Good morning and good afternoon and welcome to the Novartis Oncology Update. Please note that during the presentation, all participants will be in listen only mode and the conference is being recorded. There will be an opportunity to ask questions by pressing star and one at any time during the conference. A recording of the conference call, including the Q and A session, it will be available on our website shortly after the call ends. With that, I would like to hand over to Mr.
Samir Shah, Head of Investor Relations. Please go ahead, sir.
Thank you, and good morning and good afternoon, everybody. Thank you so much for taking the time to join us today. We appreciate it's a really busy time, especially today with the various investor related calls. It's my pleasure to have with us today as we go through the key highlights from ASCO. Suzanne Schaeffer, who is the President of Novartis Oncology Alice Shaw, Global Head of Translational Clinical Oncology at the Novartis Institute of Biomedical Research.
Sidney Daphna, who is the President of Radioligand Therapies that and Jeff Lagos, the Global Head of Oncology Development within Novartis. Before we start, I just wanted to go through the Safe Harbor statement. The information presented today contains forward looking statements that involve known and unknown risks, that the company's results may differ materially from any future results, performance or achievements company's Form 20F that the company's most recent quarterly results on Form 6 ks that respectively were filed with and furnished to that the U. S. Securities and Exchange Commission.
And with that, I'll hand across to Suzanne.
Thank you, Samir. And also from my side, welcome to this Novartis Oncology update. So moving to Slide 6. That Novartis is a leading company in the market. And over the past 5 years, we have made significant progress bringing 6 novel first in class therapies to patients and that together with 7 in market blockbusters has led to continuous growth for the business.
That we had sales of almost €15,000,000,000 last year and served 1,200,000 patients with our medicines globally. For Novartis Oncology, 2021 is a truly breakthrough year in terms of delivering transformative innovation. We are planning to submit 3 1st in class treatments for registration this year and also expecting 2 major readouts later that we have also a promising pipeline across our platforms, that And you will hear more about it over the course of this call. So moving to Slide 8. On Slide 8, you can see what makes our portfolio sorry, Ron Beck, sorry, Slide 7.
You can see what makes our portfolio really unique. We are the only company that is present in all four therapeutic platforms to treat cancer. We are present in targeted therapies, that we have a very strong balance sheet. And I believe that our portfolio gives us the unique opportunity to approach cancer with different therapeutic approaches as well as combine that we have a very strong performance in the U. S.
And the U. S. Market. So moving to the next slide. This year's ASCO is that we have presented more than 70 abstracts with new data across all 4 therapeutic platforms And within that, 9 oral presentations.
So moving to the next slide. Let me go through each platform and share the highlights that we presented at ASCO. So let me start with targeted therapies. At ASCO, we have presented the new data on Kis that KISCALI, our CDK4six inhibitor that is used to treat advanced breast cancer. We have the updated MONALISA III data confirming that Kisqali continues to show prolonged and consistent oral survival benefit with a median of 4.5 years, Kisqali demonstrated the longest overall survival in postmenopausal patients compared to other CDK4six inhibitors and is the only CDK4six with data in first line with full restaurant.
That I believe this data further strengthens Kisqali's differentiated profile and build on Kisqali's unprecedented overall survival benefit. That in addition, we are going into earlier lines of breast cancer with our NATALI study that is exploring Kisqali in the ATTRAN setting that in both intermediate and high risk populations and these populations represent around 70% of the Advan's early breast cancer patient population and there's a clear unmet medical need. So we are also excited about Arsimile, that we plan to submit in the U. S. And in EU in the first half of twenty twenty one.
That And we are also planning to start a trial in first line later this year. And looking ahead, we have a pipeline of combination ready molecules like that our SHP2 inhibitor, a BCRuff inhibitor and a KRAS G12C that we believe can be very competitive from both a combination strategy and also from time line perspectives. So moving to the next slide on our differentiated immunotherapies platform. That we presented data from RASIONAR-three zero two, which evaluated tislelizumab in second line is efgruinal squamous cell carcinoma, as we know, a difficult to treat cancer. And efficacy and safety of tislelizumab that the has been comparable to already marketed PD-one inhibitors in monotherapy in second line.
That these data will be used as the basis for FDA and EMA registration later this year. That we aim to establish tislelizumab in key indications where PD-1s are currently market, but also pursue novel combinations with our that our strategy in immuno oncology is also focused on advancing development of canakinumab in non small cell lung cancer that And also savatolimab, which could be the 1st immuno oncology therapy for MDS. And we are we're expecting readouts of these two assets later this year. Moving to the next slide, that our cell and gene therapeutic platforms. As pioneers of cell and gene therapies, we have made strong progress in manufacturing, the supply and commercialization of this transformative onetime treatment globally.
In partnership with now more than 3 that we have shipped more than 5,000 doses of Kymriah to patients globally. We have the largest global CAR T manufacturing footprint, are exploring new targets and are also advancing our next generation technology platform. At ASCO, that At ASCO, we presented the data from Elara's primary analysis of Kymriah in patients with relapsed All refractory follicular lymphoma that demonstrated consistent results with the interim analysis that you remember we presented at ASH 2020, these outcomes are particularly impressive given that Elara included high risk patients that we have a very strong number of patients who were heavily treated and relapsed early. We got orphan drug designation from that the FDA and are planning to file for this indication later this year. And moving to the next slide, last but not least, our that the Since the acquisition of AAA in 2018, we have built a strong global expertise in commercializing radioligand therapies as the only big pharmaceutical company.
That with Utafera and neuroendocrine tumors, we are working together with 400 centers treating more than 9,000 patients since launch. That And at ASCO, we have shared the data from NETA-one, which is the final analysis that has shown that Lutathera significantly reduced the risk of progression of death by 82% and demonstrated a clinically meaningful trend towards prolongation of OS by almost 12 months. These data support Utathera's position as a valuable precision medicine option that And on the broader radioligand development side, we are advancing 4 clinical programs that And around 11 preclinical and discovery programs to identify the next wave of radioligand therapies. That So we are very excited to share how we are building our leadership on rider like therapies. And I think there's nobody better to that, and Sidonie, so Sidonie, over to you.
Thank you so much. I have on Sussan RHC has a new year in Cancer Care. So why we think that you can see the on the slide you see on the left hand side with the same target here PSMA, you can perform that the Precision Imaging via PET scan to visualize tumors, offer additional insights on disease burden, diagnose or provide benchmarks for outcome. And on the right hand side, you can treat with the same target and a radioactive payload here with Lutetium-1 hundred and seventy seven. That the radiation is directly and specifically delivered to tumor cells only.
This is precision medicine
that we are at its best.
We go to Slide 15. We are the pioneers in this space with a significant lead in the 3 key areas: 1st, our manufacturing capabilities 2nd, our commercial expertise and third, our R and D approach. That these three pillars are the key fundamentals of our RLT platform. That on Slide 16, I show that we have established a high quality and on demand manufacturing footprint that we have broken down for you this complex process that we are in single steps to showcase this very efficient model that is vertically integrated. That from raw material to patient administration.
So time is of great essence, given the short shelf life of the product and our efficiency of this model was clearly shown during the pandemic that we didn't miss a single dose, and we can very proud of this team. And as we look ahead, most importantly, that for our future launches, we continue to invest by building a new site in Indianapolis, that we are expanding our existing sites. On the Slide 17, I come to the second that we are the only player in RLT with a globally commercialized product. That we learned a lot and gained a lot momentum with Utatera. In partnership with more than 400 centers, we were able to treat more than 9,000 patients since launch.
So based on these key learnings, we structured our customer facing teams in a demand and a delivery team with deep expertise that we are not stopping here and working hard to strengthen this new commercial model ahead of our future launches. We leverage our extended footprint to drive proper referrals that from community centers, but 2 third of our patients sit today to RLT centers. That on Slide 18, you see that we are facing a kind of complex the patient journey and approach in mCRPC and launching PSMA will require a multidisciplinary approach. That the primary decision makers in prostate cancer vary by disease state. You have the urologist, you have the med onc, the red onc, that the nuclear medicine physician, so therefore doubling down in medical education is key that the decision makers to educate the value of RLT and the requirements for adoption in their routine practice.
That on Slide 19, you can see that this approach will be supported by the expansion of our disease awareness campaign on PSMA and phenotypic precision medicine across all physician groups. It's important to note that stratifying patients for a specific targeted therapy is a well supported treatment approach by medical oncologists. That So PSMA is overexpressed in more than 80% of men with prostate cancer and can be detected via noninvasive PET scanning. That the FDA has approved recently 2 PSMA imaging agents. That on Slide 20, you can see our long term approach because we know and anticipating earlier lines of launches, we have to work together with our customers to increase capacity and extend our RLT the infrastructure.
Short term, we will be able to launch PSMA in existing sites by encouraging increased that infusion hours, increased infusion days and increased infusion shares, leveraging the best practice from our highly productive centers. That long term, we double we aim to double the contracted RLT that we will target community practices that currently have optimized Alphahot Labs that to expand to better leveraging the existing infrastructure and account expertise, which will be also a quick win. That to execute this approach, we need a strong cross functional team, commercial, medical, value and access and also our development teams that we are very excited to embark into this journey together with us, that we go to Slide 21. We are the pioneers and we strongly intend to maintain our leadership position expanding our pipeline. We will continue to invest into new technologies and assets, and we have shown this in the most recent months.
We have that in licensed a library of fab targeting agents, we invest into Actis Oncology for the development of alpha that the Novartis, we are collaborating with Atios to discover novel combinations of DNA damage response inhibitors. That So we are leveraging the RLT specific R and D advantages that exist that we are well positioned to accelerate our path to market. That On Slide 22, you can also see that we are growing our RLT pipeline. And this has great potential also to address a range of other solid tumors. So besides the lifecycle management for PSMA, in the first part of that we are investing in
the next slide, we are investing in the
next slide, we are investing in the next slide, we are investing in the next stages of development. That we have shown that we have the expertise to run these programs in RLT, and we are super confident that we maintain our leadership that we have generated a unique skill set that the company has a very strong experience in manufacturing, commercial and R and D and build a sustainable platform. That new entrants to the field will need to establish access to raw materials and end to end manufacturing process that the company's proprietary insights regarding isotope and stable RLT formulations are key. That we will leverage our global commercial footprint with expertise in nuclear medicine and oncology end PSMR-six seventeen hasn't protected until 2,034 that I hand over to my colleague, Jeff, to talk about the exciting vision data.
Thank you, Sydney. And we were very excited to present the potentially practice changing vision Phase 3 clinical trial data this past Sunday during the plenary session of ASCO, I'd like to spend the next few minutes just providing some additional that the context around the clinical relevance of this results and spend some time sort of highlighting the key results coming out of that Phase 3 clinical trial. So in terms of the disease, so prostate cancer is one of the most commonly diagnosed cancers and in particular, the 2nd most commonly diagnosed cancer in males. The main goal of treatment in earlier lines of earlier stages of disease is to reduce testosterone levels and that can be accomplished through surgical castration or biochemical castration. That At the time that these patients stop responding to castration related therapies, approximately 80% or more of these patients Have seen their disease metastasized to other parts of the body beyond the lymph nodes that that the success inhibitors and or taxane based therapies, we do acknowledge and recognize that there is still a high unmet medical need and opportunities that to do better and approximately only 30% of patients who become castrate resistance are actually surviving for 5 years.
That at the time that patients have exhausted these therapies, such as taxane based chemotherapy or the novel androgen access inhibitors, that these patients are often seeing their disease progress quite quickly on average in about 4 months and their median overall survival is limited that to about 10 months. Slide 26, please. This just shows an example as to when patients that they have less and less treatment options available. And if we particularly focus on patients that in 3rd or 4th line, what you could see from this bar chart here is approximately 2 thirds of patients in the 3rd live setting that they are actually not receiving therapy to date either because they die before they actually get to that point, that their disease progresses or is progressing at a rate that makes them ineligible for therapy or the available standards of that the that was studied in the VISION trial that I'll come on to in subsequent slides. Next slide, please.
I wanted to share a little bit more about both the technology as well as the target for the VISION trial. So in particular, PSMA is a membrane bound enzyme that's highly expressed in prostate cancer that the expression in normal tissue is highly that making PSMA a very, very attractive target for both PET imaging as well as radioligand therapy. That PSMA-six seventeen is a small molecule that targets the PSMA receptor with very high affinity that and delivers a payload of beta particle emitting lutetium-1 hundred and seventy seven that the through receptor mediated endocytosis. So it's delivering it specifically to the cancer cell and minimizing radiation that the surrounding normal tissue or neighboring cells. Next slide.
That So in terms of the VISION overall study design, I'll start on the left hand side focusing on the eligible patient population. These are patients that have been previously treated with at least 1 or potentially more than 1 androgen receptor pathway inhibitors, that they will have received at least 1, but no more than 2 taxane based regimens. Patients as per protocol are permitted to receive standard of care that before randomization and after randomization, as long as those standards of care did not include chemotherapy, immunotherapy, radium-two twenty three or investigational drugs because none of these agents have been tested in combination that with Luteti and PSMA-six seventeen, in addition, one of the key eligibility criteria was for patients to have a PSMA positive PET that the study entry and randomization with Gallium PSMA-eleven and in particular patients that to have at least one gallium positive PET lesion, meaning that the gallium uptake in the tumor had to be greater than that in the liver. That and secondly, there could be no lesions that were PSMA negative. In terms of study design, 831 patients were randomized 2 to 1 to receive standard of care therapy plus or that to receive standard of care therapy plus or minus lutetium PSMA-six seventeen.
These patients were given at least 4 cycles of therapy and they were eligible to receive an additional 2 cycles of therapy if they were deriving benefit. The overall primary endpoints included both radiographic progression free survival that the and overall survival, these were alternate primary endpoints, which means that we could declare a positive trial on the basis of either or both endpoints and alpha was allocated accordingly to maintain the traditional alpha the spend of 0.025 in terms of a type 1, type 2 error. That in terms of key secondary endpoints, we have included several secondary endpoints, including time to first symptomatic skeletal event, overall response rate, disease control rate as well as treatment emergent adverse events. Next slide. That in terms of the patient population, both demographics as well as baseline disease characteristics were well balanced that across treatment arms and this represented the patient population intended to be studied.
Next slide. That Here are the key results in terms of the primary endpoint. So starting on the left was the overall survival results. That as you could see from the Kaplan Meier curve, these curves separate early and that separation is maintained throughout the entire duration of follow-up. This resulted in a hazard ratio of 0.62 or 38% reduction in the risk that the experimental arm of Lutetia and PSMA-six seventeen also significantly demonstrated that the clinical trial is a clinically meaningful improvement in median overall survival as shown here by an improvement of 4 months with medians of 15.3 versus 11.3 months in the control arm.
On the right hand side of the slide, you see that Lutetia and PSMA-six seventeen also significantly reduced the risk of radiographic disease progression or death by 60%, that, which translates into a hazard ratio of 0.40 and you can see the curve separate early and here has reflected more than 5 month improvement in median radiographic progression free survival. Next slide. That we had also demonstrated an improvement in all key secondary endpoints, including an overall response rate of 29.8% versus 1 0.7%. These include all patients evaluated by RESIST 1.1. If you look at patients that only had measurable disease at baseline, the overall response rate increased about 45% in the luteti and PSMA-six seventeen arm.
Another important and key secondary endpoint was the time to first symptomatic that we know very well that patients with advanced prostate cancer are at risk for fractures, for spinal cord compression and for palliative related chemotherapy or other related therapies to the bone because of significant related pain. Here we also show a hazard ratio of 0.5 or a 50% reduction in the time to first symptomatic skeletal event that an improvement in that median time of approximately 5 months. Next slide. That in terms of overall safety, we did observe that there was an increase in overall treatment emergent adverse events, that both in all grades as well as high grades. In particular, if we look at high grade bone marrow suppression, here we see that that anywhere from 5% to 13% of patients are experiencing high grade cytopenias.
We also noticed that there was an increase that the new patient's high grade fatigue and urinary tract infections in the loop PSMA-six seventeen arm compared to the standard of care that there was also a higher rate of treatment discontinuations that were related to treatment emergent adverse events. That and as you see on the left hand side, that was approximately 12% in patients in the lupusma arm versus 8% in the standard of care arm. That next slide. So in summary, the combination of lupusma with standard of care resulted in a 38% reduction in that the risk of death and a 60% reduction in the risk of radiographic disease progression or death compared to standard of care alone. That To put these results into context, I know the ASCO discussed it mentioned that a 4 month improvement in overall survival was consistent with previous Phase 3 data for other therapies in patients with prostate cancer.
It is very difficult, if Not impossible to make indirect cross trial comparisons to studies that were done historically in different patient population, that And different lines of therapy as well as with different control or comparator arms. That So in particular, the results of this trial are quite clinically meaningful because these patients often have no alternative and are receiving standard of share therapies that often include only palliative related therapies rather than true treatment related therapies. That in terms of the 4 month median improvement in survival that actually translates into about a 40% reduction in risk. So quite clinically significant and should not be compared to trials that were done in very different populations in the past. That I'm very proud that we continue to have dialogue with health authorities around the world and regulatory submissions in the U.
S. And the EU are on track for the second half of twenty that based on these clinically impressive and relevant results, these data support further investigating new PSMA into earlier lines of therapy that the and potentially earlier stages of disease. If we go to the next slide, here's an overview of the current development the plans and the areas that we are currently exploring to go into earlier stages. So the current trial focuses on patients that with metastatic castrateprostate resistant cancer in the 3rd and 4th line after receiving 1 and no more than 2 taxane based chemotherapies. That in terms of the upcoming clinical trials that we are currently planning and executing, we have 2 trials, 2 additional Phase III trials that this is called PSMA IV.
This is in the pre taxane, so prior to docetaxel or cabazitaxel chemotherapy and this study start is imminent. We also have a Phase 3 study that has already started enrolling patients in metastatic hormone sensitive prostate cancer. That the trial is a global Phase 3 trial and both are available on clinicaltrials.gov. Based on this data, we are also considering other combination based therapies in the castrate resistant prostate cancer patient population as well as exploring the potential to move this into earlier stages disease. With that, I will turn it over to Doctor.
Alice Shaw, who will take us through some of our other combination based and targeted therapy approaches. Alice, over to you.
Thanks, Jeff, and good morning, good afternoon. So starting at Slide 36, we're going to shift now that we are going to be conducting a few key points from our 1st in class allosteric SHIP2 inhibitor TNO155 and targeting the MAP kinase pathway. So just as a reminder, SHIP-two is a tyrosine phosphatase that links upstream activated RTKs such as EGFR and GFR to the RAS MAP Kinase pathway and specifically mediates GTP loading of RAS downstream of RTKs. That as shown here on the right, SHIP-two has also been shown to function downstream of PD-one signaling in T cells, leading to suppression of T cell mediated immune that there are multiple and diverse roles for SHIP2 in the tumor itself and in the tumor microenvironment, that we are going to be discussing many opportunities for a SHP-two inhibitor such as TNO. Next slide?
That So
on this slide, this is number 37. I've summarized one of the major areas of interest in targeting SHIP-two, which is in the setting of drug resistance. That as you can see on the left, we know that resistance in oncogene driven cancers can be mediated by many different resistance mechanisms, that the majority of which involve activation of alternative kinases or so called bypass mechanisms and these lead to MAP kinase reactivation. That many of these bypass tracks are dependent on SHP-two and so co targeting the oncogenic driver and SHP-two could be broadly effective in overcoming resistance. That Now in support of this, a number of preclinical studies, and I've shown 2 here on the right, have shown that TKI SHIP that the 2 inhibitor combinations are highly active in resistant PDX models and notably more active than the SHP-two inhibitor alone.
Next slide. That So another key combination shown here, this is Slide number 38, and this is the combination of G12C and SHP2 inhibitors. That and now many studies have demonstrated really strong preclinical synergy between G12C and SHP2 inhibitors in G12C driven cancers. That As an example, on the right, our internal data showing in general greater antitumor activity with a combination of G12C and SHP2 inhibitors that the synergies are not included in the same period. The mechanistic basis for the synergy is summarized here on the left and includes the ability of SHP-two inhibitors to enrich the GDP bound form of G12C and that's the target of currently available G12C inhibitors and also SHIP-two inhibitor mediated the expression of feedback activation of GRASMAb kinase in the setting of G12C inhibition.
And so 2 distinct mechanisms that drive a the synergistic interaction between G12C and SHP2 inhibitors. So next slide. That So Slide number 39 depicts the study design and patient population enrolled in our Phase 1 first in human study of TNO-one hundred and fifty five. As you can see, we tested multiple dose levels and schedules. And this is really done with the goal of optimizing dose that the patient's schedule in order to enable TNO based combinations.
Now to date, 125 patients have been treated in dose escalation, all with advanced solid tumors, mostly colorectal cancer and GIST, but some non small cell lung cancer and head and neck cancer as you can see in the table. I should also note that we had very few patients in this first in human study, about 5% with potentially sensitive G12C mutant tumors. Next slide? That So here on Slide number 40, as predicted by preclinical studies, TNO demonstrated favorable PK in patients that we have a very strong quarter with dose proportional exposure as you can see on the left. In addition, TNO has been shown not to induce or inhibit major that the metabolic enzymes making drug drug interactions unlikely and further supporting combinability.
There's also clear evidence of TD, your target engagement based on BEST 6 suppression and on treatment versus pretreatment biopsies, which you can see here on the right. That next slide. So shown here on Slide number 41 is the safety profile of TNO-one hundred and fifty five. Overall TNO was generally well tolerated with most AEs Grade 1 or 2 in severity and many of the common AEs that similar to what's seen with other RTK and MAP kinase pathway inhibitors, decreased ejection fraction is also an expected on target toxicity that And we saw it in about 10% of patients, again, mostly mild in severity, reversible and really detected because of the frequent monitoring mandated by the protocol. That next slide.
So here on Slide 42, the waterfall plot summarizes the best overall response across all evaluable that patients have dose escalation. And not surprisingly, with single agent TNO in a predominantly CRC and GIST population and across all different dose levels, we saw limited clinical activity with stable disease as the best response. However, I should note that there were several prolonged stable diseases in non CRC patients, including an AgIST patient whose disease has remained stable for almost 3 years. That Next slide. So next steps with this study will be to expand in indications predicted to be sensitive to single agent SHIP2 inhibition based the preclinical data, but really our main focus now that we've thoroughly examined PK, PD and safety across different doses and schedules that this is established the activity of TNO in combination with other agents.
So the various TNO combinations that we're developing are shown here. This is Slide number 43. And that all of these are supported by preclinical studies and most of these have actually already entered the clinic. As you can see, we're testing combinations of TNO with EGFR and ALK that TKI's triplet combinations of TNO with RAF MEK and RAFK inhibitors and BRAF V600 mutant CRC, TNO combined with our checkpoint inhibitor spartolizumab or our CDK4six inhibitor rivociclib and a variety of different cancers. That.
And finally, TNO in combination with our G12C inhibitors, both our own JDQ443 as well as Mirati's adaggressive in G12C driven the answers. Next slide. So here on Slide number 44, I've included one case report that was shared last fall by Mirati and that this really highlights the potentially marked activity of TNO combined with G12C inhibitors. This is a patient with G12C in lung cancer who that we have failed sotirasib previously after responding as well as the combination of Revolution Medicine SHP-two inhibitor combined with the MEK inhibitor cobimetinib. That this patient went on to receive the combination of adagrasib and TNO-one hundred and fifty five and experienced a very dramatic clinical and radiologic response as you can see here on the right.
That this is just one patient, but I think between the known preclinical synergy between G12C and SHP2 inhibitors and now this emerging clinical data, we are very excited about combining TNO with G12C inhibitors to maximize the activity and the clinical benefit of G12C inhibition.
Next slide.
That So here, and this is my last slide, number 45. You can see our current MAP kinase the pipeline and this includes small molecules targeting essentially every step of the pathway, starting with KRAS, then shipped to that BRAF and CRAF, NEC and ERK and a few other downstream map kinase targets that I haven't shown here. We know that targeting single nodes in this pathway they may not adequately suppress the pathway and so these molecules are really enabling us to explore many different MAP kinase combinations that even beyond the TNO combinations that I've already mentioned. Two examples we're highlighting include combinations with our BRAFCRAS dimer inhibitor, LXH254 for NRAS mutant melanoma BRAF mutant melanoma and other RAS driven cancers and also combinations with our G12C inhibitor JDQ that 443, which is currently in Phase 1 testing. So I think there's lots more to come in terms of TNO combinations and also other NAP kinase combinations.
So
that Thank you, Alice. And maybe just to briefly summarize our key takeaways. Novartis is a global leader in oncology and we have a strong track record in pioneering innovation. And this year the quality that we presented. We are the only company with steps and expertise in 4 therapeutic platforms, that, which we believe will be critical for the future of cancer care.
The VISION trial as presented by that the we can dramatically improve patient outcomes, not only in a rare disease like neuroendocrine tumors, but also for prostate cancer, one of the most that we have a number of relevant cancers in men.
And we believe we are
well positioned with our portfolio to tackle the re aiming unmet needs in cancer, that, including through combination across our platforms. So with that, I would hand over to Samir to kick off the Q and A.
Thank you very much, Suzanne, and thank you to all the presenters. We've got quite a lot of questions online at the moment. That So operator, if you could
have the first question, please. Of course. And your first question comes from Graham Parry from Bank of America. Please go ahead. Your line is open.
Okay. That So firstly, could you just help us understand what your expectations are around launch trajectory on lupuscept PSMA-six seventeen, Just given the need to get the radioligand therapy centers set up, so do you have enough at the moment to support what you think is needed for that The late line of therapy or do you feel that there's going to be the launch trajectory could be inhibited by the need to that And then secondly, could you help us understand the differentiation of your LAG-three and your KRAS that inhibitors, this is Bristol's SLAG3 and Gilead's lumacres or the Mirati KRAS for that matter. That So why or how do you see this differentiated? And how does that affect your combo strategy with Mirati KRAS going forward with your shift too? Thank you.
That Fantastic. Thank you, Graeme. So for the first question, I'll hand it across to Sidney and then I'll get Alice to address the question that with respect to the differentiation of the Lactria and KRAS. So, Sidney, on the launch trajectory, please?
Thank you. Capacity is an important capacity is important for a successful launch. That So indeed, to the existing Lutathera treatment centers because it's late line that the capacity is going to
be in the range of 20% to 20%
and a smaller population. Long term, we will work to expand the capacity as lined out in my short that we have a very important presentation in this presentation, infusion days, infusion hours that we will share the best practice because as usual, you have highly productive centers and less productive that the centers are sharing this best practice will be key as well. And then we will double the existing centers. We have time until the pretaxane that study reads out, we want to double these centers and set up new centers, that communities practices that currently have optimized themselves with alpha heart labs to expand for beta that that the ECLSS accounts with HOT Labs have to treat patients with PSMA-six seventeen. That we will provide them the best practice education on process and site expansion to ensure that these sites are ready
Thank you. Alice, the question on the differentiation of the LAG-three versus the KRAS. That Yes. And I'm going to come back to you, Susanne, because maybe it is difficult to hear you, Sidney. So maybe Susanne wants to come back that On that point.
Susanne?
Sure. No, I think it that I hope everybody could hear. So I think it was clear that we have enough capacity for now. So we expect that we can cover all the patients in first line. And then we have plans to double number of centers and with that capacity, that we should be well ready before the earlier trials like the pretaxan trial will read out.
That And I think we stand over to Alice now. Sure.
I'll start with KRAS and then go to LAG-three. That So with our KRAS G12C inhibitor JDQ443, this is a potent and selective irreversible G12C inhibitor that KRAS similar to other G12C inhibitors such as sotirasib and adagressive. That I mentioned that JDQ-four forty three is currently in a first in human study right now. So I would say it's difficult to make comparisons. Of that there could be potential for differentiation in terms of safety, even in terms of efficacy.
But actually where I think our differentiation really will that the combination of JV-four forty three is our ability to combine our G12C inhibitor with many other assets in our portfolio, which I highlighted during my talk. That TNO-one hundred and fifty five is one obvious combination partner. And as I mentioned, we are focusing on the JDQ TNO combination and that will be in our first in human study. That there are actually many other combinations of G12C inhibitors with other potential MAP kinase pathway inhibitors that could be highly active in the setting of G12C driven cancer. That Sure.
So that's where I believe we may have true differentiation is in terms of our JDQ based combinations. In terms of LAG-three, we do have that the LAG-three antibody, this is LAG-five twenty five and we actually have studied LAG-five twenty five as a single agent as well as in combination with our PD-one inhibitor that cargilizumab in advanced solid tumors presented the data from the Phase III study where we showed that there was very little single agent that we did see potential activity of our LAG-three inhibitor with spartolizumab and we explored a number of different expansions in our Phase II study in both IO naive as well as IO pretreated patients. And I would say in general, we did see some potential signs of added benefit with LAG-five twenty five and this has in fact supported further evaluations of LOD-five twenty five in late development. So maybe with that, I'll ask Jeff if he wants to comment.
That Thank you, Alice and Graham, thanks for the question. And we currently have an ongoing study that following up on some of those early signals that Alice mentioned in different patient populations and different subsets of patients based on that biomarker selection criteria, I think in terms of differentiation, our differentiation would be in the development approach via combinations. That And if I just spend a minute on the benefit of the tislelizumab licensing deal that we had done recently, that this gives us the ability to have data from up to 15 registration directed trials where 5 of those have already reported out positively that the number of other trials still yet to report out. In addition, the development plan for tislelizumab is quite broad with probably now more than 100 studies ongoing or soon to be started for tislelizumab, which will give us insight into other cancers that the potential addition of LAG-three inhibitor or this distinct checkpoint receptor their combination will potentially benefit patients going forward. So we are currently assessing all of the data that is merged at ASCO And that we have it in our hands to define the next steps.
Great. Thank you very much, Alice and Jeff. Operator, we're ready for the next question, please.
Thank you. Your next question comes from Mark Purcell from Morgan Stanley. Please go ahead. Your line is open.
Yeah. That Thank you for taking my question. In terms of LUT-six seventeen PSMA moving into early lines of therapy, could you help us understand your confidence in making that the challenges superficially appear to be the route of administration, the need for specialist infusion centers. And it's not clear from the presentation which of the that AEs was most problematic when it came to the 12% instance of discontinuation. So help us understand that would be great.
And then It appears that you're basically targeting lymph nodes and bone and organs in terms of binding to all PSMA Expressing cancer cells. So what's the importance of this sort of broader targeting when it comes to the move into earlier lines of therapy? Thank you.
That Great. Thank you very much, Mark. So both the questions will be for Jeff related. So both relate to the earlier lines of therapy that And it's to do with going into how much to specialist center, the route of administration, the AEs that And also targeting for the earlier lines of therapy as a secondary question. So Jeff?
That Yes. Thanks for the question, Mark. So in terms of earlier lines of therapy, both our confidence as well as the rationale to do so. That So you may have remembered a Phase 2 randomized trial that was done by the Australia New Zealand Cooperative Group has a head to head study against cabazitazole, showing a clear benefit in terms of reduction in PSA levels versus that this is taxane based chemotherapy. In that trial, in particular, we saw both clear efficacy signal that, as well as very manageable safety and there was no treatment or drug related fatalities that in that particular population.
As we go into earlier lines of therapy, there is also strong hypotheses that that androgen deprivation or inhibiting the androgen related pathways also influences PSMA expression. So this may provide a unique opportunity to demonstrate even greater clinical efficacy in these patient populations, either alone as a combination that in terms of the safety, we do know that cytopenias and bone marrow suppression is an important side effect to be cognizant of. In particular, even within the VISION trial, we noted that these side effects that we're often manageable and reversible and it's something that oncologists are very familiar that we're dealing with through supportive care measures such as growth factors. So this is something that we will continue that
Operator, next question please. And if I could
that
thank you. Your next question comes from Emmanuel Papadakis from Deutsche Bank. Please go ahead. Your line is open. That Thanks
for taking the question. Maybe a second one on the PSMA, please, competitive outlook. Point Biopharma announced a few days ago. They're initiating their that Relatively equivalent trials PSMA4. So do you see any points clinical differentiation there?
Do you have any IP barriers that To provide competitive protection, are you really expecting to share the market equally well at the peak of that asset in the near term? Thank you.
That Okay. So on that particular question, we won't comment on competitor and their design studies, etcetera. However, in terms of how we stand versus competition, perhaps I'll ask Suzanne if she wants to say anything on that particular point.
That Yes. I mean yes. Emmanuel, you asked about IP protection. So let me say the following. I mean to manufacture radioligand therapy includes many complex steps.
And as you can imagine, there is many of these processes that are proprietary. That And usually also that's know how that's not very broadly known. It's known to only a very limited group of people. In terms of patent protection, we feel we have a robust portfolio of patents on lube PSMA. That we have basic patent protection until 2,030 4, and there's also potential extension in the U.
S. And EU. So we feel we are very well protected. And as I said, it's not as trivial to just produce this ladylike in therapies at scale, and therefore, we still feel we are in a good competitive situation.
Thank you very much, Susan. Operator, we're ready for the next question, please.
That Thank you. Your next question comes from Simon Baker from Redburn. Please go ahead. Your line is open.
That Thanks for taking my question. Going back to 617 and the plenary presentation, just two things that that in the discussion, firstly, from the discussant, the suggestion that PSMA screening was unnecessary that given it's so widely expressed, I just wonder what your thoughts are on the potential for an all comers indication at some stage. That and then secondly, the presenter discussed the importance of the relationship between nuclear medicine and medical that the immunology in the trial and problems where that relationship is not strong. I just wondered if that's a real world problem that you see a lot and that the learnings that you can take from this study to the broader radioligand therapy market.
That Great. So with the first question on the likely label and do you need to do PSMA screening or not, I will give it to Geoff. The second question in terms of nuclear medicine specialists and the medical oncologists that And what their relationship is like we'll give to Sidonie. So with the first question please, Jeff.
No. Thanks. Thanks, Simon. And I think it's a very relevant question. And I think this one in particular because PSMA that expression is often found in more than 80% of prostate cancer patients.
It begs the question as to how important that screening becomes. That it is not just about selecting whether or not a patient is eligible for therapy, but it is also understanding that the heterogeneity of their disease. So coming back to the point of treating what you can see, the advantage of using PSMA PET that screening is the ability to see which lesions are PET positive and the value of radioligand based therapy is you're switching out that that Gallium based tracer for lutetium, so that you're ultimately using the same PSMA target as both a diagnostic as well as a therapeutic. That So this affords us to better understand the heterogeneity of the disease and it will also help us to better understand that the lesions and why they are responding or maybe not responding after a period of time. So it will provide unique insights into the therapeutic, that both monitoring as well as selection of patients going forward.
At a platform level, I think the screening it becomes even more important as we think about future targets that may not be expressed as high as 80%. So I do think there is value in not only screening for these patients who have prostate cancer, but also for the platform and our pipeline of assets to come. That And maybe I'll turn it over on the next question regarding the interdependency on the nuclear medicines and the medical oncologists. That
Thank
you, Jeff. And the multidisciplinary approach and really that discussing the patients and having the patients treated in strong alignment between that the disciplines that are involved is super important, not only for PSMA, that But also moving forward with our pipeline products because you will have other the disciplines as well. So the patient journey is a complex one. And as that, you have the urologist, you have the medical oncologist, the radiation oncologist and the nuclear medicine physician and I think it was Mike Morris who said that some dropouts were related to not proper handling of this relationship. So it's our task to bring them together and educate across all these decision makers the value of RLT that and then the requirements, how they set up the process together to support this approach.
That Thank you very much, Sidoti. Next question please, operator.
That Thank you. Your next question comes from Florent Cespedes from Societe Generale. Please go ahead. Your line is open.
That Good afternoon. Thank you very much for taking my question. An easy one on the Slide 22, maybe for Sidonie. That could you share with us why you have in the prostate cancer 5 radioligand the projects. Do you believe that some will be better tolerated or some could show better efficacy?
If you could
Okay. I think you're referring to the pipeline slide, Florent, in which case probably better that If it's Jeff who actually talks about the pipeline, if that's okay.
Happy to, Florent. That So in terms of why there is multiple agents listed on that slide, so we do have that we have a unique opportunity here where we can look at different PSMA targets in terms of both their dosimetry that, as well as their distribution. And as Sydney mentioned in one of her slides, it also gives us an opportunity to look at different that isotopes based on either dose or distribution. So I do think these are important parameters for us that going forward and we do have ongoing Phase 1 studies looking at the different PSMA ligands that And with different isotopes, whether it's lutetium based and or actinium based. Some of those, I can't see the pipeline slide in front of me at that they may also include the diagnostic component as well, either the Gallium 68 or the potential to have that a fluorine based PET imaging tracer as well.
So that's why you may also see a longer list for prostate cancer.
That Thank you very much, Chair. Thank you. Operator, next question please.
That. Thank you. Your next question comes from Seamus Fernandez from Guggenheim Partners. Please go ahead. Your line is open.
That Great. Thanks very much for the question. So I just have one question. I wanted to get a better sense of that the cardiac profile of TNO-one hundred
and fifty
five, it appeared that there were some cardiac toxicity. Is that that Something that's directly related to the mechanism of action or do you believe that this is some off target toxicity? And added to that, that we know that there are some KRAS agents that have some cardiac signals, PTC prolongation that As well, just wanted to get a better understanding of the combinability of TNO-one hundred and fifty five, given some of those early profile signals and again your views there. Thanks so much.
Great. Thank you, Seamus. And so it's a question for Alice. That TNO is specifically cardiac adverse events, is it MOA related off target and implications for combos?
Yes. So thank you for that question. We did highlight this toxicity from our TNO Phase I study in the ASCO presentation, that I briefly mentioned it, but just to provide some more detail, a decreased ejection fraction was seen in about 10% of our patients. That we do believe based on preclinical data that this is an on target toxicity. And as I noted, what's important is that this that the decrease in ejection fraction was typically mild and also reversible.
And I should say that because we were attuned to this being an on target that we actually did monitor for cardiac contractility very, very frequently in our protocol and so we were able to detect even these mild asymptomatic decreases in that So far, I mean, I think we haven't seen any issues with regarding TCC prolongation. So really, it's around this that potential impact on cardiac contractility, again only in 10% of patients easily monitored and reversible. I that this is quite comparable to data that we've seen with other MAP kinase pathway inhibitors, including MEK inhibitors. And of course, we are very that we're actively advancing our combinations and believe that even in the setting of combinations, because we understand this cardiac toxicity so well, we will be able to manage it.
That Thank you. Operator, next
question please. Thank you. Your next question comes from Wimal Kapadia from Doreen, please go ahead. Your line is open.
Great. Thank you very much for taking my question. I will mark it for Bernstein. So can I if I just come back to ASC six seventeen, please? I appreciate you know
that if I have a look
at previous cabo data, particularly the CARDS trial, that I look at vision and I think about therapy. How are you thinking about the efficacy and safety profile of the products versus KAVA that In this setting, how will Novartis really be discussing this profile with physicians? Do you actually believe you have a better profile
that Thank you very much, Wimal. Back to Jeff for contextualizing
that Yes. So I think it's a good question. And maybe just as a reminder in terms of patient population. So that these are patients that had to either have already received 2 prior lines of taxane based chemotherapy such as docetaxel and cabazitaxel or they had to be deemed ineligible to receive any further lines of Chemotherapy. So making a comparison around efficacy related to cabazitaxel would not be fair because that would not that the treatment alternative for these patients.
As you rightly alluded to, the therapy trial continues to be ongoing and we we'll await additional data from that particular trial in terms of the head to head data versus cabazotaxel. That and then as we talked about earlier, we have 2 upcoming trials that are in the pretaxane setting that against the appropriate comparators prior to patients being eligible or receiving taxane based chemotherapy.
Thank you very much, Geoff. And now for our final question please. Operator?
Thank you. Your final question comes from Matthew Weston from Credit Suisse. Please go ahead. Your line is open.
Thank you very much. A quick follow-up, if I can, on one of the PI's comments in the presentation during the plenary. He specifically said that that approval would require a change in the approval of the PSMA PET so that it can now be used for the selection of patients rather than that tracking patients' tumors, is that something that you anticipate and something that you believe will be done prior to lupusma being approved? And that And just if I can sneak a final one in, can you let us know whether the Endocyte manufacturing facility has been FDA approved? That There is a risk that that adds further delay at the approval end of due course.
Thank you.
Great. Thank you very much, Matthew. Jeff, do Do you want to take both the questions? The first one with respect to the PSMA and what's required in terms of selection of the test. And I don't know whether you can comment anything else with respect to the manufacturing facility.
I could take the first one and then I may defer to Sydney or Susanna on the second part of the question. So in terms of the FDA that there are already gallium based PSMA tests that are actually approved for use. I think what is unique here is that we are using the PSMA-eleven Gallium based test as a mechanism to select patients, Which would therefore then constitute a companion diagnostic or a specific regulatory pathway for that. That we have been in discussion with the FDA regarding the requirements for our upcoming that the drug submission and we would include the PSMA diagnostic as part of that upcoming submission to the health authorities accordingly.
That Thank you. And Susanna, on the sites?
I think we can also have Sidonie taking it. She's the
expert on
that Yes. So we plan to produce in Melbourne, which is that FDA approved and we can also produce in Europe in Iberia, which also has FDA approval. So we have flexibility.
And so to comment on that, these are both AAA sites. So we already prepared the tech transfer that So that's why the production for FDA will be done from established
the Fantastic. Thank you all very much and a special thanks to that The
that this concludes today's conference call. Thank you for participating. You may now disconnect.