Good day, and thank you for standing by. Welcome to the TERN-701 Interpreting Early Data Sets in CML webinar, hosted by Terns Pharmaceuticals. At this time, all participants are on a listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, you can press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today. Please go ahead. Good morning, everyone. I am Amy Burroughs, Chief Executive Officer of Terns Pharmaceuticals. On behalf of the Terns team, I thank you for joining us today for our discussion focused on interpreting early data CML datasets and highlighting the TERN-701 opportunity. Today, we will touch upon the groundbreaking work being done at Terns to transform the standard of care for patients living with chronic myeloid leukemia or CML, along with a discussion with one of the world's leading hematologists, Dr. Andreas Hochhaus. Dr. Hochhaus is Head of Department of Hematology and Medical Oncology at the Jena University Hospital and Director of the Comprehensive Cancer Center Central Germany. Before we begin, let me call your attention to the fact that throughout the course of today's program, we will be making forward-looking statements. I would also like to note that any opinions expressed by Dr. Hochhaus are his own and do not necessarily reflect the opinions of the company. Finally, please note this KOL event is for informational and educational purposes only and is not intended for the media. We are excited to focus today's discussion on how to interpret early CML datasets in preparation for our interim data readout for TERN-701 in December. Our goal is to level set expectations going into our analysis, as this will be the earliest dataset released to date for a phase I trial in CML. Despite the early nature of the interim look, we believe there is valuable information to be learned about the potential for TERN-701. We will also discuss how we view TERN-701's competitive differentiation and where TERN-701 may fit in a rapidly evolving CML treatment paradigm. Next, we will have a fireside chat with Dr. Hochhaus, a leading expert and key opinion leader within CML. Finally, we will open the event to Q&A with the audience. Prior to taking the helm at Terns, I had the privilege to work for inspiring companies such as Genentech and Connetics, where we executed bold and ambitious plans to apply innovative science to change the landscape for patients suffering from a variety of serious diseases. At Terns, we follow the science and have developed a portfolio of best-in-class small molecule product candidates to address serious diseases, including oncology and obesity. Our programs are based on mechanisms of action that have already achieved proof of concept in clinical trials and where there is opportunity to continue to innovate, to develop therapies that address clinically meaningful unmet needs. Nowhere is this more evident than in CML, a chronic indication where there continues to be a large unmet medical need and patients who require therapy for the rest of their lives. The introduction of Gleevec in 2001 was the first tyrosine kinase inhibitor, or TKI, approved to treat CML, and this breakthrough medicine transformed CML from a life-threatening cancer to a chronic disease. Yet despite the impact of Gleevec and the approval of multiple improved second-generation active site TKIs, there remains a significant unmet need for better efficacy, safety, and tolerability. Approximately 40% of patients switch therapy within five years due to lack of sufficient treatment, response, or side effects. On the efficacy front, half of patients do not achieve the desired treatment response, called deep molecular response, within four years. We have also learned the chronic use of active site TKIs are associated with a variety of serious adverse events due to off-target effects, including pleural effusion, gastrointestinal, and life-threatening cardiovascular issues. Emerging scientific evidence supports that allosteric TKIs offer the opportunity to transform the standard of care for CML. Novartis's asciminib is the first approved allosteric BCR-ABL inhibitor to treat CML and has demonstrated significant improvements on efficacy, safety, and tolerability over current standard of care. This has made the allosteric class the next exciting opportunity to transform the CML landscape. Encouragingly, Novartis has described asciminib as a key driver of growth and has expressed confidence that the drug can achieve $3 billion in annual sales. We believe that next-generation allosteric BCR-ABL inhibitors have the potential to provide superior target coverage, improved kinase selectivity, optimized dosing, and lack of food effect, along with more rapid and deeper levels of response compared with current standard of care active site TKIs. The founders of TERNS understood the science of allosteric BCR-ABL inhibitors well and saw an opportunity to design a potentially better molecule that could provide a differentiated option for patients. With this molecule and a thoughtful development plan, we believe that TERN-701 has the opportunity to provide enhanced efficacy, minimal off-target activity, improved patient convenience and quality of life, and a greater potential for treatment-free remission. So with that brief overview, let me turn the call over to our physician experts, who will discuss the challenges of treating patients faced with this chronic hematologic disease and the potential of our innovative drug candidate to address those challenges. After that, we will open the call up to questions from Doctors Kuriakose and Hochhaus. As I noted earlier, we are privileged to be joined by Dr. Andreas Hochhaus, a world-leading oncologist and a true luminary in the field. Dr. Hochhaus specializes in treatment optimization of CML, and his special interests are the molecular monitoring of minimal residual disease and mechanisms of resistance in CML, and targeted therapy in a variety of neoplastic disorders. He is currently the president of the German Society of Hematology and Medical Oncology, and a member of the European Hematology Association, the American Society of Hematology, and the German Cancer Society. He has received numerous prestigious awards, including the Endowed Professorship for Leukemia Research from the German José Carreras Leukemia Foundation, and most recently, the John Goldman Award of the International Chronic Myeloid Leukemia Foundation in 2022. Dr. Hochhaus has authored more than 680 peer-reviewed papers and is regularly invited to speak at national and international symposia. Thank you, Dr. Hochhaus, for taking time out of your busy practice to join us. Leading our discussion on TERN-701 and moderating our physician discussions is Dr. Emil Kuriakose, Terns' Chief Medical Officer. For those of you who don't know Emil, he is a medical oncologist and seasoned industry leader, with more than a decade of biopharmaceutical experience leading clinical development strategy and execution of therapeutics across multiple indications. With that introduction, let me turn the program over to our CMO. Emil? Thank you, Amy, for the kind introduction. I also want to thank the attendees online for making time to join our webinar today. I want to especially thank Dr. Hochhaus for joining and providing his expertise on our topic today. As Amy mentioned, the goal of today's webinar is to provide some grounding on how to interpret safety and efficacy data very early in the course of the development of a novel drug, specifically during the initial phase I study. Now, before we get into the details of interpreting clinical data, I think it's important to take some time to review the underlying disease biology and how changes in the biology of the tumor over time impact the response to TKIs. CML is a malignancy that probably best exemplifies the concept of oncogene addiction, where a single genetic event, the BCR-ABL fusion, encodes a constitutively active tyrosine kinase that acts as the primary driver of tumor growth throughout the course of the disease. CML has traditionally been defined as progressing through three phases: chronic phase, accelerated phase, and blast phase. Although there is currently some ongoing debate on the clinical necessity of accelerated phase. The clinical phases are primarily defined using hematologic and bone marrow criteria that includes percentage of blasts and other abnormal cell types, which typically increase as the disease progresses through the phases. What's important to note is that oncogene addiction to BCR-ABL is strongest early on in the disease, specifically in early chronic phase, when the tumor is more clonally homogeneous compared to later phase, and therefore more susceptible to BCR-ABL tyrosine kinase inhibition. So the response rate and speed of response to BCR-ABL targeting kinases is typically highest early in chronic phase, specifically in front-line or second-line patients. In patients whose disease does not respond optimally to initial TKI therapy, and the disease progresses through multiple subsequent therapies, the tumor undergoes clonal evolution and may acquire additional genetic abnormalities, including mutations in BCR-ABL itself or other pathway alterations that mediate resistance to TKIs. As a result, the response rate and response kinetics to a new TKI in multiply-relapsed disease is generally worse compared to responses in earlier phase disease, because now the tumor is biologically complex and heterogeneous, with relatively less oncogenic addiction to BCR-ABL. So how do we measure response in CML? There's three key measures of response. They're hematologic, cytogenetic, and molecular. Hematologic and molecular response are assessed in peripheral blood, whereas cytogenetic response is assessed in the bone marrow. Since CML is characterized by proliferation of immature myeloid cells in the marrow that abnormally circulate in blood, complete hematologic response is defined as normalization of blood counts. It's an important early indicator of a drug's efficacy in CML, and something to monitor for in the first few weeks to months on treatment in front-line patients and in relapsed/refractory patients who have lost their complete hematologic response. Cytogenetic response measures the change in the number of cells harboring the BCR-ABL fusion chromosome in the bone marrow. This is done via microscopic examination. It's further broken down into categories of minor, partial, and complete cytogenetic response, depending on the magnitude of decrease in positive cells in the marrow. However, since this requires bone marrow biopsies, its use as a long-term monitoring tool in the clinic is more variable than hematologic and molecular response assessments, which only require peripheral blood to perform. Finally, molecular response measures the change in BCR-ABL transcript levels in peripheral blood over the course of treatment using PCR. It's the most standardized response assessment in CML, has the widest dynamic range, and is also the most sensitive, the ability to detect very low levels of tumor, as low as one CML cell in a hundred thousand normal cells. Now, it's helpful to think of hematologic and cytogenetic responses as milestones along the very wide continuum of molecular response. It's also important to note that relapsed/refractory patients may present at variable points on this response spectrum, with some having lost cytogenetic response but maintaining hematologic response, and others having lost both cytogenetic and hematologic responses. So now a few key points on molecular response. Molecular response is measured as the decrease over time in the ratio of BCR-ABL transcript to a reference control gene, commonly wild-type ABL or beta-glucuronidase. BCR-ABL transcript levels are measured using RT-PCR. In order to calibrate transcript levels to an overall measure of leukemic burden and to normalize for variations in assay methodology among laboratories, molecular response is standardized on an International Scale, on which BCR-ABL transcript is reported as a percentage. The mean pretreatment transcript level of thirty subjects from the original IRIS study of imatinib was used to inform the two reference points on which to calibrate the IS. The mean pretreatment transcript in these patients was set as 100% IS, and a three-log reduction from that baseline, or 0.1%, was set as the second reference point. Using this reference, laboratories that are calibrated to IS utilize specific conversion factors to take local results and report on the IS, and this facilitates translatability of results across labs. BCR-ABL transcripts are followed on a log ten scale, with whole log reductions representing specific response categories. For example, early molecular response is less than 10% IS, and major molecular response is less than 0.1% IS. What's particularly important to note that BCR-ABL transcripts on the IS generally correlate with leukemic burden in the marrow, as shown on the figure, and this is on an exponential scale. To put that in perspective, the difference in leukemic burden between 1% and 0.1% is approximately nine billion cells, whereas the difference between 100% and 10% is nine hundred billion leukemic cells, even though both differ by about one log. Despite the much higher leukemic burden at the higher transcript levels, the response rate and kinetics to TKIs is robust in newly diagnosed patients with transcript levels of 100%, because, as we mentioned, oncogene addiction to BCR-ABL is high and clonal heterogeneity is low. However, in patients with more advanced disease that has progressed through several TKIs, clonal heterogeneity is higher, with relatively less oncogene addiction to BCR-ABL compared to newly diagnosed disease. So relapsed/refractory, heavily pretreated patients with transcript levels more than 1% or 10% on IS have the lowest and slowest responses to TKIs, as I'll show in the next few slides. For newly diagnosed patients starting on their first TKI therapy, response milestones are pretty well-defined. Although there are slight differences in the various guidelines defining optimal response to a TKI at specific time points, it's generally accepted that newly diagnosed patients should, at minimum, have complete cytogenetic response or BCR-ABL less than 1% IS within six to 12 months of starting a new TKI. Shown on this slide is the optimal response definition according to the 2020 ELN guidelines, which defines optimal response as achievement of BCR-ABL less than 10%, 1%, and 0.1% IS at 3, 6, and 12 months, respectively. It's important to note that despite newly diagnosed patients typically having high baseline transcripts, responses are generally robust with fast kinetics, reflecting again the overall biological complexity in this context compared to relapsed/refractory disease. Therefore, leukemic burden alone isn't the primary factor that determines the probability, speed, or depth of response, but rather the underlying disease biology, which is very different in the context of relapsed/refractory disease. Now, given the more variable biology and baseline characteristics of relapsed/refractory patients, the response milestones that we just went over for newly diagnosed patients don't universally apply in the relapsed/refractory disease context. Clinical heterogeneity in the relapsed/refractory population arises from multiple factors, including presence or absence of BCR-ABL resistance mutations, additional genetic abnormalities, and number and type of prior TKIs the patient has seen. The other complicating factor in the context of relapsed/refractory disease is the considerable practice variability with regard to TKI switching. Given this increased clinical heterogeneity, the established response milestones for frontline patients don't universally apply here. To remind you, our CARDINAL phase I study of TERN-701 is enrolling chronic phase, second-line-plus patients who have had either treatment failure or suboptimal response to at least one prior second-generation active site TKI and/or intolerance on their current TKI, including asciminib. While it enrolls patients as early as their second line, we don't specify an upper limit on number of prior therapies, as is common in phase I studies, and therefore, you can still get a wide range of baseline characteristics with regard to these disease profiles. In relapsed/refractory disease, in contrast to the frontline disease, the baseline transcript level appears to have a more pronounced impact on the chance of response and speed of response to a new TKI compared to frontline. Shown on this slide are the data from the asciminib phase I study in relapsed/refractory patients. In this study, more than 70% of enrolled patients had received three or more TKIs, including imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. Asciminib showed an overall six-month MMR rate of 24% in patients who were not in MMR at baseline. However, when achievement of MMR was analyzed according to baseline transcript levels, as shown in the figure. Those who had baseline transcript levels greater than 10% IS, had a substantially lower response rate and slower response kinetics compared to those patients with baseline of 1 to 10% or below 1% IS. In patients with baseline transcripts greater than 10%, the MMR rate at six months was less than 10%, with only about 40% of these patients achieving MMR at five years. The patients in the next two lower baseline transcript categories of 1% to 10% and 0.1% to 1%, had 30% and 45% MMR rate approximately at six months, and approximately double the rate of MMR at five years compared to those with a baseline greater than 10%. So some key takeaways from these data. Number one, the 24% overall six-month MMR rate represents a blend of the MMR rates across these considerably divergent cell populations defined by baseline transcript levels. Second, when you're very early in a phase I study with a small cohort of patients, roughly 10-20, and a median duration of treatment that's that's 3 months or less, there can be considerable skewing of the cohort towards the high or low end of the baseline transcript spectrum, limiting one's ability to make definitive conclusions on overall MMR or EMR rates at such early time points, given the very different response rates between these subsets. Lastly, the other key observation from these phase I asciminib data was that achievement of MMR at any given time point was not impacted by the number of prior therapies per se, indicating that number of prior TKIs alone is not the best indicator of the refractoriness of a patient population in CML. What's additionally important are the specific TKIs on which the patient progressed, presence or absence of resistance mutations, and what the rate and extent of disease progression on each prior TKI was, as measured by disease burden at the time of switch. Another key reason why number of prior TKIs alone is a poor measure of disease refractoriness, is that the number alone does not provide information on whether the switches were due to intolerance without resistance, versus switches due to true resistance. For example, a patient with four prior TKIs of imatinib, dasatinib, ponatinib, and asciminib, who stopped ponatinib due to an adverse event without disease progression, is likely to be less refractory than a patient with the same treatment history, who had a rise in transcript levels to more than 1% or 10% at the time of each switch. So this next slide further demonstrates why number of prior TKIs alone is not the best metric by which to assess disease refractoriness in CML. As there is no universally established guidance on switching therapy in relapsed refractory patients, there's quite a bit of practice variation in determining when to switch a patient from one TKI to another. With CML being a chronic disease where patients are essentially on lifelong treatment, there's a very wide-ranging and complex set of factors to consider when making treatment decisions. These include age, comorbidities, concomitant medications, access to TKIs, patients' lifestyle considerations, differences in the treatment goal. For example, are we aiming for TFR or not in a specific patient? Given this wide range of considerations, it's not practical to have a one-size-fits-all set of criteria for switching TKIs in the relapsed refractory setting, and therefore, switch decisions are usually individualized to specific patient circumstances. TKIs are most commonly switched for disease progression as per the discretion of the treating physician and/or intolerance to the current TKI. Depending on specific patient factors and treatment goals, physicians may have different thresholds for defining progression along the molecular response scale. This is illustrated in the figure, which shows changes in BCR-ABL transcript levels over time for three hypothetical patients, and the points at which their TKIs were switched. Now, if you look at the patients represented in the green and red lines, both of these patients have a total of three prior lines of therapy, including their frontline TKI and two subsequent switches during their disease course. However, the patient in green has more aggressive disease, with faster increases in their transcript level and a transient response to their last TKI, with continued rapid rise in transcript level to more than 10%. Compare that to the patient in red, who's hovering closer to MMR at both points when therapy is switched, with decreasing transcript levels on their latest therapy. So while both patients have had three prior TKIs, their disease biology is clearly different. And this demonstrates how a patient with multiple switches for low-level progression is not necessarily similar to another patient who had the same number of switches at higher levels of tumor burden, or where the tumor has additional complexities like mutations. The yellow line represents yet another scenario. This is a frontline patient who has decreasing transcript level, but the rate of decrease is suboptimal, where options include switching therapy to a new TKI, increasing the dose of the current TKI, or continuing as is. Not shown in the figure are other scenarios of switching for intolerance or switches for small increases in transcript level for patients who are already in MMR. This is all to illustrate why number of prior therapies alone, without the context of underlying disease biology and baseline transcript level, is not informative in predicting the chances of response to a new therapy. So what the two prior slides illustrated, is the high degree of heterogeneity in the relapsed refractory population with regard to disease biology, the variability in baseline tumor burden, and its impact on response rate and kinetics.... And the wide range of disease characteristics represented in a phase I population, where inclusion is typically based on the number of prior therapies. It's because of these factors that longer median durations of therapy and larger n's are typically required to make meaningful assessments of key endpoints like MMR. Therefore, early dose escalation data are not ideal for making direct comparisons of MMR or similar response measures. However, that does not mean that very early data from phase I studies are not informative on the clinical activity of a molecule. In addition to the key objective of assessing safety and tolerability early in phase I, there are early directional and descriptive signals of efficacy that can be assessed. These include things we've already mentioned, such as hematologic responses in patients with hematologic relapse, decline in BCR-ABL transcripts early on in patients with lower baseline transcript levels, stabilizing transcripts in patients with high baselines, and maintaining or decreasing transcript levels in patients who came on study for intolerance to their previous TKI. Early in dose escalation, individual patient profiles of response can support early proof of concept for the molecule, even if it's too early to determine the overall response rate in a robust fashion. The next few slides cover some representative examples of what this could look like. So this slide extends on the profile we saw for hypothetical patient number one in a previous slide, who has aggressive disease biology with relatively rapid increase in the transcript levels on their latter two TKIs after an initial decline on frontline therapy. Now, if this patient had come on to the TERN-701 phase I study at the point shown on the plot, their baseline transcript at that level, at that point is greater than 10% and rapidly rising. In such a patient, stabilization of their transcript levels early in therapy within the first three months would be a good outcome. Seeing reversal of the rise with the decrease in transcript levels to below 10% at three months would be a great outcome. And of course, we want to see excellent tolerability on the drug, which would allow the patient to continue deriving benefit without having safety or tolerability issues. In such a scenario, the takeaway would be that 701 demonstrates early efficacy despite heavy pretreatment and a high baseline BCR-ABL transcript, where historically other drugs have shown very low rates of achieving molecular responses. This is the second hypothetical patient scenario, which is a frontline patient having a suboptimal rate of response to their initial TKI therapy, and the physician wants to switch in order to get a faster rate of response. This is now a second-line patient who's not technically resistant but is not having an optimal response to their frontline therapy. In this scenario, you would want to see a steepening of the response slope if they switch to TERN-701, and while the specific timescale isn't shown on the X-axis here, a good outcome in the first three months would be restoring a rate of response that brings the patient back on course to achieve the recommended response milestone, for example, reaching MMR by twelve months. A great outcome would be further increasing the rate of response that meets or exceeds the recommended milestone, such that the patient is on the way to deep molecular response. Finally, slide 20 shows a patient example three, which is showing an asciminib intolerant patient who is responding to it as their third line of therapy but switches to TERN-701 due to an adverse event or other intolerance. In such a patient, the first thing to ensure is that the patient is not having the adverse event or intolerance that they were having on asciminib. If that box is checked, then from an efficacy standpoint, a good outcome here would be to maintain the same rate of transcript level decline that they were seeing on asciminib, such that they remain in major molecular response while continuing to deepen response. A great early treatment outcome within the first three months would be achieving deep molecular response with a transcript level less than 0.01%, with maintenance of excellent tolerability, so I hope the previous slides were able to convey how very early data, specifically from a phase I cohort with three months or less of median treatment duration, could still provide valuable information on early signals of efficacy, even though it's limited in terms of informing more robust efficacy measures such as EMR or MMR. This slide gives a high-level overview of prior initial datasets from CML phase I studies, showing the median treatment duration and the number of patients at the time of initial data. In the majority of these initial datasets, the primary focus was on safety and tolerability, with descriptive reporting of efficacy primarily comprised of endpoints such as early response assessments such as CHR and cytogenetic response, highlighting that MMR is not an expected therapeutic goal at three months in a highly relapsed refractory population. The initial planned disclosure from TERN's CARDINAL study will likely have even shorter treatment duration compared to these precedent phase I studies, further emphasizing that the key takeaways at this early time point are primarily safety, tolerability, and early descriptive signals of efficacy. That brings me to my last slide in this section, which attempts to essentially frame what this interim dose escalation data in December could look like for TERN-701. Based on the fact that we would have been enrolling for less than a year at the anticipated data cutoff, the parameters that we're estimating for interim data are approximately 10-20 patients enrolled, with approximately 5-10 patients with at least 3 months of treatment across at least 2 dose levels in dose escalation. This interim assessment would primarily comprise safety, tolerability, and early descriptive signs of efficacy that we covered, including hematologic response in patients who had hematologic relapse at study entry, and early changes in BCR-ABL transcript levels on treatment. The key point here is that early dose escalation data will essentially tell us if you have a safe drug that's showing early signs of efficacy at the individual patient and cohort level. But the number of patients and duration of follow-up is too small at this stage to provide robust efficacy data to serve as a benchmark, or that can be directly compared with more mature efficacy data from prior large phase I or II studies. And with that, I'll pass it back to Amy, who will provide more color on why we believe TERN-701 has the potential to be the best-in-class allosteric inhibitor based on the accumulated preclinical and clinical data we have to date, and what a future path could potentially look like for the molecule. Amy? Thanks, Emil. Next, I'll be describing the opportunity ahead for TERN-701 and next steps for the program. We are excited that TERN-701 is beginning to show early signs of differentiation within the allosteric class. Our original goal was to discover and develop an allosteric BCR-ABL with properties that would provide clinically meaningful benefits in CML. In preclinical models, we established a potency profile that is competitive with the leading allosteric inhibitor. We also designed this molecule for potential differentiation from asciminib, including once-daily dosing and lack of food effect. We are pleased to have demonstrated clinically that TERN-701 is a once-daily drug without a food effect. The ability to dose TERN-701 without regard to food represents a key potential differentiator from asciminib. As we continue to develop TERN-701, we believe there are additional ways to differentiate it, including potential for improved efficacy through higher doses than asciminib, and the potential for a simplified label, such as once-daily dosing across mutational status and an improved drug-drug interaction profile relative to asciminib. Taken together, TERN-701 is building on initial differentiation points that could make it a potentially best-in-class allosteric BCR-ABL inhibitor. Now, let's spend a few moments on the evolving CML landscape. Following the positive frontline data of asciminib at ASCO this summer, we believe that the treatment paradigm will increasingly shift towards allosteric TKIs in earlier lines of therapy, providing exciting optionality for TERN-701. Let's go over the current paradigms by line of treatment and how dynamics may change. In the frontline setting, patients are almost evenly split between receiving generic imatinib and branded second-generation active site TKIs. In the future, with an anticipated asciminib approval in frontline, we expect allosterics to capture a sizable share of frontline patients. However, as second-generation TKIs become generic in the coming years, we anticipate they will continue to see frontline usage along with imatinib. A reasonable future scenario may mirror today's dynamic, where approximately half of frontline patients receive a branded allosteric, and the other half receive generic imatinib or generic second-generation TKI. In the second-line setting, most patients currently receive a second-generation TKI. Importantly, there are no allosteric inhibitors currently or anticipated to gain approval in second line, with the exception of TERN-701. As a result, TERN-701 could become the primary allosteric option for second-line patients who have suboptimal response to active site TKIs. In the U.S., there are approximately 11,000 patients either starting therapy or moving on to a later line of therapy. I'll focus first on the second-line market potential for TERN-701. As discussed on the prior slide, we know that approximately half of patients are started on a second-generation TKI. TERN-701 could be a welcome option for those patients who are intolerant or resistant to generic active site second-gen TKIs. It also may be an option for a small segment of patients who are asciminib intolerant, and we are currently allowing those patients in our ongoing CARDINAL phase I study of TERN-701. In the frontline setting, asciminib is expected to capture a significant share of patients. As TERN-701 builds on its differentiation profile, we see a growing opportunity to compete for meaningful share of frontline patients. As a result, we believe TERN-701 has plenty of optionality in terms of development, pathway, and addressable market. Looking ahead, we are excited to share the first look of interim data from initial cohorts in December. As Emil described earlier, we think this early look will be an informative, directional assessment of TERN-701's overall potential. Next year, we anticipate the subsequent readout of data with treatment durations of six months and sufficient information to inform our registrational trial. As mentioned before, we are evaluating multiple options for our pivotal trial, including frontline and second-line patients. We would anticipate moving quickly and directly from CARDINAL into a registrational phase III trial. This future readout from the CARDINAL study in 2025 could be reasonably benchmarked against asciminib, which showed promising results at the six-month treatment duration time point. Data based on durations of treatment longer than six months and a larger pool of patients, as shown in this shift table, is required to enable a meaningful comparison of MMR rates. We are working diligently to share this level of data with you as soon as it is available. To recap, we are encouraged by the progress of TERN-701 to date and are excited for what's to come. TERN-701 has the potential to be a differentiated BCR-ABL, with advantages over asciminib, including lack of food effect and simplified dosing. We believe it has the opportunity to address broad unmet needs in frontline and second-line settings. Our development plan has been accelerated and continues to be informed by our ongoing partnership with Hansoh, who is developing TERN-701 in the Greater China region. Finally, we believe that TERN-701 represents the second in-class allosteric, with limited competition in the class. With that, I'll now turn the call back to Emil for a fireside chat with Dr. Hochhaus. Emil? Thanks, Amy. Good evening, Dr. Hochhaus, and welcome again to the call. Hello, and thank you very much for the invitation. It's a real pleasure to be here and to listen to your beautiful and comprehensive summary of what we learned in CML in the last twenty years. I think, Amy, this was re- ... A bit about your own history and your practice. Can you start with the background of your practice? How long have you been practicing, the types of patients you treat, et cetera? Yeah. You mentioned that I'm director of the Comprehensive Cancer Center here in Central Germany, and therefore responsible for patient system, medical treatment of cancer patients, but also, of course, hematological patients. My special focus is, of course, CML. Has been CML since the eighties, when I started clinical practice, and I actually started with interferon-treated patients. We learned, and this was, of course, guided by Moshe Talpaz in Houston, that complete genetic responders with interferon have a beautiful survival, in contrast to all the other patients who died after five years in median. That means Gleevec, which produced much more, many more patients in complete genetic response, changed the field significantly, and this was a revolution. That means, the initial clue was to learn that complete cytogenetic response is the guidance for success in CML, and that the BCR-ABL inhibition can prove that. But we immediately learned, and this was the second New England paper for Gleevec, that it is active in gastrointestinal stromal tumor as well, and also in hypereosinophilic syndrome. That means it was not BCR-ABL specific. It inhibited, what inhibits the PDGF receptors and also c-KIT, which was an advantage for the broad spectrum- Mm-hmm. But it's a clear disadvantage for the side effect profile, this multi-kinase inhibition. I had the pleasure and the chance to present at the plenary session at ASH in 2001 in Orlando, the first data on Gleevec resistance on BCR-ABL mutations. There was a discussion ongoing: Is this the Achilles heel for the specific BCR-ABL inhibition? It was quite clear with the development of the second generation BCR-ABL inhibitors, that such mutations can be overcome. Mm-hmm ... with other drugs, which will be active in these mutations, and this was the real chance for the development of the second-generation inhibitors, and we learned that with second-generation inhibitors, the response is faster, and of course, resistance can be overcome, and this resulted in the development of more and more drugs. Now we have six drugs available in most countries in the Western world, and I like that. I like that very much because we have now the chance to improve tolerability. We have the chance to overcome resistance and to be more individualized in the treatment of CML, and that's important, and this brings us the success. Our recent data from the TIGER trial, which was a trial with nilotinib and nilotinib plus interferon, shows that the eight-year survival of CML patients is now 95%. That means that's fantastic, and this has been achieved with the availability of a multitude of options and a multitude of drugs. But we have challenges, and these challenges are important for the scientists, important for academics, but most important for our patients. And the challenge is to increase the number of patients in treatment-free remission, and of course, to enhance and to improve tolerability of the drugs. So that's our guidance now, our current goal, what we do in the trial groups in the national trial groups, but also internationally. This international cooperation with companies, but also between the academic sides, is really well-developed, and I like that very much, and I'm happy to be part of it. No, great. Thank you for that really comprehensive overview of the history, and we have made quite a bit of progress, as you mentioned, and you did mention the majority of patients with CML do really well on their treatment, and the survival is now, you know, similar to age-matched controls. However, to your point, there is still unmet need, and, you know, in addition to your long history as a clinician treating patients, you also have extensive history as a drug developer, and you've worked essentially on every TKI in a very prominent way, from Gleevec all the way through recently, asciminib, where you were the lead investigator on the phase III study in frontline. So my question is, as a clinical trial investigator, how do you evaluate whether an investigational drug early in a phase I study is showing promise? In other words, what are the early signs that a drug is showing activity in patients with relapse refractory disease, factoring in the highly variable baseline characteristics of such patients, as we just talked about? Let's start with a general answer, not specific on CML. Mm-hmm. For the general phase I situation, why do you administer, why do you ask a patient or offer a patient participation in a phase I trial? It's either you have a specific marker which may be sensitive to a new drug, to an innovative drug, then, of course, you want to offer this drug even in second line or third line. But in most patients in a phase I, you offer an investigational drug because you don't have other chances, other choices. That means we don't like the word last line, but it's a late treatment because you have a potential chance to stabilize the disease, and that's my answer in general. That means you want to stabilize the disease, and in specific patients which may be sensitive, which may have a new genetic aberration, which might be sensitive to the drug, you have an immediate response. Mm-hmm. But it is very heterogeneous and very different, but you are, in most cases, you are happy with the stabilization of the disease, and of course, the phase I is done to test the tolerability. That's the intention of the drug from the academic side, of course, to see whether different dosages of drugs are tolerated. And of course, we don't expect in the early dose levels, a fantastic response because we want to increase the dose over time, and I think that's very important to be considered when we look at early data in a phase I trial. We need an individual dose escalation in some patients, and we need to see whether the drug is well tolerated. That means overall, we have a very heterogeneous design, outcome, and we might be happy to see a high proportion of patients with a stabilized disease and a well-tolerated drug. Oh, thanks. That's very helpful. And, you know, knowing that 701 is in this new class of allosteric inhibitors of BCR-ABL, and you've worked extensively in both the development, you know, of asciminib, as well as you're a clinician who uses it quite a bit. What has been your experience treating patients with an allosteric TKI? Yeah ... specifically asciminib, you know, relative to, the other drugs? We recently reported in the New England Journal, the 16 months follow-up data of the first-line treatment in CML. And there has been the discussion and the notion that 16 months is not enough to check for tolerability, for long-term tolerability. But this is not true because the development of asciminib took 10 years. We started the phase I in 2014. That means we have a 10-year experience now with the drug, and that means we have very robust data on the long-term tolerability of the drug as well. In the phase I, and you mentioned the data, responses were very heterogeneous. It depended on the background mutation, the BCR-ABL mutation status, not the lines of therapy, as you mentioned, but the specific biological situation of the patients. And we learned a lot from this phase I, which patients respond, what about patients without BCR-ABL mutations? What about patients with specific BCR-ABL mutations? We learned that patients with the threonine 315 isoleucine mutation, which is one of the most common resistance mutations in BCR-ABL, needs a higher dose of the drug, and therefore, the FDA registered asciminib, this 400 milligrams for this mutation versus 80 milligrams for patients without mutations. That means that's important to individualize a treatment according to the biological situation. That's what we learned in the phase I, in later line therapies. But we started then the first-line trial, as mentioned, and actually two first-line trials, and we asked the question, together with Novartis, of course, what is the medical need for such a drug? It was very obvious with the option to treat patients with immunotherapy and not with combination therapy, which used to be the initial attempt, to start with combinations, then to combine the two, inhibitor options, ATP site inhibitor and tyrosine kinase inhibitor, that this is not needed in most patients. That means BCR-ABL is still the driving force for the proliferation of the CML cells, and therefore, the monotherapy is an option. The point is, with the monotherapy, you improve the tolerability, because the BCR-ABL specific inhibition decreases or eliminates all the off-target inhibition, which I mentioned for Gleevec, for instance. Right. Therefore, improves tolerability, because the off-target inhibition causes most of the side effects. And therefore, and this is proven now in the phase III trial, which led to the registration for third line therapy, the ASCEMBL trial, that the tolerability is much better than in comparison to bosutinib, in this case. And also, the quality of life, which was measured in a standardized fashion, has improved with. Mm-hmm ... the BCR-ABL specific inhibition, and I think that's important. We talk a lot about treatment-free remission, but we know that treatment-free remission can be achieved over a longer time, only in 20% of the patients for the time being. We want to improve this proportion, but we should think, and we should consider the 80% of patients who need a long-term therapy, and they need a better tolerability. Therefore, allosteric inhibitors may be, and I'm convinced they are, a good chance to improve this tolerability. No, that's very helpful, and you mentioned the key aspect of allosteric, which is that the lack of off-target activity improves the therapeutic index that can get much better coverage over the target, and that essentially leads to the better efficacy and tolerability that we're seeing. So in terms of allosteric inhibitors, what is the role? Would there be a role for a second allosteric, and what attributes would be looking for in terms of areas for further improvement? Yeah. I mentioned the patients with BCR-ABL mutations, and there are individual cases. When you look at the phase I data published in New England as well, there is a list of mutations, and these are a few patients only with each specific mutation. But we know from preclinical data that the sensitivity of the mutations to asciminib is heterogeneous. That means we need different IC50s, so-called IC50s, for the specific mutations. And we know from the preclinical data from TERN-701 that some of these mutations or sensitivities may be improved with the new drug. And this needs to be, of course, shown in clinical practice, but theoretically, there is... As it was for the second generation, ATP site inhibitors versus Gleevec, there is an option to improve efficacy when we talk about the resistance profile of the specific patients. Data is robust for the T315I mutation, therefore, the FDA approved this, this dose, but we need more data for both asciminib and TERN-701 for all the other mutations. But the preclinical profile is promising. Okay. Great. No, thank you. That's one point, and the other point is, of course, tolerability in the individual patients. Of course, asciminib is well tolerated. We see some lipase increase, and we need to check in the phase I now, how this lipase increase is now with TERN-701. Right. But it's always important to check any chance for improvement, and I'm quite convinced that there is still an option for improvement of tolerability as well. Great. And I guess the last question is, how do you- in light of the allosterics making an entry into the field now, especially in frontline, how do you think the CML treatment paradigm will change over the next few years? Sort of your brief overview of how that could look like. When you see a newly diagnosed patient, and you ask him: What are your treatment goals? He will, of course, immediately answer: "I want to survive. Mm-hmm. I want to survive," and that has been our treatment goal for the last twenty years now since Gleevec was introduced. But when you talk to him after three months, after six months, he will say: "I want to get rid of the drug. Mm-hmm. That means treatment-free remission should be offered to more patients, which is an option when we achieve more deep molecular responses in first line therapy. But the third option, and I mentioned it already, will be most prominent in the future, and that's quality of life. Mm-hmm. That means, the improvement of quality of life for the long-term use of any of these drugs is now very important, and it's a challenge. We have now a long-term survival. We need to treat the patients for a long duration, most patients for a long duration, and therefore, I think it's a very understandable wish of all the patients now. Mm-hmm ... to have an improvement of quality of life. And you mentioned the food effect of asciminib and versus TERN-701. That's part of the quality of life. When we have a chance to give a drug after a meal, and we have a chance to live the normal life over the day without starving and so on, I think that's another step... for the improvement of quality of life. I think that's a reasonable option, and therefore, I think, and I agree with all the with the patient community, which formulates their wishes for the future and for the change of the treatment paradigm, that quality of life is now in the center of our development of our clinical observations and trials. Great. Now, thank you so much for your insights and your expertise. We really appreciate you sharing your thoughts with us today. I'll now ask the operator to please open the line for questions. I think we have time for a few questions, online. Thank you. At this time, we will conduct a question-and-answer session. As a reminder, to ask a question, you need to press star one one on your telephone. You will wait to hear your name announced. To withdraw your question, please press star one one again. We'll pause for a moment while we compile our Q&A roster. Our first question comes from Etzer Darout with BMO Capital Markets. Your line is open. Great, thanks for taking the question and thanks for this event today. First question for me is, when you think about sort of the efficacy measures in this update, is the best way to think about the update is really just sort of maybe patient by patient sort of history, you know, prior therapy, BCR-ABL levels, to kinda get a sense on a maybe more of a sort of measure of efficacy on a patient by patient sort of assessment? And I have a follow-up question. Yeah, no, I can start. Thanks for the question. I think that's overall accurate. You know, like I said, and like Dr. Hochhaus also mentioned in his response, I think at a very early stage in a phase I study, again, we're primarily looking at safety tolerability, obviously, but there are directional indicators of efficacy, and it would primarily be done at sort of an individual patient level. Because, again, the duration of treatment and number of patients is typically too small at that point to make robust assessments of response rates and other more mature endpoints. But Dr. Hochhaus, maybe if you wanna elaborate more. Yeah, but I mean, you can, of course, put the patients into different log levels at baseline, and you- Mm-hmm. You may see a shift from a higher log level to a lower log level, which is a response. Right. And therefore, I think it's very individual when you shift from 10% to 1%, that's a response, but also when you shift from 1% to 0.1%. That means we can look at this with individual shifts per patient. Mm-hmm. But as I said. Got it. When you have a stable BCR-ABL level, with the maintenance of hematologic response, in a case of a rapid developing resistance, and you see an elimination of the mutated clone, that means you look at the proportion of the BCR-ABL mutations, then you have a response as well. That means it depends on the baseline situation. Got it. Thank you. And the second question, you know, think about sort of the second-line opportunity for 701. I guess in terms of, you know, ultimately, you know, the way you would enroll patients, are these patients that would be, I guess, maybe refractory and tolerant to first and second generation and those intolerant to Scemblix, I guess, similar to CARDINAL in terms of the types of patient you would enroll in that second-line trial? And does the change or maybe sort of the rate of penetration of Scemblix in frontline sort of change sort of the way you think about that second-line design? Yeah, exactly. So, I mean, in terms of the first part of your question, which is what the specific patient population would be, right now, the CARDINAL study can enroll a, you know, a second-line patient who has suboptimal response or resistance to a 2G TKI. And so, you know, it, it's specifically 2G TKI because if a patient starts on Gleevec and has a suboptimal response, they can technically be salvaged with a 2G TKI. Now, knowing what you said in the second part of your question, that asciminib is entering frontline and is anticipated to capture a large share of frontline patients, we think approximately 50%, that's still the case, that the remaining 50% will likely start their first-line therapy with a second-gen TKI, given that essentially all the 2G TKIs will be generic by the time we run the study. And so knowing that, you know, approximately 20% of those patients will have a suboptimal response or resistance and additional percent on top of that will be intolerant, given the tolerability profile that we already know about with those drugs. That's the patient capture that we would initially anticipate primarily for the second-line study. Then as we get more data from asciminib in terms of the tolerability in frontline, there's still a fraction of patients who have intolerance, and we've talked about some of the reasons. It could include elevations in lipase, for example, or other issues that could then also be captured in that second-line population. Dr. Hochhaus, I mean, we welcome to hear your thoughts as well. The asciminib first-line registration by the FDA is expected soon. I'd say soon. I'm not the FDA, I don't know when. But of course, it will take a while until the first-line use outside is in the real-life situation. That means I expect for the second line study with TERN- 701, most patients will be patients with second generation inhibitors, either generic or branded in first line. And I see here according to the resistance profile and the clinical preclinical data, I see here a good chance for an allosteric inhibitor in second line. Mm-hmm. Great. Thank you. One moment for our next question. Our next question comes from Ellie Merle with UBS. Your line is open. Hey, guys. Thanks so much for taking my question and for providing all the color. Maybe just starting with Dr. Hochhaus. How would you think about potentially switching a patient who is in MMR on asciminib to 701 for say, better convenience? Maybe specifically, I guess, how burdensome is the fasting requirement for your patients? And then I have some follow-up questions. Thanks. To be honest, I think that's a little too much expectation. I think it's in general an advantage for 701 to have this profile, but I would not expect to switch just for this reason, a patient in MMR from one to the other allosteric inhibitor. I think that sets too much expectation here if you want to be realistic and... But if there's any other intolerance, of course, I would switch. Okay, understood. That's helpful, and then maybe just for Terns management, I guess, for the second line registrational study, I guess, how are you thinking about the potential design here? And in particular, would you expect there to be a comparator arm, and if so, what would that be? And then just a second question on obesity, can you give any more color on when in September we can expect the phase I data? And I guess, do you expect to have a go-forward dose at that update? And I guess, if so, can we assume that you've already identified the go-forward dose since you're giving more granularity now on timing? Thanks. Yeah, thanks for that. I'll just say for the last part, we should follow up offline. Again, this is focused more on CML, and we're happy to answer the questions about the other elements of the portfolio separately. Regarding your second question around the potential registrational study in second line, you know, we don't have a final design yet. We've obviously given it quite a bit of thought. We think that absolutely that there needs to be a control arm, a standard of care control arm for a registrational design. And in this case, it would be a dealer's choice, potentially a dealer's choice, switch to another 2G TKI, because I'd say from a current regulatory standpoint, at least in the U.S., that's the primary on-label option for patients. If they have a suboptimal response to a 2G TKI, they would switch to another 2G TKI. So that would reflect real-world practice. That would be a control arm that would reflect that real-world practice. And we you know in a sense it would look similar to ASCEMBL, given where but ASCEMBL used bosutinib specifically. But the idea is that you would have an allosteric 701 compared to an active site 2G TKI. And again, we would expect that the probability of success would be high. We see that in our ongoing CARDINAL study, that the response rate at that specific six-month time point looks to be trending towards a differentiated number from what we know the 2G TKIs do in second line. I think this dealer's choice option is a very, very good design in second line because there's a difference between ASCEMBL and the second line study. In ASCEMBL, the options were limited- Mm-hmm. And therefore, bosutinib was set here as a comparator. But in second line, you have more options, of course, and therefore, for the comparator arm, you need to look at the, for the time being, best available drug. And therefore, I think dealer's choice is a good way. Mm-hmm. Great. Thanks. One moment for our next question. Our next question comes from Graig Suvannavejh with Mizuho Securities. Your line is open. Hey, thanks. Thanks so much for the presentation today, and thanks for taking my questions. I had a question with regards to the 701 data that has been generated by your partner, and I was just wondering if you could remind us of what has been seen in the hands of Hansoh, and whether you feel that there is translatability of that data over to what you might expect with your own study. And then secondly, I just want to make sure that I understand this correctly, but it seems as if there are gonna be a fair amount of caveats with the interim CARDINAL readouts. And so with that in mind, just to confirm, it is really more the six-month data that you would expect to be more confirmatory of the profile for the product, or perhaps, is there a later time point that you think would be a good representation of the product? Thanks. Great. Thanks for the question. To answer your first question, yes, our partner in China, Hansoh, is actively developing the molecule in China. They're, you know, still enrolling to that phase I study in China. And really, what we were able to leverage from that data set was to be able to use the head start that they had in terms of enrolling that study to inform our starting dose for our phase I, where we were able to take a very wide range of doses, where they started at 40 milligrams, and all the way up to 400, and given how they had a head start on enrollment, we were able to use the safety, early efficacy and PK data. They were very collaborative partners to allow us to use that data confidentially with both regulators and confidentially with our investigators, to be able to use the data to support a starting dose of 160 milligrams once a day, where we, as we, disclosed last year, we made a qualitative disclosure that we were, that was a dose that appeared both safe and clinically active. I think that was an important advantage for us in that, you know, being able to get to a starting dose where we actually saw PK coverage that was fully in the therapeutic range, and where we saw initial evidence of clinical activity, was able to alleviate a typical concern that investigators have when putting a CML patient on a phase I study, that they don't want to risk putting patient at a very low, potentially subtherapeutic dose. So that really allowed us to more kickstart our enrollment on our study, and I think that was the key function of Hansoh. They continue to actively develop the drug. They haven't formally reported data from that study yet, because, again, to the point I made earlier on the slide, showing sort of the time frames typical for initial data disclosures, they're still well within that time frame. And so that's sort of how we're working with Hansoh, and they continue to be really great partners in terms of the drug's development. To your second question around caveats to the phase I disclosure this year, I wouldn't call it as much caveats as just sort of practicalities of what you expect from an early phase I data set, which is what we discussed in the presentation. That again, these are small n's. These are still interim dose escalation data and, you know, the time duration of follow-up and the number of patients. The reason why the more relative heterogeneity of patients in a chronic phase CML study is high, and so you need a larger number and a longer duration of follow-up to get you know to get a more blended assessment of what a full MMR rate is. We do agree that the six-month endpoint is probably most informative for what the PTS and the design for a registrational study would look like. We won't be at that time point in December. Again, we've been enrolling the study for less than a year, and the whole purpose of this was to show if we won't be there, then what can we assess of the molecule at this early time point? To your point, and as Amy said, we think that in 2025, we'll be able to meaningfully report on what a six-month MMR rate or a, you know, EMR cytogenetic response rate would look like, because that's the time we think we'll have enough duration and patients to be able to do that. Thank you. Just one follow-up for the doctor. Doctor, just thank you for your participation today, but, given the interim data that is expected in December, and relative to what you know about asciminib, are you anticipating at that time point any meaningful differences? And, if you don't see meaningful differences, is that in any way a sign of whether your enthusiasm for the 701 profile would be more or less, depending on what that data show? Thanks. We don't have a comparative study between asciminib and TERN-701. Therefore, from the scientific point of view, we cannot expect meaningful differences. We have meaningful differences in the preclinical profile, and that's important for the development of the drug. But of course, eventually, when you want to see specific differences for specific situations, you need a direct comparison scientifically. But of course, overall, with more data and with more patients, we may see differences in the tolerability, but also, and that's what I expect, specifically, differences in the activity in the specific mutations. Okay, thank you very much. One moment for our next question. Our next question comes from Corinne Jenkins with Goldman Sachs. Your line is open. Yeah, good morning, guys. Maybe a couple for me. First, from the company, I guess, what will you be looking for within this data set as you think about determining the registrational path, whether you'll go into 1 L or 2 L? So, like, what in the data could influence that decision, and then what else are you monitoring that will help you make that final decision around registrational development path? And then, for the doctor, you were pretty clear that you wouldn't switch a patient who is doing well based on tolerability around, you know, the fasting alone. But if you have a newly diagnosed patient and all else is equal, how would you think about that differentiation in determining what treatment a patient would get in the frontline setting, so asciminib or 701, if they look to be comparable, except for you don't have the fasting requirement with 701? Thanks. Andreas, you want to go first on the second? Yeah, I want to go first. Depends on the development of the quality of life. We mentioned the differences, we mentioned the starting situation with asciminib, which is not the case with TERN-701. We need more data on the once daily schedule with asciminib, which is ongoing, the development for once daily. But it's of course a difference whether you take a drug twice daily or once daily. And I think these are all questions in first line. These are all questions on the quality of life and the tolerability here. We know that BCR-ABL specific inhibition in first line works, and therefore, I think either of the drugs will be efficacious in first line. The differences which we mentioned are the differences in specific mutations. but therefore, I think the major differences over time will be measured on the quality of life. Okay. Right. You know, to your first question, Corinne, around what types of data will inform a registrational path from this study? I mean, I think you know, as we mentioned, this molecule, at least on the preclinical side, looks at least as good or better in terms of potency against various mutations. I think we'll be looking for an efficacy profile that is similar to or better than asciminib, and I think I've mentioned to you, and there's you know, the opportunity for a better dose optimization with TERN-701. Specifically with regard to the fact that we think given the very wide therapeutic index of allosterics as a class, that you could get to higher doses that achieve a better target coverage than the asciminib 80 milligram dose does, specifically in the non-T315I population. And we know from long-term data with asciminib that there's not a real meaningful difference between the safety and tolerability profile between the 80 mg dose and the 400 mg dose, which is approved for T315I patients. So the argument is that allosterics can be dosed higher in a larger group of patients. So we see that as an opportunity, and we're working to, again, really dose optimize. The CARDINAL study is designed to do that by testing two doses in expansion, where we could test this hypothesis, and then again, if we see a differentiated efficacy profile and a potentially differentiated safety profile, we think second line and frontline are equally good opportunities for us to pursue. But again, we'll need more data in 2025 to inform that decision on which path we take or whether we take both. Thank you. One moment for our next question. Our next question comes from Ritu Baral with TD Cowen. Your line is open. Hi, guys. Thanks for taking the question. I wanted to ask some further questions about the dose. As mentioned, you are starting in the current trial at the 160, and you mentioned two doses over the course of the presentation. Have you dosed down to 80 milligrams, as you previously had the option of doing, or have you elected to dose up? And how are you viewing stratification across the doses in CARDINAL for now? Yeah. What could we expect in the interim data? Then I have a follow-up. Thanks. Right. So the 160 mg is this dose level one or starting dose, and the intent is to escalate from 160 to 320, 400, subsequently 500. 80 milligrams is a minus one dose, and that's typical of any phase I study. That's sort of given a sort of a you know an option in the event that you run into a you know protocol-defined reasons to drop the dose to a lower dose level because of safety. We don't anticipate that again, because we've already seen data from our partners dosing at dose escalation in China. And so 80 milligrams is not being tested in our CARDINAL study again, because it's not the starting dose. 160 mg is the starting dose. To your point about stratification, you know, in these small phase I dose escalation cohorts of three to six or nine patients, it's really not very practical to be able to meaningfully stratify patients according to any single, even a single covariate or more than one covariate. We do see stratification as an option for the expansion, where again, now you can randomize to two doses and then stratify, for example, based on baseline transcript level or prior TKI, for example, or mutation, to be able to get a more balanced population across your expansion arms. But in dose escalation, typically stratification is not something that you see. Got it. And then my follow-up is just on how the data will be released. I guess, even though MMR would be far too preliminary to be useful or, or achieved, do you anticipate disclosing transcript decline rates on an individual patient, sort of like by spaghetti plot? And will you clarify, to help us discern what sort of transcript decline is seen in these- Yeah ... these different groups? At the beginning- Yeah ... of the description of CARDINAL, you mentioned, you know, patients could be looking, could be enrolling, moving to second line because of intolerability. Right ... inadequate response or relapse. So how will we visualize that transcript decline? Yeah, I think you kinda hit some of the aspects of how to visualize that in terms of what I already mentioned, and Andreas mentioned. Dr. Hochhaus already mentioned that you know, it's on an individual patient by patient profile. But what's very important is the history of that patient in terms of the underlying disease biology, in terms of their prior therapies, and in terms of what their disease slope was before starting TERN-701. Some of the ways you described could be how we display the data in terms of, you know, putting all that information into a visual that conveys sort of what the drug is doing specific to each patient's circumstance, whether that be stabilization as a good outcome in a very refractory, high-baseline transcript patient or a less refractory, you know, a lower disease burden patient, where you want to see a decline in transcript levels. And that could be shown in the context of a spaghetti plot or potential shift table, depending on how the data pan out. ... Got it. And last question, when could we see first meaningful data on the differential tolerability or safety profile of 701 versus the Novartis compound? Is that something that- Yeah. Could emerge from the final CARDINAL data, or would that require the pivotal? That'll be emerging over time and again, I think from in a very early dose escalation standpoint, you know, you're primarily assessing dose-limiting toxicities, as sort of your key metric of safety, but that being said, you can get more than DLTs. You get sort of, you know, all treatment-emergent AEs, the grades of that. You can look for specific differences or trends in the AEs of special interest that we know impact asciminib, like amylase, lipase elevation, so if you're trending towards numerically better numbers with regard to that, that's encouraging, but final determinations on safety obviously can't be made with small sample sizes either, which is why we think, you know, longer-term duration follow-up is necessary. But that also points to another advantage we have in that, you know, the safety data set coming out of China is also pretty robust for us to be able to combine the two data sets to get a more meaningful assessment of how safety compares to, say, asciminib or other TKIs. Dr. Hochhaus, sorry, where would you expect to start seeing signals, just given your real-world experience with asciminib? Where? At which time point or what do you mean? Yeah, just within development. Just given your real-world experience, where do you think in sort of a data set in a holistic data set, you'd say, "Oh, this is where I would expect to see a difference in the tolerability profile of two similar drugs? Of course, we- The patient number. In a typical phase I trial, there is a dose escalation, and, of course, we escalate from one dose to the other when we soon see no DLT, and that's, of course, my measure. How far can we go with the dose escalation? When we see a beautiful efficacy with a given dose without any DLT, then, of course, I assume that the drug is well tolerated at this dose. That means that's a typical phase I design, and I would follow this design with my expectations. Thank you. One moment for our next question. Our next question comes from Eric Joseph with J.P. Morgan. Your line is open. All right. Thanks, and thanks for taking the questions. Maybe the first one for Dr. Hochhaus. Kind of speak to the extent to which speed to response or speed to MMR is a priority with the currently available treatment options in CML. I guess, how long will you typically keep a patient on therapy before concluding perhaps suboptimal response and then moving them on to another line therapy? And then perhaps for the company, can you speak to sort of how well characterized or understood the mutational profile is of patients either non-responding or progressing with asciminib, and whether those might be represented in the CARDINAL trial? The milestones, the definition of the milestones and the different levels of molecular response have been developed for first-line and second-line use of the drug. That means in first and second line, we want to see a rapid decline of the BCR-ABL levels because we know that this is the path, the best path for to treatment-free remission. In the third-line situation, that's much different. In the third-line situation, we defined in our expert recommendations the level of 1% BCR-ABL as the actual treatment goal, which we expect, and there is no specific definition on the speed because we acknowledge that the speed is very individual. That means the expectation that the deep molecular response is achieved very rapidly in a third-line situation is not realistic. And therefore, I think... I treat patients, actually. I treat patients with another investigational drug currently in an investigational study, who is very stable on 50% BCR-ABL. But previously, he had always cytopenias, and his cytopenias disappeared now. He's now stable in the hematologic level, and that's happy. He is happy, I am happy, and I don't care about the BCR-ABL level in his specific situation. That means we want to improve the general performance of the patients, and the PCR level is one part of this performance. But a stable hematology without dangerous cytopenias is another important point, and this needs to be considered individually. And to your point, the question about mutations, like, I think it's hard in the third, fourth, fifth-line setting to really see the evolution of mutations on, say, asciminib, if there were other TKIs prior to that, that the mutations may have developed in. So the mutational context is a bit more complex in the relapsed/refractory setting to attribute it to one drug or the other, where I think the frontline setting is much cleaner in terms of seeing what the mutational evolution would be to any given drug, and that's how I think the asciminib frontline experience over the next several years will inform that. And so again, we are not restricting any specific mutation. We're looking at sort of on a case-by-case basis in terms of the CARDINAL study on whether or not the patient should come on based on what information there is about a specific mutation and whether or not it prevents, for example, any allosteric from working if there's mutations that block the binding of the drug from the myristoyl pocket. But maybe, Andreas, your views here would be helpful, too, in terms of how to think about mutational, the mutations that we enroll to the phase I study. Yeah, I think you summarized it in a very good way, and I would be comprehensive as well. I would not exclude any specific mutation which has not been tested pre-clinically in a negative way. That means, which is not predictive for a non-response. And these mutations are very rare, and therefore, I think we should be very comprehensive in the inclusion, and we are, and I know that, yeah- Mm-hmm ... from our practice. Great. Operator, we have time for one last question now. I think we're coming to half past the hour, so we'll take one more question. One moment. Our next question comes from Josh Warman with Citizens JMP. Your line is open. Hi, thank you to the Terns team for putting on this great event, and thank you, Dr. Hochhaus, for the really informative session. And thank you for taking my question as well. Yeah, so I guess this is for Dr. Hochhaus. From the ASCEMBL trials, we did see discontinuations, and that most likely will be the case with any new inhibitors. So can you briefly touch on how physicians think about after treatment failure or discontinuation of allosteric TKIs, and therefore, how that may impact physicians' decisions to use the allosteric TKIs, such as 701, in earlier lines? Thank you. Yeah. It depends, of course, on the specific situation again. What was the intention of the trial? If it was a third line situation, we know from the ASCEMBL trial that about 55% of patients have the 1% BCR-ABL level, and the others don't respond. And after two years of therapy, of course, I would like to see a less than 1% BCR-ABL level. And therefore, it's not surprising that these colleagues will discontinue the drugs. The competitor against this situation, and we must not forget this, is allogeneic stem cell transplantation. Allogeneic stem cell transplantation is the way to cure a CML patient. With all the disadvantages, of course, but we should offer the option for a cure for a patient who did not achieve a molecular response to three or four lines of therapy with resistance. Therefore, in such a situation, I would be very cautious with any new drug. You could ask about ponatinib as well here in this situation, but I would be very cautious with any of the other drugs and should consider allo transplant in this late line situation. Overall, we transplant 3% of all CML patients for the time being, but too late. Some of them too late. That means we should consider allo transplant in this setting as well. Okay, great. Thank you. I think that brings us to the end of our question and answer session. I'll pass it back to Amy. Yeah. Thank you all for joining us for this engaging and dynamic discussion on new treatment options in CML. I thank Dr. Hochhaus for sharing his wealth of information and expertise in this area and answering so many questions. Andreas, you really brought the patient perspective into this clinical and scientific discussion, which we greatly appreciate, as it is core to all that we do at Terns. For any written questions that we not get to on the call, we look forward to following up with you through our investor relations team. I just wanna say have a great day, and enjoy the rest of the summer. Thank you. Thank you. Thank you, ladies and gentlemen. This does conclude today's presentation. You may now disconnect and have a wonderful day, and we thank you for your participation.