Denali Therapeutics Inc. (DNLI) 2026 Q2 法說會逐字稿

Good day, and thank you for standing by. Welcome to the second-quarter 2026 financial results and business highlights. (Operator Instructions) Please be advised that today's conference is being recorded.

大家好，感謝您耐心等候。歡迎參加 2026 年第二季財務業績與業務重點說明。(接線員指示) 請注意，今天的電話會議將被錄音。

I would now like to hand the conference over to your speaker today, Laura Hansen. Please go ahead.

現在我想把電話會議交給今天的講者 Laura Hansen。請開始。

Good afternoon, everyone, and thank you for joining us today to discuss Denali Therapeutics' second-quarter 2026 financial results and business highlights. Earlier today, we issued our earnings press release and filed our quarterly report. The press release, financial tables, and today's presentation are available in the investor relations section of our website.

各位下午好，感謝大家今天加入我們，一同討論 Denali Therapeutics 2026 年第二季財務業績與業務重點。今天稍早，我們已發布盈餘新聞稿並提交季度報告。新聞稿、財務表格以及今天的簡報可在我們網站的投資人關係專區取得。

Before we begin, I would like to remind everyone that today's discussion will include forward-looking statements. These statements are based on our current expectations and are subject to risks and uncertainties that could cause actual results to differ materially. Please refer to our SEC filings and the cautionary language in today's press release and presentation for a discussion of these risks. Denali undertakes no obligation to update these forward-looking statements except as required by law.

在開始之前，我想提醒各位，今天的討論將包含前瞻性陳述。這些陳述係基於我們目前的預期，並受風險與不確定性影響，可能導致實際結果與陳述內容出現重大差異。關於這些風險的討論，請參閱我們向 SEC 提交的文件，以及今天新聞稿與簡報中的警示性語言。除法律要求外，Denali 不承擔更新這些前瞻性陳述的義務。

Joining me today are Ryan Watts, our Chief Executive Officer; Katie Peng, our Chief Commercial Officer; Alexander Schuth, our Chief Operating and Financial Officer; and Peter Chin, our Chief Medical Officer and Head of Development. Ryan will begin with opening remarks. Katie will provide an update on the US launch of AVLAYAH. Ryan will return to discuss pipeline highlights. Alex will review our financial results. Peter will join the team for the question-and-answer session.

今天與我一同出席的有：我們的執行長 Ryan Watts；首席商務長 Katie Peng；首席營運與財務長 Alexander Schuth；以及首席醫療長兼研發主管 Peter Chin。Ryan 將先做開場致詞。Katie 將提供 AVLAYAH 在美國上市的最新進展。Ryan 之後將回來討論研發管線重點。Alex 將回顧我們的財務業績。Peter 將與團隊一同參與問答環節。

Ryan?

Ryan？

Thanks, Laura. Thank you everyone for joining us today. We will begin on slide five. This was a transformative quarter for Denali. We completed the first full quarter of the AVLAYAH launch, advanced two Transport Vehicle-enabled Alzheimer's disease programs into clinical development, further strengthened our financial position. Before I discuss those highlights, I want to begin with why we are here. At Denali, our purpose is to transform life for people living with serious diseases. That includes children and adults with rare genetic diseases such as Hunter syndrome, Sanfilippo syndrome, FTD-GRN, Pompe disease, as well as the millions of people living with common neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Across both groups, our mission is the same: to bring the power of biologic medicine to the brain. Slide six. The common challenge across many of these diseases is the blood-brain barrier.

謝謝你，Laura。也謝謝各位今天加入我們。我們將從第 5 張投影片開始。這一季對 Denali 而言具有轉型意義。我們完成了 AVLAYAH 上市後的第一個完整季度、推進兩項以 Transport Vehicle 技術為基礎的阿茲海默症計畫進入臨床開發，並進一步強化了我們的財務狀況。在我討論這些重點之前，我想先從我們為何在此開始。在 Denali，我們的宗旨是為罹患嚴重疾病的人們帶來生活的轉變。這包括罕見遺傳疾病的兒童與成人，例如 Hunter 症候群、Sanfilippo 症候群、FTD-GRN、龐貝氏症，以及數以百萬計罹患常見神經退化性疾病的人，例如阿茲海默症與帕金森氏症。在這兩大族群中，我們的使命相同：將生物製劑醫療的力量帶進大腦。第 6 張投影片。許多這類疾病共同面臨的挑戰是血腦屏障。

For over a decade, we have built the Transport Vehicle platform to address that challenge by engineering biologic medicines to cross the blood-brain barrier through receptor-mediated transport. Earlier this year, that work reached an important milestone. Slide seven. With FDA approval of AVLAYAH, Denali became a commercial company and began delivering our first medicine to patients. For the Hunter syndrome community, AVLAYAH is the first new FDA-approved therapy in nearly 20 years and a new treatment option designed to reach both the body and the brain. Importantly, AVLAYAH became the first approved medicine developed using our Transport Vehicle platform and the first FDA-approved biologic specifically designed to cross the blood-brain barrier. For Denali, AVLAYAH is much more than a product. It is the first proof that our platform can progress from scientific concept to an approved medicine for patients. Slide eight.

十多年來，我們打造了 Transport Vehicle 平台，透過受體介導的運輸，將生物製劑工程化以跨越血腦屏障，來解決這項挑戰。今年稍早，這項工作達成了一個重要里程碑。第 7 張投影片。隨著 FDA 核准 AVLAYAH，Denali 成為一家商業化公司，並開始將我們的第一款藥物提供給病患。對 Hunter 症候群社群而言，AVLAYAH 是近 20 年來第一個新的 FDA 核准療法，也是為同時作用於身體與大腦而設計的新治療選擇。更重要的是，AVLAYAH 成為第一個使用我們 Transport Vehicle 平台開發並獲核准的藥物，也是第一個專為跨越血腦屏障而設計、獲 FDA 核准的生物製劑。對 Denali 而言，AVLAYAH 遠不只是一項產品。它是我們平台能從科學概念推進到獲核准、可供病患使用之藥物的第一個證明。第 8 張投影片。

We believe Denali today represents a powerful and differentiated combination to create significant value for patients, the healthcare system, and investors in the near and long term. We have a commercial product in AVLAYAH and an encouraging early launch. We have a broad clinical pipeline spanning rare genetic diseases and common neurodegenerative diseases, each with substantial market potential. We have a validated and scalable Transport Vehicle platform and scientific leadership in the field of BBB transport. We have the operational capabilities and financial strength to execute from discovery through development, manufacturing, and commercialization. Together, these attributes position Denali to create near-term growth and sustainable long-term value. Slide nine. Turning to the quarter, AVLAYAH generated $3.6 million in net product revenue in its first full commercial quarter.

我們相信，今日的 Denali 具備強大且差異化的組合，能在短期與長期為病患、醫療體系與投資人創造顯著價值。我們擁有商業化產品 AVLAYAH，且早期上市表現令人鼓舞。我們擁有涵蓋罕見遺傳疾病與常見神經退化性疾病的廣泛臨床研發管線，各自具備可觀的市場潛力。我們擁有已獲驗證且可擴展的 Transport Vehicle 平台，以及在血腦屏障（BBB）運輸領域的科學領導地位。我們具備從探索研究到開發、製造與商業化的營運能力與財務實力以落實執行。綜合而言，這些特質使 Denali 能夠帶來短期成長並創造可持續的長期價值。第 9 張投影片。回到本季，AVLAYAH 在其第一個完整商業季度創造了 360 萬美元的產品淨營收。

The positive response from the Hunter syndrome community and the physicians caring for these individuals reflects years of partnership with patients, families, advocacy organizations, and clinicians. We could not have achieved this milestone without their unwavering commitment to advancing new treatment options. I also want to recognize the outstanding execution by our commercial team in the early stages of this launch. In the pipeline, DNL628 targeting tau and DNL921 targeting Aβ both advanced into clinical development for Alzheimer's disease, with initial clinical data expected in 2027. Following the sale of our Priority Review Voucher in July, our pro forma cash equivalents, and marketable securities exceeded $1.1 billion. Slide 10. A key focus of today's call will be the AVLAYAH launch.

Hunter 症候群社群以及照護這些病患的醫師所給予的正面回饋，反映了我們多年來與病患、家庭、倡議組織與臨床醫師的合作夥伴關係。若沒有他們堅定不移地致力於推動新的治療選項，我們不可能達成這個里程碑。我也要肯定我們商業團隊在此次上市初期階段的卓越執行力。在研發管線方面，針對 tau 的 DNL628 與針對 Aβ 的 DNL921 皆已推進至阿茲海默症的臨床開發，預計於 2027 年取得初步臨床數據。在 7 月出售我們的優先審查憑證（Priority Review Voucher）後，我們的備考現金及約當現金與有價證券超過 11 億美元。第 10 張投影片。今天電話會議的一個重點將是 AVLAYAH 的上市進展。

Katie will walk through the early commercial indicators, what we are learning, and how we are building the foundation for continued growth.

Katie 將說明早期商業指標、我們正在學到的內容，以及我們如何建立持續成長的基礎。

Thank you, Ryan. On slide 12, I'd like to start by reinforcing why we believe AVLAYAH is setting a new bar for the treatment of MPS II. For the first time, a therapy is designed to reach the whole body, including the brain, and can normalize key disease biomarkers both in the CNS and peripherally. These data continue to reinforce physician confidence and resonate with families, supporting the strong momentum we are seeing in the launch.

謝謝你，Ryan。在第 12 張投影片，我想先再次強調，為何我們相信 AVLAYAH 正在為 MPS II 的治療樹立新的標竿。這是首次有療法被設計為可到達全身（包括大腦），並能在中樞神經系統（CNS）與周邊同時使關鍵疾病生物標記正常化。這些數據持續強化醫師的信心，也引起家庭的共鳴，支持我們在上市過程中所看到的強勁動能。

Slide 12. Hunter syndrome represents one of the more prevalent mucopolysaccharidoses and affects a meaningful patient population within the rare disease community. The US opportunity is highly concentrated, with most eligible patients already identified and receiving conventional IDS enzyme replacement therapy at a relatively small number of specialized treatment centers. These are pediatric patients with pre-symptomatic or symptomatic neurologic manifestations who have not progressed to advanced neurologic impairment. We estimate that there are approximately 2,000 patients worldwide in the addressable market, including approximately 500 prevalent patients with Hunter syndrome in the United States. Based on the FDA-approved indication, approximately 75% of the US prevalent population, or roughly 375 patients, are currently eligible for AVLAYAH.

第 12 張投影片。Hunter 症候群是較常見的黏多醣症之一，並在罕見疾病社群中影響相當規模的病患族群。美國市場機會高度集中，多數符合條件的病患已被辨識，並在相對少數的專科治療中心接受傳統 IDS 酵素替代療法。這些是具有無症狀前期或已有症狀之神經學表現、且尚未進展至嚴重神經功能損害的兒科病患。我們估計全球可觸及市場約有 2,000 名病患，其中美國約有 500 名現存 Hunter 症候群病患。依據 FDA 核准的適應症，美國現存病患中約 75%（約 375 名）目前符合 AVLAYAH 的使用資格。

In addition, about 30 children are born each year with Hunter syndrome, providing an ongoing opportunity to initiate treatment early. Our ongoing Phase 3 COMPASS study is an important next step in advancing AVLAYAH, with the goal of supporting full approval and expansion of the label to include adults. Ultimately, our goal is to reach all eligible patients worldwide.

此外，每年約有 30 名兒童出生即罹患 Hunter 症候群，帶來持續的機會以更早啟動治療。我們正在進行的第 3 期 COMPASS 研究，是推進 AVLAYAH 的重要下一步，目標是支持取得完整核准，並擴大標籤以涵蓋成人。最終，我們的目標是觸及全球所有符合條件的病患。

Slide 13. Our launch is being executed against four core strategies. First, partnering closely with the Hunter syndrome community through a high-touch, community-centered approach. In rare diseases, families often learn from and support one another. We believe that positive experience with both AVLAYAH and the Denali team helps build trust, increase awareness, and encourage additional families to seek treatment. Second, helping physicians evaluate AVLAYAH and supporting treatment centers as they prepare to initiate therapy.

投影片 13。我們的上市推進係依循四項核心策略執行。第一，透過高接觸、以社群為中心的方法，與亨特氏症社群緊密合作。在罕見疾病領域，家庭往往彼此學習並互相支持。我們相信，對 AVLAYAH 與 Denali 團隊的正向體驗有助於建立信任、提升認知，並鼓勵更多家庭尋求治療。第二，協助醫師評估 AVLAYAH，並在治療中心準備啟動治療時提供支援。

Strong clinical conviction is creating urgency amongst physicians to switch eligible patients and engage payers to accelerate access. Third, helping each patient and family navigate the steps from prescription through their first infusion. Fourth, driving fast label-aligned coverage decisions that help remove payer roadblocks. After our first full quarter of launch, what has been particularly encouraging is how these four strategies have reinforced one another. Strong clinical conviction has driven physicians and patient demand. That demand has accelerated payer coverage, and together, these dynamics are enabling more patients to begin therapy.

強烈的臨床信念正促使醫師產生迫切感，將符合條件的病患轉換治療，並與支付方合作以加速取得用藥。第三，協助每位病患與家庭從處方到首次輸注，順利完成各項步驟。第四，推動快速且符合標籤適應症的給付決策，以協助移除支付方障礙。在上市後第一個完整季度之後，特別令人鼓舞的是，這四項策略彼此相互強化。強烈的臨床信念帶動了醫師與病患端的需求。該需求加速了支付方的給付涵蓋；而這些動態相互作用，正使更多病患得以開始治療。

Slide 14. Beginning with physicians, we entered the launch with a strong foundation. Before approval, more than 80% of physicians surveyed were already aware of AVLAYAH. 90% viewed the biomarker and clinical data as motivating to prescribe. Since approval, we have reached approximately 80% of targeted healthcare organizations with AVLAYAH's launch information through our field engagements, scientific exchange, educational webinars, and treatment center support. These activities have been highly impactful and are driving strong engagement across a significant number of treating physicians.

投影片 14。先從醫師端來看，我們在上市時已具備堅實基礎。在核准前，受訪醫師中已有超過 80% 知悉 AVLAYAH；90% 認為其生物標記與臨床數據足以促使其開立處方。自核准以來，我們透過外勤拜訪、科學交流、教育網路研討會以及治療中心支援，已向約 80% 的目標醫療機構傳達 AVLAYAH 的上市資訊。這些活動成效顯著，並在相當多的治療醫師之間帶來高度互動與參與。

Physicians constantly tell us that the ability to address neurologic manifestations is highly meaningful and that most patients experience neurologic symptoms at some point during the course of their disease. That belief is translating into action, as many treatment centers with eligible patients are working with families to navigate reimbursement and transition patients to AVLAYAH.

醫師不斷告訴我們，能夠處理神經學表現具有高度意義，而且多數病患在疾病進程中的某個階段都會出現神經學症狀。這樣的信念正轉化為行動：許多擁有符合條件病患的治療中心，正與家庭合作，協助其因應給付與報銷流程，並將病患轉換至 AVLAYAH。

Slide 15. We have seen equally strong engagement from patients and caregivers. Through our launch webinars focused on clinical data and access, as well as with Denali Patient Services, we reached more than 100 families. That represents greater than one-quarter of the eligible US patients. This high level of engagement reflects both unmet need in Hunter syndrome and the extent to which families have followed the development of AVLAYAH. We are also seeing families share their experiences through advocacy networks and local media, helping other members of the community learn about the availability of a new treatment option.

投影片 15。我們也看到病患與照護者同樣強勁的參與度。透過聚焦臨床數據與可近性的上市網路研討會，以及 Denali 病患服務，我們觸及了超過 100 個家庭。這相當於美國符合條件病患的四分之一以上。如此高的參與度反映了亨特氏症的未被滿足需求，以及家庭對 AVLAYAH 開發進展的高度關注。我們也看到家庭透過倡議網絡與在地媒體分享其經驗，協助社群其他成員了解新的治療選項已可取得。

Slide 16. One of the most powerful aspects of launch has been hearing directly from families and advocates about their experience with AVLAYAH and Denali. They have described the opportunity to begin AVLAYAH as a source of hope, and in some cases, as the possibility of gaining more meaningful time with their children. We are careful not to draw clinical conclusions from individual experiences. However, these stories illustrate how much the approval of AVLAYAH means to this community that has waited many years for a therapy designed to reach both the brain and the body.

投影片 16。上市過程中最具力量的面向之一，是直接聽到家庭與倡議者分享他們對 AVLAYAH 與 Denali 的體驗。他們形容開始使用 AVLAYAH 的機會是希望的來源；在某些情況下，更是有可能與孩子擁有更有意義的相處時光。我們謹慎避免從個別經驗推導臨床結論。然而，這些故事說明了 AVLAYAH 的核准對這個等待多年、期盼一種能同時到達大腦與身體之治療的社群而言，具有多麼重大的意義。

We are also hearing very positive feedback about the way the Denali team is supporting families and healthcare organizations. For many patients, initiating a new therapy involves coordinating physicians, infusion centers, insurers, specialty distributors, and patient services. Our team works closely with each family and treatment center to help them navigate those steps. The feedback from families and advocacy organizations has consistently highlighted the responsiveness, compassion, and partnership of the Denali team. That experience matters. It builds confidence in treatment, helps patients move through the access process, and supports continuity once treatment begins.

我們也聽到對 Denali 團隊支援家庭與醫療機構方式的非常正面回饋。對許多病患而言，啟動新療法需要協調醫師、輸注中心、保險公司、專科經銷商與病患服務等多方。我們的團隊與每個家庭及治療中心緊密合作，協助他們完成並掌握這些步驟。來自家庭與倡議組織的回饋一再強調 Denali 團隊的即時回應、同理心與夥伴合作精神。這樣的體驗很重要。它能建立對治療的信心，協助病患完成可近性流程，並在治療開始後支持其持續性。

Slide 17. Turning to payer access. We have made exceptional progress during the first quarter of launch. Commercial policies covering more than 50% of lives have already been established. As with many rare diseases, a significant portion of MPS II patients is covered by Medicaid.

投影片 17。接著談支付方可近性。我們在上市第一季取得了卓越進展。涵蓋超過 50% 受保人數的商業保險給付政策已經建立。如同許多罕見疾病，MPS II 病患中有相當比例由 Medicaid 承保。

Recognizing that not every state will publish a product-specific policy, 14 state Medicaid programs publicly listed AVLAYAH as covered. Separately, we are also seeing managed Medicaid policy align their coverage with commercial plans. These results compare favorably with early coverage achieved by analogous rare disease launches. Importantly, the absence of published policy does not mean a patient cannot obtain access. To date, physicians and families have successfully used prior authorizations, appeals, and medical exceptions while formal policies are being developed. The willingness of physicians to initiate these requests reflects their conviction in AVLAYAH, and our payer and patient access teams are working closely with them to move eligible patients towards treatment.

考量並非每個州都會公布特定產品的政策，已有 14 個州的 Medicaid 計畫公開列示 AVLAYAH 為可給付。另外，我們也看到管理式 Medicaid 的政策正使其給付與商業保險方案趨於一致。這些結果與類似罕見疾病產品在上市初期所取得的給付涵蓋相比，表現相當有利。重要的是，未公布政策並不代表病患無法取得用藥。截至目前，醫師與家庭已在正式政策制定期間，成功透過事前授權、申訴與醫療例外等方式取得用藥。醫師願意啟動這些申請，反映其對 AVLAYAH 的信念；而我們的支付方與病患可近性團隊也正與他們密切合作，推動符合條件的病患邁向治療。

Slide 18. We are extremely pleased with the trajectory of the US launch. In our first full commercial quarter, we generated $3.6 million in net product revenue and secured commercial coverage for more than 50% of covered lives.

投影片 18。我們對美國上市的發展軌跡感到非常滿意。在第一個完整商業季度，我們創造了 360 萬美元的產品淨營收，並取得涵蓋超過 50% 受保人數的商業保險給付。

Before discussing the outlook, I want to briefly address our approach to communicating launch dynamics and metrics. We understand that visibility is important to our investors, and we are committed to maintaining an open dialogue. There are many factors that influence the trajectory of AVLAYAH adoption, and every patient journey is unique, from the initial expression of interest through reimbursement approval, and ultimately dosing. In addition, because AVLAYAH is weight-based, the number of vials used can vary meaningfully between a newly diagnosed infant and a 16-year-old adolescent. For the first two quarters of launch, we therefore plan to provide guidance on expected net product revenue for the following quarter. We believe that this approach, together with the prior quarter's reported net product revenue, will provide the clearest view of the launch trajectory during this early period. Before launch, we described an adoption curve that would build over time.

在討論展望之前，我想先簡要說明我們溝通上市動態與衡量指標的方法。我們理解能見度對投資人很重要，並承諾維持開放的對話。影響 AVLAYAH 採用軌跡的因素很多，而每位病患的歷程皆獨一無二，從最初表達興趣、到報銷核准、最終到實際給藥。此外，由於 AVLAYAH 以體重計價（weight-based），新診斷嬰兒與 16 歲青少年之間的使用瓶數可能有顯著差異。因此，在上市的前兩個季度，我們計畫提供下一季度預期產品淨營收的指引。我們相信，這種做法搭配前一季度已揭露的產品淨營收，將在此早期階段提供最清晰的上市軌跡視角。在上市前，我們曾描述採用曲線將隨時間逐步建立。

We expected the earliest patients to be highly engaged families who are waiting for AVLAYAH and were prepared to move quickly through the medical exceptions process. That initial demand has been stronger than we anticipated, reflecting both the high awareness of AVLAYAH and the significant unmet need in the Hunter syndrome community. While many patients have already started therapy, others continue to move through the reimbursement and treatment journey. As payer coverage expands and treatment centers gain experience with AVLAYAH, we expect the patient journey from prescription to infusion to become increasingly efficient, enabling more eligible patients to begin treatment. Given the pace of adoption, expanding access, and continued strong execution, we expect Q3 net product revenue to be in the range of $10 million to $12 million.

我們預期最早開始的病患會是高度投入、一直等待 AVLAYAH 的家庭，且已準備好快速完成醫療例外流程。這股初期需求比我們預期更強，反映了 AVLAYAH 的高知悉度，以及亨特氏症社群中顯著的未被滿足需求。雖然許多病患已開始治療，仍有其他病患持續在報銷與治療流程中推進。隨著支付方給付涵蓋擴大、治療中心累積 AVLAYAH 的使用經驗，我們預期病患從處方到輸注的流程將愈加高效，使更多符合條件的病患得以開始治療。考量採用速度、可近性擴張以及持續強勁的執行力，我們預期第三季產品淨營收將落在 1,000 萬至 1,200 萬美元之間。

Most importantly, families continue to tell us that AVLAYAH and the support they receive from the Denali team is making a meaningful difference in their lives. Slide 19. The AVLAYAH launch also has significance beyond a single product. It establishes the first commercial foundation for our Enzyme Transport Vehicle franchise across lysosomal storage disorders. The ETV platform is designed to reach the whole body, including the brain, and it provides opportunities across Hunter syndrome, Sanfilippo syndrome, FTD-GRN, Pompe disease, Gaucher disease, and Hurler syndrome. The ERT market alone represents more than a $9 billion opportunity. Across these diseases, we expect to benefit from shared scientific expertise, established relationships with treatment centers and advocacy organizations, and commercial capabilities that could be leveraged across future launches. Each patient we support and each treatment center we activate strengthens the infrastructure that can serve the broader ETV franchise.

最重要的是，家庭持續告訴我們，AVLAYAH 以及他們從 Denali 團隊獲得的支持，正在他們的生活中帶來實質且有意義的改變。第 19 張投影片。AVLAYAH 的上市也具有超越單一產品的意義。它為我們的酵素運輸載體（Enzyme Transport Vehicle, ETV）產品線在溶小體儲積症領域建立了第一個商業化基礎。ETV 平台旨在到達全身，包括大腦，並在亨特氏症、聖菲利波症候群、FTD-GRN、龐貝氏症、戈謝氏症以及赫勒氏症候群等領域提供機會。僅酵素替代療法（ERT）市場本身就代表超過 90 億美元的機會。在這些疾病領域，我們預期可受益於共享的科學專業、與治療中心及倡議組織既有的關係，以及可在未來上市中加以運用的商業能力。我們所支持的每一位病患，以及我們所啟動的每一個治療中心，都在強化可服務更廣泛 ETV 產品線的基礎設施。

AVLAYAH is therefore both an important medicine for Hunter syndrome community and an early demonstration of our ability to discover, develop, manufacture, and commercialize innovative therapies efficiently and successfully. We are proud of the start while recognizing that this is still the beginning of the launch. Our priorities remain expanding access, supporting a positive treatment experience, reaching additional eligible patients, and preparing for the international expansion.

因此，AVLAYAH 既是亨特氏症社群的重要藥物，也是我們能夠以高效率且成功的方式發現、開發、製造並商業化創新療法的早期證明。我們為目前的起步感到自豪，同時也認知到這仍只是上市初期。我們的優先事項仍是擴大可近性、支持正向的治療體驗、觸及更多符合資格的病患，並為國際擴張做好準備。

With that, I'll turn it back to you, Ryan, to discuss the broader pipeline.

接下來，我把時間交還給你，Ryan，來討論更廣泛的研發管線。

Thanks, Katie. Slide 21. Earlier, I described AVLAYAH as the commercial foundation for Denali and the first proof that the Transport Vehicle platform can enable medicines for patients. I would now like to provide an update on the broader pipeline and then spend most of my time on our Alzheimer's disease programs. Our 3x3 strategy remains unchanged: deliver, develop, and discover. Over the 2026-2028 period, our goals are to build two growing commercial brands, generate five clinical proofs of concept, and advance four to six additional programs into the clinic through continued leadership and invention in blood-brain barrier technologies.

謝謝，Katie。第 21 張投影片。先前我將 AVLAYAH 描述為 Denali 的商業化基礎，也是運輸載體（Transport Vehicle）平台能為病患帶來藥物的第一個證明。現在我想就更廣泛的研發管線提供最新進展，並將大部分時間放在我們的阿茲海默症計畫上。我們的 3x3 策略維持不變：交付（deliver）、開發（develop）與發現（discover）。在 2026 至 2028 年期間，我們的目標是打造兩個持續成長的商業品牌、取得五項臨床概念驗證（proof of concept），並透過在血腦障壁技術上的持續領導與創新，推進另外四到六個計畫進入臨床。

Slide 22. Next, I would like to briefly update you on DNL593. DNL593 is a direct progranulin replacement therapy designed to deliver progranulin across the blood-brain barrier and restore the missing protein to key cell types in the brain, including the lysosome where progranulin normally functions. Earlier this year, we regained full ownership and control of the program from Takeda. That provides us with greater flexibility over the development strategy and timing of the data analysis. We have decided to allow for a longer period of observation in the open label extension portion of the ongoing Phase 1 and 2 study. We now expect data in the first half of 2027, updated from our prior expectation of results by the end of the year.

第 22 張投影片。接下來，我想簡要向各位更新 DNL593。DNL593 是一種直接的 progranulin 補充替代療法，旨在將 progranulin 跨越血腦障壁輸送，並將缺失的蛋白質恢復至大腦中的關鍵細胞類型，包括 progranulin 正常發揮功能的溶小體。今年稍早，我們從武田（Takeda）重新取得該計畫的完整所有權與控制權。這使我們在開發策略以及數據分析時程上擁有更大的彈性。我們已決定在正在進行的第 1/2 期研究之開放標籤延伸（open label extension）部分，延長觀察期間。我們目前預期在 2027 年上半年取得數據，較先前預期於年底前取得結果的時程有所更新。

The additional follow-up will allow us to better characterize treatment effects across multiple biomarkers, including neurofilament light chain, or NfL, which may change gradually following treatment. Pending the totality of the data, we also plan to explore whether a biomarker-driven accelerated approval path may be appropriate. NfL has regulatory precedent in the related neurodegenerative disease ALS, although any potential path for DNL593 would require discussion and alignment with regulators.

額外的追蹤將使我們能更好地刻畫治療在多項生物標記上的效果，包括神經絲輕鏈（neurofilament light chain, NfL），其在治療後可能會逐步變化。視整體數據而定，我們也計畫探索是否適合採取以生物標記為基礎的加速核准（accelerated approval）途徑。NfL 在相關的神經退化性疾病 ALS 中已有法規先例，不過 DNL593 的任何潛在途徑仍需與監管機關討論並取得一致。

We are excited about DNL593 because it directly addresses the genetic cause of FTD-GRN by replacing progranulin. This week, the FDA granted orphan drug designation to DNL593 for FTD-GRN, underscoring the significant unmet need facing individuals affected by this disease and the potentially promising rationale of our approach with PTV:PGRN. Earlier, healthy volunteer data demonstrated dose-dependent increases in cerebrospinal fluid progranulin following intravenous administration, providing evidence of brain delivery and further validation of the Transport Vehicle platform.

我們對 DNL593 感到振奮，因為它透過補充 progranulin，直接針對 FTD-GRN 的遺傳致病原因。本週，FDA 授予 DNL593 用於 FTD-GRN 的孤兒藥資格認定（orphan drug designation），凸顯受此疾病影響者所面臨的重大未被滿足需求，以及我們以 PTV:PGRN 方法所具備的潛在可行且令人期待的科學依據。先前，健康受試者數據顯示在靜脈投與後，腦脊髓液中的 progranulin 呈現劑量依賴性增加，提供了藥物可送達大腦的證據，並進一步驗證運輸載體平台。

Slide 23. I will now turn to what we believe is one of the most exciting areas of our pipeline, Alzheimer's disease. A few weeks ago, I had the privilege of delivering a plenary presentation at the Alzheimer's Association International Conference in London.

第 23 張投影片。接下來我將談到我們認為研發管線中最令人興奮的領域之一：阿茲海默症。幾週前，我有幸在倫敦舉行的阿茲海默症協會國際會議（Alzheimer's Association International Conference）上進行全體大會（plenary）演講。

After working in Alzheimer's disease for more than 20 years, I believe the field has entered a transformative period because of extraordinary progress in three historically challenging areas: biology, biomarkers, and the blood-brain barrier. Human genetics and pharmacology are sharpening our understanding of the multifaceted biology of disease. Imaging and blood-based biomarkers are enabling earlier diagnosis and increasingly precise measurements of disease progression and treatment response. Brain transport technologies are creating the potential to deliver biologic medicines broadly throughout the brain. Together, these advances create new opportunities for the next generation of Alzheimer's therapies.

在阿茲海默症領域工作超過 20 年後，我相信本領域已進入一個轉型期，原因在於三個歷來極具挑戰的面向取得了非凡進展：生物學、 生物標記，以及血腦障壁。人類遺傳學與藥理學正使我們對疾病多面向的生物學理解更加清晰。影像與血液型生物標記使更早期的診斷成為可能，並能以日益精準的方式量測疾病進展與治療反應。腦部運輸技術正在創造將生物製劑廣泛輸送至整個大腦的可能性。綜合而言，這些進展為下一代阿茲海默症療法帶來新的機會。

Slide 24. We believe the next advances in Alzheimer's disease may depend on delivering therapies more effectively throughout the brain. Amyloid plaque clearance is now clinically validated, but currently available antibodies are limited by modest efficacy and the risk of amyloid-related imaging abnormalities, or ARIA.

第 24 張投影片。我們相信，阿茲海默症的下一步進展可能取決於能否更有效地將療法輸送至整個大腦。清除類澱粉斑塊（amyloid plaque）如今已獲臨床驗證，但目前可用的抗體受限於療效有限，以及類澱粉相關影像異常（amyloid-related imaging abnormalities, ARIA）的風險。

Tau reduction has also shown encouraging clinical signals, but current antisense approaches rely on intrathecal administration and may not achieve uniform distribution throughout the brain and have other limitations. Our two clinical programs are designed to address these limitations through better brain delivery. DNL921 is a potential best-in-class BBB-crossing anti-amyloid antibody designed to improve plaque engagement while reducing ARIA potential and peripheral immune activation. DNL628 is a potential first-in-class BBB-crossing tau antisense oligonucleotide designed for intravenous administration and broad uniform distribution throughout the capillary network.

Tau 降低也已顯示令人鼓舞的臨床訊號，但目前的反義核酸（antisense）方法仰賴鞘內投與（intrathecal administration），可能無法在整個大腦達到均勻分布，且還有其他限制。我們的兩項臨床計畫旨在透過更佳的大腦遞送來解決這些限制。DNL921 是一種可能同級最佳（best-in-class）的可跨越血腦障壁（BBB-crossing）抗類澱粉抗體，設計目標是在提升斑塊結合（plaque engagement）的同時，降低 ARIA 潛在風險與周邊免疫活化。DNL628 是一種可能同級首創（first-in-class）的可跨越血腦障壁 tau 反義寡核苷酸（antisense oligonucleotide），設計用於靜脈投與，並在毛細血管網絡中達到廣泛且均勻的分布。

Slide 25. Starting with DNL921, one of the important features of Transport Vehicle-enabled delivery is the route of entry into the brain. When conventional anti-amyloid antibodies enter the brain, they concentrate around larger arteries and arterioles where vascular amyloid is present. We believe that localization contributes to ARIA risk.

第 25 張投影片。先從 DNL921 談起，運輸載體（Transport Vehicle）所促成的遞送有一項重要特徵：進入大腦的途徑。當傳統的抗類澱粉抗體進入大腦時，會在存在血管類澱粉的較大動脈與小動脈周圍聚集。我們相信這種局部聚集會增加 ARIA 風險。

By engaging the transferrin receptor, antibody transport vehicle-enabled antibodies enter the brain through the extensive capillary network and distribute more evenly throughout the brain. In preclinical models, this route of entry was associated with substantially fewer MRI lesions than a conventional anti-amyloid antibody, including at dose levels that achieved strong target engagement. These data support our hypothesis that improved brain delivery and biodistribution may enhance plaque engagement while reducing ARIA potential.

透過結合轉鐵蛋白受體（transferrin receptor），抗體運輸載體所促成的抗體可經由廣泛的毛細血管網絡進入大腦，並在整個大腦更均勻地分布。在臨床前模型中，這種進入途徑與相較於傳統抗類澱粉抗體顯著更少的 MRI 病灶相關，即使在達到強勁標的結合（target engagement）的劑量水準亦然。這些數據支持我們的假設：改善的大腦遞送與生體分布（biodistribution）可能在降低 ARIA 潛在風險的同時，提升斑塊結合。

Slide 26. We've also engineered DNL921 to address the broader attributes required for a successful medicine. Unlike fusion approaches that append a transferrin receptor binding arm to an antibody, our transport vehicle binding is embedded directly into the Fc. DNL921 is designed to achieve robust brain concentrations while remaining intact and minimizing effects on immature reticulocytes. With the goal of preserving activity at amyloid plaques while reducing peripheral immune activation, DNL921 incorporates conditional effector function through our cisLALA design.

第 26 張投影片。我們也對 DNL921 進行了工程設計，以滿足成功藥物所需的更廣泛特性。不同於將轉鐵蛋白受體結合臂附加到抗體上的融合（fusion）方法，我們的運輸載體結合位點是直接嵌入 Fc 區。DNL921 的設計目標是在維持完整性的同時達到強健的大腦濃度，並將對未成熟網狀紅血球（immature reticulocytes）的影響降至最低。為了在保留對類澱粉斑塊活性的同時降低周邊免疫活化，DNL921 透過我們的 cisLALA 設計納入條件式效應功能（conditional effector function）。

Slide 29. Turning to DNL628, the central opportunity is to improve both distribution and convenience for antisense therapy. Intrathecally administered antisense oligonucleotides distribute from cerebrospinal fluid and can produce uneven exposure across brain regions with greater treatment burden for patients. By contrast, intravenous oligonucleotide transport vehicle OTV delivery uses the capillary network to distribute the antisense oligo broadly across the brain and spinal cord. This distribution includes key cell types involved in neurodegeneration, including neurons, astrocytes, and microglia.

投影片 29。談到 DNL628，核心機會在於同時改善反義療法的分佈與便利性。以鞘內給藥的反義寡核苷酸會自腦脊髓液分佈，可能導致不同腦區暴露不均，並增加患者的治療負擔。相較之下，靜脈注射的寡核苷酸運輸載體（OTV）遞送可利用毛細血管網路，將反義寡核苷酸廣泛分佈至全腦與脊髓。此分佈涵蓋與神經退化相關的關鍵細胞類型，包括神經元、星狀膠質細胞與小膠質細胞。

Slide 28. In mice expressing human tau and the human transferrin receptor, DNL628 produced robust reductions in MAPT RNA and tau protein. Importantly, tau protein reduction persisted for more than 12 weeks after dosing, supporting the potential for a practical dosing interval. These data support the design of the ongoing Phase 1b study, where we are evaluating safety, dose selection, effects on tau levels, and imaging measures in people with biomarker-confirmed early Alzheimer's disease.

投影片 28。在表達人類 tau 與人類轉鐵蛋白受體的小鼠中，DNL628 使 MAPT RNA 與 tau 蛋白顯著下降。重要的是，tau 蛋白的降低在給藥後持續超過 12 週，支持具可行性的給藥間隔之潛力。這些數據支持目前進行中的第 1b 期研究設計；我們正在生物標記物確認之早期阿茲海默症患者中評估安全性、劑量選擇、對 tau 水準的影響，以及影像學指標。

Slide 29. Both Alzheimer's disease programs are now in clinical development. DNL628 Phase 1b study is ongoing, and we expect initial clinical biomarker data in the first half of 2027. DNL921, the clinical trial application was submitted in the first half of this year, and we expect initial safety and clinical proof of concept data in 2027. These readouts will be important not only for individual programs, but also for the broader validation of our oligonucleotide and antibody Transport Vehicle platforms in common neurodegenerative disease.

投影片 29。兩個阿茲海默症計畫目前皆已進入臨床開發。DNL628 第 1b 期研究正在進行中，我們預期於 2027 年上半年取得初步臨床生物標記物數據。DNL921 的臨床試驗申請已於今年上半年提交，我們預期於 2027 年取得初步安全性與臨床概念驗證數據。這些讀出不僅對各個計畫本身重要，也將對我們在常見神經退化性疾病中之寡核苷酸與抗體運輸載體平台的更廣泛驗證具有重要意義。

Taken together, our progress this quarter demonstrates the breadth of Denali, a growing commercial business, broad clinical pipeline, and a repeatable platform capable of supporting multiple therapeutic modalities, all focused on delivering meaningful medicines to patients and families. Slide 30.

綜合而言，我們本季的進展展現了 Denali 的廣度：持續成長的商業化業務、廣泛的臨床產品線，以及可重複運用、能支援多種治療形式的平台；一切皆聚焦於為患者與家庭帶來具意義的藥物。投影片 30。

With that, I will turn the call over to Alex to review our financial results.

接下來，我將把電話會議交給 Alex，請他回顧我們的財務結果。

Thank you, Ryan. Slide 31. I will close our prepared remarks today with a look at our portfolio, capital allocation priorities, and second quarter financial results. We have built a broad portfolio based on the Transport Vehicle platform, which is now clinically and commercially validated through AVLAYAH. The portfolio has the potential to create significant value in the near and long term, with each program designed to offer first or best-in-class potential in its respective indication, and we are well-capitalized to execute against it. Our portfolio has two key components. First, we have a pipeline of next-generation enzyme and protein replacement therapies designed to treat the whole body, including the brain. Across these programs, we can apply the clinical and regulatory learnings from AVLAYAH and leverage our existing capabilities in development, manufacturing, and commercialization.

謝謝你，Ryan。投影片 31。我將以檢視我們的產品組合、資本配置優先事項，以及第二季財務結果，作為今天預先準備講稿的結尾。我們已基於運輸載體（Transport Vehicle）平台建立了廣泛的產品組合，而該平台如今已透過 AVLAYAH 在臨床與商業上獲得驗證。此產品組合在短期與長期皆具創造重大價值的潛力；每個計畫皆以在其適應症中成為同類首創或同類最佳為目標設計，我們也具備充足資本以推動執行。我們的產品組合有兩個關鍵組成。第一，我們擁有一系列下一代酵素與蛋白替代療法的產品線，旨在治療全身（包括大腦）。在這些計畫中，我們可運用 AVLAYAH 的臨床與法規學習成果，並利用我們既有的研發、製造與商業化能力。

We estimate that each program represents a potential market opportunity ranging from approximately $500 million to more than $1 billion, creating a multibillion-dollar opportunity across the franchise. These programs benefit from a well-established therapeutic modality, measurable biomarkers, and in certain diseases, the potential for biomarker-based accelerated development paths. In addition, and shown on the right, is our portfolio targeting common neurodegenerative diseases. This includes two clinical-stage blood-brain barrier-enabled molecules targeting tau and amyloid beta for Alzheimer's disease with first and/or best-in-class potential. If successful, these programs could reach millions of patients and represent substantial multibillion-dollar market opportunities.

我們估計每個計畫所代表的潛在市場機會約介於 5 億美元至超過 10 億美元，使整個產品群合計形成數十億美元的機會。這些計畫受益於已相當成熟的治療形式、可量測的生物標記物，以及在某些疾病中，可能採用以生物標記物為基礎的加速開發路徑。此外，如右側所示，我們亦有針對常見神經退化性疾病的產品組合。其中包括兩個臨床階段、具血腦障壁穿越能力的分子，分別針對阿茲海默症的 tau 與類澱粉 β，並具同類首創及／或同類最佳的潛力。若成功，這些計畫可觸及數百萬名患者，並代表可觀的數十億美元市場機會。

Slide 32. Turning to the financials and capital allocation. We ended the second quarter with approximately $940 million in cash equivalents, and marketable securities. In July, we received $195 million in proceeds from the sale of the rare pediatric disease Priority Review Voucher awarded following the approval of AVLAYAH.

投影片 32。接著談財務與資本配置。第二季結束時，我們持有約 9.4 億美元的約當現金與有價證券。7 月，我們出售因 AVLAYAH 獲准而取得之罕見兒科疾病優先審查憑證（Priority Review Voucher）並收到 1.95 億美元款項。

Together, this brings our pro forma cash equivalents, and marketable security to more than $1.1 billion. This gives us flexibility to pursue three priorities with discipline. First, it allows us to invest in the execution of our portfolio, including the commercial activities for AVLAYAH, as outlined by Katie, preparations for the potential launch of DNL126 or zafinofusp alfa in 2027, and advancement of clinical programs. Second, we can continue to build capabilities and infrastructure for efficiency. In particular, our internal manufacturing facility in Salt Lake City provides opportunities for speed and development and attractive costs as we bring additional products forward. Third, our balance sheet provides strategic flexibility with respect to potential future partnerships and diversified sources of capital.

合併計算後，我們的備考（pro forma）約當現金與有價證券超過 11 億美元。這使我們能以紀律性方式靈活推進三項優先事項。第一，使我們得以投資於產品組合的執行，包括 Katie 所概述的 AVLAYAH 商業活動、為 2027 年可能推出 DNL126（或 zafinofusp alfa）所做的準備，以及臨床計畫的推進。第二，我們可持續建置能力與基礎設施以提升效率。特別是，我們位於鹽湖城的內部製造設施，能在推進更多產品時提供速度與開發上的優勢，並具備具吸引力的成本結構。第三，我們的資產負債表在潛在未來合作夥伴關係與多元化資金來源方面提供策略彈性。

Slide 33. The complete details of our financial results are included in today's press release in Form 10-Q, I will focus only on the key items. AVLAYAH generated $3.6 million in net product revenues during the first full quarter of commercial availability. Research and development expenses were $97 million, compared with $102.7 million for the same period in 2025. The decrease primarily reflected the timing of AVLAYAH commercial supply manufacturing in the prior year period and lower external spending on small molecule programs. Selling general and administrative expenses were $36.3 million, compared to $32.3 million in the second quarter 2025. The increase primarily reflected investments to support the AVLAYAH commercial launch. As noted, we ended the quarter with approximately $940 million in cash equivalents, and marketable securities before receipt of the $195 million in PRV proceeds in July.

投影片 33。我們財務結果的完整細節已載於今日新聞稿與 10-Q 表格中；我將僅聚焦於關鍵項目。AVLAYAH 在商業供應後的第一個完整季度，產生 360 萬美元的淨產品收入。研發費用為 9,700 萬美元，較 2025 年同期的 1.027 億美元下降。下降主要反映前一年度期間 AVLAYAH 商業供應製造時點的影響，以及小分子計畫外部支出降低。銷售、一般及行政費用為 3,630 萬美元，較 2025 年第二季的 3,230 萬美元增加。增加主要反映為支持 AVLAYAH 商業上市所做的投資。如前所述，在 7 月收到 1.95 億美元 PRV 處分款項之前，我們於季末持有約 9.4 億美元的約當現金與有價證券。

In closing, we believe Denali is entering this exciting next phase from a position of strength with a commercial product, a broad pipeline, a validated platform, and the capabilities and capital to deliver value for patients and investors.

最後，我們相信 Denali 正以強勢姿態進入令人振奮的下一階段：擁有商業化產品、廣泛的產品線、已驗證的平台，以及為患者與投資人創造價值所需的能力與資本。

With that, I will turn the call back to the operator to begin the Q&A session. Thank you.

接下來，我將把電話會議交回給主持人，開始問答環節。謝謝。

(Operator Instructions) Jessica Fye, JPMorgan.

（主持人指示）JPMorgan 的 Jessica Fye。

Hello, this is Adam on for Jess. Thanks for taking our question. I just was curious, what in the launch so far has helped you come up with the next quarter's guidance? Can we assume that growth trajectory to continue through the end of the year? Could we see maybe OpEx guidance in the future?

你好，我是代 Jess 發言的 Adam。謝謝讓我們提問。我想請教，到目前為止在上市推進上，哪些因素幫助你們形成下一季的指引？我們是否可以假設這樣的成長軌跡會持續到年底？未來是否可能看到 OpEx（營運費用）指引？

Thanks, Adam. Thanks for your question. What's giving us confidence is all of the leading indicators are moving in a very positive direction. As you saw from the presentation, physician awareness is extremely high of the AVLAYAH data. They're highly motivated to switch patients. In addition, we've seen tremendous engagement from families as well. We've also had great success moving patients through reimbursement with the medical exceptions process. As you can see, also, we've had success with payer access. We have now greater than 50% of commercial lives covered as of the end of Q2. Given all the dynamics are moving in the right direction, we feel very confident that the momentum will continue.

謝謝你，Adam。謝謝你的問題。讓我們有信心的是，所有領先指標都正朝非常正面的方向發展。如你從簡報中所見，醫師對 AVLAYAH 數據的認知度極高。他們也高度有動機將患者轉換用藥。此外，我們也看到家庭端的高度參與。我們也在透過醫療例外（medical exceptions）流程推進患者給付核准方面取得很大成功。同時，如你所見，我們在付款方准入方面也有進展。截至第二季末，我們目前已覆蓋超過 50% 的商業保險人群。鑑於各項動態都朝正確方向前進，我們對動能將持續非常有信心。

I can take the second part. This is Alex. I can take the second part on OpEx. Capital efficiency is very important to us, and we are pleased that we're able to keep OpEx flat in Q2 of 2026 versus Q2 of 2025, actually slightly lower on a six-month basis, while at the same time preparing for the launch and advancing important new programs into the clinic. With respect to an outlook, we generally provide an outlook for the full year at the beginning of the year. Please stay tuned for that.

我可以回答第二部分。我是 Alex。我可以回答營運費用（OpEx）的第二部分。資本效率對我們非常重要，我們也很高興能在 2026 年第二季相較於 2025 年第二季將 OpEx 維持持平，實際上以六個月基礎來看還略低一些，同時也在為產品上市做準備，並推進重要的新計畫進入臨床。至於展望，我們通常會在年初提供全年展望。請持續關注。

Salveen Richter, Goldman Sachs.

Salveen Richter，高盛。

Good afternoon. This is Lydia on for Salveen. Congrats on the progress and on your first earnings call. Could you just speak to the patient profile of the initial patients on therapy and the breakdown between the newly diagnosed versus switched patients?

午安。我是 Lydia，代 Salveen 發言。恭喜你們的進展以及首次財報電話會議。能否請你談談最初接受治療患者的患者輪廓，以及新診斷患者與由既有治療轉換而來患者之間的比例分布？

Great. Thanks for that question, Lydia. As you know, with this patient population, majority of the patients are already treated on idursulfase. We expect 90% of prevalent patients would be then switching. The majority of that. Of course, we are seeing as well newly diagnosed patients being put on AVLAYAH, but the majority will come from patients that are switching. In terms of patient profiles, we initially believe that patients may skew to the younger population because those are the families that were most engaged and have been following the development of AVLAYAH. We've been really pleased to see that what we can gather today is that it's very broad. In fact, patients across the different age groups within the pediatric population have demonstrated interest in being prescribed AVLAYAH.

很好。謝謝你的問題，Lydia。如你所知，在這個患者族群中，多數患者已經在使用 idursulfase 接受治療。我們預期 90% 的現有患者會轉換治療。其中大多數都是如此。當然，我們也看到新診斷患者開始使用 AVLAYAH，但主要來源仍會是轉換治療的患者。就患者輪廓而言，我們起初認為患者可能會偏向較年輕族群，因為那些家庭最投入、也一直關注 AVLAYAH 的開發進展。我們很高興看到，從目前能蒐集到的資訊來看，實際上分布非常廣。事實上，小兒族群中不同年齡層的患者都表現出希望被處方 AVLAYAH 的興趣。

Andrew Tsai, Jefferies.

Andrew Tsai，Jefferies。

Hey, good afternoon. Thanks for sharing all these positive updates. Maybe one more on Hunter. You're guiding to a strong sales number for Q3. I think in your prepared remarks, the original guidance for an S-shaped curve still seems to hold. To me, that would mean that come next year, could we be talking about a quarterly revenue number that's significantly larger than $10 million? Is that the right way to think about it? Secondly, Biogen just shared their Phase 2 tau data set. I'd be curious to gauge your thoughts on the degree of efficacy they're seeing. How much do you think that is attributed to too much tau lowering, or is it the mode of administration or something else? It'd be nice to gauge your views on these possibilities or variables around efficacy.

嗨，午安。謝謝分享這些正面的最新進展。我可能再問一個關於 Hunter 的問題。你們對第三季給出強勁的銷售數字指引。我記得在你們的事先準備講稿中，原先對 S 型曲線的指引似乎仍然成立。以我理解，這代表到了明年，我們是否可能在談一個顯著高於 1,000 萬美元的單季營收數字？這樣理解對嗎？第二，Biogen 剛分享了他們第二期 tau 的資料集。我想了解你們對他們所看到療效程度的看法。你認為這有多少是因為 tau 降得太多，或是給藥方式，或其他因素所致？希望能聽聽你對這些可能性或影響療效變數的看法。

Thanks, Andrew. I'll start with the first part of your question. Yes, we still believe that this year is a foundational year. We talked about getting as many patients on therapy as possible. We are definitely at the beginning stages of that S curve. Of course, our goal is to tighten that S shape curve and bring in the inflection point as soon as possible. That's why our focus on driving awareness, making sure the experience on AVLAYAH is very positive so that the community can further share that and drive the momentum. As well as with payer access, that will drive that inflection point.

謝謝，Andrew。我先回答你問題的第一部分。是的，我們仍然認為今年是奠基的一年。我們談到要讓盡可能多的患者開始接受治療。我們確實正處於那條 S 型曲線的起步階段。當然，我們的目標是讓這條 S 型曲線更緊湊，並盡快把拐點提前。因此我們聚焦於提升認知度，確保使用 AVLAYAH 的體驗非常正向，讓社群能進一步分享並推動動能。同時也包括付款方（payer）可近性，這將推動拐點到來。

I'm happy to take the second question, Andrew. As you know, we spoke before the data was shared at AAIC in London. Of course, a lot came out after the data presentation. I think our response is that, in general, it's the first data set to show that tau lowering may lead to a clinical benefit. I think what's probably the most compelling is you look across not just ADAS-Cog, or sorry, CDR Sum of Boxes, but also ADAS-Cog and MMSE, and you're seeing consistency in potential clinical benefit. I think the challenge is, as you have highlighted, is a question around was there not a dose response? Why did the higher doses not lead to more efficacy? I think just a couple of points without going into too much detail. Obviously, there were more discontinuations and adverse events in the higher doses.

我很樂意回答第二個問題，Andrew。如你所知，在倫敦 AAIC 公布資料之前，我們就曾談過。當然，在資料發表後有很多討論出來。我想我們的回應是，整體而言，這是第一個顯示降低 tau 可能帶來臨床獲益的資料集。我認為最具說服力的可能是，你不只看 ADAS-Cog，或抱歉，是 CDR 盒總和（CDR Sum of Boxes），也看 ADAS-Cog 與 MMSE，而你會看到潛在臨床獲益的一致性。我認為挑戰在於，如你所指出的，存在一個問題：為什麼沒有看到劑量反應？為什麼更高劑量沒有帶來更高療效？我先提幾點，不深入太多細節。顯然，在較高劑量組有更多停藥與不良事件。

I think it's well understood with intrathecal administration that this is not uncommonly seen, including transient confusion. I think we, like others, look forward to seeing more details and the differences between the doses and that may this actually be masking some of the efficacy. In general, first data set showing tau lowering and potential clinical benefit.

大家普遍理解，採用鞘內給藥（intrathecal administration）時，這種情況並不少見，包括短暫性意識混亂。我想我們和其他人一樣，期待看到更多細節，以及不同劑量之間的差異；也可能這其實在某種程度上掩蓋了部分療效。總體而言，這是第一個顯示降低 tau 與潛在臨床獲益的資料集。

Tazeen Ahmad, Bank of America.

Tazeen Ahmad，美國銀行。

I wanted to just focus on 593 for a second. I'm sorry if I missed this in your prepared remarks. Can you share any color on what level of data you plan to share when you release it? What in your view would be good data? Can you just clarify why you want to wait for NfL data? I think in the past you mentioned the focus was going to be on lysosomal function.

我想先把焦點放在 593 上一下。如果我在你們的事先準備講稿中漏聽了，先說聲抱歉。你能否分享一下你們在發布資料時，計畫分享到什麼層級的數據細節？以你們的觀點，什麼樣的數據會是好的數據？也能否說明一下為什麼你們想等 NfL 的數據？我記得過去你們提到重點會放在溶酶體功能。

Yeah, thanks, Tazeen. I'm happy to take that. I think the most important point here is that as we've regained full rights to this program, we're now in a position where we can essentially drive the strategy on this program. I think in our experience I think point number one is that longer-term data is often needed when looking at biomarkers like NfL. I think what's unique about FTD-GRN from, let's say, some of our other lysosomal storage disease programs, is that this is a haploinsufficiency in terms of the underlying disease. As a result, as we look at some of the lysosomal biomarkers historically, there's elevation, but it's modest, not like what you see with heparan sulfate in Hunter syndrome. What we've decided to do is we're trying to find an accelerated path.

好的，謝謝，Tazeen。我很樂意回答。我認為這裡最重要的一點是，隨著我們重新取得這個計畫的完整權利，我們現在能夠基本上主導這個計畫的策略。依我們的經驗，第一點是，在觀察像 NfL 這類生物標記時，往往需要較長期的數據。FTD-GRN 與我們其他一些溶酶體儲積症計畫不同之處在於，這個疾病的根本機制屬於半量不足（haploinsufficiency）。因此，當我們回顧一些溶酶體生物標記的歷史表現時，雖然有升高，但幅度不大，不像 Hunter 症候群中的硫酸乙醯肝素（heparan sulfate）那樣明顯。我們決定採取的作法是，嘗試找到一條加速的路徑。

As you may have also noted, we received orphan drug designation for this program just recently as well. We think we have the best chance of seeing robust data, specifically on the distal biomarkers such as NfL, and more broadly, just looking at the entire biomarker set, including lysosomal biomarkers as well. I think the key here is just giving this program the best chance of a potential accelerated path. Obviously, with data in hand, we'd have to address that with regulators.

你可能也注意到，我們最近也剛取得這個計畫的孤兒藥資格認定（orphan drug designation）。我們認為最有機會看到強勁數據的會是遠端生物標記（distal biomarkers），特別是 NfL；更廣泛地說，也會檢視整套生物標記資料，包括溶酶體生物標記在內。關鍵在於，讓這個計畫有最佳機會走向潛在的加速路徑。當然，在取得數據之後，我們仍需與監管機關討論並處理相關事宜。

Michael Yee, UBS.

Michael Yee，瑞銀。

Hi, this is Madeline on from Michael. I just wanted to ask a couple more on the launch. Congratulations on such a strong number right out of the gate. Just wondering, given your comments around stronger than expected early demand and the fact that we sort of know the number of Hunter patients that are out there, should we expect a sort of bolus effect in the US of these patients who are covered on the label now coming on? For those patients that are having to go through sort of medical exceptions and prior auth, do you have any sense of what the time is from getting a script to actually getting infused?

嗨，我是 Madeline，代 Michael 發言。我只是想再問幾個關於上市的問題。恭喜一上市就交出這麼亮眼的數字。想請教，考量到你們提到早期需求強於預期，而且我們大致知道目前有多少 Hunter 病患，是否可以預期在美國會出現一種「一次性湧入（bolus）」效應，也就是現在已納入適應症標籤、且有給付覆蓋的這些病患會集中開始用藥？至於那些必須走醫療例外（medical exceptions）與事前授權（prior auth）流程的病患，你們是否掌握從開立處方到實際完成輸注大概需要多久時間？

Thank you. Thank you for that question. In terms of what we expected, we definitely expected that pool of patients, who've been following AVLAYAH's development very closely. That pool of highly interested families is bigger than we initially had expected. We are working through with the early experience with these early families, though, we are seeing expansion into the broader patient population, as I described earlier. We're very excited about the fact that it's going beyond just those early families. We're going to expect to see continued growth into the broader population. As you stated, the total eligible population is around 375 that are considered pediatric patients in the US In terms of, I think your question was starting the interest to infusion and what's the timeline for that.

謝謝。謝謝你的提問。就我們原先的預期而言，我們確實預期會有一群一直非常密切關注 AVLAYAH 開發進展的病患。而這群高度關注的家庭規模，比我們一開始預期的更大。我們正在與這些早期家庭的初期使用經驗一同推進；同時，如我先前所述，我們也看到正在擴展到更廣泛的病患族群。我們對於不僅限於這些早期家庭、而是能擴及更廣泛族群這件事感到非常振奮。我們預期會持續成長並滲透到更廣泛的族群。如你所說，美國符合資格的總族群約為 375 名、被視為兒科病患。至於我想你問題的後半段，是從表達興趣到完成輸注的時間軸是多久。

As you know, with this early in launch and without payer coverage initially, although of course that's expanding now, there is huge variability in the time between patients expressing interest to when they actually get infused. It's really hard to comment on that this early in launch. However, with payer coverage improving over time, that timeline should get more straightforward, more efficient.

如你所知，在上市初期、且一開始尚未有保險支付方（payer）給付覆蓋的情況下（當然現在覆蓋正在擴大），病患從表達興趣到實際完成輸注之間的時間差異非常大。在上市這麼早期，真的很難對此做出評論。不過，隨著支付方給付覆蓋隨時間改善，這個時間軸應該會變得更清楚、更有效率。

Sean Laaman, Morgan Stanley.

Sean Laaman，Morgan Stanley。

Hi, this is Michael Riad on for Sean. Thank you for taking our questions. Congratulations on the strong start. Can you remind us how is progress going on for the adult confirmatory study? Given what you've learned so far, acknowledging it's only one quarter into the launch, is there anything that has changed your excitement or views as to how that adult study could influence launch trajectory or pricing?

嗨，我是 Michael Riad，代 Sean 發言。謝謝你們回答我們的問題。恭喜有個強勁的開局。可以請你們提醒一下成人確證性研究（confirmatory study）的進展如何嗎？基於目前為止的學習（也理解上市才過了一季），是否有任何事情改變了你們的期待或看法：這項成人研究可能如何影響上市推進軌跡或定價？

What we're hearing today, certainly there are adult patients that are very much interested in getting treated with AVLAYAH. I think that's your question. I don't think the launch price will change since we've already gone into market, even when we hopefully will get the label expansion. I'll let Peter comment on the study.

我們目前聽到的情況是，確實有成人病患非常有興趣接受 AVLAYAH 治療。我想這就是你在問的重點。我不認為上市價格會改變，因為我們已經進入市場；即便未來我們希望能取得適應症標籤擴增也是如此。我讓 Peter 來補充研究的部分。

Yeah, in terms of the COMPASS Phase 2/3 study, we're excited about reading out the study, which is set to end at the end of next year. It is going to be the basis for expanding the label, both in the US as a confirmatory study and for potential global launches.

好的，關於 COMPASS 第 2/3 期研究，我們很期待研究讀出結果；該研究預計在明年年底結束。它將成為擴大適應症標籤的基礎：在美國作為確證性研究，同時也支援潛在的全球上市。

Thank you. That's very helpful. Then just thinking about the 2Q-3Q revenue guidance in ramp, can you walk us through any key drivers of that acceleration? How much of it is coming from new patient starts versus patients converting to reimbursement?

謝謝。這非常有幫助。接著談到 2Q-3Q 營收指引的爬坡（ramp），你們能否說明推動加速的關鍵驅動因素？其中有多少來自新病患開始治療，多少來自病患轉為獲得給付（reimbursement）？

I think it's a combination of all those factors. We're seeing, as I stated earlier, all of the leading indicators, the high level of engagement from physicians and families, the conviction that physicians have in going for a medical exceptions process, then the fact that our payer coverage is getting better every day. I think all of those things are going to be contributing to the growth over the next quarter.

我認為這是上述因素的綜合。如我先前提到，我們看到所有領先指標都很正向：醫師與家庭高度投入、醫師對於推進醫療例外流程的信心，以及我們的支付方給付覆蓋每天都在改善。我認為這些因素都將共同促成下一季的成長。

Thank you. Congrats again.

謝謝。再次恭喜。

Paul Matteis, Stifel.

Paul Matteis，Stifel。

Great. Thanks very much, and congrats on the early launch progress. I guess taking a step back, given everything you kind of understand around this patient population, the degree to which families are plugged in and were waiting for AVLAYAH, do you think you're seeing a bolus right now? Might we see some attenuation in the ad rate later this year? Do you feel like this is actually potentially sustainable? Then as it relates to tau and the upcoming data next year, Ryan, I think you've talked about CSF tau data being an interesting early biomarker, given that PET changes can take some time. I'm wondering, though, do you think your CSF tau data for the shuttle will be comparable to the CSF tau data for an intrathecal drug, given that IT-administered drugs can maybe bias CSF biomarkers, given sort of the site of administration?

很好。非常感謝，也恭喜上市初期進展順利。我想先退一步看，基於你們對這個病患族群的理解、家庭參與度很高且一直在等待 AVLAYAH 的程度，你們覺得現在看到的是一個「一次性湧入（bolus）」嗎？今年稍晚我們會看到採用速度（ad rate）有所趨緩嗎？你們覺得這樣的表現可能是可持續的嗎？另外，關於 tau 與明年即將公布的數據，Ryan，我記得你提過 CSF tau 數據作為有趣的早期生物標記，因為 PET 的變化可能需要一些時間。不過我想問的是：你們的 shuttle 的 CSF tau 數據，會不會很難與鞘內（intrathecal, IT）給藥的藥物 CSF tau 數據相比？因為 IT 給藥可能會因為給藥部位而對 CSF 生物標記造成偏差。

Thanks. I will take the bolus question first. Certainly, you're correct that we expected this bolus. The bolus is bigger than we expected. I think the key thing that we're seeing is that this early experience from this initial patient population is translating to the broader population. Over time, especially as physicians gain more experience and the stories are shared more broadly through the patient community, we expect the growth to continue into the full eligible population.

謝謝。我先回答一次性湧入（bolus）這個問題。當然，你說得沒錯，我們原本就預期會有這個 bolus。而這個 bolus 比我們預期的更大。我認為我們看到的關鍵是：這個初始病患族群的早期使用經驗，正在轉化並擴散到更廣泛的族群。隨著時間推進，特別是當醫師累積更多經驗、且相關故事在病患社群中更廣泛分享時，我們預期成長將持續，並擴及全部符合資格的族群。

Thanks, Katie. Paul, fantastic question. Obviously very mechanistic. Obviously my kind of question. I think you are exactly right. It is really difficult to compare CSF tau in an intrathecally delivered molecule versus one that is delivered through capillaries, through the Transport Vehicle, through transferrin receptor. The experience we have related to this is actually with early days of tividenofusp alfa, now AVLAYAH, and its comparison with intrathecal delivery of iduronate 2-sulfatase, where there is a regional very high concentrations of enzyme. In this case, it would be high concentration of the antisense oligo. I think it is really apples to oranges in terms of percent reduction and what we would correlate ultimately with clinical benefit. What we can say is that our biodistribution is even and robust.

謝謝你，Katie。Paul，這是個很棒的問題。顯然非常偏機制層面。也很符合我會問的那種問題。我認為你完全說對了。要比較鞘內投遞的分子與透過毛細血管、透過 Transport Vehicle、透過轉鐵蛋白受體（transferrin receptor）投遞的分子之 CSF tau，確實非常困難。我們在這方面的相關經驗，其實來自早期的 tividenofusp alfa（現在是 AVLAYAH），以及它與鞘內投遞 iduronate 2-sulfatase 的比較；後者會在局部區域形成非常高的酵素濃度。在這個情境下，則會是反義寡核苷酸（antisense oligo）的高濃度。我認為就降低百分比以及最終與臨床效益的關聯而言，這真的很難直接類比（有點像拿蘋果比橘子）。但我們可以說的是：我們的生體分佈（biodistribution）是均勻且強健的。

When we look at different cell types throughout the brain and brain regions, we get basically roughly the same knockdown of gene expression across these various cell types. When we measure CSF levels of tau, we are confident that that is the level of knockdown we are getting throughout the brain. I think if you then relate that to maybe some disappointment in the maximal efficacy seen with intrathecal delivery, that may be simply because you are not penetrating deeper brain regions that may be impacted by tau and tau pathology. Then to the sort of first half of your question around CSF tau and tau PET, I think what is really remarkable, and we mentioned this at AAIC, the intrathecal data has essentially proven that tau PET can be reversed. That was actually a fundamental question, and many mouse models actually had never really necessarily shown that.

當我們觀察大腦各處不同細胞類型與不同腦區時，基本上在這些不同細胞類型之間，我們得到的基因表現抑制（knockdown）幅度大致相同。當我們測量 CSF 中的 tau 濃度時，我們有信心那反映的是整個大腦範圍內所達到的 knockdown 水準。我認為如果你再把這點與鞘內投遞在最大療效上的一些可能失望連結起來，原因可能只是因為你沒有深入滲透到更深層、可能受 tau 與 tau 病理影響的腦區。至於你問題前半段關於 CSF tau 與 tau PET，我認為真正值得注意的是——我們在 AAIC 也提到——鞘內數據基本上已證明 tau PET 是可以被逆轉的。那其實是一個根本性的問題，而許多小鼠模型過去也未必真的能顯示這一點。

In other words, if you reduce the expression of MAPT, which codes for tau, then you reduce the expression of tau protein, over time, you start to see a reduction in the tau PET signal. If you look at the totality of the data, including the new data that has been presented, it seems like the shortest window is about a year from when they see tau PET reduction. The early data set did not really show much reduction at six months, then they looked later. It was either 18 months or two years. This data set shows that at a year they are seeing, albeit variable from patient to patient, and actually, if you look at the data sets carefully that have been published, some patients get no tau reduction by PET and others get robust. We think this is actually heterogeneity in intrathecal delivery.

換句話說，如果你降低 MAPT（其負責編碼 tau）的表達，就會降低 tau 蛋白的表達；隨著時間推移，你會開始看到 tau PET 訊號的下降。如果你看整體數據（包含剛發表的新數據），看起來從觀察到 tau PET 降低開始，最短的時間窗大約是一年。早期數據集在六個月時其實沒有顯示太多下降，之後他們再往後看。那時點不是 18 個月就是兩年。這個數據集顯示在一年時他們就看到了（雖然病人之間差異很大）；而且實際上，如果你仔細看已發表的數據集，有些病人用 PET 看不到 tau 降低，另一些則有很明顯的降低。我們認為這其實是鞘內給藥遞送的異質性所致。

The take home is biodistribution is going to be critically important and different with the Transport Vehicle technology, and CSF tau will still be very informative, just like heparan sulfate. CSF was informative for our Hunter program. We are not comparing percent reductions because of exactly the point you made. These are fundamentally different delivery approaches.

重點是：生體分佈將會極其重要，而且在 Transport Vehicle 技術下會有所不同；而 CSF tau 仍然會非常有資訊性，就像硫酸乙醯肝素（heparan sulfate）一樣。CSF 對我們的 Hunter 計畫很有資訊性。我們不比較百分比降幅，原因正如你指出的那一點。這些在根本上是不同的遞送方式。

Mayank Mamtani, B. Riley Securities.

Mayank Mamtani，B. Riley Securities。

Good afternoon. Thanks for taking the question and congrats on a strong AVLAYAH launch. Maybe, Ryan, on the prior point on the OTV:MAPT strategy, are there any genetic tauopathies you could potentially look at? Just taking the logic that you're applying to the GRN program, there are FTD MAPT tauopathies also that could be looked at. Maybe just a higher level question, there's a lot still we need to see from a biomarker standpoint in the CELIA study. What are sort of the right things to kind of look out for as you obviously think about the biomarkers you want to look at in your six to eight cohort reading out next year?

午安。謝謝讓我提問，也恭喜 AVLAYAH 上市開局強勁。也許 Ryan，延續前面關於 OTV:MAPT 策略的問題，有沒有任何遺傳性 tau 蛋白病（genetic tauopathies）是你們可能會去看的？沿用你們在 GRN 計畫上採用的邏輯，也有 FTD 的 MAPT tau 蛋白病可以研究。再問一個較高層次的問題：從生物標誌物角度來看，CELIA 研究仍有很多我們需要看到的地方。當你們思考明年將讀出的 6 到 8 個隊列時，就你們想看的生物標誌物而言，有哪些是我們應該特別留意的重點？

Yeah, great. Thanks, Mayank. Again, great questions. My take is I think with MAPT, the key point here is really focusing on tau reduction, showing that the OTV works, that you can deliver a medicine systemically and get tau reduction. We're definitely interested in these genetic subpopulations, but our experience actually with FTD-GRN is that initially it was very difficult to enroll these more rare cases. The tauopathies are not unlike FTD. In fact, there are FTD sort of tauopathies, sort of rare, hard to diagnose initially, and then you have to genetically diagnose them. We're interested in that. I just don't think that it's the fastest path to really proving the platform and then subsequently driving for the first approval. In terms of what to look for, we're essentially looking for tau reduction in CSF, not really hitting a target.

好的，很棒。謝謝你，Mayank。同樣地，問題問得很好。我的看法是：對 MAPT 而言，關鍵點在於聚焦 tau 的降低，證明 OTV 有效，也就是你可以用全身性給藥把藥物送達並降低 tau。我們確實對這些遺傳性亞族群有興趣，但我們在 FTD-GRN 的經驗是，一開始要招募這些更罕見的病例其實非常困難。這些 tau 蛋白病與 FTD 類似。事實上，確實存在一些 FTD 類型的 tau 蛋白病，屬於罕見、起初難以診斷，之後還需要做基因診斷。我們對此有興趣。只是我不認為那是最快能證明平台、並進一步推動取得首個核准的路徑。至於要看什麼，我們基本上是在看 CSF 中 tau 的降低，而不是單純達到某個目標值。

The genetic data in mice suggests that the haploinsufficiency loss of one copy of tau is highly protective in the Alzheimer's models. You could imagine somewhere between 25%-70% reduction. I think that fundamentally, what's actually very interesting about the data set that has recently been presented is that there was a non-dose proportional reduction in tau. As you go up 2x in dose and 4x in dose, there's only really about a 20% difference in overall tau reduction in that range. Yet there is sort of a different, obviously, AE profile for those higher doses.

小鼠的遺傳數據顯示，在阿茲海默症模型中，tau 的單倍體不足（haploinsufficiency；缺失一個 tau 拷貝）具有高度保護性。你可以想像大概介於 25% 到 70% 的降低幅度。我認為從最近發表的數據集中，真正很有意思的一點是：tau 的降低並非與劑量成比例。當劑量提高 2 倍與 4 倍時，在那個範圍內整體 tau 降低其實只差大約 20%。然而更高劑量顯然會有不同的 AE（不良事件）特徵。

We feel like the CSF data for intrathecal is apples to oranges, but we look at our own data and our own pre-clinical data and what's sort of been published to set the tone that we really need to see CSF tau reduction as really a proof of the platform. I don't know, Peter, if you want to add anything there.

我們覺得鞘內給藥的 CSF 數據是「蘋果比橘子」無法直接類比，但我們會看我們自己的數據、我們自己的臨床前數據，以及已發表的資料，來建立一個基調：我們確實需要看到 CSF tau 的降低，作為平台的概念驗證。我不確定 Peter 你是否想補充？

No, I think you covered it well. I think we're really focused on executing the program, generating the data that Ryan alluded to. I think other potential indications is something that we can consider in the future.

沒有，我覺得你講得很完整。我想我們真的專注在把計畫執行好，產出 Ryan 剛提到的那些數據。至於其他潛在適應症，是我們未來可以再考慮的事情。

Ananda Ghosh, H.C. Wainwright & Co.

Ananda Ghosh，H.C. Wainwright & Co.。

Hi. Thanks, guys, and congrats on the great quarter. I have actually two questions. In 2025 SITA, Biogen presented some data using their zirconium dye, where they tried to show their intrathecal, the tau modality, like how well they kind of distribute throughout the CNS. You would see that it's a very poor distribution. The question is that, despite such a poor distribution, they do see, as you rightly mentioned, that they can move the clinical endpoints, at least in a trend setting. Just wanted to get your thoughts on that aspect of it, that even with such a poor distribution, how can they see some efficacy with respect to both as a biomarker as well as some clinical endpoints?

嗨。謝謝各位，也恭喜這一季表現很棒。我其實有兩個問題。在 2025 年 SITA，Biogen 用他們的鋯染料（zirconium dye）展示了一些數據，嘗試說明他們的鞘內給藥、tau 相關療法在 CNS 的分佈情況。你會看到分佈其實非常差。問題是：儘管分佈這麼差，他們仍如你剛才提到的，至少在趨勢上能推動臨床終點。想請教你對這點的看法：在分佈如此差的情況下，他們怎麼可能在生物標誌物以及一些臨床終點上看到某些療效？

The second question is, there are also these ideas that, and especially from the donanemab trial, that in patients where you have low tau, there you can see those patients are much more amenable to either both anti-amyloid beta therapy or anti-tau therapy. As you are thinking about your Phase 1b, is there a way to enrich patients with low tau in your Phase 1b trial population? Thanks.

第二個問題是，也有一些觀點（尤其來自 donanemab 試驗）認為，在 tau 較低的病人中，這些病人對抗類澱粉 β 治療或抗 tau 治療都更容易有反應。當你們在規劃 Phase 1b 時，有沒有方法在 Phase 1b 的受試者族群中富集（enrich）低 tau 的病人？謝謝。

Yeah. Good questions. I'll try to be brief because we have a number of other questions. I think let's look at additional data that hopefully will be presented on BIIB080 to really understand that dynamic. You're right. There's enormous heterogeneity. We've published this already in monkey. I think the positive clinical signal across three different endpoints, ADAS-Cog, CDR Sum of Boxes, and MMSE is really encouraging. There are some patients that get really decent biodistribution in the particular study that you're referencing. I think that's the main point.

是的。問題很好。我會盡量簡短，因為我們還有不少其他問題。我想我們先看希望能針對 BIIB080 發表的更多數據，以真正理解那個動態。你說得對。異質性非常大。我們已經在猴子的研究中發表過這點。在三個不同終點（ADAS-Cog、CDR Sum of Boxes，以及 MMSE）上看到正向的臨床訊號，確實令人鼓舞。在你提到的那項研究中，有些病人確實能獲得相當不錯的生體分佈。我想重點就在這裡。

Joseph Thome, TD Cowen.

Joseph Thome，TD Cowen。

Hi, this is Jacob on the line for Joe. Thanks for taking our question. Going along with patient enrichment or patient selection. I was curious how you're thinking about some of these co-pathologies that often come along with AD, like alpha-synuclein and TDP-43, and how those could play a role in patient selection or pre-specified subgroup analyses. Just additionally, looking farther ahead, how you're thinking about what a bar might look like given some of the currently approved amyloid beta therapies on things like CDR-SB. Thanks.

嗨，我是 Jacob，代 Joe 參與這通電話。謝謝讓我們提問。延續病人富集或病人選擇的話題。我想了解你們如何看待一些常與 AD 伴隨出現的共病理（co-pathologies），例如 α-突觸核蛋白（alpha-synuclein）與 TDP-43，以及它們可能如何在病人選擇或預先指定的亞組分析中扮演角色。另外再往前看，在目前已核准的類澱粉 β 療法背景下，你們如何思考像 CDR-SB 這類指標的門檻（bar）可能會是什麼樣子？謝謝。

I'll address the first one on the co-pathologies. Peter, why don't you address the bar on assuming what you're asking is the bar for approval or for clear differentiation existing anti-amyloids.

我先回應第一個關於共病理的問題。Peter，不如你來談談你所問的門檻——也就是核准所需的門檻，或是與現有抗類澱粉蛋白藥物之間清楚差異化的門檻。

I think with co-pathologies, the two, obviously the most common co-pathology, which is actually in some ways defines Alzheimer's, is Aβ plaque or amyloid plaque and tau neurofibrillary tangles. I think what you're referencing is also it's been shown like you see Lewy bodies and other sort of vascular pathologies. The challenge with those type of co-pathologies is there aren't imaging biomarkers yet that allow you to look at the level of, let's say, Lewy bodies that can also be observed with amyloid plaque or tau. At this point, our focus is on the two most common and prevalent. I'll add that there's, by the way, a fourth one, TDP-43 pathology, which I think represents roughly 30% of Alzheimer's. All of this being said, amyloid appears to be at the top of the cascade.

我認為就共病理而言，兩者——顯然最常見、而且在某種程度上其實定義了阿茲海默症的共病理——是Aβ斑塊或類澱粉蛋白斑塊，以及tau神經纖維纏結。我想你所指的也包括：研究顯示會看到路易氏體以及其他一些血管性病理。這類共病理的挑戰在於，目前還沒有影像生物標記能讓你去觀察例如路易氏體的程度，同時也能像觀察類澱粉蛋白斑塊或tau那樣被量測。在現階段，我們的重點放在最常見、最普遍的兩種。另外補充一下，順帶一提，還有第四種：TDP-43病理，我認為大約佔阿茲海默症的30%。總而言之，類澱粉蛋白似乎位於這個級聯反應的最上游。

Amyloid eventually drives the formation of tau pathology, tau pathology correlates with cognitive decline. We're keen on targeting both amyloid and tau. I think as biomarkers improve, hopefully we'll be able to identify patients that have other pathologies, which in some ways is probably complicating the clinical picture. With that in mind, I'll hand it to Peter to talk about what the bar might be for anti-amyloid approvals.

類澱粉蛋白最終會驅動tau病理的形成，而tau病理與認知衰退相關。我們很積極同時鎖定類澱粉蛋白與tau。我認為隨著生物標記的進步，希望我們能辨識出具有其他病理的患者，而這在某種程度上可能正在使臨床表現更為複雜。基於這點，我把時間交給Peter，請他談談抗類澱粉蛋白藥物核准的門檻可能會是什麼。

Yeah. Thank you, Ryan, and thanks for the question. I think I'll start by saying this is a very exciting time for Alzheimer's, coming off the vast amount of data that was presented at AAIC, there's a lot that's being learned about different aspects of the patient populations. I think it's premature to say exactly where we're headed. I do think that with all the data that's being generated and understanding both progression rates and response to different types of therapies, this is something that we'll definitely pay attention to, both with targeting tau as well as with amyloid. I think from an amyloid perspective, we're very excited about the differentiating potential of DNL921 and I think our goal is really to generate proof of concept with that first.

好的。謝謝你，Ryan，也謝謝這個問題。我想先說，對阿茲海默症而言，這是一個非常令人振奮的時刻；在AAIC發表了大量數據之後，我們正在學到許多關於不同患者族群面向的資訊。我認為現在就斷言我們確切會走向哪裡還為時過早。但我確實認為，隨著持續產生的數據，以及對疾病進展速度與不同療法反應的理解加深，這會是我們一定會關注的事情，無論是在鎖定tau或是類澱粉蛋白方面。從類澱粉蛋白的角度來看，我們對DNL921的差異化潛力感到非常興奮，而我們的目標確實是先用它產生概念驗證（proof of concept）。

Laura Chico, Wedbush.

Laura Chico，Wedbush。

Congrats, guys, on the quarter. Maybe one for Katie. I'm wondering if you could expand a little bit further. What capacity do the centers have for switch patients? Just wondering if there's any additional considerations that the physicians need to work through for a switch patient versus perhaps somebody that's new to treatment. You indicated in the webinars that you encompass or encountered over 100 families or about greater than 25% of the eligible patient pool. I guess I'm just trying to understand if there's any capacity considerations that we should be making as you're progressing here. Thanks very much.

恭喜各位本季表現。我可能有一題想問Katie。想請你再多延伸說明一下。各中心對於轉換用藥患者（switch patients）的收治量能有多大？也想了解，醫師在面對轉換用藥患者，相較於新開始治療的患者，是否需要額外考量或處理哪些事項。你在網路研討會中提到，你們涵蓋或接觸到超過100個家庭，或約占符合資格患者池的25%以上。我想更了解的是，隨著你們推進到這個階段，我們是否需要考量任何量能方面的限制。非常感謝。

Thank you, Laura. That's a great question. You're exactly right. There are definitely dynamics both for the newly diagnosed patients and for the switchers. As you remember, majority of the idursulfase patients are treated at home. These are patients coming back to the clinic. Definitely infusion scheduling is one of the steps that families have to work through. With all the families coming back, there is a sequencing. Depending on the center, depending on if you're at a center that has specialized centers of care, they are going to have a little bit more capacity than other centers. That is the dynamic that has significant variability that we're going to be working through. What we've seen is the sense of urgency and the motivation from families have been very strong.

謝謝你，Laura。這是個很好的問題。你說得完全正確。對於新診斷患者與轉換用藥者，確實存在不同的動態。如你所記得，多數idursulfase患者是在家中接受治療。這些患者現在要回到診所。因此，輸注排程絕對是家庭需要處理的其中一個步驟。當所有家庭都回到院所時，確實會有先後順序的安排。依不同中心而定，若是在具備專科照護中心（specialized centers of care）的院所，他們的量能會比其他中心更大一些。這種動態的差異性很大，而我們也會在推進過程中逐步解決。我們看到的是，家庭的急迫感與動機都非常強。

Thank you. We will take our next question. The question comes from Marc Goodman from Leerink Partners. Please go ahead. Your line is open.

謝謝。我們將進入下一個問題。問題來自Leerink Partners的Marc Goodman。請開始提問。您的線路已開通。

Hi. Good evening, everyone. This is Alyssa on for Marc. Thank you for taking our question. I was wondering if you could help us think about the average price per patient for AVLAYAH, given the weight-based dosing and titration schedule. Since many patients will initially be uptitrating over the course of the first few months, when should we expect pricing to reach a steady state run rate? Secondly, on the manufacturing facility in Salt Lake City, do you have any plans to use that facility to manufacture commercial batches of AVLAYAH, or will that be used only for clinical manufacturing? Thank you.

嗨。各位晚安。我是Alyssa，代Marc提問。謝謝你們回答我們的問題。我想請你們協助我們思考：考量以體重為基礎的劑量與滴定（titration）時程，AVLAYAH每位患者的平均價格大概會是多少？由於許多患者在最初幾個月會逐步上調劑量（uptitrating），我們應該在何時預期定價會達到穩態的運行水準（steady state run rate）？第二個問題，關於鹽湖城（Salt Lake City）的製造設施，你們是否計畫使用該設施來生產AVLAYAH的商業批次，還是只用於臨床用製造？謝謝。

Great. Thanks. I'll address the pricing question. At maintenance, for a 10 kg patient, it's roughly around $270,000 per year, and up to 30 kg patient, which is about $800,000 per year. As you described, there is a dose escalation described in our label. What's been provided to physicians, and this is ultimately a physician's decision on how quickly to do the escalation, is that we expected escalation to be about four weeks at each step before they get to maintenance dose. There may be variability as patients' dose escalate, depending, and it'll be very individualized and physician-decided.

好的。謝謝。我先回答定價問題。在維持期（maintenance），以10公斤患者來看，每年大約是27萬美元；而到30公斤患者則約為每年80萬美元。如你所述，我們的標籤（label）中有描述劑量遞增（dose escalation）。我們提供給醫師的資訊是——當然最終仍由醫師決定要多快進行遞增——我們預期每一個階段大約四週，之後才會到達維持劑量。隨著患者劑量上調，可能會有差異，取決於各種因素；這將會非常個別化，並由醫師決定。

I'll answer the second question. We do not have plans to manufacture in Salt Lake City for AVLAYAH. In fact, our plans are to go to larger scale with Lonza and onshore to Portsmouth to go to 6,000 L.

我來回答第二個問題。我們沒有計畫在鹽湖城為AVLAYAH進行製造。事實上，我們的計畫是與Lonza擴大規模，並將產能移回本土到Portsmouth，做到6,000公升（6,000 L）。

Okay. Thank you very much.

好的。非常感謝。

Michael DiFiore, Evercore ISI.

Michael DiFiore，Evercore ISI。

Hi, guys. Thanks so much for taking my question, and congrats on the progress so far. Two from me. Now that you have a full commercial quarter under your belt, at this juncture, could you give us the number of patients on drug as well as the number of cumulative start forms? If not, when might you be able to share this information? The second question is, as patients switch off of ELAPRASE, have you seen any competitive response from Takeda, either on contracting pricing or account-level pushback for that matter? Thank you.

嗨，各位。非常感謝你們回答我的問題，也恭喜目前為止的進展。我有兩個問題。現在你們已經有完整的一個商業化季度，在這個時間點，能否提供目前用藥患者人數，以及累計的start forms數量？如果現在不方便，何時可能可以分享這些資訊？第二個問題是，當患者從ELAPRASE轉換離開時，你們是否看到Takeda有任何競爭性回應，例如在合約定價上，或在帳戶層級（account-level）的阻力／施壓？謝謝。

Okay. Let me see if I can address all the questions. Your first question was on start forms and patient numbers. At this stage, we intentionally focus on communicating the overall trajectory rather than providing individual operational metrics. Right? I shared earlier why we have confidence is we're seeing all of the progress with the various stakeholders within the ecosystems, with physicians being highly aware and engaged, families highly engaged and driving towards switching, as well as centers working through reimbursement and payer access. With regard to start forms, we also feel that at this point, start forms are not predictive of revenue, and it's because each individual patient journey is very unique. The time, depending on what their insurance plan is, which centers they're getting treatment at, that is highly variable at this point.

好的。我看看能不能把所有問題都回答到。第一個問題是關於start forms與患者人數。在這個階段，我們刻意聚焦於溝通整體趨勢（overall trajectory），而不是提供個別的營運指標。對吧？我先前分享過我們為何有信心：我們看到生態系中各個利害關係人都在推進——醫師高度知悉且投入、家庭高度投入並推動轉換，以及各中心正在處理給付（reimbursement）與付款方（payer）可近性。至於start forms，我們也認為在目前這個時間點，start forms並不能預測營收，因為每位患者的就醫旅程都非常獨特。所需時間會因其保險方案、在哪些中心接受治療等而異，目前差異性非常大。

We haven't provided guidance as to when in the future we may provide patient or start form information. For now, we really want our investor to rely on the revenue guidance because we feel like it's the most clear quantitative indicator of how our launch is progressing. Did you have one more question?

我們尚未提供關於未來何時可能提供病患或起始表單資訊的指引。目前，我們確實希望投資人依據營收指引，因為我們認為這是最清楚的量化指標，可反映我們的上市推進情況。你還有一個問題嗎？

Yeah, I did. Just regarding the switch off from ELAPRASE. Any competitive response from Takeda that you've seen?

是的，我有。就關於從 ELAPRASE 轉換停用這件事。你們有看到武田（Takeda）任何競爭性的回應嗎？

Yeah. In terms of competitive response, we've been very much focused on making sure that the clinical value and the biomarker data is well-recognized. I think we haven't seen a ton of pushback because it's very well recognized that ELAPRASE does not address neurologic manifestations. We haven't seen the other activities that you've described, which is contracting, and I think you've described another one, but we haven't seen any activity related to that.

有。就競爭回應而言，我們一直非常專注於確保臨床價值與生物標誌物數據能被充分認可。我認為我們沒有看到太多反彈，因為大家很清楚 ELAPRASE 無法處理神經學表現。我們沒有看到你所描述的其他作法，例如簽約（contracting），以及我想你還提到另一項，但我們沒有看到任何與此相關的活動。

Myles Minter, William Blair.

Myles Minter，William Blair。

Hey, team. This is John on for Myles. Congrats on a strong first launch quarter and thanks so much for taking our question. For AVLAYAH, wondering if any of your commercial patients have previously been clinical trial participants. Wondering if you can give us any color on the cadence you expect for clinical trial participants to transition over to commercial therapy.

嗨，各位團隊。我是 John，代替 Myles 發問。恭喜第一個上市季度表現強勁，也非常感謝回答我們的問題。關於 AVLAYAH，想請問你們的商業用藥病患中，是否有人先前是臨床試驗參與者。也想請你們分享一下，你們預期臨床試驗參與者轉換到商業治療的節奏會是如何。

Yeah. The majority of patients that have started today are not actually our clinical trial patients. We expect all of our clinical trial patients to be able to convert to commercial patients by the end of this year.

是的。目前開始用藥的病患大多其實不是我們的臨床試驗病患。我們預期到今年年底，我們所有臨床試驗病患都能轉換為商業病患。

David Hoang, Deutsche Bank.

David Hoang，德意志銀行（Deutsche Bank）。

Hi, this is Rosemary on for David. Thank you so much for taking my question and congrats on the quarter. I was just wondering how you might be thinking about the competitive landscape evolution for AVLAYAH as there's some competitor resubmission happening this year and JCR Pharmaceuticals's IZCARGO may be having a global Phase 3 readout next year. Thank you.

嗨，我是 Rosemary，代替 David 發問。非常感謝回答我的問題，也恭喜本季表現。我想請問，隨著今年有一些競品重新送件（resubmission），以及 JCR 製藥的 IZCARGO 可能在明年有全球第三期（Phase 3）結果讀出，你們如何看待 AVLAYAH 的競爭格局演變？謝謝。

Yes. Thanks for that question. Of course, we're always very encouraged to see continued innovation in Hunter syndrome, we are very confident in our biomarker and clinical evidence. As you know, we've shown normalization for the first time in this disease area for key disease biomarkers. Our focus is on executing on our launch and driving the momentum that we're seeing today.

是的。謝謝這個問題。當然，我們總是很受鼓舞能看到亨特氏症（Hunter syndrome）持續有創新，我們對自身的生物標誌物與臨床證據非常有信心。如你所知，我們在這個疾病領域首次顯示關鍵疾病生物標誌物達到正常化。我們的重點是把上市執行好，並推動我們目前所看到的動能。

Charles Moore, Baird.

Charles Moore，Baird。

Hey, guys. Thanks for taking the question and congrats on the great quarter. Just kind of following up on the last question. I recall your analogous trial for AVLAYAH included patients who had been treated with gene therapy. Looking toward the DNL126 trial, are there any patients there who have been treated with a gene therapy previously, considering that there's the possibility for a Sanfilippo gene therapy to be approved ahead of DNL126? Thank you.

嗨，各位。謝謝回答問題，也恭喜這個很棒的季度。我想延續上一題。我記得你們 AVLAYAH 的類比試驗（analogous trial）納入了曾接受基因治療的病患。展望 DNL126 試驗，考量到可能有一個 Sanfilippo 的基因治療在 DNL126 之前獲批，你們那邊是否有任何病患先前接受過基因治療？謝謝。

Peter, maybe I'll have you take that. I'll just make one comment. We haven't gone into great detail on the 126 patient population, obviously presented new data earlier this year at World and very excited about that program. Great question around the competitive landscape. Peter, do you want to add anything to that? I just don't think we've gone into much detail on the nature of those patients.

Peter，也許我請你來回答。我先補充一點。我們尚未就 126 的病患族群做很詳細的說明；我們今年稍早在 World 上已發表新的數據，對這個計畫非常興奮。關於競爭格局的問題問得很好。Peter，你想補充什麼嗎？我只是覺得我們對這些病患的性質確實還沒有談太多細節。

Thanks, Ryan. I would just say, we haven't presented the baseline characteristics of the full cohort yet, but we do intend to present the data early next year at the WORLDSymposium.

謝謝，Ryan。我只能說，我們尚未發表完整隊列（full cohort）的基線特徵，但我們確實打算在明年年初的 WORLDSymposium 上發表數據。

I'll just add, great memory. We did have both gene therapy and cell therapy patients in the Hunter data set, where we saw robust normalization in those patients' data in terms of CSF heparan sulfate. I think the key here is really focused on the sustained biomarker response across our ETV franchise. Thanks for the question.

我再補充一下，你記得很清楚。在亨特氏症的資料集中，我們確實同時有基因治療與細胞治療病患；就腦脊髓液（CSF）硫酸乙醯肝素（heparan sulfate）而言，我們在這些病患的數據中看到強勁的正常化。我認為關鍵在於，我們整個 ETV 產品線（franchise）都聚焦於持續性的生物標誌物反應。謝謝你的問題。

Got it. Yeah. Thank you very much.

了解。是的。非常感謝。

Thank you. This concludes today's question and answer session. I'll now hand the call back to Ryan Watts for closing remarks.

謝謝。今天的問答環節到此結束。我現在把電話交回給 Ryan Watts 作結語。

We thank everyone for joining the call today. We're very excited about where we are and look forward to continued momentum. Thanks, everyone.

感謝各位今天加入電話會議。我們對目前的進展感到非常振奮，並期待動能持續。謝謝大家。

This concludes today's conference call. Thank you for participating. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以掛線。