Hello, welcome to the Ipsen conference call and broadcast on the acquisition of Albireo. I'll now hand you over to David Loew, Ipsen's CEO. Please go ahead, sir. Thank you, operator. Good afternoon or good morning, everyone. As you just heard, I'm David Loew, chief executive of Ipsen. We're live at the J.P. Morgan Healthcare Conference in San Francisco. I'm delighted that you have joined us today as we take you through today's exciting news on the acquisition of Albireo. Please turn to slide two. This is our usual safe harbor statement which outlines the routine risks and uncertainties contained within this presentation. Please turn to slide three. I'm joined today by Howard Mayer, Ipsen's head of research and development, as well as our CFO, Aymeric Le Châtelier. We'll provide a brief presentation before using the majority of the time to answer your questions. Please turn to slide four. I will begin the presentation by taking you through the strategic rationale for the acquisition. I'll then hand over to Howard, who will explain the development of Bylvay. I will go through the commercial opportunities before Aymeric runs through the financials. I'll then conclude the presentation before we move to your questions. Please turn to slide five. Firstly, let me turn to the strategic rationale for today's news. Please turn to slide six. Underpinning our vision is a focus on three therapy areas. Within oncology, we have strengthened our position in the last two years by adding 12 assets to our clinical and pre-clinical pipeline. We have also added further assets to our neuroscience pipeline. In rare disease, we look forward to the forthcoming phase three results in primary biliary cholangitis for elafibranor, which was in-licensed around a year ago. We do want to expand the scope in rare disease further, and it's this focus that has supported our decision to acquire Albireo. Please turn to slide seven. This expansion in rare disease is perfectly aligned to our external innovation strategy, which is designed to replenish our pipeline and add further medicines to our portfolio. The focus of this deal is on the potential of Bylvay, a possibly best-in-class rare liver disease medicine with global rights that's already on the market for progressive familial intrahepatic cholestasis, or PFIC, in Europe and U.S. There are multiple opportunities presented by this deal. We have the possibility of adding two further indications to the currently approved indication for Bylvay with Alagille syndrome and biliary atresia. The acquisition also comes with an early-stage pipeline in adult cholestatic liver diseases. Bylvay and the clinical and pre-clinical novel bile acid transport inhibitors are clearly an excellent potential strategic fit in rare liver disease with elafibranor. Financially, we anticipate sales of around $800 million and an accretive impact to core operating income from 2025. Please turn to slide eight. I hand over to Howard. Thanks, David. Hello everyone. I'd like to spend a few minutes taking you through pediatric cholestatic liver diseases as well as the development of Bylvay. Please turn to slide nine. Bile acids are chemical compounds found in the liver made from cholesterol. Bile acids have several roles in the body, including promoting the flow and excretion of bile and assisting in the intestinal absorption of fat and fat-soluble vitamins and nutrients. 95% of bile acids are recycled back into the liver from the intestine and reused within the body. A disruption to this process can lead to the buildup of bile acids in the liver, which is known as cholestasis. Neonatal cholestasis reflects an underlying condition causing impaired flow of bile from liver cells into the intestine. This affects approximately 1 in 2,500 live births. About 50% have a known genetic origin. Patients with cholestasis experience symptoms such as intense and severe itching, poor sleep, delayed growth, and diminished quality of life. Failure of bile outflow can ultimately cause obstructed bile ducts, portal hypertension, cirrhosis, and end-stage liver disease, with some patients requiring liver transplantation. Please turn to slide ten. Bylvay or odevixibat is a potent oral non-systemic ileal bile acid transporter inhibitor approved in the U.S. and E.U. in 2021 for PFIC. By blocking the actions of IBAT, Bylvay reduces the reabsorption of bile acids from the terminal ileum and their return to the liver. Reducing buildup of bile acids or cholestasis prevents liver damage leading to cirrhosis, end-stage liver disease, and the need for liver transplantation. Please turn to slide eleven. PFIC refers to a rare heterogeneous group of autosomal recessive disorders of childhood that disrupt bile production or secretion and presents with cholestasis that can lead to significant morbidity. The PEDFIC trials represented the largest trials ever completed in children with PFIC. PEDFIC 1 was a randomized, double-blind, placebo-controlled phase III trial aiming to evaluate the efficacy and tolerability of Bylvay in reducing pruritus and serum bile acids in children with PFIC. All patients enrolled in PFIC1 were eligible to participate in PFIC2, a long-term open label extension phase. Bylvay achieved the primary efficacy endpoint versus placebo and demonstrated efficacy across multiple PFIC types, including the% of patients with improved pruritus score, mean reduction in pruritus score from baseline, and reductions in serum bile acids from baseline. Bylvay was generally well-tolerated. Most treatment-emergent adverse events were mild to moderate in severity. There were no serious treatment-emergent adverse events, discontinuations, or deaths. Please turn to slide twelve. Alagille syndrome is a rare autosomal dominant disorder caused by either inherited or spontaneous mutations in the JAG1 or NOTCH2 gene, which can affect normal development of multiple organ systems, including the liver. Many patients with Alagille syndrome will ultimately require biliary diversion or liver transplantation. ASSERT is a double-blind, randomized, placebo-controlled 24-week trial designed to evaluate the safety and efficacy of Bylvay for people living with Alagille syndrome. Top line results were presented at the American Association for the Study of Liver Diseases annual meeting in November of last year. In 52 patients with a mean age of six, those who received Bylvay experienced statistically significant improvements in observer-reported scratching score from baseline to month six compared with placebo. Looking at the key secondary endpoint, serum bile acid levels dropped significantly with Bylvay versus placebo at 24 weeks. There were no trial discontinuations. All patients completed the initial 24-week treatment duration. 96% rolled over into the open label extension trial. Please turn to slide thirteen. Biliary atresia is a rare pediatric liver disease with symptoms typically developing about two to eight weeks after birth and no approved pharmacological therapies. The disease is characterized by destruction or absence of all or a portion of the extrahepatic bile duct system. This results in bile and bile acids being trapped inside the liver, quickly resulting in cirrhosis and liver failure. Kasai surgery or a hepatoportoenterostomy can be life-saving in patients that respond. About 50% of patients undergo a liver transplant in the first two yeara of life. BOLD is a double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of Bylvay in children who have biliary atresia and have undergone a Kasai procedure before age three months and who are eligible to start treatment and randomized within three weeks of the procedure. The primary efficacy endpoint is the proportion of patients who are alive and have not undergone a liver transplant after two years in the Bylvay arm compared to placebo. The study has enrolled 205 patients, and based on our due diligence, we are confident in the trial design and may increase the sample size of the study to maximize its probability of success. The FDA and EMA have indicated that a single pivotal study is sufficient to support filing. Thank you for listening. I'll now hand back to David. Please turn to slide fourteen. Thanks, Howard. I'm now going to outline commercial opportunities for Bylvay. Please turn to slide fifteen. As you have seen, the development of Bylvay is advanced and is at various stages across the three indications. It's worth noting that competition is very limited, with only one launch so far in Alagille syndrome. We have outlined here our broad assumptions for the numbers of patients across the indications. On pricing, we assume a higher price in Alagille syndrome and then biliary atresia than in PFIC. Our assumption is that the overwhelming majority of patients will stay on treatment until they need a liver transplant. The time to liver transplant is dependent on the native liver survival rate per indication and per response to the treatment. Please turn to slide sixteen. Pulling this together means that we have substantial commercial opportunities to increase the sales of Bylvay. A strong Bylvay efficacy and safety profile has been established. There are very limited number of competitors in this space. It is leading in PFIC and biliary atresia, where competition is in phase two. Bylvay is already on the market in the U.S. and in Europe for PFIC, and already been launched and reimbursed in a number of countries, including in the U.S., where favorable coverage has been secured, as well as nine countries in Europe. The profile of Bylvay has been augmented by compelling results from the ASSERT trial for Alagille syndrome. Regulatory submissions were made in the U.S. and EU late last year. We would expect regulatory decision in this indication at the end of 2023. Global rights in the hands of a truly global company mean that we can leverage our infrastructure, capabilities, and strengths to fully accelerate the sales of Bylvay. It's also worth highlighting the convenient dosing with food via capsules once a day, which are preferred by children and teens. Bylvay can be sprinkled over food via oral pellets for babies. Finally, we have a good patent life in both U.S. and in Europe. With success in all three indications, we can deliver peak sales of around $800 million, of which approximately half would come from Biliary Atresia. I'll now hand you over to Aymeric, who will summarize the financials. Please turn to slide seventeen. Thanks, David. Please turn to slide eighteen. The terms of the agreement include an offer to acquire all outstanding shares of Albireo for $42 per share in cash at closing, which will represent an initial consideration slightly in excess of $950 million. The agreement has been structured to include a contingent value payment based on the approval of Bylvay in biliary atresia in the U.S. by FDA. One contingent value right per share will entitle its holder to a deferred cash payment of $10 per severe, which will represent about $240 million. As you can see, this transaction will be fully financed by our existing available cash and line of credit, we will keep, after the transaction, sufficient firepower to continue our business development strategy. Subject to the satisfaction of all closing conditions, including regulatory, we anticipate the closing of the transaction by the end of this quarter. The acquisition of Albireo will immediately provide incremental sales, and we anticipate short-term dilution to our profitability until the end of next year. It's very similar to the Epizyme acquisition. From 2025, we expect accretion to our core operating income. As you can see, this financial profile is consistent with our outlook to do this and make operating investment under the external innovation strategy to promote the long-term and sustainable growth of Ipsen. I will now hand over back to David. Please turn to slide nineteen. Thank you, Aymeric. I'd now like to conclude our presentation before we go to your questions. Please turn to slide twenty. As we make more progress with the execution of our external innovation strategy, I'm pleased to announce today's news. It's another step in our journey of delivering sustainable growth over the long term and supporting excellent medicines to get to more patients. We're expanding the scope of our rare disease business by acquiring a leading innovator in bile acid modulators for rare liver diseases with real expertise in bile acid modulation. In Bylvay, we'll have an on-market and potentially best-in-class medicine that has an advanced development program and significant commercial opportunities. Finally, it is an excellent fit for Ipsen in line with a consistent strategy for growth. Please turn to slide twenty-one. Thanks for listening to our presentation. We now have time for questions. Operator, over to you. Ladies and gentlemen, we now begin the question-and-answer session. If you wish to ask a question, please press star one and one on your telephone. We are now taking the first question. The first question from Jo Walton from Credit Suisse. Please go ahead. Your line is open. Thank you very much. I think the main question that people have is why you are able to get something with peak sales potential of around $800 million for something in the region of $1 billion. Normally, you seem to pay a much higher multiple of potential peak sales. I wonder if there is something unusual in the profitability that we can't see from looking at consensus forecasts that would take the profitability down. Secondly, I note from the company that their guidance was for $24 million of sales for this year. They've already done around $18 million or so. There's only $6 million left, which is less than the third quarter. Now, they did make a comment that sales would go down because we're beyond the end of the German free pricing period. Perhaps you could tell us a little bit about how you see pricing developing in Europe. And for our modeling, I wonder if you can help us on what sort of avoidance of interest charge, I mean, given that you've got cash or what sort of interest rate we should put against this and whether you are able or intending to get rid of the Sagard Healthcare Partners royalty program. Presumably you can just buy that out and add that to the initial cost. Many thanks. Thank you, Jo. On the $800 million, you have seen that actually there were already analyst reports which were much higher. We actually came to the conclusion that with the $800 million, that is about the right price, the right figure for peak sales, which I think we're gonna achieve in 2029-ish, 2030-ish. Now I can't really, you know, comment on the multiples of the market. You know, of course, that the market has taken a hit on biotech. It's really something that we were also not quite sure, you know, how it is explained. I think we made a fair offer and with a 100% premium, I think that's a very fair premium. That's all I can say on this point. Regarding the sales, I think we need to see, you know, the official results that Albireo is gonna publish. I think they have been doing quite nicely. In terms of the pricing in Europe, we don't think next to this effect that you have mentioned on Germany, there are other effects. Of course, Pricing in Europe is somewhat lower than in the U.S., as usual. There is no, you know, special explanations, so watch the space for the Q4 sales. In terms of the modeling, I will hand over to Aymeric. Yeah. Maybe back a little bit to your question about the profitability. I think it's a rare disease company, there is nothing specific that will impair the profitability. There is no specific royalties. The cost of goods are pretty standard and pretty low. Clearly you were asking the question about the royalty debt financing. As you can see, there is a possibility to potentially buy this out, and that will reduce clearly the level of royalties which are not assumed in our model. Today, the dilution is assuming we're gonna find a way to buy out this royalty debt. Regarding the financing, we have a revolving credit facility that has been set up a couple of years ago, which is a very favorable interest rate in terms of margin. This shouldn't be a very huge cost of financing for us. We also have available cash. The transaction is gonna be financed with a combination of our existing cash and some drawing on our revolving credit facility. Last one, maybe on the guidance of the company, I think the company has been quite conservative given the track record since the beginning of the year. I would assume that the fourth quarter is gonna be lower than the previous one. This was a guidance provided in October on the EUR 24 million sales. We'll provide more when we close our books in February. Operator, can I just check? We've had a couple of people say they couldn't hear the first part of David's answer. Can I just check you were able to hear that? Yes, I was, sir. Okay. Thank you. Thank you. Jo, you got the answer to your questions? Did you understand that? Yes, I did. I got all the answers. I do know that some people who are on the webcast are finding it more difficult than those of us who have dialed in. Interesting. It seems to be linked to the webcast, so perhaps if people on the webcast have difficulties, please dial in through the phone. Operator, next question. Thank you, Jo. We are now taking the next question. Please stand by. The next question from Michael Leuchten from UBS. Please go ahead. Your line is open. Thank you very much. It's Michael Leuchten from UBS. Three questions, please. I'm just going back, Aymeric, to your comment around sort of the operating expenses, efficiencies and margin accretion. Given that you have the palovarotene infrastructure sitting there with somewhat of an uncertain future until we exactly know what's happening with the FDA, like how much of the cost that you're taking on will you be able to absorb? Or is there a scenario where you have to keep both your and the other infrastructure in place until you get more clarity? At that point, there might actually be more efficiencies that allow you to get a better margin accretion than maybe in the first two years. How are you gonna absorb or not the OpEx, both in terms of SG&A and R&D, that you're taking on with this transaction? The second question, just wondering how you think about the competition. You did mention Livmarli, the Mirum product that's out there for Alagille. As they now at some point get their phase III readout, how do you think competition is gonna shape up in PFIC? Just any thoughts would be helpful. Is there any timeline to the CVR? Is there any sort of point in time where the CVR expires regardless of what happens with the approval, or is it open-ended? Thank you. Maybe to start with your question on the, on the OpEx and the palovarotene. I mean, as you know, I mean, on the R&D side, there will be very limited synergy, as these are very different study to be run. By the way, there is not that much left for palovarotene. I think your question is more on the SG&A. Clearly we are building a rare disease infrastructure. It's quite limited, as you don't need a lot in this ultra-rare space. Yes, if we were to launch both palovarotene and Bylvay, we may have some limited synergy, but that's not a major driver today of the cost base. We believe that there is the right investments behind Bylvay. We need more of the sales to ramp up, and the dilution is really coming from a progressive ramp up. We expect by the end of this year to get the second indication and then to progressively ramp up on these two indications. R&D is gonna be mainly related to the BOLD study. On your second question, Michael, on the competition. Basically Livmarli is already registered in ALGS. We are gonna come on the market towards the end of the year. They have shown positive results also in PFIC. It's really hard to compare across studies and, we see the profile as pretty similar regarding efficacy. Perhaps there is a safety advantage for Bylvay, but it's very, very hard to say because, you know, there is less diarrhea, but this cross-site comparison, very low numbers of patients, one needs to be super careful when looking at cross-study comparisons. What I can say is where we do see a differentiation is clearly on the dosing. Bylvay has capsules and pellets. You know, when you need to give a dose to a baby or to a toddler, sometimes it can be hard for those of you who have babies or toddlers. The dosing on Bylvay is actually very convenient. If you have a baby, you can sprinkle the pellets over, for example, an applesauce or a chocolate pudding, and the babies usually like that. Once they grow a bit older and they can start to swallow, then they can take the capsules, which in this market is, I think, very important because, you know, this market can go up to teenagers and also some adults. Having a capsule, I think is something which we really liked. Another important point is on BA, which is about 50% of the forecast. Clearly Bylvay has a strong head start, being in a very advanced phase III, while competition is in phase II and is measuring on a surrogate endpoint. All in all, this is what actually seduced us on Albireo. Then on the CVR and the exploration, I hand over to Aymeric. As you can see from the press release, the drop date for the CVR is end of December of 2027. As we have room to potentially adjust the number of patients in the BOLD study. As Howard explained, that's a way to maximize the probability of success of that study, which represents a large part, almost 50% of the $800 million peak sales. Thank you. Operator, next question. Yes. We are now taking the next question. The next question from Simon Baker from Redburn. Please go ahead. Your line is open. Thank you for taking my questions. A few quick ones, if I may. On Bylvay, this is going back to Jo's question about royalties, but specifically on Bylvay. There have been quite a few deals done, regionally in the US, Israel, Turkey, the Gulf, Japan. I just wonder if you could give us a summary of where those deals stand in terms of royalties that you're paying away, in any key territories on Bylvay. The second one, a number of other IBAT inhibitors are being tried in PBC. Bylvay doesn't appear to be in PBC at the moment. I just wonder if that's an additional opportunity. Second and final question, you haven't talked about elobixibat, which I think is only approved in Japan and Thailand. I just wonder if you could give us your thoughts on the commercial potential of that as well. Thanks so much. Thank you. On the royalties, I think, we can have Aymeric elaborate on that. Yeah. I think that there is only a back-to-back agreement on Japan. This has no impact for us. There has been a transaction which we don't intend to change, contrary to the big royalty financing that was set up by Albireo in September. Clearly Japan is not in the scope, and that's the only territory, assuming we pay out the Sagard royalty financing, that will exist, and this will have no impact as it is fully back-to-back. On the IBAT used in PBC, Howard, do you wanna elaborate on this? We're aware that other IBAT inhibitors are being tried for pruritus in primary biliary cholangitis. Right currently there's no such program for Bylvay. However, there is an oral systemic IBAT inhibitor in the pipeline from Albireo called A3907, that has the potential to be used in adult cholestatic liver diseases, currently PSC, but potentially others. That's, you know, that's the situation with the pipeline as it stands today. Thank you, Howard. On your third question on elobixibat. The acquisition includes all of Albireo's marketed products and pipeline assets, and EA Pharma is the exclusive licensee of elobixibat for the treatment of gastrointestinal disorders in Japan and other select countries in Asia, but not including China. Albireo currently has own commercial rights to elobixibat in the U.S., Europe and China and otherwise outside of the territories licensed to EA Pharma. We are currently assessing all of our opportunities across the whole of Albireo's portfolio, both marketed and pipeline. Sure. Thank you very much. Thanks. Next question. Yes, sir. We are now taking the next question. The next question from Rosie Turner from Jefferies. Please go ahead. Your line is open. Hi. Thank you very much for taking my questions. Just a few quick ones left, if I may. Maybe continuing on in terms of the broader pipeline. I think there's A3907, if that's the correct way to say it. It's like that was going into phase II in 2022, but I can't see an update on the website. Has that happened, and is that kind of still planned to go into phase II kind of under Ipsen ownership? Kind of going a little bit back to the royalty question. Does that mean there are opportunities kind of ex Japan, for kind of additional sales, thinking about kind of China, et cetera? Just finally, the CVR, do we know, is that going to be tradable or is that going to be something that's OTC? Thank you. Okay. Perhaps we start with the A3907. It indeed has just started the phase II. I'll let Howard elaborate on this one. Yes. A3907, if you look on ClinicalTrials.gov, it is a public information that it has started a phase II study with two doses in patients with primary sclerosing cholangitis. That has actually been posted and our understanding is they're imminently going to start that study. On the question two, we do have the rights for Bylvay in China, and we anticipate that it could probably come on the market in 2026 there. I wasn't quite sure about your question because you asked on royalties and then China, but so, we don't have Japan. Yeah. Yeah, we don't have Japan, as you know. Yes. We do have China. Perhaps you can quickly clarify your question. Yeah, no, that's perfect. That's answered my question. Yeah, I was just checking. Oh, okay. Are there any opportunities where you don't have royalty payments? Yeah. Yes. The biggest would obviously be China. Sounds like it's safe to- Yes. The answer is yes. Yes. Okay. Then on the CVR tradable, I'll give it to Aymeric. No. The answer is no. The CVR is not gonna be tradable. Okay. Thank you. Thank you. Operator, next question. Thank you for your question. We are now taking the next question from the line of Matthew Weston from Barclays. Please go ahead. Your line is open. Hi. Thank you very much for taking my question. Matthew Weston from Barclays. Just a few questions from me. Firstly, just on the kind of strength of IP, could you give us a little bit more detail around the strength of your IP for Bylvay, given the footnote on in your slide suggests that your currently protects out to November 2031, but then based on patent term extensions, that will extend to 2036. Just give me an idea of the kind of confidence you have on those extensions. This is on your kind of M&A strategy. This is naturally a more de-risked acquisition already being on the market. Is this a kind of strategic change in your strategy going forward? Can you just talk a bit more around the reasoning for ensuring the CVR link just to the approval of BA whilst it's suspected to be 50% of your peak sales? Then just a quick clarification question. During the call, I think you said it was 50% of patients require a liver transplant in the first two yeara, in the appendix it says 80%. Can you just clarify which of these is the correct amount? Thanks. On the IP, yes, we are comfortable on the IP. Exploration in the U.S. will be end 2023 is our read. Then it's 2033, sorry, 2033, I want to say. End 2033, sorry for that, for the U.S. and for Europe, the loss of exclusivity is end 2035. Regarding your second question on the CVR, in with BA, I'll hand over to Aymeric. Yeah. I think your question is, yes, this transaction is partly the risk because as you can see, BA is a significant part and there's still a phase III, we thought that was the appropriate way of structuring the deal. I think as you can see, timing also of BA may take a little bit longer than what was anticipated. That's why we structured the deal to be de-risked. That's the way we intend to continue our M&A strategy. That's the way we did it also for Epizyme. As you know, the elafibranor transaction was also a royalty. It was a licensing agreement where we pay a limited up-front. I think it's very consistent on our M&A strategy. Operator, can I just confirm? We just had a couple people saying they couldn't hear Aymeric. Can I just confirm you can hear? Yes, sir. I can hear loud and clear. Okay. Thank you. Okay. On the third question regarding native liver transplant survival, I hand over to Howard regarding the BA question. Yes. The correct answer is that about 50% of patients who've undergone a Kasai procedure will require a liver transplant within the first two yeara of life and with at least 80% requiring liver transplantation by age 20 years. Apologies if that wasn't clear. Thank you very much. Operator, next question. Thank you for your question. We are now taking the next question. The question from Richard Parkes from Exane BNP Paribas. Please go ahead. Your line is open. Hi. Thank you very much for taking my questions. Firstly, there's a perception, I think, that maybe Albireo did a good job in terms of development, but less in terms of commercial execution. I don't know whether that's correct or not, but just wondered if you feel that's the case as well, and maybe understand how you plan to improve on that and how things could have been done better so far. The second question for Howard, just wondered if you could help us understand what a 1 to 2 point reduction in pruritus score means for a patient. Just help us put that in context. That would be really helpful. Finally, just a couple of minor things. I just wondered if you can help us understand what you've assumed in terms of market shares with the competitor, in your $800 million potential. I know you're not gonna be specific there, but if you can help us broadly there, that would be helpful. Finally, sorry, just one more on pricing. Could you just help us by confirming the current pricing? I think you mentioned that you expected Alagille syndrome pricing to be higher than the other indications. I don't know if I misheard that. Just wondering why that might be. Is the dosing the same across all the indications or is there some other difference there? Thank you very much. Okay. Regarding the commercial execution, I think, you know, always when you have start-up biotechs, launching themselves, it's, you know, not necessarily the same performance than if you have a larger company who has been in a field, for example, in a rare disease. You know, we had Somatuline in acromegaly, we had Increlex, et cetera. We have kind of a very strong organization. It's not the same performance. We do indeed, assume that we can get a stronger performance by throwing the full force of Ipsen globally, behind the product. That was also one of the reasons why this acquisition saw the light because the board also saw that this is an advantage for the drug. Albireo is very committed to patients, very purposely, and so are we. Therefore, that is also a motivation for the acquisition. On your second question, Howard, on the 1-2 points on pruritus, what does it mean? Yes. basically, when you, when you look at the precision scale that was used by Albireo for these programs, it's based on a 0 to 4 scale with no itching versus the most severe itching. A 1-point change, obviously in a 4-point scale, is significant. When you talk to key opinion leaders, they consider a 1-point change to be, you know, very clinically meaningful. As you know, many of these children have, you know, really debilitating pruritus where, you know, there's blood on the bedsheets, et cetera, so it can really impact quality of life. A 1-point change is felt to be clinically meaningful. Thank you, Howard. On your third question regarding market share, as you said, we're not guiding on a number. What I can say is that efficacy, if you look cross-study comparison, and as I said, you have to be very careful when doing that, but it looks broadly similar. We think we have an advantage on the dosing. It is more convenient, and there might also be a slight benefit on the side effect profile. Again, this is cross-study comparison, so we need to be extremely careful. Having said that, we would assume, obviously, you know, attractive market shares for Bylvay. Regarding pricing, your question was, is the pricing going up because of the dose? The answer is yes. As you know, the dose registered in PFIC is 40 micrograms. It's potentially now a GL, it's gonna be $40 or $120. We have to see what comes out in the discussions with the FDA. We think it should be $120. On DA, it will also be $120. Of course, you can't just multiply by a 3 that price. That's not gonna work. We will have to take this into account, but we do assume a somewhat higher price in these two other indications. With this, operator, next- One follow-up. Yeah. Could you just confirm what the current WAC annual pricing is in the U.S. and maybe what kind of average pricing in other territories? Thank you. It's super complex actually, to give that because, you know, it's dose dependent, and if you give it to a baby, of course, it's a much, much lower dose than if you give it to a 17-year-old. What we can help you in the modeling is to say, in the U.S., if you take, you know, an average price, we would estimate that it's about $350,000. In the EU, the list prices are between $120,000-$195,000 in average per year. But you know, of course, that in Europe, you then have to deduct also net prices. So there is a bit of a difference there. Thank you. With this, operator, next question. Yes, sir. We are now taking the next question. The next question is from Alistair Campbell from Royal Bank of Canada. Please go ahead. Hi. Yeah, Alistair Campbell from Royal Bank of Canada. Just a couple of questions following up on biliary atresia. First of all, just looking at the BOLD study, obviously, placebo arm, you're probably expecting about 50 of those patients to progress towards liver transplant. I'm kind of curious what sort of efficacy you're hoping to see from BOLD. If you did see a significant delay of liver transplant within the lifetime of the product in terms of its IP life, could you see that incidence rate in the U.S. or sort of the prevalence rate in the U.S. of about 600 increase significantly, and ultimately to a bigger sales number? The second question is, again, on BA. I was sort of reading some article this morning saying that incidence in Asia is, I mean, significantly higher than Europe's. Multiples of Europe. Given that, are there any sort of, how important in your forecast is Asia ex-Japan, or are your forecast largely based on US/Europe? Thanks. Yeah. very good questions. Thank you, Alistair. regarding the BOLD study, perhaps I hand over to Howard. The BOLD study is statistically powered to show a minimum of a 15% improvement in patients who are treated with Bylvay in addition to having the Kasai procedure versus the Kasai procedure alone. Obviously, it could be greater than that and that would be great. It's basically minimally powered to show a 15% improvement in native liver survival at two yeara. Is the prevalence gonna, you know, kind of accumulate over time? Of course, we do hope that there is an impact on the timing to liver transplant so that this gets pushed out. That would indeed mean that you have an accumulative effect on the prevalence pool. This is a very good question because the modeling is actually not easy on the three indications, I have to say. What we modeled is on PFIC that you have a small incidence pool of new babies. It's one in 100,000 births. There is, of course, as you have seen on the slide, with the prevalence, a bit of a larger pool on the prevalence. That prevalence pool is also gonna start decreasing, and the incidence pool is gonna start kind of fermenting the new prevalence pool. ALGS is a bit the same thing. You have 3 in 100,000, and the prevalence figures you have seen also are quite significant already. Again, the prevalence pool of people already been in there today is gonna start decreasing over time with the natural liver transplant survival curve. Of course, the new births are gonna replenish that pool. Then on BA, it's gonna be mostly driven by the incidence pool. You have also a prevalence pool, but the ratio is a bit smaller, as you have seen on our slide. Again, over time, if indeed we manage to prolong the time to transplant, that prevalence pool should increase over time. To your second question on the BA incidence, is it higher in Asia, and what are the rest of the world sales? We did a bottom-up forecast for China, and the rest of the world sales that we have modeled are somewhat higher indeed than the European sales. That is also often the case. We are not at the level of detail yet on our forecast model. You know, having modeled all the other Asian countries, we have taken a kind of a multiplier on the rest of the world there. To be clear, I mean, the majority of the peak sales are really coming from the U.S., so there's not a disproportion due to that potential upside due to the incidence prevalence in Asia. Okay, great. Hope you've been... Thank you. Next question, operator. We are now taking the next question. The next question from Delphine Le Louët from SEB. Please go ahead. Your line is open. Thank you. Happy New Year, everyone. I was wondering, who is gonna be responsible for the manufacturing going forward? First question. Second question. We had roughly EUR 80 million R&D spent over the past three years on the the protect the pipeline. How should we consider that's looking forward, especially the sequence 2023, 2024, and to be able to ask. Third question, more clinical question. I was just wondering if you have a cohort of 100 patient going for... So regarding BA, going for a Kasai procedure. How many of them reach 20 years old, and how many of these 100 patient, let's say two yeara old, having the Kasai, are gonna have a liver transplant in between 2 and 20 years old? Thank you very much. First, on the manufacturing. Albireo has contracted with very well-known CMOs, out of which one in France as well. On the manufacturing plants, we are very confident there is no issue there. Regarding your second question on the clinical development, I hand over to Howard. Sorry, the question around the biliary atresia and liver transplant incidence? Yeah. Basically the incidence of patients who have a Kasai procedure requiring a liver transplant at, within the first two yeara of life is 50%, based on most recently available data. Even the patients that basically have a successful Kasai procedure, those patients tend to continue to have progressive disease. At least 80% of those patients require liver transplantation by age 20 years. Of those patients who survive into the 3rd decade after birth, almost all have portal hypertension or other complications of cirrhosis. Even those patients that actually have a liver transplant, or have a successful Kasai, and have native liver survival, those patients tend to continue to progress, and 80% of those or more require liver transplant by age 20. Even of those patients continue to progress in terms of their liver disease. That's why we think there's really an urgent need for a pharmacological therapy to be available in addition to the Kasai procedure. Thanks. Okay. on your third question. Regarding the R&D. Yeah. Yeah. On your third question on the R&D expenditure, so that's Aymeric. Yeah. Delphine, on the R&D, I'm not sure about the number you were talking about, as you know, we spend about 15% of our sales in R&D. You should expect that ratio to significantly increase over time, by a third over time in 2023, given first, on one side, the Epizyme R&D spend, which will come from both the Tazverik clinical trials also the early-stage pipeline. We're gonna add clearly the R&D spend of Albireo, mainly being the cost of the BA study that needs to be completed also some of the development of the more earlier stage assets. This is very consistent with our overall outlook, where R&D is gonna increase. This is gonna be across 2023, also in 2024. In 2024, we're gonna have more leverage from the sales, both from Epizyme and Albireo, and leverage the infrastructure. Okay. For the phase three for, BA, can we guess, an envelope, some of the cost? I think it's a classical phase III. As you know, the number of patients is not that high, so I don't think it's very significant. This will be on top of the development of the other, earlier stage assets also of the Albireo pipeline. Okay. Super. Thank you very much. Very good. Thank you, Delphine. Operator, next question. We have. That's our last question. We are now taking the next question. The next question from Sachin Jain for Bank of America. Please go ahead. Your line is open. Hi there, thanks for taking my question. I just had one on if you could elaborate on the side effects experienced by patients on Bylvay and how they are managed. Yeah. Howard, you wanna take the side effect questions on Bylvay, how they are being managed? Howard? Sorry. I was speaking into mute. The basically, the main side effects are gastrointestinal adverse reactions. And obviously, those, you know, can be minimized with with obviously the need to take it with food, with hydration, as needed. But as David Loew alluded to before, we actually think that there might be differences between the available IBAT inhibitors in terms of those types of side effects. Other side effects that are known are fat-soluble vitamin deficiency, which really occurs in a small number of patients, and can be managed with adequate vitamin supplementation. So we don't think that that is a major issue. In general, I would say, as I said in my presentation, that most of the adverse events that are seen with Bylvay are mild to moderate and really don't result in discontinuation typically. We think this is a generally well-tolerated drug both in PFIC, but also in the Alagille program, which was recently filed to the agencies. Very good. Thank you, Sachin. That was our last question. I would like to thank everybody for participating. I hand over to the operator. That concludes the conference for today. Thank Thank you for participating. You may all disconnect.