Welcome to the Enliven Therapeutics June 2026 clinical data update. All participants will be in listen-only mode during this call. Throughout the presentation, you can submit your questions via the Ask a Question tab on the right side of your webcast screen. As a reminder, this conference call is being recorded. I would now like to turn the call over to Rick Fair, CEO of Enliven Therapeutics.
Greetings from EHA in Stockholm. Thank you all for joining us today. With me from Enliven are Helen Collins, our Chief Medical Officer, and Damiette Smit, our Vice President of Early Clinical Development. We are also honored to be joined by Dr. Dennis Kim, Professor of Medicine in the Department of Medical Oncology and Hematology at the Princess Margaret Cancer Centre in Toronto. Dr. Kim will join us later in the call for Q&A. On today's call, we will be making forward-looking statements. These statements have risks. We encourage you to review our SEC filings for more information. Today, we are thrilled to provide important updates on our lead program, ELVN-001. We will provide an overview of the ELVN-001 opportunity and share exciting new clinical data from the ENABLE phase I study that will be presented by Dr. Kim later today at the European Hematology Association meeting.
We will also provide an update on recent FDA interactions and next steps for the program. At the end of the call, we will open it up to the audience for a live Q&A. Please submit your questions any time during the call. Today's data and regulatory updates reinforce our conviction that ELVN-001 has the potential to be the best-in-class tyrosine kinase inhibitor in CML. ELVN-001 is the only highly selective ATP competitive BCR-ABL1 TKI designed to avoid off-target adverse events and enable dosing levels to maximize efficacy. ELVN-001 was built for the long-term treatment CML patients require, with convenient once-daily dosing with or without food and reduced drug-drug interaction potential. Today's data update will show, in a large phase I data set, a highly encouraging efficacy, safety, and tolerability profile that compares favorably to currently available therapies.
We believe this clinical profile positions ELVN-001 to compete across all lines of therapy. We are pushing aggressively in this direction. We are on track to initiate our initial phase III trial in second-line plus CML and a phase II IST in newly diagnosed CML before year-end. We are also well-capitalized to execute on our plan, with sufficient cash to fund us through the second-line plus phase III top-line data readout. With that quick overview, let me take you through our view of the ELVN-001 opportunity before we dive into the new clinical data. Since imatinib's approval 25 years ago, BCR-ABL TKIs have transformed CML into a chronic disease for most patients. That said, significant unmet needs remain. Most CML patients require daily treatment for their entire lives. As such, an ideal CML treatment would provide excellent disease control, have very few side effects, and be simple to take.
Currently approved TKIs fall short from this ideal in several ways. They are associated with adverse events that can impact patients' quality of life and, in rare cases, can be life-threatening. Even the most effective available TKIs fail to drive major molecular response by key regulatory time points in 1/3 to 3/4 of patients, depending on line of therapy. Approved TKIs have clinically meaningful drug-drug interactions and administration requirements that can make them challenging to fit into patients' daily lives. As a result, we see significant switching in the market as physicians and patients actively search for the best treatment for each patient. CML is a BCR-ABL-driven disease. Today, we have two mechanistic approaches to targeting BCR-ABL: ATP-competitive TKIs and allosteric TKIs, each with distinct profiles. ATP-competitive inhibitors built the foundation of modern CML treatment and remain the most prescribed TKIs in CML.
The first generation, imatinib, transformed CML care and launched the targeted therapy era in oncology. Second- and third-generation TKIs improved upon imatinib's response rates and addressed imatinib resistance mechanisms, but all significantly inhibit off-target kinases. These off-target effects cause adverse events that can impair adherence and quality of life and can limit dosing below levels necessary for optimal long-term efficacy. asciminib is the only currently approved allosteric TKI. Allosteric TKIs improved selectivity and tolerability, but still have liabilities. Because asciminib improves upon first- and second-generation TKIs, adoption of asciminib is occurring in earlier lines, and that's currently ongoing. As a result, we're now seeing a growing number and incidence of resistance mutations. asciminib carries some treatment burden, including many clinically meaningful drug-drug interactions and a fasting requirement before and after dosing.
The current dual-mechanism landscape creates a clear opportunity for a next-generation selective ATP-competitive inhibitor that can address the limitations of both approaches. Why do we need a more selective ATP-competitive agent? You can clearly see from these kinase maps, every approved ATP-competitive TKI in CML has meaningful off-target activity. Broad kinome inhibition drives clinically meaningful toxicities, fluid retention disorders like pleural effusion and edema, cardiovascular events, and GI effects like nausea and diarrhea. In rare cases, these effects can be life-threatening. nilotinib and ponatinib carry boxed warnings for sudden death, heart failure, or arterial occlusive events. These effects create a burden for CML patients and can be a barrier to successful long-term treatment.
This led to the question Enliven's founders asked when they started the company: Can we develop a highly selective ATP-competitive TKI that avoids these off-target effects, can be dosed to optimal efficacy, and can be rationally sequenced with allosteric TKIs to address different resistance mechanisms? Fortunately, the answer to that question is yes. Yes, we can. ELVN-001 uniquely binds a P-loop "folded-in" active conformation of ABL1. This drives its exquisite ABL1 selectivity, as you see in this beautiful Kinome tree. ELVN-001 was also purposely designed with the current treatment landscape in mind, with broad mutational coverage across the clinically important resistance mutations to other ATP inhibitors, including T315I. Given its different binding mechanism, it also retains activity against the emerging class of allosteric resistance mutations, positioning ELVN-001 as complementary to asciminib in the CML landscape.
Finally, ELVN-001 was developed with a favorable PK and dosing profile to make it as suitable for long-term use as possible. Based on currently available data, ELVN-001 differentiates from other drugs in this class in this regard. It has reduced potential for clinically meaningful drug-drug interactions, particularly CYP3A4-mediated interactions. ELVN-001 is not a substrate for common efflux transporters, avoiding an important mechanism of resistance. Further, ELVN-001 is dosed once daily with no food restrictions. Combining these design features with the efficacy and safety profile you will see shortly, we believe ELVN-001 has the potential to be a best-in-class CML TKI. Given its profile, we believe ELVN-001 is well-positioned to compete across all lines of CML therapy over time. With two mechanisms, we expect physicians to sequence between them as they do in many other oncology indications.
When a patient doesn't achieve treatment goals with one mechanism, we expect they will try the other. At the time of our predicted first approval in second-line-plus patients, asciminib will be approaching peak share in front-line and second-line CML. For patients who don't meet their treatment goals on asciminib, we expect ELVN-001 will be a preferred next choice as the best ATP-competitive alternative. With a potential future approval in front-line CML, we expect to compete with allosterics for front-line share. Of course, the outcome will be dependent on the relative clinical profiles. While we don't yet have front-line data to compare, relative safety and efficacy in later line patients have historically translated to earlier lines in CML. Our efficacy and safety data in more heavily pretreated patients compare favorably to asciminib. This makes us optimistic about our chances to play an important role in newly diagnosed patients if approved.
The U.S. branded CML market has the potential to be approximately $10 billion, split roughly evenly between first-line and second-line-plus patient populations. Our near-term priority is to initiate our phase III trial, ENABLE-2, in the second-line-plus setting in the second half of 2026. Based on the data that we will present today and a successful end-of-phase I meeting we recently conducted with FDA, we are on track and more confident than ever. We believe this is a study with a high probability of success that will give us access to the $5 billion second-line-plus CML market in the U.S. To gain health authority approval to initiate a pivotal trial in newly diagnosed CML, we believe we will need a meaningful safety database at our phase III dose and potentially some safety data in newly diagnosed patients.
Of course, our phase I ENABLE safety database is large and growing, so it will serve to support these discussions. To address the potential need for front-line data, we plan to support a phase II investigator-sponsored study expected to start before the end of this year. These plans should enable health authority interactions regarding a pivotal study in newly diagnosed patients in 2027 and a potential study start in 2028. Upon successful completion, this study would give us full access to the $10 billion opportunity in the U.S. We've made a lot of progress this year, and we're excited to showcase that progress today. First, hot off the presses, we just completed a successful end-of-phase I meeting with the FDA, where we reached alignment on the most critical elements of our phase III plans.
We aligned with FDA on 80 mg QD as the phase III dose, second-line-plus as the study population, and the plan to randomize patients to ELVN-001 versus physician's choice of ATP competitive TKI. This has exceeded our expectations for the end-of-phase I meeting. My congratulations and thanks to Helen, Damiette, and our entire clinical and regulatory team. We will meet with the FDA in Q3 to align on the detailed phase III protocol, then we'll be off to the races to initiate the trial this year. Damiette and Helen will walk you through the details of the data to be presented today at EHA in a minute. You see a few of the highlights here. 48% MMR achieved by 24 weeks at our phase III dose of 80 mg QD.
A 55% MMR achieved in earlier second and third-line patients, with consistent response rates regardless of prior asciminib exposure across all lines of therapy. Additionally, with longer follow-up and more patients treated since our presentation at last year's EHA meeting, the safety and tolerability profile remains impressive and appears differentiated from all the approved TKIs. We appear to have a great-looking CML drug. With these data and our regulatory and operational progress, we are on track to initiate ENABLE-2 in the second half of 2026. This trial is a clear and de-risked path to our first approval in second-line plus CML. With that, I'll turn it over to Damiette to take you through the data.
Thank you, Rick. Good afternoon. My name is Damiette Smit, and I'm the Vice President of Early Clinical Development at Enliven Therapeutics. I'm excited to have the opportunity to share the updated data from the ongoing first-in-human ENABLE study with you today. I will start with the design of the study. Patients were eligible for the study if they had chronic phase CML and had failed, were intolerant to, or were not candidates for available active therapies. As a phase I study, the primary endpoint is safety, with key secondary endpoints of centrally assessed molecular response by BCR-ABL qPCR and pharmacokinetics. After dose escalation, three dose levels were expanded in phase I-B, 60 mg, 80 mg, and 120 mg once daily. The 80 mg once daily dose was selected as the optimal biological dose and the phase III dose based on safety, anti-CML activity, and PK/PD modeling.
Study has continued to enroll at the 80 mg once daily dose to generate additional safety and efficacy data. At the time of the snapshot, a total of 49 patients were enrolled at the 80 mg once daily, 20 in the original dose optimization cohort and 29 in the additional expansion cohort. Key demographics and baseline characteristics are presented here. First column shows all patients enrolled in the study across phase I-A and phase I-B. Second column shows demographics and baseline characteristics of the 49 patients enrolled to the 80 mg once daily dose in phase I-B. Overall, a heavily pretreated patient population was enrolled. 70% of patients had received at least three prior unique TKIs. More than half received prior asciminib.
It's important to note that most of the post-asciminib patients had received asciminib in the late-line setting, and the majority had discontinued asciminib due to lack of efficacy, again highlighting the difficult-to-treat patient population. Overall, the safety and efficacy data presented today should be viewed in the context of this heavily pretreated patient population, where remaining treatment options are limited. We have now dosed 161 patients. The median duration of exposure was 35 weeks, with over 1/3 of patients on therapy for over one year. Importantly, the safety data being presented today represents an extensive data set, with 146 person-years of exposure and 118 patients treated at doses of 80 mg once daily or higher. The data shows us that ELVN-001 is well-tolerated, with the vast majority of patients remaining on study and only 6% having discontinued due to adverse events.
This slide summarizes the safety data. As you can see, ELVN-001 demonstrated a favorable safety and tolerability profile with a wide therapeutic window. The table on the right shows treatment-emergent adverse events, regardless of attribution. Most events were low-grade. Importantly, at the selected 80 mg once daily dose, the safety profile was similar to the overall patient population, with low rates of Grade 3 or higher events. During dose escalation, ELVN-001 was escalated to 120 mg twice a day, which is 3x as high as the optimal dose of 80 mg once a day. 80 mg twice a day dose was determined to be the maximum tolerated dose after two patients experienced a DLT at 120 mg twice a day dose.
Overall, the incidence of arterial occlusive events was low. All patients with these events had pre-existing cardiovascular disease and risk factors, such as exposure to prior TKIs with a cardiovascular risk profile, including nilotinib and ponatinib. As Rick mentioned earlier, ELVN-001 was designed to reduce off-target toxicities. Now that we have over 150 patients with safety data, the safety profile continues to be favorable and is consistent with the high selectivity of ELVN-001 for ABL1. Now we'll review the efficacy data. Overall, encouraging anti-CML activity was observed across the study, especially keeping in mind this very heavily pretreated patient population. On the left, key efficacy milestones are presented. At the selected dose of 80 mg once daily, 17 of 28 evaluable patients, or 61%, were in MMR by week 24.
Among patients not already in MMR at baseline, 10 of 21, or 48%, achieved MMR. All seven patients who entered the study in MMR maintained MMR. In addition, 30% of patients achieved a deep molecular response, reinforcing the potent efficacy of ELVN-001. Helen will speak next about these results in the context of clinical data from other TKIs. We believe the best comparative data is asciminib Phase I study, given the similar phase of the study and sufficiently large sample size to interpret efficacy data. In this study, asciminib achieved an MMR rate of 24% in a less heavily pretreated patient population. Therefore, ELVN-001's achieved MMR rate of 48% is highly encouraging, noting that the ELVN-001 data is not quite as mature as the asciminib data set. The graph on the right shows the cumulative incidence of MMR in patients who were not in MMR at baseline.
Key observation is that responses occurred early. As expected, patients receiving more optimal therapeutic doses in phase I-B, as depicted in the green and red lines, are more likely to respond by week 24 than the whole population depicted in the blue line, since that population includes both patients treated in phase I-A and phase I-B. Black curve beyond the week 24 time point in phase I-B is explained by the relatively short follow-up for these patients and the reduced testing frequency from monthly to every three months. As follow-up continues, we believe that MMR will continue to rise over time, as it does in a more mature overall phase I data set. Now, let's take a deeper dive into anti-CML activity observed in individual patients. This shift table shows changes in molecular response category for each of the MMR evaluable patients.
The top row shows the molecular response category at baseline, and the left column shows the molecular response category by week 24. Please note that this table does not take into account a key predictor of response, number of prior TKIs. We will discuss that further in the next slide. The table is color-coded so that if a patient's transcript category does not change or improves, the patients are reflected in the green part of the table, light green for no change and dark green for improvement. If the patient's transcript category worsens, they would be reflected in the yellow part of the table. This shift table shows that the majority of evaluable patients showed an improved response category and none had worsening by week 24.
I would like to draw your attention to the subgroup of patients with baseline transcripts of 10% or higher, as this subgroup has a high disease burden. In the context of a generally heavily pre-treated patient population, this group has the lowest likelihood of responding. In this subgroup, 10 of 17 evaluable patients, or 59%, improved by at least one category, which is highly encouraging and supports the potency of ELVN-001. As mentioned previously, the majority of patients enrolled in the study were exposed to multiple prior unique TKIs and to prior asciminib. We evaluated the clinical relevance of both of these aspects of prior therapy for ELVN-001 in the current data set. On the left, we show MMR by week 24 by number of prior TKIs. Responses were observed independent of the number of prior TKIs that patients were exposed to.
As expected, rates were higher in patients who had been exposed to fewer prior TKIs and lower in patients who had been exposed to a higher number of prior TKIs. That said, meaningful MMR rates were still observed, even in patients with exposure to five or more prior TKIs. To the right, we present MMR by week 24 for the subgroup of patients which was exposed to prior asciminib. The key observation is that responses were still observed after prior asciminib exposure, and the responses were in line with response rates seen in our overall phase I-B data. Now that asciminib is being used more in first and second-line patients, we think it's important to highlight that ELVN-001 does not appear to be affected by prior use of asciminib, which we believe is due to its complementary mechanism of action.
I will now share two patient case studies to complement the cohort-level data presented today. As Rick stated earlier, although allosteric TKIs have resulted in improved tolerability compared to existing ATP competitive TKIs, the emergence of allosteric resistant mutations is of growing concern, especially with the increasing uptake of asciminib globally. Based on preclinical data, ELVN-001 has activity against these mutations. In phase I-B of the ENABLE study, 10 out of 90 patients, or 11%, were enrolled with mutations associated with resistance to allosteric inhibition. As anticipated, anti-CML activity was observed after treatment with ELVN-001 in patients with these mutations. Here, we present a patient who had developed an A344D myristoyl pocket mutation on asciminib. Patient enrolled in ENABLE at 80 mg once daily and achieved a rapid, deep molecular response with only low-grade adverse events reported.
The case illustrates the biological rationale for using ELVN-001 in patients with allosteric resistance mutations and supports ELVN-001's potential use in patients after asciminib. As previously stated, ELVN-001 was also designed to be active against clinically important mutations that can confer resistance to other ATP-competitive inhibitors, including T315I. After developing T315I mutation on asciminib, this patient received ELVN-001 at 80 mg twice a day and achieved MMR, only reporting low-grade adverse events. While the T315I dose evaluation is ongoing, and we are not presenting a formal cohort-level update today, this individual patient provides an illustrative example of preliminary activity of ELVN-001 in the T315I mutation. The ENABLE study has now identified an optimal biological dose for ELVN-001 of 80 mg once daily, which will be taken into phase III.
In the updated data set, ELVN-001 demonstrated a favorable tolerability profile, an encouraging anti-CML activity in a heavily pre-treated patient population, including in patients with prior asciminib exposure. Case studies further support ELVN-001's broad activity against a variety of mutations, including those that arise from treatment with asciminib. In summary, the data today exemplify that ELVN-001 was designed for today's treatment paradigm, with activity across prior lines of therapy and regardless of prior treatment. We believe these data provide a strong foundation for the next clinical stage of development. I will now turn it over to Helen Collins, our Chief Medical Officer, who will present the next steps for ELVN-001.
Thank you, Damiette. I'm now going to present a few slides which put the efficacy and safety data that you have just seen into context, and I think you'll see why we're so excited about the updated data being presented at EHA. I'll then conclude with some additional details on the path forward for ELVN-001. First, I'll start with the efficacy. The first point to keep in mind when comparing this latest ELVN-001 data to historical data from other TKIs is that differences in patient population have a meaningful impact on MMR rates. This slide highlights several important differences between patients enrolled in the ELVN-001 study and those enrolled in the phase I asciminib trial and the TERN-701, now known as MRK-4208, phase I trial. For the ELVN-001 phase I trial, the initial enrollment criteria specified that patients could not be candidates for any other available therapy.
As a result, the study enrolled a difficult-to-treat patient population, including a high proportion of patients in the fourth line of therapy or later, most of whom had received prior asciminib and many had also received ponatinib. In addition, the trial did not exclude any specific subgroups. Patients with CML resistant to prior asciminib, including resistance associated with BCR-ABL mutations, were eligible to enroll. This is an important distinction when comparing ELVN-001 data with results from other programs. For example, TERN-701 initially enrolled patients in the second-line plus setting and excluded patients with CML resistant to asciminib. Similarly, the phase I study of asciminib enrolled predominantly third or later line patients and by definition, did not include any post-asciminib patients.
With asciminib continuing to move into earlier lines of therapy, we believe the high proportion of post-asciminib patients enrolled in the ELVN-001 study, including patients with CML resistance to asciminib, is particularly important. Not only is this a challenging population to treat, but it is also likely more representative of the patients expected to enroll in an initial phase III trial. On the right side of the slide, you can see the significant impact that line of therapy has on MMR rates. These bars show asciminib MMR rates by treatment line. As expected, MMR rates decline as the number of prior therapies increase. In fact, there is approximately a threefold difference in MMR rates between second-line and fifth-line patients. As a reminder, more than 35% of the patients enrolled in the ELVN-001 study were fifth-line of therapy or beyond.
The takeaway from this chart is simple: line of therapy matters, and it matters a lot. When evaluating efficacy across studies, differences in patient populations must be taken into account. With this context, let us move to the next slide. Here you see a cross-trial comparison of the ELVN-001 phase I data with historical data from asciminib and also from bosutinib, which was the most recently approved second-generation TKI and also the comparator arm in asciminib's first phase III trial. The first key point is the high MMR rate achieved by ELVN-001 in this heavily pretreated patient population. The achieved MMR rate was 48% in the phase I-B 80 mg QD cohort, which is our planned phase III dose, and 40% across the overall I-B population.
As we had previously described, the proportion of enrolled patients who have not completed the full 24-week assessment period affects the denominator and therefore may influence the achieved MMR rate over time. Even with that consideration, we believe these results are highly encouraging. Importantly, these data compare favorably with historical results for asciminib, which achieved an MMR rate of 24% in its phase I trial, despite enrolling a less heavily pretreated patient population. The comparison is even more compelling versus historical bosutinib data, where the achieved MMR rate in phase I was 15%, again, in a less heavily pretreated patient population. Taken together, these data support our belief that ELVN-001 has the potential to be the best-in-class ATP competitive BCR-ABL1 inhibitor, and the data provide confidence in the design and rationale for our planned phase III program.
The second point is that historically in CML, phase I efficacy has been predictive of subsequent phase III outcomes. As shown on this slide, the MMR rates observed in phase I studies are similar to the MMR in the subsequent phase III trials. Based on the efficacy and safety profile generated to date, we believe ELVN-001 is well-positioned to demonstrate superiority to second generation ATP competitive TKIs in our first phase III trial. Overall, these data give us confidence as we advance 001 into phase III and strengthens our conviction that ELVN-001 has the potential to compete across multiple lines of therapy, including the frontline setting. Next, I'll provide some context on the safety. Now that we have safety data on 158 patients, we're increasingly confident that 001's selectivity profile has the potential to provide meaningful differentiation from currently available TKIs.
Starting with the top chart, which shows hematologic toxicity, I would like to highlight that these data are new and were not included in the EHA presentation. The EHA presentation reports hematologic adverse events, which is standard for phase I presentation. Adverse events require a laboratory to be both abnormal and the investigator to deem the abnormality to be clinically meaningful. There is an element of subjectivity. In contrast, the data shown here are laboratory abnormalities, which provide a more objective measure and are the metrics typically included in prescribing information.
Viewing ELVN-001 lab data in this more objective way suggests 001 may have less hematologic toxicity, particularly for Grade 3 and Grade 4 events, compared with historical asciminib data. This is potentially important because neutropenia and thrombocytopenia were the leading causes of dose interruptions, and thrombocytopenia was the most common cause of dose reduction in asciminib's late line phase III study. If ELVN-001 can reduce hematologic toxicity, it potentially could improve patient tolerability and support better long-term treatment outcomes. Another important toxicity is highlighted in the bottom of the chart, which is cardiovascular safety. To date, the incidence of arterial occlusive events has been low at 4.4% for all grades and 1.9% for Grade 3 and 4, with events only reported in patients with cardiovascular risk factors, including prior exposure to nilotinib or ponatinib.
One important point regarding arterial occlusive events is that these events are defined using a broad grouping of preferred terms rather than a single diagnosis. In our analysis, we have attempted to apply an approach consistent with that used by the FDA in its review of asciminib. As a result, we believe the reported incidence is closely aligned with the rates described in the U.S. prescribing information for asciminib. Supporting the potential for a favorable cardiovascular profile, rates of hypertension as an adverse event have also been low, with 5.7% of any grade and 1.9% of Grade 3. While cross-trial comparison should always be interpreted cautiously, these rates compare favorably with historical data. We have previously discussed our expectation that 001's selectivity profile could reduce off-target toxicities such as gastrointestinal events and rash, which are often associated with inhibition of kinases such as KIT, SRC, PDGFR, and VEGFR, et cetera.
As Damiette showed earlier, we are indeed seeing lower rates of these toxicities compared to historical ADP inhibitors. What we have not emphasized before is that 001 also has an approximate 32-fold specificity for ABL1 over ABL2. To our knowledge, no currently available CML therapy demonstrates this degree of specificity. Even allosteric inhibitors are reported to inhibit ABL1 and ABL2 at roughly similar levels because of the close homology of these two kinases. The distinction between ABL1 and ABL2 matters because preclinical data suggests this selective ABL1 inhibition might reduce both hematologic and vascular toxicity. Ultimately, only randomized trials can determine whether these observations will translate into clinically meaningful differences. However, it's exciting to see the emerging clinical data align with the underlying preclinical hypothesis.
More good news is that we recently had an end-of-phase I FDA meeting, which not only confirmed the go-forward dose of 80 mg QD, but the agency supported our proposed design for the initial phase III pivotal trial, including enrollment in patients in second-line and later setting, in comparison against physician's choice of an ATP competitive TKI. Alignment with the FDA on these key elements significantly advances our planning efforts, and we are looking forward to finalizing the phase III protocol with the FDA in Q3 and initiating the trial before the end of the year. This final slide summarizes our registrational strategy as of June 2026. On the upper left, you see the ongoing phase I study. This is the trial that generated the data presented today.
In the top middle, you see the first phase III trial, which was just discussed, will be in the second-line and beyond, and we expect to initiate this trial prior to the end of the year. The goal of this first phase III trial is to demonstrate that 001 is the best-in-class ATP competitive inhibitor for patients with CML. The lower box outlines our planned second phase III trial in the frontline setting. Given the data presented today, we believe ELVN-001 has the potential to be a compelling option for newly diagnosed patients with CML. We want to bring that option to patients as quickly as possible and will start preparing internally in 2027 with a view to initiating this frontline trial in early 2028. As a reference point, asciminib's frontline trial enrolled over 400 patients in approximately 12 months.
We are considering including asciminib in the comparator arm and will make a decision based on our conversations with the FDA and asciminib's positioning when we initiate the trial. The goal of this frontline trial is to demonstrate that ELVN-001 is the best treatment option for newly diagnosed CML, regardless of class. Now, I will turn the presentation back to Rick for some closing remarks.
Thanks, Helen. There you have it. We've covered a lot of ground, maybe to summarize, we have a highly differentiated, potentially best-in-class CML TKI, as evidenced by the compelling data we shared today. We're on track to start a high probability of success phase III trial by the end of this year. We have a strong balance sheet with cash into 2029 and runway beyond the anticipated top-line data from ENABLE-2. Last but certainly not least, we have a great team. Over the last year, we've built upon the great foundation already in place at Enliven to be ready for this transition to late-stage development. I can say with confidence we're ready. With that, I'd like to bring Dr. Kim into the discussion. Operator, please open the chat for Q&A.
Thank you. As a reminder, if you would like to ask a question, please use the Ask a Question tab on the right side of your screen. We will wait one moment to allow the queue to form.
All right. Looks like Dr. Kim, we have some questions already rolling in for you. I think it's phrased in a couple of different ways, maybe can you discuss your view of the data? What stands out to you compared to other drugs, or what stands out to you from the data that are being presented today?
I think that the beauty of ELVN-001 is tolerability, tolerability, which make us to continue the treatment, which is durability and which will increase the efficacy. I think that these are the combination. It's not just the one. However, I have to emphasize that it does have a excellent tolerability. Because of that, we can increase the efficacy, and the patient can continue their treatment, and in future, maybe we might be able to achieve maybe operational cure in future. Thank you.
Maybe another one for you, Dr. Kim. How will you incorporate this in your practice? Maybe talk about your clinical experience in the study so far. You've, I think, been our highest enroller. Maybe talk about how you envision using ELVN-001 in the future.
Yeah. I think that in my practice, I think that as a part of this phase I study, I try to find out someone who doesn't have any other option. In that case, I think that I'm stuck. I couldn't go ahead to any potential other drug in their CML therapy. However, now I do feel more comfortable to recommend it to my patients. If they are in trouble for intolerance or they are in trouble for any other kinds of issue, even they have some other comorbidity, I strongly recommend them to go ahead to that kind of treatment switch. I'm pretty sure that the phase III study that we are now planning, it is going to become very positive at the end, and I hope I can utilize this drug in my clinical practice as soon as possible.
Awesome. Thank you. A question for, let's say, Helen. There's a question about why we chose 80 mg versus the 60 mg or 120 mg dose that showed better efficacy in the prior update. You tackle why did we pick 80 mg, I'll handle the 60 mg/120 mg better at the last update comment. Yeah.
Well, we had an advantage that a lot is known about the BCR-ABL as a target. I think as you heard from Damiette's presentation, the decision was a combination of factors. Obviously, we look at safety across those three dose levels, 60 mg, 80 mg, and 120 mg, as well as efficacy. There was no appreciable difference. It really came down to PK/PD modeling. Whereas 80 mg and 120 mg both mean a complete coverage of the target by more than 99% of patients, there's no particular reason to pick 80 mg over 120 mg other than the goal was always the biologically optimal dose. That's how we landed on 80 mg.
Maybe I'll tackle the other part of that question, which was about the "better" 60 mg and 120 mg group from our last update. Those of you on the call probably recall that in January, we presented data in two groups, an 80-mg cohort, which at that time was fully mature, meaning every patient was past 24 weeks, and a 60 mg and 120 mg combined cohort that was less mature. We did that to specifically show the impact of data immaturity on MMR achieved rates. In that update, 60 mg and 120 mg looked better than 80 mg QD because it was less mature data, not because we see a dose effect. For clarity, we do not see meaningful differences in efficacy or tolerability in the dose range of 60 mg and 120 mg QD. At this data update, two things have happened.
Our 60 mg and 120 mg group have matured, so those patients are now past 24 weeks, and we've continued to enroll patients at 80 mg. You see that data set is a little less mature. Correspondingly, the efficacy at 80 mg has gone up. The efficacy at 60 mg and 120 mg have gone down. Ultimately, when the overall data set are fully mature, meaning all patients are past 24 weeks, based on the patient populations that we're enrolling now at 80 mg, it seems like our achieved MMR rates would be somewhere in the 40% range± . Obviously, results may vary. These are small data sets. The 48% we're reporting today does reflect some data maturity, and many of you have asked those questions, so I want to be clear and direct about that.
Dr. Kim, how would you use ELVN-001 versus SCEMBLIX in second-line CML after a frontline ATP competitive first or second-generation TKI?
As a second-line specifically? Okay.
Sorry, second-line specifically.
So second-
This, I presume they're asking in the context of a future approval in that setting.
Yeah, assuming the future approval of a second-line, I think that in terms of the tolerability, I'm also using the SCEMBLIX or asciminib in my clinical practice, sometimes I have some patients ended up to develop some myristoyl pocket mutation, or they ended up to have some issue for their thrombocytopenia or peripheral neuropathy, et cetera, et cetera. My patient who is on ELVN-001 in a phase I study, I think that they are showing a very excellent tolerability. They do feel nothing, I have to tell you, and I think that their feedback is really good. That is the reason that I'm going to continue to enroll that patient. Probably at the end, our practice in a CML, even in a second-line setting, I think that we were paying attention to the tolerability profile rather than anything else.
That tolerability is going to turn out to be a higher efficacy. I think that because that is the strength of ELVN-001. I think that based on this, maybe our practice is going to adapt ELVN-001 in the second-line setting. Later on, once you have frontline data, I am pretty sure that we will also be able to utilize ELVN-001 even in a frontline setting later on. Thank you.
Appreciate that. Helen, a number of questions is unsurprisingly about the second-line plus pivotal trial. Maybe starting with this one. Based on our data, are we planning to cap enrollment of patients who switch from asciminib primarily for efficacy versus tolerability reasons in our phase III?
No, we would not. We see responses, as we said, in patients who have received prior asciminib, whether they stopped asciminib due to intolerability or to resistance, there would be no reason to cap that patient population.
Can you share which options you primarily expect to be used from among the ATP competitive TKIs in the physician's choice arm?
I'll-
What level-
Dr. Kim
What level of efficacy do you anticipate from the control arm?
First I'll say which one will you pick for you think more often in the phase III trial?
Maybe depending on their reason for the failure for their frontline therapy, if it is related to their resistance. You also have to look at their comorbidity, et cetera. Probably if they failed asciminib, then as a control arm, I expect that maybe nowadays, I think based on the ASCEMBL first data, lots of people may consider the dasatinib. However, frankly speaking, we have no data. I published some in vitro data, but that is more for the combination. We don't have any data to support to get the direct answer, which TKI is better in the patient who failed asciminib. I think that it would be a very fair comparison between the asciminib versus dasatinib in that scenario. For the other cases, like who failed the other ATP binding inhibitor, for example, dasatinib and developed a pleural effusion.
Maybe in that case, who knows? Maybe someone would like to pick up the asciminib or imatinib as a control arm. I think that it really depends on different scenario. You have to accept a very diverse population and the different scenario in that kind of standard TKI drug selection in comparison to ELVN-001. Thank you.
In terms of what we expect the comparator arm to perform, I think you've seen us make this comparison again with all the caveats of a cross trial comparison between the data we're seeing and the data in the third- line plus for asciminib and in particular second generation. You can see that, clearly ELVN-001's, we don't think it's going to have difficulty beating a second-gen. At the same time, there is not as much information in the second- line, and this will be a mixture of people, second-line plus. We haven't presented publicly all the details of our statistics, but you can imagine that we're expecting to be at least 15% better, and we'll want to make sure that we have some confidence interval around.
Thank you, Helen. One clarifying question here was based on the FDA feedback, confirm that we are not planning on including asciminib in the control arm.
Yes, we are not planning on including asciminib.
That is aligned with FDA?
Again. The goal of this first trial is to demonstrate we're the best ATP inhibitor.
Yeah.
Goal of our second trial in that frontline setting is to demonstrate.
You are going to.
the best drug overall.
You are going to enroll any patient who failed the asciminib frontline.
Yes. Regardless.
Then we will get the answer. In that case, after the asciminib failure.
Which TKI we should go ahead?
Yeah.
My expectation is we will be superior to other conventional ATP binding inhibitors in that setting. Thank you.
One for you, Dr. Kim. This is about what you anticipate doing with ELVN-001 versus another allosteric, like TERN-701. Question, we saw TERN's MMR degradation with more asciminib usage in prior asciminib patients, I presume. Whereas ELVN-001 was able to maintain MMR regardless of prior asciminib usage. Do you think there's enough data here to shut down the class switching debate, i.e., that physicians really ought to make the automatic decision that after an allosteric inhibitor like SCEMBLIX, it's best to use an ATP competitive agent like ELVN-001?
Oh, that's a tough question. You are now putting in a very difficult position. We don't have the data, but I think that we assume that maybe if they already failed allosteric inhibition, probably, maybe we may need some new medication with some new mechanism of action. My bet is probably the ATP binding inhibitor would be better than the TERN-701. However, we have to generate the data.
Very clear. There are a number of questions about frontline here. I think there's questions about just confirm what the frontline plan is, what do we need to show, et cetera. Maybe I'll reiterate what we described in the presentation, and Helen, you can add anything I miss. I think our belief is that we will need safety data at our phase III dose, 80 mg or above. A safety database that has an adequate number of patients with adequate follow-up to confirm that we have a safe agent before we expose newly diagnosed CML patients to an experimental medicine. Further, we believe that we will probably need a small cohort of patient safety data in frontline CML patients.
The plan that we have is to continue to accrue patients at 80 mg QD, and we're doing that in our phase I ENABLE study, and obviously we'll begin doing that shortly in our randomized phase III study, ENABLE-2. In addition, we are supporting an investigator-sponsored trial, phase II study in newly diagnosed CML to generate some data beginning in 2027. I think with that combined package, we would engage with health authorities in 2027 with the expectation we could start a study in as early as early 2028. Anything to add to that, Helen?
No.
I know our plan. That's good. Let's see. We're making good progress here. We showed data that said in patients with one or two prior TKIs, we achieved 55% MMR. How are the patients split between one versus two prior TKIs, Helen?
Well, we haven't made that data public. We don't have that many patients in the second-line, so majority of that is the third-line setting.
We'll leave it at that.
Which again, is exciting to see that high number and when it's mostly third-line patients.
The question, do you expect the 80 mg cohort to look more like the 60 mg/120 mg cohort when data are mature? Any color you can provide on these patients or when these patients are responding in the 24-week timeframe? I think maybe I'll take the first part, and then Helen or Damiette, you can comment on the time-to-response question. I think I tried it earlier to describe that we acknowledge that the 80 mg cohort is less mature in this update, so may benefit from some patients who have not yet responded or reached 24 weeks. That it is reasonable to assume that that will converge to something that looks more like the overall phase I-B population when those patients mature. I will say that when comparing specifically to the 60 mg and 120 mg group, the 60 mg and 120 mg group were a little more heavily pretreated.
I think ultimately, their MMR achieve rate would be a little bit lower, or at least the expected MMR achieve rate there would be a little bit lower than the 80 mg cohort. Helen or Damiette, comment on time to response. When do we see responses typically?
I can say that the way the trial is designed is that transcript levels are drawn once every month until they're at six months, then every three months. You can see from those curves, is that in general, we see the responses quite quickly. We do see responses and, again, going back to that slide, you look at the overall patient population. You'll see that you'll continue to see responses beyond that time point. The majority of them do happen in those first 24 weeks, which is what we want. I think, with some of these questions, I just want to add about comparing 60 mg, 80 mg, 120 mg.
I want to reiterate what Rick is saying, is that as we keep pointing out, the things that we know that impact response are the number of prior therapies, the transcript level at baseline, then whether patients have stopped a prior drug due to resistance or intolerance. Again, we made no limitations on any of those. I think that's why we look forward to getting more and more patients at the 80 mg. I think looking at the whole set of phase I-B, 60 mg, 80 mg, and 120 mg, as Rick said, we expect that the MMR rate to fall somewhere around that 40% ± .
Question here about, efficacy in asciminib-resistant versus intolerant patients. I think this was covered on our slide, Helen, do you want to reiterate what we observed there?
Yeah. Obviously, we've spent a lot of time looking at this because, as Dr. Kim said, we expect more and more use of asciminib early line, and we need that data as we plan for our phase III trial. I think we're very happy, and it's what we would expect, that we don't see a difference between patients who have had asciminib and not had asciminib. Once you take into account line of therapy and other impact, there is some impact, just like there is for all of the drugs if, as I said, patients stop for resistance. If you stop, whether it's resistance to imatinib, second-gen asciminib, those patients respond at a lower rate than those who stop any of those drugs for intolerance. There's no difference between asciminib and other drugs.
Question about safety. It appears many of the treatment emergent adverse events are just part of the background disease. Can you discuss what's considered treatment-related versus treatment emergent?
I think we take a conservative view of this. Adverse events, obviously, as Dr. Kim pointed out, it's the most important thing, really, I think, for these patients who are going to hopefully have a normal life expectancy. Other than that, I guess if we're going to guess, I'll put it back to Dr. Kim. If you think there are some adverse events that you will see in every drug no matter what, even 001 with its selectivity.
Yeah. For example, like a thrombocytopenia, I think that it happen all the CML drug. That is a kind of evidence that the drug is working. All the CML drug, it does also induce pancreatic enzyme elevation. Amylase, lipase. It's not just one drug is maybe better than the other. I think the older drug, even some other drug in other cancer therapy, tyrosine kinase inhibitor, it affect the pancreatic enzyme elevation a lot. It is not quite just particular for the ELVN-001. I think these are the most common drug-related side effect, even regardless of the type of the TKIs. Other than that, what kind of other side effect do we see in ELVN-001? I will say nothing. Actually, my patient is now giving out that kind of feedback. It is not an objective finding. It is more subjective.
Their experience, they do feel nothing. In comparison to the other TKIs, while they are on other TKIs, they do experience lots of fatigue, or sometimes they do feel lots of other types of musculoskeletal pain and et cetera, et cetera, GI toxicity or skin toxicity, et cetera. Now, after switching over to ELVN-001, they do feel nothing. They can go back to their normal activity. That is the reason that I really like this compound from my practice perspective. That's why I can recommend this drug to my patients. Thank you.
Thanks. Do we think the competitive phase III are designed in a way that can produce definitive answers, whether ELVN-001 and TERN-701 are superior in the respective categories? I'll take a stab at that and Helen can weigh in. No. We aren't going to conduct a randomized study versus TERN-701, I think that obviously, there will be inherent bias in the patients enrolled. For example, I think it highly likely that our phase III study will include a lot of patients who've failed asciminib due to efficacy, we won't see as many of those patients enroll in a TERN-701 study. I think it'll be very difficult to do that cross-trial comparison. Ultimately, as we do bigger studies, we'll learn more. As Merck presents more data, we'll learn more. I would say ultimately, the acid test will be in newly diagnosed patients.
That's the most homogeneous patient population, a cross-trial comparison there will probably be the most valid. Helen's nodding her head, I won't ask her a further question there. Another question about TERN-701. Can I get your thoughts on a poster that was released this morning for HS-10382, which is Hansoh's name for TERN-701? What are your learnings and working conclusions? That was a small patient data set out of a single center in China, 21 patients in newly diagnosed CML, where the efficacy looked similar to asciminib the safety looked directionally worse. Obviously, small data set, cross-trial comparison, caveats apply, et cetera. I think our thesis on TERN-701 has been that it is a very similar molecule to asciminib, it appears to be an experiment about high dosing and allosteric to see if you get better outcomes.
I think what we've seen so far from very early data is promising. I think Novartis has done quite a bit of experimentation with dose with asciminib, high dose asciminib looked moderately more effective than standard dose asciminib also had higher toxicity liability. I think maybe the small data set seems to support that, very early days, it's 21 patients, the data from a single center. I don't think we should overreact to that. We look forward to seeing more data from Merck to understand what they're seeing with that asset. Dr. Kim, is there a potential to combine ATP competitive with allosteric inhibitors in the future to increase the number of responders as well as more patients in MMR?
Why not? My short answer is why not? Right now, we don't have that kind of clinical trial data. I think that I'm also working on. In future, I think that to me, the best combination, maybe as a frontline tab, if your trial is going to be successful, then you don't need a combination. I think that still there is a room that we might be able to utilize that kind of combination of allosteric inhibitor with the ATP binding site inhibitor as a combination because their mutation profile, and that is somewhat different. I think that there would be some way to supplement that kind of a mutation profile, or why not? I think that if your trial is successful, for example, your second-line trial or your frontline trial, then maybe the combination strategy is going to die. I'm working on it.
I have to say, I want to see whether my hypothesis is working or it is not working. We just need to generate that kind of data.
Thanks. We're running short on time. I'll take one more question here, and of course, we can follow up offline after the call today. For post-SCEMBLIX patients, the 60% MMR rate in six patients looks broadly consistent with the 55% MMR rate across all 27 patients treated at the 80 mg dose. Can you discuss how median follow-up in the proportion of patients with prior intolerance compare between these subgroups and versus the later line subgroups? I know that the 60% is in patients who've received one or two prior lines of therapy and prior exposure to asciminib. All of those patients that were evaluable for MMR achievement failed asciminib due to lack of efficacy in that group. That's obviously a higher proportion than in the overall population. As we'd expect, that has no bearing on efficacy for ELVN-001, given its different binding mechanism.
I think we can say that safely. Any sense of how the mix between intolerance and lack of efficacy spans across the subgroups in later lines, Helen? I mean, it's a majority of the overall population. What we said, 65% of the prior asciminib patients failed due to efficacy, not tolerability.
Yeah. Majority.
Did that vary by line, or was it
No
pretty consistent across?
No. Of course, many of our sites also had competitive phase I trials, and there was a reason we probably got more of those.
Well, I appreciate all the questions. I see we have a few more to get to, but unfortunately, we're at time. I think we're going to have to conclude the Q&A portion of today's call. Maybe I'll just wrap up by saying we're really excited about the data and the regulatory updates we shared today, and we're really excited about starting the phase III trial ENABLE-2 later this year. Thanks to all of the Enliveneers who drive our progress every day, to our ENABLE investigators and their patients, to Dr. Kim for joining us today, and to everyone who participated and listened today. If you have remaining questions or questions in the chat that we didn't get a chance to answer, please feel free to reach out and we'd be happy to follow up. Thanks very much.
This concludes today's call. You may now disconnect.