Krystal Biotech Inc (KRYS) 2024 Q4 法說會逐字稿

Thank you for holding, we sincerely appreciate your patience. Please stay on the line and we'll be back in a moment.

感謝您的關注，我們真誠地感謝您的耐心。請保持通話，我們馬上回來。

Thank you for holding. We look forward to talking with you soon. Please hold the line and we'll be right back with you.

謝謝您持續。我們期待很快與您交談。請稍候，我們很快就會回覆您。

Thank you for standing by and welcome to the Krystal Biotech Q4 2024 earnings call. (Operator Instructions) As a reminder, today's conference is being recorded. I would now like to hand the conference over to your host, Stephane Paquette, Vice President of Corporate Development. You may begin.

感謝您的支持，歡迎參加 Krystal Biotech 2024 年第四季財報電話會議。（操作員指示）提醒一下，今天的會議正在錄音。現在，我想將會議交給主持人、企業發展副總裁 Stephane Paquette。你可以開始了。

Good morning and thank you all for joining today's call. Earlier today, we released our financial results for the fourth quarter and full year of 2024. The press release is available on our website at www.krystalbio.com. We also filed our earnings 8-K and 10-K with the SEC earlier today.

早安，感謝大家參加今天的電話會議。今天早些時候，我們發布了 2024 年第四季和全年財務表現。新聞稿可在我們的網站 www.krystalbio.com 上查閱。今天早些時候，我們也向美國證券交易委員會提交了 8-K 和 10-K 收益報告。

Joining me today will be Krish Krishnan, Chairman and Chief Executive Officer; Suma Krishnan, President of Research and Development; Jennifer McDonough, Senior Vice President of Patient Access Analytics and Operations; Christine Wilson, Senior Vice President and Head of US Sales and Marketing; and Kathryn Romano, Chief Accounting Officer.

今天與我一起出席的還有董事長兼首席執行官克里什·克里希南 (Krish Krishnan)；研發總裁 Suma Krishnan； Jennifer McDonough，患者訪問分析和運營高級副總裁；克里斯汀·威爾遜 (Christine Wilson)，高級副總裁兼美國銷售和營銷主管；以及首席會計官凱瑟琳·羅馬諾（Kathryn Romano）。

This conference call will, and our responses to questions may contain forward-looking statements. You are cautioned not to rely on these forward-looking statements, which are based on current expectations using the information available as of the date of this call and are subject to certain risks and uncertainties that may cause the company's actual results to differ materially from those projected. A description of these risks, uncertainties, and other factors can be found in our SEC filings.

本次電話會議以及我們對問題的回答可能包含前瞻性陳述。請注意不要依賴這些前瞻性陳述，這些陳述是基於使用截至本次電話會議之日可用的資訊做出的當前預期，並受某些風險和不確定性的影響，這些風險和不確定性可能導致公司的實際結果與預測結果有重大差異。這些風險、不確定性和其他因素的描述可以在我們的美國證券交易委員會文件中找到。

With that, I will turn the call over to Krish.

說完這些，我將把電話轉給克里什 (Krish)。

Stephane, thank you. Good morning and welcome to the call. 2024 was a strong year for Krystal. VYJUVEK US launch continued to progress well and tracks in the top tier of rare disease launches. The strength of the launch speaks to the robust efficacy and safety profile of VYJUVEK. And our relentless focus on patient and physician experience.

史蒂芬，謝謝你。早安，歡迎來電。 2024 年對 Krystal 來說是豐收的一年。VYJUVEK 在美國上市繼續進展順利，並躋身罕見疾病上市的頂級行列。此次上市的強勁表現證明了 VYJUVEK 強大的功效和安全性。我們始終堅持不懈地關注患者和醫生的體驗。

In addition, in 2024, we demonstrated that we can safely and repeatedly deliver genes to the lung with a nebulizer across our cystic fibrosis, alpha-1 antitrypsin, and NSCLC programs. Clearly validating the lung as the second target tissue for our platform.

此外，2024 年，我們證明，我們可以透過囊性纖維化、α-1 抗胰蛋白酶和 NSCLC 計劃，使用霧化器安全且重複地將基因輸送到肺部。明確驗證肺是我們平台的第二個目標組織。

There were also strong early signs of efficacy in our readouts, and we fully expect the data to mature later this year. Looking ahead at 2025, we have three primary things to accomplish.

我們的讀數中也出現了強烈的早期療效跡象，我們完全預期數據將在今年稍後成熟。展望2025年，我們有三件主要的事情要做。

First, a successful VYJUVEK launch in EU and Japan. Second, to translate the early signs of efficacy into strong results across our CF and A1AT programs. And the third is to prepare for the anticipated launch of B-VEC to treat lesions in the eye of deaf patients.

首先，VYJUVEK 在歐盟和日本成功上市。其次，將早期的療效跡象轉化為我們 CF 和 A1AT 計畫的強勁成果。第三是為即將上市的B-VEC做準備，用於治療聾啞患者眼部病變。

If we do this right, we believe the company will be in a much stronger place with respect to revenue, net income, and market cap going into 2026. For the year, net income per share was $3.12 per share, subsequentially from $0.40 per share in 2023.

如果我們做得對，我們相信到 2026 年，公司的收入、淨收入和市值將處於更強勁的地位。全年每股淨利潤為 3.12 美元，高於 2023 年的每股 0.40 美元。

This is our sixth straight quarter of positive EPS and fourth straight quarter of sequential earnings growth. In addition to operational success, we have also put ourselves in a strong financial position of future growth.

這是我們連續第六個季度實現每股收益為正，連續第四個季度實現盈利增長。除了營運上的成功之外，我們還為未來的成長建立了強大的財務狀況。

In aesthetics, Jeune Aesthetics reported a strong KB301 Phase 1 data for the treatment of decollete, and we plan to start a Phase 2 study later this year. We're in the process of building out a season management team at Jeune Aesthetics, with more to come on this later in 2025.

在美學方面，Jeune Aesthetics 報告了用於治療胸部的強烈 KB301 第 1 階段數據，我們計劃在今年稍後啟動第 2 階段研究。我們正在為 Jeune Aesthetics 組建一個季節管理團隊，並將在 2025 年下半年推出更多內容。

$341 million in net revenue within 18 months of launch and sequential revenue growth for six straight quarters is a tremendous achievement and a testament to the tireless contributions by our commercial and patient support teams on behalf of patients with DEB.

在推出後 18 個月內實現 3.41 億美元的淨收入並連續六個季度實現收入增長，這是一項巨大的成就，也是我們的商業和患者支持團隊為 DEB 患者做出的不懈貢獻的證明。

Net VYJUVEK revenue for the Q came in at $91.1 million, bringing revenue for 2024 to 290.5 million. Gross margins and GTN were consistent with prior Qs.

VYJUVEK Q 的淨收入為 9,110 萬美元，使得 2024 年的收入達到 2.905 億美元。毛利率和 GTN 與前幾季度一致。

I'll now turn it over to Jen and Christine to share more details on the US launch.

現在我將把主題交給 Jen 和 Christine，分享更多有關美國發布的細節。

Thank you, Krish. Looking back on 2024 and now the early days of 2025, I'm incredibly proud of what our team has been able to accomplish. With steady progress over the entire year in a strong access landscape carrying over from 2024 into 2025, a growing number of dead patients have or will soon benefit from fundamentally corrective by VYJUVEK therapy.

謝謝你，克里什。回顧 2024 年以及現在的 2025 年初，我為我們團隊所取得的成就感到無比自豪。隨著 2024 年至 2025 年強勁的可及性格局在全年穩步推進，越來越多的死亡患者已經或即將從 VYJUVEK 療法的根本性矯正中受益。

I'm also happy to share a major milestone achievement for our United States team as we recently crossed 500 reimbursement approvals nationwide. As of February, the number of patients with reimbursement approvals exceeds 510. This is in spite of losing a few weeks to holidays in the fourth quarter. With a good pick up of the pace of approvals to start 2025, as well as strong underlying demand trends, we remain confident in our ability to hit our ambitious pre-launch penetration targets.

我也很高興與大家分享我們美國團隊取得的一個重要的里程碑式成就：我們最近在全國範圍內獲得了超過 500 份報銷批准。截至2月份，獲得報銷批准的患者人數超過510人。儘管第四季因假期損失了幾週時間，但業績仍然保持良好。隨著 2025 年開始審批速度的良好加快，以及強勁的潛在需求趨勢，我們仍然有信心實現我們雄心勃勃的上市前滲透目標。

Reimbursement approval splits were again largely in line with recent quarters and roughly evenly split between commercial and government plans. Approvals continue to come across the entire dead population, including patients of all ages and with either dominant or recessive forms of the disease.

報銷批准比例與最近幾季的情況基本一致，商業計劃和政府計劃的比例大致相等。核准的治療對象涵蓋整個死亡族群，包括各個年齡層、患有顯性或隱性遺傳疾病的患者。

With effectively full nationwide commercial and Medicaid coverage, the access landscape for VYJUVEK remains strong. Reauthorizations are getting processed smoothly, all have either been approved or are in process. In the community, we are still seeing a lag from prescription to approval dictated primarily by the availability of genetic test results and prescriber familiarity with access pathways.

由於全國範圍內商業和醫療補助的有效覆蓋，VYJUVEK 的可及性前景仍然強勁。重新授權正在順利進行，所有授權要么已獲得批准，要么正在處理中。在社區中，我們仍然看到從處方到批准存在滯後，這主要取決於基因測試結果的可用性和處方者對獲取途徑的熟悉程度。

As always, our Krystal Connect team is working closely with home healthcare providers to meet patient needs and preferences. It is this infrastructure and patient-centric approach that has allowed us to navigate scheduling constraints and holidays to ensure patients can get on and stay on treatment.

與往常一樣，我們的 Krystal Connect 團隊正與家庭醫療保健提供者密切合作，以滿足患者的需求和偏好。正是這種基礎設施和以患者為中心的方法使我們能夠克服時間安排限制和假期限制，以確保患者能夠接受並繼續治療。

Patient preference for at-home administration is again effectively unchanged, with 97% of the weekly treatments occurring in the home setting. Patient applies to weekly treatments while on drugs with 85% as of the end of the fourth quarter, and the third quarter it was at 87%.

患者對在家治療的偏好其實並沒有改變，每週 97% 的治療都是在家中進行。截至第四季末，患者在服藥期間申請每週治療的比例為 85%，第三季為 87%。

As we progress our US launch, we are thrilled to see that patients are achieving durable wound closure and getting to live fuller, more active lives. This, of course, is the whole point of VYJUVEK. As patients enjoy their first pauses in therapy and then settle into a more regular maintenance regimen, we do expect to see compliance to continue to trend towards the rates that we guided at launch.

隨著我們在美國市場推出該產品，我們很高興地看到患者實現了持久的傷口閉合併過著了更充實、更積極的生活。當然，這就是 VYJUVEK 的全部意義。隨著患者享受到治療的最初停頓，並逐漸適應更規律的維持治療方案，我們確實預計會看到依從性繼續趨向我們在推出時指導的水平。

We are learning from real world experience that the treatment journey for each patient is unique and dynamic. A 21-year-old initiating therapy after decades of blistering and wounding may have a very different journey than a very active toddler.

我們從現實世界的經驗中了解到，每位患者的治療過程都是獨特且動態的。一個 21 歲的年輕人在經歷了幾十年的水泡和傷口後開始接受治療，他的經歷可能與一個非常活潑的幼兒的經歷截然不同。

The time to wound closure and durability are dependent on a myriad of inputs, including nutritional status and iron levels, as well as the patient's age, their mobility and activity levels, and of course the location and the age of the specific wound treated. Because each patient and each wounded area is unique, the length and frequency of treatment pauses are personalized to the patient.

傷口癒合時間和持久性取決於多種因素，包括營養狀況和鐵水平，以及患者的年齡、活動能力和活動水平，當然還有所治療的特定傷口的位置和時間。由於每個病人和每個受傷部位都是獨一無二的，治療暫停的長度和頻率也是根據病人個人化的。

Critically, patients and their prescribers understand the importance of treatment persistence, and patients that have benefited from a pause due to full wound closure are now transitioning into an ongoing wound maintenance routine with VYJUVEK, helped by our Krystal Connect team. As always, our team will be with them every step of the way to ensure they have a steady access and can continue to enjoy the benefits of regular VYJUVEK treatment.

至關重要的是，患者及其開藥醫生了解堅持治療的重要性，在我們的 Krystal Connect 團隊的幫助下，因傷口完全閉合而受益於暫停治療的患者現在正過渡到使用 VYJUVEK 進行持續的傷口維護程序。像往常一樣，我們的團隊將陪伴他們走過每一步，以確保他們能夠穩定地獲得治療並繼續享受定期 VYJUVEK 治療的好處。

I will now hand it off to Christine to discuss recent sales and marketing activities which are keeping us on our top tier launch trajectory. Christine?

現在我將把主題交給克里斯汀，討論最近的銷售和行銷活動，這些活動使我們保持頂級的發布軌跡。克里斯汀？

Thank you, Jen. As we enter 2025, it is my pleasure to report that tactics that we developed in 2024 continue to pay dividends, driving significant growth in reimbursement approvals and strong patient demand across the country.

謝謝你，Jen。當我們進入 2025 年時，我很高興地報告，我們在 2024 年制定的策略繼續帶來回報，推動全國報銷批准的顯著增長和強勁的患者需求。

Prescribing trends, claims analytics, and patient engagement all point to strong and sustained underlying demand. Education and patient activation remain core focus areas for our field team as we look to further penetrate into the identified patient pool.

處方趨勢、索賠分析和患者參與度均顯示強勁且持續的潛在需求。當我們尋求進一步深入已確定的患者群體時，教育和患者活化仍然是我們現場團隊關注的核心領域。

We partnered with multiple advocacy groups in EB in the fourth quarter to host live webinars led by prescribing physicians and patients who shared their experience with VYJUVEK and positive progress that they've experienced since starting on therapy in 2023.

我們在第四季度與 EB 的多個倡導團體合作，舉辦了由開處方的醫生和患者主持的現場網路研討會，他們分享了使用 VYJUVEK 的經驗以及自 2023 年開始治療以來取得的積極進展。

In addition, and in honor of EB awareness week, we hosted a national broadcast led by Dr. John Browning. The virtual platform allowed us to reach healthcare professionals across the United States and showcase our clinical trial data, longer term safety and efficacy data, and case studies of patients on VYJUVEK.

此外，為了紀念 EB 宣傳週，我們舉辦了由約翰·布朗寧博士主持的全國廣播活動。虛擬平台使我們能夠接觸到美國各地的醫療保健專業人士，並展示我們的臨床試驗數據、長期安全性和有效性數據以及 VYJUVEK 患者的案例研究。

This event also included a patient ambassador on VYJUVEK sharing their firsthand experience. This comprehensive showcase of trial data and real world insights emphasized the clear and durable benefits of therapy, and critically demonstrated the significant impact it can have for patients.

本次活動還包括一位 VYJUVEK 患者大使分享他們的第一手經驗。這次試驗數據和現實世界見解的全面展示強調了治療的明顯和持久的好處，並批判性地證明了它對患者可能產生的重大影響。

We also equipped our sales team with new promotional material that emphasizes the long-term safety and efficacy of VYJUVEK. These materials not only reinforce the durable wound healing benefits that can be achieved only with a collective therapy like VYJUVEK. They also underscore that all the patients can benefit from therapy with actual patient images demonstrating healing in both the RDEB and DDEB subtypes across both the adult and pediatric spectrum.

我們也為銷售團隊配備了新的宣傳資料，強調 VYJUVEK 的長期安全性和有效性。這些材料不僅增強了只有透過 VYJUVEK 等集體療法才能實現的持久傷口癒合益處。他們也強調，所有患者都可以從治療中受益，實際患者影像顯示成人和兒童 RDEB 和 DDEB 亞型均已痊癒。

Most importantly, these efforts have yielded tangible results. Not only did we achieve significant reimbursement approval growth over the past few months, we also continue to expand our prescriber base. Over 65% of prescribers in the fourth quarter were new writers. With each new prescriber, awareness of DEB and VYJUVEK grows, extending our reach into new communities.

最重要的是，這些努力已經取得了實際的成果。在過去的幾個月裡，我們不僅實現了報銷批准數量的大幅增長，而且還繼續擴大了我們的處方基礎。第四季超過 65% 的開處方者都是新手開處方者。隨著每位新開處方者的出現，人們對 DEB 和 VYJUVEK 的認識不斷增強，將我們的影響力擴展到新的社區。

As the number of patients on therapy grows, I would also like to highlight that we have personalized and ongoing communication with patients and their caregivers to ensure they are supported throughout their journey. These communications are via phone call, email, or text, all based on the preferences of patients and their families.

隨著接受治療的患者數量不斷增長，我還想強調的是，我們與患者及其照護者保持個人化和持續的溝通，以確保他們在整個治療過程中得到支持。這些溝通是透過電話、電子郵件或簡訊進行的，完全取決於患者及其家人的喜好。

These touch points are another part of our commitment to patients, allowing us to move proactively to meet their needs with practical resources and EB community connections, while also gaining valuable insights to support new patient starts.

這些接觸點是我們對患者承諾的另一部分，使我們能夠主動利用實用資源和 EB 社區聯繫來滿足他們的需求，同時也能獲得寶貴的見解來支持新患者的開始治療。

With strong underlying demand, growing awareness, and a broadening prescriber base, we are excited to continue growing the number of patients on VYJUVEK across the US.

隨著強勁的潛在需求、日益增長的認識和不斷擴大的處方者基礎，我們很高興能夠繼續增加美國使用 VYJUVEK 的患者數量。

Now I will hand it back to Krish to share an overview of our global expansion plans for 2025.

現在，我將把主題交還給 Krish，讓他分享我們 2025 年全球擴張計畫的概述。

Thanks, Christine. We expect a positive CHMP opinion on our application later this month, and based on this timeline, we expect our first EU launch in Germany around mid-year, along with commencing an access pre-cause AP2 program in France.

謝謝，克里斯汀。我們預計本月稍後 CHMP 將對我們的申請做出積極評價，根據這一時間表，我們預計我們的藥物將於年中左右在德國首次在歐盟推出，同時在法國啟動一項 AP2 前因治療計劃。

The opportunity that exists in Europe is significant, with many already identified deaf patients in urgent need of fundamentally corrective therapy. In Germany and France alone, there are over 1,000 identified DEB patients.

歐洲存在的機會是巨大的，許多已經確診的耳聾患者迫切需要從根本上進行矯正治療。光是在德國和法國，就有超過 1,000 名已確診的 DEB 患者。

As in the US, our initial focus will be to penetrate the identified patient pool. We're also on track for a regulatory decision in Japan later this year, enabling launch into another market with hundreds of already identified DEB patients.

與美國一樣，我們最初的重點是深入已確定的患者群體。我們還有望在今年稍後獲得日本的監管決定，從而能夠進入另一個已經擁有數百名 DEB 患者的市場。

In support of this filing and our launch, we have established our head office team in Tokyo and have started hiring our field force. It has always been our goal to treat debt globally and comprehensively. And thanks to the continued efforts of our development team, we're also working steadily towards treating lesions in the eye of DEB patients.

為了支持此次申請和我們的發布，我們在東京建立了總部團隊，並已開始招募現場工作人員。全球化、綜合地處理債務一直是我們的目標。並且由於我們開發團隊的持續努力，我們也穩步致力於治療 DEB 患者眼部病變。

Suma will now share more detail on both our ophthalmic B-VEC program and our broader pipeline.

Suma 現在將分享有關我們的眼科 B-VEC 計劃和更廣泛的管道的更多細節。

Thank you, Krish. As Krish just noted, we are committed to treating DEB comprehensively and are very excited to be progressing our second product, KB803, towards a potential approval to address the ocular complications associated with DEB.

謝謝你，克里什。正如 Krish 剛才所說，我們致力於全面治療 DEB，並且非常高興我們的第二款產品 KB803 正在取得進展，有望獲得批准，用於治療與 DEB 相關的眼部併發症。

In support of this goal, we initiated a natural history study last year to prospectively collect data on the frequency of corneal abrasions in DEBM patients. This study is providing valuable information on the burden of disease and is helping us refine endpoint selection for our Phase 3 study.

為了實現這一目標，我們去年啟動了一項自然史研究，前瞻性地收集 DEBM 患者角膜擦傷頻率的數據。這項研究提供了有關疾病負擔的寶貴信息，並幫助我們改進第三階段研究的終點選擇。

The natural history study may also serve as a run-in to our registrational trial, adding more baseline data to contextualize our Phase 3 results. The high rate of enrollment in the study with approximately 50 patients enrolled underscores the unmet need and demand for a corrective therapy for the eye, and given the run in options should provide us an opportunity to rapidly enroll our Phase 3 once initiated.

自然史研究也可以作為我們註冊試驗的補充，增加更多的基線數據來為我們第三階段的結果提供背景資訊。該研究招募了大約 50 名患者，招募率很高，這凸顯了眼部矯正治療尚未滿足的需求，考慮到可選方案，一旦啟動，我們就有機會迅速招募第 3 階段的患者。

We are finalizing the study design and statistical analysis plan with the agency and remain on track to initiate our registrational Phase 3, which we refer to as our light study in the first half of the year. Assuming rapid enrollment, given the run an option, we continue to expect top line data before year end.

我們正在與該機構一起完成研究設計和統計分析計劃，並將繼續按計劃啟動我們的註冊第 3 階段，我們將其稱為上半年的輕度研究。假設快速入學，考慮到運行選項，我們將繼續預計年底前的收入數據。

We look forward to sharing updates on IOLITE and our natural history study in the coming months. We also announced a series of updates on our in-health programs last quarter. That in our view validate the lung as a second target tissue for our HSV-1 based gene delivery platform.

我們期待在接下來的幾個月分享有關 IOLITE 和我們的自然歷史研究的最新消息。上個季度我們也公佈了一系列有關健康計劃的更新。我們認為，這證實了肺部是我們基於 HSV-1 的基因傳遞平台的第二個目標組織。

Included in these updates was a first look at safety and gene delivery data for our KB408 program, which collectively demonstrated that we could safely deliver functional genetic cargo to the lung. KB408 is a redosable inhale therapy for the treatment of AATD, a serious disease linked to the absence of functional AAT in the lung.

這些更新包括首次查看我們的 KB408 計劃的安全性和基因傳遞數據，這些數據共同證明我們可以安全地將功能性基因貨物輸送到肺部。KB408 是一種可重複給藥的吸入療法，用於治療 AATD，這是一種與肺部缺乏功能性 AAT 有關的嚴重疾病。

KB408 is designed to deliver two copies of the SERPINA1 gene which encodes for normal human AAT protein to enable local AAT production in the lung itself.

KB408 旨在傳遞兩份 SERPINA1 基因，該基因編碼正常人類 AAT 蛋白，從而實現肺部局部 AAT 的產生。

KB408 is currently being evaluated in our first in human phase one SERPINA1 study, an open label single dose escalation study in adult patients with AATD, SERPINA1 is designed to include up to three dose escalation cohorts evaluating single administration of 10A9, 10A10 and 10A11 PFU of KB408 via inhalation.

KB408 目前正在我們第一階段人體 SERPINA1 研究中進行評估，這是一項針對 AATD 成年患者的開放標籤單劑量遞增研究，SERPINA1 旨在包括最多三個劑量遞增隊列，評估通過吸入單次給藥 10A9、10A10 和 10A11 PFU 的 KB408。

In December of last year, we announced an interim clinical data update, including safety data for seven patients enrolled. And the first two dose escalation cohort of SERPINA1 as well as molecular data from two patients in the second cohort that had consented to bronchoscopy.

去年 12 月，我們宣布了中期臨床數據更新，其中包括七名患者的安全數據。以及 SERPINA1 的前兩個劑量遞增隊列以及第二組中兩名同意接受支氣管鏡檢查的患者的分子數據。

KB408 was found to be well tolerated at both tested dose levels, with only mild to moderate and transient adverse events observed. No serious adverse events or dose limiting toxicities were reported.

結果表明，KB408 在兩種測試劑量水平下均具有良好的耐受性，僅觀察到輕度至中度和短暫性的不良事件。未報告嚴重不良事件或劑量限制性毒性。

In addition, clear evidence of successful gene delivery was observed in both patients that underwent bronchoscopies, with the proportion of conducting airway epithelial cells positive for AAT increasing from 0% to 39% in one patient and from 3% to 35% in the other.

此外，在接受支氣管鏡檢查的兩名患者中都觀察到了基因傳遞成功的明顯證據，其中一名患者的傳導氣道上皮細胞對 AAT 呈陽性的比例從 0% 增加到 39%，另一名患者的傳導氣道上皮細胞比例從 3% 增加到 35%。

Secretion and functionality of encoded AAT was also demonstrated in the patient with available [Lava] samples. With AAT levels in epithelial lining fluid reaching 729 nanomolar and the proportion of free neutrophil elastase dropping from 97.2% to 40.2% after a single KB408 dose.

透過可用的 [Lava] 樣本也證明了患者編碼的 AAT 的分泌和功能。單次 KB408 劑量後，上皮襯液中的 AAT 水準達到 729 奈摩爾，遊離嗜中性球彈性蛋白酶的比例從 97.2% 下降到 40.2%。

Following this data update, we simultaneously expanded the second SERPINA1 cohort and open enrollment in the third for more comprehensive molecular assessment at both those levels. We are working closely with the Alpha-1 Foundation and the Therapeutic Development Network on the SERPINA1 study and expect to announce complete study results later this year.

在這次數據更新之後，我們同時擴大了第二個 SERPINA1 隊列並在第三個隊列中開放註冊，以便在這兩個層面上進行更全面的分子評估。我們正在與 Alpha-1 基金會和治療發展網絡密切合作進行 SERPINA1 研究，並預計在今年稍後公佈完整的研究結果。

Our second rare respiratory disease program, KB407, is also progressing well. KB407 is a reducible inhale therapy designed to deliver two copies of full length CFTR trans gene for the mutation agnostic treatment of cystic fibrosis.

我們的第二個罕見呼吸系統疾病計畫KB407也進展順利。KB407 是一種可減少的吸入療法，旨在提供兩份全長 CFTR 轉基因，用於囊性纖維化的突變不可知治療。

As summarized on this slide, we have built out a robustly clinical data package that demonstrates that KB407 efficiently transduces target airway epithelial cells, leading to the expression of full length, properly localized, glycosylated and functional CFTR.

如本投影片所總結的，我們已經建立了一個強大的臨床資料包，證明 KB407 有效地傳導目標氣道上皮細胞，從而表達全長、正確定位、糖基化和功能性的 CFTR。

On the back of this data, a growing clinical data set, I'm pleased to report that we recently received full sanctioning of our KB407 Phase 1 protocol providing further validation of our program and opening up access to network trial sites for future clinical development efforts.

基於這些數據和不斷增長的臨床數據集，我很高興地報告，我們最近獲得了 KB407 第 1 階段協議的全面批准，這進一步驗證了我們的計劃，並開放了網絡試驗站點的訪問權限，以供未來的臨床開發工作使用。

We also recently announced an initial safety update on cystic fibrosis patients treated with KB407 in the first two dose escalation cohorts of CORAL-1. Our ongoing first inhuman Phase 1 study, both single and repeat in the health administration of KB407, was well tolerated with only mild to moderate and transient adverse events.

我們最近也公佈了 CORAL-1 前兩個劑量遞增組中使用 KB407 治療的囊性纖維化患者的初步安全性更新。我們正在進行的首次非人體 I 期研究（包括 KB407 的單次和重複健康管理）耐受性良好，僅發生輕度至中度和短暫性的不良事件。

Again, there were no reports of serious adverse events or dose limiting toxicities, reinforcing the attractive safety profile of a vector when delivered via inhalation. With the first two cohorts successfully cleared and KB407 well tolerated, we have progressed to our third cohort and expect to report topline results, including molecular data around the middle of this year.

再次，沒有嚴重不良事件或劑量限制毒性的報告，這進一步證明了透過吸入方式輸送載體的安全性。隨著前兩組試驗成功完成並且 KB407 耐受性良好，我們已進入第三組試驗，預計將在今年年中報告包括分子數據在內的主要結果。

These are just a few of the recent highlights from our clinical stage pipeline. We also recently reported early evidence of monotherapy activity with inhaled KB707 in heavily pre-treated patients with advanced lung cancer.

這些只是我們臨床階段研發管線的最新亮點。我們最近也報告了吸入 KB707 對接受過大量治療的晚期肺癌患者進行單一治療的早期證據。

And earlier in the year she had positive safety and efficacy results of our aesthetic candidate KB301, which we are progressing into Phase 2. As we look forward, 2025 is shaping up to be another busy year. Some of the key development milestones for our team are laid out here.

今年早些時候，她對我們的美容候選藥物 KB301 的安全性和有效性進行了積極的研究，目前該藥物正在進入第 2 階段。展望未來，2025 年又將是繁忙的一年。這裡列出了我們團隊的一些關鍵發展里程碑。

In addition to the initiation and completion of our registrational study evaluating KB803 for ocular complications of that. We are also expecting to provide molecular data updates for a rare respiratory disease program KB408 and KB407. As well as first in human data for a second aesthetic product candidate KB304, which encodes both type III collagen and elastin.

除了啟動和完成評估 KB803 治療眼部併發症的註冊研究之外。我們也期望為罕見呼吸系統疾病計畫 KB408 和 KB407 提供分子數據更新。以及第二個美容產品候選藥物 KB304 的首次人體數據，它編碼 III 型膠原蛋白和彈性蛋白。

Our oncology programs will continue to progress with the potential of interim updates later in the year. As our recent data announcement have demonstrated, the potential HSV-1 based team delivery goes well beyond the skin. We are looking forward to making rapid progress of our pipeline in 2025 and further validating the breadth of the opportunities in front of us, targeting the skin, lung, and eye.

我們的腫瘤學課程將繼續進展，並可能在今年稍後進行中期更新。正如我們最近的數據公告所顯示，潛在的基於 HSV-1 的團隊交付遠遠超出了皮膚的範圍。我們期待在 2025 年快速推進我們的產品線，並進一步驗證我們面前的廣闊機遇，針對皮膚、肺和眼部。

With that, I would like to turn the call to Kate.

說到這裡，我想把電話轉給凱特。

Thank you, Suma. In the fourth quarter, Krystal saw continued VYJUVEK revenue growth with net product revenue of $91.1 million representing an increase of approximately $49 million over the fourth quarter of 2023. Which was the first full quarter that Krystal had revenue after our approval in May of 2023.

謝謝你，蘇瑪。第四季度，Krystal 的 VYJUVEK 營收持續成長，淨產品收入為 9,110 萬美元，比 2023 年第四季增加約 4,900 萬美元。這是自 2023 年 5 月我們批准以來 Krystal 實現收入的第一個完整季度。

Cost of goods sold for the quarter was $4.9 million resulting in a gross margin of 95%. In the fourth quarter of 2023, cost of goods sold was $2.9 million resulting in a 93% gross margin.

本季銷售成本為 490 萬美元，毛利率為 95%。2023 年第四季，銷售成本為 290 萬美元，毛利率為 93%。

Research and development expenses for the quarter were $13.5 million inclusive of stock-based compensation of $2.3 million compared to $11.4 million for the prior year's fourth quarter, inclusive of $2.4 million of stock-based compensation.

本季研發費用為 1,350 萬美元，其中包括 230 萬美元的股票薪酬，而去年同期研發費用為 1,140 萬美元，其中包括 240 萬美元的股票薪酬。

Higher research and development expenses in the fourth quarter of 2024 were mainly due to increased clinical trial related costs, increased R&D manufacturing costs for our pipeline candidates, and increased license and regulatory fees.

2024 年第四季研發費用增加主要是由於臨床試驗相關成本增加、我們候選藥物的研發製造成本增加以及許可證和監管費用增加。

Selling general and administrative expenses for the quarter was $31.3 million inclusive of stock-based compensation of $11 million. Compared to $24.8 million for the prior year's fourth quarter, which was inclusive of stock-based compensation of $7.5 million.

本季銷售一般及行政開支為 3,130 萬美元，其中包括 1,100 萬美元的股票薪酬。相較之下，去年同期第四季的營收為 2,480 萬美元，其中包括 750 萬美元的股票薪酬。

Higher selling general and administrative expenses in the fourth quarter of 2024, were primarily the result of increased personnel related costs, increased professional service fees, and increased VYJUVEK sales and marketing costs as compared to the prior year's fourth quarter.

2024 年第四季銷售一般和行政費用增加，主要是由於與去年同期相比，人員相關成本增加、專業服務費增加以及 VYJUVEK 銷售和行銷成本增加。

Net income for the quarter was $45.5 million which represented $1.58 per basic and $1.52 per diluted share. I'd also like to provide some perspective on our forecast for operating expenses in 2025. We expect to incur between $150 million and $175 million in combined non-GAAP R&D and SG&A costs this year.

本季淨收入為 4,550 萬美元，即每股基本收入 1.58 美元，每股攤薄收入為 1.52 美元。我還想對 2025 年的營運費用預測提供一些看法。我們預計今年的非 GAAP 研發和銷售、一般及行政費用總計將在 1.5 億至 1.75 億美元之間。

This projection excludes stock-based compensation. This expected increase in operating expenses compared to 2024 is driven primarily by increased SG&A costs for our planned commercial launches outside of the United States and increased R&D costs from our continued clinical and regulatory costs associated with our expanded pipeline programs.

此預測不包括股票薪酬。與 2024 年相比，預計營業費用將增加，主要是由於我們計劃在美國以外進行商業發布的銷售、一般和行政費用增加，以及與我們擴大的管道計劃相關的持續臨床和監管成本導致的研發成本增加。

In closing, we ended the fourth quarter with $344.9 million in cash on hand. And $749.6 million in total cash plus short term and long term investments, noting quarterly growth in our overall cash and investments position with an increase over our third quarter of 2024 cash and investments balance by about $55 million.

最後，我們在第四季結束時持有 3.449 億美元現金。總現金加上短期和長期投資為 7.496 億美元，我們的整體現金和投資狀況按季度增長，比 2024 年第三季的現金和投資餘額增加約 5,500 萬美元。

And now I will turn the call back over to Krish.

現在我將把電話轉回給克里什。

Thanks, Kate. As you heard from Christine and Jan, patients are achieving profound benefits with VYJUVEK and getting to live fuller, more active lives. We're steadily expanding our prescriber base and further penetration into the community setting.

謝謝，凱特。正如您從 Christine 和 Jan 那裡聽到的，患者透過 VYJUVEK 獲得了巨大的益處，過著更充實、更積極的生活。我們正在穩步擴大我們的處方基礎並進一步滲透到社區環境。

With one full calendar year of launch in the US behind us. An increasing presence in key European markets in Japan. Our conviction in the global peach sales estimate of over $1 billion for VYJUVEK has only strengthened.

我們已經在美國上市整整一年了。日本在歐洲主要市場的份額不斷增加。我們更加確信 VYJUVEK 的全球桃子銷售額將超過 10 億美元。

As we look forward, I'd like to share a few key lessons we have learned since launch. So we aligned on how we get to realize the opportunity in front of us. The first lesson has to do with timing. From initial patient interest to starting treatment.

展望未來，我想分享自推出以來我們學到的一些重要經驗教訓。因此，我們就如何抓住眼前的機會達成了一致。第一課與時間有關。從最初患者的興趣到開始治療。

As Jen mentioned earlier, patients and prescribers in the community often need more support to navigate the path to success. Our turnaround time on average is still between 45 and 60 days with respect to these patients.

正如 Jen 之前提到的，社區中的患者和開藥者通常需要更多的支持才能走上成功之路。對於這些患者，我們的平均週轉時間仍然在45到60天之間。

The second lesson is the realization that we never really get a full quarter when we are talking about VYJUVEK. VYJUVEK is a weekly therapy administered at home by HCP, and light gets in the way for these patients in each quarter.

第二個教訓是，當我們談論 VYJUVEK 時，我們實際上從未得到完整的季度。VYJUVEK 是 HCP 在家中進行的每週一次的療法，每季這些患者都會受到光線幹擾。

In the first quarter, many families will be changing insurance. In the second We have to work through summer holidays. In the third, Labor Day, and back to school for families, and in the fourth, we navigate around major US holidays.

第一季度，很多家庭都會更換保險。第二，我們必須在暑假期間工作。第三個是勞動節，家庭返校節；第四個是美國主要假日。

In spite of that, I'm pleased and proud to report sequential net VYJUVEK revenue growth and continue to have strong conviction in our global VYJUVEK peak sales estimates. The third lesson has to do with high compliance, which has been well above what we estimated at the time of launch.

儘管如此，我很高興和自豪地報告 VYJUVEK 淨收入連續增長，並繼續對我們的全球 VYJUVEK 峰值銷售估計充滿信心。第三個教訓與高合規性有關，這遠遠超出了我們發佈時的估計。

That said, we are entering a phase where some patients are now able to take initial pauses, enjoy the benefits of durable wound closure, and come back on drugs when there is a wound disruption. This is a fantastic outcome for patients and their families.

儘管如此，我們正進入這樣一個階段：一些患者現在可以最初暫停用藥，享受持久傷口閉合的好處，並在傷口破裂時再次用藥。對於患者及其家屬來說，這是一個非常好的結果。

Our Krystal Connect team remains in close contact with all of our patients, and when new wounds emerge, re-initiation of treatment is seamless. Our relationship with our patients is for the long term, and we want them to feel the freedom of being able to live their lives as they choose independently, actively, with the confidence of knowing that they can now control their wounds with VYJUVEK.

我們的 Krystal Connect 團隊與所有患者保持密切聯繫，當新的傷口出現時，可以無縫地重新開始治療。我們與患者的關係是長期的，我們希望他們能夠感受到自由，能夠按照自己的選擇獨立、積極地生活，並有信心知道他們現在可以透過 VYJUVEK 控制自己的傷口。

Finally, we've done a terrific job of accruing for the price cap of VYJUVEK. We've had no volatility in net revenues in 2024, and we do not expect to have any going forward.

最後，我們出色地完成了 VYJUVEK 價格上限的累積工作。2024 年我們的淨收入沒有波動，我們預計未來也不會出現任何波動。

Finally, in closing, as you can see from the slide, we have several important clinical and regulatory milestones in 2025 to demonstrate the full breadth of our platform, and we're excited for 2025 with what we can deliver to patients and shareholders.

最後，正如您從幻燈片中看到的，我們在 2025 年有幾個重要的臨床和監管里程碑，以展示我們平台的全部廣度，我們對 2025 年能夠為患者和股東帶來什麼感到興奮。

I'd like to thank my Krystal colleagues for their dedication and perseverance that underscore our excitement in the long term outlook for crystal and the patience we aim to serve.

我要感謝我的 Krystal 同事們的奉獻和毅力，這凸顯了我們對水晶長期前景的興奮以及我們致力於服務的耐心。

Thanks for listening and I'd like to open the call for Q&A.

感謝大家的聆聽，我想開始問答環節。

(Operator Instructions)

（操作員指令）

Alec Stranahan, Bank of America.

美國銀行的亞歷克‧斯特拉納漢 (Alec Stranahan)。

Hey guys, thanks for taking our questions and congrats on the continued progress. Just two from us first on VYJUVEK. Wondering if you saw any year-end stocking in 4Q and maybe you could just remind us how accounting for patient annual cap fed into the 4Q results and sequentially into 2025 as this is reset.

嘿夥計們，感謝你們回答我們的問題，並祝賀你們不斷取得的進步。我們先在 VYJUVEK 上發表兩篇文章。想知道您是否在第四季度看到了任何年終庫存，也許您可以提醒我們，隨著重置，患者年度上限的核算如何納入第四季度業績並連續納入 2025 年。

Thanks, Alec. Thanks for your question. Nothing substantially different in Q4 versus any other quarters. So there was no any change in stocking or inventory with respect to Q4 as compared to Q3 or Q2 or Q1. And in terms of price cap, I think I've gone through this many times.

謝謝，亞歷克。感謝您的提問。第四季與其他季度相比沒有顯著差異。因此，與第三季、第二季或第一季相比，第四季的庫存沒有變化。至於價格上限，我想我已經經歷過很多次了。

At the end of every quarter, we look back starting at the beginning of 2024, see how we're going to, how patients are doing. We revisit the calculation at the end of Q2, Q3 and Q4. So we actually believe, as I said in my speech that we do a really good job of making sure there's no volatility in revenue.

每個季度末，我們都會回顧 2024 年初的情況，看看我們將如何發展，患者的狀況如何。我們重新檢視了 Q2、Q3 和 Q4 末的計算。因此，正如我在演講中所說，我們確實相信，我們在確保收入不會出現波動方面做得很好。

Of course, cap calculation is complicated because it is at a payer level and has a lot to do with the mix within each payer, the number of patients and when they start during the year. But we've done a pretty good job of maintaining, taking volatility out of the equation.

當然，上限計算很複雜，因為它處於付款人層面，並且與每個付款人的組合、患者數量以及他們在一年中開始治療的時間有很大關係。但我們在維持和消除波動性方面做得相當不錯。

Okay, that makes sense. And maybe one quick one on the CF study, I guess how is enrollment going? Is Cohort 3 maybe accruing faster or in line with Cohorts 1 and 2 and maybe walk us through how the CFF TDN sanctioning, maybe helps with this. Thank you.

好的，這很有道理。也許我可以快速問一下 CF 研究，我猜入學情況如何？第 3 組是否可能累積得更快或與第 1 組和第 2 組一致，也許可以向我們介紹一下 CFF TDN 批准如何對此有所幫助。謝謝。

No, it's definitely super helpful, but it just got started. So there's always a time lag when you just get started. It takes a few months to get a few patients on drugs. But enrollment in Cohort 3 has already begun, and I'll Suma add some more to this story.

不，它確實非常有用，但它才剛剛開始。因此，當你剛開始時總會有一個時間差。讓幾個病人服用藥物需要幾個月的時間。但第三組的招生已經開始了，Suma 將為這個故事添加更多內容。

Yes. Absolutely. I mean, obviously, getting TDN sanctioning was very important because all the academic major sites that can do broncho and have expertise in CF and have these patients now are very excited. In fact, many of them reached out to us directly to participate.

是的。絕對地。我的意思是，顯然獲得 TDN 批准非常重要，因為所有能夠進行支氣管檢查、在 CF 方面擁有專業知識並且擁有這些患者的主要學術站點現在都非常興奮。事實上，他們中的許多人直接聯繫我們，希望參與。

We have seven to eight sites active. We are in the process of doing all of the administrative stuff for these contracts, budgets, as Krish mentioned. But we have two sites that are part of TDN that are up and running, and we have already enrolled patients for this cohort. It's going pretty well.

我們有七到八個活躍的站點。正如克里什所提到的，我們正在處理這些合約和預算的所有行政事務。但是我們有兩個屬於 TDN 的網站已經啟動並運行，我們已經為這個群體招募了患者。一切進展順利。

Alright. Thank you.

好吧。謝謝。

Ritu Baral, TD Cowen.

Ritu Baral，TD Cowen。

Good morning, guys. Thanks for taking the question. I wanted to ask a little bit about what you guys are expecting from Europe in the second half of the year. Krish, I believe you mentioned that there are about 1,000 patients total between Germany and France that are identified.

大家早安。感謝您回答這個問題。我想問一下你們對今年下半年歐洲的期望。Krish，我相信您提到過，德國和法國共有大約 1,000 名已確診的患者。

Can you give any additional breakdown of that 1,000 between the two geographies, are they treated at centers of excellence like in the US? And if so, is there a number between the two geographies?

您能否對這兩個地區這 1,000 名員工的詳細情況進行進一步分析，他們是否像在美國一樣在卓越中心受到待遇？如果是的話，這兩個地理位置之間有數字嗎？

And then I have my second question, my follow up question is on pricing. How right now are you thinking about the initial sort of German free price range and the French at least expanded access price and how should we be thinking about modeling longer term price in Europe.

然後我有第二個問題，我的後續問題是關於定價。您現在如何考慮德國最初的免費價格範圍和法國至少擴大的接入價格，以及我們應該如何考慮為歐洲建立長期價格模型。

Thanks, Ritu. At a high level, both Germany and France are a bit more concentrated than the United States. That said, Germany is closer to the US and France is much more concentrated among centers of excellence. And the spread of the 1,000 is about 600 in Germany at a very high level, 400 in France.

謝謝，Ritu。從較高層次來看，德國和法國的集中度都比美國高一點。話雖如此，德國更接近美國，而法國的卓越中心集中度更高。在這 1000 例病例中，德國約有 600 例，處於非常高的水平，法國約有 400 例。

In terms of pricing, in Germany, for the first six months, we get to launch with the US price as we put the dossier in place and start the negotiations. At the end of six months, depending on how we feel, how the negotiations are going, we start accruing for the next six months. And the expectation is in 12 months, we would get an actual German price and be steady state from that point on.

在定價方面，在德國，前六個月我們將按照美國價格推出產品，因為我們已經準備好資料並開始談判。六個月後，根據我們的感覺、談判的進展情況，我們開始為接下來的六個月累積。我們預計 12 個月後我們將獲得實際的德國價格，並且從那時起保持穩定狀態。

In France, we're under the AP2 program, and it kind of forces us to start accruing from day one. So the expectation, I mean and the AP2 program should start maybe slightly after the German launch but not too far out. And in France, maybe in about 15, 18 months from approval, we expect to get a price in France. And that's how they're laid out.

在法國，我們實行 AP2 計劃，這迫使我們從第一天就開始累積。所以我的意思是，AP2 計畫應該會在德國發射後不久啟動，但不會太遠。在法國，從批准到上市大概需要 15 到 18 個月，我們預計就能在法國獲得定價。這就是它們的佈局方式。

Got it. Very quick follow up. Should we be thinking about home dosing in in Europe as well?

知道了。非常快速的跟進。我們是否也應該考慮在歐洲推行家庭​​用藥？

Yes, you should. For sure.

是的，你應該這麼做。一定。

Okay. Thanks for taking all the questions.

好的。感謝您回答所有問題。

Gavin Clark Gartner, Evercore ISI.

加文·克拉克·加特納（Gavin Clark Gartner），Evercore ISI。

Good morning. Thanks for taking the questions. Just on the reimbursement approvals first, if I'm doing my math correctly, last quarter, about 50% of new patients coming on were dominant patients, and this quarter that seems to be about up to 75% dominant patients.

早安.感謝您回答這些問題。首先談談報銷批准，如果我的計算正確的話，上個季度，大約 50％ 的新患者是主要患者，而本季度這一比例似乎高達 75％。

Is that math correct? Do you think this trend will continue and how do you account for that in your compliance assumptions?

這個數學計算正確嗎？您認為這種趨勢會持續下去嗎？您如何在合規假設中考慮到這種趨勢？

Gavin, look, the percentage of dominant and recessive varies quarter by quarter. As we go into the community, I mean, your math is right that we did seem more dominant in Q4 than we saw in Q3 as we go into the community.

加文，你看，顯性和隱性基因的百分比每季都是不同的。當我們進入社區時，我的意思是，你的計算是正確的，我們在第四季度確實比第三季度更占主導地位。

But although at a high level, people think about recessive being more severe than dominant, there are a lot of patients who are in the cusp. There are dominant patients who are just as severe as recessive and recessive patients who are just as mild as dominant.

但儘管人們從較高層次認為隱性遺傳比顯性遺傳更嚴重，但仍有許多患者處於危險之中。有的顯性患者病情與隱性患者一樣嚴重，也有的隱性患者病情與顯性患者一樣輕微。

So I would not, I mean, in terms of compliance going forward. I do not expect the material change in the way, I do not expect a big change based on the percentage of dominant in the study. But it is, yeah, it is true, but that said, we don't like when we report Q1, our expectation is not that dominant will continue to go up. It could easily shift back to what it was in Q3 or Q2.

所以，就今後的合規性而言，我不會這麼做。我不期望在方式上發生實質的改變，我也不期望在研究中基於主導百分比發生巨大的變化。但確實如此，但話雖如此，我們不喜歡報告第一季的情況，我們的預期並不是主導地位會繼續上升。它很容易就會回到第三季或第二季的水平。

Very helpful and then just one bigger picture question. So you have about $750 million cash on the balance sheet. Consensus has you doing around $250 million cash flow this year, ballpark $300 million next year, depending on how exactly ex US launch goes.

非常有幫助，然後只是一個更大的問題。因此你的資產負債表上有大約7.5億美元現金。普遍的共識是，今年的現金流約為 2.5 億美元，明年約為 3 億美元，具體取決於美國以外的發布情況。

So even if you did want to allocate, a good chunk of capital to additional R&D, you still have a lot of financial flexibility. So how are you thinking about buybacks, capital allocation overall as you kind of progress to the next phase here? Thank you.

因此，即使你確實想分配大量資金用於額外的研發，你仍然擁有很大的財務彈性。那麼，當您進入下一階段時，您如何考慮回購和整體資本配置？謝謝。

Look, I mean, it's a valid point. It's definitely, a discussion point within Krystal. We're just figuring out the timing of such a buyback and the extent that is meaningful and measurable. So definitely a valid question, Gavin, and we're thinking about it pretty seriously going forward.

你看，我的意思是，這是一個有效的觀點。這絕對是 Krystal 內部討論的一個主題。我們只是在確定回購的時機以及有意義且可衡量的程度。所以這絕對是一個有效的問題，加文，我們正在非常認真地考慮這個問題。

Got it thank.

明白了，謝謝。

Sami Corwin, William Blair.

薩米·科溫、威廉·布萊爾。

Hey, good morning. Thanks for taking my question. Congrats on the progress. I was wondering if you could provide a high level update on the EU regulatory process. I think we initially expected to hear a decision from CHMP in late 2024, so I was curious if you had any insight into the reason behind the delay.

嘿，早安。感謝您回答我的問題。祝賀你取得進展。我想知道您是否可以提供有關歐盟監管流程的詳細更新資訊。我認為我們最初預計將在 2024 年底聽到 CHMP 的決定，所以我很好奇您是否了解延遲的原因。

And then my second question is, given you could face some DEB commercial competition as early as 2Q, just how you're kind of thinking about maintaining and expanding market share in the face of that competition. Thank you

我的第二個問題是，鑑於您最早在第二季就可能面臨一些 DEB 商業競爭，面對這種競爭，您如何考慮保持和擴大市場份額。謝謝

Yeah, I can address the first question. Obviously the delay was because we were trying to get the best label. I mean, we have a very favorable label, as the [SMPC], so obviously the home dosing and caregiver administrations, all of those nuances needed to be ironed out.

是的，我可以回答第一個問題。顯然，延遲是因為我們想獲得最好的標籤。我的意思是，我們有一個非常有利的標籤，例如 [SMPC]，因此顯然家庭劑量和照顧者管理，所有這些細微差別都需要解決。

So there were training materials that needed to be prepared to support that on the label. So that was the reason for the delay, and I think the two months helped us get all of those documentations and training materials in place to achieve that, to get a favorable label.

因此，需要準備培訓材料來支援標籤上的內容。這就是延遲的原因，我認為這兩個月的時間幫助我們準備了所有的文件和培訓材料，以實現這一目標，並獲得有利的標籤。

On the competition, look, at a high level, it's tough to beat the value proposition of VYJUVEK both in terms of, and if you look at how 98% of our patients are opting for home dosing and not even going to the local physician office, we have learned that the profile of VYJUVEK is well aligned with the expectations of the patients.

在競爭中，從高層次來看，很難在價值主張上超越 VYJUVEK，如果你看看我們的 98% 的患者都選擇在家服藥，甚至不去當地的醫生辦公室，我們就會了解到 VYJUVEK 的特點與患者的期望非常一致。

But that said, we are putting in, we are not ignoring that the market could potentially become more competitive later in the year. And our medical affairs team is having the right kind of conversations with the physicians. Our patient services team are having the right kind of conversation with patients. And we feel pretty good about our ability to hit the two year target and the overall peak sales in spite of the competitive nature of the market.

但話雖如此，我們正在投入，我們並沒有忽視今年稍後市場可能會變得更具競爭力。我們的醫療事務團隊正在與醫生進行正確的對話。我們的患者服務團隊正在與患者進行正確的對話。儘管市場競爭激烈，但我們對自己達成兩年目標和整體銷售高峰的能力感到非常滿意。

Got it. Thank you.

知道了。謝謝。

Ry Forseth, Guggenheim.

賴·福塞斯，古根漢。

Hi, this is Ry Forseth with Guggenheim. For 407, how are you thinking about FEV1 in terms of the bar for advancing the program and is that bar sort of consistent across genotypes?

大家好，我是古根漢美術館的 Ry Forseth。對於 407，您如何看待 FEV1 作為推進該計劃的標準，以及該標準在各個基因型之間是否一致？

Look, we're just starting to dose our patients in the efficacy cohort, realized that the long-term direction for Krystal is to target the null population, which is a complete unmet medical need. There have been comments made, interest from other competing companies that in null patients, any kind of FEV improvement, over 3%, 4%, 5% all the way up to 10% is considered a very positive outcome for these patients.

你看，我們才剛開始對療效隊列中的患者進行劑量測定，我們意識到 Krystal 的長期方向是針對零人群，這是一個完全未滿足的醫療需求。其他競爭公司對此表示關注和評論，他們認為，在無效患者中，任何類型的 FEV1 改善，超過 3%、4%、5% 一直到 10% 都被認為對這些患者而言是非常積極的結果。

But please realize we are at the redosing paradigm. So no matter where we start with these patients, we have the opportunity to build upon the FEV levels over time. And so we feel really good about our focused strategy on going after the null mutation and then as a secondary effort maybe, as Suma mentioned in her speech, become mutation agnostic.

但請認識到我們正處於重新給藥模式。因此，無論我們從何處開始治療這些患者，我們都有機會隨著時間的推移提高 FEV 水平。因此，我們對我們的重點策略感到非常滿意，即追求無效突變，然後作為次要的努力，也許，正如 Suma 在她的演講中提到的那樣，變得對突變不可知。

Yeah. I mean there's null patients and there's also a set of population where they don't get correctors these kind of therapies. They're not inducive to it. So it's both the populations that we are targeting. And obviously, as Krish mentioned, we are redosable so we have that flexibility.

是的。我的意思是，存在無效患者，還有一部分人群沒有接受此類矯正治療。他們對此沒有誘導作用。因此，我們的目標群體是這兩個群體。顯然，正如克里什 (Krish) 所提到的，我們是可以重複做的，所以我們有這種靈活性。

We will look at improvements in FEV1. There's flexibility from a regulatory strategy for us to go, just like we did in the eye, to do a single label, open-label study with some sort of natural history.

我們將觀察 FEV1 的改善情況。監管策略為我們提供了靈活性，就像我們在眼睛方面所做的那樣，可以進行某種自然歷史的單一標籤、開放標籤研究。

So I think from a regulatory perspective, if we have any improvements, I mean, we show functionality, we show them expression and we show even a slight improvement in FEV1. I think we have a very favorable regulatory environment and a pathway to move this program very rapidly into the inter-clinic and to an approval path, just like we did with the eye.

因此我認為從監管角度來看，如果我們有任何改進，我的意思是，我們展示功能性，我們展示它們的表達，我們甚至展示 FEV1 的輕微改善。我認為我們擁有非常有利的監管環境和途徑，可以將該計畫迅速推向臨床間並獲得批准，就像我們對眼科所做的那樣。

Thanks for that.

謝謝。

Josh Shimmer, Cantor.

喬許希默（Josh Shimmer），領唱。

Great, thanks for taking the questions. Two quick ones. First, can you help quantify the impact of the annual cap on VYJUVEK in 2024 and how you think that might impact in 2025 and whether you're planning any changes to that cap.

太好了，感謝您回答這些問題。兩個簡單的。首先，您能否協助量化 2024 年年度上限對 VYJUVEK 的影響，以及您認為這可能會對 2025 年產生什麼影響，以及您是否計劃對該上限進行任何更改。

And then second, the 10-K has some new language around VYJUVEK manufacturing process changes and some risks around that at least theoretical. Have there been any changes to the VYJUVEK manufacturing process and, if so, can you explain what?

其次，10-K 對 VYJUVEK 製造工藝的變化進行了一些新的表述，並至少在理論上提出了一些風險。VYJUVEK 製造流程有任何變化嗎？如果有，您能解釋一下嗎？

You want to go?

你想去嗎？

For the cap, we have been seeing about 8% of commercial patients on the cap consistently from the beginning.

就上限而言，我們從一開始就一直看到大約 8％ 的商業患者處於上限狀態。

For the manufacturing process, we just scaled up. And so we have gone to the higher level bioreactor level. And we have filed the PS and we got approval for it. So again, so we have a scale up process that is approved by the FDA. And the beauty about it is this process is can be adaptable across our pipeline.

對於製造過程，我們只是擴大了規模。因此我們已經進入更高水平的生物反應器水平。我們已經提交了 PS 並獲得批准。再次強調，我們有一個經 FDA 批准的擴大規模流程。它的美妙之處在於這個過程可以適用於我們的整個管道。

So if you see 407, I mean, the limitation is not going to be CMC anymore. We can scale up, we can make the material, the processes pretty much cut in place across all of our pipeline products. So CMC, we de-risk CMC for these other products that may need more commercial material. So I think that was very positive for us, getting that scale up approved by the FDA.

因此，如果您看到 407，我的意思是，限制不再是 CMC。我們可以擴大規模，可以製造材料，所有管道產品的流程基本上都可以實現。所以 CMC，我們為這些可能需要更多商業材料的其他產品降低 CMC 的風險。所以我認為，獲得 FDA 批准對我們來說非常有利。

Thank you.

謝謝。

Yigal Nochomovitz, Citi.

花旗的 Yigal Nochomovitz。

Hi, this is Reena on Yigal. Thanks for taking my question. I just wanted to ask on AATD, could you give us a little bit more color on what we should expect to see from the expanded Cohort 2 and Cohort 3 data?

你好，我是 Yigal 的 Reena。感謝您回答我的問題。我只是想在 AATD 上問一下，您能否向我們詳細介紹一下我們應該從擴展的第 2 組和第 3 組數據中看到什麼？

What are more comprehensive molecular assessments that you're considering beyond AATD levels and what therapeutic effect do you hope to see that you would consider clinically meaningful for these patients? And have a follow up.

除了 AATD 水平之外，您還考慮進行哪些更全面的分子評估，您希望看到哪些治療效果，您認為這些患者俱有臨床意義？並進行跟進。

Yes. So on Cohort 2, pretty much not much of a change than what we reported previously. We're just adding more patients to confirm what we saw. We were pretty pleased with what we saw, and we just want to add one or two patients more to confirm both the levels in the lung, the increase in the levels in the systemic circulation and to quantify in terms of at a molecular level what they are, so Cohort 2.

是的。因此，對於第 2 組來說，與我們先前報告的相比，變化並不大。我們只是增加了更多的患者來確認我們所看到的情況。我們對所看到的結果非常滿意，我們只想再增加一到兩名患者，以確認肺部的水平和體循環中水平的增加，並在分子水平上量化它們，因此是第 2 組。

And Cohort 3 is simply exactly Cohort 2 but at a higher dose. So I do not expect anything dramatically different between the two.

而第 3 組與第 2 組完全一樣，但劑量較高。所以我並不認為兩者之間會有什麼顯著的差異。

Obviously, we are looking for dose response. I mean, we know Cohort 2. We didn't even expect that the cohort dose level to see these levels of AAT in the lung. So we're very pleased to see that. I mean, obviously, it's a very safe and we feel it's a dose that showed functional AAT expression at a pretty decent level.

顯然，我們正在尋找劑量反應。我的意思是，我們了解第二組。我們甚至沒有想到該劑量水平的人群肺部會出現這種水平的 AAT。所以我們很高興看到這一點。我的意思是，顯然它是非常安全的，而且我們認為這個劑量能夠顯示出相當不錯的功能性 AAT 表現。

So we do want to see what we get at the third dose, because again it's safe. So we want to see that's an increase and what does that correlate to levels in the serum 2. So it's lung and serum. If we see a good correlation and increase, then maybe that's the dose we will move forward for repeat dose administration and beyond.

所以我們確實想看看第三劑的效果，因為它仍然是安全的。因此，我們想看看這是否是一種增加，以及這與血清 2 中的水平有何關係。所以它是肺和血清。如果我們看到良好的相關性和增加，那麼也許這就是我們將繼續重複給藥及以後使用的劑量。

Okay. Great. And just as a quick follow-up. I understand that plasma AATD should be sort of a relevant benchmark if synthesis were to occur in the liver because of the need to transport into the circulatory system to get to the lung.

好的。偉大的。這只是快速的後續行動。我理解如果合成發生在肝臟中，那麼血漿 AATD 應該是一個相關的基準，因為需要運送到循環系統才能到達肺部。

But since you're already synthesizing in the lung to start with, should we maybe not put too much weight on plasma AATD since it's not relative to the therapeutic goals? I guess if you could give more color on that, how we should be thinking about that or.

但既然您已經開始在肺部進行合成，我們是否不應該過度重視血漿 AATD，因為它與治療目標無關？我想如果你能對此進行更詳細的說明，我們應該如何思考這個問題。

Yeah. I think what you're going to look is correlationship of a dose response of how much level are we seeing in the lung and what levels are we seeing in the plasma? So we want to see that correlationship with increasing and going to the next dose, we want to see what that increases.

是的。我認為您要觀察的是劑量反應的相關性，即我們在肺部看到的水平是多少以及我們在血漿中看到的水平是多少？因此，我們想了解增加劑量和下一劑量之間的相關性，我們想看看會增加多少。

So once we have that correlationship, then we can go to the FDA and let them know that a biomarker approach. We can say, yes, we see this level of lung and the plasma levels to this level in the lung based on the kind of dose that we are giving these patients, this is the ratio.

所以一旦我們有了這種相關性，我們就可以去 FDA 並讓他們知道生物標記方法。我們可以說，是的，我們看到了肺部的這個水平，以及根據我們給予這些患者的劑量，肺部的血漿水平達到這個水平，這就是比例。

So I think that will help us to go into from a regulatory pathway to sit down with the agency and discuss about biomarker pathway. We don't have to, these patients, but can use serum levels, that is meaningful for a lung administration for this patient population.

因此我認為這將有助於我們從監管途徑與機構坐下來討論生物標誌物途徑。對於這些患者，我們不需要，但可以使用血清水平，這對於該患者群體的肺部治療很有意義。

Yes. I do want to repeat what she just said. We do not care fundamentally, you're right. We do not care about levels in the lung levels in the systemic circulation, I apologize. We look for levels in the lung and maybe a correlation between the two so we could avoid potentially bronching for molecular approval.

是的。我確實想重複她剛才說的話。我們從根本上不在乎，你是對的。我們不關心體循環中的肺部水平，我很抱歉。我們尋找肺部的水平以及兩者之間的相關性，這樣我們就可以避免潛在的支氣管擴張以獲得分子批准。

Makes sense. Super helpful, thanks so much.

有道理。非常有幫助，非常感謝。

Andrea Newkirk, Goldman Sachs.

高盛的安德里亞紐柯克 (Andrea Newkirk)。

Good morning. Thanks for taking our question. For Jen and Christine, I'm just curious here based off of what you're seeing right now in terms of the rate of reimbursement approvals, what is needed to reaccelerate patients coming on to drug in order to reach your 60% penetration goal within two years of launch?

早安.感謝您回答我們的問題。對於 Jen 和 Christine，我只是很好奇，根據您現在看到的報銷批准率，需要做些什麼才能重新加速患者用藥，以便在推出後的兩年內達到 60％ 的滲透率目標？

Yes, I can start that. I mean I think we definitely, as I said in the speech, saw some slowdown over the holidays virtually with physician offices and payers sort of delaying and not answering the phone during this time. So we feel like we've increased our trajectory already. We have a healthy pipeline right now of potential patients. And we're right on path for that.

是的，我可以開始。我的意思是，正如我在演講中所說的那樣，我們確實在假期期間看到了一些放緩，醫生辦公室和付款人在這段時間裡有些拖延，不接電話。因此我們感覺我們已經增加了我們的軌跡。目前，我們擁有一群健康的潛在患者。我們正朝著這個方向努力。

So we already started seeing that comp. Obviously, the first few weeks of January, the same thing was occurring with reverification season and payers being sort of distracted at that point. So there were delays happening there as well.

因此我們已經開始看到那個comp。顯然，一月份的頭幾個星期也發生了同樣的事情，因為正值重新驗證季節，付款人此時有點心不在焉。因此那裡也發生了延誤。

Okay, and Krish, just when you think about that billion plus peak sales opportunity globally, just curious if you could provide a little bit more granularity on how the US versus the EU opportunity breaks down across that that billion plus, or even with Japan as well.

好的，Krish，當您想到全球超過 10 億美元的峰值銷售機會時，我很好奇您是否可以提供更詳細的信息，說明美國與歐盟在這一超過 10 億美元的銷售機會之間的對比，或者甚至與日本的對比。

Hi. Look, there are 3,000 patients in the US, 3,000 patients in Europe at a high level and about 3,000 worldwide. The pricing in US versus the pricing in Europe makes accounts for the ratio. The expectation on pricing in Europe is anywhere at the high end at 60%, 70% discount, 60%, 70% of the US price to maybe 50%, 60% of the US price.

你好。你看，美國有 3,000 名患者，歐洲有 3,000 名高水準患者，全世界約有 3,000 名患者。美國定價與歐洲定價形成了這個比率。歐洲的定價預期處於高端，為美國價格的 60%、70% 折扣，為美國價格的 60%、70%，甚至可能是美國價格的 50%、60%。

But that said, if you look at our drug, it was a blinded Phase 3 study. The efficacy results were very powerful. The convenience is amazing. It is a loud disease, right meaning very visible, loud disease, unmet medical need, some chances of getting squamous cell carcinoma in a handful, in a certain percentage of these patients.

但話雖如此，如果你看看我們的藥物，你會發現這是一項盲法 3 期研究。療效結果非常顯著。其便利性令人驚艷。這是一種很嚴重的疾病，確切的說是一種非常明顯的、很嚴重的疾病，有未滿足的醫療需求，其中有一小部分患者，或者說有一定比例的患者，有患鱗狀細胞癌的幾率。

So we have a compelling case to make in the dossier with respect to pricing in Europe. And so we feel good about going into the negotiations. So to answer your question at a high level, the way you split the $1 billion plus across the nations is purely a function of the ratio of the pricing between across these nations. And so if your assumption is 70% of the US price, and that's how they split because the prevalence is pretty identical across the three centers.

因此，我們在有關歐洲定價的檔案中提出了令人信服的案例。因此，我們對參與談判感到十分高興。因此，從高層次回答你的問題，你在各國之間分配 10 多億美元的方式純粹取決於這些國家之間的定價比率。因此，如果您的假設是美國價格的 70％，那麼這就是它們的分割方式，因為三個中心的盛行率非常相同。

Thank you. This does conclude today's conference call. You may disconnect your phone lines at this time and have a wonderful day. Thank you for your participation.

謝謝。今天的電話會議到此結束。此時您可以斷開電話線並享受美好的一天。感謝您的參與。

Thank you all.

謝謝大家。