Good morning. Welcome to the Terns Pharmaceuticals Conference Call. My name is Amanda from IR. As a reminder, this conference call is being recorded, and the webcast of this call will be archived on the Terns website. At this time, all participants are in listen-only mode. Following the presentation, we will open the line for any remaining answer question. We would like to remind you that the statements made on this call will be forward-looking and are subject to risks and uncertainties. Our actual results may differ materially from those described. We encourage you to review our risk factors in our most recent quarterly report on the Forms 10-Q , which can be found on our website. While we may like to update these forward-looking statements in the future, we specifically disclaim any obligation to do so.
With that, I want to turn the call over to Erin Quirk, President and R&D at Terns Pharmaceuticals.
Thanks, Amanda, welcome everyone to today's call. I'm going to start us off by providing a brief overview of Terns, then I will hand things over to our Chief Medical Officer, Oncology, Dr. Emil Kuriakose, to provide a more fulsome overview of today's call. Next slide, please. Terns is a publicly traded biopharma company with a strong discovery effort that has resulted in the discovery of three internally discovered clinical or near clinical stage programs, which we've advanced in our five years of existence. There are three key characteristics that all of our development stage pipeline molecules have in common. They are all small molecules aimed for oral administration that were internally developed and are based on clinically validated mechanisms of action, where we see room for improvement.
We are excited to be focusing today's discussion on TERN-701, our allosteric BCR-ABL inhibitor, which is in phase I clinical development for the treatment of chronic myeloid leukemia, or CML, with our partner in China, Hansoh. Terns is planning to initiate a U.S. phase I study of TERN-701 in CML patients later this year, with interim top-line data from initial cohorts expected in 2024. Among our internally discovered assets are TERN-501 and TERN-601. TERN-501 is a thyroid hormone receptor beta agonist, currently in phase II development for NASH. We fully enrolled our phase II DUET study in February of this year and are expecting top-line week 12 data in the third quarter of this year, which should include evaluations of liver fat content reduction and sex hormone binding globulin changes from baseline.
TERN-601 is our preclinical oral small molecule glucagon-like peptide one receptor agonist or GLP-1, for the treatment of obesity. We plan to advance TERN-601 into a phase I study in the second half of this year, we anticipate having multiple ascending dose, 28-day weight loss data in the 2024 timeframe. Next slide, please. Today's call will focus on TERN-701, our allosteric BCR-ABL inhibitor for the treatment of CML. We are fortunate to be joined today by two influential key opinion leaders who specialize in treating CML patients and who will cover many of the topics which I'm showing here. I'll just provide a brief overview. Although CML is an orphan indication, prevalence is growing as patients are living longer, oftentimes for decades on their CML treatment.
There's a need for additional treatments to address patients' needs over time, including an alternative to active site TKIs, from which many patients switch due to a variety of reasons. In recent years, we have seen the emergence of a new class of BCR-ABL inhibitors, the allosteric class, for which there's only one approved drug, asciminib. Allosteric inhibitors of BCR-ABL bind the myristoyl pocket on ABL, and therefore have a different mechanism of action than all first and second generation tyrosine kinase inhibitors approved for the treatment of CML, which instead bind the active ATP binding pocket and have the potential, therefore, for off-target kinase inhibition. In a Phase 3 trial, asciminib had superior efficacy and improved tolerability compared to a second-generation TKI. This profile has created rapid uptake among CML patients, creating blockbuster potential and an important new treatment option for patients.
TERN-701 is an internally developed allosteric tyrosine kinase inhibitor, with an expected profile of efficacy at least as good, and tolerability, at least as good, if not better, than asciminib. A Phase I trial in CML patients was initiated by our partner, Hansoh, in the second quarter of last year in China. Terns plans to initiate a Phase I clinical trial in the second half of 2023 in Terns territory, including the U.S. Next slide. It's now my great pleasure to introduce you all to Dr. Emil Kuriakose, a clinical oncologist who joins Terns with more than a decade of pharmaceutical industry experience. He is leading the clinical development strategy and execution of therapeutics across multiple indications.
His most recent role as Chief Medical Officer at Calithera Biosciences, he led the transition of 2 mid-stage clinical programs with subsequent rapid initiation of 2 phase II studies. Previously, Dr. Kuriakose served as Global Clinical Program Lead at Novartis Institutes for BioMedical Research, where he was the global head of early development for MDM2 inhibitor-targeted therapy and adenosine inhibitor programs in solid and hematologic malignancies. Earlier in his career, Dr. Kuriakose served as a hematology oncology fellow at Weill Cornell Medical College and as a research fellow at Memorial Sloan Kettering Cancer Center. He completed his residency at the University of Texas Southwestern Medical Center, where he also served as an attending physician. Dr. Kuriakose earned an MD from the SUNY Stony Brook University School of Medicine and a BS in neuroscience from New York University. With that, it's my pleasure to turn the call over to you, Emil.
Thank you so much, Erin. Next slide. I would like to just quickly go over the agenda for today's meeting. Today's call will begin with an introduction and overview of the CML landscape from Dr. Jorge Cortes. I will then lead a fireside chat with Dr. Michael Mauro on the advancements in CML, after which I will provide a review of Terns' clinical development program with TERN-701. We will conclude the event with a brief question and answer session. As we're dedicating today's call to our oncology pipeline, we'll be limiting our questions to those topics discussed today. Next slide, please. With that, it's my pleasure to introduce you to our KOLs. Today, we are fortunate to be joined by two luminaries in the field, Dr. Jorge Cortes, who's the director of the Georgia Cancer Center, Augusta University, and Dr.
Michael Mauro, the Leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center. Both of them are distinguished leaders in the field who have dedicated their careers to better serving patients with a variety of leukemias. Doctors, we really appreciate your time and sharing your expertise with us today. Now let's turn the call over to Dr. Cortes for an overview of the treatment landscape in CML. Jorge?
Thank you very much. It's my pleasure to be here with you today. Again, my name is Jorge Cortes. I'm currently the Director of the Georgia Cancer Center, and I just want to give you a brief update on the state of the art of the management of chronic myeloid leukemia in 2023. First, on the next slide, you'll see my disclosures. All right, next slide. There's no question that we made a lot of progress in chronic myeloid leukemia. We have now six TKIs that have been approved, and with these, we have very high rates of response on our patients. We have very few patients who progress to the accelerated or the blast phase.
It's been said in many settings that we've approached near normal life expectancy for a patient, meaning that patients are not gonna die of CML if they're diagnosed today, and they have access to good treatment, good management, good monitoring. We can even stop therapy in a number of patients, something that we didn't imagine we could do when we started introducing the tyrosine kinase inhibitors more than 20 years ago. Next slide. There are a number of areas where we can improve. In the pivotal studies for frontline therapy, it's been clear that by 5 years, 40% of patients approximately have changed therapy, and by 10 years, 50% of patients have changed therapy.
Once you change therapy, that means that you, the physician, has determined that it's either not worked or the drug is not well tolerated. Half of the patients at least do that in that, in clinical trials, perhaps more in standard practice. We aim to achieve these deep molecular responses, but only at best, 60% of patients in clinical trials, reach that MR4.5 by 10 years. I emphasize this is clinical trials, because, of course, in the general population, where the population is not as selected, these numbers are not gonna look as good. What we want the treatment, for treatment discontinuation is a sustained, deep molecular response by 10 years, and that's not achieved in more than 50% of the patients.
Then those patients that stop therapy, 50% will lose their response after treatment discontinuation, and they have to resume therapy. When you go down into the second line and the third line of therapy, although we feel good about the number of treatment options that we have, the response rates keep going down, and the number of patients that discontinue therapy keeps going up. Of course, we have issues with safety, particularly arterial occlusive events, with most of the tyrosine kinase inhibitors. There's clearly room for improvement, as good as we feel with the, with the progress that we've made with chronic myeloid leukemia. Next slide, please. This is the description of the tyrosine kinase inhibitors that we have today. imatinib, of course, was the initial one.
Came the second-generation tyrosine kinase inhibitors, nilotinib, dasatinib, bosutinib, then the third-generation, ponatinib. All of these are ATP competitive inhibitors of tyrosine kinase inhibitors. Most recently, we had the very first inhibitor that is that specifically targets that myristoyl pocket that makes it unique, that is asciminib, and we're gonna talk a little bit about all of these options. Let's start from the beginning. Next slide. When we see a patient in the clinic, what we first need to decide is: What are we gonna give? Are we gonna give a patient a newly diagnosed imatinib, or are we gonna give a second-generation tyrosine kinase inhibitors? And if so, which of the three that are approved for frontline therapy are we gonna use? If you click one more time, please.
Why would we give imatinib? Well, we have the longest. Nope. Go back, please. We have the longest follow-up of all the tyrosine kinase inhibitors. It is very safe. We particularly don't have much cardiovascular or arterial occlusive event toxicity. The event-free survival, overall survival, this is all the same as with the second-generation TKIs. Of course, we have good salvage if a patient doesn't respond well to imatinib, and the cost is the lowest because of the availability in the U.S. of generic imatinib. Next slide. Why would we use a second-generation TKI? Well, we have faster responses, deeper responses, more sustained deep molecular responses, which allow more patients to be eligible for treatment-free remission.
We have fewer transformations, for some events, we have less, of course, we do have more arterial occlusive events. That's kind of our decision. On the next slide, you can see a summary of these pivotal trials comparing a second-generation TKI to imatinib as frontline. The first one, DASISION, is dasatinib, ENESTnd is nilotinib, BFORE is bosutinib, they are all pretty much giving us the same results. Meaning, with the second generation, we get deeper molecular responses, faster molecular responses, fewer transformations. Importantly, we don't get more or improved progression-free survival or overall survival. Granted, with imatinib, we've already reached pretty much normal life expectancy, we don't expect an improvement in survival beyond that.
However, next slide, as I mentioned earlier, there is a plateau in the number of patients that reach these deep molecular responses. On the left, you see the major molecular response. By 5 years, you get to the maximum of about, somewhere about 75%, 80% of patients who get the, these major molecular responses. MR4.5 on the right, you see that by 10 years, you already again reached a plateau, and that's at around 60% with the nilotinib, only about, probably 40% with imatinib. Next slide. The most important, these sustained deep molecular responses, as I mentioned earlier, not even 50% of patients get to that point, and that's important. That's what we want for the treatment-free remission. Next slide.
When we do these treatment-free remission studies, we know that about half of the patients who stop therapy will relapse and need to resume therapy again. If you look at that, then next slide, you put in the information that I just provided on the number of patients who are eligible, next slide, it is clear that only about 25%-30% of patients can successfully stop therapy. It is good that it's a reality, but there's a lot of room for improvement. Next slide, please. I mentioned earlier that in these studies, by five years, about 40% of patients end up changing therapy, and you can see that this is true across the board.
No matter whether you're using imatinib or a second-generation or what second-generation TKI, by 5 years, about 40% of patients have changed therapy, and by 10 years, with the 1 study that we have data that long, 50% of patients have changed therapy. Half of our patients are not doing as well as we want them to do. Next slide shows the data of second-generation TKI after imatinib failure, and we feel like we have pretty good therapy there. As you can see here, only about 40%-45% of patients achieve a complete cytogenetic response. This is clearly not what we're thinking, where that we have such a very highly effective therapy.
Sure enough, subsequent studies have shown some improvement in these outcomes, but clearly, there is room for improvement in the second-line therapy, and even more, considering that this is after imatinib failure. When we start patients with a second-generation TKI, we don't really have good treatment options for second line in that setting. Next slide. It is not just a matter of not getting response. Once you go from a second-line TKI to a third-line TKI to a fourth-line TKI, as you can see on the left, the overall survival expectation of the patient drops significantly. Once you move to your third TKI, the survival expectation by 5 years is only 60%, not that normal life expectancy that I was talking about earlier. These lack of responses, these failures, really matter to the patient.
Next slide. When you, when you've gone through a imatinib and a second-generation TKI, what we've been doing for some time was just recycling to another second-generation TKI and another second-generation TKI. The problem with that is, number one, there's very few prospective studies that have looked at that. It's mostly case series, but most important is that those case series show that the response rate is very low. You see here the complete cytogenetic response in all these studies is mostly around 20%-25%. Clearly, from second-generation TKI to second-generation TKI does not work. Next slide. That brought ponatinib, which was a third-generation TKI with activity against T315I, but also in patients that have received 2 or more tyrosine kinase inhibitors.
This study, called the PACE trial, was demonstrated the efficacy of ponatinib, very high rates of response. The primary endpoint in that test at the time was major cytogenetic response. 60% of patients overall responded, but even some deep molecular responses, and you can see on the right that those responses are very durable. Next slide. The problem with ponatinib is the high rate of arterial occlusive events that have seen reported in up to 30% of patients. That is heart attacks, strokes, gangrene in the lower extremities, and so on, who has made many clinicians and many patients avoid the use of ponatinib, even when from the clinical perspective, from the leukemia perspective, there may be an indication. Next slide. That created this study that looked at different starting doses of ponatinib, 45, 30, or 15 milligrams.
The study showed that starting with 45 milligrams was more effective, but the distinctive feature here was reducing the doses after the patient responded, so that you minimize the exposure, decrease the toxicity, and it certainly did that. The rate of arterial occlusive events went down, but it is still higher at the 45 milligrams, 4.5 events per 100 patient years. It is something that's still an important consideration for many patients. Next slide. I mentioned asciminib is the first myristoyl pocket inhibitor. It is also a tyrosine kinase inhibitor, but it binds in a very different domain, that very importantly, that myristoyl pocket is unique to the BCR-ABL. It is not present in other kinases.
In principle, at least, 1 of the advantages of such a drug is that it would have much less off-target toxicity because again, this pocket is not present in any of these other kinases. Next slide. Well, the data from the initial phase 1 study was very impressive, with asciminib very high rates of response, both in patients that did not have the T315I, but also because it binds in this different pocket, very, very far away from where that mutation sits, it is also effective against the T315I mutation. That led to the pivotal trial that you see on the next slide, which randomized patients that had received 2 TKIs or more to receive asciminib or bosutinib. The primary endpoint was the major molecular response at 48 weeks.
I'm showing you here a longer follow-up, showing significant benefit of asciminib compared to bosutinib. There is still some arterial occlusive events, more with asciminib than with bosutinib. The overall rate is relatively low, lower than ponatinib, of course, there is still some that has some patients that have had these problems. Next slide. In this study that I just showed you, there were no patients with T315I because the control arm does not work against T315I, asciminib is also indicated for T315I, however, at a much higher dose, 200 milligrams twice daily. This is a little complicated for patients because it requires an empty stomach, which is sometimes complicated for the patients. The efficacy effect is important. You see here a high rate of responses.
Even on patients who had already received ponatinib, you still see a robust, almost 30% rate of major molecular responses. Next slide, please. One thing that we're still trying to understand is the mechanisms of resistance. We do see persistence or emergence of some of the mutations that are more typical of the ATP-binding tyrosine kinase inhibitors. Even though in the preclinical setting, they would not cause resistance to asciminib, we do see that happening. This is something we're still trying to understand better. In the end, next slide, we can summarize here by saying: What is the role of these third generation and ponatinib and asciminib TKIs? Next slide.
clearly, for third line, for T315I. Next slide. Thank you. no, move back, move back, move back. There you go. In third line and in T315I, they're clearly established. We still don't understand which one is better. We still want to understand better the arterial occlusive events. Very importantly, for T315I, the dosing schedule for asciminib is a complicated schedule. Next, in second line, for patients who have received a prior or second-generation TKI, we really need a better therapy, even for patients who received only imatinib, but particularly for patients that have received a second-generation TKI. I think that this is a very good area to explore for these drugs.
Finally, next slide, I think there is the potential of combining these drugs with traditional TKIs to improve the deep molecular responses, and also the potential to have them as frontline therapy if we are gonna improve the long-term outcomes, where we still have the gaps that I emphasized at the beginning of my presentation. Next slide. There are some attempts of looking at this with asciminib. This is the add-on to patients who are responding to imatinib, but not having a great response. And when you add asciminib, you can see that there is some patients who improve their response, so that is just early data, but some potential there. Next slide, also early data emerging using it as frontline therapy on this study from Australia called the ASCEND trial.
Those are the green bars, and you can see how compared to a prior study that gave outstanding results, that TIDEL-II, but we get very early on, at 3 months, already almost 50% of patients with a major molecular response. Great potential for these for this drug in this setting. Next slide, just to conclude, are we done with CML? No, we're not. There's a lot of areas for improvement. I'm not gonna go into too much detail into these, but I see ways to improve everything from our frontline therapy to our suboptimal and failures, and even for the patients that have good responses, but not quite these deep molecular responses.
I think that there's many roles where we can, that we can assign to better new drugs, and we should aim to continue improving on our outcomes. Next slide. I would say that then in frontline, we could improve our deep molecular responses. The combinations could be helpful to decrease the rate of relapse after having these continuations. We still need to figure out how we combine this potential of combining a myristoyl pocket and an ATP binding pocket inhibitor is very intriguing. Second-line therapy could be improved, particularly after second-generation TKIs frontline. Of course, the safety profile, the third line, and T315I, we don't have enough options, especially since we still have some questions about the safety of ponatinib, the schedule of asciminib, and then, of course, the more advanced stages of the BC.
With this, I will conclude, and I thank you for your attention.
Thank you very much, Dr. Cortes. That was truly a comprehensive overview of the current landscape, involving landscape and the unmet needs, and you eloquently described the current situation in CML. Dr. Cortes will be available for the Q&A session. At this point, I would like to move on to our Fireside Chat session with Dr. Michael Mauro at Memorial Sloan Kettering. Dr. Mauro, thank you for joining us. Maybe I'll just start with the question of: what has been your own experience in treating patients with an allosteric TKI?
Well, hello, everyone, thanks. Well, you know, the CML history has been long, and I think unfortunately, I missed my colleague, Dr. Cortes, some of his presentation for, 'cause I was joining late, but I'm sure he gave us a terrific overview of how things have evolved. I view this allosteric inhibitor story as, you know, what was the best targetable, druggable area of the kinase from the very beginning? You know, how do we approach BCR-ABL inhibition and CML treatment? I think we, you know, we looked for available therapeutics, and then now we've seen evolution of a, you know, one myristoyl pocket inhibitor, and I'm glad to see we have development of others. I think our quest in CML has always been the most selective, the most active drug.
I think so far, my experience with myristoyl pocket inhibitors are, that they are very good at controlling leukemia in a very stable way. They may not be, we need to learn what some of the nuances of complicated forms of resistance. You know, some people may have control, but you either need different doses or, potentially different, even beyond just the myristoyl pocket inhibitor strategy, for example, combination therapies. I find them to be very broadly effective in the resistant population. Obviously, as we've tested them, I'm particularly encouraged with some of this frontline data we're seeing.
I think there's room for use as combinations in multiple different settings, but I'm particularly impressed by the ability to control disease that's been through multiple lines of therapy, in a very stable fashion with low you know, low toxicity profile so far for asciminib, although, obviously, some questions. I'm looking forward to seeing how we can continue to build on the allosteric inhibitor, you know, area. Other allosteric inhibitors have come and gone, actually, prior to asciminib and novel compounds like Terns compound. I think there's obviously more work to do, but it's the right direction to go in. I think I've always quoted allosteric inhibitor, you know, approval and development as the next big thing that's happened in CML.
We've had a lot of the same thing happening with evolution of ATP pocket inhibitors, and they've been huge advances, very good, but this is a different step.
Thank you. That's very helpful. I mean, given that this is, it's a new class, you know, in your opinion, specifically, how are allosteric TKIs distinct from the active site drugs, and specifically sort of focusing in on the mechanistic rationale, obviously, around the different binding pocket, but really how that turns or translates into, benefits with regard to both safety as well as efficacy?
The allosteric inhibitors are correcting, you know, something that's created with BCR-ABL genesis, with, you know, with BCR-ABL fusion. In comparison, ATP pocket inhibitors are, you know, trying to target an area, an active area of the kinase. Just, you know, one quick offshoot is that, one of the most interesting questions we had in the early days of imatinib development is: how is it that we see ATP binding pocket mutations in patients that had never had exposure to ATP pocket inhibitors? Meaning that patients with often accelerated blastic disease, honestly. Some of them had, for example, T315I mutations, having never had any ATP pocket, and never having had any therapy with, you know, novel therapies like imatinib, and that was the novel drug at the time.
Telling us that the ATP binding pocket and ATP pocket inhibitors have a certain set of challenges, that mutations may be, you know, a priority. They may be there even before you start. Compound mutations are an issue, which can, the kinase, you know, the cellular survival can withstand multiple mutations in the same kinase, and obviously, suffer drug activity. Allosteric inhibition, I'm particularly impressed that mutation rates seem lower, although I think the data with asciminib is incomplete. I think we'd probably need more data, I don't think the opposite is true, that if we had, you know, mutation data on every single patient, then we'd all of a sudden notice that, oh, there's a lot of mutations in the allosteric site. I think it's less prone to mutations based on the mechanism of action.
It's obviously distinct from the ATP binding pocket, so there's a possibility to combine. That's a huge benefit. We've never had anything like that, and that's a proven strategy in infectious disease and cancer in general, you know, multi-target inhibition. I'm trying to think of what else, but I think those are my, you know, some of my top differentiators, in that I think it's potentially a better target. I think it's less prone to resistance, a priority de novo and with therapy, and seems to be a very efficient way to quell BCR-ABL-driven cancer.
No, that's very helpful. Specifically, you know, with regard to the safety aspect, given the overall lack of the myristoyl pocket being found, do you find any key advantages there?
Say that again. I missed the second half, what you said there.
With respect to the safety profile of the.
Yeah
allosteric inhibitors versus the active site.
Safety's been a challenge. I'm gonna again, I hope I'm not repeating anything my same colleague has already gone through, 'cause he probably may have touched on this as well. Safety has been obviously a question of what's intrinsic to the compound itself with regards to targets and kinases affected. I think we've had the challenge to say, or to speculate that, you know, the more potent ATP directed ABL inhibitors, the more potent the inhibitor, the more potential we've seen for potential toxicity, possibly even driven by ABL inhibition, which. 'Cause ABL isn't, you know, unique to blood, I mean, cardiac ABL and other questions we have. I think it's probably more of an off-target effect.
If you had a small molecule that was cleanly correcting a, you know, this myristoyl pocket defect, rather than an ATP competitive inhibitor, which may have, obviously, analogs that can combine, you know, KIT, PDGF, ABL, you know, sort of the spectrum of typical overlap with the available ATP pocket inhibitors, as well as, quote, "off targets." I think, you know, I think you might have either shared or can share some data with regards to, like, the kinome and the, you know, the targets that certain inhibitors hit. If we had a small molecule that was clean and was very, very specific and targeting something more distinct, the tolerability profile is going to be better. That being said, what have we seen with asciminib? I think Dr.
Cortes might have touched on this already as well. The toxicities we've seen with the available myristoyl pocket inhibitors are. There's overlap with or ATP competitive inhibitors. Some of them are just disease-intrinsic. Blood count suppression is, I think, disease intrinsic. I don't believe it's necessarily a targeted drug effect. However, pancreas toxicity, lipase elevation, and some degree of pancreatitis, there's probably something to be learned there. I'm eager to see, as we see better and newer drugs in development, what we might be able to spare in some of those other toxicities. General symptoms that patients experience, musculoskeletal symptoms, fatigue, things like that, are, again, I think they may be disease intrinsic, they may be target or therapy-related as well.
We have a very strong agenda to look at cardiovascular toxicity in a very broad sense, you know, we're very keen to be analyzing that. I'm not sure if we can ascertain what, if any, signal we're seeing from myristoyl pocket inhibitors just yet, 'cause we have a very cloudy picture with a lot of pre-treated patients with other therapies and patients with common comorbidities. I would say that the tolerability profile of asciminib as a prototype myristoyl pocket inhibitor is favorable.
Mm-hmm.
I'm expecting that we may be able to build on that with better, more specific, perhaps the optimized myristoyl pocket inhibitors like Terns, and have essentially very potent drugs with very good tolerability profiles, which is what we're looking for, kind of fill the gaps that Dr. Cortes was alluding to, frontline therapy, early switch, second and third-line therapy, resistance, et cetera.
No, thank you. That was very helpful. Dr. Cortes covered this from a data standpoint in terms of the remaining unmet needs and the challenges, but in your own personal experience, given the current CML treatment paradigm, where do you see the unmet medical need, and what remains, in your view, the greatest challenge for managing CML patients?
You know, I think, unfortunately, a lot of people think we're. We actually even quoted ourselves, we call it that we have a spoil of riches. We have so many medications. Many of them, some people on the call might be asking, like-
Mm-hmm
... "Is there room for more? Do we really need more?" Don't you dare go into the clinic, like, right outside this door and tell the patient that, "Well, we're kind of backing off on developing new CML drugs. We think we have enough," 'cause you always wanna have a better and a broader option. The unmet needs, I, specifically, are pretty comprehensive. I think, again, I think that this was summarized already, but, in the ideal world, we should be hopefully finding a better frontline therapy where we can optimize in that window. CML is not a disease you want to save therapies for, you know, and treat when, you know, you've kind of saved for a rainy day. Definitely not.
As we bring therapies into later lines of therapy, we're always thinking, and the field's pretty interested in moving novel agents into the frontline setting, so we can avoid all the trouble that we have to deal with all of the other unmet needs. I would say that one of the biggest unmet needs is, can we increase the cure fraction? That's a twofold question. Can we increase the number of patients who get into a stable deep remission, which is protective and avoids, you know, palpable, calculable risk of progressive disease and death from CML, or needing to go to transplant or other, you know, sort of more high-risk procedures. The second part of that equation is treatment-free remission. Can we have a therapy that is efficient enough to extinguish BCR-ABL-driven hematopoiesis to the point where treatment-free remission is successful?
I believe that's what we're doing. We're extinguishing, you know, the disease that at least can cause volumetric relapse. We may not completely eradicate every, you know, BCR-ABL clone, or every last evidence of BCR-ABL. We may have some background signal that we see in patients who are successfully treated with TFR that's of unclear, you know, relevance. It's probably not myeloproliferative disease anymore. Frontline is, I think, one of our biggest unmet needs. At present, where we're studying the drugs and where we have approvals, we obviously don't always use our, you know, our best foot forward, and we obviously have issues with adherence, tolerability.
Mm-hmm
... switching therapies. You know, a third of patients who switched off their frontline therapy in a very broad observational study that was done, called the SIMPLICITY trial. Switching is common, intolerance is an option 'cause this paradigm is unique to CML, chronic, you know, maintenance therapy for several years. The ability to find better options to switch people to, if they have any sign of failure or any significant intolerance to a prior therapy, would be important. I, you know, I'd rather them go on the best therapy they can initially, as long as it's safe.
Mm-hmm.
That's clearly a, another huge unmet. Then selective resistance, yeah, clearly, I don't know if we know all of the story with regards to resistance. We clearly have T315I mutation, which I think, you know, the myristoyl pocket inhibitors seem to be relatively agnostic to, in a general sense, although dose is an important question, and differential dosing may be needed given the configuration and the stereo changes that happen with those kinds of substitutions, like a T315I. Resistance may be driven by other mechanisms, which again, I don't think that's not what we're going for in these more targeted and smarter ABL inhibitors. We're looking for better BCR-ABL inhibitors.
We're not looking for off-target effects and hitting other.
Mm-hmm
... targets that are mechanisms of resistance. Thank goodness, everything seems to be BCR-ABL centric and BCR-ABL driven in CML. We really still haven't defined a resistance mechanism that is unique and an offshoot, where BCR-ABL inhibition really doesn't matter anymore. It always matters. I think even in high-level resistance and select mutations, I think we have an unmet need there. We rarely see blastic, you know, transformation to the same degree we used to, but it's still an issue.
You know, if we step back, and we're privileged in North America, but if you think about this as a global market, global scale, treatment for CML is not that easy in the rest of the world, and people don't always have easy access to the right initial therapies or broad access to all agents. You know, if we had a more potent drug or a safer drug that could survive resistance, we might do even more, have more impact in other parts of the planet, where resistance may be a little bit more pervasive and common. We're a little luckier here.
Sure. You know, based on that, as the, you know, only additional allosteric inhibitor at least currently in development, what role do you think TERN-701 could potentially serve in the, in the evolving treatment landscape?
If we look at the example we set with ATP pocket inhibitors, you know, we thought, you know, man, it was great, and it still is, but we obviously have many other alternatives, many of them having advantages in dosing, ease of dosing and tolerability, clearly in adverse events. If TERN-701 turns out to be, as we expect, you know, or we hope, you know, if it has the properties of being a drug that's easier to deliver, whether it's from a schedule, or a drug-drug interaction, or food interaction standpoint, those are seemingly lesser important.
Actually, with chronic therapy and chronic maintenance therapy, they unfortunately become even more important, because that's actually a fairly big challenge, is adherence to chronic therapy in CML, and so that's one advantage. I think it could fill the unmet need of people who have exhausted all therapies, of course. We have to see what sequential allosteric inhibitor therapy looks like. There may be significant overlap in the populations, but I would keep that door open.
You may not always get it right the first time with your first drug, so if we have a better, easier to deliver, potentially, in a number of important ways, better agent, you could better serve the target population, which would be resistant patients, and can start to explore the same areas that asciminib is exploring.
Mm-hmm.
Obviously, you know, earlier switch combinations. Broad question, we don't have a lot of data there. I think that's a very ripe area for exploration. You know, there are questions regarding combinations with our most potent ATP competitive inhibitor, our most, you know, our sort of our prototype ATP pocket inhibitor, imatinib. I'm talking about, you know, combination with ponatinib for the most difficult, you know.
Mm-hmm
scenario we might envision. Combination with safe drugs and a imatinib, or lower doses of second-generation inhibitors, some of which are gonna be very much more prominent because they're gonna be now available in generic forms, and lower dose schemes have gained a lot of momentum and traction. We're very keen to think about how we could do better, and I think TERN-701 could hit all of these areas. I think they're all up for grabs, and we're clearly not done. I think we could use improvements in frontline, in salvage, in highly resistant disease. Probably the area that we haven't spoken about, I'm not sure if Dr. Cortes mentioned, but, you know, advanced-phase disease is a little bit of a continued challenge.
It's rarer. There may be other mechanisms of resistance indeed there. We obviously have a track record in lymphoid disease with chemotherapy, and chemotherapy combinations, and immunotherapy, and there's been a lot of advances there, which have de-emphasized, and to a degree, the role of the BCR-ABL-targeted drugs. We still need to work there because it obviously still happens, and I think that's another area for exploration.
Yeah, no, thank you. That was very helpful. You kind of touched on this in the, in the answer you just said, but, you know, you've alluded to combinations and talked about sort of the next sort of paradigm shift, and potentially in the disease being getting patients more quickly to a deep remission or deep molecular response. In your opinion, you kind of already touched on this, sort of, what's the most sort of acute need in terms of combination therapy with an allosteric plus an active site inhibitor that you think would have the most impact in the, you know, in the near future, as far as, that you would be most interested in exploring of the options that you mentioned?
Well, if I had my way, I think, I guess we've been a little bit concerned about combination therapy with our most potent and perhaps most complex ATP competitive inhibitor, which is ponatinib, given the tolerability profile. I think we should venture forth and look at you know, the combinatorial safety and potential for that, 'cause I think there's some very nice.
Mm-hmm
... preclinical work that shows you may not need as much of the ATP competitive inhibitor, for example, to synergize with an allosteric inhibitor. I think we all have patients out there that... You know, simply using sequential ATP competitive inhibitors, sequential allosteric inhibitors may not be successful. That would be a nice step up, is to think about an aggressive combination for highly resistant disease, where ponatinib could play a role.
Right.
The other combination strategies, you know, we've been more careful and deliberate to say that, what's the need, and how do we strike a balance? There's been a lot of, I would say, buzz about, is it worth it, you know, to expose someone to two drugs, you know, with safety and tolerability issues, when, you know, honestly, maybe the allosteric inhibitor alone does the work. Do you really need the ATP competitive inhibitor? Dr. Cortes presented the initial frontline asciminib trial, and he's championing one in the North America that we're enrolling patients on.
Mm-hmm.
You know, both studies have been correct to add an option to add an ATP competitive inhibitor, and I don't think that's happened in the first trial. We're gonna try to be flexible in the in the US or North America in this, in our trial. We're unclear whether we need it in frontline. The next area would be the challenge, I would say, of sort of suboptimal response or tolerability issues, where you could come in with tolerable doses of ATP competitive inhibitors, with excellent allosteric inhibitors-
Right
... to rectify the patient who can't take a correct dose of an ATP competitive inhibitor to gain successful deep remission, or a patient who has some shortcoming, either, you know, chronic phase disease, but inadequate response, failure to achieve a deep remission, which is amenable to a treatment cessation, a host of different areas. Again, I think we've really done a fairly good amount of work, although it's not completely done with what's the best dose of all of our ATP competitive inhibitors. Many would say lower dose asciminib really may have advantages. I know it's not the label, but I know that's fairly convincing. We've seen data about lower doses of the other ATP competitive inhibitors as well, either forced to lower due to tolerability with dasatinib or deliberately lower with nilotinib.
I think we could explore all of those different options with an allosteric inhibitor.
Mm-hmm. No, very helpful. Thank you. With that, you know, I think we're up on time with regard to this session. I know you're in clinic. I truly appreciate you carving out some time for this, and thank you so much for your insights, and your viewpoints. Appreciate it.
Sure. Well, I'm glad to join the conversation, and thank you for having me.
Thank you, Dr. Mauro. The next part of the agenda is that I will give you an overview of our own development plans for TERN-701. In light of what you heard from both Dr. Cortes and Dr. Mauro, who highlighted very clearly what the current landscape and the unmet needs are, we're obviously gonna use that and leverage the profile of this molecule to be able to develop most appropriately and meet unmet needs in CML that still exist. With that, I'll move on to the next slide. This slide is just showing you a timeline of our progress so far with TERN-701, which is our internally discovered allosteric TKI inhibiting BCR-ABL for the treatment of CML.
As Erin alluded to earlier, this was an internally discovered molecule at the very sort of founding of Terns back in 2017. Again, we were very happy to execute a licensing agreement with a Chinese company partner, Hansoh, that happened in July of 2020, who then went on to do the IND-enabling work and started a phase I study in China in May of 2022. Under the licensing agreement, I'll remind you that Terns retained all rights to develop the drug outside of China and the rest of the world.
We initiated our internal development of this molecule in August of 2022, and I'm happy to say that the team has made dramatic progress over the last year, and we do anticipate starting our phase 1 study in the U.S. and other regions in the second half of this year. We had an enrollment update from Hansoh's ongoing phase 1 study, which was presented at a Trials in Progress poster at this year's ASCO. Again, the fact that we have emerging clinical data from our partner, Hansoh, in China, we think gives us a big advantage in terms of using and leveraging that clinical data to accelerate our own development of the molecule ex China and borrowing from that data.
I think we're on a very good track here to develop this molecule rapidly going forward. Next slide. This slide shows you sort of a comparative potency profile of TERN-701 versus asciminib. As you can see on the radar plot there on the left, this is a very potent molecule in terms of its potency of inhibition of both native BCR-ABL, as well as BCR-ABL with the mutations that you commonly see in the clinical setting. On the right half of the radar are the more commonly observed ATP site mutations, including T315I. On the left, you can see the myristoyl site mutations, which are much less commonly observed in the clinical setting.
The main takeaway here is that this molecule looks essentially equipotent to slightly more potent than asciminib in several of these disease settings, again, which we think will, well, speaks to a high probability that the molecule will behave as such or better from an efficacy standpoint, also, as Erin was alluding to earlier. Next slide, please. This slide shows some additional preclinical data. These are in vivo data, looking at the molecule's antitumor activity in two settings. On the left is a K562 xenograft. The K562 is a CML cell line that is a native BCR-ABL cell line that does not have active site mutations. The main points there, as you can see, the drug clearly shows a dose-related efficacy against this in this model.
Secondly, at equivalent doses of the drug compared to asciminib, it appears to have more potency in this tumor model, which again, speaks to the point we made that this might translate to equal or better efficacy in the clinic. On the right is a BAF3 BCR-ABL1 T315I xenograft, so these are BAF3 cells transduced with the T315I mutation. Again, looking at that, this drug also looks to be active against this very difficult-to-treat gatekeeper mutation that you see in the clinic, which impacts approximately 15% of patients. Again, we see at least an evidence of superior or increased greater antitumor effect versus asciminib at equivalent doses. Next slide.
This slide is showing you the kinome profile for TERN-701, and the main point of this slide is that this drug looks exquisitely selective for the fusion BCR-ABL protein. As both Dr. Cortes and Dr. Mauro alluded to, the selectivity profile and lack of off-target kinase inhibition is a key important feature of these molecules that would speak to a potentially much improved safety profile and a much better therapeutic index in the clinic.
In a panel of 375 kinases at a concentration of 1 micromolar, which is at least 2-3 logs above the IC50s that I showed you in the earlier slides, you can see that this molecule is very clean in that no kinase, including wild-type ABL1, was inhibited by more than 50%, which speaks to a clearly reduced potential for off-target kinase inhibition. As Dr. Mauro talked about in our fireside, wild-type ABL1 inhibition may play a role in the vascular toxicities that you see with some of the other actives like TKIs. I think having a clean molecule, especially that doesn't hit wild-type ABL1, is an important factor going forward, especially from a safety standpoint. Next slide.
This slide shows you the design of the currently ongoing study that's being run by Hansoh in China. This study overall aims to enroll roughly 100 patients, and this intended to provide full efficacy as well as safety evaluation, you know, in China as they develop the drug. Just to quickly go over this, the population is CML patients who are resistant or intolerant to active site TKIs, at least 2 prior TKIs in the non-T315I and 1 prior TKI in the T315I population, with endpoints primarily of safety as well as cytogenetic and molecular response and PK. Part one is a rolling six design dose escalation, and as you can see, the lowest dose being evaluated is 40 milligrams all the way up to a 320-milligram cohort.
We're happy to provide the update, which is again presented at ASCO Trials in Progress, that cohort 5 was enrolled as of April of this year. Again, we are hoping to leverage the data coming out of the Chinese study to be able to accelerate our own phase I study, and then, you know, make the overall program development more efficient in terms of identifying the optimal doses to take to pivotal studies. We think that this is a big advantage for us in terms of having this head start from Hansoh in terms of getting clinical data. Part 2 of this study intends to select a recommended dose for expansion, and essentially select the dose then to take to further registrational trials in China. Next slide, please.
This is a high-level overview of our own phase 1 trial design that we're starting this year. Again, we aim to leverage the Hansoh phase 1 data to evaluate dose ranges expected to be both safe and therapeutic within the wide dose range that they are already evaluating. The study population is chronic phase CML patients treated with at least one prior TKI. As Dr. Cortes clearly indicated in his presentation, that second-line patient population who have either been treated with imatinib or a 2GTKI, have very limited options currently, in terms of the fact that asciminib is not approved, and nor will it be expected to be approved in that group of patients.
From a label standpoint, third-gen drugs like ponatinib are also not approved for the non-T315I mutant subset of patients in second line. As Dr. Cortes eloquently showed in his slide, even imatinib-treated patients who switched to a 2GTKI in that second line only get to about a 40% response, and with lower numbers in patients who are treated with first-line 2GTKIs. We think this is a big gap that TERN-701 can fill off the bat, and we hope to be able to evaluate that population in this study and future studies. The dose escalation is going to follow a BOIN algorithm design.
As you can see, part 2 is a randomized dose expansion, evaluating two recommended doses for expansion, and we're in light of the recent guidelines from the FDA with Project Optimus. Next slide, please. To put this all on a timeline, as you can see on this high-level slide, 2023 has been a very busy year for us at Terns, and we've been executing on activities to help us get into the clinic this year, and we're on track to do that. We completed manufacturing the initial drug supply to support our phase I study start, and we expect to start the study, not just in the U.S., but in the EU as well as other territories. So this will be a global trial.
Given that we have somewhat of a head start with clinical data from Hansoh, we hope to leverage that information and especially the safety data, to pick a dose range that's expected to be both safe as well as therapeutic. Because of that, we anticipate that we expect initial data from our study next year in 2024. Again, based on all the things that we heard from Dr. Cortes, as well as Dr.
Dr. Mauro, in terms of the current landscape, in terms of the current gaps with the with stan or allosteric inhibitors, and also the fact that we have sort of an established regulatory playbook for these drugs in CML in terms of the milestones that you need to get to for approvals, we feel confident that a phase III registrational study can be accomplished potentially with this drug in a 2- to 3-year time frame. As such, we're evaluating multiple options for where we would go in terms of pivotal trials after we complete the study that we're starting with. If you go to the next slide, this shows you one possible option on what a pivotal program could look like.
We do believe that there is a potential for TERN-701 monotherapy registration path in earlier line CML patients, namely, that second-line patient population that Dr. Cortes and Dr. Mauro talked about with regard to the fact that there is no allosteric inhibitor approved for those patients who have either failed a 2G or a first-generation TKI. That clearly represents a clear gap where this drug could potentially be developed for an initial registration strategy and an initial approval. Again, with the fact that second-gen TKI drugs are essentially all going generic, we expect their share to remain stable over the future in terms of frontline therapy, which also brings up the feasibility, we think, of being able to take TERN-701 as monotherapy, potentially into frontline patients.
As you heard both Dr. Cortes and Dr. Mauro talk about combination strategies and other options, to take it into earlier lines include combos as well as in the frontline, as well as potentially in the refractory patient population, which we have the option to explore with this drug, especially knowing the safety profile of allosteric inhibitors in general. We think that gives us a lot of room to explore in terms of where to take it. This slide clearly shows that this drug has a clear path forward from a monotherapy standpoint, that could fit within the time frame to initial registration that I showed on the previous slide. Next slide.
This is largely a summary slide to show that this drug, TERN-701, is addressing a sizable and still unmet medical need market opportunity in CML. As our experts have already shown, the unmet need in CML is still there. There's still a lot of room for improvement in outcomes for patients, despite the progress, the dramatic progress that's been made so far with all the drugs that we have. CML remains an orphan indication with a sizable market and need for multiple agents, both as single agent and potentially as combination. As you heard, frequent switching occurs between TKIs, and Dr. Cortes showed the numbers, approximately half the patients during the course of their 5-10 years of initial therapy end up switching, most commonly due to intolerance.
More, you know, drugs with exquisite selectivity profiles, with limited off-target liabilities are clearly in need. Allosteric BCR-ABL TKIs have clearly shown that selectivity profile, as well as efficacy improvement over the older standard of care active site inhibitors, and therefore, there's clearly room, we feel, for TERN-701 as an allosteric inhibitor, to make inroads into the CML landscape. We know, the first approved allosteric drug, asciminib, is expected to be a blockbuster in third-line CML and is currently being developed for front line. TERN-701 is our own internally developed molecule with an expected profile we feel is preclinically that looks as good or better than asciminib.
We will see in terms of clinical data as we enter into the phase I study later this year, and we already have ongoing clinical study in China that will also inform the overall strategy with the molecule. With that, I believe, we can go to the next slide, and we were happy to open it up to a Q&A session for those on the meeting. Thank you for your attention.
Thank you very much, Emil, Dr. Cortes, Dr. Mauro, for those great, summaries and presentations. Operator, can we please open the line for questions now?
Sure. One moment for our first question. Our first question will be coming from Ellie Merle of UBS. Your line is open.
Hey, guys, thanks so much for taking the question, and thanks for the all the information and insights today. Does seven-oh-one bind to the same myristoyl pocket as asciminib? I guess with that in mind, could seven-oh-one potentially circumvent some of the allosteric site resistance mutations we've seen develop? Thanks.
All right. Thanks very much for the question, Ellie. Your question had to do about 701 binding the myristoyl pocket, I think, and then whether it would be affected by myristoyl pocket mutations. Emil, do you mind starting us off with a response for that question, please?
Sure. Yeah, that's a great question. I think what you can see in that radar plot is that, you know, the IC50s for this molecule look essentially similar to asciminib at those same myristoyl site mutations. At this point in time, based on that data, we predict that the molecule to have an equal sensitivity/resistance profile to asciminib.
Yeah. Ellie, thanks again for the question. To address your first question about whether 701 binds the same pocket as asciminib, yes, indeed, it is designed to bind the myristoyl pocket, just like asciminib does.
Okay, understood. Then I guess thinking, you know, as you head into potential pivotal studies, of course, thinking longer term, I guess, are there specific mutation populations or particular, you know, patient indicators in these patients with prior TKI failures that you could, you know, potentially enrich for in your clinical studies? Thanks.
Yeah. Emil, do you mind taking that question also?
That's a great question, and you bring up an important point that, you know, there's a lot of focus on T315I, but there are several other mutations. So part of some of those were shown on that radar plot. You know, we do in fact plan to include those patients. There's no restriction as far as mutation profiles for our study. We will gather data on not only T315I, but these additional mutations. You know, too, I would love to hear both Mike's and Jorge's thoughts on this.
You know, the non T315I population, which comprises roughly 85% of patients, is a very heterogeneous disease biology, that you're dealing with, and several of these mutations that you alluded to, are in that group of patients, and therefore, that gives you an opportunity to really optimize the dose and, you know, in terms of finding the correct dose that not only hits the native BCR-ABL, but the spectrum of BCR-ABL mutations that we know exist, within that large group of non T315I.
Again, that's why we're designing our study to be able to efficiently interrogate the dosing of this drug in order to make sure that we capture that wide heterogeneity in disease biology within the non T315I group, as well as the T315I group. Maybe Jorge first, and then, Mike, you can offer your insights on that additional mutation question.
Yeah, I'm happy to take that first. As you mentioned, we kind of have gotten to cluster these mutations into T315I and the others, but the others are a widely heterogeneous group of diseases that have different sensitivities to different TKIs, different proliferative potential in the laboratory. You know, for example, the mutations in residue 255, those patients have a pretty poor prognosis, and for example, with ponatinib, they have the highest IC50 to ponatinib higher than T315I. I and one of the worries with asciminib, for example, is that we don't know if we've optimized the therapy.
It's true that with TKIs and with many biologic agents, we don't necessarily need to go to a maximum tolerated dose, are we really giving the right dose for every patient when we're doing 80 milligrams per day? Are there some patients who really need a different dose from the beginning, just as we know that the T 259 need 200 twice a day? There is a lot of heterogeneity there. Of course, for the patients that don't have a mutation, where we even know less about what the mechanism of resistance may be and how we can address those patients. Again, taking the example of ponatinib, they have the lowest response rate, those patients that don't have a mutation.
There's still a lot of diversity within that group of non T259 mutated patients.
Mike, would you add anything?
I'm not sure how much I can add to that. I think that's covered most of the bases. I guess, it's hard to do clinical trials looking at specific mutations and assuming that that's what you're looking at. You know, like a study in T315I mutated patients, even that's heterogeneous because it might be secondary mutations or other mechanisms. I think it's going to be important as we move forward with clinical trials to try to characterize patients ahead of therapy, and then clearly, you know, based on clinical response. We learned because we had some, I wouldn't say surprises, but, you know, some interesting findings, like Jorge mentioned, with, you know, P-loop mutations, posing a challenge for other compounds and even with asciminib.
I think you know, the question was about myristoyl pocket mutations, and we'll, you know, what we might see. I think that's an open question. I'm not sure we really know. We might expect similar resistance patterns. I'm hopeful that the resistance is less, but we still have to tackle the resistance in front of us, which is resistance to ATP pocket inhibitors, and as I mentioned, resistance that can be intrinsic to CML itself.
All right. Thank you very much, Dr. Mauro and Dr. Cortes, for the responses, and Emil also. Ellie, thanks again for the question.
Thank you. One moment while we prepare for the next question. Our next question will be coming from Etzer Darout of BMO. Your line is open.
Great, thanks for taking the question and the call today. For the two KOLs, if you can just, you know, in your evaluation of sort of, you know, new therapies, given the potential for durable responses with standard of care, are there clinical signs, sort of beyond, you know, just molecular responses, you look at as an indicator of effectiveness? I guess, you know, particularly, early on and sort of the patient's sort of experience with new treatments. Just curious your thoughts on that. Thank you.
Thanks so much for the question, Etzer. Perhaps we could have Dr. Mauro start off on this question, and then, if Dr. Cortes could add his thoughts, that would be great.
Sure. I think it all kinda comes back to disease volume and disease volume reduction. You know, we obviously are looking for a drug that's, we're marrying tolerance and efficacy. It's true, we have different points. We look at it at different points of treatment, whether it's, you know, fifth-line therapy or front-line therapy, you know, sort of significant disease volume reduction after early exposure, 3-month, 6-month time frame. Pretty important to tell you about sensitivity to the drug and good clinical outcome. You know, you can turn around a resistant patient and put them into more of a primary treatment success path if you put them on that kind of trajectory, where they have very rapid and deep response, and they may have very high odds of gaining deeper remission.
I think the caller was asking, or the questioner was asking about other things we look at. CML, interestingly, doesn't carry a lot of other visible or palpable clinical parameters that we can, you know, assess for benefit. You know, we're mainly looking for resolution of disease symptoms, absence of specific drug intolerances, and then again, kinetic disease reduction. There are patterns, you know, early rapid reduction, having time reduction, have all mattered in front line and probably matter in salvage as well. A little bit more murky as we get to, like, plateaus and low-level disease burden and some other questions. I hope I've answered. Maybe Jorge has some other thoughts.
No, I think that Dr. Mauro really touched on everything that we know. Although I know that your question is about efficacy, one element that I think we've increasingly recognized as part of driving the efficacy is the tolerability of the drug. When we have drugs that you cannot give because of their toxicity profile, you know, somebody who has already a very high risk of arterial occlusive events, and you know you have ponatinib, but you cannot give it, or drugs, you know, or when you have to be stopping and restarting and stopping and restarting and all of that, you know that patient's not gonna do well. That's, that safety profile, so that tolerability is driving the efficacy of the patient.
That's why we're increasingly focusing more on tolerability and the toxicity profile and all that, so that we can have the patients stay on the drug early on, so they can get to the early markers, and long term, because we know that at least today, most patients are gonna be on the drug for most of their lives, if not all of their lives. I think that that's, you know, when I'm in the clinic, I frequently, you know, there's particularly those patients that have a lot of problems, I tell the patients, "You know, the first thing I want to do is to see that you can stay on one of these drugs, and then I'll worry about the efficacy. Let me just see what you can take, and then we'll go up from there.
Great. Thank you.
Thanks for the question, Etzer. Operator, do we have more questions?
One moment for the next question. We have the next question. It's gonna come from Corinne Jenkins of Goldman Sachs. Your line is open.
Good morning, everyone. Maybe one for the docs to start. Just how do you expect the availability of generic second-generation TKIs to shape like, the frontline treatment choices? What would you need to see from asciminib in this ongoing, you know, first-line trial so that you would use it in front of generics? Maybe I'll start there, and then I have a follow-up question.
Great. Thanks very much, Corinne, for the question and for joining the call. Dr. Cortes, do you mind starting us off there, and then maybe Dr. Mauro could provide just any additional thoughts about the impact of generic entrants in the class and what you need to see from asciminib to really feel comfortable prescribing it first line?
First, in terms of the generics, I do think that the when not only they become available, but when they become cheap, because that's when they start becoming widely used. You know, when imatinib was first became generic, it, the difference in price was not enough to make really a difference, but now we have very inexpensive generics. It's gonna take some years before that happens. When it happens, and when you have a generic that is really a very small fraction of the cost of the brand names, I do expect that there's gonna be more patients being treated with second-generation TKIs. When, and, you know, 'cause the there are advantages, particularly for those patients who are aiming for a treatment-free remission.
Sure, we know that going with a 2GTKI is no warranty to give me a treatment-free remission, but it increases my chances by probably about a good 15, 20 percentage points. I think that that's, you know, I gave that gross about 25%-30%. That's with the 2GTKI. It'll be probably about 15%-20% with imatinib. I do think that they will become more widely used in the frontline setting. Right now, imatinib is the single most used drug as frontline, and I think that that will change once these drugs become generic. Now, what would I want to see with the asciminib data to make me change the pattern?
I do want to see more deep molecular responses. You know, you hear some colleagues say, "Well, it doesn't improve survival." No. We're at the top of survival. These drugs are not gonna generate life, but we want the patients to live better, and part of that living better for many of them is the treatment-free remission. For those patients who are interested in that's what I want to see. That's what would make me change my pattern.
Okay, that's helpful. Maybe, I don't know, Dr. Mauro, did you wanna add something?
Oh, I'm not sure I could really add much more to that. I think, you know, I'd just reiterate all the same points. I mean, I think it's a complicated equation, and generic drug availability should be cost-driven, and it's not. That's not the immediate effect often. I always think about tolerability, you know, when it comes to the practice of CML in the US, and your prescribers want a drug that they can give to their patients that is easy to tolerate and is getting them where they wanna go. If our newer drugs are very well-tolerated and very efficient, that might be a real boost. I think I'd like to see not only, you know, We can't generate life, but we can generate high-quality life.
Sure. Okay. I guess, as you think about the registrational study, the phase III in a second-line patient population, how will you feature prior asciminib use in that study, considering, like, the real-world utilization could change while you're running it? How will that factor into the study design?
Yeah, you know, like...
I'll start.
Go ahead. Sorry.
Oh, sorry. Yeah, go ahead.
I think, to your point, you know, again, first of all, that slide was one of the options that we have thinking about currently, as we develop the drug. To your point, and as Jorge outlined, you know, the second-gen drugs, as they become generic, we'll still expect to have use in the front line. Given that, they will probably take away some of the share that Gleevec has in that front line as they also go generic. Therefore, you know, if you're expecting that proportion, which Gleevec is roughly half the patients right now, that will remain stable, those patients will still have very poor outcomes in the second line, even with asciminib in the front line being approved because of the cost factor.
Again, we don't know the data yet from the front line, but unless it meets that high bar for data, we expect that use of the second-gen drugs as well as imatinib in the front line will remain stable for the most part. Therefore, there's that pool of patients that's still available for second line who don't have any of the available options for first salvage. We'll evolve the thinking.
Okay.
as we get more data.
Great.
Great. That's really helpful. Thank you.
Thanks so much for the question. Operator, I see we only have nine minutes left. Perhaps we could just do one short question and answer in the time remaining from questions that are on the line. Perhaps save a minute or two at the end for our CEO, Sundar, to provide any other closing remarks. That would be great.
The next question will be coming from Ritu. I'm sorry, Silvan Tuerkcan from J.P. Morgan. JPM, please go ahead.
Hello. Thanks for the great presentation, and thanks for taking my question. Just a quick question for Emil here. What are the key differences to the asciminib early phase I/II trial? I've noticed that they did their trial after 2 prior TKIs versus yours, is scheduled to be in after 1. Is that a key difference? Is it important for you? Could you just talk about these, the impact of that? Thank you.
Certainly, yeah. I think, you know, the asciminib phase I trial was done, you know, in 2013, 2014, when it initiated. I think one of the key differences, again, is the more recent guidance from the FDA with regard to Project Optimus and sort of that element of dose optimization that, you know, that all sponsors, all companies need to look at in terms of early phase development.
From a patient population standpoint, I think you hit the point right, is that, you know, we are targeting to get that second-line-plus population, again, just based on the fact that because allosteric inhibition with asciminib has shown to be validated in the clinic, both from a safety as well as a efficacy, as well as safety standpoint, compared to the active site inhibitors, I think gives us an opportunity here, again, focusing on the unmet need that we just outlined in that second-line-plus population to target at least enrolling some patients with that profile in our initial study, to be able to get some preliminary data to inform our development strategy going forward.
Again, that's our goal, and we hope to achieve that in terms of getting that patient population and not necessarily just restricting it to the very refractory patient, which again, we'll have some data on as well.
Great. Thanks very much, Emil, and thanks for the question, Sylvain. Operator, any other questions?
Okay, one moment. Let me go ahead here. Our next question will be coming from Ritu Baral of TD Cowen. Your line is open.
Hi, guys. Can you hear me?
Yes. Hi, Ratu.
Hi. Thanks for taking the question. I wanted to ask about the strategy behind your dose selection in your phase I. Given the doses that Hansoh is investigating and the discussion today, both between an argument for maybe one of the doses being lower and more appropriate for future combination use and maybe another dose being higher, in the pursuit of treatment-free remission, how are you guys thinking about balancing those two potential goals as you go forward into that sort of dose one, dose two, dose expansion,
Yes.
as indicated on slide 44?
Well, that's a great question. You outlined the problem very nicely in the question. I think, especially, you know, we're leveraging the fact again, that this drug has a very nice selectivity profile and agrees preclinically nice safety margins to be able to allow us to interrogate a pretty wide dose range. We know that at the lowest end of that dose range, you still expect, you know, exposures to be within therapeutic range. What I think the Hansoh data allows us to do is really sort of zoom in within that dose range they're evaluating to see, you know, can we get a start in our study that's at a high enough dose and a safe enough dose where we know or can predict that majority of patients would be in the therapeutically relevant exposures.
I think that's very important, especially in CML when you're doing a phase I study, because, you know, it's gonna be hard for clinicians to be able to convince themselves and their patient that, you know, to start at the lowest end of the dose range and where you can be... In the scenario where you didn't have any data whatsoever with regard to safety and PK, that can become a big roadblock in terms of getting that initial enrollment up and running. We think the Hansoh data clearly give us get us over that initial hump in terms of providing us data that allows us to focus in on doses that are expected to be both safe as well as therapeutic.
The second part of your question was, how do you then take that information and design the optimal expansion where you evaluate the right two doses? I think you kind of, you know, you kind of alluded to our kind of thinking around that is, you know, we would have to look at a low dose and a high dose, and ideally, that low dose would have sufficient target coverage to ensure efficacy but leave headroom for combination strategies, and then a high dose where you can think of a TFR type approach, where you might think of something like an induction strategy, like Dr. Cortes went over in the OPTIC study. Can you do something similar with an allosteric inhibitor, even as a monotherapy to get better, deeper responses up front?
You know, that, you know, we know that that's not being, at least in the registrational trial, being done with asciminib. Again, we have opportunities to really tweak what we do there, without overly exploring or having to explore a wide range of options, again, because we have the Hansoh data to guide us on which doses to zoom in on.
Yeah.
I think we're in a good situation with regard to that.
Great. Thanks so much, Emil, and thanks very much for the question, Ritu. I think just to allow one other question briefly, I think, Ritu, sorry, I think we probably need to move on, but thanks very much for joining for the question. Operator, I think there might be one more.
This is going to the top of the hour. Our last question will be coming from Eric Joseph of J.P. Morgan.
From the mouse data with TERN-701, it looks like you need to, like, you need to go higher in dose to have activity against T315I versus native. Can you talk a bit about how the PK from mouse translates to human, and do you think that dose range evaluated in the Hansoh Phase 1 trial will include exposures predicted to be active against T315-- excuse me, T315I? Or do you anticipate sort of for any need to go higher than what they're looking at in your Phase 1 trial? Thank you.
No, great question.
We'll have a great response. Thanks.
Yeah. Yeah, great question, and I think the mouse data, number one, don't translate 100% into the clinic, again, because the pharmacology can be very different in humans. Again, we are planning on, in the Hansoh and our study, we're planning on evaluating a wide enough dose range that covers both subpopulations.
Great. Thanks very much for the response, Emil. Thanks so much for the question, Eric. Great to hear your voice. All right, at that point then, I think I'll just turn it over to Sen to see if there are any closing comments from your perspective.
Thanks, Erin. I wanna thank Doctors Cortes and Mauro for joining us today. I think we've learned quite a bit about CML. Yeah, I will say on behalf of Terns and the broader patient community, you know, it's great to see continued development and continued work going on here in the CML space. I think folks with CML are fortunate to have a wide pharmacopoeia, but, you know, there's certainly an unmet need, and we are proud to be able to potentially contribute to that pharmacopoeia going forward. Thank you again, everyone on the line, and we look forward to continuing to keep you up to date on the progress of this important program.
Great. Thank you so much, Sen. I echo your thanks to Doctors Mauro and Dr. Cortes, and thank you, Emil, for getting us through today. I think at this point, that concludes our call. And thank you so much to all who joined, for your participation and your great questions.
Thank you.