Ionis Pharmaceuticals Inc (IONS) 2023 Q1 法說會逐字稿

Good morning, and welcome to Ionis First Quarter 2023 Financial Results Conference Call. (Operator Instructions) As a reminder, this call is being recorded.

早上好，歡迎來到 Ionis 2023 年第一季度財務業績電話會議。 （操作員說明）提醒一下，此通話正在錄音中。

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, sir.

此時，我想將電話轉給投資者關係高級副總裁 Wade Walke 主持電話會議。請開始，先生。

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

謝謝。在我們開始之前，我鼓勵大家去 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 財務的對賬。我們相信非 GAAP 財務業績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。我們還在我們的網站上發布了今天電話會議的幻燈片。

With me this morning are Brett Monia, Chief Executive Officer; Richard Geary, Chief Development Officer; and Beth Hougen, 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.

今天早上和我在一起的是首席執行官 Brett Monia； Richard Geary，首席開發官；和首席財務官 Beth Hougen。研究執行副總裁 Eric Swayze； Eugene Schneider，首席臨床開發官；首席全球產品戰略和運營官 Onaiza Cadoret 也將加入我們的電話問答環節。

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

我想提請您注意幻燈片 3，其中包含我們的前瞻性聲明。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語言聲明。這些陳述受某些風險和不確定因素的影響，我們的實際結果可能存在重大差異。我鼓勵您查閱我們提交給美國證券交易委員會的文件中包含的風險因素以獲取更多詳細信息。

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

有了這個，我會把電話轉給布雷特。

Thanks, Wade. Good morning, everyone, and thanks for joining us today. This year is off to a strong start with several important achievements already, especially from our neurology franchise. Last week, the FDA granted QALSODY accelerated approval for the treatment of SOD1-ALS. This approval represents a major scientific breakthrough. QALSODY is the first and only approved treatment to target a genetic form of ALS. And with this approval, QALSODY joined SPINRAZA as our newest product to reach the market for patients with a devastating neurological disease.

謝謝，韋德。大家早上好，感謝今天加入我們。今年開局良好，已經取得了幾項重要成就，尤其是我們的神經病學專營權。上週，FDA 加速批准 QALSODY 用於治療 SOD1-ALS。這一批准代表了一項重大的科學突破。 QALSODY 是第一個也是唯一一個獲得批准的針對 ALS 遺傳形式的治療方法。獲得這一批准後，QALSODY 加入了 SPINRAZA，成為我們為患有毀滅性神經系統疾病的患者投放市場的最新產品。

In addition to being a tremendous advance for the ALS community, this approval further validates our RNA-targeted therapeutic platform to treat neurological diseases that today includes 12 medicines in clinical development. We also just reported positive data from the Phase III NEURO-TTRansform study of eplontersen in patients with ATTR polyneuropathy. In this study, eplontersen was shown to halt neuropathy disease progression with approximately half of patients experiencing improvement in the co-primary efficacy endpoints, mNIS+7 and Norfolk Quality of Life. Eplontersen also demonstrated favorable safety and tolerability. Based on the totality of the data, we are confident in Eplontersen's strong product profile and its potential to be an important treatment for the largely untapped hereditary ATTR polyneuropathy population.

除了對 ALS 社區來說是一個巨大的進步之外，這一批准進一步驗證了我們用於治療神經系統疾病的 RNA 靶向治療平台，該平台目前包括 12 種處於臨床開發中的藥物。我們還剛剛報告了 eplontersen 在 ATTR 多發性神經病患者中的 III 期 NEURO-TTRansform 研究的陽性數據。在這項研究中，eplontersen 被證明可以阻止神經病變的進展，大約一半的患者在共同主要療效終點、mNIS+7 和諾福克生活質量方面得到改善。 Eplontersen 還表現出良好的安全性和耐受性。基於全部數據，我們對 Eplontersen 強大的產品概況及其成為很大程度上未開發的遺傳性 ATTR 多發性神經病人群的重要治療方法的潛力充滿信心。

With these data, we and our partner, AstraZeneca, are working towards additional regulatory submissions in countries outside the U.S. This, of course, is in addition to our NDA, which is under review with a PDUFA date of December 22 of this year. And as Onaiza discussed during our webcast last week, we're working hand in hand with AstraZeneca to bring this important medicine to the market as quickly as possible.

有了這些數據，我們和我們的合作夥伴阿斯利康正致力於在美國以外的國家/地區提交更多的監管文件。當然，這是對我們的 NDA 的補充，NDA 正在接受審查，PDUFA 日期為今年 12 月 22 日。正如 Onaiza 上週在我們的網絡廣播中所討論的那樣，我們正在與阿斯利康攜手合作，盡快將這種重要藥物推向市場。

Our 2 other near-term commercial opportunities, olezarsen and donidalorsen are also progressing very well. With olezarsen, we remain on track for data from the Phase III BALANCE study in FCS in the second half of this year. And we're preparing for our first independent commercial launch in this rare disease indication. We also continue to make really good progress in our pivotal SHTG studies of olezarsen. With donidalorsen, we're on track to complete enrollment in the Phase III OASIS-HAE study soon, keeping us on track for data in the first half of next year.

我們的另外 2 個近期商業機會，olezarsen 和 donidalorsen 也進展順利。有了 olezarsen，我們仍有望在今年下半年獲得 FCS III 期 BALANCE 研究的數據。我們正在為我們在這種罕見疾病適應症中的首次獨立商業發布做準備。我們還在 olezarsen 的關鍵 SHTG 研究中繼續取得真正的良好進展。有了 donidalorsen，我們有望很快完成 III 期 OASIS-HAE 研究的招募，使我們能夠在明年上半年獲得數據。

Additionally, our robust late-stage pipeline continues to expand, now at 7 programs advancing in 9 separate indications with the initiation of Phase III development of bepirovirsen in chronic HBV. Our expanding late-stage pipeline sets us up for a steady and growing cadence of data readouts over the next few years, increasing the potential for a substantial number of new Ionis medicines to reach the market. And importantly, we remain on track to accomplish our key strategic goals across the business and achieve our 2023 financial guidance.

此外，我們強大的後期管道繼續擴大，目前有 7 個項目在 9 個獨立的適應症中取得進展，並啟動了慢性 HBV 貝匹羅韋森的 III 期開發。我們不斷擴大的後期管道為我們在未來幾年穩定和不斷增長的數據讀取節奏奠定了基礎，增加了大量新 Ionis 藥物進入市場的潛力。重要的是，我們仍有望實現整個企業的關鍵戰略目標，並實現我們的 2023 年財務目標。

With that, I'll turn the call over to Richard to discuss our recent pipeline progress and preview our upcoming key events. Next, Beth will review our first quarter financial results, and then I'll wrap up our prepared remarks before taking your questions. Over to you, Richard.

有了這個，我會把電話轉給理查德來討論我們最近的管道進展並預覽我們即將到來的關鍵事件。接下來，貝絲將回顧我們第一季度的財務業績，然後我將在回答您的問題之前總結我們準備好的評論。交給你了，理查德。

Thank you, Brett. As Brett just mentioned, we have met a number of goals in key programs already this year. We believe that the positive data we reported from the NEURO-TTRansform study demonstrate eplontersen's potential to substantially improve outcomes in patients with ATTR polyneuropathy. Eplontersen met all co-primary and all secondary efficacy endpoints, demonstrating consistent benefit for ATTR polyneuropathy patients across a range of important neuropathy and quality of life measures. Eplontersen demonstrated robust and sustained reductions in serum TTR and significant improvements in measures of neuropathy and quality of life with a substantial number of patients demonstrating improvement at both week 35 and week 66. Eplontersen also showed statistically significant and clinically meaningful benefit across all 4 secondary end points, and continued to demonstrate a favorable safety and tolerability profile.

謝謝你，布雷特。正如布雷特剛才提到的，我們今年已經在關鍵項目中實現了一些目標。我們相信，我們從 NEURO-TTRansform 研究中報告的積極數據表明，eplontersen 具有顯著改善 ATTR 多發性神經病患者預後的潛力。 Eplontersen 達到了所有共同主要和所有次要療效終點，證明在一系列重要的神經病和生活質量指標中對 ATTR 多發性神經病患者俱有一致的益處。 Eplontersen 在第 35 周和第 66 週時顯示出血清 TTR 的穩健和持續降低以及神經病變和生活質量指標的顯著改善。Eplontersen 還在所有 4 個次要終點中顯示出具有統計學意義和臨床意義的益處點，並繼續表現出良好的安全性和耐受性。

In addition to publishing results from this study, we're set to present additional data at upcoming medical conferences. We and our partner, AstraZeneca, remain on track for a potential approval in the U.S. in December and are preparing regulatory submissions in additional markets around the world for later this year and next year. The positive efficacy and safety results we've seen from the NEURO-TTRansform study give us even greater confidence for the performance of eplontersen in our ongoing CARDIO-TTRansform study in patients with ATTR cardiomyopathy. CARDIO-TTRansform is the longest and largest study in this indication to date, designed to demonstrate benefit in a broad set of patients that represents the current treatment landscape. We anticipate completing enrollment midyear.

除了公佈這項研究的結果外，我們還準備在即將召開的醫學會議上展示更多數據。我們和我們的合作夥伴阿斯利康（AstraZeneca）仍有望於 12 月在美國獲得批准，並準備在今年晚些時候和明年在全球其他市場提交監管申請。我們從 NEURO-TTRansform 研究中看到的積極療效和安全性結果使我們對 eplontersen 在我們正在進行的 ATTR 心肌病患者的 CARDIO-TTRansform 研究中的表現更有信心。 CARDIO-TTRansform 是迄今為止針對該適應症進行的最長、規模最大的研究，旨在證明代表當前治療情況的廣泛患者的獲益。我們預計在年中完成註冊。

Our broad olezarsen development program for 2 indications, characterized by severely elevated triglycerides, FCS and severe HTG is also continuing to progress well. The Phase III BALANCE FCS study is fully enrolled, and we remain on track for data in the second half of this year. And our multi-study Phase III program designed to evaluate olezarsen in the broader SHTG indication is also continuing to progress. Additionally, our donidalorsen development program remains on track. We expect to fully enroll the Phase III OASIS-HAE study shortly, which keeps us on schedule for data in the first half of next year. During the first quarter, we reported additional positive longer-term data from the donidalorsen Phase II open-label extension study in patients treated for 1 year, reinforcing its potential competitive profile which included rapid onset of action with clinically meaningful improvements in quality of life, durable, attack protection and a continued favorable safety and tolerability profile.

我們廣泛的 olezarsen 開發計劃針對 2 個適應症，其特點是甘油三酯、FCS 和嚴重 HTG 嚴重升高，也繼續取得良好進展。 III 期 BALANCE FCS 研究已全部入組，我們仍有望在今年下半年獲得數據。我們旨在評估 olezarsen 在更廣泛的 SHTG 適應症中的多項研究 III 期計劃也在繼續取得進展。此外，我們的 donidalorsen 開發計劃仍在進行中。我們預計很快就會完全納入 III 期 OASIS-HAE 研究，這使我們能夠按計劃在明年上半年獲得數據。在第一季度，我們報告了 donidalorsen II 期開放標籤擴展研究對接受治療 1 年的患者的額外積極長期數據，加強了其潛在的競爭優勢，包括快速起效和臨床上有意義的生活質量改善，耐用，攻擊保護和持續有利的安全性和耐受性。

Our neurology franchise includes 12 medicines in development, including 2 in Phase III studies and 8 in Phase II. I would like to spend a couple of minutes highlighting 2 of these medicines that have important recent updates. As Brett mentioned, we are pleased that the FDA recently approved QALSODY, making it the first and only approved treatment to target a genetic form of ALS. This is a monumental breakthrough for the ALS community. QALSODY's approval was based on the reduction in plasma neurofilament light chain or NfL, a marker of neuronal damage that correlates with disease progression in ALS patients. The approval was supported by the 12-month integrated results from the Phase III VALOR study and the open-label extension.

我們的神經病學專營權包括 12 種正在開發的藥物，其中 2 種處於 III 期研究，8 種處於 II 期。我想花幾分鐘時間重點介紹最近有重要更新的 2 種藥物。正如 Brett 提到的，我們很高興 FDA 最近批准了 QALSODY，使其成為第一個也是唯一一個被批准的針對 ALS 遺傳形式的治療方法。這對 ALS 社區來說是一個巨大的突破。 QALSODY 的批准是基於血漿神經絲輕鍊或 NfL 的減少，NfL 是與 ALS 患者疾病進展相關的神經元損傷標誌物。該批准得到了 III 期 VALOR 研究和開放標籤擴展的 12 個月綜合結果的支持。

The integrated results showed patients who started treatment earlier experienced a slowing decline in measures of clinical function as well as respiratory and muscle strength. Additionally, QALSODY demonstrated a favorable safety profile. QALSODY is under review in the EU and additionally, the ongoing Phase III ATLAS study and presymptomatic SOD1-ALS study. Patient is also progressing nicely.

綜合結果顯示，較早開始治療的患者在臨床功能以及呼吸和肌肉力量方面的指標下降緩慢。此外，QALSODY 表現出良好的安全性。 QALSODY 正在歐盟接受審查，此外，正在進行的 III 期 ATLAS 研究和症狀前 SOD1-ALS 研究也在進行中。患者也進展順利。

We are encouraged by the recent data Biogen presented at the AD/PD Conference and published in Nature Medicine from the IONIS-MAPTRx Phase 1b study. Our MAPT medicine, also known as BIIB080 is our medicine aimed at reducing the production and aggregation of tau protein associated with disease progression in patients with Alzheimer's disease. Results in early AD patients treated for up to 100 weeks showed a rapid, substantial and sustained reduction in type of pathology as measured by both CSF levels and tau PET imaging. In fact, our MAPT drug is the first to demonstrate this magnitude of a reduction of tau pathology across important brain regions to date.

我們對 Biogen 在 AD/PD 會議上展示並發表在 Nature Medicine 上的 IONIS-MAPTRx 1b 期研究的最新數據感到鼓舞。我們的 MAPT 藥物，也稱為 BIIB080，是我們的藥物，旨在減少與阿爾茨海默病患者疾病進展相關的 tau 蛋白的產生和聚集。治療長達 100 週的早期 AD 患者的結果顯示，通過 CSF 水平和 tau PET 成像測量，病理類型迅速、實質和持續減少。事實上，我們的 MAPT 藥物是迄今為止第一個證明跨重要大腦區域的 tau 病理學減少程度的藥物。

Biogen is advancing the Phase II study in patients with early AD, which includes 2 different dose cohorts dosed every 6 months and 1 dose cohort dosed every 3 months. Our MAPT drug is just one example of advances we are making with our technology to potentially extend duration and reduce dosing frequency for CNS diseases and even more broadly. Our late-stage pipeline expanded this year to 7 drugs advancing in a total of 9 separate indications with the start of a pivotal program for bepirovirsen in patients with chronic HBV. We expect our late-stage pipeline to expand further this year when Roche advances IONIS-FB-LRx into a Phase III study for IgA nephropathy.

Biogen 正在推進針對早期 AD 患者的 II 期研究，其中包括每 6 個月給藥一次的 2 個不同劑量組和每 3 個月給藥一次的劑量組。我們的 MAPT 藥物只是我們利用我們的技術取得進步的一個例子，可以延長 CNS 疾病甚至更廣泛的持續時間並減少給藥頻率。我們的後期管線今年擴大到 7 種藥物，在 9 個獨立的適應症中取得進展，並啟動了針對慢性 HBV 患者的貝匹羅韋森關鍵項目。當羅氏將 IONIS-FB-LRx 推進 IgA 腎病的 III 期研究時，我們預計今年我們的後期管線將進一步擴大。

We recently took steps to further focus our R&D efforts and prioritize our pipeline with the discontinuation of 2 programs: cimdelirsen in acromegaly and sapablursen in beta-thalassemia. With both drugs, we saw evidence of good target engagement and favorable safety and tolerability, but efficacy results in the mid-stage studies did not meet our minimum target product profile to justify further development. We continue to advance the Phase II study of sapablursen for polycythemia vera and we plan to share data from this study as it becomes available.

我們最近採取措施進一步集中我們的研發工作，並通過終止 2 個項目來優先考慮我們的管道：肢端肥大症中的 cimdelirsen 和 β-地中海貧血中的 sapablursen。對於這兩種藥物，我們看到了良好的目標參與度和良好的安全性和耐受性的證據，但中期研究的療效結果不符合我們的最低目標產品概況，無法證明進一步開發的合理性。我們繼續推進 sapablursen 治療真性紅細胞增多症的 II 期研究，我們計劃在該研究可用時分享該研究的數據。

We remain on track for a number of key events, including regulatory decisions and late-stage pipeline achievements. These include U.S. eplontersen approval and Phase III data for olezarsen, our next potential medicine to launch after eplontersen. We will keep you updated on our progress on these events and more throughout the year.

我們在一些關鍵事件上保持正軌，包括監管決策和後期管道成就。其中包括美國對 eplontersen 的批准和 olezarsen 的 III 期數據，這是我們在 eplontersen 之後推出的下一個潛在藥物。我們將讓您了解我們在這些活動以及全年更多活動中的最新進展。

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

有了這個，我會把電話轉給貝絲。

Thank you, Richard. Our first quarter financial results reflect our ability to generate meaningful revenue while making investments in key growth opportunities across our business. We earned revenues of $131 million for the first quarter, was approximately half from our commercial products and half from numerous partnered programs. Our operating expenses and operating loss for the first quarter increased over the same period last year as we advanced our commercial readiness activities and advanced our pipeline, especially our late-stage programs.

謝謝你，理查德。我們第一季度的財務業績反映了我們在對整個業務的關鍵增長機會進行投資的同時產生可觀收入的能力。我們第一季度的收入為 1.31 億美元，其中大約一半來自我們的商業產品，一半來自眾多合作項目。我們第一季度的運營費用和運營虧損比去年同期有所增加，因為我們推進了商業準備活動並推進了管道，尤其是後期項目。

We ended March with substantial cash and investments of $2.3 billion, enabling us to continue making investments to create future growth opportunities. We earned $50 million in SPINRAZA royalty revenue based on global product sales of $443 million in the first quarter. Our SPINRAZA royalties reset annually and based on our revenue expectations, we anticipate reaching the highest royalty tier by midyear. Additionally, we continued to record 100% of our SPINRAZA royalties as commercial revenue under our royalty pharma transaction.

截至 3 月底，我們擁有 23 億美元的大量現金和投資，使我們能夠繼續進行投資以創造未來的增長機會。基於第一季度 4.43 億美元的全球產品銷售額，我們獲得了 5000 萬美元的 SPINRAZA 專利使用費收入。我們的 SPINRAZA 特許權使用費每年重置一次，根據我們的收入預期，我們預計到年中達到最高特許權使用費等級。此外，我們繼續將 SPINRAZA 特許權使用費的 100%記錄為我們特許權使用費製藥交易下的商業收入。

With SPINRAZA product sales were slightly lower in the first quarter compared to last year, we and Biogen continued to see signs of stabilization in Biogen's patient base. Importantly, Biogen remains focused on expanding into new markets and expanding existing markets. while also generating important efficacy data from its robust life cycle management program. Based on all these efforts, we and Biogen believe SPINRAZA can return to growth. We earned R&D revenue of $63 million in the first quarter for advancing numerous programs partnered with Biogen and AstraZeneca, among others. And already in the second quarter, we earned a $16 million milestone payment for QALSODY U.S. approval.

與去年相比，第一季度 SPINRAZA 產品銷售額略有下降，我們和百健（Biogen）繼續看到百健（Biogen）患者群穩定的跡象。重要的是，百健（Biogen）仍然專注於開拓新市場和擴大現有市場。同時還從其強大的生命週期管理程序中生成重要的功效數據。基於所有這些努力，我們和百健（Biogen）相信 SPINRAZA 可以恢復增長。我們在第一季度獲得了 6300 萬美元的研發收入，用於推進與百健（Biogen）和阿斯利康（AstraZeneca）等公司合作的眾多項目。在第二季度，我們獲得了 1600 萬美元的 QALSODY 美國批准里程碑付款。

Our non-GAAP operating expenses increased in the first quarter compared to the same period last year. As we advanced our robust pipeline, our study costs increased as most of our ongoing Phase III studies were either fully enrolled or approaching full enrollment, which resulted in higher R&D expenses. Additionally, as we continue to prepare to launch eplontersen, olezarsen and donidalorsen, our SG&A expenses also increased modestly year-over-year. We bolstered our working capital by adding $500 million from Royalty Pharma in exchange for a minority share of our SPINRAZA and potential pelacarsen royalties. As a result, we recorded a long-term liability, which we will reduce when we make payments to Royalty Pharma. Additionally, we will recognize imputed noncash interest expense which for the first quarter of 2023 was $16 million.

與去年同期相比，第一季度我們的非美國通用會計準則運營費用有所增加。隨著我們推進我們強大的管道，我們的研究成本增加了，因為我們正在進行的大多數 III 期研究要么完全註冊或接近完全註冊，這導致更高的研發費用。此外，隨著我們繼續準備推出 eplontersen、olezarsen 和 donidalorsen，我們的 SG&A 費用也同比小幅增長。我們增加了來自 Royalty Pharma 的 5 億美元，以換取我們 SPINRAZA 的少數股份和潛在的 pelacarsen 特許權使用費，從而增加了我們的營運資金。因此，我們記錄了一項長期負債，我們將在向 Royalty Pharma 付款時減少該負債。此外，我們將確認 2023 年第一季度的估算非現金利息支出為 1600 萬美元。

Looking ahead, we expect our revenues in Q2 to be modestly higher compared to Q1. We also anticipate that second half revenues will be weighted toward the back end of the year.

展望未來，我們預計第二季度的收入將略高於第一季度。我們還預計下半年的收入將集中在年底。

We project operating expenses to increase slightly in Q2 and to gradually increase over the course of the remainder 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 we made last year.

我們預計第二季度的運營費用將略有增加，並在今年剩餘時間內逐漸增加。根據我們的指導意見，其中包括與我們的資本密集型 III 期研究相關的費用，我們估計我們的全年研發費用將同比增長 20% 至 25%，不包括我們去年支付的 Metagenomi 預付款。

We also project our full year SG&A expenses to increase in the range of about $35 million year-over-year from our investments in our commercial preparations for eplontersen, olezarsen and donidalorsen. For the next few years, we are planning to continue to be in a period of investment as we advance our late-stage clinical programs, and prepare to independently commercialize our medicines. As a result, we project our operating expenses to grow modestly.

我們還預計，由於我們對 eplontersen、olezarsen 和 donidalorsen 的商業準備投資，我們全年的 SG&A 費用將同比增加約 3500 萬美元。在接下來的幾年裡，我們計劃在推進後期臨床項目的過程中繼續處於投資期，並準備將我們的藥物獨立商業化。因此，我們預計我們的運營費用將適度增長。

Additionally, by keeping more programs for ourselves, we anticipate a greater proportion of commercial revenues compared to R&D revenue. And as we add increasing commercial revenues on top of our substantial and sustained base of R&D revenue, we project our commercial revenues to be the primary driver of future revenue growth. With our goal to continue to build our Ionis-owned pipeline, we expect our investments today and into the future to drive greater value for Ionis and our shareholders.

此外，通過為我們自己保留更多項目，我們預計與研發收入相比，商業收入的比例更大。隨著我們在大量和持續的研發收入基礎上增加商業收入，我們預計我們的商業收入將成為未來收入增長的主要驅動力。我們的目標是繼續建立 Ionis 擁有的管道，我們希望我們今天和未來的投資能夠為 Ionis 和我們的股東帶來更大的價值。

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

有了這個，我會把電話轉回布雷特。

Thank you, Beth. We anticipate continuing our positive momentum as we advance our key priorities with additional important regulatory and late-stage pipeline events still come this year. We're well on our way to achieving our goal of delivering an abundance of new genetic medicines to the market. We just added QALSODY to our commercial portfolio. And with the December PDUFA date, we could also add eplontersen late this year. And with our rich late-stage pipeline, we're well positioned to bring additional medicines to the market on a steady cadence over the next several years.

謝謝你，貝絲。我們預計，在我們推進我們的關鍵優先事項時，我們預計會繼續保持積極的勢頭，今年還會有更多重要的監管和後期管道活動。我們正朝著向市場提供大量新基因藥物的目標邁進。我們剛剛將 QALSODY 添加到我們的商業產品組合中。根據 12 月的 PDUFA 日期，我們還可以在今年晚些時候添加 eplontersen。憑藉我們豐富的後期管道，我們有能力在未來幾年以穩定的節奏將更多藥物推向市場。

Additionally, with the progress we're making in all of our pre-commercial activities, our first planned launch of eplontersen with AstraZeneca in patients with ATTR polyneuropathy is in sight with our independent launches for olezarsen and donidalorsen also clearly in view. We continue to make innovative technological advancements for future medicines. And finally, our strong financial foundation enables us to invest in areas with the greatest potential to drive growth and drive value. We look forward to sharing our progress as we build on our recent achievements and accomplish our important objectives.

此外，隨著我們在所有商業化前活動中取得的進展，我們首次計劃與阿斯利康一起在 ATTR 多發性神經病患者中推出 eplontersen，我們的 olezarsen 和 donidalorsen 的獨立上市也清晰可見。我們繼續為未來的藥物做出創新的技術進步。最後，我們強大的財務基礎使我們能夠投資於最有潛力推動增長和創造價值的領域。我們期待在我們最近的成就和實現我們的重要目標的基礎上分享我們的進展。

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

有了這個，我們現在將打開它來提問。

(Operator Instructions) Our first question comes from Joseph Stringer with Needham & Company.

（操作員說明）我們的第一個問題來自 Needham & Company 的 Joseph Stringer。

Just wanted to get any additional color on the 2 program discontinuations. You mentioned it didn't fit your target product profile. But just curious, was it sort of efficacy threshold that didn't meet? Or were there any safety signals or any additional comment, that would be helpful.

只是想在 2 個程序中斷時獲得任何額外的顏色。您提到它不符合您的目標產品配置文件。但只是好奇，是不是達到了某種功效閾值？或者是否有任何安全信號或任何其他評論，這將有所幫助。

Sure, Joey. Happy to. So no safety issues at all. The safety profile for sapablursen in beta thalassemia intermedia and cimdelirsen in acromegaly, were clean pristine. It was all about efficacy. In both of these cases, these 2 drugs were being tested in a scenario for the first time. No one's ever targeted focusing first on acromegaly, to your question, growth hormone receptor on hepatocytes to block IGF-1 production.

當然，喬伊。高興。所以完全沒有安全問題。 sapablursen 在中間型 β 地中海貧血和 cimdelirsen 在肢端肥大症中的安全性是乾淨的。這一切都與功效有關。在這兩種情況下，這兩種藥物都是首次在一個場景中進行測試。沒有人首先關注肢端肥大症，對於你的問題，肝細胞上的生長激素受體會阻止 IGF-1 的產生。

As you know, acromegaly is caused by excessive GH, growth hormone and our hypothesis was that if we block the receptor on the hepatocyte, we can lower IGF-1 levels substantially that it could be a competitive treatment for acromegaly. We tested in refractory, and we reported that data last year, and this was the monotherapy data. It didn't meet our minimum target product profile for IGF-1 reductions. And we saw some reductions, but wasn't good enough. And considering the richness of our pipeline, it just didn't clear the bar. So we're moving on for acromegaly.

如您所知，肢端肥大症是由過多的 GH、生長激素引起的，我們的假設是，如果我們阻斷肝細胞上的受體，我們可以顯著降低 IGF-1 水平，這可能是肢端肥大症的競爭性治療方法。我們在難治性藥物中進行了測試，去年我們報告了該數據，這是單一療法的數據。它不符合我們降低 IGF-1 的最低目標產品概況。我們看到了一些減少，但還不夠好。考慮到我們管道的豐富性，它只是沒有清除障礙。所以我們繼續治療肢端肥大症。

Sapablursen is more interesting in my view. Sapablursen, we're developing for multiple indications. The first was beta-thalassemia intermedia. As a reminder, we showed that sapablursen targeting TMPRSS6 GalNAc targeting strategy. So really quite remarkable signs of efficacy in -- or target engagement, I should say, in our Phase I normal volunteer study. We reported that a couple of years ago. We showed a very significant elevations in hepcidin levels, which is what we're trying to achieve with -- by targeting TMPRSS6, and expected predicted changes in iron metabolism exactly as we had predicted in normal volunteers.

在我看來，Sapablursen 更有趣。 Sapablursen，我們正在開發多種適應症。第一個是中間型β-地中海貧血。作為提醒，我們展示了 sapablursen 靶向 TMPRSS6 GalNAc 靶向策略。因此，在我們的第一階段正常志願者研究中，我應該說，在 - 或目標參與方面確實非常顯著的療效跡象。我們在幾年前報導過。我們顯示出鐵調素水平非常顯著的升高，這正是我們試圖通過靶向 TMPRSS6 來實現的，並且預期鐵代謝的預測變化與我們在正常志願者中預測的完全一樣。

In polycythemia -- I'm sorry, in beta thalassemia intermedia, we didn't see those changes. As a reminder, TMPRSS6 is a pathway target. It's not a genetically validated target and keep that in mind. And we didn't see the biology translate from preclinical to clinical in that setting. With that said, so it didn't meet the product profile. With that said, in parallel, we advanced into polycythemia vera, and I'm very pleased to say that we're very encouraged by some of the initial data we're seeing in PV. PV seems -- the biology seems to be very different by target -- with targeting TMPRSS6 versus beta-thalassemia intermedia.

在紅細胞增多症——對不起，在中間型β地中海貧血中，我們沒有看到這些變化。提醒一下，TMPRSS6 是一個通路目標。它不是經過基因驗證的目標，請記住這一點。在那種情況下，我們沒有看到生物學從臨床前轉化為臨床。話雖如此，但它不符合產品配置文件。話雖如此，我們同時進入了真性紅細胞增多症，我很高興地說，我們對 PV 中看到的一些初始數據感到非常鼓舞。 PV 似乎——生物學似乎因目標而異——目標是 TMPRSS6 與中間型β-地中海貧血。

So it's all about biology. We're laser-focused on ensuring that the drugs that we invest in, in our pipeline meet a minimum target product profile, so we can focus our attention on the drugs that are going to bring the greatest value and that drug for acromegaly and that indication for sapablursen did not meet the bar.

所以這一切都與生物學有關。我們非常專注於確保我們投資的藥物在我們的管道中滿足最低目標產品概況，因此我們可以將注意力集中在將帶來最大價值的藥物和肢端肥大症的藥物上sapablursen 的適應症不符合標準。

The next question comes from Jessica Fye with JPMorgan.

下一個問題來自摩根大通的 Jessica Fye。

Question on eplontersen. First, with the IRA changes to Part D, can you talk about how you think about the annual out-of-pocket costs of eplontersen for Medicare patients in 2024 and 2025 and beyond. And how that compares to the out-of-pocket costs for your competitor product reimbursed through Part B? And then also related to eplontersen, I'm curious what you'll be watching for when the Acoramidis attribute data reads out this summer.

關於 eplontersen 的問題。首先，隨著 IRA 對 D 部分的更改，您能否談談您如何看待 2024 年和 2025 年及以後醫療保險患者使用 eplontersen 的年度自付費用。這與通過 B 部分報銷的競爭對手產品的自付費用相比如何？然後也與 eplontersen 相關，我很好奇當 Acoramidis 屬性數據在今年夏天讀出時你會關注什麼。

Great question. And as you would take the IRA, Eugene, maybe you could talk a little bit about data readouts from competitor programs in CM?

很好的問題。就像你接受 IRA 一樣，Eugene，也許你可以談談 CM 中競爭對手程序的數據讀出？

Jess, so first of all, it's important to understand the payer mix as we're going into the marketplace. So we're estimating about 1/3 of the patients in polyneuropathy are Medicare, 2/3 will be commercial. So they will not be subjected to the Medicare Part B, D, design you're talking about. They'll go through the normal hopefully, Tier 2, Tier 3 co-pays, which will -- which we obviously will offer some level of co-pay relief with co-pay cards with most manufacturers do.

Jess，首先，在我們進入市場時了解付款人組合非常重要。所以我們估計大約 1/3 的多發性神經病患者是 Medicare，2/3 是商業患者。因此，他們不會受到您所說的 Medicare B、D 部分設計的約束。他們將通過正常的希望，第 2 層，第 3 層共同支付，這將 - 我們顯然會與大多數製造商一起使用共同支付卡提供一定程度的共同支付減免。

On specific, the Part D path for eplontersen for the 1/3 of the patients that go through it, their patient out-of-pocket costs starting in 2024 for all Medicare Part D recipients will be capped at $2,000. As you know, currently, it goes into -- until it gets to catastrophic care, it ranges in the $20,000. So it's going to come down tenfold for these patients, which is a huge positive change for patients in Medicare Part D. And then I would say that we still expect to provide access for these patients to the foundations for the disease, for TTR diseases as is currently being used for first-generation silencers as well for stabilizers.

具體而言，對於 1/3 的患者，eplontersen 的 D 部分路徑，從 2024 年開始，所有 Medicare D 部分接受者的患者自付費用上限為 2,000 美元。如您所知，目前，它進入 - 直到它進入災難性護理，它的範圍在 20,000 美元。所以對於這些患者來說，它會下降十倍，這對 Medicare D 部分的患者來說是一個巨大的積極變化。然後我會說我們仍然希望為這些患者提供獲得疾病基礎的途徑，對於 TTR 疾病目前正用於第一代消音器和穩定器。

In terms of the Part B, I think that's a very different dynamic in terms of what is happening for those patients. They still have to think about, depending on their coverage, what level of coinsurance they would be paying. If they don't have supplemental, then that could be actually really high for them. And then the office costs have to be considered as well because you really have some dynamics there in terms of increasing the number of staff you have on board for those particular offices to make sure they have the ability to administer patients that are coming in.

就 B 部分而言，我認為就這些患者正在發生的事情而言，這是一個非常不同的動態。他們仍然需要考慮，根據他們的承保範圍，他們將支付什麼水平的共同保險。如果他們沒有補充劑，那麼這對他們來說實際上可能真的很高。然後還必須考慮辦公室成本，因為在增加這些特定辦公室的員工數量方面，你確實有一些動力，以確保他們有能力管理即將到來的病人。

And then I just characterize our benefit of self-administration at home. It really reduces the burden on both the patient as well as the physician particularly if you're not close to our center of excellence. It's a really far drive for many of these patients as well. And that ability to self-administer at home is really -- continues to be a really big driver of preference for eplontersen.

然後我只是描述我們在家自我管理的好處。它確實減輕了患者和醫生的負擔，特別是如果您不靠近我們的卓越中心。對於這些患者中的許多人來說，這也是一個非常遠的車程。而且這種在家自我管理的能力確實 - 繼續成為偏愛 eplontersen 的一個非常大的驅動因素。

Eugene, what are you looking for what's most interesting in the upcoming Acoramidis readout?

尤金，你在尋找即將到來的 Acoramidis 讀數中最有趣的是什麼？

Well, the most interesting thing to me would certainly be the effect that we see on outcomes in a modern trial. And by modern, I mean the trial that really was conducted post tafamidis sort of the -- within the last couple of years relative to what was seen in the past. And I think the most interesting bit for me would be to see the background rate in placebo arm, not even the active arm, although, of course, we're all focused on and also seeing the treatment effect. This is the study now was followed -- has followed these patients over a number of years. So this is going to be the first readout, as I said, for the population, which we believe is more reflective of what the current population of newly diagnosed patients may look like.

嗯，對我來說最有趣的事情當然是我們在現代試驗中看到的對結果的影響。所謂現代，我指的是真正在 tafamidis 之後進行的試驗——在過去幾年內相對於過去所見的情況。我認為對我來說最有趣的一點是看到安慰劑組的背景率，甚至不是活性組，當然，我們都關注並看到治療效果。這是現在被跟踪的研究——已經跟踪這些患者多年。因此，正如我所說，這將是人口的第一個讀數，我們認為這更能反映當前新診斷患者的人口情況。

So whether or not the patients indeed are more mild than what they were in the placebo group compared to the ATTRACT study. And it will also be interesting to see how a stabilizer looks up, it matches up to some of the early days we've seen with the silencer as well. That would be interesting.

因此，與 ATTRACT 研究相比，患者是否確實比安慰劑組更溫和。看看穩定器的外觀也很有趣，它也與我們早期看到的消音器相匹配。那會很有趣。

The next question comes from Yanan Zhu with Wells Fargo.

下一個問題來自富國銀行的 Yanan Zhu。

Congrats on the progress. Eplontersen, maybe 2 questions here. Maybe one, to follow up on what you're just talking about cardiomyopathy study. what to look out from the competitor study. I was wondering with your CARDIO-TTRansform study nearing completion of enrollment, could you provide an update on the mix of on tafamidis versus tafamidis naive patients in terms of proportions? And any update on the ongoing blinded event rate?

祝賀進步。 Eplontersen，這裡可能有 2 個問題。也許一個，跟進你剛才談論的心肌病研究。從競爭對手的研究中要注意什麼。我想知道您的 CARDIO-TTRansform 研究即將完成入組，您能否提供有關 tafamidis 與 tafamidis 初治患者比例的最新信息？關於正在進行的盲目事件率的任何更新？

And also, would we be able to learn about the baseline characteristics of these patients? Once you complete enrollment before you read out the data so that we could, as you suggested, look at compared to different studies and anticipate the event rate with a relatively more than comparator? And lastly, on eplontersen polyneuropathy, wondering about your pricing strategy that you and AstraZeneca is -- I assume you're working on, whether it would be a parity strategy with competitor drugs or whether it could be a competitive price?

而且，我們是否能夠了解這些患者的基線特徵？在您讀出數據之前完成註冊，以便我們可以像您建議的那樣，比較不同的研究並預測事件發生率相對高於比較？最後，關於 eplontersen 多發性神經病，想知道你和阿斯利康的定價策略——我假設你正在研究，它是否是與競爭藥物的平價策略，或者它是否可以是有競爭力的價格？

Thanks, Yanan, all great questions. So when we upsized the study, the CARDIO-TTRansform study, we had several objectives that we sought to achieve. One was to ensure that we had the size of the study to support the powering that was necessary for a patient population that has become more mild due to earlier diagnosis in detection and awareness of disease. The second was to ensure that we had about a 50-50 well-balanced usage in the study of tafamidis versus naive patients. And then thirdly, to increase the percentage of patients that are varying versus wild type.

謝謝，亞南，所有很好的問題。因此，當我們擴大這項研究，即 CARDIO-TTRansform 研究時，我們有幾個想要實現的目標。一是確保我們有足夠的研究規模來支持由於早期診斷和疾病意識而變得更加溫和的患者群體所必需的動力。第二個是確保我們在 tafamidis 與無經驗患者的研究中有大約 50-50 的均衡使用。第三，增加變異型與野生型患者的百分比。

Obviously, we're coming close to completing the study, and we're very confident in our decision to have upsized the study to around 1,400 patients, and we're going to be wrapping up enrollment very soon. So we're well on our way there, of course. But we're also very pleased that our objectives for a good balance between tafamidis and naive as well as increasing the percentage of variant patients in the CM study is -- we're achieving it. We're well on our way to achieving all of our goals there. So that's well in hand.

顯然，我們即將完成這項研究，我們對將研究擴大到大約 1,400 名患者的決定非常有信心，我們將很快結束招募。當然，我們正在順利進行。但我們也很高興我們的目標是在 tafamidis 和天真之間取得良好平衡，並增加 CM 研究中變異患者的百分比——我們正在實現它。我們正在朝著那裡實現所有目標的方向前進。所以這很好。

As far as the blinded event rates, we're monitoring those very carefully. And that, too, is doing -- is performing very well as we had hoped it would when we upsized the study and prioritize sites when we upsized the study where we think patients would be sicker, wouldn't have such a high percentage of mild disease. So that's working very well, too. We're seeing what we want to see in the blinded event rates. With respect to publishing demographics, I don't have that plan in front of me. I don't think -- this is a very competitive space. We will publish or present that data at the right time, but I don't think we're going to be rushing to do that. And as far as pricing strategy, Onaiza, would you like to comment on that?

至於盲目事件發生率，我們正在非常仔細地監控它們。而且，這也正在做——表現非常好，正如我們在擴大研究範圍時所希望的那樣，並在我們擴大研究範圍時優先考慮我們認為患者會病情加重、不會有如此高百分比的輕症患者的研究地點疾病。所以這也很好用。我們在盲目事件發生率中看到了我們想要看到的。關於發佈人口統計數據，我面前沒有那個計劃。我不認為——這是一個競爭非常激烈的領域。我們會在合適的時間發布或展示這些數據，但我認為我們不會急於這樣做。至於定價策略，Onaiza，你想對此發表評論嗎？

Yes. Yanan, really simply, we're going to price accordingly to where we believe we're going to get the best and strong access and coverage for our patients. And that work is ongoing right now with AstraZeneca. And in terms of your comment on parity pricing, it's just a reminder that we're launching in multiple markets outside of the U.S. where we will be first. So we will be setting the price in those markets as well. So those are both going into consideration. And again, the goal is to get access for these 40,000 patients, both mixed phenotype as well as in polyneuropathy and make sure we have broad access and coverage.

是的。延安，真的很簡單，我們將根據我們認為我們將為我們的患者獲得最佳和強大的訪問和覆蓋範圍的地方定價。阿斯利康目前正在進行這項工作。就您對平價定價的評論而言，這只是一個提醒，我們將首先在美國以外的多個市場推出。因此，我們也將在這些市場設定價格。所以這些都在考慮之中。同樣，我們的目標是為這 40,000 名患者提供服務，包括混合表型和多發性神經病，並確保我們有廣泛的訪問和覆蓋範圍。

Next question comes from Mike Ulz with Morgan Stanley.

下一個問題來自摩根士丹利的 Mike Ulz。

Maybe just a quick follow-up on sapablursen, specifically in PV. I guess, do you anticipate any read-through to PV from the beta-thal study. It sounds like you don't based on some biology, but maybe you could just explain why the biology may be different in those 2 different indications?

也許只是對 sapablursen 的快速跟進，特別是在 PV 方面。我想，您是否期望從 beta-thal 研究中讀到 PV。聽起來你不是基於某些生物學，但也許你可以解釋為什么生物學在這兩種不同的適應症中可能不同？

We thought -- thanks. It's a very good question. We thought that there could be some read-through from beta-thal to PV because in both -- our objectives for both studies was to elevate hepcidin production in a disease that's really caused by very low or nonexistent hepcidin levels. But we didn't see the read through. We're not seeing the read through. We're seeing very encouraging early signs in polycythemia vera that the biology in beta thalassemia intermedia just isn't reading through. And we think that this bodes really well for other indications that we're thinking of for our sapablursen and TMPRSS6 drug.

我們認為——謝謝。這是一個很好的問題。我們認為從 beta-thal 到 PV 可能會有一些通讀，因為在這兩者中——我們兩項研究的目標都是在一種真正由非常低或不存在的鐵調素水平引起的疾病中提高鐵調素的產量。但是我們沒有看到通讀。我們沒有看到通讀。我們在真性紅細胞增多症中看到了非常令人鼓舞的早期跡象，表明中間型地中海貧血的生物學機制並未完全解讀。我們認為這預示著我們正在考慮的 sapablursen 和 TMPRSS6 藥物的其他適應症。

I wish I had an answer for why the biology is different. We don't. What was really surprising was the preclinical data in beta-thalassemia intermedia, which we have published on extensively in models that we thought were predictive of beta-thalassemia intermedia. I mean they had all the right signs and profiles of those animal models was very strongly similar to the human condition didn't happen. So we were surprised, but I really wish we knew the biology of what was going on there more. What I can tell you is that in beta-thal, we did not get the hepcidin increases that we expected to get that we got in normal volunteers, and we're seeing elsewhere. So it's just there's something more complex about that patient population.

我希望我能回答為什么生物學不同。我們沒有。真正令人驚訝的是中間型 β 地中海貧血的臨床前數據，我們已經在我們認為可以預測中間型 β 地中海貧血的模型中廣泛發表了這些數據。我的意思是他們有所有正確的跡象和這些動物模型的概況與人類狀況非常相似並沒有發生。所以我們很驚訝，但我真的希望我們能更多地了解那裡發生的事情的生物學原理。我可以告訴你的是，在 beta-thal 中，我們沒有得到我們預期在正常志願者中得到的 hepcidin 增加，我們在其他地方也看到了。所以這只是關於患者群體的一些更複雜的東西。

I completely agree, Brett, that there's no read-through on the efficacy. But on the safety, I would say it's reading through very, very nicely. And that means we're not seeing any safety issues. And in fact, the sensitivity in the PV patients, at least in the early look, seems to think we may be driving doses even lower and so big margins.

我完全同意，布雷特，沒有通讀功效。但就安全性而言，我會說它的通讀非常非常好。這意味著我們沒有看到任何安全問題。事實上，PV 患者的敏感性，至少在早期看來，似乎認為我們可能會降低劑量並獲得如此大的利潤。

Yes. We -- a great point, Richard. And if I could expand on your expanding on me. We've really pushed the dose in beta-thal and we treated a long time because we expected to see effects in beta-thal. And as Richard said, even though we pushed the dose, the safety was pristine. And we came into another indication, we realized that we didn't need that dose. So we're looking at -- so the dose is going to be lower than what we pushed in beta-thal. And that just further gives us confidence in why we shows this target and why we pursued it for various indications. It looks like it's going to be a low dose treatment for indications we develop.

是的。我們 - 一個很好的觀點，理查德。如果我可以擴展你對我的擴展。我們確實提高了 beta-thal 的劑量並且我們治療了很長時間，因為我們希望在 beta-thal 中看到效果。正如理查德所說，即使我們加大了劑量，安全性還是很不錯的。我們發現了另一個跡象，我們意識到我們不需要那個劑量。所以我們正在研究 - 所以劑量將低於我們在 beta-thal 中推出的劑量。這進一步讓我們對為什麼我們顯示這個目標以及為什麼我們追求它的各種適應症充滿信心。看起來這將是針對我們開發的適應症的低劑量治療。

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

下一個問題來自 Yale Jen 和 Laidlaw & Company。

My first question is regarding olezarsen in FCS. I know the data will be presented later this year. I'm just curious what you guys have learned from the prior experience from WAYLIVRA and in terms of the future sort of steps that will further sort of improve the commercial outlook and other aspects of this drug? Then I have another follow-up.

我的第一個問題是關於 FCS 中的 olezarsen。我知道數據將在今年晚些時候公佈。我只是好奇你們從 WAYLIVRA 的先前經驗中學到了什麼，以及未來將進一步改善這種藥物的商業前景和其他方面的步驟？然後我有另一個後續行動。

Rich?

富有的？

Yes, that's a great question. And looking back at our not only previous but current experience with WAYLIVRA, we have really nice growth in the commercial space. And I think what's really driving that are not only the significant triglyceride lowering activity of this approach, APOCIII inhibition. But what appears to be a very strong connection to the downstream events of pancreatitis. And so patients are feeling better, functioning better. And so all of these things drive obviously hopefully, commercial. So that's the learning, I think, that we've gotten and learnings that we have even today from our WAYLIVRA experience.

是的，這是一個很好的問題。回顧我們過去和現在與 WAYLIVRA 的經驗，我們在商業領域取得了非常好的增長。而且我認為真正推動的不僅僅是這種方法顯著的甘油三酯降低活性，APOCIII 抑制。但是，這似乎與胰腺炎的下游事件有著非常密切的聯繫。因此，患者感覺更好，功能更好。因此，所有這些事情顯然都充滿希望地商業化。因此，我認為，這就是我們從 WAYLIVRA 經歷中獲得的知識，甚至是我們今天所獲得的知識。

Yes. And I'll just add to that, Richard, that olezarsen is a more potent molecule and we expect even deeper reductions in APOCIII and triglycerides that we saw with the early generation WAYLIVRA, of course, with a pristine safety profile like we're seeing for our -- all of our [like us] to date. And the other thing is that we're going to be paying attention to is, in addition to patients just feeling better, reductions potentially strong trends, hopefully, in pancreatitis event reductions. With WAYLIVRA, we saw reductions in liver fat, and that's important, too. And we'll be looking at that as well because, again, we're seeing greater reductions in APOCIII and we're going to be very -- we're going to want to replicate that. And then you had another question, Yale?

是的。我還要補充一點，理查德，olezarsen 是一種更有效的分子，我們預計我們在早期的 WAYLIVRA 中看到的 APOCIII 和甘油三酯的減少會更深，當然，具有我們所看到的原始安全性對於我們 - 我們所有 [like us] 迄今為止。另一件事是，我們要注意的是，除了患者感覺好些之外，減少潛在的強烈趨勢，希望能減少胰腺炎事件。使用 WAYLIVRA，我們看到肝臟脂肪減少，這也很重要。我們也會關注這一點，因為我們再次看到 APOCIII 的減少幅度更大，我們將非常——我們想要復制它。然後你有另一個問題，耶魯？

Yes. Just in terms of sapablursen and PV. First of all, is the data will be reported later this year? And secondly, that in terms of Acoramidis, if it's a positive Acoramidis for a pivotal study, what do you think the approvable endpoint will be used or contemplate?

是的。就 sapablursen 和 PV 而言。首先，數據是今年晚些時候上報嗎？其次，就 Acoramidis 而言，如果它是一項關鍵研究的陽性 Acoramidis，您認為將使用或考慮可批准的終點是什麼？

So maybe, Eugene, you help a little bit about what an approvable endpoint would be for PV. We don't know if we're going to have the sufficient data this year, Yale, to report on the PV, again, in dose ranging. I wouldn't rule it out, but I'm not -- we certainly are not promising it at this point. We're just going to have to really figure out the dose and look at what the profile is. So I'll leave it at that. And Eugene, where do you look at?

所以也許，Eugene，你可以幫助了解 PV 的可批准終點是什麼。耶魯大學，我們不知道今年是否會有足夠的數據來報告劑量範圍內的 PV。我不會排除它，但我不是——我們現在當然不承諾它。我們只需要真正弄清楚劑量並查看配置文件是什麼。所以我會保留它。尤金，你看哪裡？

It's a good question. There's a number of things we're going to explore in early in proof-of-concept studies. Obviously, the goal is to maintain these patients hematocrit level within the range that doesn't require phlebotomy. That's kind of the main clinically significant endpoint. But there's a number of other exploratory endpoints. We're examining these patients experience pretty low quality of life related to their PV symptoms such as fatigue, and we're obviously going to explore the impact of improving their hematocrit control and being phlebotomy-free, but also whether this impact translates into them actually experiencing better quality of life.

這是個好問題。在概念驗證研究的早期，我們將探索許多事情。顯然，目標是將這些患者的血細胞比容水平維持在不需要放血的範圍內。這是一種主要的臨床重要終點。但還有許多其他探索性終點。我們正在檢查這些患者的生活質量與他們的 PV 症狀（如疲勞）相關，我們顯然將探索改善他們的血細胞比容控制和無靜脈切開術的影響，以及這種影響是否轉化為他們實際體驗更好的生活質量。

Onaiza, do you want to add to that?

Onaiza，你想補充嗎？

Yes, I'll just add that it's a really attractive commercial opportunity. There is a significant addressable population, both in the U.S. as well as outside of the U.S. And in addition to what Eugene said in terms of reducing phlebotomy or phlebotomy-free, there's also a significant portion of this market that's at high risk for thrombotic events. So we do believe that both things are going to be really important.

是的，我只想補充一點，這是一個非常有吸引力的商業機會。無論是在美國還是在美國以外，都有大量可尋址的人群。除了尤金所說的減少放血或不放血外，這個市場中還有很大一部分人處於血栓事件的高風險中.所以我們確實相信這兩件事都將非常重要。

Maybe (inaudible) which is -- is this strictly for first line or second line index. Sorry.

也許（聽不清）這是——這是否嚴格用於第一行或第二行索引。對不起。

I think that's going to be a bit of -- I think it would be first line if there were no payers involved. But because there are payers involved, we do think, and we're doing some work on this, that they may have to step through some of the generics certainly not -- that was too restrictive, but there may be a step too in this.

我認為這將有點——我認為如果不涉及付款人，這將是第一線。但是因為有付款人參與，我們確實認為，並且我們正在為此做一些工作，他們可能必須逐步通過一些仿製藥，當然不是——那太嚴格了，但在這方面可能也有一個步驟.

The next question comes from Yaron Werber with TD Cowen.

下一個問題來自 Yaron Werber 和 TD Cowen。

This is Brendan on for Yaron. Just a couple of quick ones from us, really on HAE here. Can you just remind me, are you prepared to file in the U.S. next year if the data hits in the first half, so we could potentially see donidalorsen sales maybe starting in 2025. And then honestly, just wondering if you have any new or additional feedback from some of these HAE physicians on how you think the drug maybe fit into the existing paradigm and maybe where you're seeing kind of the highest unmet need and lowest hanging fruit that you think you could most quickly move into in an HAE launch?

這是 Yaron 的 Brendan。我們只是幾個快速的，真的在 HAE 上。你能不能提醒我一下，如果數據在上半年出現，你是否準備好明年在美國提交申請，那麼我們可能會看到多尼達羅森的銷售可能從 2025 年開始。然後老實說，只是想知道你是否有任何新的或額外的這些 HAE 醫生中的一些人對您認為該藥物可能如何適應現有範式的反饋，以及您認為您認為可以在 HAE 發布中最快進入的最高未滿足需求和最低掛果的地方？

Yes. The first question -- the second question I'll ask Onaiza to address. The first question is an easy answer. We're expecting data readout early next year, filing next year, launch in '25. We're very much getting ready to do that.

是的。第一個問題——第二個問題，我將請 Onaiza 解決。第一個問題很容易回答。我們預計明年初數據讀出，明年提交，25 年推出。我們非常準備這樣做。

Yes. We're -- the teams are working very diligently on launch preparations over here. We continue to do research in the marketplace, and our best-in-class profile holds true on a couple of very important parameters that will be important for switch and/or uptake in new patients. But the -- our data in terms of the mean reduction in HAE attacks is really, by far, the most compelling point for physicians and for patients that really want to have virtually as many zero attacks as they can, right, in a given year.

是的。我們 - 團隊正在這裡非常努力地進行發布準備工作。我們繼續在市場上進行研究，我們一流的資料適用於幾個非常重要的參數，這些參數對於新患者的轉換和/或吸收很重要。但是，我們關於 HAE 攻擊平均減少的數據，到目前為止，對於真正希望在給定年份盡可能多地發生零攻擊的醫生和患者來說，確實是最有說服力的一點。 .

We also have really strong quality of life data that emerged. If you took a look at our OLE data, which is also in testing reading out really well as an important point, duration of activity. and our rapid onset. So all of those are really important best-in-class profile features. And of course, our Q1 monthly beats kind of what standard of care is right now in the marketplace, which is 2 weeks.

我們還出現了非常強大的生活質量數據。如果你看一下我們的 OLE 數據，它也在測試中作為一個重要點、活動持續時間真的很好地讀出。和我們的快速發作。所以所有這些都是非常重要的一流配置文件功能。當然，我們的第 1 季度月度擊敗了目前市場上的護理標準，即 2 週。

The next question comes from Salveen Richter with Goldman Sachs.

下一個問題來自高盛的 Salveen Richter。

Congrats on the progress. This is Tommie on for Salveen. So now that we've seen positive data from 2 Phase III Alzheimer's studies. How are you thinking about the [AD] and any read-through and more broadly, on the cardio portfolio, as you start to advance these programs in larger markets, how do you go through the process of thinking about reimbursement access dynamics or models here for longer-acting treatments in these indications where oral treatments may already be available?

祝賀進步。這是 Salveen 的 Tommie。所以現在我們已經看到了 2 項 III 期阿爾茨海默氏症研究的積極數據。當你開始在更大的市場推進這些項目時，你如何看待 [AD] 和任何通讀，更廣泛地說，在有氧運動組合上，你如何在這裡完成考慮報銷訪問動態或模型的過程對於這些可能已經有口服治療的適應症的長效治療？

Eric, you want to comment on what we're doing in dementia and how the recent success is?

埃里克，你想評論我們在癡呆症方面所做的工作以及最近取得的成功嗎？

I mean well, I think -- so certainly for AD patients, positive data is fantastic to see. And so clearly, there are obviously different mechanisms, right? So the therapies with positive data and the one from Lilly this morning was an amyloid reducing antibody, which is affecting one of the pathologies involved in Alzheimer's disease. The other key pathology is the accumulation of tau and that's what BIIB080 addresses.

我的意思是，我認為——所以對於 AD 患者來說，積極的數據是非常棒的。很明顯，有明顯不同的機制，對吧？因此，具有積極數據的療法和今天早上來自禮來公司的療法是一種澱粉樣蛋白減少抗體，它正在影響阿爾茨海默氏病所涉及的一種病理學。另一個關鍵病理是 tau 的積累，這就是 BIIB080 所解決的問題。

So we think there -- we're nicely positioned to be the first drug that can really test the tau hypothesis in Alzheimer's disease and lower pathogenic tau accumulations. And that's the data that was shown by Biogen from the open-label extension at the recent AD/PD meeting, where by tau PET, where you can actually visualize the accumulation of pathogenic tau inside the brain, we were able to reduce that with the MAPT drug of BIIB080 and that generated lots of enthusiasm and it has prompted Biogen to take that forward into a pretty large Phase IIb study where they're looking at 6-month dosing in form of those -- importantly, dosing intervals of 2 different doses of the drug to see if it really makes a difference and lowering that tau pathology can make a difference in clinical outcomes. So certainly, I think that you can make the fact that improvements have been seen with other drugs is encouraging, and we look forward to testing the tau hypothesis. I think it's a great program.

所以我們認為 - 我們有很好的定位，可以成為第一種能夠真正測試阿爾茨海默病中的 tau 假說並降低致病性 tau 積累的藥物。這就是 Biogen 在最近的 AD/PD 會議上從開放標籤擴展中顯示的數據，通過 tau PET，您可以在其中實際可視化腦內致病性 tau 的積累，我們能夠通過BIIB080 的 MAPT 藥物引起了極大的熱情，它促使百健（Biogen）將其推進到一項相當大的 IIb 期研究中，他們正在研究以這些形式進行的 6 個月給藥——重要的是，2 種不同劑量的給藥間隔的藥物，看看它是否真的有所作為，降低 tau 病理學可以對臨床結果產生影響。所以當然，我認為你可以證明其他藥物的改善是令人鼓舞的，我們期待著檢驗 tau 假說。我認為這是一個很棒的節目。

The intracellular tau hypothesis, which hasn't been tested before. and we have a great-looking drug in BIIB080. The other thing is just to expand on that a bit more. We have several programs, a rich program in dementia, programs in dementia that are coming behind tau. So stay tuned for those in the future. It's not -- our whole bet is not on just tau, although we're very excited about it as is Biogen.

細胞內 tau 假說，之前沒有經過檢驗。我們在 BIIB080 中有一個很好看的藥物。另一件事只是對此進行更多擴展。我們有幾個項目，一個豐富的癡呆症項目，落後於 tau 的癡呆症項目。因此，請繼續關注未來的那些人。這不是——我們的全部賭注不僅僅押在 tau 上，儘管我們和 Biogen 一樣對此感到非常興奮。

And then Tommie, can you repeat your second question? I'm sorry.

然後 Tommie，你能重複你的第二個問題嗎？對不起。

Right. It was on some of the cardio programs and generally more prevalent markets. How do you think about reimbursement and access for longer-acting treatments, whereas oral may already be available because we've seen some headwinds here with other programs.

正確的。它出現在一些有氧運動項目和更普遍的市場上。您如何看待長效治療的報銷和獲得，而口服可能已經可用，因為我們在這裡看到了其他項目的一些不利因素。

Onaiza?

女座？

Yes. It's a really good question. I mean I go back to kind of basics on this, I think you have to really think about what the continued unmet need is in the marketplace and what your products bringing in terms of its profile to deliver on that. We take that combination and say, okay, with the value proposition we're bringing to this particular disease state is unmet need and then price accordingly to that. So we have done some really good work if you're talking about olezarsen in the broader prevalent SHTG market. And we do see really good pricing potential in the kind of higher premium cardiovascular product ranges, which, again, our triglyceride reduction is like 3x the magnitude of what the orals are right now. So we really do believe we have a very compelling value proposition to price in that CV premium range.

是的。這是一個非常好的問題。我的意思是我回到這方面的基礎知識，我認為你必須真正考慮市場上持續未滿足的需求是什麼，以及你的產品在其概況方面帶來了什麼來實現這一目標。我們採用這種組合併說，好吧，我們為這種特定疾病狀態帶來的價值主張是未滿足的需求，然後據此定價。因此，如果您在更廣泛的 SHTG 市場上談論 olezarsen，我們已經做了一些非常好的工作。而且我們確實看到了更高的心血管產品系列的定價潛力，同樣，我們的甘油三酯降低幅度是目前口服產品的 3 倍。所以我們真的相信我們有一個非常有吸引力的價值主張來定價 CV 溢價範圍。

The next question comes from Paul Matteis with Stifel.

下一個問題來自 Stifel 的 Paul Matteis。

This is James on for Paul. Maybe just a kind of broader high-level question. Assuming olezarsen hits in SHTG and donidalorsen hits in HAE, what do you think Ionis looks like in 2025, 2026, specifically with respect to what your sales force could look like and what type of synergy there would be between -- for those 2 assets, if at all? Any thoughts there would be great.

這是詹姆斯換保羅。也許只是一種更廣泛的高級問題。假設 olezarsen 在 SHTG 中取得成功，而 donidalorsen 在 HAE 中取得成功，您認為 Ionis 在 2025 年、2026 年會是什麼樣子，特別是關於您的銷售團隊會是什麼樣子以及兩者之間會有什麼樣的協同作用——對於這兩種資產，如果有的話？任何想法都會很棒。

Well, I'll just start. I'll ask Onaiza to address your sort of vision for the build of our commercial organization, something we're working with -- we're obviously working on and preparing for launches in the near term with olezarsen and donidalorsen. But we're expecting a half dozen or so new drugs on the market in that time frame, James. And that includes, of course, wholly owned and drugs we commercialize as well as our partner, we're pretty confident in that. But Onaiza, you want to talk a little bit about the growth?

好吧，我就開始吧。我會請 Onaiza 談談你對我們商業組織構建的願景，我們正在與之合作——我們顯然正在努力並準備在短期內與 olezarsen 和 donidalorsen 一起推出。但我們預計在那個時間段內會有六種左右的新藥上市，James。當然，這包括我們的全資擁有和商業化的藥物以及我們的合作夥伴，我們對此非常有信心。但是 Onaiza，你想談談增長嗎？

Yes, it looks really exciting. I mean we have 2 cross-functional teams planning for both launches and they're not overlapping. I will just say that behind the scenes of all the commercial infrastructure that you need, there are a lot of synergies, right? So what we're building for even for eplontersen with our patient services and hubs and where we have our field medical team we're thinking about how we bring them forward to our next independent launches and then all the systems that go behind it as well, and we'll see lots of synergy there.

是的，看起來真的很令人興奮。我的意思是，我們有 2 個跨職能團隊為兩次發布做計劃，而且他們沒有重疊。我只想說，在你需要的所有商業基礎設施的幕後，有很多協同作用，對吧？因此，我們正在為 eplontersen 構建我們的患者服務和中心，以及我們擁有現場醫療團隊的地方，我們正在考慮如何將他們帶到我們的下一次獨立發布，然後是它背後的所有系統，我們會在那裡看到很多協同作用。

But where we will see differences is obviously in our sales teams eventually for these 2 products, and they will be different. There are different call points. And for olezarsen, we know it's a large opportunity, but we're really honing in on 2 specialties, which is cardiology and endocrinology. And these are very severely elevated triglycerides. So this is not a place where a lot of PCPs or GPs are actually prescribing, they're referring out to those specialties. So we're working on the sizing of that team.

但是，對於這兩種產品，我們最終會在我們的銷售團隊中看到差異，而且它們會有所不同。有不同的調用點。對於 olezarsen，我們知道這是一個巨大的機會，但我們真正專注於 2 個專業，即心髒病學和內分泌學。這些是非常嚴重升高的甘油三酯。所以這不是很多 PCP 或全科醫生實際開處方的地方，他們指的是那些專業。所以我們正在研究該團隊的規模。

And then for donidalorsen, it's allergists and it's very, very concentrated 50% of the docs actually prescribe 80% of the prescriptions and you can bench it really easily to where the market leader Takeda is, and they have about 50 reps or so that are going after that opportunity. and very well concentrated and sizable. So it is different, but they're really good ways that we're thinking about ensuring that the teams get the focus that they need and are calling on the right docs with the most efficient model.

然後對於 donidalorsen，它是過敏症專家，它非常非常集中 50% 的醫生實際上開出了 80% 的處方，你可以很容易地把它放到市場領導者武田那裡，他們有大約 50 次左右的代表追求那個機會。並且非常集中且相當大。所以它是不同的，但它們確實是我們正在考慮確保團隊獲得他們需要的焦點並使用最有效的模型調用正確文檔的好方法。

The next question comes from Konstantinos Biliouris with BMO Capital Markets.

下一個問題來自 BMO Capital Markets 的 Konstantinos Biliouris。

Congrats on the progress. A couple of questions from us. The first one on AD. Given the relatively small size of the market there, -- how are you thinking about the competitive gene editing therapies or gene therapies, which if they are really won and done, they can shrink the market size even further? And then I have a follow-up.

祝賀進步。我們有幾個問題。第一個關於AD。鑑於那裡的市場規模相對較小，你如何看待競爭性基因編輯療法或基因療法，如果它們真的贏得併完成，它們可以進一步縮小市場規模？然後我有一個後續行動。

Well, I'll start, and I'll ask Onaiza if she wants to expand or not but. HAE patient population -- well, first let me start here. DNA editing is still very early on. There's a lot to prove with respect to all aspects of the pharmacology. That includes the safety, the off-target potential to potentially permanently edit DNA in an unplanned manner in a non-preferred manner as well as the durability. Is it really won and done.

好吧，我要開始了，我會問問 Onaiza 是否要擴展，但是。 HAE 患者群體——好吧，首先讓我從這裡開始。 DNA 編輯仍處於早期階段。關於藥理學的各個方面，還有很多東西需要證明。這包括安全性、以非首選方式以計劃外方式永久編輯 DNA 的潛在脫靶可能性以及耐用性。是不是真的贏了，完了。

We've heard that for gene therapy. DNA editing truly be won and done as well. And if it's not, can you redose. There's so much to learn here for DNA editing. The second thing is when you start getting into these younger patient populations, which HAE largely is. This is a disease that's getting diagnosed earlier and earlier. The interest. There's real concerns from patients about editing their DNA, to be blunt at an early -- at such an early age when you're thinking about building families and those sorts of things.

我們聽說過基因治療。 DNA 編輯也真正贏得併完成了。如果不是，你能重做嗎？這裡有太多關於 DNA 編輯的知識。第二件事是當你開始進入這些年輕的患者群體時，其中大部分是 HAE。這是一種越來越早被診斷出來的疾病。興趣。患者確實擔心編輯他們的 DNA，在早期就直言不諱——在你考慮建立家庭和諸如此類的事情的這麼早的時候。

So there's a lot of headwind on DNA editing specifically for HAE. As you know, Kostas, we are investing in DNA editing. We have a different strategy for targeted identification and drug development that we're trying to address those types of concerns as we bring our molecules forward. It's still early days. But we believe in our investment in DNA editing, but we don't think HAE is going to be the right place for this approach. What do you think, Onaiza?

因此，專門針對 HAE 的 DNA 編輯存在很多阻力。如你所知，Kostas，我們正在投資 DNA 編輯。我們有一個不同的目標識別和藥物開發策略，我們正在努力解決這些類型的問題，因為我們提出了我們的分子。現在還為時尚早。但我們相信我們在 DNA 編輯方面的投資，但我們認為 HAE 不會成為這種方法的合適場所。你怎麼看，Onaiza？

No, I think you summarized it well. I would say, in addition to kind of the long-term safety that still needs to be demonstrated, this patient population is appetite for actually taking a DNA edit so early in their lifespan and not knowing what the long-term consequences are major. And then I'll add in a third. I think the third one is what will be the continued remaining unmet need in HAE because we are really going to fulfill that. We have a great product. And again, it is -- I think it's going to be fully satisfied by the time being, get there.

不，我認為你總結得很好。我想說的是，除了仍然需要證明的長期安全性之外，這個患者群體很想在他們生命的早期進行 DNA 編輯，並且不知道長期後果是什麼。然後我會添加第三個。我認為第三個是 HAE 中仍未滿足的需求，因為我們真的要滿足它。我們有很棒的產品。再一次，它是——我認為它暫時會完全令人滿意，到達那裡。

And then you had a second question, Kostas?

然後你有第二個問題，Kostas？

Yes. And the second quick one on olezarsen. How are you thinking about the pricing because you are potentially launching into different markets where the size of the targeted population is different. How are you thinking about pricing there in these 2 different populations? And I would assume that the drug will be exactly the same in terms of dosing and all these.

是的。第二個是關於 olezarsen 的。您如何考慮定價，因為您可能會進入目標人群規模不同的不同市場。您如何考慮在這兩個不同的人群中定價？而且我認為藥物在劑量和所有這些方面將完全相同。

Yes. Yes, it's a good question. We know that we have a rare disease population with FCS and then more prevalent, broader with SHTG. So we don't expect the rare disease pricing obviously, for the broader population. We are working through the pricing strategy in terms of what our launch pricing will be. But stay tuned. We're thinking through a lot of like different strategic ways to get at it. But you should know if you're looking at the broader population that we don't expect that obviously to be in the rare disease pricing range at all. Again, as I said earlier, we'll be in the cardiovascular kind of premium pricing range that you see for more prevalent.

是的。是的，這是個好問題。我們知道我們有一個罕見的 FCS 疾病人群，然後更普遍、更廣泛的 SHTG。因此，對於更廣泛的人群，我們預計罕見病的定價不會明顯。我們正在根據我們的發布定價制定定價策略。但敬請期待。我們正在考慮通過很多類似的不同戰略方法來實現它。但是你應該知道，如果你正在研究更廣泛的人群，我們預計這顯然根本不在罕見病定價範圍內。同樣，正如我之前所說，我們將處於您看到的更普遍的心血管溢價定價範圍內。

The next question comes from Gena Wang with Barclays.

下一個問題來自巴克萊銀行的 Gena Wang。

Three very quick questions. One more question regarding the HAE program. You already described quite a lot of clinical profile you're looking for. Do you also consider once every 2 months dosing as a to-go choice to become more competitive? My second question -- quick question is regarding the Angelman program. What is the expected timing for data update? And what kind of safety signals you have seen so far? And lastly, very quickly on commercial readiness for eplontersen. Is AstraZeneca taking full charge? And what is the marketing strategy giving future already in the market?

三個非常快速的問題。還有一個關於 HAE 項目的問題。您已經描述了很多您正在尋找的臨床資料。您是否也考慮將每 2 個月給藥一次作為提高競爭力的必經之路？我的第二個問題——快速問題是關於 Angelman 計劃的。數據更新的預期時間是什麼時候？到目前為止，您看到了什麼樣的安全信號？最後，eplontersen 的商業準備非常迅速。阿斯利康是否全面負責？什麼是營銷策略給未來已經在市場上？

Thanks, Gena. That was quite thorough. These are 3 very different topics, a very good question. So I'll let Onaiza handle the HAE 2-month dosing and the commercial readiness for eplontersen, because the -- but I'll take the Angelman, as a quick answer. There's no -- nothing new to report on timing. The enrollment is going well. And the study is going very well, and we're very pleased with the safety profile that we're seeing to date. No, there are no concerns. For the Angelman's program. Onaiza,, bimonthly dosing HAE and readiness?

謝謝，吉娜。那是相當徹底的。這是三個截然不同的主題，一個很好的問題。所以我會讓 Onaiza 處理 HAE 2 個月的劑量和 eplontersen 的商業準備，因為——但我會把 Angelman 作為快速回答。沒有 - 沒有什麼新的時間報告。招生工作進展順利。研究進展順利，我們對迄今為止看到的安全狀況感到非常滿意。不，沒有顧慮。對於天使人的計劃。 Onaiza，每兩個月服用一次 HAE 並準備好了嗎？

For HAE, our competitive profile is so strong that we actually don't really need the 2-month dosing as a way to differentiate in the marketplace. We'll wait for the Phase III data. But certainly, it's an option for us to make that available for physicians and for patients if need be, but it will all be data dependent on Phase III.

對於 HAE，我們的競爭優勢如此強大，以至於我們實際上並不真正需要將 2 個月的劑量作為在市場中脫穎而出的方式。我們將等待 III 期數據。但可以肯定的是，如果需要，我們可以選擇將其提供給醫生和患者，但所有數據都取決於 III 期。

For eplontersen commercial readiness, lots of work going on, as you can imagine, we're right in that L minus X months of a window over here. And we're going at it in a very strong way. We do believe that this is a market where there is a lot of growth because of the number of patients who haven't been identified, diagnosed or treated yet. And we're planning for that approach in terms of really understanding where centers of excellence currently are and where they could be in the future and really trying to hit both. It's an and versus an or for us, and we have the ability to do that with the scale of AstraZeneca.

對於 eplontersen 的商業準備，很多工作正在進行，正如你可以想像的那樣，我們正處於 L 減去 X 個月的窗口期。我們正在以一種非常強有力的方式進行。我們確實相信這是一個有很大增長的市場，因為有很多患者還沒有被確認、診斷或治療。我們正在計劃這種方法，以真正了解卓越中心目前的位置以及未來可能的位置，並真正嘗試同時實現這兩個方面。這對我們來說是一個和一個或一個，我們有能力用阿斯利康的規模來做到這一點。

And then I would say that the clinical data in and of itself speaks for itself. So it has a really nice strong profile. And then lastly, I'll add, it is important to note that even though we're coming in second in the U.S., that's not necessarily the order of entry that you should expect outside of the U.S. in many, many markets as well. Of course, the some European markets will be second, but there are a lot of European markets, Eastern Europe and China and Japan, where we expect to be first.

然後我會說臨床數據本身就說明了一切。所以它有一個非常好的強大的形象。最後，我要補充一點，重要的是要注意，即使我們在美國排名第二，但這也不一定是您在美國以外的許多許多市場中應該期望的進入順序。當然，一些歐洲市場會排在第二位，但有很多歐洲市場，東歐、中國和日本，我們預計會排在第一位。

Next question comes from Luca Issi with RBC.

下一個問題來自 RBC 的 Luca Issi。

I have 2 quick ones. Maybe, Brett, big picture. Can you just talk about how your relationship with Biogen has evolved now that there's a new leadership team in place sounds like (inaudible) is pretty focused on actually containing costs. And obviously, we've seen them discontinuing your collaboration with ataxin 3. So just wondering if the bar for progressing 1/4 molecule is now higher given their focus on cost. Again, any color there would be much appreciated.

我有2個快速的。也許，布雷特，大局。你能不能談談你與百健（Biogen）的關係是如何發展的，因為現在有一個新的領導團隊聽起來（聽不清）非常專注於實際控製成本。顯然，我們已經看到他們停止了你們與 ataxin 3 的合作。所以只是想知道，考慮到他們對成本的關注，現在推進 1/4 分子的門檻是否更高。同樣，任何顏色都會非常感激。

And then maybe on APOCIII, circling back on the prior question, can you remind us what your commercial plan ex U.S. for APOCIII? Would you partner the right? Will you use a distributor like (inaudible)? Will you have your own sales force on the ground? Again, any color is much appreciated.

然後也許在 APOCIII 上，回到前面的問題，你能提醒我們你在美國以外的 APOCIII 商業計劃嗎？你會選擇合適的伙伴嗎？您會使用像（聽不清）這樣的分銷商嗎？您會在當地擁有自己的銷售團隊嗎？同樣，任何顏色都非常受歡迎。

Great. Second question for Onaiza. On the first one, Luca, thank you for the questions. Our relationship with Biogen is as strong as it has ever been. It's a great relationship. We're very pleased by the fact that Biogen is prioritizing very highly while working with us programs like the BIIB080 tau program that Eric commented on before, a really exciting program to them very important. It's getting all the resources. You can imagine that is needed as they are the Angelman's program as well. We just -- they did a great job in bringing QALSODY through the finish line and onto the market, and it's already launched. So they're totally ready to launch that drug.

偉大的。 Onaiza 的第二個問題。關於第一個問題，Luca，謝謝你提出的問題。我們與百健（Biogen）的關係一如既往地牢固。這是一個很好的關係。我們感到非常高興的是，百健（Biogen）在與我們的項目合作時非常重視，比如 Eric 之前評論過的 BIIB080 tau 項目，這是一個非常令人興奮的項目，對他們來說非常重要。它正在獲取所有資源。您可以想像這是需要的，因為它們也是 Angelman 的計劃。我們只是 - 他們在將 QALSODY 通過終點線並推向市場方面做得很好，而且它已經推出。所以他們完全準備好推出這種藥物。

And several of the other mid-stage and research programs are progressing and going very well. Absolutely, Biogen, I'm not saying anything that's not -- hasn't been in the public. They're focusing their efforts on programs that they think are going to bring the greatest value to their company. And we are a large part of that pipeline. So we are a top priority for them. Relationship is growing very well.

其他幾個中期和研究項目正在取得進展，進展順利。當然，百健（Biogen），我不是在說任何不是——沒有公開的事情。他們將精力集中在他們認為會為公司帶來最大價值的項目上。我們是該管道的很大一部分。所以我們是他們的首要任務。關係發展得很好。

As far as the ataxin-3 and a bit of a kind of like an ultra-rare disease, if you will, clearly was a portfolio prioritization exercise that was communicated directly to me as the -- was the reason behind the drug being returned, program being returned to Ionis. That's not surprising. As it's probably not -- we know it's not in their sweet spot, or in the areas that they want to focus on. We are evaluating what to do with that program today, whether to keep it or to re-partner it. We have a rich neuro pipeline that's growing that's wholly owned by Ionis, and we will emphasize this pipeline going forward, and we will expand on it as well.

至於 ataxin-3 和有點像一種超罕見疾病，如果你願意的話，顯然是直接傳達給我的投資組合優先級排序練習——是藥物被退回的原因，程序返回給 Ionis。這並不奇怪。因為它可能不是——我們知道這不在他們的最佳位置，或者在他們想要關注的領域。我們正在評估今天如何處理該計劃，是保留它還是重新與它合作。我們有一個豐富的神經管道，它正在增長，由 Ionis 全資擁有，我們將強調這條管道的未來，我們也會對其進行擴展。

So this also bodes well for Ionis to build out our wholly owned pipeline drugs that we're interested in commercializing come back from Biogen. But the relationship is going strong and we absolutely have no concerns about any programs that are returned to Ionis because for the most of them would love to have them back. And if we don't keep them ourselves, we'll seek to re-partner. APOCIII ex-U.S. commercialization, that's a quite interesting question. It is something we have been talking about.

因此，這也預示著 Ionis 建立我們有興趣商業化的全資管線藥物從 Biogen 回來。但是這種關係正在變得牢固，我們絕對不擔心任何返回給 Ionis 的程序，因為他們中的大多數人都希望將它們返回。如果我們自己不保留它們，我們將尋求重新合作。 APOCIII ex-U.S.商業化，這是一個很有趣的問題。這是我們一直在談論的事情。

Thanks, Luca. I'd say, listen, first of all, we're getting very ready for launch readiness in the U.S. for both indications for FCS and for severe hypertriglyceridemia. Our plans -- current plans, O-U.S. is to look for a partner. The type of partnership is where you're going for has not yet been determined. But it's important to note, like we're going to look for a really good quality partner that can reach as many patients as possible in a swift manner, and that's going to be a really important frame.

謝謝，盧卡。我會說，聽著，首先，我們已經做好了在美國推出 FCS 和嚴重高甘油三酯血症適應症的準備工作。我們的計劃——目前的計劃，O-U.S.是尋找夥伴。合作夥伴關係的類型尚未確定。但值得注意的是，就像我們要尋找一個非常優質的合作夥伴一樣，它可以迅速接觸到盡可能多的患者，這將是一個非常重要的框架。

We're still working on that Luca, so stay tuned. And I think we have time for one last question before wrapping up.

我們仍在研究那個 Luca，敬請期待。我認為我們有時間在結束前提出最後一個問題。

Yes. Our last question for today comes from Myles Minter with William Blair.

是的。我們今天的最後一個問題來自 Myles Minter 和 William Blair。

Again, on olezarsen. I just wanted your updated thoughts on the potential need, if any, for a cardiovascular outcome study in severe hypertriglyceridemia maybe not so much for regulatory approval, but certainly for reimbursement, just given the comments that it seems like you are trying to seek a slight premium pricing range for that product relative to (inaudible)?

再次，關於 olezarsen。我只是想知道您對嚴重高甘油三酯血症的心血管結局研究的潛在需求（如果有的話）的最新想法，可能不是為了獲得監管批准，但肯定是為了報銷，只是考慮到您似乎在試圖尋求輕微的評論該產品相對於（聽不清）的溢價定價範圍？

Yes. Since it's focused on reimbursement, I'll ask Onaiza to take that as well.

是的。既然是報銷的重點，那我就讓禦奈座也來收下吧。

Yes. It's a good question. We actually tested that hypothesis pretty early in the program, and we continue to for all sorts of payers, as you can imagine. The 500-plus population it has, is severely elevated. It has a clear regulatory path, as you said, without a CVOT study. And given the unmet need and the fact that this is really a different population and we're looking for different risks for many of these patients, which is acute pancreatitis risk. This is not a place where even payers are wanting or expecting a CVOT from a reimbursement perspective.

是的。這是個好問題。我們實際上在項目的早期就測試了這個假設，我們會繼續為各種付款人測試，正如您可以想像的那樣。它擁有的 500 多名人口嚴重增加。正如你所說，它有一個明確的監管路徑，沒有 CVOT 研究。鑑於未滿足的需求以及這確實是一個不同的人群這一事實，我們正在為這些患者中的許多人尋找不同的風險，即急性胰腺炎風險。從報銷的角度來看，這不是一個連付款人都想要或期待 CVOT 的地方。

So it's going right in line with where the unmet need is and the value proposition of what we bring, again, this 3x magnitude of what's currently available for triglyceride reduction for the severely elevated trig patients with high risk for acute pancreatitis is where the payer focus is. So in there without the cardiovascular study.

因此，它與未滿足的需求和我們帶來的價值主張一致，再次，對於急性胰腺炎高風險的重度高甘油三酯患者，目前可用於降低甘油三酯的 3 倍量級是付款人關注的地方是。所以在那裡沒有心血管研究。

Thanks, Myles, and thanks, everybody, for joining us on our call today. Looking ahead and plan to continue our momentum by delivering additional key updates, progress against our objectives on the commercial front, the pipeline and on our technology. And we're going to provide updates throughout the second half of the year, and we're very much looking forward to it. So with that, we'll close. And thank you again, and have a great day, everybody.

謝謝邁爾斯，也謝謝大家今天加入我們的電話會議。展望未來併計劃通過提供額外的關鍵更新、在商業方面、管道和我們的技術上實現我們的目標取得進展來繼續我們的勢頭。我們將在整個下半年提供更新，我們非常期待。因此，我們將關閉。再次感謝大家，祝大家有美好的一天。

The conference is now concluded. Thank you for attending today's presentation. You may all now disconnect.

會議現已結束。感謝您參加今天的演講。你們現在可能都斷開連接了。