Blueprint Medicines Corp (BPMC) 2022 Q4 法說會逐字稿

Good morning and welcome to the Blueprint Medicines Conference Call. (Operator Instructions) Please be advised, that this call is being recorded.

早上好，歡迎來到 Blueprint Medicines 電話會議。 （操作員說明）請注意，此通話正在錄音中。

At this time, I'd like to turn it over to Jenna Cohen, Head of Investor Relations at Blueprint Medicines. Please proceed.

在這個時候，我想把它交給 Blueprint Medicines 的投資者關係主管 Jenna Cohen。請繼續。

Thank you, operator. Good morning, everyone. Welcome to Blueprint Medicines Fourth Quarter and Full-Year 2022 Financial and Operating Results Conference Call. This morning, we issued a press release, which outlines the topics we plan to discuss today. You can access the press release, as well as the slides that we'll be reviewing today by going to the Investor section of our website at www.blueprintmedicines.com.

謝謝你，運營商。大家，早安。歡迎來到 Blueprint Medicines 第四季度和 2022 年全年財務和經營業績電話會議。今天上午，我們發布了一份新聞稿，概述了我們今天計劃討論的主題。您可以訪問我們網站 www.blueprintmedicines.com 的投資者部分，訪問新聞稿以及我們今天將要審查的幻燈片。

Today on our call, Kate Haviland, our Chief Executive Officer, will provide a perspective on Blueprint's 2022 accomplishments and how that positions us to continue to grow and drive value in 2023. Philina Lee, our Chief Commercial Officer will review AYVAKIT's performance and our upcoming opportunity to expand the label and treat many more patients with SM. Christy Rossi, Chief Operating Officer, will provide a preview of how we will further our SM leadership at Quad AI, as well as touch on portfolio milestones for the year and Mike Landsittel, our Chief Financial Officer, will review our fourth quarter 2022 financial results and 2023 guidance. Fouad Namouni, President of Research and Development and Becker Hewes, Chief Medical Officer are also joining our call and will be available for Q&A.

在今天的電話會議上，我們的首席執行官凱特哈維蘭 (Kate Haviland) 將介紹 Blueprint 2022 年的成就，以及這些成就如何使我們在 2023 年繼續增長和推動價值。我們的首席商務官 Philina Lee 將回顧 AYVAKIT 的業績和我們即將到來的擴大標籤並治療更多 SM 患者的機會。首席運營官克里斯蒂·羅西 (Christy Rossi) 將預覽我們將如何進一步提升 SM 在 Quad AI 的領導地位，並談到今年的投資組合里程碑，我們的首席財務官邁克·蘭西特爾 (Mike Landsittel) 將回顧我們 2022 年第四季度的財務業績和 2023 年指導。研發總裁 Fouad Namouni 和首席醫療官 Becker Hewes 也加入了我們的電話會議，並將接受問答。

Before we get started, I would like to remind everyone that the statements we make on this conference call will include forward-looking statements. Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factor section of SEC filings.

在我們開始之前，我想提醒大家，我們在本次電話會議上發表的聲明將包含前瞻性聲明。由於各種風險、不確定性和其他因素，包括美國證券交易委員會備案文件中風險因素部分規定的因素，實際事件或結果可能與任何前瞻性陳述中明示或暗示的事件或結果存在重大差異。

In addition, any forward-looking statement made on this call represents our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements.

此外，就本次電話會議發表的任何前瞻性聲明僅代表我們截至今天的觀點，不應被視為代表我們在任何後續日期的觀點。我們特別聲明不承擔任何更新或修改任何前瞻性陳述的義務。

I'll now hand the call over to Kate.

我現在將電話轉給凱特。

Thank you, Jenna. Good morning, everyone and thank you for joining the call today. In 2022, we significantly advanced our business, making important progress across our AYVAKIT launch in advanced systemic mastocytosis and research and development execution on our portfolio of precision therapies. As we kick off 2023, Blueprint offers a compelling value proposition and a unique profile. I would like to highlight three of the most important components of that position that suits us or positions us well for substantial growth this year and beyond.

謝謝你，珍娜。大家早上好，感謝您今天加入電話會議。 2022 年，我們顯著推進了我們的業務，在我們推出 AYVAKIT 晚期系統性肥大細胞增多症以及我們精準療法產品組合的研發執行方面取得了重要進展。在我們開啟 2023 年之際，Blueprint 提供了引人注目的價值主張和獨特的形象。我想強調該職位的三個最重要的組成部分，這些組成部分適合我們或使我們在今年及以後實現大幅增長。

The first is our leadership in systemic mastocytosis. In 2022, our first full year of AYVAKIT launch in advanced SM, we doubled our net product revenue year-over-year. The U.S. accounted for the majority of these product sales. And in 2023, we will see our international launches in advanced SM gaining momentum as we work through the access and reimbursement process in key countries. Importantly, through the launch of AYVAKIT in advanced SM, we have built a strong team and a foundation of commercial capabilities and infrastructure. We are ready now to scale the impact of AYVAKIT with our potential label expansion in ISM. Philina will go into more detail on AYVAKIT's performance in 2022 in preview how we plan to build what will become a blockbuster therapeutic category through our anticipated launch in ISM midyear.

首先是我們在系統性肥大細胞增多症方面的領導地位。 2022 年是我們在高級 SM 中推出 AYVAKIT 的第一個全年，我們的產品淨收入同比翻了一番。美國占這些產品銷售額的大部分。到 2023 年，隨著我們在主要國家/地區完成准入和報銷流程，我們將看到我們在高級 SM 方面的國際發布勢頭強勁。重要的是，通過在高級 SM 中推出 AYVAKIT，我們建立了一支強大的團隊以及商業能力和基礎設施的基礎。我們現在準備通過我們在 ISM 中的潛在標籤擴展來擴大 AYVAKIT 的影響。 Philina 將更詳細地介紹 AYVAKIT 在 2022 年的表現，並預覽我們計劃如何通過預期在 ISM 年中推出來打造將成為重磅炸彈的治療類別。

The second component is our clinical stage pipeline focused on best-in-class investigational therapies that address serious medical problems in large patient populations. Our development efforts are focused in mast cell disorders, lung cancer and breast cancer. Within these areas, each of our programs have a strong mechanistic rationale and a development strategy to achieve a first or best-in-class position.

第二個組成部分是我們的臨床階段管道，專注於解決大量患者群體中嚴重醫療問題的一流研究療法。我們的開發工作主要集中在肥大細胞疾病、肺癌和乳腺癌。在這些領域內，我們的每個項目都具有強大的機械原理和發展戰略，以實現一流或一流的地位。

In 2022, we worked to build the foundation for these programs through dose escalation and dose optimization and we are poised this year to rapidly advance these programs into earlier lines of treatment, where we have the greatest opportunity to impact significant medical needs.

2022 年，我們努力通過劑量遞增和劑量優化為這些項目奠定基礎，今年我們準備將這些項目迅速推進到更早的治療階段，我們有最大的機會來影響重大的醫療需求。

We also continue to broaden our discovery efforts, expanding the range of high-value targets we can pursue, as we aim to increase our already impressive research productivity, most recently demonstrated by the announcement of our new research program targeting wild-type KIT for common mast cell diseases adjacent to systemic masocytosis, including chronic urticaria.

我們還繼續擴大我們的發現工作，擴大我們可以追求的高價值目標的範圍，因為我們的目標是提高我們已經令人印象深刻的研究生產力，最近通過我們針對常見的野生型 KIT 的新研究計劃的宣布證明了這一點與系統性肥大細胞增多症相鄰的肥大細胞疾病，包括慢性蕁麻疹。

The third and last component is that we are operating from a position of financial strength. Our strong cash position and disciplined approach to capital allocation ensures that we are well positioned to execute on the range of opportunities we have in front of us, while driving towards a sustainable financial profile. Today, we have greater than $1 billion in cash on our balance sheet and we are growing product revenue, which will continue to become a more significant portion of overall revenue this year.

第三個也是最後一個組成部分是我們在財務實力的基礎上運營。我們強大的現金狀況和嚴格的資本分配方法確保我們能夠很好地執行我們面前的一系列機會，同時推動實現可持續的財務狀況。今天，我們的資產負債表上有超過 10 億美元的現金，而且我們的產品收入正在增長，這將在今年繼續成為總收入的更重要部分。

Mike will go into our financial performance in more depth later on in the call. At Blueprint, we have an incredible growth story right in front of us in 2023 and beyond. We call this precision at scale. This story starts with our existing commercial portfolio, which provides a certainty of value and a near-term opportunity to drive revenue acceleration.

邁克將在稍後的電話會議中更深入地討論我們的財務業績。在 Blueprint，我們將在 2023 年及以後看到一個令人難以置信的增長故事。我們稱這種精度為規模。這個故事從我們現有的商業組合開始，它提供了確定的價值和推動收入加速的近期機會。

Beyond SM, our discovery in clinical stage portfolios provide multiple opportunities for us to tackle increasingly large opportunities in oncology and beyond. This diversity of fundamental value drivers creates multiple avenues for growth and upside across all aspects of our business. As a fully integrated company, we have critical mass, including the expertise, the infrastructure and most importantly, the right people to deliver on these opportunities, creating extraordinary value for patients, the medical community and for our shareholders.

除了 SM 之外，我們在臨床階段投資組合中的發現為我們提供了多種機會來應對腫瘤學及其他領域越來越大的機會。這種基本價值驅動因素的多樣性為我們業務各個方面的增長和上升創造了多種途徑。作為一家完全整合的公司，我們擁有關鍵的質量，包括專業知識、基礎設施，最重要的是，合適的人才可以抓住這些機會，為患者、醫學界和我們的股東創造非凡的價值。

Now let me turn it over to Philina to review AYVAKIT's performance and provide a perspective on the upcoming ISM launch.

現在請 Philina 回顧 AYVAKIT 的表現，並提供對即將推出的 ISM 的看法。

Thanks, Kate. Good morning, everyone. Let's start with AYVAKIT performance. In 2022, we doubled AYVAKIT net product revenue, achieving $111 million. Fourth quarter revenues were $30.1 million, with $26.3 million in the U.S. We have established AYVAKIT as the standard of care in advanced SM in the U.S., where we continue to grow the number of patients treated with AYVAKIT year-over-year.

謝謝，凱特。大家，早安。讓我們從 AYVAKIT 性能開始。 2022 年，我們將 AYVAKIT 產品淨收入翻了一番，達到 1.11 億美元。第四季度收入為 3010 萬美元，其中美國為 2630 萬美元。我們已將 AYVAKIT 確立為美國晚期 SM 的護理標準，我們在美國繼續增加接受 AYVAKIT 治療的患者人數。

In 2022, we exited the year with nearly 500 patients on AYVAKIT. The percentage of patients on free drug remain stable. In Q4, AYVAKIT growth was driven by several important measures. We added nearly 50 new accounts, increasing the breadth of prescribing to approximately 400 accounts with AYVAKIT experience. AYVAKIT penetration increased across all subtypes of advanced SM. Approximately 75% of patients who start AYVAKIT are treatment naive, which is a promising lead indicator, as we focus on growing the treated advanced SM market.

2022 年，我們結束了這一年，有近 500 名患者使用 AYVAKIT。免費藥物患者的百分比保持穩定。在第四季度，AYVAKIT 的增長受到幾項重要措施的推動。我們增加了近 50 個新賬戶，將處方範圍擴大到約 400 個具有 AYVAKIT 經驗的賬戶。 AYVAKIT 滲透率在高級 SM 的所有子類型中都有所增加。大約 75% 的開始使用 AYVAKIT 的患者是未接受過治療的，這是一個很有前途的領先指標，因為我們專注於發展經過治療的晚期 SM 市場。

We are confident in our guidance of $130 million to $140 million in AYVAKIT net product revenue this year across GIST, an advanced SM. I want to emphasize, this guidance is specific to our current indication. The midpoint of this range represents a more than 20% increase in AYVAKIT revenues year-over-year and we also expect to achieve additional revenue for AYVAKIT this year, above and beyond our base guidance due to our anticipated launch in ISM.

我們對今年 GIST 的 AYVAKIT 產品淨收入達到 1.3 億至 1.4 億美元的指導充滿信心，GIST 是一種高級 SM。我想強調的是，該指南特定於我們當前的適應症。該範圍的中點代表 AYVAKIT 收入同比增長超過 20%，我們還預計今年 AYVAKIT 的收入將超過我們的基本指導，因為我們預計將在 ISM 中推出。

Now let's turn to ISM. Upon approval, AYVAKIT will be the first FDA-approved therapy for patients with ISM. Patients and providers have been waiting for this a long time. With our PDUFA date in hand, our team is laser-focused on building the market to deliver on this incredible opportunity to transform patients' lives. AYVAKIT represents a blockbuster opportunity in SM, with an estimated $1.5 billion global annual peak. Chances to make this kind of patient impact are rare in our industry and this has enabled us to rapidly recruit talent, as we've incrementally expanded our highly experienced field team.

現在讓我們轉向 ISM。獲得批准後，AYVAKIT 將成為 FDA 批准的第一個用於 ISM 患者的療法。患者和提供者已經等待了很長時間。有了我們的 PDUFA 日期，我們的團隊將專注於建立市場，以抓住這個改變患者生活的難得機會。 AYVAKIT 代表了 SM 的一個重磅機會，估計全球年度峰值達到 15 億美元。在我們的行業中，對患者產生這種影響的機會很少見，這使我們能夠快速招募人才，因為我們逐漸擴大了我們經驗豐富的現場團隊。

Our U.S. launch strategy focuses on 7,500 patients with moderate to severe ISM. These patients are actively seeking treatment, which is limited to symptom directed polypharmacy today. We expect early adoption of AYVAKIT in patients with severe symptom burden, followed by patients with moderate symptom burden over time.

我們在美國的啟動策略側重於 7,500 名中度至重度 ISM 患者。這些患者正在積極尋求治療，目前僅限於針對症狀的多藥治療。我們預計症狀負擔較重的患者會儘早採用 AYVAKIT，隨著時間的推移，症狀負擔會較輕的患者也會採用 AYVAKIT。

To prepare for ISM launch, we're focused on three key areas. First, we're engaging a broader provider base who are managing ISM patients. Our field team is on the ground engaging the Hem/Oncs and allergist immunologists who are seeing the most ISM patients, to understand their practices and to educate on SM. Our greatest focus is on the top 350 providers who are managing approximately 1,500 moderate to severe ISM patients today.

為準備 ISM 發布，我們專注於三個關鍵領域。首先，我們正在與更廣泛的供應商合作，他們正在管理 ISM 患者。我們的現場團隊正在實地與接診最多 ISM 患者的 Hem/Oncs 和過敏症免疫學家合作，以了解他們的做法並對 SM 進行教育。我們最關注的是當今管理著大約 1,500 名中度至重度 ISM 患者的前 350 家供應商。

From our field intelligence and primary market research, providers say about half of their patients are not well controlled on current therapies, which ties well to the 7,500 patients we can see in claims. Our second area of focus is activating patients to consider a new treatment option. Our patient and caregiver campaign, it's something has now enrolled thousands of highly motivated prospective patients who suspect they may have SM. And we know than an educated and motivated patient is a catalyst for treatment.

根據我們的實地情報和主要市場研究，供應商表示，他們的患者中約有一半在目前的治療中沒有得到很好的控制，這與我們在索賠中看到的 7,500 名患者密切相關。我們的第二個重點領域是激發患者考慮新的治療方案。我們的患者和護理人員運動現在已經招募了數千名懷疑自己可能患有 SM 的高度積極的潛在患者。我們知道，受過良好教育和積極進取的患者是治療的催化劑。

Third, we're focused on maintaining strong and rapid patient access to therapy. Today's favorable access environment for AYVAKIT provides a strong foundation. All doses are currently on the market today with virtually no access challenges and industry-leading time to fill.

第三，我們專注於保持患者獲得強大而快速的治療。今天有利的訪問環境為 AYVAKIT 提供了堅實的基礎。所有劑量目前都在市場上銷售，幾乎沒有獲取挑戰和行業領先的填充時間。

Now let's talk more about expectations for our initial launch ramp in ISM, which we expect to reflect our rare disease launch trajectory. We think the HAE market is a good example for how ISM can develop into a blockbuster market. We see several similarities. First, HAE is a rare disease treated by allergists. Multiple disease modifying therapies are approved and reimbursed today with price points above AYVAKIT's current list price. Over the past 15 years, the introduction of these therapies catalyze development of the HAE market, enabling linear sales growth over this time frame.

現在讓我們更多地談談對我們在 ISM 中的初始發射坡道的期望，我們希望這能反映我們罕見疾病的發射軌跡。我們認為 HAE 市場是 ISM 如何發展成為重磅炸彈市場的一個很好的例子。我們看到了幾個相似之處。首先，HAE 是一種由過敏症專家治療的罕見疾病。多種疾病改善療法今天獲得批准並報銷，價格高於 AYVAKIT 當前的標價。在過去的 15 年裡，這些療法的推出促進了 HAE 市場的發展，實現了這段時間的線性銷售增長。

In 2021, global sales of prophylactic HAE therapies were approximately $1.5 billion and still growing. There are 7,500 diagnosed and treated HAE patients in the U.S. today, which is remarkably similar to the number of diagnosed and treated patients with moderate to severe ISM. So collectively, the HAE experience gives us confidence in the commercial launch trajectory for AYVAKIT in ISM. As you see with HAE, we expect a rare disease ramp.

2021 年，預防性 HAE 療法的全球銷售額約為 15 億美元，並且仍在增長。今天美國有 7,500 名診斷和治療的 HAE 患者，這與診斷和治療的中度至重度 ISM 患者的數量非常相似。因此，總的來說，HAE 的經驗讓我們對 AYVAKIT 在 ISM 中的商業發布軌跡充滿信心。正如您在 HAE 中看到的那樣，我們預計罕見疾病會出現上升趨勢。

While we don't expect an initial launch bolus, there are several factors that should accelerate the development of the SM market, including our efforts over the past several years to increase disease awareness and diagnosis rates, as well as our advanced patient identification capabilities and this will further help to catalyze treatment and market growth.

雖然我們不期望首次推出推注，但有幾個因素應該會加速 SM 市場的發展，包括我們過去幾年為提高疾病意識和診斷率所做的努力，以及我們先進的患者識別能力和這將進一步有助於促進治療和市場增長。

As we drive towards the PDUFA date for ISM, AYVAKIT has all the harbingers of a strong launch, high medical need, first to market with a strong product profile and a highly motivated group of patients and providers who are waiting for an FDA-approved therapy. With our experience and our leadership in SM, we're confident in our ability to capture the significant ISM opportunity ahead.

隨著我們朝著 ISM 的 PDUFA 日期邁進，AYVAKIT 擁有強大的發布、高醫療需求、首先以強大的產品形象和積極性高的患者和正在等待 FDA 批准的治療的供應商群體推向市場的所有預兆.憑藉我們在 SM 領域的經驗和領導地位，我們有信心抓住未來重要的 ISM 機遇。

With that, I'll turn it over to Christy, who will speak to Blueprint's leadership at Quad AI.

有了這個，我將把它交給克里斯蒂，她將在 Quad AI 與 Blueprint 的領導層交談。

Thanks, Philina. Good morning, everyone. Next week at Quad AI, we are proud to share data across multiple presentations that further solidify our long-standing scientific leadership and commitment to SM. The PIONEER study definitively demonstrates that AYVAKIT's potent and selective inhibition of KIT D816V reduces mast cell burden, improve symptoms and therefore, transforms the quality of life of SM patients.

謝謝，菲麗娜。大家，早安。下週在 Quad AI 上，我們很自豪能夠在多個演示文稿中共享數據，進一步鞏固我們長期的科學領導地位和對 SM 的承諾。 PIONEER 研究明確表明，AYVAKIT 對 KIT D816V 的有效和選擇性抑制可減輕肥大細胞負擔，改善症狀，從而改變 SM 患者的生活質量。

Since presenting the top line data last August, we've met with a variety of health care providers who treat SM patients to understand what data is most meaningful to them. While the specific outcome measures that are most impactful will vary by physician and at times by specialty as allergists have a different reference frame for clinical trials and are much more used to PROs, for example, than hematologists are, some themes have emerged consistently. The first is that safety is key.

自去年 8 月公佈頂級數據以來，我們會見了各種治療 SM 患者的醫療保健提供者，以了解哪些數據對他們最有意義。雖然最有影響力的具體結果測量因醫生而異，有時因專業而異，因為過敏症專家對臨床試驗有不同的參考框架，並且比血液學家更習慣於 PROs，例如，一些主題一直出現。首先是安全是關鍵。

A clean safety profile lowers the hurdle for prescribers and patients to consider a disease-modifying therapy like AYVAKIT, shifting the conversation from why try a new therapy like AYVAKIT to why not? The second is that the totality of impact across symptoms and quality of life is paramount. Our primary endpoint of mean change in TSS captures the symptom benefit broadly. In addition, SM treaters are interested in the impact on patients' most bothersome symptom, which can motivate a patient who want to initiate therapy, as well as the impact of treatment across the specific symptoms captured in the TSF.

一個乾淨的安全概況降低了處方者和患者考慮像 AYVAKIT 這樣的疾病緩解療法的障礙，將談話從為什麼嘗試像 AYVAKIT 這樣的新療法轉移到為什麼不嘗試？第二個是症狀和生活質量的總體影響是最重要的。我們的 TSS 平均變化的主要終點廣泛地捕捉了症狀益處。此外，SM 治療師對對患者最煩人的症狀的影響感興趣，這可以激發想要開始治療的患者，以及治療對 TSF 中捕獲的特定症狀的影響。

Finally, prescribers are looking for symptom improvement to translate into impact on a patient's quality of life, which is the ultimate goal of therapy. Third, data on measures of mast cell burden helps to explain the biological rationale for the benefit that health care providers are seeing in their patients. Seeing meaningful and consistent impacts in these measures, increases prescriber confidence in a therapy's potential to alter the course of disease.

最後，開處方者正在尋求症狀改善以轉化為對患者生活質量的影響，這是治療的最終目標。第三，關於肥大細胞負荷測量的數據有助於解釋醫療保健提供者在患者身上看到的益處的生物學原理。在這些措施中看到有意義和一致的影響，增加了處方者對治療改變疾病進程的潛力的信心。

Finally, in a chronic lifelong disease like SM, prescribers are very interested in understanding the impact of treatment over time. We designed Part 3 of PIONEER specifically to assess and capture the benefit of treatment over the longer term.

最後，對於像 SM 這樣的慢性終身疾病，開處方者非常有興趣了解治療隨時間的影響。我們專門設計了 PIONEER 的第 3 部分，以評估和獲取長期治療的益處。

With that feedback in mind, we are looking forward to sharing more from PIONEER in three presentations at Quad AI. An oral presentation on Sunday, February 26, we'll detail the statistically significant and clinically meaningful results that AYVAKIT achieved across the primary and all key secondary endpoints in PIONEER. We plan to show additional data on our primary and secondary endpoints, including information on individual symptom benefit, as well as data from the 48-week crossover portion of the study.

考慮到這些反饋，我們期待在 Quad AI 的三個演講中分享 PIONEER 的更多信息。在 2 月 26 日星期日的口頭報告中，我們將詳細介紹 AYVAKIT 在 PIONEER 的主要終點和所有關鍵次要終點上取得的具有統計學意義和臨床意義的結果。我們計劃顯示有關我們的主要和次要終點的更多數據，包括有關個體症狀益處的信息，以及來自該研究 48 週交叉部分的數據。

We will also have two additional presentations that will focus on AYVAKIT's effect on skin signs and symptoms and on quality of life. We are excited to share these important results in detail for the first time, demonstrating the disease-modifying benefits of AYVAKIT and showing how AYVAKIT empowers physicians to address the most important concerns of their ISM patients.

我們還將有兩個額外的演示文稿，重點介紹 AYVAKIT 對皮膚體徵和症狀以及生活質量的影響。我們很高興首次詳細分享這些重要結果，展示 AYVAKIT 的疾病緩解益處，並展示 AYVAKIT 如何幫助醫生解決 ISM 患者最關心的問題。

Other presentations at the meeting will characterize the burden of disease and showcase new approaches to accelerate diagnostic rates and continue to grow the ISM market. We look forward to this important conference and to sharing more detail during our corporate call on Monday, February 27.

會議上的其他演講將描述疾病負擔的特徵，並展示加快診斷率和繼續發展 ISM 市場的新方法。我們期待著這次重要的會議，並期待在 2 月 27 日星期一的公司電話會議上分享更多細節。

I'll now turn briefly to our portfolio updates for this year. In January, we guided to a variety of milestones across our portfolio, as we work to expand our impact on patients globally. We discussed two important AYVAKIT milestones already this morning, the upcoming presentation of the PIONEER data at Quad AI, as well as our anticipated approval and launch in ISM by midyear.

我現在將簡要介紹一下我們今年的投資組合更新。 1 月份，隨著我們努力擴大對全球患者的影響，我們在產品組合中實現了多個里程碑。我們今天早上已經討論了兩個重要的 AYVAKIT 里程碑，即將在 Quad AI 上展示 PIONEER 數據，以及我們預計在年中獲得批准並在 ISM 推出。

Today, we are also pleased to confirm that we have received EMA validation of our type two variation for AYVAKIT and ISM, bringing us a step closer to this important indication expansion and launch in Europe. We're on track for our other corporate milestones for the year, including IND submission for BLU-525 and presentation of initial dose escalation data from both BLU-451 and BLU-222 in the first half of the year.

今天，我們也很高興地確認，我們已經收到了 AYVAKIT 和 ISM 的二類變體的 EMA 驗證，使我們離這一重要適應症的擴展和在歐洲的上市又近了一步。我們正朝著今年的其他公司里程碑邁進，包括 BLU-525 的 IND 提交以及今年上半年 BLU-451 和 BLU-222 的初始劑量遞增數據的展示。

Last week, we announced that the FDA had issued a partial clinical hold on the VELA trial due to visual adverse events observed in a limited number of patients. Patients who are currently enrolled in the study are continuing to receive study drug and we are working expeditiously with the FDA to resolve the partial hold and resume study enrollment. More broadly, we look forward to sharing additional data across our portfolio as we reach these milestones and make progress towards our 2027 Blueprint.

上週，我們宣布，由於在有限數量的患者中觀察到視覺不良事件，FDA 已經對 VELA 試驗進行了部分臨床暫停。目前參加研究的患者將繼續接受研究藥物，我們正在迅速與 FDA 合作解決部分暫停問題並恢復研究參加。更廣泛地說，隨著我們達到這些里程碑並在我們的 2027 年藍圖方面取得進展，我們期待在我們的產品組合中共享更多數據。

With that, I'll turn the call over to Mike to review our financial updates.

有了這個，我會把電話轉給邁克來審查我們的財務更新。

Thanks, Christy. Earlier this morning, we reported detailed financial results in our press release. For today's call, I'll touch on a few highlights. For the full-year, total revenues were $204 million, including $111 million in net product revenues from sales of AYVAKIT and $93 million in collaborations and license revenues, exceeding the high end of our prior 2022 total revenue guidance of $200 million.

謝謝，克里斯蒂。今天早上早些時候，我們在新聞稿中報告了詳細的財務結果。對於今天的電話會議，我將談及一些要點。全年總收入為 2.04 億美元，其中包括 1.11 億美元的 AYVAKIT 銷售淨產品收入和 9300 萬美元的合作和許可收入，超過了我們之前 2022 年總收入指導值的上限 2 億美元。

Of these full year revenues, $30.1 million of AYVAKIT net product revenues and $8.7 million in collaboration revenues were recorded in the fourth quarter. As Philina noted for AYVAKIT, we saw continued growth in advanced SM patient starts and product revenue. Our total operating expenses were $723.7 million for the full year and $183.7 million for the fourth quarter. Our Q4 operating expenses showed a quarter-over-quarter decline from Q3, as we continue to leverage operating efficiencies across our businesses.

在這些全年收入中，第四季度記錄了 3010 萬美元的 AYVAKIT 淨產品收入和 870 萬美元的合作收入。正如 Philina 為 AYVAKIT 指出的那樣，我們看到高級 SM 患者開始和產品收入持續增長。我們全年的總運營費用為 7.237 億美元，第四季度為 1.837 億美元。我們的第四季度運營費用比第三季度環比下降，因為我們繼續在我們的業務中利用運營效率。

In 2023, we anticipate that we will achieve $130 million to $140 million in AYVAKIT net product revenues for advanced SM and GIST. We also anticipate full year collaboration revenues of $40 million to $50 million from existing collaborations. This guidance highlights our expectations for both the continued diversity of revenue and a continued, but more moderate growth of AYVAKIT product revenue in advanced SM and GIST.

到 2023 年，我們預計 AYVAKIT 高級 SM 和 GIST 的產品淨收入將達到 1.3 億美元至 1.4 億美元。我們還預計現有合作的全年合作收入為 4000 萬至 5000 萬美元。該指南強調了我們對收入持續多樣化以及 AYVAKIT 產品收入在高級 SM 和 GIST 中持續但更為溫和的增長的期望。

I want to reemphasize that this guidance is specific to our existing AYVAKIT indications and it does not include growth from our anticipated label expansion into ISM. We expect our operating expenses to grow moderately in the first quarter of 2023 and this will be driven by our preparations for the launch of ISM, including the impact of our incremental field force expansion, as well as planned manufacturing investments to support the continued progress of our clinical programs. We then anticipate operating expense growth will flatten in the second half of the year as we recognize economies of scale across our portfolio.

我想再次強調，該指南特定於我們現有的 AYVAKIT 適應症，它不包括我們預期的標籤擴展到 ISM 的增長。我們預計我們的運營費用將在 2023 年第一季度適度增長，這將受到我們為推出 ISM 所做的準備工作的推動，包括我們增量現場人員擴張的影響，以及計劃的製造投資以支持持續取得進展我們的臨床項目。然後，我們預計營業費用增長將在今年下半年趨於平緩，因為我們認識到我們投資組合的規模經濟。

As we enter 2023, we are in an exceptionally strong financial position with nearly $1.1 billion in cash that will fuel our 2027 Blueprint to achieve precision at scale and create transformative value for patients and shareholders.

隨著我們進入 2023 年，我們的財務狀況異常強勁，擁有近 11 億美元的現金，這將推動我們的 2027 年藍圖實現大規模精準化並為患者和股東創造變革性價值。

With that, I'll now turn the call over to the operator for questions. Operator?

有了這個，我現在將把電話轉給接線員提問。操作員？

Thank you. (Operator Instructions) Our first question today comes from Dane Leone from Raymond James.

謝謝。 （操作員說明）我們今天的第一個問題來自 Raymond James 的 Dane Leone。

I think for the guidance that you've outlined this morning, we have a number of questions coming in that are pretty similar from investors that are kind of focused around, when you look at the current prescriber base of AYVAKIT and ASM, what the overlap is at those centers with patients you identified as being ISM patients who could be eligible for treatment once you get the approval? And I think the genesis of that is trying to help people of once you get the approval, where the launch could be initially focused and kind of what percentage of the target population would be representative of your current prescriber base?

我認為對於你今天早上概述的指導，我們有一些問題非常相似，這些問題來自投資者，他們關注的焦點是，當你查看 AYVAKIT 和 ASM 目前的處方者基礎時，有什麼重疊在那些有您確定為 ISM 患者的中心，一旦您獲得批准，這些患者有資格接受治療嗎？而且我認為它的起源是試圖幫助人們一旦你獲得批准，發射可能最初集中在哪里以及目標人群中有多少百分比將代表你當前的處方者基礎？

Yeah, thanks, Dane for that question and Philina do you -- can you weigh in on?

是的，謝謝 Dane 提出這個問題，而 Philina - 你能談談嗎？

So as you know, our teams are in the market, but on the ground today, engaging with top volume prescribers of AYVAKIT, as well as the top volume providers who are treating ISM patients. And in fact, we do see some overlap. And so within those top 350 high-volume prescribers, they are treating nearly 400 moderate to severe ISM patients today who are potential candidates to start AYVAKIT rapidly upon approval.

如您所知，我們的團隊在市場上，但今天在實地，與 AYVAKIT 的頂級處方者以及治療 ISM 患者的頂級供應商合作。事實上，我們確實看到了一些重疊。因此，在前 350 名大批量處方醫生中，他們目前正在治療近 400 名中度至重度 ISM 患者，這些患者有可能在獲得批准後迅速開始使用 AYVAKIT。

Our next question today comes from Marc Frahm from Cowen & Co.

我們今天的下一個問題來自 Cowen & Co. 的 Marc Frahm。

This is Ernie Rodriguez for Marc. So you mentioned the multiples of endpoint that will be presented with the PIONEER data later this month. So this endpoint obviously focuses more on seams that with more severe impact on any given patient. Do you think that gives you a bigger range to show symptom benefit versus the overall composite? And how do you see the threshold clinical meaningfulness differs from the digital domains of the TSS score?

這是 Marc 的 Ernie Rodriguez。所以你提到了本月晚些時候將與 PIONEER 數據一起呈現的終點的倍數。因此，這個終點顯然更多地關注對任何給定患者俱有更嚴重影響的接縫。你認為這會給你一個更大的範圍來顯示與整體綜合相比的症狀益處嗎？您如何看待閾值臨床意義與 TSS 評分的數字域的不同？

So Ernie, sorry, I think you're breaking up a little bit, we appreciate the question. I believe what you're asking is, how are we thinking about the breadth of impact across various symptoms in the PIONEER data versus kind of the interaction with the most bothersome symptom? I believe that was your question. So maybe what we can -- is that correct? Okay. So I think what Christy -- great. So I think what Christy was laying out is really that we have -- in PIONEER, we have demonstrated statistically important and clinically meaningful benefits to patients across a range of ways of looking at treatment impact. And that as includes the impact of pathological mast cells from our quantitative measures, it includes the impact on both the overall symptom burden a patient experiences as measured by the TSS, as well as impact across all the individual symptoms and in domains. And so we really look forward at Quad AI to be able to put that data out to show those -- the impact the broad and kind of impact that AYVA has.

所以厄尼，抱歉，我想你有點分手了，我們很感激這個問題。我相信您要問的是，我們如何考慮 PIONEER 數據中各種症狀的影響廣度，以及與最令人煩惱的症狀的相互作用類型？我相信那是你的問題。所以也許我們能做的——對嗎？好的。所以我認為克里斯蒂 - 太棒了。因此，我認為 Christy 所展示的確實是我們所擁有的——在 PIONEER 中，我們已經通過一系列查看治療影響的方式向患者展示了具有統計學意義和臨床意義的益處。這包括來自我們定量測量的病理性肥大細胞的影響，它包括對患者經歷的總體症狀負擔的影響（由 TSS 測量），以及對所有個體症狀和領域的影響。因此，我們真的很期待 Quad AI 能夠發布這些數據來展示這些——AYVA 所產生的廣泛影響和影響。

And I think importantly, it is that the early impacts we see, as well as the deepening over time, that is going to be important to prescribers as we have talked about.

我認為重要的是，正如我們所討論的那樣，我們看到的早期影響以及隨著時間的推移而加深的影響對開處方者來說很重要。

Our next question today comes from Brad Canino from Stifel.

我們今天的下一個問題來自 Stifel 的 Brad Canino。

Maybe on the CDK2, I'd like to ask if over the past week, have any more patients completed eye exams, particularly the patient that have the Grade 3 event and have those results been consistent with what you previously saw? And then if you can just quickly walk through the current thinking of why those vision events are unlikely to impede the full development of this asset and the logistical steps to reactivate this trial?

也許在 CDK2 上，我想問一下過去一周是否有更多患者完成眼科檢查，尤其是發生 3 級事件的患者，這些結果是否與您之前看到的一致？然後，您是否可以快速瀏覽一下當前的想法，即為什麼這些願景事件不太可能阻礙該資產的全面開發以及重新啟動該試驗的後勤步驟？

Becker, will you take that?

貝克爾，你會接受嗎？

Yeah, so with respect to the question on the eye exams for the patient with grade 3 and this really applies to all of the patients that we have full eye exams on. There's really absolutely nothing abnormal showing up on these ophthalmogic exams and they're very extensive ophthalmologic exams. And I think this is really consistent also with the symptomatology, which are very brief episodes of either changing of the intensity of line of bit of blurriness, patient with Grade 3 also had an MRI showing that there was nothing in the central nervous system that could explain the symptoms, but it's really the really brief nature of the symptoms and the fact that they resolve so quickly upon either briefly stopping the drug and then restarting at a lower dose.

是的，所以關於 3 級患者的眼科檢查問題，這確實適用於我們進行全面眼科檢查的所有患者。在這些眼科檢查中絕對沒有任何異常出現，而且它們是非常廣泛的眼科檢查。而且我認為這也與症狀學非常一致，這些症狀是非常短暫的，或者是線強度的變化，或者是模糊，3 級患者也有 MRI 顯示中樞神經系統中沒有任何東西可以解釋症狀，但這確實是症狀的真正短暫性質，以及它們在短暫停止藥物然後以較低劑量重新開始時如此迅速解決的事實。

So -- and then with respect to the time line or the steps needed to get the program back on track, we've been working very closely with the FDA, who've been extremely cooperative. The main reason, as we said, for the partial clinical hold is simply to modify the protocol to put ophthalmologic specific dose adjustment criteria in there and grading criteria and then to change the informed consent, so that everyone is aware that these are potential things that could occur.

所以——關於時間表或讓項目重回正軌所需的步驟，我們一直在與 FDA 密切合作，他們非常合作。正如我們所說，部分臨床暫停的主要原因只是修改方案，將眼科特定劑量調整標準和分級標準放入其中，然後更改知情同意書，以便每個人都意識到這些是潛在的事情可能發生。

And then in terms of why -- how I'm thinking about this in the overall development, as we said before, we're nearing the end of dose escalation. I think we have a range of potential doses available. And so we see the end of the single-agent dose escalation insight. These events again are very brief. They are usually Grade 1 and they -- having some ophthalmologic or visual changes in many cancer drugs, it's really not uncommon. And this is so mild and so transient that I really don't see this as potentially dose limiting.

然後就為什麼——正如我們之前所說，我在整體開發中如何考慮這一點，我們即將結束劑量遞增。我認為我們有一系列可用的潛在劑量。因此，我們看到了單一藥物劑量遞增洞察力的終結。這些事件同樣非常短暫。它們通常是 1 級，並且它們 - 在許多抗癌藥物中有一些眼科或視覺變化，這確實並不少見。這是如此溫和和短暫，我真的不認為這是潛在的劑量限制。

And again, with a drug that has such a clean kinome and it's so targeted to CDK2, I think we have a good range where we can see potential in the future for clinical benefit for patients.

再一次，有了一種具有如此乾淨的激酶組並且如此靶向 CDK2 的藥物，我認為我們有一個很好的範圍，我們可以看到未來對患者臨床益處的潛力。

Our next question comes from Eun Yang from Jefferies.

我們的下一個問題來自 Jefferies 的 Eun Yang。

So we are awaiting details on the PIONEER data at Quad AI, but I wanted to just ask you for this secondary endpoint responder rate. What's the minimum delta between the two arms needed to achieve statistical significance?

所以我們正在等待 Quad AI 的 PIONEER 數據的詳細信息，但我只想問你這個次要端點響應率。達到統計顯著性所需的兩個臂之間的最小增量是多少？

Thanks for the question, Eun and I'm going to hand over to Christy to talk more about that.

謝謝你提出這個問題，Eun 和我將交給 Christy 來詳細討論這個問題。

Yes. So thanks, Eun. As you know, I mean, we hit -- we were highly significant across all of our primary and key secondary endpoints. And so I think part of what the question is just sort of how we interpret the variety of data on these endpoints and how do clinicians interpret them in terms of being meaningful? And as we've engaged on this, I would say two things. One, as we said before, the totality of the data across all of these endpoints is really what is most impactful.

是的。所以謝謝，恩。如你所知，我的意思是，我們達到了——我們在所有主要和關鍵次要終點上都非常重要。因此，我認為問題的一部分只是我們如何解釋這些端點上的各種數據，以及臨床醫生如何根據有意義的方式解釋它們？在我們討論這個問題時，我想說兩件事。第一，正如我們之前所說，所有這些端點的數據總量確實是最有影響力的。

Different health care providers interpret different pieces of data in different ways. What's interesting about response rate is that it's actually not an endpoint that is used in allergy frequently. And so as we engage in allergists with allergists, they found ORR to kind of be the least interpretable of all the endpoints, but we're very eager to share it and certainly some hematologists find it incredibly compelling. And so, we will be looking at both responder analyses, as we've indicated across the secondary endpoints. It will be also really interesting to see how those rates evolve over time, again, kind of demonstrating the long-term impact of AYVAKIT. And it's that totality of the data along with the other secondaries and the primary that we found prescribers have that very compelling and we're looking forward to sharing all of that data in a couple of weeks.

不同的醫療保健提供者以不同的方式解釋不同的數據。響應率的有趣之處在於它實際上並不是過敏中經常使用的端點。因此，當我們與過敏症專家進行接觸時，他們發現 ORR 是所有端點中最難以解釋的，但我們非常渴望分享它，當然一些血液學家發現它非常引人注目。因此，正如我們在次要終點上指出的那樣，我們將研究兩種響應者分析。看看這些比率如何隨著時間的推移而變化也將非常有趣，這再次證明了 AYVAKIT 的長期影響。正是這些數據以及其他二級數據和我們發現處方者的主要數據非常引人注目，我們期待在幾週內共享所有這些數據。

And I think you were in such a unusual position, Eun, that study has demonstrated significant impact across multiple ways of looking at it, right? Everything from kind of the most fundamental biological impacts on kind of the pathologic measures of mast cells, as well as the patient impacts on symptomatology, all the way through to quality of life. And it's very rare to have such statistically and clinical meaningful outcomes across such a broad array of measures in the study. And so we're really looking forward to showing that data.

我認為你處於如此不尋常的位置，Eun，這項研究已經證明了通過多種方式看待它的重大影響，對吧？從最基本的生物學影響到肥大細胞的病理學指標，以及患者對症狀學的影響，一直到生活質量。而且在研究中通過如此廣泛的措施獲得如此具有統計學意義和臨床意義的結果是非常罕見的。所以我們真的很期待展示這些數據。

Our next question comes from Derek Archila from Wells Fargo.

我們的下一個問題來自富國銀行的 Derek Archila。

Just two quick ones from us. First one, just on the 2023 guidance. I just want to understand, is this more about driving new account activations or is this more about depth at current accounts? And I guess, if it's the latter, how much depth is really left in terms of new patients at these current practices that you're already at? And then I just want to make sure I heard you correctly. I think it was Dan's question, so I think on the 350 providers, I think that you're initially targeting, you said the overlap for ISM patients is about 400 out of the initial 1,500. So is it fair to assume those other 1,000 patients are being seen by allergists?

我們只是兩個快速的。第一個，關於 2023 年的指導。我只是想了解，這更多是關於推動新帳戶激活還是更多關於當前帳戶的深度？而且我想，如果是後者，那麼在您已經採用的這些當前實踐中，新患者真正剩下多少深度？然後我只想確保我沒聽錯。我認為這是 Dan 的問題，所以我認為在 350 名提供者中，我認為你最初的目標是，你說 ISM 患者的重疊大約是最初 1,500 名中的 400 名。那麼假設其他 1,000 名患者正在接受過敏症專科醫生的診治是否公平？

Yes. Derek, thanks so much for the question. I'll hand it over to Philina to answer the specifics. I think -- but to your first part of your question, I mean, I think what we're so pleased to see in this launch is that we are -- we have the dominant share of the current market of patients who are treated with advanced SM. And we're seeing that consistent demand where we continue to drive new patients, broadening the prescriber base, adding new accounts and new prescribers as we really work to expand the overall size of the SM market as well. And so I think we're going to continue to see both of those dynamics play out to launch.

是的。德里克，非常感謝你提出這個問題。我會把它交給 Philina 來回答具體問題。我認為 - 但對於你問題的第一部分，我的意思是，我認為我們很高興在這次發布中看到的是 - 我們在當前接受治療的患者市場中佔據主導地位高級SM。我們看到持續不斷的需求，我們繼續推動新患者，擴大處方者基礎，增加新賬戶和新處方者，因為我們也在努力擴大 SM 市場的整體規模。因此，我認為我們將繼續看到這兩種動力在發佈時發揮作用。

And then Philina, do you want to talk about the numbers in more depth?

然後是 Philina，你想更深入地談談這些數字嗎？

I think at the heart of your question, your first question is really about, has the advanced SM opportunity peaked for what is sort of the headroom on that? So to be really clear, we see headroom significantly to continue to grow the advanced SM opportunity. We know that this is going to happen at a more measured rate than the growth trajectory that we saw early in the launch. And that growth is driven by several factors. We're still early in penetrating into the overall advanced SM patient population.

我認為你的問題的核心是，你的第一個問題實際上是關於高級 SM 機會是否達到頂峰，這方面的淨空是多少？所以要非常清楚，我們看到了繼續增長高級 SM 機會的巨大空間。我們知道，這將以比我們在發布初期看到的增長軌跡更謹慎的速度發生。這種增長是由幾個因素驅動的。我們仍處於滲透到整個晚期 SM 患者群體的早期階段。

We are the standard of care in the treated patient population, but the biggest lever of growth is truly activating the fuller breadth of advanced SM patients to be treated for their SM. And so penetration across all sub-types, significant room to continue expanding on the breadth and depth of the prescriber base, as well as for the durations of therapy, which are favorable. And as we shift towards a more treatment-naive patient population, that is also a favorable harbinger of longer durations of therapy over extended periods of time.

我們是接受治療的患者群體的護理標準，但最大的增長槓桿是真正激活更廣泛的晚期 SM 患者接受 SM 治療。因此，對所有子類型的滲透，在處方者基礎的廣度和深度以及治療持續時間方面繼續擴大的巨大空間，這是有利的。隨著我們轉向更多未接受過治療的患者群體，這也是長期治療持續時間延長的有利預兆。

So to your second question about the 400 patients, so just to be really clear, that is just the moderate to severe ISM patients who are treated by the top 350 of our current prescriber base. And importantly, we know that it's important to engage a broader prescriber base who are treating that 7,500 moderate to severe ISM patients who are diagnosed and actively seeking treatment today.

因此，對於您關於 400 名患者的第二個問題，需要明確的是，這只是由我們目前的前 350 名處方者治療的中度至重度 ISM 患者。重要的是，我們知道，吸引更廣泛的處方者基礎非常重要，他們正在治療今天被診斷出並積極尋求治療的 7,500 名中度至重度 ISM 患者。

So when we think about where early adoption of AYVAKIT could happen post ISM approval, we see it not only among those 400 patients treated by the current top volume prescribers, but also among that broader group of patients who really have severe symptomology.

因此，當我們考慮在 ISM 批准後早期採用 AYVAKIT 的地方時，我們不僅在目前最大量處方者治療的 400 名患者中看到它，而且在真正有嚴重症狀的更廣泛的患者群體中看到它。

Our next question comes from (inaudible) from Goldman Sachs.

我們的下一個問題來自高盛（聽不清）。

This is [Anu Midan] for Salveen. So on the ISM launch, we're just trying to understand what patients would be the early adopters? So from the 400 patients that you mentioned, what proportion would not be well controlled on current treatments? And then just quickly on the CDK2 program, with your proposed action, is the FDA aligned on the changes to the protocol?

這是 Salveen 的 [Anu Midan]。所以在 ISM 發佈時，我們只是想了解哪些患者會成為早期採用者？那麼在你提到的400名患者中，有多少比例是目前的治療無法很好控制的？然後在 CDK2 項目上，根據你提議的行動，FDA 是否對協議的變更保持一致？

Maybe we'll start with the overall numbers of ISM. I think we're getting a little bit confused on the 400. So I just want to make that really clear for people. So maybe, Christy, you can take that and then Becker, if you could take the CDK2.

也許我們將從 ISM 的總體數據開始。我認為我們對 400 有點困惑。所以我只想向人們說明這一點。所以也許，克里斯蒂，你可以接受它，然後是貝克爾，如果你可以接受 CDK2。

So both of the last two questions, I think are getting a little bit to sort of where the patients are in breadth and depth. So just to be clear on the 400, we see 400 moderate-to-severe, not well-controlled ISM patients amongst physicians who currently have (inaudible) experience. So I think that gets to the earlier question on overlap as well. So I think the overall idea here is that there's a lot of potential with ISM amongst prescribers who have current AYVAKIT experience and certainly early in the launch, that is a place that we will focus to drive growth.

因此，我認為最後兩個問題都對患者的廣度和深度有所了解。因此，為了明確 400，我們在目前有（聽不清）經驗的醫生中看到 400 名中度至重度、控制不佳的 ISM 患者。所以我認為這也涉及到之前關於重疊的問題。所以我認為這裡的總體想法是，在擁有當前 AYVAKIT 經驗的處方者中，ISM 有很大的潛力，當然在發布初期，這是我們將重點推動增長的地方。

The 7,500 patients in total when we throw that number out and talk about that, all of those patients are patients that we view to be moderate to severe, not well controlled and candidates for therapy. And maybe just to close out on kind of the breadth and depth questions that are coming up, we see opportunity in both places, right? So if I think about Advanced SM, we are continuing to deepen usage at existing prescribers, what the dynamics that you see is often that they will get comfortable treating a patient and then they will start to identify additional potential candidates. And so we definitely see room to deepen.

當我們拋出這個數字並談論這個時，總共有 7,500 名患者，所有這些患者都是我們認為中度至重度、控制不佳且適合治療的患者。也許只是為了解決即將出現的廣度和深度問題，我們在這兩個地方都看到了機會，對吧？因此，如果我考慮 Advanced SM，我們將繼續深化現有處方者的使用，你看到的動態通常是他們會對治療患者感到舒服，然後他們將開始確定其他潛在候選人。因此，我們肯定看到了深化的空間。

But breast continues to be really important in a rare disease market like this. And so we're really pleased to see the number of new accounts that we added in Q4 and expect to see that continue through the year.

但在像這樣的罕見病市場中，乳房仍然非常重要。因此，我們真的很高興看到我們在第四季度添加的新帳戶數量，並希望看到這一年繼續下去。

Yes and this is Becker. And so with respect to the process with the FDA, just a little bit of background about how this generally happens. So the initial call that we had with them started the process and the way it will end will be with written notification that the partial hold has been ended or have been lifted. And we've been working very closely with the FDA. We're rapidly modifying the informed consent and protocol and the IB. And so far, it's been going extremely smoothly. This is a collaborative action or interaction with the FDA and we had alignment all along the way.

是的，這是貝克爾。因此，關於與 FDA 的流程，只需了解一下這通常是如何發生的背景知識。因此，我們與他們進行的最初通話啟動了流程，流程結束的方式將是書面通知部分擱置已結束或已解除。我們一直在與 FDA 密切合作。我們正在迅速修改知情同意書和協議以及 IB。到目前為止，一切都非常順利。這是與 FDA 的協作行動或互動，我們一直保持一致。

So this is really about informing people and making sure that their right grading system is in the protocol and any dose adjustments are very clear. So there's been really a quite a bit of alignment.

所以這實際上是關於通知人們並確保他們在協議中使用正確的分級系統並且任何劑量調整都非常清楚。所以真的有相當多的一致性。

And just add, so that collaborative nature of the conversations have been really -- have been very constructive. We are working to submit the documents. Of course, we're not in control of the FDA time line on the other side, but I think that collaboration and kind of joint sense of getting the study back on track gives us lot of confidence that will result this in a short time frame.

並且只是添加，所以對話的協作性質真的 - 非常有建設性。我們正在努力提交文件。當然，另一方面我們無法控制 FDA 的時間表，但我認為合作和讓研究重回正軌的共同意識給了我們很大的信心，將在短時間內實現這一目標.

Our next question comes from Michael Schmidt from Guggenheim Securities.

我們的下一個問題來自古根海姆證券公司的邁克爾施密特。

This is Paul on for Michael. Just one from us on the CDK2. Maybe you could help set expectations for that initial clinical readout this year, specifically on the pharmacodynamic markers of activity, anything that you could highlight that we should expect such as reduction in passive Rb or cyclin e-protein, that would be really helpful.

這是保羅替邁克爾。只有我們在 CDK2 上的一個。也許你可以幫助設定今年初步臨床讀數的預期，特別是關於活性的藥效學標誌物，任何你可以強調我們應該預期的東西，例如被動 Rb 或細胞週期蛋白 e 蛋白的減少，這將非常有幫助。

Becker, will you take that?

貝克爾，你會接受嗎？

Yeah, so just as we said earlier, our guidance has been for dose escalation data midyear and then an early look at the combination. We are able to start the combination before we reach a recommended Phase 2 dose. And so we look forward to presenting that including safety and biomarker data midyear this year. With respect to biomarkers, we have a number of them. They are circulating biomarkers, they're tumor biomarkers. And so what we'll be presenting is an emerging holistic look at the activity and selectivity of BLU-222 in these multiply relapsed Phase 1 patients.

是的，正如我們之前所說，我們的指導是針對年中的劑量遞增數據，然後早期查看組合。我們能夠在達到推薦的 2 期劑量之前開始聯合用藥。因此，我們期待在今年年中展示包括安全性和生物標誌物數據在內的數據。關於生物標誌物，我們有很多。它們是循環生物標誌物，它們是腫瘤生物標誌物。因此，我們將展示的是對 BLU-222 在這些多次復發的 1 期患者中的活性和選擇性的新興整體觀察。

Our next question comes from Mike Ulz from Morgan Stanley.

我們的下一個問題來自摩根士丹利的 Mike Ulz。

Maybe I can just ask another question on ISM opportunity and how you're thinking about the early trajectory here. I know in your prepared remarks, you commented you're not anticipating a bolus here. But I'm just curious, what impact could presentation of the data at Quad AI next week have on those views? Could it drive additional interest? And could it potentially change your view on the early trajectory?

也許我可以再問一個關於 ISM 機會的問題，以及你如何看待這裡的早期軌跡。我知道在你準備好的評論中，你評論說你不期待這裡有推注。但我很好奇，下週在 Quad AI 上展示的數據會對這些觀點產生什麼影響？它能引起額外的興趣嗎？它可能會改變您對早期軌蹟的看法嗎？

Let me take the first part on the bolus. I think -- and then point I can weigh in on the impact of Quad AI. I think from both perspective, the reason why we're not saying that we don't expect it is because we designed the PIONEER study to evaluate long-term follow-up of the patients. And so in a product launch, when you see a bolus, it's often because you're switching patients off of clinical trials into commercial drug. And we believe long-term experience of AYVAKIT treatment in these patients is critically important to the overall value as we continue to look at that impact over time.

讓我來談談丸劑的第一部分。我認為——然後我可以權衡 Quad AI 的影響。我認為從這兩個角度來看，我們之所以沒有說我們不期望它，是因為我們設計了 PIONEER 研究來評估患者的長期隨訪。因此，在產品發布中，當您看到丸劑時，通常是因為您正在將患者從臨床試驗轉移到商業藥物。我們相信，在這些患者中接受 AYVAKIT 治療的長期經驗對於整體價值至關重要，因為我們會隨著時間的推移繼續關注這種影響。

So we're retaining patients within the PIONEER study for up to five years. So that is why we don't expect a bolus coming of clinical trials into commercial therapy. And Philina, do you want to talk about the -- how you see the impact of Quad AI?

因此，我們將患者保留在 PIONEER 研究中長達五年。所以這就是為什麼我們不期望臨床試驗會進入商業治療。 Philina，你想談談——你如何看待 Quad AI 的影響？

Yeah, sure. So I mean, I think, first and foremost, I want to also talk about the efforts that the team is doing to prepare for the launch and sort of feed towards the ultimate ramp upon approval as well. So as I mentioned, we're hyper-focused on three critical areas; the broader provider engagement, both within the existing prescriber base for AYVAKIT, as well as that broader prescriber base, future prescriber base, including allergists, immunologists. We're focused on activating patients and maintaining our strong patient access.

好，當然。所以我的意思是，我認為，首先，我還想談談團隊為準備發布所做的努力，以及在獲得批准後為最終的提升做準備。因此，正如我提到的，我們高度關註三個關鍵領域；更廣泛的提供者參與，包括 AYVAKIT 的現有處方者基礎，以及更廣泛的處方者基礎、未來的處方者基礎，包括過敏症專家、免疫學家。我們專注於激活患者並保持我們強大的患者訪問。

And so among that, when we think about the importance of Quad AI, clearly, it will increase the awareness of AYVAKIT, especially among that allergist and immunologist community, awareness of AYVAKIT, as well as the data. As far as our teams focus as well, a couple of factors that we think will help with the ramp is that for many years, we have been engaging to increase disease awareness as well as diagnosis rates. And our team has been really honing and perfecting our skills with the advanced SM launch.

因此，其中，當我們考慮 Quad AI 的重要性時，很明顯，它將提高 AYVAKIT 的知名度，尤其是在過敏症和免疫學家社區中，AYVAKIT 的知名度以及數據。就我們的團隊所關注的而言，我們認為有助於提升的幾個因素是，多年來，我們一直致力於提高疾病意識和診斷率。我們的團隊一直在通過高級 SM 發布磨練和完善我們的技能。

So we know how to leverage advanced analytics and our field acumen to find patients. We know how to identify their providers and we know how to engage these providers leveraging our deep disease state expertise. So we are confident as we think about that overall $1.5 billion peak opportunity, that we will ultimately be able to capture this opportunity.

所以我們知道如何利用高級分析和我們的現場敏銳度來尋找患者。我們知道如何識別他們的提供者，並且我們知道如何利用我們的深度疾病狀態專業知識來吸引這些提供者。因此，當我們考慮到 15 億美元的峰值機會時，我們有信心最終能夠抓住這個機會。

Our next question comes from Ren Benjamin from JMP Securities.

我們的下一個問題來自 JMP 證券的 Ren Benjamin。

Can you talk a little bit about how we should be thinking about the sales force and their switch to focused on allergists. Is this something that likely we're going to have to increase as we get into the year and after approval? Do you have a sense as to how many docs are currently aware of AYVA and ISM versus not as well?

你能談談我們應該如何考慮銷售人員以及他們轉向專注於過敏症專家的問題嗎？隨著我們進入這一年並在獲得批准後，我們是否有可能不得不增加這些東西？您是否了解目前有多少醫生了解 AYVA 和 ISM，而有多少醫生不了解？

I'll turn it over to Philina to answer the question about the sales force. I think one of the great attributes of this launch for us is that it is really an extension of what we've been doing in SM. And it is still -- it's a specialty market. So it's a market that we can certainly access with incremental growth in our field infrastructure, but Philina talk a little bit about how you're thinking about that?

我會把它交給 Philina 來回答有關銷售人員的問題。我認為這次發布對我們來說最重要的特點之一是它確實是我們在 SM 中所做的事情的延伸。它仍然是——它是一個專業市場。因此，隨著我們現場基礎設施的逐步增長，我們當然可以進入這個市場，但 Philina 談談你是如何考慮的？

Yeah, so as Kate mentioned, with -- advanced SM provides a strong foundation, right? So the primary specialty focus historically for us has been hematology and oncology. But as we prepare for the ISM launch, we know that we'll need to engage a broader provider and specialty base, including allergists. And so we've incrementally expanded our field force and strengthened our capabilities in allergy, immunology, as well as rare disease.

是的，正如凱特提到的那樣，高級 SM 提供了堅實的基礎，對吧？因此，我們歷史上主要的專業重點是血液學和腫瘤學。但在我們為 ISM 發布做準備時，我們知道我們需要與更廣泛的供應商和專業基礎合作，包括過敏症專科醫生。因此，我們逐漸擴大了我們的現場力量，並加強了我們在過敏、免疫學和罕見疾病方面的能力。

And to your question on awareness, at this point, we're in a very strong position with awareness of AYVAKIT among target prescribers of over 40%.

對於你關於意識的問題，在這一點上，我們處於非常有利的地位，目標處方者中對 AYVAKIT 的意識超過 40%。

So that's unaided awareness. So I think that's unusual at this point and this early in a prelaunch phase to have that level of awareness. And so I think -- I also think it's important, as Philina had mentioned before, our data analytic capability is critical here. This is not a reach and frequency model. This is about getting to health care providers at a time when it's most relevant to them, meaning they've seen a patient recently. And so that is something again, that we have really worked hard on and the team has done an incredible job through the advanced SM launch, getting that model up and running.

所以這是無助的意識。因此，我認為在這一點上以及在啟動前階段的早期就具有這種意識水平是不尋常的。所以我認為 - 我也認為這很重要，正如 Philina 之前提到的那樣，我們的數據分析能力在這里至關重要。這不是覆蓋面和頻率模型。這是關於在與他們最相關的時間聯繫醫療保健提供者，這意味著他們最近看過病人。所以這又是一件事，我們真的很努力，團隊通過先進的 SM 發布完成了令人難以置信的工作，讓該模型啟動並運行。

Our next question comes from Joel Beatty from Baird.

我們的下一個問題來自 Baird 的 Joel Beatty。

How is the current payer coverage for ISM? And are you able to help frame what approval rate you've been seeing by this for ISM?

ISM 目前的付款人覆蓋範圍如何？您能否幫助確定您看到的 ISM 的批准率是多少？

I think I'll fit to Philina, but I have to say that market access has been an incredible strength of our launches to date and we are very well positioned moving into the ISM launch. Do you want to talk more about that,Philina?

我想我會適合 Philina，但我不得不說，市場准入一直是我們迄今為止推出的令人難以置信的優勢，我們在進入 ISM 推出方面處於非常有利的地位。你想多談談這個嗎，菲琳娜？

Yeah and so to be clear, ISM is just a small fraction of our current business today and coverage and access are strong across the full spectrum of SM patients. There's one broad SM code and so payers aren't necessarily able to distinguish the difference between advanced SM and ISM today. And as we've talked about previously, we have exceptionally strong payer coverage with virtually no access challenges.

是的，所以要明確一點，ISM 只是我們目前業務的一小部分，覆蓋範圍和訪問範圍在所有 SM 患者中都很強大。有一個廣泛的 SM 代碼，因此付款人不一定能夠區分當今高級 SM 和 ISM 之間的區別。正如我們之前談到的那樣，我們擁有非常強大的付款人覆蓋範圍，幾乎沒有訪問挑戰。

Our next question comes from Peter Lawson from Barclays.

我們的下一個問題來自巴克萊銀行的彼得勞森。

Maybe a question for Becker just on getting to a recommended Phase 2 dose with your CDK2 inhibitor or if that's a moot point because you've kind of have the ability to start the combination regimen. Just so any sense whether we should see that recommended Phase 2 dose in the first half or if we should be kind of waiting until you're off partial clinical hold?

也許 Becker 的問題只是關於使用你的 CDK2 抑製劑達到推薦的 2 期劑量，或者這是否是一個有爭議的問題，因為你有能力開始聯合治療。所以我們是否應該在上半年看到推薦的第 2 階段劑量，或者我們是否應該等到你結束部分臨床試驗？

Yeah, I mean, so first of all, as Kate mentioned, the FDA time line is the FDA time line. We don't have control over that, but we are encouraged by how quickly we are working with them. I think that both the recommended Phase 2 dose and the combination dose are important because this is potentially very broad program that involves a number of tumor types. The combination is relevant for breast cancer, but CDK2 is really central to the biology of quite a few different tumor types and different biology.

是的，我的意思是，首先，正如凱特提到的，FDA 的時間線就是 FDA 的時間線。我們無法控制這一點，但我們對與他們合作的速度感到鼓舞。我認為推薦的 2 期劑量和聯合劑量都很重要，因為這可能是一個涉及多種腫瘤類型的非常廣泛的計劃。該組合與乳腺癌相關，但 CDK2 確實是許多不同腫瘤類型和不同生物學的生物學核心。

So with respect to -- we've gone really quickly through dose escalation. And so in terms of -- it's really not just is recommended Phase 2 dose, it's a range of activity where we have a good safety profile. And I already think we have that in sight. So I think that the data that we are able to present midyear will provide a clear view of where we're going both with single agent and then very early data on the combination. They'll need more time to escalate more deeply into that ribociclib combination. It's also important to realize that we can start the chemotherapy combination as well in the near future after we come off of the partial clinical hold. So I think it's important to focus not just on that one dose but also on the holistic program.

因此，關於 - 我們已經非常快速地完成了劑量升級。因此，就-它真的不僅僅是推薦的第 2 階段劑量，它是我們具有良好安全性的一系列活動。我已經認為我們已經看到了這一點。因此，我認為我們能夠在年中提供的數據將清楚地表明我們將使用單一代理以及組合的早期數據。他們將需要更多時間來更深入地升級到 ribociclib 組合。同樣重要的是要認識到，在我們結束部分臨床試驗後，我們也可以在不久的將來開始聯合化療。所以我認為重要的是不僅要關注那一劑，還要關注整體計劃。

Is this captured under [Project Optimus] as well?

這也是在 [Project Optimus] 下捕獲的嗎？

We have the Project Optimus philosophy in mind as we look at the doses and we intend to have a very close relationship with the FDA with respect to making sure that we've covered the basis that they're looking as to understand the right single agent and combination dose so that as we go into bigger trials, we're not having to do a lot of dose finding beyond this initial trial. So Project Optimus is really the lens that we look at all of our programs through at this point.

我們在考慮劑量時牢記 Project Optimus 理念，我們打算與 FDA 建立非常密切的關係，以確保我們已經涵蓋了他們正在尋找的基礎，以了解正確的單一代理和組合劑量，這樣當我們進入更大的試驗時，我們不必在這個初始試驗之外做很多劑量發現。因此，Project Optimus 確實是我們此時審視所有項目的鏡頭。

Our next question comes from David Lebowitz from Citi.

我們的下一個問題來自花旗銀行的 David Lebowitz。

I got one on ASM and one on ISM. On ASM, I guess, to start, there was -- we talked last quarter about specifically the adoption and the associated hematological neoplasm group. And I know you had data at ASH, a lot of it focused on that specific group. I guess my thoughts are what -- how are things looking now? And how do you think that data could help?

我在 ASM 上得到了一個，在 ISM 上得到了一個。在 ASM 上，我想，首先，我們在上個季度專門討論了採用和相關的血液腫瘤組。我知道你在 ASH 有數據，其中很多都集中在那個特定的群體上。我想我的想法是——現在情況如何？您認為這些數據有何幫助？

And then, David, you said you had a second question on ISM, just...

然後，大衛，你說你有關於 ISM 的第二個問題，只是......

You want the ISM upfront? On the ISM, I guess, specifically, you were talking about how different doctors are going to prescribe the therapy in different ways. And my question is, when reporting your data at Quad AI later this month, how deeply will you go into the benefit on each specific symptom within the TSS score? And is there any thoughts as to which symptoms most doctors are emphasizing most in your view?

你想要預先的 ISM 嗎？關於 ISM，我想，具體來說，您是在談論不同的醫生將如何以不同的方式開出治療處方。我的問題是，當本月晚些時候在 Quad AI 報告您的數據時，您將在多大程度上深入了解 TSS 評分中每個特定症狀的益處？在您看來，大多數醫生最強調哪些症狀，您有什麼想法嗎？

I think starting with advanced SM and SMA, I mean as we have talked about, we are the standard of care in the patients who are treated for their advanced SM, which tend to be the patients who have MCL and aggressive SM and that it's the SM-AHN patients where they're just a very complex clinical presentation. And that's the group of patients that we have worked through that very compelling data, as you mentioned, that we saw at ASH.

我認為從晚期 SM 和 SMA 開始，我的意思是正如我們所說的，我們是接受晚期 SM 治療的患者的標準治療，這些患者往往是患有 MCL 和侵襲性 SM 的患者，這是SM-AHN 患者的臨床表現非常複雜。正如您提到的，我們在 ASH 看到的，這就是我們通過非常有說服力的數據處理的患者群體。

We're looking at monotherapy impact of AYVAKIT both on response rate, symptoms and overall survival. It is certainly fueled conversations with prescribers. And in that group of patients, we're changing practice, right? And they're very complex clinical patients. And so that's where we'll continue to see that work as we expand the overall size of the SM market, which is why the growth has moderated a bit there.

我們正在研究 AYVAKIT 單一療法對反應率、症狀和總生存期的影響。這肯定會推動與開處方者的對話。在那組患者中，我們正在改變做法，對嗎？他們是非常複雜的臨床患者。因此，隨著我們擴大 SM 市場的整體規模，我們將繼續看到這項工作，這就是為什麼那裡的增長有所放緩的原因。

As you think about the ISM presentation at PIONEER, we're going to show kind of the totality of data, including the impact on patients across all symptoms within the TFS. In terms of -- as Christy was mentioning, different specialties have different context for clinical trial data. PROs are commonly used in the allergy immunology space, not as much in hematology. Other measures are more common to hematology. And so what is great about this data set is that we see compelling and consistent impact across all of these measures. And so that is -- it's something that can appeal to all of our potential prescribers. And so I think we're really looking forward to getting that out.

當您考慮 PIONEER 上的 ISM 演示時，我們將展示某種數據的整體性，包括 TFS 內所有症狀對患者的影響。就-正如克里斯蒂提到的那樣，不同的專業對臨床試驗數據有不同的背景。 PRO 通常用於過敏免疫學領域，而不是血液學領域。其他措施更常見於血液學。因此，該數據集的優點在於，我們看到所有這些措施都產生了令人信服且一致的影響。這就是 - 它可以吸引我們所有潛在的處方者。所以我認為我們真的很期待將其發布。

In terms of the symptomatology that physicians are most focused on, it's really what impacts the patient the most. It's not that they want to see one or the other, they want their patient's quality of life to improve. And so that is, again, why we design the PRO to look at a array of symptoms because one given patient may have predominantly neuro cog symptoms and very -- not much in other domains. Another given patient may have predominant skin symptoms and not on other domains. And so it's a very heterogeneic disease presentation. And that's exactly why we designed the PRO's we did and we'll be showing all of that data.

就醫生最關注的症狀而言，它確實對患者影響最大。這並不是說他們想看到其中之一，他們希望患者的生活質量得到改善。因此，這又是為什麼我們設計 PRO 來查看一系列症狀，因為給定的患者可能主要有神經齒輪症狀，而在其他領域則很少。另一個給定的患者可能有主要的皮膚症狀，而不是在其他領域。所以這是一種非常異質的疾病表現。這正是我們設計 PRO 的原因，我們將展示所有這些數據。

Our next question comes Zhi Shu from Berenberg.

我們的下一個問題來自貝倫貝格的直樹。

I want to ask a question related to market access. Do you anticipate a separate code for ISN and when the product is going to launch? And then related to that, what's your expectation for gross to net?

我想問一個關於市場准入的問題。您是否預計 ISN 會有單獨的代碼以及產品何時發布？然後與此相關，您對毛淨值的期望是什麼？

And I'll hand over the question on the codes to Philina and then Mike can take gross to that.

我會將有關代碼的問題交給 Philina，然後 Mike 就可以解決這個問題。

Yeah, I mean I think at the heart of your question is what kind of access we anticipate as IFM comes to market. And just to answer that head on, we expect and are highly focused on maintaining strong patient access to ISM. Today, we have virtually unencumbered payer coverage. And we expect based on the payer market research that we've done that, that's not expected to change or limit the target patients that should adopt. And your specific question about the code, no, at this point, we don't expect a new code for SM.

是的，我的意思是我認為你的問題的核心是我們預期 IFM 進入市場時會獲得什麼樣的訪問權限。為了正面回答這個問題，我們期望並高度關注保持患者對 ISM 的強大訪問。今天，我們幾乎沒有阻礙付款人的覆蓋範圍。我們希望根據我們所做的支付市場研究，這不會改變或限制應該採用的目標患者。而你關於代碼的具體問題，不，在這一點上，我們不期望 SM 的新代碼。

So just to be really clear, there's just one code for SM and you can't distinguish between subtypes within it. And so that's what we'd expect to continue. Mike, do you want to take the gross to net?

所以要明確一點，SM 只有一個代碼，您無法區分其中的子類型。這就是我們希望繼續的。邁克，你想把總收入減為淨收入嗎？

Yeah, for gross to net, so currently with AYVAKIT, we see a gross to net range in about the mid-80% range as per gross margin. In the near term, we expect that to continue once we announce pricing for ISM and get further into that launch. We said there will be some flexibility and how we think about contracting going forward. If we need to do that, that could lead to some erosion, but the mid-80s is a good starting point.

是的，對於毛淨值，所以目前使用 AYVAKIT，根據毛利率，我們看到毛淨值範圍在 80% 左右。在短期內，我們預計一旦我們宣布 ISM 的定價並進一步進入該發布，這種情況將繼續下去。我們說會有一些靈活性以及我們如何考慮未來的合同。如果我們需要這樣做，那可能會導致一些侵蝕，但 80 年代中期是一個很好的起點。

And I think on the ISM market, it's also important to remember, there's going to be puts and takes here, right? So the ISM market, we have a larger percentage of our patients are covered by commercial insurance. So there -- that will give us some tailwinds. And then we have that room, as Mike mentioned, that if we need to do any type of contracting to ensure that seamless market access, which we may or may not, but we have some space there as well. So it is -- there is a slightly different payer mix in this group than we've seen in advanced SM.

我認為在 ISM 市場上，記住這一點也很重要，這裡會有看跌期權，對吧？因此，在 ISM 市場，我們有更大比例的患者被商業保險覆蓋。所以那裡 - 這會給我們帶來一些順風。然後我們有那個空間，正如 Mike 提到的，如果我們需要進行任何類型的合同以確保無縫市場准入，我們可能會也可能不會，但我們也有一些空間。所以它是——這個群體中的付款人組合與我們在高級 SM 中看到的略有不同。

Our next question today comes from Ami Fadia from Needham.

我們今天的下一個問題來自 Needham 的 Ami Fadia。

Just ahead of the Quad AI data presentation, I wanted to just sort of understand how to interpret some of the data that will be presented there. I mean it's clear that there's a huge heterogeneity in the patient population base with each patient having a very different symptom domains bothersome. So how do we take the change in TSS score across each of the domains that you will be presenting at the meeting and think about how clinically meaningful it may be for an individual patient? And how will physicians really interpret that data?

就在 Quad AI 數據展示之前，我想了解一下如何解釋將在那裡展示的一些數據。我的意思是，很明顯，患者群體中存在巨大的異質性，每個患者都有非常不同的症狀域，令人煩惱。那麼，我們如何看待您將在會議上展示的每個領域的 TSS 評分變化，並考慮它對個體患者的臨床意義？醫生將如何真正解讀這些數據？

Christy, do you want to take that?

克里斯蒂，你要拿那個嗎？

So as we said before, what physicians are looking at is the consistency and totality of the data. When we look at sort of change in individual symptoms, again, the TSS is a new endpoint. It's not used in clinical practice. The lens that I think physicians are interpreting this data through is to say, one, whatever my symptom -- whatever symptom my patient is suffering from, do you have confidence that AYVAKIT will improve their quality of life and improve those symptoms? And so I think what we've heard is that what physicians are looking for is consistency of improvement across individual symptoms. I think looking at that longitudinally over time is going to be interesting as well.

因此，正如我們之前所說，醫生關注的是數據的一致性和完整性。當我們查看個體症狀的某種變化時，TSS 再次成為一個新的終點。它不用於臨床實踐。我認為醫生解釋這些數據的鏡頭是說，一個，無論我的症狀是什麼——無論我的病人患有什麼症狀，你有信心 AYVAKIT 會改善他們的生活質量並改善這些症狀嗎？所以我認為我們所聽到的是醫生正在尋找的是個體症狀改善的一致性。我認為隨著時間的推移縱向觀察也會很有趣。

And then importantly, addressing a patient's most bothersome symptom because we know that these patients are heterogeneous as you say and what specific symptom may be most impactful to a patient is going to be different from patient-to-patient. And so I think what is compelling about AYVAKIT is that we do see consistent impacts and we know that regardless of the specific presentation of a patient symptomatology, we're confident that, that patient will benefit. And I think that's the ones that the prescribers will be looking at this data set through as well.

然後重要的是，解決患者最煩人的症狀，因為我們知道這些患者正如您所說的那樣是異質的，並且可能對患者影響最大的具體症狀因患者而異。因此，我認為 AYVAKIT 的引人注目之處在於，我們確實看到了一致的影響，而且我們知道，無論患者症狀的具體表現如何，我們都相信，患者會受益。我認為開處方者也將通過這些數據來查看這些數據。

Our next question today comes from Matt Biegler from Oppenheimer.

我們今天的下一個問題來自奧本海默的馬特比格勒。

I wanted to ask about median duration on therapy in ASM. If you can comment on that, is it getting longer or shorter and I guess that would be indicative of the severity of patients you're treating and whether you're making inroads into that agents component?

我想問一下 ASM 治療的中位持續時間。如果您可以對此發表評論，它會變長還是變短，我想這將表明您正在治療的患者的嚴重程度以及您是否正在進入該代理組件？

And Philina, do you want to take that?

Philina，你想接受嗎？

Yeah, so our median duration of therapy is trending towards 18 months. We're highly encouraged that this is standing up well in clinical practice. And certainly, as we shift towards a mix of more treatment-naive patients, we expect that over time to increase.

是的，所以我們的治療持續時間中位數趨向於 18 個月。我們非常高興這在臨床實踐中表現良好。當然，隨著我們轉向更多未接受過治療的患者，我們預計隨著時間的推移這種情況會增加。

Our final question comes from Chris Raymond from Piper Sandler.

我們的最後一個問題來自 Piper Sandler 的 Chris Raymond。

This is Nicole Gabreski on for Chris. So I guess we were just wondering, of those 400 moderate your ISM patients that you had referenced, just given the experience of AYVA with those providers, are any of those patients currently receiving drug off label? And also sorry if I missed it, but would you be in a position to provide updated 2023 AYVAKIT guidance that includes ISM revenues potentially later this year post approval?

這是克里斯的妮可加布雷斯基。所以我想我們只是想知道，在您提到的那 400 名溫和的 ISM 患者中，根據 AYVA 與這些提供者的經驗，這些患者中是否有任何患者目前正在接受標籤外藥物治療？如果我錯過了，也很抱歉，但是您能否提供更新的 2023 AYVAKIT 指南，其中包括可能在今年晚些時候獲得批准後的 ISM 收入？

Yeah, thank you very much for that question. So starting with -- I'll answer knowing that we're coming up against time here. But the 400 patients are really not being treated today with AYVA. We see small number of patients with ISM who are being treated, but it's not substantial relative to our overall number of patients being treated. And then as we talk about guidance, I mean, I think our goal today is to align on where our current business stands with our approved indications of advanced SM and GIST. And to really set that foundation for all of us as we move towards this anticipated launch. And in any given launch, there are uncertainties, including what our label will look like as we go through the FDA negotiation process and how the first few months will play out. So we look forward to working with all of you as we move into this really exciting launch. So thank you very much for that.

是的，非常感謝你提出這個問題。所以首先——我會回答，因為我們要趕時間了。但是今天這 400 名患者實際上並沒有接受 AYVA 治療。我們看到少數正在接受治療的 ISM 患者，但相對於我們正在接受治療的患者總數而言，這並不重要。然後當我們談論指導時，我的意思是，我認為我們今天的目標是使我們當前的業務與我們批准的高級 SM 和 GIST 適應症保持一致。並在我們朝著這個預期的發布邁進時真正為我們所有人奠定基礎。在任何給定的發布中，都存在不確定性，包括我們在 FDA 談判過程中的標籤會是什麼樣子，以及前幾個月的結果如何。因此，我們期待著在我們進入這個真正令人興奮的發佈時與大家合作。非常感謝你。

That concludes the Q&A portion of today's call. I'll now hand back over to Kate Haviland for closing remarks.

今天電話會議的問答部分到此結束。我現在將交還給凱特·哈維蘭 (Kate Haviland) 作結束語。

Thank you, operator. And really, as we kind of come out of the Q&A and taking a step back, I mean, today, we have highlighted the significant opportunities that we have as Blueprint right in front of us, to create value for patients and for our shareholders, including our continued commercial execution, our anticipated launch in ISM, as well as the ambitious and achievable goals we have for our pipeline. And we are confident in our ability to deliver on these opportunities this year and beyond. We thank you all for taking the time and joining us today and your continued support of Blueprint Medicines. And we look forward to talking to you again soon this time from San Antonio in the Quad AI conference. So looking forward to it.

謝謝你，運營商。實際上，當我們結束問答並退後一步時，我的意思是，今天，我們強調了我們作為藍圖擺在我們面前的重要機會，可以為患者和我們的股東創造價值，包括我們持續的商業執行、我們在 ISM 中的預期發布，以及我們為管道製定的雄心勃勃且可實現的目標。我們相信我們有能力在今年及以後抓住這些機會。我們感謝大家今天抽出時間加入我們，感謝您對 Blueprint Medicines 的持續支持。我們期待這次在 Quad AI 會議上再次從聖安東尼奧與您交談。好期待啊。

That concludes today's Blueprint Medicines 4Q and FY 2022 earnings call. You may now disconnect your line.

今天的 Blueprint Medicines 第四季度和 2022 財年財報電話會議到此結束。您現在可以斷開線路。