Biogen Inc (BIIB) 2023 Q4 法說會逐字稿

Good morning. My name is Katie, and I will be your conference operator today. At this time, I'd like to welcome everyone to the Biogen Fourth Quarter and Full Year 2023 Earnings Call and Business Update. (Operator Instructions) Today's conference is being recorded. Thank you.

早安.我叫凱蒂，今天我將擔任你們的會議操作員。此時此刻，我謹歡迎大家參加百健 (Biogen) 2023 年第四季和全年財報電話會議和業務更新。 （操作員指示）今天的會議正在錄音。謝謝。

I would now like to turn the conference over to Mr. Chuck Triano, Head of Investor Relations. Mr. Triano, you may begin your conference.

現在我想將會議交給投資者關係主管查克·特里亞諾 (Chuck Triano) 先生。特里亞諾先生，您可以開始會議了。

Thank you, Katie. Good morning, and welcome to Biogen's Fourth Quarter and Full Year 2023 Earnings Call. Before we begin, I'll remind you that the earnings release and related financial tables, including our GAAP financial measures and a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today are located in the Investors section of biogen.com. Our GAAP financials are provided in Tables 1 and 2, and Table 4 includes a reconciliation of our GAAP to non-GAAP financial results. We believe non-GAAP financial results better represent the ongoing economics of our business and reflect how we manage the business internally. We have also posted the slides on our website that will be used during this call.

謝謝你，凱蒂。早安，歡迎參加百健 (Biogen) 2023 年第四季和全年財報電話會議。在我們開始之前，我要提醒您，收益發布和相關財務表格，包括我們今天將討論的 GAAP 財務指標以及 GAAP 與非 GAAP 財務指標的調整表，位於 biogen.com 的投資者部分。表 1 和表 2 提供了我們的 GAAP 財務數據，表 4 包括我們的 GAAP 與非 GAAP 財務結果的調整表。我們相信非公認會計準則財務績效更能代表了我們業務的持續經濟狀況，並反映了我們內部管理業務的方式。我們也在我們的網站上發布了本次電話會議期間將使用的幻燈片。

I'd like to point out also that we'll be making forward-looking statements, which are based on our expectation. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail.

我還想指出，我們將根據我們的預期做出前瞻性陳述。這些陳述存在一定的風險和不確定性，我們的實際結果可能有重大差異。我鼓勵您查閱我們向 SEC 提交的文件中討論的風險因素，以了解更多詳細資訊。

On today's call, I'm joined by our President and Chief Executive Officer, Chris Viehbacher; Dr. Priya Singhal, Head of Development; and our CFO, Mike McDonnell. Chris, Priya and Mike will each make some opening comments, and then we'll move to our Q&A session. To allow us to get through as many questions as possible, we ask that you limit yourself to one question.

我們的總裁兼執行長 Chris Viehbacher 也參加了今天的電話會議。 Priya Singhal 博士，開發主管；和我們的財務長麥克麥克唐納。 Chris、Priya 和 Mike 將分別發表一些開場評論，然後我們將進入問答環節。為了讓我們能夠回答盡可能多的問題，我們要求您只回答一個問題。

With that, I'll now turn the call over to Chris.

這樣，我現在將把電話轉給克里斯。

Thank you, Chuck. Good morning, everybody. A year ago, I had the -- an opportunity of presenting Biogen's quarterly results for the first time. At that time, we expressed the objective of returning Biogen to sustainable growth. And I think in the intervening year, we've made substantial progress. And today, it is a great -- with a great amount of prior and pleasure that we can announce earnings guidance, which Mike will go into in greater detail, which says that we will -- we are expecting to see positive earnings per share growth.

謝謝你，查克。大家早安。一年前，我有機會首次展現百健（Biogen）的季度表現。當時，我們表達了讓百健恢復永續成長的目標。我認為在接下來的一年裡，我們取得了實質進展。今天，我們很高興能夠宣布獲利指引，麥克將對此進行更詳細的介紹，這表明我們將期待看到每股收益的正增長。

And as I have said on a number of occasions, once we can get Biogen growing, we really see Biogen becoming a growth company for the foreseeable future. We have very little we have, in fact, no exposure to Inflation Reduction Act with our current portfolio. We don't have any new patent expiries really coming in anytime soon other than those that are already known. And I think we've undertaken a number of other measures that really repositioned Biogen for growth. And if I just review some of those things.

正如我在許多場合說過的那樣，一旦我們能夠讓百健（Biogen）不斷成長，我們就會真正看到百健（Biogen）在可預見的未來成為一家成長型公司。事實上，我們目前的投資組合幾乎沒有受到《通膨削減法案》的影響。除了已知的專利之外，我們並沒有任何即將到期的新專利。我認為我們已經採取了許多其他措施，真正重新定位了百健（Biogen）的成長。如果我只回顧其中的一些事情。

The first is -- was really to refocus the company on growth drivers, in particular, our new product launches. Biogen had 4 new product launches from -- approvals from the FDA last year. That's the second highest of anyone in our industry. And that required though quite an awful lot of cultural change. The multiple sclerosis franchise has been the stalwart of our company for -- since its inception, 45 years ago. Our people are passionate about the physicians to treat multiple sclerosis and the patients who have multiple sclerosis. And we are still the market leader in this space. However, that is a franchise that is facing increasing competition and we have to embrace new therapeutic categories and new businesses.

第一個是－真正讓公司重新專注於成長動力，特別是我們的新產品發布。去年，百健 (Biogen) 推出了 4 款新產品，並獲得了 FDA 的批准。這是我們行業中第二高的。但這需要進行大量的文化變革。自 45 年前成立以來，多發性硬化症專營權一直是我們公司的支柱。我們的員工對治療多發性硬化症的醫生和患有多發性硬化症的患者充滿熱情。我們仍然是這個領域的市場領導者。然而，這是一個面臨日益激烈的競爭的特許經營權，我們必須接受新的治療類別和新業務。

And so we have really had a major shift in resources and focus, particularly towards LEQEMBI, ZURZUVAE, SKYCLARYS and QALSODY. We also, though, have still some products with patent protection, again, with substantial competition. And if I take a product like SPINRAZA, analyst forecast had shown forecast that this product would decline, particularly proud of our teams and demonstrating that they could bring this product back to actually even modest growth.

因此，我們在資源和重點方面確實發生了重大轉變，特別是轉向 LEQEMBI、ZURZUVAE、SKYCLARYS 和 QALSODY。不過，我們仍然有一些產品受到專利保護，同樣存在激烈的競爭。如果我採用像 SPINRAZA 這樣的產品，分析師預測該產品將會下降，特別為我們的團隊感到自豪，並證明他們可以使該產品恢復到實際的適度增長。

Obviously, the mode of administration of products is -- can be a competitive advantage. So if you have a pill, you're going to be a lot more preferred than if you have an infusion for example. But what we see in some of these really devastating diseases, is that efficacy is still the most important factor. And that is why SPINRAZA continues to be a leader in this segment. And Biogen is extremely good at being able to develop the medical evidence to support the value proposition of its products.

顯然，產品的管理模式可以成為競爭優勢。因此，如果您有藥丸，那麼您會比輸液等更受歡迎。但我們在一些真正具有破壞性的疾病中看到的是，療效仍然是最重要的因素。這就是為什麼 SPINRAZA 繼續成為該領域的領導者。百健（Biogen）非常擅長開發醫學證據來支持其產品的價值主張。

As many of you told me when I first came into the company, you've got a mature product portfolio, but you've got one of the highest cost bases in our industry and we took steps to address that. We -- but it wasn't just around reducing cost. We wanted to reengineer the business. We were shifting our focus, entering new therapeutic categories and we needed to think about capabilities. We needed to think about the agility of the organization, the number of layers of management that we have.

正如我第一次進入公司時你們中的許多人告訴我的那樣，你們擁有成熟的產品組合，但你們擁有我們行業中成本最高的基礎之一，我們採取了措施來解決這個問題。我們——但這不僅僅是為了降低成本。我們想要重新設計業務。我們正在轉移注意力，進入新的治療類別，我們需要考慮能力。我們需要考慮組織的敏捷性以及我們擁有的管理階層數量。

And so we implemented a Fit for Growth reengineering project. We've already achieved $200 million of savings and we're on track to realize approximately half of the $800 million of net savings by the end of 2024. That's, of course, a gross savings of $1 billion. And then we had to look at research and development. And Biogen is an extremely interesting company.

因此，我們實施了「適合成長」再造計畫。我們已經實現了 2 億美元的節省，並且預計在 2024 年底之前實現 8 億美元淨節省的大約一半。當然，這總共節省了 10 億美元。然後我們必須關注研究和開發。百健（Biogen）是一家非常有趣的公司。

All of the diseases that Biogen targets are really devastating diseases. And we target -- and there's a lot of pride in the fact that we go and try to find solutions for diseases where nobody else is doing that. But of course, we do that by you are pioneering -- you are pioneering because we don't really understand often the underlying disease biology of these conditions. And so we end up taking a lot of risk and these trials can be really quite expensive. And yet we do need a company like Biogen in our world.

百健（Biogen）所針對的所有疾病都是真正的毀滅性疾病。我們的目標是——我們努力尋找其他人沒有這樣做的疾病的解決方案，這一事實讓我們感到非常自豪。當然，我們透過你們的開拓來做到這一點——你們之所以開拓，是因為我們通常並不真正了解這些疾病的潛在疾病生物學。因此，我們最終承擔了很大的風險，而且這些試驗可能非常昂貴。然而，我們的世界確實需要像百健（Biogen）這樣的公司。

And so our objective has been to really focus research and development investments on those products that will have the greatest impact. And of course, we have to manage the risk in the portfolio. We have to have Biogen as a sustainably growing company and one which is attractive to investors. We need the capital to go and invest in new projects. And so I think with Prius Health, we've been able to take an extremely disciplined and objective view of the pipeline. We have 4 data readouts this year, again, on extremely important illnesses, and Priya will talk more about that.

因此，我們的目標是真正將研發投資集中在那些將產生最大影響的產品上。當然，我們必須管理投資組合中的風險。我們必須讓百健成為一家可持續發展的公司，並且對投資者有吸引力。我們需要資金來投資新項目。因此，我認為透過 Prius Health，我們能夠對管道採取極其嚴格和客觀的看法。今年我們再次發布了 4 個關於極為重要疾病的數據，Priya 將詳細討論這一點。

And as we go into next year, we're going to be looking at how do we reinforce that pipeline, how do we rethink our research efforts. A lot has changed in science, but we haven't necessarily done that kind of change at Biogen. So I think research and development is extremely important to Biogen and I think continue to be a source of growth for the future.

當我們進入明年時，我們將考慮如何加強這個管道，如何重新思考我們的研究工作。科學領域發生了許多變化，但我們在百健（Biogen）公司卻不一定會做出這樣的改變。因此，我認為研發對百健（Biogen）極為重要，我認為繼續成為未來成長的來源。

Now as we look at what does drive growth, clearly, we have LEQEMBI. And I'll remind everybody that, again, we are not just pioneering in science but pioneering in commercial. One of the interesting things about this disease is that if we talk about the efficacy of the product, in a lot of cases, we're looking at the characteristic of a product. But actually, when you talk about efficacy, you're talking about, are you in the right patient.

現在，當我們審視推動成長的因素時，很明顯，我們有 LEQEMBI。我要再次提醒大家，我們不僅在科學領域處於領先地位，在商業領域也處於領先地位。關於這種疾病的一個有趣的事情是，如果我們談論產品的功效，在許多情況下，我們關注的是產品的特性。但實際上，當你談論療效時，你談論的是你是否針對合適的患者。

And in fact, for decades, our industry invested in drugs, which failed to demonstrate a benefit in Alzheimer's disease. And there were 2 main problems with that. One was we couldn't get enough drug across the blood-brain barrier, and we weren't in the right patient. Clarity was the first study to really convincingly demonstrate the importance of reducing plaque and the impact on cognition. But we know that some data that we showed at CTAD that we believe that the earlier you can go, the more likely it is you're going to show even greater efficacy because we're not -- we're really in the business of trying to protect neurons or create an environment where injured neurons can recover.

事實上，幾十年來，我們的行業投資於藥物，但未能證明對阿茲海默症有好處。這有兩個主要問題。一是我們無法讓足夠的藥物穿過血腦屏障，而且我們也沒有針對合適的患者。 Clarity 是第一個真正令人信服地證明減少牙菌斑的重要性及其對認知影響的研究。但我們知道，我們在 CTAD 上展示的一些數據表明，我們相信越早開始，就越有可能表現出更大的功效，因為我們不是——我們真正從事的是試圖保護神經元或創造一個讓受傷的神經元可以恢復的環境。

And so we have a huge investment in our AHEAD study to look at presymptomatic patients. We're investing in what happens when you remove the plaque and looking at maintenance. We're trying to make this more convenient for patients by having a subcutaneous formulation. And so this -- the pioneering continues and the pioneering also is out there in the marketplace. Patients with Alzheimer's are not in the system today and are coming into the system. So we've got approximately 2,000 patients on therapy at the moment.

因此，我們對 AHEAD 研究進行了大量投資，以觀察出現症狀前的患者。我們正在投資當您去除牙菌斑並考慮維護時會發生什麼。我們正在嘗試透過皮下製劑使患者更方便。因此，先鋒仍在繼續，先鋒也出現在市場上。阿茲海默症患者目前尚未進入系統，但正在進入系統。目前我們約有 2,000 名患者正在接受治療。

Now we don't have as companies direct access to the patient registries. You all know about the CMS registry. But there are a few other registries out there like Altinet, for example. And we have seen some analysts have been able to access that data. There was one analyst report of 3,300 patients on the registry, latest information that we have, and again, this is not perfect information, but we have an indication that there are about 3,800 patients as of last week on the registry.

現在，作為公司，我們無法直接存取病患登記處。大家都知道 CMS 註冊表。但還有其他一些註冊機構，例如 Altinet。我們已經看到一些分析師已經能夠存取這些數據。有一份關於登記處 3,300 名患者的分析報告，這是我們掌握的最新信息，同樣，這不是完美的信息，但我們有跡象表明，截至上週，登記處約有 3,800 名患者。

When you look at that, that suggests we're getting about 260, 265 patients per week in the month of January. And as far as we can tell, that's about a 56% increase over what we were seeing in December. So we are clearly seeing that there is demand for the product. We're clearly seeing that IDNs are moving to put in place the care pathways and the treatment protocols to improve access. 70 out of the top 100 IDNs have had positive P&T committee decisions. 80% of those have now actually ordered LEQEMBI.

當您查看該數據時，您會發現 1 月我們每週接收約 260 至 265 名患者。據我們所知，這比 12 月增加了約 56%。所以我們清楚地看到對該產品的需求。我們清楚地看到，IDN 正在採取行動落實照護途徑和治療方案，以改善醫療服務的可近性。前 100 個 IDN 中有 70 個做出了積極的 P&T 委員會決定。其中 80% 的人現在已經實際訂購了 LEQEMBI。

But if we talk to the people who are doing the PET scans, the MRIs, the people who sell the blood diagnostics, everybody is reporting increased activity and volume. And so -- and as you saw with Eisai's results, their belief is that for all the patients on treatment, they are at least three or fourfold of those who are actually in waiting rooms. So we do believe we're making a very solid progress. And we believe that we have validated the go-to-market model. And now that we have enough IDNs with reimbursement and care pathways in place, we believe it's also time now to increase our level of promotion out there.

但如果我們與進行 PET 掃描、核磁共振成像的人員以及銷售血液診斷的人員交談，每個人都報告活動和數量增加。因此，正如您在衛材的結果中看到的那樣，他們相信，對於所有接受治療的患者來說，他們至少是實際在候診室的患者的三到四倍。所以我們確實相信我們正在取得非常堅實的進展。我們相信我們已經驗證了上市模式。現在我們已經擁有足夠的 IDN，並提供了報銷和護理途徑，我們相信現在也是時候提高我們的促銷水平了。

And so as Eisai has announced, we will be expanding total U.S. field force by about 30%. And as was already previously agreed last year that once we had the go-to-market model really validated, that it's now time for Biogen colleagues to also go and visit physicians. And of course, we've seen the launch in Japan. I was there for the launch meeting, and Biogen is very proud to be working alongside our colleagues from Eisai on the launch in Japan.

正如衛材 (Eisai) 所宣布的那樣，我們將把美國現場總兵力擴大約 30%。正如去年所達成的共識，一旦我們的上市模式真正得到驗證，百健（Biogen）的同事們現在也應該去看醫生了。當然，我們已經在日本看到了該產品的推出。我參加了發表會，百健（Biogen）非常自豪能夠與衛材（Eisai）的同事一起在日本進行發表會。

And we've seen LEQEMBI approved in China and that launch will be for later this year. So everywhere we look with LEQEMBI, we are making solid progress. This is, as we have said before, and a launch that really doesn't have an analog. We have always guided investors to the fact that this would be a progressive ramp and that's what we're seeing. And we continue to believe in the long-term importance of LEQEMBI both to patients and to our financial results.

我們已經看到 LEQEMBI 在中國獲得批准，並將於今年稍後推出。因此，我們在 LEQEMBI 的各個方面都取得了紮實的進展。正如我們之前所說，這是一次真正沒有類似產品的發布。我們一直引導投資者認識到這將是一個漸進式的成長，而這就是我們所看到的。我們仍然相信 LEQEMBI 對患者和我們的財務表現具有長期重要性。

Moving on to SKYCLARYS. You've seen the launch numbers for the U.S. We have about 1,000 patients now on therapy. We don't have a pediatric indication yet. So the potential population is about 4,500. So we've got a little over 20% of the patients on therapy within about 6 months of launch.

轉向 SKYCLARYS。您已經看到了美國的啟動數據。我們現在有大約 1,000 名患者正在接受治療。我們還沒有兒科適應症。所以潛在人口約4,500人。因此，我們有超過 20% 的患者在啟動後約 6 個月內接受了治療。

There's an awful lot of complexity in launching these rare diseases. And I think this is where Biogen has an awful lot of strength. There's a lot of logistics issues with specialty pharmacy and reimbursement. And so we have already been able to demonstrate that we can reduce the time from the start form to shipment by 45%. We've got about 2/3 coverage out there in terms of reimbursement. And of course, patients and their physicians need an awful lot of support out there.

推出這些罕見疾病的過程非常複雜。我認為這就是百健（Biogen）的強大優勢。專業藥房和報銷存在許多物流問題。因此，我們已經能夠證明，我們可以將從開始表格到發貨的時間縮短 45%。在報銷方面，我們有大約 2/3 的承保範圍。當然，患者和他們的醫生需要大量的支持。

And so we have patient services and family access managers who are assisting patients and physicians to navigate the care pathways. One of the things that we see with SPINRAZA is that we do about 1/3 of our sales in the U.S. and 2/3 ex U.S., and we expect that to be a model for SKYCLARYS. Last night, we announced the formal approval by the European Commission for SKYCLARYS. We have expanded access program in a number of European countries, and we are in the process of setting those up in the countries, including those outside of the U.S.

因此，我們有患者服務和家庭訪問經理，他們正在協助患者和醫生找到護理途徑。我們在 SPINRAZA 上看到的一件事是，我們約 1/3 的銷售額在美國，2/3 在美國以外，我們預計這將成為 SKYCLARYS 的典範。昨晚，我們宣布 SKYCLARYS 獲得歐盟委員會的正式批准。我們已經在許多歐洲國家擴大了准入計劃，我們正在這些國家（包括美國以外的國家）建立這些計劃。

We have a global filing strategy that is underway to make sure that all patients with Friedreich's ataxia and can benefit from SKYCLARYS. And of course, we are actively working on (inaudible) that would be needed to obtain the indication for children under age 16.

我們正在製定一項全球申請策略，以確保所有弗里德賴希共濟失調患者都能從 SKYCLARYS 中受益。當然，我們正在積極努力（聽不清楚），以獲得 16 歲以下兒童的適應症。

ZURZUVAE, postpartum depression enormous unmet need. Tremendous media coverage. We're talking about maternal health and we're also talking about mental health. And those are 2 key trends in our societies today. It has been difficult often from others to seek treatment and get treatment. This estimated about 80,000 women are diagnosed every year, but the incidence leave to be way in excess of 0.5 million.

ZURZUVAE，產後憂鬱症巨大的未滿足的需求。媒體報道龐大。我們正在談論孕產婦健康，我們也在談論心理健康。這是當今社會的兩個主要趨勢。向其他人尋求治療並獲得治療往往很困難。據估計，每年約有 8 萬名女性被診斷出來，但發病率遠遠超過 50 萬人。

So there's an awful lot of work to do to really get outreach to women who are suffering from postpartum depression. I have to say the initial indications of launch are well above expectations and very promising. But it's 6 weeks of data. So I think we want to see more data to really come to any firm conclusions, but everything that we are seeing is extremely positive. We were originally positioning this product for major depressive disorder and we pivoted to postpartum depression that meant we've had to go back and recontract with payers. I have to say I'm highly appreciative of payers because they have actually been honoring prescriptions even though we haven't got all of our contracting in place.

因此，要真正幫助患有產後憂鬱症的女性，還有大量工作要做。我不得不說，發射的初步跡象遠遠超出了預期，而且非常有希望。但這是 6 週的數據。所以我認為我們希望看到更多的數據才能真正得出任何確定的結論，但我們所看到的一切都是非常積極的。我們最初將該產品定位為重度憂鬱症，後來轉向產後憂鬱症，這意味著我們必須回去與付款人重新簽訂合約。我必須說，我非常感謝付款人，因為儘管我們還沒有簽訂所有合同，但他們實際上一直在遵守處方。

And I think that is actually also helping with demand. So with that, I'll turn it over to Priya because I think increasingly, what we'd like to also start to talk about is not only what we're selling, but the new hope for patients that's coming out of our pipeline. So I'll turn that over to you, Priya.

我認為這實際上也有助於滿足需求。因此，我將把它交給 Priya，因為我越來越認為，我們也想開始談論的不僅是我們所銷售的產品，而且是我們管道中的患者的新希望。所以我會把它交給你，Priya。

Thank you, Chris. As we previously discussed, we have focused on reviewing and prioritizing our development pipeline with a keen eye towards maximizing probability of success and increasing potential return on investment, as Chris noted. The intention was always to focus our pipeline to better represent a risk-reward balance and one that we believe could help Biogen reach the goal of achieving sustainable growth.

謝謝你，克里斯。正如我們之前所討論的，正如克里斯指出的那樣，我們專注於審查和優先考慮我們的開發管道，並敏銳地關注最大限度地提高成功機率和增加潛在投資回報。我們的目的始終是集中我們的產品線，更好地體現風險回報平衡，我們相信這種平衡可以幫助百健實現可持續成長的目標。

While this effort resulted in a number of program discontinuations last year, specifically in areas we perceived significant regulatory development or commercialization challenges. We also highlighted areas where we had deep expertise and promising pipeline programs, and therefore, warranted an invest to win approach. One such area is Alzheimer's disease, where we have an industry-leading pipeline, and we do expect to continue investing in order to expand our leadership. This starts first with building upon our opportunity with LEQEMBI. Our first priority is to continue working with Eisai to help ensure that LEQEMBI is available globally to patients suffering from early Alzheimer's disease. With approvals now obtained in the U.S., Japan and China and filings currently under review in 14 additional markets, we believe we are well on our way to achieving this goal.

雖然這項努力導致去年許多項目被終止，特別是在我們認為存在重大監管發展或商業化挑戰的領域。我們也強調了我們擁有深厚專業知識和有前途的管道計劃的領域，因此需要採取投資取勝的方法。其中一個領域是阿茲海默症，我們在該領域擁有領先業界的產品線，我們確實希望繼續投資以擴大我們的領導地位。這首先要從我們與 LEQEMBI 的合作機會開始。我們的首要任務是繼續與衛材合作，幫助確保 LEQEMBI 在全球範圍內為患有早期阿茲海默症的患者提供服務。目前，該產品已在美國、日本和中國獲得批准，另外 14 個市場的申請正在接受審查，我們相信我們正在順利實現這一目標。

Second is creating additional treatment options for patients. The data presented at CTAD last year on LEQEMBI suggests that there is continued benefit associated with treatment out to 24 months. And that treatment earlier in the disease course had a greater effect on clinical outcome. For this reason, we are working with Eisai to submit a filing for maintenance dosing with IV LEQEMBI or every 4-week treatment as well as evaluating LEQEMBI administration in preclinical AD, as Chris mentioned, in the AHEAD 3-45 trial, which is before the onset of symptoms.

其次是為患者創造額外的治療選擇。去年在 CTAD 上公佈的 LEQEMBI 數據表明，治療長達 24 個月仍能帶來持續益處。病程早期的治療對臨床結果有較大的影響。因此，我們正在與衛材合作，提交一份關於靜脈注射LEQEMBI 或每4 週治療一次的維持劑量的申請，以及評估LEQEMBI 在臨床前AD 中的給藥，正如Chris 在AHEAD 3-45 試驗中提到的，該試驗是先前的症狀出現。

Eisai also aims to submit a filing for subcutaneous version of LEQEMBI by the end of March. Beyond LEQEMBI, Biogen is also advancing pipeline programs targeting tau. We believe tau represents the next frontier in Alzheimer's therapeutics, and we are working to support the development of diagnostic tests and pathways. Our ASO targeting tau, BIIB080, represents a new mechanism for targeting tau distinct from prior antibody attempt.

衛材還計劃在 3 月底之前提交 LEQEMBI 皮下注射版本的申請。除了 LEQEMBI 之外，百健（Biogen）也正在推進針對 tau 的管道計畫。我們相信 tau 代表了阿茲海默症治療的下一個前沿，我們正在努力支持診斷測試和途徑的發展。我們的 ASO 靶向 tau 蛋白 BIIB080 代表了一種不同於先前抗體嘗試的靶向 tau 蛋白的新機制。

In the Phase Ib study, we saw a convergence of target engagement, reduction in tau pathology in the brain and improvement in exploratory measures of clinical outcome. We are very encouraged by these results and are currently evaluating BIIB080 in the Phase II CELIA study. We also have BIIB113, a Phase I small molecule aiming to reduce the aggregation of tau. Importantly, [Jane] and the research organization is also focused on the future of Alzheimer's treatments and is pursuing a multi-modality approach to evaluate a number of other potential targets implicated in Alzheimer's disease biology. Looking beyond Alzheimer's disease, Biogen has an opportunity to expand our growing rare disease portfolio. We see rare disease expertise as a core competency at Biogen.

在 Ib 期研究中，我們看到了目標參與、大腦 tau 病理學減少以及臨床結果探索性測量的改善的融合。我們對這些結果感到非常鼓舞，目前正在 II 期 CELIA 研究中評估 BIIB080。我們還有 BIIB113，一種旨在減少 tau 聚集的 I 期小分子。重要的是，[Jane] 和研究組織也關注阿茲海默症治療的未來，並正在尋求一種多模式方法來評估與阿茲海默症生物學相關的許多其他潛在目標。除了阿茲海默症之外，百健還有機會擴大我們不斷增長的罕見疾病產品組合。我們將罕見疾病專業知識視為百健（Biogen）的核心能力。

I will now address BIIB121 in Angelman syndrome. Angelman syndrome is a rare genetic neurodevelopmental disorder that occurs in approximately 1 in 15,000 live birds worldwide. It is diagnosed in early childhood and is characterized by symptoms such as severe developmental delays, speech impairment, problems with movement and balance, and may involve seizures. While there is no specific treatment approved, individuals with Angelman syndrome will generally have a near-normal life expectancy. However, they will generally require continuous care and are unable to live independently. Normally, the paternal allele of the UBE3A gene is silenced in neuron leading to expression of only the maternal allele.

我現在將討論天使症候群中的 BIIB121。安格曼症候群是一種罕見的遺傳性神經發育障礙，全世界大約每 15,000 隻活禽中就有 1 隻患有這種疾病。它在兒童早期被診斷出來，其特徵是嚴重發育遲緩、言語障礙、運動和平衡問題等症狀，並可能涉及癲癇發作。雖然沒有批准的特定治療方法，但患有天使症候群的人通常會有接近正常的壽命。然而，他們通常需要持續的護理並且無法獨立生活。通常，UBE3A 基因的父係等位基因在神經元中被沉默，導致僅表達母係等位基因。

In Angelman syndrome, the maternal allele is either absent or inactivated through genetic mutation, leading to loss of UBE3A gene expression and impairment of synaptic connections and brain network activity. This can be visualized by an increase in slow brain waves or called delta waves. BIIB121 aims to remove the silencing of the paternal allele in order to restore expression of the UBE3A gene. While the Phase I HALO study is designed as an open-label, multiple-ascending dose study across age groups and those levels to assess safety and tolerability. Importantly, the study also utilizes clinical measures that we can use to assess therapeutic potential. This includes objective EEG assessment as well as clinical assessments evaluating multiple domains of Angelman syndrome, like cognitive function and gross and fine motor skills.

在 Angelman 症候群中，母體等位基因要麼缺失，要麼因基因突變而失活，導致 UBE3A 基因表現喪失，突觸連接和大腦網絡活動受損。這可以透過慢腦電波或稱為 δ 波的增加來觀察。 BIIB121 旨在消除父係等位基因的沉默，以恢復 UBE3A 基因的表達。 I 期 HALO 研究被設計為跨年齡層和這些程度的開放標籤、多劑量遞增研究，以評估安全性和耐受性。重要的是，該研究也利用了我們可以用來評估治療潛力的臨床措施。這包括客觀腦電圖評估以及評估天使症候群多個領域的臨床評估，例如認知功能以及粗大和精細運動技能。

The HALO study has completed enrollment for the multiple ascending dose portion of the study. And last year, Ionis presented some encouraging early interim results. Overall, safety and tolerability support continued dosing in the long-term extension with no concerning safety trends having been observed to date. The EEG data was suggestive of early trends to a reduction of slow delta wave activity as compared to baseline. And clinician-assessed clinical end points show a majority of participants demonstrating some level of improvement in overall functioning.

HALO 研究已完成該研究的多劑量遞增部分的入組。去年，Ionis 公佈了一些令人鼓舞的早期中期業績。總體而言，安全性和耐受性支持長期繼續給藥，迄今尚未觀察到有關安全性的趨勢。腦電圖數據表明，與基線相比，慢δ波活動有減少的早期趨勢。臨床醫師評估的臨床終點顯示，大多數參與者的整體功能都有一定程度的改善。

Overall, we are encouraged by these early trends and look forward to sharing a more comprehensive top line study readout expected midyear. Following our review of those results, Biogen will be in a position to make its decision whether to opt in to conduct a pivotal study.

總體而言，我們對這些早期趨勢感到鼓舞，並期待在年中分享更全面的頂線研究結果。在我們審查這些結果後，百健（Biogen）將能夠決定是否選擇進行關鍵研究。

Moving to lupus. This is another area with significant unmet medical need. We currently have 2 Phase III assets in systemic lupus erythematosus or SLE. First is dapirolizumab pegol being developed in collaboration with UCB, where we expect a top line readout of the Phase III study midyear this year. If positive, we expect to conduct a second Phase III study.

轉向狼瘡。這是另一個醫療需求未被滿足的領域。我們目前在系統性紅斑狼瘡或 SLE 領域擁有 2 個 III 期資產。首先是與 UCB 合作開發的 dapirolizumab pegol，我們預計今年年中將發表 III 期研究的頂線數據。如果結果呈陽性，我們預計將進行第二項 III 期研究。

The second is litifilimab, our anti-BDCA2 antibody developed in-house at Biogen. We currently have 2 Phase III studies of litifilimab in SLE ongoing. These studies are enrolling and utilize a 52-week primary endpoint. Litifilimab also has the potential to be a first-in-class biologic in cutaneous lupus erythematosus or CLE a skin-based autoimmune disease that can be associated with severe scarring and dispigmentation and can be distinct from SLE.

第二種是 litifilimab，這是我們在 Biogen 內部開發的抗 BDCA2 抗體。目前，我們正在進行 2 項 litifilimab 治療 SLE 的 III 期研究。這些研究正在招募並利用 52 週的主要終點。 Litifilimab 還有潛力成為治療皮膚紅斑狼瘡或 CLE 的一流生物製劑，CLE 是一種基於皮膚的自體免疫疾病，可能與嚴重疤痕和色素脫失有關，與 SLE 不同。

As I've previously discussed, we have focused on reviewing our pipeline to identify and prioritize the areas where we believe we have both sufficient expertise and confidence in the science to deliver meaningful new treatments for patients. While this initial review is complete, this process remains dynamic, and we are committed to holding ourselves accountable to efficiently seeking out scientific insights and continuing to build the pipeline with what we believe is the right risk/reward balance.

正如我之前所討論的，我們專注於審查我們的管道，以確定並優先考慮我們認為擁有足夠專業知識和科學信心的領域，為患者提供有意義的新療法。雖然初步審查已經完成，但這個過程仍然是動態的，我們致力於讓自己負責有效地尋求科學見解，並繼續以我們認為正確的風險/回報平衡建立管道。

While we look forward to 4 important near-term readouts this year, we continue to focus on identifying additional near-term opportunities as well as continued expansion beyond neuroscience. Through collaboration with Jane and research organization as well as Adam Keeney, our Head of Corporate Development, we are taking a holistic look across a spectrum of opportunities with both a research and development focus to identify strategic assets that we believe can contribute to Biogen's growth story now and in the long term.

雖然我們期待今年有 4 個重要的近期報告，但我們將繼續專注於尋找其他近期機會以及神經科學以外的持續擴張。透過與 Jane 和研究組織以及我們的企業發展主管 Adam Keeney 合作，我們正在全面審視一系列機會，重點關注研發，以確定我們認為可以為百健 (Biogen) 的增長故事做出貢獻的戰略資產現在和長遠來看。

With that, I would now like to pass the call over to Mike.

有了這個，我現在想把電話轉給麥克。

Thank you, Priya. Good morning, everyone. I'm going to provide some highlights and color regarding our financial performance for the fourth quarter of 2023, and I'll follow that with some detail on our 2024 financial guidance assumptions. Please note that all the financial comparisons that you will hear are versus the fourth quarter of 2022.

謝謝你，普里亞。大家，早安。我將提供有關 2023 年第四季財務業績的一些亮點和色彩，隨後我將提供有關 2024 年財務指導假設的一些細節。請注意，您將聽到的所有財務比較都是與 2022 年第四季的比較。

Total revenue for the fourth quarter of 2023 was $2.4 billion. That's a decrease of 6% at actual currency and 5% at constant currency. Non-GAAP diluted earnings per share in the fourth quarter was $2.95, and that includes a $0.35 negative impact from the recently disclosed closeout costs related to ADUHELM. For the full year of 2023, total revenue of $9.8 billion represents a decline of 3% at actual currency and 1% at constant currency, and that's consistent with our most recent guidance of a low single-digit decline.

2023 年第四季的總營收為 24 億美元。以實際貨幣計算下降 6%，以固定匯率計算下降 5%。第四季度非 GAAP 攤薄每股收益為 2.95 美元，其中包括最近披露的與 ADUHELM 相關的清倉成本帶來的 0.35 美元負面影響。 2023 年全年，總營收為 98 億美元，以實際貨幣計算下降 3%，以固定匯率計算下降 1%，這與我們最近的低個位數下降指引一致。

Full year 2023 non-GAAP diluted EPS was $14.72 and that's also consistent with our most recent guidance range of $14.50 to $15. Total MS product revenue was $1.2 billion in the fourth quarter. That's a decrease of 8% at actual currency and 6% at constant currency. And that decline is broadly attributable to competition among the impacts from generic TECFIDERA.

2023 年全年非 GAAP 攤薄後每股收益為 14.72 美元，也符合我們最新的 14.50 美元至 15 美元的指導範圍。第四季 MS 產品總營收為 12 億美元。以實際貨幣計算下降 8%，以固定匯率計算下降 6%。這種下降主要歸因於仿製藥 TECFIDERA 的影響之間的競爭。

I'd like to now provide just a couple of quick updates to the MS business during the fourth quarter. First, for TECFIDERA in Europe. In December, the European Commission revoked a centralized marketing authorization for generic versions of TECFIDERA. And in reaching this decision, the European Commission affirmed that Biogen is entitled to marketing protection for TECFIDERA until February of 2025, which makes TECFIDERA the only dimethyl fumarate treatment for MS that may be lawfully placed on the market for sale in the EU until that date.

我現在想簡單介紹一下第四季微軟業務的一些最新情況。首先是歐洲的 TECFIDERA。 12 月，歐盟委員會撤銷了 TECFIDERA 仿製藥的集中行銷授權。在做出這項決定時，歐盟委員會確認百健(Biogen) 有權在2025 年2 月之前獲得TECFIDERA 的營銷保護，這使得TECFIDERA 成為該日期之前唯一可以在歐盟合法上市銷售的富馬酸二甲酯治療藥物。 。

Also a TYSABRI biosimilar is now launched in a small number of countries in Europe. We expect that biosimilars will continue to launch in the first half of 2024 in other European geographies as well as in the U.S. Biogen has patents related to TYSABRI and we will continue to seek to enforce our IP. And although VUMERITY grew modestly in 2023, we are seeing continued effects from pricing pressure and overall contraction of the oral segment of the market in the U.S., which we expect to continue to see in 2024.

此外，TYSABRI 生物相似藥現已在歐洲少數國家上市。我們預計生物相似藥將於 2024 年上半年在其他歐洲地區以及美國繼續上市。百健 (Biogen) 擁有與 TYSABRI 相關的專利，我們將繼續尋求執行我們的智慧財產權。儘管 VUMERITY 在 2023 年略有成長，但我們看到價格壓力和美國口腔市場整體收縮的持續影響，我們預計這種情況將在 2024 年繼續出現。

Now an update on our rare disease portfolio, which includes SPINRAZA, SKYCLARYS and QALSODY. In the fourth quarter, we reported revenue of $472 million, which is an increase of 3% at actual currency and 6% at constant currency. On our third quarter call, we noted that SPINRAZA outside the U.S. benefited from the timing of shipments in certain markets. This prior period benefit negatively impacted fourth quarter performance.

現在更新我們的罕見疾病產品組合，其中包括 SPINAZA、SKYCLARYS 和 QALSODY。第四季度，我們報告營收為 4.72 億美元，以實際貨幣計算成長 3%，以固定匯率計算成長 6%。在我們第三季的電話會議上，我們注意到美國以外的 SPINRAZA 受益於某些市場的出貨時間。前期效益對第四季的業績產生了負面影響。

While we expect continued shipment timing impacts for SPINRAZA in 2024, we remain encouraged by its overall performance. SPINRAZA outside the U.S. was also modestly impacted by pricing pressure and competition in Europe in the fourth quarter. As the market leader in SMA, we continue to believe that we can return SPINRAZA to growth over time. SKYCLARYS delivered $56 million of revenue in the first full quarter as a Biogen product, and we are encouraged by the continued patient growth that we've seen.

雖然我們預計 2024 年 SPINRAZA 的出貨時間將繼續受到影響，但我們仍然對其整體表現感到鼓舞。第四季度，美國以外的 SPINRAZA 也受到歐洲定價壓力和競爭的輕微影響。作為 SMA 的市場領導者，我們仍然相信隨著時間的推移，我們能夠使 SPINRAZA 恢復成長。作為百健 (Biogen) 產品，SKYCLARYS 在第一個完整季度實現了 5,600 萬美元的收入，我們看到患者的持續成長令我們感到鼓舞。

Biosimilars fourth quarter revenue of $188 million, increased 8% at actual currency and 10% at constant currency. We continue to explore strategic alternatives for this business and are working to ensure that we maximize its value for our shareholders. Our anti-CD20 revenue of $436 million included a $12 million operating loss related to our economics for LUNSUMIO. Contract manufacturing royalty and other revenue of $118 million in the fourth quarter was notably lower year-over-year, mainly driven by the timing of batches and I'll provide some additional detail on this dynamic shortly when I discuss our 2024 guidance.

生物相似藥第四季營收為 1.88 億美元，以實際貨幣計算成長 8%，以固定匯率計算成長 10%。我們將繼續探索該業務的策略替代方案，並努力確保為股東實現價值最大化。我們的抗 CD20 收入為 4.36 億美元，其中包括與 LUNSUMIO 的經濟效益相關的 1,200 萬美元營運虧損。第四季的合約製造特許權使用費和其他收入為1.18 億美元，同比顯著下降，這主要是由於批次時間的影響，我將在討論我們的2024 年指導時很快提供有關這一動態的一些額外細節。

Now a few things to note regarding fourth quarter expenses. Fourth quarter non-GAAP cost of sales was 25% of total revenue, and that includes $52 million of idle capacity charges. Fourth quarter non-GAAP R&D expense decreased $34 million and that's notwithstanding approximately $45 million related to our portion of the LEQEMBI collaboration and approximately $60 million in closeout costs relating to ADUHELM. Non-GAAP SG&A expense decreased $44 million in the fourth quarter, which was driven by approximately $110 million in cost savings initiatives and that was partially offset by an increase in commercialization expenses related to the launches of SKYCLARYS and LEQEMBI.

現在有一些關於第四季度支出需要注意的事情。第四季非 GAAP 銷售成本佔總收入的 25%，其中包括 5,200 萬美元的閒置產能費用。第四季非公認會計原則研發費用減少了 3,400 萬美元，儘管與我們 LEQEMBI 合作部分相關的費用約為 4,500 萬美元，以及與 ADUHELM 相關的結算成本約為 6,000 萬美元。第四季度非 GAAP SG&A 費用減少了 4,400 萬美元，這是由約 1.1 億美元的成本節約舉措推動的，但部分被與 SKYCLARYS 和 LEQEMBI 的推出相關的商業化費用的增加所抵消。

Next, a brief update on our balance sheet. We ended the year with $1 billion in cash and marketable securities and $6.9 billion in debt, which puts us in a net debt position of $5.9 billion. In the fourth quarter, we utilized approximately $1.3 billion of cash for final acquisition payment obligations related to the Reata transaction. We also paid down roughly $350 million of the $1 billion term loan that we put in place at the time of this acquisition. It's important to note that included in the $1.3 billion I just mentioned, $393 million was reflected in cash flow from operations for a onetime payment related to equity-based compensation for the Reata transaction.

接下來，簡要更新我們的資產負債表。年底，我們擁有 10 億美元的現金和有價證券以及 69 億美元的債務，這使我們的淨債務部位達到 59 億美元。在第四季度，我們使用了約 13 億美元現金來履行與 Reata 交易相關的最終收購付款義務。我們也償還了本次收購時發放的 10 億美元定期貸款中的約 3.5 億美元。值得注意的是，在我剛才提到的 13 億美元中，有 3.93 億美元反映在與 Reata 交易股權補償相關的一次性付款的營運現金流中。

So absent this full year 2023, free cash flow of $1.3 billion would have been approximately $1.7 billion. We expect to continue to generate strong cash flow this year and expect to receive a payment of $437 million from Samsung in early Q2 of this year.

因此，如果沒有 2023 年全年，13 億美元的自由現金流將約為 17 億美元。我們預計今年將繼續產生強勁的現金流，並預計在今年第二季初從三星收到 4.37 億美元的付款。

So now I'm going to discuss our full year 2024 guidance ranges and assumptions. We expect full year 2024 non-GAAP diluted earnings per share of between $15 and $16 and that reflects expected EPS growth of approximately 5% at the midpoint of the range compared to 2023. We -- while total revenue is expected to decline by a low mid-single-digit percentage, we expect our core pharmaceutical revenue or product revenue plus Biogen's 50% share of LEQEMBI revenue net of cost of sales and royalties to be relatively flat for 2024 as compared to 2023. This assumption is driven by the expected increase in revenue from new product launches over the course of the year, roughly offsetting the declines in our MS product revenue. As has been the case in previous years, we expect Q1 to be seasonally weaker quarter as compared to Q4 for our MS business in the U.S., and that's driven by higher discounts and allowances and some channel dynamics.

現在我將討論 2024 年全年指導範圍和假設。我們預計 2024 年全年非 GAAP 攤薄後每股收益將在 15 美元至 16 美元之間，這反映出與 2023 年相比，預期每股收益增長約為 5%。中個位數百分比，我們預計2024 年我們的核心藥品收入或產品收入加上百健(Biogen) 在扣除銷售成本和特許權使用費後在LEQEMBI 收入中所佔的50% 份額將與2023 年相比相對持平。這一假設是由預期成長推動的全年新產品推出帶來的收入，大致抵消了我們 MS 產品收入的下降。與前幾年的情況一樣，我們預計，與第四季度相比，我們在美國的 MS 業務第一季將出現季節性疲軟，這是由更高的折扣和補貼以及一些管道動態推動的。

We also expect contract manufacturing revenue to be significantly lower throughout 2024 as compared to 2023. This is in part due to completing certain batch commitments in 2023 as part of the 2020 sale of Hillerød, which is located in Denmark. We had manufacturing operations there. And these batch commitments contributed roughly $320 million in 2023, which will not recur in 2024. The increase in revenue from new product launches and decrease in contract manufacturing revenue along with lower idle capacity charges are expected to have a favorable impact on cost of sales as a percentage of revenue for 2024.

我們也預計 2024 年全年合約製造收入將顯著低於 2023 年。部分原因是作為 2020 年出售位於丹麥的 Hilleräd 的一部分，在 2023 年完成了某些批次承諾。我們在那裡有製造業務。這些批次承諾將在2023 年貢獻約3.2 億美元，而到2024 年將不會再出現。新產品推出帶來的收入增加、合約製造收入的減少以及閒置產能費用的降低預計將對銷售成本產生有利影響，因為2024 年收入的百分比。

We also believe we can grow our operating income at a low double-digit percentage in operating margins by a mid-single-digit percentage as compared to 2023. We expect this to be driven by improved cost of sales as a percentage of revenue as well as lower expected operating expenses resulting from our Fit for Growth initiative.

我們也相信，與 2023 年相比，我們的營業利潤能夠以較低的兩位數百分比增長，營業利潤率達到中個位數百分比。我們預計這也將受到銷售成本佔收入百分比改善的推動由於我們的「適應成長」計畫導致預期營運費用降低。

On Fit for Growth, we continue to expect to generate approximately $1 billion in gross savings and $800 million in savings net of reinvestments by 2025. We have achieved approximately $200 million of savings in 2023 and are on track to realize another $200 million in 2024, which would put us at $400 million or half of the overall net savings by the end of this year with the remainder in 2025.

在「適合成長」方面，我們繼續預計到2025 年將產生約10 億美元的總儲蓄和8 億美元的儲蓄（扣除再投資）。我們在2023 年已實現約2 億美元的儲蓄，並有望在2024 年再實現2 億美元的儲蓄。這將使我們在今年年底前達到 4 億美元，即總淨節省額的一半，剩餘部分將在 2025 年實現。

In 2024, we expect our 50% portion of SG&A spend for LEQEMBI, which as a reminder is not included in our Fit for Growth assumptions and the reallocation of resources for ADUHELM to roughly offset. With all of these considerations in mind, we expect our full year 2024 combined R&D and SG&A spend to total approximately $4.3 billion. We expect our other income and expense line to continue to be a headwind this year given the reduction in interest income and increase in interest expense as a result of the Reata acquisition. And so in 2024, we expect an improving revenue profile, improved margins and a return to non-GAAP EPS growth. Our #1 goal remains to return to sustainable growth and we remain committed to this goal and to creating long-term value for our shareholders.

到 2024 年，我們預計 SG&A 支出的 50% 用於 LEQEMBI，提醒一下，這並不包括在我們的「適合成長」假設中，且 ADUHELM 的資源重新分配可大致抵銷。考慮到所有這些因素，我們預計 2024 年全年研發和銷售、一般行政費用總計約為 43 億美元。鑑於收購 Reata 導致利息收入減少和利息支出增加，我們預計今年其他收入和支出項目將繼續成為不利因素。因此，到 2024 年，我們預期收入狀況會改善，利潤率會提高，且非 GAAP 每股盈餘將恢復成長。我們的第一目標仍然是恢復永續成長，我們將繼續致力於實現這一目標並為股東創造長期價值。

And now back to Chris for some closing remarks.

現在回到克里斯的總結發言。

Thanks, Mike. So we have a number of milestones this year that we'll all be watching carefully. You've seen we have a scientific advisory group for LEQEMBI in the first quarter and assuming a positive result for the CHMP that should hopefully lead to an approval in -- by the European Commission in the first half -- later in the first half of this year.

謝謝，麥克。因此，今年我們有許多里程碑，我們都將密切關注。您已經看到，我們在第一季度為 LEQEMBI 設立了一個科學諮詢小組，並假設 CHMP 取得積極成果，預計將在上半年獲得歐盟委員會的批准，並在上半年晚些時候獲得批准。今年。

SKYCLARYS in the European Union, of course, we've just achieved, as we announced last night and the European approval for QALSODY, there's an expected decision by the CHMP and the European Commission in the first half. We have regulatory submissions coming up, as you know, with the subcutaneous formulation for LEQEMBI and IV maintenance dosing also for LEQEMBI. And then as Priya has noted, we have 4 data readouts expected sometime midyear for core programs. As I said earlier, I think we are going to be spending an increasing amount of time focused on our pipeline and building out that pipeline.

當然，我們剛剛在歐盟獲得了 SKYCLARYS，正如我們昨晚宣布的那樣，歐洲批准了 QALSODY，CHMP 和歐盟委員會預計將在上半年做出決定。如您所知，我們即將提交有關 LEQEMBI 皮下製劑和 LEQEMBI 靜脈維持劑量的監管意見。然後，正如 Priya 所指出的，我們預計將在年中某個時候公佈核心專案的 4 個數據。正如我之前所說，我認為我們將花費越來越多的時間專注於我們的管道並建立管道。

So Chuck, I turn that back to you for questions.

所以查克，我把這個問題轉回給你。

Right. Thanks, Chris. Katie, could you please open polling for questions?

正確的。謝謝，克里斯。凱蒂，你能打開投票提問嗎？

(Operator Instructions) Our first question comes from the line of Marc Goodman with Leerink Partners.

（操作員說明）我們的第一個問題來自 Leerink Partners 的 Marc Goodman。

Can you walk us through just the subcu and the maintenance approvals, obviously, time lines, I guess, would be around the end of the year, but just talk about the impact into the market. Let's assume Lilly's on the market as well, they're going to get approved soon. So how do you expect this to change the dynamics and the uptake, and just give us a sense of that, please? And then also maybe you could just talk about the uptake in Japan that you expect?

您能否向我們介紹一下 subcu 和維護批准，顯然，我猜時間線將在今年年底左右，但只談談對市場的影響。我們假設禮來公司也上市了，他們很快就會獲得批准。那麼，您希望這會如何改變動態和接受度，並讓我們有這樣的感覺？然後也許您可以談談您期望的在日本的採用情況？

Priya, do you want to just start with kind of the time lines and I can hit the commercial.

Priya，你想從時間軸開始嗎，我可以播放廣告。

Thanks, Marc, for that question. So overall, we shared our 6-month data for the subcutaneous formulation at CTAD last year. We believe we've achieved the bio-equivalents with the IV formulation. Eisai has communicated very recently about the FDA meeting that is on the book to finalize strategy for submission. And currently, the aim is still to file by end of March 2024 for the subcutaneous formulation. In addition, there is data on the potential and need for IV maintenance, and that is also being aimed to file by Q1 2024. So that's the plan currently. I'm going to turn it over to Chris for the dynamics and the commercial implications.

謝謝馬克提出這個問題。總的來說，我們去年在 CTAD 上分享了皮下製劑的 6 個月數據。我們相信我們已經實現了靜脈注射製劑的生物等效性。衛材最近就 FDA 會議進行了溝通，該會議即將確定提交策略。目前，皮下製劑的目標仍是在 2024 年 3 月底前提交申請。此外，還有有關 IV 維護的潛力和需求的數據，目標是在 2024 年第一季之前提交。這就是目前的計劃。我將把它交給克里斯來了解動態和商業影響。

Yes. So Marc, I mean the main benefit of subcutaneous is going to be convenience for patients. And as we talked about earlier, over time, we're looking at the AHEAD study, where we could potentially when they get an indication for much earlier-stage patients. We're looking at maintenance, where patients should continue on if we get approved, to prevent the recurrence of plaque.

是的。馬克，我的意思是皮下注射的主要好處是為患者帶來便利。正如我們之前談到的，隨著時間的推移，我們正在研究 AHEAD 研究，當他們獲得針對早期患者的適應症時，我們可能會進行這項研究。我們正在考慮維持治療，如果我們獲得批准，患者應該繼續治療，以防止斑塊復發。

So the time on drug is expected to expand as we do these studies and having a subcutaneous formulation at any stage of this disease could be quite beneficial. In terms of the actual competitiveness with donanemab, I think there's going to be a number of points. We do know that physicians are highly sensitive to ARIA and safety. And we have a significantly better safety profile with LEQEMBI than donanemab. There's an interesting thing with donanemab study, which their study actually followed patients until there was a decrease in plaques. So where CLARITY looked at an endpoint for everybody at the same time point after 18 months, there was a variable endpoint in terms of time on donanemab -- and so the stopping criteria are not quite clear. And I think we need to see what those are if you need a PET scan, for instance, that could be quite onerous.

因此，隨著我們進行這些研究，用藥時間預計會延長，並且在這種疾病的任何階段使用皮下製劑都可能非常有益。就與donanemab的實際競爭力而言，我認為有很多要點。我們確實知道醫生對 ARIA 和安全性高度敏感。而 LEQEMBI 的安全性明顯優於多南單抗。 donanemab 研究有一個有趣的事情，他們的研究實際上追蹤患者，直到斑塊減少。因此，當 CLARITY 在 18 個月後的同一時間點查看每個人的終點時，就多納奈單抗的時間而言存在一個可變的終點，因此停止標準並不十分明確。我認為我們需要看看這些是什麼，例如，如果您需要 PET 掃描，這可能會非常繁重。

Now we don't know whether that's going to be the case or not. But I think we're going to have a number of variables with which we can compete with donanemab. And subcutaneous at some point will be helpful. Obviously, Lilly guidance, looks like donanemab is an indicated is going to be on the market before the subcutaneous formulation is. So we're going to be focused on some of those nonsubcutaneous factors and competition. And then once we see the label for Lilly, once we see the label for the subcu, then we'll develop our commercial strategy accordingly.

現在我們不知道情況是否會如此。但我認為我們將有許多變數可以與多南單抗競爭。皮下注射在某些時候會有所幫助。顯然，根據禮來公司的指導，多南單抗似乎將在皮下製劑上市之前上市。因此，我們將重點放在一些非皮下因素和競爭。一旦我們看到禮來公司的標籤，一旦我們看到 subcu 的標籤，我們就會相應地制定我們的商業策略。

Do you want to comment on Japan?

您想對日本發表評論嗎？

In Japan. Yes, I think -- we certainly have a -- Eisai is basically putting all of its field force, not just the ones for LEQEMBI behind this. And you've got the government-managed health care system. So I think some of the complexity that we have in the United States with reimbursement and different actors could be simpler. We do expect that there will be some of the same constraints in terms of access to neurologists, the PET scans. They will probably use a lot more of the CSF markers and PET scans in Japan. But I think we could potentially see a faster uptake in Japan than we saw even in the United States just because of the current system.

在日本。是的，我認為——我們當然有——衛材基本上投入了所有的現場力量，而不僅僅是 LEQEMBI 的力量。而且您還擁有政府管理的醫療保健系統。因此，我認為美國的報銷和不同參與者的一些複雜性可能會更簡單。我們確實預計在接觸神經科醫生和 PET 掃描方面也會存在一些相同的限制。他們可能會在日本使用更多的腦脊髓液標記和 PET 掃描。但我認為，由於目前的製度，我們可能會在日本看到比美國更快的吸收速度。

So we're just out there since January, and we'll give an update, obviously, again at first quarter. But certainly, from what we're hearing from our own people in the field that there's been a very positive reception by physicians in Japan.

因此，我們從一月份開始就在那裡，顯然，我們將在第一季再次提供更新。但可以肯定的是，從我們從該領域的人員那裡聽到的消息來看，日本醫生對此給予了非常積極的歡迎。

We'll go next to Salveen Richter with Goldman Sachs.

接下來我們將討論高盛的薩爾文·里克特 (Salveen Richter)。

I have one with regard to the bottlenecks on the LEQEMBI launch. Could you speak to maybe 2 of those aspects. One is your expectations for Medicare Advantage to get to the same level of coverage as traditional Medicare and over what time frame? And then secondly, just an update on the patient access to neurologists?

我有一個關於 LEQEMBI 啟動瓶頸的問題。您能談談其中的兩個面向嗎？一是您對 Medicare Advantage 達到與傳統 Medicare 相同的承保水平的期望以及在多長時間內實現？其次，只是關於病人接觸神經科醫師的最新情況？

Yes. So I'll have to get back here -- I haven't heard anything that Medicare Advantage is any different than Medicare. So I haven't ever asked that question before, but I'll go check, but as far as I know, it's the same. The bottlenecks are still -- if you think about it, if the data from the patient registries are accurate and again, we don't have direct access to that. But it suggests that we've got almost twice as many people on the registry as we do on treatment.

是的。所以我必須回到這裡 - 我沒有聽說過 Medicare Advantage 與 Medicare 有何不同。所以我以前從未問過這個問題，但我會去檢查一下，但據我所知，情況是一樣的。瓶頸仍然存在——如果你想一想，如果患者登記處的數據準確的話，我們無法直接存取這些數據。但這顯示我們登記的人數幾乎是接受治療的人數的兩倍。

And so that says that in addition to the bottleneck of getting into the neurologist that there's -- when you get to the registry, you've got a clear intent to prescribe because on the registry at least for CMS you have to describe how you actually validated the diagnosis. So by then, you've triaged the patient, you've done either the PET scan or the CSF markers, and you're looking for reimbursement. And what we're hearing a little bit is, is that there is some challenge in just scheduling the first MRI because when we initiate the infusion, you have to have the first MRI within the first 2 weeks.

所以這就是說，除了進入神經科醫生那裡的瓶頸之外，當你到達登記處時，你有一個明確的開處方意圖，因為在登記處，至少對於CMS 來說，你必須描述你實際上是如何開藥的。驗證了診斷。到那時，您已經對患者進行了分類，您已經完成了 PET 掃描或腦脊髓液標記，並且您正在尋求報銷。我們聽到的一點是，安排第一次 MRI 存在一些挑戰，因為當我們開始輸液時，您必須在前兩週內進行第一次 MRI。

So people don't want to initiate the infusion until they've got that MRI scheduled. And the MRI -- there isn't an MRI capacity constraint per se. But you are looking for a specific date and then you have to back up the infusion. So there's just, I think, until people get the hang of this, getting all that coordination, I think that seems to be where one of the bottlenecks is.

因此，人們在安排好 MRI 之前不想開始輸液。 MRI 本身並沒有容量限制。但你要尋找一個特定的日期，然後你必須備份輸液。因此，我認為，在人們掌握竅門並進行所有協調之前，我認為這似乎是瓶頸之一。

We'll go next to Umer Raffat with Evercore ISI.

接下來我們將與 Evercore ISI 一起前往 Umer Raffat。

I thought I'd ask for something a little different today, your CD40 Phase III in lupus. And my question is 2 things. One, the trial size, this was shrunk from 450 down to 320. Could you speak to the recruiting challenges and whether they bode well or not well on efficacy? And then secondly, the primary endpoint, this 1 has 3 components, but the FDA guidance appears to want one clear index like (inaudible) et cetera. Is there alignment with regulator on that?

我想今天我會要求一些不同的東西，你的 CD40 III 期狼瘡。我的問題是兩件事。一是試驗規模，從 450 人縮減到 320 人。您能否談談招募挑戰以及它們是否預示著效果好？其次，主要終點，該終點有 3 個組成部分，但 FDA 指南似乎需要一個明確的指標，例如（聽不清楚）等。是否與監管機構就此保持一致？

I'll take that. So just starting off, I think we expect our results from the first Phase III mid-2024, we expect that we'll need a second Phase III if this is positive to generate the safety and efficacy to support a reg filing. We did make a protocol amendment. And this was really working very closely with Biogen and UCB looking at the study design, balancing our commitment to execute a well-designed informative study with a desire to potentially expedite the delivery of dapB if positive to patients in need.

我會接受的。因此，剛開始時，我認為我們預計第一個III 期試驗的結果將在2024 年中期獲得，如果這對產生支持註冊備案的安全性和有效性是積極的，我們預計我們將需要第二個III 期試驗。我們確實對協議進行了修改。這實際上是與百健（Biogen）和 UCB 密切合作研究研究設計，平衡我們執行精心設計的資訊研究的承諾，以及如果對有需要的患者呈陽性的話可能加快交付 dapB 的願望。

So we do think it's appropriately powered. And we continue with regulatory engagements and facilitate a discussion on the next step. So we think, yes, it is positioned to give us a clear readout on the therapeutic potential as of now, yes.

所以我們確實認為它的動力適當。我們將繼續進行監管活動並促進下一步的討論。所以我們認為，是的，它能夠讓我們清楚地了解目前的治療潛力，是的。

We'll go next to Evan Seigerman with BMO Capital Markets.

接下來我們將採訪蒙特婁銀行資本市場部的 Evan Seigerman。

Chris, can you walk me through some of the rationale for adding more Biogen resources to the LEQEMBI launch? And maybe kind of what's changed or evolved with your partnership with Eisai, where you think you needed to add more Biogen resources in the United States?

Chris，您能否向我介紹一下在 LEQEMBI 上市中添加更多 Biogen 資源的一些理由？也許您與衛材的合作關係發生了一些變化或發展，您認為您需要在美國增加更多百健（Biogen）資源？

I mean to be clear, we're adding both more Biogen as well as more Eisai. A year ago, CEO of Eisai and I talked about the launch of LEQEMBI and for the U.S., just discussed the complexity of the launch. And we've been through all that and they won't necessarily bore everybody again with that complexity. But we just felt that we wanted to really make sure we understood the go-to-market model. In addition to these neurology account specialists you've got MSLs, you've got some patient care navigators, you've got some people looking after KMEs in the region.

我的意思是明確地說，我們將添加更多百健（Biogen）和衛材（Eisai）。一年前，衛材執行長和我談到了 LEQEMBI 的推出，而對於美國來說，只是討論了推出的複雜性。我們已經經歷了這一切，他們不一定會因為這種複雜性而再次讓每個人感到厭倦。但我們只是覺得我們想真正確保我們理解上市模式。除了這些神經病學帳戶專家之外，您還有 MSL、一些病患照護導航員以及一些負責該地區 KME 的人員。

And there's probably -- for every NAS, there's another 2 or 3 people who are actually out there in the field. And there's an awful lot of coordination that is needed. And even the role of the NAS is quite complex because you've got to go in there, you've got to work with the office around helping them to understand the safety. You have to help them understand what the care pathway is. You have to help them to understand the reimbursement, not just for LEQEMBI, but there's the reimbursement for the PET scans, the MRIs and further care. And then finally, there's what people in the field have as a principal objective via LEQEMBI.

對於每個 NAS，可能還有另外 2 到 3 個人實際在現場。並且需要大量的協調。甚至 NAS 的角色也相當複雜，因為你必須進入那裡，你必須與辦公室合作，幫助他們了解安全性。您必須幫助他們了解護理途徑是什麼。你必須幫助他們了解報銷，不僅僅是 LEQEMBI 的報銷，還有 PET 掃描、MRI 和進一步護理的報銷。最後，該領域的人們透過 LEQEMBI 將其作為主要目標。

So we wanted to make sure we understood all of that. And to be honest, whenever you do these co-promotions, they require an awful lot of coordination between the companies. And we just felt that it would be simpler if one company went out at the start. We were sure that we knew exactly how the role of the NAS was going to work in relation to the other accompanying roles that are out there in the field. And we also needed to get a certain number of core IDNs ready and signed up because there's not a lot of point in increasing the number of people out in the field unless you've got enough sites that are activated and ready.

所以我們想確保我們理解所有這些。說實話，每當你進行這些聯合促銷時，都需要公司之間進行大量的協調。我們只是覺得如果一家公司一開始就退出會比較簡單。我們確信我們確切地知道 NAS 的角色將如何與該領域的其他伴隨角色一起發揮作用。我們還需要準備好並註冊一定數量的核心 IDN，因為除非您有足夠的已啟動和準備好的網站，否則增加現場人員數量沒有多大意義。

So now we're more than 6 months into the launch. I think we feel very comfortable about how the role of the NAS works. We understand how long it takes between going to visit a neurologist or an IDN and how long it's going to take for them to be activated because I say there's you can put an awful lot of resource out there but if you're not able to pull the drug through, it's not a very efficient process. So that's just where we are. We're confident in that model. Obviously, it is -- we need to now reach out to more sites. So we're looking at this from both a geographic expansion. But also, I think even within certain geographies, perhaps reducing the territory side because when these NASs go in, they spend quite a long time with the specialists.

現在距離發布已經 6 個多月了。我認為我們對 NAS 的作用感到非常滿意。我們了解去拜訪神經科醫生或 IDN 之間需要多長時間，以及激活它們需要多長時間，因為我說你可以在那裡投入大量資源，但如果你無法拉動藥物通過，這不是一個非常有效的過程。這就是我們現在的情況。我們對這個模型充滿信心。顯然，我們現在需要接觸更多網站。所以我們從地理擴張的角度來看這個問題。而且，我認為即使在某些地區，也可能會縮小地理範圍，因為當這些 NAS 進入時，他們會花相當長的時間與專家在一起。

So it was always the agreement between the 2 CEOs that when we scale up that Biogen would come in. But we both -- our objective is to make the joint venture as efficient as possible. And so we just felt that the efficiency at the start would be maximized if we have had one company in the field. Now we've obviously learned from that, and that's what also gives us the confidence to put 2 companies out into the field immediately in Japan, for example, because while there are differences in the market, a number of the dynamics would be the same pretty much in most markets. So it is an increase. Eisai is increasing their resource and so -- and Biogen will be out there as well. And that could still evolve over time. We're going to be in this business together for many years to come.

因此，兩位執行長之間始終一致認為，當我們擴大規模時，百健（Biogen）就會加入。但我們倆的目標是使合資企業盡可能高效。因此，我們認為，如果我們在該領域擁有一家公司，那麼一開始的效率將會最大化。現在我們顯然已經從中吸取了教訓，這也讓我們有信心立即在日本將兩家公司投入該領域，因為雖然市場存在差異，但許多動態是相同的幾乎在大多數市場上。所以這是一個增加。衛材（Eisai）正在增加他們的資源，因此百健（Biogen）也將在那裡。而且這種情況仍可能隨著時間的推移而演變。我們將在未來的許多年裡共同從事這項業務。

We'll go next to Paul Mattias with Stifel.

我們將和史蒂菲爾一起去保羅·馬蒂亞斯旁邊。

This is James on for Paul. Just one more on the lecanemab subcu and specifically in treatment-naive patients. Just wondering if you're confident that you have enough data from a regulatory perspective here, if you've aligned with regulators, you and Eisai aligned with regulators and specifically, if you have enough safety data in that treatment-naive patient population. Any color there would be great.

這是詹姆斯對保羅的回應。這是另一篇關於 Lecanemab subcu 的文章，特別是針對未接受過治療的患者。只是想知道您是否有信心從監管角度獲得足夠的數據，您是否與監管機構保持一致，您和衛材是否與監管機構保持一致，特別是，您是否在未經治療的患者群體中擁有足夠的安全資料。任何顏色都會很棒。

So yes, overall, this has been a topic that we've discussed Eisai and Biogen have discussed with the FDA. And just to step back, the design was to add a sub-study, a subcutaneous sub-study in the Phase III CLARITY study open-label extension and the cohort that was treatment naive from lecanemab was about 72 patients. And then there was a whole cohort of 322 additional patients that provided safety and tolerability. So this was -- the 72 patients is the premise for the PK/PD and bioequivalents. But there's a larger subset of data that speaks to the safety data. So yes, discussions are ongoing, but overall, these have been discussed with regulators prior to starting them.

所以，是的，總的來說，這是我們討論過衛材和百健（Biogen）與 FDA 討論過的話題。退一步來說，設計是在 III 期 CLARITY 研究開放標籤擴展中添加一項子研究，一項皮下子研究，並且未接受過 lecanemab 治療的隊列大約有 72 名患者。然後還有另外 322 名患者組成的整個隊列提供了安全性和耐受性。所以這就是——72 名患者是 PK/PD 和生物等效性的前提。但還有一個更大的資料子集涉及安全資料。所以，是的，討論正在進行中，但總的來說，這些問題在開始之前已經與監管機構進行了討論。

We'll go next to Phil Nadeau with TD Cowen.

接下來我們將和 TD Cowen 一起去 Phil Nadeau。

Question on SKYCLARYS following last night's approval in the EU. Chris highlighted the importance of the U.S. markets. Could you discuss the expected cadence and trajectory of SKYCLARYS' launch outside the U.S. and Europe, in particular, when will be available in the major territories? And would you expect the uptake in those major territories to be as fast as it has been here in the United States?

昨晚歐盟批准 SKYCLARYS 後出現的問題。克里斯強調了美國市場的重要性。您能否討論一下 SKYCLARYS 在美國和歐洲以外地區推出的預期節奏和軌跡，特別是何時在主要地區推出？您是否預期這些主要地區的採用速度會像美國一樣快？

So there's 2 aspects, I guess, to the launch. One is the early access programs and the other is the former launch. So for example, we'll be able to launch now in Germany with this approval. So we will -- this will be a formal launch. We still have an early access program and naive patients on that will now convert to commercial patients, remembering that actually, the patients in early access programs in Europe are expected to be revenue generating for the most part.

我認為此次發布有兩個面向。一個是搶先體驗計劃，另一個是之前的發布。例如，獲得批准後我們現在就可以在德國推出。所以我們將——這將是一次正式發布。我們仍然有一個早期訪問計劃，天真的患者現在將轉換為商業患者，請記住，實際上，歐洲早期訪問計劃中的患者預計將大部分產生收入。

We have another program that's up and running in France. And we are negotiating the establishment of early access programs in 2 other European countries and there are some early access programs under discussion in countries outside of the EU. And the early access program is important because as we all know, in Europe, getting pricing and reimbursement can take some time. So it's a little hard to predict just because we have to understand the cadence of these early access programs. So I would expect that it's not going to be quite as fast as it was in the U.S.

我們還有另一個項目正在法國啟動並運行。我們正在談判在另外兩個歐洲國家建立搶先體驗計劃，而歐盟以外的國家也正在討論一些搶先體驗計劃。搶先體驗計畫很重要，因為眾所周知，在歐洲，獲得定價和報銷可能需要一些時間。因此，預測有點困難，因為我們必須了解這些搶先體驗計畫的節奏。所以我預計它不會像美國那麼快。

That said, there is some suggestion that there are some patients, the warehousing effect could well be in Europe, but as I said and as a general matter, just because of the time to get reimbursement all increase in the fact that we are not going to be able to have early access programs in all countries that, that will be a slower uptake than in the U.S. That said, there's also probably more patients actually per capita. Remember, this is a disease that is related to European descent. And so the incidence of Friedreich’'s ataxia is slightly higher in Europe than (inaudible). The next big market opportunity to be Latin America, and we are submitting in Brazil and perhaps, Priya, you can give us an update on the regulatory time lines there.

也就是說，有人建議，有一些患者，倉儲效應很可能在歐洲，但正如我所說，一般而言，只是因為獲得報銷的時間都增加了，事實上我們不會去能夠在所有國家實施早期訪問計劃，這些國家的接受速度將比美國慢。也就是說，實際上人均患者數量也可能更多。請記住，這是一種與歐洲血統有關的疾病。因此，弗里德賴希共濟失調的發生率在歐洲略高於（聽不清楚）。下一個巨大的市場機會是拉丁美洲，我們正在巴西提交，Priya，也許您可以向我們提供有關那裡監管時間表的最新資訊。

Yes. I can comment on the fact that really, we are trying to expedite our regulatory filings in Latin America, Brazil, Argentina. We haven't yet communicated the time lines, but our teams are working very expeditiously, meeting with regulators to really define the pathways that could provide earliest access to patients.

是的。我可以評論這樣一個事實：我們確實正在努力加快在拉丁美洲、巴西、阿根廷的監管備案。我們尚未傳達時間表，但我們的團隊正在非常迅速地工作，與監管機構會面，以真正確定可以儘早接觸患者的途徑。

We estimate, it's hard to get the numbers precisely, but we do estimate there's around 2,000 to 4,000 patients in Latin America. So -- and when we look at the experience of SPINRAZA, we are expecting particularly Latin America to contribute substantially to our revenue outlook as well. As you know, there are very few patients in Asia just because of the genetics. So we don't intend to be filing or launching in Asia.

我們估計，很難得到準確的數字，但我們確實估計拉丁美洲有大約 2,000 到 4,000 名患者。因此，當我們審視 SPINAZA 的經驗時，我們預期拉丁美洲尤其會對我們的收入前景做出重大貢獻。如您所知，僅僅因為遺傳因素，亞洲的患者很少。因此，我們不打算在亞洲申請或推出。

We'll go next to Michael Yee with Jefferies.

接下來我們將與 Jefferies 一起前往 Michael Yee。

We had a question on SKYCLARYS. Can you maybe shed some more light on the dynamics of 800 patients to 1,000? And then the trajectory as we go forward into 2024, I know you mentioned there's about 4,000 patients, but how many of those are actually identified. Do you expect growth to moderate just from an expectation standpoint? Talk a little bit about the complexities in 2024 that you commented about.

我們有一個關於 SKYCLARYS 的問題。您能否進一步闡明 800 至 1,000 名患者的動態？然後是我們進入 2024 年的軌跡，我知道您提到大約有 4,000 名患者，但其中有多少人實際上得到了識別。僅從預期的角度來看，您是否預期成長會放緩？談談您所評論的 2024 年的複雜性。

Yes. Certainly, the growth is going to moderate. Remember, this was -- when this product was in hands of Reata, they had approval. I think it was back in the first quarter. I think it was February, if I remember accurately. And -- but they were not able to commercially launch because of a manufacturing specification issue. So -- and that did not get cleared until July. So in other words, the market and physicians knew the product would be coming to the market that it was approved and they were just waiting for product availability.

是的。當然，成長將會放緩。請記住，當該產品交到 Reata 手中時，他們就獲得了批准。我認為這是第一季的情況。如果我沒記錯的話，我想那是二月。但由於製造規格問題，他們無法商業化推出。所以——直到七月才得到澄清。換句話說，市場和醫生知道該產品將進入市場並獲得批准，他們只是在等待產品上市。

So I think the warehousing effect was even greater than what you would normally see for any rare disease drug. Now we're back into the process of finding the patients. I have to say the Friedreich’'s Ataxia Research Alliance, otherwise known as FARA, is an extraordinarily effective patient association and we're working with them to help identify patients. There is a requirement really to diagnose a patient accurately a genetic test. But this genetic test is not sold readily available. And so we're having to look and make sure that the supplier of that test can make the tests readily available.

因此，我認為倉儲效應甚至比任何罕見疾病藥物通常看到的效應還要大。現在我們又回到尋找病人的過程了。我必須說弗​​里德賴希的共濟失調研究聯盟（也稱為 FARA）是一個非常有效的患者協會，我們正在與他們合作以幫助識別患者。確實需要透過基因測試來準確診斷患者。但這種基因測試並不是現成出售的。因此，我們必須尋找並確保該測試的供應商可以隨時提供測試。

And then we're also doing the contracting really to make sure that as patients have start forms that they can quickly get on drug. So we'll be back to, I think, a regular growth cadence on SKYCLARYS in the U.S. I don't think we're necessarily going to get another 20% this year but we're growing every month. And certainly, SKYCLARYS is contributing significantly to our return to growth in 2024.

然後我們還進行了簽約，以確保患者在獲得開始表格後可以快速接受藥物。因此，我認為，我們將回到美國 SKYCLARYS 的常規成長節奏。我認為今年我們不一定會再獲得 20% 的成長，但我們每個月都在成長。當然，SKYCLARYS 為我們在 2024 年恢復成長做出了重大貢獻。

We'll go next to Colin Bristow with UBS.

接下來我們將介紹瑞銀集團的 Colin Bristow。

I just wanted to clarify something in your slides that says that the subcu that we can be filing is now first half of '24. But in your commentary, it sounds like it's still 1Q '24, so if you could just clarify that? And just talk to specifically what FDA is waiting to see, I think it was a 12-month data last time we spoke. What is it within that? And then maybe just as a follow-on, AHEAD 3-45 study, what is the timing or thresholds for any interim analysis there?

我只是想澄清一下幻燈片中的一些內容，即我們可以提交的 subcu 現在是 24 年上半年。但在你的評論中，聽起來仍然是 24 年第一季度，所以你能澄清一下嗎？具體談談 FDA 正在等待看到的內容，我認為上次我們談論的是 12 個月的數據。那裡面是什麼？然後，也許作為後續的 AHEAD 3-45 研究，任何中期分析的時間或閾值是什麼？

I can get started. So overall, I think with the subcutaneous, just to be very clear, Eisai has communicated as recently as their earnings a few days ago that we aim to file by Q1 2024, which is end of the first quarter this year. And just shifting gears to AHEAD 3-45, this is really a platform -- a set of platform trials with different amyloid levels for defining preclinical Alzheimer's disease. So at a very high level, A45 is preclinical Alzheimer's disease with an enrollment target of 1,000 patients and patients need to have an amyloid level of 40 centiloids or more. There are 3 phases of dosing with different doses, which is titration, induction and maintenance. And in this particular trial, the outcome is a PACC5, which is a preclinical composite for Alzheimer's disease, where it's sensitive to patients who are still in the preclinical phase.

我可以開始了。因此，總體而言，我認為在皮下業務方面，需要非常明確的是，衛材幾天前就其收益進行了溝通，我們的目標是在2024 年第一季（即今年第一季末）之前提交。轉向 AHEAD 3-45，這確實是一個平台——一組用於定義臨床前阿茲海默症的不同澱粉樣蛋白水平的平台試驗。因此，在非常高的水平上，A45 是臨床前阿茲海默症，入組目標為 1,000 名患者，患者的澱粉樣蛋白水平需要達到 40 centiloids 或更高。不同劑量的給藥分為3個階段，分別為滴定階段、誘導階段、維持階段。在這個特殊的試驗中，結果是 PACC5，它是阿茲海默症的臨床前複合藥物，它對仍處於臨床前階段的患者敏感。

The A3 trial is -- has a target enrollment of about 400 and the preclinical amyloid cutoff is between 20 and 40 centiloids. And then again, it's got a different holding schedule of titration and then maintenance. Now the primary endpoint for the A3 trial is really a biomarker endpoint. We haven't really communicated exact time lines. These are very large trials. I think the Eisai and Biogen are very pleased with how they are being enrolled. And I think we'll communicate more. There is an opportunity to do an interim analysis and Eisai has spoken to this, but we haven't communicated a time line yet.

A3 試驗的目標招募人數約為 400 人，臨床前澱粉樣蛋白截止值在 20 至 40 個厘素之間。話又說回來，它有不同的滴定和維護保持時間表。現在 A3 試驗的主要終點實際上是生物標記終點。我們還沒有真正傳達確切的時間表。這些都是非常大的試驗。我認為衛材和百健對他們的招募方式非常滿意。我想我們會進行更多的溝通。有機會進行中期分析，衛材已經談到了這一點，但我們尚未傳達時間表。

And Colin, just a quick note on Slide 28, right. The docs that does show Q1, right? We have wordings as expected midyear, if there's something sort of in the middle of the year. So I get the confusion because it says half 1, half 2, but the docs are kind of at the end of the quarter there. So if you were looking at -- see if there was a disconnect, there's not it is. They have said in the end of March is what we're looking at here. So Priya...

Colin，請在投影片 28 上做一個簡短的說明，對吧。文件確實顯示了 Q1，對嗎？如果年中有什麼事情的話，我們會在年中做出預期的措詞。所以我很困惑，因為它說一半 1，一半 2，但文件是在季度末的。因此，如果您查看是否存在斷開連接，則事實並非如此。他們在三月底表示，這就是我們在這裡關注的情況。所以普里亞...

I think there was the latter part of the question. I'll just wrap it up that with regards to FDA, I think I mentioned previously, there have been a lot of discussions. Eisai has recently mentioned the scheduling of more meeting another meeting. And so that strategy will be finalized. Looking at the 6-month data, we are very encouraged with what we saw. We believe that the highest threshold, really, the biggest hurdle was to meet bioequivalence, which we believe we've met. So we'll continue to wait for more data. But we are very encouraged with what we've seen so far.

我認為問題的後一部分。我想總結一下，關於 FDA，我想我之前提到過，已經有很多討論了。衛材最近提到了安排更多會議的另一次會議。這樣該戰略就會最終確定。看看 6 個月的數據，我們對所看到的感到非常鼓舞。我們認為，最高的門檻，實際上最大的障礙是滿足生物等效性，我們相信我們已經滿足了。所以我們將繼續等待更多數據。但我們對迄今為止所看到的情況感到非常鼓舞。

We'll go next to Chris Raymond with Piper Sandler.

接下來我們將和派珀·桑德勒一起去克里斯·雷蒙德。

I wanted to maybe circle back on the Angelman's program, and I wanted to understand a little bit better previous commentary around the program. Can you maybe clarify the calculus that goes into deciding to participate in future development. And obviously, there's a competitive approach with Ultragenyx's program. Curious how you're thinking about approvable endpoints? That's obviously been a big question mark. And how you think this product, if successful, would sort of compare and any sort of commentary there in terms of the competitive set?

我可能想回顧一下天使人的計劃，並且我想更好地理解之前圍繞該計劃的評論。您能否澄清一下決定參與未來開發的計算過程。顯然，Ultragenyx 的計劃具有競爭性。好奇您如何考慮可批准的終點？這顯然是一個很大的問號。您認為該產品如果成功的話，會如何與競爭對手進行比較和評論？

Sure. Sure. So overall, just to step back, this is a program that Ionis, our partner is operationalizing and the way the contractual agreements are written, we have the option of opting in to take the data that we see midyear and decide whether we would like to do a pivotal program -- a pivotal study. So that's how it's set up. And then to step back, I described it briefly in my opening remarks that this is a Phase Ib trial. So this is a Phase I trial that's being conducted in patients. It has a multiple ascending dose component for 3 months followed by a long-term extension. So we will get data. This is across different age groups and different doses. So we'll get a composite of data.

當然。當然。因此，總的來說，退一步來說，這是我們的合作夥伴 Ionis 正在實施的一個計劃，並且按照合約協議的編寫方式，我們可以選擇獲取年中看到的數據，並決定是否願意進行一項關鍵計劃—一項關鍵研究。這就是它的設定方式。然後退一步，我在開場白中簡要描述了這是 Ib 期試驗。這是一項在患者身上進行的第一階段試驗。它具有為期 3 個月的多次遞增劑量成分，然後長期延長。這樣我們就會得到數據。這是不同年齡組和不同劑量的。所以我們將得到數據的組合。

And importantly, we'll be looking for trends on EEG, which we know these patients suffer from the delta waves as I spoke to the slowing. So we'll be looking at that as well as clinical endpoints. And very specifically, there are quite a few clinical endpoints. There's the Bayley score, there's the CGI and there's a Vineland. We'll be looking at all of them. Stepping out into what do we feel about the competitive landscape? We feel that this as designed the program is well positioned. Just from an ASO perspective, the backbone of the BIIB121 ASO, we believe, is different. That's one from the Ultragenyx ASO.

重要的是，我們將尋找腦電圖的趨勢，正如我談到放緩時我們知道這些患者患有δ波。因此，我們將關注這一點以及臨床終點。非常具體地說，有相當多的臨床終點。有貝利配樂、CGI 配樂和瓦恩蘭配樂。我們將研究所有這些。深入了解我們對競爭格局的看法？我們認為該計劃的設計定位很好。僅從 ASO 的角度來看，我們認為 BIIB121 ASO 的支柱是不同的。這是來自 Ultragenyx ASO 的一款。

Second, we believe that the dosing may be needed at a quarterly level to really see the PK/PD impact that we need to have -- make an impact in this disease. And we do have a 3 monthly dosing in the LTE. So the MAD is 2 doses being given 1 month apart. And then the third dose, 2 months later, and then patients go into a 3-month dosing. So we are -- we feel that we will have a data set that we can look at and really assess whether we see an adequate signal to really take it into a Phase III. And with regards to Roche discontinuing their program, we believe, again, that this is a different product and we believe we may have a competitive advantage. Ultimately, of course, we need to see the data.

其次，我們認為可能需要每季給藥一次，才能真正看到我們需要的 PK/PD 影響——對這種疾病產生影響。我們確實在 LTE 中進行了 3 個月一次的給藥。因此，MAD 是間隔 1 個月注射 2 劑。然後在 2 個月後進行第三次給藥，然後患者開始為期 3 個月的給藥。因此，我們認為我們將擁有一個資料集，我們可以查看並真正評估我們是否看到足夠的訊號以真正將其納入第三階段。關於羅氏終止他們的計劃，我們再次相信這是一個不同的產品，我們相信我們可能擁有競爭優勢。當然，最終我們需要看到數據。

We'll go next to Mohit Bansal with Wells Fargo.

接下來我們將與富國銀行 (Wells Fargo) 一起前往莫希特·班薩爾 (Mohit Bansal)。

Maybe I can -- if you can comment a little bit on the previous comments you made regarding SPINRAZA returned to growth. What is happening in the market right now? And how do you plan to get back to growth on this product?

也許我可以——如果你能對你之前關於 SPINRAZA 恢復增長的評論發表一點評論。目前市場正在發生什麼？您計劃如何恢復該產品的成長？

Sure. So as you know, we have an oral therapy out there. We have a gene therapy, and we have SPINRAZA with the intrathecal. So short term, I think one of the data points that was very important was demonstrating the efficacy of SPINRAZA following Zolgensma because there has been some feeling that Zolgensma wanes over time. So we're getting what we call switch packs, and the other on the oral therapy is that there has sometimes appear to be that the efficacy is limited to certain body weights. So we can actually go after more adult populations.

當然。如您所知，我們有口服療法。我們有基因療法，還有鞘內注射的 SPINRAZA。因此，短期來看，我認為非常重要的數據點之一是證明 SPINRAZA 在 Zolgensma 之後的功效，因為有人感覺 Zolgensma 隨著時間的推移而減弱。因此，我們得到了所謂的轉換包，而口服療法的另一個問題是，有時似乎效果僅限於某些體重。所以我們實際上可以追求更多的成年人口。

We believe that only about 30% of patients with SMA are actually treated. Clearly, the pediatric patients are screened for and readily identified. But there are a number of adult patients where the disease is manifest, but it is sometimes difficult to diagnose. And so we're back to the rare disease job of hunting for patients. But we think, actually, we will be the most appropriate treatment for that patient population. So that's one source of growth.

我們相信只有大約 30% 的 SMA 患者得到了真正的治療。顯然，兒科患者經過篩檢並易於識別。但也有一些成年患者雖然有明顯的疾病表現，但有時難以診斷。所以我們又回到了尋找病人的罕見疾病工作。但我們認為，實際上，我們將是最適合該患者族群的治療方法。所以這是成長的來源之一。

And then longer term, as you know, we have a high-dose SPINRAZA program in development, which could, if it's successful, lead to just one intrathecal injection procured. And that would make an enormous difference to patients in terms of patient convenience and make SPINRAZA even more competitive compared to the others. Now that's still going to take a number of years, but we do expect that still to come to market before the patent on SPINRAZA occurs.

從長遠來看，如您所知，我們正在開發一項高劑量 SPINRAZA 計劃，如果成功，可能會導致僅進行一次鞘內注射。這將為患者帶來巨大的便利，並使 SPINRAZA 與其他藥物相比更具競爭力。現在這仍需要數年時間，但我們確實預計該產品仍會在 SPINRAZA 專利獲得之前上市。

Yes. And I'll just quickly add to that, Mohit, that in the -- as we mentioned in our prepared remarks, there tends to be some lumpiness quarter-over-quarter, particularly outside of the U.S. with shipments. But overall, when you look at the full year of 2023, we actually saw modest growth in the U.S., modest decline OUS and overall, moving back toward the modest growth trajectory that we're hoping for, and we are pleased with how that franchise has stabilized over time.

是的。莫希特，我要快速補充一點，正如我們在準備好的發言中提到的那樣，季度環比往往會出現一些波動，特別是在美國以外的地區。但總體而言，當你審視 2023 年全年時，我們實際上看到了美國的溫和增長，OUS 的溫和下降，總體而言，回到了我們希望的溫和增長軌跡，我們對該系列的表現感到滿意隨著時間的推移已經穩定下來。

Yes, there's a dynamic as sort of the oral comes into a market at one point or the gene therapy comes into a market. If you have 100% market share and the competitor comes in mathematically, you're going to lose market share. But what we see is that there is some churn for a year or 2. And then the markets settle out, and that's when people start focusing on efficacy and patient populations. And as I say, so far, we have been able to maintain leadership in SMA despite the competition. And I think that's where they'll be. There'll be different products for different patients, but there's still enough of the patient population and even with the switchbacks that we can find reservoirs of growth.

是的，隨著口服藥物進入市場或基因療法進入市場，存在著一種動態。如果你擁有 100% 的市場份額，而競爭對手在數學上出現，你就會失去市場份額。但我們看到的是，在一兩年內會出現一些波動。然後市場穩定下來，那時人們開始關注療效和患者群體。正如我所說，到目前為止，儘管存在競爭，我們仍然能夠在 SMA 中保持領先地位。我認為他們會在那裡。針對不同的患者會有不同的產品，但仍有足夠的患者群體，即使出現折返，我們也可以找到成長的水庫。

And operator, can we move to our last question, please.

接線員，我們可以轉到最後一個問題嗎？

We'll go next to Jay Olson with Oppenheimer.

接下來我們將和奧本海默一起去傑·奧爾森。

This is Matt on for Jay. Jason's regards. So we were wondering, I guess, it's still early, of course, with the PPD launch so far just in terms of any metrics or signals that you see that support your confidence in the launch so far. And of course, over the next few months to quarters, what kind of metrics do you believe will become meaningful and that you might plan to share? And maybe just your overall longer-term goals for that PPD launch and your general interest in the psychiatry space would be interesting to hear as well.

這是為傑伊代言的馬特。傑森的問候。所以我們想知道，我想，當然，到目前為止 PPD 的推出還為時過早，就您所看到的任何指標或訊號而言，這些指標或訊號都支持您對迄今為止的推出的信心。當然，在接下來的幾個月到幾個季度中，您認為哪些指標將變得有意義並且您可能計劃分享？也許您對 PPD 發布的整體長期目標以及您對精神病學領域的整​​體興趣也會很有趣。

Sure. We -- there are a number of things that I think are quite encouraging. One is our initial target has been high-prescribing psychiatrists in this space as well as OB-GYNs. And one of the things that we are wondering about is, are the OB-GYNs really going to be willing to prescribe. And so one of the encouraging signs is that they, in fact, are doing so. So we're seeing quite a high percentage of the prescriptions coming from them. Another has been, I think, as I mentioned earlier, that payers have really wanted to ensure access to patients, and I'm quite thankful to them.

當然。我們——我認為有很多事情非常令人鼓舞。一是我們的最初目標是該領域的高處方精神科醫生以及婦產科醫生。我們想知道的一件事是，婦產科醫生真的願意開處方嗎？因此，令人鼓舞的跡象之一是他們實際上正在這樣做。所以我們看到很大比例的處方來自他們。我認為，另一個原因是，正如我之前提到的，付款人確實希望確保能夠接觸到患者，我非常感謝他們。

I think Medicaid, for example, where 40% of births occur have moved very quickly on that in a number of states. And some of the large -- at least one of the large commercial insurers is moving much quicker than we expected as well. So I think the reimbursement is a key statistics. Now personally, I'm interested in knowing how many patients are treatment naive versus people who have been on treatment what is interesting is, is there a warehousing effect here as well. There's been an awful lot of media coverage. The product was approved in July. We were not able to launch because of the DEA inspection until the very end of 2023.

例如，我認為醫療補助計劃（40% 的出生率）在許多州的進展非常迅速。一些大型商業保險公司——至少其中一家大型商業保險公司的行動也比我們預期的要快得多。所以我認為報銷是關鍵的統計數據。現在就我個人而言，我很想知道有多少患者未曾接受過治療，而有多少患者已經接受過治療。有趣的是，這裡是否也存在倉儲效應。有大量媒體報導。該產品於7月獲得批准。由於 DEA 檢查，我們直到 2023 年底才能夠啟動。

So what we don't know is are we seeing a bolus of patients come in because these are patients, physicians have been following for some time, who've been identified as being particularly important for to have ZURZUVAE. So I think we'll need to see a little bit more data about who are the patients and where they're coming from. But I say so far, we're running for the first month, I mean we're certainly doing much better than what we had anticipated, and we'll give you another update at Q1. We'll sit with Sage sometime in March to look at the data and say, what do we see as some of the trends. But so far, so good.

所以我們不知道的是，我們是否看到大量患者進來，因為醫生已經追蹤這些患者一段時間了，他們被認為對 ZURZUVAE 特別重要。所以我認為我們需要看到更多關於患者是誰以及他們來自哪裡的數據。但我說到目前為止，我們正在運行第一個月，我的意思是我們的表現肯定比我們預期的要好得多，我們將在第一季向您提供另一個更新。我們將在三月的某個時候與 Sage 坐在一起查看數據並討論我們認為的一些趨勢。但到目前為止，一切都很好。

Thanks, Chris, and that will conclude our call. Appreciate you all joining us today.

謝謝克里斯，我們的通話就到此結束。感謝大家今天加入我們。

That concludes today's call. We appreciate your participation. You may now disconnect.

今天的電話會議到此結束。我們感謝您的參與。您現在可以斷開連線。