Novartis has projected robust sales for its new chronic myeloid leukemia (CML) treatment, Scemblix, during its latest earnings call. The pharmaceutical giant anticipates at least $3 billion in peak sales globally, buoyed by Scemblix's superior efficacy and favorable safety profile compared to other tyrosine kinase inhibitors (TKIs). The drug has already garnered breakthrough therapy designation from the FDA and completed the submission process for approval. Novartis plans to activate patients and physicians to ensure broad access and successful launch of the medicine.
Key Takeaways
- Scemblix demonstrated superior efficacy in Phase 3 ASC4FIRST study with nearly 20% major molecular response rate at week 48.
- The drug showed favorable safety, fewer adverse events, and lower rates of hematologic toxicities compared to other TKIs.
- Novartis targets a sizable patient population and expects Scemblix to reach peak sales of at least $3 billion worldwide.
- Three key physician groups identified for early adoption: aggressive treaters, splitters, and imatinib loyalists.
- The company remains confident despite potential challenges like generic competition and drug access barriers.
Company Outlook
- Novartis expects a successful launch of Scemblix by activating patients, securing broad access, and preparing physicians.
- The company is optimistic about gaining broad label for its medicine NATALEE and is preparing for potential advisory committee meetings.
Bearish Highlights
- Speed of genericization and uptake across different physician segments could impact Scemblix's performance.
- Arterial occlusive events were reported in the Scemblix arm, but also in the comparator arm.
- Potential friction points include prior authorizations and step edits for drug access.
Bullish Highlights
- Scemblix's superior efficacy and safety profile is expected to appeal to aggressive treaters and splitters among physicians.
- The company is confident in Scemblix's ability to secure coverage and inclusion in NCCN guidelines.
- China is viewed as an important market, with approval and significant uptake anticipated by 2027.
Misses
- The company announced the discontinuation of their KRAS program due to other available options for patients.
Q&A Highlights
- Updated data on arterial occlusive events and cardiovascular risks are being closely monitored.
- Long-term follow-up data and quality-of-life findings from trials are forthcoming and important for payers.
- Regulatory engagement updates provided for OS status in PSMAfore and further guidance on opnurasib is pending after data assessment.
Novartis' earnings call shed light on the potential of Scemblix to become a key player in the CML treatment landscape. With a strategic focus on patient and physician engagement and a confident outlook on overcoming market challenges, Novartis appears poised to cement its position in the oncology sector.
InvestingPro Insights
Novartis' bullish outlook on Scemblix is supported by strong fundamental metrics, as reflected in the latest data from InvestingPro. The company's adjusted market capitalization stands at a robust $214.87 billion, indicating a significant presence in the pharmaceutical industry. With a Price to Earnings (P/E) ratio of 19.22 for the last twelve months as of Q1 2024, Novartis trades at a valuation that reflects investor confidence in its earnings potential, particularly as it relates to the anticipated success of Scemblix.
InvestingPro Tips suggest that Novartis' Gross Profit Margin of 74.61% for the same period is a testament to the company's operational efficiency and ability to maintain profitability despite market fluctuations. This is an essential factor for investors considering the long-term viability of Novartis as it rolls out new treatments like Scemblix.
Furthermore, with a Revenue Growth of 14.48% for the last twelve months as of Q1 2024, Novartis demonstrates a strong capacity for increasing its sales, which is critical as it seeks to achieve the projected $3 billion in peak sales for Scemblix. Investors should note that InvestingPro offers additional insights on Novartis, with PRONEWS24 providing an extra 10% off a yearly or biyearly Pro and Pro+ subscription. Explore these tips to gain a more comprehensive understanding of Novartis' market position and future prospects.
Full transcript - Novartis AG (SIX:NOVN) ADS (NVS) Q1 2023:
Parag Mahanti: Hi, everyone. 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 3 ASC4FIRST study data for Scemblix in newly diagnosed CMO patients. But first, a couple of housekeeping notes. We will start with the presentation. The slides are uploaded on the website, followed by 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 to everyone's questions. Our aim is to wrap up the presentation and Q&A by about 7:00 PM. 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 forms 20-F and its most recently 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.
Shreeram Aradhye: Thank you, Parag. Good evening to everybody. Hello to those joining us on the web in Europe. 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 Glivec 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 Glivec, 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. And 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 they need to be conveyed -- 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're first being 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. And 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. And 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 asciminib targets the myristoyl pocket specifically. The great results in our Phase 3 ASC4FIRST 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 Scemblix have translated over time into a very rapid update 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, Head of Oncology Development to share with you the amazing data that we presented earlier on Friday. Jeff?
Jeff Legos: Thank you, Shreeram. Hello, everyone. Good evening. I have the honor and privilege of actually sharing the results from our landmark Phase 3 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, as part of a longstanding 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. 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. And that's why we had put this pre randomization criteria into the study design where patients were previously identified in consultation with their physician to be randomized to either imatinib or one of second generation TKIs. 405 patients were randomized one-to-one to either Scemblix or any one of investigator selected TKIs. The primary endpoint 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 end points 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. And if you look similarly also at week 48 comparing Scemblix to imatinib in the imatinib stratum, 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 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. And if you look on the right-hand side of the slide, 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 stratum 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 dose adjustment or drug interruption. All of these factors, we believe, 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 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. And if we look at the secondary endpoints, this improvement in major molecular response rate, the earlier rates 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 rates 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 scientific institutions as well as regulatory agencies. It was clear as highlighted here at ASCO as part of the press congress that only one of less than 1% of abstracts receive this designation. It's highlighted as one of the best six abstracts coming up as part of the ENCORE presentation at the European Hematologic 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 1st 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. And 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. And then lastly, we will continue our global submissions planned in the second half of 2024 and into 2025. And with that, I'd like to invite my good friend and colleague, Reshema up.
Reshema Kemps-Polanco: So, 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., and 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. So, 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 and being in this in this area, and I will tell you a little bit about my background. About a decade ago, I actually led, the Glivec and the Tasigna portfolio at Novartis. So have been with this space, for a very long time. And 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 and that they will be able to have an end 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 Glivec and then the introduction of the Tasigna. When we look at the launch of the 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. And, 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. And 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 incident 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 patients 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 frontline 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 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 frontline 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 for where they need to know about Scemblix and what it can offer for them so that they can have, a good dialogue with their physicians and informed dialogue and really participate in shared decision-making, not only in second and third line, but also in the frontline 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 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 generalization, in this space over the next 12 to 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 a meaningful medicine 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 put, tend to work in the oncology setting and even outside of oncology. And so, we think these things offset, some of the genericization and that we expect, over time. And then, making sure also that we are really bringing our, 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 in 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 that 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. And so, 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 the 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 end 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 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. And 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 in 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 medicine. So, with that, I will, now we'll move to Q&A, and I'll invite my colleagues back to the stage.
A - Shreeram Aradhye: 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.
Emmanuel Papadakis: Thanks for taking the question. Emmanuel Papadakis from DB. 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., Tasigna versus that particular molecule? And then commercial question, I mean, Tasigna clearly showed it was superior as a second gen Glivec. It has not placed it effectively. Imagine if it's still used, as you pointed out by half of 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 Q1 call in regards to half a market that's Medicare skewed and biased using imatinib, how you're 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 will encompass node-negative Stage 2 patients and where we are in terms of timing of potential advisory committee?
Shreeram Aradhye: Why don't you start with the first question on second gen in TKIs?
Jeff Legos: Yes. Thanks, Emmanuel. So, I think with respect to the data that I showed today, I have obviously presented data on the overall kind of investigator selected second gen TKIs, right? So collectively looking at kind of dasatinib, nilotinib, bosutinib, et cetera. As you could imagine, the majority of those patients were either split between sort of nilotinib 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 the benefits observed over the individuals. With respect to I think your second question relative to imatinib, just commenting on the clinical data itself as shown from a 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. Our expectation in general was probably going to be that the safety and the tolerability imatinib. So, we were very pleasantly surprised and pleased, right, that the tolerability and safety was in fact numerically better than what we see for imatinib. So, I think, Reshema, you talked about it very nicely that we don't have to compromise on efficacy or safety here. We believe that Scemblix can deliver both.
Shreeram Aradhye: Would you mind more of that?
Reshema Kemps-Polanco: 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 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 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.
Shreeram Aradhye: And, Emmanuel, you had a question on NATALEE. 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.
Steve Scala: Steve Scala from Cowen & Company -- 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' latest intelligence as to whether an FDA Adcom will be required to get the NATALEE data in the label?
Shreeram Aradhye: Yes. I think maybe I'll start with the second one first, Steve. And, I mean, at this point, we have no indications of leading 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…
Jeff Legos: Yes. 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 the prespecified criteria for being eligible for treatment free remission, 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.
Shreeram Aradhye: Maybe I'll go there to the right.
Emily Field: Emily Field from Barclays (LON:BARC). I'll ask two. The first was I know you said at least 3 billion, but I think at a prior conference this year, Novartis had said that this class of medicine could be 3 billion to 5 billion. So maybe if you could comment, 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. Do you see that as being an issue in terms of having a superior tolerability profile to the second gen TKI?
Shreeram Aradhye: Reshema, do you want to take the first question?
Reshema Kemps-Polanco: Sure. Hi, Emily. Thank you for the question. Good 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 in the 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 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, in 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.
Shreeram Aradhye: Jeff, do you want to add?
Jeff Legos: Yes. 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 well. So, reflecting a 1% rate in AOEs and Scemblix and then a 2% rate in the 2G TKI arm. We obviously recognize this is an 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.
Unidentified Analyst: [indiscernible] 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 axis question in terms of prior authorization step edits? And then secondly, apologies, pardon my ignorance, in terms of when you gave that guidance, I think 2 billion frontlines. Was that before or after you've seen the Scemblix data in the first line setting?
Reshema Kemps-Polanco: So, I'll take the first question around the friction points. I think the friction points potentially could be the prior authorizations and any types of step edits. Having said that, we have seen that where -- again, where there's 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. 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.
Shreeram Aradhye: Jeff, 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?
Jeff Legos: Yes. Happy to. And I think consistent with 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 a safety. And the interestingly enough those that watch the ASCO, there is an interesting question during the panel discussion around, are there any patients where you wouldn't consider using Scemblix because those interesting to hear that those a very rare intensive of patient had a high cardiovascular risk. They may consider using imatinib, but otherwise they felt Scemblix could be a good opportunity for nearly all patients with newly diagnosed CML.
Reshema Kemps-Polanco: Yes. And maybe I can just go back because there was a second part of the question 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 have been just in Parag. You'll have to just make sure keep me honest here that the 2 billion wasn't encompassing like all lines of therapy, but that's the clarification.
Mark Purcell: It's Mark Purcell from Morgan Stanley (NYSE:MS). 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 points you made in the U.S. are very clear. But given the category is going to be almost entirely generic in the next 18 months, and so just to understand, what payers outside the U.S. are thinking and how physicians think with selective escalation? And then I guess related to mutational profile is quite different between Scemblix and the other second gen TKIs. So, I think there were eight mutations on the myristoyl pocket. So, it's non-overlapping with the P-loop of the other second generation TKIs. So, 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?
Reshema Kemps-Polanco: So, we'll take the commercial question first. Given that, I am 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.
Rodney Gillespie: 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 EU5, Japan as well. So, we are making really good progress. Obviously, an EU is where we tend to see the most challenge or questions in order to how do you look versus standard-of-care and where you 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 to talk to some of the providers as well, and they're excited and ready for this to be approved.
Shreeram Aradhye: Jeff, do you want to comment on the mutational profile?
Jeff Legos: Mark, I'm happy to address 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 two decades worth of experience from the basic science experiments all the way up through the clinical and commercial experience. Our understanding for Scemblix around the mechanisms of resistance is limited to the data that was actually presented 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, during the ASCO discussion, these all 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 mechanisms of resistance in the number of patients who actually 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 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 and second gen TKI. So, they can fall back to the current standards of care should it be needed.
Seamus Fernandez: Seamus Fernandez from Guggenheim Security. 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 [indiscernible] study as well as the [indiscernible] studies to be clearly superior on the basis of efficacy. But it appears that the imatinib loyalists live by the mantra of 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're already seeing two events or 2% of patients actually seeing cardiovascular events in the Scemblix study, which maybe 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 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.
Shreeram Aradhye: Jeff, do you want to take that?
Jeff Legos: Yes. 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 two cases in each arm. It is a small number of cases and they may be confounded by any prior cardiac history. I think because the number of cases are small in 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 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 Phase 2 and Phase 3 evidence generation trials ongoing for Scemblix and we will continue to look at any cardiovascular risk or arterial occlusive events in those trials as well.
Reshema Kemps-Polanco: Yes. And I would just follow on and make the point that in the U.S., 60% of patients in the 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 already physicians who may launch to imatinib and then at the second generation TKI. If actually more of the majority are actually starting on and 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 cardio protectiveness 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 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.
Peter Welford: Peter Welford of Jefferies. A few questions. Firstly, just do you have quality of life data from this study? 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 that you think will be useful to the payers the relative pay disclosure that you mentioned of the ex-U.S. From a U.S. perspective, is this data really all was 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 '25 contracting period given obviously you won't have the approval or 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 or likely to be meaningful realistically in first line given this drug, given obviously what we know about going to second generation going generic?
Shreeram Aradhye: Just only the quality of life and then Reshema you?
Jeff Legos: Yes. 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. This is a trial with a very similar design 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 trials ongoing and enrolling incredibly well, incredibly fast and we look forward to having the results presented at a congress probably in a future year.
Reshema Kemps-Polanco: And 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 at certain the 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 get prostate cancer, breast cancer as well as certain leukemias, what we don't necessarily see is a significant amount of axis 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.
Jeff Legos: And, Peter, maybe two other points which I forgot to mention. I recognize I highlighted maybe some of the bookings either the 48-week QoL data that we presented or data from a subsequent trial. I think two important points that are 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 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 for those 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.
Shreeram Aradhye: Yes. 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. We're not 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, but I think that's at the heart of all of our enthusiasm. Rodney, you want to talk about the…
Rodney Gillespie: Thank you, Peter, for the question. The other market, I think, which would be important is China, right. And we're working towards our solution for China as we speak. And hopefully, we will have approval in mid to late '25. And then, of course we would hopeful, a very hopeful that we get NRDL, which is critical in terms of utilization. If it's not in early '26 in terms of having that, designation, then it would be probably '27 before we start to see significant uptake. But of course, China represents probably about 33% of what we would see coming out of the EU5 as well. So, a really important market for us.
Shreeram Aradhye: Alright. Emmanuel, last one.
Emmanuel Papadakis: Maybe a couple of other topics. It's been reported you've discontinued your KRAS program. I'm not sure whether it's been misinformed. Perhaps you can give us an update. Pluvicto, can you give us an update on the status of regulatory engagement around the OS status in PSMAfore?
Shreeram Aradhye: Yes. Sure.
Emmanuel Papadakis: And are you taking questions on opnurasib yet?
Shreeram Aradhye: Go ahead. Finish.
Emmanuel Papadakis: Opnurasib, are you commenting or not?
Shreeram Aradhye: We can. Just want to take one off the other.
Emmanuel Papadakis: There was a fairly skeptical discussion take on the oral around who should receive combinatorial therapy upfront. Perhaps you could give us your thoughts.
Shreeram Aradhye: Maybe I'll take opnurasib first, and I'll say that 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 regulatory interactions run safety is that we now are looking to understand the data and 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…
Jeff Legos: On KRAS, I think some of you may have seen that we have routinely reviewed the strategy of our programs and have taken the decision not to further progress JDQ-443 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.
Shreeram Aradhye: 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. Alright, thanks everyone for coming.
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