Ionis Pharmaceuticals Inc (IONS) 2024 Q3 法說會逐字稿

Good morning, and welcome to the IONA's Third Quarter 2024 financial results conference call.

早上好，歡迎參加 IONA 2024 年第三季財務業績電話會議。

As a reminder, this call is being recorded.

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 off the call.

現在，我想將電話轉給投資者關係高級副總裁韋德沃克 (Wade Walke)，讓他主持電話會議。

Please begin.

請開始。

Thank you, Danielle.

謝謝你，丹妮爾。

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.

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。

We believe non-GAAP financial results better represent the economics of our business and how we manage our business.

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。

We've also posted the slides on our website that accompany today's call.

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 this morning's call are Brett Monia, our Chief Executive Officer; Eugene Schneider, Chief Clinical Development Officer; Kyle Jenne, Chief Global Product Strategy Officer; and Beth Hougen, Chief Financial 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；施耐德 (Eugene Schneider)，首席臨床開發長； Kyle Jenne，首席全球產品策略長；以及財務長 Beth Hougen。

Richard Geary, Chief Development Officer; Eric Swayze, Executive Vice President of Research; and Jonathan Birchall, Chief Commercial Officer, will also join us for the Q&A portion of the call.

Richard Geary，首席開發長； Eric Swayze，研究執行副總裁；商務長 Jonathan Birchall 也將參加本次電話會議的問答環節。

I would like to draw your attention to slide 3, which contains our forward-looking language statement.

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。

During this call, we will be making forward-looking statements that are based on our current expectations and beliefs.

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。

These statements are subject to certain risks and uncertainties, and our actual results may differ materially.

這些聲明受一定風險和不確定性的影響，我們的實際結果可能有重大差異。

I encourage you to consult the risk factors contained in our SEC filings for additional detail.

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.

謝謝，韋德。

Good morning, everybody, and thank you for joining us on today's call.

大家早安，感謝大家參加今天的電話會議。

This is a pivotal time for Ionis.

對 Ionis 來說，這是一個關鍵時刻。

Nearly five years ago, we set out to execute on a new vision focused on bringing our innovative medicines directly to patients in need.

近五年前，我們開始實施一項新願景，致力於將我們的創新藥物直接帶給有需要的患者。

And today, we're on the cusp of achieving that vision with our first planned independent launch just a few weeks away.

今天，我們即將實現這一願景，距離我們計劃的首次獨立發布僅有幾週時間。

Furthermore, we anticipate three additional independent launches over the next three years, positioning Ionis to enter a new era marked by delivering a steady cadence of important new medicines to people with serious diseases.

此外，我們預計未來三年內還將有另外三款獨立產品上市，這將使 Ionis 邁入一個新時代，即為患有嚴重疾病的患者持續提供重要的新藥。

Olezarsen represents one of the most meaningful wholly owned opportunities in our late-stage pipeline today.

Olezarsen 是我們目前後期研發管線中最有意義的全資擁有機會之一。

It has the potential to address two important patient populations.

它有可能解決兩類重要的患者問題。

With an FDA action date next month, we're ready to first bring Olezarsen to people with familial chylomicronemia syndrome, or FCS, a serious and rare disease that today has no approved treatments in the United States.

隨著 FDA 下個月的行動日期，我們準備先將 Olezarsen 帶給家族性乳糜微粒血症綜合症 (FCS) 患者，這是一種嚴重而罕見的疾病，目前在美國尚無批准的治療方法。

And with Phase III data in people with severe hypertriglyceridemia, or sHTG, planned for the second half of next year, we expect to bring olezarsen to a much larger patient population in 2026.

我們計劃於明年下半年公佈針對嚴重高三酸甘油酯血症 (sHTG) 患者的 III 期數據，預計到 2026 年，olezarsen 將惠及更廣泛的患者群體。

With significant first-mover advantage in both populations and compelling results already demonstrated in FCS, coupled with our expectation for similarly positive data in sHTG, we believe olezarsen could be the standard of care for both disease indications.

憑藉在兩個人群中顯著的先發優勢和已經在 FCS 中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 olezarsen 可以成為這兩種疾病適應症的治療標準。

In parallel, we're leveraging the capabilities established for WAINUA and olezarsen in our preparations to launch donidalorsen next year, our first-in-class treatment for HAE prophylaxis.

同時，我們正在利用為 WAINUA 和 olezarsen 建立的能力，為明年推出 donidalorsen 做準備，這是我們針對 HAE 預防的首創治療藥物。

We're pleased that our NDA submission was recently accepted for review by FDA with no plan for an AdCom.

我們很高興我們的 NDA 提交最近已被 FDA 接受審查，且無需召開 AdCom。

Our PDUFA date is set for August 21, 2025.

我們的 PDUFA 日期定為 2025 年 8 月 21 日。

And outside the US, our commercial partner, Otsuka, expects to file for marketing approval in Europe soon.

在美國以外，我們的商業合作夥伴大塚製藥預計很快就會在歐洲申請行銷批准。

We've generated important and compelling positive data from our comprehensive donidalorsen clinical program, including encouraging data from our OASIS-Plus Switch cohort.

我們從全面的 donidalorsen 臨床計劃中獲得了重要且令人信服的積極數據，包括 OASIS-Plus Switch 隊列的令人鼓舞的數據。

These results, together with the potential for monthly or every two-month self-administration using an auto-injector, strengthen our belief that if approved, donidalorsen has the potential to advance the treatment paradigm for people living with HAE.

這些結果，加上每月或每兩個月使用自動注射器進行自我給藥的可能性，增強了我們的信念：如果獲得批准，donidalorsen 有可能推進 HAE 患者的治療模式。

Looking further ahead, our next wave of wholly owned opportunities is progressing rapidly and includes our program for Angelman syndrome, ION582.

展望未來，我們下一波全資擁有的機會正在迅速進展，其中包括針對 Angelman 症候群的計畫 ION582。

Based on the positive results from the HALOS Phase I/II study and our alignment with FDA on the Phase III study design, we're on track to advance this potentially transformational medicine into Phase III development in the first half of next year.

基於 HALOS I/II 期研究的積極成果以及我們與 FDA 在 III 期研究設計上的一致性，我們有望在明年上半年推進這種具有轉化潛力的藥物進入 III 期開發。

ION582 is an important program in our growing wholly owned neurology franchise, which now includes seven medicines in clinical development.

ION582 是我們不斷發展的全資神經病學特許經營中的一個重要項目，目前包括七種處於臨床開發階段的藥物。

On top of the great progress we're making across our wholly owned pipeline, our partner programs are also advancing very well, allowing more Ionis discovered and developed medicines to reach more and more people, as demonstrated this year with the successful launches of WAINUA and QALSODY.

在我們全資擁有的產品線取得巨大進展的同時，我們的合作夥伴計畫也進展順利，使得更多由 Ionis 發現和開發的藥物能夠惠及更多的人，正如今年 WAINUA 和 QALSODY 的成功上市所體現的那樣。

The launch of our first Ionis co-branded medicine this year, WAINUA, for people with hereditary ATTR polyneuropathy continues to progress well with AstraZeneca.

我們今年推出了第一款 Ionis 聯合品牌藥物 WAINUA，用於治療患有遺傳性 ATTR 多發性神經病變的患​​者，與阿斯特捷利康的合作進展順利。

WAINUA is now approved and available in major markets, including the US, Canada and the UK; and recently received a positive CHMP opinion in Europe.

WAINUA 現已獲得批准，並在美國、加拿大和英國等主要市場上市；並且最近獲得了歐洲CHMP的正面評價。

And we're confident in the potential of WAINUA to address the larger ATTR cardiomyopathy population with our ongoing landmark CARDIO-TTRansform trial on track to deliver the most comprehensive and most robust data set in these patients in the second half of 2026.

我們相信，WAINUA 有潛力解決更大規模的 ATTR 心肌病變患者問題，我們正在進行的具有里程碑意義的 CARDIO-TTRansform 試驗預計在 2026 年下半年為這些患者提供最全面、最可靠的數據集。

We believe WAINUA has the potential to be the treatment of choice for the global ATTR population based on its strong efficacy profile in hereditary ATTR polyneuropathy and the freedom of simple, at-home self-administration together with AstraZeneca's global cardiovascular leadership and our leadership in TTR amyloidosis.

我們相信，WAINUA 有可能成為全球 ATTR 族群的首選治療方案，因為它在遺傳性 ATTR 多發性神經病變方面具有強大的療效，並且可以輕鬆在家中自行給藥，再加上阿斯特捷利康在全球心血管領域的領導地位以及我們在 TTR 澱粉樣變性方面的領導地位。

And we're also pleased that QALSODY, the first approved treatment for a genetic cause of ALS, a medicine that was conceived and discovered by Ionis and commercialized by our partner, Biogen; is now launched and available in Europe and China in addition to the US.

我們也很高興 QALSODY 成為首個獲準治療 ALS 遺傳性疾病的藥物，該藥物由 Ionis 構思和發現，並由我們的合作夥伴 Biogen 商業化；現已推出，除美國外，也將在歐洲和中國發售。

Our other partner programs are also progressing well.

我們的其他合作夥伴計劃也進展順利。

This includes the ongoing Phase III HORIZON study of pelacarsen for Lp(a)-driven cardiovascular disease being developed by Novartis, with data expected next year, and bepirovirsen in Phase III development with GSK for chronic HBV infection now fully enrolled, with data expected in 2026.

這包括諾華公司正在開發的用於治療 Lp(a) 驅動的心血管疾病的 pelacarsen 的 III 期 HORIZON 研究，預計明年將獲得數據，以及與葛蘭素史克公司合作開發的用於治療慢性乙型肝炎的 bepirovirsen 的 III 期開發，目前已完全入組，預計 2026 年將獲得數據。

Our accomplishments so far this year and the investments we're making move us closer to achieving our goal of bringing a steady cadence of new transformational medicines to patients for years to come and generating increased value for all Ionis stakeholders.

我們今年迄今為止的成就和正在進行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 利益相關者創造更大的價值。

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

說完這些，我會把電話轉給尤金。

Thank you, Brett.

謝謝你，布雷特。

Our pipeline has delivered many important achievements this year, including bringing two new medicines to people with serious diseases, eight positive data readouts from our mid- and late-stage pipeline and enrollment completion in 6 Phase III studies.

我們的產品線今年取得了許多重要成就，包括為患有嚴重疾病的患者帶來兩種新藥、從中後期產品線中獲得八個積極的數據以及完成六個 III 期研究的入組工作。

Our progress positions us well to deliver important value-driving events, still to come this year and throughout 2025.

我們的進步使我們能夠在今年和 2025 年舉辦重要的價值驅動活動。

These events include several potential regulatory approvals, two launches for wholly-owned medicines and 3 Phase III readouts.

這些事件包括幾項潛在的監管批准、兩項全資藥品的上市和三項 III 期臨床試驗的讀數。

In addition to all this, we will continue to expand and advance our pipeline of potentially transformational wholly-owned medicines.

除此之外，我們也將持續擴大並推動具有潛在變革性的全資藥品管道。

We look forward to the upcoming December 19 PDUFA action date for olezarsen and FCS and bringing olezarsen to patients, assuming approval.

我們期待即將到來的 12 月 19 日 olezarsen 和 FCS 的 PDUFA 行動日期，並將 olezarsen 帶給患者（假設獲得批准）。

Our NDA submission was based on a positive Phase III BALANCE study in FCS patients that showed substantial and durable triglyceride reductions with olezarsen treatment.

我們的 NDA 提交是基於對 FCS 患者進行的積極的 III 期 BALANCE 研究，該研究表明，olezarsen 治療可以顯著且持久地降低三酸甘油酯。

Importantly, olezarsen also demonstrated substantial and clinically meaningful reductions in acute pancreatitis attacks.

重要的是，olezarsen 也表現出顯著且具有臨床意義的減少急性胰臟炎發作。

In patients taking our planned commercial dose, we observed a 90% mean reduction in acute pancreatitis events, with only one event in the treatment group, which occurred after nearly one year of treatment.

在服用我們計劃的商業劑量的患者中，我們觀察到急性胰臟炎事件平均減少了 90%，治療組中僅發生一次事件，該事件發生在近一年的治療之後。

This was compared to 11 events in the placebo group, with the first event occurring after only nine days.

相較之下，安慰劑組僅發生了 11 起此類事件，其中第一起事件僅在 9 天後發生。

Olezarsen also reduced hospitalizations by remarkable 84% and showed a favourable safety and tolerability profile in the study.

Olezarsen 也將住院率降低了 84%，並在研究中表現出良好的安全性和耐受性。

We're also developing olezarsen for the much larger sHTG patient population.

我們也正在為更廣大的 sHTG 患者群體開發 olezarsen。

Many patients living with sHTG today are unable to manage their triglycerides with current standard of care.

如今，許多患有 sHTG 的患者無法透過目前的標準治療來控制他們的三酸甘油酯。

As a result, we believe that olezarsen has the potential to make a meaningful difference in the lives of people living with sHTG.

因此，我們相信 olezarsen 有可能為 sHTG 患者的生活帶來有意義的改變。

Our comprehensive Phase III program for sHTG fully enrolled.

我們針對 sHTG 的綜合 III 期計劃已全部招募完畢。

We remain on track for data in the second half of next year.

我們將繼續按計畫發布明年下半年的數據。

Following closely behind olezarsen is donidalorsen for the prophylactic treatment of hereditary angioedema.

緊接在olezarsen之後的是donidalorsen，用於預防性治療遺傳性血管性水腫。

Our NDA submission was based on positive data generated from our Phase II study and Phase III program, which includes the OASIS-HAE and OASIS-Plus studies.

我們的 NDA 提交基於我們第二階段研究和第三階段計劃產生的積極數據，其中包括 OASIS-HAE 和 OASIS-Plus 研究。

OASIS-Plus comprises an open-label cohort of patients rolling over from the Phase III study and a separate cohort that we refer to as the Switch study.

OASIS-Plus 包括從 III 期研究中轉移出來的開放標籤患者群組和我們稱為 Switch 研究的單獨隊列。

In the Phase III program, donidalorsen demonstrated an overall sustained mean reduction in HAE attack rates of more than 90% with one year of treatment for both monthly and bimonthly dosing regimens while maintaining a favourable safety and tolerability profile in the study.

在 III 期臨床試驗中，donidalorsen 顯示在為期一年的治療過程中，每月和每兩個月給藥一次的 HAE 發病率總體持續平均降低率超過 90%，同時在研究中保持了良好的安全性和耐受性。

This reduction translated to high level of disease control and clinically meaningful improvements in quality of life across multiple measures in a vast majority of patients.

這種減少意味著大多數患者的疾病控制水平較高，並且透過多項措施在臨床上顯著改善了生活品質。

These positive data were bolstered by the encouraging Switch study results that showed a 62% further reduction in mean monthly HAE attack rates for patients who switched to donidalorsen from their prior prophylactic treatment.

這些積極的數據得到了令人鼓舞的 Switch 研究結果的支持，該結果顯示，從先前的預防性治療轉換為 donidalorsen 的患者的平均每月 HAE 發作率進一步降低了 62%。

Importantly, more than 80% of patients surveyed reported a preference for donidalorsen over their prior treatment.

重要的是，超過 80% 的受訪患者表示，他們更喜歡 donidalorsen 而不是先前的治療方法。

Additionally, we recently presented new long-term Phase II open-label data that showed an overall sustained mean reduction in HAE attack rates of up 96% in up to three years of treatment with monthly or every two months dosing.

此外，我們最近發布了新的長期 II 期開放標籤數據，數據顯示，透過每月或每兩個月服藥一次，在長達三年的治療中，HAE 發病率總體持續平均降低率高達 96%。

Based on these robust results, we believe donidalorsen could become a preferred prophylactic treatment for people with HAE.

基於這些可靠的結果，我們相信 donidalorsen 可能成為 HAE 患者的首選預防治療方法。

With a PDUFA date of August 21 next year, we look forward to bringing this important medicine to HAE patients, assuming approval.

PDUFA 的生效日期為明年 8 月 21 日，如果獲得批准，我們期待將這種重要藥物帶給 HAE 患者。

Recent clinical outcomes data in ATTR cardiomyopathy with another TTR silencer further reinforce our confidence in the potential of WAINUA to improve cardiovascular outcomes and people living with this disease worldwide.

ATTR 心肌病變與另一種 TTR 抑制劑的最新臨床結果數據進一步增強了我們對 WAINUA 改善全球心血管結果和患有這種疾病的患者的潛力的信心。

With over 1,400 patients enrolled, our ongoing cardio transform study is the largest and most comprehensive study ever conducted in ATTR cardiomyopathy.

我們正在進行的心臟轉化研究已招募超過 1,400 名患者，是迄今為止在 ATTR 心肌病變領域進行的最大、最全面的研究。

As a result, we expect the data from this study will enable physicians to make more informed treatment decisions in this dynamic treatment landscape.

因此，我們希望這項研究的數據將使醫生能夠在這種動態的治療環境中做出更明智的治療決策。

In addition, and as part of our Phase III program, we're conducting advanced cardiac imaging sub studies using MRI and Syntigraphy, which will generate valuable data about the potential benefit of WAINUA in cardiomyopathy patients.

此外，作為我們第三階段計劃的一部分，我們正在使用 MRI 和 Syntigraphy 進行先進的心臟成像子研究，這將產生有關 WAINUA 對心肌病變患者的潛在益處的寶貴數據。

We expect the data readout from our Phase III program in the second half of 2026.

我們預計第三階段計畫的數據將於 2026 年下半年公佈。

The rest of our impressive Phase III pipeline is also advancing nicely.

我們令人印象深刻的第三階段管道的其餘部分也進展順利。

Of the nine investigational medicines in Phase III, over half are ones that Ionis is co-commercializing or wholly owned.

在第三階段的九種研究藥物中，超過一半是 Ionis 共同商業化或全資擁有的藥物。

The vast majority have Phase III data readouts or key regulatory filings expected in the next two years.

絕大多數預計在未來兩年內公佈第三階段數據或進行關鍵監管備案。

In addition, Biogen recently presented positive Phase II/III data from the DEVOTE study evaluating higher dose nusinersen in patients with spinal muscular atrophy across all age groups.

此外，Biogen 最近公佈了 DEVOTE 研究的 II/III 期積極數據，該研究評估了高劑量 nusinersen 對各年齡層脊髓性肌肉萎縮症患者的療效。

Building on these positive results and the all characterized profile of SPINRAZA established over the past 10 years, Biogen plans to file for approval with global regulatory agencies for higher dose nusinersen later this year.

基於這些積極成果和過去 10 年來 SPINRAZA 所建立的所有特徵，Biogen 計劃在今年稍後向全球監管機構申請更高劑量 nusinersen 的批准。

Biogen is also conducting additional studies evaluating nusinersen in SMA patients previously treated with risdiplam and patients with a suboptimal response to gene therapy.

Biogen 也正在進行其他研究，評估 nusinersen 對先前接受過 risdiplam 治療的 SMA 患者以及對基因治療反應不佳的患者的療效。

These studies aim to address remaining unmet needs and better informed treatment decisions.

這些研究旨在解決剩餘的未滿足的需求並做出更明智的治療決策。

Our next wave of wholly-owned medicines now includes seven investigational medicines with three recent study starts to treat both rare and more common neurological diseases.

我們下一波全資藥品目前包括七種研究藥物，其中三種最近開始研究，用於治療罕見和更常見的神經系統疾病。

Zilganersen is our medicine in Phase III development to treat Alexander's disease, the type of leukodystrophy with Phase III data expected in the second half of next year.

Zilganersen 是我們處於 III 期研發階段的藥物，用於治療亞歷山大病，這是一種腦白質營養不良症，預計 III 期數據將於明年下半年公佈。

Zilganersen was also recently granted fast track designation by the FDA, reflecting the serious unmet need that exists for this rare disease.

Zilganersen 最近也獲得了 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。

We believe ION582, our poly owned investigational medicine for Angelman Syndrome has transformational potential for the tens of thousands of people living with a serious rare disorder.

我們相信，我們獨資擁有的用於治療天使綜合症的試驗藥物 ION582 具有為數以萬計患有這種嚴重罕見疾病的人帶來轉變的潛力。

Positive early results from the HALO study of ION 582 and people with Angelman Syndrome demonstrated consistent and encouraging improvement in all key functional areas across multiple assessments, with improvements observed across different ages and genotypes.

HALO 對 ION 582 和天使人症候群患者所進行的研究取得了積極的早期結果，經過多次評估，所有關鍵功能領域均取得了持續且令人鼓舞的改善，並且在不同年齡和基因型中均觀察到了改善。

We also saw favorable safety and tolerability at all those levels, including no discontinuation or adverse events that were considered related to study drug.

我們也看到了所有這些水平上的良好安全性和耐受性，包括沒有與研究藥物有關的停藥或不良事件。

We had a positive end of Phase II discussion with the FDA, where we reached alignment on a robust and comprehensive Phase III study design.

我們與 FDA 的第二階段討論取得了積極的成果，我們就穩健而全面的第三階段研究設計達成了一致。

And as a result, we remain on track to advance IM-582 into pivotal development in the first half of next year.

因此，我們仍有望在明年上半年推動 IM-582 進入關鍵開發階段。

Our planned Phase III study focuses on clinical endpoints that reflect the most pressing and meaningful outcomes for people living with Angelman syndrome and their caregivers.

我們計劃的第三階段研究重點關注臨床終點，這些臨床終點反映了患有天使症候群的人及其照護者最緊迫和最有意義的結果。

And we designed the study to deliver robust data in patients representative of the broader Angelman syndrome population.

我們設計了這項研究，以便為代表更廣泛的 Angelman 症候群族群的患者提供可靠的數據。

(technical difficulty) global Phase III study will enrol approximately 200 infants, children, and adults with Angelman syndrome who have a maternal UBE3A gene deletion or mutation.

（技術難題）全球 III 期研究將招募約 200 名患有 Angelman 症候群且母體 UBE3A 基因缺失或突變的嬰兒、兒童和成人。

The trial will be placebo-controlled, which is the gold standard for scientific integrity and enables a simple and straightforward way to operationalize the study.

該試驗將採用安慰劑對照，這是科學完整性的黃金標準，並能夠以簡單直接的方式進行研究。

We plan to evaluate two dose levels, dosed quarterly without a loading regimen for approximately one year.

我們計劃評估兩種劑量水平，每季給藥一次，不採用負荷方案，持續約一年。

Primary endpoint will be improvement in expressive communication as assessed by the Baileys scale for infant and toddler development (technical difficulty), which is an objective and direct clinician-administered assessment instrument.

主要終點是透過貝利嬰幼兒發展量表（技術難度）評估表達性溝通的改善，這是一種客觀、直接的臨床醫生管理的評估工具。

Secondary endpoints include evaluation of overall symptoms of disease severity, cognition, communication, sleep, motor functioning and daily living skills.

次要終點包括對疾病嚴重程度、認知、溝通、睡眠、運動功能和日常生活技能的整體症狀的評估。

We observed positive results for these same endpoints in our HALO Phase I/II study with IM 582 treatment.

我們在 HALO I/II 期研究中觀察到了 IM 582 治療對這些相同終點的正面結果。

We look forward to sharing our planned Phase III program at the test Global Science Summit this weekend.

我們期待在本週末的測試性全球科學高峰會上分享我們計劃的第三階段計劃。

As our pipeline continues to mature, the remainder of this year and next year is going to be very significant for us in terms of regulatory actions and new product launches, reflecting our transformation to a commercial stage company.

隨著我們產品線的不斷成熟，今年剩餘時間和明年對我們來說在監管行動和新產品發布方面將非常重要，這反映了我們向商業階段公司的轉型。

Built to come this year are two important regulatory milestones, including the FDA approval decision of olezarsen [for] FCS and following the recent positive CHMP opinion, the potential approval of WAINUA for ATTR polyneuropathy in Europe.

今年將有兩個重要的監管里程碑，包括 FDA 批准 olezarsen 用於 FCS 治療，以及根據最近的 CHMP 積極意見，WAINUA 可能在歐洲獲得批准用於治療 ATTR 多發性神經病變。

As we look to 2025, in addition to bringing olezarsen to people with FCS, we're poised to deliver donidalorsen to people with HAE assuming approval.

展望 2025 年，除了為 FCS 患者提供 olezarsen 之外，如果獲得批准，我們還準備為 HAE 患者提供 donidalorsen。

We're also on track for 3 Phase III data readouts next year.

我們也計劃明年進行第三階段的第三期資料讀取。

These include two wholly-owned medicines olezarsen for SHTG, a large patient population with high unmet need and zildanersen for Alexander's disease, our most advanced wholly-owned neurology medicine.

其中包括兩種全資藥​​物：用於治療 SHTG 的 olezarsen，該疾病患者群體龐大，且未滿足的醫療需求很高；以及用於治療亞歷山大病的 zildanersen，這是我們最先進的全資神經病學藥物。

And our partner, Novartis, expects Phase III data for pelacarsen, first potential treatment targeting LP(a), a major novel independent risk factor for cardiovascular disease.

我們的合作夥伴諾華公司正在等待 pelacarsen 的 III 期數據，這是首個針對 LP(a) 的潛在治療方法，LP(a) 是心血管疾病的一種重要的新型獨立危險因子。

We also expect multiple data readouts next year from our mid-stage pipeline.

我們也預計明年將從中期管道中讀取多個數據。

This includes data from sapovlirsen or potential treatment for polycythemia vera.

這包括 sapovlirsen 或真性紅血球增多症的潛在治療的數據。

And ION464, our medicine that targets alpha-synuclein that we're studying in multiple systems atrophy.

我們的藥物 ION464 針對的是 α-突觸核蛋白，我們正在研究其在多系統萎縮症中的作用。

Positive outcomes for ION464 or sapovlirsen could support advancing these programs into Phase III development.

ION464 或 sapovlirsen 的積極成果可以支持這些計畫推進到第三階段的開發。

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, Eugene.

謝謝你，尤金。

We are pleased with the continued strong progress for the WAINUA US launch with AstraZeneca and hereditary ATTR polyneuropathy, which has demonstrated substantial sequential quarterly growth this year, driven by strong demand.

我們很高興看到 WAINUA 與阿斯特捷利康合作在美國推出的用於治療遺傳性 ATTR 多發性神經病變的藥物繼續取得強勁進展，在強勁需求的推動下，該藥物今年實現了連續幾個季度的大幅增長。

We continued to see good uptake in the third quarter with product sales increasing 44% compared to the second quarter.

我們繼續看到第三季的良好成長勢頭，產品銷售額與第二季相比成長了 44%。

Patient growth came from patients new to treatment, some switching from other treatments and some using WAINUA as an add-on treatment to their existing therapy.

患者成長主要來自部分新接受治療的患者，部分患者從其他療法轉換而來，部分患者使用 WAINUA 作為現有療法的附加療法。

We are also encouraged by the breadth of prescribers.

我們也對處方人員的廣度感到鼓舞。

Physicians are reporting that patients are having a positive experience on WAINUA.

根據醫生報告，患者對 WAINUA 的體驗良好。

This includes physicians and patients seeing quality of life improvements, patients' ability to access treatment and patients' ability to easily self-administer WAINUA.

這包括醫生和患者的生活品質得到改善、患者獲得治療的能力以及患者輕鬆自我管理 WAINUA 的能力。

And as we and AstraZeneca are progressing our pre-commercialization activities to support the substantial opportunity, WAINUA represents for the ATTR cardiomyopathy population estimated to be between $300,000 and $500,000 worldwide.

隨著我們和阿斯特捷利康推進商業化前活動以支持這一巨大機遇，WAINUA 為全球 ATTR 心肌病變患者帶來的收益估計在 30 萬至 50 萬美元之間。

Ionis has a rich pipeline of potentially life-changing medicines, and we are poised to deliver four independent launches, assuming FDA approvals over the next three years.

Ionis 擁有豐富的可能改變生活的藥物產品線，假設在未來三年內獲得 FDA 批准，我們準備獨立推出四種藥物。

We are just weeks away from the first launch with olezarsen, where Ionis is leading the way in the triglyceride lowering space.

距離 olezarsen 的首次上市僅有幾週時間，Ionis 在降低三酸甘油酯領域處於領先地位。

Olezarsen represents a blockbuster opportunity for Ionis.

Olezarsen 對 Ionis 來說代表著一次巨大的機會。

We have substantial first-mover advantage for two indications: FCS and SHTG.

我們在兩個適應症上擁有明顯的先發優勢：FCS 和 SHTG。

Our first planned launch is for FCS, which is a rare and the most severe form of SHTG.

我們計劃的首次發射是為了進行 FCS，這是一種罕見且最嚴重的 SHTG 形式。

We then plan to launch in the much larger SHTG patient population with triglyceride levels of greater than 500 milligrams per deciliter.

然後，我們計劃在三酸甘油酯水平超過 500 毫克/分升的更大 SHTG 患者群體中推出該藥物。

People with FCS and SHTG suffer from debilitating chronic physical symptoms that impact all aspects of their life.

患有 FCS 和 SHTG 的人會遭受使人衰弱的慢性身體症狀，影響他們生活的各個方面。

There are no approved treatments for people with FCS in the United States.

在美國，尚無針對 FCS 患者的核准治療方法。

People with SHTG are severely underserved by current treatment options and in many cases, are unable to reduce triglyceride levels to current recommended guidelines.

目前的治療方案嚴重不足，SHTG 患者在許多情況下無法將三酸甘油酯水平降低至目前建議的水平。

And in the most severe manifestations of FCS and SHTG, patients can suffer from potentially fatal pancreatitis events that require intensive hospital care.

在 FCS 和 SHTG 最嚴重的表現中，患者可能遭受致命的胰臟炎事件，需要住院重症監護。

We are right where we should be in preparing for our first independent launch for olezarsen and FCS as we approach our upcoming FDA action date.

隨著 FDA 行動日期的臨近，我們正準備首次獨立推出 olezarsen 和 FCS。

Since this is a rare underdiagnosed disease, our medical affairs team has been working to increase disease awareness.

由於這是一種罕見的未被充分診斷​​的疾病，我們的醫療事務團隊一直致力於提高人們對疾病的認識。

This includes engaging with KOLs and physicians currently diagnosing and treating FCS patients, such as endocrinologists, lipidologists, and cardiologists.

這包括與目前診斷和治療 FCS 患者的 KOL 和醫生（例如內分泌學家、脂質學家和心臟病專家）合作。

Building on a strong foundation of increasing disease awareness, the team is identifying physicians most likely to prescribe olezarsen and working to identify FCS patients.

在提高疾病意識的堅實基礎上，該團隊正在尋找最有可能開出 olezarsen 的醫生並努力尋找 FCS 患者。

As with any rare disease launch, it takes time to identify patients, so this work will continue as we build launch momentum.

與任何罕見疾病的推出一樣，識別患者需要時間，因此隨著我們建立推出勢頭，這項工作將繼續進行。

To bolster our field team's efforts, we are executing a tailored omnichannel strategy to drive deeper engagement and real-time insights from patients and health care professionals.

為了支持我們現場團隊的努力，我們正在執行客製化的全通路策略，以推動患者和醫療保健專業人員的更深入參與和即時洞察。

We are deploying a world-class patient and caregiver team to provide a seamless customer experience that supports patients initiating and remaining on therapy.

我們正在部署一支世界一流的患者和護理人員團隊，以提供無縫的客戶體驗，支持患者開始並堅持治療。

The US FCS expanded access program is in place, enabling patients to have access to treatment ahead of potential approval.

美國FCS擴大准入計畫已經到位，使患者能夠在潛在批准之前獲得治療。

And now the sales team is trained and in the field calling on potential treaters.

現在，銷售團隊已經接受培訓並在現場拜訪潛在的治療師。

All of this, along with the learnings from our co-commercialization launch of WAINUA sets us up to execute successfully on our first independent launch.

所有這些，加上我們從 WAINUA 聯合商業化發布中獲得的經驗，為我們成功執行首次獨立發布做好了準備。

And as we look beyond our first launch, we plan to further scale our commercial capabilities for SHTG to realize the full blockbuster potential of olezarsen.

在展望首次發布之後，我們計劃進一步擴大 SHTG 的商業能力，以充分發揮 olezarsen 的轟動潛力。

The team is also preparing to bring donidalorsen, a potential first-in-class medicine to the market next year by leveraging and building upon our efforts and learnings from the WAINUA launch and upcoming olezarsen launch.

團隊也準備好利用和借鑒我們在 WAINUA 發布和即將推出的 olezarsen 發布過程中所取得的努力和經驗，於明年將潛在的同類首創藥物 donidalorsen 推向市場。

HAE is a well-defined patient population with an estimated 20,000 people affected in the US and Europe, while prophylactic treatment in the US is well accepted by patients and physicians, the market continues to grow.

HAE 是一個明確的患者群體，在美國和歐洲估計有 20,000 人受到影響，而美國的預防性治療已得到患者和醫生的廣泛接受，市場持續增長。

Additionally, a meaningful segment of patients in the US are switching treatments seeking a better option.

此外，美國有相當一部分患者正在轉換治療方法，尋求更好的治療選擇。

Outside the US, acute therapies have historically been the standard of care.

在美國以外，急性療法一直是治療的標準。

However, prophylactic treatments are gaining ground, especially in Europe.

然而，預防性治療正逐漸普及，尤其是在歐洲。

Many people with HAE are unsatisfied with the current treatments and are looking for an option that reduces frequency and severity of attacks while also offering good tolerability and convenience.

許多 HAE 患者對目前的治療方法不滿意，正在尋找一種既能減少發作頻率和嚴重程度，又能提供良好耐受性和便利性的治療方案。

Based on donidalorsen strong clinical data, including the Switch data and the simplicity of monthly or every two-month self-administration be an auto-injector, we believe donidalorsen offers the attributes that many people with HAE are looking for.

基於 donidalorsen 強大的臨床數據，包括 Switch 數據以及每月或每兩個月使用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。

Therefore, we believe donidalorsen, if approved, could be a preferred prophylactic treatment for both patients new to therapy and patients currently on available therapies.

因此，我們相信，如果獲得批准，donidalorsen 將可能成為新接受治療的患者和目前正在接受可用療法的患者的首選預防性治療方法。

I am pleased to share that the team is prepared for our upcoming launches.

我很高興地告訴大家，團隊已經為我們即將推出的產品做好了準備。

All of our key commercial leaders and their teams are in place today including our Chief Commercial Officer, Market access, patient services and marketing and sales.

我們所有的主要商業領導人及其團隊均已到位，包括我們的首席商務官、市場准入官、患者服務官以及營銷和銷售官。

We have built out a highly experienced top-tier team who have led or contributed to hundreds of product launches.

我們已經建立了一支經驗豐富的頂級團隊，他們領導或參與了數百種產品的發布。

We are executing on all of the initiatives needed to successfully launch our medicines.

我們正在實施成功推出我們的藥品所需的所有措施。

Importantly, we are ready for our first independent launch, which is just a few short weeks away.

重要的是，我們已經為首次獨立發布做好了準備，只需短短幾週即可完成。

We're right where we need to be with three additional launches planned over the next three years with more to follow.

我們正處於需要的狀態，計劃在未來三年內再發射三次，隨後還會有更多。

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

現在我將把發言權交給貝絲。

Thanks, Kyle.

謝謝，凱爾。

This year, we've made significant strides in advancing our pipeline and achieving our business goals, positioning Ionis to deliver on our vision of bringing a steady cadence of innovative medicines to patients in need.

今年，我們在推進產品線和實現業務目標方面取得了重大進展，使 Ionis 能夠實現我們的願景，即為有需要的患者提供穩定的創新藥物。

To maximize the impact of our potentially transformational medicine and fully realize the opportunities ahead, sustained investment is essential.

為了最大限度地發揮我們潛在的變革性醫學的影響並充分抓住未來的機遇，持續的投資至關重要。

Consequently, we recently executed an equity offering to extend our cash runway.

因此，我們最近進行了股票發行以延長我們的現金流。

This strategic move enable us -- enables us to continue investing ahead of our near-term commercial launches, which collectively have multibillion dollar peak sales potential.

這項策略性舉措使我們能夠在近期的商業發布之前繼續進行投資，這些產品的總峰值銷售潛力高達數十億美元。

Additionally, it allows us to continue to independently advance our next wave of wholly-owned medicines to maximize our potential for sustainable revenue growth.

此外，它使我們能夠繼續獨立推進下一波全資藥品，以最大限度地發揮我們可持續收入成長的潛力。

We earned revenues of $134 million and $479 million in the three and nine months ended September 30, 2024, reflecting a 7% decrease and 3% increase compared to the same period last year, respectively.

截至 2024 年 9 月 30 日的三個月和九個月，我們的營收分別為 1.34 億美元和 4.79 億美元，與去年同期相比分別下降 7% 和成長 3%。

Our diversified revenue streams continued to serve us well, including commercial revenue primarily from royalties and R&D revenue from multiple partner programs.

我們多元化的收入來源繼續為我們帶來良好的服務，包括主要來自特許權使用費的商業收入和來自多個合作夥伴計劃的研發收入。

SPINRAZA remains the primary source of commercial revenue with $57 million and $152 million of royalties for the third quarter and year-to-date.

SPINRAZA 仍然是商業收入的主要來源，第三季和年初至今的特許權使用費為 5,700 萬美元和 1.52 億美元。

We were encouraged that US SPINRAZA product sales increased 2% in the third quarter compared to the same period last year.

我們很高興看到美國SPINRAZA產品第三季銷售額年增2%。

Outside the US, SPINRAZA product sales were impacted primarily due to an annual order from a single country that did not recur in 2024.

在美國以外，SPINRAZA 產品銷售受到影響主要是因為來自某個國家的年度訂單在 2024 年沒有重複出現。

This onetime loss is not expected to impact fourth quarter sales.

預計這筆一次性損失不會影響第四季的銷售。

WAINUA product revenue continued to reflect accelerating growth on a sequential basis, driven by strong underlying demand, increasing 44% in the third quarter compared to the second quarter.

在強勁的潛在需求的推動下，WAINUA 產品營收持續呈現連續加速成長，第三季較第二季成長了 44%。

WAINUA product sales were $23 million and $44 million for the third quarter and year-to-date.

WAINUA 產品第三季和年初至今的銷售額分別為 2,300 萬美元和 4,400 萬美元。

As a result, our royalties for WAINUA over $5 million and $10 million for the respective period.

因此，我們在相應期間向 WAINUA 支付的特許權使用費分別超過 500 萬美元和 1000 萬美元。

R&D revenue for the quarter was in line with the same period last year and increased on a year-to-date basis, reflecting the value that our pipeline and technology continues to generate.

本季的研發收入與去年同期持平，年初至今有所增加，反映了我們的產品線和技術持續創造的價值。

As planned, our non-GAAP operating expenses increased for the third quarter and year-to-date over the same period last year, excluding certain onetime costs in 2023.

按照計劃，除 2023 年的某些一次性成本外，我們的第三季和年初至今的非 GAAP 營運費用較去年同期有所增加。

The increase was driven by higher sales and marketing expenses as we continue to make investments to prepare for our upcoming independent US launches of olezarsen and donidalorsen.

由於我們繼續進行投資，為即將在美國獨立推出的 olezarsen 和 donidalorsen 做準備，因此銷售和行銷費用的增加推動了這一增長。

Our sales and marketing expenses also included our minority portion of WAINUA US launch expenses.

我們的銷售和行銷費用還包括 WAINUA US 上市費用的少數部分。

These investments resulted in our overall SG&A expenses increasing 13% and 26% for the third quarter and year-to-date, respectively.

這些投資導致我們第三季和年初至今的整體銷售、一般及行政費用分別增加了 13% 和 26%。

In line with our plan, R&D expenses were essentially flat for the third quarter and year-to-date compared to the same period last year.

根據我們的計劃，第三季和年初至今的研發費用與去年同期基本持平。

As we have continued to build our commercial infrastructure and support functions to support our back-to-back planned launches with olezarsen and donidalorsen, we have grown our employee base to just over 1,000 employees.

隨著我們不斷建立商業基礎設施和支援功能，以支援與 olezarsen 和 donidalorsen 的背靠背計劃發布，我們的員工人數已增長到 1,000 多人。

Achieving this milestone with modest expense growth highlights our financial discipline and our commitment to drive operating leverage while advancing our strategic priorities as we transform to a commercial stage company.

在費用適度成長的情況下實現這一里程碑，凸顯了我們的財務紀律和我們在向商業階段公司轉型過程中推動營運槓桿和推進策略重點的承諾。

Our year-to-date results keep us on track to meet our 2024 P&L financial guidance, including revenue of more than $575 million, of which approximately $175 million will come from noncash amortization of partner payments we received in prior years.

我們今年迄今的業績使我們預計將實現 2024 年損益財務指引，包括超過 5.75 億美元的收入，其中約 1.75 億美元將來自我們在前幾年收到的合作夥伴付款的非現金攤提。

Our confidence to achieve our 2024 revenue guidance was bolstered by the recent $30 million milestone payment we earned from AstraZeneca for the UK approval of WAINUA.

我們最近從阿斯特捷利康獲得了 3000 萬美元的里程碑付款，用於批准英國的 WAINUA，這增強了我們實現 2024 年收入預期的信心。

We continue to project our full year 2024 operating expenses to increase by a mid- to high single-digit percentage compared to 2023, excluding the impact of onetime costs last year.

不包括去年一次性成本的影響，我們繼續預測 2024 年全年營運費用將比 2023 年成長中高個位數百分比。

And similar to our year-to-date results, the increase will be driven primarily by sales and marketing expenses as we prepare for our sequential independent launches.

與我們今年迄今的業績類似，隨著我們為連續獨立發布產品做準備，成長主要將受到銷售和行銷費用的推動。

And with our recent equity offering, we are now projecting that we will end 2024 with $2.2 billion in cash.

透過最近的股票發行，我們預計到 2024 年底我們將擁有 22 億美元現金。

Looking beyond this year, we plan to deploy our cash to realize the substantial opportunities before us.

展望今年，我們計劃部署現金來實現我們面前的巨大機會。

We will continue to invest in go-to-market preparations for the planned olezarsen and donidalorsen launches.

我們將繼續投資於計劃中的 olezarsen 和 donidalorsen 的上市準備工作。

Additionally, with our increased confidence in the potential of WAINUA and olezarsen to address broader patient population, -- we plan to scale our capabilities in line with the significant potential that these important medicines represent.

此外，隨著我們對 WAINUA 和 olezarsen 滿足更廣泛患者群體的潛力的信心不斷增強，我們計劃根據這些重要藥物所代表的巨大潛力擴大我們的能力。

In parallel, we are investing to ensure sustainable growth with our next wave of medicines.

同時，我們正在進行投資，以確保下一波藥品的可持續成長。

This includes pre-commercialization activities and Phase III development for ION582 for Angelman syndrome and ziganersen for Alexander disease.

這包括針對 Angelman 症候群的 ION582 和針對亞歷山大病的 ziganersen 的商業化前活性和 III 期開發。

Importantly, we expect our focused investments to drive strong revenue growth and create shareholder value as our medicines reach more and more patients in need.

重要的是，隨著我們的藥品惠及越來越多有需要的患者，我們預計我們的重點投資將推動強勁的收入成長並創造股東價值。

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

說完這些，我會把電話轉回給布雷特。

Thank you, Beth.

謝謝你，貝絲。

It's worth emphasizing that the achievements you've heard about today and throughout the last few years position us well as we look to enter a new era for Ionis as a fully integrated commercial-stage biotechnology company poised to directly bring a steady cadence of medicines to people with serious diseases.

值得強調的是，您今天聽到的以及過去幾年所取得的成就為我們奠定了良好的基礎，因為我們期待著讓 Ionis 進入一個新時代，成為一家完全整合的商業階段生物技術公司，準備直接為患有嚴重疾病的人提供穩定的藥物。

We've arrived at this point 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.

我們透過專注於清晰的願景和明確的策略目標達到了這一點，其中包括建立和推進我們的產品線以及將我們構思、發現和開發的藥物直接提供給患者。

Our pipeline has consistently delivered positive Phase II and Phase III data, resulting in the approvals and launches of WAINUA and CalCadi, the anticipated approval and launch of olezarsen this year and the expected approval and launch of donidalorsen next year with much more to come.

我們的研發管線持續提供積極的 II 期和 III 期數據，從而推動了 WAINUA 和 CalCadi 的批准和上市、olezarsen 預計於今年批准和上市、donidalorsen 預計於明年批准和上市，未來還將有更多項目。

And in parallel, our partner programs are progressing on track with important Phase III readouts next year and beyond.

同時，我們的合作夥伴計畫也順利推進，明年及以後將迎來重要的第三階段數據。

In addition, we're extending our leadership position in (technical difficulty) therapeutics by expanding and diversifying our technology, further optimizing our capabilities in established therapeutic areas and opening up new disease areas for drug discovery.

此外，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研發疾病領域，擴大我們在（技術難度）治療學方面的領導地位。

And we recently further strengthened our financial foundation, providing the means to continue advancing our strategic objectives to power future revenue growth and positive cash flow.

我們最近進一步加強了財務基礎，為繼續推進我們的策略目標提供了手段，以推動未來的收入成長和正現金流。

All of this sets us up to deliver on our goal to bring new medicines to patients for years to come.

所有這些都為我們在未來幾年內為患者提供新藥的目標奠定了基礎。

And with that, I'll now open the call for questions.

現在，我開始回答問題。

Danielle?

丹妮爾？

(Operator Instructions) GordGary Nachman, Raymond James.

（操作員指示）GordGary Nachman，Raymond James。

So first on olezarsen for FCS, how soon will you be able to launch post approval?

那麼首先關於 FCS 的 olezarsen，批准後多久可以推出？

And maybe talk about the expected pricing there.

也許可以討論一下預期的定價。

Are you in labelling discussions?

你們正在參與標籤討論嗎？

And anything to call out on those expectations?

有什麼可以強調這些期望嗎？

And just generally, how we should be thinking about that ramp?

一般來說，我們該如何看待這個坡道？

And then I have one follow-up.

然後我還有一個後續問題。

Gary, we are in labelling discussions.

加里，我們正在討論標籤問題。

We're pleased with how things are going, but it inappropriate for me to comment further on that since we are in discussions with the FDA.

我們對事情的進展感到滿意，但由於我們正在與 FDA 進行討論，所以我不宜對此發表進一步評論。

But everything is on track.

但一切都在按計劃進行。

I'll ask Kyle to address the rest of your question regarding pricing and launch and what our expectations are on timing as well.

我將請凱爾回答您關於定價和發布的其他問題，以及我們對時間的期望。

Yes.

是的。

Thanks, Gary.

謝謝，加里。

So like I mentioned in my remarks, we're very pleased with the team that's in place.

正如我在演講中提到的，我們對現有的團隊非常滿意。

We're ready to go.

我們準備出發了。

Leadership is here.

領導力就在這裡。

The sales team is in place.

銷售團隊已到位。

Medical affairs is in place.

醫務事宜已就緒。

So everything is ready to go for December 19.

因此，一切準備就緒，將迎接 12 月 19 日的到來。

And in terms of launch timing, we do expect to launch this year and get product into the channel before the end of the year.

就發佈時間而言，我們確實預計將在今年推出，並在年底前將產品推向通路。

So that's exciting.

這很令人興奮。

In terms of pricing for FCS, we will launch with an ultrarare pricing, which would be expected in this category based on somewhere between 1,000 and 4,000 patients that are appropriate for the therapy.

在 FCS 的定價方面，我們將以極其罕見的定價推出，該定價基於適合該治療的 1,000 至 4,000 名患者預計的這一類別價格。

So that pricing will be communicated on approval and look forward to sharing that with you on December 19 or sooner.

因此，定價將在批准後進行傳達，並期待在 12 月 19 日或更早與您分享。

Okay.

好的。

Great.

偉大的。

And then just on the Phase III Angelman study.

然後就是第三階段 Angelman 研究。

So will there be any interim looks over the course of the year since it's a one-year endpoint any monitoring of these patients required on the safety side?

那麼，由於這是一個一年的終點，因此今年內是否會進行中期觀察，是否需要在安全方面對這些患者進行監測？

And maybe just comment if there was any back and forth in terms of the right primary endpoint for these patients or if there was easy agreement there with the FDA?

也許只是評論一下在這些患者的正確主要終點方面是否有任何來回，或者是否與 FDA 達成了簡單的協議？

Very briefly, Gary.

非常簡短，加里。

The -- we have no plans for an interim look at data during the course of the Phase III REVEAL study.

我們沒有計劃在第三階段 REVEAL 研究過程中對數據進行中期查看。

It's a robust study design.

這是一個嚴謹的研究設計。

And as you all know, Gary, we have a very strong relationship with the neurology division of the FDA.

加里，眾所周知，我們與 FDA 的神經病學部門保持著非常密切的關係。

We came in with our proposals.

我們帶著我們的提案來了。

And after some minor back and forth, the FDA was fully supportive of our proposal.

經過一些小小的反覆討論之後，FDA 完全支持我們的提議。

So it was very little negotiating at the end of Phase II meeting.

因此，第二階段會議結束時談判很少。

Jessica Fye, JPMorgan.

摩根大通的傑西卡·菲伊 (Jessica Fye)。

I have a question about the timing for cardio transform.

我對心臟轉變的時間有疑問。

So I think enrollment completed on July 31, 2023, and 140 weeks after that is April 6, 2026.

所以我認為入學將於 2023 年 7 月 31 日完成，之後 140 週是 2026 年 4 月 6 日。

And in the past, you talked about that readout coming in the first half of '26, then mid-'26.

過去，您曾談到數據會在 26 年上半年和 26 年中期公佈。

And now it sounds like data in the back half of '26.

現在聽起來像是 26 年下半年的數據。

So did anything change with the approach to that study?

那麼該研究方法有什麼改變嗎？

For example, I think I recall the follow-up originally being planned is up to 140 weeks for those who entered the trial towards the end having variable but a little bit shorter follow-up than that.

例如，我記得最初計劃的追蹤時間為 140 週，對於那些在試驗結束時進入試驗的人來說，追蹤時間會有所不同，但會比這稍短。

So is the plan now to follow all patients out to 140 weeks?

那麼現在的計畫是追蹤所有患者直至 140 週嗎？

Or are you really just budgeting like a full three months or more for data cleanup and analysis?

或者您真的只是預算了整整三個月或更長時間用於數據清理和分析？

Thanks, Jess.

謝謝，傑西。

We're really, really continue to be very pleased with not only the conduct of the Phase [III] cardio transform study, but the design of the study is set up to deliver the richest, most comprehensive data set ever delivered in -- for an investigational medicine for TTR cardiomyopathy.

我們真的非常高興，這不僅是因為第三階段心臟轉化研究的開展，還因為該研究的設計旨在為 TTR 心肌病變的研究藥物提供有史以來最豐富、最全面的數據集。

And we think that, that is going to provide a very significant advantage once we get to the market with our partner, AstraZeneca.

我們認為，一旦我們與合作夥伴阿斯特捷利康一起進入市場，這將帶來非常顯著的優勢。

Prior to recent outcome data with another silencer in this class for this disease indication, we were considering the possibility of an early readout.

在獲得針對該疾病的同類另一種消音器的最新結果數據之前，我們正在考慮進行早期讀數的可能性。

However, it is very clear to us and our partner in AstraZeneca that the best decision would be to run the study out towards full completion in which all patients completed 140 weeks of treatment.

然而，我們和我們的伴侶阿斯特捷利康都非常清楚，最好的決定是讓研究全面完成，讓所有患者完成 140 週的治療。

So that's the only change really.

所以這實際上是唯一的改變。

And the last part of your question is exactly on -- if you do the arithmetic and you look at 140 weeks, last patient in compared to when we announced that we completed enrollment it brings you to about midyear of 2026, and then you need to close the database, you need to go through the blocking and tackling and then read the study out.

你問題的最後一部分正是如此——如果你進行算術運算，並且查看 140 週的數據，與我們宣布完成招募時相比，最後一位患者的時間大約是 2026 年中，然後你需要關閉數據庫，你需要經過阻斷和處理，然後讀出研究結果。

So there's nothing there has changed except that we have made a decision to go to full completion through 140 weeks.

所以，除了我們決定在 140 週內全面完成之外，什麼都沒有改變。

Mike Ulz, Morgan Stanley.

摩根士丹利的 Mike Ulz。

It's (technical difficulty) on the line for Mike.

對 Mike 來說，這是 (技術難題)。

Yes, I guess just on FCS, given that it's a pretty small patient population, can you -- could you be able to give us some color on approximately how many patients you've identified and with the competitor possibly coming to market just a few quarters after you.

是的，我想僅就 FCS 而言，考慮到患者群體相當小，您能否告訴我們大約有多少患者，以及競爭對手可能在您之後幾個季度進入市場。

What's your confidence in being able to potentially saturate the market before they can reach it.

您對能夠在他們進入市場之前就飽和市場的能力有何信心？

Yes.

是的。

Thanks for the question.

謝謝你的提問。

First, I'll just reiterate, we're really excited about the launch, and we're ready to go.

首先，我要重申，我們對這次發布感到非常興奮，我們已經準備好了。

We've been in this space for quite some time.

我們已經在這個領域待了很長一段時間了。

And fortunately, we've had our medical affairs team in the field educating physicians and spending time talking about the diagnosis of FCS and the importance in the way that these patients, unfortunately, are being impacted by their disease.

幸運的是，我們的醫療事務團隊已經在現場對醫生進行培訓，並花時間討論 FCS 的診斷以及這些患者不幸受到疾病影響的方式的重要性。

Recently, we have the sales organization that has been hired and is now in place as well.

最近，我們已經招募了銷售人員，現在也已經到位了。

And they've been deployed, not only are they profiling accounts, but they're also educating around how to identify these patients and physicians are beginning to assess who could potentially have FCS within their within their practices.

他們不僅在分析帳戶，還在教育人們如何識別這些患者，醫生也開始評估在他們的實踐中誰可能患有 FCS。

Keep in mind, we have an EAP that has been established in the US.

請記住，我們已經在美國建立了 EAP。

We also have open-label extension that is ongoing.

我們還在進行開放標籤擴展。

So there are patients that are currently being treated and benefiting from therapy, fortunately.

幸運的是，有些患者目前正在接受治療並從治療中受益。

We are continuing to talk about the launch and figuring out exactly where these patients reside, that will go on for quite some time, as you would expect, being that FCS is a rare disease, as a treatment comes to market.

我們將繼續討論上市事宜，並確切了解這些患者居住在哪裡，這將持續相當長一段時間，正如你所預料的那樣，因為 FCS 是一種罕見疾病，作為一種治療方法進入市場。

And as you mentioned, olezarsen potentially will be the first indicated treatment for FCS.

正如您所說，olezarsen 有可能成為 FCS 的首個適應症治療方法。

We expect that patient identification will go up because as physicians know that there's a treatment available, they will be looking to figure out where these patients are, bring them in, and obviously, I get them started on olezarsen.

我們預計患者識別率將會上升，因為醫生知道有可用的治療方法，他們會想辦法找出這些患者在哪裡，把他們帶進來，顯然，我會讓他們開始使用 olezarsen。

So the nine-month plus lead that we have over the competition, I think, is very relevant and will allow us to secure a good launch in a bolus of patients upfront and we continue to do that patient identification longer term, and we expect that ramp to continue over time.

因此，我認為，我們領先競爭對手九個月以上是非常重要的，這將使我們能夠提前確保在患者群體中取得良好開端，並且我們將長期繼續進行患者識別，我們預計這種增長將隨著時間的推移而持續下去。

Okay.

好的。

And then just as a quick follow-up.

然後只是進行快速的跟進。

I guess, how quickly do you expect to be able to enrol patients from the open-label extension as well as the early access program onto paying commercial drug?

我想，您預計多快能夠將來自開放標籤擴展以及早期使用計劃的患者招募到付費商業藥品上？

Yes.

是的。

That's a process that can happen pretty rapidly.

這個過程可以非常迅速地發生。

We expect to be able to communicate things once we have the approval for olezarsen, the commercial approval.

我們希望在獲得 olezarsen 的商業批准後能夠進行溝通。

And we have a patient support program in place, and we'll be able to obviously communicate appropriately with those offices that have those patients and be able to get prescriptions in fairly quickly and start that transition.

我們已經制定了患者支持計劃，我們顯然能夠與有這些患者的辦公室進行適當的溝通，並且能夠相當快地獲得處方並開始轉變。

So I don't want to put an exact time frame on it, but we have a plan in place in order to execute that transition, and we're very confident in being able to make that happen.

所以我不想為此設定一個確切的時間表，但是我們已經制定了計劃來實現這一轉變，並且我們非常有信心能夠實現這一目標。

Yes.

是的。

And just to add to that, Avi, just as a reminder, that will be in the United US patients in the open-label extension that are in the US Obviously, the balance today was a global study. and it will take time to get the approvals in Europe, elsewhere enrol those patients in.

另外，Avi，提醒一下，這將是在美國進行開放標籤擴展研究的美國患者，顯然，今天的平衡是一項全球研究。並且獲得歐洲的批准以及在其他地方招募這些患者也需要時間。

Yanan Zhu, Wells Fargo Securities.

朱亞南，富國證券。

Great.

偉大的。

Congrats on the progress.

祝賀你取得進展。

Maybe first, a couple of very quick follow-ups to earlier questions and answers.

也許首先，我們對先前的問題和答案進行幾個非常快速的跟進。

On FCS, I was wondering, how do you anticipate the payer dynamic given that this is likely a highly priced drug.

關於 FCS，我想知道，考慮到這可能是一種昂貴的藥物，您如何預測付款人的動態。

Would that reimbursement dynamic to the launch in any way?

這種報銷是否會對產品發布產生影響？

And for the ATTR cardiomyopathy program, I was just wondering, you just talked about the 140-day full completion.

關於 ATTR 心肌病變計劃，我很好奇，您剛剛談到了 140 天的完整完成。

Is there any possibility or desire to expand it further, given that Alnylam study had some of the secondary end points out to 42 months.

鑑於 Alnylam 研究的一些次要終點事件延長至 42 個月，是否有可能或希望進一步擴大？

And I have a follow-up after that.

此後我也會進行後續跟進。

And I'll take the (technical difficulty) question, Kyle, I'll take the FCS payer dynamics question.

我將回答（技術難度）問題，凱爾，我將回答 FCS 付款人動態問題。

So again, as you know, we're really like this trial design, most comprehensive study ever conducted in this patient population.

所以，如您所知，我們真的很喜歡這種試驗設計，這是針對該患者群體進行的最全面的研究。

And we are committed to reading it out to its completion through 140 weeks in second half.

我們致力於在下半年的140週內將其讀完。

Of course, we will do what makes the most sense for the drug WAINUA to have the most robust data set as possible, of course, the trial.

當然，我們會盡力讓 WAINUA 藥物擁有盡可能最可靠的數據集，當然就是進行試驗。

So that's something that we and AstraZeneca will continue to think about and potentially act on, but we'll do what's best for the drug.

因此，我們和阿斯特捷利康將繼續考慮這個問題，並可能採取行動，但我們將盡最大努力使該藥物發揮最佳作用。

On the STS payer dynamics.

關於 STS 付款人動態。

Yes.

是的。

We've done a lot of work with the payers as you would expect in terms of pricing and also educating them on FCS as an ultraorphan ultrarare disease, excuse me, in the potential patient population that resides there.

正如您所期望的，我們在定價方面與付款人做了很多工作，並且還對他們進行了教育，讓他們了解 FCS 是一種極為罕見的疾病，對不起，是針對那裡的潛在患者群體。

The EPI for this is between 1 and 13 per million, which takes us in at most up to the 4,000 patient range in the US.

其 EPI 為每百萬 1 至 13 人，這意味著美國最多有 4,000 名患者。

Payers as they're looking at this, doing their budget impact models and understanding their exposure rate potentially within the disease area in the way that these patients are going to present have been very accepting and very understanding of the price point in which they expect to see olezarsen -- we launched at.

付款人正在研究這個問題，建立他們的預算影響模型，並了解他們在疾病領域內的潛在暴露率，以及這些患者將要出現的情況，他們非常接受並且非常理解他們期望看到的 olezarsen 的價格點——我們推出時的價格點。

The approval process from a prior authorization standpoint will be a question in the learning as we go into the launch.

從事先授權的角度來看，審批流程將是我們在啟動過程中需要學習的問題。

But what we do know is that we have a good pathway here.

但我們確實知道，我們在這裡有一條良好的道路。

We've got great data sets, not only in terms of triglyceride lowering that are deep, that are sustained.

我們獲得了出色的數據集，不僅在深度降低三酸甘油酯方面，而且在持續降低方面。

The patients can self-administer this drug.

患者可自行服用該藥。

But we also have great data around hospitalizations and hospitalization rates.

但我們也擁有大量有關住院和住院率的數據。

And so that information, combined with the patient population that is anticipated to be treated by these physicians, we expect the payers to work effectively through the process, get these prior authorizations approved and ultimately get patients on drug very quickly.

因此，根據這些訊息，結合這些醫生預計治療的患者群體，我們期望付款人能夠有效地完成整個流程，獲得這些事先授權的批准，並最終讓患者迅速獲得藥物。

Got it.

知道了。

Very helpful.

非常有幫助。

Then I just have a question about the Phase III design for the Angelman syndrome study.

那我只想問一下關於 Angelman 症候群研究的第三階段設計。

Could you compare and contrast your design with Ultragenyx design Obviously, the primary endpoint is different.

您能將您的設計與 Ultragenyx 設計進行比較和對比嗎？

And I think that's congrats on getting expressive communication as the primary end point.

我認為，祝賀你獲得了富有表現力的溝通作為主要終點。

But in terms of whether it's placebo controlled versus sham control patient age range -- can you talk about the design differences and what the implications might be for enrollment speed and data.

但就安慰劑對照還是假對照患者年齡範圍而言——您能否談談設計差異以及對入組速度和數據可能產生的影響。

Yes.

是的。

I prefer not to comment on other people's trial design, but I can focus on our trial design.

我不願意對其他人的試驗設計發表評論，但我可以專注於我們的試驗設計。

You hit on some of the some of the key differentiating features, I think, in our trial design already in your question.

我認為，您在問題中已經提到了我們試驗設計中的一些關鍵的區別特徵。

We really like a trial design.

我們非常喜歡試驗設計。

We think it's the right trial design for the most definitive outcome in our Phase III REVEAL study.

我們認為這是我們第三階段 REVEAL 研究中最明確結果的正確試驗設計。

We -- first of all, I have to start with the fact that we have a proven platform.

我們——首先，我必須先說明我們有一個經過驗證的平台。

We have a platform that has delivered SPINRAZA, (technical difficulty) and several mid-stage pipeline readouts in CNS diseases.

我們有一個平台，已經提供了SPINRAZA（技術難度）和幾個中樞神經系統疾病的中期管道讀數。

Well with good safety and efficacy, including our HALO Phase I/II study in Angelman's, where we showed strong benefit across all endpoints that were measured, including communication, cognition, and motor function and more.

具有良好的安全性和有效性，包括我們在 Angelman 進行的 HALO I/II 期研究，我們在測量的所有終點方面都顯示出強大的優勢，包括溝通、認知、運動功能等。

Our Phase III trial will examine a broad age group, including children, adolescents, and adults.

我們的第三階段試驗將檢查廣泛的年齡組，包括兒童、青少年和成人。

Our study will examine two dose groups, which we think is going to be very important to maximize the probability for success and strong success, especially (technical difficulty) since we are looking at different age groups in the study.

我們的研究將考察兩組劑量，我們認為這對於最大限度地提高成功率和取得巨大成功的機率非常重要，特別是（技術難度）因為我們在研究中關注的是不同的年齡層。

Thirdly, our study, because we have three cohorts will be randomized 2:1.

第三，由於我們的研究有三個隊列，因此將以 2:1 的比例隨機分配。

We think patients will like that.

我們認為患者一定會喜歡這個。

Patients don't like going on placebo when they're suffering with debilitating disease like Angelman's.

當患者患有像安格曼那樣的使人衰弱的疾病時，他們不喜歡服用安慰劑。

They have an opportunity to benefit -- have a greater probability to be on treatment and receiving benefit because it is a 2:1 randomization.

他們有機會受益——有更大的機率接受治療並獲得益處，因為這是 2:1 的隨機化。

And I also want to mention that the doses we're examining in the Phase III study or the mid- and high dose that we examined in the Phase I/II study, where we showed strong efficacy at both doses, all with very good tolerability.

我還想提一下，我們在 III 期研究中檢查的劑量，或者我們在第一/第二期研究中檢查的中劑量和高劑量，都顯示出兩種劑量的強大功效，並且都具有非常好的耐受性。

So there's not going to -- we don't expect any surprises here with these doses.

所以不會——我們預計這些劑量不會帶來任何意外。

As far as placebo control versus sham, as Eugene said in his prepared remarks, placebo-controlled trials is a gold standard in trial conduct.

至於安慰劑對照與假對照，正如尤金在其準備好的發言中所說，安慰劑對照試驗是試驗實施的黃金標準。

It is viewed by regulatory agencies as the preferred trial design produces the most definitive outcomes without bias, and it's the way to go.

監管機構認為，它是首選的試驗設計，可以產生最明確的結果而無偏見，而且是正確的做法。

Furthermore, we have treated now several thousands of patients with intrathecal bolus injection with our molecules with our chemistries, all with very good safety and tolerability.

此外，我們現在已經透過鞘內推注我們的化學分子治療了數千名患者，兩者均具有非常好的安全性和耐受性。

And that was certainly very important to the FDA that convinced them that a placebo-controlled trial is the trial that is appropriate for -- in our study.

這對 FDA 來說當然非常重要，因為這讓他們相信安慰劑對照試驗是適合我們研究的試驗。

So we have a very well-designed study, and we're looking forward to getting it started in the first half of next year.

因此，我們有一個非常精心設計的研究，我們期待在明年上半年開始進行。

Luca Issi, RBC.

盧卡·伊西（Luca Issi），RBC。

Maybe if I can circle back on a prior question, Eugene.

也許我可以回到之前的問題上，尤金。

You're obviously using express communication as a primary endpoint versus obviously your competitors using cognition.

您顯然使用快速溝通作為主要終點，而您的競爭對手顯然使用認知。

Can you just talk about you think the former is the better way to go versus the latter, any call there, I much appreciate it.

您能否談談您認為前者比後者更好，如果您有任何意見，我將不勝感激。

And then on APOC3, I think ElaLily discontinued their siRNA going after APOC3 wondering what was your reaction to the news and how we should think about implications for your program?

然後關於 APOC3，我認為 ElaLily 在追逐 APOC3 時停止了他們的 siRNA，想知道您對這個消息有何反應以及我們應該如何看待它對您的計劃的影響？

Sure.

當然。

Thanks for the question, Luca.

謝謝你的提問，盧卡。

I'll start with the Angelman question.

我先從 Angelman 的問題開始。

And I'm not sure I would necessarily characterize it as the best endpoint.

而且我不確定我是否一定會將其描述為最佳終點。

It's certainly the end point that is the strongest in terms of our support from our early phase experience from the PAVO study.

從 PAVO 研究早期經驗的支持來看，這無疑是最有力的終點。

It is the one that has very robust results in various age groups and both dose regimens.

它對不同年齡組和兩種劑量方案均有非常顯著的效果。

It's also the endpoint, the expressive communication based on all of the surveys that were conducted in this space in this patient population and community is the endpoint that families indicate consistently as the most important one, they would like to see benefits in a new treatment.

這也是終點，基於在該患者群體和社區中進行的所有調查的表達性溝通是家屬一致表示最重要的終點，他們希望看到新療法的益處。

So again, from the perspective of having the evidence from our proof-of-concept study as well as combination of being an area that is certainly very problematic for people living in Angelman and their caregivers.

因此，再說一次，從我們的概念驗證研究的證據以及結合該地區對居住在安吉爾曼的人們及其護理人員來說肯定非常成問題的因素來看。

We feel that this is the right endpoint to put at the top of the hierarchy right?

我們認為這是放在層次結構頂部的正確端點，對嗎？

So it is what we have proposed and provided.

這就是我們所提出和提供的。

We thought was very good, compelling argument and certainly got buy-in from the agents.

我們認為這個論點非常好，令人信服，也得到了代理商的認可。

Rich, do you take the APOC3 question?

Rich，你會回答 APOC3 問題嗎？

Yes, I'll give it a shot.

是的，我會嘗試一下。

So we don't know internally what Lilly's reasons were.

因此我們內部並不清楚禮來公司這麼做的原因是什麼。

But -- they are looking at a strong position -- strongly positioned drug in (technical difficulty) is a fast mover and they would be coming in behind.

但是——他們正在尋找一個強勢地位——強勢定位的藥物（技術難度）是一個快速的行動者，他們將會落後。

But I think the other piece to this was Lilly was very much looking at cardiovascular risk APOC3 and deemed it to be high risk and may have also added into their discomfort.

但我認為，另一個原因是禮來公司非常關注心血管風險 APOC3，並認為它具有高風險，也可能增加他們的不適感。

I'll just add to that, Richard.

我只想補充一點，理查。

Thank you.

謝謝。

They came to the conclusion on evaluating an APOC3 inhibitor in a cardiovascular indication like an outcome trial.

他們得出結論，要像結果試驗一樣對 APOC3 抑制劑在心血管適應症中的應用進行評估。

They came to our conclusion we made several years ago, I guess, just recently.

我想，他們最近才得出了我們幾年前的結論。

We believe that the unmet need is not in that space nor do we believe that, that is the -- that is something we're pursuing for APOC3.

我們相信未滿足的需求並不在那個領域，我們也不相信，那是──那是我們為 APOC3 所追求的。

We believe that the unmet need is in severe hypertriglyceridemia.

我們認為，未滿足的需求是嚴重的高三酸甘油脂血症。

We're pleased to see that they came around and so we saw several years ago.

我們很高興看到他們回心轉意，幾年前我們就見過這種情況。

David Lebowitz, Citi.

花旗銀行的 David Lebowitz。

In terms of your launches for donidalorsen and olezarsen.

就您為 donidalorsen 和 olezarsen 所做的發布而言。

Even that these are really the first more significant launches that you're doing yourself.

即使這些實際上是你自己進行的第一次更重要的發布。

Could you describe how the sales operation is coming together?

您能描述一下銷售業務的進度嗎？

What the sales team will look like for both indications and how you intend to receive, especially with respect to HAE given that it's a very competitive market.

針對這兩種適應症，銷售團隊將會是什麼樣的，以及您打算如何獲得，尤其是對於 HAE 而言，因為這是一個競爭非常激烈的市場。

Yes.

是的。

Let me turn that over to Jonathan Birchall, our CCO, to talk specifically about those details.

讓我把這個問題交給我們的首席商務官喬納森·伯查爾 (Jonathan Birchall)，來具體談談這些細節。

Thanks, Kyle.

謝謝，凱爾。

We're definitely making good progress.

我們確實正在取得良好進展。

In fact, we're ready to go with the olezarsen and FCS launch.

事實上，我們已經準備好推出 olezarsen 和 FCS。

And we've got all the commercial functions in place market access, patient services, omnichannel commercial operations as well as the brand teams.

我們已具備所有商業功能，包括市場准入、病患服務、全通路商業營運以及品牌團隊。

And some months ago now, we completed the hiring of the field force think Kyle talked about the size of the opportunity there.

幾個月前，我們完成了現場工作人員的招聘，凱爾談到了那裡的機會規模。

And we're very comfortable with both the quality of the candidates that have joined Ionis and also the size of the commercial field force to really maximize the olezarsen opportunity and FCS.

我們對加入 Ionis 的候選人的素質以及商業領域力量的規模都非常滿意，這確實最大限度地發揮了 olezarsen 的機會和 FCS。

As you can imagine, there's a lot of synergy with the second donidalorsen launch in HAE across the commercial functions.

你可以想像，HAE 第二次推出 donidalorsen 將在商業功能上產生很大的協同作用。

We've just started the hiring for the Head of Sales, which is really the last commercial function that we are putting in place.

我們剛開始招募銷售主管，這實際上是我們正在設立的最後一個商業職能。

And that process will complete through the first half of next year in preparation for launch in the second half of next year -- couple of about the competitive marketplace there.

這個過程將在明年上半年完成，為明年下半年的推出做準備——那裡的市場競爭很激烈。

We're very comfortable with the data package that we've got for donidalorsen and the commercial capabilities we're building out that we're certainly ready to be competitive in what while very competitive.

我們對為 donidalorsen 提供的數據包和正在構建的商業能力感到非常滿意，我們已準備好在競爭激烈的環境中保持競爭力。

It still remains an underserved market.

它仍然是一個服務不足的市場。

Jason Gerberry, Bank of America.

美國銀行的傑森·格貝利（Jason Gerberry）。

Just a couple on the pelacarsen readout next year.

明年的 pelacarsen 讀數中只有幾個。

First, with the primary, you're looking at this 90 mg per (technical difficulty) subgroup.

首先，對於主要部分，您正在查看每個子組（技術難度）90 毫克。

If the event reduction looks more compelling in this subgroup, clinically meaningful, how does that alter the addressable market, which I think you guys have framed about [$8] million to [$10] million for secondary prevention, high-risk Lp(a) greater than 70.

如果事件減少在這個亞組中看起來更有說服力，具有臨床意義，那麼這將如何改變潛在市場，我認為你們已經為二級預防、高風險 Lp(a) 大於 70 設定了約 [8] 百萬到 [10] 萬美元的預算。

But how does that change if it's 90 or greater?

但如果達到 90 或更大，情況會如何改變？

And then ultimately, the other question is just what underpins your confidence that you'll have the events to read out around middle of next year versus the potential need to run that trial out longer?

最後，另一個問題是，是什麼支撐著您有信心在明年年中左右宣讀這些事件，而不是可能需要將試驗延長更長時間？

I think your assumed event rates a couple of percentage points higher than what we've seen in like the typical LDL lowering trials in the past.

我認為您假設的事件發生率比我們過去在典型的 LDL 降低試驗中看到的事件發生率高出幾個百分點。

So just kind of wondering, I assume that there's been some assessment of rates on a binded basis and that sort of underpins and firms up the outlook for timing next year.

所以我只是有點好奇，我認為已經對有約束力的利率進行了一些評估，並且這在某種程度上支撐並鞏固了明年時機的前景。

But I just wanted to confirm on that.

但我只是想確認這一點。

Yes.

是的。

So thanks, Jason.

所以謝謝你，傑森。

Those are very good questions.

這些都是非常好的問題。

They're probably best for Novartis. -- you're asking some very specific detailed answers to that.

它們可能對諾華來說是最好的。 —— 你問的是一些非常具體詳細的答案。

But in short, certainly, Novartis has been watching the blinded event rates all along.

但簡而言之，諾華確實一直在關注盲法事件的發生率。

They have regular oversight meetings in which they examine those, and they're based on the events that they're seeing in the study.

他們定期召開監督會議來審查這些情況，並根據他們在研究中看到的事件做出決定。

They're confident they've reiterated recently that they plan to read the study out next year.

他們確信他們最近重申計劃明年宣布這項研究。

And if successful, they would also plan to file next year.

如果成功的話，他們還計劃明年提交申請。

So that is based on the events that they're seeing in the study for sure.

所以這肯定是基於他們在研究中看到的事件。

Regarding the 70 versus 90, if the study hits on 90 but not on 70, it will be a somewhat smaller indication.

至於 70 與 90，如果研究達到 90 但沒有達到 70，那麼這將是一個較小的跡象。

It will be people above 90.

年齡在 90 歲以上的人。

But it's still a massive, massive patient population that were to happen.

但患者人數仍然非常龐大。

The boat were to hit, but the 90 was more compelling than the 70.

船要撞上了，但 90 比 70 更有吸引力。

I don't think that would have a significant impact.

我認為這不會產生重大影響。

I mean there are these people -- I mean, normal Lp(a) in the 30 range or so.

我的意思是，這些人的正常 Lp(a) 在 30 左右的範圍內。

And so even people with 70 milligrams (technical difficulty) with a history of cardiovascular disease are in desperate need for treatment like talocarcin.

因此，即使是患有心血管疾病且體內含有 70 毫克（技術難度）的人也迫切需要像塔羅卡星這樣的治療。

So I think that if the study hits on regardless of the risk reduction was greater in 90 versus 70, I think it will be indicated for all those patients. with the history of CBD.

因此我認為，如果研究結果顯示無論 90% 或 70% 的風險降低幅度更大，我認為它對所有這些患者都適用。了解 CBD 的歷史。

Again, to emphasize, this is a massive patient population, which there are no effective treatment options available today.

再次強調，這是一個龐大的患者群體，目前尚無有效的治療選擇。

Jay Olson, Oppenheimer.

傑伊奧爾森、奧本海默。

Congrats on all the progress.

祝賀你取得的所有進展。

Does the Phase III study design for (technical difficulty) support regulatory filings ex-US?

第三階段研究設計（技術難度）是否支持美國以外的監理備案？

And if so, how are you thinking about ex-US partnering opportunities for 582?

如果是的話，您如何看待 582 與美國以外的國家的合作機會？

And then -- and then I had a follow-up if I could.

然後——如果可以的話我會進行跟進。

Yes.

是的。

So the Thanks, Jay.

所以謝謝你，傑伊。

The -- we're wrapping up.

我們—快結束了。

We're getting close to getting alignment with the EU on the Phase III trial design for an human syndrome.

我們即將與歐盟就人類症候群的第三階段試驗設計達成協議。

We don't see any roadblocks there or anything that's going to cause us to significantly change anything about the study design to get approval in Europe.

我們沒有看到任何障礙，也沒有看到任何會導致我們大幅改變研究設計以獲得歐洲批准的因素。

As far as OUS partnerships for commercializing Angelman's, it's very early.

就 OUS 合作實現 Angelman 商業化而言，現在還為時過早。

It's too early to comment on that.

現在評論這一點還為時過早。

As you know, we have an OUS commercial partner for donidalorsen and we're making great progress for olezarsen, we expect soon. there will be a time that Ionis will emerge from the US market for commercialization.

如您所知，我們在 donidalorsen 方面有一個 OUS 商業合作夥伴，並且我們在 olezarsen 方面正在取得巨大進展，我們期待很快實現。總有一天，Ionis 會從美國市場脫穎而出，實現商業化。

Maybe Angelman's could be that program or maybe something else.

也許 Angelman 可以成為那個程序，或者可能是別的。

It's just too early to -- for us to draw any conclusions there.

現在我們得出任何結論還為時過早。

But it's certainly an area of active conversation within Ionis.

但這無疑是 Ionis 內部積極討論的一個領域。

Great.

偉大的。

Super helpful.

超有幫助。

And then we had a question on 269, your APP ASO.

然後我們對 269（您的 APP ASO）提出了一個問題。

It's great to see research being done in Down syndrome based on the huge unmet need in that population.

很高興看到針對唐氏症的研究正在進行，因為該群體還有大量未滿足的醫療需求。

Can you talk about the rationale for choosing that indication to start with and maybe elaborate on the development strategy and any plans for other indications and differentiating features for your program versus other RNA therapeutics.

您能否談談選擇該適應症作為開始的理由，並詳細說明開發策略和其他適應症的計劃以及您的項目與其他 RNA 療法的差異化特徵。

Yes.

是的。

I'd like our way to comment on the rationale for us starting in down syndrome patients first.

我想以我們的方式評論一下我們首先從唐氏症患者開始的理由。

And then Eugene, maybe you can comment on additional potential indications.

然後尤金，也許你可以評論一下其他潛在的跡象。

Eric?

埃里克？

Yes, sure.

是的，當然。

Thanks, Brett.

謝謝，布雷特。

Well, so Down syndrome is due to triplications of chromosome [21] and APP is on that chrome zone.

那麼，唐氏症是由於 [21] 號染色體的三倍體引起的，而 APP 就位於那個鉻區上。

So they have an extra copy of the APP gene, which causes what you'd expect from having extra gene copies, you get an accumulation of excess amyloid and down syndrome patients are known to have early onset of Alzheimer's disease and dementia relating from accumulation of excess amyloid.

因此，他們擁有額外的 APP 基因拷貝，而這會導致與額外基因拷貝相符的結果：過量的澱粉樣蛋白會積聚，而唐氏症患者則會因過量澱粉樣蛋白的積聚而早發阿茲海默症和癡呆症。

So it was a logical thing for us to look at, and we know that and the down syndrome community has been a little bit underserved, and we think it's a great place to go with a drug that lowers production of a gene product when you have a disease caused by excess gene.

因此，這對我們來說是一個合乎邏輯的事情，我們知道，唐氏症患者群體一直沒有得到充分的醫療服務，我們認為，當患者患有由過量基因引起的疾病時，使用一種可以降低基因產物產生的藥物是一個很好的選擇。

So that's really the logic for going into the patient population.

所以這其實是深入患者群體的邏輯。

We know there's a great need there.

我們知道那裡有很大的需求。

And it makes sense for our technology.

這對我們的技術來說很有意義。

And I'll just add one more thing on the technology.

我只想補充一點關於技術的內容。

This is -- we've been working on chemistry of our drugs, and this is the first MSPA backbone chemistry of our drug going into clinical development, and we expect this to give us improved duration of effect of one benefit of the chemistry, which we hope to see in the trial.

這是 — — 我們一直在研究我們的藥物化學，這是我們藥物進入臨床開發的第一個 MSPA 主幹化學，我們預計這將延長化學益處的有效持續時間，我們希望在試驗中看到這一點。

Yes.

是的。

So further indications, of course, are TBD and the first proof-of-concept experiment and overproduction, clear overproduction of ATP model is critical.

因此，進一步的跡象當然還有待確定，而第一個概念驗證實驗和過剩生產，明確的 ATP 模型的過剩生產至關重要。

But certainly, the most logical one is sporadic AD or forms of AD that are perhaps a little bit better described.

但可以肯定的是，最合乎邏輯的是散發性 AD 或可能更容易描述的 AD 形式。

This approach to kind of addressing the overproduction problem first and then moving into larger indications that are at least thought to be mostly clearance problems, if you will, of APP is probably somewhat similar to what we're doing with WAINUA, right?

這種方法首先解決生產過剩問題，然後轉向更大規模的適應症（至少被認為主要是清除問題），如果你願意的話，APP 可能與我們對 WAINUA 所做的事情有些類似，對嗎？

So the kind of the initial indication with focusing on hereditary then where we could suppress production of TTR and prove that it's beneficial.

因此，最初的適應症重點關注遺傳，我們可以抑制 TTR 的產生並證明它是有益的。

And then following with the broader, more heterogeneous group that includes wild-type that is mostly thought to be a clearance problem -- is something that we potentially could think of as an analogue.

然後，接下來是更廣泛、更異質的組，其中包括野生型，這主要被認為是一個清除問題——這是我們可能認為的類似物。

So we are certainly thinking of AD and potentially other relatively more common indications than Down syndrome.

因此，我們肯定會考慮 AD 以及其他可能比唐氏症更常見的症狀。

But down syndrome experiment is going to be really, really critical for us.

但唐氏綜合症實驗對我們來說確實非常關鍵。

Mani Foroohar, Leerink.

Mani Foroohar，Leerink。

I know a lot of pipeline questions have been answered.

我知道很多有關管道的問題已經得到解答。

I want to circle back on the growth in TTR polyneuropathy, obviously, accelerating from where your revenue base was prior product.

我想回顧一下 TTR 多發性神經病變的成長情況，顯然，您的收入基礎是從先前的產品開始加速的。

Perhaps a question that is for both you guys and AstraZeneca, that you have some insight.

也許這個問題是針對你們和阿斯特捷利康的，你們有一些見解。

To what extent are we seeing patients switching from the existing oligo therapy, which is two, three months, then may lose some efficacy at the end of that time horizon. -- to your at-home therapy with eplontersen?

我們在多大程度上看到患者從現有的寡核苷酸療法轉換而來，這種療法需要兩三個月的時間，然後可能會在這段時期結束時失去一些療效。 —— 您在家中使用 eplontersen 進行治療嗎？

And what -- so what proportion of your growth is coming from patient switching versus previously untreated patients who are getting up once.

那麼 — — 那麼，您的成長比例有多少來自於病患的轉換，以及先前未接受過治療但起床一次的病患的比例是多少？

Yes.

是的。

Thanks for the question, Mani.

謝謝你的提問，Mani。

The growth strategy here in a market that is largely underdiagnosed, less than 20% of these patients are currently on a treatment is really about identifying new patients and securing those patients to initiate treatment from the very beginning.

在這個很大程度上未被充分診斷​​的市場中，只有不到 20% 的患者正在接受治療，我們的成長策略實際上是識別新患者並確保這些患者從一開始就接受治療。

WAINUA and the strategy there, obviously, is playing out.

顯然，WAINUA 及其策略正在發揮作用。

That's why we saw the 44% growth quarter-over-quarter.

這就是我們季度環比增長 44% 的原因。

The profile is exactly what we had expected to benefit these patients in terms of quality of life, the efficacy that they're seeing and the ability to self-administer.

該概況正是我們所期望的，它將在生活品質、療效和自我管理能力方面為這些患者帶來益處。

So the question about switching, it is happening.

因此，關於轉換的問題正在發生。

I don't want to quantify that.

我不想量化這一點。

But what I would say is it's occurring because there is a request from patients and physicians see the benefit of patients being able to self-administer with a simple used auto injector.

但我想說的是，這種情況之所以發生，是因為有病人要求，醫生也看到了病人能夠使用簡單的自動注射器自行注射的好處。

It's a differentiating feature here within the category.

這是此類別的一個差異化特徵。

Patients are getting reimbursed very quickly from a market access standpoint.

從市場准入的角度來看，患者很快就能獲得報銷。

Our patient engagement manager team, they're connecting directly with these patients, having very productive conversations with them about getting initiated on WAINUA and what to expect.

我們的患者參與管理團隊直接與這些患者聯繫，並與他們進行了非常有成效的對話，了解如何開始 WAINUA 以及預期效果。

And overall, the patients are performing very well, and we expect to continue to see the growth in the naive patient population.

總體而言，患者的表現非常好，我們預計初始患者數量將繼續增長。

I expect that we will still see some switches, and we will probably see some combination as well for the mixed phenotype patient in which some of these patients have hereditary polyneuropathy and could benefit from a silencer such as WAINUA.

我預計我們仍會看到一些轉換，對於混合表型患者，我們可能還會看到一些組合，其中一些患者患有遺傳性多發性神經病，並且可以從諸如 WAINUA 之類的抑製劑中受益。

Great.

偉大的。

And a quick follow-up.

並快速跟進。

Your Oligo competitor has talked about in part for the cardiomyopathy market but also in polytropic a belief that those patients who are receiving an in-office therapy the Medicare Part B may have less out-of-pocket or more favorable reimbursement from a facility perspective than an at-home Part D therapy.

您的 Oligo 競爭對手部分談到了心肌病變市場，但同時也認為，那些接受 Medicare B 部分門診治療的患者，從設施角度來看，與接受 D 部分居家治療的患者相比，自付費用可能會更少，或者報銷更優惠。

Can you clarify whether or not you're seeing any headwinds whatsoever from patient auto pocket costs, reimbursement headwinds, et cetera, that would support or refute that competitive argument counter detail.

您能否澄清一下，您是否看到患者汽車自付費用、報銷阻力等方面的任何阻力，以支持或反駁該競爭性論點的反駁細節。

Yes.

是的。

I think the short answer is, with the inflation Reduction Act and the changes for out-of-pocket expenses on Medicare Part D access to care has gone up significantly within that channel.

我認為簡短的回答是，隨著通貨膨脹削減法案和聯邦醫療保險 D 部分自付費用的變化，該管道內的醫療服務自付費用大幅上升。

You're seeing that across not only this category, but I think across all Medicare Part D products ultimately out-of-pocket expenses for patients within WAINUA, the majority of them pay nothing on the commercial side of the business because we have programs to help support those patients.

您不僅會看到這個類別，而且我認為在所有 Medicare Part D 產品中，對於 WAINUA 內的患者來說，最終的自付費用，大多數患者在商業方面無需支付任何費用，因為我們有幫助支持這些患者的計劃。

And then in the Medicare population, keep in mind you have Medicare Advantage and then you have the other population that have some supplemental or some support with their Medicare reimbursement.

然後在醫療保險人群中，請記住您有醫療保險優勢計劃，然後其他人群可以獲得一些補充或醫療保險報銷支持。

And so a lot of those patients are paying very little to nothing because of the way that they have their Medicare Part D plan reimbursed through a secondary insurer.

因此，許多患者只需支付很少的費用甚至不需要支付任何費用，因為他們的聯邦醫療保險 D 部分計劃是透過二級保險公司報銷的。

So overall, very, very good access to care with WAINUA, greater than 75% to 80% of these patients have very little out-of-pocket expenses, and we have the opportunity to help them accordingly with the programs that we have in place.

因此總體而言，透過 WAINUA 獲得醫療服務的機會非常非常好，超過 75% 到 80% 的患者自付費用很少，我們有機會透過現有的計畫為他們提供相應的幫助。

Andy Chan, Wolfe Research.

安迪陳（Andy Chan），沃爾夫研究公司（Wolfe Research）。

So regarding the Doni launch in HAE, so a fraction of these patients, my understanding is either on androgen therapy, they're not on (technical difficulty) , there's not

關於 Doni 在 HAE 中的應用，我的理解是，這些患者中有一小部分正在接受雄性激素治療，他們沒有接受（技術難度），

(technical difficulty).

（技術難度）。

Do you believe that there's an opportunity there to convert these patients to Doni?

您是否相信有機會將這些病人轉變為 Doni？

Or do you just believe that they're very part of reach?

或者您只是相信它們是非常可實現的？

And on the side note, do you think payers are going to begin to play favourites in this market because it's kind of becoming crowded.

另外，您是否認為付款人將開始在這個市場上偏袒任何一方，因為這個市場變得有點擁擠了？

Yes.

是的。

Let me make a couple of intro comments and then I'll turn it over to Jonathan for his perspective as well.

讓我先做幾點介紹性評論，然後我會把它交給喬納森來聽聽他的看法。

The patients that are not on therapy today in the US market, they're approximately 20% to 25% of the overall population.

目前美國市場上未接受治療的患者約佔總人口的 20% 至 25%。

And there are varying reasons that they would not be on treatment yet.

他們尚未接受治療的原因多種多樣。

One would be potentially the current therapies have some sort of aspect that they're not interested in or don't feel comfortable with, or the other aspect is maybe the frequency of tax or whatnot are not severe enough that they feel that they can manage their disease otherwise.

一個原因可能是目前的治療方法可能存在一些他們不感興趣或感覺不舒服的方面，或者另一個原因可能是稅收頻率或諸如此類的因素不夠嚴重，以至於他們覺得可以透過其他方式來控制疾病。

We do believe that there's an opportunity to address this population in three different ways.

我們確實相信有機會透過三種不同方式來解決這個問題。

One, our patients new to therapy, so newly diagnosed patients that are coming in.

第一，我們新接受治療的患者，也就是新診斷的患者。

The second area are the switch patients, which is going to be the bolus of about 75% of the patients in the US that are currently treated on a therapy for HAE could potentially move over to donidalorsen.

第二個領域是轉換患者，即將在美國接受 HAE 治療的約 75% 的患者轉而使用 donidalorsen。

And then the third bucket is the one that you just described, which are the ones that have been diagnosed but are not treated today with a prophylactic -- and we believe that with the profile like donidalorsen, we could potentially capture all three of those buckets based on the way that the data is coming together.

第三個類別就是您剛才描述的類別，即那些已經被診斷但目前尚未採用預防措施進行治療的患者。

Jonathan, anything to add there and then also with payers.

喬納森，還有什麼需要補充的嗎？

No, not really.

不，不是真的。

I think the only thing I would add is, despite the treatment options that have increased in more recent years, -- we know from claims data, there's a large proportion of patients who do switch therapies every year. and some of the patient advocacy group, their survey show that patients are still having breakthrough attacks on the current treatment.

我想我唯一要補充的是，儘管近年來治療選擇有所增加，但是我們從索賠數據中了解到，每年都有很大一部分患者會更換治療方法。以及一些病人維權組織的調查顯示，病人對目前的治療仍產生突破性的攻擊。

So we definitely think there's an opportunity for patients to switch to a new treatment like donidalorsen.

因此我們確實認為患者有機會轉換到像 donidalorsen 這樣的新療法。

And with the payer environment, the full spectrum of treatments -- and we're still comfortable that the payers will support the market at the current prices, given the fairly well-established treatment population to date.

並且在付款人環境中，在全方位的治療範圍內——考慮到迄今為止相當完善的治療人群，我們仍然相信付款人將以當前價格支持市場。

Thanks, Andy.

謝謝，安迪。

And looking at the clock, we have time for one more question, please.

看了看時鐘，我們還有時間再回答一個問題。

Akash Tewari, Jefferies.

傑富瑞 (Jefferies) 的 Akash Tewari。

This is (technical difficulty) on for Akash.

這對 Akash 來說是一個（技術難題）。

On Angleman you previously showed that you could show a shift towards EEG pattern normalization -- in the long-term extension, are you continuing to see the same EEG benefit that you reported at earlier for a six-month time points?

在 Angleman 上，您之前已經展示了可以向 EEG 模式正常化的轉變 - 從長期來看，您是否會繼續看到您之前報告的六個月時間點的相同 EEG 益處？

And also, are you thinking about this as an endpoint of clinical efficacy or more of a make -- and is there any sense of variation in the signal to noise for EEG given that you're looking at both adults and children?

此外，您是否認為這是臨床療效的終點或更多的指標——考慮到您同時觀察成人和兒童，腦電圖的信噪比是否有變化？

Yes.

是的。

So -- we certainly will continue to measure EEGs in our long-term extension as well as in our Phase III trial design.

所以——我們肯定會在長期擴展以及第三階段試驗設計中繼續測量腦電圖。

It will be exploratory and viewed more as a biomarker.

它將具有探索性，並更多地被視為一種生物標記。

It's really -- we're really using this to more better understand the biology in people living with Angelman syndrome and to determine whether or not there's any predictive value of an -- of an abnormal EEG pattern with respect to disease progression different as to your question, the other part of your question is different age groups, whether there's any impact there.

這確實是 — — 我們確實在使用它來更好地了解天使綜合徵患者的生物學特性，並確定異常腦電圖模式對病情進展的預測價值，至於您的問題，您的問題的另一部分是不同的年齡組，是否有任何影響。

We know that adults have been much more muted abnormal EEG pattern than children.

我們知道，成年人的異常腦電圖模式比兒童弱得多。

We want to study that.

我們想研究一下這個。

We want to study that with treatment too.

我們也想透過治療來研究這一點。

However, the EEGs will be more exploratory in nature in our trial.

然而，在我們的試驗中，腦電圖的性質將更具探索性。

And we just haven't done the assessment in long term in our LTE study yet to comment on how that data is looking like.

我們還沒有對 LTE 研究進行長期評估，也無法評論這些數據的狀況。

We will examine a new data cut from our LTE at some point in the future, and we're looking forward to sharing that at the right time.

我們將在未來某個時間點研究從我們的 LTE 中剪切出的新數據，並期待在適當的時間分享這些數據。

But it's a very good question.

但這是一個非常好的問題。

So thank you for that.

非常感謝你。

And with that, I'd like to thank everybody who joined us and asked great questions participated in our call today.

最後，我要感謝今天參加電話會議並提出精彩問題的所有人。

I know we've accomplished a lot, a great deal and have substantial opportunities ahead here at Ionis.

我知道我們在 Ionis 已經取得了很多成就，並且擁有巨大的發展機會。

And we look forward to sharing updates on the progress we're making regularly as we move forward.

我們期待在前進的過程中定期分享我們所取得的進展。

So until then, thanks, everybody, and have a great day.

所以到那時為止，謝謝大家，祝大家有個愉快的一天。