Takeda Pharmaceutical Company Limited

Thank you very much for joining us today. This is quite a very busy schedule for this FY23 Q1 earnings announcement. My name is O'Reilly. I am the head of IR. I'll be the master of ceremony for today's meeting. Allow me to explain about the language setting. Please find the language button at the bottom of Zoom window. If you wish to listen in Japanese, please choose Japanese. If you wish to listen in English, please choose the English channel. And if you want to listen to the original, please turn that off. Before starting, I'd like to remind everyone that we will be discussing forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those discussed today. The factors that could cause actual results to differ materially are discussed in our most recent form, 20F, and in our other SEC filings. Please also refer to the important notice on the page two of the presentation regarding forward-looking statements and our non-IRFS financial measures, which will also be discussed during this call. Definitions of our non-IRFS measures and reconciliations with our comparables, comparable IRFS financial measures are included in the appendix in the presentation. It's also most important notices are attached to the presentation material. Now we would like to start the presentation. Today we have President and CEO Christophe Weber, R&D President Andy Plumb, Chief Financial Officer Kostas Saroukos presenting to you. This will be followed by a Q&A session. Now we would like to begin.

Christophe, please go ahead. Thank you, Chris. Thank you everyone for joining us today. It's a pleasure to be with you all. Our performance in the first quarter of this fiscal year again underscores the strength of our business and our ability to continue to deliver life-transforming treatments to patients and communities over the long term. Looking at our financial results, in the first three months of fiscal year 2023, revenue was 1.06 trillion yen. Year-over-year growth at a constant exchange rate was plus 3.7%. Driven by momentum in our growth and launch products, which represent 40% of total revenue and grew in this first quarter at 16.2%. At actual exchange rate, our top line growth was 8.9%. Our top line performance contributed to cooperating profit of 326.3 billion yen. The year-over-year decline at constant exchange rates reflect the impact of loss of exclusivity and lower coronavirus vaccine demand, as well as our strategic investment in R&D and data and technology to ensure Takeda long-term competitiveness. Core EPS for the period was 150 yen, flat versus prior year at a constant exchange rate. On a reported basis, EPS declined due to the impact of one-time financial income gains in the first quarter of last year. Our results at constant exchange rate are tracking well against our full year management guidance for fiscal year 23, and there is no change to our guidance at this time. Moving to the right of the slide, we are advancing our innovative pipeline to reach new patient population, address unmet needs, and provide new treatment options to improve patient outcome and quality of life. Our dengue vaccine, Scudenga, was recently approved in Argentina and Thailand, and we are pleased with the momentum we are seeing in both endemic and travel market. I will discuss Scudenga further on the next slide. In other regulatory development, we have filed GammaGard Liquid in the US for the treatment of chronic inflammatory demyelinating polyneuropathy, or CIDP. This follows on from the submission of IQVIA for CIDP in Q4 of last year. representing near-term indication expansion opportunities for two of the growth and launch products in our PDT immunology portfolio. We have also filed frucitinib in the US and Europe for previously treated metastatic colorectal cancer, receiving priority review designation in the US. Metastatic colorectal cancer remains an area of high unmet needs with poor outcomes, and limited treatment options, and we are pleased to take a step further toward advancing treatment for patients. Priority review in the US has also been granted for TAC755, for congenital thrombocytopenic purpura, or CTTP, and ultra-rare bleeding disorder, also with limited treatment options. In neuroscience, our ongoing phase 2b study of oral orexin agonist TAC861 for both narcolepsy type 1 and narcolepsy type 2 is progressing well on track. We believe in the transformative efficacy potential of our orexin programs, and this is supported by data published today in the New England Journal of Medicine from our discontinued study of TAC994. Andy will explain the details in a few minutes. We are proud of all this progress, which represents the potential of our portfolio to make a meaningful difference in the lives of patients and to serve communities around the world. Turning to updates on our dengue vaccines, CUDENGA. We are very early in the launch phase for CUDENGA, but we are encouraged by the positive momentum we are seeing in markets where it is now available. And we are already seeing early sign of higher than expected demand. We made significant progress in the last quarter with approval in Thailand and Argentina on our first launches in endemic countries, including Brazil and Indonesia. The vaccine's significant progress in endemic countries underscores its strong clinical data and the urgent need for safe and effective vaccines to prevent dengue fever. which is why we remain laser focused on endemic market, which make up roughly 80 to 85% of our projected peak sales of 1.6 to 2 billion US dollar. At the global level too, dengue prevalence has continued to grow. The World Health Organization reported just last week that there have been close to 3 million cases of dengue reported so far this year, already surpassing the 2.8 million cases registered for the entire year of 2022. In travel markets, we have continued to see country-level approval on launch across the EU following the EMEA broad approval late last year. In the US, we made the difficult decision to voluntarily withdraw our biologics license application filing due to FDA requests for additional data, including data that was not part of the previously agreed upon protocol and which could not be addressed within the current review cycle. This decision will not affect our overall approach for TAG003 for Kudengar, which we believe can be extremely effective to limit the public health impact of dengue in endemic countries. Looking ahead, we are continuing to work closely with the WHO and look forward to the release of the recommendation from SAGE, the WHO Advisory Group, which is anticipated later this year. We are also in active discussion with a number of supranational procurement bodies, such as the Pan American Health Organization relating to large scale procurement, following the WHO recommendation. To meet the vaccine's anticipated global demand, we have been expanding our manufacturing capabilities. We recently, in fact last week, celebrated the opening of a state-of-the-art building dedicated to drug substance manufacturing for our dengue vaccines in Singen, Germany. This was an important step in achieving our goal of end-to-end in-house production capability for CUDENGA by 2025 and achieving an annual supply capacity of around 100 million doses by the end of the decade. While we ramp up our manufacturing capabilities, we are exploring partnership with vaccines manufacturers, especially in endemic countries, to secure additional capacity to meet current and future supply needs. We look forward to continued momentum of these programs in 2023 and beyond. Now I'd like to turn to our high level outlook for the near, medium and long term. Based on our current assumption for fiscal year 23, we expect to return to revenue, profit and margin growth in the near term, driven largely by the continued expansion of our growth and launch product. We also see significant potential in our late-stage pipeline assets and anticipate significant data and regulatory milestones this year. Following the generic competition for vivance, which will impact revenue and profit growth in fiscal year 23, We will have limited loss of exclusivity exposure until the launch of Antivio biosimilars, which could occur as late as 2032. The momentum for our growth and launch product, combined with our continued investment in R&D, will drive progress in the medium and long term. Looking ahead, we remain committed to returning to co-operating profit margin in the low to mid 30s, supported by value creation enabled by data and technology, including AI. We will also continue to evaluate asset-specific business development opportunities to further enhance our pipeline and reinforce our growth profile. Finally, our progressive dividend policy of increasing or maintaining the dividend each year will allow us to continue to return value to shareholders. In closing, this quarter demonstrates that our growth strategy remains on track. We continue to deliver on our financial commitment to progress our pipeline and to create long-term value for our stakeholders while we fulfill our purpose of bringing better health for people and a brighter future for the world. With that, I will turn the call over to Andy to update you on our pipeline. Thank you.

Thank you very much, Christophe, and a big hello to everyone on today's call. If we go to the next slide, please. Our pipeline continues to advance, including considerable progress with ATT&CK 279 and Ericsson franchises, which we will describe later in this presentation. This quarter, the rest of our pipeline featured a number of incremental but important program milestones and a few small headwinds. As Christoph just mentioned, important regulatory milestones include filing for Quintinib in both the US and EU for metastatic colorectal cancer. filing tax 755 in again the U.S. and EU for congenital thrombotic thrombocytopenic purpura, or TTP, and filing GammaGard Liquid in the U.S. for chronic inflammatory demyelinating polyneuropathy, or CIDP. Frequentative and TAC-755 are granted priority reviews by the FDA, reflecting their potential for increased effectiveness and or better safety in areas of high unmet medical need. If approved, TAC-755 would be the first available therapy for routine prophylaxis in congenital TTP. Supporting these and other programs were a number of key publications and presentations. These include IQVIA's Phase III Advanced I study results demonstrating an approximate 10% relapse rate with IQVIA. This is the lowest relapse rate observed in CIDP maintenance studies across mechanisms. Frequentinib data from FRESCO2 was published in the Lancet and showed a greater than 30% increase in overall survival versus the control arm in patients with metastatic colorectal cancer. In June, TAC755 data were presented. These data demonstrate a reduction in the incidence of thrombocytopenia by 60% versus the standard of care, and no acute TTP events were observed. And also in June, updated data from the Phase II sequoia study of Fazir Saran was presented at the European Association for the Study of Liver Congress, or ESIL. Fazir Saran continued to demonstrate a dose-dependent reduction in the pathological alpha-1 antitrypsin ZAAT protein in both serum and liver, leading to directional decreases in liver inflammation and fibrosis. We've started our phase three Redwood study earlier this year. Now, headwinds this quarter include PAC 611 for metachromatic leukodystrophy, or MLD, which missed its primary and secondary endpoints in our phase two study. We are disappointed and wish to express our gratitude to the MLD children, parents, and caregivers. We're currently evaluating options, but given these outcomes, the program, unfortunately, is likely to be discontinued. Following a planned interim analysis, the phase three EXCLAIM-2 trial was stopped for futility. The trial compared EXCIVITY monotherapy to chemotherapy in first line non-small cell lung cancer with exon 20 insertion mutations. We will be engaging with regulators regarding these data and determining next steps for the program. As a reminder, EXCIVITY demonstrated a median duration of response of 17.5 months and a median overall survival of 24 months in patients being treated in the second line who had progressed after chemotherapy. And lastly, as Christoph discussed, we had some positive and negative developments for Cudanga this quarter. It's very important to recognize that the unmet need for a dengue vaccine is not equally distributed around the world. We remain confident in the overall benefits of Cudanga. However, timing of approval may vary depending on local needs and experience. Finally, yesterday, as Christoph again mentioned, Phase IIb data from the first-ever oral orexin receptor 2 agonist, TAC994, was published in the New England Journal of Medicine. Next slide, please. We conducted a phase 2B dose-ranging trial that tested three doses of TAC994 in an eight-week study with the option for patients to continue into an eight-week extension. The trial was stopped early due to liver toxicity. Now, even with a truncated study, the impressive efficacy data indicate orexin receptor 2 is a promising novel biologic target for patients with narcolepsy type 1. The mean wakefulness test scores range from 26 to 35 minutes on a placebo-adjusted basis. For benchmarking, currently marketed agents have shown a placebo-adjusted benefit of eight minutes or less. Similar effects were observed with the Epworth Sleepiness Scale, a subjective test used to measure daytime sleepiness in which patients were normalized to equivalent levels as those seen in healthy subjects at all doses. And weekly cataplexy rates were reduced or abolished, again, at all doses tested. We believe orexin-2 receptor agonists may be the first agents to address the underlying cause of narcolepsy type 1, offering the potential for functional cures. We are applying our learnings from PAC-994, and our deep understanding of erection biology as we advance the research and development for multiple erection assets. For example, TAC861 has been enrolling ahead of schedule in two Phase IIb trials that started in January of this year. one for narcolepsy type 1 and a second for narcolepsy type 2. TAC861 is a more potent agent than TAC994 and thus provides efficacy at a much lower dose, therefore significantly reducing the potential for adverse effects, including liver toxicity. We're very pleased to report that a recently conducted external review by the Data Safety Monitoring Committee confirmed no liver toxicity signals to date. In addition, nearly all of the patients that completed the trial to date have enrolled in the long-term extension study and will be followed for up to 102 weeks. We are expecting a go-no-go decision to advance to phase three in the next fiscal year. TAC 925, our IV orexin receptor 2 agonist, showed exciting data earlier this year. In sedated healthy volunteers, TAC 925 reversed opioid-induced respiratory depression and sedation without impacting pain control. The phase 2 trial has started and is on track to have proof of concept in fiscal year 2024, which will inform the registrational studies. Later this year, we plan to file an IND for our next generation oral orexin receptor 2 agonist. Our goal is to expand into additional indications by developing orexin agonists that are tailored to meet unmet patient needs and ultimately make a meaningful impact on patients' lives. Next slide, please. Depicted here are exciting late stage development programs. TAC 279, our highest priority, is on track to start a phase three program in psoriasis later this fiscal year. We continue to believe we have a best in class oral therapy for psoriasis. We will have a phase two B readout for psoriatic arthritis this fall and are preparing at risk to start a pivotal development program for these patients in fiscal year 2024. We are accelerating development of TAC279 additionally in Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, as well as exploring a range of other indications. These expansion opportunities are being developed in parallel with psoriasis. Finally, we want to remind everyone that we have important lifecycle management approvals and data readouts later this year. These include potential approval of intivio subcutaneous in the U.S. for ulcerative colitis and alofacil phase three data for perianal fistulas. Life cycle management program milestones can be found in the appendix. And now at this point, thank you very much. I'll turn it over to Costa.

Thank you, Andy. And hello, everyone. This is Costa Saruco speaking. Today, I'll walk you through the financial highlights of our fiscal 2023 Q1 results. Starting with the top line, revenue was 1.06 trillion yen or 7.3 billion US dollars, delivering strong growth of 3.7% versus prior year at a constant exchange rate, or 8.9% on an actual basis, reflecting foreign exchange upside from the depreciation of the yen. Our top line performance was driven by our growth and launch products, which represents approximately 40% of total revenue and grew at 16.2% at constant exchange rate. Core operating profit was 326.3 billion yen or 2.3 billion US dollars with a core operating profit margin of 30.8%. Reported operating profit was 168.6 billion yen. We continue to see stable cash generation from the business with operating cash flow up 9.7% to 92.4 billion yen. Free cash flow is negative at minus 207.5 billion yen, reflecting 223 billion yen cash out for acquisitions and in licensing, including TAC 279 and for Quintinib, which occurred in Q1 as expected. Importantly, I want to note that there is no change to our four-year free cash flow forecast of 400 to 500 billion yen, as these deals were already included in the forecast, which we gave in May. I'm also happy to announce that Moody's recently upgraded our credit rating from BAA2 positive to BAA1 stable. This is important to highlight because it's a reflection on the strong financial foundation of the business. with our robust cash flow outlook and manageable debt profile with 100% of debt at approximately 2% fixed rates. With regards to the outlook for full year 2023, there is no change from the guidance we presented in May. As we flagged since the start of the year, starting from Q2, we expect to see more significant loss of exclusivity impact with generic versions of Zilver having launched in Japan in June, and more importantly, generics for Vyvanse in the US expected to launch in August. Finally, while we are not changing our reported and core forecast at this time, we do see potential, some potential upside if the current FX rates continue. We'll provide an update on this at our Q2 earnings in October. Slide 13 shows our Q1 results in more detail. On the left hand side, you can see our reported results with reported operating profit up 12% reflecting revenue growth, completion of inventory step up related to the Shire acquisition and lower impairment charges compared to the prior year. Meanwhile, reported net profit and reported EPS declined as a result of substantial one-time financial income book in Q1 of last year. Our core results are on the right-hand side. And as mentioned, we saw strong revenue growth of 8.9% or 3.7% at a constant exchange rate driven by our growth and launch products. Cooperating profit grew at 2.3% on an actual foreign exchange basis with a slight decline of minus 2% at constant exchange rate. This decline reflects product mix due to generic entry and lower COVID-19 vaccine revenues, and also continued investment in R&D and data and technology to secure long-term success of the business. Even with this incremental investment, margins for Q1 remained above 30%. Core net profit and core EPS benefited from a lower core tax rate, with core EPS for the quarter of 150 yen up plus 0.3% versus prior year at a constant exchange rate. And as mentioned on the prior slide, free cash flow reflected the expected cash payments for TAC 279 and for Quintinib, and there is no change to our full year forecast of 400 to 500 billion yen. Slide 14, on slide 14, we highlight our portfolio of growth and launch products, which are the key drivers of top line growth. These products generate 424.1 billion yen or 40% of total revenue in Q1 with 16.2% growth at constant exchange rate. Within our five key business areas, GI grew at 3% on a constant exchange rate, a slight slowdown versus last year, mainly due to generic entry of Dexilin in January this year. Our largest product, Intibio, continues to perform well with growth of 7%. This is a little behind our expectations for the full year, reflecting single-digit market growth, timing of US inventory shipments in the prior year and pricing headwinds in Europe. Intibio maintains the lead in US market share, both in overall IBD prescriptions and in IBD BioNoiv new patient starts. And with an approval decision in the US on the subcutaneous device expected in the coming months, we remain fully confident in the continued growth outlook for the product. In rare diseases, TaxZyro continues its strong momentum with growth of 15%, having successfully launched now in 56 countries and with sustained demand in the US. We also recently launched in the pediatric indication in the US, making it the first HAE product indicated for using children over two years old. We also see continued launch successful intensity up 71% with strong market penetration in the US and rapid geographic expansion within Europe. PDT Immunology continues to deliver outstanding growth of 24%, including 23% growth of immunoglobulin and 36% growth of albumin. Both our IG and albumin products continue to see strong demand, with albumin also benefiting in Q1 from recovery in China following the lockdowns in prior year. We have continued to expand our plasma donation centre network, adding three more centres in Q1, with the intent to increase by more than 20 new centres by the end of the fiscal year. And we have seen donor compensation continuing on a downward trend since fiscal year 2022, after significant increases during the pandemic. Next is oncology, which continues to decline as a result of Velcade generics. However, the timing of loss of exclusivity in May 2022 does mean that the impact should wash out in the coming quarters. Excluding Velcade, the rest of the portfolio grew 5% driven by products such as Alunbrigg, Excivity, Etcetera and Eclucig. Finally, neuroscience had a very strong performance in Q1 with growth of 17%. with Vyvanse benefiting from the expanding ADHD adult population, as well as lower supply of other ADHD medicines in the US. However, as a reminder, we are expecting multiple Vyvanse generics to enter the US market in August this year. Finally, the other segment is declining in Q1, mainly due to the lower revenue from COVID-19 vaccines in Japan. However, this other segment now includes our dengue vaccine, Hudenga, our newest growth and launch product, which is seeing strong initial demand in both endemic and travel markets. On slide 15, you can see that versus prior year, the growth and launch products were the main driver of the 3.7% growth at constant exchange rate, more than offsetting the headwinds from loss of exclusivity and lower coronavirus vaccine revenue. On top of this solid growth, we had a constant exchange rate upside on the foreign exchange tailwind due to the depreciation of the yen, taking our top line growth on an actual FX basis to 8.9%. Moving to the year-on-year cooperating profit bridge on slide 16. Here you can see how loss of exclusivity and coronavirus vaccines are having a larger impact on profit compared to revenue due to their higher margins impacting our product mix. On the investment side, we continue to allocate resources to R&D to support high potential programs such as TAC 279 and our Ericsson franchise, while also making substantial investment in data and technology, including AI, across the value chain. We believe these investments will have a transformational impact on Takeda's long-term competitiveness, and therefore we continue to allocate capital in these areas as they will play a major role in our return to growth in the near and long term. At the same time, we are applying strict cost discipline to hold other OPEX flat year on year. All these factors combined result in a Q1 core operating profit decline of minus 2% on a constant exchange rate basis, but when including foreign exchange benefit, we realise growth of 2.3%. Finally, moving to slide 17 and our outlook for full year fiscal 2023. Based on the Q1 results, we do not see any need to make changes to our management guidance or our reported and core forecasts at this time. We are still expecting a significant loss of exclusivity impact in the remainder of the year due to Vyvanse and Azilva. And therefore we are keeping our management guidance unchanged. Low single digit percentage decline in revenue, low 10s percentage decline in cooperating profit and low 20s percentage decline in core EPS or on a constant exchange rate basis. With regards to the reported and core forecast on an actual FX basis, there is some potential upside if current FX rates continue. We'll continue to monitor foreign exchange as well as the underlying business and we'll revisit our full year outlook at the Q2 earnings announcement in October. Thank you for your attention and I'd like to now open it up for Q&A. Thank you.

Thank you. Now, we'd like to take questions from the participants. And in the Q&A session, Christophe, Andy Costa, and Ramona Sequeira, Global Portfolio Division President, Julie Kim, US Business Unit President, Giles Platform, PDT Business Unit President are also joining. If you want to ask a question, please click the... and raising the button of the Zoom. And if you selected Japanese, please ask your question in Japanese. And if you selected English, please ask your question in English. And if you turn off the translation features, you may ask a question in either language. We'd like to entertain as many as possible people. Therefore, please limit the number of questions per person to two. Now I'd like to ask for your kind cooperation. Please raise your hand. The first question from Yamaguchi-san, Citi Group, please.

Can you hear me? You talk about the market is a little bit slow and there's a price pressure in Europe as well. And also there's some kind of yellowing effect of inventory building up. Can you elaborate a little bit, especially in the United States, which the core market of this product is weak? Why is the case? Is it coming from the Humira or other biosimilars coming to the market, or just needs related to the COVID? So that's the first question on antibio market weakness. Sorry, antibio weakness comments. That's the first one. The second one is regarding 994. On the New England Journal of Medicine, it is really efficacious, which is really unfortunate situation out there because it did show the results. But at the same time, you have a more 861 and also talk about some next generation product. Can you give me the sense that you are kind of efficacy level of which you are sort of Yamaguchi- getting so far as far as six times cosine it's the same range of nine and four is better than nine and four. Yamaguchi- About the efficacy level and and also the second generation product as well, thank you. Greg Phillips, M.D.:

: Thank you yamaguchi sound for your question, so the first question on in tvo and the market performance. Greg Phillips, M.D.: : So first i'd like to ask Julie to comment on the situation in the US and then perhaps if Ramona has anything to add. on the situation in Europe or other regions? And then on 994, the New England Journal posting, what implications does this have on 861? And more particularly, what are the efficacy levels that we've seen so far for 861? And what are our expectations for the next generation, oral or exonagonist? I'd like to ask Andy to comment on that one.

Hi, this is Julie. So thank you for the question, Yamaguchi-san. In terms of Intivia, I'm sorry, can you hear me?

Yes, sorry.

Okay. Okay. Sorry about that. So in terms of Intivio in the US, a few comments in regards to your questions is you had multiple components in your question there. First, in terms of the impact of biosimilars to Humira, it's a little bit too early to say. the impact of those biosimilars. We are monitoring that closely, but so far, as anticipated, the biosimilars are really within class versus having an effect across different products within IBD. When we look at antiviral performance in particular, we're pleased with a very strong market share of Intivio and we continue to be the leader when it comes to IBD share and particularly in terms of bio-naive share. For the market growth, as you mentioned, their market growth is still in the single digits. So it hasn't returned to double digit growth as we've seen in the past. So those are the different parameters of the impact on Intivio in the U.S. Ramona, do you want to add anything for Europe?

Thank you, Julie. Yeah, I can comment a little bit outside the US. So in general, the market is growing double digits and actually volume is also growing double digits. OUS, you know, really the impact OUS is due to rebates and price cuts in Europe specifically. The underlying fundamentals though are looking good. So shares increasing, the market is growing. We do continue to lead in new starts. you know, globally, both in the U.S. and outside the U.S. You know, as you know, we've got the sub-Q expecting to launch in the U.S. later this year, and we're continuing our evidence generation, phase four trials, looking at Intivio in different lines of therapy. So we feel the fundamentals are looking good and continue to keep an eye on Intivio as we go through the year.

Thank you. Yeah, thank you, Chris. Yamaguchi-san, thank you very much. So we're just so excited to have now the 994 data out there in the New England Journal publication, both us and the principal investigators with whom we've been working for many years. And it's terrific that you now have a chance to see these data and understand why we're so enthusiastic about this mechanism. The question with respect to 861, 861 has every possibility to be as strong as 994 in terms of its efficacy profile. We don't have enough data now to know whether it will be equivalent to 994 across the multiple different parameters. And as you saw with 994, we're essentially able to take a type 1 narcolepsy patient and make them look like a healthy individual. The issue with 861 is going to be dose. So we're very thoughtful in terms of what our dose selection will be. And as we've said, because we want to be careful around the potential for liver toxicity, we'll cap our daily dose at somewhere around 10 milligrams. And so the question that we'll be asking with the Phase 2b study is, with the dose cap, what does that efficacy profile look like? And those are data that we'll have in-house at some point over the course of this year and we'll share next year and will be the basis of a go-no-go decision to Phase 3. With respect to our backup programs, our first next generation molecule will be coming into the clinic later this year, and they're really too intense behind the backup program. The first, if 861 doesn't have what I would say is a maximally efficacious profile in type 1 narcolepsy, then there's the potential for a next in class, best in class. If 861 is the ultimate molecule for type 1 narcolepsy with maximal benefits, then our intent would be to develop these molecules across a range of other indications. And then I'll just add that we've only presented in this New England Journal paper a subset of the overall data that we have. from our oral orexin. And there's data that point us in many different directions for this particular pathway. And so that's one of the reasons we've been so really proactive in bringing a suite of molecules forward.

Thank you. Thank you very much. Moving to the next question, we'd like to call on Seiji Wakau from JP Morgan. Please unmute and ask your question.

JP Morgan, I have two questions. In this first quarter, the gross margin is lower now. Why is this? Is this according to the plan and PDT margin? I was expecting to see some improvement there, but what is your view on this? I just want to understand whether the margin is improving for PDT business. And continuing on what Yamaguchi-san asked, 994 and 861. I read New England Journal and the factors for liver toxicity for 994 was a reactive metabolites, impact of a reactive metabolites. What about 861? Is it a different type of a metabolite or are you going to do a dosing correctly so that the metabolites will be lower or smaller? Can you please explain again why you expect a lower liver toxicity with 861? Thank you.

was on reasons for the lower gross margin in Q1 versus prior year. Also related to that, the margins in the PTT business, how are they improving? So I'd like to ask Costa to take that question. And then the next question was on 994 and 861 and the reactive metabolites being the cause of liver injury for TAC 994. what's our thinking on that around the 861 program? I'd like to ask Andy to comment on that.

Thank you very much, Wakawa-san, for your question. Regarding the core gross profit margin, as you rightfully highlighted, there is a softening versus Q1 of last year, and the main drivers for that are three. The first one being the impact of loss of exclusivity. Products such as Velcade, loss of exclusivity happened in May of 2022. So we're seeing the bulk of the impact of Q1 this year versus last year. So that's Velcade, loss of exclusivity headwinds, as well as Azulva, which we experienced loss of exclusivity in Japan in June. And furthermore, Dexilent in the US, loss of exclusivity in Q1. So those three products alone have very high margins. So having that loss of exclusivity had an impact on the overall product mix there. The second one is the European clawbacks that we experienced in Q1 versus last year. There was the impact on clawbacks in Europe. was not impactful in Q1 of last year versus this year. So that's another key contributor to the erosion of the gross profit. And then the third component is really the strengthening of the euro versus the yen. Given that we have more of our manufacturing plants and a lot of the OPEX is in euros for cost of goods, we are experiencing some of those headwinds there. To your second part of the question on PDT, we are seeing in Q1 an improvement overall in PDT business, not only on the top line, but also on the gross profit margin as well, given that the reduction in donor fees from last year, we did start to see a reduction in donor fees of anywhere between 10% to 15%. that's helping the improvement in the gross profit overall start to filter through the P&L this fiscal year, but not enough to offset the other components that I mentioned, mainly being the loss of exclusivity and the clawbacks. But overall, very pleased with the PDT performance. You saw it's a key driver for growth and launch, growing at 24% at a constant exchange rate, and we're seeing really positive momentum on the gross profit and cooperating profit lines. Thank you.

Well, Khaosan, it's Christophe here. I will add that we are pleased with this start. You asked whether it was, how do we see this first quarter. For us, it's a good start of the year. It's a line above our expectations. So let's see how things evolve for the remaining of the year, but a good start for sure.

Dr. Andy Bauschard, M.D.: : What costs on it dandy with respect to your question on the similarities and differences of 861 and 994 the 861 and 994 are distinct molecules they have they have overlapping metabolic pathways and so it's hard for us to know. exactly whether 861 at a high enough dose would contain, would have the same liver toxicity liabilities as 994. And so that's one of the reasons why we're proceeding with caution and limiting our dose to an empirical level where below which across the industry, we just don't see liver toxicity. And as I think we all know, toxicity is always a function of dose, and this is particularly true for liver toxicity. Just to put this in context, the liver toxicity for 994 was seen at the 90 milligram BID dose, so that's 180 milligrams per day of exposure. At the 30 milligram BID dose, 60 milligrams per day of exposure, we didn't see the liver toxicity. And if we were to make simplistic assumptions that there's a one-to-one equivalence, which I don't think is fair, we're targeting a less than 10 milligram per day dose for 861. So we're looking at a six to 18-fold margin to where that potential toxicity is with 994. With respect to the backup programs, our next generation programs, we've developed a very distinct pharmacophore or very distinct chemistry. So the series looks quite differently. They're entirely novel metabolic pathways and pathways for elimination. So we've dialed out fully any potential issues, I would say, with the next generation programs. And that's why we've spent so much time trying to rework some of the novelty in this space.

Thank you very much.

That's very clear.

Thank you. Thank you for your question. I'd like to take the next question from Hashiguchi-san from Daiwa. Please unmute and ask your question.

Thank you. My question is on orexin agonist. Other than narcolepsy type 1,

other sleep disorders. What about the potential of the orexin franchise in indications other than narcolepsy type 1? Looking at the New England Journal paper regarding the dose, demonstrating Efficacy, it is low dose for narcolepsy type 1, but in other indication, sleep disorders may require higher dose that's discussed. And regarding symptoms other than narcolepsy type 1 patients, there may be safety concern. That view was also described. And what is Takeda's view on this? And going forward, narcolepsy type 1 and others, what is your strategy going forward to develop for those different indications?

Sure, Chris. Thank you, Asaguchi-san. So we're actively developing TAC861 in both narcolepsy type 1 and narcolepsy type 2. We'll be looking at the data from those studies later this year and making a decision as to whether we move forward in type 1 narcolepsy, type 1 plus type 2, plus additional indications, or whether we limit our future development in type 1 narcolepsy. So we're interested in a range of disorders, and the data that emerged from the Phase 2b study on the 861 will inform on how broadly we intend to bring that molecule. And again, we're bringing additional molecules. We have TAC925 for postoperative indications, and then we have our next generation molecules, which we'll intend to develop more broadly as well.

Thank you very much. Thank you very much for the question. So next question we'd like to invite Mike Nadelkovich from Cowen. Please unmute and ask your question.

Thank you for the question. So my first question is on TAC994. I was curious, the urinary urgency and urinary frequency, AE, was relatively prevalent. Are you seeing something similar with the next generation agent? And is the dose reduction that's intended to address the active metabolite, is that also addressing to some extent the urinary urgency? um that's my first question and then my second question is on antivio do you anticipate a return to double digit growth in the us and if so do you have a general time frame over which you expect that to happen and to what extent might this subcutaneous formulation contribute to that growth if you expect it thank you thank you mike um so the first question on 994 the urinary urgency and whether we're seeing that with 861 i'd like to ask andy to answer and then the question on antivio

potential return to double-digit growth. I'd like to ask Julie to comment on that.

Morning, Mike. The urinary urgency appears to be an on-target tolerability issue with the orexin-2 receptor agonist, not related, we think, to any of the metabolites. Even though it's prevalent in a large percentage of patients, it seems to be fairly mild. And one of the indicators that makes us feel quite confident that this is going to be something that won't be a problem for these patients is that we see almost no dropouts in our studies, both for 994 and for the ongoing 861 study. And we see almost 100% conversion from the main trial to our open label extensions.

Hi, Mike. And in terms of antiviral growth, I would say there are a few factors that we're looking at to have double digit growth for Antivio. First, as you heard Ramona say, we are anticipating approval and launch of Antivio sub Q in the US, and we do expect that to bring a lift to our growth. And then there are two other factors that we are working on. One is in terms of further evidence generation to support Antivio. We have three planned studies in the US, one of which has already begun initiation in terms of work with our HCPs and clinical sites. And the second is in terms of leveraging data, digital and technology to further enhance our marketing capabilities. Excuse me, excuse me, to have more targeted and precise segments and marketing for Antivio. So those are the three aspects that we are looking at to help drive Antivio to double growth this year. Thank you.

Okay, thank you, Mike. So next question, I would like to call upon Muraoka-san from Morgan Stanley. Muraoka-san, please go ahead.

Morgan Stanley, Muraoka desu.

This is Muraoka, Morgan Stanley. Can you hear me? This is Muraoka speaking. Yes, we can. Thank you. Maybe I think it's too early to talk about the next fiscal year. But so far in this fiscal year, I think you are on track. And there may be some upside in your performance. That's my understanding. And the next fiscal year, no longer Vyvanse. And then Taivyo may take a little longer time to recover. Then in the next fiscal year, core operating profit Do you think it achieves positive growth or it may be flat or negative growth in two years running? Do we have to consider that possibility, that risk?

So I'd like to ask Christoph perhaps to comment on this question.

Thank you, Moura Kassan. Well, it's way too early to give a guidance for the next fiscal year. I think the one key factor here will be the violence generic impact. Today, we plan for a generic entry in August, but you can imagine that if it will be delayed, for example, or if the number of generic would be lower or higher than what we have in our plan, that would have an impact on the erosion curve. At the present time, our assumption is that we will rebound in 2024-2025 because we think that there will be a much more limited impact of generic in 2024-2025. But it's really important that we look at what happened this fiscal year in order to predict better how we will rebound. If we rebounce as planned, it will be a rebounce on both the corporating profit and the revenue. But let's see during the fiscal year 23 how things are evolving with both Vivant and Azilva, actually, in order to predict better how we can see 24, 25 rebounds. Thank you.

Great. Thank you very much. Um, next question I'd like to call upon Steve Barker of Jefferies. Please unmute and ask your question.

Yes, Steve Barker from Jefferies. Thanks very much. Two questions, one about 861. I'd like to ask Andy about the choice of the 10 milligram dose. I understand the logic regarding wanting to reduce the risk of side effects, but given if you could explain what you're seeing in terms of the potency, and therefore what you might theoretically expect to see in terms of the efficacy. Some comments around that would be much appreciated. And then my second question is perhaps for Christoph, maybe Costa. Christoph, you mentioned in your comments that you would expect to see the core OPM get back up to uh low uh low 30s uh low to mid 30s and you mentioned that application of uh ai might be able to help efficiency um i'd actually be very interested to see to hear what how you think ai can be applied to the the pharmaceutical business thank you okay thank you steve so i guess um

first question, Andy, and then maybe Christoph to start on that second question. Thank you.

Stephen, thank you very much. So firstly, 861 is a significantly more potent molecule when we look at the in vitro pharmacology relative to 994. It's also a molecule that has a more extended exposure and a longer half-life. So it has very different properties than TAC994. So It's going to be important for us to look at the data that come out of our phase to be studied to understand whether, with our dose limit, our dose cap, we can achieve the same level of efficacy as tack 994. But intrinsically, the molecule has the potential to do that even at lower doses. And I'll add that we plan to begin sharing data from the 861 program and type 1 narcolepsy patients later later this year. So some of the healthy volunteer, sleep deprived data, some of the modeling that we've used, those data will start to be out there in the coming months.

Thank you, Steve, for the question. We see a very high potential for the utilization of AI in our business. But I will emphasize that it's data, technology, and AI. Without the data, you cannot train the AI. And without some technology like image recognition, you don't generate data in many parts of our business. So we have been focusing on having data lake and data domain well-structured in order to train the AI algorithm, and we are seeing application across our value chain. For example, in manufacturing, we are using image recognition on our manufacturing line in order to improve the efficiency of the line, for example. We are using AI as well to do some visual recognition that we had done manually in the past. So in the manufacturing side, we see a lot of productivity implication. On the research side, we are using AI for molecule design or for toxicity modelization, for example. We will use also the AI to accelerate clinical trials, test protocol, have higher patient activation. On the commercial side, we are looking at optimizing our interaction with doctors in a digital way, and we are using an algorithm as we speak already. On the PDT side, for example, we are using some algorithm to have a better relationship with our donors. And so it's really across the board. And I didn't talk about back office, but we are also using this type of technology in our back office. In fact, we think that all our employees eventually will have some application of AI for their jobs. So this is really a very high priority for us. Thank you.

Thanks very much. Thank you, Steve. And with that question, it brings us to the end of our time today. So thank you, everybody, for joining us on this conference call. And we look forward to talking with you again at a later date. Thank you and good night.