Prothena Corporation PLC (PRTA) 2023 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Prothena's Biosciences' fourth quarter and full-year 2023 financial results conference call. My name is Krista, and I will be your coordinator for today. (Operator Instructions) I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at Prothena. Please proceed.

女士們、先生們，美好的一天，歡迎參加 Prothena's Biosciences 的第四季度和 2023 年全年財務業績電話會議。我叫克里斯塔，我將擔任你們今天的協調員。（操作員說明）我現在想將簡報交給 Prothena 投資者關係副總裁 Mark Johnson。請繼續。

Thank you, operator. Good afternoon, everyone, and welcome to today's call to review Prothena's business progress fourth quarter and full-year 2023 financial results and 2024 financial guidance. Please review the press release we issued earlier today, which is available on our website at prothena.com and is also attached to a Form 8-K filed today with the SEC. In addition, we are using supplemental slides which are available on our investor website's events and presentations section.

謝謝你，接線生。大家下午好，歡迎參加今天的電話會議，回顧 Prothena 第四季和 2023 年全年財務業績以及 2024 年財務指引的業務進展。請查看我們今天早些時候發布的新聞稿，該新聞稿可在我們的網站 prothena.com 上獲取，並且還附在今天向 SEC 提交的 8-K 表格中。此外，我們還使用補充幻燈片，這些幻燈片可在我們的投資者網站的活動和簡報部分找到。

On today's call, Dr. Gene Kinney, our President and Chief Executive Officer will provide opening remarks including an overview of Prothena's corporate and development strategy. And Brandon Smith, our Chief Operating Officer, will provide an update on our precommercial progress for our wholly owned birtamimab program, which is in Phase 3 for the treatment of patients with Mayo Stage for AL Amyloidosis.

在今天的電話會議上，我們的總裁兼執行長 Gene Kinney 博士將致開幕詞，包括 Prothena 的公司和發展策略的概述。我們的營運長 Brandon Smith 將提供我們全資擁有的 birtimab 計畫的商業前進展的最新信息，該計畫正處於治療 AL 澱粉樣變性梅奧期患者的第三階段。

Dr. Hideki Garren, our Chief Medical Officer, will provide an update on our ongoing clinical programs. Tran Nguyen, our Chief Financial Officer and Chief Strategy Officer, will then discuss our 2023 financial results and 2024 financial guidance, before turning it back to Gene for closing remarks, at which point we will open up the call for a Q&A session.

我們的首席醫療官 Hideki Garren 博士將提供我們正在進行的臨床項目的最新資訊。然後，我們的財務長兼首席策略長 Tran Nguyen 將討論我們的 2023 年財務業績和 2024 年財務指引，然後返回給 Gene 進行結束語，屆時我們將開始問答環節。

Before we begin, I would like to remind you that during today's presentation, we'll be making forward-looking statements that are subject to certain risks, uncertainties, and other factors that could cause actual results to differ materially from those referred to in any forward-looking statements. For discussion of the risks and uncertainties associated with our forward-looking statements, please see our press release issued today as well as our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements.

在開始之前，我想提醒您，在今天的演示中，我們將做出前瞻性聲明，這些聲明受到某些風險、不確定性和其他因素的影響，這些因素可能導致實際結果與任何聲明中提到的結果有重大差異。有關與我們的前瞻性陳述相關的風險和不確定性的討論，請參閱我們今天發布的新聞稿以及我們最近向 SEC 提交的文件。我們不承擔更新前瞻性陳述的任何義務。

With that, I'd like to turn the call over to Gene.

說到這裡，我想把電話轉給吉恩。

Thank you, Mark, and thank you all for joining us today to review our 2023 financial results and business highlights.

謝謝馬克，也謝謝大家今天加入我們回顧我們 2023 年的財務表現和業務亮點。

Let's begin on slide 5. Our mission at Prothena is to create transformational therapies, addressing significant unmet medical needs for the millions of patients and their loved ones that are affected by devastating diseases caused by protein dysregulation. That mission is enabled by our deep scientific expertise, which serves as a unifying thread connecting our corporate strategy, our portfolio development, and the dedication that propels Prothena every day.

讓我們從幻燈片 5 開始。Prothena 的使命是創造變革性療法，解決數百萬因蛋白質失調引起的毀滅性疾病而受到影響的患者及其親人未得到滿足的重大醫療需求。這項使命是透過我們深厚的科學專業知識來實現的，這些專業知識是連接我們的企業策略、產品組合開發和每天推動 Prothena 的奉獻精神的統一主線。

We continue to advance our mission which has fueled our robust late-stage clinical pipeline moving us closer to becoming a fully integrated commercial biotechnology company. As a result of our commitment to our mission, we have created a robust portfolio of therapeutic drug candidates targeting both neurodegenerative and rare peripheral amyloid diseases as shown on slide 6.

我們繼續推進我們的使命，這推動了我們強大的後期臨床管道，使我們更接近成為一家完全一體化的商業生物技術公司。由於我們對使命的承諾，我們創建了一個強大的候選治療藥物組合，針對神經退化性和罕見的周邊澱粉樣蛋白疾病，如幻燈片 6 所示。

Our portfolio includes four wholly owned programs and five partnered programs. This intentional mix allows us to advance a fulsome portfolio by leveraging the benefits of working with key strategic partners on some programs, while still maintaining the full upside potential for our wholly owned programs where we feel that we have unique insights and expertise.

我們的投資組合包括四個全資項目和五個合作項目。這種有意的組合使我們能夠利用與關鍵策略合作夥伴在某些專案上合作的優勢來推進豐富的投資組合，同時仍保持我們認為擁有獨特見解和專業知識的全資專案的全部上行潛力。

I'll discuss four of our ongoing clinical programs on the next slide. PRX012, prasinezumab, birtamimab, and NNC6019. But first, I'd like to highlight the exciting progress across our earlier stage programs. In July of 2023, we presented compelling preclinical results in a late breaker poster presentation at AAIC for PRX123, our dual A-beta/Tau vaccine program. And by year end 2023, PRX123 received IND clearance and fast track designation from the FDA.

我將在下一張投影片上討論我們正在進行的四個臨床項目。PRX012、prasinezumab、birtimab 和 NNC6019。但首先，我想強調一下我們早期階段專案所取得的令人興奮的進展。2023 年 7 月，我們在 AAIC 的後期海報展示中展示了 PRX123（我們的 A-beta/Tau 雙疫苗計畫）令人信服的臨床前結果。到 2023 年底，PRX123 獲得了 FDA 的 IND 許可和快速通道指定。

Our ongoing neuroscience R&D collaboration with BMS made meaningful advancements in 2023 and into this year. BMS-986446, formerly PRX005, is a potential best-in-class antibody for the treatment of Alzheimer’s disease that specifically targets a key epitope within the microtubule binding region of Tau. In 2023, BMS opted into the global rights for this program with an additional milestone payment of $55 million and announced that the Phase 1 data supports advancing the program into a Phase 2 clinical trial in 2024.

我們與 BMS 正在進行的神經科學研發合作在 2023 年和今年取得了有意義的進展。BMS-986446（以前稱為 PRX005）是一種潛在的同類最佳抗體，用於治療阿茲海默症，專門針對 Tau 微管結合區域內的關鍵抗原決定位。2023年，BMS選擇獲得該計畫的全球權利，並額外支付了5,500萬美元的里程碑付款，並宣布一期數據支持該計畫於2024年進入第二期臨床試驗。

And for PRX019, a potential best-in-class antibody for the treatment of neurodegenerative diseases, we recently received FDA clearance for the IND application for this program as well. This is the second of three programs in our BMS collaboration. We remain well-funded to execute on our strategic objectives, taking us well beyond our upcoming clinical readouts. As you will hear about in more detail later in this call, we ended 2023 with a strong cash position of $621 million.

對於 PRX019，一種用於治療神經退化性疾病的潛在同類最佳抗體，我們最近也獲得了 FDA 批准該計畫的 IND 申請。這是我們 BMS 合作的三個專案中的第二個。我們仍然有充足的資金來執行我們的策略目標，使我們遠遠超出即將到來的臨床結果。正如您稍後將在本次電話會議中更詳細地了解到的那樣，我們在 2023 年結束時擁有 6.21 億美元的強勁現金頭寸。

Moving now to slide 7. Our clinical expertise and differentiated approach enables us to advance best-in-class and or first-in-class therapies that have the potential to transform the treatment landscape for protein dysregulation diseases. Today, I'd like to focus on the four clinical programs that are nearing significant inflection points within the next 12 to 18 months.

現在轉到投影片 7。我們的臨床專業知識和差異化方法使我們能夠推進一流和/或一流的療法，這些療法有可能改變蛋白質失調疾病的治療模式。今天，我想重點關注未來 12 至 18 個月內接近重要拐點的四個臨床項目。

First, I'll discuss our wholly owned programs, PRX012 and birtamimab, and then move on to our partner programs precedent prasinezumab with Roche and NNC6019 with Novo Nordisk.

首先，我將討論我們的全資專案 PRX012 和 birtimab，然後討論我們的合作夥伴專案先例，包括與羅氏合作的 prasinezumab 和與諾和諾德合作的 NNC6019。

PRX012 is our next generation investigational treatment for Alzheimer's disease, which targets a key epitope at the amino terminus of amyloid beta with high binding potency. PRX012 was designed with the patient in mind, and we believe it has the potential to be best in class, transforming the treatment of Alzheimer's disease by meaningfully reducing treatment burden associated with the currently available anti-beta therapies.

PRX012 是我們針對阿茲海默症的下一代研究性治療方法，它以具有高結合效力的β澱粉樣蛋白氨基末端的關鍵表位為目標。PRX012 的設計以患者為中心，我們相信它有潛力成為同類最佳藥物，透過有意義地減輕與目前可用的抗β療法相關的治療負擔來改變阿茲海默症的治療方法。

Based on our market research, we understand that a treatment with similar efficacy and safety that currently approved anti-beta therapies, but delivered as a once-monthly at-home subcutaneous treatment has potential to be the dominant player in the market.

根據我們的市場研究，我們了解到，與目前批准的抗β療法具有相似功效和安全性但每月一次在家皮下治療的治療方法有可能成為市場的主導者。

In 2023, we presented compelling preclinical data at ADPD and AAIC demonstrating the PRX012 binds to amyloid plaques with high avidity. PRX012 is currently being evaluated in a double-blind, placebo-controlled Phase 1 trial, with the goal of identifying an optimal dose level or levels for a registration-enabling trial. The preclinical data combined with the initial clinical data from our ongoing Phase 1 trial are supportive of a once monthly subcutaneous treatment with a potential best-in-class profile.

2023 年，我們在 ADPD 和 AAIC 上提供了令人信服的臨床前數據，證明 PRX012 以高親和力與澱粉樣斑塊結合。PRX012 目前正在一項雙盲、安慰劑對照的 1 期試驗中進行評估，目的是確定註冊試驗的最佳劑量水平或水平。臨床前數據與我們正在進行的一期試驗的初始臨床數據相結合，支持每月一次的皮下治療，具有潛在的同類最佳效果。

birtamimab seeks to address the high risk of early mortality that remains an urgent unmet medical need for patients with Mayo stage IV AL amyloidosis, through its differentiated depleter mechanism which is designed to clear accumulated amyloid and neutralize toxic light chain aggregates that are thought to cause organ dysfunction and failure. We are conducting a confirmatory Phase 3 AFFIRM-AL clinical trial, evaluating birtamimab in patients with Mayo stage IV AL amyloidosis under a special protocol assessment or SPA agreement with the FDA with a primary endpoint of all-cause mortality at an unprecedented significant level of 0.10. We expect top line results between the fourth quarter of 2024 and second quarter of 2025.

birtimab 尋求透過其差異化的清除機制來解決早期死亡的高風險，這對於Mayo IV 期AL 澱粉樣變性患者來說仍然是一個緊迫的未滿足的醫療需求，該機制旨在清除積累的澱粉樣蛋白併中和被認為會導致器官損傷的有毒輕鏈聚集體。我們正在進行一項驗證性3 期AFFIRM-AL 臨床試驗，根據特殊方案評估或與FDA 簽訂的SPA 協議，評估birtimab 對Mayo IV 期AL 澱粉樣變性患者的療效，主要終點是全因死亡率達到前所未有的顯著水準0.10 。我們預計 2024 年第四季至 2025 年第二季將公佈頂線業績。

prasinezumab is an antibody for the potential treatment of Parkinson's disease designed to target a key epitope within the C-terminus of a-Synuclein, and is the focus of a worldwide collaboration with Roche. Roche is currently conducting the Phase 2b PADOVA clinical trial in patients with early Parkinson's disease. Roche completed enrolment of this trial in the first quarter of 2023 and expects to report top line data later this year.

prasinezumab 是一種用於帕金森氏症潛在治療的抗體，旨在針對 a-Synuclein C 端的關鍵表位，是與羅氏全球合作的重點。羅氏目前正在針對早期帕金森氏症患者進行 2b 期 PADOVA 臨床試驗。羅氏於 2023 年第一季完成了該試驗的註冊，預計將在今年稍後報告頂線數據。

And finally, NNC6019 is an amyloid depleter antibody for the potential treatment of ATTR cardiomyopathy. Novo Nordisk is currently conducting an ongoing Phase 2 signal detection trial in patients with ATTR cardiomyopathy. The trial has fully recruited its patients with top-line results expected in the first half of next year. This is an exciting year of clinical trial execution for both for Prothena and our strategic partners.

最後，NNC6019 是一種澱粉樣蛋白消耗抗體，可用於 ATTR 心肌病變的潛在治療。諾和諾德目前正在 ATTR 心肌病變患者中進行一項正在進行的 2 期訊號檢測試驗。該試驗已全面招募患者，預計明年上半年獲得頂線結果。對於 Prothena 和我們的策略夥伴來說，今年都是令人興奮的臨床試驗執行年。

As we look ahead, we are also thoughtfully building out our commercial leadership and market insights for birtamimab. So to provide a little more context on our pre-commercial efforts, I will now turn the call over to Brandon.

展望未來，我們也在深思熟慮地建立我們對 birtimab 的商業領導地位和市場洞察力。因此，為了提供更多關於我們的商業前工作的背景信息，我現在將把電話轉給布蘭登。

Brandon?

布蘭登？

Thanks, Gene. Moving to slide 9. As we continue executing on our ongoing confirmatory Phase 3 AFFIRM-AL clinical trial, we are focused on building out our commercial -- capabilities to support birtamimab as our first potential commercial product.

謝謝，吉恩。轉到投影片 9。隨著我們繼續執行正在進行的 3 期確認性 AFFIRM-AL 臨床試驗，我們專注於建立我們的商業能力，以支持 birtimab 作為我們的第一個潛在商業產品。

Among patients with AL amyloidosis , a rare, progressive, and fatal disease in newly diagnosed individuals with significant cardiac involvement such as Mayo stage IV are at the highest risk for early mortality. This remains a serious unmet need for patients and their families. birtamimab is the only candidate to have shown a survival benefit in patients with Mayo stage IV AL Amyloidosis in a randomized clinical trial, our previous Phase 3 VITAL trial.

在 AL 澱粉樣變性患者中，這是一種罕見的進行性致命疾病，對於新診斷的具有嚴重心臟受累的患者（例如 Mayo IV 期），早期死亡的風險最高。對於患者及其家人來說，這仍然是一個嚴重未滿足的需求。 birtimab 是唯一在一項隨機臨床試驗（我們先前的 3 期 VITAL 試驗）中顯示 Mayo IV 期 AL 澱粉樣變性患者存活獲益的候選藥物。

The ongoing confirmatory AFFIRM-AL trial was designed based on the SPA agreement with the FDA to approve for birtamimab at a p-value of less than or equal to 0.1 for the primary endpoint of all-cause mortality. Showing an early and sustained impact on mortality is a powerful differentiator and if approved, we are confident that birtamimab will be welcomed a major advancement in the field and a key treatment option.

正在進行的驗證性 AFFIRM-AL 試驗是根據與 FDA 的 SPA 協議設計的，以批准 birtimab 的全因死亡率主要終點 p 值小於或等於 0.1。顯示對死亡率的早期和持續影響是一個強大的差異化因素，如果獲得批准，我們相信 birtimab 將成為該領域的重大進步和關鍵的治療選擇。

Moving to slide 10. The market dynamics for birtamimab as our potential first commercial product are quite compelling. Our plan is to independently commercialize birtamimab, and we believe that we will be able to efficiently reach prescribers for advanced patients with a focused commercial presence.

轉到投影片 10。作為我們潛在的第一個商業產品，birtimab 的市場動態非常引人注目。我們的計劃是獨立地將 birtimab 商業化，我們相信我們將能夠透過集中的商業存在有效地接觸到晚期患者的處方者。

This is a rare disease patient population with a targeted call point for haematologists with support from specialized cardiologists of the primary treating specialist. KOLs in the community at-large recognized the urgent need for treatments that improve survival in patients with AL amyloidosis who are at high risk for early mortality.

這是一個罕見疾病患者群體，在主要治療專家的專業心臟病專家的支持下，血液科醫生有針對性的呼叫點。整個社區的 KOL 都意識到迫切需要改善早期死亡風險高的 AL 澱粉樣變性患者存活率的治療方法。

Based on epidemiology studies, we estimate there are over 20,000 patients with Mayo stage IV for AL amyloidosis across the major markets, including the United States, Europe, China, Brazil, and Japan. This is further supported by our claims data analysis to identify patients who are actively receiving treatment for AL amyloidosis in the United States.

根據流行病學研究，我們估計美國、歐洲、中國、巴西和日本等主要市場有超過 20,000 名 Mayo IV 期 AL 澱粉樣變性患者。我們的理賠數據分析進一步支持了這一點，該數據分析旨在確定在美國積極接受 AL 澱粉樣變性治療的患者。

Based on this, we believe there are approximately 4,000 Mayo Stage IV patients in the US. In addition, our US and European market research indicates that approximately 75% of patients are treated in approximately 500 centres of excellence and amyloidosis specialty centres, usually within academic hospitals.

據此，我們認為美國約有 4,000 名 Mayo IV 期患者。此外，我們的美國和歐洲市場研究表明，大約 75% 的患者在大約 500 個卓越中心和澱粉樣變性專科中心接受治療，這些中心通常位於學術醫院內。

Our team continues to build upon the existing relationships we've established with KOLs and experts in the field through our extensive clinical programs for birtamimab. We will continue to collaborate with these KOLs and experts along with the organizations that publish treatment guidelines such as NCCN and the International Society of Amyloidosis to ensure they are fully aware of and informed about birtamimab. This includes continuing to present our data at top medical congresses and publications in peer-reviewed journals. Today, we are building our commercial leadership team thoughtfully as we prepare for launch.

我們的團隊透過廣泛的 birtimab 臨床項目，繼續鞏固與該領域 KOL 和專家建立的現有關係。我們將繼續與這些 KOL 和專家以及發布治療指南的組織（例如 NCCN 和國際澱粉樣變性協會）合作，以確保他們充分了解和了解 birtimab。這包括繼續在頂級醫學大會上展示我們的數據，並在同行評審期刊上發表文章。今天，我們在準備推出時正在深思熟慮地建立我們的商業領導團隊。

I'll now turn it over to Hideki to review our clinical programs.

我現在將把它交給 Hideki 來審查我們的臨床項目。

Thank you, Brandon. Let's continue with birtamimab and review the results for previous VITAL trial, which were published at ASH peer-reviewed journal, Blood, last year. Importantly, we observed a survival benefit in the subset of approximately 30% of patients who are categorized as Mayo stage IV baseline. The capital Mayo curve illustrating the separation is shown here on slide 12, demonstrating an early and a sustained benefit.

謝謝你，布蘭登。讓我們繼續使用 birtimab 並回顧先前 VITAL 試驗的結果，該試驗去年發表在 ASH 同儕審查期刊 Blood 上。重要的是，我們觀察到大約 30% 的梅奧 IV 期基線患者的生存獲益。說明分離的資本梅奧曲線如幻燈片 12 所示，顯示了早期和持續的效益。

In this high-risk group, we observed a survival benefit favouring birtamimab, reflecting approximately 60% relative reduction of all-cause mortality at a p-value of 0.021. This was further supported by meaningful and significant improvements in function as measured by six-minute walk tests and quality of life as measured by SF-36.

在這個高風險組中，我們觀察到有利於 birtimab 的生存獲益，反映出全因死亡率相對降低約 60%（p 值為 0.021）。六分鐘步行測試測量的功能和 SF-36 測量的生活品質的有意義和顯著的改善進一步支持了這一點。

Turning to slide 13. To expand on Brandon's earlier remarks, based on our extensive analysis of the VITAL data as well as further confirmation of the data with the external statistical experts and leading physicians in the field, we actively engaged with the FDA to align on the path towards regulatory success for birtamimab.

轉到投影片 13。為了擴展佈蘭登先前的言論，基於我們對 VITAL 數據的廣泛分析以及與外部統計專家和該領域領先醫生對數據的進一步確認，我們積極與 FDA 合作，以在監管成功的道路上保持一致對於比爾他單抗。

As SPA was agreed to between Prothena and the FDA put confirmatory Phase 3 AFFIRM-AL clinical trial to be conducted in patients with AL amyloidosis categorized as Mayo stage IV baseline, with a pre-agreed-upon significant level of alpha less than or equal to 0.10 on a primary endpoint of all-cause mortality.

由於Prothena 和FDA 就SPA 達成一致，因此將在AL 澱粉樣變性患者中進行驗證性3 期AFFIRM-AL 臨床試驗，該患者被歸類為Mayo IV 期基線，且預先商定的顯著α 水平小於或等於全因死亡率的主要終點為 0.10。

This is a time-to-event trial and patients are randomized two to one on birtamimab plus standard of care or placebo plus standard of care. At the end of 2023, based on a predetermined number of mortality events, we were able to estimate that top line results of AFFIRM-AL will be available between the fourth quarter of 2024 and second quarter of 2025.

這是一項事件發生時間試驗，患者被隨機分為二對一，接受 birtimab 加標準護理或安慰劑加標準護理。到 2023 年底，根據預定的死亡事件數量，我們預計 AFFIRM-AL 的頂線結果將在 2024 年第四季至 2025 年第二季之間提供。

We very much look forward to the results of the trial, moving us one step closer to getting this treatment to patients and families in need. Let's discuss PRX012 our potential best-in-class anti-amyloid beta treatment starting on slide 14.

我們非常期待試驗的結果，使我們離為有需要的患者和家庭提供這種治療又更近了一步。讓我們從幻燈片 14 開始討論 PRX012，我們潛在的同類最佳抗澱粉樣蛋白治療藥物。

We believe PRX012 is the best-in-class anti-amyloid beta treatment for early Alzheimer's disease. In order to achieve this target product profile, we need to establish efficacy, convenience, and safety. PRX012 was intentionally designed with the antibody attributes required to achieve this similar or better efficacy and safety profile to currently approved anti-A-beta therapies, with a clear differentiation as seen administered in a much more convenient and accessible once-monthly at-home subcutaneous treatment. PRX012 is a humanized IgG1 monoclonal antibody designed to provide a longer half-life than improved anti-A-beta treatment with low immunogenicity.

我們相信 PRX012 是治療早期阿茲海默症的同類最佳抗澱粉樣蛋白治療藥物。為了實現這一目標產品概況，我們需要建立功效、便利性和安全性。PRX012 特意設計了與目前批准的抗A-β 療法相似或更好的療效和安全性所需的抗體屬性，並具有明顯的差異化，可以更方便、更方便地每月一次在家皮下注射給藥。PRX012 是一種人源化 IgG1 單株抗體，旨在提供比改良的抗 A-β 治療更長的半衰期，且免疫原性較低。

We have demonstrated a highly potent binding, highly affinity and avidity, and a slow off-rate, allowing for confirm target engagement, all of which are optimal for once-monthly subcutaneous treatments. The ongoing PRX012 Phase 1 trial, which we will discuss on slide 15, 16, is designed to demonstrate a potential best-in-class profile in the clinic.

我們已經證明了其高效結合、高親和力和親和力以及緩慢的解離速率，從而可以確認目標接合，所有這些都是每月一次皮下治療的最佳選擇。我們將在投影片 15,16 上討論正在進行的 PRX012 一期試驗，旨在展示臨床中潛在的同類最佳概況。

Moving to slide 15. ASCENT-1 is a double-blind, placebo-controlled single-ascending dose clinical trial evaluating PRX012 in healthy volunteers and participants with early Alzheimer's disease. The trial enrolled approximately eight participants for single ascending dose cohort, randomized three to one to receive a single subcutaneous dose of PRX012 or placebo and doses ranging from 70 to 400 milligram.

轉到投影片 15。ASCENT-1 是一項雙盲、安慰劑對照、單劑量遞增臨床試驗，在健康志願者和早期阿茲海默症的參與者中評估 PRX012。該試驗招募了大約 8 名參與者進行單次遞增劑量隊列，隨機三對一接受單次皮下劑量的 PRX012 或安慰劑，劑量範圍為 70 至 400 毫克。

Moving on to the multiple-ascending dose cohorts on slide 16. ASCENT-2 is our double-blind, placebo-controlled, multiple ascending dose clinical trial evaluating PRX012 in people with early Alzheimer's disease. Each MAD cohort is randomized three to one to receive PRX012 or placebo once monthly for six months in multiple ascending dose level.

繼續看投影片 16 上的多劑量遞增組。ASCENT-2 是我們的雙盲、安慰劑對照、多劑量遞增臨床試驗，評估 PRX012 在早期阿茲海默症患者中的作用。每個 MAD 隊列被隨機分為 3 比 1，接受 PRX012 或安慰劑，每月一次，持續六個月，接受多種遞增劑量水平。

The objectives of the trial are twofold. One is to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of PRX012 in patients with early Alzheimer's disease. And two is to find the optimal dose level or levels for a registration-enabling clinical trial. There are a couple of key aspects to the MAD trial design that I like to highlight today. Participants are assigned to two groups of cohort-based on a Q4W status, which we refer to as A Cohorts or B Cohorts.

試驗的目標是雙重的。一是評估PRX012在早期阿茲海默症患者的安全性、耐受性、免疫原性、藥物動力學和藥效學。二是找到適合註冊的臨床試驗的最佳劑量水平。今天我想強調一下 MAD 試驗設計的幾個關鍵面向。參與者根據 Q4W 狀態被分配到兩組隊列，我們稱之為 A 隊列或 B 隊列。

Participants in A Cohorts are either APOe4 non-carriers or heterozygous carriers. Each of these A Cohorts is evaluating approximately 32 participants with early Alzheimer's disease and doses ranging from 45 to 400 milligrams. In addition, we are evaluating APOe4 homozygous carriers in a separate the B Cohorts for approximately 12 participants with early Alzheimer's disease in doses ranged from 45 to 200 milligrams.

A 隊列的參與者要么是 APOe4 非攜帶者，要么是雜合攜帶者。每個 A 隊列正在評估約 32 名患有早期阿茲海默症的參與者，劑量範圍為 45 至 400 毫克。此外，我們正在單獨的 B 隊列中評估大約 12 名患有早期阿茲海默症的參與者的 APOe4 純合攜帶者，劑量範圍為 45 至 200 毫克。

Following the first six months which is placebo-controlled for instance, previously taken PRX012 of placebo are eligible to receive an additional six monthly doses of PRX012 in open-label extension.

例如，在前六個月（安慰劑對照）之後，先前服用 PRX012 安慰劑的患者有資格在開放標籤延期中接受額外六個月的 PRX012 劑量。

We have completed all cohorts and the double-blind portion of the initial 70 milligram MAD A cohort. The Phase 1 clinical trial continues as planned as the initial data supports once monthly subcutaneous treatment and dose escalation in additional cohorts. We look forward to evaluating the full exposure response relationship of PRX012 and expect to update you later this year.

我們已經完成了所有隊列和最初 70 毫克 MAD A 隊列的雙盲部分。一期臨床試驗按計劃繼續進行，初始數據支持每月一次皮下治療和在其他隊列中增加劑量。我們期待評估 PRX012 的完整曝光響應關係，並預計在今年稍後向您更新。

Turning out to prasinezumab on slide 17. prasinezumab is the first anti alpha-synuclein antibody to demonstrate slowing the progression of measures of Parkinson's disease in Phase 2 trial. Our partner Roche previously presented data from the Phase 2 prasinezumab trial, starting prasinezumab reduced one year motor progression by 35% as measured by the MDS-UPDRS Part III, a scale of moderate function in comparison to placebo.

幻燈片 17 上的 prasinezumab 是第一個在 2 期試驗中證明可減緩帕金森氏症進展的抗 α-突觸核蛋白抗體。我們的合作夥伴羅氏先前提供了 prasinezumab 2 期試驗的數據，根據 MDS-UPDRS 第 III 部分（與安慰劑相比中等功能量表）測量，開始 prasinezumab 可使一年的運動進展減少 35%。

Roche continues to provide meaningful updates on the ongoing open-label extension from the trial, including recently at the Movement Disorder Society Congress in August. First compares three-year progression of motor signs in the prasinezumab population, with a propensity score balanced cohort of real-world data from the Parkinson's progression markers initiative or PPMI.

羅氏繼續就正在進行的開放標籤擴展試驗提供有意義的更新，包括最近在八月的運動障礙協會大會上。首先將 prasinezumab 族群的運動體徵三年進展與來自帕金森氏症進展標記計畫 (PPMI) 的真實世界數據的傾向評分平衡隊列進行比較。

The prasinezumab population of 63% slowing progression as measured by the MDS-UPDRS Part III in the early start prasinezumab population as compared to the real-world data cohort. These data continue to support prasinezumab potential effect on delaying motor progression in Parkinson's disease.

根據 MDS-UPDRS 第 III 部分測量，與真實世界數據隊列相比，早期開始 prasinezumab 群體中 prasinezumab 群體的進展速度減慢了 63%。這些數據繼續支持普拉辛珠單抗對延緩帕金森氏症運動進展的潛在作用。

Roche has an advanced prasinezumab in Phase 2b PADOVA trial, which is a double-blind, placebo-controlled trial evaluating 586 patients with early Parkinson's disease. Participants are randomized one-to-one to receive prasinezumab or placebo every four weeks for at least 18 months.

羅氏在 2b 期 PADOVA 試驗中擁有先進的 prasinezumab，該試驗是一項雙盲、安慰劑對照試驗，評估了 586 名早期帕金森氏症患者。參與者被一對一隨機分配，每四周接受 prasinezumab 或安慰劑治療，持續至少 18 個月。

Roche announced they had completed enrolment in the first quarter of 2023. The primary endpoint is time to clinically meaningful progression or motor signs of the disease as assessed by a five point or greater increase in the MDS-UPDRS Part III from baseline. This disease progression may be correlated to (technical difficulty) worsening on the Clinical Global Impression Improvement Scale. Roche expects to report top line data from PADOVA trial later this year.

羅氏宣布已於 2023 年第一季完成註冊。主要終點是疾病出現有臨床意義的進展或運動體徵的時間，透過 MDS-UPDRS 第 III 部分較基線增加 5 個點或更多來評估。這種疾病進展可能與臨床整體印象改善量表（技術難度）惡化有關。羅氏預計將在今年稍後報告 PADOVA 試驗的主要數據。

Moving to NNC6019 on slide 18. NNC6019 is being developed by Novo Nordisk as a potential first-in-class amyloid depleter antibody for the treatment of ATTR cardiomyopathy. This is a rare, progressive, and fatal disease characterized by deposition of abnormal non-native forms of TTR protein in amyloid and vital organs.

轉到幻燈片 18 上的 NNC6019。NNC6019 是由諾和諾德 (Novo Nordisk) 開發的一種潛在的一流澱粉樣蛋白消除抗體，用於治療 ATTR 心肌病變。這是一種罕見的進行性致命性疾病，其特徵是異常非天然形式的 TTR 蛋白沉積在澱粉樣蛋白和重要器官中。

NNC6019 is thought to depleat typically both deposited amyloid and circulating non-native TTR to prevent further deposition to improve all the function. This mechanism of action has the potential to provide benefit for ATTR patients at high risk for early mortality due to amyloid deposition in vital organs. Novo Nordisk is progressing this program in ongoing double-blind, placebo-controlled signal detection Phase 2 clinical trial. The trial has completed recruitment and Novo estimates primary completion in the first half of 2025.

NNC6019 通常被認為可以消除沉積的澱粉樣蛋白和循環非天然 TTR，以防止進一步沉積，從而改善所有功能。這種作用機轉有可能為因重要器官中澱粉樣蛋白沉積而導致早期死亡高風險的 ATTR 患者帶來益處。諾和諾德正在正在進行的雙盲、安慰劑對照訊號檢測二期臨床試驗中推進此計畫。該試驗已完成招募，Novo 預計將於 2025 年上半年初步完成。

Now I'd like to turn the call over to Tran for discussion of our 2023 financial performance and our 2024 financial guidance.

現在我想將電話轉給 Tran，討論我們 2023 年的財務表現和 2024 年的財務指導。

Tran?

特蘭？

Thanks, Hideki. Today, we reported financial results that were favourable to our 2023 financial guidance. Please refer to our press release for a detailed breakdown of our financial results.

謝謝，秀樹。今天，我們報告了有利於我們 2023 年財務指引的財務表現。請參閱我們的新聞稿，以了解我們財務表現的詳細細目。

As Gene mentioned during his opening remarks, our robust portfolio of wholly owned and strategically partnered programs allows us to leverage partner payments while still maintaining full upside potential of our wholly owned programs.

正如吉恩在開場白中提到的那樣，我們強大的全資和戰略合作項目組合使我們能夠利用合作夥伴的付款，同時仍然保持我們全資項目的全部上行潛力。

In 2023, BMS opted in to secure their global rights for BMS-986446 formerly known as PRX005 for $55 million. In terms of our 2023 financial performance relative to guidance, we had net cash used in operating and investing activities of $136.7 million, which was favourable to our guidance range of $148 million to $161 million.

2023 年，BMS 選擇以 5,500 萬美元的價格獲得 BMS-986446（原名 PRX005）的全球權利。就我們 2023 年相對於指引的財務表現而言，我們用於營運和投資活動的淨現金為 1.367 億美元，這有利於我們 1.48 億至 1.61 億美元的指引範圍。

Net loss was $147 million, which was favourable to our guidance range of $153 million to $171 million. As of December 31, 2023, Prothena had $621 million in cash, cash equivalents, and restricted cash, which is favourable to our guidance of $600 million. As of February 9, 2024, Prothena had approximately $53.7 million ordinary shares outstanding. Additionally, we continue to have a simple capital structure with zero debt.

淨虧損為 1.47 億美元，有利於我們 1.53 億至 1.71 億美元的指導範圍。截至 2023 年 12 月 31 日，Prothena 擁有 6.21 億美元的現金、現金等價物和限制性現金，這有利於我們 6 億美元的指引。截至 2024 年 2 月 9 日，Prothena 已發行普通股約 5,370 萬美元。此外，我們仍然擁有零債務的簡單資本結構。

Turning to our 2024 financial guidance on slide 21, we expect our full year 2024 net cash used in operating and investing activities to be between $208 million and $225 million. We expect to end the year with approximately $405 million in cash, cash equivalents, and restricted cash, which represents the midpoint of the range.

轉向投影片 21 上的 2024 年財務指引，我們預計 2024 年全年用於營運和投資活動的淨現金將在 2.08 億美元至 2.25 億美元之間。我們預計到年底現金、現金等價物和限制性現金約為 4.05 億美元，這是該範圍的中點。

The estimated full year 2024 net cash used in operating and investing activities is primarily driven by an estimated net loss of $229 million to $255 million, which includes an estimated $51 million of non-cash share-based compensation expense.

預計 2024 年全年營運和投資活動使用的淨現金主要是由預計 2.29 億至 2.55 億美元的淨虧損推動的，其中包括預計 5,100 萬美元的非現金股份補償費用。

With that, I'll turn the call back over to Gene to discuss our upcoming milestones. Gene?

接下來，我會將電話轉回吉恩，討論我們即將到來的里程碑。基因？

Thanks, Tran. Moving to slide 23. I'd like to acknowledge and thank the patients, their families, physicians, and study site staff who participate in all our clinical trials. Without their support, we could not elucidate the potential impact of the new medicines we're developing. I'd also like to thank our talented Prothenians for their ongoing commitment to advancing protein dysregulation science to make a real impact for the patients and families we serve.

謝謝，特蘭。轉到投影片 23。我要感謝參與我們所有臨床試驗的病人、他們的家人、醫生和研究中心工作人員。沒有他們的支持，我們無法闡明我們正在開發的新藥的潛在影響。我還要感謝我們才華橫溢的 Prothenians 不斷致力於推廣蛋白質失調科學，為我們服務的患者和家庭帶來真正的影響。

As we look ahead, we're excited to have meaningful catalysts across our programs with potential clinical readouts from four ongoing clinical trials within the next 12 to 18 months, which include top line results from our confirmatory AFFIRM-AL Phase 3 trial evaluating birtamimab in patients with Mayo stage IV AL amyloidosis; clinical data from our ongoing Phase 1 trial evaluating PRX012 as a potential best-in-class treatment in early Alzheimer's disease; top line results from the Phase 2b PADOVA trial evaluating prasinezumab for Parkinson's disease being conducted by Roche; And finally, clinical data from a Phase 2 signal detection trial evaluating NNC6019 for the treatment of ATTR cardiomyopathy by Novo Nordisk.

展望未來，我們很高興能夠在我們的計畫中獲得有意義的催化劑，並在未來12 至18 個月內從四項正在進行的臨床試驗中獲得潛在的臨床讀數，其中包括我們評估birtimab 的驗證性AFFIRM-AL 3 期試驗的頂線結果Mayo IV 期 AL 澱粉樣變性患者；我們正在進行的 1 期試驗的臨床數據，該試驗評估 PRX012 作為早期阿茲海默症的潛在最佳治療方法；羅氏正在進行的評估 prasinezumab 治療帕金森氏症的 2b 期 PADOVA 試驗的頂線結果；最後，來自諾和諾德評估 NNC6019 治療 ATTR 心肌病變的 2 期訊號檢測試驗的臨床數據。

I am proud of the progress that Prothena made in 2023 and continued into 2024. We are well capitalized with a robust cash position and remain focused on advancing our clinical programs as we strive to become a fully integrated commercial biotechnology company.

我對 Prothena 在 2023 年取得的進展並持續到 2024 年感到自豪。我們資本充足，現金狀況強勁，並繼續專注於推進我們的臨床項目，並努力成為一家完全一體化的商業生物技術公司。

With that, we'll now open the call to Q&A. Operator?

現在，我們將開始問答電話。操作員？

(Operator Instructions)

（操作員說明）

Charles Duncan, Cantor Fitzgerald.

查爾斯鄧肯，坎托菲茨杰拉德。

Yeah, hi. Good afternoon, Gene and team. You've got a lot going on, and limiting to one question will be a challenge. But I'll try to do that. I wondered if you could provide a little bit more clarity on the patient enrolment in ASCENT-2, specifically, what patients or cohorts had been enrolled, both A and B, in terms of which doses? And I'm wondering if you could provide a sense of what you meant with regard to giving an update later on this year on data, could you anticipate being possibly in a pivotal program in later part of 2005 -- 2025?

是的，嗨。下午好，吉恩和團隊。你有很多事情要做，限制一個問題將是一項挑戰。但我會嘗試這樣做。我想知道您是否可以更清楚地說明 ASCENT-2 中的患者入組情況，具體來說，入組了哪些患者或隊列（A 和 B）以及劑量？我想知道您是否可以解釋今年稍後提供數據更新的含義，您是否預計可能會在 2005 年下半年 - 2025 年參與關鍵計劃？

Yes, thanks for the questions, Charles. I appreciate them. So I think first, just with respect to timeline, obviously, this is an ongoing trial, and we plan to share additional data as that data become substantive. I think in terms of when we plan to give an update on PRX012, we would be planning to provide an update this year. Whether that update is to update on timing or data is something that we will still determine. And I think in terms of your question around enrolment in the various cohorts, maybe I can ask Hideki to address that question. Hideki?

是的，謝謝你的提問，查爾斯。我很欣賞他們。因此，我認為首先，就時間表而言，顯然這是一項正在進行的試驗，我們計劃在數據變得實質時分享更多數據。我認為就我們計劃何時提供 PRX012 的更新而言，我們計劃今年提供更新。該更新是按時間更新還是按數據更新，我們仍將確定。我認為，就你關於各個群體的入學問題而言，也許我可以請秀樹來解決這個問題。秀樹？

Yeah, thanks, Gene. So yeah, enrolment has been very strong in our PRX012 Phase 1 trial, with a high level of interest with a once-monthly subcutaneous anti-beta treatment. And it is important to note that the Data Safety Monitoring Board has allowed clearance of 45 to 400 milligrams, and we're proceeding cohorts plan. And this will allow us to fully explore the dose response curve.

是的，謝謝，吉恩。所以，是的，我們的 PRX012 一期試驗的入組人數非常多，人們對每月一次的皮下抗β治療非常感興趣。值得注意的是，資料安全監測委員會已允許清除 45 至 400 毫克，我們正在實施隊列計劃。這將使我們能夠充分探索劑量反應曲線。

Jay Olson, Oppenheimer.

傑·奧爾森，奧本海默。

Hey, thanks for the update and congrats on the progress. We have another question about the PRX012 MAD study. Can you talk about the six-month open-label extension and what do you hope to learn from that? Will patients on low doses switch to high doses, and how will it impact your next steps for 012? Thank you.

嘿，感謝您的更新並祝賀取得的進展。我們還有另一個關於 PRX012 MAD 研究的問題。您能談談六個月的開放標籤延期嗎？服用低劑量的患者是否會轉而服用高劑量？謝謝。

Thanks, Jay. Thanks for the question. Well, maybe I can just start with a reminder that the study is a double-blind, placebo-controlled six-month in duration with patients receiving their specified dose level of placebo once a month by subcutaneous administration. Obviously, after that six-month period, we do provide the potential for an open-label extension for patients and maybe, Hideki, if you can just speak a little bit about that period.

謝謝，傑伊。謝謝你的提問。好吧，也許我可以先提醒一下，這項研究是一項為期六個月的雙盲、安慰劑對照研究，患者每月透過皮下注射一次接受指定劑量水平的安慰劑。顯然，在那六個月之後，我們確實為患者提供了開放標籤延期的可能性，也許，Hideki，如果你能談談那段時期的話。

Yeah. Each patient within each cohort is allowed to enroll in open-label extension for six months, as you mentioned. And again, very strong enrolment and people very excited about the once monthly subcu dose.

是的。正如您所提到的，每個隊列中的每位患者都可以參加為期六個月的開放標籤延期。再次，報名人數非常多，人們對每月一次的 subcu 劑量感到非常興奮。

And here we won't have a -- Hideki is saying, it is not placebo-controlled, where placebo patients will now receive drug. Of course, that will be the first time they receive it, but the other patients will continue to go on to have up to 12 months potential treatment of PRX012, which we are attaching both safety, tolerability, and of course, PK -- pharmacodynamic measurement.

在這裡我們不會有——Hideki 說，它不是安慰劑對照的，安慰劑患者現在將接受藥物治療。當然，這將是他們第一次接受治療，但其他患者將繼續接受長達 12 個月的 PRX012 潛在治療，我們附加了安全性、耐受性，當然還有 PK——藥效學測量。

Michael DiFiore, Evercore ISI.

邁克爾·迪菲奧裡，Evercore ISI。

Hi, guys. Thanks so much for taking my question. I just wanted to zero in on the comparable ARIA rates that we're seeing between the 70-milligram dose of 012 and placebo. So when you consider how subcutaneous prasinezumab had less ARIA rates compared to the IV version, and while lecanemab subcu had about equal ARIA rates versus the IV version, how do you reconcile this? And given that the engineering of 012 was optimized off of prasinezumab, do you foresee similarly low ARIA rates for 012 at higher dosages? Thank you.

嗨，大家好。非常感謝您提出我的問題。我只是想將我們在 70 毫克劑量的 012 和安慰劑之間看到的可比 ARIA 率歸零。因此，當您考慮與 IV 版本相比，皮下注射 prasinezumab 的 ARIA 率較低，而 Lecanemab subcu 與 IV 版本的 ARIA 率大致相同時，您如何協調這一點？鑑於 012 的工程設計是針對 prasinezumab 進行優化的，您是否預計 012 在較高劑量下也會出現類似的低 ARIA 率？謝謝。

Yeah, it's a great question and you've got a lot built in there on the science, so I appreciate the question. I think what you're alluding to is really just how the biology of ARIA plays into dosing with these anti-amyloid agent. And as you say, there is evidence across the anti-A-beta field that there is a exposure response relationship between -- certainly, it's almost on a linear basis with respect to amyloid reduction. But on the case of ARIA, a little different between antibodies and I think that's what we're seeing. So you're making point between prasinezumab and birtamimab. And I think those are astute observations, as you say, prasinezumab that work, I think as approximately equivalent exposures on an AUC basis, we managed to be attained what was observed, at least in the published literature with lesser ARIA with that molecule, with lecanemab data a little bit more comparable.

是的，這是一個很好的問題，裡面有很多科學知識，所以我很欣賞這個問題。我認為你所指的實際上是 ARIA 的生物學如何影響這些抗澱粉樣蛋白藥物的劑量。正如你所說，抗 A-β 領域有證據表明，兩者之間存在暴露反應關係——當然，它與澱粉樣蛋白減少幾乎呈線性關係。但就 ARIA 而言，抗體之間略有不同，我認為這就是我們所看到的。所以你在普拉辛珠單抗和比爾他單抗之間做出了區分。我認為這些都是精明的觀察，正如你所說，prasinezumab 有效，我認為在AUC 基礎上大約相當的暴露量，我們設法達到了觀察到的結果，至少在已發表的文獻中，該分子的ARIA較小， Lecanemab 數據更具可比性。

So what that indicates to us is really that it is a molecule dependent. And what we need to understand as we see multiple dose level cohorts with our molecule PRX012 is that we need to understand that relationship. And we look forward to determining that as we explore the exposure-response relationship, as Hideki mentioned, from the 45-milligram monthly dose level through to the 400-milligram monthly dose level.

所以這向我們表明它確實是分子依賴性的。當我們看到 PRX012 分子的多個劑量水平隊列時，我們需要了解的是，我們需要了解這種關係。正如 Hideki 所提到的，我們期待在探索從每月 45 毫克劑量水平到每月 400 毫克劑量水平的暴露-反應關係時確定這一點。

With that said, I think you also kind of asked a little bit of a question there just in terms of what but consistency meant with placebo. And maybe I can just Hideki to comment on that please.

話雖如此，我認為你也問了一些關於安慰劑的一致性意味著什麼的問題。也許我可以請 Hideki 對此發表評論。

Yeah, thanks, Gene. So just to remind you we are running a double blind placebo-controlled trial. And as reported, at 70-milligram dose, those factors and ARIA rates consistent with placebo. And those data allows us to provide us (inaudible) indexes for a full dose response curve with once monthly subcu dose -- again, just to remind you, we have the ability to go up to 400 milligrams and all these cohorts are actively enrolled.

是的，謝謝，吉恩。謹提醒您，我們正在進行雙盲安慰劑對照試驗。據報導，在 70 毫克劑量下，這些因素和 ARIA 率與安慰劑一致。這些數據使我們能夠為我們提供（聽不清楚）每月一次 subcu 劑量的完整劑量反應曲線指數 - 再次提醒您，我們有能力達到 400 毫克，並且所有這些隊列都在積極招募。

Neena Bitritto-Garg, Deutsche Bank.

Neena Bitritto-Garg，德意志銀行。

Hey, guys. Thanks for taking my question. But just to kind of piggyback on the ARIA discussion here. I'm just wondering if you can talk a little bit about was the comment on ARIA being consistent with placebo, is that true for both the Cohort A and Cohort B patients so far, so both the APOe4 non-carriers and the heterozygous as well as the homozygous?

嘿，夥計們。感謝您提出我的問題。但只是為了在這裡討論 ARIA。我只是想知道您是否可以談談對 ARIA 的評論是否與安慰劑一致，到目前為止，A 組和 B 組患者都是如此，所以 APOe4 非攜帶者和雜合子患者也是如此作為純合子？

And then I was just wondering if you could also talk a little bit about some of the differences in activity that you're expecting between the 70 mg dose versus 200 and 400, and why you selected 200 and 400 for those SAD and MAD? I know you talked a lot about selection of 70 margin as being based off of the average to 10 mg/ per kg aducanumab. But just wondering how we should think about the higher doses? Thanks.

然後我想知道您是否也可以談談您預期的 70 毫克劑量與 200 和 400 毫克劑量之間的活動差異，以及為什麼您為 SAD 和 MAD 選擇 200 和 400 劑量？我知道您多次談到選擇 70 裕度是基於平均每公斤 10 毫克阿杜卡單抗。但只是想知道我們應該如何考慮更高的劑量？謝謝。

Yes, thanks, Neena, for the question. Maybe I can start, then Hideki can again jump in here. I think first, with respect to your question about the data that informs what we've said about this molecule to date, which just again, as a reminder, I think what we've indicated is that with the A cohort, which is the 70 milligram monthly cohort, we've seen evidence of what we would characterize as encouraging reduction in amyloid beta. Obviously, that helps us to understand that we believe this is a once monthly subcutaneous drug, and obviously, ARIA rates, as you had mentioned, consistent with placebo.

是的，謝謝妮娜提出的問題。也許我可以開始，然後秀樹可以再次跳到這裡。我認為首先，關於你關於數據的問題，這些數據告訴我們迄今為止關於該分子的言論，再次提醒一下，我認為我們已經表明的是 A 隊列，即每月70 毫克的隊列，我們已經看到了我們所說的鼓勵減少β澱粉樣蛋白的證據。顯然，這有助於我們理解，我們相信這是每月一次的皮下注射藥物，而且顯然，正如您所提到的，ARIA 率與安慰劑一致。

What goes into informing that is obviously the data from the single-dose study as well as the cohort, the 70-milligram cohort I'm referring to, in the multiple dose study. The additional ongoing cohorts remain blinded. So those are -- it is a double-blind placebo-controlled study.

顯然，這來自單劑量研究以及多劑量研究中的隊列（我指的是 70 毫克隊列）的數據。其他正在進行的隊列仍然處於失明狀態。這是一項雙盲安慰劑對照研究。

I think the other question was really just around the selection of the dose level. And I think maybe I'll just ask Hideki to speak to that other than to say that these dose levels that are being explored are the dose levels that we anticipated to be explored, and that we are continuing to conduct this study as we had anticipated and it's moving forward in an encouraging pace as Hideki indicated.

我認為另一個問題實際上只是圍繞劑量水平的選擇。我想也許我會請 Hideki 談談這一點，而不是說正在探索的這些劑量水平是我們預期探索的劑量水平，並且我們正在按照我們的預期繼續進行這項研究正如Hideki 所指出的那樣，它正在以令人鼓舞的速度向前發展。

Hideki?

秀樹？

Yeah, thanks, Gene. So as you mentioned, we continue to explore the doses in a Phase 1 study, that's the purpose of the Phase 1 study is. And just to remind you that 70 milligram, we just see the encouraging amyloid reduction and a consistent ARIA rates with placebo. And that allows to really explore the full dose response, 45 the way up to 400 milligrams.

是的，謝謝，吉恩。正如您所提到的，我們繼續探索第一階段研究的劑量，這就是第一階段研究的目的。只是提醒您，70 毫克，我們只是看到令人鼓舞的澱粉樣蛋白減少以及與安慰劑一致的 ARIA 率。這樣就可以真正探索完整的劑量反應，從 45 毫克到 400 毫克。

And again, just to remind you that (inaudible) once monthly subcu administration and potentially the best-in-class anti-Abeta amyloid.

再次提醒您，（聽不清楚）每月一次 subcu 給藥，可能是同類中最好的抗 Abeta 澱粉樣蛋白。

Yasmeen Rahimi, Piper Sandler.

亞斯明·拉希米，派珀·桑德勒。

Hi, Gene. This is [Jong yu] for Yasmeen. Thanks for taking our question. I'll just kind of dive more into the details of the ARIA rates. Given that you're enrolling both APOe4 homozygous and heterozygous, we know that there are sometimes differences in ARIA rates, how does it [started] expectations regarding both safety and efficacy across these populations?

嗨，吉恩。這是亞斯明的[Jong yu]。感謝您提出我們的問題。我將更深入地了解 ARIA 費率的詳細資訊。鑑於您同時登記了 APOe4 純合子和雜合子，我們知道 ARIA 率有時存在差異，那麼它是如何[開始]對這些人群的安全性和有效性的預期的呢？

Yeah. Thanks for the question. I think there's kind of two questions built into that one in terms of how we're thinking about ARIA just across the entirety of the patient population. And I think the second is really just around how we think about this trial design.

是的。謝謝你的提問。我認為，就我們如何在整個患者群體中考慮 ARIA 而言，其中存在兩個問題。我認為第二個問題其實就是我們如何看待這個試驗設計。

So let me start with ARIA. And obviously, as we talk about ARIA rates, we are being specific to our patient of cohort. We are reporting data out as one would into phase study relative to placebo. And I think that's what we indicated in our release in January that ARIA rates in the 70-milligram cohort after six months of treatment were consistent with placebo.

讓我從 ARIA 開始。顯然，當我們談論 ARIA 率時，我們是針對我們的隊列患者。我們正在報告數據，就像進入相對於安慰劑的階段研究一樣。我認為這就是我們在 1 月發布的新聞稿中指出的，經過 6 個月的治療後，70 毫克隊列中的 ARIA 率與安慰劑一致。

I think you’re -- the point you're making about testing separately APOe4 homozygous carriers in the B cohorts is something that we're learning from the field. So as we continue to iterate in this field across multiple companies, it does take a village to develop therapeutics in this space, we are learning from each other, I think on the clinical side as well as the preclinical side.

我認為您提出的關於在 B 群體中單獨測試 APOe4 純合攜帶者的觀點是我們從該領域學到的東西。因此，當我們繼續在多個公司的領域進行迭代時，確實需要一個村莊來開發這個領域的治療方法，我認為在臨床方面以及臨床前方面，我們正在互相學習。

And one of the lessons I think that's become clear is that APOe4 homozygousity does tend to lead itself to a higher ARIA rate. And in the context of clinical trials that can lead to, in some cases, missed dosing or skipped dosing. Obviously, that's less than ideal as we start to think forward to efficacy-driven studies and registrational studies. We want doses that are optimized for the entirety of the population, not just portions of the population.

我認為已經很清楚的教訓之一是 APOe4 純合性確實會導致更高的 ARIA 率。在臨床試驗的背景下，在某些情況下可能會導致錯過給藥或跳過給藥。顯然，當我們開始考慮功效驅動的研究和註冊研究時，這並不理想。我們希望劑量針對整個人群而不僅僅是部分人群進行優化。

So we chose in the context of the Phase 1 study to be a little bit more deliberate in evaluating these APOe4 homozygous patients, so that when we bring the entirety of the patient population back together in a clinical study, that we're selecting dose levels and approaches that are optimized for the entirety of the population. So that's kind of how we think about it from an ARIA perspective, and not just from an ARIA perspective, but from a therapeutic index perspective.

因此，我們選擇在 1 期研究的背景下更加謹慎地評估這些 APOe4 純合子患者，以便當我們在臨床研究中將整個患者群體重新聚集在一起時，我們正在選擇劑量水平以及針對全體人口優化的方法。這就是我們從 ARIA 角度思考的方式，不僅是從 ARIA 角度，而是從治療指數角度。

At the end of the day, as we think about best in class for a molecule in this space, we think about three important variables: convenience, and efficacy, and safety. Efficacy and safety, of course, leading to the therapeutic index. But obviously, with the convenience factor, we think that's quite important with respect to patient burden.

歸根結底，當我們考慮這個領域的最佳分子時，我們會考慮三個重要的變數：便利性、有效性和安全性。療效和安全性當然決定治療指數。但顯然，考慮到便利因素，我們認為這對於減輕患者負擔非常重要。

And as we've indicated in January, relative to the data that we have seen to date, we've given some directional guidance in terms of where we are in all of those encouraging levels of amyloid reduction, once monthly subcu, we believe, is supported based on the data we've seen to date. It is the approach we're continuing to take moving forward in our trial as planned. And then, of course, we've just talked about the ARIA being comparable with placebo.

正如我們在一月份所指出的，相對於我們迄今為止所看到的數據，我們已經就我們在所有這些令人鼓舞的澱粉樣蛋白減少水平方面的情況給出了一些方向性指導，我們相信，每月一次subcu，根據我們迄今為止看到的數據得到支持。這是我們在試驗中繼續按計劃推進的方法。當然，我們剛剛談到了 ARIA 與安慰劑的可比性。

Rudy Li, Leerink Partners.

Rudy Li，Leerink 合夥人。

Thanks for taking my question. Just a quick follow-up on your dosing selection. So can you maybe talk about the rationale including the 45-milligram dose in ASCENT-2 which was not tested in ASCENT-1? I'm trying to get a better safety and any color would be helpful.

感謝您提出我的問題。只需快速跟進您的劑量選擇即可。那麼您能否談談基本原理，包括 ASCENT-2 中未在 ASCENT-1 中測試的 45 毫克劑量？我正在努力獲得更好的安全性，任何顏色都會有幫助。

Thanks.

謝謝。

Yeah, maybe I -- thank you for the question and maybe I can just take this one. I think what we're looking for is to really have a fulsome understanding of the exposure-response relationship. And we believe that evaluating dose level from 45 milligrams to 400 milligrams provides us with a pretty comprehensive overview of that.

是的，也許我——謝謝你提出這個問題，也許我可以接受這個問題。我認為我們正在尋找的是對暴露-反應關係有真正充分的理解。我們相信，評估 45 毫克到 400 毫克的劑量水平可以為我們提供一個相當全面的概述。

And obviously, that exposure-response relationship is something that we're interested in, both in terms of amyloid reduction but also in terms of ARIA rates to understand is that therapeutic index. So that's really what defined it. I think Hideki has already mentioned, there's a very high level of interest in this study.

顯然，我們對這種暴露-反應關係感興趣，無論是在澱粉樣蛋白減少方面，還是在 ARIA 率方面，都需要了解治療指數。這就是它的真正定義。我想 Hideki 已經提到過，人們對這項研究非常感興趣。

So we've been afforded also the opportunity to include a number of cohorts, and we've been able to enroll those cohorts in a pretty favourable way. So I think that really is the rationale for it. Other than that, I would just say that these were the dose levels that we had preplanned on testing. As we saw the first dose level cohort, 70 milligram dose level cohort data, the decision was to continue to conduct this study in a way that had been previously envisioned.

因此，我們也有機會納入許多群體，並且我們能夠以非常有利的方式招募這些群體。所以我認為這確實是其理由。除此之外，我只想說這些是我們預先規劃的測試劑量等級。當我們看到第一個劑量水平隊列（70 毫克劑量水平隊列數據）時，我們決定繼續以先前設想的方式進行這項研究。

Michael Yee, Jefferies.

麥可葉，杰弗里斯。

Hey, guys, thanks for the question. I know there's been a lot of questions around ARIA, and we just wanted to ask more specifically, when you say consistent with placebo, was there actually one case of ARIA in the placebo, and whether you would have expected that? And then if so, would you have expected ARIA in that type of range in the drug arm, given you have very little exposure, whereas the IV drugs (inaudible) have ARIA rates that are around 12% to 20%.

嘿，夥計們，謝謝你的提問。我知道圍繞 ARIA 有很多問題，我們只是想更具體地說一下，當你說與安慰劑一致時，安慰劑中是否真的存在一例 ARIA，以及你是否會預料到這一點？如果是這樣，考慮到您的暴露量很少，您是否會預期藥物組中的 ARIA 處於該類型的範圍內，而靜脈注射藥物（聽不清楚）的 ARIA 率約為 12% 至 20%。

So could you tie those two together and what drives our confidence today, for those listening, that you can go to 200 milligrams and three times the dose and still thread the needle? Thank you.

那麼，您能否將這兩者結合起來，是什麼讓我們今天對聽眾充滿信心，您可以服用 200 毫克和三倍劑量，但仍然可以穿針？謝謝。

Yeah, thanks for the question, Mike. I mean, obviously this study is double-blind placebo controlled. And as we reported at the 70 milligram dose level, the ARIA rates, as you say, were consistent with placebo. And I think that's some -- I think the statement around where we are from a therapeutic index perspective and what we think that therapeutic index then provide is the ability to move up in dose range, as you've indicated.

是的，謝謝你的提問，麥克。我的意思是，顯然這項研究是雙盲安慰劑對照的。正如我們在 70 毫克劑量水平所報告的，ARIA 率，如您所說，與安慰劑一致。我認為這就是一些 - 我認為從治療指數的角度來看，我們所處的位置以及我們認為治療指數提供的能力是在劑量範圍內上升的能力，正如您所指出的。

So I think that Hideki has already mentioned that the 200-milligram dose level cohort, in fact, all dose level cohorts are active. And so we're moving forward and exploring a full exposure-response relationship ranging all the way from 45 to 400.

所以我認為Hideki已經提到了200毫克劑量水平隊列，事實上，所有劑量水平隊列都是活躍的。因此，我們正在繼續探索從 45 到 400 的完整暴露-反應關係。

So I think what that should indicate is that we believe that the therapeutic index provides us with the sense that we have the potential for a best-in-class molecule. And again, for us, the best-in-class molecule is a function of three variables, the convenience factor, which is really around patient burden; the efficacy, which in the case here, we're talking about really reduction of amyloid; and then, of course, the safety, which I think everyone's very focused on ARIA, but we'll talk about safety in general as being permissive from a therapeutic index perspective to continue to explore this exposure-response relationship range.

所以我認為這應該表明我們相信治療指數讓我們感覺我們有潛力成為一流的分子。再說一次，對我們來說，一流的分子是三個變數的函數，便利因素，實際上是圍繞著患者負擔；功效，在這裡的例子中，我們談論的是澱粉樣蛋白的真正減少；當然，還有安全性，我認為每個人都非常關注 ARIA，但我們將總體討論安全性，因為從治療指數的角度來看，安全性是允許繼續探索這一暴露-反應關係範圍的。

Jason Butler, Citizens JMP.

Jason Butler，公民 JMP。

HI, thanks for taking the questions. I guess wanted to switch gears here and just ask a question about prasinezumab. Can you just speak to us about how we should think about the magnitude of benefit or clinical meaningfulness around the primary endpoint? And then, how do you envisage the product being incorporated into clinical practice? Thanks.

您好，感謝您提出問題。我想在這裡換個話題，問一個關於普拉辛珠單抗的問題。您能否跟我們談談我們應該如何考慮主要終點的效益程度或臨床意義？那麼，您如何設想該產品融入臨床實務？謝謝。

Yeah. Thanks for the question. Yeah just maybe -- just a quick refresher of what Roche has already shown with this molecule. So starting with the Movement Disorder Society data last year, where they showed the three-year open-label extension data from the prior Phase 2b PASADENA study. And importantly, relative to the PPMI demographic matched group, it showed a 63% slowing of progression as measured by MDS-UPDRS Part III.

是的。謝謝你的提問。是的，只是也許——只是快速回顧一下羅氏已經用這種分子展示的東西。因此，從去年運動障礙協會的數據開始，他們展示了先前 2b 期 PASADENA 研究的三年開放標籤擴展數據。重要的是，相對於 PPMI 人口統計配對組，根據 MDS-UPDRS 第三部分測量，其進展速度減緩了 63%。

And more recently, we've seen the abstract published for the ADPD meeting, which will occur here in early March, where while that presentation hasn't happened yet, they have published the abstract, and there they're talking now about full year open-label data, at least on the MDS-UPDRS Part III scale, 117% less progression than that PPMI database group.

最近，我們看到 ADPD 會議發布的摘要，該會議將於 3 月初在這裡舉行，雖然該演示尚未進行，但他們已經發布了摘要，他們現在正在談論全年開放標籤數據，至少在MDS-UPDRS 第三部分量表上，進展比PPMI 資料庫組少117%。

And in fact, even on the activity of daily living, the MDS-UPDRS Part II, a 39% slowing of -- for less progression than that PPMI data group. So we're very interested in this. Obviously, the PADOVA study is fully enrolled as per Roche. This is a large study that is being run with high integrity.

事實上，即使在日常生活活動方面，MDS-UPDRS 第二部分也比 PPMI 資料組放緩了 39%，進展幅度較小。所以我們對此非常感興趣。顯然，根據羅氏的說法，PADOVA 研究已全部入組。這是一項高度誠信的大型研究。

We've got 586 patients in this study randomized on a one-to-one basis. And so we're excited to see those results. I think it's based on strong science, it is based on previous clinical data. I think the way they are thinking about the endpoints is informed by the prior study. And then ultimately, the go forward regulatory path -- and I think to your question, how this will ultimately be positioned will be determined by the data and obviously, also, continued conversations between our partners at Roche and the regulators. And we have very high confidence that Roche will be as aggressive as is appropriate based on the dataset that they obtained.

在這項研究中，我們對 586 名患者進行了一對一的隨機分組。因此，我們很高興看到這些結果。我認為它是基於強有力的科學，基於先前的臨床數據。我認為他們對終點的思考方式是根據先前的研究得出的。最後，未來的監管路徑——我認為對於你的問題，最終將如何定位將由數據決定，顯然，還有我們羅氏合作夥伴與監管機構之間的持續對話。我們非常有信心羅氏將根據他們獲得的數據集採取適當的激進措施。

I think one thing to add to in terms of the time-to-event endpoint is that it captures the five-point or greater increase rate of progression in the scale, which in and of itself, Roche believes to be clinically meaningful. They're also working on other clinical functional endpoints within the trial to correlate.

我認為就事件發生時間終點而言需要補充的一件事是，它捕捉了量表中五個點或更高的進展率，羅氏認為這本身就具有臨床意義。他們也正在研究試驗中的其他臨床功能終點以進行關聯。

So we look forward to their continued discussion with regulators and of course, the data later this year.

因此，我們期待他們與監管機構繼續討論，當然還有今年稍後的數據。

And we have time for one more question today.

今天我們還有時間再問一個問題。

Ananda Ghosh, H.C. Wainwright.

阿南達‧戈什 (Ananda Ghosh)，H.C.溫賴特。

Yeah, hi. So just wanted to get your opinion on some of these concepts, which I don't think the Street understands very well with respect to PRX012 program. So what has been -- how do we think at the AUC, the C-max and relative of fractional occupancy, when you are looking at data which comes from lecanemab subcutaneous c-type data and with respect to your idea on the PRX012 development program. So any ideas with respect to those three factors will be very helpful to understand how to think about PRX012 development going forward? Thank you.

是的，嗨。所以只是想聽聽您對其中一些概念的看法，我認為華爾街對 PRX012 計劃的理解不是很好。那麼，當您查看 Lecanemab 皮下 C 型資料的資料以及您對 PRX012 開發計劃的想法時，我們如何看待 AUC、C-max 和相對佔有率。那麼關於這三個因素的任何想法都將非常有助於理解如何思考 PRX012 的未來發展？謝謝。

Yes, no, I appreciate the question. And yeah, it's an important question. And you talked about lecanemab and aducanumab, and I think they're relevant as amino-terminus targeting anti A-beta antibodies. And I think what we see with those antibodies, as you look through the Phase 2 dataset and into the Phase 3 dataset, is a relationship between removal of plaque and the dose response, so exposure-response relationship.

是的，不，我很欣賞這個問題。是的，這是一個重要的問題。您談到了lecanemab 和aducanumab，我認為它們與靶向抗A-β 抗體的氨基末端有關。我認為，當您查看第 2 階段資料集和第 3 階段資料集時，我們透過這些抗體看到的是斑塊去除與劑量反應之間的關係，即暴露-反應關係。

In the case of lecanemab and aducanumab, that relationship is close to linear. That's not true with every anti-beta antibody. Other antibodies show a much more than all or none effect in endpoint to (inaudible) from that perspective around plaque clearance.

就 Lecanemab 和 aducanumab 而言，這種關係接近線性。並非所有抗β抗體都是如此。從這個角度來看，其他抗體在斑塊清除的終點上表現出的效果遠大於全部或沒有效果（聽不清楚）。

I think with respect to ARIA, it's a little bit different. It is a little bit more molecule dependent. Although that being said, there clearly is a dose effect relationship within molecules, but between molecules, there's a little bit of a difference. And we continue to believe that ARIA is a mechanistically driven events. Meaning if you're removing plaque, you're going to increase the risk of observing ARIA. But as I said, the relationship between that and difference between antibodies maybe a little bit different.

我認為 ARIA 有點不同。它更依賴分子。話雖這麼說，分子內顯然存在劑量效應關係，但分子之間卻存在一些差異。我們仍然相信 ARIA 是一個機械驅動的事件。這意味著如果您去除牙菌斑，就會增加 ARIA 的風險。但正如我所說，這與抗體之間的差異之間的關係可能​​有點不同。

so what we need to be informed by now is our data from multiple dose level cohort from our ongoing Phase 1 trial, so that we can better characterize relationship between PRX012 exposure and ARIA-E rate. And we think that as we collect additional dose level cohort data. And as we think about future substantive data updates, we would be able to talk in more detail about what that means specifically for PRX012.

因此，我們現在需要了解的是我們正在進行的 1 期試驗的多劑量水平隊列數據，以便我們能夠更好地描述 PRX012 暴露與 ARIA-E 率之間的關係。我們認為，當我們收集額外的劑量水平隊列數據時。當我們考慮未來的實質數據更新時，我們將能夠更詳細地討論這對 PRX012 的具體含義。

Well, thank you, everyone. This is all the time we have today. I'll now turn it over to Gene Kinney, Chief Executive Officer, for closing remarks.

嗯，謝謝大家。這就是我們今天的全部時間。現在我將請執行長吉恩金尼 (Gene Kinney) 致閉幕詞。

Thank you very much, operator, and I want to thank you all for joining us on the call today. We appreciate your interest in Prothena, and we look very much forward to sharing further updates on our programs . Have a good afternoon.

非常感謝您，接線員，我要感謝大家今天加入我們的電話會議。我們感謝您對 Prothena 的興趣，我們非常期待分享我們計劃的進一步更新。祝你下午好。

Thank you for participating in today's conference call. This concludes the presentation,and you may now disconnect. Good day.

感謝您參加今天的電話會議。演示到此結束，您現在可以斷開連接。再會。