Ionis Pharmaceuticals Inc (IONS) 2024 Q4 法說會逐字稿

Good morning, and welcome to Ionis' fourth-quarter and full-year 2024 financial results conference call. As a reminder, this call is being recorded.

早安，歡迎參加 Ionis 2024 年第四季和全年財務業績電話會議。提醒一下，本次通話正在錄音。

At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead the call. Please begin.

現在，我想將電話轉給投資者關係高級副總裁 Wade Walke 來主持會議。請開始。

Thank you, MJ. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call.

謝謝你，MJ。在我們開始之前，我鼓勵大家前往 Ionis 網站的投資者部分查看我們今天將討論的新聞稿和相關財務表，包括 GAAP 與非 GAAP 財務狀況的對帳。我們相信非公認會計準則財務結果更能反映我們業務的經濟狀況以及我們如何管理業務。我們也在我們的網站上發布了今天電話會議的幻燈片。

With me on the call this morning are Brett Monia, our Chief Executive Officer; Kyle Jenne, Chief Global Product Strategy Officer; Richard Geary, Chief Development Officer; and Beth Hougen, our Chief Financial Officer. And joining us for the Q&A portion of our call will be Eric Swayze, Executive Vice President of Research; and Eugene Schneider, Chief Clinical Development Officer.

今天早上與我一起參加電話會議的還有我們的執行長 Brett Monia； Kyle Jenne，首席全球產品策略長； Richard Geary，首席開發長；以及我們的財務長 Beth Hougen。研究部執行副總裁 Eric Swayze 將參加我們電話會議的問答環節；以及首席臨床開發長 Eugene Schneider。

I would like to draw your attention to slide 3, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail.

我想提請大家注意投影片 3，其中包含我們的前瞻性語言聲明。在本次電話會議中，我們將根據目前的預期和信念做出前瞻性陳述。這些聲明受某些風險和不確定性的影響，我們的實際結果可能存在重大差異。我鼓勵您查閱我們提交給美國證券交易委員會 (SEC) 的文件中包含的風險因素以獲取更多詳細資訊。

And with that, I'll turn the call over to Brett.

說完這些，我會把電話轉給布雷特。

Thanks, Wade. Good morning, everyone, and thank you for joining us on today's call. As we begin a new year, I'm thrilled to share that Ionis has begun a new chapter as a fully integrated commercial-stage biotechnology company with our first independent launch of TRYNGOLZA underway.

謝謝，韋德。大家早安，感謝大家參加今天的電話會議。在新的一年開始之際，我很高興地告訴大家，Ionis 作為一家完全整合的商業階段生物技術公司，已經開啟了新篇章，我們首次獨立推出了 TRYNGOLZA。

With the FDA approval of TRYNGOLZA in late December, adults with familial chylomicronemia syndrome, or FCS, for the first time, have access to a treatment that substantially and sustainably reduces triglyceride levels and substantially reduces the risk of life-threatening acute pancreatitis. Our highly experienced team has been executing the launch flawlessly which enables TRYNGOLZA to be in the hands of patients within a couple of weeks following the December 19 approval.

隨著 FDA 於 12 月底批准 TRYNGOLZA，患有家族性乳糜微粒血症綜合症 (FCS) 的成年人首次能夠接受治療，從而大幅、持續地降低三酸甘油酯水平，並大幅降低危及生命的急性胰臟炎風險。我們經驗豐富的團隊一直完美地執行此次發布，這使得TRYNGOLZA能夠在12月19日批准後的幾週內送到患者手中。

And TRYNGOLZA is just the beginning. We're on track to deliver three additional independent launches over the next three years. Donidalorsen, a potential treatment -- preferred treatment for hereditary angioedema later this year; a second indication for Olezaresen in severe hypertriglyceridemia, or SHTG, a large patient population with high unmet need; and Zilganersen for Alexander's disease, a rare leukodystrophy with no approved therapies. These programs collectively provide the opportunity to help tens of thousands of patients and represent multibillion-dollar revenue potential.

而TRYNGOLZA只是一個開始。我們計劃在未來三年內再獨立發射三次。Donidalorsen，一種潛在的治療方法——今年稍後將成為遺傳性血管性水腫的首選治療方法； Olezaresen 的第二個適應症是治療嚴重高三酸甘油脂血症（SHTG），該類疾病患者群體龐大，且未滿足的醫療需求很高； Zilganersen 用於治療亞歷山大病，這是一種罕見的腦白質營養不良症，目前尚無核准的治療方法。這些計畫共同提供了幫助成千上萬患者的機會，並帶來了數十億美元的收入潛力。

In addition to our independent launches, we also expect four launches from late-stage partnered programs over the next three years. These important medicines are poised to treat a range of serious life-threatening diseases, including several that target broad patient populations. Pelacarsen for Lp(a) cardiovascular disease, addressing an independent cardiovascular disease risk factor with high unmet need with no approved therapies.

除了我們獨立推出的產品外，我們還預計未來三年內透過後期合作項目推出四款產品。這些重要藥物將用於治療一系列嚴重的危及生命的疾病，其中包括幾種針對廣大患者群體的疾病。Pelacarsen 用於治療 Lp(a) 心血管疾病，解決一種獨立的心血管疾病風險因素，目前尚無批准的療法，且需求尚未滿足。

Eplontersen for a TTR cardiomyopathy, a progressive fatal condition that continues to be underdiagnosed with a significant need for more effective treatments. Bepirovirsen for chronic hepatitis B virus, a serious disease that affects hundreds of millions of people globally. And Sefaxersen, previously referred to as IONIS-FB-LRx in development for IgA nephropathy, one of the most common causes of chronic kidney disease and kidney failure.

Eplontersen 用於治療 TTR 心肌病變，這是一種進行性致命疾病，目前仍未得到充分診斷，因此迫切需要更有效的治療方法。貝匹羅韋森用於治療慢性B型肝炎病毒，這是一種影響全球數億人的嚴重疾病。Sefaxersen（之前稱為 IONIS-FB-LRx）用於治療 IgA 腎病，這是導致慢性腎病和腎衰竭的最常見原因之一。

If approved, these important investigational medicines would join our other marketed partnered medicines, including SPINRAZA for SMA and WAINUA for hereditary TTR polyneuropathy, which are generating considerable value for patients and revenue for Ionis.

如果獲得批准，這些重要的在研藥物將加入我們其他已上市的合作藥物，包括用於治療 SMA 的 SPINRAZA 和用於治療遺傳性 TTR 多發性神經病變的 WAINUA，這些藥物將為患者創造可觀的價值，並為 Ionis 帶來收入。

Our partnered medicines enable our innovative science to reach even more patients, bolster our strong revenue base and provide substantial growth potential, while allowing us to focus our efforts on advancing the medicines we plan to commercialize. Ionis is on a path to bring important medicines to patients for years to come. And in turn, we are positioned to achieve substantial and sustained revenue growth and positive cash flow. Our recent accomplishments and ongoing investments position us well to drive accelerated value for all Ionis stakeholders.

我們的合作藥物使我們的創新科學能夠惠及更多患者、增強我們強大的收入基礎並提供巨大的成長潛力，同時使我們能夠集中精力推進我們計劃商業化的藥物。Ionis 致力於在未來幾年為患者提供重要的藥物。反過來，我們有能力實現可觀且持續的收入成長和正現金流。我們最近的成就和正在進行的投資使我們能夠為所有 Ionis 利害關係人創造加速價值。

And with that, I'll turn the call over to Kyle.

說完這些，我會把電話轉給凱爾。

Thank you, Brett. As we start this important new chapter as a fully integrated commercial stage biotech, I cannot be prouder of our team. Their seamless execution of initial launch activities ensured that our first independently launched medicine, TRYNGOLZA, got to FCS patients quickly.

謝謝你，布雷特。當我們作為一家完全整合的商業階段生物技術公司開啟這一重要的新篇章時，我對我們的團隊感到無比自豪。他們無縫執行初始發布活動確保了我們第一款獨立發布的藥物 TRYNGOLZA 能夠迅速送達 FCS 患者。

Following the approval of TRYNGOLZA, the first prescription was written within 24 hours. The team got drug in channel within one week and the first patient self-administered TRYNGOLZA within two weeks of approval. And today, we are encouraged by seeing both genetically confirmed and clinically diagnosed patients on drug.

TRYNGOLZA 獲得批准後，第一張處方在 24 小時內就開出了。該團隊在一周內就獲得了藥物，第一位患者在獲得批准後兩週內就自行服用了TRYNGOLZA。今天，我們看到基因確診和臨床診斷的患者都接受藥物治療，這讓我們感到很鼓舞。

While it's early in the launch, we are encouraged by the positive response in several key areas: The breadth of physicians identifying FCS patients and prescribing TRYNGOLZA; the mix of prescribers, including endocrinologists and cardiologists with an interest in lipids and that we're already seeing numerous repeat prescribers, the rapid time from prescription to patients receiving TRYNGOLZA and coverage by payers for both commercial and Medicare patients.

雖然該藥物還處於上市初期，但我們對幾個關鍵領域的積極響應感到鼓舞：識別 FCS 患者並開出 TRYNGOLZA 處方的醫生廣度；處方人員的組合，包括對脂質感興趣的內分泌學家和心臟病專家，並且我們已經看到大量重複處方人員，從處方到患者收到 TRYNGOLZA 的時間很快，並且商業和醫療保險患者的付款人都承擔了費用。

Our experienced team is laser focused on continuing this momentum. As the first ever treatment in the US, we are capitalizing on our first-mover advantage that is enabling us to develop the market, identify and onboard patients early, and create positive treatment experience that encourages long-term adherence. Additionally, it has enabled us to establish a strong presence in the patient community, all of which we expect will drive long-term success for TRYNGOLZA.

我們經驗豐富的團隊全心全意地致力於延續這一勢頭。作為美國首個治療方法，我們利用先發優勢，能夠開發市場、儘早識別和接納患者，並創造鼓勵長期堅持的積極治療體驗。此外，它使我們能夠在患者群體中建立強大的影響力，我們預計所有這些都將推動 TRYNGOLZA 的長期成功。

The total addressable US FCS patient population is estimated to be up to approximately 3,000 people. And currently, the vast majority of the FCS population remains unidentified and undiagnosed. As a result, there are multiple critical steps that we are taking to get patients identified and on TRYNGOLZA. First, our team is focused on patient finding efforts, working to identify FCS patients who are not yet diagnosed.

預計美國可治療的FCS患者總數約3000人。目前，絕大多數FCS患者仍未被識別和診斷。因此，我們正在採取多項關鍵措施來確認患者身份並讓他們服用 TRYNGOLZA。首先，我們的團隊專注於尋找患者，並努力識別尚未確診的 FCS 患者。

Building on these efforts, our team is working to increase FCS awareness through HCP education to drive increased diagnosis and our commercial field team is actively engaging with HCPs who treat patients with high triglycerides. Once patients are identified and diagnosed, the team works closely with prescribers and patients to obtain coverage and initiate treatment for TRYNGOLZA.

基於這些努力，我們的團隊正在致力於透過 HCP 教育來提高人們對 FCS 的認識，從而推動診斷的增加，並且我們的商業領域團隊正在積極與治療高三酸甘油酯患者的 HCP 合作。一旦確定並診斷出患者，團隊就會與處方人員和患者密切合作，以獲得保險並開始 TRYNGOLZA 治療。

We have deployed a suite of services to accomplish this anchored by our innovative Ionis every step patient support program. As part of this program, dedicated patient education managers provide patient disease and nutrition education, auto-injector administration training, reimbursement support and more. For HCPs, Ionis every step streamlines the TRYNGOLZA prescribing process by offering insurance authorization and coverage assistance as well as coordinating delivery, reauthorizations, and refills.

為實現這一目標，我們部署了一套服務，以我們創新的 Ionis 每一步患者支援計畫為基礎。作為該計劃的一部分，專門的患者教育經理提供患者疾病和營養教育、自動注射器管理培訓、報銷支援等。對於 HCP，Ionis 透過提供保險授權和承保協助以及協調交付、重新授權和補充，每一步都簡化了 TRYNGOLZA 處方流程。

To date, we have had very high engagement with patients sharing their excitement as they now have a treatment in the services that they are experiencing from the program. Our market access and reimbursement teams have been actively engaged with a broad set of US payers, representing the vast majority of covered lives.

到目前為止，我們已經與許多患者進行了交流，他們分享了自己對透過該計劃接受治療服務的興奮之情。我們的市場准入和報銷團隊一直積極與廣泛的美國付款人合作，代表了絕大多數受保人群。

And through these efforts, payers have recognized the significant burden FCS places on patients. With this recognition, we are pleased to report that in the early days of the launch, patients have received timely access to TRYNGOLZA.

透過這些努力，付款人已經認識到FCS 給患者帶來的沉重負擔。憑藉這項認可，我們很高興地報告，在上市初期，患者能夠及時獲得TRYNGOLZA。

Finally, our omnichannel capabilities extend the reach of our commercial team and amplify our efforts with patients and physicians. Our launch trajectory will reflect the time it takes to execute on these efforts which we fully expect will gain momentum as the year unfolds. To realize the full blockbuster potential of Olezaresen, we plan to further scale our commercial organization and infrastructure to address the much larger SHTG patient population, where we have substantial first-mover advantage.

最後，我們的全通路能力擴大了我們的商業團隊的覆蓋範圍，並加強了我們與患者和醫生的努力。我們的發布軌跡將反映執行這些努力所需的時間，我們完全預計，隨著時間的推移，這些努力將獲得動力。為了充分發揮 Olezaresen 的轟動潛力，我們計劃進一步擴大我們的商業組織和基礎設施，以滿足更大規模的 SHTG 患者群體的需求，在這方面我們擁有明顯的先發優勢。

SHTG is comprised of people with triglycerides over 500 milligrams per deciliter and is a symptomatic disease where people can suffer debilitating chronic symptoms that impact all aspects of their life, including severe abdominal pain and cognitive impairment. In the most severe manifestation, SHTG patients can suffer from life-threatening pancreatitis events that require intensive hospital care.

SHTG 由三酸甘油酯每分升超過 500 毫克的人群組成，是一種症狀性疾病，患者會遭受影響其生活各個方面的嚴重慢性症狀，包括嚴重的腹痛和認知障礙。在最嚴重的情況下，SHTG 患者可能出現危及生命的胰臟炎事件，需要住院重症監護。

As a result, physicians recognize the importance of lowering severely elevated triglycerides with established guidelines already in place. Many people with SHTG are severely underserved by current treatment options and in many cases, are unable to reduce triglyceride levels to current recommended guidelines with available options. This is why we are excited about the potential Olezaresen could offer to people with SHTG. Today, the team is focused on pre-commercialization activities ahead of an anticipated launch next year.

因此，醫生認識到降低嚴重升高的三酸甘油酯的重要性，並已製定了指導方針。目前的治療方案嚴重不足，無法為許多 SHTG 患者提供治療，在許多情況下，他們無法透過現有的治療方案將三酸甘油酯水平降低至目前建議的水平。這就是為什麼我們對 Olezaresen 能夠為 SHTG 患者提供的潛力感到興奮。目前，該團隊正專注於預計明年上市的商業化前活動。

WAINUA, our co-commercialized medicine with AstraZeneca for hereditary ATTR polyneuropathy has now been on the market for about a year, and we couldn't be more pleased with the strong progress of the launch. WAINUA delivered accelerating sequential growth throughout last year, including strong demand in the fourth quarter, with product sales nearly doubling compared to the third quarter. Uptake continues to be strong with the majority of top centers of excellence prescribing WAINUA and broadening use into the community setting.

WAINUA 是我們與阿斯特捷利康共同開發的用於治療遺傳性 ATTR 多發性神經病變的藥物，目前已上市約一年，我們對該產品上市的強勁進展感到非常高興。WAINUA 去年全年實現了連續成長，其中第四季度需求強勁，產品銷售額與第三季相比幾乎翻了一番。隨著大多數頂級卓越中心開出 WAINUA 處方並將其使用範圍擴大到社區環境，其使用率持續保持強勁。

Patient growth continued to come from patients new to treatment as well as switches and patients adding WAINUA to their existing therapy. We consistently receive positive feedback from physicians about their patients' experience with WAINUA, including patients' quality of life improvements, their ability to rapidly access WAINUA, and patients' ability to easily self-administer WAINUA.

患者成長繼續來自於接受新治療的患者、轉換治療的患者以及在現有療法中添加 WAINUA 的患者。我們不斷收到醫生對其患者使用 WAINUA 體驗的正面回饋，包括患者生活品質的改善、他們快速獲得 WAINUA 的能力以及患者輕鬆自我管理 WAINUA 的能力。

And we are pleased with the reimbursement and affordability dynamics we saw in 2024. The vast majority of patients who initiated a WAINUA treatment regardless of insurance type paid zero dollars out of pocket. We and AstraZeneca are confident WAINUA will continue to provide a differentiated experience for patients. The growing global ATTR polyneuropathy launch sets the foundation for our efforts to address ATTR cardiomyopathy, a substantial opportunity with 300,000 to 500,000 people estimated worldwide.

我們對 2024 年的報銷和可負擔性動態感到滿意。無論保險類型為何，絕大多數接受 WAINUA 治療的患者都無需自掏腰包。我們和阿斯特捷利康都堅信 WAINUA 將繼續為患者提供差異化的體驗。全球範圍內 ATTR 多發性神經病變的不斷增加為我們應對 ATTR 心肌病變的努力奠定了基礎，這是一個巨大的機遇，全球估計有 30 萬至 50 萬人患有該疾病。

Switching gears to Donidalorsen with the potential approval just six months away, the team is preparing for our second independent launch. In fact, we recently hired the Head of Donidalorsen sales and plan to add the customer-facing team soon, ensuring that they will be ready to bring Donidalorsen to patients quickly after anticipated approval.

由於距離獲得批准僅剩六個月，因此團隊正在將重點轉向 Donidalorsen，為我們的第二次獨立發布做準備。事實上，我們最近聘請了 Donidalorsen 銷售主管，並計劃很快增加客戶團隊，確保他們能夠在預期批准後迅速將 Donidalorsen 帶給患者。

Our team is also leveraging and building upon the WAINUA and TRYNGOLZA launches. For example, we will expand our innovative Ionis every Step patient support program to include the needs of HAE patients. Our medical affairs team has been in the field meeting with physicians. This includes ensuring high visibility at key medical conferences, building awareness of Ionis' platform technology, and presenting the positive clinical data generated from our robust Phase 3 program ahead of our anticipated launch.

我們的團隊也正在利用和建構 WAINUA 和 TRYNGOLZA 的發布。例如，我們將擴展我們創新的 Ionis every Step 患者支援計劃，以滿足 HAE 患者的需求。我們的醫療事務團隊一直在現場與醫生會面。這包括確保在主要醫學會議上具有較高的知名度，提高人們對 Ionis 平台技術的認識，並在我們預期的發布之前展示我們強大的第 3 階段計劃所產生的積極臨床數據。

More than 20,000 people are estimated to have HAE in the US and Europe. In the US, while the HAE market is well defined, prophylactic treatment continues to grow with a meaningful segment of patients switching treatment in search of a better option. Based on Donidalorsen's strong clinical data, including the positive data in patients switching from current prophylactic treatments to Donidalorsen and the simplicity of monthly or every two-month self-administration via an auto-injector, we believe Donidalorsen offers the attributes that many people with HAE are looking for.

據估計，美國和歐洲有超過 20,000 人患有 HAE。在美國，雖然 HAE 市場定義明確，但預防性治療仍在持續成長，有相當一部分患者為了尋求更好的治療選擇而轉換治療方法。基於 Donidalorsen 強大的臨床數據，包括從目前預防性治療轉為 Donidalorsen 的患者的積極數據，以及每月或每兩個月透過自動注射器進行自我給藥的簡便性，我們相信 Donidalorsen 具有許多 HAE 患者所尋求的特性。

And while we expect the Donidalorsen launch ramp to take time as we work to convert patients from existing treatment, we believe Donidalorsen has the potential to be a preferred prophylactic treatment for many HAE patients.

儘管我們預期 Donidalorsen 的推出需要一些時間，因為我們致力於將患者從現有的治療方法中轉變出來，但我們相信 Donidalorsen 有可能成為許多 HAE 患者的首選預防性治療方法。

We have built a highly experienced, efficient, and scalable commercial organization. With the TRYNGOLZA-FCS launch underway, we are focused on delivering its full potential, while preparing to successfully execute our three additional launches planned over the next three years with more to follow positioning Ionis for sustained growth and long-term success.

我們已經建立了一個經驗豐富、高效且可擴展的商業組織。隨著 TRYNGOLZA-FCS 的發射，我們專注於充分發揮其潛力，同時準備成功執行未來三年計劃的另外三次發射，並將隨後進行更多發射，為 Ionis 的持續增長和長期成功做好準備。

With that, I'll now turn it over to Richard.

現在我將把發言權交給理查。

Thank you, Kyle. We had many important pipeline achievements in 2024 that position us well for success in 2025. These included numerous positive late-stage data readouts, which resulted in multiple regulatory submissions and our first independent launch. Additionally, as our pipeline advances, we are on track for multiple late-stage data readouts and regulatory actions this year and next, positioning Ionis to bring transformational medicines to people with serious diseases for years to come.

謝謝你，凱爾。我們在 2024 年取得了許多重要的成果，為我們在 2025 年取得成功奠定了基礎。其中包括大量積極的後期數據讀數，這導致了多次監管提交和我們的首次獨立發布。此外，隨著我們產品線的不斷推進，我們有望在今年和明年獲得多個後期數據並採取監管行動，這將使 Ionis 在未來幾年內為患有嚴重疾病的人提供變革性藥物。

Starting with TRYNGOLZA, the first-ever approved treatment for adults with FCS in the US, the positive data from the Phase 3 BALANCE study formed the basis for TRYNGOLZA's approval. In the BALANCE study, TRYNGOLZA 80 milligrams, demonstrated substantial and sustained triglyceride reductions, clinically meaningful reductions in acute pancreatitis a substantial reduction in all-cause hospitalization and days spent in the hospital, and a favorable safety and tolerability profile in people with FCS. We believe these positive data underscore the tremendous benefit TRYNGOLZA can brain to adults with FCS.

從美國首個核准的FCS成人治療藥物TRYNGOLZA開始，第3階段BALANCE研究的積極資料構成了TRYNGOLZA獲準的基礎。在 BALANCE 研究中，TRYNGOLZA 80 毫克顯示出顯著且持續的三酸甘油酯降低作用、急性胰臟炎發病率臨床意義上的降低、全因住院率和住院天數顯著減少，並且對 FCS 患者俱有良好的安全性和耐受性。我們相信這些積極的數據強調了 TRYNGOLZA 可以為患有 FCS 的成年人帶來的巨大益處。

And while we are starting with FCS, we expect to quickly expand to a second broader indication, SHTG. Many SHTG patients are unable to manage their triglycerides with currently available treatments and physicians are eager for a more effective treatment.

雖然我們從FCS開始，但我們希望迅速擴展到第二個更廣泛的適應症，SHTG。許多 SHTG 患者無法透過現有的治療方法控制三酸甘油酯，醫生渴望找到更有效的治療方法。

As a reminder, we have three separate studies. We expect to report top line results from ESSENCE, our supported safety EXPOSURE study first with data expected in mid this year. ESSENCE is being conducted primarily in patients with triglyceride levels between 150 and 500 mgs per deciliter who are not at high risk for acute pancreatitis. This is not the patient population we're targeting commercially. Rather the ESSENCE study was designed to satisfy the regulatory requirements for a safety database to support a highly prevalent disease.

提醒一下，我們有三項獨立的研究。我們預計將首先報告我們支持的安全暴露研究 ESSENCE 的頂線結果，數據預計在今年年中發布。ESSENCE 研究主要針對三酸甘油酯水平在 150 至 500 毫克/分升之間且急性胰臟炎風險不高的患者。這並不是我們商業目標的患者群。相反，ESSENCE 研究的目的是滿足支持高度流行疾病的安全資料庫的監管要求。

We look forward to data from our pivotal studies CORE and CORE2 to truly understand the Olezaresen profile in SHTG. These studies are evaluating Olezaresen in our target patient population who have triglycerides greater than 500 milligrams per deciliter. We are on track for data from CORE and CORE2 in the second half of this year. And once we have data in hand for both of these studies, we will report the results.

我們期待來自我們的關鍵研究 CORE 和 CORE2 的數據，以真正了解 SHTG 中的 Olezaresen 概況。這些研究正在對 Olezaresen 在三酸甘油酯大於每分升 500 毫克的目標患者群體中的效果進行評估。我們正按計畫在今年下半年獲得 CORE 和 CORE2 的數據。一旦我們掌握這兩項研究的數據，我們就會報告結果。

And assuming these data are positive, we plan to submit our sNDA before year-end. With significant first mover advantage in both FCS and SHTG and compelling results already demonstrated in FCS coupled with our expectation for similarly positive data in SHTG, we believe Olezaresen could be the standard of care for both diseases.

假設這些數據是積極的，我們計劃在年底之前提交 sNDA。憑藉在 FCS 和 SHTG 方面顯著的先發優勢以及在 FCS 中已經展現出的令人信服的結果，再加上我們對 SHTG 中同樣積極數據的預期，我們相信 Olezaresen 可以成為這兩種疾病的治療標準。

Following closely behind TRYNGOLZA is Donidalorsen, a potential advance for patients with hereditary angioedema. We're pleased that Donidalorsen is now under regulatory review in both the US and EU. Our regulatory submissions were based on positive data generated from our Phase 2 and Phase 3 studies, including a separate SWITCH study.

緊隨 TRYNGOLZA 之後的是 Donidalorsen，這對患有遺傳性血管性水腫的患者來說是一項潛在的進步。我們很高興 Donidalorsen 目前正在接受美國和歐盟的監管審查。我們的監管提交是基於我們第 2 階段和第 3 階段研究（包括單獨的 SWITCH 研究）產生的積極數據。

In the Phase 3 program, long-term Donidalorsen treatment demonstrated substantial reductions in HAE attack rates of more than 90% with both monthly and by monthly dosing and a favorable safety and tolerability profile. These reductions translated to a high level of disease control and clinically meaningful improvements in quality-of-life measures.

在第三階段計劃中，長期 Donidalorsen 治療顯示，每月和每月給藥均可使 HAE 發病率大幅降低 90% 以上，且具有良好的安全性和耐受性。這些減少意味著高水準的疾病控制和生活品質指標的臨床意義上的改善。

In the SWITCH study, patients who switched to Donidalorsen from prior prophylactic treatment showed a further reduction in HAE attack rates from baseline with nearly 85% of the patients surveyed preferring Donidalorsen. With a PDUFA date of August 21, we look forward to bringing this potential preferred prophylactic treatment to HAE patients later this year, assuming approval.

在 SWITCH 研究中，從先前的預防性治療轉而使用 Donidalorsen 的患者 HAE 發作率較基線進一步降低，近 85% 的受訪患者更喜歡使用 Donidalorsen。PDUFA 日期為 8 月 21 日，如果獲得批准，我們期待在今年稍後為 HAE 患者提供這種潛在的首選預防性治療方法。

Rounding out our Ionis on late-stage pipeline is Zilganersen, our medicine to treat Alexander's disease, an ultrarare leukodystrophy that profoundly impacts patients and families and has no approved disease-modifying treatments. Last year, Zilganersen was granted fast track designation by the FDA, reflecting the serious unmet need that exists for this rare disease. We are looking forward to reporting Phase 3 data for this program late this year. The rest of our rich pipeline is also making excellent progress.

Zilganersen 是我們 Ionis 後期研發線的補充，它是我們用於治療亞歷山大病的藥物，亞歷山大病是一種極為罕見的腦白質營養不良症，對患者及其家庭影響巨大，目前尚無批准的病情改良治療方法。去年，Zilganersen 獲得了 FDA 的快速通道資格，反映出這種罕見疾病存在著嚴重的未滿足需求。我們期待在今年稍後報告該計劃的第三階段數據。我們其餘的豐富產品線也取得了良好的進展。

This includes ION582, our wholly owned investigational medicine for Angelman syndrome, which we believe has transformational potential for the tens of thousands of patients living with this serious rare disorder last year, based on the positive early results from the HALO study of ION582 in children and adults with Angelman Syndrome, we reached alignment with FDA to conduct the most robust and comprehensive Phase 3 study in this patient population to date.

其中包括 ION582，這是我們全資擁有的用於治療天使人綜合症的試驗藥物，我們相信該藥物具有為數以萬計患有這種嚴重罕見疾病的患者帶來轉變的潛力，基於去年 ION582 對患有天使人綜合症的兒童和成人進行的 HALO 研究的早期積極結果，我們與 FDA 達成協議，在該患者群體中開展的迄今為止最強大的研究。

Our study will focus on clinical end points that reflect the most pressing and meaningful outcomes for people living with Angelman syndrome, endpoints that showed positive results in our HALO study. We remain on track to start ION582 Phase 3 study in the first half of this year.

我們的研究將重點放在反映天使症候群患者最緊迫和最有意義的結果的臨床終點，這些終點在我們的 HALO 研究中顯示出積極的結果。我們仍計劃在今年上半年啟動 ION582 第三階段研究。

As we look to our key value-driving events, we have already made excellent progress. In addition to launching TRYNGOLZA, we are pleased that higher dose Nusinersen is one step closer to the market with the recent FDA and EMA acceptances of Biogen's regulatory submissions. With the well-characterized profile of SPINRAZA established over the past 10-plus years and the positive data from the higher dose SPINRAZA, we believe SPINRAZA is well positioned to continue to bring benefit to SMA patients around the world.

回顧我們的關鍵價值驅動事件，我們已經取得了卓越的進展。除了推出 TRYNGOLZA 之外，我們很高興看到，隨著 FDA 和 EMA 最近接受 Biogen 的監管提交，更高劑量的 Nusinersen 距離上市又近了一步。憑藉過去十多年建立的 SPINRAZA 的良好特性和大劑量 SPINRAZA 的積極數據，我們相信 SPINRAZA 能夠繼續為全球 SMA 患者帶來益處。

To summarize, key near-term value-driving events, we anticipate many late-stage data readouts, significant regulatory actions, and numerous product launches. By the end of 2026, we expect seven Phase 3 data readouts, including two Ionis owned medicines. This year, Olezaresen for the broad SHTG indication in Zilganersen for Alexander's disease.

總而言之，近期的關鍵價值驅動事件，我們預計將有許多後期數據讀數、重大監管行動和大量產品發布。到 2026 年底，我們預計將有 7 個 3 期數據讀數，其中包括兩種 Ionis 擁有的藥物。今年，Olezaresen 因 Zilganersen 的廣泛 SHTG 適應症而用於治療亞歷山大病。

Next five Ionis discovered medicines are on track for Phase 3 data, most of which are for very broad patient populations. If positive, these groundbreaking medicines could start to reach patients as soon as next year. And we expect to have five launches underway, including four independent launches. All of this sets us up to bring a steady cadence of new Ionis medicines to patients for years to come.

Ionis 接下來發現的五種藥物正在進行第 3 階段數據研究，其中大多數針對非常廣泛的患者群體。如果結果呈陽性，這些突破性的藥物最快將於明年開始送達患者手中。我們預計將進行五次發射，其中包括四次獨立發射。所有這些都為我們在未來幾年內向患者提供穩定的新型 Ionis 藥物奠定了基礎。

With that, I'll turn it over to Beth.

說完這些，我會把話題交給貝絲。

Thank you, Richard. We've made excellent progress advancing our strategic growth priorities, including executing our first independent launch while simultaneously upholding our commitment to drive operating leverage. This important progress is reflected in our strong financial results for last year and our outlook for this year, both of which I am happy to share with you today.

謝謝你，理查。我們在推動策略成長重點方面取得了顯著進展，包括執行我們的首次獨立發布，同時堅持推動營運槓桿的承諾。這項重要進展體現在我們去年強勁的財務表現和今年的展望中，今天我很高興與大家分享。

We delivered a non-GAAP operating loss of $345 million, a significant improvement compared to our 2024 guidance. We also substantially exceeded our 2024 revenue guidance by more than $130 million, earning revenues of $705 million last year. During 2024, SPINRAZA remained the primary source of commercial revenue with $216 million of royalties for the year.

我們的非公認會計準則營業虧損為 3.45 億美元，與 2024 年的指引相比有顯著改善。我們也大幅超出了 2024 年的營收預期 1.3 億美元以上，去年的營收達到了 7.05 億美元。2024年，SPINRAZA 仍然是商業收入的主要來源，當年的特許權使用費為 2.16 億美元。

We were encouraged by SPINRAZA's performance and look forward to the anticipated launch of the higher dose options. WAINUA product revenue achieved accelerating sequential growth throughout last year, driven by strong underlying demand. Notably, WAINUA product revenue increased 84% in the fourth quarter compared to the third quarter. WAINUA product sales were $85 million for last year, which we earned for which we earned $20 million in royalties.

SPINRAZA 的表現令我們感到鼓舞，並期待更高劑量選擇的推出。在強勁的潛在需求的推動下，WAINUA 產品收入去年全年實現了連續成長。值得注意的是，WAINUA產品營收第四季較上季成長了84%。去年 WAINUA 產品的銷售額為 8,500 萬美元，我們從中賺取了 2,000 萬美元的特許權使用費。

As planned, our non-GAAP operating expenses increased slightly for 2024 over 2023. The 12% increase year-over-year in sales and marketing expenses reflected our investments in the US launch of TRYNGOLZA and preparations for the upcoming launch of Donidalorsen. Our SG&A expenses also included our minority portion of WAINUA's sales and marketing costs, which are in the high teens to low 20% range.

根據計劃，我們 2024 年的非 GAAP 營運費用較 2023 年略有增加。銷售和行銷費用年增12%，反映了我們對美國推出TRYNGOLZA的投資以及即將推出Donidalorsen的準備工作。我們的銷售、一般及行政費用還包括 WAINUA 銷售和行銷成本的少數部分，這些費用在 10% 到 20% 之間。

In line with our plan, we kept R&D expenses stable year-over-year, while appropriately funding our rich pipeline. Our excellent progress last year, coupled with our disciplined financial management, positions us well for continued growth and value creation.

按照我們的計劃，我們保持研發費用年比穩定，同時適當資助我們豐富的產品線。我們去年的出色進展，加上我們嚴格的財務管理，為我們繼續成長和創造價值奠定了良好的基礎。

Our financial guidance for this year reflects our evolution to a fully integrated commercial-stage biotech company, focused on maximizing the value of our innovative medicines while remaining steadfast in our commitment to deliver strong operating leverage. We project to earn more than $600 million in revenue from numerous sources including a shift towards commercial revenue with the addition of TRYNGOLZA product revenues and initial Donidalorsen product revenues, assuming approval.

我們今年的財務指引反映了我們向完全整合的商業階段生物技術公司的演變，專注於最大化我們的創新藥物的價值，同時堅定不移地致力於提供強大的經營槓桿。我們預計，將從多個來源獲得超過 6 億美元的收入，包括轉向商業收入，增加 TRYNGOLZA 產品收入和初始 Donidalorsen 產品收入（假設獲得批准）。

With TRYNGOLZA, it's important to remember that FCS is a rare and under-recognized disease, and we anticipate an initial gradual buildup of launch momentum, especially in the first few quarters. As our efforts aimed at driving physician awareness and patient identification progress, we expect the number of new patients diagnosed with FCS to increase, which in turn will translate to an acceleration of our launch progress.

對於 TRYNGOLZA，重要的是要記住 FCS 是一種罕見且未被充分認識的疾病，我們預計該產品的上市勢頭將逐漸增強，尤其是在最初幾個季度。隨著我們旨在提高醫生意識和患者識別的努力取得進展，我們預計被診斷患有 FCS 的新患者數量將會增加，這反過來將加速我們的推出進度。

We're also looking forward to adding Donidalorsen product revenues beginning in late Q3, assuming approval in August. And since this is primarily a [switch] market, we expect the launch to reflect the time it takes to convert patients from their existing therapy to Donidalorsen.

我們也期待從第三季末開始增加 Donidalorsen 產品收入，假設 8 月獲得批准。由於這主要是一個[轉換]市場，我們預計這次發布將反映出患者從現有療法轉換為 Donidalorsen 所需的時間。

From our partnered programs, we anticipate earning substantial royalties from medicines on the market today. These include SPINRAZA, which continues to be our largest commercial revenue source. We expect the resilience SPINRAZA has demonstrated to continue and our royalties to reflect that. And this also includes WAINUA, which we expect will continue its upward trajectory this year. With these expected launch dynamics, coupled with the resetting of the royalty rate for SPINRAZA at the beginning of each year, we anticipate that our commercial revenue will increase as the year progresses.

透過我們的合作項目，我們期望從目前市場上的藥品中獲得可觀的特許權使用費。其中包括 SPINRAZA，它仍然是我們最大的商業收入來源。我們預計 SPINRAZA 所展現的韌性將持續下去，而我們的版稅也將反映這一點。這其中也包括 WAINUA，我們預計今年將持續呈現上升趨勢。透過這些預期的發布動態，再加上每年年初重新設定 SPINRAZA 的專利費率，我們預計我們的商業收入將隨著時間的推移而增加。

Our R&D revenue remains a meaningful contributor to our total revenue guidance, although we expect it to be lower this year than it was last year. With a rich pipeline and many partnered programs advancing, we have the potential to earn numerous milestone payments. And based on the timing of anticipated milestones, we expect to earn much of our R&D revenue in the second half of the year.

儘管我們預計今年的研發收入將低於去年，但我們的研發收入仍是我們總收入預期的重要貢獻者。隨著豐富的產品線和眾多合作項目的推進，我們有可能獲得無數里程碑付款。根據預期里程碑的時間安排，我們預計大部分研發收入將在今年下半年獲得。

Additionally, as we continue to conduct the cardio transform study, we will continue to earn revenue from AstraZeneca for its 55% share of the study cost. We project our 2025 operating expenses to increase in the high single-digit percentage range compared to last year. This modest increase reflects our commitment to bring our medicines directly to patients and advance our pipeline while also continuing to exercise sound fiscal stewardship.

此外，隨著我們繼續進行心臟轉化研究，我們將繼續從阿斯特捷利康獲得其 55% 的研究費用份額的收入。我們預計，2025 年的營運費用將比去年增加高個位數百分比。這一適度增長反映了我們致力於將藥品直接提供給患者並推進我們的產品線，同時繼續實行健全的財務管理。

[Business] in 2024, our planned expense growth will come from increases in our sales and marketing expenses and as we invest to support the success of our multiple ongoing and planned launches. We expect our R&D expenses to remain steady in 2025 similar to last year, as several of our late-stage studies have recently concluded or are on track to wrap up this year, we are able to reallocate our resources toward our next wave of opportunities, just as we have done for the Phase 3 development of ION582 for Angelman Syndrome.

[業務] 2024 年，我們計劃的費用增長將來自銷售和行銷費用的增加，以及我們為支持我們正在進行和計劃中的多項發布活動的成功而進行的投資。我們預計，2025 年我們的研發費用將與去年保持穩定，因為我們的幾項後期研究最近已經結束或即將在今年完成，我們能夠將資源重新分配到下一波機遇上，就像我們為治療 Angelman 綜合徵的 ION582 的 3 期開發所做的那樣。

With sizable revenues and modest expense growth, we are projecting a non-GAAP operating loss of less than $495 million. We project to end the year with cash and investments of approximately $1.7 billion. Our projected year-over-year change in cash reflects our investments to bring our medicines directly to patients in addition to advancing our wholly-owned medicines in development while exercising prudent fiscal responsibility.

由於收入可觀且支出成長適度，我們預計非 GAAP 營業虧損將少於 4.95 億美元。我們預計今年底的現金和投資總額將達到約 17 億美元。我們預期的現金同比變化反映了我們在履行審慎的財務責任的同時，為了將藥品直接提供給患者而進行的投資以及推進我們全資藥品的開發。

Looking beyond 2025, with the numerous opportunities before us, we are on track to deliver substantial and sustained revenue growth. This revenue growth, combined with our commitment to drive operating leverage positions us well to also generate positive cash flow. To achieve our goal, we expect to continue making significant investments to advance our pipeline and bring our growing portfolio of medicines directly to patients.

展望 2025 年，我們面臨眾多機遇，可望實現可觀且持續的營收成長。收入成長加上我們致力於推動經營槓桿，使我們能夠產生正現金流。為了實現我們的目標，我們希望繼續進行大量投資，以推進我們的產品線並將不斷增長的藥物組合直接帶給患者。

We estimate that the programs in our pipeline today have a combined multibillion-dollar peak revenue potential. This includes estimated annual peak sales of more than $3 billion from our Ionis-owned medicines including Olezaresen and ION582.

我們估計，我們目前正在籌備的項目總計具有數十億美元的最高收入潛力。這包括我們 Ionis 旗下藥物 Olezaresen 和 ION582 預計超過 30 億美元的年高峰銷售額。

Additionally, based on our partner's peak sales estimates, we could earn more than $2 billion annually in royalties from our late-stage partnered medicines. So as you can see, with robust revenue growth potential, we have a clear path to achieve positive cash flow.

此外，根據我們合作夥伴的高峰銷售估計，我們每年可以從後期合作藥物中獲得超過 20 億美元的特許權使用費。因此，正如您所看到的，憑藉強勁的收入成長潛力，我們有明確的途徑實現正現金流。

And with that, I'll turn the call back to Brett.

說完這些，我就把電話轉回給布雷特。

Thank you, Beth. Becoming a fully integrated commercial stage biotechnology company required the commitment and hard work for all Ionis employees, and we expect to continue our great progress as we enter this next exciting chapter for Ionis. Innovation has always been a key differentiator for Ionis. And through innovation, we've established a proven and prolific discovery and development engine that has provided us with a rich pipeline of medicines with transformational potential and this will continue.

謝謝你，貝絲。要成為一家完全整合的商業階段生物技術公司，需要所有 Ionis 員工的承諾和努力工作，我們期望在進入 Ionis 的下一個激動人心的篇章時繼續取得巨大進步。創新一直是 Ionis 的關鍵差異化因素。透過創新，我們建立了經過驗證、高效的發現和開發引擎，為我們提供了具有轉化潛力的豐富藥物管線，而這一趨勢也將持續下去。

Our pipeline is consistently delivering with three important FDA drug approvals in just under two years, (technical difficulty), WAINUA for ATTR polyneuropathy, and now TRYNGOLZA for FCS, and a fourth FDA approval anticipated later this year, Donidalorsen for HAE.

我們的研發管線穩步推進，在不到兩年的時間內獲得了三種重要的 FDA 藥物批准（技術難題），即用於治療 ATTR 多發性神經病的 WAINUA 和現在用於治療 FCS 的 TRYNGOLZA，第四種藥物 Donidalorsen 預計將於今年晚些時候獲得 FDA 批准，用於治療 HAE。

We've also achieved several important approvals outside the US, and we expect a great deal more this year and incoming years. And with an advancing late-stage pipeline, we have delivered several positive Phase 3 data readouts with more expected this year and next that are being developed to treat both rare and broad patient populations.

我們還在美國以外取得了幾項重要批准，預計今年和未來幾年我們將取得更多批准。隨著後期研發管線的持續推進，我們已發布了數份積極的第 3 階段數據，預計今年和明年還會有更多研究成果發布，用於治療罕見疾病和廣大患者群體。

And today, we have a scalable, highly experienced, innovative commercial organization in place currently launching TRYNGOLZA for FCS and positioned for three additional launches over the next three years. This progress provides us with a clear path to achieve positive cash flow driven by our expectation for substantial top-line revenue growth. This sets us up to deliver accelerating value for all on stakeholders.

如今，我們已擁有一個可擴展、經驗豐富、富有創新精神的商業組織，目前正在為 FCS 推出 TRYNGOLZA，併計劃在未來三年內推出另外三次。這項進展為我們提供了一條實現正現金流的明確途徑，而這得益於我們對大幅營收成長的預期。這使我們能夠為所有利害關係人提供加速價值。

And with that, we'll now open the call over for questions. MJ?

現在，我們將開始回答問題。喬丹？

(Operator Instructions) Mike Ulz, Morgan Stanley.

（操作員指示） 摩根士丹利的 Mike Ulz。

Maybe just one on Olezaresen and SHTG, just given the ESSENCE study is supposed to read out midyear ahead of the core studies. And I realize it's more of a safety study and you're enrolling a different population. But what kind of read-through could we make from ESSENCE to your core studies? Thanks.

也許只有一篇關於 Olezaresen 和 SHTG 的文章，因為 ESSENCE 研究應該在核心研究之前在年中公佈。我意識到這更像是一項安全性研究，而且你招募的是不同的人群。但是，我們可以從 ESSENCE 對您的核心研究進行什麼樣的解讀呢？謝謝。

Thank you, Mike. The ESSENCE study, just as a reminder, is the patient population as Richard described before, that is not our target commercial patient population. It's mildly elevated triglycerides 150 to 500. Our target patient population is SHTG 500 milligrams per deciliter (technical difficulty) So it is a safety study, as you say, Mike.

謝謝你，麥克。需要提醒的是，ESSENCE 研究的對像是理查德之前描述的患者群體，而不是我們的目標商業患者群體。三酸甘油酯輕度升高，為 150 至 500。我們的目標患者群體是 SHTG 500 毫克/分升（技術難度）所以這是一項安全性研究，正如你所說，麥克。

As for read-through, safety will certainly be a key read-through to demonstrate and we think confirm further validate the safety that we've seen in the FCS patient population. So that's very important. As well, the APOC3 reductions that we expect in that study. We, of course, will be looking at triglyceride reductions in that study. That as a predictor of what we'll see in SHTG is somewhat less direct, but we still think it will be -- still an indicator of what to expect in SHTG to some extent, a lesser extent because it's a slightly different patient population.

至於通讀，安全性肯定是需要證明的關鍵通讀內容，我們認為可以進一步驗證我們在 FCS 患者群體中看到的安全性。所以這非常重要。同樣，我們在該研究中預計 APOC3 會減少。當然，我們將在該研究中關註三酸甘油酯的降低。雖然這對於我們在 SHTG 中會看到的情況的預測不太直接，但我們仍然認為它在某種程度上仍然是 SHTG 預期結果的指標，但程度較小，因為患者群體略有不同。

But we're really focused on the safety in that study and the target engagement as a read-through to SHTG.

但我們真正關注的是研究中的安全性和作為 SHTG 指南的目標參與度。

Jessica Fye, JPMorgan.

摩根大通的傑西卡·菲伊 (Jessica Fye)。

I was hoping if you could talk a little bit about what you're seeing in the TTR polyneuropathy market? For example, what portion of new starts do you think you're capturing there?

我希望您能談談您對 TTR 多發性神經病變市場的看法？例如，您認為您在那裡佔據了多少新起點？

Yeah. Thanks, Jess. As Beth communicated earlier, we're so excited about the continued progress here with the launch of WAINUA and ATTR polyneuropathy, the growth quarter-over-quarter of an increase of 84% and $42 million in Q4 and $85 million on the year. I think what that speaks to is the strong demand and the continued growth that's within that category right now.

是的。謝謝，傑西。正如 Beth 之前所說的，我們對 WAINUA 和 ATTR 多發性神經病變的推出所取得的持續進展感到非常興奮，環比增長 84%，第四季度增長 4200 萬美元，去年同期增長 8500 萬美元。我認為這說明目前該類別的需求強勁且持續成長。

Currently, the new to brand share is about 40% for WAINUA. So we are continuing to capture in terms of new patient starts, a significant portion of those, and we expect that to continue to grow over time. We're seeing not only centers of excellence, but also community physicians begin prescribing. So the expansion, neuros and cardiologists are both prescribing and we're still seeing a mix of naive switches as well as combination treatment for WAINUA.

目前，WAINUA 的新品牌市佔率約為40%。因此，我們將繼續捕捉新患者開始數量的變化，其中很大一部分變化預計會隨著時間的推移而繼續增長。我們不僅看到卓越中心，社區醫生也開始開處方。因此，神經科醫生和心臟科醫生都在擴大處方範圍，我們仍然看到針對 WAINUA 的混合初始轉換和聯合治療。

So 2025 is really setting up, I think, to be a very strong year for WAINUA to see the continued growth that we saw in 2024 quarter-over-quarter.

因此，我認為 2025 年對 WAINUA 來說確實是個非常強勁的一年，它將繼續保持 2024 年的環比成長。

Akash Tewari, Jefferies.

Akash Tewari，傑富瑞（Jefferies）。

Can you talk a little more about your design for SHTG, the Phase 3? I mean you've mentioned previously the enrollment rate in that trial is 10x that of FCS. What does that imply for the effect size you've powered for, particularly on acute pancreatitis and severe abdominal pain?

能否進一步談談 SHTG 第三階段的設計？我的意思是您之前提到過，該試驗的入學率是 FCS 的 10 倍。這對於您所追求的效果大小意味著什麼，特別是對急性胰臟炎和嚴重腹痛的影響？

And really, how does your event rate assumption maybe differ versus FCS, but also that ESSENCE study that you mentioned isn't necessarily representative of your other trials? And then any feedback from KOLs on what would be a clinically meaningful reduction would be very helpful as well. Thank you.

實際上，您的事件發生率假設與 FCS 相比可能有何不同，而且您提到的 ESSENCE 研究不一定代表您的其他試驗？然後，任何來自 KOL 的關於臨床上有意義的減少的回饋也將非常有幫助。謝謝。

Thank you, Akash. Let me take a stab that there were a few things there to unpack, very important questions, but then also Eugene can jump in. So our study -- our SHTG Phase 3 study CORE and CORE2 are powered -- of course, while powered for diglyceride reductions, which is our primary end point. As far as acute pancreatitis -- impact acute pancreatitis events in the SHTG core studies, this has really never been studied before.

謝謝你，阿卡什。讓我猜一下，有幾個問題需要解答，是很重要的問題，但 Eugene 也可以插話。因此，我們的研究 — — 我們的 SHTG 第 3 階段研究 CORE 和 CORE2 — — 當然是為降低甘油二酯而開展的，這是我們的主要終點。就急性胰臟炎——影響 SHTG 核心研究中的急性胰臟炎事件而言，這實際上從未被研究過。

We did not believe we were well powered for a positive AP outcome in FCS, and we were pleasantly surprised to see what a tremendous impact we had at reducing AP events in that patient population, even though it was a very small study. The higher the triglycerides in patients, the greater the risk of acute pancreatitis, that's obvious and well established.

我們不認為我們有足夠的能力在 FCS 中獲得積極的 AP 結果，但我們驚訝地發現，儘管這是一項規模非常小的研究，但在減少該患者群體中的 AP 事件方面，我們發揮了巨大的作用。患者的三酸甘油酯越高，罹患急性胰臟炎的風險就越大，這是顯而易見且已得到充分證實的。

The SHTG population has somewhat milder triglycerides on average compared to FCS. So you might expect a lower rate of acute pancreatitis in that study -- in that patient population. Nevertheless, we have more than 10 times the number of patients in our core studies, which, of course, allows us to accumulate potentially more events.

與 FCS 相比，SHTG 族群的平均三酸甘油酯水平略低。因此，您可能會預期該研究中該患者群體的急性胰臟炎發生率較低。儘管如此，我們核心研究中的患者數量是這個數字的 10 倍多，這當然使我們能夠累積更多的事件。

So although we're not necessarily powered and no one's ever studied this before so it would be difficult to power a study on the reduction of AP in SHTG, certainly, the balance FCS data lends us some confidence that we'll see a significant or a meaningful signal in acute pancreatitis and SHTG.

因此，儘管我們不一定有足夠的證據，而且之前也沒有人研究過這一點，因此很難為 SHTG 中 AP 減少的研究提供證據，但平衡的 FCS 數據確實讓我們有信心，我們會在急性胰臟炎和 SHTG 中看到顯著或有意義的信號。

You like to add anything to that, Eugene?

尤金，你還有什麼要補充的嗎？

No, not really. There was another question about clinical meaningfulness of reduction. Of course, that's -- as Brett said, it's not really clear. There is no particular threshold that is considered to be clinically meaningful in terms of AP reduction. So what we're hoping to see is really any significant reduction overall. But as Brad said, of course, the powering of the study is not something that we were able to model based on any existing data.

不，不是真的。還有一個問題是關於減少的臨床意義。當然，正如布雷特所說，這並不十分清楚。就 AP 減少而言，沒有特定的閾值被認為具有臨床意義。因此，我們希望看到的是整體上確實有顯著的減少。但正如布拉德所說，當然，我們無法根據任何現有數據來模擬這項研究的動力。

Yanan Zhu, Wells Fargo Securities.

朱亞南，富國證券。

First, I wanted to have a quick follow-up to a prior question on the WAINUA polyneuropathy 84% quarter-over-quarter growth. How much of that growth is driven by switching because this year, they're both naive patients and switching patients, but wondering how much of a force is the switch from siRNA.

首先，我想快速跟進一下有關 WAINUA 多發性神經病季度環比增長 84% 的先前問題。這種增長有多少是由轉換推動的，因為今年，他們既是初治患者，也是轉換患者，但想知道 siRNA 的轉換有多大力量。

And my main question: I think Biogen announced a couple of updates to some neurology collaboration programs. Could you provide a little more color and what's the plan for those programs? Thank you.

我的主要問題是：我認為 Biogen 宣布了一些神經病學合作計劃的更新。您能否提供更多詳細資訊以及這些項目的計劃是什麼？謝謝。

Sure. Kyle, please take the question on quarter-over-quarter the growth, what's driving that. And I'll happy to comment on Biogen.

當然。凱爾，請回答關於季度環比成長的問題，推動這一成長的因素是什麼。我很樂意對 Biogen 發表評論。

Yeah. The growth, as we know in this market, less than 20% of the patients are currently being treated in the polyneuropathy space with the therapy today. So the opportunity here remains to grow this market. And that's really what we're seeing, and that's the focus that AstraZeneca and our teams have in terms of identifying newly diagnosed patients and getting those naive patients started on treatment.

是的。據我們所知，在這個市場中，目前只有不到 20% 的患者在多發性神經病變領域接受這種療法的治療。因此，這個市場仍然存在成長機會。這確實是我們所看到的，也是阿斯特捷利康和我們的團隊在識別新診斷患者並讓這些初治患者開始治療方面的重點。

What we are hearing consistently from physicians is that there is improvement in quality of life, the safety profile, and the tolerability of WAINUA is very strong and access to treatment is extremely strong. The majority of patients, as I highlighted, have a zero-dollar out-of-pocket expense. That's regardless if they are commercial or Medicare patients.

我們不斷從醫生那裡聽到的是，生活品質有所改善，安全性得到提高，WAINUA 的耐受性非常強，並且獲得治療的機會也非常大。正如我強調的，大多數患者的自付費用為零。無論他們是商業患者還是醫療保險患者。

So to be able to afford the medication on top of the profile and the ability to self-administer WAINUA at a place that they're choosing continues to resonate extremely well. So as the market expands, physicians are choosing way over some of these other treatments.

因此，能夠負擔得起檔案上的藥物，並且能夠在他們選擇的地方自行管理 WAINUA，這繼續產生非常好的反響。因此，隨著市場的擴大，醫生們正在選擇一些其他的治療方法。

Now, in the instances where there are switches from other therapies, the main driver for that really is the ability of the self-administer. We're seeing very good access and very good coverage. And if patients were able to do this on their own and not have some of the challenges associated with site of care and they can do this at a place of their choosing, physician and patients are choosing WAINUA.

現在，在從其他療法轉換過來的情況下，主要的驅動力實際上是自我管理的能力。我們看到了非常好的訪問和非常好的覆蓋。如果患者能夠自行完成治療，且不會遇到與治療地點相關的一些挑戰，並且可以在自己選擇的地方進行治療，那麼醫生和患者就會選擇 WAINUA。

So with a very highly performing medication combined with the ability to self-administer, it's really making a differentiation possible quarter-over-quarter, and we're seeing that growth due to that.

因此，透過將高性能藥物與自我管理的能力相結合，它確實使得季度環比差異化成為可能，我們看到了由此帶來的成長。

And then regarding the other part of your question, Yanan, we couldn't be more pleased to retain global rights for both of these programs. These programs that you're referring to or our alpha-synuclein program that is in development, Phase 2 development for multiple system atrophy and the [LRRK2] program, which is indicated for Parkinson's disease. We couldn't be more thrilled to retain full control of these programs.

然後關於你問題的另一部分，亞南，我們非常高興保留這兩個節目的全球權利。您所提到的這些項目或我們正在開發的 alpha-synuclein 項目、針對多系統萎縮的第 2 階段開發和 [LRRK2] 項目，該項目適用於治療帕金森氏症。我們非常高興能夠完全控制這些程序。

Just a little color to add to these, the alpha-synuclein program required a decision by Biogen to opt in on this based on partial data. It's a study that's ongoing -- and in fact, they really only had access to the low-dose cohort at the time. This was based on the contract with Biogen for this particular program. And like I said, we're thrilled to have the full control of this very important drug.

只要加入一點色彩，α-突觸核蛋白計畫就需要 Biogen 根據部分數據做出選擇。這是一項正在進行的研究——事實上，他們當時實際上只能接觸到低劑量組。這是基於與 Biogen 就該特定項目簽訂的合約。正如我所說，我們很高興能夠完全控制這種非常重要的藥物。

Going forward, the LRRK2 program was a very small study, 12 weeks of treatment. Obviously, you're not going to have any clinical data, meaningful data in a 12-week study in PD patients. The study was designed for safety and target engagement, and we're very pleased with what we saw in safety. We were very pleased with the magnitude of LRRK2 reductions we saw in the study. This drug definitely deserves to be further developed, and we're looking forward to forging a path forward for both programs, LRRK2 and alpha-synuclein.

展望未來，LRRK2 計畫是一項非常小規模的研究，治療期為 12 週。顯然，在針對 PD 患者的 12 週研究中，你不會獲得任何臨床數據和有意義的數據。這項研究的目的是確保安全和目標參與，我們對安全方面的結果非常滿意。我們對研究中看到的 LRRK2 減少的幅度感到非常滿意。這種藥物絕對值得進一步開發，我們期待為 LRRK2 和 alpha-synuclein 這兩個項目開闢前進的道路。

For alpha-synuclein, we're expecting to have data in MSA later this year. Our partnership with Biogen remains very strong, and this was essentially a R&D prioritization decision by Biogen.

對於 alpha-synuclein，我們預計今年稍後會在 MSA 中獲得數據。我們與 Biogen 的合作關係仍然非常牢固，這本質上是 Biogen 的研發優先決策。

Jay Olson, Oppenheimer.

傑伊奧爾森、奧本海默。

Congrats on all the progress. TRYNGOLZA, I think you mentioned 3,000 patients in the US. Can you just talk about how many of those patients are currently diagnosed and available for treatment? And if it's not too early, how many of those patients are on treatment or any other important metrics you could share to help track the launch of TRYNGOLZA?

恭喜你所取得的所有進步。TRYNGOLZA，我記得您提到過美國的 3,000 名患者。您能談談目前有多少患者已被診斷並可接受治療嗎？如果不是太早的話，有多少患者正在接受治療，或者您可以分享任何其他重要指標來幫助追蹤 TRYNGOLZA 的推出？

Yeah. Thanks, Jay. I can't be more excited than to kind of talk about TRYNGOLZA. Obviously, a rare disease population, we're doing a lot of work right now to number one, identify; number two diagnosed and then finally, get prescriptions written and get these patients on drug. The launch is going very, very well. When you look at the label that we received, it's a very broad label. It's a clean label. It allows the physicians to prescribe TRYNGOLZA for clinically or genetically diagnosed patients.

是的。謝謝，傑伊。我非常興奮能夠談論 TRYNGOLZA。顯然，對於罕見疾病人群，我們目前正在做大量工作，第一，識別；第二，進行診斷，最後開出處方，讓這些病人服用藥物。發布會進展非常順利。當您查看我們收到的標籤時，您會發現這是一個非常廣泛的標籤。這是一個乾淨的標籤。它允許醫生為臨床或基因診斷的患者開出 TRYNGOLZA。

We have AP in the label, demonstrating substantial reductions in acute pancreatitis and we got first-mover advantage, which allows us to develop this market and to take the patients that you're asking about and move them on to TRYNGOLZA very quickly. The feedback that we're receiving already is that all of the stakeholders, be it patients, HCPs, the advocacy groups, payers, et cetera, have been very, very positive about TRYNGOLZA. They are really excited to have a treatment option when they've never had a treatment option before.

我們的標籤中有 AP，顯示出急性胰臟炎的顯著減少，並且我們具有先發優勢，這使我們能夠開發這個市場，並迅速將您所詢問的患者轉而使用 TRYNGOLZA。我們已經收到的回饋是，所有利益相關者，無論是患者、醫療保健人員、倡導團體、付款人等等，都對 TRYNGOLZA 持非常非常積極的態度。他們非常高興能夠獲得一種從未有過的治療選擇。

In terms of execution around this plan, we had product and channel before the end of the year. we launched in 2024 and everything that we've been trying to do to be able to deliver treatment to these patients is going very well. Now of the 3,000 patients, there are several hundred right now that are currently identified and they are continuing to come in, as I mentioned, and become diagnosed formally and get prescriptions written for us. So we've got some time in terms of the momentum in the launch ramp here.

就該計劃的執行而言，我們在年底之前就有了產品和通路。我們於 2024 年啟動該項目，為了向這些患者提供治療，我們一直在努力做一切，目前進展順利。現在在 3,000 名患者中，目前已有數百人被確診，正如我所提到的那樣，他們正在繼續前來就診，接受正式診斷並為我們開出處方。因此，從這裡的發射坡道的勢頭來看，我們還有一些時間。

On the metrics, we're not disclosing too many metrics. Obviously, this is a competitive market that we're in. But what we're really encouraged by right now is the number of physicians that we've seen identifying and prescribing. So we've got a good breadth of prescribers. We are seeing a mix of specialties prescribing as well. So we have endocrinologists and cardiologists. Those that have an interest in lipids and also pancreatology, are prescribing TRYNGOLZA, which was to be expected.

關於指標，我們不會透露太多指標。顯然，我們所處的市場競爭激烈。但目前真正令我們感到鼓舞的是，我們看到許多醫生正在識別和開處方。因此，我們擁有廣泛的處方人員。我們也看到了多種專科處方的出現。所以我們有內分泌學家和心臟病學家。對脂質和胰臟病學有興趣的人正在開TRYNGOLZA，這是意料之中的事。

The other thing that we're keeping an eye on is time to prescription and how long it takes to go from prescription to actually getting the drug filled into the patient. And that's going very, very quickly, faster than we had expected here early on. And what that's telling us is that the FCS diagnosis, if it's either clinical or genetic is confirming these patients and physicians are working through the medical exception process in order to justify the prescription and getting these patients on treatment quickly.

我們關注的另一件事是開立處方的時間，以及從開立處方到實際將藥物注入患者體內需要多長時間。而且這進展非常非常快，比我們早期預期的還要快。這告訴我們，FCS 診斷（無論是臨床診斷還是遺傳診斷）都確認了這些患者患有此病，而醫生正在透過醫療例外程序來證明處方的合理性並讓這些患者迅速接受治療。

And the final thing I'll say is our Ionis Every Step program is executing very well, and that allows us to interact directly with patients and do disease education and product education and support them through the reimbursement process and patients are giving us very positive feedback about the ability to self-administer with an auto-injector on a monthly basis. And the profile of the drug is playing out very positively here in the first couple of weeks of launch.

最後我要說的是，我們的 Ionis Every Step 計劃執行得非常順利，這使我們能夠直接與患者互動，進行疾病教育和產品教育，並透過報銷流程為他們提供支持，患者對於每月使用自動注射器進行自我注射的能力給予了非常積極的反饋。在推出後的頭幾週，這款藥物的市場表現非常積極。

So thanks for asking.

感謝您的提問。

Jason Gerberry, Bank of America.

美國銀行的傑森·格貝利（Jason Gerberry）。

This is Chi on for Jason. I guess I would like to follow up TRYNGOLZA launch in FCS. Thanks for all the commentary on early launch experience so far. I'm curious, based on early launch experience, what insurance company you think are requiring in terms of documentation for reimbursement consideration?

這是 Jason 的 Chi。我想我會關注 TRYNGOLZA 在 FCS 的推出。感謝大家對迄今為止早期發布體驗的評論。我很好奇，根據早期發布經驗，您認為保險公司在報銷方面需要哪些文件？

With (technical difficulty) and one thing that we have heard is that genetic confirmation is the most straight-forward documentation to get insurance company on board, somewhat a bit of a gray area when it comes to clinical diagnosis, part of it is the lack of consensus that knows this criteria. Some of it is what insurance company, except as clinical diagnosis criteria. Can you talk about that?

由於（技術困難）以及我們聽說的一件事是，基因確認是讓保險公司接受的最直接的文件，當涉及到臨床診斷時，這有點灰色地帶，部分原因是缺乏對這一標準的共識。有些是保險公司規定的，除非是臨床診斷標準。你能談談這個嗎？

And when you talk about several hundred patients currently identify and become formally diagnosed, how many of those are getting genetically confirmed? and How many of those are getting clinically diagnosed. And if you can talk about that mix within that 3,000 patients US prevalence that you have estimated, that will be great as well.

當您談到目前已確認身份並得到正式診斷的數百名患者時，其中有多少人得到了基因確診？其中有多少人得到臨床診斷。如果您能談談您估計的 3,000 名美國患者中的這種組合，那就太好了。

Yeah. Thanks, Chi. First, let me just touch on the insurance process. The first three to six months as is typical is going to go through a medical exception process. So there are really -- there are very few plans so far that have established formal criteria to say this is what's absolutely required.

是的。謝謝，Chi。首先，讓我簡單介紹一下保險流程。通常情況下，前三到六個月要經過醫療例外程序。所以實際上——到目前為止，只有很少的計劃建立了正式的標準來表明這是絕對必要的。

So then the question becomes what is the history of the patient, what steps has the physician gone through to actually substantiate or validate that this truly is an FCS patient so that they can get the coverage by the plan and ultimately get the drug approved. The most straightforward is a genetic confirmation. I think that's the easiest one.

那麼問題就變成了患者的病史是什麼，醫生採取了哪些步驟來實際證實或確認這確實是一名 FCS 患者，以便他們能夠獲得計劃的承保，並最終獲得藥物批准。最直接的就是基因確認。我認為那是最簡單的一個。

However, we have seen both clinically and genetically diagnosed patients work through the medical exception process very efficiently with justification of outpatient triglyceride levels, the history of the patient, age of diagnosis, symptomatology, right abdominal pain, acute pancreatitis potentially in their history. So there are a lot of other things to unpack in terms of the patient presentation that ultimately will justify or qualify that patient for an approval from the health plan.

然而，我們已經看到臨床和基因診斷的患者非常有效地完成了醫療例外程序，並根據門診三酸甘油酯水平、患者病史、診斷年齡、症狀、右腹痛、可能存在的急性胰臟炎病史進行了證明。因此，在患者表現方面還有很多其他事情需要解決，這些事情最終將證明或使該患者有資格獲得健康計劃的批准。

And as I mentioned as well, we're seeing this through both the commercial and Medicare segments of the business. So what we're most optimistic about is that physicians are doing this the right way. They're identifying FCS patients, they're justifying it through one of those two means and supporting that patient through the process very quickly.

正如我剛才提到的，我們在商業和醫療保險業務兩個領域都看到了這一點。因此，我們最樂觀的是醫生們正在以正確的方式做這件事。他們正在識別 FCS 患者，並透過這兩種方式中的一種進行驗證，並在整個過程中為該患者提供快速支援。

I don't have a number that I can share with you in terms of how many have been clinically versus genetically confirmed at this point that have gone through our process. But obviously, both are being approved in terms of getting that approval. The lack of consensus we have not heard yet. Using the NAFCS scoring tool that [Dr. Hagley] published at the end of last year, seems to be a pretty straightforward tool for them to be able to use and substantiate and validate for these patients is what we're seeing based on the fact that it has been published.

目前我無法告訴大家有多少位患者已經透過我們的流程得到了臨床或基因確診。但顯然，兩項批准都已獲批准。我們還沒聽說缺乏共識。使用 NAFCS 評分工具 [Dr. Hagley] 在去年年底發表的研究似乎是一個非常簡單的工具，他們能夠使用、證實和驗證這些患者的情況，這就是我們根據它已經發表的事實所看到的。

So not to break out the mix, but other than that, I'm very encouraged early on at the coverage -- there's more to learn in terms of coverage, and then payers will be establishing criteria throughout the first six months or so, and we're working directly with the payers in order to make sure that there's a reasonable path forward for these patients to be able to have access to TRYNGOLZA.

因此，不要打破這種局面，但除此之外，我對早期的覆蓋範圍感到非常鼓舞——在覆蓋範圍方面還有更多的知識需要學習，然後付款人將在前六個月左右建立標準，我們正在直接與付款人合作，以確保這些患者能夠獲得 TRYNGOLZA 的合理途徑。

And just -- points that I'll just add to that, Chi. We're very pleased with the speed to genetic diagnosis that we're experiencing so far in one to two weeks with a genetic diagnosis (technical difficulty) go that route. And I also think it's reasonable to assume that any aspect of diagnosis that physicians are unfamiliar with today, they will become more familiar with it as time goes on. And we're driving a lot of that work, especially utilizing the North American FCS diagnosis criteria to build that familiarity or physicians. So expect that to improve as we go forward.

而且 — — 我只想補充一點，Chi。我們對基因診斷的速度感到非常滿意，到目前為止，我們只花了一到兩週的時間就完成了基因診斷（技術難度）。我還認為，可以合理地假設，醫生今天不熟悉的任何診斷方面，隨著時間的推移，他們都會變得更加熟悉。我們正在推動大量此類工作，特別是利用北美 FCS 診斷標準來建立醫生的熟悉度。因此，我們期望隨著我們前進，這種情況會有所改善。

David Lebowitz, Citi.

花旗銀行的 David Lebowitz。

This is (technical difficulty) on for David Lebowitz. I also have one on the SHTG readout. It's regarding the 12-month time point in the trial is on the primary. So we know that these SHTG patients, they're going to be coming in lower -- with much lower TG levels than in FCS and likely different rates of FCS at baseline as well. And so I'm wondering if there's no clinical consensus on how much TG lowering is actually beneficial as you said, just wondering what the reasoning was behind the selection of that 12-month time line?

對 David Lebowitz 來說，這是（技術難題）。我在 SHTG 讀數上也有一個。這是關於試驗中的 12 個月時間點的主要內容。因此，我們知道這些 SHTG 患者的 TG 水平會比 FCS 低得多，且基線時的 FCS 率也可能不同。所以我想知道，是否正如您所說，臨床上沒有就 TG 降低多少才真正有益達成共識，只是想知道選擇 12 個月時間線的理由是什麼？

And just overall, what is our understanding in this population so far as to what they need?

整體而言，我們對這個群體的需求有何了解？

So thank you for the question, and Richard follow up with anything that you want to touch on after my comments. So the primary endpoint is triglyceride lowering at six months. The full study readout is at 12 months. So the primary end point is at six months on TGs. We have a very rapid response on APOC3 reductions, substantial lowering of APOC3, substantial and rapid lowering of triglycerides based on our previous clinical data for TRYNGOLZA as well as our balanced FCS data. So we're out -- we strongly -- well powered on the primary end point.

感謝您的提問，在我發表評論之後，Richard 將跟進您想談論的任何事情。因此主要終點是六個月時三酸甘油酯的降低。完整的研究讀數是在 12 個月時得出的。因此，主要終點是 TG 的六個月。根據我們先前對TRYNGOLZA的臨床數據以及我們平衡的FCS數據，我們對APOC3的降低有非常快速的反應，APOC3大幅降低，甘油三酯大幅且快速降低。因此，我們在主要終點方面表現出色。

Regarding acute pancreatitis, as I mentioned earlier, although the rate of AP in SHTG patients is not well documented in the literature, it will be after our Phase 3 outcome. We believe that we have -- we're in a good position based on our FCS REIT data as a read-through to show clinically meaningful reductions in acute pancreatitis in this study. And that's based on what we saw in BALANCE. I think that's driving a lot of that. Don't you, Richard?

關於急性胰臟炎，正如我之前提到的，雖然文獻中沒有對 SHTG 患者的 AP 發生率進行充分記錄，但在我們的第 3 階段結果之後將會有所記載。我們相信，根據我們的 FCS REIT 數據，我們處於有利地位，可以顯示本研究中急性胰臟炎的臨床意義的減少。這是基於我們在 BALANCE 中看到的情況。我認為這在很大程度上推動了這一現象。不是嗎，理查德？

Yeah -- I would also say that we see events being adjudicated by our independent adjudication committee, and the events are accruing over the course of the study, and it's looking very good. The other thing I would say about triglycerides and clinically meaningful. That has been determined by the regulatory agencies. Certainly, the FDA has said significant risk occurs above 500 and it increases as the triglyceride levels increase.

是的——我還要說的是，我們看到事件正在由我們的獨立裁決委員會進行裁決，並且事件在研究過程中不斷累積，看起來非常好。我想說的另一件事是有關三酸甘油酯和臨床意義的。這已由監管機構決定。當然，FDA 已經表示，500 以上時風險會顯著增加，而且風險會隨著三酸甘油酯水平的增加而增加。

So by decreasing triglyceride levels by whatever the amount is, you are decreasing the risk for these patients having an acute pancreatitis. So I think that's the primary goal of the study, obviously, is to reduce their triglyceride and risk for acute pancreatitis, and we'll be able to monitor that and see the results very soon.

因此，無論降低多少三酸甘油酯水平，都可以降低這些患者患急性胰臟炎的風險。因此，我認為這顯然是這項研究的主要目標，即降低他們的三酸甘油酯和急性胰臟炎的風險，我們將能夠對此進行監測並很快看到結果。

Yeah. And let me add to that from a commercial viewpoint. Currently, patients with severely elevated triglycerides are on fibrates and fish oils and other things, statins to try to reduce their triglycerides. And cardiologists and endocrinologists are not getting these patients low enough. They need a better, more effective triglyceride-lowering treatment in order to meet the established guidelines that are already in place.

是的。讓我從商業角度補充。目前，三酸甘油酯嚴重升高的患者正在服用貝特類藥物、魚油、他汀類藥物等來降低三酸甘油酯。心臟科醫師和內分泌科醫師並沒有讓這些患者得到足夠低的治療。他們需要更好、更有效的降低三酸甘油酯的治療方法，以滿足已經制定的指導方針。

So the guidelines are there already that say you need to be below 500 in order to get out of risk as Richard was talking about from a regulatory standpoint, but most importantly, from a commercial standpoint, we know that physicians are trying to get there, and they're treating hundreds of thousands of patients already, and they're just unfortunately not able to do so because they don't have a therapy that's sufficient in order to accomplish that. And that's what we hope to be able to bring to the market shortly with an approval in SHTG with Olezaresen.

因此，現有的指導方針已經表明，為了擺脫風險，你需要低於 500，正如理查德從監管角度所說的那樣，但最重要的是，從商業角度來看，我們知道醫生正在努力達到這一點，他們已經在治療數十萬名患者，但不幸的是，他們無法這樣做，因為他們沒有足夠的治療方法來實現這一目標。我們希望能夠在獲得 Olezaresen 的 SHTG 批准後很快就將該產品推向市場。

Yeah. I think it's also important to emphasize that this, SHTG is not an asymptomatic disease. It's a very serious symptomatic disease that in addition to acute pancreatitis, these patients suffer from serious cognitive [problems] serious cognitive impairment, serious body pains, nausea, and so forth and often land in a hospital even without an AP event, because they are in such fear of having an AP event because of the body pain. And we think that, that will go a long way in the commercial success of TRYNGOLZA and SHTG.

是的。我認為還需要強調的是，SHTG 不是一種無症狀疾病。這是一種非常嚴重的症狀性疾病，除了急性胰臟炎之外，這些患者還會遭受嚴重的認知 [問題] 嚴重的認知障礙、嚴重的身體疼痛、噁心等，並且經常即使沒有發生 AP 事件也住院，因為他們非常害怕因身體疼痛而發生 AP 事件。我們認為，這對 TRYNGOLZA 和 SHTG 的商業成功將產生重大影響。

Gary Nachman, Raymond James.

加里納赫曼、雷蒙詹姆斯。

Hi. Thanks, and my congrats as well on the progress. So as you prepare for new launches for Doni in HAE and Olezaresen in SHTG, just talk about how you're scaling the commercial organization following the FCS launch. What's in place versus what you need to add, specifically in terms of reps for those other programs? And then just for the Angelman program, just what's your expectations for enrollment timing given the competitive dynamics there? Thank you.

你好。謝謝，我也祝賀你的進步。因此，當您準備在 HAE 推出 Doni 和在 SHTG 推出 Olezaresen 新產品時，只需討論一下在 FCS 發布之後如何擴大商業組織的規模。目前已存在哪些內容以及需要添加哪些內容，特別是就其他程式的代表而言？那麼對於 Angelman 計劃，考慮到那裡的競爭動態，您對招生時間的期望是什麼？謝謝。

Yeah, Gary, thanks for the question. I'll start. This is Kyle. Fortunately, with the co-commercialization on WAINUA, then we were able to build towards our FCS readiness internally. So we've got teams around commercial operations and our market access group, we have our capability with our Ionis every step patient support program. Those are the core fundamental foundational components to the commercial team that we've got in place and they're ready to go that allow us to scale accordingly whenever we add on new commercial therapies into the mix, such as Donidalorsen, later this year and SHTG to follow.

是的，加里，謝謝你的提問。我先開始。這是凱爾。幸運的是，隨著 WAINUA 的共同商業化，我們能夠在內部建立 FCS 準備。因此，我們擁有圍繞商業運營和市場准入小組的團隊，我們有能力開展 Ionis 每一步患者支援計劃。這些是我們現有的商業團隊的核心基本基礎組成部分，它們已準備就緒，每當我們添加新的商業療法（例如今年稍後的 Donidalorsen 和隨後的 SHTG）時，它們可以讓我們相應地擴大規模。

Where we're at right now, for example, with Donidalorsen is, we hired the Vice President of Sales, we will build out our Regional Director team and ultimately our customer-facing field teams from there. And that is in time and in sequence with what we are doing for the regulatory process for the anticipated approval on August 21.

例如，我們現在與 Donidalorsen 合作，聘請了銷售副總裁，我們將從那裡組成區域總監團隊，並最終組建面向客戶的現場團隊。這與我們為 8 月 21 日預計批准而進行的監管流程是同步且有序的。

So I mean, I think right now, as we build -- it's been a sequential build over time, and it's been a purposeful build and it's been an intentional build as well to make sure that we're building the right capabilities at the right time and also investing the right amount within those respective functions. When we get to SHTG, it will grow exponentially as you would expect, based on the size of the market that we'll be entering into but we'll be able to add our customer-facing and field teams at the right time.

所以我的意思是，我認為現在，隨著我們的建設——這是一個隨著時間推移而連續的建設，這是一個有目的的建設，也是一個有意的建設，以確保我們在正確的時間建設正確的能力，並在相應的功能中投入正確的金額。當我們進入 SHTG 時，它將像您預期的那樣指數級增長，這取決於我們將進入的市場規模，但我們將能夠在適當的時間增加面向客戶和現場的團隊。

And I'm just excited about the talent and the tremendous accomplishments that we have already had with our teams that are in place and the good product that we have within the commercial group overall.

我對我們現有的團隊所擁有的人才和所取得的巨大成就以及我們整個商業集團的優質產品感到非常興奮。

And Gary, on the Angelman's enrollment. So we are still well on track to initiate our Phase 3 study in the first half of this year, things are going well. (technical difficulty) we've also established internal metrics to achieve with respect to enrollment this year by our team. That sets us up for completing enrollment in 2026 next year. We do not believe that this trial will be difficult to enroll. There's pent-up demand.

還有加里 (Gary)，關於 Angelman 的入學事宜。因此，我們仍有望在今年上半年啟動第三階段研究，一切進展順利。 （技術難度）我們也制定了與今年我們的團隊招生相關的內部指標。這意味著我們將在明年完成 2026 年的招生。我們不相信這次試驗的報名會很困難。存在被壓抑的需求。

We're really encouraged by the enthusiasm by the community inquiring about our program when they will be able to enlist enrolling the study. And this is a relatively large patient population with tremendous unmet need. So that's our expectations for enrollment.

社區熱情地詢問我們的計劃，並詢問他們何時可以參與這項研究，這讓我們感到非常鼓舞。這是一個相對龐大的患者群體，還有大量未滿足的醫療需求。這就是我們對招生的期望。

Yaron Werber, TD Cowen.

亞倫·韋伯（Yaron Werber），TD Cowen。

I have a quick question also as you think about -- if you think about how do you power the Angelman Phase 3 study, I know you haven't announced before full [product] design yet, but on expressive communications. And then maybe just for Beth, as you think about revenue, as you mentioned, it's more second half weighted. Are there particular milestones we need to keep in mind that are driving that? Thank you.

我也有一個簡單的問題，如果你想知道如何推動 Angelman 第三階段研究，我知道您還沒有宣布完整的[產品]設計，而是在表達性溝通方面。然後也許只是對於貝絲來說，當你考慮收入時，正如你所提到的，它更多的是下半年的權重。我們需要牢記哪些推動這項進程的特定里程碑？謝謝。

Eugene, would you comment on the powering -- of course, Richard can jump in too.

尤金，你能評論一下動力嗎——當然，理查德也可以加入。

Yeah, sure. So as you know, our primary endpoint is expressive communication as assessed by [daily 4]. There is quite a bit of natural history data available, utilizing slightly older version of daily, but nonetheless is we are able to see and kind of make estimates on how the patients are expected to progress with regard to their ability to communicate, which is unfortunately kind of unknown primary deficiency in this population. They have little to no expressive communication.

是的，當然。如你所知，我們的主要終點是透過以下方式評估的表達性溝通[每日4]。有相當多的自然史數據可用，利用稍微舊一點的日常數據，但儘管如此，我們仍然能夠看到並估計患者在溝通能力方面預計會如何進步，不幸的是，溝通能力是該人群中一種未知的主要缺陷。他們幾乎不進行任何富有表現力的交流。

So that, combined with our Phase 2 very encouraging Phase 2 data really allowed us to make some assumptions on the treatment effect size that we're expecting to see in a placebo-controlled setting for Phase 3. As you know, we're also testing two dose levels. So again, it's a 2:1 randomization. But essentially, that and the knowledge of natural history trajectory in this patient population is what we used in our assumptions.

因此，結合我們第 2 階段非常令人鼓舞的數據，我們確實可以對我們期望在第 3 階段的安慰劑對照環境中看到的治療效果大小做出一些假設。如您所知，我們也正在測試兩種劑量等級。所以再次強調，這是一個 2:1 的隨機化。但本質上，我們在假設中運用的就是這一點以及對該患者群體的自然病史軌跡的了解。

Are both doses powered against placebo? Thank you.

這兩種劑量都與安慰劑有療效嗎？謝謝。

Yes. So our -- our goal is to see an effectiveness of both doses.

是的。因此我們的目標是觀察兩種劑量的有效性。

So the two doses are the same two doses that we studied in the Phase 2 HALO study, both of which showed really, really encouraging evidence of efficacy across all domains that we examined using all instruments, whether it be daily, for Vinland, VASCGI, et cetera, at Orca. And as a reminder, expressive communication uniformly demonstrated (technical difficulty) best outcome in our Phase 2 HALO study, which that, combined with the fact that this end point, this part of the Angelman's phenotype is the most burdensome among the families.

因此，這兩種劑量與我們在第 2 階段 HALO 研究中研究的兩種劑量相同，這兩種劑量都在我們使用所有儀器檢查的所有領域中顯示出非常令人鼓舞的療效證據，無論是每日劑量、用於 Vinland、VASCGI 等，在 Orca。需要提醒的是，在我們的第 2 階段 HALO 研究中，表達性溝通一致地表現出（技術難度）最佳結果，再加上這個終點，Angelman 表型的這一部分是各個家庭中最沉重的負擔。

That, coupled with that's where we integrated magnitude is why we settled on the expressive communication in our Phase 3 study. And that certainly was very important along with the natural history data that Eugene mentioned in the power and our powering assumptions for our study, which is what, nearly 300 patients to three cohorts in the Phase 3 study design, randomized 1:1 or 2:1 when you look at on treatment versus placebo.

這就是為什麼我們在第 3 階段的研究中決定採用表達性溝通，再加上我們整合了量級的原因。這當然非常重要，尤金在研究的功效和支撐假設中提到的自然史數據也是如此，也就是說，在第三階段的研究設計中，將近 300 名患者分成三個組，在治療組和安慰劑組隨機分配比例為 1:1 或 2:1。

Beth, you had -- there's also a question for you in the room.

貝絲，房間裡還有一個問題想問你。

Yeah. So on the -- on our revenue guidance for this year, I think just to reemphasize, really anticipate a shift to commercial revenue this year with SPINRAZA, WAINUA continuing to grow quarter-over-quarter, the addition of TRYNGOLZA revenues and in the back half of the year, the Donidalorsen in revenues assuming approval.

是的。因此，關於我們今年的收入預期，我想再次強調，我們確實預計今年商業收入將出現轉變，SPINRAZA、WAINUA 將繼續逐季增長，TRYNGOLZA 收入也將增加，而在今年下半年，Donidalorsen 的收入也將獲得批准。

As we think about R&D revenues, as you know, we have lots of different partnerships, some optemedicines in development under those partnerships. No one particular medicine has a very significant milestone. So there's no sort of large milestones that I could point to that are going to really be the cornerstone of our R&D revenue this year. A big piece of it will be the continued R&D funding we get from AstraZeneca as we conduct the cardio transform Phase 3 study.

當我們考慮研發收入時，如您所知，我們有很多不同的合作夥伴關係，在這些合作夥伴關係下，一些光學藥物正在開發中。沒有哪一種特定的藥物具有非常重要的里程碑。因此，我無法指出任何能夠真正成為我們今年研發收入基石的重大里程碑。其中很大一部分將是我們進行心臟轉換第 3 階段研究時從阿斯特捷利康獲得的持續研發資金。

We get 55% of those all-in costs reimbursed to us from AstraZeneca and that we book as revenue. And then there's a whole host of partnered programs, particularly with Biogen and others AstraZeneca that as they advance, we would anticipate seeing milestones over the course of the year with, as I said, much of that being back-end loaded.

阿斯特捷利康向我們報銷了其中 55% 的總成本，並將其記為收入。然後還有一大堆合作項目，特別是與 Biogen 和其他阿斯特捷利康公司的合作，隨著它們的進展，我們預計在今年內會看到里程碑，正如我所說的，其中大部分都是後端加載的。

Thanks, Beth. Thank you, Yaron. We have time for one more question.

謝謝，貝絲。謝謝你，亞龍。我們還有時間再回答一個問題。

Myles Minter, William Blair.

邁爾斯·明特、威廉·布萊爾。

This is Jake on for Myles. A couple for you. The first is on SHTG. We're wondering if you get some color on your plans for potential ex-US launch and whether you would be comfortable going in alone or whether you're looking to find a partner in that as you did for Donidalorsen.

這是傑克 (Jake) 取代邁爾斯 (Myles)。給你一對。第一個是關於SHTG。我們想知道您是否透露了一些有關在美國以外地區上市的潛在計劃，以及您是否願意獨自開展業務，或者您是否希望尋找合作夥伴，就像您對 Donidalorsen 所做的那樣。

And then second, we wanted any updates you have on the next-generation (technical difficulty) targeting asset with Novartis and whether clinical development or clinical entry is contingent on a positive readout from the HORIZON study. Thank you.

其次，我們希望您能了解與諾華合作的下一代（技術難度）靶向資產的最新進展，以及臨床開發或臨床進入是否取決於 HORIZON 研究的積極結果。謝謝。

Thanks, Jake. So before we get into ex-US SHTG, let me start with FCS. For both FCS and then, subsequently, SHTG, we're planning to secure a US commercial partner like we did for Donidalorsen Morrison. Discussions are progressing very nicely. And it's consistent with our commercial strategy that we laid out five years ago that initially, we will focus on the US market and secure OUS commercial partners programs we bring to the market ourselves.

謝謝，傑克。因此，在我們討論前美國 SHTG 之前，讓我先從 FCS 開始。對於 FCS 以及隨後的 SHTG，我們都計劃尋找一個美國商業夥伴，就像我們為 Donidalorsen Morrison 所做的那樣。討論進展非常順利。這與我們五年前製定的商業策略一致，最初我們將專注於美國市場，並確保我們自己推向市場的 OUS 商業合作夥伴計劃。

And that will evolve, and that will change in due time. And we're working on that now, where we will emerge from the US market. But today, we will secure an OUS partner to commercialize TRYNGOLZA, for SCS and HT outside the US.

這將會發展，並且會在適當的時候發生改變。我們現在正在努力實現這一目標，以便走出美國市場。但今天，我們將確保有一個 OUS 合作夥伴將 TRYNGOLZA 商業化，用於美國以外的 SCS 和 HT。

I really do not have much to offer with respect to whether or not Novartis will wait for the (technical difficulty) readout before initiating clinical testing for our follow-on molecule that we provided to them and they licensed last year. It's a great (technical difficulty) but the follow-on really does look like a best-in-class molecule with respect compared to everything that's been publicly disclosed to date.

關於諾華是否會等待（技術難度）讀數後再啟動我們提供給他們並於去年獲得許可的後續分子的臨床試驗，我真的沒有太多可以提供的資訊。這是一個很大的（技術難題），但與迄今為止公開披露的所有產品相比，後續產品確實看起來是同類產品中最好的。

I don't think it matters much on the timing because (technical difficulty) isn't that far away first half of next year. And the follow-on molecule for Lp(a) CBD that we provided is starting IND-supporting toxicology studies now. So I think it has to run its course through there and then prepare for clinical testing. So that's really a question more specifically that's best suited for Novartis. But thank you.

我認為時間上並不重要，因為（技術難度）距離明年上半年不遠。我們提供的 Lp(a) CBD 後續分子現已開始 IND 支持的毒理學研究。所以我認為它必須在那裡完成，然後準備進行臨床測試。所以這確實是一個更具體地最適合諾華的問題。但謝謝你。

Thank you for the questions, and thanks to everybody who joined us today and participating in our call. We're really looking forward to an outstanding year ahead and sharing our progress along the way with you. But until then, thanks again, and everybody, have a great day.

感謝您的提問，也感謝今天加入我們並參與電話會議的每個人。我們真誠地期待未來的一年能夠取得輝煌的成就，並與您分享我們一路以來的進步。但在此之前，我要再次感謝大家，祝福大家有美好的一天。

Goodbye. The conference has now concluded. Thank you for your participation. You may now disconnect your lines.

再見。會議現已結束。感謝您的參與。現在您可以斷開線路了。