Ionis Pharmaceuticals Inc (IONS) 2024 Q1 法說會逐字稿

Good morning, and welcome to Ionis' First Quarter 2024 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin.

早安，歡迎參加 Ionis 2024 年第一季財務業績電話會議。提醒一下，此通話正在錄音。此時，我想將電話轉交給投資者關係高級副總裁韋德沃克 (Wade Walke) 主持。請開始。

Thank you, Keith. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release and the related financial tables we will be discussing today, including the 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've also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer; Kyle Jenne, Chief Global Product Strategy Officer; and Beth Hougen, Chief Financial Officer. Richard Geary, our Chief Development Officer; Eric Swayze, Executive Vice President of Research; Eugene Schneider, Chief Clinical Development Officer; and Jonathan Birchall, Chief Commercial Officer, will also join us for the Q&A portion of the call.

謝謝你，基斯。在我們開始之前，我鼓勵大家造訪 Ionis 網站的投資者部分，查看新聞稿和我們今天將討論的相關財務表格，包括 GAAP 與非 GAAP 財務數據的調整表。我們相信非公認會計原則財務表現更好地代表了我們業務的經濟狀況以及我們管理業務的方式。我們也在我們的網站上發布了今天電話會議附帶的幻燈片。今天早上與我在一起的是首席執行官布雷特·莫尼亞 (Brett Monia)； Kyle Jenne，首席全球產品策略長；和財務長 Beth Hougen。 Richard Geary，我們的首席開發長； Eric Swayze，研究執行副總裁；施奈德 (Eugene Schneider)，首席臨床開發長；首席商務官 Jonathan Birchall 也將參加我們電話會議的問答部分。

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

我想提請您注意投影片 3，其中包含我們的前瞻性語言聲明。在這次電話會議中，我們將根據我們目前的期望和信念做出前瞻性聲明。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 提交的文件中包含的風險因素以了解更多詳細資訊。這樣，我就把電話轉給布雷特。

Thanks, Wade. Good morning, everybody, and thanks for joining us today. 2024 is off to a great start for Ionis as we continue to execute on our vision to bring better futures to people with serious diseases. With the recent U.S. launch of our first Ionis co-branded medicine, WAINUA, Ionis discovered medicines are now reaching even more people living with serious diseases. And we're on the cusp of independently delivering a steady stream of new transformational medicines to patients beginning with our planned launches of olezarsen and donidalorsen. By uniting groundbreaking science and technology with a relentless passion to discover, develop and deliver new transformational medicines to people in need, we believe Ionis is well positioned to unlock next level value.

謝謝，韋德。大家早安，感謝您今天加入我們。 2024 年對 Ionis 來說是一個好的開端，我們將繼續執行我們的願景，為患有嚴重疾病的人帶來更美好的未來。隨著我們的第一個 Ionis 聯合品牌藥物 WAINUA 最近在美國上市，Ionis 發現藥物現在正在惠及更多患有嚴重疾病的人。從我們計劃推出的 olezarsen 和 donidalorsen 開始，我們正處於獨立向患者提供源源不斷的新轉化藥物的風口浪尖。透過將突破性的科學技術與發現、開發並向有需要的人們提供新的轉化藥物的不懈熱情相結合，我們相信 Ionis 處於有利地位，可以釋放更高水平的價值。

Renewal launch for ATTR polyneuropathy is on track in the U.S. with our co-commercialization partner, AstraZeneca. While it's early days in the launch, we're pleased with the collective team's progress. The approval decisions in Europe and Canada expected later this year and additional regulatory submissions already completed, we expect to soon bring WAINUA to even more patients around the globe.

ATTR 多發性神經病變的續訂上市工作正在與我們的商業化合作夥伴阿斯特捷利康一起在美國順利進行。雖然現在還處於發布的早期階段，但我們對整個團隊的進展感到滿意。歐洲和加拿大預計將於今年稍後做出批准決定，並且其他監管提交也已完成，我們預計很快就會將 WAINUA 帶給全球更多患者。

And based on we know a strong efficacy profile, together with the freedom of simple, at-home monthly self-administration, we believe WAINUA is poised to become the therapy of choice for ATTR patients.

基於我們所知的強大療效，以及每月在家中簡單自我給藥的自由，我們相信 WAINUA 有望成為 ATTR 患者的首選治療方法。

We continue to advance our cardio transform study of WAINUA for the larger ATTR cardiomyopathy indication with the potential for data as early as 2025. As the largest study ever conducted in this patient population, the landmark cardio transform trial is on track to deliver the most comprehensive and robust data set. We expect the data we generate will enable physicians and payers to make informed treatment decisions in this dynamic treatment landscape. And with AstraZeneca's global leadership in the commercialization of novel cardiovascular treatments, coupled with our leadership in TTR amyloidosis, we believe we are well positioned to bring WAINUA to patients in the U.S. and around the globe.

我們繼續推進WAINUA 的心臟轉化研究，以適應更大的ATTR 心肌病變適應症，並有可能最早在2025 年獲得數據。轉化試驗有望提供最全面的研究和強大的數據集。我們期望我們產生的數據將使醫生和付款人能夠在這個動態的治療環境中做出明智的治療決策。憑藉阿斯特捷利康在新型心血管治療商業化方面的全球領先地位，加上我們在 TTR 澱粉樣變性領域的領先地位，我們相信我們有能力將 WAINUA 帶給美國和全球的患者。

Our next planned launches for olezarsen in FCS, a severe rare disease with no approved treatments in the U.S. Olezarsen is also in development for the much larger SHTG patient population with more than 3 million estimated patients in the U.S. alone. By addressing these 2 indications, olezarsen represents one of the most meaningful opportunities in our pipeline today. Last month, we presented and published very positive Phase III results for olezarsen in FCS.

我們計劃在 FCS 中推出 olezarsen，這是一種嚴重的罕見疾病，在美國尚未獲得批准的治療方法。透過解決這兩個適應症，olezarsen 代表了我們當今管道中最有意義的機會之一。上個月，我們展示並發表了 olezarsen 在 FCS 中的非常積極的 III 期結果。

In the Phase III BALANCE study in patients with FCS, olezarsen showed substantial triglyceride reductions. Importantly, for patients, physicians and payers, olezarsen also demonstrated substantial and clinically meaningful reductions in attacks of acute pancreatitis as well as a favorable safety and tolerability profile.

在針對 FCS 患者的 III 期 BALANCE 研究中，olezarsen 顯示三酸甘油酯顯著降低。重要的是，對於患者、醫生和付款人來說，olezarsen 也證明了急性胰臟炎發作的顯著且具有臨床意義的減少，以及良好的安全性和耐受性。

BALANCE is truly groundbreaking as it is the first trial to demonstrate that reducing triglycerides can reduce the incidence of acute pancreatitis. In addition to the Phase III BALANCE study, we presented and published positive data from the BRIDGE study in patients with high cardiovascular risk and moderately elevated triglycerides. In this study, 93% of patients with moderately elevated triglycerides at baseline achieved normal triglyceride levels, reinforcing our confidence in olezarsen's potential for success in FCS and SHTG.

BALANCE 確實具有開創性，因為它是第一個證明降低三酸甘油酯可以降低急性胰臟炎發生率的試驗。除了 III 期 BALANCE 研究之外，我們還介紹並發表了針對心血管風險高且三酸甘油酯中度升高的患者的 BRIDGE 研究的積極數據。在這項研究中，93% 基線時三酸甘油酯中度升高的患者達到了正常三酸甘油酯水平，這增強了我們對 olezarsen 在 FCS 和 SHTG 方面取得成功的潛力的信心。

I'm pleased to report that we submitted the NDA for olezarsen and FCS with the FDA last month putting Ionis one step closer to our first independent launch. Assuming priority review, we're on track for a potential U.S. approval by the end of this year. We're also preparing to file for regulatory approval in Europe later this year.

我很高興地報告，我們上個月向 FDA 提交了 olezarsen 和 FCS 的 NDA，這使 Ionis 距離我們的首次獨立上市又近了一步。假設優先審查，我們預計在今年底獲得美國的批准。我們也準備在今年稍後向歐洲監管機構申請批准。

Olezarsen is poised to be the first approved medicine for FCS in the United States and our strong results to date further increase our confidence that if approved, the olezarsen could be the standard of care for both FCS and SHTG. Our ongoing Phase III studies for SHTG continue to progress well.

Olezarsen 預計將成為美國首個獲準用於 FCS 的藥物，迄今為止我們取得的強勁成果進一步增強了我們的信心：如果獲得批准，olezarsen 可能成為 FCS 和 SHTG 的治療標準。我們正在進行的 SHTG III 期研究繼續進展順利。

I'm pleased to also report that we have now completed enrollment in 2 of the 3 Phase III studies in SHTG, CORE in ESSENCE. With our remaining study CORE II expected to complete enrollment very soon. This puts us on track for SHCG Phase III data mid next year.

我還很高興地報告，我們現在已完成 SHTG 的 3 項 III 期研究中的 2 項，以及 ESSENCE 的 CORE。根據我們剩餘的研究，CORE II 預計很快就會完成註冊。這使我們有望在明年年中獲得 SHCG 第三期數據。

Following closely behind olezarsen and FCS is our next expected commercial launch with donidalorsen, our potentially first-in-class prophylactic treatment for hereditary angioedema. Early in the first quarter, we reported positive top line data from the Phase III OASIS-HAE study. Donidalorsen met the primary endpoint with a statistically significant reduction in the rate of HAE attacks in patients treated every 4 weeks and patients treated every 8 weeks.

緊隨 olezarsen 和 FCS 之後，我們預計將推出下一個與 donidalorsen 商業化的產品，這是我們潛在的一流遺傳性血管水腫預防性治療藥物。第一季度初，我們報告了第三階段 OASIS-HAE 研究的積極頂線數據。 Donidalorsen 達到了主要終點，每 4 週接受治療的患者和每 8 週接受治療的患者的 HAE 發作率顯著降低，具有統計學意義。

The study also met other important secondary endpoints and had a favorable safety and tolerability profile. We're looking forward to presenting data from the Phase III OASIS and OASIS-Plus studies in the late-breaker oral session at the European Academy of Allergy and Clinical Immunology Congress, the EAACI Congress at the end of this month. OASIS-Plus includes an open-label cohort for patients rolling over from the Phase III study and a separate cohort that we refer to as the Switch study. Switch study is a first-of-its-kind study evaluating patients who have transitioned to donidalorsen from other prophylactic HAE medications.

該研究還達到了其他重要的次要終點，並具有良好的安全性和耐受性。我們期待在本月底舉行的歐洲過敏和臨床免疫學會大會（EAACI 大會）的後期口頭會議上介紹 OASIS 和 OASIS-Plus III 期研究的數據。 OASIS-Plus 包括一個針對從 III 期研究轉入的患者的開放標籤隊列和一個我們稱為 Switch 研究的單獨隊列。 Switch 研究是一項首個評估從其他預防性 HAE 藥物轉向多尼達洛森的患者的研究。

We plan to hold a webcast in conjunction with the clinical data presentation at EAACI. With these positive data in hand, we're working to finalize our regulatory submission to the FDA, which will include both 4-week and 8-week dosing options. Additionally, our European commercial partner, Otsuka, is preparing to file for marketing approval in Europe. Based on our Phase III results and the long-term efficacy and favorable safety data seen in the ongoing Phase II open-label extension study, we believe donidalorsen, If approved, could evolve the HAE prophylactic treatment paradigm. Beyond our near-term opportunities, we have made important progress in advancing additional areas of our rich pipeline, including our leading neurology franchise.

我們計劃在 EAACI 上結合臨床數據展示舉辦網路廣播。有了這些積極的數據，我們正在努力完成向 FDA 提交的監管申請，其中包括 4 週和 8 週的給藥方案。此外，我們的歐洲商業夥伴大塚正準備在歐洲申請上市許可。根據我們的 III 期結果以及正在進行的 II 期開放標籤擴展研究中看到的長期療效和有利的安全性數據，我們相信 Donidalorsen 如果獲得批准，可以發展 HAE 預防性治療範例。除了我們的近期機會之外，我們在推進我們豐富的產品線的其他領域方面也取得了重要進展，包括我們領先的神經病學特許經營權。

Our leading neurology pipeline today includes 12 medicines and we remain on track to have 6 wholly owned neurology medicines in clinical development by the end of this year. We just recently added one of these medicines to our neurology pipeline with the initiation of the Orbit study, a first inpatient study for ION356, targeting PLP1 for PMD, a rare X-linked recessive leukodystrophy. In addition to our neurology franchise, we also reported positive Phase II data for ION224, our medicine targeting DGAT2 in development to treat metabolic dysfunction-associated steatohepatitis or MASH.

目前，我們領先的神經病學產品線包括 12 種藥物，我們仍有望在今年年底前將 6 種全資擁有的神經病學藥物投入臨床開發。最近，隨著Orbit 研究的啟動，我們剛剛將其中一種藥物添加到我們的神經病學產品線中，這是ION356 的第一項住院研究，針對PLP1 治療PMD（一種罕見的X 連鎖隱性腦白質營養不良）。除了我們的神經病學專營權之外，我們還報告了 ION224 的積極 II 期數據，這是我們正在開發的針對 DGAT2 的藥物，用於治療代謝功能障礙相關的脂肪性肝炎或 MASH。

These data provided clinical evidence demonstrating for the first time that targeting DGAT2 to reduce hepatic fat production, can improve MASH histological endpoints, including improving fibrosis.

這些數據提供的臨床證據首次證明，以 DGAT2 為標靶來減少肝脂肪產生，可以改善 MASH 組織學終點，包括改善纖維化。

Study minutes primary and key secondary endpoints, while also demonstrating the ION224 was safe and well tolerated. These results support advancing this program to the next stage of development. This program is outside of our key focus areas, we intend to license in ION224 to maximize its value for the millions of people living with MASH today.

研究記錄了主要和關鍵的次要終點，同時也證明了 ION224 的安全性和耐受性。這些結果支持將該計劃推進到下一發展階段。該計劃不屬於我們的重點領域，我們打算在 ION224 中獲得許可，以最大限度地提高其對當今數百萬 MASH 患者的價值。

Our accomplishments this year and the investments we're making over the next few years move us closer to achieving our goal of bringing a steady cadence of new transformational medicines to patients for years to come and generating next-level value for all Ionis stakeholders. With that, I'd like to introduce Kyle Jenne, who recently rejoined Ionis to lead our global product strategy and spearhead our next phase of growth.

我們今年的成就以及未來幾年的投資使我們更接近實現我們的目標，即在未來幾年為患者提供穩定的新型轉化藥物，並為所有 Ionis 利益相關者創造更高水平的價值。在此，我想介紹一下 Kyle Jenne，他最近重新加入 Ionis，領導我們的全球產品策略並引領我們下一階段的成長。

With his extensive commercial and biopharma leadership experience and familiarity with our programs, Kyle hit the ground running and has already seamlessly added value to our commercial and medical organizations during this very important time.

憑藉豐富的商業和生物製藥領導經驗以及對我們項目的熟悉，凱爾一馬當先，並在這個非常重要的時刻為我們的商業和醫療組織無縫地增加了價值。

After Kyle provides a brief update on the WAINUA launch and the status of our go-to-market activities for olezarsen and donidalorsen, that overview our financials, including our first quarter results.

Kyle 簡要介紹了 WAINUA 的推出以及我們 olezarsen 和 donidalorsen 的上市活動的狀態，概述了我們的財務狀況，包括我們第一季的業績。

And then I'll wrap things up before taking your questions. And with that, over to Kyle.

然後我會在回答你們的問題之前先把事情總結一下。就這樣，轉向凱爾。

Thank you, Brett. I'm excited to be back at Ionis, working with a highly accomplished team with deep commercial experience who are ready to bring our important medicines to patients in need. Over the last 4 years, we have approached our commercial build in a thoughtful and purposeful manner focusing on hiring the right roles at the right time. We now have a team in place executing on the co-commercialization of WAINUA with AstraZeneca and preparing for the upcoming independent launches of olezarsen and donidalorsen.

謝謝你，布雷特。我很高興回到 Ionis，與一支擁有豐富商業經驗、卓有成效的團隊合作，他們準備將我們的重要藥物帶給有需要的患者。在過去的四年裡，我們以深思熟慮和有目的地的方式進行我們的商業建設，重點是在正確的時間僱用正確的角色。我們現在有一個團隊負責與阿斯特捷利康共同商業化 WAINUA，並為即將推出的 olezarsen 和 donidalorsen 做準備。

The capabilities we've established include medical affairs as well as commercial expertise and marketing, market access, patient services, commercial operations and sales. We also recently appointed the first Ionis National Sales Director to the team and are beginning to hire our field organization in preparation for the FCS launch. .

我們建立的能力包括醫療事務以及商業專業知識和行銷、市場准入、病患服務、商業營運和銷售。我們最近也任命了該團隊的第一位 Ionis 全國銷售總監，並開始聘請我們的現場組織，為 FCS 的推出做準備。 。

Following the U.S. approval at the end of last year for WAINUA, We started bringing this important medicine to patients in the first quarter. As Brett noted, WAINUA represents Ionis' first co-branded medicine and is poised to be the treatment of choice for hereditary ATTR polyneuropathy based on its efficacy and safety profile and the ability to self-administer.

繼去年底美國批准 WAINUA 後，我們在第一季開始將這種重要的藥物帶給患者。正如 Brett 指出的那樣，WAINUA 代表了 Ionis 的第一個聯合品牌藥物，並且基於其功效、安全性以及自我給藥的能力，有望成為遺傳性 ATTR 多發性神經病變的首選治療方法。

With an estimated 40,000 patients worldwide and fewer than 20% of patients on an approved treatment, patients with hereditary ATTR polyneuropathy remain significantly underdiagnosed and largely underserved. As a result, a high unmet need remains that we and AstraZeneca are uniquely positioned to address.

全球估計有 40,000 名患者，但只有不到 20% 的患者接受了核准的治療，遺傳性 ATTR 多發性神經病變患者的診斷率和服務水準仍然嚴重不足。因此，我們和阿斯特捷利康擁有獨特的優勢來解決大量未滿足的需求。

Overall, the launch is tracking to plan based on predefined launch performance indicators. We are seeing good uptake among patients, some of whom are new to this class of medicine and some of whom have switched from other brands. The cross-functional teams that Ionis and AstraZeneca are working well together and the early phase of the launch is benefiting from the expertise of both organizations.

總體而言，此次發布正在根據預先定義的發布績效指標進行追蹤計畫。我們看到患者的使用情況良好，其中一些是此類藥物的新手，其他人已經從其他品牌轉向了該藥物。 Ionis 和阿斯特捷利康的跨職能團隊合作良好，發布的早期階段受益於兩個組織的專業知識。

Under our co-commercialization partnership with AstraZeneca, we have a one customer team approach that's designed to drive broad uptake. We are leading the patient support aspect of the launch, while AstraZeneca is leading the other customer-facing commercial and medical teams. The combined team is working together seamlessly with a shared goal to make WAINUA the preferred choice for newly diagnosed patients with ATTR polyneuropathy. Prescribers and patients are recognizing WAINUA's strong clinical profile and value the ability to easily self-administer WAINUA from their home. We are pleased with the initial phase of the launch and expect to continue reaching a growing number of patients as more prescribers learn about the value that we knew it brings.

根據我們與阿斯特捷利康的共同商業化合作夥伴關係，我們採用了單一客戶團隊方法，旨在推動廣泛採用。我們正在領導此次發布的患者支援方面，而阿斯特捷利康則領導其他面向客戶的商業和醫療團隊。合併後的團隊正在無縫地合作，以實現共同的目標，使 WAINUA 成為新診斷的 ATTR 多發性神經病變患者的首選。處方者和患者正在認識到 WAINUA 強大的臨床特徵，並重視在家中輕鬆自我管理 WAINUA 的能力。我們對推出的初始階段感到滿意，並希望隨著更多的處方者了解我們所知道的它帶來的價值，我們將繼續接觸到越來越多的患者。

Establishing our co-commercialization partnership with AstraZeneca for WAINUA was an important step to efficiently prepare Ionis for our upcoming independent commercial launches of olezarsen and donidalorsen. We are developing olezarsen for 2 indications: the rare FCS indication and the broader SHTG indication with anticipated first mover advantage in both settings. We expect the approval of olezarsen for FCS by the end of this year, assuming priority review.

與阿斯特捷利康為 WAINUA 建立聯合商業化合作夥伴關係是為我們即將推出的 olezarsen 和 donidalorsen 獨立商業化推出高效準備 Ionis 的重要一步。我們正在開發 2 個適應症的 olezarsen：罕見的 FCS 適應症和更廣泛的 SHTG 適應症，在這兩種情況下都具有預期的先發優勢。假設優先審查，我們預計 olezarsen 用於 FCS 的治療將在今年年底獲得批准。

Last month, we presented the positive FCS Phase III data, which were simultaneously published in the New England Journal of Medicine. These data generated very positive feedback from key opinion leaders. They were especially impressed with the reduction in acute pancreatitis attacks. Additionally, they were encouraged that the reductions in triglycerides translated to substantial reductions in hospitalizations and inpatient hospital days supporting the potential for olezarsen to make a profound difference in the lives of people with FCS and we expect that these data will also be very important in securing access with payers.

上個月，我們公佈了FCS III期陽性數據，同時發表在《新英格蘭醫學雜誌》。這些數據得到了關鍵意見領袖的非常正面的回饋。他們對急性胰臟炎發作的減少印象尤其深刻。此外，令他們感到鼓舞的是，三酸甘油酯的降低轉化為住院治療和住院天數的大幅減少，這支持了olezarsen 對FCS 患者的生活產生深遠影響的潛力，我們預計這些數據對於確保FCS 患者的生活也非常重要。

And I'm happy to report that we recently initiated an expanded access program for olezarsen in the U.S., enabling patients to have access to treatment ahead of potential approval. Our launch preparations are well underway for FCS. We are building for this launch using the substantial capabilities we've already established for WAINUA. Our medical affairs team has been out connecting with physicians for nearly 3 years, improving disease awareness and urgency around identifying and diagnosing FCS through disease education. We have conducted extensive market research to identify the physicians most likely to diagnose FCS and treat patients with olezarsen. These are the physicians that we will focus on initially after launch. Additionally, we aim to build meaningful relationships with patients and health care professionals through a differentiating omnichannel strategy. And by leveraging our omnichannel capabilities, we expect to efficiently broaden our access to a larger base of treating physicians and accelerate the patient journey process.

我很高興地向大家報告，我們最近在美國啟動了 olezarsen 的擴大准入計劃，使患者能夠在獲得批准之前獲得治療。我們的 FCS 發布準備工作正在順利進行中。我們正在利用我們已經為 WAINUA 建立的大量功能來為本次發布做好準備。我們的醫療事務團隊已經與醫生聯繫了近 3 年，透過疾病教育提高了疾病意識和識別和診斷 FCS 的緊迫性。我們進行了廣泛的市場研究，以確定最有可能診斷 FCS 並使用 olezarsen 治療患者的醫生。這些是我們在推出後最初關注的醫生。此外，我們的目標是透過差異化的全通路策略與患者和醫療保健專業人員建立有意義的關係。透過利用我們的全通路能力，我們希望有效地擴大我們接觸到更大的治療醫生群體的機會，並加速患者的治療過程。

We are building a world-class patient and caregiver support team to help patients through every step of their treatment journey. This includes helping patients to understand their disease, be informed about their medication and provide the appropriate support for access and reimbursement programs. The goal of this team is to provide a seamless customer experience that helps patients initiate treatment and remain on therapy long term. With our national sales director in place, we plan to hire our customer-facing account champion team leading up to the launch. The team will be sized appropriately for this rare disease population and focus on FCS disease education product information and reimbursement and access once approved.

我們正在建立一支世界一流的患者和護理人員支援團隊，以幫助患者完成治療過程的每一步。這包括幫助患者了解他們的疾病，了解他們的藥物治療並為獲得和報銷計劃提供適當的支持。團隊的目標是提供無縫的客戶體驗，幫助患者開始治療並長期維持治療。隨著我們的全國銷售總監就位，我們計劃在推出之前聘請面向客戶的客戶冠軍團隊。該團隊的規模將根據這一罕見疾病人群進行適當調整，並在獲得批准後重點關注 FCS 疾病教育產品資訊以及報銷和獲取。

In addition, we are also expanding our market access capabilities with trade and distribution and account management teams to interact directly with payers, integrated delivery networks, and other essential reimbursement channels. And as we prepare for the SHTG indication, we plan to further scale all of these capabilities to realize the full potential of olezarsen.

此外，我們還透過貿易、分銷和帳戶管理團隊擴大我們的市場准入能力，以直接與付款人、綜合交付網絡和其他重要報銷管道進行互動。當我們為 SHTG 適應症做準備時，我們計劃進一步擴展所有這些功能，以充分發揮 olezarsen 的潛力。

Donidalorsen for the prophylactic treatment of HAE is our next planned launch after olezarsen. And just like olezarsen, we recently initiated an expanded access program for donidalorsen in the U.S. so that patients have access to treatment ahead of potential approval. HAE is an attractive opportunity for Ionis. There are more than 20,000 patients with HAE in the U.S. and Europe. Within the U.S., prophylactic treatment is well accepted by patients and physicians.

用於預防性治療 HAE 的 Donidalorsen 是我們繼 olezarsen 後計劃推出的下一個產品。就像 olezarsen 一樣，我們最近在美國啟動了 donidalorsen 的擴大准入計劃，以便患者能夠在獲得批准之前獲得治療。 HAE 對 Ionis 來說是一個有吸引力的機會。美國和歐洲有超過 20,000 名 HAE 患者。在美國，預防性治療被患者和醫生廣泛接受。

We know where this concentrated base of treating physicians are, and they are primarily located in large centers of excellence. Many patients with HAE are unsatisfied with their current treatments and looking for an option that reduces frequency and severity of attacks with attractive tolerability and convenience. We plan to build an efficiently sized field team to reach prescribers and support the needs of these patients.

我們知道治療醫生的集中基地在哪裡，他們主要位於大型卓越中心。許多 HAE 患者對目前的治療並不滿意，正在尋找一種能夠降低發作頻率和嚴重程度、且具有良好耐受性和便利性的選擇。我們計劃建立一支規模有效的現場團隊，以接觸處方者並支持這些患者的需求。

Based on the Phase III results, we anticipate donidalorsen could evolve the HAE prophylactic treatment paradigm and address the unmet needs of patients. Patients tell us that they would welcome a medicine that provides strong efficacy along with an attractive tolerability and administration profile. And we believe that donidalorsen could be that medicine. Donidalorsen has the potential to extend dosing at intervals to every 4 to 8 weeks using an auto-injector.

根據 III 期結果，我們預計多尼達洛森可以發展 HAE 預防性治療範式並解決患者未滿足的需求。患者告訴我們，他們會歡迎一種具有強大功效以及有吸引力的耐受性和給藥方式的藥物。我們相信多尼達洛森可以成為這種藥物。 Donidalorsen 有可能使用自動注射器將給藥間隔延長至每 4 至 8 週一次。

The current standard of care is dosed every 2 to 4 weeks using a vial and syringe. We're looking forward to the upcoming Phase III OASIS-HAE and OASIS-Plus data presentations for donidalorsen at the end of this month.

目前的照護標準是使用小瓶和注射器每 2 至 4 週給藥一次。我們期待著本月底即將為 donidalorsen 提供的第三階段 OASIS-HAE 和 OASIS-Plus 資料演示。

The OASIS-plus presentations will include open-label extension data in patients treated up to 1.5 years. In addition, we will be presenting data from the first-of-its-kind switch study, which we believe will be very informative for physicians and patients for 2 important reasons.

OASIS-plus 演示將包括治療長達 1.5 年的患者的開放標籤擴展資料。此外，我們將展示第一個此類轉換研究的數據，我們相信該研究將為醫生和患者提供非常豐富的信息，原因有二。

First, we expect these data will assist physicians in understanding how to manage patients effectively when switching to donidalorsen. And second, these data will include a patient preference survey answering the important question, "Do you prefer donidalorsen or -- or your prior treatment?"

首先，我們期望這些數據將幫助醫生了解在轉用多尼達洛森治療時如何有效地管理患者。其次，這些數據將包括一項患者偏好調查，回答一個重要問題：“您更喜歡多尼達洛森還是——或者您之前的治療？”

With positive Phase III and long-term Phase II OLE data, together with every 4- or 8-week self-administration, we believe donidalorsen could be an important new prophylactic treatment for HFE if approved. I'm pleased to say that we are right where we should be in preparing for our upcoming launches. Our commercial infrastructure is in place, and we will be ready to begin delivering our medicines to people in need as these new therapies come to the market. This is a very exciting time for Ionis, and I'm proud to be a part of it. Now over to Beth.

憑藉積極的 III 期和長期 II 期 OLE 數據，再加上每 4 週或 8 週的自我給藥，我們相信，如果獲得批准，donidalorsen 可能成為 HFE 的一種重要的新型預防性治療方法。我很高興地說，我們為即將推出的產品做好了準備。我們的商業基礎設施已經到位，隨著這些新療法進入市場，我們將準備好開始向有需要的人提供我們的藥物。對於 Ionis 來說，這是一個非常令人興奮的時刻，我很自豪能成為其中的一部分。現在輪到貝絲。

Thank you, Kyle, and I couldn't agree more. This really is an exciting time at Ionis as we launched our first co-commercialized medicine. And we are closer than ever to bringing a steady cadence of our own medicines to the market.

謝謝你，凱爾，我完全同意。這對 Ionis 來說確實是一個令人興奮的時刻，因為我們推出了第一個共同商業化的藥物。我們比以往任何時候都更接近將我們自己的藥物穩定地推向市場。

Our first quarter financial results reflect our progress toward achieving this important goal. We earned revenues of $119 million in the first quarter. Half of our revenue was from commercial products comprised primarily of substantial SPINRAZA royalties. Our commercial revenue also included the addition of royalties from the U.S. launch of WAINUA. The other half of our revenue was from programs under our R&D collaborations, reflecting the value that our pipeline and technology continued to generate. Our non-GAAP operating expenses modestly increased year-over-year as we continue to invest our capital resources toward growth opportunities.

我們第一季的財務表現反映了我們在實現這一重要目標方面取得的進展。第一季我們的營收為 1.19 億美元。我們一半的收入來自商業產品，主要包括大量的 SPINRAZA 特許權使用費。我們的商業收入還包括在美國推出 WAINUA 所獲得的特許權使用費。我們的另一半收入來自我們的研發合作項目，反映了我們的管道和技術持續產生的價值。隨著我們繼續將資本資源投資於成長機會，我們的非公認會計準則營運費用較去年同期小幅成長。

As expected, our SG&A expenses increased as we and AstraZeneca initiated the launch of WAINUA in the U.S. and as we made investments ahead of the olezarsen and donidalorsen launches. Our R&D expenses also increased due to the timing of our late-stage program activities. We expect our R&D expenses to stabilize this year as several late-stage studies have ended. And we ended the first quarter with cash and investments of $2.2 billion.

正如預期的那樣，由於我們和阿斯特捷利康在美國啟動了 WAINUA 的上市，以及我們在 olezarsen 和 donidalorsen 上市之前進行了投資，我們的 SG&A 費用有所增加。由於後期專案活動的時間安排，我們的研發費用也有所增加。隨著幾項後期研究的結束，我們預計今年的研發費用將穩定。第一季結束時，我們的現金和投資為 22 億美元。

Our first quarter results keep us on track to meet our 2024 financial guidance. Looking ahead, we project our revenues in subsequent quarters to be modestly higher compared to the first quarter based on anticipated regulatory milestones, license fees and R&D funding from partners. For example, we will earn $20 million if QALSODY is approved in the EU and $30 million if WAINUA is approved in the EU. Additionally, we expect our royalty revenue to grow as the WAINUA launch ramps up and as the QALSODY EU launch gets underway, assuming approval. We continue to project our full year 2024 operating expenses to increase in the mid- to high single-digit percent range compared to 2023, excluding the impact of onetime costs last year.

我們第一季的業績使我們預計將達到 2024 年的財務指引目標。展望未來，根據預期的監管里程碑、授權費用和合作夥伴的研發資金，我們預計後續幾季的營收將略高於第一季。例如，如果 QALSODY 在歐盟獲得批准，我們將獲得 2000 萬美元的收入；如果 WAINUA 在歐盟獲得批准，我們將獲得 3000 萬美元的收入。此外，我們預計，隨著 WAINUA 的推出以及 QALSODY EU 的推出（如果獲得批准）的啟動，我們的特許權使用費收入將會成長。我們繼續預計，與 2023 年相比，2024 年全年營運費用將在中高個位數百分比範圍內成長，不包括去年一次性成本的影響。

This increase will be driven primarily from SG&A expenses as we continue investing in our go-to-market activities to support our planned independent launches and our minority portion of WAINUA's sales and marketing costs, which are in the high teens to low 20% range. We expect to end the year with $1.7 billion in cash and investments. And as we invest in the substantial opportunities before us today, that we expect will unlock next level value. So as you can see, we delivered a solid first quarter.

這一增長主要來自 SG&A 費用，因為我們繼續投資於上市活動，以支持我們計劃的獨立發布，以及我們佔 WAINUA 銷售和營銷成本的少數部分，這些成本在十幾％到 20％ 的範圍內。我們預計到年底將擁有 17 億美元的現金和投資。當我們投資於今天擺在我們面前的大量機會時，我們預計這些機會將釋放出新的價值。正如您所看到的，我們第一季的業績表現強勁。

And now I'd like to provide you with a compelling financial vision of our clear path to drive increased value. With a rich pipeline that includes a growing number of wholly owned programs, we have a clear path to positive cash flow, powered by sustained revenue growth to fully realize the opportunities before us, we will continue to make significant investments over the next few years.

現在，我想為您提供令人信服的財務願景，說明我們推動價值成長的明確路徑。憑藉豐富的管道（包括越來越多的全資項目），我們有一條清晰的正現金流路徑，在持續的收入增長的推動下，充分實現我們面前的機會，我們將在未來幾年繼續進行重大投資。

We are investing efficiently in 4 key areas: First, as you just heard from Kyle, we are making significant investments in the launch of WAINUA in the United States. To execute on a successful launch for this important medicine, we built key commercial functions and are gaining important experience that we can leverage as we prepare for our upcoming launches for olezarsen and donidalorsen. As we prepare for these launches over the next couple of years, we will scale our capabilities and increase our go-to-market activities in line with the combined multibillion-dollar revenue potential that these medicines represent.

我們正在 4 個關鍵領域進行有效投資：首先，正如您剛從 Kyle 那裡聽到的，我們正在為在美國推出 WAINUA 進行大量投資。為了成功推出這種重要藥物，我們建立了關鍵的商業功能，並獲得了重要的經驗，我們可以在為即將推出的 olezarsen 和 donidalorsen 做準備時利用這些經驗。當我們為未來幾年的上市做準備時，我們將根據這些藥物所代表的數十億美元的綜合收入潛力來擴大我們的能力並增加我們的上市活動。

Second, we will continue to invest in advancing our late-stage medicines. We expect that our level of investment in this area will be relatively stable over the next few years. Because, first of all, all of our large Phase III studies today are at or near full enrollment, which is the heaviest period of investments. And we have concluded several studies recently and are now able to reallocate R&D resources from these programs to our third area of investment, our earlier-stage wholly owned program. Our investments in advancing these programs set us up to deliver our next wave of medicines to patients.

其次，我們將繼續投資推進我們的後期藥物。我們預計未來幾年我們在該領域的投資水準將相對穩定。因為，首先，我們今天所有的大型三期研究都已達到或接近全部入組，這是投資最重的時期。我們最近完成了幾項研究，現在能夠將這些專案的研發資源重新分配到我們的第三個投資領域，也就是我們的早期全資專案。我們對推進這些項目的投資使我們能夠向患者提供下一波藥物。

And finally, we are investing in cutting-edge technologies to ensure we continue to deliver innovative medicines with competitive profiles. With these investments, we have an outsized opportunity to deliver medicines to patients in need, which in turn positions us to earn multibillion dollar revenues and achieve positive cash flow on a sustained basis. This slide depicts these opportunities. And as you can see, we have many medicines that can power our revenue growth.

最後，我們正在投資尖端技術，以確保我們繼續提供具有競爭力的創新藥物。透過這些投資，我們有巨大的機會向有需要的患者提供藥品，這反過來又使我們能夠賺取數十億美元的收入並持續實現正現金流。這張投影片描述了這些機會。正如您所看到的，我們有許多藥物可以推動我們的收入成長。

Beyond our upcoming launches for olezarsen for FCS and donidalorsen for HAE, we have several additional wholly-owned medicines in development that could reach patients over the next several years. This includes our planned launch of olezarsen, Our wholly owned medicine for the treatment of severe high triglycerides, that has blockbuster potential.

除了即將推出用於 FCS 的 olezarsen 和用於 HAE 的 donidalorsen 之外，我們還有幾種正在開發的全資藥物，可能會在未來幾年內到達患者手中。這包括我們計劃推出的 olezarsen，這是我們全資擁有的用於治療嚴重高甘油三酯的藥物，具有重磅炸彈的潛力。

Additionally, we have a growing pipeline of potential groundbreaking disease-modifying neurology medicines we expect to bring to patients over the near to midterm including zilginersen for Alexander's disease, which is currently in Phase III development. We also have multiple partnered programs that are poised to provide substantial future royalty revenue and sales milestones assuming continued advancement.

此外，我們還有不斷增長的潛在突破性神經病學藥物研發管線，預計在近期到中期為患者提供，其中包括用於治療亞歷山大病的 zilginersen，該藥物目前正處於 III 期開發階段。我們還有多個合作計劃，如果繼續取得進展，這些計劃將在未來提供可觀的特許權使用費收入和銷售里程碑。

These include pelacarsen, a first-in-class investigational medicine that Novartis is developing to address the millions of patients with Lp(a)-driven cardiovascular disease.

其中包括 pelacarsen，這是諾華正在開發的一種一流的研究藥物，旨在解決數百萬 Lp(a) 驅動的心血管疾病患者的問題。

Data and a regulatory submission for pelacarsen are planned for next year. Bepirovirsen, an investigational medicine that GSK is developing in a large Phase III program to treat the millions of patients with HPV infection. And of course, we have WAINUA with the ATTR polyneuropathy launch on track and our landmark CARDIO-TTRansform study progressing well, we believe that WAINUA has the potential to become the preferred treatment for ATTR in the substantial and growing market.

pelacarsen 的數據和監管提交計劃於明年進行。 Bepirovirsen 是 GSK 正在一項大型 III 期計畫中開發的一種研究藥物，用於治療數百萬 HPV 感染患者。當然，我們的 WAINUA 與 ATTR 多發性神經病變的上市已步入正軌，而且我們具有里程碑意義的 CARDIO-TTRansform 研究進展順利，我們相信 WAINUA 有潛力成為 ATTR 在龐大且不斷增長的市場中的首選治療方法。

All of these programs combined could generate up to $6 billion in milestone payments, and that's in addition to royalties up to the mid-20% range. And all of this is on top of our substantial and sustainable current revenues. So as you can see, over the next few years, we plan to make strategic investments in our commercial opportunities in advancing our rich pipeline and in our technology. We expect these investments to power strong revenue growth and positive cash flow as our medicines reach more patients in need, positioning us to deliver next level value for all Ionis stakeholders, 3 years to come.

所有這些計劃加起來可產生高達 60 億美元的里程碑付款，這還不包括高達 20% 中間範圍的特許權使用費。所有這一切都是在我們目前可觀且可持續的收入之上的。正如您所看到的，在未來幾年中，我們計劃對商業機會進行策略性投資，以推進我們豐富的產品線和技術。我們預計，隨著我們的藥品惠及更多有需要的患者，這些投資將推動強勁的收入成長和正現金流，使我們能夠在未來 3 年內為所有 Ionis 利益相關者提供更高水準的價值。

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

說完，我會把電話轉回給布雷特。

Thank you, Beth. Indeed, Ionis is well positioned to continue building on our positive momentum as we execute on all our strategic priorities. We have arrived where we are today by being focused on a clear vision and a clear set of strategic objectives, which include building and advancing our pipeline and delivering medicines that we conceive discover and develop directly to patients. We've established Ionis as a leader in organically tied therapeutics with several approved drugs and one of the richest mid- and late-stage pipelines in the industry.

謝謝你，貝絲。事實上，Ionis 處於有利位置，可以在執行所有策略重點時繼續鞏固我們的積極勢頭。我們之所以能取得今天的成就，是因為我們專注於清晰的願景和一套明確的策略目標，其中包括建立和推進我們的產品線，以及將我們設想、發現和開發的藥物直接提供給患者。我們已將 Ionis 打造成有機結合療法領域的領導者，擁有多種已獲批准的藥物以及業內最豐富的中後期產品線之一。

Our pipeline is delivering. We achieved multiple marketing approvals and positive key data readouts over the past year and are poised to build on the strong momentum in the near term.

我們的管道正在交付。在過去的一年裡，我們獲得了多項行銷批准和積極的關鍵數據讀數，並準備在短期內繼續保持強勁勢頭。

We've prioritized building our wholly owned pipeline, and we expect to advance several of these medicines into clinical development this year. In parallel, our partner programs are progressing on track with key Phase II data readouts planned this year and important Phase III readouts next year and beyond. We're extending our leadership position in oligonucleotide therapeutics by expanding and diversifying our technology, further optimizing our capabilities for existing therapeutic areas and opening up new areas for drug discovery.

我們優先考慮建造我們的全資管道，並預計今年將其中幾種藥物推進臨床開發。同時，我們的合作夥伴專案正在按計劃取得進展，計劃今年進行關鍵的第二階段資料讀出，並在明年及以後進行重要的第三階段資料讀出。我們正在透過擴展和多樣化我們的技術、進一步優化我們在現有治療領域的能力以及開闢新的藥物發現領域來擴大我們在寡核苷酸治療領域的領導地位。

All of this sets us up to continue bringing a steady cadence of new medicines, transformational medicines to patients for years to come. We're looking forward to sharing our progress as we build on our recent achievements and accomplish all our strategic objectives. And with that, I'll now open the call up for questions. Keith, and we can take questions now.

所有這些都使我們能夠在未來幾年繼續穩定地為患者提供新藥、轉化藥物。我們期待分享我們在近期成就的基礎上再接再厲並實現所有戰略目標的進展。現在，我將開始提問。基思，我們現在可以回答問題。

(Operator Instructions) And the first question comes from Debjit Chattopadhyay with Guggenheim Securities.

（操作員說明）第一個問題來自古根漢證券公司的 Debjit Chattopadhyay。

Firstly, on donidalorsen and olezarsen. Between the expanded access, the OLE and Switch, how many FCS and HAE patients do you currently have on therapy who could be low-hanging fruits for the early commercial adoption?

首先，關於多尼達洛森和奧萊扎森。在擴大的訪問範圍、OLE 和 Switch 之間，目前有多少 FCS 和 HAE 患者正在接受治療，他們可能是早期商業採用的唾手可得的成果？

So for olezarsen, virtually all of the patients, which was approximately 60 patients or so, Eugene, in the Phase III study rolled over into the open-label extension and they're continuing in that trial in the open label extension now. So that's a -- I mean that's a pretty good measure there. For the expanded access program for olezarsen and FCS, that's just getting started. So it's early days. We'll provide an update later on. But so far, reception has been very positive.

因此，對於 olezarsen 來說，III 期研究中的幾乎所有患者（大約 60 名患者左右，Eugene）都轉入了開放標籤擴展，現在他們正在繼續進行開放標籤擴展的試驗。所以這是一個——我的意思是這是一個非常好的措施。對於 olezarsen 和 FCS 的擴展存取計劃來說，這才剛開始。所以現在還為時過早。我們稍後將提供更新。但到目前為止，反應非常積極。

Similar story for donidalorsen. Donidalorsen, virtually all of the patients that completed the trial, which was the vast majority, well in excess of 90% of the patients completed the trial, elected to roll over into the open-label extension, and they've stayed and they've remained in the open-label extension. The EAP has just got started, I think, last week for donidalorsen.

多尼達洛森也有類似的故事。 Donidalorsen 表示，幾乎所有完成試驗的患者（佔絕大多數，遠遠超過 90% 的完成試驗的患者）都選擇轉入開放標籤擴展，他們留下來了，他們’ ve 仍處於開放標籤擴展中。我想，對多尼達洛森來說，EAP 上週才剛開始。

Got it. And one quick one. Are there any Part D dynamics we should be monitoring with respect to WAINUA launch versus Amvuttra.

知道了。還有一個快的。關於 WAINUA 與 Amvuttra 的發布，我們是否應該監控任何 D 部分的動態？

Yes, I'd be happy to talk about that. Thanks for the question. So First, I'll just say the launch is going really well. The payers are covering the medication as expected. There's experience in the space already with polyneuropathy and so the criteria for use is largely understood from the majority of payers.

是的，我很樂意談論這個。謝謝你的提問。首先，我想說的是，發布進展非常順利。付款人按預期支付了藥物費用。該領域已經有治療​​多發性神經病變的經驗，因此大多數付款人基本上都了解使用標準。

On the Part D side of things, we're continuing to navigate that very efficiently. AstraZeneca is leading the way on the market access side of things, and they're doing a fantastic job. And our patient services program is really supporting patients effectively to educate them on the process and also provide out-of-pocket support where appropriate for commercial patients and supporting them just through the regular reimbursement process that you would expect and also working directly with the offices. So overall, I think the payer landscape is positive. The patient experience is very positive. And we're continuing to execute the launch very effectively.

在 D 部分方面，我們將繼續非常有效地解決這個問題。阿斯特捷利康在市場准入方面處於領先地位，而且他們做得非常出色。我們的患者服務計劃確實有效地支持患者，對他們進行流程教育，並在適當的情況下為商業患者提供自付費用支持，並透過您期望的定期報銷流程為他們提供支持，並直接與辦公室合作。總的來說，我認為付款人的前景是正面的。患者的體驗非常正面。我們將繼續非常有效地執行發布。

And the next question comes from Gary Nachman with Raymond James.

下一個問題來自加里·納赫曼和雷蒙德·詹姆斯。

So on olezarsen, when will you know the exact review time line for FCS? I know you're assuming a priority review, but when will that be confirmed. And then talk a bit more about the commercial launch preparations for olezarsen for FCS. How big of a team will you need overall and describe some of the synergies with the infrastructure already built in there for WAINUA, how that could be leveraged.

那麼olezarsen上，什麼時候能知道FCS的具體審核時間線呢？我知道您正在考慮優先審查，但是什麼時候會得到確認。然後再談談 olezarsen for FCS 的商業發布準備。您總體上需要多大的團隊，並描述與 WAINUA 已內建基礎設施的一些協同效應，以及如何利用它。

Thanks, Gary. I'll take the first one and Kyle, could talk a little bit about the field prep and plans for commercialization. Maybe Jonathan could jump in too -- so the -- we expect to hear from the FDA -- 60 days or so after we submitted and we submitted it in March. And at -- in April, sorry, we submitted in April and it's a 60-day time line for that. Once we hear from the FDA, we'll expect to hear about our PDUFA date. Whether or not we are -- they expecting to have an ad com, we don't expect to have an outcome, but that would be information that would come in that uptake. And thirdly, whether we receive priority review as well in addition to that. And we'll announce all that at the same -- when we hear from the FDA on the acceptance of the NDA. Kyle will you talk a little bit about the launch for FCS?

謝謝，加里。我將採取第一個和凱爾，可以談談現場準備和商業化計劃。也許喬納森也可以加入——所以——我們希望在我們提交後 60 天左右收到 FDA 的消息，我們是在 3 月提交的。抱歉，我們在 4 月提交了申請，期限為 60 天。一旦我們收到 FDA 的來信，我們將期望聽到我們的 PDUFA 日期。無論我們是否——他們期望有廣告公司，我們不期望有結果，但這將是在吸收過程中會出現的訊息。第三，除此之外我們是否還受到優先審查。當我們收到 FDA 接受 NDA 的消息時，我們將同時宣布這一切。凱爾（Kyle）您能談談 FCS 的推出嗎？

Yes. I will talk about the synergies, and then I'll turn it over to Jonathan to talk about some of the field force sizing and the thinking around the go-to-market strategy there. But the synergies with WAINUA, I think what's important within the organization is, first of all, we've been very calculated and very measured in terms of the way that we build the internal infrastructure so that we're efficient and being smart about the capabilities that we're building and the timing of that build. But we've currently got in place marketing capabilities, which I think are very robust with strong leadership and experience in the marketing capacity.

是的。我將討論協同效應，然後將其交給喬納森（Jonathan）討論一些現場人員規模以及圍繞市場進入策略的思考。但與 WAINUA 的協同效應，我認為在組織內部最重要的是，首先，我們在構建內部基礎設施的方式方面經過深思熟慮和衡量，以便我們高效且明智地對待我們正在構建的功能以及構建的時間。但我們目前已經具備了行銷能力，我認為這種能力非常強大，在行銷能力方面擁有強大的領導力和經驗。

Our commercial operations group has stood up. So things like the CRM and data and analytics and those types of infrastructures are in place. Our market access team is doing a fantastic job of doing market insights work and understanding the way that the market is anticipated to look from a payer standpoint and trade and channel and distribution.

我們的商業營運團隊已經站起來了。因此，諸如 CRM、數據和分析以及這些類型的基礎設施之類的東西都已就位。我們的市場准入團隊在市場洞察工作以及從付款人的角度以及貿易、通路和分銷的角度了解市場預期的方式方面做得非常出色。

And finally, and really importantly, is the medical affairs group, we established that team a little over 3 years ago. And that team has been interacting with KOLs. They've had strong presence at Congresses. There's been a lot of data in dissemination. We've collected a lot of information externally and brought that knowledge back into the organization as well.

最後，也是非常重要的，是醫療事務小組，我們在三年多前成立了該小組。該團隊一直在與 KOL 互動。他們在國會中表現強勁。大量數據正在傳播。我們從外部收集了大量信息，並將這些知識帶回組織中。

So I mean, overall, I think what you're hearing is the capacity and the ability and the infrastructure and the timing of all of this is really coming together nicely. And the execution. I've been very impressed with and very pleased with where we're at right now. So Jonathan, maybe specific to FCS?

所以我的意思是，總的來說，我認為你聽到的是容量、能力、基礎設施以及所有這些的時機確實很好地結合在一起。還有執行。我對我們現在的處境印象深刻，也非常滿意。那麼喬納森，也許是針對 FCS 的？

Yes. I think there are, as Kyle alluded to, a lot of synergies between the capabilities we've built to support the WAINUA launch, particularly around areas such as patient services. that will transfer very relevantly to the FCS launch. A bit of background, as I'm sure you're aware, the FCS launch is a rare disease. There are a relatively small number of patients who are managed by a relatively small number of HCPs. So as you can imagine, the footprint or the scale of our commercial build will meet the needs of those customer group. That customer group and indeed those patients. So given the rare disease nature, it will be appropriately built to service that population.

是的。我認為，正如凱爾所提到的，我們為支持 WAINUA 的推出而建立的能力之間存在著許多協同作用，特別是在患者服務等領域。這將與 FCS 的發布密切相關。一點背景知識，我相信您已經知道，FCS 的推出是一種罕見的疾病。由數量相對較少的 HCP 管理的患者數量相對較少。正如您可以想像的那樣，我們商業建築的佔地面積或規模將滿足這些客戶群的需求。那個客戶群，其實還有那些患者。因此，考慮到罕見疾病的性質，它將被適當地建造來為該人群提供服務。

All right. Great. And then on doni, just described the latest thinking on the data you'll be including in the NDA. And how are you thinking about positioning the drug from a competitive standpoint in terms of switches versus getting naive patients in that market? And Kyle, how big of an effort you'll need there from a commercial standpoint relative to olezarsen?

好的。偉大的。然後，多尼剛剛描述了有關您將包含在保密協議中的數據的最新想法。您如何考慮從競爭的角度來定位該藥物，而不是在該市場上吸引初次接受治療的患者？凱爾（Kyle），從商業角度來看，相對於奧萊扎森（olezarsen），你需要付出多大的努力？

Yes. Let me start by talking a little bit about the market. We strongly believe, based on the profile of donidalorsen that we'll be able to evolve the prophylactic treatment paradigm. This is a very competitive market, as you just outlined. It is a Switch market, right? A lot of these patients are already identified. They're currently being treated and we anticipate Switch and the Switch data that we're going to roll out at the end of the month to be very, very relevant in this space and also innovative and different.

是的。讓我先談談市場。我們堅信，根據多尼達洛森的概況，我們將能夠發展預防性治療模式。正如您剛才所概述的，這是一個競爭非常激烈的市場。這是一個 Switch 市場，對嗎？其中許多患者已經被識別出來。他們目前正在接受治療，我們預計 Switch 和我們將在本月底推出的 Switch 數據在這個領域非常非常相關，而且也具有創新性和差異性。

The prevalence overall, we're looking at 20,000-plus patients between the U.S. and EU. And the data sets in terms of differentiation and the way that we're going to go about this really support a couple of things. Number one, the primary endpoint, obviously, around reduced rates of HAE attacks. But the durability of that, I think, is really, really important to note in the data. We've got 4- or 8-week dosing that's differentiated versus the competition. We've got a safe and tolerable therapy. And the switch data and being able to show patient preference is going to be really critical, I think, not only to patients but also to prescribers in terms of how to do this and to payers in terms of what is the cost of doing this and how do we do this effectively to make sure that it's efficient in terms of making that transition.

我們正在研究美國和歐盟之間 20,000 多名患者的整體盛行率。差異化方面的數據集以及我們將要採取的方式確實支持了幾件事。第一，主要終點顯然是圍繞著降低 HAE 攻擊率。但我認為，在數據中註意到這一點的持久性非常非常重要。我們有 4 週或 8 週的給藥方案，與競爭對手不同。我們有一種安全且可耐受的治療方法。我認為，轉換數據並能夠顯示患者的偏好將非常重要，不僅對患者而言，而且對處方者來說，如何做到這一點，對付款人來說，這樣做的成本是多少，以及我們如何有效地做到這一點，以確保在實現這一轉變方面是有效的。

So overall, I think between the data and the marketplace and the way things are setting up, we're going to be really poised to do a great job here in this space. In terms of the commercial size, we'll probably be competitive in terms of the sizing 50 to 100 ballpark in terms of field infrastructure. And I expect to be able to start putting that team in place later this year, pending the regulatory time lines and process that will be outlined later.

總的來說，我認為在數據、​​市場以及事物的設定方式之間，我們將真正準備好在這個領域做得很好。就商業規模而言，我們可能在 50 至 100 球場規模和現場基礎設施​​方面具有競爭力。我預計能夠在今年稍後開始組建該團隊，等​​待稍後概述的監管時間表和流程。

Yes. And regarding Gary, the NDA, thanks, Kyle. We plan to submit for approval both for every 4-week dosing as well as every 8-week dosing, we'll include open-label extension data to support the safety database is necessary for approval. We're also expecting to include instructions based on the Switch data on how physicians will be able to Switch patients from an existing prophylactic over to donidalorsen.

是的。關於加里，保密協議，謝謝凱爾。我們計劃提交每 4 週給藥一次和每 8 週給藥一次的批准，我們將包括開放標籤擴展資料以支援批准所需的安全資料庫。我們還希望包含基於 Switch 數據的說明，說明醫生如何將患者從現有的預防藥物切換到多尼達洛森。

And related to that, we're very much looking forward to sharing in-depth the Switch data along with the open label -- Phase III open-label extension data in the Phase III data at EAACI on May 31 of this month. The Switch data is really -- is absolutely the first prospective study ever conducted in patients with HAE, switching them from one prophylactic to another. And we're looking forward to sharing data not only on how well patients are protected from HAE attacks compared to baseline rates, but also compliance, how long they stay on treatment and a preference that whether patients prefer donidalorsen over their previous treatment. And why they choose that. So it's a very important study. It's the first of its kind, and it's also a litmus test for the market in the United States, which is a Switch market.

與此相關的是，我們非常期待在本月 5 月 31 日在 EAACI 的第三階段資料中深入分享 Switch 資料以及開放標籤——第三階段開放標籤擴充資料。 Switch 數據確實是——絕對是有史以來第一項針對 HAE 患者進行的前瞻性研究，將他們從一種預防措施轉換為另一種預防措施。我們期待分享的數據不僅包括與基線率相比患者免受 HAE 攻擊的程度，還有依從性、治療持續時間以及患者是否更喜歡多尼達洛森而不是之前的治療的偏好。以及他們為什麼選擇那個。所以這是一項非常重要的研究。這是同類產品中的首創，也是對美國這個Switch市場的試金石。

And the next question comes from Jessica Fye with JPMorgan.

下一個問題來自摩根大通的 Jessica Fye。

On that path to sustained positive cash flow, can you talk a little bit about over what time horizon you see the company being able to achieve that? And then just a quick second one for ION541, your ataxin-2 asset for ALS, can you set the stage for what to watch for in those Phase 2 results? And just remind me the timing for that readout?

在實現持續正現金流的道路上，您能談談您認為公司能夠在什麼時間範圍內實現這一目標嗎？然後，快速介紹一下 ION541（您用於 ALS 的 ataxin-2 資產）的第二個，您能為 2 期結果中值得關注的內容奠定基礎嗎？只是提醒我讀出的時間？

Sure, Jess. So as you think about Ionis, if you think about our opportunities. Obviously, we've got a substantial opportunity ahead of us with the rich pipeline that we have, particularly the late-stage pipeline, multibillion-dollar revenue opportunity. it's going to take us a few years of continued investment to bring those drugs through development, through the regulatory process and launch those medicines. And we want those launches then, obviously, to be ramping. But it's really the strength of multiple sources of revenue are sustained and substantial base of revenue today, the ability for that to grow, the ability for partnered programs to reach the market and generate substantial royalties and sales milestones. And then to build on that with our product revenues with our wholly owned medicines, as those come to market, and those launches ramp up that will really drive the positive cash flow.

當然，傑西。因此，當您想到 Ionis 時，如果您想到我們的機會。顯然，我們擁有豐富的管道，特別是後期管道，數十億美元的收入機會，我們面前有一個巨大的機會。我們將需要幾年的持續投資才能使這些藥物通過開發、通過監管程序並推出這些藥物。顯然，我們希望這些產品的發布能夠加速。但這實際上是多種收入來源的力量，是當今持續且堅實的收入基礎，成長的能力，合作項目進入市場並產生大量特許權使用費和銷售里程碑的能力。然後，隨著我們全資藥品的產品收入進入市場，這些藥品的上市量不斷增加，這將真正推動正現金流。

And I think what's important to remember about Ionis, which is very unique for us versus others in our space is that we're not that far away. Unlike a lot of companies who are launching their first medicines, we already have a very substantial base of revenue that generates cash for the company and helps offset our investments today. We anticipate that will continue. And that means that the delta that we have to cover when we finally get these products to market, is actually fairly modest and a very achievable goal for us. So hopefully, that gives you a perspective on how to think about it.

我認為，關於 Ionis，需要記住的重要一點是，與我們所在領域的其他公司相比，Ionis 對我們來說非常獨特，因為我們離我們並不遙遠。與許多推出首款藥物的公司不同，我們已經擁有非常可觀的收入基礎，可以為公司創造現金，並有助於抵消我們今天的投資。我們預計這種情況將會持續下去。這意味著當我們最終將這些產品推向市場時，我們必須涵蓋的增量實際上相當適度，並且對我們來說是一個非常可實現的目標。希望這能讓您了解如何思考它。

Looking forward to the other part of your other question, Jess, having data results from the Phase II study for ataxin 2 in nongenetic ALS around midyear this year. Eugene, please comment on what we're looking for.

Jess，期待您的其他問題的另一部分，今年年中左右，我們將收到針對非遺傳性 ALS 中的 ataxin 2 的 II 期研究的數據結果。尤金，請評論我們正在尋找什麼。

Yes, thanks for the question, Jess. It's our first inpatient experience. And primarily, this is a safety study. It's a dose-ranging study, we're obviously assessing safety of increasing doses of oligo in patients with sporadic ALS as Brett said. So really, the key goal of that study is to demonstrate NSS safety of various dose levels of intrathecal medicine.

是的，謝謝你的提問，傑西。這是我們第一次住院。首先，這是一項安全研究。這是一項劑量範圍研究，正如 Brett 所說，我們顯然正在評估增加寡核苷酸劑量對散發性 ALS 患者的安全性。事實上，該研究的主要目標是證明不同劑量等級的鞘內藥物的 NSS 安全性。

We're obviously, or Biogen is looking at other surrogates of ALS progression, and those have been well described, such as neurofilament. So of course, there will be some of those exploratory endpoints that are used to assess whether there is any activity on key ALS progression measures.

顯然，我們或百健（Biogen）正在研究 ALS 進展的其他替代物，這些替代物已經得到了很好的描述，例如神經絲。因此，當然，會有一些探索性終點用於評估關鍵 ALS 進展指標是否有任何活動。

Based on the QALSODY outcome, neurofilament light chain will obviously be a key measure on that. There will also be exploratory measures of ALS functional rating scale and other sub domains within there.

根據 QALSODY 結果，神經絲輕鏈顯然將是關鍵指標。其中還將有 ALS 功能評級量表和其他子領域的探索性措施。

And the next question comes from Joseph Stringer with Needham & Company.

下一個問題來自 Needham & Company 的 Joseph Stringer。

Just a follow-up on donidalorsen. In the Switch study, you mentioned a patient survey and some other data. But maybe can you put a little bit finer point on what data specifically you will need to see from the Switch study that would resonate most from a commercial uptake perspective?

只是多尼達洛森的後續行動。在 Switch 研究中，您提到了一項患者調查和一些其他數據。但也許您可以更詳細地說明您需要從 Switch 研究中看到哪些數據，從商業採用的角度來看最能引起共鳴？

Well, I'll start and Kyle can jump in. It's really the totality of the data, Joey. We're going to -- first of all, we will share data with current treatment that are available on the market today. So it won't just be 1 treatment that we're switching. We're going to be looking at patients that have been on -- previously been on TAKHZYRO, ORLADEYO or other prophylactic treatments. What their baseline HAE attack rates were coming into the study and then how the HAE attack rate evolves as patients continue to be on donidalorsen treatment. That's very important for the commercial -- to have that data for the commercial launch. Second, as I mentioned, it's going to -- we're going to also ask patients which they prefer in the trial and why? And that will be a survey that we're looking forward to sharing in the study as well.

好吧，我開始，凱爾可以介入。首先，我們將分享目前市面上現有治療方法的數據。因此，我們改變的不僅是一種治療方法。我們將關注先前接受 TAKHZYRO、ORLADEYO 或其他預防性治療的患者。研究中納入了他們的基線 HAE 發病率，以及隨著患者繼續接受多尼達洛森治療，HAE 發病率如何變化。這對於商業廣告來說非常重要——為商業發布提供這些數據。其次，正如我所提到的，我們還將詢問患者在試驗中他們更喜歡哪一個，為什麼？這也將是我們期待在研究中分享的調查。

And then thirdly and very importantly, we'll be able to have the data, the instructions and the algorithms, if you will, which are different for different prophylactic treatments on how much time it takes before donidalorsen will -- how much time they need to be on and wean off existing prophylactic treatments and move on to donidalorsen based on previous treatments. But it's really important, right, Kyle, to have this data for the launch on donidalorsen?

第三，也是非常重要的一點，如果你願意的話，我們將能夠獲得數據、指示和演算法，對於不同的預防性治療，多尼達洛森需要多長時間，這些數據、指示和演算法是不同的——他們需要多長時間繼續使用或停止現有的預防性治療，並在先前的治療基礎上繼續使用多尼達洛森。但凱爾，在多尼達洛森上發布這些數據確實很重要，對嗎？

Yes. I think first, it's highly differentiated. This hasn't been done before. And I think that differentiation is going to help us. This is an unsatisfied market. Right? I mean we already see that patients are moving between therapies as it is right now. And they're moving because they're either not adequately controlled or they're having breakthroughs or sometimes it's because of the way that the delivery mechanism works for the treatment that they're on.

是的。我認為首先，它是高度差異化的。以前沒有這樣做過。我認為差異化會對我們有幫助。這是一個不滿意的市場。正確的？我的意思是，我們已經看到患者正在不同的治療方法之間轉換，就像現在一樣。他們正在移動，因為他們要么沒有得到充分的控制，要么正在取得突破，或者有時是因為傳遞機制對他們正在接受的治療的工作方式。

And so when we're thinking about the data, it's going to be helpful for us to know in a very formal way, the feedback from patients, number one and number two, to help inform physicians about how to do this safely and effectively. And finally, on the payer side, payers want to make sure that they're not paying for multiple medications at the same time.

因此，當我們考慮數據時，以非常正式的方式了解患者的回饋（第一和第二）將很有幫助，以幫助告知醫生如何安全有效地做到這一點。最後，在付款人方面，付款人希望確保他們不會同時支付多種藥物的費用。

And so this will help us with the payer messaging as well to talk about how to effectively get on to donidalorsen and stay on donidalorsen without them having to have multiple therapies overlapping or that they're having to pay for and cover for these patients.

因此，這也將幫助我們向付款人傳遞訊息，討論如何有效地繼續使用多尼達洛森並繼續使用多尼達洛森，而不必讓多種療法重疊，或者他們必須為這些患者付費和承保。

And the next question comes from Jason Gerberry with Bank of America.

下一個問題來自美國銀行的 Jason Gerberry。

Two for me. Just can you comment on the Phase III SHTG trials and how acute pancreatitis events are accruing on a blended basis versus events you've seen in other trials or your best estimate of what that event rate may look like? And then my second question is around TTR cardiomyopathy and the potential for combination therapy. .

給我兩個。您能否評論一下 III 期 SHTG 試驗，以及與您在其他試驗中看到的事件相比，急性胰臟炎事件是如何在混合基礎上發生的，或者您對事件發生率的最佳估計？我的第二個問題是關於 TTR 心肌病變和聯合治療的潛力。 。

Alnylam seems pretty adamant that just payers won't cover a stabilizer and a silencer. And there's questions if tafamidis will even go generic this decade. So I'm just curious like what work you've done around combo that it will get covered and that there's an attainable clinical bar for combo. I know there's a lot in that, but just love if you can address that?

Alnylam 似乎非常堅定地認為，只有付款人才不會支付穩定器和消音器的費用。還有人質疑，tafamidis 是否會在這十年內成為仿製藥。所以我只是好奇你圍繞組合做了哪些工作，它將被覆蓋，並且組合有一個可實現的臨床標準。我知道其中有很多問題，但如果你能解決這個問題，我會很高興嗎？

All right. Before handing over to Kyle and Jonathan about the dynamic TTR cardiomyopathy market, combination monotherapy when we comment on the SHTG. So, as a reminder, Jason, we saw remarkable reductions in acute pancreatitis in our FCS balance study for olezarsen. Not only was the reduction substantial, the number of AP events in the placebo group were much more than we anticipated going into that study point. I guess, a very important point that I want to emphasize is that we don't really know people. It's not really understood well what the AP event rates are in FCS or SHTG. Is these trials that we're conducting that are going to add a lot of light -- shed a lot of light on to what the true AP events are for both FCS and SHTG. .

好的。在向 Kyle 和 Jonathan 介紹動態 TTR 心肌病變市場之前，我們在評論 SHTG 時結合單一療法。因此，Jason，提醒一下，在 olezarsen 的 FCS 平衡研究中，我們發現急性胰臟炎的發生率顯著降低。不僅減少幅度很大，安慰劑組的 AP 事件數量也比我們在該研究點的預期多得多。我想，我想強調的非常重要的一點是，我們並不真正了解人。目前還不太清楚 FCS 或 SHTG 中的 AP 事件發生率是多少。我們正在進行的這些試驗是否會增加許多線索——揭示 FCS 和 SHTG 的真實 AP 事件是什麼？ 。

Virtually all of the AP events that occurred in the FCS study were in the placebo group. Certainly, in SHTG, we would expect and do expect fewer AP events just based on -- compared to FCS based on the fact that the mean triglyceride reductions are lower in SHTG than they are in FCS. But with that said, we have many patients in our SHTG trial that are in the thousands in the FCS range in the study. But the mean reduction -- mean TG levels will be less, and therefore, you would expect the rate of events to be a bit lower in SHTG. With that said, we are seeing in a blinded manner AP events, and they're accumulating a pretty robust line study.

事實上，FCS 研究中發生的所有 AP 事件都發生在安慰劑組。當然，在 SHTG 中，我們預計並且確實預期 AP 事件會比 FCS 更少，因為 SHTG 中的平均三酸甘油酯降低量低於 FCS 中的事實。但話雖如此，我們的 SHTG 試驗中有許多患者在研究中的 FCS 範圍內有數千名患者。但平均 TG 水平會降低，因此您預計 SHTG 中的事件發生率會稍低一些。話雖如此，我們正在以盲目的方式看到美聯社事件，他們正在累積相當可靠的線路研究。

If we can replicate anything like what we saw in FCS, the majority of those patients, we would expect to be in the placebo group because the olezarsen is expected to reduce triglycerides even better from a magnitude standpoint in SHTG versus FCS. So at the balance, FCS study certainly gave us more confidence in a positive AP outcome in the study. A reminder, the primary endpoint is triglyceride reductions, AP events in the SHTG study is a key secondary.

如果我們能夠複製在FCS 中看到的情況，那麼對於大多數患者來說，我們預計會屬於安慰劑組，因為從SHTG 與FCS 的量級角度來看，olezarsen 預計會更好地降低甘油三酯。因此，總的來說，FCS 研究無疑讓我們對研究中正向的 AP 結果更有信心。提醒一下，主要終點是三酸甘油酯降低，SHTG 研究中的 AP 事件是關鍵的次要終點。

Jonathan, you want to comment on the changing dynamics in TTR cardiomyopathy, how we're seeing monotherapy combination play out?

Jonathan，您想對 TTR 心肌病變的動態變化發表評論，我們如何看待單一療法組合的效果？

Yes. I think the specific question for me around that is willingness to cover the combo. And I guess my first point is very difficult to answer the question, given that we don't yet have any data and therefore, don't really understand the profile of the combination. That said, I think there are plenty of other therapy areas, whether it's Gilead's work in hep C, where treatments were 7 figures, plenty of oncology drugs where there are very expensive combinations that are still covered by payers.

是的。我認為對我來說具體的問題是是否願意涵蓋組合。我想我的第一點很難回答這個問題，因為我們還沒有任何數據，因此並不真正了解組合的概況。也就是說，我認為還有很多其他治療領域，無論是吉利德在丙型肝炎方面的工作（治療費用為7 位數），還是許多腫瘤藥物，其中有非常昂貴的組合，但仍由付款人承擔。

What I can tell you specifically with regards to cardio transform and the combination usages, the market research that we've completed has shown that there is a willingness from payers to cover the combination. Obviously, the caveat to that is it will be data dependent. But so long as with data from what's effectively the largest study in this area, we're fairly confident that we -- if we're able to demonstrate the benefit that, that will then ultimately be covered by the payers.

我可以具體告訴您，關於有氧運動變換和組合用途，我們完成的市場研究表明，付款人願意支付組合費用。顯然，需要注意的是它取決於數據。但只要利用該領域最大規模研究的數據，我們就相當有信心——如果我們能夠證明其好處，那麼最終將由付款人承擔。

And we're very well positioned to demonstrate an added benefit in combination based on the design of our trial, the size of our trial and the percentage of patients we have in -- on tafamidis versus monotherapy.

基於我們的試驗設計、試驗規模以及我們的患者比例，我們非常有能力展示聯合用藥與單一療法相比的額外益處。

And the next question comes from Yanan Zhu with Wells Fargo.

下一個問題來自富國銀行的朱亞楠。

Great. Maybe to follow up on ATTR cardiomyopathy, -- just curious, any color on the blinded event rate, any update there? And any thinking about the primary endpoint analysis? And also as a competitor readout their data, what are the key data points that you will be focused on learning?

偉大的。也許是為了跟進 ATTR 心肌病變——只是好奇，盲法事件發生率有什麼顏色嗎？對主要終點分析有什麼想法嗎？當競爭對手讀出他們的數據時，您將重點學習哪些關鍵數據點？

So thank you, Yanan. So the blinded event rates in the cardio transform trial are tracking well. They're on track for what we expected. And that -- when I say that, I'm referring to both mortality as well as hospitalizations and the nature of those hospitalizations. We're looking at it very quickly -- very carefully. .

謝謝你，亞南。因此，有氧運動轉換試驗中的盲法事件發生率追蹤良好。他們正朝著我們的預期發展。當我這麼說時，我指的是死亡率、住院率以及這些住院的性質。我們正在非常迅速、非常仔細地研究它。 。

And there's no changes to our plans on primary endpoint or timing, as we said in our presentation as early as next year still on track. The study we were to go to its completion, 140 weeks of treatment that would be midyear 2026. And we're focused almost very much on the blinded event rate to drive the decision with our partner, AstraZeneca, When this REIT study out. We're very much looking forward to the readout of the first silencer in TTR cardiomyopathy from a Phase III trial later this year. If we learned something from it, it could influence our timing for reading out the study. We're very much looking forward to it and I really can't go say much more about it than that at this point.

正如我們在演示中所說，我們的主要終點或時間安排沒有變化，最早將於明年進行。我們的研究將在 2026 年年中完成，治療時間為 140 週。我們非常期待今年稍後從 III 期試驗中讀出 TTR 心肌病變的第一個消音器。如果我們從中學到了一些東西，它可能會影響我們宣讀研究的時間。我們非常期待它，此時我真的不能說更多。

Great. If I may ask a follow-up on Angelman syndrome readout. What might be the value? And how do we think about the relative importance of the biomarker EEG versus clinical endpoints like CGI and Bayley-4 when we learn the data?

偉大的。我可以詢問有關天使綜合症讀數的後續情況嗎？可能有什麼價值？當我們了解數據時，我們如何考慮生物標記 EEG 與 CGI 和 Bayley-4 等臨床終點的相對重要性？

Yes. Eugene will comment on the clinical endpoints, biomarker EEG and other Bayley-4, et cetera. We don't -- we haven't settled on how and when exactly we will report out the next step for the Angelman program. As you know, Yanan, Biogen has an option to license this program. And as we've said before, when we do announce the next step for the program, when the data reads out, we will be also planning to comment on what Biogen's plans are for the next steps if they option in for the program.

是的。 Eugene 將評論臨床終點、生物標記 EEG 和其他 Bayley-4 等。我們沒有——我們還沒有確定如何以及何時報告 Angelman 計劃的下一步。如您所知，延安、百健（Biogen）可以選擇許可該程序。正如我們之前所說，當我們確實宣布該計劃的下一步時，當數據讀出時，我們還將計劃對百健（Biogen）選擇參與該計劃的下一步計劃發表評論。

As far as forum, we have not settled on that either. There is an Angelman conference in August of this year, which we regularly attend each year. That could be a forum, but we haven't made any firm decisions. And of course, if Biogen licensed this is the program, they will be in the driver's seat to make those calls ultimately. Eugene, talk a little bit about the endpoints that we're looking at in Angelman?

至於論壇，我們也還沒確定。今年8月份有一個Angelman會議，我們每年都會定期參加。那可能是個論壇，但我們還沒有做出任何明確的決定。當然，如果百健（Biogen）許可了這個項目，他們最終將掌握主動權。尤金，談談我們在 Angelman 中看到的終點？

Yes, sure. Thanks for your question, Yanan. Yes. So of course, we're -- this is a truly a learning study for us. And as such, we're really exploring a range of different outcomes, including, of course, EEG, which has built quite a bit of data both through natural history as well as some of the early data that was shared with the community. But importantly, of course, the clinical assessments that include standard scale that you mentioned Bayley-4, of course, Vineland is another very common scale used in neurodevelopmental disorders. But we're also looking at other aspects of this disease, essentially covering a very broad range of presentation and symptoms for Angelman, and that includes things like sleep and behavior and other things. So we're truly trying to learn as much as possible about the impact that our drug may have on all of those features of this pretty complex disorder.

是的，當然。謝謝你的提問，亞南。是的。當然，這對我們來說確實是一項學習研究。因此，我們確實正在探索一系列不同的結果，當然包括腦電圖，它透過自然歷史以及與社區共享的一些早期數據建立了大量數據。但重要的是，當然，臨床評估包括您提到的 Bayley-4 標準量表，當然，Vineland 是神經發育障礙中使用的另一個非常常見的量表。但我們也在研究這種疾病的其他方面，基本上涵蓋了天使人非常廣泛的表現和症狀，其中包括睡眠和行為等其他方面。因此，我們確實在努力盡可能多地了解我們的藥物可能對這種相當複雜的疾病的所有這些特徵產生的影響。

And the next question comes from Luca Issi with RBC.

下一個問題來自 RBC 的 Luca Issi。

Great. Congrats on the progress. Maybe one on TTR cardiomyopathy, Eugene, if I may, -- what was your reaction to AstraZeneca powering their Phase III trial for the monoclonal antibody at 1,000 patients? Basically, we now have Alnylam HELIOS-B has 665 patients. Your trial is 1,400 patients and AstraZeneca's monoclonal antibody in 1,000 patients. Does this mean that Alnylam is under-powered, you are overpowered and monoclonal antibody in the purpose of power. Any thoughts there, most appreciated. And then maybe on AGT, what's the latest thinking on this target. Roche is clearly very excited about it and even willing to run a cardiovascular trial, while it feels that -- your target is not getting the same amount of airtime that it once did. Am I off here?

偉大的。祝賀取得的進展。也許是關於 TTR 心肌病變的，尤金，如果可以的話，您對阿斯特捷利康在 1,000 名患者中進行單株抗體 III 期試驗有何反應？基本上，我們現在 Alnylam HELIOS-B 有 665 名患者。您的試驗涉及 1,400 名患者，阿斯特捷利康的單株抗體則用於 1,000 名患者。這是否意味著Alnylam力量不足，你被壓倒了，單株抗體的力量目的。有任何想法，非常感激。然後也許在 AGT 上，關於這個目標的最新想法是什麼。羅氏顯然對此非常興奮，甚至願意進行心血管試驗，但它感覺——你的目標不再像以前那樣獲得同樣多的播出時間。我離開這裡了嗎？

And if so, what's the next sort of this program? And then finally, on HAE. I think on Page 17, you're citing that these assets obvious includes near elimination of attacks. Wondering if you can comment on whether that applies to both Q4W and Q8W or only Q4W?

如果是這樣，這個計劃的下一個類型是什麼？最後，關於 HAE。我認為在第 17 頁，您提到這些資產顯然包括幾乎消除攻擊。想知道您是否可以評論一下這是否適用於 Q4W 和 Q8W 還是僅適用於 Q4W？

Lot to unpack there. Coming on the question of trial design. So -- we're not that close to AstraZeneca's antibody depleter for TTR cardiomyopathy, Luca, and so the size of their study, the powering assumptions that went into all that, it's not in our area. We, of course, talk to them pretty regularly about how these 2 mechanisms could synergize down the road. So -- but certainly, we're not involved in the design of their trial. I don't think powering assumptions, anything.

那裡有很多東西要打開。關於試驗設計的問題。因此，我們距離阿斯特捷利康針對 TTR 心肌病變的抗體消耗劑 Luca 還不太了解，因此他們的研究規模、所有這些研究的有力假設都不在我們的領域。當然，我們經常與他們討論這兩種機制如何在未來發揮協同作用。所以——但當然，我們沒有參與他們的試驗設計。我不認為任何支持假設。

No. Just on our trial, as you know, we spoke about it a lot -- and certainly, we feel pretty confident in our assumptions that are based on emerging data. So that's what I feel comfortable speaking about. I can't speculate what others use in their assumptions.

不。所以這就是我覺得很舒服的談話。我無法推測其他人在他們的假設中使用了什麼。

A different mechanism. We believe in our trial design. We believe that we have the right size of the trial design and the makeup and the demographics in our cardio transform study. With that, I can't really -- I don't want to comment any more on what others are doing. AGT, no change. We are continuing to progress our plans, as we've stated earlier that we plan to partner this program and we're still planning to do that, and we're making progress. For HAE, we know we -- as we will share with you at EAACI at the end of this month, both every 4-week and every 8-week dosing showed a highly statistically significant benefit in reducing HAE attack rates, but every 4-week dosing had a greater reduction in HAE attacks. So when we refer to near-elimination I certainly every 4-week data comes closer to that than every 8-week dosing.

不同的機制。我們相信我們的試驗設計。我們相信，我們的有氧運動轉化研究中的試驗設計規模、組成和人口統計都是合適的。有了這個，我真的不能——我不想再評論其他人在做什麼。 AGT，沒有變化。我們正在繼續推進我們的計劃，正如我們之前所說，我們計劃與該計劃合作，我們仍然計劃這樣做，而且我們正在取得進展。對於HAE，我們知道，正如我們將在本月底在EAACI 上與您分享的那樣，每4 週和每8 週給藥一次都顯示出在降低HAE 發作率方面具有高度統計學意義的益處，但每4-每週給藥可顯著減少 HAE 發作。因此，當我們提到接近消除時，我肯定每 4 週的給藥數據比每 8 週的給藥數據更接近這一數據。

And the next question comes from Salveen Richter with Goldman Sachs.

下一個問題來自高盛的 Salveen Richter。

SP-3 This is Tommy on for Salveen. So just to follow up on the previous commentary about the Medicare Part D design. Do you think that -- how are you thinking about the possibility that there could be a higher level of scrutiny, especially in cardiomyopathy, given the entrance of another stabilizers potentially this year.

SP-3 這是湯米為薩爾文代言的。因此，我想跟進之前有關 Medicare D 部分設計的評論。鑑於今年可能會出現另一種穩定劑，您如何看待可能進行更高水平的審查的可能性，特別是在心肌病變方面。

For the Medicare D population, I mean, things are evolving a little bit, right, with the IRA regulations and things that have come into play. And historically, there's been quite a bit of distinction around the out-of-pocket expenses for patients and the way that those had to be paid in terms of timing and time lines around that. I think where we're at right now with Medicare Part D is a much more favorable position than we have been historically, and it's only anticipated to get better in the coming years. .

我的意思是，對於 Medicare D 人群來說，隨著 IRA 法規和已經開始發揮作用的事情，情況正在發生一些變化，對吧。從歷史上看，患者的自付費用以及支付方式在時間和期限方面存在很大差異。我認為我們目前在 Medicare D 部分方面的處境比歷史上更加有利，而且預計在未來幾年只會變得更好。 。

So out-of-pocket expenses are going to be limited for those patients, either $3,000 or so this year. It goes down to $2,000 or so next year. And then there's also the ability to spread those costs over time. So it's not onetime assessment for the patient, which I think is very positive.

因此，這些患者的自付費用今年將受到限制，約為 3,000 美元。明年價格會降至 2,000 美元左右。然後還有能力隨著時間的推移分攤這些成本。所以這不是對患者的一次性評估，我認為這是非常積極的。

So when we're thinking about WAINUA and other programs that we have that will go through the Medicare Part D channel, I think we're very encouraged that we'll be able to work effectively within that system and support patients appropriately. And keep in mind, it's not just about our treatment for Medicare Part D, but it's a combination of all of the therapies that those patients are on that will hit that ultimate cap of $3,000 or $2,000, respectively.

因此，當我們考慮 WAINUA 和我們將透過 Medicare D 部分管道進行的其他計劃時，我認為我們感到非常鼓舞，因為我們將能夠在該系統內有效地工作並為患者提供適當的支持。請記住，這不僅僅是我們對 Medicare D 部分的治療，而是這些患者接受的所有治療的組合，將分別達到 3,000 美元或 2,000 美元的最終上限。

So I think we're well positioned in a good place to the reimbursement channels to allow patients to have access and appropriate access to our treatments.

因此，我認為我們在報銷管道方面處於有利地位，可以讓患者獲得並適當地獲得我們的治療。

And the next question comes from David Lebowitz with Citi -- (Operator Instructions).

下一個問題來自花旗集團的 David Lebowitz－（操作員指令）。

Would you be able to comment on ION224 and DGAT2 you as far as the data that you recently presented and what you think about that therapy given the burgeoning MASH landscape ?

您能否根據您最近提供的數據對 ION224 和 DGAT2 發表評論，以及考慮到蓬勃發展的 MASH 領域您對該療法的看法？

Sure, David. Yes, we couldn't have been more pleased with the Phase II data we reported earlier this year on DGAT2 in patients with MASH. This is the first time. So our target of DGAT2 -- by targeting DGAT2 and blocking the triglyceride synthesis pathway in the liver. We certainly expected robust reductions in liver fat based on this mechanism. We were very pleasantly surprised to see not only that, we also saw reductions in MASH resolution, that is inflammation of the liver by biopsy as well as a turnaround of fibrosis, positive reduction in fibrosis in these patients, first time ever, a treatment that blocks fat synthesis was shown to actually achieve this.

當然，大衛。是的，我們對今年稍早報告的 MASH 患者 DGAT2 的 II 期數據感到非常滿意。這是第一次。因此，我們的目標是 DGAT2——透過靶向 DGAT2 並阻斷肝臟中的三酸甘油酯合成途徑。我們當然期望基於這種機制，肝臟脂肪會大幅減少。我們非常驚訝地看到，不僅如此，我們還看到MASH 分辨率的降低，即活檢顯示的肝臟炎症以及纖維化的好轉，這些患者的纖維化明顯減少，這是有史以​​來第一次，這是一種治療方法事實證明，阻止脂肪合成實際上可以實現這一目標。

As we mentioned, this program as exciting as it is, doesn't fit really well within our focus, Ionis on for our wholly owned pipeline in neurology, cardiovascular and maybe specialty rare opportunities. So we think this program fits best with a partner. And that's what we're doing, is we're moving towards partnering this program to take it to the next stage of development, which could certainly be a Phase III program. There's certainly interest, and those conversations are progressing pretty well. It's early in the discussions, but they're progressing well.

正如我們所提到的，這個計畫雖然令人興奮，但並不完全符合我們的重點，Ionis 為我們在神經病學、心血管病學以及也許是專業領域的全資管道提供了難得的機會。因此，我們認為該計劃最適合與合作夥伴合作。這就是我們正在做的，我們正在努力與該專案合作，將其帶入下一階段的開發，這當然可能是第三階段專案。當然有興趣，而且這些對話進展順利。討論還處於早期階段，但進展順利。

And maybe we have time for one last question before wrapping things up.

也許在結束之前我們還有時間問最後一個問題。

Last one comes from Kostas Biliouris with BMO.

最後一位來自 BMO 的 Kostas Biliouris。

Can you remind us what is the status of sapablursen in PV? And when should we expect updates from this program given the increasing activity in that space and the multiple readouts in 2024. Also any thoughts around the commercial opportunity of that program would be helpful?

您能提醒我們一下sapablursen在PV中的地位嗎？鑑於該領域的活動不斷增加以及 2024 年的多次讀數，我們什麼時候應該期待該計劃的更新。

Thank you, Kostas. Yes, yes, the sapablursen program in polycythemia vera Phase II continues to progress well. I think we've said before, it's an open-label study, and we've been -- we've said before that we're clearly seeing evidence of robust activity, efficacy in this study. What we're doing in this Phase II study, that is reductions in hematocrit, red cell accounts normalizing in many cases, in many patients. And what we're doing is dose ranging to understand what the right dose and dose regimen will be for a potential advancement into Phase III development. So we're looking forward to sharing that data potentially this year. It continues.

謝謝你，科斯塔斯。是的，是的，sapablursen 真性紅血球增多症第二期計畫繼續進展順利。我想我們之前已經說過，這是一項開放標籤研究，我們之前已經說過，我們在這項研究中清楚地看到了強有力的活動和功效的證據。我們在這項二期研究中所做的就是減少血球比容，在許多情況下、許多患者中紅血球帳戶恢復正常。我們正在做的是劑量範圍，以了解正確的劑量和劑量方案將有可能推進到 III 期開發。因此，我們期待今年可能共享這些數據。它還在繼續。

The -- as far as the market opportunity to create a question, we're assessing that now. We don't have an answer for you. It's a very interesting area. And our commercial organization is well on its way in doing all the market research for the opportunity in the United States and outside of the United States. So we have not decided on where this program fits best at Ionis or the partner. We're going to try to provide an update by the end of the year on the program. Thanks for the question, Kostas, and thanks, everybody, for joining us today who participated on our call.

至於提出問題的市場機會，我們現在正在評估。我們無法為您提供答案。這是一個非常有趣的領域。我們的商業組織正在順利地進行所有市場研究，以尋找美國和美國以外的機會。因此，我們尚未決定該計劃最適合 Ionis 或合作夥伴。我們將嘗試在今年年底前提供該計劃的最新資訊。感謝科斯塔斯提出的問題，也感謝今天參加我們電話會議的所有人。

We plan to continue all this great momentum throughout the year, focused on next level value for our shareholders and all stakeholders. We're also looking forward to providing a comprehensive overview recap of the Phase III donidalorsen data we are presenting at EAACI on May 31. So stay tuned for that, and we're looking forward to the webcast as well on that day. We hope you can join us on the webcast. And until then, thank you, everybody, for joining in, and have a great day.

我們計劃全年繼續保持這一巨大勢頭，專注於為我們的股東和所有利益相關者創造更高水平的價值。我們也期待對 5 月 31 日在 EAACI 上展示的 III 期 donidalorsen 數據進行全面概述。我們希望您能加入我們的網路廣播。在此之前，謝謝大家的加入，祝您有美好的一天。

Conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連線。