Ipsen S.A. (IPN) Earnings Call Transcript & Summary

Good afternoon, and good morning, everybody. It's my great pleasure to welcome you to our Capital Markets Day here, live in London and also through our webcast. My name is David Loew, I'm the CEO of Ipsen. And for those of you who joined us through the webcast, our slides are available on ipsen.com. It's a great opportunity this afternoon for me to take you through the transformation journey that Ipsen has gone through to the achievements and illustrate together with my team, the growth journey that we're going to go through in the coming years. Next slide, please. This is our safe harbor statement. Next slide, please. We're going to structure our Capital Markets Day in 2 sections. On the first section, I will give you an introduction on the strategy and our priorities followed then by Aymeric Le Chatelier, our CFO, who is going to give you an insight on our financial sustainability and capital allocation, which is then going to be followed by Christelle Huguet, our Head of R&D, taking you through our pipeline. This first section is going to be followed by a question-and-answer session, which is going to take about half an hour and is going to focus on the strategy, the financials and the pipeline. We then will break for 15 minutes. For those of you who are through the webcast connected, you can submit your questions in the webcast, and we're going to take them in this first question-and-answer session. This second session is then going to focus on our brands, our medicines, and Bartek is our head of product strategy is going to start focusing on Dysport, Somatuline, Decapeptyl and Cabometyx, which is then going to be followed by our President of North America, Stewart Campbell, who is going to talk to you about Onivyde, Tazverik and Sohonos. And then I have Mari Scheiffele, our Head of President, International. She's going to focus on Bylvay and elafibranor. And this second session is going to be followed again by a question-and-answer session, this time with everybody being here available for you also to answer detailed questions on our medicines. So with this, I would like to start with our strategic outlook. Next slide, please. So we have established our strategy in 2020. Next slide, please. And we put it under a very consistent vision. We want to be a midsized leading pharmaceutical company focused on medical unmet needs in oncology, hematology, rare disease and neuroscience. And we strive to achieve this position because we have great capabilities that we can bring in into these 3 therapeutic areas as well as having a lot of unmet medical needs still and also leverage the potential of those 3 therapeutic areas. Next slide, please. Central to the execution of the strategy and the vision and achieving division is our executive team. You can see here, we have 7 new members, which have joined us since 2020 and they all bring deep industry knowledge from the pharmaceutical industry into Ipsen. So it's a pleasure to have them on board, and you will be able in the break to interact with many of them. Next slide, please. Our strategy in 2020 was put under the umbrella of Focus. Together. For Patients and society. It has 4 pillars bringing the full potential of innovative medicines to patients, building a high-value, sustainable pipeline, delivering on efficiencies to enable the investments that we have done and will do as well as supporting our growth and boosting a culture of collaboration, excellence and also impact to society. We have seen strong achievements built on that strategy. We have more patients on the treatments from Ipsen medicines than ever before. We have strong financial performance that we have shown and delivered, and we have built a platform with our pipeline, which bodes very well for our future success. So I would like to now zoom in on to our achievements and then take you through our growth journey. Next slide, please. It's exciting to say that since 2020, we have seen on our growth platforms, double-digit growth. And that has overcompensated the gradual erosion that we have predicted for Somatuline and where we are optimizing the value. It was made possible through our excellence in execution on the commercial but also on medical affairs and the capabilities that we have in-house. Furthermore, we have executed on our pipeline where we have seen the advancement of several key trials and also regulatory approval and we have enriched and diversified our pipeline by adding more than 20 new medicine candidates into our pipeline over the last 2 years alone. This was made possible through in-licensing activities but also through the medicines we acquired through acquisitions like on Epizyme or Albireo, which we have closed this year in March. We went, at the same time, in parallel through a deeper transformation in the R&D and looking at the portfolio with a close eye. So you have seen that, for example, the rightly enabled antibodies, we have licensed out, and we think we have now a very strongly well-focused pipeline. On our third pillar on efficiencies, we have been able to actually decrease the marketing investment, and that has freed up resources to invest into our pipeline and advance our new medicines. We have also used the cash flow generation to do either acquisitions, but we also have in fact, expanded our manufacturing capacity, for example, on this part, which was so important to be able to drive the growth of the neurotoxin franchise. And we have instilled into the company a simplification mindset being agile and leveraging digital initiatives. On our fourth pillar, I'm very proud to say that we have already now 50% women in our global leadership team, which are the top 170 leaders, and I think that's a benchmark in the pharmaceutical industry. Furthermore, we have been recognized in 25 countries as a great place to work. We have to also go as a company beyond serving patients. We also serve society. And I'm very proud to say that we have reduced our greenhouse gas emissions on CO2 by 28% since 2019, and we have switched, in 90% of the cases, to renewable energies. So a reason for us to really be proud of. Now I want to take you through our growth journey. Next slide, please. You can see on this slide that in the period of 2020 to 2023, we have really laid the foundations with our new strategy. We have licensed in multiple new drugs. We have sold the Consumer Healthcare division, and we are now a fully focused specialty care company. Now this bodes well for the next phase of growth, 2024 to 2027, where we will see a dynamic growth with several launches and with the firepower that we have, further pipeline expansions. And that's going to build the momentum, which is going to be a lasting momentum for the long-term future, 2028 and beyond, where you will see with the new drugs that we are launching and our growth platforms that we will have a much more balanced and diversified portfolio across the 3 therapeutic area. And we will continue making more deals. It's obvious. And actually, in the 7% guidance that we have given you or at least the 7% guidance that we have given to you, we have already the early and mid-stage compounds that we are licensing in included there, so we are ready for the future. Next slide, please. I will now go through the individual pillars, and I will start with our first pillar. Next slide, please. You will see the portfolio evolution over the future to develop with a strong growth coming from the growth platforms with Onivyde, Cabometyx, Decapeptyl and Dysport. And that's going to be enriched by the launches of our new medicine with elafibranor, Tazverik, Bylvay and Sohonos. And as I mentioned, we have the firepower to do more external innovation. So you can expect that we will do more deals. And that's going to vastly overcompensate the erosion of Somatuline. Next slide, please. In fact, to give you an idea. In 2020, we had one product, which was exceeding EUR 500 million of sales. This year, in 2023, we already have 4 products exceeding EUR 500 million, and we will see in 2027 and beyond, actually 7 products, which are exceeding this EUR 500 million. So quite exciting times in front of us, and I would now like to walk you through the regulatory approvals. Next slide, please. You can see here our 4 launches that we are executing next year. The first one with Onivyde is going to have a new indication in first-line metastatic pancreatic ductal adenocarcinoma, a particularly aggressive form of pancreatic cancer. We have the rights in the U.S., and we're expecting a regulatory decision by quarter 1 of 2024. We are in the midst on Bylvay on launching the Alagille indication in the United States. We got the approval last July, and we have just submitted the second brand submission for the odevixibat in Europe, and we expect a regulatory decision by mid-2024. And then very excitingly, on elafibranor, you have seen the news that we published also this morning, the FDA has not only accepted our filing, but they also gave us priority review with elafibranor. So actually, have to update this slide already. It's not going to be the second half. It's actually going to be at the end of the first half that we have the PDUFA date because it's June 10 for elafibranor in the United States. In Europe, we expect a regulatory decision in the second half of 2024. Very exciting. Biliary -- primary biliary cholangitis is a relatively frequent form of a rare disease. It affects 9 women out of 10 patients. We're going to get the second line indication here. So we're really excited about the potential of elafibranor. And then we are in the middle of the launch of Sohonos for fibrodysplasia ossificans progressiva, or FOP. It's a disease where bone are forming where they should not form. So for example, in your ankles, and that can be a very crippling disease for patients where they can require a wheelchair or even die early because the bone suffocate them. So it's a terrible disease, and we're very proud that we got the approval in August in the United States, and we are going to submit the file also in some selected Rest of the World markets. Now these launches are going to change the composition of our sales and next slide, I want to walk you through that. You can see here on the left side, we are today relying on oncology to about 3/4 of our sales. That's going to change in terms of weight. Clearly, we still see strong growth potential in oncology with obviously, Onivyde, which has a great sales potential, but also further development of Cabometyx, but we're going to see an even stronger growth coming from our rare disease franchise based on the multiple launches with Bylvay, elafibranor and Sohonos as well as seeing strong growth also in the neuroscience field based on our neurotoxin franchise where we are commercializing Dysport in the treatment space and in the aesthetic space, also together with our partner, and we're expecting significant growth there. We are, in fact, adding new indications with the migraine indications, and we're going to hear more about that. You're going to see a rebalancing of this portfolio, not just on a therapeutic area, but also on a geographic area. And I would like to have my next slide, please. You can see that we have about 1/3 of our sales coming from North America, 40% from Europe, and we have about 25% of the sales coming from the Rest of the World. That split is going to change because we will see a strong acceleration in the United States. We have multiple launches there. On Europe, we have a bit more moderate growth based on further growth on Dysport and Cabometyx mainly. And then in the Rest of the World, we have multiple opportunities in Asia Pacific and in Latin America where, in fact, some of the access restrictions that we're seeing in Europe are less acute. So with this, I would like to now zoom on the United States. And next slide, please. You can see that the U.S. has gone through a [ prominent ] growth of a compounded annual growth rate in the last 5 years of 16%. And we project this growth to continue based on the high potential that we have with Onivyde. In fact, the first-line indication is going to allow us to expand the patient pool. It's a much larger patient pool in first line than in second line and also by longer treatment duration. Furthermore, we have also the relaunch of Tazverik, which is ongoing, and we are going to add the second line indication there. And then we're going to have all our rare disease products kicking in with Bylvay in PFIC, ALGS, on elafibranor and also on Sohonos. And you have observed a strong growth of our neurotoxin franchise sales in the treatment space in the United States. All of this will be driven by operating leverage, and we have a strong organization in place. Next slide. So let me focus now on our pipeline. Next slide, please. I will let Christelle elaborate on the details of our pipeline, but I would like to really highlight 2 points. We have a much fuller and more diverse pipeline than ever. We have many combines now in the preclinical space and in the early clinical and late-stage clinical space. But importantly also, we have a more diverse portfolio with oncology drugs, rare disease drugs, but also on the neurotoxins with the long-acting neurotoxin and new indications coming on Dysport. So very exciting. So give me a bit more detail on this one next slide. In fact, we anticipate to achieve up to 3 regulatory approvals in 2024 based on Onivyde, odevixibat in Europe and elafibranor, and then we're going to see the completion of up to 5 pivotal trials with Cabometyx in prostate cancer with Tazverik in the second-line indication of follicular lymphoma with Bylvay in biliary atresia, Fidrisertib also for the treatment of FOP and Dysport in migraine. You can see also that we are advancing very, very interesting compound, which is called LANT. We call it the LANT. It's the long-acting neurotoxin that we are developing. It has been uniquely engineered with a recombinant formulation, adhering much better to the nerve strengths and having less distribution in the interstitial tissue. So very excited about that. We are anticipating to see a truly longer duration of action here with the LANT. And then we are going to continue to expand our early-stage programs. All of this also supplemented by the external innovation. And I would like to now walk you through what is our strategy on external innovation. Next slide, please. You can see that our strategy is crystal clear on external innovation. We are focused on solid tumors and hematological tumors for niche tumors and for biomarker segments. And I would just like to kind of take a pause here on this point. On oncology, you see with the science that there is a lot of progress understanding the patient pools much better. So a breast cancer, a colorectal cancer, a lung cancer is not one cancer anymore. We see many, many different patient segments inside of these cancer types, and that means there are smaller patient pools with more precise therapies. And that's a unique opportunity for a midsized company. That's very attractive to us because it means actually that the peak sales goals that we have given for us, which is between EUR 300 million to EUR 800 million bodes very well for those smaller patient pools in oncology or in hematology. The same applies in rare diseases. There are 7,000 rare diseases, which do not have a solution today. Also often, these are small patient pools. We have, of course, now already a strong franchise in liver, and we have a bone franchise, but we are going to tag on other franchises. So we will expand. We are agnostic in rare disease on which diseases we go because, in fact, it's a very good fit for a midsized company in terms of the go-to-market model and the clinical development model where we know how to do this. On neuroscience, we're going to focus on rare neurological disorders, but we are also going to expand beyond our neurotoxin franchise into adjacent non-rare areas. And we are quite excited by that because there is a strong progress on the basic science happening in the neuroscience area with better predictive markers that's relatively recent and new, and so we are excited about that. Next slide, please. I will now talk shortly about the efficiencies. Next slide, please. We have been capturing efficiency levers through 3 ways. One is we have a very strong budget discipline because we do targeted investments. So we are disinvesting on Somatuline allocating our investments now on the new launches and the pipeline. We have been generating efficiencies by swiftly integrating new assets and the 2 companies that we have acquired, and we are gaining economies of scale because we have added products, and we don't need a lot of more headcount to actually do that. Second, we have a strong goal and ambition to actually shorten the time from unblinding to submission. I can illustrate that with elafibranor. We have submitted in a record time from the unblinding to the submission in 3 months. We have told the market we are going to announce it to you once we have the acceptance, that has happened today. So we have the acceptance for elafibranor from the U.S., from EU and also in Great Britain. We want to also submit faster now to emerging markets because there is quite an unmet medical need and potential, and we want to launch much faster, and we will also focus on increasing the automation into our R&D department. And then we will leverage digital and data and analytics where it can inform where we go on R&D and what kind of patient segments we want to tap into as well on the execution on our go-to-market where we can have a much more refined go-to-market strategy now today, which is important, for example, for rare diseases. Then we're going to boost the data collection through medical records and that's going to be important, for example, on some of our rare diseases, and we're going to elaborate a bit more on that. And then we are going to strengthen our decision-making based and powered by Big Data and artificial intelligence. So great progress there. Next slide, please. So now I want to go on to our fourth pillar, which is boosting a culture of collaboration, excellence and the impact on society and delivering a strategy without having the best employees and having a holistic view on the company is not possible. So let me elaborate a bit on this. Next slide, please. We have a very intentional approach about our culture. We think it is a big lever and a big enabler. We can actually build on the above-industry benchmark level of engagement of our employees. We're very proud of that. And we have now a very attractive employee value proposition because we are nimble. We are a midsized company, yet we have a global presence, and that attracts many people. We have a good pipeline now, many launches to come up, and we have a very strong purpose orientation. We're also being very people-centric, and we develop our leaders. We have now invested into modernizing our headquarters. We have already done this in Boston, where we united everybody in Boston in the headquarters. We are doing that now in Paddington here in London, and we are going to also move office and bring research and all the core asset teams and the brand teams together in one building to really foster that stronger collaboration in Paris in 2025. Furthermore, we have a rely on diversity because we want to supplement and bring in different views into the company. All of that relies on a relentless focus on making an impact for patients and we put them really at the center. Now we can't just focus on patients. We also want to focus on society and that leads me now to our next slide, which, next slide, please, is our generation Ipsen, which stands for our ESG agenda. So we have clear goals here. We want to reduce by 50% our greenhouse gases in absolute on Scope 1, 2, but also on Scope 3 by 2030. We want to be at net 0 in 2045, and I'm proud to say that we are climate-neutral already in 2025. On patients, we want to reduce the submission not just to the FDA and the EMEA that I have just explained to you, but also to the emerging markets. And we have a tiered pricing framework that we are rolling out to tap into the unmet medical needs in these emerging markets and allow patients to get on our medicines. And then on people, we want to maintain our 50% women in the global leadership team ratio as well as focusing on getting to an equitable gender pay by 2026 at the latest. And then on governance, we are linking these ESG criteria to the compensation of our top senior leaders and we're going to go for the ISO certification again. We have it already for this year, but also in the future for the anticorruption. So next slide, please. So that concludes my first section. I think our midterm priorities are really clear. We're going to continue to expand and advance our pipeline, supported by external innovation and the firepower that we have. We are going to continue to maximize the value of our medicines, and I'm excited to say that we have these 4 launches coming up in 2024, and we are going to continue to deliver on our sustainability road map. And with this, I'm going to hand over to our CFO, Aymeric Le Chatelier.

Thank you very much, David. It's my pleasure to be with you. Good morning. Good afternoon. I'm Aymeric Le Chatelier, Ipsen Chief Financial Officer. And now I'm going to talk about our midterm financial outlook and also the way we see our capital allocation priorities and framework. So let's start now maybe with the very solid foundation that we have based on our 2023 financials. So next slide, please. As you can see, we are confirming today our guidance for 2023, where we expect to continue to grow our top line by at least 6% at constant exchange rate. This is going to be driven by our growth platform. We'll continue to deliver double-digit growth, but also by the contribution of our new medicines being Tazverik, being Bylvay and Sohonos that we recently launched and also the gradual erosion of Somatuline, which continue as expected. We are also confirming our core operating margin to exceed 30% of net sales. This will be driven by the very solid profitability of our base business, which is compensating for the significant investment we are making for the recent acquisition of Albireo and Epizyme. And finally, we have a very solid balance sheet. And as you can see, at the end of June, we had EUR 1.7 billion of firepower for external innovation. This is based on 2x net debt, 2x EBITDA, and this is also relying on a very strong free cash flow and a very low level of debt. So let's now look at how we've been performing since our last Capital Market Day in 2020. So next slide, please. As you can see here, we are well on track to deliver our 2020 objective and targets that we set up in December 2020. So if we start with the top line, we gave the guidance at that time that we will be growing the top line by 2% to 5% per year. And today, I'm very proud to say that by 2023, we have grown our business by 8% per year. Strong achievement with our portfolio, but also the significant resilience of Somatuline. If we talk about the cost, our commitment was to lower our SG&A and to be able to invest in R&D. And here, we are fully delivering also because our SG&A have been lowered from almost 40% to 36%. So this is a 4 percentage point improvement between 2019 and 2023. And at the same time, this is basically due to efficiency but also leveraging our top line growth. We have been able to reinvest in R&D. And our R&D ratio to net sales has grown from 15% to 19% in 2023. So this is a 4 percentage points increase related to both investments in our internal pipeline, but also supported by external innovation and the recent acquisition, especially supporting Bylvay and Tazverik. If we talk about the balance sheet. We committed to generate a cumulative EUR 3 billion firepower by 2024. And up to 2023, we already generated a cumulative EUR 3.5 billion firepower. And as you know, we utilize this firepower to complete transaction for about EUR 2 billion, especially the licensing agreement with -- on elafibranor, but also the acquisition of Epizyme and this year of Albireo. So based on that very strong track record, I'm very pleased to now get more into the detail of our midterm outlook. So next slide, please. Our midterm outlook, first, as David was talking about, our next phase of growth is going to be 2023 to 2027. Secondly, those numbers do not include what we call late-stage external innovation transaction. But by the way, they assume that we're going to do early to mid-stage external innovation transaction. First, on the top line, our plan is to exceed 7% top line growth per year over the period. This is going to be sustained by all the launches of new medicines or new indications that you've seen from David, but also by the continued strong performance of our growth platform. Regarding Somatuline, we expect that the erosion will continue, and there will be some further erosion based on a more competitive market for Somatuline, whether it's generic competitors or other players entering these markets. Regarding the bottom line on the margin, we're expecting that by 2027, we should be able to get a core operating margin at 32%, at least 32% of total sales. This will be driven by a significant improvement of our SG&A ratio, but also maintaining a sustained level of R&D and managing properly the mix of our product. I will go more into the detail of the cost base of that core operating margin by 2027. But let's start maybe with the top line. And on the next slide, let's go through the key medicines that will be driven -- driving our top line growth. As you can see here, we are providing today the detailed peak sale for each of our key medicines. And first and very importantly, these are global peak sales for all the territory for which we have the rights today. Secondly, they are nonrisk-adjusted peak sales we used in the past to provide. So today, all the peak sales are non-risk-adjusted. And lastly, they're all in euro, and we used to provide in the past some peak sales in dollars. With this very unified way, as you can see, and David was mentioning it, we have 7 medicines that will exceed EUR 500 million peak sales during the period, exceeding by the way, '23 to 2027. This is across the 3 therapeutic areas of oncology, rare disease and neuroscience. Let's start with oncology. And as you see, Cabometyx, we are confirming that Cabometyx will deliver peak sale in excess of EUR 700 million based on the current approved indication. Then we have Onivyde, and based on the expected launch following expected FDA regulatory decision in early 2024, we are planning anticipating peak sale sales for Onivyde to exceed EUR 500 million. Regarding Tazverik, as you know, the prelaunch of Tazverik was a bit somewhat disappointing. So we are revising our peak sales. But with a successful SYMPHONY-1 trial, we are expecting Tazverik to be able to reach at least EUR 500 million peak sales. And finally, Decapeptyl. We believe Decapeptyl can continue to grow, and our expectation is a mid-single-digit growth. If we now return to rare disease. Rare disease, first, we are confirming the peak sale potential for Bylvay. And based on the successful billiary atresia indication, and Christelle will go more into the design of the study, which is going on today. We are confirming that we expect in excess of EUR 700 million of peak sales for Bylvay. Regarding elafibranor, building on the strong momentum of the FDA priority review and the strong data that was presented recently at Medical Congress [ AASLD ], we are confident that we can exceed EUR 500 million peak sales for elafibranor based on the current PBC indication. And finally, I think for Sohonos, we are now adjusting our peak sales based on the recent FDA approval of the product on top of some selected Rest of the World country. So now we are expecting Sohonos to be able to deliver more than EUR 100 million peak sales. And finally, in neuroscience. With a very attractive neurotoxin market, both in aesthetic and therapeutic, we are planning this part to continue to grow at the high single-digit growth. So this is really for the top line. So now let's focus to the baseline of our costs supporting our core operating margin or at least 32% by 2027. Next slide. And here, let's start with the gross margin. We're expecting the gross margin to decline over the period, but this is mainly due by the way, of the erosion of Somatuline and the mix of product, even if we have some very high-margin products which will be launched and will contribute to the solid gross margin. This is why we believe we should be able to maintain a gross margin above 85%. This will be complemented by manufacturing efficiency to lower the unit cost of the product and that we are manufacturing in-house. And on top of that, we are benefiting of the other revenue coming from our partnership for Onivyde ex U.S. and for Dysport in the aesthetic market. On the R&D, very important component. As I said before, here, our guidance is based on external innovation for early to mid-stage, our objective will be to maintain and even to go slightly above 20% of sales to really support both our internal pipeline, but also that ambition in terms of external innovation. While at the same time, we continue to be efficient, we're going to continue to optimize organization footprint and also leverage the recent acquisition that we've done to deliver the expected synergies on our portfolio. And finally, on the selling and marketing expenses. We really want to leverage our current organization. So we expect that ratio to go below 35% of sales by 2027. This will be also driven by the synergies that we are delivering very well this year and will continue to deliver for the recent acquisition and the continued effort on efficiency driven by procurement, driven by digital across the entire organization. So based on that very strong cost discipline, we are very confident that we will be exceeding the 32% profitability by 2027. Let's now turn of how we're going to invest and what are our priority in terms of investment for the future. Next slide, here. As you can see, our capital allocation will remain quite consistent. Our priority is towards external innovation. We will continue to see a limited evolution of the dividends. We will continue to see a limited share buyback. Most of the share buyback will be only to cover management incentive plan. And we will build on a very strong free cash flow generation, and there will be some limited milestones especially in 2024, where we're going to pay milestone for Onivyde in first line, but also a sales milestone to our partner for Cabometyx based on the strong performance of Cabometyx since the licensing agreement was signed. So based on that priority, we will maintain our policy at net debt at 2x EBITDA and I think we're very pleased to announce that we have a firepower for external innovation, a cumulative firepower by 2027, up to EUR 5 billion. This firepower is not going to be used for one single transaction or acquisitions, so there are going to be multiple transactions over the period. This is going to be across our 3 therapeutic area. This is going to be across the various stage of development, early stage, mid-stage but also later stage assets. And this is going to be also from acquisition of company or asset to licensing transaction. We will also maintain a very strict financial policies based on financial return, but also in the way we are structuring transaction. As you know, we highly structure the recent transaction that we did with contingent value rights for Epizyme and Albireo, and we will continue to structure and derisk the transaction. Based on that strong momentum, I think we can continue to fuel long-term growth and value creation for all the stakeholders and shareholders. So if you go to the next slide, as you can see, our G&A will continue to be driven by top line growth. We'll continue to transform that top line growth with our operating leverage to improve our profitability, convert that profitability into cash flow and be able to reinvest the cash flow into external innovation. With all of that, we think that there is long-term growth and long-term value creation at Ipsen. With all of that, now I will hand over to Christelle, which will go through the pipeline and the R&D. Thank you. Next slide.

Thank you, Aymeric. Good afternoon, everyone. It's my pleasure to join you today. And since it's my first time meeting you, let me take a few moments to introduce myself. I'm Christelle Huguet, I lead R&D at Ipsen. I come from a pharma background, more than 25 years in the industry, Pfizer, Alexion, Biotech. My passion is in translating pharmacology into medicine that adds value to patients. And I'm very proud to have the opportunity to shape the next phase of the Ipsen R&D portfolio. In this next section, I will cover the strength of the R&D organization, our strategy of partnering by design to fuel the pipeline. We will review the progress we have made since 2020, where we continue to expand and I will wrap up with some near-term key milestone. So let's get started by looking at our R&D organization on the next slide, please. We have a strong R&D organization of more than 700 colleagues, and we are present in 4 major geographic hubs. That gives us access to sourcing and accelerating innovation worldwide. In addition, it gives us the ability to build in our clinical trial, a very deep understanding of the patient journey, the treatment paradigm and the requirement of health authorities that vary in various regions. In addition, at the heart of a medicine, there is a molecule. So our well-established expertise and capabilities in both small molecule and complex biologics development really allow us, in combination with clinical know-how and a series of very strong CRO partnership, to have access to a rapid scale-up model that is required to execute on the pipeline as we continue to expand. So with that in mind, let's look at how we're fueling the pipeline with our R&D engine. Next slide, please. We have chosen at Ipsen, a strategy of accelerating innovation through partnership by design. The right partnership is rooted in science first. We strive to deliver best-in-class or first-in-class program into our portfolio, and we strongly believe that the best innovation is taking place in the academic and biotech community. So what the partner brings to the table is a very strong understanding of the biology of the target, the platform modality that is required to optimize and deliver a clinical candidate molecule. We bring, at Ipsen, the strength to evaluate, but also identify strong scientific potential for differentiation and clinical positioning. When you combine this with our deep expertise in translational and clinical development in oncology, rare disease and neuroscience, we are able to drive rigorous clinical trial and key regulatory expertise that allow us to have a straightforward path to submission. Finally, we bring to bear our in-house end-to-end capabilities in both pharmaceutical development and manufacturing to turn the molecule into a medicine. So when you combine the R&D strength and our partnership by design strategy, let's look at what we've achieved in the past 3 years. Next slide, please. When you think of partnership by design, what you can see here on this diagram is what it looks like. We know that great partnerships create great possibilities. We have expanded our pipeline through every stage of the development in the 3 therapeutic area, but also we source from the full ecosystem: academic research, small biotech and large biotech. As with every portfolio in action, we have managed some data-driven attrition. But importantly, we have had some great successes that we're going to touch on in the coming section. So on the next slide, please, when I reflect on the past 3 years -- next slide, please, Ipsen has had a more than 20 program into the portfolio. We have integrated Epizyme and Albireo's pipeline within 9 months. We have continued to strengthen our expertise and presence in rare disease, in particular, in rare liver diseases, and we have expanded into hem-oncology. We have achieved this whilst maintaining a laser focus on execution on the pipeline. And you will have heard already, we have had approval of Cabometyx nivolumab in first-line advanced renal cell carcinoma. Also approval of Sohonos in fibrodysplasia ossificans progressiva, both in the U.S. and Canada and 2 strong positive Phase III readout with Onivyde and elafibranor. This, while continuing to advance earlier program in the clinical development. So let's have a look at what the pipeline looks today. Next slide, please. First of all, let's take a moment to orient ourselves. The first thing to notice is we have been very active in external innovation. We have expanded the pipeline in all stages of development through the 3 therapeutic area. In teal green, you can see our oncology pipeline; dark blue, rare disease; and in orange, the neuroscience pipeline. I would like to start by drawing your attention to the left-hand side column, where we display our early development pipeline in contrast to quarterly update, where we focus more on the clinical trial advancing. So what you notice is we have added a number of assets in that early stage. And this is in order to generate a regular entry of Phase I program into our portfolio. The top 1 coming from our partnership with AGV signed only 3 years ago in 2020 that has already delivered a clinical candidate, IPN01194 is ready to enter Phase I next year. Now if we focus on oncology with the Epizyme acquisition, we have brought a number of epigenetics program in the pipeline with our important Tazverik compound in Phase III. Our partnership with GENFIT marked our entry into rare liver disease with elafibranor in primary biliary cholangitis. We have augmented our presence in rare liver disease, with the earlier acquisition of Albireo this year, bringing again a number of assets in a number of indications in rare liver disease, the most advanced being Bylvay. In addition, we continue to invest in our neuroscience, in particular, neurotoxin portfolio. And here, I would like to highlight the start of 2 new Phase III in episodic and chronic migraine with Dysport, an important medicine for patients that we continue to evaluate for further indication. Now we're going to take the time to dive a little deeper in some of our clinical assets. Next slide, please. Starting in oncology, with our topoisomerase inhibitor 1 investigated in first-line metastatic pancreatic ductal adenocarcinoma. Onivyde has delivered the first positive Phase III trial in first-line PDAC in more than a decade. Our NAPOLI-3 study has shown some very strong efficacy as measured by OS and PFS, whilst importantly, using a lower dose of Oxaliplatin and irinotecan equivalent compared to FOLFIRINOX. So in the NALIRIFOX combination therapy with Onivyde, this lower dose has shown an enhanced tolerability with less neuropathy compared to FOLFIRINOX. What we've also seen in NAPOLI-3 is a lower incident of neutropenia when compared to Gem Abraxane. We are expecting early feedback from the FDA in 2024 with our PDUFA date on the 13th of February. Next slide, please. Continuing with oncology with Cabometyx, a tyrosine kinase inhibitor, investigated in metastatic castration-resistant prostate cancer, the CONTACT-02 Phase III has delivered positive PFS earlier on in the summer and encouragingly, a trend towards positive OS. The study is ongoing and we are expecting a readout in the second half of next year. Next slide, please. Now focusing on the latest entry in our oncology portfolio which is Tazverik, a selective EZH2 inhibitor, investigated in relapsed refractory follicular lymphoma. Tazverik received accelerated approval in third-line follicular lymphoma in the U.S. in 2020. Our ongoing confirmatory study SYMPHONY-1 is a Phase Ib/III global double-blind randomized active control trial, and the Phase Ib is fully enrolled. We are now exciting to further evaluate the potential of Tazverik in combination with R2 in both the wild type and the mutant population. Based on the strong results we are displaying here in a Phase Ib 18-month data cut, you can see a PFS of 79.5% and a nice response in both wild-type and mutant population. In addition, we're excited to be able to share further data, the 22.5 month data cut at an upcoming overall poster presentation at the ASH meeting. This well-tolerated treatment with Tazverik really has the potential to reach more patients. Its low toxicity brings advantage, especially in combination. The SYMPHONY-1 study is actively recruiting, and we are expecting early data readout in 2026. This concludes our deep dive in oncology, and we can now move to our rare disease portfolio on the next slide, please. Starting with Bylvay, a gut-restricted transporter inhibitor that has potential in a number of rare liver diseases. Bylvay received approval for PFIC, progressive familial intrahepatic cholestasis, in the U.S. and the EU in 2021. We secured an additional approval for Alagille syndrome in the U.S. earlier on this year in 2023 based on the strong results of the ASSERT Phase III study displayed here, where you can see that both the primary endpoint of improvement on pruritus and the key secondary end point on lowering circulating serum bile acid levels have been achieved. The strongest data has received positive opinion from the CHMP and forms the basis of our resubmission in the EU as a second brand for odevixibat. Next slide, please. We are excited to further evaluate the potential of Bylvay in the third rare liver disease indication in biliary atresia. The BOLD study is a -- it's a randomized, double-blind, placebo-controlled, global multicenter trial. In this study in biliary atresia, it is important to know that the most critical is to maintain the native liver in these very young patients. We're talking about babies here. And therefore, in agreement with the FDA, we have chosen a hard primary endpoint of time to liver transplant or death. Following a protocol amendment in order to adequately power the study, the BOLD study will now enroll 245 patients. It is ongoing, and we're expecting data readout in 2026. Next slide, please. Continuing in rare disease with elafibranor. An overall dual PPAR-alpha/delta agonist investigated in patients with primary biliary cholangitis. We were delighted to join the liver community at the AASLD meeting in November, where we presented the ELATIVE Phase III result in addition to concomitantly publishing the full Phase III data set in the New England Journal of Medicine. And some more excitement this morning with the acceptance of our submission dossier in the U.S. by the FDA giving us a priority review and a PDUFA date in June 2024, concomitantly submission in the EMEA and MHRA to cover EU in the U.K. The data from ELATIVE is very strong. So let me take some time to step through some of the key endpoints. Here, we're displaying the primary endpoint of biochemical response. And what you can see is a 47% treatment effect. This is a large effect, and I want to draw your attention to a very low placebo response. So it's very important. In Phase III efficacy data, when you see a low placebo response, you know that the efficacy you're measuring is driven by your treatment here driven by elafibranor. If we move to the next slide, we're looking at key secondary end points. Only patients treated with elafibranor achieved ALP normalization. Let me take you through some of the elements of the study because they are quite important, which treated a severe population in this study. We started high baseline mean of elevation of ALP of 321 and 324 unit per liter, respectively, in the treated and placebo arm. And we set a strict cutoff of 104 unit per liter for normalization. Despite the high baseline, 15% of our patients achieved full normalization. So if you think of where we started around the 320 and the strict cutoff of 104, that is more than 200-fold lowering. When we look at the profile of the ALP reduction, you will note that we have both a rapid and sustained treatment effect of 41%. And here again, of note, the placebo response is very low. And finally, on the very important endpoint of pruritus, we used 3 different instruments to measure each. We received positive trend on the Worst Itch NRS score and importantly, a significant reduction in both the PBC-40 and the 5-D Itch score instrument that are most relevant, most important to the patient. So altogether, we have a very strong Phase III efficacy demonstration for elafibranor. If we move to the next slide, this potential of elafibranor can be further evaluated in other rare disease. Here, we are testing elafibranor's potential in primary sclerosing cholangitis in a Phase IIb evaluating safety and efficacy. And we are also continuing to expand our presence in rare liver disease, adding another mechanism of action, a systemic bile acid transporter inhibitor that will target both the intestine and the kidney and the bile duct directly in the liver. And we're running a Phase IIa, measuring safety, tolerability, pharmacokinetic and pharmacodynamic. Moving on to our presence in rare bone disease with fidrisertib, a highly potent selective inhibitor of the mutated form of the ALK2 receptor that is present in FOP. FALKON is a registrational study, randomized placebo-controlled global multicenter trial. I want to highlight that fidrisertib has a differentiated mechanism to that of Sohonos. They both work in the bone metabolism pathway. Fidrisertib inhibits specifically the mutated version of the ALK2 receptor that is a driver in the FOP pathophysiology. And it blocks at the top of the cascade inhibiting activation by either bone morphogenesis protein or activins. We are very proud to leverage our expertise in rare bone liver disease to bring a potential second treatment for FOP patient, in particular, to younger children living with FOP. The FALKON study will enroll patients of 5 years onward following an observation safety period in the ongoing 15 years old cohort. We're expecting a data readout in 2025 with fidrisertib. Next slide, please. This concludes our rare disease portfolio, and now we're turning our attention to an important part of our neuroscience portfolio. We have been present in neurotoxin in a variety of disease indication with Dysport in particular. But here, let's focus on our latest innovative approach with our long-acting neurotoxin AB that is being evaluated in both adult upper limb spasticity and severe upper facial line. The LANT AB, as David mentioned, has been specifically engineered to introduce a higher receptor affinity and a longer duration of action compared to the currently available bond As. We have seen with the higher affinity at the receptor, an enhanced internalization of the toxin within the cell and measured less spread in our preclinical studies, indicative of the potential for a better therapeutic index for patients. So we believe that LANT AB has the potential to bring better outcomes for patients with a longer duration of action together with a potential decrease in frequency of injection and finally, a higher tolerability. This is a very exciting time for us when we have engineered specific property into a molecule and that we are starting to see the translation into clinical trial. So this concludes our deep dive in clinical assets. And now I would like to bring it all together by looking at near-term key milestone. Next slide, please. So when we look at the next 3 years, we have a very busy active portfolio in R&D at Ipsen, up to 3 approval in 2024 and 5 Phase III readout between now and 2026. On the next slide, I would like to summarize that it's a very exciting time to be in R&D at Ipsen. I am confident we will continue to apply the strength of our R&D engine to execute on the pipeline, and I'm very proud to work with the entire organization to continue to fuel the pipeline through external innovation with our strategy to partnering by design. I would like to thank you for your attention. And next slide, please. I'd like to hand back to David. Thank you.

Thank you very much. We are going to now have our first question-and-answer session. I would like to ask Aymeric Le Chatelier to join us on the stage here. [Operator Instructions] Please remind you that we are going to focus on the strategy, the financials as well as the pipeline. Deep dive questions on the brands, we're going to take in the second session of the Q&A later this afternoon.

John Priestner from JPMorgan. Just 2, if I may. So the first one on the top line sales growth trajectory. How should we think of that in terms of phasing? Is it possible that could be kind of 7% or more growth per year? Or is that a bit more back-end weighted and maybe in a blue sky scenario, kind of what things would have to happen for that to maybe hit more than 8%? And then maybe just in terms of the margin. So you've said your guidance doesn't include late-stage deals, but does include the kind of earlier Phase I/II deals. Maybe just an update in terms of your preference for late-stage deals versus early-stage deals? Could we expect kind of one late-stage deal per year as you've kind of done over recent years? And that would be it for me.

Yes. Great. Thanks a lot. In terms of the phasing of the growth, we have a fairly regular phasing of the growth. Of course, we are not going to give you the 2024 guidance right now. We're going to do that when we have the annual results presentation. But it is going to be rather gradual because, in fact, we have our growth platform, as you have seen on the illustration, which are really delivering very nice growth. And on top of this now with the launches we are going to supplement that. So of course, we will still see further erosion on Somatuline. But so these kind of 2 effects are going to be on top of each other. And so that's why it's going to be fairly gradual and not just backloaded. What would have to happen if you would have to exceed, let's say, 8%. Of course, you need to always execute very, very well. So sometimes you can have slowness of competitors or they are not executing well. As an example, you might also find that you can tap faster into patient pools that you have not expected. So for example, on elafibranor, we see that there are about these 9,000 patients in second line currently, but there are quite a number of patients in first line, which have not been switched to second line. So those are the kind of things which could happen. Then on the margin, I will have Aymeric, answer that.

So your question on the margin was twofold about the strategy of business development [indiscernible] to David. Regarding our margin just to confirm that our 32% [indiscernible] margin by 2027, as you said, is mainly including early and mid-stage in external innovation transaction. Our objective is to be able to use fire power across the different type of transaction. And clearly, may be some short-term dilution if we were to do some later-stage transactions. And as you know, we are managing very well synergy and being able to create not only value but also margin enhancements on the medium to longterm.

Perhaps on the question on do we have a preference on early or late? The answer is no. We want to do deals across the full spectrum. You have seen from the shape of the pipeline, we still want to have a bit more Phase I compounds, but the preclinicals are going to start moving into that space. So Christelle has talked about having the first entrance from these licensing in deals into the clinic now next year. So there is no preference in terms of the rhythm of making, let's say, late-stage deals -- of course, ideally, we would want to try to get to one deal per year, but it's all going to be down to the science, the opportunity. So it's not so, let's say, arithmetic or algorithmic. You need to really look at the science, you need to look at the opportunities. Are they convincing, yes, no, and that's when we're going to pace ourselves and really take that as a criteria rather than look let's just make a deal per year. That's -- that's not our key objective. Our key objective is to make the right deals. There's a question here.

Alistair Campbell from RBC. Just a couple, please. On -- coming back to the external innovation, I wonder if you could talk about what you're currently seeing in the current environment? I mean sort of Biotech funding issues and stuff like that. Is this a more productive period to be looking at acquisitions or in-licensing opportunities? Would you ever consider breaking the 2x EBITDA rule or something special came across the horizon? And then maybe just turning to elafibranor, I think CymaBay has started a first-line combination trial in inadequate responders. And just given the strength of the ALP normalization you see with elafibranor, is that something you're also thinking about?

Yes. I mean, clearly, in 2020 and 2021 regarding your Biotech question, we have seen a lot of, I would say too high prices for some of the biotechs. This has started to normalize in 2022. And I think this is actually an opportunity for us to now look at some of these biotechs because several of them have difficulties to refinance. Sometimes they have great science, but they don't have enough cash to actually keep the company running. So this might indeed open up opportunities for us. I think it has normalized again. So it has come to more reasonable levels. And we definitely have the intention to seize those opportunities. Perhaps a question to you, Aymeric, on the 2x EBITDA?

Yes. So as you know, this is a very strict policy that we apply for quite a long time. As you see, given our very strong free cash flow generation, also our improved profitability and top line growth, we already have EUR 5 billion to spend to do BD. So today, I think we are pretty pleased with the 2x EBITDA as we've said, if there were something really outstanding with a very quick deleverage, we can always discuss with our Board at sometimes, but I think our policy is really to remain within this 2x EBITDA. .

And then on our third question on elafibranor, I hand this over to Christelle.

Thank you. So on -- your question was about the ALP normalization with elafibranor in first line. So currently, first-line patients are mostly treated with UDCA. And about 40% of them are really not adequately treated. So there is a potential to further expand. For now, what we have seen is very strong data in ELATIVE, as you have seen a really strong effect on lowering ALP, a very strong effect on biochemical response and pruritus. So we believe we have a very good asset that has potential to be further explored in different lines of treatment in time, but also in other rare liver disease indications.

Very good. Thank you. As a change, we take also a question from the webcast. We have here a question from Richard Parkes from Exane. Does Ipsen expect Onivyde generics post patent expiry? If so, what should we assume for timing? So yes, we do expect generics. Although we have to say the hurdle, again, is relatively high because it's a difficult to manufacture a drug, it's nano encapsulated. So that needs a very, very specific know-how. You have seen with Somatuline that we didn't have that many new competitors, again, because it was a difficult-to-manufacture a drug. When they could appear? It's difficult to say. We are doing a bioequivalence study just on a production change. So that's certainly something which might be an additional hurdle for generics to come. So I don't want to speculate on the precise timing on this one, but we do not anticipate that it's exactly at the patent expiration. With this, we can take another question from the room.

Charles Pitman from Barclays. Two, if I may, as well. Just first on your 7 products, expected to have more than EUR 500 million peak potential by 2027 plus. I was wondering if you could just confirm how many products you expect to be reporting greater than EUR 500 million in 2027? And then just secondly, on the margin target, so the market is currently expecting around 34%. You're saying that there will be at least 32%. I was wondering if you could just break down how you're thinking about each of the individual products, which of them are likely to be kind of accretive or more dilutive to that target?

Very well. Okay. So we had the EUR 500 million in 2027-plus on the chart. So have to now remember from the top of my head. So it's going to be the Tazverik, Cabometyx. We are going to have certainly Bylvay and elafibranor. We have Dysport also being bigger and which one did I forget?

No, I mean to answer your question maybe more in detail, I mean the 7 products that you've seen are all the product except Sohonos, which will -- so your question is how much of those are going to be beyond 2027? As you know, Bylvay for sure will be beyond '27 because this is subject to biliary atresia study approval. I think Tazverik, as we've said consistently, the majority of the peak sales are to be expected from the SYMPHONY-1 second line expansion. So this is going to be beyond -- and I think elafibranor is probably a little bit too early to call, but this is a disease, as you're going to see later today where they're going to need some time to educate the markets to go there.

And Onivyde, which I just mentioned, though. So then on the margin on the 34% consensus versus our guidance on the at least 32%. Aymeric, do you want to elaborate on this one?

Yes. I mean the question was about product. I don't think it's a question of product. I think we're quite aligned with the consensus. I think the top line, as we said, is at least 7%. The consensus is slightly lower. This is a combination, so I will let you make the calculation. I think it's more on the R&D. So something really important on the margin. I will say it's more the significant effort that we want to sustain in terms of R&D. The fact that our outlook today for 2027 include external innovation and I think that the SG&A efficiency are not fully captured by the consensus. But overall, with a margin above 32, I don't think we are very far from the consensus.

Perhaps you can take another question from the webcast, if there is one. We have one from Arnaud Cadart, from CIC. On elafibranor, you outlined the little placebo response on the contrary of CymaBay with Seladelpar. Will it be a major argument to address to the FDA and the medical community to differentiate from this competitor? Christelle, do you want to elaborate on this one?

Sure. Thank you, Arnaud, for the question. So I'm not going to comment on another medicine. But what I want to reiterate here is that we have some very strong results from our ELATIVE study on primary and secondary end point. And this is the entire package we have submitted to the authorities. And as you know, that we dose has been accepted in all 3 regions: the U.S., the EMA and the U.K. And I expect the health authority and HCP to really look at the totality of the benefit you can extract from the data that we have produced. The ALP normalization, the lowering, the rapid and sustained response and improvement in pruritus. And there are other endpoints fully detailed in our Phase II/III result in the New England Journal of Medicine, but the effect on bilirubin and every aspect of the efficacy and safety will be reviewed by regulators. Thank you for that question.

And I think it's fair to say that we are very encouraged by the priority review status we got. So we're looking forward to the regulatory decision on June 10 next year. So that's going to give us an early launch. I mean the U.S. affiliate is obviously already in deep preparation phase to get this on the ground. We have already an organization established since some time on rare disease. So that's going to allow us to go very fast on this one. And next question from the room?

Xian Deng from UBS. Just 2, please. The first one is, if I may ask a follow-up on the M&A, please. So on 1 side, you mentioned the challenging funding environment for biotech opened up some opportunities, but at the same time, some really popular targets and biotechs really never short of interest and some of the recent deals doesn't look very cheap at all. So just wondering, from your side, for the specific deals like the sort of interest you are looking after, do you see any changes at all? Do you see them being more competitive or less competitive? So that's the first question. And the second one is on elafibranor launch next year. So just wondering, in terms of the SG&A spend next year on this, do you think you will have to invest a lot more on the infrastructure, hiring a lot of more sales or you think you can actually leverage a lot more of the Bylvay infrastructure, so it's more to do with the flexible cost?

Yes. Very good. Thanks a lot. On the popular targets. Yes, there is sometimes a bit of a race, I would say, also mostly from actually the large multinational companies, I would say, less so from the midsize -- and this is why I've said, actually, the therapeutic areas we are in are quite attractive for us now because we see a bit less competition here. I think the bigger companies several of them have pretty large patent cliffs that they need to address. So they sometimes pay quite significant premiums on it. And I would say we have almost the luxury now to have a more robust pipeline. We do not have a gigantic patent cliff in front of us. We have a phase of the coming years in front of us where we are having to execute actually a lot of launches and are going to go through a very strong growth rate. So that gives us kind of the calm and the discipline to making sure that when we acquire, we acquire with a price which we really can justify. And I think that's a very important distinction here. I would like to park your second question for after the elafibranor presentation this afternoon, if I may. Thank you. Do we have another question? I take one from the webcast. We have Richard Parkes again from Exane. Can you help us understand why the second-line PBC market is currently so poorly penetrated when a drug has been available for some time and what will transform it? Can I also park this for after the elafibranor because we're going to go into great depth actually through those pools and what is happening in those pools. So Mari Scheiffele is going to address that. So next question in the room.

I'm [indiscernible] from Citi. Just going into your investment or external innovation strategy, and particularly you said you're kind of looking to expand on the liver and bone franchises that you have in rare diseases. Are you able to give any more details on particular areas that might have synergies with your existing indications and places that we're pursuing? I know that there's obviously unique challenges across different rare diseases. So if you can leverage and the work that I'm sure you're doing as you come into launching those products more? And then just going into 2024 as well, I'd be interested to hear a bit more about launch activities for the 3 products that you're launching next year, 3 launches that you have where you are now and what level of kind of ramp up and investment we can see? And any specifics you're able to give on the actual activities that you're doing and the kind of timing to that and how we can expect that to ramp over 2024, will be really useful?

Perhaps I start saying that, of course, we're very pleased that we actually have now 2 drugs in the liver franchise setting, and we're going to have potentially 2 drugs in the FOP as well. So this has obviously synergistic effects, and there might be also combination studies that we're going to do, for example, in the rare liver hepatic space, but I want to give Christelle also the opportunity to talk about first, perhaps, are there other targets which might be interesting to look at in the liver diseases and what are other rare diseases that we're looking at.

Thank you, David. So as David said, we are really strengthening and further developing our expertise both in bone rare metabolism and in rare liver disease. So anything that is adjacent in bone metabolic diseases. We have a strong base, strong expertise and the connection with the HCP and the research community. So we leverage that when we review opportunity. In a rare liver franchise, we've only talked at the moment about primary biliary cholangitis and primary sclerosing cholangitis. But you can think about a number of cholestasis indication that are adjacent and some of them viral cholestasis we already have in the portfolio. And there, again, we can leverage a growing expertise, our connection with the research and the HCP to further expand and the knowledge we develop in our clinical trial and the deep understanding of the patient need really is positioning us as a partner of choice in that space. We're also interested in expanding in hematology in the rare hematology indication, building on our understanding of rare heme oncology. So we really have that potential to grow adjacency without diluting our efforts. So we are very careful about leveraging our understanding, but pushing also the boundary of innovation in the area where we have strength. Thank you for that question.

Thank you, Christelle. So on the ramp-up of the investment for the launches, Aymeric, perhaps you can talk about the speed or the shape of the curve of the investment?

Yes. Your question was most related to 2024. So as you know, I'm not going to provide a guidance for 2024. But I think in 2024, yes, we will invest for the launches, and you're right to say that. And there are some very critical launches where we want to be competitive, where we are facing also high competition. So clearly, for Onivyde, clearly for elafibranor in the U.S., and clearly, we want to continue to be competitive for Bylvay. So you should expect -- but this is going to be very targeted. And at the same time, we expect some significant ramp-up. If you take Onivyde in the U.S. we already have part of the infrastructure. So we -- yes, we were going to invest, and we expect also to be able to get sales pretty quickly. I think elafibranor will be probably a little bit slower to ramp-up. investment is probably a little bit more significant. And you have to remember also that the dilution from the 2 acquisitions that we've done will be also lower, so will be favorable to our margin. So 2024, you should not expect that the margin will move significantly.

Very good. Perhaps we can take one last one from the webcast before we break, if there is one. No, we don't have one from the webcast, perhaps so then one last one from the room? Everybody wants to get a coffee, that's good. So we're going to break, and we are back here at 2:15 U.K. time in this room. Thank you. [Break]

Welcome back. I hope you enjoyed the break. Good morning, good afternoon. My name is Bartek Bednarz, I lead global and product and portfolio strategy at Ipsen. I've been with the industry for about 25 years, of that 20 with Novartis and AstraZeneca and most recently, at Ipsen. Today, I will try to take you through an overview of our in-market portfolio, zoom in on a few key assets on our growth platforms. And then I will hand over to Stewart and Mari to take you through the rest of our portfolio. Let me begin with outlining our commercial priorities. Next slide, please. So first and foremost, obviously, new medicines launches. And that would be Bylvay, elafibranor, Sohonos, but also Tazverik, which is still in the relaunch case and also our first-line PDAC for Onivyde. So this is absolutely our focus for the next few years. Second is fully unlocking potential of our new -- of our growth platforms, Decapeptyl, Dysport and Cabometyx and last but not least, optimizing the value of Somatuline seeing the new generics on the horizon. Now there are a few things that I would like to outline for you as a key reasons to believe. The first one being strong commercial, medical and access capabilities that we have developed over the years. That is combined with our global footprint and our presence in more than 40 countries and many more through our partners. And last, but not least, I'm very proud to say that we have a very strong track record of securing either first or second position in the areas where we compete, and that would include launches. So let me take you through the outline of our in-line of in-market portfolio. Next slide, please. So we're now we're now strongly present in oncology. With Onivyde in the PDAC indication with Cabometyx with Renal cell carcinoma as well as Hepatocellular carcinoma, Decapeptyl in prostate cancer, Somatuline with neuroendocrine tumors and Tazverik marks our entry to hemato-oncology and is an option now for follicular lymphoma. Our successful efforts from external innovation and business development, looking at here with the big smile, we're now targeting 3 rare liver diseases, PFIC and Alagille syndrome with Bylvay and PBC, or primary biliary cholangitis with elafibranor. I'm also very happy to tell and Stewart will speak a little bit more about this, so we're now in the process of launching first-ever medicines for FOP, as mentioned also by David. And last, but not least, in neuroscience, we cover broad spectrum of indications in both segments in therapeutics and aesthetics. And Dysport has been really key in driving is Ipsen growth and maybe I will now delve into it a little bit further. Next slide, please. So over the last few years, I'm very proud to tell you that we have significantly increased understanding of our market, but also gained valuable insights. On top of that, we allocated appropriate level of resources to drive full potential of Dysport. That produced the results that I'm really happy to share with you today with the growth of 14% over the last 5 years, very strong momentum, gaining shares in both aesthetics and therapeutics and especially in those indications that are addressable, which are in label. We've seen new entrants to the market in aesthetics, but they really haven't had any impact on Dysport. Moving forward, we continue to believe that the markets, aesthetic and therapeutic continues to be very attractive. However, we think it's going to get normalized and come back to the levels of pre-pandemic. We are expecting new competitors, but also continue to believe that there are significant hurdles for them to be successful. There are 2 reasons. First, manufacturing capability, which is very requisite but also we haven't really seen a proper clinical differentiation yet. Now speaking of manufacturing, I'm happy to tell you that we're investing in our manufacturing capability and capacity in Rexam here in the U.K. to make sure that we're able to deliver for the market growth and patient demand. All of that makes us believe that ahead of us Dysport will deliver high single-digit growth moving forward. So I did mention manufacturing capability is a key imperatives. I would like you to take a look at the short video and then we will switch to the aesthetics market. Thank you. [Presentation]

Thank you. Next slide, please. So let me speak to you a little bit about the aesthetic market. It's already quite large, as you can see, it's EUR 4 billion in 2022 and is expected to grow at the pace of between 8% and 10% moving forward. There are several drivers that we have seen behind that dynamics. The first one being obesity pandemics and the so-called Zoom-boom as we all switch to video conferences. We also see the influence of social media that drives a little bit more acceptance and awareness across actually all age groups. We see more segments emerging, such as, for example, males or younger demographics. And we also see increase of number of clinics, different settings, different providers. And all of this is happening as the -- we're able to offer also quite a mix of products that would include those toxins that are powder-based or liquid toxins. So let me then show you a little bit on how Dysport perform in this market. Next slide, please. So global player with 75% of the global aesthetic market covered by the partnership. We're now holding either #1 or #2 position globally. We have seen very strong performance across geographies with share gains in U.S. and Europe. I did mention new entrants that we saw them. We haven't seen much of an impact, and we expect some of them to come in the future. But overall, we believe that Dysport is really well positioned to continue the growth in aesthetics. Let me switch to therapeutic market. Next slide, please. So the market is already quite significant. The size of it is about EUR 3 billion in 2022. We're expecting this to grow with the pace of 6% to 8% per year. On the left-hand side, we delineated for you the key segments and also highlighted those indications where Dysport has in the label. Moving forward, we continue to believe that there is large opportunity, huge unmet need and large opportunity in post-stroke spasticity. You can see there is really significant number of patients, but only a fraction of those patients are treated. So we will continue our efforts with awareness, diagnosis and treatment and believe that this is going to propel the growth into the future. I would like to highlight, you heard from Christelle, about the new indication of migraine. This is a big and expanding segment. So we're looking forward to enter this, but overall, Dysport is really well established in therapeutics. It holds globally #2 position. We are gaining really good traction in spasticity. And I believe that with our unwavering commitment to operational excellence and the new indication in migraine, we're really well positioned to grow above the market. Let me quickly touch base on Somatuline. Next slide, please. Thank you. So you will have seen that over the last quarters, we presented gradual sales decline over quarters. Moving forward, we are expecting more competition to come in. That would include generic of lanreotides, but also other products that would be used in this setting, such as somatostatin analogs, and we expect them in U.S., in Europe and potentially in some other markets globally. As a consequence, we're adjusting our efforts in sales and marketing to make sure that this is proportionate to the business we can generate. One thing to note, there are still countries outside Europe and outside the U.S., where we are generating strong growth and these are the countries that are not having any competition from a generic perspective. So moving forward, we expect further erosion of Somatuline. Next slide. Decapeptyl. It's a really important product for us. It's been a growth driver. You can see the CAGR of 9%. We've established leadership in Europe, which we're very proud of. Moving forward, we can -- we think there are several drivers to help us propel the growth of Decapeptyl. One of them is the fact that androgen -- ADTs will remain the backbone therapy in prostate cancer, but also we see aging population will continue to increase the diagnosis. Moreover, we have a proprietary formulations, such as 3 months and 6 months. And in particularly, the 6-month formulation can deliver a lot of significance, a lot of significance in terms of convenience to patients, HCPs, but also health care systems. So we do recognize increasing competition in Europe. Having said that, we're pretty confident in our ability to execute our strategy. And moving forward, we see and forecast Decapeptyl to grow with the mid-single-digit growth. Next slide, please. Now this is an asset which gives me a lot of pride I believe it is showcasing our commercial and launch capabilities in oncology. That's Cabometyx. We have, over the last 5 years, demonstrated exceptional performance with remarkable 32% CAGR. The business comes from both lines of RCC, mainly from the second line, but we're now witnessing the launch in the first line in combination with nivolumab. RCC stands a cornerstone of our business. And moving forward, we still see headroom for growth, and we see that in both first line and the second line, and I will deep dive into it on the next 2 slides. On top of that, as Christelle mentioned, we're eagerly awaiting the completion of the trial of CONTACT-02. And if we're able to demonstrate positive OS then it would open up another avenue for growth for Cabometyx, where we would be able to leverage synergies that we currently have with Decapeptyl, but also draw upon years of experience of being in prostate cancer. So as Aymeric said, we're expecting no less than EUR 700 million from Cabometyx. Let's take a look at the first-line dynamics. Next slide, please. Thank you. So it was about 3 years ago when we showed you a forthcoming dynamics in the first line. And indeed, we expected a significant penetration of combinations in the first line. Very happy to report that we were quite accurate in those markets where we achieve reimbursement. We see a strong penetration of around 70% of combinations. Within that, when you look at performance of CaboNivo in the markets like Italy, France and Germany, where we're reimbursed, we're currently at 16% total share. If you take a closer look at the new patient share, we achieve as high as 29% new patient share in Italy. Now this is happening because we have really good differentiated clinical profile, but also very committed to commercial excellence and driving our launch strategy. Our ambition. So today, as you know, we are leading TKI in the second line, and our ambition in the first line is, in fact, to become a #1 combination. Let's take a look at the second line. Next slide, please. Thank you. So we're observing also a shift in the dynamics in the second line -- and this is predominantly driven by the fact that with the use of immunotherapy in the first line, physicians choose to use TKIs in the second line. And us being a TKI of choice have benefited from that dynamics quite a lot. So today, in the EU 5, our market share is 34%. This is driven by the strong confidence from HCPs, strong differentiated profile of Cabometyx, but also our strong operational excellence. We do have an ambition to consolidate that leadership in the second line. There's still opportunities for growth. And there's 3 drivers that I would like to list today. First, combinations have not yet reached peak sales in the first line. That's one. Two, there are still many patients who have not yet progressed from first line to the second line because of the duration of treatment. And third, we have actually observed that the duration of treatment on Cabometyx after IOS is longer than after TKIs. So there's 3 drivers that we believe is going to -- are going to help us grow further. So overall, we're very, very proud. We have a leading compound in RCC, leading TKI in some countries, a leading molecule in RCC, but there is more we think we can generate. So that optimistic outlook at Cabometyx concludes my part of the presentation, and I would like to invite now Stewart Campbell. Next slide, please. Thank you.

Good afternoon, everybody. Good morning for those of you back in North America. So I'm President, I'm Stewart Campbell, I'm the President of North America. I've been in the biopharmaceutical space for about 23 years, 17 of which most recently at Roche Genentech. I was fortunate over that period of time to lead development and commercialization over a number of different molecules and medicines. Over a number of different therapeutic areas. I will say one of the main factors that drove me to Ipsen about 2 years ago was the opportunity to join an organization that was approaching the inflection point in growth, and the joint management team that due to its midsized was agile and active in the business. So today, I'm excited to talk to you about 3 medicines that are going to provide part of the foundation for what will be substantial growth in the U.S. over the coming years. So Onivyde has [indiscernible]. So why don't we start with Onivyde. Next slide, please. So as Christelle mentioned, Onivyde is currently indicated in the post-gemcitabine mPDAC indication. And in that space, these pancreatic diagnosis is extremely severe. These patients have an OS of less -- sorry, have a 5-year survival of less than 3%. So you can imagine the opportunity to have a huge unmet patient need is tremendous. If you take a look at our sales growth over the last 5 years, our CAGR of about 10%, really driven by 2 mean factors. First factor is modest growth in the post-gemcitabine group. But more importantly, where we focus most of our efforts in the U.S. is on driving share within that to where we are today at 39%. But we have significant upside that we're looking for with Onivyde, and you've talked a little bit about that already today. First-line PDAC is going to provide us a real opportunity to impact patients at an earlier stage of the disease. That, coupled with our existing post-gem indication and a limited number of new competitors really provides us a forecast and confidence that we will exceed sales of more than EUR 500 million. So let me walk you through a little bit of how this evolution is going to happen in first line. Next slide, please. So you see here that, unfortunately, pancreatic patients do not progress through multiple lines of therapy. Very few of them do. And the challenge here is that as we move from second line to first line, we have an opportunity to enhance the patient population that we impact by three to fivefold. You see a 35,000 patients in first line. that's really the opportunity that we're looking for. And I'll explain that to you in the next slide where I break this down in further detail. Increasing the duration of therapy in that space to 6 months. If we take a look at the NAPOLI-3 trial. So again, Christelle mentioned, this is the first new data that exists in this space in 10 years. So when you take a look at what we have, there's an opportunity for patients, we really, for the first time, have a better option for them in first line. Of course, we're super excited about what's happening on February 13 with the PDUFA and the commercial teams are already in heavy preparation mode for full activation post approval. Next slide, please. So now as said, I'm going to walk you through a little bit more detail in this complex piece of first line. So I'm going to take my time and walk you through the components. So that's a snapshot of the current first-line marketplace in the U.S. You'll see that the 41% and 43% is pretty much an even share between the gem-based therapies and irinotecan-based therapies where FOLFIRINOX resides. So of course, NALIRIFOX was the therapy in the NAPOLI-3 trial, and we showed superiority over the [indiscernible] combination. So that's really what we're going to utilize to drive initial share in that first segment. In Wave 2, the second segment, this is really where we start to build on our value proposition. When you look at the NALIRIFOX regimen, I think Christelle did an amazing job of walking you through exactly how. We have a lower doses of oxaliplatin and lower total irinotecan, which provide a better side effect profile than FOLFIRINOX, That, coupled with maintaining our best-in-class overall survival really gives us the opportunity to be super optimistic about Onivyde being the potential to be the first -- the standard of care in first line, taking share in both of those segments. And that's the important piece I wanted to share on this slide. The second piece is that our teams are already active and they're already being super effective in the pancreatic space. So we're going to be leveraging the commercial medical affairs functions and the market access functions. So with that, I'm going to start to talk a little bit about Tazverik. Next slide, please. And the Epizyme acquisition really afforded us the opportunity to build a foundation in hematology. Really, if you look at what we were talking about a little bit earlier today, Tazverik is currently indicated in third-line follicular lymphoma or FL. And this is an indolent slow developing hematologic malignancy, so a low-grade non-Hodgkin's lymphoma. And what -- because of that, many of the patients are actually treated in the community hematology oncology centers or hem-onc. And those are spread out across the entire country. The average hem-onc will see about 5 to 6 patients in an entire year. So the opportunity for the field force, while we've had suboptimal results upon the acquisition, we've really got an opportunity to turn things around. We refocused the strategy. We've got full deployment of the field force. If you look at what we're focusing on, we've done a nice job of penetrating into the third-line mutant population. Now we're in full expansion mode into the wild type. That's step 1. In the midterm, I'll talk to you about step 2 in a second. In the midterm, focus is on us really focusing on the execution. And that was something that was lacking when we took over that we've really focused and honed in on. Secondarily, that community hem-onc setting really affords us an opportunity to leverage the beneficial side effect profile, coupled with the oral administration. So I'm going to pause here for a second and give you a little bit of a double click on the oral administration because that's something that's unique to the U.S. oral oncolytics versus IV oncolytics there's an out-of-patient cost that's associated with those orals that does not exist with the IVs to the tune of about $14,000 per patient today for Tazverik. The IRA, or Inflation Reduction Act, actually is going to pose a cap for all medicines in the oral oncolytics space. So that's going to be in 2025, it will be reduced down to about $2,000, and that will be for all their medicines. So you can see just how to think about how that's going to impact the patient acquisition piece. So the second piece, and this is what I was going to get to, is the long-term opportunity for us, and Christelle nailed it with SYMPHONY-1, it's opportunity for us to drive utilization in second line. Next slide, please, I'm going to walk you through why that's so important for us. second-line population doubles the size of the effective pool for us, up to 4,600 patients in the U.S. It also increases the duration of therapy up to 10 months. What we need for that is combination data. This is not a monotherapy space. SYMPHONY-1 is going to give us that combination data with R squared, and we'll utilize that to really drive home the message that we're an amazing opportunity in second line. So let me summarize the opportunity for Tazverik on the right side here. So in second line, we're going to drive combination. In our current third line indication, we're going to expand beyond the mutant population into wild type. When I take that and then we're going to explore the rest of world opportunities we spoke a little bit about. Those 3 factors give us full confidence that we'll exceed our EUR 500 million peak sales, okay? And with that, I'm going to shift gears a little bit and talk to you about an exciting new launch that we have happening right now in the U.S. with FDA approval of Sohonos. Next slide, please. So Sohonos is the first and only treatment approved for FOP. And I think we're extremely excited, and it's a proud moment for us at Ipsen to get this across the finish line with the FDA. And what we want to share with you today is a snapshot from some of the key stakeholders in the FOP community, who share that excitement. And I think most notably for me is the key -- the world's key thought leader for FOP at the bottom. We have active engagement and it was a huge supporter for us to get this across I'll remind you that Bartek talked a little bit about it, but FOP is a disease that sees ossification of the muscles and tendons. So you can imagine the tremendous visibility associated with that. Sohonos is the first asset that's going to be able to provide value for patients to fight against that ossification. So really, really nice opportunity. Next slide, please. I'm proud to say that currently in the U.S., we've identified about 250 patients. Of course, there's a segment for which those patients -- Sohonos is not appropriate. It's typically due to age restrictions or that the disease has advanced beyond the point where this is an appropriate therapy. The current recommendations and negotiations that we've had with payers have been successful. So that's very encouraging and very exciting for us. and really laying the groundwork for us to be able to continue to say as we grow within other countries, and we can bring EUR 100 million as our peak sales for Sohonos. So with that, I thank you, and I'll pass it over to my colleague, Mari.

Thank you, Stewart. Hello, everyone. My name is Mari Scheiffele, and I'm the President of Ipsen International. My responsibility covers all the markets and organization across the world, excluding North America. I've been at Ipsen just over 2 years and my focus has been on growth and transformation. So now I will first speak about Bylvay. So next slide, please. Bylvay, as you know, is our key medicine in pediatric rare hepatology that we brought into our portfolio earlier this year through the acquisition of Albireo. Our focus is currently on the PFIC indication where we have commercialization and launch in 9 countries, including the United States and our top European countries. Our current focus is on both broadening and accelerating our uptake in the PFIC indication. Let me also remind you that in Alagille syndrome indication, we did get FDA approval earlier this year in June 2023, and we're already treating our first patients in United States. So as we look forward for Bylvay, we have a very strong potential that we see across both the PFIC and Alagille indication. And they're namely the main drivers, which are focused on four areas: The first, which is the continued increase in the number of new patients that we see treated with Bylvay. The second, which is a very important one to highlight is the increase in dose of Bylvay that we would use or patients would get as they gain weight over time. The third is the mode of administration, which is the capsule formulation of Bylvay and the fourth, which is, of course, the ongoing geographic expansion as Bylvay launches in additional countries around the world. I'll also want to talk about some of our long-term opportunity with the biliary atresia or BA indication, where there is a very significant unmet need. We have what we call the Phase III BOLD study, Christelle talked about it. It's a very robust Phase III study that we have ongoing, and we see a very significant potential for Bylvay in the BA indication not least of all because of the significant unmet need, but also because of the very large incident population that for BA is greater than PFIC and Alagille together. I'd like to also call your attention to the rare liver portfolio that we're building. So I'll talk about Bylvay and next about elafibranor. And this combination is a real synergy for us, especially in certain adult hepatology settings. So taking all of this together, which is a very significant unmet need across all these different indications and the clinical profile Bylvay that we already see and expect to see. We anticipate that peak sales for Bylvay will exceed EUR 700 million globally. I'd like to note that about 50% of that peak sales is expected to come from the BA indication. So I'd like to now spend a bit of time talking about the U.S. and Bylvay. So next slide, please. We're already having very strong growth, continuing the growth, and you see a bit of an inflection also as we've taken the asset on and have a very strong collaboration as we grow the asset in the PFIC indication. We're also treating already the first patients in Alagille. And you see here on the left side of the page, the number of reimbursed patients for PFIC. And as we look forward in PFIC, we see growth both from the pediatric population and increasingly also in the adult PFIC population. The teams with Stewart are focusing on not just the core physicians, but also expanding into secondary hepatology centers and also working with physicians who haven't used iBATs before. So we anticipate that there's going to continue to be an acceleration in patient finding, both into pediatric as well as in the adult setting. Now on Alagille, even though it's been a few months, we see very good early indicators of uptake in the prevalent population, and I'd like to call your attention to the very large overall pool for Alagille, which is 3x larger than PFIC. So combined, the PFIC and Alagille growth is really going very well. And in the U.S., there's a very strong momentum that we anticipate through the next years. Now on our next slide, please. I'd like to focus for just a moment on the other markets. So we have 8 other countries where we currently have PFIC approved and reimbursed. We have additional countries to come. But the PFIC growth momentum, which is progressing extremely nicely is coming also from the same trends, which is the patient uptake, the dose increase as well as the adult population. And as we look ahead, we see multiple additional countries where we will first get regulatory approval and then reimbursement and pricing agreements. So we will see further growth, both from the PFIC and Alagille indication. And as Christelle mentioned, importantly to note, in EMA, we are working towards the launch of a second medicine for odevixibat, and we anticipate a regulatory decision in 2024 with a very fast launch after that. So next slide, please. I'd like to finally speak about elafibranor. So elafibranor is an anchor medicine for us in the rail liver franchise that we're continuing to build. We're all very excited about the very strong and exciting data readout that we had at ASLD in Boston just a few weeks ago with the simultaneous publication in the New England Journal of Medicine. Our teams in the U.S. but also across the world are getting very strong and good feedback from physicians on the clinical profile of elafibranor. I'd like to also remind everybody that elafibranor is a global asset for us, which is in line with our business development strategic priorities. So this means that we not just have the rights in the U.S. or Europe, but also across the world, excluding China. On elafibranor, we're very excited because we also see this as a very interesting medicine in that the large population that we see about 200,000 diagnosed PBC patients is quite large for a rare disease. It's in the combination of rare and almost specialty medicine. And so we're going to be working off not just the strong clinical data for elafibranor, but I want to highlight the strong capabilities that we already have. First, we have established organizations in 40 affiliates. This means we have end-to-end integrated organizations from regulatory to quality to pharmacovigilance, marketing, medical and market access. So we have this integrated setup and teams are ready to go. The second is that we have launch capabilities in place. We will be making targeted investments, especially in medical affairs and commercial, as we ramp up the launch over the next months. And then the third, I would like to call your attention to the strong patient pathway and market development experience that we have at Ipsen. And we think this is going to be particularly important in PBC. I'll talk a little bit more about the second-line PBC market there. So we believe there's no other company with this set of capabilities that is going to be launching a medicine in PBC in the near future, and we're really set to go for this growth. Next slide, please. So with elafibranor, we're going to be addressing a very significant unmet need. I think many of you are quite familiar with the discussion that's been going on in second-line PBC but to maybe walk you through some of the numbers. First, they're about 75,000 patients in the U.S., taking the U.S. as an example, treated today with some sort of medicine, mostly UDCA. There are a very large portion of these patients that we call highly uncontrolled. So about 40% of these patients, about 30,000 patients who are highly uncontrolled, which means that their ALP value is greater than 1.67 of upper limit of normal. In addition, only about 9,000 patients are currently treated with second-line medicines. So you can see there's a very significant gap in the market. And maybe said in another way, we would see the second-line PBC market is currently very significantly undeveloped. And so some of the reasons are, one, a very significant dissatisfaction frankly, with the current treatment options. There are some questions also around patient eligibility criteria. And so there's a large pool of patients for remaining in first line, not moving to second line, and that's a portion of patients that we will need to tap as we build the opportunity in second-line PBC. Now with elafibranor coming to market and launching, there will now be a medicine with a very significant biochemical benefit and a very strong clinical efficacy profile that patients would have available. And so we anticipate a very significant acceleration of patients from first line and second line as well as for those in second line today, elafibranor would be a very significant opportunity. So as we think about this, and we bring together both elafibranor and the opportunity in second line, we see the second line PBC market as exceeding EUR 1.5 billion in global sales. I'd like to maybe also mentioned that if we look at the pool of patients who are between 1 and 1.67 of upper limit of normal on the ALP value, those patients are also uncontrolled. And so if we think about that patient population, this estimate may still actually be an underestimate. So as we think about the significant unmet need in PBC, we look at the clinical profile of elafibranor and also the excellent and proven launch capabilities we have here at Ipsen, we see a very strong potential for elafibranor and anticipate peak sales to exceed over EUR 500 million. So next slide, please. I'd like to maybe share a little bit about the patient landscape as our teams are very actively preparing for the launch, especially in the United States. So as you may know, a very significant portion of patients are women. In fact, over 80% of patients in PBC are women. The mean age of diagnosis is 50 with many patients also taking a very long time to diagnosis, and it's a very debilitating disease with, unfortunately, over 70% of patients having also comorbidity. Patients are treating it in a variety of settings, hepatologists, see them, gastroenterologists see them, they're also internal medicine specialists. And in the U.S., and specifically, there's quite a concentrated number of HCPs who are currently treating the patients, we would see also an expansion of this over time. So our teams, I'm happy to say, are working very, very actively to prepare for a very rapid launch. We're certainly very excited about the developments that will come in 2024. I'd highlight a few areas that the teams are working on. First is very importantly HCP education for all the reasons that we just talked about. The second is around setting up patient support programs, which we know will be very important in the United States. And the third is actually ensuring that there will be access, so working with the payers and ensuring that there will be reimbursement that we can ensure a very fast uptake in this patient population. I'd like to also highlight our very strong customer overlap. So elafibranor together with Bylvay will be a very important franchise for us, and again, especially in the adult hepatology study, these are the same customers who are seeing patients with PBC as well as those with PFIC. So I'm also very excited as you saw in the press release this morning because I think being able to have the FDA submission and acceptance of that as well as a priority review means that we actually anticipate not an FDA decision on second half of 2024 as we had written on this slide, but in fact, in second quarter, of next year, and our teams are really, really geared up to be able to do that successfully. So overall, I'd like to conclude our commercial section together with Bartek and Stewart to say that our teams at Ipsen are just really, really passionate about the innovative medicines that we're bringing into our portfolio. Those within our existing portfolio, the in-line portfolio, but also the upcoming launches, and we're really looking forward to being able to treat more patients in need across the world. So next slide, please. With that, I'd like to turn it back to David to conclude our presentation. Thank you.

Thank you, Mari. Next slide, please. It's now my privilege to conclude. I think we can say Ipsen today is in a great spot. We have enriched the pipeline. We have diversified the pipeline. We have advanced the pipeline and have seen several regulatory approvals. We are going to launch several drugs and there is more to come from the pipeline on very interesting compounds that we have licensed in or internally developed like with the long-acting neurotoxin. So we have a strong platform now in the three therapy areas, and we are fully focused. Based on this attractive pipeline and based on the launches, we're going to leverage the excellence in execution, which we have shown pushing our growth platforms and the launches of our new medicines. So we are going to see a much more balanced and diversified business standing on several legs and this is going to be the growth engine behind our guidance, which is that we forecast at least 7% growth on a compounded annual growth rate in the period from '23 to '27 and also seeing an at least 32% core operating margin on sales for 2027. So a very exciting period in front of us. I'm excited to bring Ipsen into an even better spot with my executive team that I'm now asking to come on the stage and join me for questions. As a reminder, you can ask questions on the webcast for those of you who are joining us through the Internet.

Thibault Boutherin, Morgan Stanley. Maybe my first couple of questions on Dysport maybe just to start to confirm that your growth expectation for the product is not dependent on what's happening with your partner in relation with their new generation toxin as in, if they decide to focus more on the new product Dysport? Is there any risk here to your cost assumption? And then second question on the therapeutic migraine indication. Just the question is why now? We've known that botulinum toxin is effective in -- to treat migraine for a certain time. I think it was conscious decision for Ipsen not to go there until now. So what has basically changed your mind to start Phase III studies in migraine?

So first answer on your growth and the dependence on the partner. There is no correlation at all on the long-acting neurotoxin arbitrations, which have been triggered by Galderma. In fact, the collaboration on this board works very well. You have seen very strong growth rates in aesthetics in the territories that they have in the territories that we have, but also very strong growth in the treatment space. So there is no connection there at all. On migraine, I would say why now? Perhaps Bartek, you can take that question.

Yes. Thank you. So I did show you a couple of segments in the therapeutic markets, and you've noticed that migraine is quite significant and it's expanding, and it's very attractive. That's the first answer. The second answer is we plan to be with our neurotoxins in this space for a long time. And obviously, we're having long-acting toxin in mind as well. as we develop this and bring this to the market. So we think there is a really strong rationale and strategic perspective on going to migraine as quickly as possible.

Perhaps just one addition to this. I mean, we have now established what we call core asset teams. And these core asset teams, which have a leader, which we call kind of the CEO of a medicine are looking now much more systematically on life cycle opportunities. And I think it's fair to say that on this board, we do have a broader field still of neurotoxin use that we could develop. There was, of course, the debate should we do it directly with long-acting or with this board. We came to the conclusion that there are very attractive areas for example, like on migraine, where we can have a fast-to-market strategy and with the long-acting neurotoxins being in Phase II, we will then have a stepping stone with this board and leading us to launch them on the longer-acting neurotoxin, where we will go even broader than the Dysport indications and including a migraine. So on the long-acting neurotoxins, we are going to go for many, many more indications. There is one question coming on the webcast from Brian Balchin from Jefferies. On the period of '23 to '27 sales drivers on Onivyde, how much of that larger than EUR 500 million is driven by first line? And how confident are you in seeing an inflection there maybe based on any doctor feedback you have had. So perhaps, Stewart, do you want to address that question on Onivyde?

Sure. I am happy you do it, actually. Thanks for the question, Brian. Any time I got a chance to talk about Onivyde, I am excited to do that. Our peak sales when we look at that peak sales forecast, the split, as we talked about, will retain the post-gem setting. So the split is about 1/3 post-gem, 2/3 first line. If we take a look at the -- about the second piece of the question, which was about the doctor feedback. So we've had a lot of discussions with our physicians. As we talked about, we're already active in that space. So we have a really strong knowledge of the space. If you recall in my slides, I talked about how we have a 2-wave approach into what we believe the adoption to be in the share. So that first share is coming out of the gemcitabine utilization and then a second weight in the FOLFIRINOX or TK-based therapies. So that's the triage and that's built off of feedback that we've had with our thought leaders over the last year, 1.5 years.

Xian from UBS. So just first one, if I may. The follow-up on the migraine please, for Dysport. So just wondering, given there are quite a few CGRPs and also potentially new targeted therapy for PACAP, so just wondering where do you think this board would be positioned versus those targeted therapies. And you mentioned this is being a quite attractive market. I'm just wondering how do you think about the competition? Is it fair to say that neurotoxin is going to be used after the targeted therapies. And do you think the emergence of new and more and more targeted therapies can potentially actually reduce your patient pool. So that's the first one. And second one, so it's still on elafibranor. So given that it looks like the physician is likely to be a range of different type of specialists. Just wondering, in terms of launch costs next year, do you think this is -- you probably have to hire a bit more sales? Or do you think this is going to be mainly flexible cost so you can still leverage the Bylvay infrastructure?

Great questions. Thank you very much. On the first one, I would refer to Christelle. How do you see the different therapies. There are new therapies coming into migraine. Where is the role and the positioning of neurotoxins?

Thank you for that question. So migraine, we use long term for, in fact, very different presentation. If you're a migraine sufferer, you can respond to some type of therapy like CGRPs, and there have been other therapies for a number of years. The truth is we still not today understand the fundamentals of what drives migraine in one patient versus another. So there really is a pool of patients that will respond better to neurotoxin, some episodic versus chronic, that respond better to other therapies. So there really is more scientific advances to be made, and we see a real potential here with this sport, but also with the long-acting to bring a different presentation and treatment with neurotoxin.

Thank you, Christelle. On the second question, I refer to Mari on elafibranor, how does it look like on the visiting the specialists, the clients that were going to go and see and what does it mean actually for our infield resources that we're going to deploy.

Yes. So certainly, on elafibranor, as I mentioned, there are a range of specialists but there are physicians who are already identified, whether they're hepatologists or gastroenterologists. So it's a relatively concentrated population of physicians, especially in the United States, but certainly also across the other markets. We do anticipate both a mix of shifting existing resources. So for example, some of the people and individuals have been working on Somatuline, some of the variable spend in that area in terms of resource allocation as well as increasing targeted investments in very particular areas, whether it be in patient access, in medical affairs or in commercial, but we don't anticipate a very significant uplift in terms of resources required.

Very good. Perhaps we can take one from the webcast. There is Richard Parkes from Exane, does Ipsen still stand by its short-term CEREC target for sales of EUR 150 million to EUR 200 million? Or is this now too optimistic before the second-line trial reports? Stewart or Aymeric, you want to take this one?

I can take that one. Yes, if you remember, I mean, a very initially, we were targeting $800 (Sic) [ EUR 800 ] million, of which EUR 150 million to EUR 250 million could be related to the existing third line plus indication. Today, we are revising that peak sales to in excess of EUR 500 million. And I think it's fair to say that the proportion that will be contributed by the second line combination indication will be the majority. So clearly, we have also to adjust the current [indiscernible] expectation.

We can take another question from the room.

John Priestner, JPMorgan. Just 2 more questions for me. So one -- the first one on elafibranor. So you suggested that the second-line PBC market could be about EUR 1.5 billion in 2030. So I was just trying to work out kind of how much of that would be accessible and maybe how you see that in terms of patient split and how much share elafibranor could take and how that kind of calculates down to your EUR 500 million peak sales target? And then the second 1 being around Cabometyx. So just how much of an incremental opportunity do you see for Contact O2 and just trying to contextualize that ahead of the LOE at the end of the decade.

Thanks, John. On the first question on elafibranor and how do you think about the second-line pool and the sales potential. Mari?

Yes. So on elafibranor, in terms of the peak sales, they're composed of a few different components. One is the current patients who are already moving from first line to second line. So there's already an existing pool of patients or moving a second line. So we would anticipate capturing a portion of those given the strong clinical profile of elafibranor. Then on top of that, over time, there will be an increase in number of patients who are currently not moving and still staying with their first-line therapies. And so we anticipate being relatively competitive in both categories, and we're going to need to be driving this shift from first line to second line PBC as a treatment option. We do see there being a mix of treatment options today available in second line. So depending on the country, the options for patients are very different. So therefore, the key piece will also be that patients have availability to the medicine in second line. And so the pace and the timing by which we can get that reimbursement is also going to drive the timing to peak sales. So I think those are the factors that we're going to be looking for, which is both the HCPs who need to see the benefit of elafibranor, and I think they really see the benefit already. Those have been exposed to the drug through the ELATIVE trial, but then also the patients who are very significantly under-satisfied right now. We have a lot of active work also with patient organizations, and there is a very significant unmet need. We anticipate there'll be active contributors to be able to have that patient population access, and we'll be working through all those stakeholders as we see the growth of elafibranor over the next years.

Very good. Coming to your second question on Cabometyx in prostate cancer. We probably need to be a little bit careful on this trial because we have seen clear PFS benefit. There was only a trend so far in overall survival. So we're going to go to the end on the kind of mid next year to see if that trend is going to actually translate into a significant benefit. So perhaps you can elaborate on what would that add if there is a significant benefit.

Yes. So first of all, I think you probably know that the population of that trial is very, very different than Decapeptyl. So please do not expect the same revenues as from Decapeptyl. We're talking about the patients who have gone through ADT therapy, Decapeptyl, and they had one hormonal therapy before that. So we're looking at relatively narrow patient population. And what is going to be the exact increment will really very much depend on what are going to be the magnitude of overall survival that we're going to see to what extent is going to be clinically meaningful, but also from a payer's perspective because, as you know, we're operating mainly ex United States, and therefore, there is also a game of protecting the price and potentially having the price cuts in case you enter a new indications. So it's going to be roughly maybe 10% or 20% of the Decapeptyl. But when I just look at the patient population, but really we have to take a look at the data.

Okay. Perhaps we take a question from the room here. He was waiting since a long time.

Alistair Campbell from RBC. Just a couple of quick questions. On Tazverik, obviously, resetting expectations, so quickly for Aymeric. Should we be assuming you'll also revisit the balance sheet valuation of the deal at some stage? And then on Sohonos, if possible, can I get a bit of flavor on pricing because, obviously, different doses price differently and patients have to titrate up at a flare. So what would you suggest is a an appropriate level for kind of average dosing to think about pricing as a [indiscernible], please?

So first question, I guess your question is on an impairment potentially. That's for Aymeric.

So on that question, as part of the IFRS accounting, we're going to assess at the year-end closing procedures, what are the impact of the lower peak sales. It's probably too early to tell at this stage.

Then on the Sohonos pricing, Stewart, the difference between chronic and flares and perhaps to understand also, okay, how often are the flares and how significant would it be if the price would actually be higher when people have a flare?

Yes. I don't know that I'm super comfortable with the absolute pricing, but I can give you the differential. If we look at chronic therapies, the differential with flare is about 30% more. And right now, we're seeing about 25% of the prescriptions are covering the flare. It's still fairly new, as you can imagine, right? The patient numbers are extremely small in general, right? Ultrarare disease doesn't get much smaller. And the sample size that we have of the patients going through reimbursement is also very small at this stage.

There's another question in the room here.

Manos Mastorakis from Deutsche Bank. Just want to ask a question on Tazverik and how do you expect competition to evolve by the time of SYMPHONY data and potential launch there?

Yes. On Tazverik, of course, when we licensed in the drug through the acquisition. We knew that bispecifics are going to come in and the CAR-Ts. They are mostly being used in the academic setting today. I think we can project that CAR-Ts are going to stay in the academic setting. And as you have heard Stewart talk about Tazverik, we think this is mostly a drug which is going to be used in the office space setting with the hematologists because it's probably more for the more elderly and frail patients that are not eligible for CAR-T, and that's actually quite a substantial number when you look at the number of patients in follicular lymphoma. We do, however, see that bispecifics eventually one day are going to be also starting to be used in the office-based setting perhaps less so because today, they still have cytokine release syndrome. And even in the subcu version, you see more than 10%, 15% of cytokine release syndrome. So that's not an easy thing to handle in the office space setting. However, we actually believe that you could combine the two. And so we're already conducting studies now in combination with bispecific antibodies because if the two of them, Tazverik being so combinable and well tolerated, but at the same time being efficacious adds to bispecifics, you could actually get rid of chemotherapy. And so that's a very interesting new avenue that we are looking at. as well on top of, of course, of our registration trial, which is based on our Square plus or minus Tazverik. I would encourage you also to look at the data, which is going to be presented at ASH next week, there is a poster on the lead-in portion and Christelle has alluded to that, very, very interesting data.

Charles Pitman from Barclays. Two for me, please. First, just on Dysport. I was wondering if you could give us any more details on what the market share of Dysport is in both the therapeutic and aesthetic market? And you mentioned there's going to be a normalization of growth post pandemic. What does -- what should -- how should we think about this in terms of future market share opportunities for Dysport. And then just secondly, Decapeptyl, you mentioned in the slides that you expect to continue to grow in China. I was wondering if you could just outline your confidence here and how VBP may play a role.

Thank you very much. So Dysport, Bartek, if you can elaborate on market shares in the treatment space and aesthetics?

Yes. Thank you for the question. So there are 2 separate questions. I think first of all, our market share is growing. It will very much depends on the geography. In some countries, we're #1. In some countries we're #2. We're oscillating around 20%, 25% all the way to 70% market share, depending on the segment. So it's really a broad variety of performances. In terms of market share moving forward, as I said to you, we believe in our commercial execution, and we intend to grow our share irrespectively of the market growth. So we expect that market to slow down a little bit after the what we saw after the pandemic, but ultimately, we will continue to be more competitive and gain share across key segments moving forward.

And then on Decapeptyl for China. Mari?

So certainly, China is a very important market for us. In Decapeptyl, as you know, it's growing quite nicely. We do have a very specific focus now on prostate cancer, which we see as the key growth area. We are making nice share gains. The market growth is a bit muted over the last few quarters, given patients coming out of COVID, but also the more challenging economic situation, but we are seeing more than greater than about 15% market growth, and we anticipate that this is going to continue. So we will keep a very strong focus on China growth for Decapeptyl in addition to all the other geographies. And maybe just to make the point that we are very committed to the China Ipsen organization. So beyond the current formulations. We're also launching 3-month CPP, which is a new formulation as well as 6-month prostate. So those additional indications will drive even further growth for Decapeptyl in the years to come.

We seem not to have any questions coming from the webcast, so we can continue in the room.

It's [indiscernible] from Citi. Just a couple of questions on Bylvay specifically biliary atresia indications coming up. So I think you mentioned that 50% of your sales expectations rely on the indication. So just wondering if you can give any more details on penetration assumptions underlying that please in that indication? And then also in the BOLD study, I understand you're measuring time to transplant, but also, are you looking at, a, any kind of biomarkers that can be indicative of need for transplant, such as bilirubin levels and just a bit more on the biomarker strategy behind the trial. And also maybe time to listing of -- for transplant because obviously, there can be delays on registries. So just understanding how you're getting around those aspects of the trial.

So on your first question regarding biliary atresia and penetration assumption, I mean we are not giving forecast on market share penetrations. We have given you the peak sales. We have said in the past that about half of the sales are assumed to come from biliary atresia. So you kind of can calculate to what this equates to. Perhaps on the second question regarding biomarkers and the correlation with the need to liver transplant, Christelle, do you want to answer this one?

Thank you. So on the BOLD study, as I mentioned earlier on, what's very important, which we think are very young patients here. We're talking about babies. In addition, we start treating after a Kasai surgery procedure, which is quite a heavy procedure. So the most important for those patients is to maintain their native liver. This is why, in discussion with FDA, we have chosen a very hard endpoint. And that is that time to transplant, how long can you maintain the native lever and also other outcomes like death unfortunately. In terms of biomarker, yes, we will measure bilirubin level, but there is no clear correlation or indicator at the moment that lead us to believe we could use or instead of the hard endpoint. They maybe later on, but today, it's really important that we have that clear evidence, and that's why we have designed the BOLD studies the way we have to have strong end points.

Perhaps to your third question on the time to listing for a liver transplant, obviously, we have a hope that we are going to actually see liver transplantation happening later. So this is the outcome trial question, in fact. Are we going to push out the liver transplant or perhaps even spare certain babies from having to require liver transplant when they become toddlers and kids and adults, that would be, of course, a fantastic outcome, and that's what we are hoping to show with this trial.

[indiscernible] Maybe a sort of higher-level question. The focus today has been on '23 to '27. You talked a bit about '28 and beyond. I was just wondering how you think about your ability to actually grow in that period given the pipeline readouts, but also the LOEs that have been mentioned Onivyde and Cabometyx mainly?

So there are kind of a couple of questions in your question. So what's going to happen in the period 2028 onwards, right? So on the one hand side, we're going to see many more drugs coming through the pipeline in this period, actually delivering sales and additional registration and launches with our current pipeline. Second, you have seen that chart, we are going to add more drugs into our portfolio, either on market, Phase III, II, I or preclinical. Now the preclinical are not going to hit in usually in 2028 period, it's going to be a bit later. It's probably post 2030, I would say, unless there is an accelerated approval, for example, in oncology or hematology which can happen. But clearly, the Phase II, III and the on markets, they are going to impact into this period. So the ones that we have in the pipeline, they are going to start delivering in this period. Second, we will add new ones also. So we are actually very optimistic because we have the firepower needed in the coming years to establish kind of the next generation of growth beyond that period of 2028 onwards. And couple of indications can be pretty big. And over the land and for example, could become very, very big drugs if they have the profile that we want to see. There are no questions on the webcast. Is that correct? Good. I think if there are no more questions in the room, I would like to thank you for your attendance. You're now invited here for the people in the room to join us for an [indiscernible]. For the people on the webcast, thank you very much for joining. We wish you a good rest of your day. Thank you.