Thank you for standing by and welcome to the Enliven Therapeutics ELVN-001 Clinical Data Update Conference Call. Currently, all participants are in a listen-only mode. As a reminder, today's program will be recorded. After the speaker's presentation, there will be a question-and-answer session. If you have a question, please use the Ask a Question tab at the top right of the webcast player. Questions can be submitted at any time during the program. I would like to turn the call over to Sam Kintz, co-founder and CEO of Enliven Therapeutics. Please go ahead.
Thank you all for joining us today. We are excited to share an update on our ELVN-001 program. We will begin with a brief introduction of the speakers and the ELVN-001 opportunity. We will then provide an overview of the evolving chronic myeloid leukemia landscape and 001's preclinical profile. Next, we will provide an update on our ongoing ELVN-001 phase 1 trial based on data recently presented at the European Hematology Association Conference in Milan. After that, we will wrap up with a summary of next steps for our 001 program. Finally, we will open it up to the broader audience for a live Q&A. On today's call, for management, I am Sam Kintz, CEO and co-founder of Enliven. With me is Helen Collins, our Chief Medical Officer, and Damiette Smit, our Vice President of Clinical Development and the ELVN-001 clinical lead.
Before diving in, I want to take a moment to summarize why we are so excited about ELVN-001 and the opportunity it presents. CML is a large market with clear remaining unmet needs, and 001 is designed to address these needs as well as to be complementary to the evolving treatment paradigm. Based on the phase 1 data and late-line CML presented today, 001 has demonstrated a potentially best-in-class profile despite enrolling a more heavily pretreated patient population. Finally, unlike many cancer indications, precedent-pivotal trials in CML support a straightforward regulatory path. Namely, historical phase 1 data have accurately predicted success in pivotal trials. Given that no single TKI has established an overall survival benefit over another, biomarker-based endpoints can be used, allowing for smaller, faster pivotal studies.
With the encouraging phase 1 update today, we believe 001 has the potential to compete for share across all lines of therapy. Our primary focus is getting ready to start our first head-to-head phase 3 trial next year. The treatment of chronic myeloid leukemia, or CML, represents one of the greatest success stories in precision medicine. In fact, since the first approval of Gleevec, or Imatinib, roughly 25 years ago, the median overall survival for newly diagnosed patients with CML has still not been reached. Despite the relatively low incidence of CML, it has become one of the largest TKI markets of all time, driven by the fact that these drugs have turned the disease into a chronic condition requiring up to decades of daily therapy. Accordingly, treatment goals have evolved, with emphasis today on quality of life and better tolerability.
Despite the huge advances in the treatment of CML, a significant need remains. Nothing demonstrates the unmet need in CML more than the treatment switching dynamics. Today, approximately one in four patients switch therapy in their first year of treatment, and 30% switch within the first year of their second treatment. This has led to a growing third-line plus patient population, and these patients have limited effective treatment options remaining. When you dive into the reasons why patients are switching, it is clear that the current agents simply aren't good enough to meet today's treatment goals. Notably, approximately 60% of patients switch TKIs due to intolerance or lack of an early molecular response. This is not surprising given that most of the approved agents are older drugs, and several were originally designed to inhibit other kinases.
All of the approved ATP-competitive TKIs are limited by their off-target kinase activity, which results in suboptimal tolerability, often requiring dose modifications, which can in turn impact efficacy. Finally, burdensome administration requirements can also impact long-term adherence to the existing TKIs. For example, drug-drug interactions need to be carefully navigated as the average CML patient is on five different co-medications, and all of the approved TKIs have restrictions. The recent Scemblix launch validates the need for better treatment options for patients with CML. As a reminder, Scemblix, or asciminib, is Novartis' allosteric TKI, and it was first approved in late 2021 for third-line plus CML. Importantly, asciminib received an accelerated broad approval late last year based on its frontline trial, which only took two years from start to top-line data and expanded its addressable market by almost 5x.
Already, it has had a phenomenal launch with almost $1 billion of annualized sales, most of which coming from the third-line plus setting. Additionally, asciminib received an NCCN Category 1 designation at the end of last year, which is important for reimbursement. Based on the Q1 results this year, asciminib is already penetrating earlier lines of therapy with 10% of new-to-brand prescriptions in frontline and 40% in second line in the U.S.. Despite asciminib's favorable profile compared to the prior generation TKIs, we believe a large opportunity exists for ELVN-001. Notably, discontinuation rates on asciminib are still high, with approximately 50% of patients discontinuing within two years and switching to other TKIs in the third-line plus setting.
Before I dive into how 001 may address the limitations of asciminib and, more importantly, the unmet need in patients that switch off asciminib, let's take a look at where we believe both drugs will ultimately end up in the CML treatment paradigm. First, it's important to point out that unlike many other cancer indications, in CML, the approved TKIs are used interchangeably across lines of therapy depending on the treatment goals and specific patient needs. Because patients with CML have normal expected survival, TKI switching has resulted in a market that supports multiple blockbuster drugs despite generic options. As noted previously, asciminib is already the market leader in the third-line plus setting and has started to rapidly penetrate earlier lines of therapy.
Assuming asciminib and allosteric TKI does capture significant market share in the first and second line, we believe that 001 will be well-positioned to follow asciminib given its complementary mechanism of action as an ATP-competitive active form inhibitor of BCR-ABL. Importantly, as you can see by the figure on the left, which represents how Novartis is positioning asciminib relative to first and second-generation agents, there is an opportunity to differentiate from these prior-generation ATP-competitive TKIs based on improved efficacy and tolerability across lines of therapy. As a highly selective ATP-competitive inhibitor of BCR-ABL, we believe 001 has the potential to achieve similar or better profile than asciminib. If 001 achieves this profile, as a base case, we believe it will be well-positioned to compete for use in nearly every patient who switches therapy in the second-line plus setting.
Finally, we believe there's an opportunity to directly compete for frontline share based on differentiated efficacy, tolerability, or administration requirements. Building on my previous comments, ELVN-001 is a highly selective active site inhibitor of BCR-ABL. It binds preferentially to the ATP-binding site of the active conformation of ABL1 in a unique P-loop folded-in conformation, which we believe contributes to its excellent selectivity against the broader kinome. 001 is a potent inhibitor of native BCR-ABL and maintains broad activity against multiple clinically important mutations, including T315I, as well as those that confer resistance to asciminib. Unlike all of the approved TKIs, 001 is not a substrate for the common drug efflux transporters PGP and BCRP, which may play a role in resistance to TKIs in CML.
Finally, 001's PK supports once-daily dosing with or without food, and it has a low risk of drug-drug interactions, which we believe may drive uptake in a setting where patients require up to decades of daily therapy, similar to the treatment preference evolution for patients with HIV. As previously emphasized, 001's kinome selectivity is a key differentiating factor compared to the prior-generation ATP-competitive inhibitors. The figure on the left highlights 001's exquisite selectivity in cells against several known off-target kinases associated with the approved prior-generation ATP-competitive TKIs. Against a broad panel of 372 kinases, 001 was also highly selective for ABL1. Finally, given the important role we believe asciminib will play in the future CML treatment paradigm, we evaluated 001's activity against the clinically emergent BCR-ABL mutations known to confer resistance to asciminib.
As you can see in the table on the right, 001 maintains activity against all of these clinically emergent asciminib-resistant mutations. We believe this profile could be favorable in a post-asciminib setting. The bar in CML is high, but we believe there remains ample opportunity to improve on existing therapies. Because our target product profile is both complementary to and competitive with asciminib, we believe that 001 could reach that bar. Next in the presentation, we will provide an update on our ongoing phase 1 trial for patients with late-line CML. Looking ahead, we expect to initiate our first head-to-head pivotal trial in 2026. At the end of today's presentation, we will give an update on potential trial designs.
Longer term, if 001 continues to demonstrate a potentially best-in-class profile, we believe there's an opportunity to succeed in a frontline setting for broad approval and to compete for market share across all lines of therapy. With that, I would like to introduce Damiette Smit, our Vice President of Clinical Development and the ELVN-001 clinical lead. Damiette will take us through the updated 001 phase 1 data recently presented at EHA.
Thanks, Sam. First, I will describe the trial design of the phase 1 enabled study. Patients were allowed to enroll if they had chronic phase CML and failed, were intolerant to, or not a candidate for available therapy. The trial consists of a phase 1a dose escalation and a phase 1b dose expansion.
As you can see, doses of 60, 80, and 120 milligram daily were chosen to evaluate in the phase 1b in patients without the T315I mutation. Enrollment is currently ongoing in the 60 and 120 milligram daily cohorts. The protocol also allows for dose expansion in patients with CML with T315I mutation. However, this expansion arm will open in the future as we want to conduct additional exploration in the subgroup first. The primary endpoint is safety, and key secondary endpoints are molecular response to measure the efficacy of ELVN-001 and pharmacokinetic parameters. Molecular response is assessed by measuring the BCR-ABL transcript level in the patient's blood in a central laboratory. The data being presented today is as of April 28, 2025, at which time 90 patients had enrolled in the study. Data for both the phase 1a and the phase 1b are presented together.
Overall, a heavily pretreated patient population was enrolled, as you can see by the number and type of prior TKI therapy that the patients received. 23% of patients were exposed to four prior TKIs and 26% exposed to five or more prior TKIs. In addition, over half of patients were exposed to prior asciminib and almost half to prior ponatinib. The reason for discontinuation of the last prior TKI is also relevant, as discontinuation due to lack of efficacy has historically been associated with a lower MMR rate compared to patients who discontinued due to intolerance. About 72% of patients who enrolled to the study discontinued their last TKI due to lack of efficacy. The majority of patients enrolled to date have remained on study with a median duration of exposure of 29 weeks.
Notably, only four patients discontinued due to adverse events: one patient with alcoholic pancreatitis, two patients with thrombocytopenia who had also discontinued prior TKIs due to cytopenias, and one patient with dyspnea, although this was confounded by pulmonary comorbidities. One patient died while on study due to a postoperative complication after hip surgery that was deemed unrelated ELVN-001 by the investigator. This swimmer's plot shows all patients who enrolled to the study. The Y-axis shows the dose cohorts the patients were enrolled in, and the X-axis shows the time since enrollment. Intrasubject dose escalation was allowed, as shown by change in color. The majority of patients have remained on study with more than half of patients more than 24 weeks and the longest 126 weeks, which is about two and a half years.
As you can see, the swimmer plot reflects that additional dose exploration was done at daily doses of 40 milligram or higher. This was supported by non-clinical target coverage analysis showing that doses of 40 milligram or higher have improved anti-CML activity compared to second-generation TKIs. Before I share the updated efficacy results, let's go over the key molecular response milestones in CML. This chart shows the transcript levels with their associated molecular response milestone. The first key milestone is MR3, also called major molecular response. When MR3 is achieved within a certain timeframe in first and second-line therapy, close to 100% CML-specific survival is predicted. There is no standard definition of an acceptable response to third or later lines of treatment, but in general, there is consensus that MR1 is insufficient for optimal survival. Therefore, MR2 is considered a clinically meaningful endpoint in the late-line setting.
Here are the MMR and MR2 endpoints for the ENABLE study. Overall, 47% of patients were in MMR by 24 weeks, with 32% of patients achieving MMR and 100% of patients maintaining MMR. Several key subgroups are included for the MMR endpoints. 32% of patients exposed to prior asciminib and 35% of patients exposed to prior ponatinib were in MMR by 24 weeks. In addition, 41% of patients who discontinued their last TKI due to lack of efficacy were in MMR, and 53% of patients who discontinued due to intolerance. As I mentioned on the previous slide, MR2 is considered a clinically meaningful endpoint in the late-line setting. On the right, we show that 77% of patients were in MR2 by 24 weeks, with 52% of patients achieving MR2 and 100% of patients maintaining MR2.
In ELVN-001 has robust efficacy despite the heavily pretreated patient population, including in patients exposed to prior asciminib or ponatinib. Let's now put the efficacy results from the ENABLE study into context of the published historical phase I data from asciminib and bosutinib. Although there are limitations to the conclusions you can draw comparing data across trials conducted at different times and with different patient populations, this type of comparison is still the best way to put the emerging data into context. The first two columns of this slide include data from the phase I studies for asciminib and bosutinib, and the right column shows ELVN-001 data.
As you can see, the patients enrolled to the ENABLE study were more heavily pretreated compared to those enrolled to the asciminib and bosutinib phase 1 studies, with 26% exposed to five or more TKIs for ELVN-001 compared to 8% for asciminib. Another key difference is that over 50% of patients in the ENABLE study were exposed to prior asciminib. When we move to the bottom half of the slide, we see the overall MMR by 24 weeks for all the studies: 37% for asciminib, 15% for bosutinib, and 47% ELVN-001. in addition, we can see the number of patients who achieved MMR by 24 weeks, which was 24% for asciminib and 32% ELVN-001. as I mentioned previously, discontinuation of the last TKI due to lack of efficacy has historically been associated with a lower MMR rate.
The MMR rate in these patients was 9% for asciminib, 6% for bosutinib, and 41% for ELVN-001. In short, putting the ELVN-001 data into context of prior phase 1 trials supports the encouraging findings to date. Now we take a deeper dive into the efficacy data by looking at changes in molecular response category for each of the MMR evaluable patients. This slide shows a shift table. The top row shows the molecular response category at baseline, and the left column shows the molecular response category by week 24. 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. As you can see, almost all patients had an improved or stable category by 24 weeks.
What's important about this table is that despite the heavily pretreated patient population, improvement was observed both in patients with low baseline transcripts as well as in those with higher baseline transcripts. As Sam mentioned, resistance is a key unmet need, specifically for mutations emerging from targeting the myristoyl pocket. Here we present a patient with an F359V mutation, a mutation that can emerge on both asciminib and second-generation TKIs. This patient received prior nilotinib and enrolled to the ENABLE study in the 80 mg daily cohort. The graph on the left shows the change in transcript levels over time. The X-axis shows the number of days the patient was on study, while the Y-axis shows the BCR-ABL transcript level. The patient had a rapid improvement in BCR-ABL transcript after initiation of ELVN-001 and achieved a major molecular response by 90 days on study.
This response is particularly encouraging because F359C and V mutations were the most frequent mutations at baseline in patients resistant to asciminib in the assembled study. Overall, ELVN-001 was well tolerated with no observed dose toxicity relationship. The majority of treatment emergent adverse events were low grade. For clarity, treatment emergent adverse events are events that occur at any time during the study, regardless of attribution. The hematologic adverse event profile was similar to or better than other TKIs. Most importantly, there was a low frequency of non-hematologic adverse events. Very few patients needed dose adjustments due to adverse events. 16% of patients had a dose interruption, 3% a dose reduction, and 4% discontinued ELVN-001 due to an adverse event. The maximum tolerated dose has not been identified. The table on the right shows treatment emergent adverse events occurring in 10% or more patients.
As you can see, there were relatively few of these events, and most were low grade, consistent with ELVN-001's high selectivity for ABL1. Let's now take a look at grade three or four adverse events. Overall, these were uncommon and not dose-dependent. Only thrombocytopenia and neutropenia were reported in more than 5% of patients, which is consistent with the clinical data from other TKIs. Notably, only two patients reported a grade three arterial occlusive event, with no grade four being reported. Both patients had prior ponatinib and nilotinib, which is relevant as both confer a higher risk of arterial occlusive events. Both events reported in the study were considered unrelated to ELVN-001 by the investigator. In addition, both patients remain on study. I will now summarize the three key takeaways for this data update.
First, ELVN-001 shows encouraging anti-CML activity in a heavily pretreated patient population, with an overall MMR rate of 47%, an achieved MMR rate of 32%, and an achieved MR2 rate of 52%. In addition, anti-CML activity was observed in patients exposed to prior asciminib or ponatinib and with asciminib emergent mutations. Second, ELVN-001 was well tolerated across dose levels, with low rates of dose reductions and discontinuations. Finally, the ELVN-001 pharmacokinetic profile supports once-daily dosing with or without food, which, in addition to low potential for drug-drug interactions, addresses key challenges with currently available TKIs. 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.
Next, we have a few slides that will help put the phase I results you just saw into further context and explain why we are so optimistic about the potential for success for ELVN-001 and our planned next steps. With CML, historically, the results of the phase I trial project the results of phase III trials, which is different to what you often see in solid tumor studies. Also, importantly, the endpoint we look at in phase I CML trials, which is MMR by 24 weeks, is similar to the endpoint used for accelerated approval in later-line phase III trials. Overall, you can use the phase I results in CML studies as a good read-through of what to expect in a phase III trial.
On this slide, you can see two bars on the bottom left for bosutinib, two bars next to it for asciminib, and then one bar for ELVN-001. The dark blue bars represent the MMR rate by 24 weeks observed in phase I trials. The turquoise bars represent the MMR rate by 24 weeks observed in the assembled phase III trial that compared bosutinib to asciminib and led to the ultimate approval of asciminib. You can see two things from these bar graphs. Both for bosutinib and asciminib, the phase I results and the phase III results are nearly identical. The phase I results accurately predicted the phase III outcomes.
The second point from these graphs is that ELVN-001, with its 32% MMR by 24 weeks, compares favorably to the second-generation drug bosutinib and even to asciminib, despite the 001 study being conducted in a more heavily pretreated patient population. The take-home message from this slide is that the 32% achieved MMR result we have observed in our phase I study makes us confident that ELVN-001 should be superior to a second-generation TKI like bosutinib in a head-to-head trial in the same way asciminib was superior to bosutinib in the ASCEMBL trial. On the next slide, Sam will review the studies that led to asciminib's approval in both the late-line and front-line settings.
Thanks, Helen. Before going into the details of the recent precedent trials, I want to take a step back and talk through the history of TKI development in CML.
Because no single TKI has demonstrated an overall survival benefit over another, today, biomarkers are used as primary endpoints in pivotal trials. Most recently, major molecular response, or MMR, at 24 weeks has been used in late-line trials, and MMR at 48 weeks is used in the front line. It is also important to note that regulatory authorities, recognizing that there is no survival outcome difference between TKIs, have historically supported the sponsor's choice of comparator TKI, so long as it is indicated for use in the intended patient population. There has not been a requirement to use the most recently approved agent. With that in mind, on this slide, we summarize the first two pivotal trials Novartis ran with asciminib. On the left is ASCEMBL, the third-line plus trial leading to asciminib's first approval. Here, bosutinib, a second-generation TKI, was used as a single comparator.
Of note is the relatively small trial size. Despite the resulting third-line plus label, asciminib has had a remarkable commercial launch, demonstrating that even the third-line plus market in CML has blockbuster potential. On the right, we summarize ASC4FIRST, the front-line trial leading to asciminib's broad accelerated approval in the U.S. late last year. In this trial, once again, MMR rate at 48 weeks compared to imatinib was a primary endpoint. The second primary endpoint was MMR rate at 48 weeks compared to the combined comparator arms of imatinib and a physician's choice of second-gen TKI. Notably, ASC4FIRST initiated immediately following ASCEMBL, and Novartis reported positive top-line data only two years later. Based on this trial, asciminib is now indicated for use by any patient with CML in the U.S., giving access to a potentially $9 billion opportunity in the U.S. alone.
With that, I'll turn it back to Helen, who will provide an update on how we are thinking about pivotal trial options and the potential regulatory path for ELVN-001.
We are considering two options for our first phase 3 trial. One option is to conduct a trial similar to Assemble, the first pivotal trial for asciminib that Sam just described. This trial would be a study in patients who have received two or more prior TKIs, in other words, a third-line plus study, comparing 001 head-to-head against the second-generation drug bosutinib. As we have been reviewing today, the ELVN-001 phase 1 data looks similar to or even better than asciminib's phase 1 data. We think that a third-line plus trial is low risk from both a regulatory and technical perspective. The second option is a second-line plus trial.
This would be a trial where patients have received at least one prior therapy, and ELVN-001 is compared to the physician's choice of an ATP-competitive TKI, which would be dasatinib, nilotinib, bosutinib, or imatinib. We prefer the second option, and we have heard from investigators this is also their preference because there are about two and a half times more patients in the second-line setting than in the third-line setting and beyond. This study design is also preferable to investigators because the control arm better reflects real-world pattern of care. As Sam just reviewed, historical precedent in CML trials has shown that if there's a benefit with a specific TKI in late line, the benefit is also observed in the earlier line setting. We are equally confident that a second-line plus trial is just as low risk as the third-line plus trial.
Although the second-line trial would be slightly larger, we expect it to enroll significantly faster than a later-line trial because of the higher interest by investigators and the larger patient population. Assuming data continue to be supportive, we would want to follow our first late-line trial with a front-line pivotal trial. Our base case assumption is that a front-line trial would largely mimic the first-line asciminib trial ASC4FIRST. Keep in mind that in the front-line setting, MMR is also the regulatory endpoint, allowing a relatively quick readout. For example, in the case of asciminib, the first-line trial started enrolling one month after approval in the late-line setting and then achieved accelerated approval in the front-line setting only three years later. Now I'll turn it back to Sam to wrap up our presentation.
Thank you, Helen, for summarizing how we are thinking about next steps for ELVN-001.
With today's update, we are more excited than ever about the opportunity to potentially make ELVN-001 a treatment option for patients with CML. In summary, CML continues to be a large market despite generic options. We believe there is a $9 billion opportunity for differentiated TKIs in the US alone. With asciminib moving up in lines of therapy as a base case, we believe that ELVN-001 could become the preferred option in the second-line plus setting. Based on the phase 1 data reported today, we believe that 001 could ultimately compete for use across all lines of therapy based on differentiated efficacy, tolerability, and convenience. Looking ahead, we believe there is a straightforward regulatory path for 001, and we expect to initiate our first pivotal trial next year.
As we wrap up our prepared remarks, I want to take a moment to recognize and thank all of the patients, caregivers, and investigators who are participating in the ELVN-001 trial. We offer them our sincere gratitude. We will now start the Q&A portion of the call. Thank you to those of you who have already submitted questions. We've begun to group them into specific themes, and we'll try to touch on everything. You can also continue to submit questions, and we will do our best to capture them as we go here. If we are unable to answer your specific question or do not have time, we would be happy to follow up offline to discuss at a later date. Here we will start with questions about our anticipated phase 3 trial. I'll direct these first few questions to Helen.
You presented two potential options for the first ELVN-001 phase 3 trial. How and when will you make your decision about which trial to run?
Yeah. Thank you, Sam, and/or thank you for whoever's sending in that question. At this point, we think the best study for ELVN-001 is a second-line plus trial. That means where the inclusion criteria is any patient who has been intolerant or failed at least one prior TKI. They could have failed more, but they had to have at least one. There are two reasons for this. One is you've just seen this great data from approximately 90 patients, and the safety profile and the MMR rate are holding up. That makes us more confident about 001's potential benefit. The data you've just seen, as you saw, is across a broad spectrum of patients.
More importantly, as we talk to investigators both on our study as well as other ones that, of course, we would like to be on our part of our phase 3 trial, it's very clear that they strongly favor this second-line plus trial design because that's where they're not quite certain what to do for those patients right now. There's many more of them than there are in the later-line patient. The trial design they like in particular is the fact that they then can have their choice of any second-generation or imatinib. Of course, a final decision can't be made until we have regulatory interactions next year. Assuming this data continues to hold up, there's every reason to think this trial design is low regulatory risk. It also allows us we can still keep that fallback position of a third-line plus trial.
It does not close that door if need be. Sam, if you want to add anything to that?
No, I think that's great. Actually, we can just slip in this question that kind of builds on that. Can you explain why you have confidence ELVN-001 would succeed in that second-line plus trial?
Yeah. I think we have not shown a lot of the subgroups, but I can tell you that as we look at them, and of course, one of the reasons for that is because as you start looking at subgroups of subgroups, the numbers get small. Across every subgroup we look at, we see benefits. We did highlight some of those: post-asciminib, post-ponatinib, all-comers, patients who are resistant. We did not show you by line of therapy, but we feel confident that we see benefits across all the various lines.
That is, of course, true also to the most recent drug that was approved, asciminib. They showed benefit in fifth-line plus, fourth-line, third-line, and then, of course, most recently, first-line. Yeah. I think, again, going back to this being a large patient population, not really having a standard treatment in that second-line setting. The data that we've seen so far makes us really confident that this should be a successful trial.
Yeah. I mean, we're biased. I completely agree. I think we've had this hypothesis from the beginning and starting with asciminib that if you can safely and with good toleration achieve these higher target coverage thresholds, you should be able to beat second-gen TKIs on a 24-week or 48-week time point. I think Novartis has nicely demonstrated that now across every line of therapy. The only gap is second-line.
With their ask to Escalate study, which was recently presented at ASCO, I think that gives even more confidence that that effect size versus second-gen is holding up. I think this is a situation where it might require a slightly larger study. We have talked about that with investors off and on. It is a study that we have a lot of confidence in. Okay. Helen, you mentioned subgroup analysis and comparisons to asciminib. We have a couple of questions here about efficacy. I will start, and you can always feel free to chime in. The first question is, the 001 efficacy looks even better than asciminib, which is impressive given the late-line context. Would you consider going head-to-head against asciminib? I will take this one.
Just to be very clear here, our primary takeaway from this data update is that from a late-line efficacy perspective, 001 looks at least as good as asciminib. Most importantly, potentially clearly differentiated from a second-gen TKI. I think there are certainly reasons to believe that 001 could be a preferred option compared to asciminib, whether it's based on efficacy in certain settings or other factors like tolerability and drug-drug interactions. It's probably too early to make that conclusion here. As we've emphasized, our primary goal is to establish 001 as the best-in-class ATP-competitive TKI. We feel that the data so far are supportive of that. Regarding our first pivotal study, as Helen just outlined and explained, we do not plan to compare head-to-head versus asciminib.
Instead, we'll aim to generate data in the likely real-world setting 001 will initially be used in, which is when a physician and a patient are deciding which ATP-competitive TKI to switch to. I think longer term, for example, in earlier lines of therapy, we may consider including asciminib as a comparator. We do not anticipate ever being required to do so. Okay. Next question. How should we think about the subgroups? For example, the patients post-asciminib, are you providing any more detail? Okay. Yeah. We get this question a lot, and I think it's an important question. I'll start with this one, and I'll probably give a fair amount of detail here. Bear with me. To start, we're really encouraged by the activity and clinical benefit we're seeing in this very late-line context, and specifically in patients that have had prior asciminib and/or ponatinib.
Just to give a little bit more context on the types of patients that had prior asciminib or ponatinib, of the efficacy evaluable patients that had prior asciminib, roughly 70% had discontinued asciminib due to resistance. All of the patients had discontinued at least one other TKI, and almost every patient had been heavily pretreated, with over 70% having discontinued at least four prior unique TKIs. Additionally, almost 90% of these post-asciminib patients had discontinued TKIs other than asciminib due to resistance. This should just give a sense for how truly difficult this subgroup is, especially if you recall that in the asciminib phase I, in patients resistant to their last prior TKI, only 9% achieved MMR by 24 weeks.
Despite the context, within this very difficult subgroup, we have observed multiple patients with very high transcript levels at baseline that achieved MMR by 24 weeks, including one six-line patient and one tenth-line patient. Most importantly, of the 19 patients that discontinued asciminib due to resistance, 001 had a cumulative MMR rate by 24 weeks of 26%. Overall, we feel really good about 001's efficacy in this very late-line context. We'll continue to kind of look at this subgroup and monitor 001's performance. As you know, we've also detailed where there are specific resistance mutations that confer resistance or reduce sensitivity to asciminib. 001's had outstanding performance. Okay. Let's move on to some of the safety-related questions. I'll direct these to you, Helen. Okay. This is the first time you are reporting AOEs.
Is there a concern that this could be the sign of an emerging new safety signal?
Yeah. I think I can speak pretty confidently that based on the data, we do not have a concern that 001 increases the risk of arterial occlusive events. As you saw, we had two grade 3 or higher events that were categorized as AOEs. One was a patient who had a history of recurrent pericarditis and reported angina pectoris. Later, after the data snapshot, that chest pain, if you will, was determined to be due to her pericarditis. Another patient had a history of hypertension and high cholesterol and was diagnosed with coronary artery disease while on the study. Neither of these events were thought by the investigator nor by us, obviously, when we talked to the investigators.
Actually, we also have group safety meetings so that all the investigators can hear about each of these events. Nobody thought any of these were related to 001, and both these patients remain on study. We do get questions. Sam has been telling me he's getting lots of questions about how do we decide what is or is not an AOE? Historically, some companies have just relied on the judgment of their internal medical team to essentially look at all the reported adverse events and then make a decision, "Okay. This is potentially an arterial occlusive event. This one isn't," etc. We wanted to make sure that we aren't looking at this data in any biased way or that we're missing something that some other reviewer might consider an AOE.
We use something called SMQ or standardized medical queries, which essentially generate a very broad list of hundreds of adverse terms that could potentially be considered an AOE. We then run our safety data through this, all our adverse events, and that is how these ones get identified. That is what really makes us confident that we are neither missing an event that somebody else might consider an AOE and that we are capturing events that might fall under different categories. For example, if somebody had an arterial clot in their leg, it might show up in a different category than somebody having, I do not know, a coronary artery clot. I do not know if I explained that very well, Sam. Please feel free to.
No, I think it is great. I think it really hits on where a lot of the questions are coming from.
We understand, just given the history of TKI development in CML, certainly, I think it was over 10 years ago now, pretty scary toxicity observed specifically at the high dose of ponatinib, which led to the withdrawal and discontinuation of that study. I think there's the perception that these cardiovascular toxicities or the cardiovascular toxicities associated with high-dose ponatinib really showed up later and weren't really seen till the phase 3. I just think it's important to dispel that notion entirely. In fact, they showed up preclinically. You could see it in vitro. You see it in their animal studies. Helen, I think part of the problem was that there were never these group terms used to kind of collect all the potential arterial occlusive events.
When that was done, the frequency and severity was very high, right, in the above 30% with a significant number of high-grade and grade 5 AOEs. They just did not show up because these were never group terms. On the analysis, and you can find this in FDA regulatory documents, the median time to onset for high-dose ponatinib for patients on high-dose ponatinib to event AOE was 4.5 months. It was not like this happens years later. It only became an issue kind of more externally later. Investigators knew it was an issue early. They had been reporting these events. Unfortunately, it just was not disclosed, and it did not show up till later. Yeah, we have spent a lot of time on that. We are thrilled about the safety profile for 001.
As Helen just laid out, we feel 90 patients in, many patients now, several patients at least over two years. The overall safety profile, in particular, the cardiovascular safety program with respect to 001 is really, really good. It's the best we could hope for. We've had no patients with treatment-related AOEs. We've had no patients dose-reduce or discontinue due to cardiovascular toxicity. It's about as good as we could hope for at this point in time in this patient population. Okay.
Yeah. I'll jump in there. One other thing, Sam, is, as you all saw, about half our patients came on the study who had not had prior ponatinib. I can't say every patient that's come on to our study who had not had prior ponatinib is because they have cardiovascular risk, but that's a lot of them.
Because of our preclinical data, we are, if anything, getting patients that are higher risk of these events. The fact that we're really not seeing anything, knock on wood, I think also gives us some confidence. Great.
No, that's great. Thank you. Okay. Another safety one. Here we see lipase elevation remains the highest frequency treatment emergent AE. Can you tell us more about this? Is it a concern? How does it compare to other TKIs? Have you seen additional pancreatic toxicity?
Yeah. We include, obviously, patients getting a baseline lipase level and frequent lipase levels on study. That's done because all of the tyrosine kinase inhibitors have reported elevated lipase as a potential side effect, if you will, of the drug. We do think that elevated lipase, at least some of them, are probably related to ELVN-001.
I think what's important is whether or not we're getting pancreatitis. Lipase is just a blood test. It doesn't mean the patient has any symptoms or they have to do anything differently. There, as you saw, we have had the one pancreatitis at our very lowest dose. As Professor Hocko said on the podium today, the thought is this is not related to 001 because it turned out afterwards we found out this patient was an alcoholic. We've not had any pancreatitis since then. Again, it's something we'll continue to watch because there are elevated lipases in all these drugs. We know asciminib's had some reports of pancreatitis. I don't want to say we'll never have one. Right now, it does not appear to be a concern to us or to any of the investigators.
Great. Thank you. Okay.
One more for you, Helen. As you meet with investigators, is there anything beyond the data presented that's notable about the 001 profile?
Yeah. I mean, I think the biggest thing that I think I hadn't appreciated how much is this lack of drug-drug interactions, and not even in so much as it means patients don't have to worry about other medications, which we're all sort of aware about, but actually even the dietary. You may all have had yourself to take a drug where they say, "You can't have grapefruit. You can't have Seville oranges. Take it two hours after you eat," all of these various directions that you're given. The fact that 001 can be given without any of those directions, meaning take it with or without food, with or without any medication, with any type of food, really is very appealing to the investigators.
That's something to get, it's quite unique, let's just say. And to be given ever again.
I love that. I'm sure Joe's smiling. We'll give a shout-out to him.
Yeah. Hi. Yes. That's right. Oh, we got to give her a credit. Oh, well.
Okay. So let's move on now to questions about next steps and our recent financing. Okay. First question. You announced a $200 million financing this morning. Can you walk us through how this impacts Runway? Yes. First, we're just absolutely thrilled with the enthusiasm and support we received from both existing and new shareholders. With this financing, our Runway extends into the first half of 2029. And most importantly, it should get us well through top-line pivotal data for 001. Okay. What comes next in terms of additional updates? When do you anticipate presenting more data?
We always get this question right after we present data. Yeah. We have encircled a time on our calendars for the next data update. We believe that this update really represents an important, if not the most important, late-line proof of concept inflection point for the 001 program. That said, we, of course, expect to report more data from our ongoing phase 1 study. For example, we are in the process of amending our protocol to allow earlier-line patients to enroll. As we get sufficient numbers and follow-up, it will be exciting to show how 001 looks in those earlier-line settings. As Helen mentioned, we are seeing some of that and are highly encouraged and just want to build that out. We will continue to get more data in our optimal dose range.
We also hope to eventually investigate how 001 will perform in the front-line study, probably first in a new phase 1 study. All of that could kind of be the basis for multiple potential data releases in the intervening time. I just want to also note that we also view our end of phase 1 meeting and subsequent phase 3 start as important milestones. Certainly, we believe these will be very valuable for potentially catalyzing strategic interest. We are confident there is lots of good stuff to come. Okay. I think I'll make this again, we are getting kind of close to the end of time, the last question. Can you comment on the Scemblix launch and its read-through to the ELVN-001 opportunity? Yeah. We continue to be really encouraged by the Scemblix launch.
We think it could achieve about $1 billion in annualized revenue from the third-line plus setting alone by the end of this year, which continues to be great validation for the late-line opportunity. We are probably most excited by the early uptake in the second line and even in the first line. We view this early adoption as evidence that prescribers will ultimately continue to take a patient-centric approach, right, despite the widespread availability of generic options. From our perspective, the better Scemblix does, the bigger opportunity there is for 001. We are just highly encouraged and excited about what is to come here. Okay. I know there are some additional questions, but I think we are going to wrap up. That concludes the Q&A portion of today's call. Thank you to everyone who participated and listened in.
If there are any remaining questions, and I know there are a few, but I think we basically touched on most of them, please feel free to reach out. We will try to capture these as well. We would be happy to kind of sit down and go through these in more detail. Thank you very much.