Ionis Pharmaceuticals Inc (IONS) 2023 Q2 法說會逐字稿

Good morning, and welcome to Ionis' Second Quarter 2023 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 2023 年第二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, M.J. 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 the reconciliation of GAAP to non-GAAP financials. .

謝謝 M.J。在我們開始之前，我鼓勵大家訪問 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格，包括 GAAP 與非 GAAP 財務數據的調整表。 。

We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call.

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。

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

今天早上與我一起參加電話會議的是我們的執行長布雷特·莫尼亞 (Brett Monia)； Richard Geary，首席開發長；以及我們的財務長 Beth Hougen。 Eric Swayze，研究執行副總裁；施奈德 (Eugene Schneider)，首席臨床開發長；首席全球產品策略和營運長 Onaiza Cadoret 也將參加我們電話會議的問答部分。

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

我想提請您注意投影片 3，其中包含我們的前瞻性陳述。在這次電話會議中，我們將根據我們當前的期望和信念做出前瞻性的語言聲明。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。

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

這樣，我就把電話轉給布雷特。

Thanks, Wade. Good morning, everybody, and thanks for joining us today. We achieved a great deal in the first half of 2023 as we continued to focus on our most important strategic priorities. We advanced our pipeline in many important ways.

謝謝，韋德。大家早安，感謝您今天加入我們。 2023 年上半年，我們繼續專注於最重要的策略重點，並取得了巨大成就。我們在許多重要方面推進了我們的管道。

We made great progress in building our commercial capabilities. We are writing the next chapter for Ionis as we transform Ionis into a highly successful, fully integrated biopharma, focusing on delivering an abundance of new medicines to patients.

我們在商業能力建構方面取得了巨大進展。我們正在為 Ionis 譜寫新的篇章，將 Ionis 轉變為一家非常成功、完全整合的生物製藥公司，專注於為患者提供大量新藥。

Launch preparations for our 3 near-term commercial opportunities, eplontersen, olezarsen, and donidalorsen are right on track. Eplontersen is currently under regulatory review for ATTR polyneuropathy in the U.S., and we're on track to submit additional filings outside the U.S. before the end of the year. We and AstraZeneca share the goal of bringing eplontersen to ATTR patients globally, who today have limited treatment options.

我們的 3 個近期商業機會（eplontersen、olezarsen 和 donidalorsen）的啟動準備工作正在順利進行。 Eplontersen 目前正在美國接受 ATTR 多發性神經病變的監管審查，我們預計在今年年底前在美國境外提交更多申請。我們和阿斯特捷利康的共同目標是為全球 ATTR 患者提供 eplontersen，這些患者目前的治療選擇有限。

We're also pleased with the longer-term week 85 data for eplontersen from the Phase III NEURO-TTRansform study that we reported last month. These longer-term data showed continued improvements from baseline out to 19 months, highlighting eplontersen's durable efficacy and contributing further to its overall attractive profile. And in a few minutes, Richard will dive deeper into the importance of these data.

我們也對我們上個月報告的 III 期 NEURO-TTRansform 研究中的 eplontersen 第 85 週的長期數據感到滿意。這些長期數據顯示從基線到 19 個月的持續改善，凸顯了 eplontersen 的持久功效，並進一步增強了其整體吸引力。幾分鐘後，理查德將更深入探討這些數據的重要性。

And just last week, we reported that our landmark CARDIO-TTRansform study of eplontersen in patients with ATTR cardiomyopathy completed full enrollment with more than 1,400 patients. This is the largest study ever conducted in this patient population.

就在上週，我們報告了我們對 ATTR 心肌病變患者的 eplontersen 具有里程碑意義的 CARDIO-TTRansform 研究完成了 1,400 多名患者的全面入組。這是迄今為止針對該患者群體進行的最大規模的研究。

Our next major late-stage milestone is the top line readout of the olezarsen Phase III BALANCE study in FCS in the second half of this year. We expect olezarsen in FCS to be the first independent commercial launch for Ionis, and we're well prepared. In parallel, we're advancing our olezarsen Phase III pivotal studies in the much-larger patient population, severe hypertriglyceridemia, or sHTG, which we're also well prepared for.

我們的下一個重要後期里程碑是今年下半年 olezarsen FCS III 期 BALANCE 研究的頂線讀數。我們預計 FCS 中的 olezarsen 將成為 Ionis 的第一個獨立商業發布，我們已經做好了充分準備。同時，我們正在針對更大的患者群體、嚴重高三酸甘油酯血症或 sHTG 推進 olezarsen III 期關鍵研究，我們也為此做好了充分準備。

We also completed enrollment in the Phase III OASIS-HAE study with donidalorsen earlier this year. This important milestone keeps us on track for data in the first half of next year. We continue to be encouraged by the efficacy data donidalorsen has generated to date. We recently announced 2-year open-label extension data that showed consistent and sustained protection against HAE attacks in line with what we previously reported from our randomized Phase II study and our open-label extension study at 1 year.

今年早些時候，我們也與 donidalorsen 完成了 OASIS-HAE 研究 III 期的入組。這一重要的里程碑使我們能夠在明年上半年的數據上保持在正軌上。到目前為止，多尼達洛森產生的療效數據繼續令我們感到鼓舞。我們最近公佈了 2 年開放標籤擴展數據，該數據顯示了針對 HAE 攻擊的一致且持續的保護，與我們先前從隨機 II 期研究和 1 年開放標籤擴展研究中報告的結果一致。

I also want to highlight the continued success we've achieved developing medicines for patients with neurological diseases.

我還想強調我們在為神經系統疾病患者開發藥物方面所取得的持續成功。

SPINRAZA continues to be the global market leader for the treatment of all types of SMA. And just recently, SPINRAZA's proven strong efficacy was reinforced further with highly encouraging new data from the ongoing RESPOND study in SMA patients who had a suboptimal response to gene therapy.

SPINRAZA 繼續成為治療所有類型 SMA 的全球市場領導者。就在最近，SPINRAZA 已被​​證明的強大功效進一步得到進一步加強，來自正在進行的 RESPOND 研究的新數據非常令人鼓舞，該研究針對的是對基因療法反應欠佳的 SMA 患者。

And with the recent approval of QALSODY in the U.S., we now have 2 breakthrough commercial medicines on the market to treat 2 severe neurodegenerative diseases. The FDA's accelerated approval of QALSODY brings hope and a breakthrough treatment to people with SOD1-ALS and their families. And QALSODY approval further validates our capabilities to treat intractable neurological diseases.

隨著 QALSODY 最近在美國獲得批准，我們現在市場上有 2 種突破性的商業藥物，用於治療 2 種嚴重的神經退化性疾病。 FDA 加速批准 QALSODY 為 SOD1-ALS 患者及其家人帶來了希望和突破性治療。 QALSODY 的批准進一步驗證了我們治療疑難神經系統疾病的能力。

Today, we have 12 medicines in clinical development for neurological diseases, including treatments for other forms of ALS, dementias, neurodevelopmental diseases and much more. Our industry-leading neurology research team is also making remarkable achievements to further advance our leadership in neurology therapeutics. With a track record of driving innovation, we are focused in making great progress in advancing new cutting-edge medicines into development to address severe neurological diseases for patients in need.

如今，我們有 12 種針對神經系統疾病的藥物處於臨床開發階段，包括治療其他形式的 ALS、癡呆、神經發育疾病等。我們業界領先的神經病學研究團隊也取得了令人矚目的成就，進一步提升了我們在神經病學治療領域的領導地位。憑藉推動創新的記錄，我們致力於在推動新的尖端藥物的開發方面取得巨大進展，以解決有需要的患者的嚴重神經系統疾病。

Additionally, for the second quarter in a row, our robust late-stage Phase III pipeline has expanded. Roche recently initiated Phase III development of IONIS-FB-LRx in IgA nephropathy, increasing our late-stage Phase III pipeline to 8 drugs being developed for 10 separate indications.

此外，我們強大的後期第三階段管道已連續第二季擴大。羅氏最近啟動了 IONIS-FB-LRx 治療 IgA 腎病的 III 期開發，將我們的後期 III 期產品線增加到針對 10 個不同適應症正在開發的 8 種藥物。

Our robust late-stage pipeline systems are up for a steady cadence of Phase III data readouts over the next few years, positioning Ionis to deliver many new important transformational products to the market for years to come.

我們強大的後期管道系統將在未來幾年內以穩定的節奏進行第三階段的數據讀出，使 Ionis 能夠在未來幾年向市場提供許多新的重要轉型產品。

And just last week, we were pleased to announce our expanded collaboration with Novartis, demonstrating their confidence in Ionis' capabilities to create a next-generation compound targeting Lp(a) as a potential follow-on to pelacarsen, utilizing our latest cutting-edge technologies.

就在上週，我們很高興地宣布與諾華擴大合作，表明他們對Ionis 的能力充滿信心，即利用我們最新的尖端技術，開發一種針對Lp(a) 的下一代化合物，作為pelacarsen 的潛在後續藥物。技術。

As a reminder, pelacarsen is in an ongoing Phase III cardiovascular outcome study called Lp(a)HORIZON, which is fully enrolled with more than 8,000 patients. The HORIZON study is progressing well with data and a potential filing plan for 2025.

提醒一下，pelacarsen 正在進行一項名為 Lp(a)HORIZON 的 III 期心血管結果研究，該研究已全面入組超過 8,000 名患者。 HORIZON 研究進展順利，數據和 2025 年可能提交的計劃已出爐。

We also recently expanded our cardiovascular franchise when we advanced our first cardiac muscle LICA or the first cardiac muscle LICA drug into preclinical development. This muscle-targeting drug is our first to enter development, utilizing our in-licensed [Bicycle] technology. This achievement further highlights the potential for us to expand our drug-discovery capabilities for cardiovascular and neuromuscular diseases.

最近，當我們將第一個心肌 LICA 或第一個心肌 LICA 藥物推進到臨床前開發階段時，我們也擴大了我們的心血管業務。這種肌肉標靶藥物是我們第一個進入開發階段的藥物，利用我們獲得許可的 [Bicycle] 技術。這項成就進一步凸顯了我們擴大心血管和神經肌肉疾病藥物發現能力的潛力。

And importantly, we remain on track to accomplish our other key strategic goals across the business, including achieving our 2023 financial guidance.

重要的是，我們仍有望實現整個業務的其他關鍵策略目標，包括實現 2023 年財務指導。

And with that, I'll turn the call over to Richard to discuss our recent pipeline progress and preview upcoming key events. Next, Beth will review our second quarter and first half financial results, and then I'll wrap things up before taking your questions. Richard?

接下來，我將把電話轉給理查德，討論我們最近的管道進展並預覽即將發生的關鍵事件。接下來，貝絲將回顧我們第二季和上半年的財務業績，然後我將在回答大家的問題之前總結一下。理查德？

Thank you, Brett. Well, as Brett just mentioned, we've made important pipeline progress in the first half of this year, bringing us even closer to our goal to deliver an abundance of new medicines to patients and to the market.

謝謝你，布雷特。嗯，正如布雷特剛才提到的，我們在今年上半年取得了重要的管道進展，使我們更接近向患者和市場提供大量新藥的目標。

We believe that the positive data we have reported to date from the NEURO-TTRansform demonstrate eplontersen's potential to provide substantial benefit for patients with ATTR polyneuropathy. The recent 85 week data further strengthened our confidence in eplontersen's competitive profile.

我們相信，我們迄今為止從 NEURO-TTRansform 報告的積極數據證明了 eplontersen 具有為 ATTR 多發性神經病變患者提供實質益處的潛力。最近的 85 週數據進一步增強了我們對 eplontersen 競爭狀況的信心。

The recent 85-week data further strengthened our confidence in eplontersen's competitive profile. Through 85 weeks, eplontersen continued to demonstrate a sustained and substantial reduction in serum TTR concentration pace compared to baseline. As you can see from both the mNIS+7 and Norfolk Quality of Life graphs, the changes from baseline through 85 weeks of treatment are very encouraging.

最近的 85 週數據進一步增強了我們對 eplontersen 競爭狀況的信心。在 85 週內，與基線相比，eplontersen 繼續證明血清 TTR 濃度速度持續大幅降低。從 mNIS+7 和諾福克生活品質圖表中可以看出，從基線到治療 85 週的變化非常令人鼓舞。

Importantly, a substantial number of patients treated with eplontersen continue to demonstrate improvement in neuropathy impairment and quality of life through the 85 weeks of treatment. These data further add to the totality of data, supporting eplontersen's differentiated profile. We plan to report the full data set at a medical conference later this year.

重要的是，在 85 週的治療過程中，大量接受 eplontersen 治療的患者繼續表現出神經病變損傷和生活品質的改善。這些數據進一步增加了數據總量，支持 eplontersen 的差異化概況。我們計劃在今年稍後的醫學會議上報告完整的數據集。

Eplontersen is currently under review in the U.S., with additional filings outside the U.S., including the EU, planned the end of this year. We and AstraZeneca recently expanded our agreement to include Latin America, further underscoring our and AstraZeneca's commitment to bringing eplontersen to patients around the world.

Eplontersen 目前正在美國接受審查，計劃於今年底在美國境外（包括歐盟）提交更多申請。我們和阿斯特捷利康最近將我們的協議擴大到包括拉丁美洲，進一步強調了我們和阿斯特捷利康將 eplontersen 帶給世界各地患者的承諾。

Positive efficacy and safety results we've seen from NEURO-TTRansform study also support our confidence in eplontersen for ATTR cardiomyopathy. Notably, we recently completed enrollment in our Phase III CARDIO-TTRansform study. With more than 1,400 patients, this is the largest study ever conducted in this indication. We designed the study to demonstrate benefit on cardiovascular outcomes in a broad set of patients.

我們從 NEURO-TTRansform 研究中看到的積極療效和安全性結果也支持了我們對 eplontersen 治療 ATTR 心肌病變的信心。值得注意的是，我們最近完成了 III 期 CARDIO-TTRansform 研究的入組。這是該適應症有史以來規模最大的研究，共有 1,400 多名患者參與。我們設計這項研究是為了證明對廣大患者心血管結局的益處。

Now that enrollment is complete in CARDIO-TTRansform, we expect to report data as early in the first half of 2025. As with most outcome trials, our timelines are based on a variety of factors, including event rates and the evolving clinical landscape.

現在 CARDIO-TTRansform 的入組工作已完成，我們預計最早將於 2025 年上半年報告數據。與大多數結果試驗一樣，我們的時間表基於多種因素，包括事件發生率和不斷變化的臨床情況。

Following eplontersen, olezarsen is the next drug we expect to bring to the market and is the first we will commercialize ourselves. We are developing olezarsen for 2 indications, FCS and sHTG. And while FCS is a rare indication and sHTG represents a much broader population, both indications are characterized by severely elevated triglycerides, which can lead to fatal pancreatitis and atherosclerosis, and both are poorly managed by the current standard of care.

繼 eplontersen 之後，olezarsen 是我們預計推向市場的下一個藥物，也是我們將自己商業化的第一個藥物。我們正在開發 olezarsen 用於 2 個適應症：FCS 和 sHTG。雖然FCS是一種罕見的適應症，而sHTG代表了更廣泛的人群，但這兩種適應症的特徵都是甘油三酯嚴重升高，這可能導致致命的胰臟炎和動脈粥樣硬化，並且目前的護理標準對這兩種適應症的管理都很差。

We remain on track to report data from the Phase III BALANCE FCS study in the second half of this year. Our development program to support the broader sHTG indication is also progressing well, with over 3 million patients in the U.S.. With severe hypertriglyceridemia and first-mover advantage, we believe olezarsen represents a blockbuster opportunity for Ionis.

我們仍有望在今年下半年報告 III 期 BALANCE FCS 研究的數據。我們支持更廣泛的 sHTG 適應症的開發計劃也進展順利，在美國有超過 300 萬患者。憑藉嚴重的高三酸甘油酯血症和先發優勢，我們相信 olezarsen 代表了 Ionis 的一個重磅機會。

Following closely behind olezarsen is our next wholly owned medicine, donidalorsen, treat patients with hereditary angioedema. We recently completed enrollment in the Phase III OASIS-HAE study for donidalorsen, keeping us on track for data in the first half of next year.

緊隨 olezarsen 之後的是我們的下一個全資藥品 donidalorsen，用於治療遺傳性血管性水腫患者。我們最近完成了 donidalorsen 的 III 期 OASIS-HAE 研究的入組，使我們能夠在明年上半年獲得數據。

In June, we reported top line 2-year results on the Phase II open-label extension study of donidalorsen, showing an overall sustained mean reduction in HAE attack rates of 96% from baseline through 2 years across dosing groups. We plan to present these data at a medical conference later this year.

6 月，我們報告了 donidalorsen II 期開放標籤擴展研究的 2 年結果，顯示各劑量組的 HAE 發作率總體持續平均降低，從基線到 2 年，降低了 96%。我們計劃在今年稍後的醫學會議上展示這些數據。

Based on the totality of the data generated to date, donidalorsen continues to demonstrate sustained protection in preventing potentially fatal HAE attacks. As a result, we are confident in donidalorsen's competitive profile, providing us with a meaningful commercial opportunity.

根據迄今為止產生的全部數據，donidalorsen 繼續展示了在防止潛在致命 HAE 攻擊方面的持續保護。因此，我們對多尼達洛森的競爭優勢充滿信心，為我們提供了有意義的商業機會。

Our industry-leading neurology franchise continues to deliver groundbreaking medicines. In April, the FDA approved QALSODY for patients with SOD1-ALS, making it the first approved treatment to target a genetic cause of ALS. In addition, we have 12 medicines in clinical development to treat neurological diseases, including 2 in Phase III studies and 8 in Phase II.

我們行業領先的神經病學特許經營權繼續提供突破性的藥物。今年 4 月，FDA 批准 QALSODY 用於治療 SOD1-ALS 患者，使其成為第一個獲準針對 ALS 遺傳原因的治療方法。此外，我們還有12種治療神經系統疾病的藥物處於臨床開發階段，其中2種處於III期研究，8種處於II期研究。

One of our highest priorities is to expand our wholly owned franchises in neurology and cardiology. We currently have several wholly owned medicines that are moving quickly to the clinic. Our world-class neurology research team is working to turn great science into great medicines that we plan to develop and commercialize ourselves.

我們的首要任務之一是擴大我們在神經病學和心臟病學領域的全資特許經營權。目前，我們有幾種全資藥品正在快速進入臨床。我們世界一流的神經病學研究團隊正在努力將偉大的科學轉化為我們計劃自行開發和商業化的偉大藥物。

As a result, we expect a steady cadence of new clinical study starts over the next several years, ensuring our neurology franchise continues to lead in innovation and positioning us to deliver a growing number of new medicines to patients and the market for years to come.

因此，我們預計新的臨床研究將在未來幾年內穩步啟動，確保我們的神經病學系列產品繼續引領創新，並使我們能夠在未來幾年向患者和市場提供越來越多的新藥。

Now I would like to briefly touch on the recent positive interim results from the RESPOND study of SPINRAZA. RESPOND is an ongoing 2-year Phase IV open-label study, evaluating SPINRAZA in SMA infants and toddlers with suboptimal response to gene therapy. Results from the interim analysis showed that most patients improved in measures of motor function with SPINRAZA treatment. SPINRAZA also continued to demonstrate a favorable safety profile in these patients previously treated with gene therapy.

現在我想簡單談談 SPINRAZA RESPOND 研究最近取得的正面的中期結果。 RESPOND 是一項正在進行的為期 2 年的 IV 期開放標籤研究，評估 SPINRAZA 對基因療法反應不佳的 SMA 嬰兒和幼兒的療效。中期分析結果顯示，大多數患者在接受 SPINRAZA 治療後運動功能指標有所改善。 SPINRAZA 也繼續在這些先前接受過基因治療的患者中表現出良好的安全性。

These data add to the extensive body of evidence demonstrating SPINRAZA's benefit for SMA patients, and that includes treating more than 14,000 patients with a well-established safety profile based on data in patients treated up to 8 years. In addition to RESPOND, Biogen is conducting the ASCEND and DEVOTE studies that together aim to address remaining unmet need and inform treatment decisions for the SMA community.

這些數據進一步證明了 SPINRAZA 對 SMA 患者的益處，其中包括治療超過 14,000 名患者，並根據治療長達 8 年的患者數據得出了良好的安全性。除了 RESPOND 之外，百健 (Biogen) 還在進行 ASCEND 和 DEVOTE 研究，旨在解決尚未滿足的需求並為 SMA 社區的治療決策提供資訊。

Our late-stage pipeline expanded for the second consecutive quarter with the start of a pivotal program for IONIS-FB-LRx in patients with IgA nephropathy. We now have 8 drugs in late-stage development, advancing in a total of 10 separate indications.

隨著針對 IgA 腎病患者的 IONIS-FB-LRx 關鍵項目的啟動，我們的後期產品線連續第二季擴大。我們現在有 8 種藥物處於後期開發階段，總共針對 10 個不同的適應症取得進展。

GSK recently presented new data for bepirovirsen in chronic HBV patients, our other medicine that started a robust Phase III development program earlier this year. The data presented at EASL showed that the bepirovirsen treatment resulted in a durable response in responders from the B-Clear Phase IIb study. GSK plans to present new data later this year from the B-Together study, which is evaluating the bepirovirsen in combination with pegylated interferon.

葛蘭素史克(GSK) 最近公佈了貝匹羅韋森(bepirovirsen) 在慢性乙型肝炎患者中的新數據，貝匹羅韋森是我們於今年早些時候啟動的另一種藥物，已啟動了強而有力的III 期開發計劃。 EASL 上發表的數據顯示，B-Clear IIb 期研究的受訪者接受貝匹羅韋森治療後產生了持久的反應。葛蘭素史克計劃在今年稍後公佈 B-Together 研究的新數據，該研究正在評估貝匹羅韋森與聚乙二醇幹擾素的聯合使用。

In totality, we have had an eventful first half with many important positive data events and clinical advancements. In the second half of this year, we remain on track for a number of key additional events, including U.S. eplontersen approval and regulatory filings outside the U.S., as well as Phase III data for olezarsen and FCS, our next potential medicine to launch after eplontersen. We will keep you updated on our progress on these events and more throughout the rest of the year.

總的來說，我們度過了一個多事的去年，有許多重要的正向數據事件和臨床進展。今年下半年，我們仍有望迎來一些關鍵的額外事件，包括 eplontersen 在美國的批准和美國境外的監管備案，以及 olezarsen 和 FCS 的 III 期數據，FCS 是我們繼 eplontersen 之後推出的下一個潛在藥物。我們將在今年剩餘時間內向您通報這些活動以及更多活動的最新進展。

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

這樣，我就把電話轉給貝絲。

Thank you, Richard. In the second quarter, we continued to make progress on our goal to further strengthen our financial foundation in support of our strategic priorities. Our financial results for the second quarter reflect our ability to generate meaningful revenue to fund investments in key growth opportunities across our business.

謝謝你，理查。第二季度，我們在進一步加強財務基礎以支持我們的策略重點的目標上繼續取得進展。我們第二季的財務表現反映出我們有能力產生有意義的收入，為整個業務的關鍵成長機會的投資提供資金。

We earned revenues of $188 million and $319 million for the second quarter and first half of this year, respectively. Our revenues increased 40% for the quarter and 16% year-to-date over the same period last year, driven by significant partner payments.

今年第二季和上半年我們的營收分別為 1.88 億美元和 3.19 億美元。在大量合作夥伴付款的推動下，我們本季的營收比去年同期成長了 40%，今年迄今的營收比去年同期成長了 16%。

As anticipated, our operating expenses and operating loss for the second quarter and first half of this year increased over the same period last year as we advanced our commercial readiness activities and our pipeline, especially our late-stage programs. We remain well capitalized with $2.4 billion in cash and investments at the end of June, enabling us to continue deploying our financial resources to bring transformational medicines to the market.

正如預期的那樣，隨著我們推進商業準備活動和管道，特別是後期項目，我們今年第二季和上半年的營運費用和營運虧損較去年同期增加。截至 6 月底，我們的資本充足，擁有 24 億美元的現金和投資，使我們能夠繼續部署財務資源，將轉型藥物推向市場。

In the second quarter, we opportunistically refinanced our 2024 convertible notes, and we're able to accomplish all our objectives. We retained our cash to continue making key value-driving investments in our pipeline. We extended the maturity of our 2024 notes to 2028 while maintaining a low coupon.

在第二季度，我們機會主義地對 2024 年可轉換票據進行了再融資，我們能夠實現所有目標。我們保留了現金，以繼續在我們的管道中進行關鍵的價值驅動投資。我們將 2024 年票據的期限延長至 2028 年，同時維持較低的票面利率。

And importantly, we retained the flexibility to repay the new notes with cash, equity or a combination of the two, enabling us to mitigate potential equity dilution. We retired approximately 80% of the 2024 convertible notes. And as a result, our cash balance at the end of June included approximately [$115 million] we have earmarked to address the remaining 2024 notes.

重要的是，我們保留了以現金、股權或兩者相結合的方式償還新票據的靈活性，使我們能夠減輕潛在的股權稀釋。我們註銷了約 80% 的 2024 年可轉換票據。因此，我們截至 6 月底的現金餘額中包括約 [1.15 億美元]，我們已指定用於處理剩餘的 2024 年票據。

SPINRAZA's global sales were $437 million for the second quarter and $880 million year-to-date. As a result, we earned $61 million and $111 million in royalty revenue for the corresponding period. SPINRAZA's global sales were essentially flat compared to the same periods last year, reflecting SPINRAZA's resilience against emerging competition in the U.S. and abroad.

SPINRAZA 第二季的全球銷售額為 4.37 億美元，年初至今為 8.8 億美元。結果，我們在同一時期獲得了 6,100 萬美元和 1.11 億美元的特許權收入。與去年同期相比，SPINRAZA 的全球銷售額基本上持平，反映出 SPINRAZA 對美國和海外新興競爭的抵禦能力。

By working to expand existing markets,will also generate important efficacy data from SPINRAZA's robust life cycle management program. Biogen is making good progress on their goal of returning SPINRAZA to consistent growth.

透過努力擴大現有市場，也將從 SPINRAZA 強大的生命週期管理計畫中產生重要的功效數據。百健 (Biogen) 在使 SPINRAZA 恢復持續增長的目標方面取得了良好進展。

We earned R&D revenue of $110 million in the second quarter and $173 million year-to-date, both of which increased substantially compared to the same period last year. Our significant R&D revenue reflects the value Ionis' technology is creating as numerous partner programs advance.

第二季我們的研發收入為 1.1 億美元，年初至今為 1.73 億美元，兩者均較去年同期大幅成長。我們可觀的研發收入反映了隨著眾多合作夥伴專案的推進，Ionis 技術正在創造的價值。

Notable payments earned in the second quarter included $40 million from AstraZeneca for eplontersen, which included development cost-sharing payments and the $20 million license fee for Latin America rights. $20 million also from AstraZeneca for advancing ION839 into a Phase IIb study for NASH and a [$60 million] payment from Biogen for QALSODY U.S. approval.

第二季獲得的顯著付款包括阿斯特捷利康為 eplontersen 支付的 4000 萬美元，其中包括開發成本分攤付款和拉丁美洲權利的 2000 萬美元許可費。阿斯特捷利康還提供了 2000 萬美元，用於將 ION839 推進 NASH 的 IIb 期研究，百健（Biogen）也支付了 [6000 萬美元]用於 QALSODY 美國的批准。

As planned and aligned with our goal to invest for revenue growth, our non-GAAP operating expenses increased in the second quarter and year-to-date compared to last year. As most of our ongoing Phase III studies are either fully enrolled or approaching full enrollment, as you would expect, our clinical study costs increased, which resulted in higher R&D expenses. Additionally, as we prepare to launch eplontersen, olezarsen and donidalorsen, our SG&A expenses also increased modestly year-over-year.

按照計劃並與我們投資收入成長的目標保持一致，與去年相比，我們的非公認會計原則營運支出在第二季和年初至今有所增加。正如您所期望的那樣，由於我們正在進行的大多數 III 期研究要么已完全入組，要么接近完全入組，因此我們的臨床研究成本增加，從而導致研發費用增加。此外，隨著我們準備推出 eplontersen、olezarsen 和 donidalorsen，我們的 SG&A 費用也同比小幅增長。

Our results for the first half of this year keep us on track to meet our 2023 financial guidance, including our P&L and cash guidance. Looking ahead with many partnered programs advancing, we continue to have numerous opportunities to earn additional R&D revenue.

今年上半年的業績使我們預計將達到 2023 年的財務指導，包括損益表和現金指導。展望未來，隨著許多合作項目的推進，我們將繼續有大量機會獲得額外的研發收入。

We anticipate revenue in the second half will be weighted towards the back end of the year. For example, we are eligible to earn a $50 million milestone payment for the U.S. approval of eplontersen. And we expect to recognize additional amortization revenue from our recently expanded collaboration with Novartis.

我們預計下半年的收入將在年底加權。例如，我們有資格因 eplontersen 在美國獲得批准而獲得 5000 萬美元的里程碑付款。我們預計將從我們最近與諾華擴大的合作中確認額外的攤銷收入。

We project operating expenses to continue to gradually increase over the course of this year. Consistent with our guidance, which includes expenses related to our capital-intensive Phase III studies, we estimate our full-year R&D expenses will increase between 20% and 25% year-over-year, excluding the Metagenomi upfront payment from last year.

我們預計今年營運費用將持續逐步增加。根據我們的指導（包括與資本密集型 III 期研究相關的費用），我們估計我們的全年研發費用將年增 20% 至 25%，不包括去年 Metagenomi 的預付款。

We also continue to project our full-year SG&A expenses to increase approximately $35 million year-over-year as we prepare to bring eplontersen, olezarsen and donidalorsen to the market. For example, as we move closer to launching eplontersen, assuming an approval in late December, our SG&A expenses will include our share of the cost to build out the eplontersen salesforce as well as additional launch-readiness expenses.

隨著我們準備將 eplontersen、olezarsen 和 donidalorsen 推向市場，我們也繼續預計全年 SG&A 費用將年增約 3500 萬美元。例如，當我們距離推出 eplontersen 越來越近時，假設 12 月底獲得批准，我們的 SG&A 費用將包括我們分擔的建立 eplontersen 銷售隊伍的成本以及額外的啟動準備費用。

Over the next few years, we are poised to launch several medicines. As a result, we are in a period of investment. We project our operating expenses to grow modestly. And importantly, by keeping more programs for ourselves, we are positioned to deliver significant revenue growth.

在接下來的幾年裡，我們準備推出多種藥物。因此，我們正處於投資時期。我們預計營運支出將適度成長。重要的是，透過為自己保留更多計劃，我們有能力實現顯著的收入成長。

Additionally, we continue to expect our substantial base of R&D revenues to contribute meaningfully to our overall revenue as our partners continue to advance numerous programs. And with 3 near-term commercial opportunities that have a combined multibillion-dollar peak sales potential and a steady cadence of medicines poised to follow closely behind, we are well positioned to drive substantial revenue growth and long-term value for shareholders.

此外，隨著我們的合作夥伴繼續推動眾多項目，我們仍然預計我們龐大的研發收入基礎將為我們的整體收入做出有意義的貢獻。憑藉 3 個近期商業機會，這些機會的峰值銷售潛力合計達數十億美元，並且藥物的穩定節奏將緊隨其後，我們處於有利位置，可以推動收入的大幅增長和股東的長期價值。

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

然後，我會將電話轉回給布雷特。

Thanks, Beth. Looking forward to the rest of this year, we're laser focused on advancing our key priorities with additional important regulatory and late-stage pipeline events planned for the second half.

謝謝，貝絲。展望今年剩餘時間，我們將專注於推進我們的關鍵優先事項，並計劃在下半年開展其他重要的監管和後期管道活動。

We're well on our way to achieving our goal of delivering an abundance of new medicines to patients. We now have 2 breakthrough medicines to treat devastating neurological diseases on the market. And with the December PDUFA date, we could also add eplontersen to our commercial portfolio late this year.

我們正在順利實現向患者提供大量新藥的目標。現在，我們在市場上有兩種治療破壞性神經系統疾病的突破性藥物。隨著 12 月 PDUFA 日期的到來，我們還可以在今年稍後將 eplontersen 添加到我們的商業產品組合中。

We're on track with our go-to-market activities for each of our near-term commercial opportunities. Our first planned launch of eplontersen with AstraZeneca in patients with ATTR polyneuropathy is quickly approaching, with our independent launches for olezarsen and donidalorsen following closely behind. And with our rich late-stage pipeline, we're well positioned to bring additional medicines to patients for many years to come.

我們正在為每個近期商業機會進行市場推廣活動。我們計劃與阿斯特捷利康合作首次針對 ATTR 多發性神經病患者推出 eplontersen 的計劃即將臨近，緊隨其後的是我們單獨推出的 olezarsen 和 donidalorsen。憑藉我們豐富的後期產品線，我們有能力在未來許多年為患者提供更多藥物。

We also continue to make innovative technological advancements to enhance our leadership position in RNA therapeutics, positioning us to add to our steady cadence of new transformational medicines well into the future. And our strong financial foundation enables us to invest in areas with the greatest potential to drive increasing value. We look forward to sharing our progress as we advance our priorities.

我們也持續取得創新技術進步，以增強我們在 RNA 治療領域的領導地位，使我們能夠在未來穩步推進新型轉化藥物的開發。我們強大的財務基礎使我們能夠投資於最有潛力推動價值成長的領域。我們期待在推進優先事項的過程中分享我們的進展。

And with that, we'll now open it up for questions. Operator?

至此，我們現在開始提問。操作員？

(Operator Instructions) Today's first question comes from Myles Minter with William Blair.

（操作員說明）今天的第一個問題來自邁爾斯·明特（Myles Minter）和威廉·布萊爾（William Blair）。

Congrats on the quarter. First one is olezarsen. And I know that your stance in the severe hypertriglyceridemia trials is that you wouldn't need to conduct an outcome study or not looking to. There's been some language put out there from one of the PR companies developing in the space as well that they would be doing an outcome study. Has that language sort of changed your viewpoint on the need to conduct an outcome study in that population?

恭喜本季。第一個是奧萊札森。我知道您在嚴重高三酸甘油脂血症試驗中的立場是您不需要或不希望進行結果研究。一家在該領域發展的公關公司也發表了一些言論，表示他們將進行一項結果研究。這種語言是否改變了您對需要在該群體中進行結果研究的看法？

Thanks, Myles. Absolutely not. We're focused on patients with severely elevated triglyceride to genetically caused FCS. For severely elevated triglyceride, there's no known genetic cause of disease. These are patients that suffer from severe metabolic diseases, particularly acute pancreatitis that can evolve to chronic pancreatitis, diabetes and all kinds of other morbidities.

謝謝，邁爾斯。絕對不。我們重點關註三酸甘油酯嚴重升高而導致 FCS 的患者。對於嚴重升高的三酸甘油酯，尚無已知的遺傳原因。這些患者患有嚴重的代謝性疾病，特別是急性胰臟炎，可以演變成慢性胰臟炎、糖尿病和各種其他疾病。

There is also a cardiovascular component to severely elevate triglyceride, but our focus is on getting patients out of harm's way in the -- the have -- for suffering from severely elevated triglycerides. We've done a lot of research. We're preparing the market, and we're ready to -- we're preparing for launching olezarsen for FCS and sHTG. And I'd like to just maybe ask Onaiza to expand on Myles' question.

還有一個心血管因素會導致三酸甘油酯嚴重升高，但我們的重點是讓患有三酸甘油酯嚴重升高的患者遠離傷害。我們做了很多研究。我們正在準備市場，我們正在準備為 FCS 和 sHTG 推出 olezarsen。我或許想請奧奈札進一步闡述麥爾斯的問題。

Sure. Myles, yes, as we've spoken before, we see a great unmet need for severely elevated triglycerides in the marketplace, over 500. This is a market where we have over 3.5 million patients. The standard of care is just not sufficient to actually meet the goals that these patients are required to meet or the medical guidelines, which is to get them below 500 or as close to 500 as possible to get them out of harm's way for the risks that Brett just highlighted, particularly acute pancreatitis risk.

當然。 Myles，是的，正如我們之前所說，我們看到市場上對嚴重升高的三酸甘油酯的需求尚未得到滿足，超過 500 種。在這個市場上，我們有超過 350 萬名患者。護理標準不足以實際滿足這些患者需要達到的目標或醫療指南，即使他們的評分低於 500 或盡可能接近 500，以使他們免受以下風險的傷害：布雷特剛剛強調了特別是急性胰臟炎的風險。

So we have -- we're really looking forward to getting the drug on market for that, both for the rare disease, genetically defined as FCS. We expect to see the BALANCE data by the end of the year and then looking forward to launching into that and then -- and ultimately, into the severe hypertriglyceridemia space.

因此，我們真的很期待將這種藥物推向市場，這兩種藥物都用於治療遺傳上定義為 FCS 的罕見疾病。我們預計在今年年底之前看到 BALANCE 數據，然後期待進入該領域，然後 - 最終進入嚴重高三酸甘油酯血症領域。

And second question is just on the week 85 data for eplontersen in polyneuropathy. I do also understand that there was Vitamin A deficiency-related ocular events that were discovered in that trial. Obviously, reduction that you get Vitamin A deficiency and you can supplement that.

第二個問題是關於 eplontersen 在多發性神經病變中第 85 週的數據。我還了解到，在那次試驗中發現了與維生素 A 缺乏相關的眼部事件。顯然，減少維生素 A 缺乏的情況是可以補充的。

But my question is, have you submitted that data to the FDA just for safety purposes only? I don't think you've submitted it with the efficacy data, but will they see that safety data?

但我的問題是，你們向 FDA 提交這些資料只是為了安全目的嗎？我認為您沒有提交功效數據，但他們會看到安全數據嗎？

Eugene?

尤金？

Yes. Thanks for your question, Myles. So we submitted all of the comprehensive safety information, including the information that was routine with a day 120 update as part of the NDA. So all of the safety data that was available at the time as well as the updates related to the day 120 update were submitted to the FDA and are under review.

是的。謝謝你的提問，邁爾斯。因此，我們提交了所有全面的安全信息，包括作為 NDA 一部分的 120 天更新的常規信息。因此，當時可用的所有安全資料以及與第 120 天更新相關的更新已提交給 FDA 並正在接受審查。

Everything on track, right, Eugene?

一切都步入正軌，對吧，尤金？

Everything's on track, absolutely.

一切都在正軌上，絕對的。

The next question comes from Debjit Chattopadhyay with Guggenheim Securities.

下一個問題來自古根漢證券公司的 Debjit Chattopadhyay。

This is Robert on for Debjit. Does Ionis and [aSyn] plan to compete against siRNA options in the [ATTR-PN] market? And does [aSysn's] presence potentially allow eplontersen to be first approval to any significant global markets?

我是羅伯特為德布吉特配音。 Ionis 和 [aSyn] 是否計劃在 [ATTR-PN] 市場與 siRNA 選項競爭？ [aSysn] 的存在是否有可能使 eplontersen 成為任何重要全球市場的第一個批准者？

Thanks, Robert. Onaiza, do you want to...

謝謝，羅伯特。奧奈扎，你想…

Yes, sure, Robert. We're very excited with the data that we're seeing. The week 85 data was very encouraging. We saw a duration of effect sustained TTR suppression for TTR and then obviously, halting disease progression and seeing improvement in a substantial number of patients in both mNIS+7 and Norfolk Quality of Life.

是的，當然，羅伯特。我們對所看到的數據感到非常興奮。 85週的數據非常令人鼓舞。我們看到 TTR 的 TTR 抑制持續一段時間，然後明顯地阻止了疾病進展，並看到大量患者的 mNIS+7 和諾福克生活品質得到改善。

So we've got a really great efficacy data package. We have, from all of the research we've done, the more preferred administration profile. With self-administration at home, allows patients to be empowered in taking control of their disease and taking the medication wherever they are with them, not relying on going into the HCP's office.

所以我們有一個非常好的功效數據包。根據我們所做的所有研究，我們發現了更受歡迎的管理模式。透過在家中自我給藥，患者能夠控制自己的疾病並隨時隨地服用藥物，而無需前往醫療保健專業人員的辦公室。

The efficacy combined with this self-administration profile gives us a really strong way to end the marketplace. As I've said before, this is a market where we still have 40,000 patients, and less than 20% of those patients have been either identified, diagnosed and treated for polyneuropathy, including mixed phenotype.

這種功效與這種自我管理配置文件相結合，為我們提供了一種真正有效的方式來結束市場。正如我之前所說，這個市場仍然有 40,000 名患者，其中不到 20% 的患者已被識別、診斷和治療多發性神經病變，包括混合表型。

So our ability to get to where these patients are, identify them and get to the offices outside of the centers of excellence where they're presenting is going to be really important. And those are some of the strategies we're working on with AstraZeneca.

因此，我們能夠到達這些患者所在的地方，識別他們並到達他們所在的卓越中心之外的辦公室，這將非常重要。這些是我們正在與阿斯特捷利康合作的一些策略。

And then as to your question on whether we will be first in many global markets, yes, that is the goal. We are planning to file in different markets outside of the U.S. in the second half of the year, particularly in Europe.

然後，關於我們是否會在許多全球市場上成為第一的問題，是的，這就是我們的目標。我們計劃下半年在美國以外的不同市場提交申請，特別是在歐洲。

But as you know, we're also looking at expanding into markets such as Eastern Europe, Russia, China, Japan. And again, these are places where AstraZeneca's global scale will bring the ability to really penetrate and get these patients in care where there is needed.

但如您所知，我們也在考慮擴展到東歐、俄羅斯、中國、日本等市場。再次強調，阿斯特捷利康的全球規模將能夠真正滲透到這些地方，讓這些患者在需要的地方得到照顧。

And as you know, Robert, we're very pleased that AstraZeneca also enthusiastically licensed Latin America rights to -- for eplontersen for, of course, all indications neuropathy as well as cardiomyopathy. It demonstrates their enthusiasm for eplontersen, our partnership and their enthusiasm for the data that has been generated to date.

如你所知，羅伯特，我們非常高興阿斯特捷利康也熱情地授權拉丁美洲的權利——eplontersen，當然，用於神經病和心肌病的所有適應症。它展示了他們對 eplontersen、我們的合作夥伴關係以及他們對迄今為止生成的數據的熱情。

The next question comes from Kostas Biliouris with BMO.

下一個問題是來自 BMO 的 Kostas Biliouris。

One on pelacarsen follow-on molecule that you recently announced, can you discuss the potential technologies that you could leverage there to improve the efficacy and the dosing frequency of the first-generation molecule? And approximately how many years did you expect this follow-on molecule to enter the clinic after -- to enter the market, sorry, after pelacarsen?

您最近宣布了關於 pelacarsen 後續分子的問題，您能否討論一下可以利用哪些潛在技術來提高第一代分子的功效和給藥頻率？抱歉，在 pelacarsen 之後，您預計這種後續分子大約需要多少年才能進入臨床？

Sure, Kostas. Thanks. Very excited that Novartis came to us with a proposal to work on with them a follow-on strategy, follow-on program for pelacarsen. Let me just say right from the outset that pelacarsen -- the pelacarsen Phase III program is going well, very well on track and is on track for data readout and potential filing in 2025. .

當然，科斯塔斯。謝謝。非常高興諾華向我們提出了一項與他們合作制定 pelacarsen 後續策略和後續計劃的提案。讓我從一開始就說，pelacarsen——pelacarsen 第三階段專案進展順利，進展順利，預計在 2025 年進行數據讀出和潛在備案。

The fact that Novartis came to us really demonstrates their enthusiasm, their added enthusiasm for this opportunity for Lp(a) cardiovascular disease. They expect to be assuming for pelacarsen first on the market and to have a substantial global reach. And the follow-on program is to extend that reach, the purpose is to reach more and more patients with the follow-on program.

諾華公司來找我們這一事實確實表明了他們的熱情，他們對 Lp(a) 心血管疾病治療機會的額外熱情。他們預計 pelacarsen 將首先進入市場，並在全球範圍內擁有廣泛的影響力。後續計畫就是為了擴大這個範圍，目的是讓後續計畫涵蓋越來越多的患者。

Novartis recognizes our expanded and vast capabilities in RNA-targeted therapeutics. And we're bringing our full arsenal to the table, and they appreciate that. That's why they partnered with us on this.

諾華認識到我們在 RNA 標靶治療方面不斷擴大和巨大的能力。我們將把我們的全部武器擺到桌面上，他們對此表示讚賞。這就是他們與我們合作的原因。

That includes all the great work that our research organization has been doing over the last few years in expanding our medicinal chemistry capabilities, including [NSPA] backbone that we've talked a lot about in the past, and other chemistries, as well as our rapidly emerging capabilities in RNAi technology and combinations of both. We can utilize chemistries that we utilize in ASO technology as well as for RNAi platforms.

這包括我們的研究組織過去幾年在擴大我們的藥物化學能力方面所做的所有偉大工作，包括我們過去多次討論過的 [NSPA] 骨幹，以及其他化學，以及我們的RNAi 技術以及兩者結合的能力迅速崛起。我們可以利用 ASO 技術以及 RNAi 平台中使用的化學物質。

It's tough to beat the efficacy that pelacarsen has demonstrated in Phase II, Kostas. I mean, with 98%, 99% of patients with CBD due to high Lp(a)., we were able to get their Lp(a) levels down below the threshold associated with CBD.

Pelacarsen 在第二階段 Kostas 中所展現的功效很難被超越。我的意思是，98%、99% 的 CBD 患者由於 Lp(a) 高，我們能夠將他們的 Lp(a) 水平降至與 CBD 相關的閾值以下。

So really, we want to maintain that efficacy. We want to reproduce that efficacy in a potential follow-on molecule, but what we're really focused on is [less] dosing. We're very confident in our ability to deliver a molecule with semiannual dosing to be annual dosing, utilizing a mixture of our technology capabilities, and that is the focus with Novartis. And we're going to be working hand in hand with them to bring the best molecules forward to follow on -- as a follow-on to pelacarsen.

所以說真的，我們希望能保持這種功效。我們希望在潛在的後續分子中重現這種功效，但我們真正關注的是[更少]劑量。我們非常有信心能夠利用我們的技術能力，將半年一次給藥的分子變成每年一次給藥，這也是諾華的重點。我們將與他們攜手合作，推出最好的分子——作為 pelacarsen 的後續產品。

Sorry. No, I was going to ask approximately how many years behind is the follow-on molecule compared to pelacarsen?

對不起。不，我想問的是，與 pelacarsen 相比，後續分子大約落後了多少年？

Yes. We haven't stated -- discussed that publicly, Kostas, about what the timelines are. And obviously molecules -- we're still in research phase, so it would be a little risky to actually speculate on that right now.

是的。科斯塔斯，我們還沒有公開討論過時間表。顯然分子——我們仍處於研究階段，所以現在對此進行實際推測會有點冒險。

The next question comes from Michael Ulz with Morgan Stanley.

下一個問題來自摩根士丹利的邁克爾·烏爾茨。

Just on eplontersen and cardiomyopathy, maybe you can comment on the recent Bridge data and sort of how that impacts your thinking in terms of the CARDIO-TTRansform study? And then maybe secondly to that, is there a potential for you to maybe stop the study earlier? Or is the thinking still to go through sort of the full results there?

就 eplontersen 和心肌病變而言，也許您可以評論一下最近的 Bridge 數據，以及這如何影響您對 CARDIO-TTRansform 研究的思考？其次，你是否有可能提前停止這項研究？還是仍然需要思考那裡的全部結果？

Sure, Mike. So BridgeBio data, obviously, good patience to have another potential option for TTR cardiomyopathy. To state the obvious, we need a lot more data. We need to see more data. We're looking forward to seeing more detailed data. And I think they're planning to present later this year.

當然，麥克。因此，BridgeBio 的數據顯然需要耐心等待 TTR 心肌病變的另一種潛在選擇。顯而易見的是，我們需要更多的數據。我們需要查看更多數據。我們期待看到更詳細的數據。我認為他們計劃在今年晚些時候展示。

The demographics of the studies supports our trial design, it reinforces our trial design, gives us even greater confidence in our expanded trial design, which we're going to -- which we're going to have -- we have now as we have completed enrollment, a very good balance between tafamidis patients with [tropicamide] as well as naive patients. So it supports that.

研究的人口統計數據支持我們的試驗設計，它強化了我們的試驗設計，使我們對擴大的試驗設計更有信心，我們將要進行的試驗設計，我們將要進行的試驗設計，我們現在擁有的和我們擁有的一樣完成入組後，服用[托吡卡胺]的 tafamidis 患者與未接受治療的患者之間取得了很好的平衡。所以它支持這一點。

[CV] mortality -- overall mortality is very important in this population. And maybe I'll ask Onaiza to just really expand as on the importance of this from a physician standpoint, from a payer perspective.

[CV] 死亡率－整體死亡率在該族群中非常重要。也許我會要求奧奈札從醫生的角度、從付款人的角度真正闡述這一點的重要性。

Yes. So as you know, in eplontersen, [Michael, we read them], we love the breadth of our trial. We believe we're going to -- it's a landmark trial. It's going to generate the significant amount of data to really go in and arm the physicians with the data that they need to actually treat these patients.

是的。如你所知，在 eplontersen，[邁克爾，我們讀了它們]，我們喜歡我們試驗的廣度。我們相信我們將會—這是一次具有里程碑意義的試驗。它將產生大量數據，為醫生提供實際治療這些患者所需的數據。

This means anything from [EHA] Class I, II and III, so mild to severe hereditary and wild-type naive to silencer therapy, naive to cardiomyopathy therapies and TTR as well as on top of standard of care tafamidis as well, we really love our endpoints. We have done a fair amount of work in recent times to really understand the difference in terms of how physicians view all-cause mortality versus cardiovascular death.

這意味著從 [EHA] I、II 和 III 類，從輕度到重度遺傳性和野生型幼稚到消音療法，幼稚到心肌病療法和 TTR 以及標準護理 tafamidis 的任何內容，我們真的很喜歡我們的端點。最近，我們做了相當多的工作，以真正了解醫生如何看待全因死亡率與心血管死亡的差異。

And that is actually a more meaningful cardiovascular endpoint, along with the richness of cardiovascular hospitalizations and then some of our secondary endpoints, obviously, in 6-minute walk and other measures that are going to be a play. But the endpoint is just actually really meaningful.

這實際上是一個更有意義的心血管終點，以及心血管住院的豐富性，然後是我們的一些次要終點，顯然，在 6 分鐘步行和其他措施中，這將是一個遊戲。但終點其實非常有意義。

So all in all, we are really excited about our data set, our trial design and looking forward to seeing the output of that in the coming times.

總而言之，我們對我們的數據集、試驗設計感到非常興奮，並期待在未來看到其輸出。

And Michael, we -- there's no plans to change our -- there's no changes to our plans for when the study will complete. Based on any new emerging data that has come out recently, we love our trial design.

邁克爾，我們 - 沒有計劃改變 - 我們的研究何時完成的計劃沒有改變。根據最近出現的任何新數據，我們喜歡我們的試驗設計。

There are several factors that will impact when we read the study out. The first, of course, was to complete enrollment. We've now achieved that, and we've achieved it very successfully. We have the demographics in the study that we intended to have for -- to actually have the greatest data set when the study reads out.

當我們閱讀該研究報告時，有幾個因素會產生影響。首先，當然是完成註冊。我們現在已經實現了這一點，而且我們已經非常成功地實現了這一目標。我們在研究中得到了我們想要的人口統計數據——當研究結果出來時，我們實際上擁有了最大的數據集。

We'll also be looking at changing competitive landscape, new data as it emerges that could potentially affect the time we read the study out. We don't think the BridgeBio data is going to impact that, but there may be other data that comes out.

我們還將關注不斷變化的競爭格局和新數據，這些數據可能會影響我們閱讀研究報告的時間。我們認為 BridgeBio 數據不會影響這一點，但可能會有其他數據出現。

And thirdly, our blinded event rates will be very important for us to continue to monitor as we decide when it's best to -- but there's no change in the -- currently, there's no change in the timing of when that study is -- our CARDIO-TTRansform study is due to read out.

第三，我們的盲法事件發生率對於我們繼續監測非常重要，因為我們決定何時最好進行監測，但目前沒有變化，該研究的時間沒有變化。CARDIO-TTRansform 研究即將讀出。

Let me just address one other question, which was on the payer reimbursement that I missed, so just to make sure that we've done a fair amount of testing with payers on the trial design. And again, if we share the cardiovascular risk reduction on top of tafamidis, there is clinical meaningfulness in that for physicians, and they are not going to be kind of standing in the way in terms of reimbursing our combo product here.

讓我解決另一個問題，即我錯過的付款人報銷問題，因此只是為了確保我們已經與付款人就試驗設計進行了大量測試。再說一遍，如果我們在他法米迪的基礎上分享心血管風險的降低，這對醫生來說是有臨床意義的，他們不會在報銷我們的組合產品方面成為障礙。

Again, the data will bear out, and they're very favorable in making sure these patients who are highly at risk, it's a terminal disease, are getting the best medication and care possible. So we're really pleased to see them thinking about the disease and the patients this way and thinking about the landscape of reimbursement as either mono or combo in the space.

數據再次證明，它們非常有利於確保這些高風險患者（這是一種末期病人）獲得最好的藥物和護理。因此，我們真的很高興看到他們以這種方式思考疾病和患者，並以單一或組合的方式思考報銷格局。

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。

I was wondering if you could share your thoughts on some recent development in Angelman syndrome field, where Roche decided not to move their ASO program into the next stage of clinical development. .

我想知道您是否可以分享您對 Angelman 症候群領域最近發展的一些想法，羅氏決定不將他們的 ASO 專案進入臨床開發的下一階段。 。

And wondering if you could share any update from your Angelman syndrome clinical study that is ongoing. And any thoughts around the programs or the product candidates, efficacy and safety profile? And also, if you could also talk about for ATXN2 program and its ongoing study, that will be great. I think the data are expected around the same time as the Angelman syndrome program.

想知道您是否可以分享正在進行的天使症候群臨床研究的任何更新。對這些計劃或候選產品、功效和安全性有何想法​​？另外，如果您還可以談論 ATXN2 計劃及其正在進行的研究，那就太好了。我認為這些數據預計與天使綜合症計劃大約同時出現。

Sure. Thanks for the question. So the Angelman's program -- the Ionis-Biogen Angelman program is going very well. We're operationalizing the Phase I/II study, and we're continuing to enroll patients in this study. We are -- with Biogen, are planning to have data around midyear next year from the Angelman's program. And as I said, it's going very well so far.

當然。謝謝你的提問。因此，Angelman 計劃——Ionis-Biogen Angelman 計劃進展順利。我們正在實施 I/II 期研究，並繼續招募患者參與這項研究。我們與百健（Biogen）計劃在明年年中左右從 Angelman 計畫中獲得數據。正如我所說，到目前為止一切進展順利。

We haven't disclosed our -- we really don't have any insights into the reasoning behind why Roche ended their study. I think obviously, they've said that it wasn't a safety issue. They said they didn't meet their minimum target product profile or minimum criteria, I assume, on efficacy. We really don't have and shouldn't -- we're not disclosing anything we may think on this, so we're really focused on our program.

我們還沒有透露我們的——我們真的沒有任何關於羅氏結束他們研究背後的原因的見解。我認為顯然，他們已經說過這​​不是安全問題。他們說他們沒有達到他們的最低目標產品概況或最低功效標準，我認為。我們確實沒有也不應該——我們不會透露我們對此的任何想法，所以我們真正專注於我們的計劃。

So expect to read out from that study next year. We may be able to provide an update on the status of the program late this year. There is a -- we have a standing invitation to an Angelman's meeting called FAST, in which we always have a podium slot, and I'm sure we'll be present this year, too. But we're not necessarily expecting data -- new data at the meeting. But we haven't decided what we're going to present at that meeting yet.

因此，預計明年會宣讀該研究。我們也許能夠在今年稍後提供該計劃的最新狀態。我們有一個名為「FAST」的天使人會議的長期邀請，我們總是有一個講台位置，我相信今年我們也會出席。但我們不一定期待會議上的數據——新數據。但我們還沒有決定在這次會議上要展示什麼內容。

As far as ATXN2, this, of course, is another one of our ALS drugs. This drug is particularly exciting because it's targeting a sporadic ALS. So no known genetic cause of ALS, is enrolling. This is a study in which we're examining 4-dose cohorts with the highest dose cohort, with highest-dose cohort having expanded to add more patients, to have the most robust data set to inform on a potential Phase III study, if study is successful.

至於ATXN2，這當然是我們的另一種ALS藥物。這種藥物特別令人興奮，因為它針對的是散發性 ALS。因此，尚無已知的 ALS 遺傳原因，正在招募。在這項研究中，我們正在檢查 4 劑量組和最高劑量組，最高劑量組已擴大到增加更多患者，以便擁有最可靠的數據集，為潛在的 III 期研究提供資訊（如果研究）是成功的。

That, as you mentioned, is also due to read out around the same time next year, around midyear, next year. And all indications are that it's going well.

正如您所提到的，這也將在明年的同一時間，即明年年中左右宣讀。所有跡像都表明一切進展順利。

The next question comes from David Lebowitz with Citi.

下一個問題來自花旗集團的大衛·勒博維茨（David Lebowitz）。

Given the HAE data is coming up earlier next year, could you -- and assuming the Phase II data is replicated, could you tell us what your efforts will look like for launching the therapy and trying to convince physicians to move to a new modality?

鑑於 HAE 數據將於明年初公佈，假設 II 期數據已複製，您能否告訴我們您將如何努力啟動療法並試圖說服醫生轉向新的治療方式？

Onaiza?

奧奈薩？

David, yes, we're very excited about our preparations for donidalorsen launch and waiting for the Phase III data next year. We are thinking about the market in a variety of ways. As you know, this is going to be pretty much a switch market. So we do actually have a switch study that's going alongside our Phase III, which will be very informative and give confidence for physicians to switch patients.

大衛，是的，我們對 Donidalorsen 的上市準備感到非常興奮，並等待明年的 I​​I 期數據。我們正在以多種方式思考市場。如您所知，這幾乎將是一個交換器市場。因此，我們實際上有一項與第三階段同時進行的轉換研究，這將提供非常豐富的信息，並讓醫生有信心轉換患者。

As a confidence piece, it is going to come from the ability to make sure there are no breakthrough attacks in the process of this switch. And given our rapid onset, we believe we will be able to demonstrate that.

作為信心的一部分，它將來自於確保在轉換過程中不會發生突破性攻擊的能力。鑑於我們的快速起步，我們相信我們將能夠證明這一點。

On the patient side, I think you can see the switching behavior already in the marketplace with ORLADEYO kind of inciting more switches from [TEXYRA], which is the standard of care. So we see that patients are willing to try new treatments. And want -- they want zero attack rates, and they want more convenience, and we offer both with our profile as well. So the team is very active in understanding kind of what will drive some of the switching behavior and their go-to-market strategies alongside of that.

在患者方面，我認為您可以看到市場上已經出現的轉換行為，ORLADEYO 刺激了 [TEXYRA] 的更多轉換，這是護理標準。所以我們看到患者願意嘗試新的治療方法。他們想要零攻擊率，想要更多便利，而我們也透過我們的個人資料提供這兩種服務。因此，該團隊非常積極地了解推動某些轉換行為的因素以及隨之而來的上市策略。

And one additional question. Moving towards a potential eplontersen launch, do you have any thoughts on how market growth has shifted since the subQ was launched by Alnylam? And how that might apply to eplontersen? And how you're thinking of the launch going forward?

還有一個問題。對於潛在的 eplontersen 推出，您對 Alnylam 推出 subQ 以來市場成長發生了怎樣的變化有什麼想法嗎？這如何適用於 eplontersen？您對未來的發布有何看法？

Yes. Taking a look at how Amvuttra's uptake is going on in the marketplace, I mean they've got a good start. And it's just important to note that they're working through a lot of ONPATTRO switches right now, right? So we're really trying to understand how much market growth there is.

是的。看看 Amvuttra 在市場上的接受情況，我的意思是他們有了一個好的開始。值得注意的是，他們現在正在使用大量 ONPATTRO 交換機，對嗎？所以我們真的想了解市場成長有多大。

As I said, this continues to be an underpenetrated marketplace, lots of patients that are still not identified, diagnosed or treated. And I think Alnylam is doing their job of getting most of their patients on to their next-generation silencer. And we have a lot of work to get new patients to just silencer therapy overall in this marketplace.

正如我所說，這仍然是一個滲透不足的市場，許多患者仍未被識別、診斷或治療。我認為 Alnylam 正在盡自己的努力，讓大多數患者使用下一代消音器。我們還有很多工作要做，讓新患者在這個市場上接受消音器治療。

So we expect it to grow readily. This is when you have a couple of players in the marketplace, it's always a good thing for patients. We're looking forward to getting in, in January and starting to work. And as you -- as I said earlier, we have a very exciting product profile, efficacy as well as the self-administration profile, which we believe will do very well in the market.

所以我們預計它會迅速成長。當市場上有幾個參與者時，這對患者來說總是一件好事。我們期待在一月份進入並開始工作。正如我之前所說，我們擁有非常令人興奮的產品概況、功效以及自我管理概況，我們相信這將在市場上表現出色。

The next question comes from Allison Bratzel with Piper Sandler.

下一個問題來自艾莉森·布拉澤爾和派珀·桑德勒。

Just one for me on the Phase II GOLDEN trial in GA. Just curious, is there any update on your view of the geographic atrophy space and potential opportunity for a therapy targeting complement Factor B, just given some of the recent safety and regulatory updates in the GA space in recent weeks? Could you just explain what you're looking for in the Phase II readout next year to warrant further investment in that space?

這只是我在喬治亞州進行的第二階段 GOLDEN 試驗中的一個。只是好奇，考慮到最近幾週 GA 領域的一些最新安全性和監管更新，您對地理萎縮領域和針對補體 B 因子治療的潛在機會的看法是否有任何更新？您能否解釋一下您在明年的第二階段報告中尋找什麼，以確保對該領域的進一步投資？

Thanks, Allison. Yes, we're -- and our partner, Roche, are very enthusiastic about our GA study, our Factor B LRx geographic atrophy study GOLDEN. We're pleased that there's a benchmark to get drugs approved for GA. This helps set a path forward for all drugs that are being developed for GA, including ours. We like our drug. We like our profile.

謝謝，艾莉森。是的，我們以及我們的合作夥伴羅氏公司對我們的 GA 研究、我們的 B 因子 LRx 地理萎縮研究 GOLDEN 非常熱情。我們很高興有一個讓藥物獲得 GA 批准的基準。這有助於為所有正在開發的 GA 藥物（包括我們的藥物）指明前進的道路。我們喜歡我們的藥物。我們喜歡我們的個人資料。

So far, the GOLDEN study is a large study, around 300 patients to dose cohorts, dosing groups, in which patients are going to be treated for about 15 months. So it's a good study. And what we're looking for is the primary changes in geographic atrophy area in the study. So it's an efficacy study, a proof-of-concept study, and that study is due to read out next year. We like this. We like to target Factor B in the alternative pathway, we think is the right target for GA. We think systemic approaches to the complement pathway, particularly Factor B, is the right approach for treating GA.

到目前為止，GOLDEN研究是一項大型研究，約有300名患者參加劑量隊列、劑量組，其中患者將接受約15個月的治療。所以這是一個很好的研究。我們要找的是研究中地理萎縮區域的主要變化。所以這是一項功效研究，一項概念驗證研究，該研究將於明年發表。我們喜歡這個。我們喜歡以替代途徑中的因子 B 為目標，我們認為這是 GA 的正確目標。我們認為針對補體途徑（尤其是因子 B）的系統方法是治療 GA 的正確方法。

And we think that the overall safety profile and tolerability profile that we're going to have with Factor B LRx is going to be a very significant advantage versus [IDT] drugs, which are administered directly to the eye and have side effects as a consequence to that. We expect Factor B LRx to have an excellent safety profile, much like the rest of our LICA platform that has eplontersen, pelacarsen, donidalorsen.

我們認為，與 [IDT] 藥物相比，因子 B LRx 的整體安全性和耐受性將具有非常顯著的優勢，因為 [IDT] 藥物直接給藥於眼睛，因此會產生副作用對此。我們預計 Factor B LRx 具有出色的安全性，就像我們的 LICA 平台的其他產品（包括 eplontersen、pelacarsen、donidalorsen）一樣。

So that -- it's in Phase II, and we're seeking to achieve proof of concept for the next year. If the data is strong or the data supports, I should say, Roche is preparing to go to Phase III, and they're equally enthusiastic for the program as we are.

因此，它處於第二階段，我們正在尋求明年實現概念驗證。如果數據有力或有數據支持，我應該說，羅氏正在準備進入第三階段，他們和我們一樣對該計畫充滿熱情。

The next question comes from Paul Matteis with Stifel.

下一個問題來自保羅·馬蒂斯和斯蒂菲爾。

Congrats on all the progress. I wanted to ask about olezarsen in light of how much the cardiometabolic space has really changed since you initiated the pivotal program. Just specifically looking back at the Phase II baseline characteristics, I think most patients in the study had Type 2 diabetes, most patients had comorbid hypertension. BMI was overweighted, on average.

祝賀所有的進步。我想詢問 olezarsen，因為自從您啟動關鍵計劃以來，心臟代謝空間確實發生了多大變化。具體回顧一下 II 期基線特徵，我認為研究中的大多數患者患有第 2 型糖尿病，大多數患者患有高血壓。平均而言，BMI 超重。

I guess, how do you think about the impact of this recent [Wegovy] data and more broadly, the takeoff of these weight-loss drugs on the market for olezarsen? And I guess, what percent of patients with trigs above 500 would you say demographically wouldn't actually qualify for one of those drugs on label?

我想，您如何看待最近的 [Wegovy] 數據的影響，以及更廣泛地說，這些減肥藥在 olezarsen 市場上的起飛？我猜，您認為從人口統計學角度來看，TRIG 超過 500 的患者中，有多少百分比實際上不符合標籤上的其中一種藥物的資格？

Onaiza, you want to take that?

奧奈薩，你想接受這個嗎？

Yes, Paul. Yes, been on -- it's a lot of good data for the GLP-1s recently as well. So a couple of important things to note. First of all, they're not going to be indicated, right, for triglyceride lowering. And if you looked at some of their TG -- just their TG lowering data, it's very much in line with what current standard of care is. So they're not getting to the really high levels of TG lowering that APOC3 target can actually deliver here. So that's kind of the first thing.

是的，保羅。是的，一直在關注——最近也有很多關於 GLP-1 的好數據。有幾點要注意。首先，它們不會被用來降低三酸甘油酯，對吧。如果你看他們的一些 TG——只是他們的 TG 降低數據，它非常符合當前的護理標準。因此，他們沒有達到 APOC3 目標實際上可以實現的真正高水平的 TG 降低。這是第一件事。

If physicians do use it off-label, it's a very important reminder, and I think most of the endocrinologists know this that the GLP-1s have a warning in their label for not being used in patients with risk or a history of acute pancreatitis. And as you know, in the 500-plus severely elevated triglycerides where olezarsen is being studied, we have many, many patients who are at risk for AP.

如果醫生確實在說明書外使用它，這是一個非常重要的提醒，我認為大多數內分泌學家都知道GLP-1 的標籤上有警告，不得用於有急性胰臟炎風險或有急性胰臟炎病史的患者。如您所知，在 olezarsen 正在研究的 500 多個嚴重升高的三酸甘油酯中，我們有很多很多患者面臨 AP 風險。

So we do think both the magnitude of triglyceride reduction along with the risk for these patients who are over 500 for AP, we do not expect that to be a direct or an indirect competitor.

因此，我們確實認為三酸甘油酯降低的幅度以及 AP 超過 500 的患者的風險，我們預計這不會成為直接或間接的競爭對手。

The next question comes from Yaron Werber Cowen.

下一個問題來自 Yaron Werber Cowen。

Just on SPINRAZA, the response by the interim results are definitely encouraging. Can you give us a sense, are these potentially label-enabling? Like how do you think about it, just given your broad label? Do you need sort of label enabling? Or is this just for standard of care sort of change?

就 SPINRAZA 而言，中期績效的反應絕對令人鼓舞。您能否告訴我們，這些是否具有潛在的標籤功能？就像你如何看待它，只是考慮到你的廣泛標籤？您需要某種標籤啟用嗎？或者這只是為了改變護理標準？

And then secondly, just in terms of some of the ATXN2 program and the ATXN3 programs, I know you touched a little bit on ALS, you also have a FAST program for ALS. Just maybe give us a little bit of a sense what's the next data timing and what do you expect from the data? I know the FAST ALS is a pivotal in 2025 than the other two?

其次，就一些 ATXN2 程序和 ATXN3 程序而言，我知道您對 ALS 有所了解，您還有一個針對 ALS 的 FAST 程序。也許只是讓我們稍微了解下一個數據時間是什麼以及您對數據有何期望？我知道 FAST ALS 是 2025 年比其他兩個更關鍵的嗎？

Yaron, so it's our understanding that ASCEND or RESPOND responding -- the data you're talking about, very encouraging data, patients that haven't done that well on gene therapy moved on to SPINRAZA and really showing really good strong signs of doing very well, improving muscle strength, neuromuscular function.

Yaron，所以我們的理解是ASCEND 或RESPOND 會做出反應——你所說的數據，非常令人鼓舞的數據，在基因治療上表現不佳的患者轉向了SPINRAZA，並且確實表現出了非常好的強烈跡象。嗯，提高肌肉力量，神經肌肉功能。

Not surprisingly, there's been a lot of anecdotal data out there over the years that this is the case, but it's very helpful to that biogenetically [induced] study just to demonstrate how the study is ongoing.

毫不奇怪，多年來有很多軼事數據表明情況確實如此，但這對生物遺傳學[誘導]研究非常有幫助，只是為了證明研究是如何進行的。

It's our understanding that these studies and patients that perform suboptimally on either gene therapy or on a SPINRAZA, will be more for publication purposes and those sorts of things and which are for certainly in line with promotion.

據我們了解，這些研究和在基因治療或 SPINRAZA 上表現不佳的患者將更多地用於出版目的和此類事情，並且這肯定符合促銷目的。

It's the DEVOTE study that has the potential to actually expand label. The DEVOTE study is a randomized controlled Phase III study looking at higher doses of SPINRAZA to demonstrate even greater efficacy in SMA patients of all kinds. So that's my understanding. So, I'm getting head nods from my clinical folks, too.

DEVOTE 研究有可能真正擴展標籤。 DEVOTE 研究是一項隨機對照 III 期研究，著眼於更高劑量的 SPINRAZA，以證明對各種 SMA 患者有更好的療效。這就是我的理解。所以，我也得到了我的臨床人員的點頭。

Eric just reminded me, I didn't answer the ATXN2 question, Yaron. So the ATXN2 is enrolling [4-dose] cohorts. The top dose is an expanded cohort to have more patients in the dose that has the potential to be at the dose that goes to Phase III. That data is due to read out midyear next year, ATXN2, for nongenetic ALS. I'm sorry.

Eric 只是提醒我，我沒有回答 ATXN2 問題，Yaron。因此，ATXN2 正在招募 [4 劑] 隊列。最高劑量是一個擴大的隊列，以讓更多患者接受有可能進入 III 期劑量的劑量。該數據將於明年年中公佈，用於非遺傳性 ALS 的 ATXN2。對不起。

The next question comes from Luca Issi with RBC Capital Markets.

下一個問題來自加拿大皇家銀行資本市場部的 Luca Issi。

Maybe if I may, following up on the prior question, and Brett, you may have already alluded to it, but I want to make sure was in-licensed the next-generation molecule informed in any sort, form or shape by the blinded event trade they're seeing in the cardiovascular or is this just truly life cycle management?

也許我可以繼續之前的問題，布雷特，你可能已經提到過這一點，但我想確保透過盲事件以任何種類、形式或形狀告知的下一代分子已獲得許可他們在心血管領域看到的交易還是這只是真正的生命週期管理？

Question 2, maybe, Eugene, if I may, on TTR cardiomyopathy, wondering if you could comment on what statistical methodology are you using for the Phase III for TTR cardiomyopathy. Are you using your method similar to BridgeBio and Pfizer? Or are using the Andersen–Gill method, which is similar to Alnylam? And maybe, why did you one versus the other? And then lastly, maybe on AGT, what was your reaction to Alnylam deal? And how you thinking about BD for your molecule?

問題 2，尤金，如果可以的話，關於 TTR 心肌病，想知道您是否可以評論一下您在 TTR 心肌病變的 III 期試驗中使用的統計方法。您使用的方法是否類似 BridgeBio 和輝瑞？或正在使用與 Alnylam 類似的 Andersen-Gill 方法？也許，你們為什麼要與另一個對抗呢？最後，也許在 AGT 上，您對 Alnylam 交易有何反應？您如何考慮分子的 BD？

Sure, Luca. Before turning it over to Eugene, I'll take through those, and then you can talk about the statistical plan for CARDIO-TTRansform. So [LP(a)'s] entirely life cycle management, the pelacarsen Phase III study is going very well, on track for data in 2025, with a potential filing in 2025, has nothing to do with any particular data from the study, except to say that the study is going very well. So that lends even greater confidence by no part is to pursue life cycle management.

當然，盧卡。在將其交給尤金之前，我將完成這些，然後您可以談論 CARDIO-TTRansform 的統計計劃。因此，[LP(a)]完全生命週期管理，pelacarsen III 期研究進展順利，預計在 2025 年獲得數據，並可能在 2025 年提交，與該研究中的任何特定數據無關，只能說這項研究進展順利。因此，這為追求生命週期管理帶來了更大的信心。

We're focused, Luca, on our own programs, really don't have a reaction to any competitors in the AGT space or anywhere else in partnering strategies. We -- our plans haven't changed. We are planning to share new AGT data in the second half of this year at a medical meeting.

Luca，我們專注於我們自己的項目，實際上對 AGT 領域或其他任何合作夥伴策略中的任何競爭對手都沒有反應。我們——我們的計劃沒有改變。我們計劃在今年下半年的一次醫學會議上分享新的 AGT 數據。

And we've said all along that we think a drug like this for indications like hypertension and heart failure are best suited with a partner to reach as many patients globally around the world. And we haven't provided any details on the timing when we're going to partner the program nor with them, of course. But stay tuned to that down the road. Eugene, could you talk a little bit about the -- Luca's question about our stats plan for CARDIO-TTRansform?

我們一直以來都表示，我們認為這種治療高血壓和心臟衰竭等疾病的藥物最適合與合作夥伴合作，為全球盡可能多的患者提供幫助。當然，我們還沒有提供任何關於我們將與該計劃或他們合作的時間細節。但請繼續關注。尤金，你能談談盧卡關於我們的 CARDIO-TTRansform 統計計劃的問題嗎？

Sure. So if I understood your question, it was related to the analysis of the primary endpoint. Is that right, Luca?

當然。因此，如果我理解你的問題，它與主要終點的分析有關。是這樣嗎，盧卡？

That's correct. Yes, that's correct.

這是正確的。對，那是正確的。

Yes. So as we said, the methodology that we're utilizing or planning to utilize for that analysis is a pretty tried and true, using Andersen–Gill method to look at both CV mortality and CV events, recurrent events that are listed in our SAP. So again, there's nothing, I think, fancy about this method, has been tried and done in multiple outcome studies. It's a fairly classic way of looking at these events.

是的。因此，正如我們所說，我們正在使用或計劃用於該分析的方法是經過驗證且真實的，使用 Andersen-Gill 方法來查看 CV 死亡率和 CV 事件，以及我們的 SAP 中列出的複發事件。再說一遍，我認為這種方法並沒有在多項結果研究中嘗試完成。這是看待這些事件的一種相當經典的方式。

The next question is from Yale Jen with Laidlaw & Company.

下一個問題來自 Yale Jen 和 Laidlaw & Company。

The first question is for eplontersen that if you get approved later -- towards the end of this year in [polyneuropathy], do you anticipate the drug will also be used for treating the mixed-type patients? Then I have another follow-up.

第一個問題是eplontersen，如果你稍後在[多發性神經病變]領域獲得批准，你預計該藥物也將用於治療混合型患者嗎？然後我還有另一個後續行動。

Absolutely, we do provide they have detectable polyneuropathy, yes. This drug would be suitable for pure PN patients as well as mixed [phenotype] patients.

當然，我們確實提供了他們患有可檢測到的多發性神經病，是的。此藥物適用於純 PN 患者以及混合[表型]患者。

Okay. And my another question is on olezarsen that in terms of the sHTG enrollment, can you provide any color in terms of the status? And do you anticipate complete enrollment later this year?

好的。我的另一個問題是關於 olezarsen，就 sHTG 註冊而言，您能提供任何狀態方面的資訊嗎？您預計今年稍後將完成註冊嗎？

I missed the specific -- how are we on sHTG enrollment?

我錯過了具體內容——我們的 sHTG 註冊情況如何？

Enrollment is going very, very well. And either very late this year or very early next year is kind of the guidance that we've been giving.

報名進展非常非常順利。我們一直在提供指導，要么是今年年底，要么是明年初。

The last question today comes from Joseph Stringer with Needham & Company.

今天的最後一個問題來自 Needham & Company 的 Joseph Stringer。

Just a quick one on olezarsen Phase III FCS readout later this year, can you just frame expectations on what type of outcome you need to see to be successful commercially? What type of key metrics should we be looking at beyond the primary endpoint from -- that would be important from a physician or a payer perspective?

簡單介紹一下今年稍後 olezarsen III 期 FCS 讀數，您能否對您需要看到什麼類型的結果才能獲得商業成功制定預期？除了主要終點之外，我們應該關注什麼類型的關鍵指標——從醫生或付款人的角度來看，這很重要？

You want to take that, Eugene? I mean obviously, the primary endpoint is triglyceride lowering -- for triglyceride lowering compared to placebo, and that's important.

你想接受這個嗎，尤金？我的意思顯然是，主要終點是三酸甘油酯降低——與安慰劑相比，三酸甘油酯降低，這很重要。

And we expect what will really drive this market is substantial TG lowering in this patient population. But Eugene and then Onaiza, maybeto talk about the commercial, also what additional endpoints we're looking to see.

我們預計，真正推動該市場發展的是該患者群體中三酸甘油酯的大幅降低。但是尤金和奧奈扎也許會談論廣告，以及我們希望看到的其他端點。

Sure. Happy to. We're obviously going to also look at responder -- a variety of responder analysis, so looking at proportions of patients that get below particular clinically meaningful thresholds, thresholds like [80] for instance is in the classic [water] 500.

當然。高興。顯然，我們還將關注響應者——各種響應者分析，因此關注低於特定臨床意義閾值的患者比例，例如 [80] 等閾值位於經典的 [水] 500 中。

So again, achieving those reductions that are thought to be meaningful in terms of their risk for having acute pancreatitis events is something that we're -- and future prescribers will be very keen to see. We're also looking at quality-of-life measures. But again, we'll indicate whether these patients are actually feeling better, they're able to function better. And those, again, are included as well.

因此，我們和未來的處方者都非常希望看到，實現那些被認為對急性胰臟炎事件風險有意義的降低。我們也在研究生活品質的衡量標準。但我們會再次指出這些患者是否真的感覺更好，以及他們是否能夠更好地發揮作用。同樣，這些也包括在內。

(inaudible).

（聽不清楚）。

We've -- yes. No, that's great. I think we've done obviously some good market understanding on this as well. Just a reminder, this is a rare disease population for FCS. They really have number of tools at their disposal, leases. This is where the first-line treatment is restrictive diet, and it's just not -- I mean, they just can't continue on that level of restrictive diet that they're on for a while.

我們已經——是的。不，那太好了。我認為我們顯然對此也做了一些很好的市場了解。請注意，這是 FCS 的罕見疾病族群。他們確實擁有大量可供使用的工具和租賃。這就是第一線治療方法是限制性飲食，但事實並非如此——我的意思是，他們只是無法繼續維持目前的限制性飲食水平一段時間。

So there's just a huge unmet need. I really do think that this is going to be "Let's get the product that's efficacious, but also really safe and easy to use." And I think getting some of the safety tolerability, and here, is going to be really important versus first-generation, and it's going to be a [will] go. A lot of lipidologist, and a lot of patients are waiting.

因此，存在巨大的未滿足需求。我確實認為這將是「讓我們開發出既有效又安全且易於使用的產品」。我認為，與第一代相比，獲得一定的安全耐受性將非常重要，而且這將是一個[將會]的過程。很多脂質學家和很多患者都在等待。

Thank you. Thanks, everybody, for joining us today for today's call. We're well on our way. We're planning to continue on our strong momentum in the second half of this year by delivering across all of our aspects, key aspects of our business, commercial pipeline, technology and so on.

謝謝。感謝大家今天加入我們今天的電話會議。我們一切順利。我們計劃在今年下半年繼續保持強勁的勢頭，在我們的所有方面、業務的關鍵方面、商業管道、技術等方面提供服務。

Also, I want to highlight that we're looking forward to providing a comprehensive update on all the great progress we're making at our Investor Day on October 4. We really hope that many of you can join us in-person for that meeting. I hope to see you there. Until then, thanks, and have a great day, everybody.

另外，我想強調的是，我們期待在 10 月 4 日的投資者日上提供有關我們所取得的所有重大進展的全面更新信息。我們真誠地希望你們中的許多人能夠親自參加我們的會議。我希望能在那裡看到你。在此之前，謝謝大家，祝大家有美好的一天。

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

會議現已結束。感謝您的參與。現在您可以斷開線路。