Good afternoon and welcome once again to TD Cowen's sixth annual Oncology Innovation Summit: Insights for ASCO and EHA. I'm Phil Nadeau, one of Cowen's biotech analysts, and it's my pleasure to moderate a fireside chat with Enliven Therapeutics. We have with us this afternoon Sam Kintz, the CEO, and Ben Hull, the CFO. As I'm sure you all are aware, Enliven has some very important data coming up at EHA, so we're going to walk through that in today's session. Before we get into the nitty-gritty details of the data, Sam, I'll hand it to you to just provide a brief state-of-the-company overview. What are Enliven's strengths, what are its challenges, and what does it need to do to create shareholder value over the next year or two? Yeah, thanks, Phil. Thanks for having us. Looking forward to this somewhat quick conversation today, heading into our data update at EHA for ELVN-001. Just by way of background, Enliven Therapeutics is a clinical stage right now, primarily focused on precision oncology company. Our background is really in small molecule kinase drug discovery. All of our assets have been discovered in-house and developed in-house. A part of the founding team is Joe Licatos, who's our Chief Scientific Officer and had started the internal programs group at Array Biopharma, hence why we're located in Boulder. A long track record of success in the precision oncology space, and certainly many of those scientists are associated with the company. I think most investors are aware our lead program is ELVN-001, which is a selective ATP-competitive BCR-ABL inhibitor for the treatment of patients with chronic myeloid leukemia. We are currently generating data in a late-line phase one setting and looking forward to sharing that update in a couple of months—or no, a couple of weeks, not months. For those of you that aren't familiar with the evolving landscape that is CML, CML is a large precision oncology market. Obviously, it's been benefited from multiple approved TKI inhibitors over the last 25 years. In fact, today, newly diagnosed patients with CML are expected to live as long as the age-matched general population, thanks to the benefit these TKIs have. That has led to evolving treatment goals, notably quality of life, convenience, and better efficacy as we drive towards deeper molecular responses in hopes of getting patients potentially off therapy for long extended periods of time. In this chronic disease setting, all aspects of differentiation matter. Efficacy is always going to be important. It is still cancer, but tolerability is also a huge key factor. As we look at our upcoming data release, hoping to now see with a substantial number of patients how ELVN-001 can fit into the broader landscape. Turning to the EHA abstract, can you walk us through the highlights of the data in particular? What were the key efficacy measures? Yeah, absolutely. Last year, based on an end-of-June data cut, we presented really an updated data set for our ongoing phase one-a portion of the ELVN-001 program. For context, we're currently enrolling patients who have exhausted all available therapies known to be effective for their CML, so very, very heavily pretreated patients. When we presented data last year, we focused on a couple of key efficacy benchmarks, notably major molecular response rate. Major molecular response is equivalent to 0.1% BCR-ABL transcript. This is a molecular marker that can be measured by PCR, directly from peripheral blood samples, and is now used as a surrogate endpoint for survival and registrational studies. As when we previously presented data, it was on a smaller subset of efficacy-available patients, 18 at the time, although we had enrolled over 30 and had more considerable safety to support the overall tolerability findings. With respect to the key efficacy benchmark, major molecular response, we had a cumulative response rate of 44% by six months. Six months is relevant because that is the endpoint in a late-line setting for accelerated approval. It is actually used to advance molecules to ultimately approval and to market. Of that subset of patients, there was a portion that was evaluable for response achieved rate, so patients that do not enter the clinical study with a baseline major molecular response and then achieve that by the six-month time point. We had 3/ 13 patients meet those criteria, so 23%. That compared, we thought, quite favorably to the precedent clinical study of the now best-in-class agent, Asciminib or Scemblix, which in its phase one study had a 24% response achieved rate. What's notable about our patient population, of course, is that at the time, over 50% of our patients had already exhausted Scemblix as an option. We were really encouraged. Yes, small data set, phase 1A data, but everything trending in the right direction and comparing favorably, even though we had more heavily pretreated patients. As we head into EHA, we'll be presenting now an extended, another year, almost year's worth of data. More patients, more patients at the higher exposures that are expected to be efficacious and effective in this late-line patient population, of course, a lot more safety data as well. A couple of weeks ago, the abstract released, we had doubled the number of patients that were response-available for efficacy. We were really happy to see that the response achieved rate, the cumulative major molecular response rate had all held up well. Actually, it has slightly improved over time. As we come into the EHA presentation, we will have substantially more patients than that now available for those same efficacy metrics and, of course, all the accompanying safety and tolerability data as well. Have you disclosed how many more patients will be at EHA than were in the abstract? Yeah, so I think we were in the 70s in terms of total patients in the abstract. Of that, I think 36 were available for efficacy by six months. That was from a January data cut. We have recently completed another data snapshot to support the EHA presentation. I do not have the exact numbers in front of me, but it is going to be in the 90-ish total patients with probably in the low 50s available for efficacy by six months. Considerably more patients. That's really helpful. In terms of safety and tolerability, you noted that that's likely to be a key differentiating feature for these chronic therapies. How did ELVN-001's safety look in the fall data set as well as in the EHA abstract from a couple of weeks ago? Yeah, absolutely. I think safety overall, of course, is really important. Tolerability, assuming safety is there for this chronic disease, is really probably most important in terms of commanding more market share in the real world because we know these patients switch for a whole host of different reasons. Because overall survival is the same regardless of which TKI you take and which order you take for the broader patient population, a lot of patients are switching just because they don't feel good on the current therapies. Previously, we had reported sort of standard safety tables showing both treatment emergent toxicities as well as treatment-related as determined by investigator and the roll-up of the overall tolerability as well in terms of number of dose reductions and dose interruptions. In fact, dose reductions and dose interruptions were secondary endpoints in Novartis' pivotal studies against first- and second-gen TKIs with their novel allosteric molecule Scemblix. I think one of the things that has been so exciting is that this clinical evidence that with a selective BCR-ABL inhibitor, you can achieve both better efficacy and better safety and tolerability. You get it both for these patients, which in this market where there are multiple generic options, if you have a real benefit, real differentiation, we have seen how that has translated to commercial success for Scemblix quite substantially right off the bat. We will present data in the same way, looking at what types of AEs, the severity of those AEs, what are the AEs leading to discontinuations or reductions when they happen. In the abstract, we kind of just said the broad top-line numbers, but we did note that there were fewer than 5% dose reductions, which compares very favorably to any precedent study. We'll see how that holds up over time, but that'll be a very important metric. I think what's most important is we haven't seen any new toxicities. Still a profile that's very, very consistent with high ABL1 selectivity. We can look to Scemblix as another agent that has high specificity for ABL1. I think importantly, you're not seeing sort of the gut toxicities, the nausea, fatigue, diarrhea associated with first and second-generation TKIs. Not seeing the edemas or effusions associated with those that hit PDGFR like Imatinib, Dasatinib. Certainly, Ponatinib's in a class of its own with high rates of severe AEs and all of that. Overall, the profile continues to look consistent with what we've said all along: high specificity for ABL1, very well tolerated, as evidenced by the fact that many patients are staying on drug for a very long time, even without major molecular responses. As EHA approaches, can you help us understand how you would evaluate the data in the EHA presentation? It sounds like MMR and discontinuations may be the most important efficacy and safety numbers, but there is a whole other host of endpoints that we are going to get. How would you advise investors to look at the data? In what context should they put all these results? Yeah, it's a great question. I think we in the past have been accused of being too in the weeds and too much detail because we think every detail matters, every patient matters, and that continues to be true. I think in terms of one number, of course, the overall safety profile is really important. I don't think there'll be any surprises there. It's been very well tolerated to date. There's a lot of enthusiasm from the community about our drug. For efficacy, as we head into next year, we hope to start our first pivotal study. We've been very focused on the response achieved rate. So patients that are not in baseline major molecular response that achieve that milestone by six months. I had already noted the comparison to the Asciminib phase one. When you look at the totality of the phase one data set in the seminal publication for the Asciminib phase one, that response achieved rate was 24%. What's so notable about that is then in the phase three study, ASCEMBL, where Asciminib went head-to-head with Bosutinib, the endpoint in that study was major molecular response rate at 24 weeks. Same time frame, same molecular marker or molecular milestone. In that registrational study, Asciminib was 25.5%. That led to its accelerated approval and phenomenal commercial watch in that setting. Interestingly, Bosutinib, although that early phase one did not give a response achieved rate by six months, we did see the cumulative response rate on that phase one study for Bosutinib, which was 15%. When you look at ASCEMBL, Bosutinib was 12% at 24 weeks and then kind of topped out at about 15%. What's really, really encouraging is that despite the fact that there have been now over 13 years of time between that Bosutinib study and when Asciminib kind of fully read out, the data really hold up in this late-line patient population. This is an efficacy metric that we can rely on, that there's very good strong precedence for, and we know it holds up in these phase three studies. As we think about potentially going head-to-head against a second-gen TKI, whether it's in a second-line plus or third-line plus setting, it's really that effect size that we need to be confident in. From our perspective, if we were anywhere near the Asciminib 24% response achieved rate with a larger patient population, so more patients, more time, assuming nothing happened in terms of baseline demographics of those patients, we would have very, very high probability of success. Now as we look at we have 50 valuable patients, a big chunk of those will be available for the response achieved. I think around 40 of those patients will be available for response achieved rate. We are really excited about focusing in on that number because it gives us a huge amount of confidence moving into our phase three study. To your point, there is a lot of other things to look at. Historically, cytogenetic response has led to the approval of all the other TKIs, so the other two second gens and Ponatinib in a late-line setting. Cytogenetic response is now equivalent to BCR-ABL levels less than 1%. That is a very interesting number to look at. You can derive that from our shift table that we presented in the past, but we'll probably focus in on that because that's yet another thing that we can compare both to Asciminib and the precedent phase ones to look at those patients with higher disease burden that still have a benefit that don't quite achieve major molecular response. Then just look at the duration of treatment. How long are patients staying on drug? Obviously, the reasons that they do come off or they dose reduce, are they scary or are they just sort of as expected for this class, this patient population? There'll be a ton of data presented. Much of it will be in the EHA presentation, and then we'll be sure to have very shortly thereafter a full corporate, not confidential, corporate deck update to capture any of the details that don't make it into the 10-minute presentation slot for EHA. You referenced potential pivotal trials starting next year. What is the likely design of those pivotal trials? In particular, which lines of therapy are you likely to target and which comparators will you include? Yeah, it's a key question for us. I would love to say in two weeks, be like, "This is the trial we want to run or we're going to run." Let's break it down in a couple of different ways. In terms of the precedent late-line studies, we will do a head-to-head study. We think that is most powerful, and that has led to a very powerful watch for Scemblix, even in the third-line plus setting. If we look at ASCEMBL, which was that study that led to approval of third-line plus for Asciminib, that study was third-line plus, so patients that have had at least two prior. Big chunk of those patients had four or five prior drugs. It was comparing to just Bosutinib as the comparator. Of course, efficacy was measured at 24 weeks for that approval. That study design is a very valid study design. We know there are no differences in progression-free survival or overall survival. You can pick, there's a lot of latitude to pick what your comparator is because you've got this early molecular milestone to compare against. We know another company has already gone with that same exact trial design, third-line plus versus Bosutinib. That would be a very low risk from a regulatory perspective and very low risk, assuming data are supportive from a probability of technical success standpoint. We kind of call that our base case. On the same time frame, so no additional requirement for additional safety follow-up, we could also consider doing a more aggressive study. Going into, call it a second-line plus context. Patients having failed at least one prior TKI and then randomizing, I think in that setting, we'd want to provide a physician's choice option. Now, we can limit that in any way we thought was best in terms of managing trial size or uncertainty around certain of the arms. From our perspective, we have a huge amount of confidence that we're going to be able to show differentiation at 24 weeks in terms of an efficacy magnitude of benefit to second-gen TKIs. It's just how do we design that study? That study would likely have to be a bit larger because we know that effect size for Asciminib was a little bit smaller as you came into the earlier lines of therapy, but something that we felt is very workable. We're managing sort of size and a little bit more uncertainty in terms of what are you powering, what's that effect size you're powering for. From our perspective, we have a huge amount of confidence that we could design that and have a very high probability of technical success study. Of course, it would give access to a substantially larger patient population. It's attractive from that perspective. I think the label would be more attractive as well because you'd have a combined comparator arm, including whatever the physician thought was best for those patients in the randomized study, and that would be all the other ATP pocket inhibitors. Those are the two different trials that we're considering. We'll use our time this year. The main thing we need to work through between now and hopefully the end of the year into early next year is finalizing our dose selection. We really view choice of clinical or registrational study as a strategic decision on our part, more so than something we're worried about any sort of regulatory risk at this point in time. Is there any chance you do both trials or is that too heavy of a lift? I think that it's unlikely we would do both of those called later-line studies. I think what is very likely, again, assuming data are supportive, we have the ability to continue to finance the company is doing one of those studies, so either the third-line plus, like Asciminib did, or the bigger, better second-line plus study. We would follow shortly thereafter with the front-line study. The front-line study design would look very similar to the study Novartis just ran in the front line with Asciminib, so the ASC4FIRST study. I think there it gives you even bigger addressable patient population. What's nice about that study is we still view that as the highest probability of technical success study. Remember, ASC4FIRST had just comparison to Imatinib as a co-primary endpoint for Asciminib. A very, very powerful setting to, again, show the safety tolerability benefit to all the approved drugs. We've mentioned Scemblix a few times in this conversation. A couple of things are notable to us that happened to Scemblix over the last year. The first is $689 million in 2024 sales. The second, as you referenced, is the broad approval based on Asciminib first data. What have you learned about the market from the Scemblix launch thus far? Yeah, it's been hugely validating to see its financial success. In a lot of ways, the biggest risk we took starting Enliven was betting that Scemblix would disrupt standard of care and would be a commercial success. Remember, for about a decade, no one paid attention to CML because, again, overall survival goals had been fully achieved. Was the generic erosion going to just tip the scales and shut off all innovation? I think similar to what we've seen in other chronic disease settings like HIV is better drugs get adopted. Scemblix has been rapidly adopted with a pretty small study, right? Comparing just to Bosutinib, you noted the annual sales, but if you look at the Q2 earnings from this year, it's already annualizing close to $1 billion. Almost all of that's still from the third-line plus patient population. Launched essentially in 2022, it's now 2025, annualizing about $1 billion. Most of that in a late-line CML setting where they haven't even fully penetrated that market yet. As of end of the year 2024, at least in the U.S., they have an accelerated approval, broadly approved. Remember, that front-line study also gave the broader second-line plus label. It can be used in any situation, which is now five times greater total addressable patient population. There are some hints already if you look at the second-line adoption and even some early front-line adoption that we see this being potentially a bigger than $5 billion drug, which creates an enormous opportunity for ELVN-001, assuming we can look very similar to Asciminib, but with this differentiated mechanism of action, so ATP competitive binding mode. I'd also note just as we look at the CML payer research, it seems that although there already is some generic options available, that most patients, if not all patients, have access to Asciminib in the front line as well. It's great to see that. Where do you envision ELVN-001 ultimately fitting into the treatment paradigm? Is it going to compete with Scemblix, be used after Scemblix, be used in front of Scemblix? Where do you hope ELVN-001 ultimately lands? Yeah, I think we had the conviction to start the company. We had some insights around how to make a selective ATP competitive inhibitor, of course. As a base case, we always viewed this as by far the best option for any patient that's had prior Scemblix experience or Asciminib experience. Sequencing allosteric, then ATP competitive, which is where the field is going. There is broad acknowledgement that that makes a whole lot of scientific and clinical sense for patients. As a base case, we've really thought about it more in that second-line plus setting and differentiation. That being said, there are reasons to consider ELVN-001 over Scemblix, and especially in a younger patient population or even an elderly patient population where patients are doing fine on their drugs but have various complaints, whether it's co-administration requirements, limit into what other drugs they could take. Having a very clean drug-drug interaction profile, no food effect, once daily, just gives patients the flexibility to live their life and to manage their other ailments the way they see best fit or their physician see best fit. I also note that as we generate more data, it is interesting because we've presented comparable data in a patient population that's very clearly more heavily pretreated. I think 60% of our patients have had prior Scemblix. Substantially more patients have had prior Ponatinib experience. I was just looking at the number of patients that are fourth-line plus, so actually fifth-line plus, so have had four prior TKIs or more, or 10 times more patients have had that in our study. The fact that our efficacy is as good or better gives, there's sort of, maybe there's an opportunity to compete directly in terms of efficacy as well. We do bind more directly, so we're inhibiting the active form of the protein or the enzyme, whereas Asciminib is a little bit more indirect. It's trapping out inactive conformation. There could be some efficacy benefit in earlier line setting, as well as a later line setting where you've got multiple flavors of resistance potentially playing a role. We do have just about one minute left. I didn't want to slip in one question on ELVN-002. Since you recently announced that you're going to seek strategic alternatives for the program, what's the rationale for this decision and where ultimately could ELVN-002 be developed? Yeah, it's a good question. I mean, obviously disappointing because in many ways, the molecule works exactly as it was designed. And we've had very encouraging both clinical data, but also enthusiasm from investigators on our study. The key driver is cost, right? One of the initial plans was to develop the drug as a monotherapy in mutant non-small cell lung cancer. Frankly, we were too far behind BI. We didn't know that when we advanced the molecule into the clinic. Seeing the data for Zongertinib, it's too far ahead and too good, frankly, in terms of what's the differentiation play? We didn't design this drug to be a follow-on or competitor to BI. We had turned about a year ago, 18 months ago, and we've been very public about this, turned our attention to the HER2+ setting. The data are encouraging, right? We're continuing to get a little bit more data there. The reality is when you look at time to approval, proof of even time to proof of concept data sets, given that these are solid tumors that are late line and combination setting, it just became very, very clear that in order to ensure success for ELVN-001, which clearly looks amazing, we're super confident in that drug and the path. Frankly, that's where all the investor attention has been. It made most sense to stop spending on ELVN-002 and to see if we can get it in the right hands. That's great. With that, we are out of time. Congrats again on the EHA data. We look forward to the presentation and your webinar in a couple of weeks. Thanks so much, Phil. Looking forward to it. Appreciate it. Thanks.