Novartis AG

I'd like to thank you for taking the time to participate in the Q3 Novartis conference call. The information presented today contains forward-looking statements that involve known and unknown risks, uncertainties, and other factors. These may cause actual results to be materially different from any future results, performance, or achievements expressed or implied by such statements. For a description of some of these factors, please refer to the company's Form 20F and its most recent quarterly results on Form 6K that respectively were filed with and furnished to the U.S. Securities and Exchange Commission. And with that, I'll hand across to Vav.

Thank you, Samir, and thank you, everyone, for joining today's conference call. With me in the room, if I could have the slide up with our colleagues. On slide three, with me in the room, I have Harry, Marie-France, Susanna, John, Richard, Karen, and of course, Samir, who you've just heard from. So turning to slide four and then slide five, we wanted to start by taking a step back and really reflecting on how this quarter continues, I think, what has been a very strong trend for the company over the past four years. Looking at nine months for each of the years back to 2018, you see we've consistently demonstrated the ability to grow our sales at 6% annual CAGR, 13% on core operating income, and a consistent expansion of our innovative medicines margins. Now, looking ahead, we stand behind our belief that we can continue to grow our sales over the coming period at a CAGR of 4%, driven by, first and foremost, our key growth drivers, which we'll talk more about over the course of this call, our strong mid-stage pipeline, and the continued investment we have on technology platforms, which we think over time will differentiate us and enable us to have a steady flow of innovations to drive growth. Moving to slide six, for Q3, we had strong performance across each of our four main value drivers. We'll talk about sales growth throughout the call, and Harry and our colleagues, Marie-France and Susanna, will give you more details. We had good productivity with our core operating margin now reaching 37.8% in IM. On the innovation front, I'll go through some of the milestones in more detail later on, but I think it was a busy quarter for us. with some negatives, but more positives overall on balance, and we continue our journey on the innovation, on our innovation efforts. And then lastly, in ESG, we had our recent ESG Day, where we laid out our longer-term ESG strategy, and we continue to have the ambition to not only lead in the biopharmaceutical industry, but also across large companies. Now, moving to slide seven. Our key growth drivers and launches had good momentum in quarter three. We're very pleased with the performance. We'll go through some of the brands over the course of the call. But notably, we now have 53% of our sales in the quarter coming from these key growth brands. And that's up 26% versus prior year. And I think that demonstrates that we're a company that has replacement power that can continue to generate innovations that overcome expiries and drive that consistent growth over time. Moving to slide eight, we had particularly strong growth on some of our key brands, including Cosentix growing 18%, Entresta was up 41%, Zolgensma up 49%, Kaskali 27%, and Cosimta continues on its solid and accelerating launch trajectory. Marie-France will go through that in a bit more detail. Moving to slide nine. We denounced this morning we are raising our peak sales guidance for both Cosentix and Entrusto. So first from Cosentix, and we'll go through this in more detail a bit later, we've raised our peak sales guidance to $7 billion. This is driven by market growth, geographic expansion, as well as lifecycle management opportunities. And we expect this brand to continue to be a strong element of Novartis' story through this entire decade. And moving to Entresto, we believe we'll continue to have strong growth driven by market penetration guidelines and geographic expansion. Our peak sales guidance is consistent with our currently stated assumption of an LOE in 2025. However, we do have issued patents going out to 2027 and an additional group of patents that were recently issued out to 2033, and we'll continue to aggressively defend our IP to maximize the impact of this medicine. Now, moving to the next slide, I also wanted to say a word on China, where we continue Our strong growth trajectory, one of the leading multinationals in the market in China. We continue with a double-digit growth in the high teens, 16% and 18% on the quarter. This is driven by a few factors. One, the continued positive momentum we have on our growth drivers that have NRDL inclusion. And we believe we're outperforming other multinational companies. for the sales growth of these NRDL-listed brands. We also have limited exposure to the volume-based pricing. When you look at our commercial footprint, we've been expanding our commercial footprint to reach lower-tier cities and hospitals. And lastly, our late-stage pipeline continues to mature. In China, we had some important recent approvals in trustal hypertension, Lucentis, and additional indications. And we have 50 additional submissions planned in the next five years. So we're confident we're on track to double our China sales from the 2020 base by 2024. Moving to the next slide. Now turning to Sandoz, in Sandoz we had a mixed quarter. We see in the ex-U.S. dynamics normalizing, but a little more challenging environment in the U.S. So first in Europe, we had 2% sales growth, and this was really driven by both biosimilars as well as retail and a return to gaining market share in our key markets. In the rest of the world region, we were up 6% with steady growth across regions. However, in the U.S., we did see a 20% decline, and this was driven by price erosion as well as contract terminations in our oral solids business. We also had an impact on core operating income. This is primarily driven by the unfavorable gross margins from the product mix in the U.S. Now, turning to Q4, we do expect performance to normalize in the ex-U.S., and it will continue to work to stabilize the U.S. We expect our direct demand business segments to normalize, but at different rates. We continue to expect demand to be in line with what we saw in Q3, and we're hopeful that we'll see a cough and cold season that returns to pre-COVID levels. We did have a minor impact as well from a negative impact from Losartan in Q3, and we continue to expect to see some of those negative impacts in Q4. Now, moving to the next slide. We did announce this morning that we're commencing a strategic review of Sandoz, consistent with what we outlined a few years ago. We had stated that we wanted to create a more autonomous Sandoz within Novartis that would give us the optionality to ultimately determine where is Sandoz best owned, by Novartis or by our shareholders or another party. Now, we believe the GX market is attractive. We think Sandoz is well-placed to capitalize on its growth drivers over the next decade. And we think Sandoz is also well-placed to really be a leader in the next wave of biosimilars launches. When you take each of those in turn, attractive market, $400 billion of sales going to LOE over the coming decade, a CAGR of 4%. Sandoz was a number one position in Europe and in biosimilars, as well as a leading position in areas like antibiotics. And a clear strategic focus that Richard and his team have put in place. We have a very strong biosimilars pipeline with 15 assets in development, aiming for $3 billion in sales by 2025 and $5 billion by 2030. A clear strategy in complex small molecules. and ongoing margin improvements, primarily through improved COGS through our technical operations unit. So we expect to conduct this review over the coming period, and we would plan to provide an update on progress latest by the end of next year. It is notable that Sandoz is more integrated into Novartis than Alcon was historically, and so there are important considerations we'll need to work through from an IT and business services standpoint to really enable us to make the best decisions. And moving to slide 13, from a pipeline standpoint, we had a busy quarter, some approvals, a number of readouts, many readouts that went our way, but also important readouts that didn't go our way. And we acknowledge those and are working to learn from them to continue to improve our pipeline performance. But on balance, we would say we continue to be at the industry. Benchmarks are better in terms of pipeline success rates by phase. From a submission standpoint, a number of submissions went in, and I think importantly, we received two designations, priority reviews for both Siminib and Lu PSMA 617. Both of those reviews are ongoing and should enable a launch in the relatively near term. Moving to slide 14, going a bit deeper, and we've reframed these next two slides rather than looking at Pharma and Onco to really break it out by business franchise and global franchise of the various businesses. So starting in pharmaceuticals and cardiorenal, where of course we build on the strong position we have with Entresto. Lectio, we remain on track for an action date in January 1. We have good discussions with FDA, are continuing to progress. The assessment of our Austrian facility, no issues have been flagged, so we remain on track for that approval. Iptaclopan, we continue to have solid progress on this medicine with Phase III started in IgA, C3G, and atypical hemolytic uremic syndrome. disclosed in our quarter that the final readouts for both C3G and IgA nephropathy, which followed these patients for a bit longer, continued the trend of improving renal function. Peloparson continues to perform well in its Phase III. From an immunology standpoint, we announced today that Cosentix had a positive Phase II readout versus steroids standard of care for giant cell arteritis, and we've moved now to begin a Phase III program. And, of course, the hydradenitis readouts are continuing as well as the – on track as well as the other Phase III programs. Legolizumab remains on track for its readouts, and we'll talk about remibrutinib. I did want to highlight we see very good data, mid-stage data, for inolumab, which is our anti-BAF receptor antibody, and we'll be presenting more data in the coming quarters on this medicine. But we are excited about its potential in a range of autoimmune as well as hematological indications. Turning to neuroscience, the SMA intrathecal, AVXS-101 intrathecal FDA hold has been lifted as we previously disclosed, and the Phase III now is initiating. It's a global Phase III program covering 2- to 18-year-olds. Branoplam, our splicing inhibitor for, splicing modulator, I should say, for Huntington's disease, has its Phase IIb now starting with all the relevant regulatory clearances achieved. And we will announce, and we've announced, and I will talk a bit more about remibrutinib in a moment. Turning to the next slide, from an oncology standpoint, here we had, of course, a number of events. We'll talk about Kisgali and canakinumab, lupi-SMA we've already mentioned. I did want to flag we've started now both our earlier stage studies in the pre-taxane as well as the hormone-sensitive metastatic settings and are continuing to evaluate to potentially move this medicine into earlier lines. We did announce as well that JDQ443, which is our in-house KRAS inhibitor, has had good PK, good dose finding. We think it's a very good profile for this medicine and are now moving it into phase three studies in non-small cell lung cancer, but then we'll also look potentially at other indications. And this enables us to have in our own hands our own combination of a KRAS inhibitor and a SHIP2 inhibitor. Our TNO SHIP2 inhibitor is now in a number of early stage studies looking at combinations And we'll hopefully be able to present more data on this in the early part of next year. Turning to hematology, our first-line study for a siminib now has also started. PNH for iptaclopan is progressing well. Our sabatolamab programs remain on track. And importantly now with YTB, our next-generation CD19 card, we've seen very good data in the early phases, which will present ASH along with our multiple myeloma next-phase card therapy program. And we plan to start the pivotal studies in 2022. So moving to the next slide, I just wanted to say a few words on remibrutinib. This, I think, is a really well-designed medicine. We have excellent chemistry at Novartis, and our scientists have worked to really create a highly selective, potent, and safe covalent BTK inhibitor. And when you look at the data in CSU, we're the first BTK inhibitor to be able to demonstrate the kind of data that you see on these slides. First, a very good dose response with significant improvements versus placebo, and you can see the statistics here are very compelling with no safety signals. Then when you look at the improvements in the relevant urticaria score over placebo, you can see across the dose range we see a clear improvement versus placebo, and that improvement was very rapid as early as week one and maintained through week 12, the endpoint of the study. Moving to slide 17. When you look at the complete control that patients on remibrutinib BID were able to achieve versus the placebo group, very high response rates that were consistently maintained over the course of the study, I think showing the potency of the drug. But in terms of differentiation, particularly in dermatology as well as in multiple sclerosis, we were really pleased with the safety profile of this medicine, which we think will be critically important. One, there was no dose-dependent increases or treatment interruptions or discontinuations due to LFT elevations, no dose-dependent cytopenias or treatment interruptions for low blood cell counts, and no clinically relevant adverse events associated with what has been historically associated with the BTK inhibitor class across the entire dose range tested. So overall, we think this is a potential best-in-class profile for CSU, positive benefit-risk, and those Phase III studies are in the midst of starting right now. Moving to slide 18, and as mentioned, we're now initiating phase three trials with remibrutinib. We understand that we're behind some of our competitors, but we believe our expertise in conducting large-scale RRMS studies gives us the ability to close the gap. And importantly, we think for neurologists, what's really important is they have a very safe medicine that is also high efficacy, and we think we can deliver that with remibrutinib. And what will this allow us to do? We've already got the all clear to move ahead into our phase three studies. And what this allows us to do over the longer term is build on our multiple sclerosis per portfolio, Gilenya, Mazant, Cosimpta, and now adding, eventually, assuming success, Remy Brudnit. So moving to slide 19. You also saw in the quarter Kiskali achieved statistically significant OS in the Mona Lisa II study. This is the third study where Kiskali in the metastatic setting has demonstrated a significant overall survival benefit. That benefit now out to five years. It's really, we believe, should be the preferred treatment option for these patients given the compelling OS data that's been demonstrated. We plan to submit this OS data into our labeling in the relevant geographies Moving to slide 20, I just wanted to say a word, as I know there's a lot of interest now in the adjuvant readout, which we expect in 2022. It's on track, fully enrolled. Just to remind you, there's some unique elements of this study. One, it includes patients at high and intermediate risk, which is a larger patient population than some of our competitor studies. And the way we have designed the study is to base enrollment on the prognostic staging from the AJCC. A little bit different than the KI67 that has gotten a lot of attention, but we believe, and with regulatory sign-off, a very relevant prognostic staging to really ensure that we enrich for the risk of recurrence in this study. We have a longer treatment duration of three years versus two years. We lowered the dose to make sure this was manageable for patients in the adjuvant setting to overall improve the tolerability. So, as I said, enrollment complete. It's an event-driven study. We expect a late 22 readout. And, you know, feedback from FDA, which we reviewed again, says that the IDFS endpoint is acceptable as the primary analysis provided there's no detriment in OS. And we're, of course, taking that into account as we see the various readouts over the course of next year. Moving to slide 21. Now I wanted to turn to Canopy, and if you'll indulge me, I'll just take a few minutes to explain the data that we released yesterday to make sure it's clear, and then we'll, of course, be happy to take your questions. The Canopy program is based on the results we saw in Cantos, where we saw 60% to 70% improvement in the incidence and mortality of lung cancer in a cardiovascular trial. This was based on You know, a pretty good understanding that IL-1 beta as well as HSCRP are very relevant in the tumor microenvironment for lung cancer as well as other inflammatory cancers. The KNP2 study was in the second line there. We didn't see any signals of efficacy overall. And there, of course, as you saw at ESMO, the trend was not positive with canakinumab versus the control arm of chemo. In this study, while we did not meet our primary endpoints of OS and PFS and previously untreated locally advanced metastatic non-small cell lung cancer, in the overall population, we did see a positive trend, though not statistically significant. Importantly, we did see potentially clinically meaningful improvements in both PFS and OS. These improvements in these pre-specified subgroups and biomarker-driven subgroups were nominally statistically significant, and the upper bound of the confidence interval specifically did not include one, and we saw treatment effects that were meaningful in our view. However, we don't believe at this point in time that this would constitute a fileable program. Now, what we do believe is these results support the continued study of canakinumab in earlier stages of lung cancer. We believe they also support further evaluation of pro-tumor inflammation because the signals we saw were meaningful. On Canopy A, the study, we believe, more closely reflects the Canto study. It remains a high-risk study, to be clear, but nonetheless, we think it's important to complete this study to really understand if there's a possibility to replicate the remarkable findings of the Canto study. It's so important for patients if we could actually demonstrate that. Now, in addition, we would want to highlight, as I think there has been confusion about this, in this study, we did not see meaningful differences in the safety profile of the canakinumab arm versus the control arm of PD-1 plus chemo. So that kind of gives you an overview. We would note as well, we have a number of other pro-tumor inflammation medicines, oral medicines, as well as you have a Kizumab, which is another anti-IL-1 agent that has regulatory, or has LOE into the mid-2030s, and of course we're evaluating that medicine in a few other cancer settings, and we'll evaluate as well if there is a credible case to do anything further in metastatic non-small cell lung cancer. Then moving to slide 22. Lastly, before handing it over to Mary France, we've accelerated our ESG efforts. Twenty-nine million patients reached next-generation malarial therapy, now entering phase three studies, a 10-year commitment. to really support addressing health inequities and health disparities in the United States. And we've committed to net zero carbon on top of all of our other environmental commitments using science-based targets to achieve by 2040, consistent with many of our other large companies that will be announcing these at COP26. And with that, I will hand it over to Mary France.

Thank you, Vas. So moving on to slide 24, good morning, good afternoon to all. It's my pleasure to share the results of the pharmaceuticals division for Q3. Sales grew 8% this quarter, driven by a clear focus of our launch drivers, our growth drivers, and supported by the solid execution across geographies. As you can see, the growth drivers and launches have strong momentum. We're growing 32%, and now they account for 54% of sales. This is 10 points above prior year and in line with our strategy. Looking at year-to-date, you can see it's accelerating our momentum, and we're on track to have a strong finish to the year. Moving on to slide 25, Cosentex grew 22% with solid contribution from both dermatology and rheumatology. In the U.S., we're growing volume with the market. We're holding our leadership position in Europe, and in China, we're leveraging our NRDL listing. China is now our third biggest market. We've also strengthened our evidence base with multiple pediatric indications, further reinforcing the proven efficacy and safety of Cofentix. To maintain a momentum in Q4 and beyond, we remain focused on our competitiveness in the field, the flawless execution of our marketing teams, and the activation of two key groups of patients, those with PSO-PSA comorbidity that need strong efficacy in both skin and joints, and the axial SPA patients who can benefit from all-in-one release. If I move on to slide 26, while Cosentix has been on the market for six years, every year is a launch year. Cosentix has approved across five indications. All of them have low biologic penetration. With its strong value proposition and evidence base, Cosentix will continue to capture growth. Cosentix is also the only IL inhibitor with NRDL listing in China. we see strong growth potential in this market. We have an ambitious life cycle management plan, which is starting to deliver. We've seen positive readouts for giant cell arthritis and our IV formulation in Q3. We also expect data for hydroiodinitis superativa in Q4. Overall, we're looking at a potential of 10-plus indications in areas of high unmet need and an ambition to double the number of patients on Cosentix. This gives us confidence that we can grow Cosentix to at least 7 billion. Moving on to slide 27, Entresto grew 44% in the quarter, reaching 2.6 billion year-to-date. The ACC and ESC first-line recommendations for Entresto are translating into penetration gains, and the expanded U.S. label is driving NBRX growth and uptake in primary care. In Asia, China continues to deliver strong growth on the back of our NRDL listing and Japan is gaining traction. Both have acceleration potential based on our recent approvals and hypertension. As we pull through the US and the EU guideline recommendations and promote the expanded label in the US, we're well set up to maintain growth in Q4. On slide 28, if we think about the future story of Entresto, it continues in line with our existing trend. We know that there remains significant patient potential. We have 4 million patients on treatment with Entresto today, yet 70% of eligible patients can still benefit. In the U.S., where we have a broad chronic heart failure label, 85% of addressable patients are still on prior standard of care, and that makes ACE and ARBs our clear competitive focus. With the recent guideline changes, positioning Entresto in first line, we now have an opportunity to drive broader and earlier adoption of Entresto globally. So overall, we're bullish about the continued growth of Entresto to at least $5 billion. If I move on to slide 29, Zolgensma had a strong quarter and has just surpassed $1 billion in sales for the year. In the U.S., we're treating over 90% of babies, according to our label, due to the high rates of newborn screening, In Europe, we had strong uptake in Germany and Italy, and we saw a bolus of sales in the UK following reimbursement. We expect we've seen the bulk of this in Q3, but we have also reached agreement on reimbursement in Russia and a number of smaller EU markets. So if we look ahead, we see four key drivers of future growth. New markets with Egypt, Saudi Arabia, Ben Al-Aqsa expected to contribute in Q4. increasing newborn screening so that we can treat patients early on when the benefit of gene therapy is the greatest. Heavier patients, our SMART study aims to drive confidence in Zolgensma's value across the full EU label and intrathecal. Following the alignment of our phase three study design, we're now one step closer to bringing IT to patients aged two to 18 and thus ultimately address the full spectrum of SMA. If I move on to slide 30, While the multiple sclerosis market has contracted quarter over quarter, Casimta grew 56%. Importantly, Casimta has been a strong driver of the dynamic B-cell market with an additional 1,000 patients on treatment. Our strategy remains focused on three elements. Increasing familiarity. We're maintaining a high share of voice, and we've added more than 500 prescribers versus Q2. Driving further clinical differentiation. We just presented three and a half years of IgG data at ECTRIMS, and we're generating evidence on switching and patient-reported outcomes needed to change clinical practice. We're also focusing on customer experience, ensuring fast onboarding and broad access to make it easy to initiate patients. We continue to see more than 50% of our uptake in first-line first switch, and we know how important this is because this is where we can have the highest impact on progression and long-term outcomes. We see huge potential in this B-cell market, and we're driving the growth in the dynamic segment. We have the right strategy, and we're going to take further share as the market rebounds. Moving on to site 31. On LECVIO, you most certainly saw that we received nice approval, and we're currently working to implement our broad-reaching commercial agreement with NHS England. We have also been fully focused on the upcoming U.S. launch. We're working closely with healthcare systems to prioritize ASCVD, to identify patients, to set up buy-and-bill, and we're also leveraging our Entresto sales force to educate on the unmet need in ASCVD. For customers who may not want buy-and-bill, we're creating a network of alternative injection centers where patients can receive Lectio. We've signed up more than 1,000 centers and expect them to become a significant factor in pulling through our demand early on. We're also ensuring we generate the right evidence needed to succeed in the U.S. market. Based on our engagement, we expect the majority of the 200 prioritized healthcare systems to start treating patients in 2022. The uptake will be skewed to the second half of the year when the majority of the systems should be ready for buy-in bill and our permanent J-code should be issued. We're working with diligence. We're taking a long-term perspective on what needs to be done to transform how ASCVD is treated to make Lecvio one of the biggest medicines for Novartis. In summary, we continue to execute against our strategy, maximize our growth driver, deliver our launches, and prepare for the next wave of products. The teams are working with a strong sense of urgency and purpose to be more customer focused so we can bring our innovation to more patients faster. I want to thank the teams around the world for their commitment and show my confidence in the continued momentum for a strong year end. Now let me hand it over to Susana. Thank you, Marie-France.

Moving to slide 33, the oncology business delivered a solid quarter, growing 5% versus prior year, with sales of $3.9 billion. Our growth drivers, as well as recent launches, performed well, with 16% growth versus previous year, driven by Chakavi, Promacta, Revolade, and Qiskali. Together, these products now contribute to more than half of the overall oncology sales. In the third quarter, we have seen healthcare systems in oncology slowly returning back to normal as patient visits, diagnosis, and treatment rates are gradually improving. We are seeing that new patient starts continue to accumulate and expect this to translate into growth acceleration in segments like recent launches and hospital administered products by the end of the year. Moving to slide 34, Qiskali delivered strong performance in the third quarter, growing 27% with sales of 230 million. The uptake was mainly driven by continued very strong momentum in patient share gains ex-US, particularly in Europe. We achieved market-leading position with 40% patient share in premenopausal patients in the EU4 and UK. It is a doubling in patient share since we reported overall survival results from Lona Lisa 7. In the US, Kystrali grew 5% versus previous year, driven by increased demand in pre- and post-menopausal patients, with usage shifting to earlier lines of therapy, which is very encouraging. And as you heard from Vaas, we are very excited about the new OS data from Mona Lisa 2 that showed the longest overall survival ever reported in advanced breast cancer, achieving a median overall survival of over five years. We believe that such impressive results are the evidence of Qiskali's ability to change tumor biology to enable a better response to endocrine-based therapy. Qiskali is now the only CDK4-6 inhibitor with proven OS benefit across all three phase three trials of the Mona Lisa program. with different endocrine therapy partners, regardless of menopausal status or line of therapy. Therefore, with a lot of confidence in Qiskali, we have started a collaboration with SALTI and initiated a phase three trial called HARMONIA to evaluate ribocyclic versus pulvocyclic in patients with aggressive HER2-enriched intrinsic subtype of HR-positive HER2-advanced breast cancer. As Ma said, we are also very excited about the Ativan Natali study that is exploring Kiskali in both intermediate and high-risk population, and this would have the potential to more than triple patients of the metastatic setting. Natalie's study completed enrollment ahead of schedule in second quarter of this year, and we are looking forward to a readout in 2022. Moving to the next slide, I'm pleased to share with you that our two blockbusters in the hematology franchise, Promacta Revelate and Chaka, we continue to deliver very strong double-digit performance, driven by strong demand across all regions. Promacta Revolate is our thrombopoietin receptor agonist indicated for use in ITP and severe aplastic anemia. The brand continued to perform very strongly, driven by sustained efficacy, oral convenience, and non-immunosuppressive profile. In the U.S. alone, we have seen 10% increase in new patient starts versus previous year and expecting that further uptake will be fueled with the expansion of the U.S. indication to include persistent ITP. XUS Revolate is also performing strongly, driven by increased use in both indications and also additional demand from China. Chakavim is our Chak inhibitor and a standard of care in myelofibrosis and polycythemia vera, and has also demonstrated impressive growth with significant uptake coming from earlier use in both indication and strong momentum in China. We have completed filings in acute and chronic graft versus host disease in the EU and are actively preparing for launches in 2022. So overall, I'm very pleased with the performance of these two important hematological brands and the potential they have in terms of future growth and patient benefit. Moving to slide 36, I would like to update you on how we are preparing for the upcoming launches of Asiminib and Lutetium PSMA 617. Asiminib is our stamp inhibitor that has the potential to transform the standard of care in CML. In the Phase III Assemble study, Asiminib nearly doubled the major molecular response rate at 24 weeks compared to Bosutinib. Asiminib is well positioned for launch in third-line CML as we are preparing to leverage our broad commercial footprint and the established collaboration with the hematology community. We are pleased to see a very high pre-launch awareness of 80% amongst hematologists. We have completed FDA and EMA filing earlier in June. The U.S. FDA has granted two breakthrough therapy designations and fast-track designation for Asiminib and is reviewing the file under real-term oncology review with approval expected early next year. And just to remind you that alziminib has blockbuster potential in the third line, but we are also seeing opportunity to address the unmet need in first-line CML and therefore have initiated a phase three study of alziminib versus investigator-selected TKI's with final readout expected in 2024. Another exciting asset that we are preparing to launch is our radioligand therapy Lutetium PSMA 617 that has demonstrated significant OS and RPFS benefit in advanced metastatic prostate cancer. Our awareness campaign on PSMA in phenotypic precision medicine is progressing well with the awareness among target physicians doubling over the last 12 months. Our focus is on the top 200 treatment centers and education about process optimization, as well as on treatment site expansion to ensure site readiness at launch. We completed filing with FDA, and in addition to breakthrough therapy designation, also received priority review with the DUFA date in the first half of 2022. In addition, we have completed filing to FDA for registration of our own Gallium PSMA11 PET kit to further support availability of imaging agents. And submission of both Lutetium PSMA and Gallium PSMA PET to the EMA is on track. So we are moving this confidence into earlier lines of therapy and have initiated two phase three studies with Lutetium PSMA11 in metastatic hormone-sensitive prostate cancer and in pre-taxane metastatic prostate cancer. So overall, very much looking forward to bringing these two assets to market. And with that, I hand over to Harry.

Yeah, thank you, Susanne. Good morning and good afternoon, everyone. I'm now going to walk you through some of the financials for the third quarter and the first nine months of the year. And as always, my comments refer to growth rates in constant currencies unless otherwise noted. So on slide 38, we see the summary of our operational performance for the third quarter of the first nine months. We had a solid quarter three with strong performance of our innovative medicines division. As we had anticipated, the business was normalizing post-COVID-19, with group sales up 5% and core operating income growth of 9%. Quarter 3 net sales reached $13 billion, driven by the innovative medicines growth drivers. Core operating income of $4.5 billion was driven by higher sales and productivity programs across the business. Core EPS was up 11% to $1.71, and free cash flow grew very strongly, by plus 64% in US dollars to $4.4 billion. Year-to-date performance reflects the slower growth in the first half of the year, mainly due to the impact of COVID in certain parts of our business. We grew top and bottom line 4%, and core EPS grew 7% to $4.88, and free cash flow was $10.3 billion, growing 23% in US dollars. Next slide, please. On slide 39, I want to break down our performance by division. And as mentioned, the solid performance of the company was driven by Innovative Medicines, which delivered a strong quarter with 7% top line growth, 13% bottom line growth, and a margin of almost 38%. Looking to the first nine months for the year, Innovative medicine showed a healthy growth of 6% on top line and 8% on the bottom line, with margins of 37%. I'd just like to remind you of the seasonality of margins. As you know, the fourth quarter has usually the lowest margin due to higher spending phasing. Innovative medicine's year-to-date performance was driven by continued strong double-digit growth of the key brands Bas and Marie-France and Susanna mentioned. with 3.5 billion sales growing 18% for Cosentix, and Tresto with 2.6 billion growing 41%. So GenSmall reached already 1 billion in sales. The Cosimta launch was accelerating. Additionally, the on-cookie growth drivers continue to do very well. Moving to Sandoz, nine months' performance reflects a heavier impact from COVID than in the other parts of the business. However, in quarter three, Sanos has seen some recovery, particularly ex-US, where sales grew 3%, driven by both biopharmaceuticals and retail generics. US sales were impacted by double-digit price erosion, partnership terminations, as well as higher off-contract sales the prior year. The US continues to be a challenging business environment for the wider generics market. However, we expect the situation to improve also in the US in the midterm as the impact of COVID-19 lessens and our biosimilar launches begin to deliver. On slide 40, I just want to highlight the impressive growth we have seen in pre-cash flow, which is now 10.3 billion for the first nine months, up 23% compared to the prior year. The main drivers of this have been higher operating income, lower payment from legal matters compared to what we had last year, and favorable working capital. Now turning to our full year guidance on slide 41. Overall, for the group, we confirmed the current guidance. For sales, we continue to expect low to mid single-digit growth. And for the bottom line, we expect mid single-digit growth ahead of sales. For innovative medicines and Zandos, we are confirming the top-line guidance, but we are fine-tuning our bottom-line guidance. We continue to expect Innovative Medicine's division sales to grow mid-single digits. Reflecting the strong performance of the division, we have revised upwards co-operating income guidance, which we now expect to grow high single digit. For Sandoz, we continue to expect sales to decline in the low to mid-single digit range, But we now expect cooperating income to decline mid to high teens. The key assumption for the guidance is that we see a continuation of the return to normal global healthcare systems and prescription dynamics in the remainder of the year. And in addition, we continue to assume that no Jelenia and no Sandostaten LAR generics enter the US market in 2021. Next slide, please. We thought it might be helpful to you to outline our expectations for the fourth quarter. In short, we expect similar growth in quarter four as we had it in quarter three, with the top line growing in the mid-single digit range and bottom line growing high single digit. Taking into account our year-to-date 4% growth both for top and bottom line, this brings us to our full year guidance of low to mid-single digit growth for sales, and mid-single-digit growth for the core operating income line. Finally, on slide 43, as currencies are constantly changing, I want to bring to your attention the estimated impact currencies would have on our results using the current exchange rates. So if late October rates prevail for the remainder of 2021, the full year impact of currencies would be a positive 2.3%. on both sales and cooperating income. For quarter four, it would be negative 1% point on sales and between zero and negative 1% point on cooperating income. And as a reminder, we always update these impacts of the currencies on our website on a monthly basis. And with that, I hand it over back to Lars.

Thank you, Harry. So moving to slide 45. We did want to give you an update on some of the events we'll be holding later this year and into next year. Based on feedback from our investors, we've decided to convert our December 2nd event, our Capital Markets Day, to a focused R&D event on innovative medicines. Here we'll go over our R&D assets, lifecycle management programs, our mid-stage portfolio in each of our key therapeutic areas, as well as have our NIBR scientists on hand to discuss our technology platforms and other efforts within NIBR. And on May 23rd and 24th of 2022, we'll plan for a Meet Novartis Management event, which we hope to hold in person. Moving to slide 46, in closing, solid quarter, strong performance from Innovative Medicines. We've raised our peak sales guidance, really demonstrating our confidence in the long-term growth of the company. We remain confident in the pipeline, in the launch brands to fuel our growth, not only in the midterm, but also with our science-based innovation for the longer term. And we've announced a strategic review of Sandoz, a leading business in generics operating in an attractive market, but this is the right moment to really evaluate who is the best owner for that business for the long term. So thank you very much for listening, and we'll open the line up for questions. I would say to each of our questioners, if you could limit yourself to one question and then move back into the queue, we can do our best to accommodate everyone's questions. So with operator, please open the line.

As a reminder, to ask a question, you will need to press star and 1 on your telephone. To withdraw your question, please press the hash key. Please combine while we compile the Q&A roster. Your first question comes from the line of Graham Parry from Bank of America. Please ask your question.

Great. Thanks for taking the question. So it's on Natalie and your comments on the slide that you've re-reviewed the FDA feedback and that invasive disease-free survival is acceptable as a primary endpoint provided no detriment to overall survival. That seems contrary to how it's treated Lilly's-Vasenio where they were asking for more OS data to see if the curves were separating. So can I just clarify when was that feedback given and why do you think FDA could treat Cascali differently from Vasenio And are you stratifying by KI-67 score as well, given the FDA was also interested in or only approved in that biomarker population for Vazenio? Thank you.

Thanks, Graham. John?

Yeah, thanks for the question, Graham. And we did have discussions with the FDA on our Natalie trial. As you know, we increased the sample size for our Natalie trial, knowing the criteria that we've included for the overall study population. These discussions were recent. I would say that it was within the end of the third quarter where we had these discussions, and they gave us very clear feedback that the design and the endpoints actually would be supported based on the invasive DFS endpoint, given that obviously the results would be based upon the overall totality of the evidence that's available. As Bas disclosed earlier and shared with you, we have looked at the overall patient population. We've looked at the overall population focused on intermediate and high-risk patients in the study, which is based on the AJCC criteria. That also includes biomarkers and gene expression tests to select the high-risk patient population overall. So what we also know is based on the intermediate risk population, the IDFS rates are similar in this intermediate risk population as in the high-risk population. So based on the overall totality of the background here, we're very confident in our approach.

Maybe just one addition. I think you asked specifically. We do collect KI-67 data in the study, but right now that's not part of our statistical analysis plan. And, of course, we'll share that data with the FDA when requested. Thanks, Graham. Next question.

Thank you. Your next question comes from the line of Peter Welford from Jefferies. Please ask your question.

Hi, yes, thanks for taking my question. Just on the Sandos strategic review, I'm wondering if you can give us some insights into perhaps what internally there are metrics that you're perhaps assessing or looking at during the course of next year, and also whether or not there's still the aim to both, I guess, return this business to growth, but also still potentially put the margins back on a positive trajectory before the business is separated. or if you now believe that the U.S. world solids business is now essentially in terminal decline and that business is not a business that you feel is appropriate to be part of Novartis. Thank you.

Thanks, Peter. So I think, as always, and as we learned through our Alcon review as well, we consider a number of factors. One, of course, is the synergies between our innovative medicines business and the Sandoz as well as the dis-synergies between holding both of these businesses. We also consider, I think, capital allocation and capital allocation measures to ensure we're optimally allocating capital to maximize shareholder returns. We, of course, want to consider what would enable us to build the best generics company, the aspiration to be a leading generics company in the world, and which setup would best enable that. So, I mean, those are all, in broad strokes, the factors and I think you saw with the Alcon spin that we're adept at understanding these factors, hopefully making the best decision for our shareholders and the relevant businesses, and then taking the relevant actions. Harry, anything you want to add?

I think, Peter, of course, all of the other details, right? The different options have different tax implications. If it would not be retaining the business, all of those you would expect that we would, of course, always consider. But I think all of this will be part of our strategic review. And I think fundamentally, the question comes down to who is the best owner of this very good generic business.

Maybe Richard on the growth profile. Richard.

Yeah, thank you. I mean, Peter, you comment about the U.S. I mean, clearly that the U.S. business, we've just had very few launches in terms of oral solids over the last year, 18 months. And clearly we're washing out a number of the partnership deals. as well. The medium-long term looks much more attractive, both as we accelerate the number of small molecule launches, but also, more importantly, we bring a number of biosimilars to the marketplace over the next three, four years, which should materially change the direction of the business, both in the U.S. It's also worth noting that the European business now is back into growth, as is our international business. So, broadly, it's starting to normalize post-COVID.

Thanks, Richard. Thanks, Peter, for the question. Next question, operator.

Thank you. Your next question comes from the line of Andrew Bourne from Citi. Please ask your question.

Thank you. A question for John relates to canakinumab. John, if I remember in Kantos, the early separation of the curves, the treatment effect that we saw with canakinumab was attributed to occult metastatic disease in these patients. With that in mind, assuming it is a viable mechanism, should we expect an interim analysis to read out positively? And if it doesn't, we should therefore assume the probability of success is very low. And then separately, perhaps you could comment on whether even there's any role for this drug, given this is an increasingly well-served indication, meaning the adjuvant with T-centric to Griso and more indication, more drugs on the way. Thank you.

Yeah, Andrew, I'll take it, obviously, because I was one year for the Kento study when I was a development head. So, you know, in that result, I think first and foremost, it's important to note that the cancer study had an inclusion criteria of two milligrams of DL of HSCRP. The median was in that kind of two to five range in the overall study population. Our hypothesis at the time was that these were undetected cancers. Cancers were not detected in the screening either through physical diagnosis or imaging. that in the course of the study, canakinumab was able to reduce the incidence of these cancers becoming fulminant and the mortality of these patients. This we believed was due to IL-1 beta's role in the tumor microenvironment and IL-1 beta potentially having a role in enabling and blocking IL-1 beta enabling immune cells to enter the cancer and therefore potential synergistic effect in the metastatic setting and in the adjuvant setting that in the initial stages of a tumor's development that IL-1 beta plays an important role. So I don't think that an interim read on this is going to be meaningful. I think this study was going to have to go to the end. We believe the positioning of the medicine is very much that canakinumab, in our view, has a very favorable safety profile given the long experience we have treating children with this medicine who find it very well tolerated. We didn't see any differences in this first-line setting. And so having the potential, and I would say it's high risk to be clear, of an all-comers therapy for the adjuvant setting that does not require any PD-1 screening could be attractive. Now, whether physicians choose an IL-1 beta therapy or a PD-1 inhibitor, that will all have to be figured out, but it's important to note as well the adjuvant Canopy A study is an all-comers study based on what we knew at the time from the Kantos study and is the lowest CRP group of these studies in terms of the median CRP levels in the enrolled patients, most consistent with the Kantos study. Thank you, Andrew. Next question, operator.

Thank you. Your next question comes from the line of Laura Sutcliffe from UBS. Please ask your question.

Hello. Thank you very much. Just on your new Entresto peak sales guidance, does that $5 billion number capture the possibility of an LOE earlier than the 2025 anchor date that we've been talking about so far? Thank you.

Mary Fath?

Yeah. So for our internal forecasting assumptions, we're looking at 2025. And that's how we've forecasted. So if you'd like a little bit more detail on, you know, why we feel comfortable with the $5 billion plus on interest, though, it's really based on the significant market potential, the further implementation of guidelines, and obviously the recent launches in Asia. And that leads us to $5 billion plus mark. But that is assuming for internal guidance, a 2025 LOE.

Thanks very much. Next question, operator.

Your next question comes from the line of Simon Baker from Redburn. Please ask your question.

Thanks so much. Question for Susannah on Lupi's PSMA. I was wondering if you are pursuing on the diagnostic side a technetium PSMA imaging kit, because the feedback that we've had from from radiologists over here, is that there was huge excitement in the UK about Lu PSMA, but there is some concern that its utility beyond large centers because of the need for gallium PSMA screening will make it harder to use more broadly. I just wonder if that's feedback you've seen elsewhere, if you're looking at using the much more easy to administer, if not quite so impressive technetium PSMA in order to broaden the number of centers that can practically use it. Thanks so much.

So thank you, Simon, for the question. So we have focused on gallium PSMA really to have this ready for launch, and we wanted to make sure that there is a diagnostic available. You see the other options also focus on gallium, and then I think there is quite a push for fluoride, you know, PSMA diagnostics. As this is still, you know, I would say across the G7 markets, the most used diagnostics. I think Cygnetium is quite focused in the UK. I didn't hear so much about that ex-UK. And I mean, as we are targeting earlier lines of therapy, you have to see that we really have a diagnostic available that is very easily available, and that's certainly the fluoride one. So that's what we are focusing on, and probably technetium is quite focused in the U.S. Sorry, in the U.K.

Thanks, Susanna. And I just wanted to take a step back. I will clarify a comment I made to Graham's question. For Natalie, we are collecting KI-67. It's in about 70% to 80% of the total enrolled patients. It's part of the statistical analysis plan, but not a pre-specified stratification factor. So with that, we'll move to the next question.

Your next question comes from the line of Kier Perret from Goldman Sachs. Please ask your question.

Hi. Thank you for the question. One on LECVIO, please. Marie-France, kind of you spoke about the confidence in LECVIO launch and the preparedness for that going into 2022. Kind of the clarity around what you partnered with NHS in the England still remains very kind of dim or very clear, unclear. So just wondering if you can give us a bit more details on how we should think about the rollout of this molecule in the UK. And then just in the same vein, I think consensus is looking at about $250 million in revenue for this drug next year. Do you think that appropriately reflects what you see as the launch dynamics for this? Or should we be thinking about something lower or higher than $250 million for Lexio next year? Thank you.

All right. So thanks for the question and the opportunity to talk about Lexio. So on the UK, first of all, we're very happy with the positive NICE approval. and the commitment from the NHS to fund and treat 300,000 ASCVD patients. I think this provides solid proof that we can get the broad access prior to the outcomes data and based on the back of obviously solid evidence around LDL-C lowering. So what we're doing right now in the UK, and this is going to be the focus for the next couple of months, is really identify patients and work on the care pathways to reach 1,200 GP networks. It's early days, but we're doing We're seeing really great progress around central funding, the digital patient IDs, the incentives for GPs, and the educational programs. And the feedback from lipid specialists and GPs has also been very positive. So we expect a slow ramp in Q4, but you can expect to see some significant ramp up in Q1 of next year for the UK. If I then turn to the U.S., Again, here we're focusing on the 200 systems of care, and as we said, we're also looking to build Buy and Build. The first half of the year is going to be focused on our J-code, building up the Buy and Build infrastructure, going through the P&T reviews, and making sure that we're ready. And then you'll see that uptake towards the second half of the year. And the number you quoted, we feel extremely comfortable with that number for next year.

Thanks, Mary Fouts. Next question, Operator.

Your next question comes from the line of Simas Fernandez from Guggenheim Security. Please ask your question.

Oh, great. Thanks so much. Just a quick question. I noticed that your G12C agent moved into or is planning to move into Phase 3. Just help us understand the data that prompted the planned advancement of the KRS-G12C inhibitor. And then, you know, just as a follow-on to that, Do you think this asset can differentiate meaningfully from other therapies on its own, or is the differentiation really key to near-term development in combination with your SHIP2 inhibitor?

Thanks. Thanks, Seamus. I'll hand that to John. John?

Hey, Seamus. Thanks for the question. And our KRAS G12C, which is JDQ433 in our program, we've advanced this molecule forward and plan to have phase three in place by the first half of next year. What we've seen is really good PKPD data and good tolerability by the patients. As we move forward, you'll be hearing more about this in the Congresses next year. On your specific question about the strategy moving forward and differentiation versus the other KRAS G12Cs in the potential marketplace and in the marketplace now, we think that the approach for KRAS G12C is really in combinations. What we've seen so far is is that you are getting durability is probably not as long as what we would like, and that we're seeing mutations. And with those mutations, it will be a combination approach. And these combinations could be a number of factors, including our potential TNOs shipped to in our pipeline. You'll be hearing about that combination from our pipeline next year also.

Thanks, John. Next question, operator?

Your next question comes from the line of Sarita Kapila from Morgan Stanley. Please ask your question. Hello.

Thanks for taking my question. So could you help us understand the rationale for taking your VTK inhibitor, iremibrutinib, forward in CSU, especially when legalizumab is being trialed in this setting also? And how are you thinking about positioning of the two assets relative to one another and also to the PIXINT? Thank you.

Thank you for the question. John?

Yeah, so remibrutinib, as you probably have seen, is our highly selective and potent covalent oral BTK inhibitor. We did do an extensive phase two program in CSU, which was recently released, and what we saw is really good uptake, and the efficacy was extremely strong. Now, what we've seen is the efficacy was seen both at four weeks and at 12 weeks, And in addition to that, we saw efficacy very early at the one-week time point. So really strong efficacy data pinned back on the safety profile, which, as we think about BTK inhibitors, sometimes are saddled with LFTs, also cytopenias, and we did not see that in our overall program. So given our approach, we're very comfortable advancing CSU into our Phase III program. Now, one thing we should also note is legalizumab, we've seen phase two results, which were equally strong. And the approach that we're taking here is legalizumab would be giving patients an opportunity at Q4 week treatment with a sub-Q injection. And then remibrutinib would be an oral opportunity given the large, massive unmet need in CSU patient population. That's our overall approach.

And I think Mary-France could add a few more points. Mary-France?

Yeah, so just maybe going back to the size of the market and the unmet needs. So we know there are about 1.3 million CSU patients who are inadequately controlled in the top 11 markets. In fact, these patients are on antihistamines and steroids and really almost considered the sort of forgotten or unwanted patients. So we really want to make a difference in this space. Of course, we have a potentially strongly differentiated asset with ligalizumab. and an opportunity to increase the biologic penetration. We also have a strong footprint, right, not only with dermatologists, but don't forget that we work with Zolaire in the U.S., and so we have the strong relationships with allergists as well. And then bringing an oral to market would really sort of complete the picture and make it perhaps an attractive first option post-antihistamine for you. CSU patients. So we're very excited about this space. We think we can build on a legacy that we've already built and make a real difference for these patients.

Thanks, Mary France. Next question, operator.

Your next question comes from the line of Joe Walton from Credit Suisse. Please ask your question.

Thank you. I wonder if I could just go back to Sandoz and if you could give us a little bit more detail on your biosimilar program. If we're going to be trying to value this, we'll have to really think about this in perhaps more detail than we do when we just look at Novartis on its own. So perhaps you could just tell us a little bit about where you think you're going to be particularly successful and give us some help as to see how we're going to get to 3 billion by your 3 billion sales target. Thank you.

Thanks, Jo. I'll hand it over to Richard. Richard?

Thank you, Jo. As you know, we don't normally disclose specific details of our programs. What I will say is we intend to launch six biosimilars in both the US and Europe over the next few years, which will start rapidly accelerating our business. And currently, we have over 15 and expanding number of projects, both in-house developments or through partnership deals that we intend to launch in the coming years. So clearly, as we go through the process, and at whatever time is appropriate, we'll give greater clarity in terms of the makeup of that. But obviously, it's relatively sensitive in terms of recent disclosures.

I think the only point I would add is that I think Sandoz does its best to cover the major LOEs, and I think there really is another wave of LOEs in this kind of 24 beyond standpoint in biologics. And with an increasing interest in the U.S. to enable biosimilars to fully participate, I think it's a tremendous opportunity for the Sandoz business. Thanks, Joe. Next question, operator?

Your next question comes from the line of Richard Vosser from J.P. Morgan. Please ask your question.

Hi, thanks for taking my question. Just going on to Cosentix, obviously this year we had some formerly disruptions which you navigated very well. Maybe give us an idea how the discussions have gone for 22, and is that a normalization so that we can see volume growth coming through or manage to win back any positioning? Thanks very much.

Thanks, Richard. Mary Fox?

So, thank you, Richard. So you're absolutely right. In the U.S., we've seen strong value growth versus previous year due to this access change. What we have seen, though, in Q3 is quarter-over-quarter volume growth, and that's in line with the market. So we do expect volume growth to be the growth driver in the U.S. for 2022. We also expect our access position to stay stable, and we do believe that most major key payers will have us on formulary. So ultimately, what we need to do in the U.S. next year is really focus on our strengths, which is our existing markets. I talked about the focus on the PSO, PSA comorbid patient. There are two-thirds of the patients that have additional manifestations, and we have a really broad body of evidence in this space, the axial spa patients, and then, of course, preparing for IV, which could be a significant opportunity in the U.S. 14 to 18 percent of these patients are in medical benefit for PSA. And then, of course, our hydridonitis superativa, 220,000 patients in the U.S., so significant opportunities to prepare for in 2023. Great.

Thanks, Mary France. Next question, operator.

Your next question comes from the line of Richard Parks from McLean BMP Paribas. Please ask your question.

Hi. Thanks for taking my question. It's just on business development and M&A, you've been relatively quiet this year. So I'm just wondering if you could talk about your appetite for M&A based on opportunities out there and valuations and maybe thoughts on capital allocation if there weren't sort of near-term opportunities and thinking about buyback and when a decision might be made on that. Thank you.

Thanks, Richard. Harry?

Yeah, Richard, you know, overall, we remain with our capital allocation priorities, as we always laid out, investment in the organic business, growing dividend, as you have seen in March, coming in over $7 billion. And then, of course, bold on M&A and in-licensing, where we did the in-licensing of TISLA, LISMAP, you know, for $650 million. And we have continuously, of course, created a market and we continue to look opportunistically for bolt-on M&A opportunities that fit our franchises and existing infrastructures, if you will. But, of course, they won't happen every year. Therefore, that's what we say up to. And from that standpoint, it's not a formula. But we continue to be basically on that path. And then from a share buyback standpoint, as you know, we always buy back the employee participation program, as we did this year, to never dilute our shareholders. And we finished in the first half, you know, a $2.5 billion program that we announced end of last year. So we're working along those lines on our capital allocation and no change in our M&A and BDNL strategy.

Thanks, Harry. Next question, Operator.

Your next question comes from the line of Naresh Chauhan from Intron Health. Please ask your question.

Hi there. Thanks for taking my question. Just one on Sandals, please. You mentioned that Sandals is more integrated into Novartis than Alcon was. So it would be really helpful if you could quantify the size of these synergies in fully separating Sandals out to allow us to kind of value any value creation from a separation or a sale. Thank you.

Harry?

Yeah, Naresh, that's of course what a strategic review will inform us about. And that's why we take some time to do that very thoroughly. And, you know, I would say there are two components to this. Also, if I compare this to the ICON situation as we analyzed, of course, no decision made at all. So there could also be a decision of retaining. But also in case of a separation, I would say it's probably a bit easier at the moment because Richard and Stefan Lang and our technical operations team and the Sandoz team are focused on making the manufacturing and supply chain as autonomous as possible over the last two or three years. And that basically has been completed and within Novartis. So there we are probably ahead of where we were when we announced Alcon. On the other hand, Of course, the business has been built over 20 years plus with acquisitions and system-wise fully integrated, where Alcoa probably was a bit more separate as it was shorter with the company. So we have a couple of head and tailwinds, but that's why doing such reviews takes that time and we indicate, that in a good year, we will give an update. If things go a bit faster, we come earlier. But this is operationally complex. And of course, we have to exactly figure out synergies, dis-synergies, potential stand-up costs, tax considerations, as well as separation costs.

Thanks, Harry. Thanks, Naresh, for the question. Next question, operator.

Your next question comes from the line of Florent Caspides from Subgen. Please ask your question.

Good afternoon, everyone. Thank you very much for taking my question. A quick one on Aciminib. We're just wondering if you could elaborate a bit on your strategy in the first line, because you are just starting the clinical program, how you will position this product versus the pretty good already existing drugs. Thank you.

Yeah, thank you, Florence. As you heard us, we are quite excited about Aciminib to get this prepared for launch in third line. As you show, we saw remarkable results versus Busutinib in this setting, which tells us that this mechanism of action is very effective. And we know from medical experts and patients that there is still high need and in first line CML patients really are on a lifelong treatment and we know that if you Have a fast and deep molecular response early on this could even lead to a treatment free period and that's what really experts are aiming for so there is the the desire to be even better in first line and And the approach that we take is really to compare it to different TKIs. That's why we allow investigator-selected TKIs, so that we have a broad range of comparator products. And then we have to see. The focus certainly is then on the deep molecular response. And if we can prove that, certainly that really has significant potential. So that's the strategy we're pursuing for Asimilib in early lines.

Perfect. Thanks, Susannah. Thanks, Lauren. Next question, operator.

Thank you. Your next question comes from the line of Tim Anderson from Wolf Research. Please ask your question.

Good afternoon. Thank you for the question. This is Richard Wagner with Wolf Research on behalf of Tim. Question on Sandoz, please. How does Novartis avoid a situation similar to Pfizer's Upjohnspin where they divested a lower multiple business, that when analysts did some of the parts analysis, ended up with a figure that basically suggested the spin was destroying value because the multiple in the Upjohn business was lower than that was put on the parent Pfizer company. A Sandoz spin could end up causing the same thing to occur because generic GE multiples are pretty much always lower than pharma company multiples. So how can Novartis mitigate this? Thank you.

Yes, thanks, Richard. So first and foremost, I think we're focused on building a strong business with clear sales growth outlook, strong margin outlook that can be a leading global generics player. I'd also note that when you look in the generics sector, you see a wide range of multiples. When you look at specialty generics players, players that are more exposed to Europe or Asia versus players more exposed to the U.S. And so that's all of the work we need to do to really understand what is the best way to maximize value for our shareholders as well as enable Sandoz to be as successful as possible. And we have a range, I think, of different options we can look at, and it's very rightfully pointed out, including retaining the business. So I don't see it as an analogous situation, especially given that Sandoz is the number one generics player in Europe. the number one global antibiotics player in the industry, and the number one biosimilars company globally in sales, primarily driven by its ex-U.S. business. So relatively low U.S. exposure, which in our view is what drives the lower multiples of some of the peers. So that's kind of our perspective at the moment, and we'll, of course, update it as we do the assessment. Thanks a lot, Richard, for the question. Next question, Operator.

Your next question comes from the line of Wimal Kapadia from Bernstein. Please ask your question.

Wimal?

Apologies. It looks like the line is disconnected. So we'll go on to your next question, which comes from the line of Simon Baker from Redburn. Please ask your question.

Simon? All right, next one, operator.

One moment. It looks like I've opened Simon Baker's line. Please go ahead, Mr. Baker.

Hello, can you hear me?

Yeah, we can hear you, Simon. Thank you.

Excellent, excellent. Yes, a quick question for Harry, just following up on the subject of the buyback. Could you just remind us what your buyback mandate capacity left is? Because I noticed that This is the first Q3 for about eight years when you haven't bought back any stocks. So just a reminder on what you were left able to buy would be great. Thank you.

Yeah, thank you very much, Simon. So overall, we are pretty much, I think, close to our authority from the AGM, but we do usually then renewal of it. But overall, when you look over the last years, we have consistently done like, it's not a formula again, but roughly... $2.5 billion per year or $5 billion every two years. Again, not a formula. It completely has to do with what opportunities do we have basically on M&A and on both on M&A. And then, of course, so from a capital allocation standpoint, the first three priorities are worked through. And then, of course, in terms of where the share price is. But it's not only a question of share price, of course, also capital allocation priorities. And we just finished one. So from that standpoint, at this moment, we have not announced an additional one.

Thanks, Eric. Thanks so much. Next question, operator.

Thank you. You have a further question from the line of Graham Parry from Bank of America. Please ask your question.

Great. Thanks for taking the question again. And this one's on Remy Bruton. I just wondered what data, if any, you have on CNS tissue for remabrutinib, and if you have any brain penetration with it, any evidence of any effects on microglial cells. So that's something which Sanofi obviously talks about with tolabrutinib quite a lot.

Thanks, Graham. John?

Yes, thanks, Graham. We have done some preclinical studies in this area. We have seen CNS penetration. In this early stage, what we don't know is exactly what the extent of the clinical validation and the clinical correlation in this central when you actually have central activation in these areas. So given that, what we're confident of overall in remibrutinib is that it's a very clean profile asset, as I've stated earlier, in terms of potency and selectivity. So we look forward to sharing some of these preclinical data as well as the overall clinical profile for remibrutinib.

Great. Thanks. Thanks, John.

Next question, Operator?

Your next question comes from the line of Emmanuel Pakidakis from Deutsche Bank. Please ask your question.

Thank you for taking the question. Maybe since I'm back at the queue, I'll take a couple if I may. One, the AVEXIS pipeline in neuroscience has been a somewhat slow story since the deal. We announced a setback in Rett syndrome today. If you could just give us a bit more on that. Was that safety or efficacy related? That would be very helpful. And next steps? I think we were anticipating clinical development in Friedrichs and ALS by now, but I don't think you've announced anything to date. And then maybe the second question, if I may, just the shape of 22 looks pretty similar to 21 before you run into some LOE thereafter. So I'm thinking low mid-single digit sales growth with some margin improvement. Perhaps you could give us some initial thoughts on why that statement might be wrong. Particular heads and tailwinds for next year would be helpful. Thank you.

Yeah, so thanks, Miguel. First, on our gene therapy pipeline, first, we have a number of targets that are progressing right now in the clinic. I mean, with the intrathecal now entering into phase three, we have a number of ophthalmology programs and the recent optogenetics acquisition. With some of our neuroscience assets, we've decided to optimize our program to ensure that we really get I think the optimal capsid as well as insert combination that will enable us to maximize efficacy. We've done extensive profiling work now, and we think that's the prudent course. It doesn't change our commitment to Rett syndrome, Friedreich's ataxia. And behind that, we have a number of other programs advancing in monogenic as well as polygenic neurological diseases. So as with this field, we're always learning, and this is a case where we learn something more in our preclinical work, and it's making us just take a pause and optimize the program, and then we hope to move quickly again into the clinic. Clearly, these patients need better therapies. In terms of the shape of 22, it's really, of course, premature for us to comment, but maybe Harry could provide any perspective.

Yeah, as always, we have the tradition of guiding for next year with our full-year results, you know, end of January. And overall, on the margin progression, on the margin progression, if that was part of the question, I would expect basically incremental continued improvement over the next years so that we do expect basically sales growth. Of course, over the next year, this VAS has laid out with a 4% CAGR roughly. And with that incremental margin improvements, you know, after we have improved the margin, almost 300 basis points last year. You see another margin improvement this year, but of course last year was also due to the almost inability to partly promote given the pandemic situation. And on top of that, we have now further improved with excellent productivity programs, resource allocation, and overall, of course, cost consciousness and changing the way we run the company in a more efficient way, taking full advantage of virtual opportunities.

Thank you, Emmanuel. Next question, operator.

Thank you. Your next question comes from the line of Joe Walton from Credit Suisse. Please ask your question.

Thank you. I just wonder if you could talk a little bit more about your enthusiasm in CAR-T. So the current generation haven't done so well. Now you're bringing a new one in. What's going to be so different? And have you sort of solved the problem whereby older people's blood can actually be more effectively manipulated and just have more successful and perhaps faster treatments. Thank you.

Thanks, Jo. Our teams have done a lot of work, and we've learned a lot since 2015 when we've entered this space. We continue to believe that CART therapies, cell therapies, I have the transformational benefit when successfully delivered as you've seen in the patient populations are currently licensed and have a tremendous potential. So we invest in a new approach which we believe can optimize our cost of goods, importantly, which enables us to make a much stronger financial return, optimizes our speed of production, which enables us to flexibilize production, increase scale. but most importantly, hopefully, can generate more durable and deep responses for these patients so that we get to higher ORRs or CRs as is relevant. And we believe that, continue to believe that autologous approaches versus allo approaches are the best way to do that. I think our Nibiru scientists have done an outstanding job and will at least present the first set of data at ASH and then we'll move forward But I think it's worth remembering we have a global footprint in cell therapies, a global capability, and we have the ability, given our financial firepower, to stay the course and really try to be a long-term industry leader. Next question, operator.

Your next question comes from the line of Stefan Schneider from Global. Please ask your question.

Yes, hi, thank you. What kind of cough and cold season is captured in your full-year guidance? And maybe in this context for quarter four, you're right, you could start to return pre-COVID levels in several markets. Can you specify that a bit further? So what several width markets do you think of? Thank you.

Richard, on a cough and cold. Thank you, Stefan. In our guidance, we've assumed, I guess, a more normal cough and cold season in line with previous seasons. So we've not assumed an exceptional one, but we've assumed it in line with previous years. Clearly, it's worth noting that the previous cough and cold season was pretty much non-existent due to social distancing and mask wearing. But we're seeing that normalizing and pickup in demand of our anti-infectious business, as well as our OTC businesses, certainly in Europe and in other markets.

Great. Thanks, Richard. And I believe we have one last question. Operator?

Your final question comes from the line of Wimel Kapadia from Bernstein. Please ask your question.

Great. Thank you for taking my question. I believe that somebody already asked on the microglia for remibrutinib. So can I just ask on Kiskali, please, and just the feedback post-Mona Lisa to OS benefit. Are you really seeing any increased appetite to use the drug versus the other CDK4-6s? And what is your base assumption the share that you can now capture in the metastatic setting longer term? You know, will this data actually change dynamics? Just looking at the volume trends in the U.S., it really seems like, you know, relatively modest expansion share so far. So how should we think about the next few years? Thank you.

Thanks for more. Susanna?

Yeah, thank you for the question. So, I mean, as you rightly say, the Mona Lisa 2 data is certainly the biggest segment where we now also could demonstrate OS data. And we really hear feedback from medical experts that these are quite impressive data and confirms that there is something differentiated about Qiskali. So as I said, the last weeks we see increased demand also in the U.S. And we keep focus on really delivering this message, working on getting this education story through. And we also quite encouraged that now with COVID getting more normalized, that more patients start because that is, of course, certainly what was kind of hindering that with less patients getting new treatment initiations, there was also less opportunity to grow. So we remain confident in Kiskali. We will focus on educating patients. And I believe Kiskali is the best differentiated OS or CDK46 with strong OS. And therefore, we believe we have the confidence for Kiskali to remain a significant growth driver.

Thanks, Susanna. And then Harry just had one quick correction.

I just looked up our remaining share buyback program. So as we just renewed it recently, it's roughly $8.5 billion. So we have room. But again, no plans at the moment.

So typically that's the $8.9 billion authorization from the AGM, but no plans at the moment. So with that, we can close the call. Thank you all very much for joining. We look forward to your joining us on December 2nd, our R&D Day, where we'll have our R&D leaders walking through the pipeline, giving you relevant details, hopefully getting your understanding up and hopefully excitement up on our mid and early stage pipeline. Look forward to that discussion. In the meantime, wish you all very well. Thank you again.