Co-founder and CEO of Enliven. Sam, to start here, for those who might not be familiar with the Enliven story, could you provide a brief, brief overview of the company, your pipeline progress, upcoming milestones, and just overall strategy?
Yeah. Good to see you, Salveen, and thanks for hosting us. So Enliven is a clinical stage precision oncology company. We have two primary or parallel lead programs, ELVN-001 and ELVN-002. Both are in phase 1 studies, and we've released initial data on both programs, but a more fulsome initial proof of concept data set on ELVN-001, which is our selective, active form, active site, BCR-ABL inhibitor for the treatment of CML. And there's been, I think, a renewed interest in CML, with Novartis' Scemblix launch and recent frontline data.
So I think that's probably what we'll, we'll spend most of the time today talking about. ELVN-002 is our HER2 selective, irreversible, pan-HER2 mutant and HER2 wild type in- inhibitor.b We're really focused on developing this asset in the context of HER2-positive cancers and combination therapy, but there may still be some monotherapy opportunities as well. It's really us driving to the combination data that is taking a little bit longer and will delay any sort of initial, more in-depth, proof of concept data release till next year.
Sam, as you noted, you recently reported first clinical data from zero zero one in chronic myeloid leukemia. What do you see as the key takeaways from the data set, and how does it impact your view of how the drug can address the unmet need in CML?
Yeah. Yeah, so in April, we recently presented data, as of a late March data cut, and, you know, we're really happy with the initial data. Really encouraged from an anti-CML activity standpoint and from a tolerability standpoint. Initially, when we started the phase 1A, we were really just focused on PK, target coverage, safety, and tolerability, because we didn't know. We know that correlated really well with, you know, meaningful regulatory endpoints and early lines of therapy, and how to best manage and dictate treatment decisions across the CML treatment landscape. But in terms of late line efficacy, we weren't sure what to expect. Our phase 1A inclusion criteria required that patients had exhausted all available options known to be effective for their CML, and there are a lot of available options for patients with CML.
So these patients were heavily pretreated, highly resistant, not just to the last prior, but to multiple prior TKIs. And we were quite pleased to see clear anti-CML activity as defined by categorical decreases in BCR-ABL transcript levels from peripheral blood. Those are... You know, people make treatment decisions based on those transcript level reductions. They're also used as regulatory endpoints as a surrogate for overall survival. So these are very meaningful efficacy benchmarks, and when we compare back to precedent trials, we're pretty happy with what we're seeing, even early in dose escalation at an earlier time cut.
Can you contextualize the efficacy results in terms of your patient demographics and the—what the approved TKIs have shown in their early studies?
Yeah. As I mentioned, it's been quite a while since the last phase one study. CML has been kind of a quiet space from a drug development standpoint over the last decade, after a flurry of activity between 2000 and 2010. So the most recent approved TKI is Scemblix or asciminib, Novartis' fourth-generation allosteric. That phase one study started in 2014. Our patient demographics look somewhat similar to that patient population. It's a late-line patient population. All of the patients had seen at least one second gen TKI previously. But compared to that data set, we had more prior ponatinib patients. So ponatinib is a third-generation drug, generally regarded as the most efficacious in a late-line setting. We had double the number of prior ponatinib patients, and 56% of our patients had prior asciminib.
So when we compare efficacy, it's really difficult to make comparisons. These are different patient populations. But at a high level, we actually compared quite similar to the Scemblix data, which is really important given that our positioning is likely gonna be in a post-Scemblix or asciminib setting. We anticipate that being standard of care in a frontline and second-line setting, certainly, I think, ultimately in a frontline setting. And so if we can leverage what Novartis has shown in terms of superior target coverage, leading to better efficacy and better safety and tolerability, and compete against the already approved ATP pocket inhibitors in that setting, that would be really successful. So being as good as Scemblix in a more heavily pretreated patient population, I think would be, like, an awesome outcome, and I think so far we're looking like that's the case for ELVN-001.
Compared to the second gen TKIs, the most recent drug approved was bosutinib. It was approved fifth. It was the third second gen TKI to be approved. That phase one data wasn't published until 2012, so that study started in 2008. And all of those patients were essentially third-line patients. In a fourth-line and fifth-line patient population, we know bosutinib's response rate from a molecular response rate standpoint falls to close to zero. So in our patient population, there's not known anti-CML activity that's been established with second gen TKIs. And even compared to the third-line data, we're looking pretty good compared to bosutinib.
How would you compare the safety profile?
Yeah, so safety in CML is, and tolerability they kind of go together, but can be different, is the most important goal. This is a chronic disease, patients live for decades. In fact, from an overall survival standpoint, CML patients are expected to now live as long as the age-matched general population. So from a treatment goals perspective, quality of life is actually the most important thing. Now, efficacy cannot be forgotten, and there are more aggressive efficacy goals, which I'm sure we'll get to later. But safety tolerability standpoint, patients want drugs that allow them to return to normal lives, go back to work. They're gonna be managing this disease for up to decades. What was most notable about Novartis' data, Scemblix data, AEs.
The AEs that patients feel and cause. And from that perspective, 001 is looking excellent. Really limited patient population, a limited sample size. But to date, we haven't reached a maximum tolerated dose. We've had no grade 3 non-hematological AEs, and even the rate of grade 1, grade 2 AEs is very low, with none greater than 11% on our study. And importantly, we've had no patients dose interrupt or dose reduce due to treatment-related AEs at 40 milligrams and above.
What are your thoughts with regard to how the clinical profile may look?
Yeah, so we've gotten a lot of questions on, you know, what to expect from data and how it might mature. I think the simple way to answer that question is it depends on the context of the patient population. So as we enroll different types of patients, we might expect different efficacy outcomes in those patients. Certainly, as you get to earlier line patient populations, we'd expect response rates to go up. In a late line patient population, it depends on how many prior therapies they've had, more importantly, what their last prior therapy was and why they switched, and their baseline transcript level.
So within a subgroup of patient populations, I'd expect our initial data to hold, and then for a particular patient or sub-patient group, response rates to improve over time, as is the precedent in CML, as long as they continue to tolerate the dose exposures, that they're seeing today. And so far, that's going pretty well. But from an efficacy standpoint, it'll depend on those factors, deepening responses over time, and then the overall rate will likely depend on just the mix of patients we see and continue to enroll.
Could you walk us through next steps in the cadence of data releases for 001 going forward and frame what you plan to present with regard to the 1B data and whether we would see more 1A data this year?
Yeah, the last question is what is funny because we've been getting that question since, like, literally the day after we presented our data. And the truth is we haven't mapped out like the exact, "Here's the conference, here's the data we're looking for." We're still just continuing to ramp up our phase 1, initiating our phase 1b, and hoping to just get as much data as possible. In terms of the next look at a data update, it will likely be this year. We did an investor-focused data reveal in April. We want to give our investigators a chance to present the data. Engaging with the community, sharing that data. So we anticipate year. There are two conferences that we're eyeing.
One is a CML-specific conference called ESH CML, and the other, of course, is ASH. So we may be at one or both of those, and that would come with an updated data cut, but not substantially more, right? Probably a quarter more worth of data, since for the investor event, we had kind of a data cut, like, right up with three months more data. We'll certainly enroll more patients, and more patients continue to stay on drug. 90% of our patients have remained on therapy, so we continue to get really good data out of those patients, both in terms of potentially deepening responses, more safety and tolerability data. We've had a lot of patients dose escalate now up to the higher exposures.
So I think the most impactful update will come in just that enhanced safety package, and that will be most important both for investigators, but also to continue to build confidence that this is a drug that can fit into that future treatment landscape in an earlier line setting. But I do think continuing to see responses maintained and deepened could be part of that story. What we've pointed people to as a major catalyst is 2025 data, where we're looking to get 60-100 patients worth of data, and for a significant number of those patients, out past six months. I think that will be critical to check formally, kinda, finally check that safety box, particularly for regulatory authorities, and build out those sub-patient population groups.
So not tiny little N for third-line patients, you know, post-Scemblix patients, to continue to build confidence and show really where this could position, likely again, in a second-line plus setting post-Scemblix. But by the end of next year, that data should help us get through multiple regulatory conversations or conversations with regulatory authorities, so that we can speak in very specific details about that first head-to-head study we wanna run.
What is your current registrational strategy?
Yeah. So we want to establish ELVN-001 as the best-in-class ATP pocket inhibitor. I think the best way to do that, practically first, is in a second-line plus setting. In terms of trial design, we would probably adopt a trial design very similar to the ASC4FIRST study. So the frontline Scemblix versus imatinib, second-gen, combined comparator arm. The exact ratio of patients that end up on second-gens to imatinib, we could play around with that a little bit, and we probably stratify patients on having had prior imatinib use and not having had prior imatinib use. But all of these agents are used regularly in second-line plus setting, and there are established endpoints, six-month major molecular response as a way to get both accelerated approval and then with additional follow-up, full approval.
You talked about the, the detailed phase 3 data from Novartis's Scemblix, which was presented in the frontline setting at ASCO. What are your thoughts on, I guess, in general, the read-through to your asset, but, but how you think market share could evolve, and you could maybe see a shift of, of the existing players versus Scemblix?
Yeah, I was joking with Ben just before this meeting. We've spent, like, the last week and a half presenting Novartis's data on repeat. I think the ASC4FIRST data, as expected, were really good. I mean, really good. Scemblix is clearly better from an efficacy standpoint, and I actually think even better than expected from a safety tolerability standpoint, particularly compared to imatinib. So, there's so many, like, nuances to this data set. I think a lot of focus has been, well, how do we size up the potential benefit of Scemblix compared to a generic second-gen agent? And we'll talk about that, but I think what got maybe a little overlooked is, well, how does it size up compared to generic imatinib?
Because there, for years, physicians have had to make this trade-off between a second-gen agent that could give faster response rates, not better overall response rates, just faster response rates, but that had higher grade and more AEs, so the safety was worse. And despite the fact that imatinib became generic 8 years ago, second-gens have only grown share as the cost of generic imatinib has come down. So in the U.K., there's hard step edit, but outside the U.K., there's no hard step edit for frontline treatment decisions. And so this has already kind of played out with second-gens compared to imatinib. So now second-gens are used in over 50% of the incidence on new. The question is: what will happen now with Scemblix, with now generic dasatinib in particular?
Because I think nilotinib has fallen out of favor due to long-term safety issues and just poor overall properties, or poor overall profile. But I actually think Scemblix has the opportunity to turn over the entire generic imatinib base. When you look at that data set, the safety compared to imatinib was remarkable, and the efficacy there is crystal clear. So now you can get very rapid responses. You're gonna get more patients that have the potential to get deep responses, maintain those responses to eventually achieve treatment-free remission goals, and you have better safety tolerability profile, even compared to imatinib, which is generally considered the safe and better-tolerated drug. So I think based on the data, to me, it's a no-brainer that Scemblix will take the lion's share of newly diagnosed patients, at least in the U.S. and the major European countries and Japan.
I think there'll be, of course, some countries that force a little bit more step-through. But even in that case, you saw in the data from the ASC4FIRST study, the patients on the imatinib arm, even over a 16-month median follow-up patient, 38, 38% had switched off imatinib already over 16 months, and 25 off the second-gen. So the switching dynamics in the frontline and second-line setting have continued to go up. So patients are just switching through to get to the better drugs and to the drugs they want. So you gotta weigh all these factors, but I ultimately think the data are strong enough to support initial use in the vast majority of patients in the frontline setting. That's, of course, what we want to happen. That's our entire positioning, but, yeah, so I'll maybe let you ask more. I could just keep on forever.
Well, actually, as a follow-up to that, right? So if Scemblix is going really head-to-head versus the generics-
Yeah
and becomes that drug of choice and gets a big share, have you demonstrated enough proof of concept with regard to how you may benefit Scemblix-progressed or intolerant patients to be right there as a second line? And if I could add a question to that is-
Yeah
would you ever think of going head-to-head versus them?
Interestingly, there's so much to unpack. So I'll come back to, would we ever go head-to-head? Probably not directly, but potentially in a similar trial design in the front line. I think there could be room to differentiate or at least to show similar impact with maybe longer-term differentiation. Notably, there was a higher percentage of patients that became resistant and lost response on the Scemblix arm, and all of those were patients with the myristoyl pocket mutations. We know from the open label, single-arm studies in Europe that those patients are now reaching, like, double-digit percentages. So that'll be pretty real. Coming back to: how do we know we're the best drug of choice post-Scemblix? A lot of it just comes down to, you know, first principles, mechanism-based.
Certainly, all the preclinical work has translated for all the drugs, and in the context of both in vitro and in vivo preclinical assays were very good. But most importantly is the vast majority of patients, as they kind of go through multiple treatment options, are still driven by native BCR-ABL. So it's safety margin with respect to the primary driver of the disease, that those are gonna dictate the best drug. And so that relationship for Scemblix held in a third line, held in a front-line setting, we're really modeling our dose based on that same exact metric, compared to second-gen TKI. So as long as our safety and tolerability hold up at the exposures we have, I think it's gonna be pretty easy to show a differential benefit in any line of therapy compared to second gen TKIs.
In fact, you'd expect the effect size to be even larger in a post-Scemblix or post any prior TKI in that setting. And I think we have a unique advantage in that we're out there generating data in these patients today. So we're gonna have probably the most and most well-curated post-Scemblix data set, not just in second line Scemblix patients, but patients that have seen Scemblix with multiple prior therapies as well. So I feel quite confident that there's nothing magic about Scemblix. It's a selective inhibitor. It's getting better target coverage consistently with fewer side effects because it's not hitting these off-target kinases. The second gens are always gonna have that liability, and the bar just goes up as the disease becomes more resistant to TKIs.
Pivoting to your second program here, 002 in HER2-altered cancers, could you walk us through your focus indications? There has been some change there with regard to the program's challenges with the current treatment paradigm and your target profile for this asset.
Yeah. So for our HER2 program, we really started that program with the thesis and focusing on the HER2 positive space. We can talk a little bit more about mutant lung to the extent that makes sense. But big things are happening in the HER2 space. In a lot of ways, it's somewhat similar to CML, and we really saw this change in the treatment paradigm coming. In fact, when we started the 001 program, we were really betting on Scemblix being established as standard of care. Novartis hadn't even talked about monotherapy frontline studies. They were pursuing combination studies. In the HER2-driven cancers, Enhertu is that surrogate. So Enhertu is coming up front. In some ways, it's actually even more impactful than Scemblix because it's also expanding the patient population.
I'll tell you that we're seeing a lot more patients get sequenced, just solid tumor patients, and screened for HER2 status at diagnosis. So I think we're gonna see not only HER2 come up front in the treatment paradigm, so effectively resetting what patients see up front with any HER2-altered tumor, but a larger total population as these patients get identified earlier and then move on to Enhertu. So that's the biggest thing. We know that unlike in CML, where patients have near normal overall survival, unfortunately, all these patients with HER2-altered tumors will eventually die from their cancers. So the disease will progress, and in Enhertu's case, it's not just disease progression, but a lot of patients can't tolerate this over years. So we see a large incident post-Enhertu population across HER2-altered tumors, particularly HER2 positive tumors, that will need to be treated.
Right now, we know that the backbone therapy is a mix of Herceptin chemotherapy, whether that comes in the form of an ADC or a doublet therapy. And from tucatinib, which is the only HER2 selective TKI, actually a drug that our CSO and co-founder invented years ago, we know that dual HER2 targeting can be very effective in that later line, HER2 positive setting. So really, with this assumption that there's gonna be a new post-Enhertu patient population, which effectively resets what patients will see in a second-line plus setting, we know that adding two HER2 agents in a late-line patient population can confer benefit.
We wanna take advantage of these and be in a situation where ELVN-002 can be potentially layered on the standard of care in any post-Enhertu or even on top of Enhertu, HER2 positive setting. Everything we're doing with our development program is first establishing monotherapy dose regimen, and then identifying that therapeutic window where we can do combinations more effectively, hopefully, than tucatinib.
What did you see in the preclinical data set that leads you to believe this is a meaningful treatment option versus what's already on the market?
Yeah. So initially, it was, "Can we build a irreversible mechanism and maintain selectivity against the primary anti-target for any HER2-directed small molecule?" And that's EGFR. That's not easy to do technically, but what's harder is then to build the pharmaceutics and PK package to go with it, and that's where tucatinib has really suffered, the ability to get sustained levels of target coverage to give, you know, near complete knockdown of that pathway. So tucatinib is classically dose-limited based on pharmaceutics, and it's a reversible inhibitor, so you lose a little of that PD effect by not taking out target over time as you continue to dose these patients. That has translated clinically. So we have released some data, and really mostly safety data on 30 patients from what we've characterized as our predicted optimal monotherapy dose. That's not our maximum tolerated dose.
We have seen monotherapy objective responses at significantly lower exposures than that as well. But we're pretty happy with the tolerability profile we see there, particularly the liver signal is almost non-existent. That's an issue for tucatinib. And at the exposures we're achieving in those patients, it's lining up really nicely with the exposures that we were able to achieve preclinically in the non-clinical safety models, and we know we get much better efficacy, at least preclinically, at those exposures in the HER2-positive.
So I think what we're seeing now is we have evidence of monotherapy activity, even in monotherapy HER2-positive tumors, where historical precedent TKI response rates have been single-digit. We're getting the target coverage we know we need to test this hypothesis. Is there room for better efficacy compared to tucatinib in a HER2-positive setting? We have a very wide therapeutic window to work with to optimally combine now with other agents. And we shouldn't have any drug-drug interactions, which has been an issue with docetaxel, particularly with taxane-based therapies.
What will we see from the next data release next year?
Yeah, so what we're hoping to show, I mean, I think as people have gathered, we actually have pretty significant amount of data for this program, even more data than we have for 001, but I think it's the proof of concept that's missing. And so we've made it clear that we wanna tell not just, "Hey, this drug is working," but here's how it can differentiate like we have with 001. And so for 002, it's gonna be the monotherapy data set I've referenced and putting more details around, you know, how does this drug do in different tumor types? It's a very mixed patient population. We have started an additional phase I study, actually this quarter, where we're really focused on HER2-positive tumor types.
We're doing a Herceptin combo, and that can lead to Herceptin chemo combos as well. One of the key arms of that study will be a doublet, so Herceptin plus ELVN-002 in HER2-positive colorectal cancer. We think that's probably the best place to show that initial proof of concept, and potential differentiation compared to tucatinib, given that we can get access to patients that pretty much match the inclusion criteria on the MOUNTAINEER study. MOUNTAINEER study is what led to tucatinib's single-arm accelerated approval, in HER2-positive colorectal cancer with a 38% response rate. So we're really gonna be looking to size up our data against that as we generate that data through the second half of this year into 2025.
And we're hoping to in addition to that, be able to show at least initial safety, efficacy, in the Herceptin chemo combos as well. And that will ultimately be likely what's used for the breast cancer indication. And so I think it's that totality of data that will get people to hopefully connect the dots to see, "Hey, now we have access to this multi-billion-dollar opportunity." Thinking strategically about how best to develop it, we'll probably have to consider potential partnerships as well.
Got it. I guess in that context, you'll have to think about how Inflation Reduction Act impacts the development program here.
Absolutely. And I think that's one reason not to chase a crowded late-line mutant lung setting, especially with a strong comparator and bias on neratinib. We're on level even footing in the HER2-positive space. I think we have at least a preclinical profile that's more attractive, based on our head-to-head studies. But most importantly, we're positioned to go in the right place at the right time, and that's probably gonna be breast cancer, is the biggest opportunity still. There are probably other pockets that could lead to, but less crowded, no approved targeted therapies, endometrial cancer is a good example. Colorectal, I think, is still interesting, but I think where we know pharma is interested is gonna be in these bigger development opportunities, and there's a huge amount of space to play with.
You think about positive HER2 and the way breast cancer is treated today, a lot of late-line patients that are just seeing Herceptin and potentially a Herceptin doublet, you could maybe mix in chemotherapies. These are large markets where patients stay on therapy in a maintenance setting for long periods of time. There's also a lot of interest in HER2 de-escalation, and so if you could build a maintenance regimen with a TKI in combo with Herceptin in a de-escalation setting, these are very large markets. But we'll likely, again, take a pharma partner to really unlock most of that value.
You're also planning to disclose a third pipeline asset this year. Anything you can tell us about that asset, and then how you're thinking about resource allocation as you advance these first two assets into later-stage development?
Yeah. So we had talked about. We do have a program that's IND stage in the preclinical pipeline. Actually, it's been there now since last year. We have made the strategic decision to continue to sit on it. In fact, we're looking at potential strategic alternatives, and that's primarily just driven by the fact that we have two now fairly large development programs in ELVN-001, ELVN-002, that we're quite excited about, and we've always been very cash conscious and runway conscious.
We're doing well from a cash position, but we wanna make sure we can fully develop ELVN-001, ELVN-002 to maximize their value before we run and do, you know, another cancer program. We have other interesting programs in the pipeline that we're continuing to assess and build data sets around, and we'll look for both ways to move those forward in-house and potentially externally as well. But I think in the near term, it's gonna be mostly just ELVN-001, ELVN-002, at least through those major milestones next year.
Perfect. Well, with that, Sam, thank you very much.
Thank you.
Appreciate the discussion.
Appreciate it.