapy. Accordingly, the treatment goals have evolved, with emphasis today on quality of life and better tolerability. Despite huge advances in the treatment of CML, a significant need remains. Nothing demonstrates the unmet need in CML more than the switching dynamics. Today, approximately one in five patients switch therapy in the first year, and 40% switch within the first five years. This has led to a growing third-line-plus patient population, and these patients have limited effective treatment options remaining. When you dive into the reasons why patients are switching, approximately 60%, combining intolerance and lack of an early molecular response, can be attributed to the fact that the current agents simply aren't good enough to meet today's treatment goals. This is not a surprise, given that most of the approved agents are older drugs, and several were originally designed to inhibit other kinases... With the exception of asciminib, or Tasigna, all of the approved agents are limited by their off-target kinase activity, which results in suboptimal tolerability, often requiring dose modifications, which in turn can impact efficacy. Burdensome administration requirements can also impact long-term adherence to the existing TKIs. For example, drug-drug interactions need to be navigated, as the average CML patient is on five different co-medications, and all of the approved TKIs have restrictions. Because of these issues, and due to the fact that CML patients require years of daily therapy, the CML market continues to support multiple BCR::ABL1 inhibitors. This table represents a snapshot of the current CML landscape. As you can see in the far right column, CML remains attractive from a commercial perspective. It is important to point out that the Q4 annualized revenue shown here was achieved seven years after imatinib became generic in 2016. Despite the known off-target liabilities of the second-generation TKIs, they have done very well commercially. Take bosutinib, for example. It was the fifth approved BCR::ABL1 TKI and was originally developed as a Src kinase inhibitor. Despite the enhanced rates of gastrointestinal and liver toxicity and having undifferentiated efficacy compared to the other second-gen agents, it still made over $700 million in annualized revenue. Finally, we are encouraged by the recent launch of asciminib, which we believe offers clinical evidence that a selective BCR::ABL1 inhibitor can achieve enhanced target coverage, leading to greater efficacy and better tolerability than prior generation agents. Asciminib's successful launch demonstrates the need for better agents in the CML treatment paradigm. Asciminib, or Tasigna, is Novartis's fourth-generation allosteric inhibitor, and it was approved in late 2021 for third-line plus CML. Already, it has had a phenomenal launch, with approximately $500 million of annualized sales coming from only an approximately 20% share of the third-line plus CML market. Importantly, Novartis announced positive top-line results from its frontline pivotal trial in January of this year. Despite its favorable profile, we believe an opportunity exists for ELVN-001. Notably, discontinuation rates are still high, with approximately 50% of patients discontinuing within two years. The primary reason patients discontinued asciminib was due to lack or loss of efficacy, and given that only approximately 1% of the patients had progressive disease, it is likely that nearly all of these patients were put back on prior-generation TKIs, consistent with the switching dynamics in CML I highlighted earlier. Before I dive into how ELVN-001 may address the limitations of asciminib, and more importantly, the unmet need in patients that switch off of asciminib, let's take a look at where we believe it will ultimately end up in the CML treatment paradigm. First, it is important to point out that unlike many other cancer indications in CML, the approved TKIs are used interchangeably across lines of therapy, depending on treatment goals and specific patient needs. As noted on the previous slide, asciminib has rapidly penetrated the third-line plus setting, capturing a 20% share, as depicted by the orange slice in the bottom pie chart, and earning approximately $500 million in annualized revenue. Looking at the figure on the left, you can see both the prevalent patient population, represented by the full horizontal bar, and the annual incident patient population by line of therapy, represented by the bolded portion of the respective bars. With the positive top-line results from its frontline trial announced earlier this year, we anticipate asciminib to be broadly used by patients with CML, thereby increasing its addressable patient population by nearly fourfold. Given that the frontline trial was designed to show a benefit in both efficacy and tolerability compared to both imatinib and second-gen agents, we believe asciminib has the potential to become the standard of care in early lines of therapy. Assuming asciminib does capture significant market share in the first and second line, we believe that ELVN-001 will be well-positioned to follow asciminib in the CML treatment paradigm, given its complementary mechanism of action as an ATP site active form inhibitor of BCR::ABL1. Importantly, as you can see by the figure on the left, which represents how Novartis is positioning asciminib relative to first and second-generation agents, there is an opportunity to differentiate from these ATP- pocket TKIs based on improved efficacy and tolerability across lines of therapy. As a highly selective inhibitor of BCR::ABL1, we believe ELVN-001 has the potential to achieve a similar profile as asciminib compared to the other approved agents. If ELVN-001 achieves this profile, as a base case, we believe we will be well-positioned to compete for the roughly 16,000 patients who switch therapy annually in the second-line plus setting. Finally, we believe there may also be an opportunity to compete directly with asciminib across lines of therapy based on differentiated efficacy, tolerability, or administration requirements. Building on my previous comments, ELVN-001 is a highly selective active site inhibitor of BCR::ABL1. It binds preferentially to the ATP binding site of the active conformation of ABL1 in a unique P-loop folded conformation, which we believe contributes to its excellent selectivity against the broader kinome. ELVN-001 is a potent inhibitor of native BCR::ABL1 and maintains broad activity against multiple clinically important mutations, including T315I, the most common resistance mutation, as well as those that confer resistance to asciminib. Finally, unlike all of the approved TKIs, ELVN-001 is not a substrate for the common drug efflux transporters, PGP and BCRP, which may play a role in resistance to TKIs in CML. As previously emphasized, ELVN-001's kinome selectivity is a key differentiating factor compared to the approved active site inhibitors. The bottom table on this slide highlights ELVN-001's exquisite selectivity in cells against several known off-target kinases associated with the approved second- and third-generation agents. And against a broad panel of 372 kinases, ELVN-001 was also highly selective for ABL1. Most importantly, this in vitro selectivity profile translated into an improved safety margin in non-human primates compared to approved active site TKIs. Before I explain the figure on the right, it is important to point out that in CML patients, there is a clear correlation between the target coverage achieved by the approved active site agents and efficacy. Looking at the figure on the left, the Y-axis shows target coverage as defined by the mean average drug concentration in patients, divided by the potency of the respective agent measured in head-to-head studies in the presence of 100% human serum, in order to take into account differences in plasma protein binding. The X-axis shows the major molecular response rate at 12 months, the regulatory endpoint for frontline pivotal trials in CML. As the figure shows, the second-gen TKIs all outperformed imatinib in their respective head-to-head phase III trials and performed similarly to one another based on cross-trial comparisons. Moving to the figure on the right, we show the same target coverage metric on the Y-axis, but this time compare the mean average drug exposure at the approved dose in cancer patients with the maximum tolerated dose in non-human primates. As you can see, the approved active site inhibitors achieve similar target coverage in humans and non-human primates. In contrast, ELVN-001 had a larger safety margin in non-human primates, which represents our best preclinical evidence that ELVN-001 could potentially achieve better target coverage in cancer patients at well-tolerated doses. We will come back to this analysis in the context of the ELVN-001 initial proof of concept phase I-A data later in this presentation. Finally, given the important role we believe asciminib will play in the future CML treatment paradigm, we evaluated ELVN-001's activity against the clinically emergent BCR::ABL1 mutations known to confer resistance to asciminib. As you can see in the table on the right, ELVN-001 maintains activity against all of the clinically emergent asciminib-resistant mutations. Also of note, ELVN-001's potency shift from native BCR::ABL1 to the T315I mutant is similar to that of ponatinib and is smaller compared to asciminib. We believe that this profile, coupled with the fact that ELVN-001 is not a substrate for common drug efflux transporters such as PGP and BCRP, could be favorable in a post-asciminib setting. The bar in CML is high, but we believe there remains ample opportunity to improve on existing therapies, and because our target product profile is both complementary to and competitive with asciminib, we believe that ELVN-001 could reach that bar. Later in the presentation, we will provide an update on our ongoing phase I-A trial in patients with CML who have exhausted all available therapies known to be effective for their CML. Looking ahead, we will seek to demonstrate the potential for improved efficacy, particularly compared to first and second-generation TKIs, and especially in a post-asciminib setting. We will also aim to build a large enough data set in late-line CML to support initiating an early-line head-to-head study, where we hope to show superiority to first and second-generation TKIs for a broad label in CML. With that, I would like to introduce Damiette Smit, our Vice President of Clinical Development, who will take us through a few slides explaining how efficacy is assessed in patients with CML and how TKI switching decisions are made. After that, Helen will take us through the phase I-A ELVN-001 proof of concept data. Thank you, Sam. My name is Damiette Smit, and I'm the Vice President of Clinical Development at Enliven Therapeutics. Before we go into the clinical data from our phase I trial, I wanna walk you through how clinical benefit is assessed in CML. Since CML is a hematological cancer, response assessment is done through blood or bone marrow evaluation. The standard endpoint for clinical trials and for regulatory approval in CML is molecular response. Molecular response is assessed by measuring the number of copies of the BCR::ABL1 transcript in the blood by qPCR, and I'll go over the details of this response assessment in the next slide. Hematologic response and cytogenetic response are less specific measures of response in CML and were standard clinical endpoints before qPCR testing was available. I will not go into details on these types of response, as these are not efficacy endpoints in the phase I-A portion of the ELVN-001 study presented today. So what are key molecular response milestones when assessing clinical benefit in CML? As I mentioned in the previous slide, molecular response is assessed by the level of BCR::ABL1 transcripts in the blood. This chart shows the transcript levels with their associated molecular response milestone. When MR3 is achieved within a certain time frame in first and second-line therapy, close to 100% CML-specific survival is predicted. MR3 is also called major molecular response and is the key efficacy endpoint across clinical trials in CML today. Achieving a deep molecular response of MR4 or better that is maintained for at least two years is recommended as a minimum benchmark to stop treatment. Some patients achieve a sustained treatment recent... remission, which is the ultimate goal for a patient. There's no standard definition of an acceptable response to third or later lines of treatment, but in general, there is consensus that MR1 is insufficient for optimal survival, even in the late-line setting. It generally takes time to achieve reduction in the levels of BCR::ABL1 transcripts, and some patients do not achieve a response until six months or even later after initiation of treatment. Therefore, a reduction in the transcript levels of at least one log is a meaningful indication of early efficacy. You heard earlier from Sam about how frequently patients switch TKIs in CML, and that switching generally happens due to either lack of efficacy or intolerance. Lack of efficacy is often used interchangeably with resistance or loss of efficacy in the context of CML, and the definition has evolved over time, such that this is now assessed by molecular parameters. There are standard recommendations for switching TKI for lack of efficacy in the first- and second-line settings. Switching is recommended after failure to meet specific molecular milestones at three, six, and 12 months, as this is associated with lower overall survival. Switching is also recommended for loss of an already achieved milestone or development of resistance mutations or high-risk chromosomal abnormalities. In a third- and later-line setting, however, there is no standard recommendation of when to switch treatments. This is because fewer treatment options are available to these patients. Therefore, treatment goals may change from trying to achieve the deepest response possible to trying to maintain stable BCR::ABL1 transcript levels. In addition to lack of efficacy, patients may switch their TKI due to intolerance. Intolerance is generally characterized as an inability to continue to take the TKI due to side effects that cannot be managed through dose reduction or treatment of symptoms. There are two main types of side effects that occur on TKI treatments. The first is hematologic, such as low blood cell counts, which occurs with all TKIs and is rarely the cause of treatment switching. The second type of side effect is non-hematologic, which is the most common reason to switch TKIs. Non-hematologic side effects can be high grade and may require immediate discontinuation of the TKI, or can be low grade, but chronic, and can affect quality of life. Tolerance to treatment is increasingly important, as therapy is often lifelong, and multiple TKI options are available. It's worth noting that you will not see the term progressive disease very often in CML, as this is an uncommon experience, and it's defined as transformation to blast crisis, which is similar to an acute leukemia. It's associated with a change in treatment paradigm, and when it does occur, prognosis is poor, with a median overall survival of less than 12 months. Overall, the treatment goal for patients includes achieving at least a major molecular response and maintaining that response, as well as achieving the best possible quality of life. So now that we've reviewed how clinical benefit is assessed in CML, let's quickly review the historical benchmarks before we dive into the ELVN-001 data. This slide shows the published phase I data from the two most recently approved TKIs for CML. On the left is asciminib, the most recently approved TKI in 2021, and on the right is bosutinib, a second-generation TKI approved in 2012. The data on this slide are the phase I published data for these two agents, and we are providing them as reference point for the ELVN-001 early phase I data. In the asciminib trial, you can see that the majority of patients had received three or more prior TKIs. In the bosutinib trial, all patients had received at least two prior TKIs, and only three patients received three or more prior TKIs. So at baseline, the patients on the asciminib trial were more heavily pretreated than the patients on the bosutinib trial. Despite the limitations of cross-trial, cross-trial comparisons, you can see that the MMR rate for bosutinib was 15% overall, with a median follow-up of about 28 months, whereas the MMR rate for asciminib was 37% by six months. Asciminib, despite a more heavily pretreated patient population and shorter follow-up, had a higher cumulative MMR. In both studies, patients with CML resistant to prior TKIs have lower MMR rates of 11% for asciminib and 6% for bosutinib. As you heard Sam say earlier, our belief is that asciminib will eventually be used in earlier lines of therapy, and so our base case positioning for ELVN-001 is compared to second-generation TKIs, like bosutinib... which will likely be used in a post-asciminib setting in the future treatment paradigm. So how can we put those phase I trial results into context of later phases of development? This slide shows efficacy of asciminib versus bosutinib assessed in a single randomized trial in the third or later line setting. The MMR rates were similar to those reported in the original phase I trials of these agents, with the MMR rate of asciminib approximately double the MMR rate of bosutinib. On the left side, you can see that for both asciminib and bosutinib, the MMR rate decreased if patients have more prior TKI. So that in the fifth line or later, asciminib had only a 16% MMR rate, and bosutinib had a 0% MMR rate. On the right, you can see the probability of MMR over time for patients on this trial. As you can see, the first responses occur at around eight weeks, and as time goes on, more responses occur, with a plateau after about a year. Due to the time it takes to achieve MMR, the regulatory endpoint for second line or later has been 24 weeks for accelerated approval and 96 weeks for full approval. Although efficacy at 24 weeks is regulatory endpoint, efficacy by 12 weeks provides an early indication of cumulative efficacy over time, which is why we'll be sharing the initial efficacy data by 12 weeks for ELVN-001 today. Helen Collins will now share the proof of concept data from the phase I-A portion of the ongoing clinical trial evaluating ELVN-001 in CML. Thank you, Damiette. My name is Helen Collins, and I'm the Chief Medical Officer at Enliven. It's my pleasure to present to you the initial data from the first-in-human phase I trial of Enliven-001 in patients with chronic myeloid leukemia. First, here's the design of the 001 phase I trial. The key eligibility criteria are a diagnosis of chronic phase CML, and the disease must have failed, or the patient be intolerant or not a candidate for available therapies which are known to be active against their CML. So the phase I trial can only enroll patients who are later line and are believed by their physician to have no other good treatment options. The trial design is a standard 3 + 3 dose escalation. The trial also allows up to 10 additional patients to be enrolled at dose levels where evidence of anti-CML activity or specific target concentration has been observed. As you saw from Sam's review of the preclinical data, due to the high specificity of ELVN-001 for the target ABL1, we expect to see a wide therapeutic window and likely will stop dose escalation before reaching a maximum tolerated dose. The phase I-A dose escalation will be followed by a phase I-B dose expansion, which you can see outlined on the bottom of the slide. We are planning to enroll two dose levels of 20 patients each to address regulatory requirements for dose optimization. A third phase I-B arm is planned to be dedicated to CML with T315I mutations. The primary endpoint is safety, and the key secondary endpoints are the pharmacokinetics, parameters, and the efficacy endpoint of molecular response. Recall from Damiette's presentation, molecular response is based on the BCR::ABL1 transcript level, which in our trial was measured at a central laboratory. A blood sample's drawn at baseline, and thereafter, every four weeks for six months, and then once every 12 weeks. The data being presented today is as of March eighteenth, at which time 27 patients had enrolled across dose levels of 10 mg to 120 mg once daily. As expected, no maximum tolerated dose has been identified. Right now, we are enrolling additional patients at 40, 80, and 120 mg, and the expectation is that before the end of Q2, we will initiate the two phase I-B expansion arms. The third T315I expansion arm will open in the future, as we wanna conduct additional exploration in this subgroup first. Here is the prior treatment information about the 27 patients who have enrolled in the trial so far. The pie chart on the left shows that patients who enrolled have been heavily pretreated. Overall, 70% of patients have CML that has failed to respond to treatment, or the patient was intolerant to three or more prior TKIs. On the right, you can see a little more detail about the types of prior TKIs. 70% have received ponatinib and/or asciminib, and 41% have received both. Importantly, a little over half have received prior asciminib. As expected, in such a heavily pretreated patient population, 100% have received a second or third-generation TKI. On the bottom right, the bar graph shows 67% of patients enrolled because of lack of efficacy to their prior TKI, and 26% enrolled due to being intolerant to their prior TKI. You may recall from Damiette's slide showing the asciminib phase I data, that patients who enroll due to a lack of efficacy are expected to have a lower response rate than patients who enroll due to intolerance. So the point of this bar chart is to show that 67% or two-thirds of the patients enrolled in this trial fall into a category which has historically had a lower MMR rate. Overall, the treatment status data tells us that consistent with the inclusion criteria, patients who enrolled in this trial were heavily pretreated and the majority enrolled due to lack of efficacy of their most recent therapy. Here is a graph showing you each patient who is enrolled, the dose they received, and how long they have been on treatment with ELVN-001. The median time on study has been 18 weeks, or approximately four months. 89% of patients remain on treatment. The protocol allowed patients at the lower dose levels to dose increase or stop and re-enroll at higher doses if certain criteria were met. The six patients with dose increases are shown by a change in the color of their bar. The two re-enrolled patients are shown by blue stars, and then the legend on the left side of the slide shows where they re-enrolled. Importantly, there's been no progressive disease, no dose reductions, and only three patients have permanently discontinued, two for adverse events at 10 and 20 milligrams, and one due to a major protocol deviation when it was realized after one dose, the patient had not stopped their prior TKI, so this patient was taken off study. In future slides, this patient is included in safety analyses but is excluded from efficacy analyses. Here is the same graph showing the patients who are evaluable for efficacy by 12 weeks. In the 16 patients who are evaluable, seven achieved or maintained MMR, resulting in an MMR rate of 43.8%. The patients who achieved or maintained MMR are noted in green text on the graph. As Damiette showed earlier, the asciminib phase I and III trials presented MMR as a cumulative event over time, so we are presenting the data the same way here. In addition to the seven patients who have achieved MMR, two more patients had a decrease in their transcript, enough to improve their molecular response level, although they have not achieved MMR by twelve weeks. They are also noted in green. The gray bars are patients who are not evaluable. Again, similar to how data was presented in the asciminib phase I trial, the two patients with atypical transcripts are not evaluable because the transcript level cannot be measured by the central lab, and the two patients with T315I mutant CML will be evaluated separately in the future. On this slide, we compare the early ELVN-001 results with the published historical phase I data from asciminib and bosutinib, which Damiette showed you earlier. We all know that there are limitations to the conclusions you can make when you compare data across trials conducted at different times and with different patient populations. Despite its limitations, this type of comparison is still the best way to determine if the early data from ELVN-001 is encouraging. The first two columns of this slide you've already seen, and now we've added the right column with the ELVN-001 data. Comparing the treatment status of patients across the trials, you can see that both for the asciminib and the ELVN-001 trials, approximately 70% of patients were treated with three or more TKIs. But ELVN-001 has 26% who are treated with five or more TKIs, compared with 8% for asciminib, and 56% of our patients on study had prior asciminib. So within the group of heavily pretreated patients, those enrolled in ELVN-001 were even more heavily pretreated than in the asciminib phase I trial. When we move to the bottom half of the slide, we see the cumulative MMR for the three agents: 37% for asciminib, 15% for bosutinib, and 44% for ELVN-001. Although there are fewer ELVN-001 patients, the ELVN-001 study is also at an earlier time point of only 12 weeks, and because MMR is an endpoint that's cumulative, the numerator only has the potential to increase further with time. Also included in this chart are MMR rates for three subgroups of patients. The first subgroup includes patients whose CML was resistant to their most recent TKI. Here we see the MMR for asciminib was 11%, for bosutinib, 6%, and for ELVN-001, 40%. As we've said previously, patients who switch TKIs due to CML resistance have historically had a lower MMR rate, so the early data for ELVN-001 is encouraging in this group. The second subgroup are those patients with CML who achieved MMR on study, and the third subgroup, those who maintained MMR. Finally, ELVN-001's cumulative MMR in post-asciminib patients was four out of nine. This is especially encouraging, assuming asciminib becomes a first-line option. The point is that across each of these categories, although the small patient numbers limit the strength of the conclusions, early ELVN-001 data appears favorable compared to the second-generation TKI bosutinib and similar to asciminib. So here we take a deeper dive into the efficacy data by showing you how each individual patient has responded to ELVN-001 by 12 weeks. This slide shows a shift table, which categorizes each of the 16 efficacy evaluable patients based on their baseline transcript level compared to their transcript level by 12 weeks. Along the top row are the CML molecular response categories the patient was in the baseline, and the left column is the molecular response category they're in by 12 weeks. The table is color-coded so that if a patient's transcript level increased enough to put them into a worse molecular response category, they would be in one of the yellow boxes. If the transcript level is stable, the patient remains in the same molecular response category, and they are indicated in the pale green boxes. And finally, if the transcript level decreased enough to put them into a better molecular category, then you'll see those patients indicated in the dark green boxes. What you want to see is as many patients as possible in green boxes and as few as possible in the yellow boxes. This shift table provides the opportunity to point out specific patient groups with potential clinical benefit that you don't capture if you just look at MMR rates on their own. I'd like to give you two examples of this. For the first example, if you look at the top row, you see two patients. One enrolled at MR4, improved by two levels to the best possible molecular response, there it is, MR5, and another patient who enrolled at MR3 and improved by three levels, also to MR5. If you had just looked at MMR rates, both of these patients fall into the category of maintain MMR. Let's put these two patients into context. Achieving MR5 is the ultimate goal for the first- and second-line setting, so to see this in heavily pretreated patients by only 12 weeks is highly encouraging. We will describe one of these patients in more detail at the end of this presentation. As a second example, on the bottom right, you see two patients in the dark green box who enroll with transcripts greater than 10% and by 12 weeks have improved to MR1. Again, if you just looked at MMR rates to evaluate success, both of these patients fall into the category of not achieving MMR by 12 weeks. But the MMR endpoint tells a terrible story. These are two patients whose transcript levels decreased, and if they continue to decline, given additional time, may eventually achieve MMR. Alternatively, depending on the patient's comorbidities and their response or intolerance to prior TKI therapies, achieving MMR 1 may be the optimal endpoint for these patients. We will also describe one of these patients in more detail at the end of the presentation. Overall, six out of 16 patients improved their MR category by at least one level. These patients are the ones that are indicated in the dark green boxes. Now we'll move on to safety and tolerability. To date, ELVN-001 has been well tolerated. We've not identified a maximum tolerated dose. There have been no dose reductions, no Grade 3 non-hematologic treatment-related adverse events, and no non-hematologic adverse events reported in greater than 11% of patients. Importantly, there's no obvious relationship between dose level and adverse events, and we will show you more detail on this in the next two slides. Two patients have discontinued due to adverse events: one patient at the first dose level of 10 milligrams had asymptomatic pancreatitis, and one patient at the second dose level of 20 milligrams had Grade 3/4 hematologic cytopenias. For both patients, the events occurred in the first 30 days on study. To summarize the hematologic adverse events, we've listed here all treatment emergent, regardless of relatedness. As you can see, four patients have reported a Grade 3 / 4 hematologic adverse event, all of which occurred within the first eight weeks of treatment. As stated on the previous slide, one patient, who had not tolerated prior TKIs due to hematologic toxicity, discontinued treatment due to cytopenias. There's been no dose reductions due to cytopenias. As Damiette noted in her background slide, Grade 3/4 hematologic toxicity is observed with all the CML TKIs, and when it occurs, has a reported median time to onset of six weeks, consistent with what we've seen so far. For non-hematologic adverse events, we have listed those that are treatment-related and reported in at least two patients. Elevated lipase is the most common adverse event reported, followed by two patients each with headache, hypertension, and nausea, all Grade 1 / 2 and with no clear dose association. Importantly, there's been no Grade 3 non-hematologic treatment-related adverse events and no effusions, edema, or cardiovascular adverse events, all of which are side effects that have been reported with some of the other TKIs. Based on this early data, the adverse events observed are consistent with the selective kinase profile of ELVN-001. In summary, presented today is the initial clinical data from the phase I-A portion of the ongoing phase I trial. Anti-CML activity has been observed in this late-line patient population with MMR rates of 44% by 12 weeks. With the caveats of small numbers of patients and the limitations of comparing historical data to present data, this MMR rate compares favorably to those rates observed in historical phase I trials, particularly with the second-generation drug bosutinib. ELVN-001 has been well-tolerated to date, and there have been no reported Grade 3 non-hematologic drug-related adverse events, and the hematologic adverse events are consistent with other TKIs. Next, we would like to show you more detail about three patients on the trial who have each been chosen to highlight an important point. We've selected case studies we believe highlight potential benefits of ELVN-001 that might not be obvious from the efficacy tables we showed earlier. And now I would like to have Dr. Lang, an investigator on the ELVN-001 trial, present one of his patients as a case study. Just here, one of the patients being treated on ELVN-001 at our center. She's a roughly 50-year-old lady who just went to multiple therapy like imatinib, nilotinib, dasatinib. She had a mixture of intolerance and resistance, which is quite typical. We even were capable to bring her on one of the asciminib trials, but even under asciminib, she lost response. And at that time point, we've been planning for her an allogeneic stem cell transplantation from her sibling, fully identical matched donor. Unfortunately, the donor got diagnosed with cancer, and therefore, allogeneic transplantation was not possible. So there, we switched to ponatinib, which worked out quite well. But over the years, the patient showed a pretty annoying worsening of polyneuropathy. She was, in the end, nearly unable to walk longer distances, and that was the point where we had to switch. Finally, we then switched to bosutinib, which showed no good efficacy, and in the end, we were pretty happy to bring the patient onto the trial. As you see down here, we see a quite good maintenance or deepening of response and keeping the patient in an MR4.5 to MR5 with a quiet, okay tolerance, right? On a whole, we can say that this patient was saved from allogeneic stem cell transplantation being indicated after multiple lines of treatment and loss of efficacy on asciminib. Now we are happy to stabilize her within the phase I trial into the 20 milligram QD cohort. This case perfectly shows how intolerance and resistance go hand in hand sometimes, and that you, even after multiple therapies, still have space and options for improvement, and that's what we reached in this patient finally. Thank you, Dr. Lang. This second case is a young patient with no relevant past medical history, who received five different prior TKIs, which were all discontinued, either due to lack of efficacy or GI or hematologic toxicity. The most recent four treatments, including asciminib, were stopped due to hematologic toxicity. This patient also enrolled at the 20 milligram dose, and the graph on the left shows this patient was not in any level of molecular response, with a baseline transcript of 71%. This patient was also not in a hematologic response at baseline. You can see the decline in the transcript level over time to where the patient has now achieved MR2. In the shift table we discussed earlier, this patient was categorized as being an MR1 because the endpoint was 12 weeks. Here you can see that given more time, the transcript level has continued to decrease, and now the patient is in MR2. They have also achieved a complete hematologic response. In terms of side effects, the patient has continued to have hematologic toxicity, varying from grade one to grade three, but it's not reached the point where they've had to either stop or decrease the dose of ELVN-001. As we mentioned earlier, this is an example of a patient who has not achieved MMR, but clearly has had a clinical benefit by achieving a complete hematologic response and a two-level improvement in their molecular response to an MR2. It's also important to point out that the historical asciminib phase I trial showed that patients like these, with transcript levels greater than 10% at baseline, are less likely to achieve MMR, and only 20% achieve MR2, like this patient. The last patient we'd like to present is one who developed a resistance mutation while on asciminib and is now responding to ELVN-001. While on first-line asciminib, this patient developed an A337T mutation, which is one of the mutations associated with resistance to asciminib. The patient was then treated with ponatinib, which was also stopped due to lack of efficacy, and then enrolled in the ELVN-001 trial. At the time of enrollment, the patient's transcript level was too low to detect any mutations by the central lab. Similar to the first patient presented, this patient was in MMR at the time of enrollment and has now achieved a deep molecular response on ELVN-001, fluctuating between MR4.5 and MR5. They tolerated ELVN-001 well, with the only side effect reported being a grade one rash, which resolved without any treatment or change in ELVN-001 dose in the first 28 days on study. So this patient's story is interesting because it shows an excellent response to ELVN-001 in CML that had become resistant to asciminib through a known myristoyl pocket resistance mutation. We also believe that this patient could be an example of an important subpopulation of patients in the future with an unmet need should asciminib become the standard of care in early-line CML. I will now pass it back to Sam Kintz to speak about the PK profile and target coverage. Thank you, Helen. In addition to the encouraging clinical data, we are excited about ELVN-001's PK profile. Notably, ELVN-001 demonstrated linear PK in both cancer patients and healthy volunteers, and both Cmax and AUC increased dose proportionally. As predicted, based on its preclinical profile, ELVN-001 has a low risk for drug-drug interactions, as it is not an inhibitor or substrate for the major CYP enzymes. As you can see in the figure on the right, even at the highest dose evaluated in cancer patients, there is no significant food effect on ELVN-001's PK. In summary, although preliminary, ELVN-001's PK profile supports once-daily dosing with flexible administration requirements. We believe this could be an advantage compared to other approved TKIs and could drive potential switching decisions and use, given that CML is a chronic condition, often requiring years of daily therapy. As you will recall from the target coverage analysis I described in the opening section of this presentation, there is a very good correlation between target coverage and frontline efficacy for the approved BCR::ABL1 TKIs, as shown by the figure on the left. Turning to the figure on the right, you will see that we use the same target coverage metric on the y-axis, but this time compared the approved first- and second-generation agents with ELVN-001's target coverage at three different doses. Given how important this analysis is for guiding our ultimate dose selection for ELVN-001, we have built a preliminary population PK model based on PK from 78 healthy volunteer subjects in order to facilitate this direct comparison to the approved TKIs. In this analysis, we used the mean average drug concentration values reported for the approved drugs in their respective U.S. product labels, which used similar pop PK simulations. As you can see, at the doses equal to and greater than 40 milligrams QD, 001 achieved superior target coverage compared to second-generation TKIs. We also did an analysis compared to asciminib, using a method similar to the method Novartis referenced in support of establishing asciminib's optimal dose for the broader CML patient population. Starting with the figure on the right, here we show target coverage using two different potency metrics. One, the 90% inhibitory concentration for STAT5, a robust pharmacodynamic marker for BCR::ABL1 inhibition, and two, the 50% anti-proliferation concentration or GI50. And in both cases, we adjust the potency values based on human plasma protein binding. As you can see, based on this analysis, 001 has roughly the same target coverage as asciminib at 80 milligrams QD. In the figure on the left, we have shown the target coverage analysis using pSTAT5 IC90 for all of the approved TKIs. As expected, the second-gen TKIs had better target coverage than imatinib, whereas asciminib and 001 achieved better target coverage than the second-generation TKIs. In summary, we believe that 001's superior target coverage compared to first and second-generation TKIs is the result of a wider therapeutic window than these agents. This hypothesis is supported by our early clinical proof of concept data presented earlier. Before we move into the Q&A portion of today's presentation, I'll provide a brief summary of what we've covered so far. As we discussed throughout this presentation, CML is a chronic condition, often requiring decades of daily therapy. Despite the emergence of generic options, the commercial market supports approximately $6 billion in sales from six approved BCR::ABL1 TKIs, which are used interchangeably across lines of therapy today. Although the treatment of CML has improved considerably over the past quarter-century, there is a clear need for better agents, demonstrated by the recent asciminib launch that is already generating $500 million in annualized sales, with only 20% penetration in the third-line plus setting. Based on recently announced positive frontline phase III data, asciminib is poised to deeply penetrate earlier lines of therapy. We believe an opportunity exists to become the preferred active site TKI option post asciminib, as well as to compete directly with asciminib based on differentiated efficacy, tolerability, and/or administration requirements across lines of therapy. As a highly selective active site, active form inhibitor of BCR::ABL1, ELVN-001 represents a complementary mechanism of action compared to asciminib. Based on initial phase I-A data, ELVN-001 achieved initial cumulative MMR rates in heavily pretreated patients, including post-asciminib patients, that are favorable when compared to historical phase I MMR rates from other TKIs. This is especially encouraging, given that the MMR rate presented for ELVN-001 was by 12 weeks of treatment, compared to the 24-week cumulative MMR rate referenced from asciminib's phase I trial. Notably, ELVN-001 has been well-tolerated, with no drug-related Grade 3 or greater and low incidence of Grade 1/ 2 non-hematologic toxicities. Additionally, ELVN-001 has a PK profile that supports once-daily dosing with flexible administration requirements. Importantly, given the correlation with early line efficacy, 001 achieved target coverage superior to second-gen TKIs and similar to asciminib at well-tolerated doses. Looking ahead, we plan to initiate the phase I-B portion of the ELVN-001 phase I trial in the second quarter of 2024. A key focus for us in the near term will be to continue enrolling as many patients as possible across lines of therapy. In 2025, we plan on sharing additional phase I data on approximately 60-100 patients with significant follow-up. We also intend on having initial regulatory interactions with the aim of gaining regulatory path clarity for the first ELVN-001 head-to-head pivotal trial by the end of 2025. This is an exciting time for Enliven, and we are looking forward to progressing both ELVN-001 and ELVN-002 through the next set of clinical milestones. With that, we will now move to the Q&A portion of the presentation. I'd now like to welcome Professor Mauro from Memorial Sloan Kettering Cancer Center and Dr. Lang from Goethe University Hospital in Germany, who are both investigators on our study... I'd like to ask you both questions about the CML landscape and your experience with Enliven and 001. What do you take into consideration when you choose the CML drug for a patient? So when I'm looking at a patient and trying to choose therapy for their CML, there's a number of different considerations. I mean, first and foremost, it's the disease biology, the disease requirements, and the appropriate choice based on guidelines and data and staging, et cetera. It obviously differs for an earlier line patient or newly diagnosed patient, versus a later line patient. Early line treatment or initial treatment, it's full disease assessment, risk stratification, assessment of comorbidities, and then discussion with the patient, and there's multiple treatment options. When you move into later lines of therapy, you have to focus more in on what the patient's prior exposure has been, what the disease biology now may demand, what therapies they've been exposed to previously, and what you think your best shot at getting them into a better remission is going to be. That's obviously a much more careful decision, and there may be less choices, and we certainly need more choices. Okay, so the next question is: do you think another CML treatment option is needed for patients with CML, and why? So if we look at all these compounds, TKIs, we have and we gained over the years, there's still lack of efficacy and tolerance in many patients. So we, we're pretty aware of that many patients do not reach the therapeutic goals, so there's still room left for drugs being more effective, especially if we take into account problems with mutational resistance in later line TKI patients. Apart from that, with the current available therapies, there are still, in every compound, problems regarding tolerance, and if we think about the fact that we are aiming for a long-term treatment in these patients, many, many years in some cases, we need drugs which are as tolerable as possible, and I think there's still room for more. What toxicities with existing TKIs for CML tend to concern you the most, and is that the same for physicians or patients and... or different? So our concern about toxicities from the doctor's point of view, most concerning, are always problems with irreversible damage, like, cardiovascular toxicity, a kidney injury or liver injury, for example. From patient's point of view, most concerning are toxicities and side effects that interfere with daily living, like constant diarrhea or heavy or difficult to treat rash. So there are clearly differences between patient and doctor's points of view regarding toxicities. Do you ever switch TKI treatments on a patient when they're already in MMR, and why? Patients who are doing rather well on TKI therapy, such as those in MMR or major molecular response, still may need a change in therapy. One clear example is a patient who's in MMR but can't achieve a deep molecular remission. You know, and if our goal is a cure, a functional cure, as it's defined, but really a cure means treatment-free remission, that's not enough. And MMR is a very, fairly safe response and limits, progression events and in many settings down to near zero, but that still may not be enough. And I think all patients deserve a chance at treatment-free remission. So though it is possible to switch a patient who's in MMR. The other would be adverse events. Clearly, any patient in any degree of response who's having significant adverse events or risk of serious adverse events, if there's an alternative therapy, I think that's a reasonable place to switch. How do you interpret efficacy in a patient who is already in MMR? Efficacy for patients already in MMR is, on the one hand, patient stays in MMR. It's as simple as that. You have to keep your remission level. MMR is also referred as MR3, and there are deeper response levels like MR4 and MR5, where you still have measurable BCR::ABL1, but you wanna see whether you come to a lower level. So efficacy means you keep your molecular response, and maybe you even deepen it. What is your overall treatment goal for patients with CML? So the overall treatment goal in CML is just to make the disease go away and stay away forever. So this is how you wanna go. But there are differences in the patients you are treating. So on the one hand, you got the younger patients, where you need a quite efficacious therapy to reach as deep as possible molecular response levels in order to treat the patient in a way that he's getting rid of any kind of therapy for the rest of his life, which we call TFR, treatment-free remission. So with a kind of efficacious treatment, you can gonna reach that. On the other hand, on the other hand of the spectrum, there are patients who are elderly patients, where you just wanna control the disease. You do not have a TFR attempt, and you have patients who have gone through different lines of TKI therapy, and there, the goals are different. There, the goals are to control and maintain the disease, to just keep it chronic without any kind of acceleration or blast crisis. In these patients, you just wanna maintain your BCR::ABL1 level below 1%, and then you're happy. Because then you know that there will be no progression in the further course of treatment if you keep that kind of response. How do you think the CML treatment paradigm will change over the next few years? So we've seen a sort of a wave of new information in CML and a wave of changes. I think we now know that asciminib is been tested and is showing promise in the front line. So that's been one of our asks, is can we develop a better front line therapy? We saw previous data with ponatinib, which was tempting, but too risky based on adverse events. I think the asciminib data may not have the same trouble, and we may have a better front line therapy without adverse event risk. We have generic drugs, which are becoming available increasingly. We know we have imatinib, we'll have dasatinib, and, you know, and we're trying to be practical about how we move patients through lines of therapy. So I think we're gonna see pivots in the front line therapy, and we're going to see maybe more scrutiny about how we sequence medications moving from allosteric or STAMP inhibitors versus ATP- competitive inhibitors. That being said, for years now, there's been a quest for a better ATP- competitive inhibitor, and I say better meaning one that has a lower adverse event profile or lower adverse event risk, but with preserved efficacy, and I think that's one of the biggest unmet needs. So I think there are many medications competing for that space, but I think some have particular promise, and I think that space should evolve as well. So we'll have better salvage. We'll have a ATP- competitive inhibitor with that, for example, we could use after a STAMP inhibitor or even before a STAMP inhibitor. I think we're very interested in how are we gonna use those two classes together. For what reason do patients discontinue asciminib in your experience? So in the patients we've treated, and we treated a lot as we took part in the early phase asciminib trials, there are, like with every CML treatment, the two distinct kind of problems. Either you get patients where you're running into an efficacy problem, where asciminib does not lead to maintaining or deepening response, or people even show progressive disease under asciminib, then you have to change. On the other hand, there are also patients who do not well tolerate asciminib. There are various kind of side effects, which on the long run, make it more difficult for patients to take asciminib, just, for example, people having musculoskeletal problems, for example, or other kind of side effects we are now getting more and more aware of. How relevant are the mutations emerging from asciminib? Oh, yeah, thank you for that question. They are pretty, pretty relevant. I mean, we are all very curious because, now we've changed with asciminib the way we attack BCR::ABL1 as we're just coming from another side, okay? And now we see some really, really new mutations, which show asciminib resistance, and it's super interesting to look at the patients being treated at first line. And what we know at the moment is that also some, asciminib resistance mutations also show resistance towards the other TKIs and the other way around. So yeah, they are pretty relevant, and we are still learning how to deal with them. Could you comment on the safety of ELVN-001 to date? So regarding safety and tolerability, in this early phase I trial, we've seen a quite good tolerance, and safety. Patients tend to show side effects which are quite common in CML treatment, and at least to my knowledge, we've not observed any kind of higher grade or severe side effects yet. And we are pretty curious about the side effect profile in the further patients to come and in the longer run of the trial. Thanks, Dr. Lang. Dr. Mauro, what are your thoughts? ELVN-001 has preclinical data, which suggests that it could be the solution to what we might have been looking for, which would be a drug that might have a better safety profile, but the potency and specificity of, you know, essentially our best active site or ATP-competitive inhibitor. I'm very impressed with what I've seen, really. We don't have that much data, but we have, I think, a pretty good cohort of patients who have been treated for a reasonable length of time, some more, some less. Toxicities with these drugs do generally emerge early. That's been a pattern we've seen in all of our trials, starting with imatinib, and I think the toxicity profile is extremely good. We have to remember that the type of patients in, you know, in the current year, 2023, 2024, being put on these trials have generally had very extensive TKI exposure. They're also fairly, you know, more carefully scrutinized for adverse effects, including cardiovascular and metabolic disease. So, you know, under brighter lights, with a tougher crowd, I think the Enliven compound has been performing well when it comes to safety, and that's very important for what it's trying to achieve in this space. Could you comment specifically on the non-hematologic side effects that you've observed to date for ELVN-001? My personal experience has been miraculous with ELVN-001. I haven't seen directly my patients with non-hematologic toxicity. It's been extremely well-tolerated. I think the trial experience is showing us a very modest degree of non-hem toxicity. I think, you know, the questions we're going to have are, do we see the same intolerances we see with other TKIs, such as liver enzyme elevations, pancreas toxicity, et cetera? And as mentioned earlier, I think some of the longer-term questions are gonna be, are we seeing concerns in the cardiovascular and metabolic space? But my knowledge and my experience has been very very good. ... Could you elaborate a little bit more on your patient that actually discontinued treatment, who had an elevated lipase as well as an asymptomatic pancreatitis? We had one patient at the 10-milligram dose level, who had to stop ELVN-001 as he developed an asymptomatic pancreatitis and lipase elevation. We are pretty curious about lipase elevation and pancreatitis interaction generally in CML treatment, as we are aware that all the TKIs somehow influence the pancreas, and we know that some TKIs tend to have pancreatitis as a distinct side effect. We have not seen this in any other patient yet. Our patient suffered from this. He recovered completely. He went through an allogeneic stem cell transplantation without any kind of pancreatic problems. I saw him last week, and he's still working again, and he's fine. So we are not 100% sure whether this is an ELVN-001 specific problem, like it's the case in asciminib, where we have good data from the phase I, where we've seen that lipase elevation and asymptomatic pancreatitis is a problem. But I think we have to keep an eye on this, but from one patient, I would not draw the conclusion yet that we have a specific side effect for this compound. Thanks, Dr. Lang. Dr. Mauro, can you also comment? Lipase elevation is definitely an interesting adverse event in CML. I believe we have not cracked the code on why ABL kinase inhibitors cause what I would call hyperlipasemia, which is often not associated with symptoms or pancreas inflammation, but can be worrisome for pancreatitis. I study lipase levels in all TKI patients personally, and I see it elevated on all TKIs across the full spectrum. So I'm not surprised that ELVN-001 has some lipase elevation. I think it may be intrinsic to BCR::ABL1 inhibitors. There may be some off-target effects and a link that we haven't sorted. I'd like to emphasize that, maybe because I think about it too much, 'cause I'm drawing it all the time, and I have all this data, I think it's reassuring that it's often just a biochemical abnormality, and hyperlipemia, as I'm reminded by my GI and surgical colleagues, not pancreatitis. It can be, and we, you know, we've seen cases, including one where pancreatitis is possible, but I think we have to separate the risks and acknowledge that it's probably a class effect. As you know, we had a patient that discontinued ELVN-001 due to low blood cell counts. In your experience, do you see this often, and how clinically significant is it? Myelosuppression on TKIs, especially later-line TKIs, is really common. You know, a patient who's had several, several lines of therapy may not be in good response, may often have more limited normal hematopoiesis. They may one of their, one of the intolerances, which is very sort of specific in this scenario, would be an inability to fully treat the CML because of recurrent myelosuppression. And I think seeing a patient on study with myelosuppression that was limiting, I think, represents a case like that, where the CML biology is such that normal hematopoiesis may be challenging to recover, and any time you're treating, you may experience limiting myelosuppression. I always quote myelosuppression as part of disease response and, you know, in a more limited way, early in the course, it can be limited and transient, and later in the course, it can be persistent and sometimes permanent. Thanks, Dr. Mauro. Dr. Lang, what are your thoughts? So interference with hematopoiesis is quite common in every kind of CML treatment. Typically, you see this in the beginning, and we observe this with all TKIs, including asciminib. The question is always: Do you see a real toxicity, or do we see a first sign of efficacy with a reconstitution of the non-BCR::ABL1-driven hematopoiesis? So there are two situations. You got the first-line patients, who's getting pancytopenic during a starting treatment, and then you recover, where you just keep on giving the drug, not being in a clinical trial, so in real life. And there are patients who have a controlled CML but show constant cytopenias, as the normal hematopoiesis does not tolerate well any kind of treatment. I think the patient being treated in this trial is one of these, presumably, patients who has gone through several lines and showing cytopenias with every compound. The only treatment where you can save these patients is that you go for an allogeneic stem cell transplantation. Given this as a fact, it's quite important and interesting to see how ELVN-001 will perform in these highly pretreated patients. What are your thoughts on the efficacy data to date with ELVN-001? So with a pretty good snapshot of patients, you know, over a reasonable amount of time, I think we're seeing some very promising early glimpses of efficacy for the Enliven compound. And I think it's important to focus on what, what our goals are. You know, it might not just be getting patients with very high levels of disease burden into deep remission. That's, of course, the ultimate goal, but that can be a, a longer journey and take larger numbers of patients to see. One of the things I say to my patients is, who are on a trial like this, is if we've stopped your previous therapy, and it's three to six months into a new therapy, and you're in a very similar response category, which may not necessarily be a risky one, maybe you're in a cytogenetic or a partial molecular response. That's tremendous. That means the drug that we've brought in is doing at least as well as we were doing before. And in the scenario where toxicity has been relieved or risk has been relieved, that's a win. So a patient with stable disease with safer levels of residual disease can clearly continue, and I see that as a win. Patients who already have a relatively deep response and then can gain a deeper remission from there, of course, that would be very good to see. Some of the bigger challenges would be, you know, getting, again, high transcript level patients into safe harbor levels of remission, as we call them, you know, into MMR. I think we're starting to see that as well. Those, again, can take some more time, and we may need to study more patients to understand the likelihood of that. But the utility of stable disease and improvements of all kinds, I call them... You know, we coined the term categorical improvement, moving a patient from some cytogenetic response to full cytogenetic response, from cytogenetic response to partial molecular or major molecular response, and from major molecular response to deeper molecular response. Those all count. They're all worthwhile. And again, under most circumstances, if patients on a trial like this had stopped their previous therapy, and then ELVN-001 wasn't, sort of, filling the gap or exceeding the prior therapy, those patients would be relapsing. Can you comment on your experience with ELVN-001 to date? So, our experience is quite good, as we've seen these typical pre-treated phase I CML patients, and, we see that we have a quite good tolerated drug, who even shows efficacy in some patients. So on a whole, the first experience or the early experience with this compound is quite good. Hey. Thank you, Damiette, Dr. Lang, and Dr. Mauro. We will now move to the live Q&A session of this presentation. I will moderate the session by reading and assigning the questions as they come in, including those that we've already received throughout the presentation, so thank you for submitting those. If we don't get to your question today, we would be more than happy to schedule time for a follow-up meeting. First question, Damiette, I will direct to you, and it's more of a clarification, technical question. For the six patients that had intra-dose escalation, can you describe the protocol requirements? You know, what went into that decision? And did the dose increases contribute to efficacy, or on the flip side, tolerability? And a sub-question for that is, for the two patients with T315I mutations, can you confirm what dose those patients started at, and if dose escalation has occurred? Thanks, Sam. So yeah, absolutely. So for the intra-subject dose escalation, generally, this was allowed if patients did not meet certain criteria for response. So this could be no decrease in transcript by 12 weeks or could be an increase in transcripts. So generally, these patients didn't meet the requirement for... I mean, they didn't meet a decrease in transcript. At this time, it's too early to tell if the increase had an effect on their efficacy, but overall, patients have been tolerating ELVN-001 very well, including patients who had the intra-subject dose escalation. And then for the patients with the T315I mutation, so both the patients were originally enrolled at 40 mg, and one was then re-enrolled to 120 mg, and one was dose increased to 80 mg quite recently. At this time, we can't comment on the efficacy of patients with T315I. And I'll just chime in because, you know, T315I activity is at least a preclinical feature of the ELVN-001 design. Both these two patients that we've enrolled, both have been resistant to both ponatinib and to asciminib. And we know from this, the asciminib phase I study, it was a relatively small subset of patients that were resistant to ponatinib. But in those patients, by six months, asciminib had a 0% major molecular response rate. So these are very, very difficult to treat patients, and in our case, these patients were resistant to both ponatinib and to asciminib. So we don't believe we've really had an opportunity to test the clinical hypothesis around T315I for ELVN-001. It is something we're really interested to do. It's still a relatively rare patient population, but we're hopeful that, you know, over the course of the next year, we will continue to enroll patients, and hopefully, some patients with sort of de novo T315I mutations that haven't, you know, already developed resistance to ponatinib in particular. Based on our preclinical profile, we expect our activity in T315I to be comparable to the dose we take forward in the native patient population. And that's just based on both the clinical and preclinical modeling for both Scemblix or asciminib and ponatinib. But we haven't tested that yet, and that will be one of the things we're looking at throughout the course of the next year. Okay, so moving- Oh, Sam, could I. I just wanted to add one thing because I did wanna make sure that it was clear that the reason the trial allowed the intra-subject dose escalation was because we knew we were starting at very low doses, and we knew that these were late-line patients, and so we really wanted to give them that opportunity. But as Damiette pointed out, they could not dose increase before 12 weeks, unless they were getting worse, and none of these patients were getting a lot worse. So when you look at our MMR rate by 12 weeks, you are seeing a reflection of the initial dose level. So, I just wanna make sure that was really clear. Thank you, Helen. That's a good point. Okay, question for our investigator, key opinion leaders. For this question, maybe Dr. Mauro, I'll start with you, and then Dr. Lang, you can also comment. But this is a bigger picture question on how clinical practice might change once Scemblix is approved in the frontline setting, and how ELVN-001 might fit into that future treatment paradigm, with respect to Scemblix, potentially in an earlier line setting. And if you could comment on that, I think that would be really helpful for our audience. Sure, Sam. So, you know, if we take a look back for a second, what we have is a complicated frontline landscape now. You know, U.S., we have four approved drugs. You have the prototypical TKI imatinib and three second-generation drugs. You have one available in generic and a second soon to be available in generic form. So patients, providers make decisions based on disease and guidelines, and we generally prefer second-generation inhibitors, you know, that are more potent, for higher-risk patients, younger patients. We still use imatinib quite extensively, though, 'cause it's got this good safety track record, and it's still efficacious. The introduction of asciminib, you know, will come at a time when we might have a robust discussion about cost and efficacy. I think the data's encouraging, and we're always looking for best frontline therapy. So assuming asciminib is approved in the frontline, you know, if you ask me, I would use asciminib in as many patients as possible because it's got a good safety profile, and it may offer benefits over all therapies based on the preliminary data we're seeing. I don't know if I'll be allowed to do that based on payers' restrictions and the cost, but we'll have to see. And of course, you know, I have to... We have to think of the global, or the, you know, the big picture financially if we have multiple generics. And, but importantly, we have questions about active site inhibitors and myristoyl inhibitors and sequencing. So we definitely need our best-case active site ATP-competitive inhibitor, and there are very good candidates in the current and approved frontline setting. You know, I think dasatinib offers a good benefit-to-risk ratio and, again, will be available in generics. So that's probably favorable. But, you know, our more potent ATP-competitive inhibitor, ponatinib, that's got some persistent safety concerns, and I think there's continuing to be hesitancy. It's a long-winded answer, but, you know, when you have a newly diagnosed patient, you wanna use your best agent first. That could be asciminib, and maybe it should be in the current term. Maybe it'll be Enliven someday. But then when you wanna think, "What are you gonna use next?" And I think if it's an allosteric inhibitor, you're gonna want your best ATP-competitive inhibitor. And what is that right now? You know, ponatinib's not generally a second-line agent. It's not labelled that way. Dasatinib is a good, you know, choice there, but Enliven could be a better choice. And we also take a lot of concern over patients who fail frontline therapy, especially if they fail maybe a drug with better efficacy, like asciminib. So that's gonna be a tough population, so we're gonna need to come in with something that's good, something that's tougher, or something that's got a better profile. So I think that's the way I see the landscape changing. Asciminib will probably move in, but may have some elbowing it's gotta do to make its place, and finalize that. Then we're gonna be looking at cost and options, but we are gonna be seeking this question about sequencing allosteric and ATP- competitive inhibitors and looking to determine what is our best ATP-competitive inhibitor, and I think that race is ongoing, and I think we have to look for a winner. Thank you. Dr. Lang, do you have anything you'd like to add to that? Yeah, thank you. Hi, Mike. Yeah, only a little bit. So frontline landscape in Germany and Europe is as complicated as well in the world. You're always seeking for the best drug, and the best drug is the most efficacious, but also the most safe one, and this is where asciminib super perfectly fits in. But Mike, you raised it, the interesting question is what to do after asciminib if you used it first line. So you will have no problem in the optimal responders, and the volume of patients being dosed with asciminib first line in case approval will not be that big, but there will be patients showing resistance. And the interesting question will be: Which TKI, which you use, will you use afterwards, and what will you learn from mutations emerging in the marrow still binding pocket? There, we do not have the full picture yet, but this could be spare room where Enliven could be an option and from a future perspective. Thank you for that. Actually, it fits in... We've gotten a lot of questions about this. Really thinking about impossible to predict at this point, but for those patients that start on frontline asciminib, you know, what might be the reasons, the primary reasons they discontinue? And you talked about resistance and mutations. Maybe... So that's the question. I'll throw in my own, my own considerations that I've thought a lot about, and I just think that the way treatment decisions have been made have changed quite a lot because there are so many options. When I became a medicinal chemist, it was really right when imatinib was discovered or developed for the treatment of patients with CML, and patients that were coming off imatinib were mostly resistant, right? So changes in the biology.... Whereas now there's sort of different metrics and different levels of, you know, resistance and tolerance. It's mixed, as we've seen in some of the vignettes you've made. With asciminib up front, given that it looks to be both, you know, more efficacious, and better tolerated, you know, what do you think, you know, the primary reasons patients will discontinue asciminib in that earlier line setting? And Dr. Lang, maybe we'll start with you on that. Yeah, it's a bit difficult to assume with the data we have on hand. So, I fully agree that if you're looking on historic problem with the matter, most of the patients become resistant and TKIs, you, your portion of resistant patients getting down, and you're running into intolerance. So, asciminib, if used on a broader patient, population first line, I think will also show some distinct patients being resistant, and this will be a significant proportion of patients of, where the reason will be for switch resistance. But we are still learning about the tolerance and safety profile of asciminib, and the first-line trials will be very useful because that's the first time we can really evaluate asciminib without prior TKI exposure. And a lot of our data has been generated in patients who have been treated with all the other TKIs beforehand. There also will be a significant proportion of patients showing intolerance in one. Dr. Mauro, do you have anything to add to that? As Dr. Lang said, not much. But I'd like to just reinforce what one of his cases highlighted, the inextricable marriage between intolerance and resistance. You know, and you know, when the frontline patient has started, we're keen to look at dose intensity, dose density, adherence, to get them into remission. So that period is probably one of the most important. And if we see frontline asciminib data expand, as Fabian was, as Dr. Lang was alluding to, I forecast we may have... No matter what, we're always gonna have patients with intolerance or a mixture of intolerance and resistance, where we have a threat to achieving milestones. So the better TKIs up front may not generate as many resistance cases, then they may be more challenging and more complex, but there will always be, unfortunately, some patients who need an alternative therapy for intrinsic intolerance or a mixture therein, so that unmet need will not change. Great. Thank you. Okay, Helen, I'm gonna direct this next question to you. Can you share your thoughts on what kind of randomized trial design you might do first? And also, you know, based on that, can you tell us what ELVN-001 would need to demonstrate in order for it to be, you know, viable in that specific design? Yeah, so I think, you know, right now, we're really pleased with the type of patients who've been enrolling in the trial, and even though obviously the data set is small, you can see there's quite a variety of patients. So we think that we're getting. If we continue to do this, we'll acquire, you know, a significant amount of safety and efficacy across these later lines, and that's where there is a lot of data, historical, to compare, as you've seen some of it, to how other molecules have performed in that setting. And so I think to some of the points that Dr. Mauro and Dr. Lang are making, we hope that with that, you know, a larger data set of what we're seeing, that across the board, it's clear that, or it's promising that 001 is going to be the best ATP-competitive inhibitor. And then, of course, we'll have to take that data and go talk to regulatory agencies. And, you know, our thought right now is that the ideal trial would be us against, you know, any ATP-competitive inhibitor, and that we would win. And of course, from our point of view, the earlier the line of that trial, the better, but we'll see what the regulatory agencies think. Great. So this, this is kind of a fun question that, you know, I've personally thought about for over a decade, since I started working on active site inhibitors back at Genentech. But, so since asciminib and ELVN-001 have different, you know, binding modes, can you share your thoughts on combining ELVN-001 with asciminib? And so that's a question maybe we all can kind of chime in on. I'll start with just a little bit of background and some of the preclinical ton of context, but I'd love to get your thoughts, Dr. Lang and Dr. Mauro, on, is this interesting? Is this something to be explored? So I think, yeah, from a purely, you know, scientific perspective, preclinical perspective, when you look at the known mechanisms of resistance in CML, and there's still a lot of unknown mechanisms of resistance in CML, certainly, we don't think there are other major pathways lighting up in many of these resistant patients. You know, 001 and asciminib are highly complementary, you know, almost, almost a completely complementary mutational profile in terms of the known emergent resistance mutations to CML. And then 001, one of the unique things about its design, and this really comes from our background, designing it as a potential drug for neurodegenerative diseases, is that it's not a substrate for PGP or BCRP, which, you know, these drug efflux transporters could play a role. So just on basic scientific principles, I think they would combine very well. We actually have done some preclinical experiments with collaborators at OHSU and Dr. Druker's group, and that would reinforce that hypothesis. So it looks really good pre-clinically, and we now have done in vivo studies that look remarkable, and have been done at physiologically relevant concentrations. But I personally haven't ever thought about that as, as, like, a super exciting path to pursue because, you know, to your point, Dr. Mauro and Lang, you know, tolerability is a really important goal in CML, and you've been... You know, if you, if you, you know, offset, you know, efficacy with tolerability issues, that could be an issue. And certainly Novartis had started their initial registrational study designs were really based on adding on to frontline therapy in patients that hadn't achieved deeper molecular responses. Those have kind of gone away. There still seems to be interest in combining asciminib with ATP- pocket inhibitors, but it seems sort of mixed in terms of the level of interest and the right setting to do that. So, you know, I kind of just rambled on there a little bit, but, you know, maybe, Dr. Lang, start with you. You know, what are your thoughts on combining asciminib with 001, or any ATP- pocket inhibitor, and, you know, do you see a role for that? Yeah, so first of all, I'm super interested in combining. And it's absolutely interesting if we look at asciminib, and we all thought in the beginning that combination drug from the point of the development, and now we see it's getting really big as a monotherapy. But in a word, scientifically and from a rationale perspective, a combination is something really worthwhile. And the question is, in which context do you wanna use combination treatment? And you already mentioned it, Sam, you've always got to outweigh the efficacy and safety, and you are always afraid. And as we did the first patients in the phase I, asciminib plus TKI in the phase I trial, everybody was really anxious about what might happen, and it worked. It worked quite well. So combination is possible. We can argue whether we use it in frontline, like it's, it's done in the FASCINATION trial with TKI plus asciminib in order to eradicate as broad as possible and eradicate all potential resistant clones from the beginning. Or we go the other way around, and we say, "Okay, if we have a patient who is highly resistant to given therapies, am I might gonna benefit from combination," as we've seen in some really interesting patients who develop compound mutations and where on individual basis, asciminib combined, in rare cases with ponatinib worked out. So, I think we have to balance it between those both sides, but it's definitely worthwhile to look at the combination. Dr. Mauro, your thoughts? So I'll double down on the super excited part and state that we have to think about, you know, how can we squeeze more out of therapy for CML? I think probably the most direct answer is the highly resistant cases. 'Cause we think of resistant cases in people who, Dr. Lang's example, you know, saving someone from transplant, you know? Okay, so the combinatorial toxicity of two TKIs in that setting is probably more as a magnitude lower than the risks of transplant. So that's a natural. Earlier in therapy is a little bit more of a challenge, but, you know, I think one of the questions we're gonna have about asciminib in the frontline or better frontline therapy, so, is what, what is the cure fraction? 'Cause, you know, tolerability of adverse events and, and willingness to submit to adverse events is a function of how long you, you may be at risk, and, and the magnitude and the implications of the adverse effects. But if you have fast and deep remissions with asciminib that don't change the cure rate, don't change the success of treatment-free remission, I think we are gonna be motivated to be thinking about combinations, even upfront or even very early in therapy. So I mirror his answer. Both ends of the spectrum, there's interest. We have to be cautious, but we've learned a bit from asciminib plus ATP-competitive site inhibitors. And when you have a drug like Enliven with a, you know, with a very encouraging safety profile, but probably the potency of, you know, our best ATP-competitive inhibitors, that's, maybe that's your candidate. I encourage collaboration in the CML community to get these kinds of things launched in time. Thank you for that, and I know I believe we have some folks from Novartis on the line, so if there's interest in exploring this, please let us know. So actually, I think, you know, we've covered most of the questions. Some of the ones that came in, I think those questions were addressed in the Q&A we had earlier. So I think with that, actually, I'll conclude the Q&A portion of today's event. I would like to thank you again, Dr. Lang and Dr. Mauro, for your time and participation in this event, and more importantly, for everything you've done in support of us for a long time now and on our clinical study. And thank you to everyone who's joined to listen in today. If there are remaining questions that you didn't think we, you know, sufficiently addressed or you haven't asked, again, please feel free to reach out to us separately, and we'd be happy to schedule some time, for follow-up meetings. Thank you all very much.