Like, some of the questions, like, I could answer sooner or later, just depend on—I don't have a plan, really. I'm just gonna—okay, yeah. Where do I sit here?
Yeah, you can sit there. Good morning. Welcome once again to TD Cowen's 45th Annual Healthcare Conference. I'm Phil Nadeau, a biotech analyst here at Cowen, and it's my pleasure to moderate a fireside chat with Sam Kintz, the CEO of Enliven Therapeutics. Sam, maybe I'll kick it to you to start. Can you provide a brief state of the company? What are the key pipeline programs and most important events for the company over the next year?
Sure. Thanks, Phil. Nice to be here. Yeah, so just for those of you that don't know, the company Enliven is a small molecule discovery and development stage company with an initial emphasis in precision oncology. We are based in Boulder, Colorado, and actually one of our co-founders and CSO, Joe Lyssikatos, is probably best well-known for starting and building the Array BioPharma Internal Programs Group, hence our presence in Boulder there and emphasis on small molecule discovery. We have two clinical stage assets, both in global phase I clinical trials. Our lead asset, ELVN-001, is a selective ATP-competitive active form inhibitor of BCR-ABL for the treatment of patients with chronic myeloid leukemia, or CML. We presented initial data, proof of concept data on that program last year, which we were very encouraged with, and I think was well received.
We will likely have a mid-year update with additional data for that program later this year. It's an exciting space. CML, of course, there's been a lot of successful TKI drugs in that space, but with the recent launch of SCEMBLIX, Novartis's allosteric TKI, we see a very exciting opportunity to follow with a selective active site inhibitor in a very large and attractive market where the unmet need has really considerably shifted over the last 20 years. Our second program, ELVN-002, is a selective HER2 irreversible inhibitor. Joe, actually our co-founder and CSO, was the primary inventor of tucatinib, the only approved HER2 selective TKI. We see an opportunity with that program to replace and improve upon tucatinib, likely in a combination setting in the HER2 positive space.
We have an ongoing phase I study both in monotherapy and a phase I study with multiple different combinations. That is a program we will likely have a data update on in the second half of the year. I think, based on sort of our focus and emphasis on O1, while we're excited about the O2 opportunity, just given the complexity of developing drugs in the HER2 positive space in combination and the cost associated with that, we'll also be looking for potential strategic alternatives for that program.
Focusing on 01, there was data last year in the fall at the ECHME meeting. Can you provide the highlights from that data release?
Yeah, we gave two updates last year, and the more recent one was in September, based on an end-of-June data cut in late-line CML. Patients that had exhausted all available therapies for their CML were really encouraged with the initial data that we presented, both in terms of the safety, safety tolerability, but also in terms of the efficacy. When we started this program, or started our phase I study, just given the patient population we were expecting to enroll, late-line patients, many of whom had failed all available therapies, including SCEMBLIX, we didn't really know what to expect in terms of the efficacy signal, but we knew what we wanted to see in terms of achieving target exposures, likely to show superiority to second-gen TKIs with a very good safety and tolerability profile.
I think we achieved that and then more with efficacy even comparable to SCEMBLIX, despite the fact that these patients were more heavily pretreated.
Maybe to dive into the safety profile a bit more, what were the key adverse events? Were there any discontinuations because of it?
Yeah, so far what we've seen has been consistent with a highly selective BCR-ABL inhibitor. In terms of AEs, the most frequent AEs we've observed are hematologic in nature. All of the approved BCR-ABL TKIs, including the allosteric SCEMBLIX, have myelosuppression on their warnings and precautions on their labels. This is an adverse event that's really treatment emergent, also can be associated with efficacy, and actually, incidentally, also disease progression. It is likely also a class effect of these TKIs. What we've seen with O1, still relatively low rates, low frequency, and certainly nothing surprising. In fact, I'd say so far, potentially favorable in terms of the rates and severity of these AEs compared to the approved drugs. Again, nothing surprising, most importantly with that regard.
Most importantly, with respect to the overall tolerability profile, on the non-hematological adverse events, we've seen very few in terms of the frequency and all have been very low grade. I think that's what's most critical for this program, given likely our competitors will be generic first- and second-gen ATP-competitive inhibitors, which have known off-target kinase activity associated with non-hematological AEs, which necessitate dose interruptions, reductions, and in many cases, discontinuations that limit their efficacy. So far, very favorable with respect to those AEs. From an overall tolerability standpoint, we have not yet had any dose reductions on our study, or at least reported. I think realistically, we would expect dose reductions to show up in terms of the O1 profile, but this is actually a really important metric, both dose interruptions and reductions.
It was actually looked at as a key secondary endpoint, both the Novartis phase three studies with SCEMBLIX, where SCEMBLIX showed a pretty big advantage in terms of just that tolerability, how many patients dose interrupted or reduced on the drug. You see that actually result in a benefit over time from an efficacy standpoint too. It is something that, so far, we compare very favorably to the other ATP-competitive inhibitors, and we will look at in more detail with our next update as well.
On the efficacy side, what was the MMR rate? How does that compare to the other available TKIs?
Yeah, so in our dataset from September, just as a reminder, we had 37 individual patients that we presented sort of safety and efficacy from. Of those, 18 were evaluable for efficacy by 24- weeks. 24- weeks is the endpoint for a late-line phase III registrational study, so it's relevant. Of those 18, 44% were in MMR by 24- weeks. That included five of five patients that enrolled with baseline MMR and then maintained or deepened responses, and also three of 13, or 23%, that did not have MMR at baseline and then achieved MMR. Just in terms of how that compares, so far, very favorably. Both the cumulative MMR rate and the achieved MMR rate were very much in line with Novartis's phase I study with the asciminib.
I think what's so impressive about the fact that we're pretty much in line with that data is the fact that we actually, over half our patients had prior SCEMBLIX, and the majority of those were actually resistant to SCEMBLIX when they started our study and had been more heavily pretreated, so more prior lines of therapy than that comparative phase I study as well.
Some investors have asked about the proportion of patients with baseline MMR who were in your trial and how they acted to therapy. Can you give some context around maintenance of MMR in those patients? I think some investors look on it as maybe stable disease, but I think if you peel back the onion one extra layer, it's actually much more impressive than that. Can you go into detail about those patients in particular?
Yeah, yeah. No, I think it is interesting. You did see sort of a similar percentage of patients on the SCEMBLIX phase I that enrolled with baseline MMR. Maintaining that very deep molecular response is really important, especially in the context of a late-line study. As a reminder, we're enrolling patients that pretty much failed all available therapies. I mean, that is an inclusion criteria for us. There is a reason those patients were coming on our study. MMR is always meaningful. The reason it's meaningful is because as a patient, if you're in a major molecular response, you have a near 100% chance of normal survival compared to the age-matched general population. What we've seen over the last decade in particular are physicians treating as deep as possible molecular responses, assuming tolerability and safety are there for those patients.
Now that we have more potent agents available, like SCEMBLIX, also ponatinib, which is recently approved in the broader third line plus, you have patients that had failed prior generation therapies, moved on to these more potent agents, gotten into deeper responses, and then in some cases lost those responses. We are talking big shifts in transcript levels. Physicians know enough about the disease that they do not let those patients then lose cytogenetic response, for example, before switching them to a therapy that could benefit the CML. In the context of a phase I study, yeah, I think generally maintaining MMR is a really important efficacy goal. For our particular patients, four of five of the ones that maintained or deepened their responses, all captured in the maintained bucket that we presented, were resistant to SCEMBLIX and/or ponatinib.
Again, most potent drugs that had been resistant to those drugs. One of those patients had been on prior frontline SCEMBLIX, achieved a very deep response, lost that response with the emergence of a myristoyl pocket mutation, actually the one that's most frequent in the frontline dataset for SCEMBLIX, moved to ponatinib, did not respond to ponatinib, came into our study just a notch below the MMR criteria, so in MMR, but had been resistant to both asciminib and ponatinib. That patient now has no detectable disease and has been on 01 for well over a year. Doing very well, and it's just an example of a very meaningful outcome in that maintained MMR bucket, so to speak.
In your opening remarks, you referenced the mid-year data update. We are starting to get a lot of questions from investors on what is the bar for that update and what's good, what's bad. Maybe we'll talk through what's going to happen. Can you give us what your most recent expectations are in terms of number of patients in follow-up that'll come out in a year?
Yeah, so I mentioned just previously the context for the initial update, or the last update in September, where we had 37 patients sort of in the broader safety bucket, and then an evaluable dataset of 18 patients. In terms of total number of patients we'll expect to present updated data on, we guided to 60-100, and we'll be well within that range, likely with at least around 60 with six months or more follow-up. In terms of just an additional dataset, a lot more. Recall that data cut from the last presentation was end of June. By mid-year, we'll have significant follow-up, even on the patients we've already presented. In terms of new evaluable patients for efficacy, I know it'll be at least double what we presented on before, and likely between 40 and 50 patients.
Pretty meaningful, very meaningful update from our perspective, a lot more patients and continued follow-up on the patients we've already presented on. The update will include patients both from the phase I- A portion, because we had a number of backfill slots to explore additional doses in the I- A. We have also since, as of end of Q2 last year, started opening up our phase I- B expansion arms. There will be patients from those expansion arms that we also include in the update.
How should we think about MMR going into the update? Clearly, you've already put up a 44% number. Should that be our expectation with this new dataset? Is there a reason that that could go down in terms of the patients enrolled or the characteristics of those patients? Conversely, could it go higher? Because at least the patients who were in the prior data cut will have been followed much longer, and responses do seem to deepen over time.
Yeah. I'll try to answer all of that. I'll start with the end. In terms of deepening responses, that is for a given set of patients, typically, generally, you would expect responders to have responses deepen over time. We've seen that sort of in CML. We do know that over time, these responses can get better. It's not always true. Actually, in the two recent phase III studies that Novartis ran with asciminib comparing to second-gen TKIs, we actually know the second-gen TKIs stayed flat or actually notched down a little bit over time, likely due to reductions, interruptions that resulted in suboptimal efficacy. It's not always true, but for good selective agents, you do typically see responses deepen over time.
Now, in the context of an ongoing phase I study where you have new patients entering the denominator as you continue to enroll, that patient set shifts and changes over time. Response rates will, of course, depend on the nature of those patients. We already talked about, did they come into baseline MMR, did they not, how many prior lines of therapy did they have? Those numbers can move up and down depending on the patients you enroll. For us, we'll continue to focus on the by 24- week response rates, because that's the relevant marker for the phase III efficacy endpoint. I think we'll continue to look at that. I think when we get further down the road, we can look at 48- week, even 96- week efficacy, and that's where we'll look at the continued benefit over time.
For the mid-year update, we'll really focus on the 24- week endpoint, hoping just to then build out the numbers we've already put out with a larger patient population. Coming back to expectations, cumulative MMR will, of course, depend on a lot of these things I just mentioned, the types of patients we're enrolling, were they in baseline MMR, how many prior TKIs did they have, and that can go up or down according to the patient demographics. I think at least as of now, I think the types of patients we're enrolling are very similar to the ones that we've presented on in the past. I'm not expecting wild swings. To the extent there are swings, I think they could be explained by, again, the types of patients we're enrolling, which will, of course, include.
I think the number that investors, frankly, are most focused on for this update is the percent of patients not in MMR that then achieved MMR by 24- weeks. We talked about that earlier, where initially from our last dataset, we had 23%. That percentage compares quite favorably, given that comparing to SCEMBLIX, for example, we have a much more heavily pretreated patient population. More importantly, it's the magnitude of efficacy difference to a second-gen TKI in what will be our comparator arm for our first phase III study. We know as you get to later lines of therapy, that response rate drops to 0% in a fifth-line setting for bosutinib, for example. It is really that buffer in terms of magnitude of benefit, which is how we're going to design our phase III study.
If we're tracking close to SCEMBLIX with a later line patient population, that's kind of the home run scenario. I think actually even the most skeptical investors agree. It's just the fact that they take issue with the fact that we only had three, three out of 13, not the percentage. I think that will be potentially a very powerful component of the data update to look at how those patients, those types of patients are doing now with more patients on our study.
Got it. If I remember correctly, SCEMBLIX is also about a 23% induction rate for MMR. Patients who entered the SCEMBLIX phase I, 23% of them who were not in MMR also achieved MMR in the trial. Is that correct?
Yeah. In the phase I study, their by 24- week MMR achieved rate was 24%. I think the reason that cumulative MMR also matters is for the reasons we discussed, and really it's the totality of the data that matter most. The reason the response achieved rate, I think, gets extra attention is because if you look at ASCEMBL, which was the randomized phase III study for asciminib in that very similar patient population that they did the phase I in, so third line plus, without much prior ponatinib, and obviously no prior SCEMBLIX, they had a 25% response rate in the randomized study compared to bosutinib's 12%. Of course, in the fourth line plus, those numbers fall off quite considerably, even for SCEMBLIX. The nature of our patients are more like the fourth line plus is more comparable.
I think, again, great scenario would be, can we continue to stay close or potentially even improve on what SCEMBLIX put up? Anything in that range is going to be really exciting with a bigger numerator.
Perfect. What would be the next steps for the program? Would you move directly into a pivotal study? If so, what's the likely design? Is there any benefit to doing a phase II?
Yeah. That next step is definitely to start a randomized head-to-head study. In terms of what we're hoping to accomplish this year to be in position to potentially start that phase III study, really what's rate limiting for us at this point will just be aligning on our go forward dose. That is a big focus for this year in the I-B expansions, getting enough patients across multiple dose levels to satisfy the FDA's project optimist criteria. We feel very good about our plan. We have had a meeting with the FDA to discuss that plan. We likely should have all the data we need at the very latest by the end of this year to then submit that end of phase I package and go talk about our phase III study.
In terms of what that design, and I do think a likely, we are starting to say 2026 is when we're going to start that study. Hopefully, we can pull that in well into the first half of the year, but we'll revise that guidance as we get into later of this year and have more information. We're very confident that we're on track to start that phase III study. In terms of the design, kind of multiple components there. From a patient population standpoint, it will likely be a late line setting, so third line plus, very similar to Novartis' first registrational study ASCEMBL, which was a third line plus patient population. As a reminder, that study enrolled greater than 50% of patients had four or greater lines of therapy, and they still got that third line and greater label. We would likely expect something similar.
I think one key difference would be we expect a significant amount of prior asciminib or SCEMBLIX use on our study, which is a good thing because we want to generate that randomized dataset compared to a second gen in a late line post Semblix setting. That is going to be very relevant for our initial launch. We know certainly that SCEMBLIX in that setting showed, even with one comparator, enough of a benefit both in the safety and efficacy to get significant share, despite the fact that bosutinib is not used as frequently as the other second gens. Our patient population will be just that late line with heavy prior SCEMBLIX use. In terms of comparator arm, it really will be our choice. All of the agents, with the exception of ponatinib, have broad approval and are standard of care in all settings.
From a comparator arm standpoint, there's precedent for picking whatever standard of care you want to compare to. In a patient population that's had prior SCEMBLIX, there is no standard of care officially. There's a lot of discretion in terms of what we want to pick. The most simple thing to do would be just copy ASCEMBL and go head to head with bosutinib. The benefit there is we know bosutinib is going to have a very low response rate. Remember, 0% in fifth line plus. Probably looking at realistically something between 0 and 10% response rate for the comparator. You don't need much of a benefit to show that superiority at the 24- week endpoint. Remember, SCEMBLIX showed only a 12% benefit compared to bosutinib with 233 patients, and that was with a 2:1 randomization. Think similar design is that.
We may well pick bosutinib. I think that would be a very high probability of technical success and still a very powerful first study. The other thing we are considering, however, is including a physician's choice arm. Given the option of any second-gen TKI, where we would likely stratify and limit those arms, the benefit there is that we would have, I think, more marketing power with our label because we could compare to not just bosutinib, but dasatinib and nilotinib, which we view are likely options for a post-Semblix setting in the future. There are additional complexities that come with that. Those are the two choices that we are really thinking about. I think either way, probability of technical success should be very high, given they are all very comparable in terms of their efficacy.
It just comes down to really a strategic decision we have to make sometime before we start the study.
Would there be a subsequent pivotal study to move earlier in therapy? What's possible design of that trial and when could that begin?
Yeah. So absolutely. I think to some extent, when and what we do in terms of the front line trial design would depend on what we choose for the late line study. I think no matter what, at some point in the not too distant future, we want randomized data comparing to both first and second gen TKIs. That's going to be sort of our competitive set in a world where many patients start or cycle through to SCEMBLIX very rapidly. We want to be the number one best in class ATP-competitive inhibitor for that setting. Front line study is attractive because, as we saw with Novartis and SCEMBLIX, doing that study, it's a very high probability of technical success study because you can include a significant number of patients on a ponatinib, which has the lowest response rate, and you can get a broader label.
SCEMBLIX got the second line label without any second line patients. There is good precedent for that also with bosutinib. We would likely do that in the event that we pick only a single comparator in the late line study. In terms of when we could start that study, likely could start at some time during our first phase III. Novartis waited, basically started right at the end of the ASCEMBL phase III. There is no reason we could not start it a little earlier if we felt confident we had the capital to run that study.
Over the last few months, Novartis has provided a couple of updates on SCEMBLIX. One, it did get the broad approval that you just mentioned. Two, there were $689 million in 2024 SCEMBLIX sales. I guess, what do you find notable about SCEMBLIX's broad approval? Second, its rapid adoption, how does that inform the market opportunity?
Yeah. We're really happy. I think the labeling has been very favorable. Again, it speaks to this acknowledgment from regulatory authorities that CML is a chronic condition. You're never going to see differences in overall survival. You don't treat even to differences in progression-free survival. You're treating to these deeper molecular milestones and switching TKIs. I think that's all coming, I think really de-risking the regulatory path even further. We're very happy with what we've seen there. In terms of just looking at SCEMBLIX as a proxy for the type of launch we could expect once SCEMBLIX is and moves up front, which it's doing very rapidly, the launch in third line plus has been remarkable. You noted over $600 million in annualized, I mean, in total sales.
If you look at the Q4 revenue, it's actually close to $830 million in annualized revenue from a third line plus patient population. Now with the broad approval, they have access to four to five times as many patients, which again indicates this is a very large market, likely close to $9 billion in terms of branded potential revenue in the U.S. alone. We're really encouraged by the late line launch, especially given the trial designs we're considering. We believe that the recent efficacy updates from the asciminib front line study, the 96- week data, should only further accelerate adoption now that they have that broad approval as of November last year. That will be something to keep an eye on.
I think what we're most excited about in terms of the clinical data, the totality of the clinical data is I think SCEMBLIX has really exposed the limitations of first- and second-gen TKIs, which is going to be very relevant for us as we look to be the first option in a post-SCEMBLIX setting. I do think there's the potential longer term, we don't have time for it now, to potentially directly compete with SCEMBLIX, but initially just being the best ATP-competitive inhibitor should be a pretty attractive opportunity.
How attractive would that opportunity be? Can you give us some sense of what you think the revenue potential would be as the best active site TKI?
Yeah. I mean, I just mentioned, I mean, if you just look at, you can get there in multiple ways. You can look at U.S. prevalence and multiply by WAC pricing for sort of a TAM value. Or you can look at what peak revenue was in the U.S. for BCR-ABL TKIs right before Gleevec went generic and then gross up based on price adjustments and prevalence. Either way, you get about close to $9 billion potential revenue from the U.S. alone. Historically, rest of world has totaled about equal to U.S. total sales. Even with the expectation that there'll be greater pricing pressures ex- U.S., you're still looking at a $12 billion-$15 billion total market opportunity. You look at just getting 10% of that is pretty attractive as a very low end estimate. I think that it could do considerably better than that.
I think to some extent, SCEMBLIX will be a proxy of kind of what that ceiling could be. I do not think it is out of the question that we could get half the total revenue SCEMBLIX gets, even if we are primarily used in a post SCEMBLIX setting.
Maybe in the last minute, just a question on 02. Is there an update still coming this year? What will be in that update? In your opening remarks, you mentioned maybe looking to partner 02. What could the time course of a partnership be?
I think this year, yeah. We will have an update this year. I think what we've been waiting for, just given the enhanced focus, I'll call it, in HER2 positive space, is just enough data to feel like we have a story there. In the monotherapy setting, if you look at dasatinib as a proxy, I mean, depending again on the patient population, it's a 0% response rate to maybe a 10% response rate at best. That's really difficult to compare monotherapy data to. You see much better response rates in combination. We wanted to get some combination data to sort of support our monotherapy data, which I think is attractive. That should be ready in the second half of the year. It'll include data both from the ongoing monotherapy.
I mean, as of the end of 2024, we had enrolled over 100 patients in the monotherapy cohorts. We have ongoing combo, phase I- A combos that we can include in our update as well. Yeah, in terms of evaluating other opportunities, again, given the complexity of the development path and the cost and where we are with 01, frankly, we will be looking for potential alternatives for that program. That will play out this year.
Maybe the last question is on preclinical programs. You've disclosed that Enliven's working on them, although you haven't disclosed the next clinical candidate. Could you give us any hints what you're working on and when could we learn what your next candidate will be?
Yeah. I know we're out of time, so I'll just keep it really short. We've had a very productive research group for many years now. We haven't brought a lot beyond 01 and 02 forward because we've held a really high bar. We've stopped advancing programs at multiple stages, largely for strategic reasons. I think we're getting really close on the next one. When we do talk about it, we'll be very close to a clinical start. That's sort of where we want to be before we tell a more fulsome story. I think you can expect it to be outside of cancer, potentially large market and first in class or first wave opportunity. Pretty excited about that if we get there. Until we're there, I think expectations should be low.
Perfect. Thanks for your time. This was a great discussion.
Thanks so much, Phil.