PTC Therapeutics Inc (PTCT) 2024 Q3 法說會逐字稿

Welcome to the PTC third-quarter 2024 financial results conference call. (Operator Instructions)

歡迎參加 PTC 2024 年第三季財務業績電話會議。（操作員指令）

Again, please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Jane Hanlon, Associate Director of Investor Relations. Please go ahead.

再次請注意，今天的會議正在錄音。現在，我想將會議交給今天的第一位發言者，投資者關係副總監 Jane Hanlon。請繼續。

Good afternoon and thank you for joining us today to discuss PTC Therapeutics' third quarter 2024 corporate update and financial results. I am joined today by our Chief Executive Officer, Dr. Matthew Klein; our Chief Business Officer, Eric Pauwels; and our Chief Financial Officer, Pierre Gravier.

下午好，感謝您今天加入我們討論 PTC Therapeutics 2024 年第三季的公司更新和財務業績。今天與我一起出席活動的還有我們的執行長 Matthew Klein 博士；我們的首席商務長 Eric Pauwels；以及我們的財務長 Pierre Gravier。

Today's call will include forward-looking statements based on our current expectations. Please take a moment to review the slide posted on our investor relations website in conjunction with the call, which contains information about our forward-looking statements.

今天的電話會議將包括基於我們目前預期的前瞻性陳述。請花一點時間查看我們的投資者關係網站上與電話會議一起發布的幻燈片，其中包含有關我們的前瞻性聲明的資訊。

Our actual results could materially differ from these forward-looking statements, as such statements are subject to risks that can materially and adversely affect our business and the results of operations.

我們的實際結果可能與這些前瞻性陳述有重大差異，因為這些陳述可能受到對我們的業務和經營業績產生重大不利影響的風險。

For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q and annual report on Form 10-K filed with the Securities and Exchange Commission as well as the company's other SEC filings.

有關適用風險和不確定性的詳細描述，我們建議您查看公司向美國證券交易委員會提交的最新 10-Q 表季度報告和 10-K 表年度報告以及公司向美國證券交易委員會提交的其他文件。

We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP are available in today's earnings release.

我們將在本次電話會議中揭露某些非公認會計準則資訊。有關我們使用 GAAP 與非 GAAP 財務指標以及 GAAP 與非 GAAP 調整的信息，請參閱今天的收益報告。

With that let me pass the call over to our CEO, Matthew Klein. Matt?

說完這些，我將電話轉給我們的執行長馬修·克萊恩 (Matthew Klein)。馬特？

Thank you all for joining the call today. I'm happy to share the results of another quarter of outstanding commercial performance and pipeline execution.

感謝大家今天參加電話會議。我很高興與大家分享另一個季度出色的商業表現和管道執行成果。

In the third quarter, we achieved total revenue of $197 million, including $124 million from the DMD franchise. I want to highlight the $52 million in Emflaza revenue, which reflects our team's ability to effectively navigate a genericized and competitive marketplace in the US. With our strong third quarter revenue performance, we closed the quarter with over $1 billion in cash and are raising our 2024 total revenue guidance to $750 million to $800 million.

第三季度，我們實現了 1.97 億美元的總收入，其中來自 DMD 特許經營權的收入為 1.24 億美元。我想強調的是 Emflaza 5,200 萬美元的收入，這反映了我們團隊有效駕馭美國通用且競爭激烈的市場的能力。憑藉我們第三季強勁的營收表現，我們在本季結束時擁有超過 10 億美元的現金，並將 2024 年的總收入預期上調至 7.5 億至 8 億美元。

In the third quarter, we submitted two NDAs to the FDA, one for sepiapterin and one for Translarna. Both applications have been accepted for filing. The FDA planned action date for sepiapterin is July 29, 2025. An action date has not been provided for the Translarna NDA due to the regulatory context of the filing.

第三季度，我們向 FDA 提交了兩份 NDA，一份是 sepiapterin，一份是 Translarna。兩項申請均已受理。FDA 對 sepiapterin 的計畫行動日期為 2025 年 7 月 29 日。由於提交的監管背景，尚未為 Translarna NDA 提供行動日期。

The sepiapterin NDA includes the significant and clinically meaningful evidence of efficacy from the Phase 3 APHENITY study as well as data from the APHENITY open-label extension study demonstrating durability of the sepiapterin treatment benefit and the ability of patients to increase their protein intake while maintaining control of feed levels.

墨蝶呤 NDA 包含來自第 3 階段 APHENITY 研究的重要且具有臨床意義的療效證據，以及來自 APHENITY 開放標籤擴展研究的數據，這些數據證明了墨蝶呤治療益處的持久性以及患者在保持飼料水平控制的同時增加蛋白質攝入量的能力。

These data support that sepiapterin can provide significant benefit to PKU patients of all age groups and severity subtypes, including classical PKU. The impactful results from the APHENITY trial were recently published in the prestigious Lancet Journal, a testament to the importance of the study findings.

這些數據表明，墨蝶呤可以為所有年齡層和嚴重程度亞型的苯酮尿症患者（包括經典苯酮尿症）帶來顯著益處。APHENITY 試驗的重大結果最近發表在著名的《刺胳針》雜誌上，證明了這項研究結果的重要性。

In addition to the FDA submission, marketing authorization applications for sepiapterin are currently under review in the EU and several other countries including Brazil. We remain on schedule to submit the JNDA in Japan in December of this year. These submissions will support our planned global launch of sepiapterin in 2025. Our launch plans are progressing well as Eric will detail shortly.

除了 FDA 提交的申請外，歐盟和包括巴西在內的其他幾個國家目前正在審查 sepiapterin 的行銷授權申請。我們將按計劃於今年 12 月向日本提交 JNDA。這些提交將支持我們計劃於 2025 年在全球推出 sepiapterin。我們的發布計劃進展順利，Eric 很快就會詳細介紹。

We remain on track to submit an NDA for vatiquinone for the treatment of children and adults with Friedreich ataxia in December. This NDA submission will be the fourth approval application submitted to the FDA this year, an impressive testament to our team's execution.

我們仍計劃於 12 月提交一份關於 vatiquinone 的 NDA，用於治療患有弗里德賴希共濟失調的兒童和成人。此次 NDA 提交將是今年向 FDA 提交的第四份批准申請，這是我們團隊執行力的有力證明。

The vatiquinone NDA will be based on the findings of significant benefit on the upright stability subscale of the mFARS disease rating scale in the MOVE-FA placebo-controlled trial as well as results from two long-term extension studies.

瓦替醌的新藥申請 (NDA) 將基於 MOVE-FA 安慰劑對照試驗中 mFARS 疾病評定量表的直立穩定性分量表的顯著益處的發現以及兩項長期擴展研究的結果。

As we recently reported, both long-term extension studies met their primary endpoint with evidence of statistically significant long-term benefit in delaying disease progression. Given the extensive safety data collected to date in both children and adults, vatiquinone has the potential to fill the unmet need for pediatric and adolescent FA patients as well as provide a promising therapy for adult FA patients.

正如我們最近所報導的那樣，兩項長期延伸研究都達到了其主要終點，有證據表明，在延緩疾病進展方面具有統計學上顯著的長期益處。鑑於迄今為止在兒童和成人中收集的大量安全數據，vatiquinone 有可能滿足兒童和青少年 FA 患者尚未滿足的需求，並為成人 FA 患者提供有希望的治療方法。

Moving to our PTC518 program for Huntington's disease, the program received Fast Track Designation from FDA in September, reflecting the potential of PTC518 to be the first-ever approved disease-modifying therapy for HD.

至於我們針對亨廷頓舞蹈症的 PTC518 項目，該項目於 9 月獲得了 FDA 的快速通道認證，反映了 PTC518 有可能成為有史以來第一個獲批的亨廷頓舞蹈症疾病改良療法。

In addition, we requested two Type C meetings with FDA. One meeting is to discuss the potential for Huntingtin lowering to serve as a surrogate endpoint supportive of accelerated approval and the second meeting is to discuss the endpoint strategy for an efficacy trial in HD patients, whether that trial is completed as a Phase 3 registration trial or as a confirmatory trial in the context of an accelerated approval.

此外，我們也要求與 FDA 舉行兩次 C 類會議。一次會議將討論降低亨廷頓蛋白作為支持加速審批的替代終點的可能性，第二次會議將討論亨廷頓蛋白患者療效試驗的終點策略，無論該試驗是作為 3 期註冊試驗完成，還是作為加速審批背景下的確認試驗完成。

The FDA has asked to combine the two into a single Type C meeting, which has now been scheduled for later in the fourth quarter. The ongoing Phase 2 PIVOT-HD trial continues to progress well and we remain on track to complete the study in the first quarter of 2025 with results expected in the second quarter.

FDA 要求將兩次會議合併為一次 C 類會議，目前該會議已安排在第四季度稍後舉行。正在進行的第 2 階段 PIVOT-HD 試驗持續進展順利，我們預計在 2025 年第一季完成研究，並預計在第二季公佈結果。

Turning to our utreloxastat program for ALS. We remain on schedule to share topline results from the registration-directed CardinALS trial in the fourth quarter. Utreloxastat is the first compound being developed for ALS patients that specifically targets ferroptosis pathway of oxidative stress and cell death demonstrated to be highly relevant to ALS pathology.

轉向我們的 ALS 的 utreloxastat 計劃。我們將按照計劃在第四季度分享註冊指導的 CardinALS 試驗的頂線結果。Utreloxastat 是首個針對 ALS 患者開發的化合物，它專門針對氧化壓力和細胞死亡的鐵死亡途徑，已被證明與 ALS 病理高度相關。

Given the recent changes in the therapeutic landscape for ALS, positive results from the CardinALS study could enable utreloxastat to address the significant unmet needs of ALS patients.

鑑於 ALS 治療領域的近期變化，CardinALS 研究的積極結果可能使烏瑞洛司他能夠滿足 ALS 患者的大量未滿足需求。

Finally, we remain on schedule for the November 13th FDA action date for the AADC Gene Therapy BLA. If approved, this would be the first ever direct to brain administered gene therapy authorized by FDA and open the door to a whole new approach to treating brain diseases.

最後，我們仍按計劃於 11 月 13 日 FDA 對 AADC 基因治療 BLA 進行行動。如果獲得批准，這將是 FDA 批准的首個直接針對大腦的基因治療方法，並為治療腦部疾病的全新方法打開大門。

I am very proud of our team's ability to bring this pioneering therapy to patients. In summary, we have had a very busy and productive quarter, as we continue to execute on all of our planned objectives and achieve our many significant 2024 milestones.

我為我們的團隊能夠為患者帶來這種開創性的治療方法感到非常自豪。總而言之，我們度過了一個非常忙碌和富有成效的季度，因為我們繼續執行所有計劃的目標並實現了許多重要的 2024 年里程碑。

I will now turn the call over to Eric to discuss our commercial performance. Eric?

現在我將把電話轉給 Eric 討論我們的商業表現。埃里克？

Thanks Matt. Our global customer-facing team had another strong performance in the third quarter delivering $135 million of revenue across our five marketed products. Our global DMD franchise had a solid quarter with $124 million of revenue.

謝謝馬特。我們的全球客戶團隊在第三季再次表現強勁，為我們五種行銷產品創造了 1.35 億美元的收入。我們的全球 DMD 特許經營權本季表現穩健，營收達 1.24 億美元。

Despite CHMP's recent negative opinion on renewal, there continues to be strong support from physicians, patients, and families throughout Europe for Translarna based on the positive totality of evidence in the trials and the real-world experience.

儘管 CHMP 最近對續約發表了負面意見，但基於試驗中全部積極證據和現實世界經驗，整個歐洲的醫生、患者和家屬仍然大力支持 Translarna。

We continue to ensure that Translarna is made available to boys and young men living with nonsense mutation Duchenne muscular dystrophy in Europe, as long as it remains authorized pending review of the CHMP opinion by the European Commission.

我們將繼續確保 Translarna 能夠提供給歐洲患有無義突變杜氏肌肉營養不良症的男孩和年輕男性，只要該藥物在等待歐盟委員會對 CHMP 意見的審查期間仍然獲得授權。

Outside of Europe, our commercial teams have worked effectively with healthcare professionals, as we continue to add new patients and maintain those on existing Translarna therapy in Latin America, the Commonwealth of Independent States, the Middle East and North African countries.

在歐洲以外，我們的商業團隊與醫療保健專業人士進行了有效的合作，我們繼續在拉丁美洲、獨立國家聯合體、中東和北非國家增加新患者，並維持現有的 Translarna 療法患者。

In fact, in the third quarter, we obtained first time Translarna orders from two new countries in the Middle East and North African region. In Brazil, we delivered the remaining 50% of a group purchase to the Ministry of Health.

事實上，第三季我們首次獲得了來自中東和北非地區兩個新國家的Translarna訂單。在巴西，我們將團購剩餘的50%交給了衛生部。

As Matt mentioned, the NDA for Translarna is currently under review by FDA and our highly experienced US team is very well positioned to bring Translarna to nonsense mutation DMD patients rapidly pending potential FDA approval.

正如馬特所提到的，Translarna 的 NDA 目前正在接受 FDA 的審查，我們經驗豐富的美國團隊完全有能力在獲得 FDA 批准後迅速將 Translarna 帶給無義突變 DMD 患者。

Now, turning to Emflaza. Third quarter net revenue was $52 million. We continue to work closely with healthcare professionals, payers and specialty pharmacies to dispense the brand. Our PTC Cares team provides white glove personalized services and programs supporting each patient with co-pay assistance, brand information and timely shipments from our specialty pharmacies, greatly enhancing the experience for both new and continuing patients.

現在，轉向 Emflaza。第三季淨營收為5,200萬美元。我們將繼續與醫療保健專業人士、付款人和專業藥房密切合作，以銷售該品牌。我們的 PTC Cares 團隊提供白手套個人化服務和計劃，為每位患者提供共同支付援助、品牌資訊和來自我們專業藥房的及時發貨，大大增強了新患者和老患者的體驗。

Our customer-facing teams are extremely excited about the potential upcoming global launch of sepiapterin for PKU patients. Based on the feedback from patients, families and physicians, we believe sepiapterin has the potential to generate significant revenue including an over $1 billion opportunity in the US alone.

我們面向客戶的團隊對於即將在全球推出的針對苯酮尿症患者的墨蝶呤感到非常興奮。根據患者、家屬和醫生的回饋，我們認為，墨角蝶呤有潛力創造可觀的收入，光在美國就有超過 10 億美元的商機。

PKU has a large addressable orphan disease population of more than 58,000 patients in markets with access and reimbursement and the vast majority of patients are not receiving medical treatment due to the limitations of current options.

北大在可獲得治療和報銷的市場上擁有超過 58,000 名可治療的孤兒病患者，並且絕大多數患者由於當前治療選擇的限製而無法接受治療。

We look forward to providing physicians with this important new differentiated treatment option to address these high unmet needs in PKU patients. As Matt mentioned, sepiapterin is under review in the US and Europe, which are important steps in bringing this important new therapy to children and adults living with PKU.

我們期待為醫生提供這種重要的新差異化治療選擇，以解決苯酮尿症患者的這些未滿足的需求。正如馬特所提到的，墨蝶呤正在美國和歐洲接受審查，這是將這種重要的新療法帶給患有苯酮尿症的兒童和成人的重要一步。

Further submissions are under review by regulators in Brazil, Canada, Switzerland and Australia, with the filing planned in Japan by the end of this year, positioning PTC now for potential global launch in multiple major markets in 2025 and beyond.

巴西、加拿大、瑞士和澳洲的監管機構正在審查進一步的申請，並計劃於今年年底在日本提交申請，這使得 PTC 預計在 2025 年及以後在多個主要市場推出全球產品。

I will provide some details on our launch efforts which have been ongoing for several years. We have been working closely with key PKU healthcare providers including geneticists, pediatric metabolic specialists, and dietitians around the world to better understand the unmet needs and build a strong relationship with the PKU patient advocacy community.

我將提供一些有關我們持續數年的發射工作的細節。我們一直與世界各地的遺傳學家、兒科代謝專家和營養師等主要的 PKU 醫療保健提供者密切合作，以更好地了解未滿足的需求並與 PKU 患者權益社區建立牢固的關係。

Our teams continue to develop a deeper understanding of the PKU landscape with many of the key treatment centers and prescribers. As you know, PKU is the most prevalent inborn era of metabolism disease with reliable epidemiology via newborn screening available since the early 1960s.

我們的團隊繼續與許多主要治療中心和處方人員一起加深對 PKU 狀況的了解。眾所周知，苯酮尿症是最常見的先天性代謝疾病，自 20 世紀 60 年代初以來，透過新生兒篩檢就可以獲得可靠的流行病學數據。

PKU patients receive their care from well-defined treatment centers and clinicians around the world. We have mapped these treatment centers and healthcare providers in key markets globally.

苯酮尿症患者由世界各地指定的治療中心和臨床醫生接受治療。我們已經在全球主要市場繪製了這些治療中心和醫療保健提供者的地圖。

Since the recent publication of APHENITY data, awareness of sepiapterin has rapidly increased in many of these centers of excellence, highlighting the compound's differentiated efficacy profile seen in clinical trials as a convenient oral treatment, getting more patients to phenylalanine goal levels and enabling potential diet liberalization.

自從最近公佈 APHENITY 數據以來，許多卓越中心對墨蝶呤的認識迅速提高，突顯了該化合物在臨床試驗中所見的差異化療效特徵，作為一種便捷的口服治療方法，它能讓更多患者達到苯丙氨酸目標水平，並實現潛在的飲食自由化。

Our field-based teams have met frequently with PKU stakeholders who have expressed their excitement about a new treatment option to address their unmet needs potentially available next year. Importantly, patients highlight optimism with the ability of sepiapterin to liberalize diet and this is an important motivator for patients to seek new treatment options earlier from their healthcare providers.

我們的實地團隊經常與北大利益相關者會面，他們對明年可能出現的解決其未滿足需求的新治療方案感到興奮。重要的是，患者對墨蝶呤放鬆飲食的能力表示樂觀，這是促使患者儘早從醫療保健提供者那裡尋求新的治療選擇的重要動力。

Now, in addition, we are leveraging our established rare disease global infrastructure which has a footprint in over 50 countries. We will sequence the potential country launches of sepiapterin to maximize access in key markets and maintain a narrow pricing and reimbursement corridor globally.

現在，我們也正在利用已在 50 多個國家建立的罕見疾病全球基礎設施。我們將對可能在各國推出墨蝶呤的順序進行排序，以最大限度地擴大其在重點市場的覆蓋範圍，並在全球範圍內維持較窄的定價和報銷範圍。

Our research benchmarking of many rare disease analogs indicates a premium pricing strategy can be obtained based on the differentiated profile of sepiapterin compared to current branded treatment options available, especially in key markets where PKU treatments are reimbursed and where we are planning our initial launch sequences upon potential approvals.

我們對許多罕見疾病類似物進行的基準研究表明，與目前可用的品牌治療方案相比，可以根據墨蝶呤的差異化特性獲得溢價策略，特別是在 PKU 治療可報銷的關鍵市場以及我們計劃在獲得潛在批准後首次推出的市場。

Our customer-facing teams understand the complexities of managing rare disease treatments as well as the regulatory and payer access landscape. These core capabilities developed at PTC over the last decade along with sepiapterin's highly differentiated profile should facilitate rapid adoption for PKU stakeholders and reinforce our belief in the potential $1 billion-plus opportunity not only globally, but in the US alone.

我們面向客戶的團隊了解管理罕見疾病治療的複雜性以及監管和付款人准入狀況。PTC 在過去十年中開發的這些核心能力以及 sepiapterin 的高度差異化特性應能促進 PKU 利益相關者的快速採用，並加強我們對不僅在全球範圍內，而且僅在美國就潛在的 10 億美元以上機會的信心。

Turning to vatiquinone. With the NDA submission planned for December of this year, our commercial team is excited for the potential opportunity to launch vatiquinone for FA patients in 2025. We believe that vatiquinone is well differentiated from current treatment options and could benefit all FA patients, in particular pediatric and adolescent patients.

轉向瓦替醌。由於 NDA 提交計劃於今年 12 月進行，我們的商業團隊對在 2025 年為 FA 患者推出 vatiquinone 的潛在機會感到非常興奮。我們相信，vatiquinone 與目前的治療方案有很大區別，可以造福所有 FA 患者，特別是兒童和青少年患者。

KOLs who treat FA believe there are significant unmet needs in this devastating disease. They tell us that vatiquinone's unique mechanism of action, its compelling efficacy data in highly relevant functional parameters for FA patients, along with its favorable safety profile, provide a strong rationale for treatment as early as possible in the course of the disease. Our experienced neurology team is focusing on key projects in preparation for the US launch of vatiquinone.

治療 FA 的關鍵專家認為，這種毀滅性疾病存在大量未滿足的需求。他們告訴我們，vatiquinone獨特的作用機制、其在與FA患者高度相關的功能參數中的令人信服的療效數據、以及其良好的安全性，為在疾病過程中儘早治療提供了強有力的理由。我們經驗豐富的神經病學團隊正專注於關鍵項目，為在美國推出 vatiquinone 做準備。

Now moving to Tegsedi and Waylivra in Latin America. We continue to make good progress across these franchises with growth in both newly identified and treated patients across the region. Our geographical expansion continues with a recent approval and positive HTA assessment of Tegsedi in Mexico, following which we have initiated reimbursement discussions. In Brazil, we delivered a new government purchase order for Tegsedi in the third quarter.

目前已轉向拉丁美洲的 Tegsedi 和 Waylivra。我們在這些特許經營中繼續取得良好進展，整個地區新發現和治療的患者數量都在增加。我們的地理擴張仍在繼續，Tegsedi 最近在墨西哥獲得批准並獲得積極的 HTA 評估，隨後我們已啟動報銷談判。在巴西，我們在第三季向 Tegsedi 交付了一份新的政府採購訂單。

In conclusion, we continue to execute on all fronts based on a strong first nine months of revenue this year. As Matt mentioned, we are updating guidance with a 2024 total revenue guidance of $750 million to $800 million. Our customer-facing team is thrilled by the opportunity to potentially launch four new products, AADC Gene Therapy, Translarna, sepiapterin and vatiquinone in the US as well as sepiapterin globally in 2025.

總之，基於今年前九個月強勁的收入，我們將繼續在各方面發揮作用。正如馬特所提到的，我們正在更新指引，將 2024 年的總收入指引定為 7.5 億美元至 8 億美元。我們面對客戶的團隊很高興有機會在 2025 年在美國推出四種新產品，分別是 AADC 基因療法、Translarna、sepiapterin 和 vatiquinone，並在全球推出 sepiapterin。

I will now turn the call over to Pierre for a financial update. Pierre?

現在我將把電話轉給皮埃爾，聽取財務更新。皮埃爾？

Thank you, Eric. I'll now share the financial highlights of our third quarter of 2024. Please refer to the earnings press release issued this afternoon for additional details. Beginning with top line results, total revenue for the third quarter was $197 million, including DMD franchise revenue of $124 million. Translarna net product revenue in the quarter was $72 million, while Emflaza net product revenue of $52 million.

謝謝你，埃里克。現在，我將分享我們 2024 年第三季的財務亮點。請參閱今天下午發布的收益新聞稿以了解更多詳細資訊。從營收結果開始，第三季總收入為 1.97 億美元，其中包括 1.24 億美元的 DMD 特許經營收入。Translarna 本季淨產品收入為 7,200 萬美元，而 Emflaza 淨產品收入為 5,200 萬美元。

Moving to Evrysdi. Third quarter global net revenue of approximately $460 million was achieved by Roche resulting in royalty revenue of $61 million for PTC. Non-GAAP R&D expense was $152 million for the third quarter of 2024 excluding $9 million in non-cash stock-based compensation expense compared to $150 million for the third quarter of 2023 excluding $14 million in non-cash stock-based compensation expense.

搬到 Evrysdi。羅氏公司第三季全球淨營收約 4.6 億美元，為 PTC 帶來 6,100 萬美元的專利使用費收入。2024 年第三季的非 GAAP 研發費用為 1.52 億美元（不含 900 萬美元的非現金股票薪酬費用），而 2023 年第三季的非 GAAP 研發費用為 1.5 億美元（不包括 1,400 萬美元的非現金股票薪酬費用）。

Non-GAAP SG&A expense was $63 million for the third quarter of 2024, excluding $10 million in non-cash stock-based compensation expense compared to $68 million for the third quarter of 2023, excluding $13 million in non-cash stock-based compensation expense.

2024 年第三季的非 GAAP 銷售、一般及行政管理費用為 6,300 萬美元，不包括 1,000 萬美元的非現金股票薪酬費用，而 2023 年第三季為 6,800 萬美元，不包括 1,300 萬美元的非現金股票薪酬費用。

Cash, cash equivalents and marketable securities totaled $1.0 billion as of September 30, 2024, compared to $877 billion as of December 31, 2023. Our strong financial position provides PTC with the necessary resources to execute on our strategy and achieve our milestones over the next several years, including the anticipated launch of sepiapterin and other products.

截至 2024 年 9 月 30 日，現金、現金等價物及有價證券總額為 10 億美元，而截至 2023 年 12 月 31 日為 8,770 億美元。我們強大的財務狀況為 PTC 提供了必要的資源，以執行我們的策略並在未來幾年實現我們的里程碑，包括預期推出的 sepiapterin 和其他產品。

I will now turn the call over to the operator for Q&A. Operator?

我現在將把電話轉給接線員進行問答。操作員？

(Operator Instructions) Kristen Kluska, Cantor Fitzgerald.

（操作員指示）克里斯汀·克魯斯卡（Kristen Kluska）、領唱菲茨杰拉德（Cantor Fitzgerald）。

Hi. This is Rick on for Kristen. Thanks for taking our question. We got two for you. So first of all, thanks for the update on the Type C meeting in Huntingtin's. Do you have a sense for when you could update the community on any clarity that might come out of the meeting? Is there any chance that we'll learn more about a potential path forward here?

你好。這是 Rick 為 Kristen 表演的。感謝您回答我們的問題。我們為您準備了兩件。首先，感謝您提供有關亨廷頓氏舞蹈症 C 型會議的最新消息。您是否知道何時可以向社區通報會議中可能出現的明確訊息？我們是否有機會在這裡了解更多潛在的前進道路？

Yeah. Thanks, Rick, for the question. So we know there's a lot of excitement around the discussions we're going to have with FDA, both in terms of understanding the endpoints for an efficacy trial, but also, of course, the discussions around Huntingtin lowering as a surrogate endpoint.

是的。謝謝 Rick 提出這個問題。因此，我們知道大家對與 FDA 進行的討論感到非常興奮，這不僅是為了了解療效試驗的終點，當然也是為了討論降低亨廷頓蛋白作為替代終點。

And as we've talked about, when we think about surrogate endpoints and accelerated approval, what the FDA really wants is, is for us to be able to present a package of scientific evidence of why lowering Huntingtin protein is likely to provide clinical benefit ultimately.

正如我們所討論的，當我們考慮替代終點和加速批准時，FDA 真正想要的是，我們能夠提供一系列科學證據，證明為什麼降低亨廷頓蛋白最終可能會帶來臨床益處。

And are there specific thresholds of lowering that have been associated with that benefit. So we have been able to provide them with the rich scientific literature, including in vitro, in vivo and human studies which show that if you lower Huntingtin protein 20% to 50%, that you're likely to have a significant benefit in slowing disease progression.

且是否存在與該項福利相關的具體降低門檻？因此，我們能夠為他們提供豐富的科學文獻，包括體外、體內和人體研究，這些研究表明，如果將亨廷頓蛋白降低 20% 到 50%，就有可能在減緩病情進展方面獲得顯著的益處。

And of course, as we've shown in our 12-month PIVOT-HD update, we are achieving that threshold of lower of Huntingtin protein. We expect to have these meetings with FDA in December of this year. And as always, as soon as we have clarity, which sometimes comes at the time of the meeting or shortly thereafter or once we receive minutes, we'll be sure to share that with the broader community, including the Street, as we know there's a lot of interest in hearing about this path forward for accelerated approval of PIVOT-HD.

當然，正如我們在 12 個月的 PIVOT-HD 更新中所展示的那樣，我們正在實現降低亨廷頓蛋白的閾值。我們預計將於今年 12 月與 FDA 舉行這些會議。像往常一樣，一旦我們有了明確的結論（有時是在會議期間或會議結束後不久，或者在我們收到會議記錄後），我們一定會與包括華爾街在內的更廣泛的社區分享這一結論，因為我們知道，大家對加速批准 PIVOT-HD 的途徑非常感興趣。

Excellent. And maybe just one more if we have time. We've seen a lot of regulatory flexibility in the rare disease space recently, so given the FDA resubmission for Translarna, can you talk about how you think the FDA might sort of weigh the STRIDE registry data and Study 041 that were submitted and just kind of looking at this new evidence given sort of how things have been going in terms of regulatory flexibility? Thanks.

出色的。如果我們有時間的話，也許可以再來一個。我們最近在罕見疾病領域看到了很多監管靈活性，因此考慮到 FDA 重新提交的 Translarna 申請，您能否談談您認為 FDA 可能會如何權衡已提交的 STRIDE 註冊數據和研究 041，並根據監管靈活性方面的進展情況來看待這些新證據？謝謝。

Sure, Rick. So as we talked about before, the NDA resubmission for Translarna was based on two things. First, the evidence of significant benefit in the overall enrolled population of 359 boys in Study 041. This is where we had significant effect on six-minute walk distance, North Star Ambulatory Assessment, time function test, time to loss of 10%.

當然，里克。正如我們之前所討論的，Translarna 的 NDA 重新提交基於兩件事。首先，041 研究中納入的 359 名男孩總體顯示出顯著的益處。這就是我們對六分鐘步行距離、北極星步行評估、時間功能測試、損失 10% 的時間產生顯著影響的地方。

And that data set in a broad nonsense DMD population showing significant benefit across all those endpoints is actually pretty unique with flexibility or not. I think this is really a first data set that has in an ITT population significant effect across all these endpoints. In addition, as confirmatory evidence, which the agency likes to see in addition to a single adequate and well controlled trial, we have the STRIDE registry.

而且，在廣泛的無意義的 DMD 族群中，該資料集顯示出在所有這些端點上都具有顯著的益處，無論是否具有靈活性，它實際上都是非常獨特的。我認為這確實是第一個對 ITT 族群中所有這些端點具有顯著影響的資料集。此外，除了單一充分且控制良好的試驗之外，該機構還希望看到確認證據，即我們擁有的 STRIDE 登記系統。

And what the STRIDE registry is able to demonstrate is these significant benefits we're seeing on ambulatory function and other aspects of disease in the short-term of Study 041 are manifesting cumulatively over several years as a delay in loss of ambulation of 3.5 years. So of course, any flexibility the agency can bring to the assessment will be of the package would be great.

STRIDE 登記處能夠證明的是，我們在 041 號研究中看到的短期內行走功能和疾病其他方面顯著的益處會在幾年內累積起來，表現為行走能力喪失的時間延遲了 3.5 年。因此，當然，該機構能夠對這項方案的評估給予任何彈性都將是件好事。

But on its own, we have an efficacy package with evidence of clinical benefit in both the short-term and the long-term in nonsense DMD patients, which is quite a unique and compelling package of data.

但就其本身而言，我們有一個療效包，其中有證據表明，它對無意義的 DMD 患者有短期和長期的臨床益處，這是一套非常獨特和令人信服的數據集。

Eric Joseph, JPMorgan.

摩根大通的艾瑞克‧約瑟夫 (Eric Joseph)。

Good evening. Thanks for taking the questions. I have one on the CardinALS trial. We noticed recently that you updated the or changed modified the primary endpoint to use a participant ranked combined assessment of ALSFRS and also survival.

晚安.感謝您回答這些問題。我有一個關於 CardinALS 試驗的專案。我們最近注意到，您更新了或修改了主要終點，以使用參與者排名的 ALSFRS 和生存率綜合評估。

Can you talk about what some of the motivations were behind changing to that endpoint and what that impact might be from a statistical powering perspective? And I guess I think you've also now over enrolled the study. Was that meant to accommodate the change in endpoint or would you in fact now be sort of slightly overpowered versus prior expectations? Thank you.

您能否談談改變該端點背後的一些動機以及從統計驅動角度來看可能產生的影響？我想您現在已經參與了過多的研究。這是為了適應終點的變化，還是事實上現在與之前的預期相比會稍微有點超出預期？謝謝。

Thanks for the questions, Eric. So those two are not related. Your two questions are not related. The first is really a way of analyzing the results of the study. The outcome of interest remains the ALSFRS score, which is a continuous variable that rates disease progression over the course of the trial. However, it's well known that patients will die over the course of the study.

謝謝你的提問，艾瑞克。所以這兩者沒有關係。您的兩個問題沒有關聯。第一個其實是分析研究結果的一種方法。感興趣的結果仍然是 ALSFRS 評分，這是一個連續變量，用於評估試驗過程中的疾病進展。然而，眾所周知，患者在研究過程中會死亡。

And the FDA has recommended, in order for us to account for death in the primary analysis, they would like us to use their preferred analysis method in ALS, which is known as the joint rank test, which is the statistical test that's able to incorporate the information of decline on the ALSFRS as well as any deaths that occurred during the course of the study.

FDA 建議，為了讓我們在主要分析中考慮到死亡因素，他們希望我們使用他們在 ALS 中首選的分析方法，即聯合秩檢驗，這是一種統計檢驗，能夠結合 ALSFRS 中的衰退資訊以及研究過程中發生的任何死亡事件。

So it's really just a change in the way we're analyzing it to include deaths in the primary statistical analysis of the data. And again this came from feedback from the FDA on the analysis plan, as they have said that that is really their preferred analysis methods. And certainly, if you look back to their reviews of other ALS drugs, you'll see that is in fact the test that they like to use because it's able to incorporate information from all subjects.

所以這其實只是我們分析數據的方式的改變，將死亡納入數據的主要統計分析中。這再次來自 FDA 對分析計畫的回饋，他們表示這確實是他們首選的分析方法。當然，如果你回顧他們對其他 ALS 藥物的評論，你會發現這實際上是他們喜歡使用的測試，因為它能夠整合來自所有受試者的資訊。

Regarding your second question, as we've talked about, we had a target population for the primary analysis population based on a rate of progression observed during a two-month run-in of the study. So we had this two-month run-in study, where we observed patients and calculate how many points they change on the ALSFRS scale.

關於您的第二個問題，正如我們已經討論過的，我們根據研究兩個月期間觀察到的進展率，確定了主要分析人群的目標人群。因此，我們進行了兩個月的準備研究，觀察患者並計算他們在 ALSFRS 量表上的變化了多少分。

We need to enroll a certain number of patients in order to achieve the targeted number of patients in that primary analysis group. So what you see in the increase enrollment was really just because we had a slightly lower yield of screened subjects, who actually met the criteria for the primary analysis population.

我們需要招募一定數量的患者，以達到主要分析組的目標患者數。因此，您看到的入學人數增加實際上只是因為我們篩選的受試者的數量略低，而這些受試者實際上符合主要分析人群的標準。

Kelly Shi, Jefferies.

傑富瑞 (Jefferies) 的 Kelly Shi。

Thank you for taking my questions. Given the revenue bid for this quarter, could you help us to set up an expectation for Q4, maybe also into 2025, what would be the dynamic DMD franchise also versus relatives from Evrysdi? Thank you.

感謝您回答我的問題。考慮到本季的營收預期，您能否幫助我們設定第四季的預期，也許還有 2025 年，與 Evrysdi 的親屬相比，DMD 特許經營的動態情況如何？謝謝。

Yeah. Thank you for the question, Kelly. So, as we said, the revenue was quite strong this quarter, which allowed us to raise the overall guidance this year to $750 million to $800 million. We expect in the fourth quarter continued contributions from across our portfolio of inline products in terms in both the DMD franchise revenues we talked about Emflaza continues to perform incredibly well.

是的。謝謝你的提問，凱利。因此，正如我們所說，本季的營收非常強勁，這使我們能夠將今年的整體預期上調至 7.5 億至 8 億美元。我們預計，第四季度我們的全系列產品將繼續為我們談到的 DMD 特許經營收入做出貢獻，Emflaza 的表現也持續表現出色。

Our teams have done a great job protecting the brand in the face of generic competition. And Translarna revenue we expect to be stable over the fourth quarter, certainly as it remains available in Europe, we will have the typical lumpiness that we see quarter-to-quarter with Translarna. But overall we expect strong DMD revenue contribution in the fourth quarter.

面對通用品牌的競爭，我們的團隊在保護品牌方面做得非常出色。我們預計 Translarna 的收入將在第四季度保持穩定，當然，由於它仍在歐洲銷售，因此我們將看到 Translarna 季度間典型的波動。但總體而言，我們預計第四季度 DMD 收入貢獻將強勁。

Jeffrey Hung, Morgan Stanley.

摩根士丹利的 Jeffrey Hung。

Hi. This is Michael Riad on for Jeff Hung. Thank you for taking our question and congrats on all the progress and all the programs. Ahead of the CardinALS top line in 4Q, do you plan to share like baseline characteristics, maybe like time since diagnosis or can you comment on maybe what percent of patients are going into the OLE?

你好。這是 Jeff Hung 的 Michael Riad。感謝您回答我們的問題，並祝賀所有進展和所有計劃。在第四季度 CardinALS 營收達到頂線之前，您是否計劃分享一些基線特徵，例如自診斷以來的時間，或者您能否評論一下有多少比例的患者會進入 OLE？

Yeah, Michael, thanks for the question. So typically, with our top line results, we'll give the key baseline characteristics and results with regards to the key endpoints. We've seen excellent continuation of patients, as they roll into the OLE once they finish the CardinALS.

是的，邁克爾，謝謝你的提問。因此通常，根據我們的頂線結果，我們將提供與關鍵端點相關的關鍵基線特徵和結果。我們看到患者的治療延續性非常好，他們在完成 CardinALS 治療後就進入了 OLE。

Okay, thank you. And then maybe for the long-term FA extension studies of vatiquinone. Why do you think you start to see the meaningful separation more in the extension studies? Was it like a rapid impact on mFARS expected, or could you perhaps like add some more color on how like vatiquinone is like influencing the trajectory there?

好的，謝謝。然後也許可以進行 vatiquinone 的長期 FA 擴展研究。為什麼您認為在擴展研究中會開始看到更多有意義的分離？它是否像預期的那樣對 mFARS 產生了快速影響，或者您可以再多介紹一下 vatiquinone 是如何影響那裡的軌蹟的？

I think what we're seeing is a continued benefit in terms of preservation of function, as we reported when we read out the 72-week placebo-controlled study, we saw an approximate 50% slowing in progression in the treatment group relative to the placebo group.

我認為，我們所看到的是功能保存方面的持續益處，正如我們在讀到的 72 週安慰劑對照研究中所報告的那樣，我們發現治療組的進展速度相對於安慰劑組減緩了約 50%。

And at three years, we're still seeing that 50% benefit, 50% slowing of progression, as we reported in the patients who started on vatiquinone, they had a 3.7 point decline, whereas in the natural history cohort, there was a 7.5 point decline. So we're seeing a continuous benefit in terms of preserving function and slowing disease progression.

三年後，我們仍然看到 50% 的益處，50% 的進展減緩，正如我們在開始使用 vatiquinone 的患者中所報告的那樣，他們的病情下降了 3.7 個百分點，而在自然病史隊列中，病情下降了 7.5 個百分點。因此，我們在保留功能和減緩疾病進展方面看到了持續的益處。

Brian Abrahams, RBC Capital Markets.

加拿大皇家銀行資本市場 (RBC Capital Markets) 的 Brian Abrahams。

Hey, good evening. Thanks for taking my questions. I guess one on sepiapterin and one on Translarna. Just for sepiapterin, I'm curious if you could maybe talk a little bit more about the reactions from providers, patients and payers to the Lancet data and in particular maybe elaborating on some of the payer research and communication that's given you confidence in the potential for the premium pricing.

嘿，晚上好。感謝您回答我的問題。我猜一個是關於 sepiapterin 的，一個是關於 Translarna 的。僅就 sepiapterin 而言，我很好奇您是否可以再多談談供應商、患者和付款人對柳葉刀數據的反應，特別是詳細說明一些付款人的研究和溝通，這些研究和溝通讓您對溢價的潛力充滿信心。

And then on Translarna, just wondering if you could have any sense of the potential timelines for the next review steps there, both in the US and Europe and whether you think we might hear some updates in 2025. Thanks.

然後關於 Translarna，我只是想知道您是否可以了解美國和歐洲下一步審查步驟的潛在時間表，以及您是否認為我們可能會在 2025 年聽到一些更新。謝謝。

Yeah, sure Brian, thanks for the questions. Let me tackle Translarna first and then I'll pass the second question on sepiapterin over to Eric. So first on Translarna. So you asked about the US and the EU. In the EU, we're of course in that period now of approximately 67 days following the CHMP opinion, where the European Commission does its assessment of whether or not they want to adopt the opinion.

是的，當然了，布萊恩，謝謝你的提問。讓我先解決 Translarna 問題，然後將 sepiapterin 的第二個問題交給 Eric。首先介紹一下 Translarna。所以你問的是美國和歐盟的情況。在歐盟，我們現在當然處於 CHMP 意見發布後約 67 天的時間內，歐盟委員會將評估是否要採納該意見。

So we don't expect to hear anything further for at least approximately 67 days. And as we've talked about Translarna remains authorized in this period. And of course we're making sure that we continue to provide the drug to patients and make it commercially available while authorization remains.

因此，我們預計至少在 67 天內不會聽到任何進一步的消息。正如我們所討論的，Translarna 在此期間仍然是授權的。當然，我們會確保在授權有效期間繼續向患者提供該藥物並使其在市場上銷售。

In the US, as we've talked about, given the fact that this was a resubmission of an NDA that had initially been filed of protest in 2016 many, many years ago. Nonetheless, the FDA is not bound by a clock in terms of doing this review. However, we expect just given what's involved in the evaluation of a resubmission, which is just a portion really the efficacy package, we would expect that they'll get to the review in the next few months.

在美國，正如我們已經討論過的，鑑於這是對多年前 2016 年首次提交抗議的保密協議的重新提交。儘管如此，FDA 在進行此項審查時不受時間的限制。然而，我們預計，考慮到重新提交的評估所涉及的內容（實際上這只是功效方案的一部分），我們預計他們將在未來幾個月內完成審查。

So as soon as we have more information on the specific timeline and can provide any clarity, we will. Regarding sepiapterin, let me just make the first comment that obviously we were quite excited about the Lancet publication.

因此，一旦我們獲得有關具體時間表的更多資訊並且能夠提供任何澄清，我們就會這樣做。關於墨角蝶呤，我首先要說的是，我們顯然對《柳葉刀》的出版感到非常興奮。

I think that's a true testament to how differentiated sepiapterin is with its dual mechanism of action, not only in its ability to act as a precursor to the BH4 cofactor, but the fact that it has a second chaperone mechanism of action, which allows it then to provide benefit to patients who are not BH4 responsive, which again is a really important element of why we're seeing such significant effect across the board in PKU patients of all severities and variety of genotypes.

我認為這真正證明了墨蝶呤的差異化，它具有雙重作用機制，不僅能夠作為 BH4 輔因子的前體，而且還有第二種分子伴侶作用機制，這使其能夠為對 BH4 沒有反應的患者帶來益處，這也是我們在所有嚴重程度和各種基因型的 PKU 患者中看到如此顯著效果的一個非常重要的因素。

The physicians are very excited about this. I think they see the Lancet publication as being consistent with what they believe, which is that this is a potentially transformative therapy that can meet the significant unmet need for PKU patients. Let me turn it over to Eric to talk a little bit more about our payer discussions and how we're thinking about potential pricing.

醫生們對此感到非常興奮。我認為他們認為《柳葉刀》雜誌的出版物與他們的信念一致，即這是一種具有變革性的療法，可以滿足苯酮尿症患者尚未滿足的重大需求。讓我將話題交給 Eric，讓他進一步談談我們與付款人的討論，以及我們對潛在定價的看法。

Yeah, thanks Matt, and thanks, Brian for the question. As you can see, we're really pleased with the publication of APHENITY. We've been able to engage in a lot of payer activity, including market research, but also doing a lot of landscape research in many of the countries, where we're sequencing it.

是的，謝謝 Matt，也謝謝 Brian 提出這個問題。如您所見，我們對 APHENITY 的發布感到非常高興。我們已經能夠參與大量付款人活動，包括市場研究，同時也在許多國家進行了大量景觀研究，我們正在對其進行排序。

Clearly, what payers have told us is that they see a differentiation based on its efficacy profile and seeing that more than 8 out of 10 patients can actually achieve therapeutic goals, and importantly, that fee levels and those goals can be measured rapidly.

顯然，付款人告訴我們，他們看到了基於療效特徵的差異，並且看到超過 80% 的患者實際上可以實現治療目標，而且重要的是，費用水平和這些目標可以快速衡量。

With a very high unmet need, we know that there is close to 90% of the population that is not on medical therapy at this time. There is a high unmet need, and payers see that and they're willing to pay a premium price both in Europe as well as in the US, because they know that they can achieve, or they can actually see the levels of therapeutic gain literally in a matter of weeks with sepiapterin.

由於未滿足的需求很高，我們知道目前有近 90% 的人口沒有接受藥物治療。存在著很大的未滿足需求，付款人看到了這一點，並且他們願意在歐洲和美國支付高價，因為他們知道他們可以實現，或者他們實際上可以在幾週內透過服用墨蝶呤看到治療效果。

So obviously our pricing strategy is evolving, but as we know, we've actually looked at a number of different analogs, including many that have been recently launched that are clearly differentiated. And we believe that having a premium price over existing branded therapies can be achieved in many of these markets.

因此，顯然我們的定價策略正在不斷發展，但正如我們所知，我們實際上已經研究了許多不同的類似產品，包括許多最近推出的具有明顯差異的產品。我們相信，在許多這樣的市場中，我們可以獲得比現有品牌療法更高的價格。

Finally, I'll just say the pricing strategy really is not going to be announced until we get much closer to launch and then when we have the final label.

最後，我只想說，定價策略實際上要等到發布會臨近並確定最終標籤時才會公佈。

Ellie Merle, UBS.

瑞銀的艾莉·梅爾（Ellie Merle）。

Hey, guys. Thanks for taking the question. Can you talk a little bit more about the potential path forward and potential range of outcomes in terms of the feedback that you could specifically get from this Type C meeting? And if the FDA is not supportive of the use of Huntingtin lowering as a surrogate, I guess, what would the potential range of outcomes from there be in terms of what the clinical endpoint study and path forward for registration could look like?

嘿，大家好。感謝您回答這個問題。您能否就從這次 C 類會議中可以獲得的回饋，進一步談談潛在的前進道路和可能的結果範圍？如果 FDA 不支持使用亨廷頓蛋白降低作為替代品，我想，從臨床終點研究和註冊前景來看，可能出現的結果會是怎麼樣的呢？

And I guess in that scenario, where FDA is not supportive of the use of a surrogate, how are you thinking about your strategy around whether you would run a full Phase 3 on your own or look for a potential partner? Thanks.

我想，在這種情況下，如果 FDA 不支持使用替代品，您會如何考慮您的策略：是自行進行完整的第 3 階段研究還是尋找潛在的合作夥伴？謝謝。

Thanks for the questions, Ellie. Obviously, we're optimistic about the ability to have a productive discussion with the agency regarding the potential for Huntingtin lowering to serve as a surrogate endpoint. Because it really meets what they ask for in terms of a surrogate endpoint. That is there's evidence that shows that reductions in Huntingtin protein can have clinical benefit.

謝謝你的提問，艾莉。顯然，我們對與該機構就降低亨廷頓蛋白作為替代終點的可能性進行富有成效的討論的能力感到樂觀。因為它確實滿足了他們對替代終點的要求。有證據表明，減少亨廷頓蛋白可以帶來臨床益處。

There's a specific threshold associated with that, which we're able to achieve and just taking consideration of the disease itself, that it's a monogenetic disease that's caused by a toxic mutant Huntingtin protein. And we're able to address that. I think it's very squarely in the way they have thought about surrogate endpoints and other disorders, where there's an implicated protein in a drug targets that protein, for example, dystrophin in DMD.

與此相關的是一個特定的閾值，我們能夠達到這個閾值，僅考慮疾病本身，它是一種由有毒的突變亨廷頓蛋白引起的單基因疾病。我們能夠解決這個問題。我認為這與他們對替代終點和其他疾病的思考方式非常吻合，其中藥物靶向一種相關的蛋白質，例如杜氏肌肉營養不良症 (DMD) 中的肌肉營養不良蛋白。

We also believe that the agency has had an interest in leveraging the accelerated approval pathway for neurodegenerative disorders like Huntington's disease where there's significant unmet medical need and establishing efficacy takes a bit of time. So if there's a safe therapy that has shown the ability to impact a marker of disease that is known to be important to that disease pathology, that certainly could open the door for an accelerated approval.

我們也認為，該機構有興趣利用加速審批途徑來治療亨丁頓舞蹈症等神經退化性疾病，因為這類疾病存在大量未滿足的醫療需求，而且確定療效需要一些時間。因此，如果有一種安全的治療方法，並且顯示出能夠影響已知對疾病病理很重要的疾病標記物，那麼這肯定可以為加速批准打開大門。

And again, we believe that PTC518 lowering Huntingtin protein certainly fits. At the same time, we're also having a discussion about endpoint strategy for an efficacy trial, because what we want to do is be in a position to move forward with that efficacy trial as quickly as possible, regardless of the outcome of that meeting.

我們再次相信，PTC518 降低亨廷頓蛋白確實是可行的。同時，我們也在討論療效試驗的終點策略，因為無論會議結果如何，我們都希望能夠盡快推進此療效試驗。

For example, we could meet with FDA, and they could say, these initial data from the first 30 or so patients from PIVOT-HD look very good. Why don't you come back with a complete data set from PIVOT-HD and we'll revisit the surrogate endpoint discussion in the spring. That's a possible outcome.

例如，我們可以與 FDA 會面，他們可能會說，來自 PIVOT-HD 的前 30 名左右患者的初步數據看起來非常好。為什麼不帶著 PIVOT-HD 的完整數據集回來，我們將在春季重新討論替代終點問題。這是一個可能的結果。

And if that occurs, we still want to be ready to put in place and get started on the efficacy trial, because we're going to need that efficacy trial to be initiated either as part of accelerated approval or, as you say it, in the situation where the door is shut on a surrogate endpoint.

如果發生這種情況，我們仍然希望做好準備並開始進行療效試驗，因為我們需要將療效試驗作為加速審批的一部分來啟動，或者如您所說，在替代終點的大門關閉的情況下啟動。

We want that study up and running so we can get to the finish line as quickly as possible. In terms of conducting the study, look, we said all along that we have positioned the company and build that balance sheet to be able to conduct that Phase 3 study. We have the infrastructure and capital to do that.

我們希望這項研究能夠順利進行，以便我們能夠盡快到達終點。在進行研究方面，你看，我們一直說，我們已經定位了公司並建立了資產負債表，以便能夠進行第三階段的研究。我們擁有實現這一目標的基礎設施和資本。

Obviously, our team has worked incredibly closely with the Huntington's disease community, including the patient groups and the physicians around the world, who are incredibly enthusiastic in participating in the study, whether that's as an investigator or the patients who want to be in that study, either because they didn't have the opportunity for the previous study, where they've seen the data now and really want to be a part of a Huntington lowering trial of an oral therapy, which is easily administered and has shown to be safe and well tolerated. So we look forward to being able to advance that trial.

顯然，我們的團隊與亨廷頓舞蹈症社區進行了非常密切的合作，包括世界各地的患者團體和醫生，他們都非常熱情地參與這項研究，無論是作為研究人員，還是作為想參加這項研究的患者，他們要么是因為他們沒有機會參加之前的研究，現在他們已經看到了數據，並真正希望成為降低性治療的一部分，這種治療症是一種經耐受性試驗的一部分，這種療法被證明是良好的性治療並已被證明易於使用和耐受性試驗的一部分，這種療法已被證明是良好和耐受性試驗的一部分，這種治療已被證明是良好和耐受性試驗的一部分，這種治療已被證明是安全性。因此我們期待能夠推進該試驗。

Again, we'll do it either way, whether it becomes the registration trial or the confirmatory study in the context of an accelerated approval.

再說一次，無論它成為註冊試驗還是加速批准背景下的確認性研究，我們都會這樣做。

Great, thanks. And just a quick follow-up. I think you mentioned that you had requested two Type C meetings with the FDA, but that the FDA asked to combine the two into a single meeting. Maybe this is just logistical, but can you share maybe any context around this or maybe what this might suggest? Yeah, thanks.

太好了，謝謝。接下來是快速的跟進。我記得您提到過，您曾要求與 FDA 舉行兩次 C 類會議，但 FDA 要求將兩次會議合併為一次會議。也許這只是邏輯問題，但您能否分享有關此問題的任何背景資訊或這可能意味著什麼？是的，謝謝。

Yeah, again, this is purely logistical. We submitted the meeting request roughly the same time and as you know it's going to be the same people who review and discuss and provide their feedback. And as proud as we are of how well we've been collaborating with the agency in the neuro division, I think they, for logistical reasons, would rather just have one meeting rather than two, where the issues have such overlap, and it's the same people involved. So we look forward to having that one meeting in December.

是的，再說一次，這純粹是後勤問題。我們大約在同一時間提交了會議請求，並且如您所知，將由同一批人進行審核、討論並提供回饋。儘管我們對與神經部門機構的良好合作感到自豪，但我認為，出於後勤原因，他們寧願只舉行一次會議，而不是兩次會議，因為在兩次會議中，討論的問題有重疊，而且參與的人員是相同的。因此，我們期待 12 月舉行這次會議。

Joel Beatty, Baird.

喬爾·比蒂，貝爾德。

Thanks. For Translarna, what percent of the current ex-US sales would not be affected by any potential European Commission decision? And also how long could those sales potentially last into the future?

謝謝。對於 Translarna 而言，目前美國境外的銷售額中有多少百分比不會受到歐盟委員會任何潛在決定的影響？這些銷售未來可能持續多久？

Yeah, Joel, thanks for the question. As we've talked about, in 2023, roughly 46% of Translarna revenue was from Europe itself. That would be the revenue that we think that would be at risk in the event that the EC adopts the CHMP opinion.

是的，喬爾，謝謝你的提問。正如我們所討論的，2023 年，Translarna 約 46% 的收入來自歐洲本身。我們認為，如果歐盟委員會採納 CHMP 的意見，這部分收入就會面臨風險。

Now, we've said going forward that there's a possibility in certain countries that we can leverage patient or other individual country pathways to still make commercial product available. But obviously that will be something that will play out on the other side of an EC adoption. But again it's that European revenue that we would see at risk and only that revenue.

現在，我們已經說過，在某些國家，我們可以利用病人或其他個別國家的途徑來繼續提供商業產品。但顯然這將是在歐盟採用的另一面所發生的事情。但再次，我們認為面臨風險的是歐洲的收入，而且只有歐洲的收入。

And how long would exclusivity be in those other regions?

那麼在其他地區獨家經營權會持續多久呢？

It varies. We have in many regions exclusivity out to 2029.

它是因人而異的。在許多地區，我們擁有直至 2029 年的獨家經營權。

And then one last question for Friedreich ataxia in the US. Do you expect AdCom?

最後一個問題是關於美國弗里德賴希共濟失調症的。您期待 AdCom 嗎？

Hard to know, obviously we'll submit the package. We expect to submit it in December. We would expect there to be a prior review. We'll find out at that point whether or not there'd be an AdCom. Now, certainly the FDA is quite familiar with Friedreich ataxia having already approved a therapy for that disease.

很難知道，顯然我們會提交包裹。我們預計將於 12 月提交。我們期望事先進行審查。我們會在那時發現是否會有 AdCom。現在，FDA 對弗里德賴希共濟失調症非常熟悉，並且已經批准了一種治療該疾病的方法。

And there's obviously a number of therapies in development. So they should have a great deal of understanding of the endpoints. And particularly we know they have a very good understanding of the importance of the upright stability subscale with our discussion.

顯然有多種治療方法正在研發中。所以他們應該對端點有很深入的了解。特別是，我們知道，透過我們的討論，他們非常理解直立穩定性分量表的重要性。

So I don't know that they would need to have an AdCom from the standpoint of this being novel in terms of first disease therapy or first time they've looked at this endpoint. But if there is an AdCom, we'll be ready for it.

因此，從首次疾病治療或首次研究該終點的新穎性角度來看，我不知道他們是否需要召開 AdCom。但如果有 AdCom，我們會做好準備。

Sami Corwin, William Blair.

薩米·科溫、威廉·布萊爾。

Hey, there. Congrats on the quarter and thanks for taking my questions. As you look ahead for the launch of sepiapterin, are you envisioning specific patients to be early adopters and what are your assumptions in terms of the percentage of patients that may go on the drug, who would be classical. And based on your conversations with payers, have they kind of disclosed that many of their covered patients would have to step through generic Kuvan? And then I have a follow-up.

嘿。恭喜本季取得佳績，感謝您回答我的問題。在展望 sepiapterin 的上市時，您是否設想特定的患者會成為早期採用者，以及您對可能服用該藥物的患者的百分比（經典患者百分比）有何假設。根據您與付款人的對話，他們是否透露過，許多受保患者將需要服用仿製 Kuvan 藥物？然後我有一個後續問題。

Yeah, sure, let me start, and I'll turn it over to Eric. So as we talked about, we see several segments of the population that would be early adopters, including those that are Kuvan non-responders, which would be classical PKU patients or those not tried on Kuvan as well as those who've been on BH4 and not had optimal response.

是的，當然，讓我開始，然後我會把它交給艾瑞克。正如我們所說，我們看到人群中的幾個群體將成為早期採用者，包括對 Kuvan 無反應的人，他們是典型的 PKU 患者或未嘗試過 Kuvan 的患者，以及曾使用 BH4 但反應不佳的患者。

So those are two segments that we believe that we can easily access just based on the strength of data from the APHENITY study. And as we've heard from KOLs in our commercial detail last summer, they're saying they want to try all their patients on sepiapterin regardless of whether they fit into those buckets. But let me pass over to Eric, who can talk a bit more about how payer dynamics can play into that.

因此，我們相信，僅憑 APHENITY 研究的數據強度，我們就可以輕鬆存取這兩個部分。正如我們在去年夏天的商業細節中從 KOL 那裡聽到的那樣，他們表示他們希望讓所有患者嘗試使用墨蝶呤，無論他們是否符合上述條件。但請讓我把問題交給 Eric，他可以進一步講解付款人動態如何發揮作用。

Yes, Sami, thanks for the question. It surely is an unmet need market right now, what we've seen is 90% of the patients don't get medical treatment. They've either tried, failed or discontinued for a variety of reasons.

是的，薩米，謝謝你的提問。這肯定是一個目前尚未滿足的需求市場，我們看到 90％ 的患者都沒有得到治療。由於各種原因，他們或嘗試過，或失敗了，或放棄了。

And the current standards of care are inadequate and physicians see that, but also payers see that. So it's not a very difficult conversation when we discuss this with payers around the world in these key markets, also with US payers, that one, there is a substantial number of patients that can benefit from treatment from a highly efficacious and oral treatment that can be easily taken.

目前的護理標準不夠充分，醫生看到了這一點，付款人也看到了這一點。因此，當我們與這些主要市場的世界各地的付款人（包括美國付款人）討論這一問題時，這並不是一次非常困難的對話，因為有相當多的患者可以從一種高效且易於服用的口服治療中受益。

Second, as I mentioned earlier, we can have a premium pricing strategy simply because they recognize that these patients do not have adequate treatment. They're not controlled with diet, they're not controlled with current treatments, and they can actually measure what efficacy is very quickly and rapidly. So this isn't something that is a burden in terms of the costs. They can see fee level reductions very rapidly. They can measure diet liberalization.

第二，正如我之前提到的，我們可以採取溢價策略，因為他們認識到這些病人沒有得到充分的治療。它們不受飲食控制，也不受當前治療控制，而且它們實際上可以非常快速地測量療效。因此從成本角度來說這並不是什麼負擔。他們能夠很快地看到費用水準的降低。他們可以衡量飲食自由化。

They can also measure how many patients actually get to therapeutic goals. So everything that we presented has been supported by the APHENITY data and the head-to-head study so far has been well received by the payer community.

他們還可以衡量有多少患者真正達到了治療目標。因此，我們所提出的所有內容都得到了 APHENITY 數據的支持，並且迄今為止的頭對頭研究已經得到了付款人群體的一致好評。

And when we've talked about premium pricing strategy, we definitely know that physicians and patients already know the access pathway there will be able to get access to treatment quickly and rapidly.

當我們談到溢價策略時，我們確實知道醫生和患者已經知道了獲得治療的途徑，從而能夠快速獲得治療。

To your question about step edits, I think, it's a very simple and easy thing because again, fee levels can be measured very quickly.

對於您關於步驟編輯的問題，我認為這是一件非常簡單和容易的事情，因為費用水平可以很快地衡量出來。

So step edits we can get patients quickly onto sepiapterin through prior authorizations and rapidly through fee measurements. So overall right now the response has been overwhelming by the APHENITY data and the PKU community right now is very excited to have a new treatment option.

因此，透過逐步編輯，我們可以透過事先授權和費用測量迅速讓患者快速使用 sepiapterin。因此總體而言，目前 APHENITY 數據的反應非常熱烈，PKU 社群現在對有一種新的治療選擇感到非常興奮。

Great. Thank you. And I think the team has pointed out the $1 billion opportunity in PKU before and that was with the assumption of modest penetration. So I guess what are your internal assumptions for penetration to reach that $1 billion opportunity in the US?

偉大的。謝謝。我認為該團隊之前已經指出了 PKU 的 10 億美元機遇，而且這是基於適度滲透的假設。那麼，我猜，對於在美國達到 10 億美元機會的滲透率，您的內部假設是什麼？

Yeah, I think, right now I would say first of all we're preparing for a global launch. All right? So there's going to be contribution everywhere. But we believe that there's $1 billion opportunity in the US alone. And if you look again, if you have somewhere between 17,000 patients and 20,000 patients and 90% of them are not on medical treatment, a very modest penetration, even somewhere between 20% to 30% would get you there.

是的，我想，現在我首先要說的是，我們正在為全球發布做準備。好的？所以到處都會有貢獻。但我們相信，光在美國就有10億美元的機會。如果你再看一下，如果你有 17,000 到 20,000 名患者，其中 90％ 沒有接受治療，那麼只需非常適度的滲透率，甚至 20％ 到 30％ 之間的某個值就可以達到這個目標。

And especially if it's supported by a premium pricing strategy, which we believe we can get. And while we believe $1 billion launch in the US alone is an important opportunity, we're not ready to guide yet on the product, we're going to be, as we get closer and closer to launch, we will be guiding on product revenue. We're excited with this opportunity because of the substantial unmet need and how many patients currently are not on medical treatments.

特別是如果它得到溢價策略的支持，我們相信我們可以得到。雖然我們認為僅在美國就能獲得 10 億美元的收益就是一個重要的機會，但我們尚未準備好對產品進行指導，隨著發布的臨近，我們將對產品收入進行指導。我們對這個機會感到非常興奮，因為目前仍有大量未滿足的醫療需求，而且有許多患者沒有接受治療。

Peyton Bohnsack, TD Cowen.

佩頓·博恩薩克（Peyton Bohnsack），TD Cowen。

Hi. This is Peyton on for Joe and congrats on another strong quarter and thanks for taking our questions. I guess on the vatiquinone application for December, what's outstanding for the submission and then I know the FDA requested certain stats natural history when you were designing the analysis. Have you sent that to the FDA? Have they reviewed it and given any feedback? And then I've got a follow-up. Thanks.

你好。我是 Peyton，代替 Joe 發言，祝賀您本季取得另一個強勁成績，感謝您回答我們的問題。我想，在 12 月的 vatiquinone 申請中，提交的內容有哪些未完成，然後我知道 FDA 在設計分析時要求某些統計自然史。您將其發送給 FDA 了嗎？他們是否已審查過並給予任何回饋？然後我有一個後續行動。謝謝。

Yeah, thanks for the questions, Peyton. I'm not sure I heard the second part of your question about the statistical analysis plan? Is that what you asked?

是的，謝謝你的提問，佩頓。我不確定我是否聽清楚了你關於統計分析計劃的問題的第二部分？這就是你問的嗎？

Oh, I was asking whether or not after the readout came in October, the FDA has reviewed that or you've sent that to the FDA and if they've given any feedback on it.

哦，我想問的是，10 月數據公佈後，FDA 是否審查過該數據，或者您是否將其發送給了 FDA，他們是否給出了任何反饋。

Got it. Great. Okay. So in terms of outstanding items, we're just finishing up all of the summary reports and write ups from the long-term extension studies. Obviously, we got those results in October. It takes some time to just write that all up, format it, get the table set and send it in.

知道了。偉大的。好的。因此，就未完成的專案而言，我們剛剛完成了長期擴展研究的所有摘要報告和報告。顯然，我們在十月就得到了這些結果。把這些全部寫下來、格式化、設定表格並發送都需要一些時間。

We had our pre-NDA interaction with the agency also in October, where we reviewed with them the contents of the package, including what we were planning to show in terms of long-range, long-term outcome data. They've seen some of the data.

我們也在 10 月與該機構進行了保密協議簽署前的互動，與他們一起審查了方案的具體內容，包括我們計劃展示的長期結果數據。他們已經看到了一些數據。

And importantly, they had previously agreed to the statistical analysis plans we were using both for the analysis of the MOVE-FA long-term extension as well as the long-term extension data from the earlier placebo-controlled study completed a few years ago. So they knew exactly how we were going to analyze the data, how we were going to do, how we went about doing the matching the endpoint strategy with the primary endpoint being change in mFARS scale over time.

而且重要的是，他們之前已經同意了我們用於分析 MOVE-FA 長期擴展以及幾年前完成的早期安慰劑對照研究的長期擴展數據的統計分析計劃。所以他們確切地知道我們將如何分析數據，我們將如何做，​​我們將如何進行端點策略與主要端點（即 mFARS 量表隨時間的變化）的匹配。

And so we will fully align with them on that. And as I mentioned, they have seen some of the data. We don't expect any additional feedback from the agency until after we submit the NDA.

因此，我們將在這一點上與他們完全一致。正如我所提到的，他們已經看到了一些數據。在提交保密協議之前，我們不希望收到該機構的任何其他回饋。

Great. That makes a lot of sense. And then, I guess really quickly pivoting to Upstaza. Have all the necessary inspections been done for the manufacturing facility and then assuming approval next week, how quickly could you launch a therapy and how is patient identification going on?

偉大的。這很有道理。然後，我想很快就會轉向 Upstaza。生產設施是否已經完成所有必要的檢查？ 假設下週獲得批准，您多快可以推出治療方法，患者識別進度如何？

Yeah, so with the PDUFA date of November 13, any inspections are long since done. Everything went quite well from an inspection standpoint, and we look forward to hearing from the agency next week. We obviously remain optimistic about the potential for approval based on our interactions and we look forward to being able to bring this transformative therapy to patients in the US as quickly as possible.

是的，PDUFA 日期為 11 月 13 日，任何檢查都早已完成。從檢查的角度來看一切都進展順利，我們期待下週收到該機構的回覆。基於我們的互動，我們顯然對獲得批准的可能性保持樂觀，我們期待能夠盡快為美國患者帶來這種變革性療法。

Paul Choi, Goldman Sachs.

高盛的保羅·崔（Paul Choi）。

Hi. Good afternoon and congratulations on the quarter. Thank you for taking our questions. I want to maybe just follow up on with regard to vatiquinone payer discussions here. Can you maybe just comment on what payer feedback has been and just sort of how you may be potentially sort of thinking about pricing relative to Skyclarys here for the adult population.

你好。下午好，恭喜本季取得佳績。感謝您回答我們的問題。我可能只是想跟進一下這裡有關 vatiquinone 付款人的討論。您能否評論一下付款人的回饋，以及您可能如何考慮相對於 Skyclarys 針對成年人口的定價。

And secondly the cash position remains very healthy here. And Matt, I just wanted to sort of ask what your appetite is currently for potential external business development versus funding the upcoming multiple launches here in '25. Thank you very much.

其次，我們的現金狀況依然非常健康。馬特，我只是想問一下，您目前對潛在的外部業務發展的興趣與為 25 年即將推出的多項業務提供資金的興趣相比如何。非常感謝。

Yeah, thanks for the questions, Paul. Obviously, we're a bit early to be having the payer discussions on vatiquinone. We're focused now on getting the package in. But I would say that, look, it's we -- there's a clear unmet need for pediatric and adolescent patients and we have a data package in terms of safety and efficacy that supports an important benefit for these patients.

是的，謝謝你的提問，保羅。顯然，我們現在就 vatiquinone 的付款人討論還為時過早。我們現在的重點是收到包裹。但我想說，看，我們——兒科和青少年患者顯然存在未滿足的需求，並且我們在安全性和有效性方面擁有一套數據包，可以為這些患者帶來重要的益處。

As we know as well, there's not only an important proportion of patients who are pediatric and adolescent, but as diagnosis is increasing in the field, patients who are being diagnosed are increasingly young. And so that need, that unmet need for FA patients is getting strong.

我們也知道，不僅兒童和青少年患者佔了很大比例，而且隨著該領域診斷的增加，被診斷的患者也越來越年輕。因此，FA 患者尚未滿足的這種需求正變得越來越強烈。

And we look forward to being able to provide a safe and effective therapy for those patients. But as you raised, we also believe we can be able to provide a therapy for adult patients. We have evidence in MOVE-FA of benefit in adult patients. We have evidence on the upright stability scale, which speaks directly to the ability to reduce risk of loss of ambulation, which is incredibly important for any ambulatory Friedreich ataxia patient of any age.

我們期待能夠為這些患者提供安全有效的治療方法。但正如您所說，我們也相信我們能夠為成年患者提供治療。我們有 MOVE-FA 證據表明其對成年患者有益。我們有直立穩定性量表的證據，這直接說明了降低失去行走能力的風險的能力，這對於任何年齡的任何能夠行走的弗里德賴希共濟失調患者都非常重要。

And of course, in the long-term extension studies of both MOVE-FA as well as the earlier placebo-controlled study, which was conducted only in adults, we have evidence of importance important long-term benefit in slowing disease progression.

當然，在 MOVE-FA 的長期擴展研究以及早期僅針對成人進行的安慰劑對照研究中，我們有證據表明其在減緩疾病進展方面具有重要的長期益處。

Again, we also have a very strong safety and tolerability profile. So I believe we have really a differentiated product that we look forward to thinking about how to price and also having discussions with the payers on that. In terms of the cash position, look, we've worked very hard both in terms of restructuring the balance sheet towards the end of last year.

再次，我們也具有非常強的安全性和耐受性。因此，我相信我們確實擁有差異化的產品，我們期待考慮如何定價，並與付款人進行討論。就現金狀況而言，我們在去年年底重組資產負債表方面已經付出了很大的努力。

Our efforts to reduce operating expenses and move the company towards cash flow break even. I think having this strong cash balance not only enables us to launch the products and we would love to be in that situation rather than having needing to have the capital to launch more products within a year in the US and the global launch of sepiapterin, but we also of course remain opportunistic about business development and we have the cash we have at hand.

我們努力降低營運費用並推動公司實現現金流收支平衡。我認為擁有如此強大的現金餘額不僅使我們能夠推出產品，而且我們也很樂意處於這種情況，而不需要擁有資本在一年內在美國推出更多產品並在全球推出 sepiapterin，但我們當然也會對業務發展保持機會主義，而且我們手頭有現金。

We also have the ability, if we needed to, to draw down some of the additional royalty monetization that we did with royalty pharma if we saw an opportunity that fits well into our portfolio. Look, we're in a position where we could be launching many products in the US in the short-term.

如果需要的話，我們還有能力提取一些額外的特許權使用費貨幣化，如果我們發現一個適合我們投資組合的機會。你看，我們可以在短期內在美國推出許多產品。

And so now we need to think about how we could use business development in a strategic way to help fill out the commercial portfolio ex-US and also think about any other opportunities that can set very easily into our existing commercial infrastructure or even development infrastructure.

因此，現在我們需要考慮如何以策略性的方式利用業務發展來幫助填補美國以外的商業組合，同時也考慮任何可以輕鬆融入我們現有商業基礎設施甚至開發基礎設施的其他機會。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

Thank you. I have a few quick questions. The first one regarding sepiapterin, PDUFA date July 29, 2025, just want to confirm that FDA confirmed there will be no ad account.

謝謝。我有幾個簡單的問題。第一篇是關於 sepiapterin，PDUFA 日期為 2025 年 7 月 29 日，只是想確認 FDA 確認不會有廣告帳號。

Second question is regarding the Translarna, you mentioned that right now the 67 days in EU. So can you walk us through like say after 67 days, if the decision is unfavorable, what will be the next steps and how long would that take the process and then when we really will see the actual impact on the revenue in Europe and related questions or maybe unrelated Brazil, I know you are under independent assessment there.

第二個問題是關於 Translarna，您提到現在在歐盟的期限是 67 天。那麼，您能否向我們介紹一下，比如說，67 天后，如果決定不利，接下來的步驟是什麼，這個過程需要多長時間，然後我們何時才能真正看到對歐洲收入的實際影響以及相關問題，或者可能是不相關的巴西，我知道你在那裡正在接受獨立評估。

They have an independent approval process back in April. Any update there regarding the renewal process there?

早在四月份，他們就有一個獨立的審批流程。關於那裡的更新流程有什麼最新消息嗎？

Lastly, very quickly regarding AADC next week you will get approval hopefully keep our fingers crossed. How ready are you regarding the manufacturing? How many doses you already stocked? And how quick you think you can get ready to how many patients you already identified in the US?

最後，關於 AADC，下週您將很快獲得批准，希望您能為我們祈禱。您對製造做好準備了嗎？你已經儲存了多少劑量？您認為您能多快準備好應對美國已經確定的患者數量？

Gena, thank you for the questions. Let me walk through them one by one. First, on the PDUFA date for sepiapterin, it is July 29th, 2025. We do not expect it to be an AdCom. There's been no indication of AdCom and again, we're in a situation where the endpoint of the trial reduction of phenylalanine is published as being one of the blood tests that can support full approval.

吉娜，謝謝你的提問。讓我一一介紹一下。首先，墨角蝶呤的 PDUFA 日期是 2025 年 7 月 29 日。我們不希望它是一個 AdCom。目前還沒有任何 AdCom 的跡象，而且我們目前的情況是，試驗中減少苯丙胺酸的終點已被公佈為可以支持完全批准的血液測試之一。

Obviously, the agency understands PKU. They've approved two therapies before for PKU. So I think this is not one where we would expect to have an AdCom, in addition the clear efficacy of in the data package is also leaves very little question I think that would needed to be brought to an AdCom.

顯然，該機構了解北大。他們之前已批准了兩種治療苯酮尿症的療法。因此，我認為這不是我們期望召開 AdCom 的地方，此外，資料包中的明確功效也幾乎沒有留下任何疑問，我認為需要將其提交給 AdCom。

Your second question was about Translarna and a timeline in the EU. Look, the 67 days is an approximately 67 days, as we learned the first time we went through this in the spring, we expected 67 days to take us from late January to late March, early April and it wasn't until late May that we actually got confirmation that the EC had made the decision to not adopt opinion and send things back to the CHMP.

您的第二個問題是關於 Translarna 和歐盟的時間表。你看，67 天大約是 67 天，正如我們在春季第一次經歷這個過程時了解到的那樣，我們預計 67 天會從 1 月底到 3 月底、4 月初，但直到 5 月底我們才真正得到確認，EC 已決定不採納意見並將事情發回 CHMP。

So I think it's the approximate 67 days. And Gena, we can't say for sure what happens on the other side of that because it's going to depend what the European Commission says. They could adopt the opinion and say we're going to adopt it for immediate implementation or we're going to adopt it with delay implementation. We're in a situation here, it's important to realize that this is not being, this has not come about due to a safety issue.

所以我認為大約是 67 天。吉娜，我們不能肯定地說接下來會發生什麼，因為這取決於歐盟委員會的說法。他們可以採納該意見，並說我們將立即實施該意見，或者我們將延遲實施該意見。我們處於這樣的情況，重要的是要認識到這不是由於安全問題而發生的。

So there's no patient risks here in terms of there being an urgency to get the product off the market. So I think that may also provide a little bit of flexibility as well in terms of what exactly happens in terms of the steps following an adoption of the negative opinion. And then of course it's sent back to the CHMP, then that's a whole lot to see what those instructions are as well. So still a lot of unknown there.

因此，從緊急將產品撤出市場的角度來說，並不會對患者構成風險。因此，我認為這也可能提供一點彈性，具體到採納負面意見後採取的步驟方面。然後，它當然會被發回給 CHMP，然後也要查看大量指令。因此，仍有許多未知數。

The 67 days is approximate and obviously, we'll learn more as we reach that timeline. In terms of Brazil, it is an independent assessment. It has been ongoing. We have not gotten any additional feedback from ANVISA. What we do know is that we had two orders in Brazil, bulk orders, one in the second quarter, one in the third quarter.

67 天是大概的時間，顯然，到達這個時間線後我們就會了解更多。就巴西而言，這是一次獨立評估。它一直在進行中。我們尚未收到來自 ANVISA 的任何其他回饋。我們確實知道的是，我們在巴西有兩份訂單，都是大宗訂單，一份在第二季度，一份在第三季度。

We obviously view that as a good sign that there's obviously a strong interest for the Minister of Health to ensure that patients in Brazil remain on Translarna. And then in terms of AADC, we're ready. I mean, again, we had the EU approval in 2022, we've had approvals. We had a recent approval in Brazil for AADC deficiency. We had approval in Taiwan, approval in the UK. We're doing cross-border care. We're in the process of treating patients around the globe.

我們顯然認為這是一個好兆頭，表明衛生部長顯然有強烈的意願確保巴西的患者繼續使用 Translarna。就 AADC 而言，我們已經準備好了。我的意思是，我們在 2022 年獲得了歐盟的批准，我們已經獲得了批准。我們最近在巴西獲得了針對 AADC 缺乏症的批准。我們已獲得台灣和英國的批准。我們正在進行跨境護理。我們正在為世界各地的患者進行治療。

So we have more than adequate supply and again, once we see the label, we'll understand what the addressable patient market could look like in the US and we have, we believe, more than enough supply at hand to treat patients well through the next one to two years.

因此，我們的供應綽綽有餘，而且，一旦我們看到標籤，我們就會了解美國的潛在患者市場是什麼樣的，而且我們相信，我們手頭的供應綽綽有餘，可以在未來一到兩年內為患者提供良好的治療。

Danielle Brill, Raymond James.

丹妮爾·布里爾、雷蒙德·詹姆斯。

Great. Thank you so much for the question. I just have a quick clarification from an earlier question. I'm curious why the Translarna NDA submission is technically a resubmission under protest. Why wouldn't it be a new NDA since you now have new data to review from Study 041. Thanks so much.

偉大的。非常感謝您的提問。我只是想快速澄清一下之前的一個問題。我很好奇為什麼 Translarna NDA 提交從技術上講是抗議下的重新提交。既然您現在有了來自研究 041 的新數據需要審查，為什麼這不能成為一份新的保密協議 (NDA)？非常感謝。

Yeah, Danielle, this goes back to 2016, 2017. In 2016, the NDA was filed over protest. The agency reviewed it and issued a complete response letter. The main issue in the complete response letter was the need to conduct an additional adequate and well-controlled trial to establish efficacy.

是的，丹妮爾，這可以追溯到 2016 年、2017 年。2016 年，該保密協議不顧抗議被提交。該機構對其進行了審查並發出了完整的回复信。完整回覆信中的主要問題是需要進行額外的充分且控制良好的試驗來確定療效。

Study 041 addresses what was in that CRL and therefore this was technically a resubmission of that NDA, now fulfilling the deficiency identified that led to the complete response previously in 2016. Does that make sense?

研究 041 解決了該 CRL 中的內容，因此從技術上講這是該 NDA 的重新提交，現已彌補了導致 2016 年之前完全回應的已發現的缺陷。這樣有道理嗎？

Joe Schwartz, Leerink Partners.

Leerink Partners 的 Joe Schwartz。

Hi. Thanks so much. I have a question about vatiquinone and one on utreloxastat. So in FA, we've heard that while some patients think that they've benefited, more patients seem to not be blown away by Skyclarys' efficacy.

你好。非常感謝。我有一個關於瓦替醌 (vatiquinone) 和烏瑞洛司他 (utreloxastat) 的問題。因此在 FA 中，我們聽說雖然有些患者認為他們受益了，但更多的患者似乎並沒有被 Skyclarys 的功效所震撼。

So we're wondering how that might influence how patients might feel about vatiquinone, which is following its footsteps and works further downstream. How do you think this market is evolving now in terms of patient demand and retention for new treatment options as well as their potential to switch or try a combo with vatiquinone?

因此，我們想知道這可能會如何影響患者對 vatiquinone 的感受，vatiquinone 正在追隨其腳步並在更下游發揮作用。就患者對新治療方案的需求和保留以及他們轉換或嘗試與 vatiquinone 聯合治療的潛力而言，您認為這個市場現在如何發展？

Yeah. Thanks for the question, Joe. First, vatiquinone acts upstream of, at least mechanistically, of where Skyclarys is in terms of its effects in the ferroptosis pathway. But I would say, look, I think clearly there's no option for pediatric and adolescent patients with Skyclarys, given the age limitations of the label.

是的。謝謝你的提問，喬。首先，就鐵死亡途徑的作用而言，vatiquinone 至少在機制上比 Skyclarys 處於上游。但我想說，看，我認為顯然考慮到標籤上的年齡限制，兒科和青少年患者沒有使用 Skyclarys 的選擇。

And in terms of the adults, I think it's always hard with drugs that slow disease progressions and patients' perceptions of if they're getting better or not. It's always hard to know. But needless to say, I think that we would certainly be able to provide a therapeutic option, where we believe we can provide benefit to patients.

就成年人而言，我認為用藥物來減緩病情進展以及患者對自己是否好轉的認知總是很困難。這總是很難知道。但不用說，我認為我們肯定能夠提供一種治療選擇，我們相信我們可以為患者帶來益處。

The data from MOVE-FA show an effect not only in slowing of disease progression, but also a significant effect on the fatigue scale, which we know is the number one symptomatic complaint of patients with Friedreich ataxia. Do I think that people will be interested in combo therapies? I do. A lot to be sorted out there, of course, in terms of payers and such.

MOVE-FA 的數據不僅顯示出減緩疾病進展的效果，而且對疲勞量表也有顯著影響，我們知道疲勞是弗里德賴希共濟失調患者的首要症狀。我是否認為人們會對聯合療法感興趣？我願意。當然，在付款人等方面還有很多事情需要解決。

But I think, look, when anytime you have a complex disorder like Friedreich ataxia, it would make sense that you likely would need more than one therapy. And it might be that two therapies could have a combined effect.

但我認為，當您患有像弗里德賴希共濟失調這樣的複雜疾病時，您可能需要多種治療方法，這是有道理的。兩種療法也許能產生綜合效果。

But look we look forward to being able to offer vatiquinone to FA patients, particularly the kids and adolescents who desperately need a therapy. I mean, look, if you're going to slow disease progression, the best thing to do is to start as early as possible so that you can enjoy the benefits of slow progression as much as possible. And for adults, we welcome the opportunity to provide them with a safe and effective therapy as well.

但是，我們期待能夠為 FA 患者提供瓦替奎酮，特別是那些迫切需要治療的兒童和青少年。我的意思是，如果你想減緩病情進展，最好的方法是儘早開始，這樣你就可以盡可能享受緩慢進展的好處。對於成年人，我們也歡迎有機會為他們提供安全有效的治療。

Okay. Thank you. And then for targeting ferroptosis in ALS, can you give us some context for what you're trying to achieve mechanistically? Is there a particular threshold you're looking to meet based on any preclinical or natural history data that supports your therapeutic hypothesis? And have you done anything in the CardinALS study to select patients that might best respond?

好的。謝謝。那麼，針對 ALS 中的鐵死亡，您能否從機制上為我們介紹一下您想要實現的目標？根據支持您的治療假設的任何臨床前或自然史數據，您是否希望達到特定的閾值？在 CardinALS 研究中，您是否採取任何措施來選擇對治療反應最靈敏的患者？

Yeah, it's really good question, Joe. Obviously, this is the first disease study we have with utreloxastat in ALS, and I expect we'll learn a lot on the other side about how enrichment could possibly go. But look the rationale for targeting ferroptosis is very well established in ALS. There's a number of different preclinical studies that clearly show that if you target ferroptosis, whether that's by inducing overexpression of GPX4, which is a key enzyme in the ferroptosis pathway, you have significant phenotypic benefit.

是的，喬，這真是一個好問題。顯然，這是我們首次使用烏曲洛司他治療 ALS 疾病的研究，我期望我們能從另一方面了解到如何進行富集治療。但看起來，針對鐵死亡的理論在 ALS 中已經非常完善。許多不同的臨床前研究清楚地表明，如果你以鐵死亡為目標，無論是透過誘導 GPX4（鐵死亡途徑中的關鍵酶）的過度表達，你都會獲得顯著的表型益處。

Similarly, if you augment the ferroptosis process through any number of insults, you can accelerate decline in ALS. The whole concept of SOD1 in superoxide dismutase speaks directly to being able to affect oxidative stress and the relevance of oxidative stress in ALS.

類似地，如果透過任意數量的刺激來增強鐵死亡過程，那麼就可以加速 ALS 的衰退。超氧化物歧化酶中 SOD1 的整個概念直接說明了能夠影響氧化壓力以及氧化壓力與 ALS 的相關性。

So there's a great bit of data to support the rationale for targeting ferroptosis. But look, ALS is an incredibly complex and aggressive disease. We hope to be able to provide a therapy that could slow that progression by targeting what's known to be a key pathologic element.

因此，有大量數據支持針對鐵死亡的理論。但要知道，ALS 是一種極為複雜且具侵襲性的疾病。我們希望能夠透過針對已知的關鍵病理因素來提供一種可以減緩病情進展的治療方法。

Thank you. This concludes the question-and-answer session. I would now like to turn it back to Dr. Matthew Klein, CEO, for concluding remarks.

謝謝。問答環節到此結束。現在我想請執行長馬修·克萊恩博士作最後發言。

Okay. Thank you very much, operator. Let me just follow on the last question to Joe and just share with everyone that, as we are getting close to having data for the utreloxastat CardinALS study, following this call, we're going to not be taking any questions and being sort of quiet period for the CardinALS study just because of where we are in terms of being close to having data in the next period of time.

好的。非常感謝，接線生。讓我接著問喬的最後一個問題，與大家分享一下，由於我們即將獲得 utreloxastat CardinALS 研究的數據，在這次電話會議之後，我們將不會回答任何問題，並且將為 CardinALS 研究設定一個靜默期，因為我們即將在下一個時期獲得數據。

Overall, again, thank you everyone for joining the call. We're incredibly excited about the strength of the quarter, the revenue performance, the ability of our teams to continue to execute at an incredibly high level across all parts of the company, whether it be on the commercial side, on the clinical, and the regulatory side and all around.

總之，再次感謝大家參加電話會議。我們對本季度的強勁表現、收入表現以及我們團隊在公司各個部門（無論是商業方面、臨床方面、監管方面還是其他各個方面）繼續以令人難以置信的高水平執行的能力感到非常興奮。

We look forward to keeping you updated, as we saw the number of important milestones this year. And again thank you all for joining the call and have a good evening.

我們期待向您通報最新情況，因為我們看到了今年的許多重要里程碑。再次感謝大家參加電話會議並祝大家晚上愉快。

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

感謝您參加今天的會議。該計劃確實結束了。您現在可以斷開連線。