Thank you so much for joining us at the Novartis Investor Event at ASCO 2024. Welcome to everyone in the room and all those who are joining us in the webcast. Some of you are in Europe, so thank you for staying up late. We are very excited to discuss the phase III ASC4FIRST study data for Scemblix in newly diagnosed CML patients. But first, a couple of housekeeping notes. We will start with the presentation. The slides are uploaded on the website, followed by a Q&A and then a reception. For the Q&A, we'll take questions from both the room and online. For those in the room, please wait for the mic and state your name before asking the question. Those online, please submit your questions via the webcast.
We request you to limit to one question at a time so that we get through everyone's questions. Our aim is to wrap up the presentation and Q&A by about 7:00 P.M. With us today, we have Shreeram Aradhye, President of Global Drug Development at Novartis, and our Chief Medical Officer, Jeff Legos, Global Head of Oncology and Hematology Drug Development, and Reshema Kemps-Polanco, Chief Commercial Officer of our U.S. business. Finally, what you have all been waiting for, the safe harbor statement. The information presented today contains forward-looking statements that involve known and unknown risks, uncertainties, and other factors. These may cause actual results to be materially different from any future results, performance, or achievements expressed or implied by such statements.
For a description of some of these factors, please refer to the company's Form 20-F and its most recent quarterly results on Form 6-K, that respectively were filed with and furnished to the U.S. Securities and Exchange Commission. With that, I'd like to hand it over to Shreeram to get us started.
Thank you, Parag. Thank you, Parag. Good evening. Good evening to everybody. Hello to those joining us on the web in Europe. A special moment for us at ASCO here, and I hope that you've all had a good week, good few days, I guess, at ASCO. We are delighted all to be here because we are celebrating a pretty special moment for Novartis. We have had a long legacy with chronic myeloid leukemia. More than 20 years ago, the introduction of Gleevec turned what was a death sentence into what is now a chronic disease. 17,000 patients diagnosed with this every year, now a 10-year survival rate that exceeds 95%.
Having delivered Gleevec, we then delivered Tasigna as a second-generation TKI, aiming to deliver deeper levels of molecular response, and for the first time, started introducing the concept of achieving a treatment-free remission. Today it's about Scemblix, with the goal of transforming standard of care once again, and potentially enabling more patients to be treated to their goals, primarily on the premise of a drug that has the potential to be more efficacious as well as better tolerated, so that patients can stay on the drug in a consistent manner for the rest of their lives. Despite all of these advances, the reason we developed Scemblix was because there continue to be major unmet needs in patients with CML.
With the use of imatinib and the second-generation TKIs, nearly 40% of patients still need to change therapy over the five years after they've first been switched. Half of the patients do not achieve the deep molecular response, which is a precursor to the possibility of a treatment-free remission, and a quarter of patients achieve their goal of being potentially treatment-free over the course of their therapy. The long-term use of the second-generation TKIs has been associated with adverse events like pleural effusions or GI and CV adverse events. In keeping with the general evolution of therapies in cancer like chronic myeloid leukemia, the goal now is to treat patients with treatments that are both efficacious as well as well-tolerated.
To that end, Scemblix or asciminib was designed explicitly to offer potentially enhanced efficacy, as well as minimizing the off-target effects that are the consequence of both first and second-generation TKIs, targeting multiple kinases as they aim to engage with the ATP- binding site on the BCR-ABL protein, while Scemblix targets the myristoyl pocket specifically. The great results in our phase III ASCEMBL study, where Scemblix was studied in the third-line plus setting with more than doubling of the MMR response, as well as more than a 4x lowering of patients who needed to discontinue therapy compared to bosutinib, gave us the confidence to evaluate this therapy further in an earlier line setting. The great results of ASCEMBL have translated over time into a very rapid uptake in the third-line setting in clinical practice, with approvals now in more than 70 countries around the world.
Scemblix having a leading share in both new starts and total prescriptions in the third-line plus setting. Significant use across both academic centers and the community setting, and it was this data that then led to the design of a very specific study to evaluate a role for Scemblix in the first-line setting, which is the results that we will discuss today. This is entirely in keeping with our strategy in oncology, as we have previously discussed, where we aim to bring efficacious therapies to patients in earlier lines of therapy and make them available to larger sets of populations. So with that, let me hand it over to Jeff Legos, our Head of Oncology Development, to share with you the amazing data that we presented earlier on Friday. Jeff?
Thank you, Shreeram. Hello, everyone. Good evening. I have the honor and privilege of actually sharing the results from our landmark phase III study with you on behalf of our investigators, the patients we serve, an incredible international study team, and on behalf of all of Novartis.
... It's my incredible honor and privilege to be here, you know, as part of a long-standing legacy that Novartis has had on continuing to innovate new therapeutics for patients with CML. As we think about the ASC4FIRST trial design, I want to just remind everybody of the current CML landscape. There are a number of approved medicines in this space, of which Novartis has contributed to several of those. And if we look at current treatment practices, we see roughly about 50% of patients are currently treated with first-generation imatinib, and then the other 50% with any one of the second-generation TKIs. Despite the number of approved standards of care, we recognize that a majority of CML patients do not reach their overall efficacy goals, and we believe there are several contributing factors to this.
Some of them highlighted here on the slide, that early switches because of safety or tolerability, or the inability to reach their overall molecular goal. Now, while we recognize that the long-term goal for patients is cure or treatment-free remission, we believe it's very important that having faster and deeper molecular responses and the ability for patients to remain on therapy at full dose intensity are important contributors in order for patients to enable them to reach these long-term treatment goals. And that's how we actually designed the ASC4FIRST trial. You know, it was designed on the basis of the current clinical practice. In particular, there's a few important design features that I want to highlight for you here. First was the patient population, which is newly diagnosed patients with chronic phase CML that had not received a prior TKI.
As reflected in clinical practice, physicians often make a choice based on a patient's overall well-being and certain age and other demographic factors. That's why we had put this pre-randomization criteria into the study design, where patients were previously identified in consultation, you know, with their physician, to be randomized to either imatinib or one of the second-generation TKIs. 405 patients were randomized 1:1 to either Scemblix or any one of investigator-selected TKIs. The primary endpoints was a major molecular response rate at week 48, comparing Scemblix to the investigator-selected TKIs, and the other primary endpoint was a major molecular response, comparing Scemblix specifically to imatinib patients. You see the other secondary endpoints also listed on the slide there.
If we look at the overall baseline characteristics, you see that they were very similar across treatment arms and truly representative of the intended patient population of newly diagnosed CML. Just to orient you to the table, if you're looking for comparisons here, you would compare column one to column three and column two to column four. Of note, and as expected, if you look at the boxes highlighted in red, patients who were pre-identified to be randomized to the imatinib stratum often are more elderly, with a higher proportion of patients aged 65 or greater or had increased cardiovascular risk, as also highlighted here in the red box. If we look at the overall primary endpoint comparing Scemblix to investigator-selected TKIs, as you see here, a major molecular response rate of nearly 20% was achieved at week 48, comparing Scemblix to the overall investigator-selected TKIs.
If you look similarly, also at week 48, comparing Scemblix to imatinib in the imatinib strata, you see a very clinically meaningful and also highly statistically significant difference of almost 30% in the major molecular response rate. This benefit was consistent across all pre-specified groups based on demographics and/or known prognostic clinical factors, and you see a very consistent benefit regardless of baseline clinical criteria. If we also look at other important factors that contribute to a potentially, you know, long-term treatment-free remission or ultimately cure, speed and depth of response are very important. If you look at the left here, you see that Scemblix had reduced the median time to a major molecular response by about a third, so roughly three months sooner than the median time on the investigator-selected TKIs.
If you look on the right-hand side of the slide, you see a nearly doubling of the deep molecular response, either MR 4.0 or MR 4.5 log order drop in the BCR-ABL gene. If you also look in the second strata, comparing Scemblix to the overall imatinib, you see a very consistent pattern of these earlier and sooner median times to a major molecular response, here occurring in half the time compared to imatinib and a more than doubling in the deep molecular response at MR 4 and MR 4.5. If we look at one of our secondary endpoints, the comparison of Scemblix to the second-generation TKIs, here you see that Scemblix produced a numerically higher major molecular response rate, earlier achievement of that major molecular response, as well as deeper responses reflected in all three panels here.
Now, shifting to safety, which also is very important to the overall benefit that patients could expect to achieve over the long run. As you see on the left-hand panel, Scemblix was able to demonstrate fewer Grade 3 or higher adverse events versus all investigator-selected TKIs. And if you look on the right-hand side of the slide, there was not only fewer adverse events leading to discontinuation. You also see that there's fewer adverse events leading to actual drug dose adjustment or drug interruption. All of these factors, we believe, are, are important in order to maintain that dose intensity for the fastest and deepest molecular response, which again, could enable a long-term treatment-free remission or ultimately functional cure.
Further building upon the safety of the profile, as showed at ASCO, the overall rates of hematologic toxicities, either in incidence or severity, were lower for Scemblix-treated patients relative to the investigator-selected TKIs. And if you look at some of the non-hematologic adverse events that traditionally impact a patient's quality of life, I've highlighted a few here that tend to be most bothersome for patients. And as you could see, diarrhea and rash, some of the constitutional symptoms, and also nausea are lower compared to either of the investigator-selected TKIs. And if you look at some of the most well-known, well-established adverse events on some of the first and second-generation TKIs, you also see that muscle spasms and edema rates are lower for patients who were treated with Scemblix in this trial. So in summary, Scemblix had demonstrated superior efficacy with a favorable and safety tolerability profile.
In particular, the data that we presented and highlighted demonstrated that Scemblix had superior major molecular response rates relative to the investigator-selected TKIs, and also relative to imatinib alone. These results were consistent across all baseline demographic and prognostic subgroups. We also were able to highlight that Scemblix resulted in earlier and deeper major molecular responses. If we look at the secondary endpoints, this improvement in major molecular response rate, the earlier rate and time to median major molecular response, as well as the depth of response, were also improved relative to the second-gen TKIs. If we look on the safety side of things, there was fewer Grade 3 or higher adverse events. There was a lower rate of dose adjustments or a lower rate of discontinuations due to adverse events, approximately half the rate, you know, relative to the second-gen TKIs, as well as imatinib.
And lastly, there was overall lower rates and severity of the adverse events for Scemblix compared to the second-gen TKIs. So we believe this data positions Scemblix well to be a potential therapy of choice in newly diagnosed patients upon approval. If we also look at the overall recognition of this data that was not only received at this important ASCO event, but as well as other, you know, other scientific institutions, as well as regulatory agencies, it was clear, as highlighted here at ASCO, as part of the press congress, that less than 1% of abstracts received this designation. It's highlighted as one of the best 6 abstracts coming up as part of the encore presentation at the European Hematology Association.
The data was published simultaneously in the very prestigious New England Journal of Medicine, and thus far, our interactions with the regulatory agencies, such as the FDA, have resulted in the following. On the basis of sharing this frontline data in newly diagnosed patients with the FDA, we have been granted Breakthrough Therapy designation. This is not the first Breakthrough Therapy Designation for Scemblix. In fact, we've received two prior Breakthrough Therapy Designations, the first on the basis of the third-line data that Shreeram had highlighted earlier, and the second on the very important data showing the efficacy of Scemblix in patients with the T315I mutation, the very well-known and well-established main gatekeeper ATP mutation. Then lastly, in terms of our regulatory progress overall, we have actually completed the process or the package for the FDA submission. It is being reviewed under Real-Time Oncology Review.
Then lastly, we will continue our global submissions planned in the second half of 2024 and into 2025. With that, I'd like to invite my good friend and colleague, Reshema, up.
Good evening, everyone, and hello to those who are joining us in Europe. My name is Reshema Kemps-Polanco, and I am the Chief Commercial Officer for Novartis U.S. It is my great pleasure to talk to you just for a few minutes about our commercial opportunity, as well as what we believe to be the critical success factors for a successful launch in establishing Scemblix as a new standard of care in the first-line setting. In terms of what we believe is important in terms of creating an opportunity for this medicine, one, it's important that we have a very clear and differentiated clinical profile. The second one is having a proven track record in commercial execution, particularly in this space. And the third one is a sizable addressable patient population.
So let me just start with what Jeff has talked about, and I won't repeat what he said because he detailed the data, beautifully. I will just tell you, in my own experience, in being in this area, and I will tell you a little bit about my background. About a decade ago, I actually led the Gleevec and the Tasigna portfolio at Novartis, so have been with this space for a very long time.... What we know in talking to physicians, particularly in the community, is that historically, this has been an either/or story, meaning that based on the patient's characteristics, as you heard, comorbidities, age, they're trading off either efficacy or they're looking at the tolerability profile.
What we believe that, Scemblix will fundamentally be able to do in the first-line setting is to simplify treatment for physicians, in that they will be able to have an and versus the either/or, and that this will be, suitable for a broader segment of patients. And so, when we think about the commercial execution and the proven track record that we've had in the CML space, a long legacy, as you know, thinking about Gleevec and then, the introduction of Tasigna, when we look at the launch of, Scemblix in the third-line setting, we are seeing here continued growth, year-over-year growth worldwide of 83%. Also, when you think about, look at the U.S., we're seeing exponential growth in new writers, and that is continuing.
What has really pleased us is the adoption of this medicine in the third-line setting, where Scemblix is the market share leader and continues to see great momentum in this space. So going to the sizable addressable patient population, we know that in the first-line setting, there's nearly three times as many patients from an incidence standpoint, for us, to be able to address with this medicine. And we know that there is a clear unmet need, and we'll talk about the patient specifically in just a moment. Also importantly is the long history we've had with relationships with these physicians, with the hematologists. In the United States, there are about 10,000 hematologists, and we cover about 90% of them today.
But what's really important to note is that there are about 3,600 of them that really drive the overall CML prescribing. They're really CML specialists, and they're responsible for about 75% of the total first-line CML volume. And we know that about 20% of them have had experience with Scemblix in the third line, and so we feel that overall, we are well positioned to be able to really drive clinical conviction with Scemblix in the front-line setting once the medicine is approved. And so what do we believe are the critical success factors for a successful launch? And this is really double-clicking on our commercial execution. One is empowering and activating patients. The second is really making sure that they have broad access to the medicine. And third, ensuring that physicians are ready to prescribe.
And again, given our long track record in this space, we are very clear around the behaviors of the physicians. Who do we believe are we fast off the block in terms of adopting this medicine very early once approved? And so we'll, we'll spend some time talking about that. But then going back to the patients, one of the things that we've learned in addition to the unmet need, which I think has been detailed very nicely, is really around how do you really amplify the patient's voice? And what we know about these patients is as they become more educated, they certainly become more empowered. And we see this as they-- unfortunately, as they progress, and they go to a second-line treatment and a third-line treatment.
The job to be done here for us as a company is to bring that amplification up earlier in the front-line setting. As you can imagine, when a patient is diagnosed with cancer, it is often a surprise, and it is devastating for them, and they don't always have the education at the time of diagnosis, in between the time they're diagnosed and when the medicine is prescribed. And so what we are looking to do is to bring that amplification earlier in between that, well, I would say that sweet spot from where they need to know about Scemblix and what it can offer for them, so that they can have a, a good dialogue with their physicians, an informed dialogue, and really participate in shared decision-making, not only in second and third line, but also in the front-line setting.
And then also thinking about access to the medicine, which is incredibly important. I will say this is a managed category, but this is not new news. It's been a managed category for over a decade. And we know that 40% of covered lives are under management, either with a prior authorization or a step edit. In addition, the landscape will change, and we expect to see further genericization in this space over the next 12-18 months. Now, having said all of that, what we also know about oncology and hematologists is that where there is strong clinical conviction, we know that physicians are able to appeal, and they are able to advocate with payers to ensure access to meaningful medicines for their patients.
And then the other thing I believe is also an important opportunity for us is that we expect and we see less competitive intensity versus some of the other categories that we tend to work in in the oncology setting and even outside of oncology. And so we think these things offset, you know, some of the, the genericization and that we expect over time. And then making sure also that we are really bringing our I would—what I would say is a best-in-class capability around patient services to help patients navigate out-of-pocket costs, onboarding, as well as adherence, because importantly, these patients, this is chronic therapy, and they're on for a very long time. And so we think that these will be important.
And then last, this is really around how do we ensure that physicians are ready to prescribe? We've learned a lot about, the physicians, and I really want to double-click here on the 3,600 physicians that I talked about, who really drive the 75% of the first-line prescribing. And so if you look at the first two rows there, these are the physicians who we believe will be the earliest adopters of the medicine. I'll start with the first one, where we, refer to them as aggressive treaters, which we believe is a good thing when it comes to cancer. These physicians have mainly adopted second-generation TKIs, and they, prescribe very little, of imatinib today.
They represent about 20% of the total first-line volume, and we believe that Scemblix's profile will be well positioned for these physicians, given the fact that we see deeper molecular responses, faster major molecular responses, as well as the notable safety and tolerability profile. Secondly, and this is, I would say, a really important group, is what we call splitters. And this is where I get back to the either/or scenario that I talked about before. These physicians are pretty much equally using imatinib as well as a second-generation TKI. In a way, they are triaging patients based on if the patient is older, if the patient has a history of cardiovascular disease, we tend to see those patients if they're seen as having lower risk, they tend to go on imatinib.
If the patient is younger, we start to see those physicians gear more towards the second-generation TKI. And what we believe is because they do value efficacy and they also value a favorable safety and tolerability profile, that Scemblix will become the "and" for them and simplify treatment, particularly in the community setting. And so we believe we'll be well positioned there. I do want to say a few words about the imatinib loyalist, and I think this is going to take a little bit more time. Because if you think about it, even with the introduction of the second-generation TKIs, the majority of the prescribing continues to be with imatinib.
And so while we believe that, eventually we can convince a portion of these doctors that Scemblix is a great option for their patients, we believe that this will be a much slower ramp for us, more in the long tail, I would say. And in closing, I would say we remain confident in the profile of Scemblix.
The commercial organization is incredibly excited about the impending, the upcoming approval, and we believe that all of these things are true in terms of Scemblix becoming a catalyst and a growth driver for years to come for the company because of the differentiated clinical profile, our strong commercial readiness and proven ability to execute in this space, in the space of CML, and notably, a long patent protection outwards of 2035, and exclusion will be expected from the IRA, given its orphan disease status. For all of these reasons that you have heard from myself and my colleagues, we believe... I've been reading your models, by the way, and your reports. We believe that this medicine will, at the least, achieve $3 billion in peak sales worldwide across lines.
And of course, my role is to certainly do better than that, but I think that is a prudent, I think, position for the models, in terms of what I'm reading and what we believe for the, the medicine. So with that, I will now we'll move to Q&A, and I'll invite my colleagues back to the stage.
All right. Okay. Jeff?
Sure.
I think like Parag said, my ask is that we start in the room, maybe one question at a time. We will. I will intermittently go to the web for those that are asking questions on the web from Europe. Start with Emmanuel.
Thanks for taking the question. Emmanuel Papadakis from DB . A couple of questions on Scemblix, if I may. So you haven't disclosed the subgroup of the second-gen basket in terms of the data that was on Tasigna, but perhaps you can comment whether that was consistent with the data versus the second-gen basket overall, i.e., the dasatinib versus that-
Yeah, particular molecule.
And then a commercial question. I mean, Tasigna clearly showed it was superior as a second-gen to Gleevec. It has not replaced it effectively. Imatinib is still used, as you pointed out, by half the patients. Why would the situation be any different here? What are you going to do to drive uptake? Particularly, you made some comments, I think, in the Q1 call in regards to half the market that's Medicare skewed and biased to using imatinib. How are you going to change that practice? And then if I could ask separately on NATALEE, could you just give us an update on the regulatory status and your continued confidence on receiving a broad label that will encompass node-negative stage two patients and where we are in terms of timing a potential advisory committee? Thank you.
Yeah. Why don't you start with the first question on second-generation TKIs?
Yeah. Thanks, Emmanuel. So I think with, with respect to the data that I showed today, I have obviously presented data on the overall kind of, you know, investigator-selected second-gen TKIs, right? So collectively looking at, you know, kind of dasatinib, nilotinib, bosutinib, et cetera. As you can imagine, the majority of those patients were either split between sort of nilotinib and, and dasatinib. We haven't sort of broken down or presented detailed subgroup analyses by individual TKI, but based on my recollection, I don't recall there to be any major difference in terms of, you know, the benefits observed over, over the individuals.
With respect to, I think your second question relative to imatinib, just commenting on the clinical data itself, you know, as shown from a, you know, major molecular response rate, that nearly 30% delta in improvement in the major molecular response rate, we believe is very, very clinically meaningful. If I think back to the hypothesis we would have had at the start of the trial, and in fact, that we did have, right? Our expectation in general was probably going to be that the safety and the tolerability would have likely been comparable to imatinib. So we were very pleasantly surprised and pleased, right, that the tolerability and safety was, in fact, you know, numerically better than what we see for imatinib.
I think, you know, Reshema, you talked about it very nicely, that we don't have to compromise on, you know, on efficacy or safety here. We believe that Scemblix can deliver both.
Reshema, do you want to add?
Sure, and, on the commercial question around, Tasigna and why do we believe that Scemblix will be any different? Well, I think first of all, we believe it's a fundamentally different clinical profile, as just detailed here in the clinical trial. And you made a note around, imatinib and its share. I'll speak specifically to the U.S. because that's the market that I oversee. The share of imatinib in the U.S. is about 40%, 38, something like that, and the rest of it is really split amongst the second-generation TKIs. And so we believe, based on the clinical profile of the superiority versus all of those standards of care, that it's very compelling based on, the major molecular responses as well as, the adverse event and tolerability profile.
Particularly for those physicians who are using imatinib, they do prioritize the safety and the tolerability profile. But again, I do think that they are likely not to be the first ones to adopt this medicine, but I do believe that we will get a, a portion of them to adopt it over time. Speaking on Tasigna, I believe that around both of the second-generation TKIs, when I think about Tasigna, dasatinib, reached about, I believe, a peak sales of close to $2 billion. And so when I think about Scemblix and its profile, I feel fairly confident in the $3 billion worldwide sales.
Emmanuel, you had a question on NATALEE. I think, I think we maintain our confidence in gaining a broad label. I think in terms of we continue to make progress, and I think what we've guided around timing in terms of a launch later in the second half of this year is what we're still guiding to.
Um-
Steve Scala from TD Cowen. tWO questions. First, you spoke about the remission potential of Scemblix. I'm just curious if Novartis will do a treat-to-remission trial in which treatment is stopped, similar to what you did with Tasigna many years ago. And then secondly, also a question on Kisqali: What is Novartis's latest intelligence as to whether an FDA ad com will be required to get the NATALEE data in the label? Thank you.
Yeah, I think maybe I'll start with the second one first, Steve. And I mean, at this point, we have no indications of needing an advisory committee. Jeff, do you want to take whether we will run a trial? I think we'll get the drug approved first and then...
Yeah, no, thanks. And I would fully agree, there, Shreeram. And maybe on your question, Steve, with respect to Scemblix, I think the next key data readout for the ongoing trial, which was part of the protocol-specified key secondary endpoint, is the 96-week data. And as soon as we have that data available, we would be presenting it at an upcoming medical congress. After that, we would obviously continue to follow these patients through landmark analyses, and when those patients actually would meet, you know, the pre-specified criteria for being eligible for treatment-free remission, you know, even within the current protocol, we could assess those long-term benefits. So we wouldn't plan on doing a separate study for that. We would look to this trial to answer that question.
Okay. Maybe I'll go there, to the right.
Hi, thanks. Emily Field from Barclays, I'll ask two. The first was, I know you said at least $3 billion, but I think at a prior conference this year, Vas had said that this class of medicine could be $3 billion-$5 billion. So maybe if you could comment, you know, sort of on that delta and what could push beyond $3 billion towards maybe that upper bound. And then just on the safety, in the Scemblix arm, there were two cases of arterial occlusive events. You know, do you see that as being an issue in terms of having a superior tolerability profile to the second-gen TKIs?
Reshema, do you want to take the first?
Sure.
Jeff?
Sure. Hi, Emily. Thank you for the question. Great to see you. When I think about what could be the swing items, right, to that would cause Scemblix to do even better than the $3 billion, I think one, it is the speed of the genericization that we talked about and what happens there. I think second is the uptake amongst some of the segments that I talked about, for example, the imatinib segment and how fast the uptake ramps in the community. Because one thing to remember, when we think about launching, and I've learned this in my years in launching oncology drugs, when you launch in the back end of the disease, you tend to have a more ex-- if it's a meaningful medicine, of course, you tend to have a more exponential curve.
When you're launching in that earlier setting, you're actually going into the community where it takes a fair amount of education and KOL influence to really start to see that ramp up, and it tends to be a much more steady linear curve. And so, if that curve actually goes a bit faster because of the experience that we've seen in the third line and the overlapping of prescribers, then I think that can actually also cause us to do somewhat better.
You have the two arterial?
Yep.
Yeah. Thanks, Emily. And as you correctly pointed out, right, there were two cases of arterial occlusive events in the Scemblix arm. But as a reminder, there was also two cases in the comparator arm as well. So reflecting a 1% rate, you know, of AOEs in Scemblix and then a 2% rate in the two second-gen TKIs. We obviously recognize this is important adverse event of interest to continue to study, and we will continue to follow up and report any updated data at the 96-week readout.
Thanks. Peter from Citi. Two for Reshema. Maybe just on the friction points, where do you see most of the friction coming? Is it just physician acceptance of the data, the speed of onset, duration of effect, safety, or is it just simply the access question in terms of prior rules and step edits? And then secondly, apologies, pardon my ignorance. In terms of when you gave that guidance, I think $2 billion frontline, was that before or after you'd seen, the Scemblix data in the first-line setting?
So I'll take the first question around the friction points. I think the friction points potentially could be, you know, the prior authorizations and any types of step edits. Having said that, we have seen that, again, where there are strong clinical convictions, and you said it, right? We're making sure that physicians are educated, that physicians will advocate for their patients, and they're very adept at getting appeals approved. And again, this is not new to physicians because CML has been a managed category, and I think this is an important note. It's been a managed category for a very long time, and so they are indeed used to doing this.
And so I think, really it is our job to be done is really around convincing physicians, the clinical profile, those segments that I talked about, enabling the patient's voice. And then I feel very strongly that physicians will be able to access this medicine for patients, and that is our commitment.
Do you want to comment a little on the reactions we have had, I think, on how people have reacted to the data that we have presented, so far?
Yeah. Happy to, and I think consistent with, you know, some of the very favorable reports I've read on your behalf as well. I think there's been overwhelmingly positive sentiment among the physician investigator sort of community on the overall benefit for efficacy as well as the safety. And I think interestingly enough, for those that watched the, you know, the ASCO, there was an interesting question, you know, during the panel discussion around: "Are there any patients where you wouldn't consider using Scemblix?
Exactly.
It was interesting to hear that, you know, there was a very rare instance if a patient had a high cardiovascular risk, you know, they may consider using imatinib, but otherwise, they felt Scemblix could be a good opportunity for nearly all patients with newly diagnosed CML.
Yeah. Maybe I can just go back because there was a second part of the question-
Yes.
Right, around the $2 billion. I didn't forget. The $2 billion versus the $3 billion. So just to clarify there, the $3 billion is global or worldwide peak sales across all lines of therapy, and it may be, have been just in Parag, you'll have to, like, just make sure, keep me honest here, that the $2 billion wasn't encompassing, like, all lines of therapy, but that's the clarification.
Okay.
Thank you. It's Mark Purcell from Morgan Stanley. In terms of the debate between use of Scemblix first line versus selective escalation, could you help us understand the attitudes also outside the United States? I think your the points you made in the US are very clear, but given that the category is going to be almost entirely generic in the next 18 months, so I'd be interested to understand what payers outside the U.S. are thinking and how physicians think with selective escalation. And then, I guess, related, the mutational profile is quite different between Scemblix and the other second-gen TKIs. So I think there were eight mutations, all in myristoyl pocket, so it's not overlapping with the P- loop of the other second generation TKIs.
Could you help us understand the sort of pattern of this resistance? Is this occurring linearly? Is this something we should be concerned about, given the median follow-up is still only about 16 months?
... So we'll take the commercial question first, given that I'm mainly overseeing the commercial portfolio, inclusive oncology, in the U.S. But my colleague, Rodney Gillespie, is here from the international team, who is very close to this in the markets in ex-U.S. And so, Rodney, maybe you want to take this one.
Sure. Thanks for the question. I think you were asking specifically about the payers and how do they feel about the data. Obviously, we have really good use of Scemblix in third line. We continue to be the leader, the market leader across EU 5, Japan as well, so we are making really good progress. Obviously, in EU is where we tend to see the most challenge or questions in terms of how do you look versus standard of care in order to get reimbursement, and I think with our current data, the outlook is extremely positive.
However, we're also excited to make sure we have the 96-week data, which will give even more confidence, and that gives us real confidence that we will get approval, not just in terms of utilization in the private market, but key is making sure we get it approved by the different regulators as well. So we're confident based on the data. 96-week data is going to definitely show and allow us to get out. I think what we're looking at in Japan is extremely positive from... I've actually had a chance to visit Japan, talk to some of the providers as well, and they're excited and ready for this to be approved.
Jeff, do you want to comment on the mutation profile?
Thank you, Rodney.
Yeah. Mark, Mark, I'm happy to to address your, your second question. So obviously, we have a much deeper and better understanding around mechanisms of resistance of the first- and second-gen TKIs based on our over, you know, over two decades, you know, worth of experience, you know, from the basic science experiments all the way up through, through the clinical and, and commercial experience. Our understanding, you know, for Scemblix around the mechanisms of resistance is limited, right, to the data that was actually presented at, at ASCO, as well as other ongoing evidence generation trials. Specifically within the ASC4FIRST study, we have about a handful of cases. And as mentioned, you know, they're in the ASCO discussion. These all, you know, have been attributed to mutations in the myristoyl pocket. It is important that we continue to follow up these patients.
We will look for any, you know, mechanisms of resistance and the number of patients who actually lose their response between week 48 and week 96, and that'll be part of a subsequent discussion. I think the other point of note, which I think is very important, is even if someone does develop, you know, a mutation in the myristoyl pocket because of that unique binding site, that doesn't eliminate them from being a candidate from the original first- or second-gen TKI, so they could fall back to the current standards of care should it be needed.
Seamus Fernandez from Guggenheim Securities. So just a couple of quick questions. The first one is, as second-gen generics become available, what's your expectation for the maybe less of the imatinib loyalists, but just sort of the progression of moving those second-line agents forward in the treatment paradigm because their efficacy has clearly been demonstrated in the ENESTnd studies, as well as the DASISION studies, to be clearly superior on the basis of efficacy. But it appears that the imatinib loyalists live by the mantra of, you know, these patients are on lifelong therapy, so we're avoiding cardiovascular events. So we're kind of reserving therapy for that kind of to limit that risk of cardiovascular events.
I struggle to understand why that would be any different if we were—if we're already seeing two events or 2% of patients actually seeing cardiovascular events in the Scemblix study, which may be half of the second-gen agents. But just wondering how you see that sort of push and pull happening. And also, we're seeing lower doses being used of the second-gen agents more frequently, showing durable efficacy. It just seems like there's a lot of pushes and pulls, and when we look at the NCCN guidelines, there's definitely, I think, a challenge for Scemblix to overcome. So just trying to get a better understanding of some of those pushes and pulls. Thanks.
Jeff, do you want to take that?
Yeah, maybe I'll start from a clinical perspective, and then Reshema, feel free to comment. I think, Seamus, from the points that you've made, right, I think clearly, you know, two cases in each arm, it is a small number of cases and, you know, they may be confounded by any, you know, prior cardiac history. I think because the number of cases are small and the length of follow-up, it's probably too premature to come to any conclusions at this point in time. I think very important that we continue to monitor this over longer periods of time, as we will do in this trial.
We also have about another six or so ongoing, you know, phase II and phase III evidence generation trials ongoing for Scemblix, and we will continue to look, you know, at any, you know, cardiovascular risk or, you know, arterial occlusive events in those trials as well.
Yeah, and I would just follow on and make the point that in the U.S., 60% of patients in a first-line setting do not start on imatinib. And so I think that represents a sizable opportunity as well. In terms of, as you're talking about physicians who may want to start on imatinib and then add the second-generation TKI, it's actually more the majority are actually starting on one of the second-generation TKIs already. And so we think that bears well for the positioning of Scemblix. And of course, the 40% who are going on imatinib, we do think a portion of them could be, right, because of how you're thinking about it in terms of the cardioprotectiveness that they may perceive with imatinib in older populations.
But we also believe there's a group of them that are really just trying to optimize for adverse events and tolerability over time over a chronic therapy. And if that's what they're trying to do, and we believe a good portion of them are, then Scemblix will be well positioned there.
Okay. Pete? There it is, okay.
Thank you. Peter Welford at Jefferies. A few questions. Firstly, just, do you have quality of life data from, from this study, or will the quality of life data be available? And I guess similarly, from the U.S. perspective, is there any long-term follow-up data of this that you think would be useful to the payers? There were end payer discussions that you mentioned of the ex-U.S. From a U.S. perspective, is this data really all that's needed from this point of view now to go to the payers?
Equally then, but when we think about 2025, is it too late to start discussions for the 2025 contracting period, given obviously you won't have the approval or well, you will have the approval in a relatively expedited fashion, but just thinking from the point of view of getting on the 2025, how should we think about potentially the access you may have with payers going into next year? And finally, then, just coming back to the ex-U.S. markets, Japan was mentioned. Are there any other markets we should think of are likely to be meaningful realistically in the first line, given, given this drug and given obviously, what we know about what's going on with second generation, generation going generic?
If only the quality of life, and then Reshema, you-
Mm-hmm.
Yeah. So Peter, on your first question with respect to quality of life, so it will be presented from this trial at an upcoming medical congress. In addition to the quality of life data from ASC4FIRST, I'm sure you're already aware, we have a sister trial ongoing called ASC4START. Right? This is a trial with a very similar design, you know, with a key focus on quality of life as the primary endpoint that drove our sample size calculations, as well as the direct comparisons to a certain subset of the second-gen TKIs. So that trial's ongoing. It's enrolling incredibly well, incredibly fast, and we look forward to having the results, you know, presented at a congress, probably in a future year.
Then in terms of the question around what will be compelling for the payers. So first of all, obviously, a positive trial. Also, the publication is very important and FDA approval, and at a certain point, we would expect to be, hope to be, included also in the NCCN guidelines. And that's a very important piece as well for payers, from ensuring that they are supporting the best clinical outcomes for patients. And I also believe that having the long-term follow-up will also be important. But in terms of getting the coverage, I'm not too concerned about that.
It's more around what steps or prior authorizations may be put into place and really understanding and educating physicians about what they need to do to appeal that, which again, they're used to doing that in hematology as well as oncology. And so I guess I would say while we see step edits and prior authorizations across certain categories, I see prostate cancer, breast cancer, as well as certain leukemias, what we don't necessarily see is a significant amount of access suppression, and that is representative of, yes, the policies may be there, the prior authorizations, but we also know that physicians are adept at providing the right clinical data to support really getting access for the patient.
Peter, maybe, maybe two other points, which I forgot to mention. I recognize I highlighted maybe some of the bookends, you know, either the 48-week QOL data that were presented or data from a subsequent trial. I think two important points that are, you know, really key takeaways here. I think at the 96-week data cutoff, we will present a very extensive set of quality of life analyses, everything from, you know, the quality of life instruments to time to treatment discontinuation due to adverse events, et cetera. I think that will be very important as well with respect to payers. I think the second point would be just the investigator feedback that we continue to hear.
You know, for those, you know, physicians whose patients were randomized to receive Scemblix, they clearly report that patients are doing well and feeling better, right? So I think although it's not numerically quantified as of yet, I think that's a very important proxy for us.
Yeah, I think for us, what's been very exciting is the fact that it's the end conversation that Reshema had, that we're seeing better efficacy and combined with the ability to stay on the drug as required because of its tolerability and safety, is giving us the enthusiasm about expecting the potential to actually have patients stay on the drug long enough to be able to then achieve that ultimate goal of deep responses that make them candidates. That's still to come.
Yeah
... but I think that's at the heart of all of our-
Yeah
... enthusiasm. Rodney, you want to talk about the-
Yeah. Thank you, Peter, for the question. The other market I think which would be important is China, right? And we're working towards our submission for China, as we speak, and hopefully we will have approval in mid- to late 2025. And then, of course, we would hopeful-- be very hopeful that we get an RDL, which is critical in terms of utilization. If it's not in early 2026 in terms of having that designation, then it would be probably 2027 before we start to see significant uptake. But of course, China represents, you know, probably about 33% of what we would see coming out of the, the EU five as well. So a really important market for us.
Okay. Any final questions? Parag, do you have anybody on the web?
No.
Okay.
All right.
All right. Emmanuel, last one?
Maybe, maybe a couple of other topics. It's being reported you've discontinued your KRAS program. I'm not sure whether I've been misinformed. Perhaps you can give us an update. Pluvicto, can you give us an update on the status of regulatory engagement around the AOEs data in PSMAfore?
Yeah, sure. Sure.
Are you taking questions on pelabresib yet?
Go ahead, finish.
pelabresib, are you commenting or not?
We can. Just want to take one off the other.
There was a fairly skeptical discussion and take on the oral around who should receive combinatorial therapy up front. Perhaps you could give us your thoughts.
Maybe, maybe I'll take pelabresib first, and I'll say that, you know, having the transaction now having closed and us having complete direct access to all of the patient-level data, as well as the investigators and the regulatory interactions around safety, that, in a manner, we now are looking to understand the data in its full spectrum, and we'll give you further guidance on our thoughts once we've completed that assessment. I think on PSMAfore, we are on track, as we have said, for filing with our third interim analysis. That remains as planned. And then your first question was-
I could comment on KRAS. I think some of you may have seen that we have routinely, you know, reviewed the strategy of our programs and have taken the decision not to further progress JDQ443 or opnurasib in patients with non-small cell lung cancer. It was taken simply because of the number of available options that patients have in this space with the G12C mutation. And a very important point, none of that decision was because of any safety or efficacy concerns. It was simply on the basis of the strategic review, as well as other priority choices that we have within our pipeline and portfolio to focus on.
Okay. All right. I think with that, thank you very much for your attention. Thank you for your questions. Thank you for coming, and we look forward to catching up with you in the break. Parag, we're mingling now, right?
Yes.
Yeah. All right. Thank you. Thanks, everyone, for coming.