...with Enliven? Soon. Yeah. Okay, good. Well, I'll just start with a sort of a super generic introduction, and if Maury doesn't show up, you guys get to ask questions. So, hi, my name is Sam Kintz, Co-founder and CEO of Enliven Therapeutics. Enliven is a precision oncology company. It's okay. And we have primarily focused on targets with very validated biology, known mechanisms of action and in both cases for our lead programs, approved drugs for the corresponding targets. We have two parallel lead early clinical stage programs. ELVN-001, Maury, which is a selective active site active form BCR-ABL inhibitor for the treatment of chronic myeloid leukemia. And ELVN-002, which is a selective brain-penetrant irreversible HER2 and pan-mutant HER2 inhibitor. The team at Enliven has background in this space. My co-founder, Joe Lyssikatos, co-founded, well, not co-founded, started at the internal programs group at Array BioPharma back in 2001. Actually, he's the inventor, primary inventor of three approved precision oncology products, including TUKYSA, a HER2 selective TKI. And then on the clinical side, we have Helen Collins, who came from, most recently from Five Prime Therapeutics, following the acquisition by Amgen. So actually, now that Maury's here, I'll turn it over to you. Thanks, Sam. Good to see you. Maybe if you can talk about the data you just reported. You had some initial proof-of-concept data Phase Ia study in CML earlier this year. What's the key data and the key takeaways from that data? Yeah, thank you. So as I mentioned, we have two clinical stage programs. ELVN-001 is a program we recently presented initial proof-of-concept data on. The background for that study was it Phase Ia dose escalation. Our data from that study was Phase Ia dose escalation and last line or late line pretreated patients with chronic myeloid leukemia. So these are patients that had exhausted all available therapies known to be effective for their CML. So it was a classic 3+3 design, and we presented data in April showing safety, tolerability, PK, and initial efficacy from that study. We were highly encouraged by the results. There are very few recent precedents Phase I clinical studies in CML. For those of you that have been following the space, it's been, you know, many years since the initial ATP pocket inhibitors were approved, actually going back to imatinib, which was originally approved in 2001, Gleevec for newly diagnosed CML patients. So comparing our results to the more recent precedent, there's actually a drug that has gotten a lot of recent attention in SCEMBLIX or asciminib, which is Novartis's fourth generation allosteric inhibitor. Their Phase I study actually began back in 2013, late 2013, and had updates, you know, 2015 and then more recently at 2018. So we were able to kinda look at that clinical trial data set to compare our data, and the one previous to that was the most recent ATP pocket inhibitor approved, bosutinib, which is considered a second-generation TKI. And in comparing our initial proof-of-concept data to those precedent Phase I studies, despite the fact that we are in much more heavily pretreated patients, I think the data compared, at least initially, favorably, certainly compared to the second-gen TKI and pretty similar to SCEMBLIX. And for those of you that have been following the story, you know, our primary positioning for ELVN-001, which is an active site, active-form inhibitor of BCR-ABL, is gonna initially likely be in a setting post-SCEMBLIX or post-asciminib. We see that agent as clearly best-in-class. In fact, recently, last week, Novartis presented, or investigators on the frontline study presented data from SCEMBLIX's frontline trial going head-to-head against all the broadly approved ATP pocket inhibitors and looked really, really encouraging. So we're anticipating pretty broad and rapid uptake of SCEMBLIX in earlier lines of CML. And so if 001, as a complementary mechanism of action, can layer in following SCEMBLIX, and, you know, be a really great treatment option, delivering better safety, tolerability, and efficacy compared to the existing ATP pocket inhibitors, I think that would be, you know, a really good accomplishment. So we're encouraged by our initial Phase I data, both on the efficacy side, but importantly, given the importance of well-tolerated, convenient treatments for a chronic disease patient population on the safety tolerability side. Got it. Yeah, it's a great summary of the data and the positioning. For the data you showed, some MMR patients were MMR before they started with 001, and we think keeping patients at MMR is important when they can't tolerate the prior therapy. What are your thoughts on whether maintenance of MMR is a meaningful outcome, and is it typically achievable with first and second gen TKIs? That's a great question. Yeah, we got a lot of follow-up questions on the cumulative rate of MMR. We have had patients not in MMR that have been heavily pretreated achieve MMR, but a larger number of patients that actually came on our study, having lost response to a last prior TKI, but still technically in from an IS scale MMR. And so, you know, what does maintenance of MMR mean? I think those not familiar with CML have often associated that with stable disease. In CML, that's, that's not the case. MMR, if, if you're able to maintain MMR at any, any line of therapy, you have near 100% chance of CML-specific survival. So it's a very deep molecular response. These patients had already achieved hematological and cytogenetic responses. Maintaining MMR, of course, depends on the context, but it's always an important goal. In the context Phase Ia study design, these are patients that had seen many prior previous therapies and have struggled either from a tolerability or an efficacy standpoint. In our case, over almost 70% of the patients had come onto our trial due to lack of efficacy to their prior TKI. In the case of the 5 patients that maintained MMR, 4 of the 5 of those had actually switched on to the 001 study due to loss of response to the last prior TKI. Four of those patients had had prior asciminib and did not have efficacy or lost efficacy. One of them had prior asciminib and ponatinib. So in the maintained MMR bucket, given the context of these patients, 4 of the 5 were highly resistant patients with highly resistant CML. They had done well for a period of time on the most potent available TKIs, asciminib and ponatinib, but had lost response. And so on the IS scale, which is how molecular responses are determined, it's a, each categorical shift is a 10-fold difference in BCR-ABL transcript levels. So for agents that can get deep responses in patients, like even beyond MMR, which is MR3, so MR4 is 10x deeper than MR3, MR5 is 10x deeper than MR4. These patients had already failed multiple second-gen TKIs. So second-gen TKIs are known not to be effective for the, for 4 of the 5 of those patients, and then had lost a response on the most potent TKI. So being able to take those patients and control the disease and maintain them in that deep threshold of response, actually is, in some ways, some of the most impressive data we have. And I'll just say all 5 of those patients are still on study and have maintained MMR. Got it. Yeah, it makes sense. And for the data update, it was a three-month cut. We're wondering, and you haven't guided to this, but we're wondering if it's possible that you could show data for—at a six-month cut, for MMR, and potentially more valuable patients maybe later this year? Yeah, we are certainly thinking about when the next data update will be. What I've said, for those of you that have had meetings with us and, you know, many times, is we do intend to present again this year. I mean, our investigators, the event we did in April was really an investor-focused event. We did have two of our investigators on the call to share their thoughts and reactions to their data and their experience with 001. But our intention is to allow investigators to present the data as well, and that will likely come from a later data cut. You know, we're not putting high expectations on that just because, you know, we're really kind of pointing to 2025 with significantly more patients and significantly more follow-up to sort of flag the more sort of bigger inflection point for the program. But I do think any update is gonna be meaningful, and, you know, we're quite positive. So I think, yeah, seeing a later cut for those patients is certainly possible later this year. Okay. That's helpful. And you also mentioned on the conference call that you were enrolling some additional patients into this study as well, where it could be up to 10, 10 additional patients. Is there anything more you're saying about how many patients you have on the study and at what dose level, levels those patients are at? Yeah. So we are continuing... Enrollment has continued to pick up. I think, you know, even as certainly our investigators have seen the data earlier than all of you, but, you know, with the public data release and continued enthusiasm for the data, we're seeing enrollment pick up. We are continuing to enroll patients in dose exploration cohorts of Phase Ia. but we, as I noted on the call and in subsequent calls and notes, we are done dose escalating for the broader patient population. So the next step for us, as we indicated, would be to initiate our Ib, and we said it was in second quarter. We feel really good about that guidance, and we'll give an update on that soon. And so, you know, we'll be enrolling both Phase Ib portion of our study, exploring doses that we've already presented data on, and continuing to build out a data set, particularly at higher dose exposures, Phase Ia for patients that, you know, really have failed every single option, kinda don't meet the typical broader patient population criteria, either with rare mutations, or that have been heavily resistant, even to drugs like asciminib, ponatinib. So continue to explore safety margin. We have still not reached an MTD. One of the best attributes of 001 is its safety and tolerability profile. So there's room to go to higher exposures, but we don't believe we need that, nor are we interested in exploring those higher exposures for the broader patient population. Got it. Makes sense. And, for Phase Ib, i think you could enroll 60-100 patients and have data on that many patients as well. Just wanted to see what more you're saying about the number of patients you could show data from in 2025 from Phase Ib, and would that include the 27 patients from the dose escalation cohort as well? Yeah, when we bracketed 60-100, really as that threshold of number of patients that we felt like we could go to the FDA and other regulatory authorities and have, you know, a productive, meaningful discussion about the first head-to-head registrational study, and our goal is to have clarity on that by the end of next year. I think that in terms of catalysts, there could be an earlier data release with that number of patients, but that was the purpose of flagging 60-100 patients. That would include patients from Phase Ia. as i mentioned, we are continuing to, you know, enroll patients there that aren't necessarily eligible for our 1b or have, you know, sort of different attributes. So it'll be the totality of data that will become from the update. It won't just be 60-100 in 1b. It'll be from our entire Phase I. 1b, we have the option of opening multiple arms. The main goal for 1b, of course, as you guys might suspect, is to align on dose with the FDA for Project Optimus. ... Got it. Really helpful. And are there any differences in the patient population or inclusion, exclusion criteria that we should expect to see Phase Ib cohorts? and how much follow-up data would you report in 2025? Yeah. So in terms of the primary difference is for 1B, we do have the option of opening a T315I arm, and we will do so. We can continue to explore. We only had two patients. Those were, you know, patients that actually had blasts. They're technically still chronic phase, but they had been resistant to ponatinib and asciminib. So we don't feel like we've done enough dose exploration to be able to select the dose for the 1B. We still remain, I'd say, fairly confident that it's going to be a very similar or the same dose as the broader patient population, but we need to go get that work. So for the 1B, it'll only be in the broader patient population. That's the main difference. And then there are, you know, patients, as you might recall, that have atypical transcripts and other genetic abnormalities that, you know, we won't want to include in the 1B just because we're trying to make an argument about efficacy, exposure, and safety, and that's tough to compare if you've got patients you can't measure transcripts for. So those can continue to enroll at higher doses in our 1A as well. In terms of follow-up, I mean, it'll be the totality of data. So, you know, we have. Now you can imagine over 30 patients worth of data. Most continue, almost all continue on therapy. So it'll be a range, just like we showed in our current study, but we do hope to have a significant number of that 60 to 100 out past 6 months. Got it. That's helpful. And, you mentioned with the 60 to 100, you would use that to have a conversation with FDA. Maybe talk a little bit more about, what you would seek to ask from the FDA, and what are next steps for a registrational trial? And, when could we learn more about the outcome from that meeting with the FDA? Yeah. Good, good question. I. So, you know, from our perspective, looking out through the end of next year, we think we have two, you know, very kind of natural checkpoints with regulatory authorities. First would be a check-in on Project Optimus and dose, and we can use that opportunity to also probably ask some questions around, you know, what setting, what line of therapy we might be looking to do a registrational study. And then really, you know, the second chance would be once we've completed our Phase I, and we go and have that discussion, looking to get concrete answers to inform that head-to-head study. I think, you know, what we've said publicly and what remains our goal is to run a head-to-head study against the ATP pocket inhibitors, so particularly imatinib, bosutinib, nilotinib, and dasatinib, in as early-line setting as possible. I think practically, what we think that will be is a second-line plus, and we'll stratify but based on what those patients have had as a last prior treatment. But the study design would look not too dissimilar from the frontline ASCO first study that Novartis just presented data for at ASCO, SCEMBLIX in the front-line setting. All of these agents are relevant standard-of-care and second-line plus, and it just depends on what they had previously. So, for example, for patients that switch due to AEs or intolerance to front-line second gens, often those patients go to imatinib, so that could be an arm. Then, for patients, obviously, that fail or don't meet treatment goals on a second gen, either for efficacy or other reasons, either go to another second gen, or, you know, skip lines of therapy to ponatinib. So there's lots of different ways to design this study, but simplistically, it'll be randomized to the known ATP pocket inhibitors, and we're going to be looking for major molecular response superiority to that combined comparator arm, very similar to how the study design for asciminib was just read out on. Got it. And, for the asciminib data at ASCO, maybe talk about, what's relevant to ELVN-001 that you want to highlight, and, what does asciminib front line data mean for your development strategy? Yeah. So as I mentioned earlier, it's important for us, and we strongly believe that SCEMBLIX gets meaningful uptake in earlier lines of therapy. We know already it's doing very well in third line plus, and is commanding, you know, an increasingly larger share of that third line plus market, with revenue now over $500 million in annualized sales just from that patient population. The incident patient population in first line and second line is much larger, and Novartis actually just increased their peak sales forecast to over $3 billion and have bracketed it $3-$5 billion. So we're kind of bullish on the higher end of that case, and that will have to come from first and second line share. So the key question was, Is the data from ASCO for first enough to win significant share in that front line, potentially second line study? My opinion is it is. I mean, it is clearly the best drug. It's more efficacious, and it's safer and better tolerated, and that shows up in every single aspect of the data. I think you know, the pushback would be, you know, was the difference big enough first to second gen TKI? And specifically, with the second gens becoming generic soon, would there still be some payer pressure to potentially start on a second gen, given that the efficacy benefit was not as large compared to, you know, for example, asciminib, I mean, sorry, imatinib. And you know, that's a question that, you know, who knows? I personally think it's more than enough, because it's also better safety and tolerability. And what surprised me in a really positive way is that asciminib looked, you know, much better than imatinib from a safety tolerability standpoint. So the upside case is really that asciminib turns over that imatinib loyalist group, those docs and patients that start on generic imatinib, that the second gens kind of never really were able to turn over. I think for the docs that use second gens, it's gonna be almost a no-brainer to switch to SCEMBLIX. It'll be a harder, a higher bar to switch off the imatinib patients. But the safety was considerably better compared to imatinib, and I actually think that highlighted a point that a lot of people maybe missed in the data, which is that based on the way the study was designed, the arms were stratified to put the younger, healthier patients on second gen TKIs. 'Cause the older, more frail patients or sicker patients don't do well on second gens from a safety toxicity standpoint. And so actually, if you look at the safety data, the second gens look better than historical, and the efficacy is better, but that's likely just because they're younger, healthier patients, and they're able to maintain higher dose intensities of the second gen TKIs. So the study was sort of biased to make the second gens look better. Asciminib still looked better, but it does, it's not indicative of that real patient population. And then lastly, I know I'm kind of droning on here, but I was really encouraged to see if you look at the percent of patients that remained on therapy, the respective therapies of this study, 38% of patients had discontinued imatinib, and that was a median follow-up of only 16 months. That's incredible. So even if, even if you don't turn over or SCEMBLIX doesn't turn over the generic imatinib base, you already see that churn rate significantly higher than it was 10 years ago, and it's gonna just keep going up. 38% of patients discontinued imatinib, and it was the best imatinib ever looked in terms of efficacy on a clinical study. 25% of patients had discontinued a second-gen TKI within 16 months. So we see that churn rate continuing to increase, and so I still think you're gonna get a lot of newly diagnosed patients on SCEMBLIX and frontline, but at the very least, you're gonna have much more rapid churn. And these patients aren't truly progressive. They're just not meeting optimal goals because they know there are better options waiting for them. So why would you not switch to an option that could be better if you're having an AE, even, you know, low-grade nausea, diarrhea? That's enough, you know, for a patient that's gonna be living many, many years having to take these drugs. Got it. Makes sense. So if SCEMBLIX has really good efficacy based on the frontline profile that we saw and better tolerability as well, how does that impact the second-line market opportunity? I guess, what do you expect to happen there for Enliven? Yeah. So if you look at sort of the major markets, the for frontline to second line, second line to third line, there's about 16,000 patients switching in those settings each year. If a high proportion of those patients had prior SCEMBLIX, we think we're well positioned to capture those patients with ELVN-001, assuming our data continue to hold. All of the things that I just pointed out with respect to the ATP pocket inhibitors are gonna hold in a later line: less efficacy, poor tolerability and safety. And asciminib is a very potent drug. The mutations conferring resistance are activating mutations. Many of these drugs only bind to the inactive form of the protein and are less active against those mutations, at least in preclinical studies. And more importantly, there's just not a lot of data out there for how these drugs do. I think people suspect an ATP pocket inhibitor will work. There are examples of that. We know that's what patients progressing on asciminib go to today. That is standard-of-care. But ELVN-001 is looking really good in a super late-line patient population, and differentiating both in terms of being able to drive, you know, molecular responses and deeper molecular responses in highly resistant patients. But importantly, from a safety tolerability standpoint, we have still never had a dose reduction. At doses higher than 40 mg QD, we have not had dose interruptions. And these are important endpoints, secondary endpoints on the clinical studies Novartis is running with SCEMBLIX and part of the differentiation there. So we would hope that as we continue to put out Phase I data and ultimately in our head-to-head, that we would highlight that. And just being an ATP pocket inhibitor with established efficacy and a superior safety tolerability profile compared to the ATP pocket inhibitors, we think we would be the drug of choice there. And if anything, yeah, based on the frontline data from asciminib, I think there's actually probably more room than I had originally thought to potentially differentiate on efficacy compared to that drug as well. Got it. And, you've talked about the different mechanisms between ELVN-001 and asciminib and the potential to combine the two drugs. Maybe. And you also said that you could potentially get some feedback on that at ASCO. Yeah. Just checking, did you get any feedback on that, and what's the likelihood of exploring this, and where would that make sense to do that? Yeah, great question. I do think that that could be sort of a label expansion opportunity for Novartis but also for us. And you may recall that the initial registrational studies that Novartis ran were actually add-on frontline studies to second-gen and first-gen TKIs for patients that had not achieved optimal response in a frontline setting. I think that's the most interesting place to explore a combination. Can you increase that functional cure rate, so treatment-free remission in combination? There's high interest from the community, so we got that feedback both on our call from our investigators and more so at ASCO, and it's something we'll definitely be looking into exploring with our molecule, you know, both with SCEMBLIX, but potentially with other allosteric compounds. ... Got it. And I think we're almost out of time, but maybe I'll ask one more question and then let you close out. But with ELVN-002, we've been getting some questions on that. It's your HER2 TKI. Any learnings from ASCO based on new data in this space, and maybe just talk about how you plan on positioning that drug. And then in closing, if you can highlight the cash runway and key catalysts ahead that investors should be focused on. That's a huge question. You know, we remain highly encouraged and excited about ELVN-002. I know it's a bit of a delay on when we would have proof-of-concept data. We have put out some initial data that, you know, from our perspective, indicates the drug's working as designed. We still firmly believe the most interesting opportunity for us, and just in terms of size, is in the HER2 positive space. So I think there's just a continued, at ASCO, output of data showing that HER2 is expanding as a market, really thanks to ENHERTU. We know there are all these subtypes, even in the HER2 positive setting, that are being identified now through sequencing, so it's a rapidly growing market and I think a rapidly growing unmet need in a post-ENHERTU setting. So everything we're doing is to establish ELVN-002 as a potential option to layer on to standard-of-care in combination in that post-ENHERTU setting. I think tucatinib continues to put out data in little small cohorts that are encouraging, and I think already based on our data, we would say we at least are hitting the target harder. We believe we're hitting the target harder than tucatinib, with a good overall tolerability profile. So we've got all the pieces in place to test that hypothesis, but it's gonna take us some more time. Got it. Maybe just highlight key catalysts ahead investors should be focused on. Well, 2025 is our big year, so another big update for ELVN-001. We're not excluding the potential for a more incremental update, just more follow-up from our initial data disclosure for ELVN-001. I think that's likely at an investigator presentation. For ELVN-002, it's still gonna be 2025, because that's what we're gonna need to get that key initial proof-of-concept data in HER2-positive cancers. And cash runway is till the end of 2026. Great. Thanks so much for joining us today, Sam.