Maury Raycroft, I'm one of the Biotech Analysts at Jefferies. I'd like to welcome, CEO, and Ben Hohl, CFO of Enliven. Thanks so much for joining us today. We're going to do fireside chat format, so maybe for those who are new to the story, if you can give a brief intro for the company. Sure. Hi, everyone. Great to be here. Thanks to Maury and the Jefferies team for having us. Enliven is a company that's really founded on better chemistry against known biology, so developing novel small molecules that are better than existing drugs against known targets, and has developed a few molecules over time, but our lead asset, which seems to really have hit the mark on that vision that the founders had, is a BCR-ABL1 TKI in CML. Differentiates by its high degree of specificity to BCR-ABL1, and it really has limited activity against any other kinases, so it really avoids some of the off-target toxicities that limit first and second generation ATP competitive TKIs. We've generated quite a bit of phase I data. We'll present some updated phase I data here in a couple of weeks at EHA. I guess that's now in a week at EHA, and I look forward to sharing the profile of the drug as it's emerging from a relatively large phase I data set. Got it. Yeah, it's a great intro, and you've got the data update coming soon next week at the EHA conference. What's the latest on higher setting expectations for the data update, both in terms of total efficacy evaluable patients relative to the 45 patients you reported on in January, and maybe talk about some of the key efficacy data points we should focus on. Sure. As you'll recall, our last data update was a skinny press release in January based on a December data cut. We had 141 patients enrolled in our clinical trial at that point, and as mentioned, we had an efficacy evaluable population of 45, 46 patients out of the 60 enrolled in our phase I-B study. Fast-forward, the data cut we'll be presenting at EHA is a March data cut, so a few extra months of follow-up, and we've also continued to enroll patients at the dose we believe is appropriate for phase III development, which is 80 mg QD. What you can expect to see is a couple dozen additional patients enrolled overall. In total, another similar number of efficacy evaluable patients. Most of those are the maturing of patients who are at 60 and 120 mg QD, the randomized cohort we did to satisfy Project Optimus requirements. Those data became fully mature in that three-month period, and you'll see additionally another 5- 10 efficacy evaluable patients at our recommended phase III dose of 80 mg QD. Got it. Okay. All helpful. For the disclosure around EHA, I guess anything more you can highlight for that? Are you guys going to do a conference call? Have you decided that yet? Our data will be presented on the 11th of June in the evening in Stockholm. We will do a call pre-market on the 11th to talk about the data that we're presenting there. Got it. Okay. In thinking about the data that you've reported so far, how should we interpret your earlier line, second line, third line MMR data relative to the approximate 50% seen with Merck's TERN-701 in third line plus CML, and the approximate 54% with SCEMBLIX in second line CML? There's been a lot of discussion and debate on the amount of follow-up. How should we think about that for this update? For those of you that follow CML peripherally, achieved MMR rates in phase I or whatever you want them to be. As we've discussed extensively over the last 6 months, achieved MMR by 24 weeks is the standard endpoint in CML phase I development. It's slightly different than the landmark analysis that's done for registrational trials, MMR at 24 weeks, which is a landmark analysis. Basically, it's a rolling total of those achieving MMRs. Those that cross 24 weeks are counted, those that have an early response are counted, those that have an early non-response that are just on treatment but haven't achieved 24 weeks are not counted. Early immature data sets are inflated because you're counting early responders and censoring non-responders from the calculation. We showed that in our January data cut. We showed a mature data set at 80 mg, which had an achieved MMR rate of 38%, and we showed a less mature 60 mg and 120 mg group that had an achieved MMR rate of 53%. We don't think there's a dose response between 60 mg and 120 mg. They essentially all achieve full target coverage. What we think is driving that is data maturity. That's important to know. The second thing that's important to know is who are the patients in your phase I study? I'll use asciminib data because it's the clearest data set that we have on this point. In asciminib's phase I trial, those that were intolerant to their prior TKI, meaning they switched because of side effects, not because of efficacy, had a 73% achieved MMR rate. Those that switched because of efficacy had a 9% achieved MMR rate. The same drug performed dramatically differently on this efficacy endpoint, depending on how resistant the patient was and how resistant their disease was. Any discussion about comparing cross-trial phase I data sets, I think, has to start with that, which is what patients are in the study and how mature the data are really, really important to interpreting what you're seeing. All of that said, our phase I study has enrolled more heavily pre-treated, more treatment-resistant patients than any phase I study in CML previously conducted or currently being conducted. The protocol we initially opened was having patients who had failed all prior lines of therapy. It was a first-in-human study at a subtherapeutic dose. We got patients that literally had no other options. Conversely, the study that was enrolling for TERN-701, that gets to that sort of 50%-ish response rate, relying on phase I data that had been generated in China, opened as a second-line plus. Anyone who had failed at least one prior line for any reason could enroll in the study, and they explicitly excluded patients who failed asciminib due to efficacy, so they were selecting for intolerant patients. Their 50% response rate is down from the data they presented at ASH for two reasons. One is that the data they presented at ASH weren't fully mature, and I've already explained the math there, that over time, as patients cross 24 weeks, MMR rates will come down. They've also acknowledged that they're starting to enroll asciminib failures, and those patients are less likely to respond to another allosteric TKI. Put all that into context and set expectations. I think it's really important for us to be at least as good as asciminib. We know what their response rates are by line of therapy. In third line CML, their achieved MMR is roughly 30%, say 29%. We definitely want to be competitive with asciminib and their response rates and overall profile in terms of safety and tolerability. It would be awesome, given how heavily pre-treated our patients were, if we did better than that. If we got to 40%, that would be outstanding. We'd be really excited about that. We will present data by line of therapy to some degree. We don't have a lot of 2-line patients, but we'll show second and third line versus fourth line plus. I think there we'd like to see a number that's more competitive with Terns' headline numbers there. We want to be in the same neighborhood because, again, I think a lot of the explanation for the differences between these drugs and achieved MMR rate are about patient selection, and patients in second and third line CML are going to look more like the patients in the Terns study. Got it. That's helpful with setting expectations. I guess for that earlier line subgroup and fourth line plus subgroup looking similar to Terns', can you elaborate on what that means? Is it the 70% number or the 50% number? Oh, their current number. The ASH presentation with 64% overall achieved MMR and 75% at their high dose was very much an artifact of both patient selection and data maturity. 40% of their patients were not efficacy evaluable at that time point. They were getting the benefit of early responders, and they had a bunch of patients that when they crossed 24 weeks to bring that number down. I think we've been saying since December that that's not really reflective of the overall profile of the drug, and I think both Terns' and Merck have now acknowledged that. Got it. Okay. I think we also want to make the point that even that 50% that people are honing in on is still an unknown number. We've also heard that they were enrolling this second-line plus patient population more skewed towards the earlier lines, but since they announced that great data at ASH that they're getting a lot of harder patients to treat now, which aren't necessarily reflected in that 50% number. It's not like that 50% number is written in stone. There could definitely be further degradation there or just movement in general. Yeah. Yeah. That's really why I anchor with the data we know are the asciminib data, and that's the emerging standard of care in CML, and so I think the comparisons to them, I think, are very fair comparisons to what Merck has announced in a corporate presentation without the benefit of seeing the overall demographics of the patients enrolled, the follow-up, et cetera, is a little bit of comparing to fog, if you will. Okay. Yeah. That's helpful. Makes sense. For your earlier line patient subgroup, do you plan to provide an MMR shift table or baseline characteristics data so we can better benchmark to Novartis and Yeah. You get to really small numbers when you start cutting that way, but we will provide a shift table for our phase I-B population. Got it. I'd also just add, on the shift tables in general, as we just mentioned, patient demographics are really important in terms of line of therapy. That's a key point that's missing in the shift table. You have to take all these separate analyses and try and piece them together to really get the full picture. Okay. You guys will help with your update in doing that, or? Sure. We'll try our best. Okay. In the past, we've talked about DMR, and it seems unlikely to be a priority in this updated EHA. Have you decided if you'll disclose DMR data for the earlier line, second line, third line subgroup? How are you setting expectations for ELVN-001's potential to drive deep molecular responses on par with the allosteric inhibitors? I think what we believe is true based on target coverage and modeling is our drug is at least as effective as the allosterics. Our evidence in late line, heavily pre-treated patients suggests that it's directionally a bit better than SCEMBLIX. We would expect DMR rates to be competitive with the allosterics, including asciminib, and as you say, the patient population that we're enrolling this study, DMR is not really the treatment goal. These are largely third line and later, even a majority of our patients are fifth line and later. DMR is not the reasonable treatment objective for those patients. It's really about disease control and tolerability. Because we moved to earlier lines of therapy, and particularly a frontline study, DMR gets more important. We will report DMR so that you can see we have competitive efficacy at that higher bar endpoint, for sure. Got it. Okay. That's helpful. You reported the 38% MMR achievement in 21 patients with prior SCEMBLIX exposure in the EHA abstract. Do you plan to provide an update on the post-SCEMBLIX MMR data in the oral presentation, and are we setting expectations for the number of evaluable patients there? Yes. We did report patients post-asciminib because it was a frequently asked question from our January update. I was new to the organization at the time. I was surprised that question was being asked because the majority of the patients in our study are post-asciminib, and there's no mechanistic reason why prior asciminib use would predict for non-response in ELVN-001 because of the different binding mechanism, ATP competitive versus allosteric. That said, it was asked, so we will answer that question. Our hypothesis is there will be no effect of prior asciminib exposure to efficacy outcomes with ELVN-001. That is core to our positioning in our first launch and second-line plus CML, that if novel therapies are entering a market dominated by SCEMBLIX in first and second-line, the most important clinical question is what do I do when it doesn't work? I think the answer to that, in my view, consistent with many other oncology indications, is change mechanisms, try something different rather than try the same approach again. ELVN-001 with an ATP competitive mechanism, we think is the best next choice, and I think our data will support that, and we'll present that update at EHA. Got it. Will you have enough earlier line patients with prior SCEMBLIX to report achievement of MMR? Yeah, it's a good question. I will say that most of the asciminib patients enrolled in our study are very late-line patients. I think we gave some of the demographics of that in our abstract. We have very few early-line patients. That said, we will give it to you by line of therapy based on the sample sizes that we have to show that. I think it's safe to say overall in our study, the asciminib-treated patient population does slightly worse, not because they had asciminib, but they've mostly had five or more prior lines of therapy, and they're just multi-TKI resistant. Yeah. Makes sense. Okay. You'll have 5-15 patients additional for efficacy beyond the 60 from the initial cohorts based on our math. It implies 24-34 efficacy evaluable patients. How should we think about patient baseline characteristics, including line of therapy for these patients, amount of follow-up, and expectations for MMR for the new patients versus the prior patients? They're new patients, so they have less follow-up. That's the easy answer to that question. I think in general what we've seen in our study is a migration from an unprecedented level of pre-treatment in resistant patients in our early part of our study, particularly our phase I-A, to a more run-of-the-mill phase I population that looks a lot more like the asciminib or the Terns demographics over time. I think you can say we'd expect, setting aside the issues of data maturity and all of that sort of thing, that our efficacy rates trend up over time as we treat patients that look more normal than the very heavily late-line patients that we've seen previously. I think what we've also heard from Terns and Merck is their study seems to be going in the opposite direction, where they started with this heavily selected for intolerant versus resistant patients, earlier lines of patients. As they've reported good data, they've started to see more asciminib failures, and they've started to see more patients in later lines. We're meeting somewhere in the middle. I think over time, the patients enrolled late in these phase I studies might be more similar than different versus the early parts of the study. Yeah. Makes sense. Okay, wanted to talk about the second-line plus pivotal study. In the past, you said that the end of phase I meeting could take place potentially in June. What are your plans to disclose the results, and can you confirm whether you've had the meeting with FDA or you're on track to have the meeting? Yeah. I think we've continued to guide that our health authority interactions will generally happen mid-year, and we'll communicate an update on that in the third quarter. I think we're on track to that guidance, and we'll continue to guide to that. I'll remind that we believe that we'll need two interactions with FDA. One is a traditional end of phase I meeting where you align on dose for future development. Since we're skipping phase II, the second would be a more traditional end of phase II type meeting that it'll focus on the phase III protocol and the specific details of the study that we intend to conduct. I think we're on track for all that. We'll have an update on that as we have it, and would guide to that as that'll happen before the end of the third quarter. Got it. Okay, basically you have to have those two meetings, you get the minutes from the meetings, and then you do some sort of a press release based on that. We'll communicate as we have information, so if we get something sooner that we think is worth disclosing, we'll share that, but I would say all of that will happen no later than the end of the third quarter. Got it. Okay. I think based on our understanding, you're looking for FDA alignment on three key elements, the 80 mg dose as the pivotal dose, the second-line plus design, and then an investigator's choice comparator arm with first-gen and second-gen TKIs. How should we think about the moving parts for the pivotal design, and what are the potential scenario outcomes? Yeah, those are really important questions. Again, I think we're highly confident in our position that 80 mg is the right dose, that second-line plus is a reasonable patient population given the safety and efficacy we've demonstrated so far in phase I, and that the ATP-competitive physician's choice control arm makes a lot of sense given the market that we'll be entering in the future, which again, will be heavily penetrated by SCEMBLIX in early lines of therapy. The clinician question to answer is, which is my best choice here of these ATP-competitive agents to go to next? Those are really important questions. I think another important question is time. The second line plus as your first pivotal trial is unprecedented. We have the precedence from asciminib, which is a third line plus study, which had a 24-week endpoint and a front line study that had a 48-week endpoint. We've made the case and think it's a compelling case that 24 weeks is the right endpoint for second line plus patients, and that we can differentiate response in that timeframe, but would certainly want confirmation from health authorities on that. You get into details of stratification factors and sample size and statistical analysis plan. All of that will get resolved at end of phase II. Okay, the 24 weeks, you're going to ask FDA for that. Since there's no precedent, you don't know for sure what you're going to get on that one. I'd say we're reasonably confident in 24 weeks, but want certainty before we disclose our plan. Right. Yeah. Makes sense. Novartis took about three years to enroll ASCEMBL and third line plus CML. If you gain alignment on a second line plus pivotal, can you walk through the assumptions behind completing enrollment? I think you've mentioned could take about 18 months. Yeah 90 plus sites. What gives you confidence that timeline's attainable? Yeah. ASCEMBL actually enrolled in about two years, and ASC4FIRST enrolled in about a year. We've guided 18 months because ASCEMBL was a third-line plus study and ASC4FIRST was a front-line study, and this is a second-line plus study, so somewhere in between those two things. I would say that we've completed feasibility and site selection, and we'll have well north of 90 sites in our study. I would say based on investigators' disclosures, we feel very confident in the 18-month enrollment timeframe that we've guided to. I think all the dots align for being able to do that. You assume an 18-month enrollment and a 24-week primary endpoint where if we start the study by the end of this year, we'll get to that milestone by, say, late 2028 and probably have top-line data in early 2029. Got it. I'd also just note that enthusiasm from the investigator community for the trial is very high because we are creating the real-world decision of, I'm moving a patient from potential allosteric to an ATP-competitive inhibitor, and this really is a selection of that. We have a very attractive comparator arm reflecting a real-world decision, so the investigators are very enthusiastic about it. Yeah. Makes sense. For cost of the study, you guys have mentioned could be about $150 million. Do those projections still hold? Yeah. Feel good about that. Okay. You also plan to discuss the potential path forward to evaluating 01 in the frontline CML patients. What clarity do you need from FDA for that population? The primary question about frontline in this stage is what do we need to show before we're allowed to start? Obviously, newly diagnosed CML patients are well-served by approved therapies, and health authorities don't want to expose patients to undue risks. We think this is primarily a safety database question. We don't have primary knowledge from health authorities on this yet, but I think from precedent discussions of other CML TKIs with health authorities, we believe the questions will be about the overall safety database, how many patients you have, and how long your follow-up is at your phase III dose. The other question may be a small safety data set in frontline patients themselves. We will be prepared to answer both of those questions. We've obviously enrolled a large number of phase I patients, and many of those are at 80 mg or above. We will have a large and growing safety data set there. We will have many patients with at least one year of follow-up, which I think is important to the FDA because a lot of the concerning toxicities with second and third-generation TKIs happen in the first year. I think clearing a bunch of patients past a year will be important. That data set's accumulating now, and I think in 2027, we probably have what we need to go to the agencies for discussion. Just to ensure that we have some frontline data to show, we will be initiating a phase II study via an IST that we'll initiate before the end of this year that will allow us to have some safety data in hand in 2027 to engage health authorities. Can't really guide to a specific timeline at this point, but I think we could start a phase III study in frontline CML if things go well in 2028. 2028. Got it. For the phase II IST study, anything more you could say about what that design could look like? Is that something you would share more details on at some point? We will share more details once we have agreement. We've identified a cooperative group who's interested in doing this study, and we're sorting out the final details of that. Once we have that, we'll share it. Single arm phase II to generate some safety and preliminary efficacy data is the thought. Got it. Presumably, would that be at the same dose? Would you have to do some dose exploration work? No. We would use our phase III dose. No biologic hypothesis why second and later line patients need different dosing than front line patients. Okay. I guess why not just invest in the study on your own rather than doing it as an IST? Yeah. We evaluated a number of options, landed on this one as the best combination of speed and efficiency. It's cost-effective, and they could move a little faster than we could move given our clinical team is currently standing up a global phase III study. Yeah Executing a relatively large global phase I study. We felt like it was a good use of resources to do it this way. We've identified a cooperative group with deep experience in this area with generating regulatory quality data and felt like it was, again, fast and efficient. Got it. With the cooperative group, it means you've got a couple investigators who would use their site to help enroll patients. Yeah. It'll be a multi-center- Yeah study that will move quickly. Okay. That's helpful. We've had debate and discussion with people just about for the frontline opportunity, there's perception that allosteric inhibitors like asciminib could offer broader mutation coverage by avoiding the ATP site resistance mechanisms. What are your thoughts on mechanisms for first-line and how to think about that, and how doctors think about that? Yeah. I think what people meant by that, or maybe what you meant by that, is that asciminib was viewed as addressing known mechanisms of resistance to ATP competitive agents. Right, T315I or others, because you're binding differently and working around some of those gatekeeper mutations, that you address those well. Allosteric mechanisms also have resistance mutations of the myristoyl pocket and others, and that's really an emerging story currently, right? Until we start treating a lot of patients with this, we don't know what mutations will arise and drive resistance, and we don't know how prevalent that will be. I think scientifically, there's a good argument that an ATP competitive agent, a potent ATP competitive agent like ours, is less likely to cause resistance mutations than an allosteric mechanism, because the ATP binding site is more evolutionarily conserved than the myristoyl pocket. Cells won't remain fit if there are a lot of mutations to the ATP site where they could if there are a lot of mutations to the myristoyl pocket. I would say scientifically, there's reason to believe you have more of a resistance mutation liability with an allosteric than with an ATP competitive agent. What we know is we're seeing more of them. More of them are being identified with NGS and at each hematology meeting, there's a report on all of the identified resistance mechanisms, mutations to SCEMBLIX and the prevalence of those, and those are both going up. I can say from our personal experience, just in the time we've accrued our phase I study, the number of patients enrolling in our study who have known identified resistance mutations to SCEMBLIX has grown considerably, and we'll share some data on that at EHA. Got it. Okay. I think in short, we think it might be a competitive advantage once we get to frontline CML to select an ATP competitive agent first, like ours. It may be less likely to drive resistance mutations than SCEMBLIX or TERN-701, and that may end up being a competitive advantage for us in early lines. Got it. Mechanistically, you think it makes sense to have the? Yeah active site inhibitor. Yeah. If you actually look at the list of contraindicated mutations for the second gens, the list for SCEMBLIX is actually already bigger than that list, and it's continuing to grow. Got it. Interesting. Besides mechanism, I guess for doctors deciding which drug to use in frontline, safety's going to be critical. I guess key efficacy measures as well. How should we think about that? How should investors think about what a doctor's going to choose first line? Yeah, I think it's more like a chronic disease now than a cancer indication. We're not looking for the deepest and best response and duration of response like we would in a pancreatic cancer or something of that nature. I think it's the totality of the profile. Can a patient tolerate it? Is it effective controlling disease for those who want it? Will it drive a deep molecular response that gives them a chance at treatment-free remission? Then all of those things being equal, you get down to more treatment burden convenience factors. Is it once daily? Does it have food effects? Do I have to worry about whether I'm taking it with a meal or I can't take it with a meal? Does it have meaningful numbers of drug interactions? These are elderly patients who take lots of concomitant medications. Is it inducing or inhibiting CYP3A4, et cetera? Those are all the hierarchy of needs that you're going to cover here. I think we stack up really well. I think we're at least as good as SCEMBLIX across all of those dimensions and better in some. I think we'll be a very competitive frontline agent because of that. Got it. With the second line plus opportunity, I think makes a lot of sense. It resonates well with investors. I feel like for the frontline, there's probably more of a disconnect there. For this EHA update with the earlier line patient population data that you show, is that going to help investors appreciate the potential for frontline more? Yeah. I think as we've done in our corporate decks, if you just plot asciminib response rates by line of therapy, you see a relatively linear trend from fifth line plus all the way to front line in terms of MMR achievement. Yes, I think by giving our dataset broken out by line of therapy, you can start to see does this look, in each of those lines of therapy, competitive with SCEMBLIX, and we'll inform that. Again, that's just one of the data points. I think you have to look at treatments, discontinuations due to adverse events. I think you have to look at the types of adverse events and their severity. Again, I think you have to look at the profile of the drug and those sort of convenience, tertiary, but important decision-making factors for patients who are going to be on drug for 20 years of food effects, drug interactions, and the like. I think you have to look across all the things. Yes, I think for sure this EHA data update will give people some information to inform how competitive we might be in, say, third line, and then you can predict from there, based on what you're seeing, whether that will then make us competitive in frontline. Makes sense. We're out of time, so maybe to close up, if you want to highlight cash position and anything else investors should focus on? Roughly $450 million of cash, which gives us runway into 2029. That would be through the top line pivotal data for a second line plus trial. Yeah, I think we're just really excited about the data presentation next week and ask you all to tune in our corporate event, 8:30 A.M. Eastern on the 11th, to talk about our data just ahead of the presentation in Stockholm. Rick, Ben, thanks so much for joining us today. Yeah, likewise. Thanks.