You're just grinding through these.
It's fine.
Yeah, it's going to run around. It's like ping-pong.
It is good, though.
All set?
Yeah.
Okay.
Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'm happy to introduce Sam Kintz, the CEO of Enliven Therapeutics. Thanks for joining us today, Sam. We're going to do a fireside chat format. Maybe for those who are new to the story, if you can give a one-minute intro to Enliven.
Yeah, one minute. Anyway, thanks for having me. Good to see you again. It's great to be here at this conference. Yeah, for those of you that don't have background, Enliven is a clinical stage precision oncology company. We're based in Boulder, Colorado. So many of our scientific team come from Array BioPharma and have a deep expertise in kinase drug discovery and development. Our lead asset is ELVN-001, which is a highly selective ATP-competitive inhibitor of BCR-ABL for the treatment of patients with chronic myeloid leukemia. It's a space that has evolved considerably over the last 25 years. We see an opportunity to be a potentially best-in-class ATP-competitive inhibitor in what's become a revived and interesting market opportunity.
Got it. Yeah, it's a great overview of the company and what you're doing. Maybe let's start with 001. You're going to have a data update at EHA coming up on June 13. You've already disclosed some data in the abstract from this program. Maybe talk about what you've reported so far and what we should expect on June 13.
Yeah, absolutely. 001, we're currently conducting a phase I study in patients who are not expected to respond to the available approved BCR-ABL TKI therapies, so late-line CML context. Recently, in the abstract, we presented top-line efficacy and safety from that ongoing phase I study. That was from a data cutoff in January to support a March abstract submission. I think some highlights from that data abstract were the cumulative major molecular response rate and the response achieved rate, so patients that did not enter the study in a baseline MMR and then achieved that molecular milestone by 24 weeks. On those numbers, we reported a cumulative response rate of 44% and a response achieved rate of 26%. What's notable, particularly about the response achieved rate, is it correlates really well with precedent-pivotal studies.
You're looking at historical phase I data and how that translated in the corresponding phase III study. These numbers tend to be very reliable for multiple agents. It is the primary endpoint for those pivotal studies. It's a number that we're very excited about and focused on. Certainly, we know investors are as well. What's notable about that percentage is that it's similar to what we presented previously, but just with more patients. The consistency of that particular efficacy metric over time, to see it kind of go up and get better, despite the fact that when you compare it to the historical precedent studies, we have a more heavily pretreated patient population.
Got it. Yeah, that's helpful. Abstract data did affirm what you showed last year. In the data on June 13, I don't know if there's more you can say about just the number of patients that we could see in the different buckets of MMR.
Yeah, yeah, definitely. There's actually going to be a fair amount more data presented, largely driven by the fact that we opened up our phase I-B expansion in the middle of last year. Now a lot of those patients are becoming efficacy evaluable. I mentioned the percentages, but in terms of the efficacy evaluable patients in the abstract, I think we had about 36. For the data that will be presented next week, that denominator is going to be in the low 50s, so considerably more patients. Certainly, we'll report on the totality of the data. I think we'll have almost 90 patients. We've been on study for varying lengths of time, but some patients out past two years.
Not only is it important to see sort of a more robust number to look at the top-line efficacy, but just the overall safety tolerability now that we've had many patients on, in some cases, for several years.
Are you saying what the cutoff is versus the January abstract cutoff?
Yeah, I'm comfortable saying that. The cutoff for the presentation was end of April.
Got it. Okay. If you are going to do a company event as well, I'm wondering if you are going to show the confidence intervals for cumulative MMR, achieved MMR, and MMR in the TKI-resistant patients, along with rationale for what an expected effect size for a pivotal study could look like.
Yeah, interesting. In terms of confidence intervals, we haven't actually prepared that presentation yet. I just will note that when you report this, you're looking across many different patient subpopulations. In terms of determining the efficacy effect size, again, we're looking at the precedent clinical studies. There were no confidence intervals reported for those either in terms of this by 24-week endpoint. The pivotal studies is an at 24-week endpoint. There's also some nuance there, but they've correlated extremely well. We'll certainly present the details that we've presented previously, including the shift tables in terms of baseline status, how they did by 24 weeks. You'll get a sense of duration, too, in the swimmer and time on therapy.
Got it. In the update last year, you showed achieved response of 23.1%. This year, you're showing 26%. It's a small difference, but it seems like it could be improving a little bit. I'm wondering if this is a trend where you're starting to see numerical improvement in achievement of MMR with additional patients at the higher doses.
Yeah, and that's a very interesting observation. Just as a reminder, and maybe building on also kind of the question I didn't fully answer, we anticipate and intend to compare in a pivotal study against an ATP-competitive inhibitor, so a 2nd-gen ATP-competitive inhibitor. Asciminib, which is Novartis's 4th-generation drug and allosteric inhibitor, was successful in that pivotal study, a very similar design. They had a response achieved rate of 24% in their phase I. In the phase III, it was 25%. Bosutinib, their comparator, also similarly performed in the phase I than looking to the phase III.
Our position and hypothesis has always been if, despite the fact that we have more heavily pretreated patients, if we have a response rate that looks similar to asciminib, we can have confidence against that same comparator, a 2nd-gen TKI, our effect size is going to look similar. With that, sorry, can you remind me what your second part of the question?
Second part of the question? If the MMR achieved.
Oh, yeah, yeah. Sorry, higher doses. Yeah, we did see that go up. We were very pleased. We were not necessarily expecting that because, again, the data we presented last year, we had three out of 13, so relatively small N. We felt like if truth was 24%, the same as asciminib, we would be thrilled because it is further discounted by the fact that we have more heavily pretreated patients. Yeah, to see it go up, I think one potential reason for that is we do have a substantially higher percentage of patients that have seen the optimal doses. When we do the efficacy evaluable cut, we include all patients. That includes patients at the lower doses that we did not see efficacy, would not expect to see efficacy based on exposures. Now, as I mentioned, we have those phase I- B cohorts.
All of those cohorts are expected to have exposures that would yield potentially better efficacy than a 2nd-gen TKI. Now, with even more time between abstract and the presentation data cutoff, there'll be an even higher proportion of patients in the optimal dose range.
Got it. Interesting. As you're saying, the data that you're getting here and then the precedent data as well, that will de-risk the phase III path.
Oh, yeah, yeah. I mean, I think totally. Just to see things line up that well across studies. There are other metrics, too. It's probably a little bit too nuanced for a fireside chat. When you look at the shift table, there are also other molecular markers that have been used in historical precedent studies. For example, achievement of less than 1% BCR-ABL, which today is equivalent to a complete cytogenetic response. For other agents in a late-line setting, that was the endpoint in even single-arm studies. As an example, ponatinib was approved broadly in third-line plus using less than 1% at any point in time as the endpoint. They compared to a historical control arm of 2nd-gen TKI performance in that setting and bracketed that response rate as 20%-25%.
In our data, you'll also be able to see and we'll present what's our response achieved rate for less than 1%. Again, you can compare that both to asciminib and ponatinib as these highly potent next-gen TKIs back to historical 2nd-gen context. We want to come at this multiple ways, both comparing to the precedent studies for major molecular response, but also achievement of MR2 or less than 1%, equivalent to cytogenetic response. All of these things, in addition to the PK and the PD and overall safety profile. Our hope is it gives everyone a ton of confidence in the drug moving to a pivotal study next year.
Got it. Yeah, so the totality of what you're showing should add up and support that pivotal. Maybe one more specific question on just the updated EHA for number of patients at 80 mg and 120 mg as well. Are you providing any more specifics on that?
Yeah, so we have said we've completed enrollment, I think, in at least a couple of months ago. I think even at the beginning of the year, we had completed enrollment of the 20 expansion patients at 80. There'll be a substantial 80-milligram patient subcohort. And remember, we also had up to 10 exploratory patients in the phase I- A. Fewer from the dose randomized cohorts from 120 and 60. We only opened those at the beginning of this year. Maybe only a few of those patients evaluable for efficacy. From a safety perspective, we've gone all the way up to actually 160 milligrams as we continue the dose escalation. There are exploratory patients at 120 and above. There's plenty of safety data at the higher dose, just fewer efficacy evaluable above 80.
Talk about what gives you confidence that 80 mg is probably the optimal dose.
Yeah, we selected 80 as our first expansion purely based on PK, so exposure and target coverage. We also, at that point, had clear evidence of anti-CML activity based on the clinical data. Just we had a lot of confidence both on exposure and what we were seeing early in the patients at 80. We had the ability, through our protocol, to open up potentially five different phase I-B arms. We do not need all those arms. We were reserving two to do the sort of requisite Project Optimus dose optimization. We did select those. We have talked about those previously.
Really, it was based on matching and exceeding target coverage with respect to asciminib as we built sort of a safety data set at higher exposures to be confident we were not coming anywhere close to a maximum tolerated dose, which we still have not reached, by the way. It is basically just looking at 25 years of history in BCR-ABL inhibitors and mapping target coverage PK exposures to efficacy. It is actually pretty straightforward. There has been a lot of evidence that going up even higher, you do not get much return in terms of additional efficacy. It is more getting more patients' optimal exposure, right? Using your safety margin to get the patient population, more patients to that optimal exposure, rather than getting each individual patient higher exposures. I think the data, certainly, that we have seen internally, that has played out very consistently.
I think Novartis, with all the data they've published, not just actually with asciminib, but even with the manip, has shown that as well.
Got it. All really helpful. You mentioned the molecular response shift table. Talk about that a little bit more and just how you're setting expectations for that for EHA.
Yeah, I think in some ways, it's not important in terms of thinking about the pivotal study because in the pivotal study, you've got major molecular response at 24 weeks as the primary endpoint. You're really using that to show a difference compared to a 2nd-gen TKI. The reality is, in this late-line setting, major molecular response is not even a treatment goal, right? At this point, it's quality of life, being able to maintain control of disease, and then push for as deep a molecular response as possible because these patients have had many issues with prior therapies. I mean, many of our patients are looking to avoid transplant.
What the shift table shows is both those patients that have had issues at the lower end of the molecular response spectrum, so they have deep responses but have been unable to stay on those drugs due to tolerability issues, or they lost even deeper responses after being multiply resistant, you can see efficacy sort of in that beyond MMR category. On the higher end of the spectrum, where you have patients with, for example, greater than 10% transcript levels, getting to MMR when you have been multiply resistant to multiple TKIs is almost impossible by historical standards to show categorical molecular improvements on the international scale down to, for example, cytogenetic response, which we talked about previously. It is really important. It gives a more fulsome picture of efficacy and benefit just beyond the simple major molecular response at 24 weeks.
Got it. Okay. That's helpful. You showed impressive 40% MMR in the TKI-resistant patients in your EHA abstract, including in patients with prior SCEMBLIX or ponatinib versus SCEMBLIX's 11% that they showed in the phase I. What could explain the strong MMR signal in this patient population? Could this be due to the fact that 001 is not a substrate for efflux transporters, including PGP and BCRP like other approved TKIs?
Yeah, definitely. I think a couple of different drivers there is resistance in CML. It does not mean disease progression. It has not for many, many, many years. I will say that our sites and our investigators, high degree of overlap with the authors of that phase I publication that you referenced and that others have used as a nice comparison to our data set. There could be obviously some differences there. We highlight it. We have not said definitively that means we are better than SCEMBLIX. It is interesting to see how that signal holds up. I do think that there could be some contribution to these drug efflux transporters. We know 001 is not a substrate for PGP, BCRP.
Asciminib, it's a known, certainly in preclinical studies, but in those patient ex vivo samples that researchers have looked at, you do see expression or overexpression of these drug efflux transporters that reduce the sensitivity of these cells to asciminib and on other TKIs from that perspective. That can certainly play a role. Also, like in later line CML, you see BCR-ABL amplification. You do not see that in the molecular sequencing in terms of mutational analysis, but you see a higher percentage of activated BCR-ABL. Asciminib does not bind to activated BCR-ABL. It only preferentially binds to the inactive form and essentially traps it out so it cannot signal and drive proliferation. 001, in fact, binds preferentially to the activated form. There are all these little things beyond just mutational context of these patients that could drive differential sensitivity.
That number also includes patients that had entered our study in a major molecular response but had been resistant to, for example, asciminib or ponatinib. In some cases, you've got patients that did actually previously respond to asciminib that then had to re-respond to 001. There are some differences in that number in terms of comparing studies, but certainly, it looks favorable, and we feel like it could be quite differentiating.
Got it. Thinking about translatability from later line to earlier line, with SCEMBLIX, they had MMR increase from 24% in third-line plus patients to 68% by 48 weeks in the ASC4FIRST pivotal study. How do you think about the 26% MMR achievement that you're seeing in the more heavily pretreated patient population, how that could translate to earlier line?
Yeah. Interestingly, now that sort of the totality of our data is converging on what we view as our optimal exposure, which we have selected based on asciminib's relative target coverage. It is in some ways not surprising that we have looked similar in this late line patient population to SCEMBLIX, with maybe even some areas where you could argue we are better for various reasons, like we just discussed. In an earlier line setting, it is actually even more straightforward. In fact, there are published mechanistic models that have been used. We actually use those models in our own internal serum adjusted potency data for asciminib to predict asciminib's front-line response rate by 48 weeks. We did that prediction, submitted it to the FDA before that trial read out, right? Because we are using this to also defend our dose selection and our optimal dose.
That has accurately PK target exposures accurately predicted 48-week response rate in front line, not just for asciminib, but for the 2nd- gens relative to imatinib previously. Front line, there's even less guesswork. It is nice to see that that target coverage relationship works in a late line setting. There's probably more drivers in a late line setting, but certainly in an early line setting. I'll point in second line too, asciminib's differential efficacy compared to 2nd- gen seems to be pretty robust, as reported in the ASC2ESCALATE study they've been presenting on.
Got it. You'd expect some translation there.
Yeah, I feel super confident about that. As we generate more data and we're able to enroll some earlier line patients, I think we'll be able to put out additional data sets to further support my claims.
Got it. Maybe talk about safety. At the ESH-iCMLf meeting last year, you showed better rates of hematological AEs at the higher doses. The two patients that discontinued due to cytopenia and pancreatitis, those were at the dose less than 40 mg QD. Just wondering, was this due to the patient's baseline or just kind of one-off situations?
Yeah, so the patient that had discontinued due to, and this was at 10 milligrams, our very first dose, the asymptomatic grade 2 pancreatitis, that has actually been now recoded as alcoholic pancreatitis. We found out, the investigator found out the patient was an alcoholic. Likely, that was the attribution rather than drug. That has actually all been cleaned up and submitted in the safety reports. We have not had a single case of pancreatitis since then, right? Obviously, that was at 10 milligrams. We have had further discontinuations due to cytopenias, consistent with the class and what you'd expect. All of the patients that have discontinued due to cytopenias, and there's only been a few, have discontinued their prior TKIs due to the same thing. For those patients, often a sign of efficacy.
In fact, there were some interesting talks on this at ASCO over the weekend. There are some patients that are exquisitely sensitive to BCR-ABL and sometimes associated with efficacy where you see these cytopenias, and they just can't tolerate drugs. We have very stringent, because it's a first-in-human study, we have very stringent protocol. In the future, actually, we'll be able to both, actually investigators wanted to keep those patients on, but we didn't have enough time or flexibility in our protocol. In future studies, it's likely those patients would have more opportunity to stay on longer, dose reduced, for example, to be more optimally dosed. Yeah, we haven't had any sort of concerning new toxicities.
Got it. Maybe last question for EHA, just how are you setting expectations for safety for this update? Talk about how your safety and dose reduction rate compares with SCEMBLIX and bosutinib as well.
Yeah, so we've avoided sort of direct comparisons on dose reductions, which I think is a good overall sort of look at tolerability, and have been secondary endpoints in the studies Novartis has run with asciminib. I think it's a huge part of the reason why Novartis is getting broad uptake is because you get the efficacy, but you also have the better tolerability. I think now, with enough patients and enough duration, we can start to make those comparisons. Still, in the prior SCEMBLIX data, the median treatment duration is longer than we have, but you can still start to make those relative comparisons. Certainly, with respect to 2nd- gens, where in the precedent studies, it's been a shorter duration, more similar to the time patients have spent on our study.
I think that that should be looked at as an important thing to see, what percent of patients had to dose reduce due to AEs. In terms of broader safety, we'll show the safety tables in terms of treatment emergent AEs, and we'll certainly hone in on anything that's higher grade, but it's going to be a really low number, right? I think overall, we've always felt most important is safety tolerability because that's what drives use, and it's consistent with the number one, two, and three treatment goals for these patients with chronic myeloid leukemia. Just seeing well tolerated, no dose exposure or toxicity relationship, no AE that isn't associated with class, stuff like that, I think will be important.
Got it. Okay, that's helpful. I want to shift gears, talk about the registration path. You've got the Project Optimus cohorts ongoing. Now, maybe talk about where you're at with that and how you're thinking the dose for the phase III could look.
Yeah, so the key rate limiting step for us to start our first pivotal study is selecting our dose. I think I've talked about already a little bit here, but we have the two dose randomized cohorts going. We expect that we should have the data to submit kind of in the end-of-year time frame to have then our end-of-phase I meeting shortly thereafter. We don't feel like or have had any indication there's significant risk on our strategy. We're kind of doing the standard Project Optimus playbook. Our dose will be between 60 and 120, I think, with the most likely outcome being that it's 80. What will drive that is just no additional clinical differentiation between 60 and 120. That's our hypothesis. If there is, we'll let the data drive the way.
Any of those doses, we feel will give target coverage to be superior to a 2nd- gen. We feel quite comfortable with any of those doses. After that, it's just deciding which flavor of late line phase III we want to do. From that perspective, we feel like we believe that it's not a regulatory question. It's a strategic question. We're not contemplating anything that breaks very clear precedent. As a reminder, in CML, across all lines of therapy, there's no differences in overall survival between the TKIs. Regulatory authorities have been supportive of sponsors' choice as long as it's indicated for use. For us, it's more of a, well, what do we want our label to be, and what do we want the patient population to be, and then offsetting that with what we view the technical risk timeline and cost are.
Got it. Makes sense. Maybe with the third line plus setting, for Novartis, their study is 233 patients. It took about two years, eight months to enroll that study. How long do you think it would take for you to complete enrollment for an asciminib-like phase III with 001?
I think those would be very reasonable timeline projections. I mean, we've been kind of keeping track of our enrollment against that. Their phase I was much longer than ours. They were kind of slow on that. We feel very confident we could execute that type of study on that timeline. That study was a little smaller than we would likely design it. If anyone has done the statistics, one patient going the other way would have made their outcome not statistically significant. I think they cut that one a little too close. You just solve for that by adding more patients, but I don't think that would materially change our outcome. Yeah, that would be sort of one option we're considering. Frankly, we're leaning more into doing a second line plus study. Very similar.
Most of the patients would still look like that third line patient population Novartis went into for the label that has been sort of the background for their very successful launch. If we did second line plus, we believe we could get access to two and a half times larger patient population. So roughly 50% of all patients with CML. We would also consider a more attractive, from a patient investigator perspective, comparator arm and offer a physician's choice ATP-competitive inhibitor. The potential downside of that trial is because we do not have firm precedent data to predict effect size of 2nd- gens in a today 2nd- gen setting, it is sort of an unknown. To offset that, we would just have a slightly larger trial, which we feel quite comfortable about.
It potentially could add a little cost, but we actually believe we would offset that with much faster enrollment. Enrollment timelines, number of sites, that's the key driver of costs when we do the projections. We just think this would be perceived as a much more exciting trial, right? Not only larger patient population, but more attractive comparator arm. We actually do not think it's that materially more expensive, but obviously would take a little bit more nuance in the design, how we want to structure it. We are very actively mapping out different scenarios and thinking through that. We are getting pretty excited about that.
Got it. So haven't made that decision yet. It seems like you're leaning more toward second line plus. Did you get feedback at ASCO from doctors on what they would prefer?
Oh, yeah. I mean, it's no question. Docs would love that study. I mean, they'd be thrilled. And honestly, I think it could help us be, it could help be differentiating in terms of our positioning relative to the other drugs and SCEMBLIX as well. They'd be thrilled to run that study. That being said, they would do the late line setting. They just sort of, it's like a kind of boring, whatever. We want a new treatment option, so we'll get through it. We're not putting patients at risk. Obviously, there's crossover elements. Again, we talked about these patients don't progress, right? They'll do the late line versus bosutinib or third line plus versus bosutinib. I think it would be exciting both for us at the company and to the community if we did something a little bit more ambitious.
Got it. The third line plus opportunity, it's a big opportunity. We've seen that from SCEMBLIX with some of the sales that they've recorded there. Maybe talk about that and what the second line plus opportunity could look like commercially.
Yeah, I mean, I just said it's two and a half times the patient population. If they're annualizing three years from launch, they're annualizing close to $1 billion based on a third line plus label. Imagine what we could do with a better comparator arm, like a more attractive comparator arm and a larger patient population. I think the Novartis marketing power behind SCEMBLIX, really beating up on all the other TKIs, is only going to work in our favor. I think it's attractive for so many different angles, certainly from a commercial launch and from a strategic interest standpoint as well. I think when you look at third line, you look at the launch data's there. It's exciting. It's enough. It kind of asks, okay, when are you going to do your front line trial?
You kind of look further out for the potential bigger bump. If we're talking same timeline, second line plus, yeah, the cost of doing a slightly larger study, well worth it. I think you can get to pretty big numbers on that alone.
Got it.
Yeah.
Makes sense. Maybe briefly, you've kind of alluded to working on a couple of additional programs in your pipeline that are earlier stage. I don't know if there's anything more you could say about that or when we could have another update from that.
Yeah, no, I appreciate you asking. I think as everyone knows, we've committed to winding down the 002 program. That is really to prioritize runway and 001 because we're so excited about that program. We're also excited about what potentially could come in the pipeline. Our current focus is 001, getting to that pivotal data, getting this thing approved. We will prioritize our current capital for 001. I think we will have hopefully the opportunity to at least present what could become clinical programs as early as next year in non-oncology indications that I think could be quite exciting. If there's good reception, we could fund those separately.
Got it. This has been a great conversation. We're pretty much out of time. Maybe to close up, if you want to mention your cash position and key events ahead investors should be focused on.
Yeah, so our cash position, I don't have Ben here, but it's in the upper $200 million, yeah, upper $200 million. We have runway into late 2027 now. Pretty solid cash position heading into EHA and upcoming data.
in June 13th, and you got a company event that day.
Yeah, correct. So we'll have the presentation will be in the morning U.S. time, and then the company presentation will be midday.
Got it. Okay, thanks so much for joining us today, Sam.
Yeah, thank you very much. Thank you.
Thanks. That was good.