Insmed Inc (INSM) 2025 Q1 法說會逐字稿

Thank you for standing by. My name is Amy, and I will be your conference operator for today. At this time, I would like to welcome everyone to the Insmed first quarter 2025 financial results call. (Operator Instructions)

感謝您的支持。我叫艾米，今天我將擔任您的會議主持人。現在，我歡迎大家參加 Insmed 2025 年第一季財務業績電話會議。（操作員指示）

It is now my pleasure to turn the call over to Bryan Dunn. You may begin.

現在我很高興將電話轉給布萊恩鄧恩。你可以開始了。

Thank you, Amy. Good day everyone and welcome to today's conference call in which we will discuss Insmed's first quarter 2025 financial results and provide an update on our business.

謝謝你，艾米。大家好，歡迎參加今天的電話會議，我們將討論 Insmed 2025 年第一季的財務業績並提供我們業務的最新情況。

Before we start, please note that today's call will include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed.

在我們開始之前，請注意，今天的電話會議將包括基於我們當前預期的前瞻性陳述。這些聲明代表了我們今天的判斷，並且本身涉及風險和不確定性，可能導致實際結果與討論的結果有重大差異。

Please refer to our filings with the Securities and Exchange Commission for more information concerning the risk factors that could affect the company. The information we will discuss on today's call is meant for the benefit of the investment community. It is not intended for promotional purposes, and it is not sufficient for prescribing decisions.

有關可能影響公司的風險因素的更多信息，請參閱我們向美國證券交易委員會提交的文件。我們在今天的電話會議上討論的資訊是為了投資界的利益。它不適用於促銷目的，且不足以規定決策。

I'm joined today by Will Lewis, Chair and Chief Executive Officer, and Sara Bonstein, Chief Financial Officer, who will each provide prepared remarks, after which they will be joined by Martina Flammer, Chief Medical Officer, for a Q&A session. I will now turn the call over to Will.

今天，董事長兼首席執行官威爾·劉易斯 (Will Lewis) 和首席財務官薩拉·邦斯坦 (Sara Bonstein) 將與我一起發表準備好的講話，之後首席醫療官瑪蒂娜·弗萊默 (Martina Flammer) 將加入問答環節。現在我將把電話轉給威爾。

Thank you, Bryan, and welcome everyone. 2025 is off to an exceptionally strong start for Insmed, with our research and development, regulatory and commercial teams executing on their ambitious goals for the year. ARIKAYCE delivered another quarter of double-digit year over year revenue growth in Q1, and each of our mid to late-stage clinical programs are on or ahead of schedule.

謝謝你，布萊恩，歡迎大家。 2025 年對 Insmed 來說是一個異常強勁的開端，我們的研發、監管和商業團隊正在實現今年的雄心勃勃的目標。ARIKAYCE 在第一季再次實現了兩位數的年收入成長，我們的每個中後期臨床項目都按計劃或提前完成。

Perhaps most importantly, we have continued to facilitate the FDA's ongoing review of our NDA filing for brensocatib and bronchiectasis, which has been steadily progressing without disruption despite the changes occurring at the agency. We continue to expect the FDA's decision on their review by the August 12, PDUFA date.

或許最重要的是，我們繼續協助 FDA 對我們關於 brensocatib 和支氣管擴張症的 NDA 申請的持續審查，儘管 FDA 發生了變化，但審查仍在穩步推進，沒有中斷。我們繼續期待 FDA 在 8 月 12 日 PDUFA 日期之前對其審查做出決定。

Before I walk through our recent progress in more detail, I'd like to reflect briefly on where I currently stands on its development journey and importantly what still lies ahead. In is advancing three mid to late-stage programs with Brensocatib, TPIP, and ARIKAYCE. We have achieved an uninterrupted string of positive clinical data for at least one indication from each program, which is a rare accomplishment.

在我詳細介紹我們最近的進展之前，我想簡單回顧一下我目前在其發展歷程中所處的位置，以及更重要的是，未來還有什麼需要解決。正在推進 Brensocatib、TPIP 和 ARIKAYCE 三個中後期專案。我們針對每個項目的至少一個適應症獲得了連續不斷的積極臨床數據，這是一項罕見的成就。

These results have offered patients new hope and have given us the confidence to pursue additional indications. In the next 12 months, we look forward to reading out data from TPIP for PAH, brensocatib for CRS without nasal polyps, and the Erica Encore trial for all MAC lung disease.

這些結果為患者帶來了新的希望，也給了我們尋求更多適應症的信心。在接下來的 12 個月中，我們期待讀出 TPIP 對 PAH 的研究數據、brensocatib 對無鼻息肉的 CRS 的研究數據以及 Erica Encore 試驗對所有 MAC 肺病的研究數據。

If we are successful, these potential additional indications would represent a meaningful advancement for patients and a substantial growth opportunity for the company. Now let's dive deeper into each of these programs starting with brensocatib.

如果我們成功了，這些潛在的額外適應症將為患者帶來有意義的進步，並為公司帶來巨大的成長機會。現在讓我們從 brensocatib 開始深入研究每個程式。

Last month, the full results of the Phase 3 ASPEN trial of brensocatib and bronchiectasis were published in the New England Journal of Medicine emphasizing the importance of this data set to the medical, scientific, and patient communities.

上個月，布倫索卡蒂布和支氣管擴張症的 3 期 ASPEN 試驗的全部結果發表在《新英格蘭醫學雜誌》上，強調了該數據集對醫學、科學和患者群體的重要性。

The publication puts brensocatib among a rare category of drugs that have had both their Phase 2 and Phase 3 results for the same indication highlighted by the New England Journal of Medicine.

該出版物將 brensocatib 列為《新英格蘭醫學雜誌》重點介紹的一類罕見藥物，該類藥物針對同一適應症同時公佈了 2 期和 3 期結果。

At the FDA, the review team continues to be engaged and responsive, and we are not aware of any turnover or other disruptions to the FDA's review activities. In fact, all components of the review process have occurred on schedule, including the mid-cycle review meeting and all applicable inspections to date.

在 FDA，審查團隊繼續積極參與並做出回應，我們並未發現 FDA 審查活動出現任何人員流動或其他中斷。事實上，審查過程的所有組成部分都已按計劃進行，包括中期審查會議和迄今為止所有適用的檢查。

We look forward to the FDA's decision in the coming months and are hopeful that it will result in this important medicine finally becoming available to bronchiectasis patients waiting for a therapy like brensocatib.

我們期待 FDA 在未來幾個月內做出決定，並希望這將使這種重要藥物最終能夠用於等待 brensocatib 等療法的支氣管擴張患者。

As the regulatory process in the US progresses, we are also making meaningful strides on our launch readiness. I am pleased to report that as of the end of April, our disease state awareness website has had over a million unique visits and over 53,000 self-identified patients who have taken action such as downloading support tools or signing up to be kept informed about the latest updates in bronchiectasis.

隨著美國監管進程的進展，我們在發布準備方面也取得了有意義的進展。我很高興地報告，截至 4 月底，我們的疾病狀態意識網站已有超過一百萬次獨立訪問，超過 53,000 名自我認定的患者採取了行動，例如下載支援工具或註冊以隨時了解支氣管擴張的最新動態。

In addition, we continue to engage with both national and regional payers, which is critical as we prepare for our goal of a frictionless launch.

此外，我們繼續與國家和地區付款人合作，這對於我們為實現無摩擦啟動的目標做準備至關重要。

So far, we have found a constructive audience in response to the proposals we presented within our initial discussions. As additional US sales reps were hired and deployed in October of 2024 with the aim of educating healthcare professionals about bronchiectasis while also detailing error case.

到目前為止，我們發現聽眾對我們在初步討論中提出的建議做出了建設性的回應。2024 年 10 月，我們僱用並部署了更多美國銷售代表，目的是向醫療保健專業人員普及支氣管擴張的知識，同時詳細說明錯誤案例。

In fact, that team has already successfully engaged with more than 27,000 healthcare professionals in the US. We've also recently completed the expansion of our patient support function, building on the strong foundation that we've provided ARIKAYCE patients for many years.

事實上，該團隊已經成功與美國 27,000 多名醫療保健專業人士建立了合作關係。我們最近也完成了患者支持功能的擴展，這建立在我們多年來為 ARIKAYCE 患者提供服務的堅實基礎上。

This function will be critical to fulfilling our mission to transform the lives of patients living with serious diseases by supporting them through their journey. Another indication of the promise of brensocatib is the encouraging regulatory reception it's receiving internationally.

這項功能對於我們實現使命至關重要，即透過支持重症患者的復原過程來改變他們的生活。布倫索卡蒂布前景光明的另一個跡像是它在國際上受到的監管歡迎。

Like at the FDA, both the European and UK regulatory authorities have accepted our filings of brensocatib and are conducting their respective regulatory reviews. We also continue to advance our filing for Japanese regulators, and we look forward to submitting that application soon. Importantly, this progress keeps us squarely on track for potential approvals and launches in each region in 2026.

與 FDA 一樣，歐洲和英國監管機構都已接受我們提交的 brensocatib 申請，並正在進行各自的監管審查。我們也正在繼續推進向日本監管機構提交申請的工作，並期待很快提交該申請。重要的是，這項進展使我們預計在 2026 年獲得各個地區的潛在批准和推出。

Our second indication for brensocatib CRS without nasal polyps is also advancing at an impressive pace. After sustained strong recruitment, the Phase 2 BiRCh trial completed enrollment last month with 288 randomized patients exceeding our original 270 patient target.

我們對 brensocatib 不伴隨鼻息肉的慢性鼻竇炎的第二個適應症也在以令人印象深刻的速度推進。經過持續的大力招募，第二階段 BiRCh 試驗於上個月完成了招募，共有 288 名隨機患者加入，超過了我們最初 270 名患者的目標。

We continue to expect top line results by the end of this year. We remain encouraged by the blinded data we have seen from the study so far and look forward to what those data could mean for patients.

我們仍期待今年年底能夠取得營收業績。我們對迄今為止從研究中看到的盲法數據感到鼓舞，並期待這些數據對患者意味著什麼。

If successful, we believe that the BiRCh Phase 2 clinical study could unlock a significant additional commercial opportunity for brensocatib that could match or even exceed that of bronchiectasis given the larger number of patients suffering from this condition.

如果成功的話，我們相信 BiRCh 第 2 階段臨床研究可以為 brensocatib 帶來重要的額外商業機會，考慮到患有這種疾病的患者數量較多，這種機會可能與支氣管擴張症相當甚至超過支氣管擴張症。

I'm also pleased to mention that while still early, enrollment in our phase 2 CEDAR trial, which examines the potential role of brensocatib in hidradenitis suppurativa, is proceeding well. Based on our current enrollment rate, we anticipate the interim futility evaluation of the first 100 patients to occur in the first half of next year.

我還很高興地提到，雖然還處於早期階段，但我們的 2 期 CEDAR 試驗的招募進展順利，該試驗旨在研究 brensocatib 在化膿性汗腺炎中的潛在作用。根據我們目前的入組率，我們預計明年上半年將對前 100 名患者進行中期無效性評估。

I also want to briefly touch upon DPP1 inhibition and the meaningful progress we are making to develop our next generation of DPP1 inhibitors. The potential of this novel pathway for treating neutrophil mediated diseases is still in its infancy and represents one of the most exciting and important areas of research we are exploring for patients.

我還想簡要地談談 DPP1 抑制以及我們在開發下一代 DPP1 抑制劑方面取得的有意義的進展。這種治療中性粒細胞介導疾病的新途徑的潛力仍處於起步階段，代表了我們為患者探索的最令人興奮和最重要的研究領域之一。

As a leader in DPP1 inhibition, our research team is working tirelessly on next generation molecules with the potential to address other diseases where neutrophil inflammation is relevant, such as COPD, rheumatoid arthritis, and many others. We anticipate the first of our next generation molecules could enter the clinic as soon as next year.

作為 DPP1 抑制領域的領導者，我們的研究團隊正在不懈地研究下一代分子，以期治療與嗜中性球發炎相關的其他疾病，例如 COPD、類風濕性關節炎等。我們預計我們的下一代分子最快將於明年進入臨床。

Turning now to our TPIP program. Our phase 2 trial of TPIP in patients with pulmonary arterial hypertension continues to progress toward a top line readout. The last patient's week 16 visit occurred in late March, and we are now in the process of cleaning and locking the database before unblinding the results.

現在來談談我們的 TPIP 計劃。我們對患有肺動脈高壓的患者進行的 TPIP 第 2 期試驗正在繼續取得進展並取得頂線讀數。最後一位患者的第 16 週就診發生在 3 月下旬，目前我們正在清理和鎖定資料庫，然後揭開結果的神秘面紗。

Based on this progress, we are narrowing the expected timing for the top line readout to June or the earlier end of our previously communicated timing of mid-year. As we approach that readout, our excitement continues to grow for what it could mean for patients. Given its proximity and in keeping with our usual practice, I want to be clear about what we would see as success for this trial before we turn over those results.

基於這項進展，我們將預期的營收數據發佈時間縮短至 6 月份，或比我們先前公佈的年中時間提早。當我們接近該讀數時，我們對它對患者可能意味著什麼的興奮感不斷增長。考慮到距離較近，並且按照我們的慣例，在我們公佈結果之前，我想先明確一下我們認為這次試驗的成功程度。

If the treatment shows a placebo adjusted reduction in pulmonary vascular resistance from baseline of 20%, we would view that as a clear win. If it shows a 25% reduction on that measure, we believe it would be a home run representing a best in class PVR reduction for a prostatoid in this setting.

如果治療顯示安慰劑調整後肺血管阻力從基線降低 20%，我們將認為這是一個明顯的勝利。如果該指標顯示減少了 25%，我們相信這將是一支全壘打，代表著在這種環境下前列腺類藥物 PVR 減少的最佳水平。

When you also consider that participants in this trial are heavily pre-treated. And that we are measuring this end 24 hours after the most recent dose of TPIP. In other words, at trough or the most conservative time point, such a result would be all the more impressive.

當您也考慮到本次試驗的參與者都接受過大量預先治療。我們是在最近一次注射 TPIP 後 24 小時測量這一結果的。也就是說，在低潮或最保守的時間點，這樣的結果更令人印象深刻。

Separately, although this study is not powered to show a definitive effect on six-minute walk distance, our hope is that we will see a 15 meter to 20 meter directional benefit favoring TPIP. Regardless of the efficacy results that are achieved in this phase two, it is important to remember that this could be the starting point for TPIP's efficacy profile, given that the study's max tolerated initial dose was set at 640 micrograms.

另外，雖然這項研究無法證明對六分鐘步行距離有明確的影響，但我們希望看到有利於 TPIP 的 15 公尺到 20 公尺的方向性優勢。無論第二階段所獲得的療效結果如何，重要的是要記住，這可能是 TPIP 療效概況的起點，因為該研究的最大耐受初始劑量設定為 640 微克。

While this max dose represents about 60% more treprostinil than the combination of four daily doses of TYVASO DPI, we have been encouraged by our studies investigators to allow for even higher dosing. In our phase 3 program, we intend to allow patients to titrate their dose up to a maximum of 1,280 micrograms or double the highest dose that was allowed in this phase 2 study.

雖然這最大劑量比 TYVASO DPI 每日四次劑量的總劑量大約多出 60% 的曲前列尼爾，但我們的研究人員鼓勵我們允許更高的劑量。在我們的 3 期計劃中，我們打算允許患者將劑量調整至最大 1,280 微克，或為本 2 期研究中允許的最高劑量的兩倍。

Given that higher doses of treprostinil have been shown both in clinical trials and in real world practice to yield greater efficacy in a dose dependent fashion, the potential for safely increasing the dose of TPIP is extremely exciting.

鑑於臨床試驗和實際實踐均表明，較高劑量的曲前列尼爾能夠以劑量依賴性方式產生更大的療效，因此安全增加 TPIP 劑量的潛力極其令人興奮。

Taken together, the prospect of greater efficacy combined with once-a-day dosing emphasizes how potentially powerful this therapy could be for improving patient outcomes in PAH and PH-ILD.

綜合起來，更高的療效與每日一次給藥的前景強調了這種療法在改善 PAH 和 PH-ILD 患者預後方面具有潛在的強大潛力。

One final update that we believe underscores the excitement of our investigators and study participants. Of the patients who completed the full 16 weeks of treatment in our phase 2 PAH trial, about 95% of them have chosen to enroll in the open label extension, which allows patients to titrate up to a max of 1,280 micrograms, and some have already reached that high dose.

我們相信，最後的更新凸顯了我們的研究人員和研究參與者的興奮。在我們的 2 期 PAH 試驗中，完成全部 16 週治療的患者中，約有 95% 選擇參加開放標籤擴展試驗，該試驗允許患者將劑量滴定至最高 1,280 微克，並且有些患者已經達到了這一高劑量。

Data from this open label extension will be made available at a future medical conference after the top line readout. Collectively we will use the information from our phase 2 trials of TPIP to finalize our clinical plans for phase 3 trials in both PH-ILD and PAH, with PH-ILD expected to start in the second half of 2025 and PAH to follow shortly thereafter.

此開放標籤擴展的數據將在頂線讀數之後在未來的醫學會議上提供。我們將共同利用 TPIP 第 2 階段試驗的資訊來最終確定 PH-ILD 和 PAH 第 3 階段試驗的臨床計劃，PH-ILD 預計將於 2025 年下半年開始，PAH 則將緊隨其後。

Finally, let me touch on our air case development program which aims to satisfy the post marketing requirement for full approval of its current refractory MAC lung disease indication while also supporting the expansion of the label to include all patients with MAC lung disease.

最後，讓我談談我們的空氣箱開發計劃，該計劃旨在滿足其當前難治性 MAC 肺病適應症的全面批准上市後要求，同時支持擴大標籤以涵蓋所有患有 MAC 肺病的患者。

The phase 3 encore trial continues to progress on schedule to its anticipated readout. As this trial has a primary endpoint that is based on a patient reported outcome measure applicable for the US regulators, which will be measured at month 13. It also has a separate durable culture conversion primary endpoint that is applicable for the Japanese regulators, and that is measured at month 15.

第三階段再試驗繼續按計畫進行，並達到預期結果。由於該試驗的主要終點是基於適用於美國監管機構的患者報告結果測量，將在第 13 個月進行測量。它還具有適用於日本監管機構的單獨的持久文化轉換主要終點，並在第 15 個月進行測量。

It is our intention to wait to unblind all the data until the month 15 culture conversion results are available. As a result, we expect that top line results will be available in the first half of 2026, and we will provide more detail as this time approaches.

我們打算等到第 15 個月的培養轉換結果出來後再公佈所有數據。因此，我們預計頂線結果將於 2026 年上半年公佈，並且我們將在此期間提供更多詳細資訊。

Encouragingly, we have been monitoring the data from ENCORE on a blinded basis, which continues to look very similar to what we saw in the successful AI study. Before I hand the call over to Sara, let me simply say that Insmed is ready for the exciting future ahead.

令人鼓舞的是，我們一直在盲法監測 ENCORE 的數據，其數據與我們在成功的 AI 研究中看到的數據非常相似。在我將電話交給 Sara 之前，我想先說一句，Insmed 已經為令人興奮的未來做好了準備。

Each of our development programs is showing meaningful progress. Our regulatory filings and launch preparations for brensocatib are all advancing on or ahead of schedule, and our commercial performance continues to deliver strong year over year revenue growth in each of our regions.

我們的每個發展項目都取得了有意義的進展。我們對 brensocatib 的監管備案和上市準備工作均按計劃或提前進行，我們的商業表現在各個地區繼續實現強勁的同比收入增長。

Let me now turn the call over to Sara.

現在讓我把電話轉給薩拉。

Thank you, Will, and good morning everyone. I'm thrilled to be addressing you during one of the most inspiring periods that we have ever seen at Insmed. In the midst of all the excitement going on inside the company, I want to take a moment to address concerns that I often hear about what is happening outside the company, particularly as it relates to tariffs.

謝謝你，威爾，大家早安。我很高興能在 Insmed 史上最鼓舞人心的時期之一向你們發表演講。在公司內部發生各種令人興奮的事情之際，我想花點時間來談談我經常聽到的關於公司外部發生的事情的擔憂，特別是與關稅有關的擔憂。

We have done extensive work to understand the potential impacts of various tariff policies on Insmed, and based on that work, we are comfortable that Insmed is well positioned to thrive even in an environment of relative geopolitical uncertainties.

我們做了大量工作來了解各種關稅政策對 Insmed 的潛在影響，並且基於這項工作，我們相信，即使在相對地緣政治不確定的環境中，Insmed 也能夠蓬勃發展。

Importantly, Insmed's US intellectual property resides in the US. This means we would expect tariffs to be applied only to the actual cost base of the product without any additional exposures due to markups or transfer price strategies, which are commonly used by others in our industry.

重要的是，Insmed 的美國智慧財產權位於美國。這意味著我們預期關稅僅適用於產品的實際成本基礎，而不會因加價或轉移價格策略而產生任何額外風險，而這些風險在我們行業中通常被其他人使用。

In addition, Insmed intends to expand its current US manufacturing footprint. We've had underway for some time to establish a second source of manufacturing for brensocatib in the United States. Importantly, all manufacturing for gene therapy programs is already based in the US.

此外，Insmed 還打算擴大目前的美國製造業。我們已著手在美國建立 brensocatib 的第二個生產基地。重要的是，所有基因治療項目的製造都已在美國進行。

Based on the tariffs currently in place, we estimate the impact on our business to be in the single digit millions annually over the next few years. We will continue to monitor and assess any impacts as the macro environment evolves.

根據現行關稅，我們估計未來幾年對我們業務的影響將每年達到數千萬。隨著宏觀環境的變化，我們將繼續監測和評估任何影響。

Let's move on to our first quarter results, beginning with the strong commercial performance of ARIKAYCE, which is illustrated on this slide. We were pleased to deliver double digit year over year growth in each of our geographic regions in the first quarter, representing the sixth quarter in a row for this achievement.

讓我們繼續討論第一季的業績，首先是 ARIKAYCE 強勁的商業表現，這張投影片就對此進行了說明。我們很高興看到第一季我們各地區都實現了兩位數的同比增長，這是我們連續第六個季度取得這一成就。

Particularly striking was the percentage growth rates we saw in Japan and Europe, both hovering around 50%. These impressive results were driven by strong volume trends due to an increase in new patient starts. In addition, our US commercial team delivered strong 14% growth for ARIKAYCE this quarter, a remarkable result for a product in its seventh-year post launch.

尤其引人注目的是，我們看到日本和歐洲的成長率均徘徊在 50% 左右。這些令人印象深刻的成果是由新患者數量的增加所導致的強勁數量趨勢所推動的。此外，我們的美國商業團隊本季為 ARIKAYCE 實現了 14% 的強勁成長，對於一款推出七年的產品來說，這是一個了不起的成績。

Due to the strength of this performance across each of our commercial regions, we remain on track to achieve our 2025 full year case net revenue guidance of $405 million to $425 million. As a reminder, this guidance range is specific to ARIKAYCE and does not include any future contributions from brensocatib if approved.

由於我們各個商業區域的強勁表現，我們仍有望實現 2025 年全年淨收入預期 4.05 億美元至 4.25 億美元。提醒一下，此指導範圍特定於 ARIKAYCE，不包括 brensocatib（如果獲得批准）的任何未來貢獻。

On slide 18 you can see our cash balance as of the end of the quarter at approximately $1.2 billion in cash, cash equivalents and marketable securities. We are well capitalized as we approach our upcoming clinical and commercial catalyst later this year.

在第 18 張投影片上，您可以看到截至本季末我們的現金餘額約為 12 億美元，包括現金、現金等價物和有價證券。隨著我們在今年稍後迎來即將到來的臨床和商業催化劑，我們已擁有充足的資本。

As is typically the case in the first quarter, our cash bur was higher than our usual quarterly cadence as a result of the timing of our annual employee incentive compensation payout. If you remove the impact of that payment as well as the cash we received due to stock option exercises in the quarter, our underlying burn in the quarter was comparable to prior quarters.

與第一季的典型情況一樣，由於我們年度員工激勵薪酬支付的時間安排，我們的現金支出高於通常的季度節奏。如果消除該付款的影響以及我們在本季因行使股票選擇權而收到的現金，我們本季的基本消耗與前幾季相當。

Although we don't guide to cash burn levels, in general, we continue to expect our burn to increase as we build out the necessary personnel and infrastructure in anticipation of the brensocatib launch. On the other side of that launch, we anticipate that increases in spending will more than offset, will be more than offset by revenue growth, leading to progressively smaller quarterly operating cash outflows.

雖然我們沒有對現金消耗水準進行指導，但總體而言，隨著我們為 brensocatib 的推出而建立必要的人員和基礎設施，我們預計現金消耗將會增加。另一方面，我們預期支出的成長將超過收入的成長，導致季度營運現金流逐漸減少。

As I've said many times, we are not currently funded through profitability, but importantly, that is by our own choice because we believe the investments we are making now will lead to outsized returns in the future.

正如我多次說過的，我們目前的資金來源不是盈利能力，但重要的是，這是我們自己的選擇，因為我們相信我們現在所做的投資將在未來帶來超額回報。

We continue to have line of sight to becoming a cash flow positive company and believe our purposeful investments, along with future potential revenue growth have put us on that path. Additionally, we expect to have many options for accessing the capital we need when the appropriate time.

我們繼續致力於成為一家現金流為正的公司，並相信我們的有目的的投資以及未來潛在的收入成長已使我們走上這條道路。此外，我們期望在適當的時候擁有多種獲取所需資金的選擇。

Last month we announced that we were calling the remaining $570 million of convertible debt on our balance sheet, which would have matured in 2028 with a redemption date of June 6, 2025. If all the debt is converted prior to redemption, it would result in the issuance of approximately 17.8 million additional shares of common stock.

上個月，我們宣布將贖回資產負債表上剩餘的 5.7 億美元可轉換債務，這些債務將於 2028 年到期，贖回日期為 2025 年 6 月 6 日。如果所有債務在贖回之前轉換，將導致發行約 1780 萬股額外普通股。

This conversion would not only lower our ongoing interest expense but would also meaningfully reduce our outstanding debt. We look forward to providing you with an update after the redemption date. Moving to the next slide, you can see our operating expenses for the quarter. Cost of product revenues for first quarter 2025 was $21.3 million or 22.9% of revenues, which is consistent with our historical performance.

這種轉換不僅可以降低我們持續的利息支出，而且還會大幅減少我們的未償債務。我們期待在兌換日期之後為您提供更新資訊。轉到下一張投影片，您可以看到我們本季的營運費用。2025 年第一季的產品收入成本為 2,130 萬美元，佔營收的 22.9%，與我們的歷史表現一致。

As expected, both our research and development in SG&A expenses were higher this quarter than they were in the previous year's first quarter, due to the significant growth of our company during the past year to support our commercial readiness initiatives in anticipation of the US launch of brensocatib, as well as our increasing investments in our early and mid to late-stage pipelines.

正如預期的那樣，本季度我們的研發費用、銷售、一般及行政費用均高於去年第一季度，這是由於我們公司在過去一年中實現了顯著增長，以支持我們為美國推出 brensocatib 而製定的商業準備計劃，以及我們加大對早期和中後期研發管線的投資。

However, I will point out that our operating expenses this quarter were down from the levels we saw in the first quarter of 2024. In the fourth quarter of 2024, this was driven largely by lower research and development costs across brensocatib for bronchiectasis and TPIP.

不過，我要指出的是，本季我們的營運費用低於 2024 年第一季的水準。2024 年第四季度，這主要是由於用於治療支氣管擴張和 TPIP 的 brensocatib 研發成本降低。

We anticipate that research and development expenses will increase going forward as we kick off the phase 3 programs for TPIP, continued investments to advance brensocatib in both CRS and HS and advance multiple gene therapy product candidates into the clinic.

我們預計，隨著我們啟動 TPIP 的 3 期計劃、繼續投資推進 brensocatib 在 CRS 和 HS 中的應用以及推進多種基因治療候選產品進入臨床，未來的研發費用將會增加。

In closing, we believe Insmed is in a unique position of strength both financially and operationally. We continue to deliver strong ARIKAYCE revenue growth in all of our regions. The expected launch of brensocatib later this year has the potential to significantly accelerate our revenue growth.

最後，我們相信 Insmed 在財務和營運方面都具有獨特的優勢地位。我們繼續在所有地區實現強勁的 ARIKAYCE 收入成長。預計今年稍後將推出的 brensocatib 有可能顯著加速我們的營收成長。

In parallel, our team continues to execute with meaningful clinical and data catalysts in the near term. All of this is supported by our strong cash position. I couldn't be more pleased with where Insmed stands.

同時，我們的團隊將在短期內繼續執行有意義的臨床和數據催化劑。所有這些都得益於我們強大的現金狀況。我對 Insmed 的現狀非常滿意。

With that, we would now like to open the call to your question. Operator, may we take the first question, please.

好了，我們現在開始回答您的問題。接線員，請問我們可以回答第一個問題嗎？

(Operator Instructions)

（操作員指示）

Your question comes from the line of Andrea Newkirk with Goldman Sachs. Your line is now open.

您的問題來自高盛的安德里亞紐柯克 (Andrea Newkirk)。您的線路現已開通。

Good morning. Thanks for taking the question and congratulations on the progress. Well, as you think about brensocatib launching globally and given what you've mentioned as what you think peak sales could be, how much does potential MFN legislation factor into your thinking on how to price both in the US and abroad? And then I have a follow up.

早安.感謝您提出這個問題，並祝賀您取得進展。那麼，當您考慮在全球範圍內推出 brensocatib 時，考慮到您提到的銷售高峰，潛在的最惠國立法對您在美國和國外定價的考慮有多大影響？然後我有一個後續行動。

So I think you know it's hard to speculate on what really will end up being the outcome. It is the pattern of behavior that we've observed that sometimes things are said that are quite dramatic, and then there's a period of time for reflection and consideration. And then the ultimate outcome is some compromise that orbits around what was originally said, but it's pretty distant from it.

所以我想你知道，很難猜測最終結果會是什麼。我們觀察到的行為模式是，有時人們說的話會非常戲劇化，然後需要一段時間來反思和考慮。最終的結果就是圍繞著最初所說的內容達成某種妥協，但又與最初所說的內容相差甚遠。

Regardless of what the actual outcome is, I think we're in a uniquely strong position because of course we don't have to look at brensocatib through the lens of what has already happened. We're setting the price in the US first and then we're going to be setting prices in Europe and UK and Japan second, third, and fourth respectively.

無論實際結果如何，我認為我們都處於獨特的優勢地位，因為我們當然不必透過已經發生的事情來看待布倫索卡蒂。我們先在美國定價，然後分別在歐洲、英國和日本定價，排名第二、第三和第四。

And the consequence of that is it gives us tremendous flexibility to respond to whatever the new environment will be. Importantly for everyone's recollection, ARIKAYCE was priced at parity between the US, Europe, and Japan when it was launched.

結果是，它為我們提供了極大的靈活性，可以應對任何新環境。值得大家記住的是，ARIKAYCE 推出時的價格與美國、歐洲和日本的價格相同。

Right, okay, and then just one more here just, given the increased engagement with your bronchiectasis disease awareness website that you mentioned, can you speak to what trends, if any, that you're picking up on?

好的，好的，然後這裡再問一個問題，鑑於您提到的支氣管擴張疾病宣傳網站的參與度不斷提高，您能否談談您注意到了哪些趨勢（如果有的話）？

And when you think about this patient group, how motivated are they to actively seek out pulmonologists for treatment and should we expect there to be a bolus of patients coming on to therapy upon approval? Thanks so much.

當您考慮這個患者群體時，他們有多大的動力去積極尋求肺科專家的治療？我們是否應該期望有大量患者在獲得批准後接受治療？非常感謝。

Sure, so one thing we know about commercial launches is that there's always something that's unexpected that occurs within them, at least, oftentimes more than one thing. What I can tell you is that the backdrop that we're, approaching here is favorable across the board.

當然，我們知道商業發射總是會發生一些意想不到的事情，至少，通常不只一件事。我可以告訴你們的是，我們現在所處的背景是全面有利的。

The number of patients that are active, the interest and enthusiasm level from them parallels that that we're receiving from the physicians, the response we got to. The New England Journal of Medicine publication was overwhelming, and I would just say I feel very good about the landscape we're stepping into, and I think we're ready for it.

活躍患者的數量、他們的興趣和熱情程度與我們從醫生那裡得到的反應是一致的。《新英格蘭醫學雜誌》的出版物令人震撼，我只想說，我對我們正在進入的局面感到非常滿意，我認為我們已經準備好了。

What that will look like, whether it will be a bolus up front or whether it will be more gradual, it's hard to say, as we mentioned in the opening remarks, we've now reached all the pulmonologists basically in the United States, and that's almost 30,000 physicians. So we have very good understanding of the landscape. We're ready to launch this drug assuming approval, and I'm expecting that that will go well.

這會是什麼樣子，無論是預先推注還是逐漸增加劑量，都很難說，正如我們在開場白中提到的，我們現在基本上已經聯繫到了美國所有的肺科專家，也就是近 30,000 名醫生。因此我們對景觀有很好的了解。一旦獲得批准，我們就會準備好推出這種藥物，我預計一切都會很順利。

I think it's hard to say what the pattern will look like, but we certainly are targeting a frictionless launch, and by that we mean easy and rapid uptake for patients that are appropriate to go on therapy, and the physicians that are identifying them have an easy process to get them on medicine.

我認為很難說這種模式會是什麼樣子，但我們的目標肯定是實現無摩擦啟動，這意味著適合接受治療的患者可以輕鬆快速地接受治療，並且識別出他們的醫生可以輕鬆地讓他們接受藥物治療。

Thank you. Your next question comes from the line of Jason Zemansky of Bank of America. Your line is now open.

謝謝。您的下一個問題來自美國銀行的 Jason Zemansky。您的線路現已開通。

Great, good morning. Congrats on the progress and thank you for taking our questions. I had to follow up on your comments just now, but again, the patient numbers seem pretty compelling in terms of kind of driving that frictionless launch. But what you see is sort of the big levers there in terms of transitioning a patient who might be interested on to therapy.

太好了，早安。恭喜您的進展，並感謝您回答我們的問題。我剛才必須跟進您的評論，但再次強調，就推動這種無摩擦啟動而言，患者人數似乎非常引人注目。但您所看到的是，在幫助可能對治療感興趣的患者轉變方面，存在著巨大的槓桿作用。

I appreciate that you're in the field here, been curious as to what you're hearing about, potential headwinds here. And how you intend to make, the process kind of seamless and moving that interest into, an actual revenue generating patient.

我很感激您來到這個領域，我很好奇您所聽到的以及這裡可能遇到的阻力。以及您打算如何使整個過程變得無縫銜接，並將這種興趣轉化為實際產生收入的患者。

Yeah, so again, I think it's going to be hard to know until we're actually in the middle of it. What I can say is that, when we talked about the numbers we were targeting out of the gate here, we are, it was very important that people understand we're talking about patients that are already diagnosed and have two or more exacerbations.

是的，所以我認為，除非我們真正身處其中，否則很難知道。我可以說的是，當我們談論我們一開始就瞄準的數字時，讓人們明白我們談論的是已經確診並且病情加重兩次或兩次以上的患者，這一點非常重要。

So this is the label we anticipate receiving. Obviously, that will drive what is an appropriate patient for use, and the physicians are prepared knowing that they have patients that have two or more. Within the last 12 months and that this medicine is coming, so I think making sure we connect those dots and just execute on that is going to be, the first order of business.

這是我們期望收到的標籤。顯然，這將決定適合使用哪種藥物的患者，而醫生已經做好準備，因為他們知道患者有兩種或兩種以上的藥物。在過去的 12 個月內，這種藥物即將問世，所以我認為確保我們把這些點連接起來並執行下去將是首要任務。

There is a second order that will be occurring in parallel which is looking at those patients who are very likely bronchiectatic and probably have had two or more exacerbations, but perhaps they have not had their CT scan, or I have not seen a pulmonologist recently.

同時還將進行第二項檢查，即觀察那些很可能患有支氣管擴張且可能出現過兩次或兩次以上病情加重的患者，但也許他們還沒有做過 CT 掃描，或者我最近沒有看過肺科醫生。

We've been encouraging through disease state awareness both for patients and physicians to explore those conditions and patients and try to line them up so that they, if appropriate, can be diagnosed as bronchiectatic with two or more exacerbations and would therefore be on label for treatment.

我們一直鼓勵患者和醫生透過了解疾病狀態來探索這些病症和患者，並嘗試將他們排列起來，以便在適當的情況下診斷為支氣管擴張，並出現兩次或兩次以上的加重，從而得到治療。

Once again, I think we have a healthy number of patients that we've identified. We think we know where they are and we have built those relationships over the last many months. I think it's not unfair to say that we have a strong reputation in the pulmonology community as a result of the way we've handled ourselves with ARIKAYCE, and that we'll pay dividends in this setting.

我再次認為我們已經確定了相當數量的患者。我們認為我們知道他們在哪裡，並且在過去的幾個月裡我們已經建立了這些關係。我認為，可以公平地說，由於我們在 ARIKAYCE 的處理方式，我們在肺病學界享有盛譽，我們將在這種環境下獲得回報。

I just met with the leadership of the US commercial team, and I can tell you to a person they are exceptional, and we are going to do an extremely good job at this launch, but the specifics of what that will look like, we're just not going to know it until we're in the middle of it.

我剛剛會見了美國商業團隊的領導層，我可以告訴你，他們非常出色，我們將在這次發布會上做得非常出色，但具體情況是什麼樣的，我們只有到了發布會中才會知道。

And I just add one additional comment. I'll remind you all that the COPD Foundation, they had an initiative to create 150-ish sites over the next three years that specialize in NTM and bronchiectasis, and my understanding is sort of the first cohort of those have been established in excess of three. New sites that specialize in treating NTM and bronchiectasis. So that is obviously encouraging to see for patients as well.

我只想補充一則評論。我要提醒大家，COPD 基金會曾計劃在未來三年內建立 150 個左右專門治療 NTM 和支氣管擴張的站點，據我了解，第一批站點已經建立了三個以上。專門治療 NTM 和支氣管擴張症的新地點。因此，這對患者來說顯然也是令人鼓舞的。

And you asked about levers. So Sara, it's an excellent point. The COPD Foundation efforts, similarly, there are guidelines out there to treat bronchiectasis. I don't know, Martina, if you want to just comment on those.

您也詢問了槓桿。所以，薩拉，這是一個很好的觀點。同樣，慢性阻塞性肺病基金會也做出了努力，並制定了治療支氣管擴張的指南。我不知道，瑪蒂娜，你是否想對此發表評論。

Yeah, so I think the guidelines are expecting, of course they've been waiting for the publication. We know that tests and as well as the ARIKAYCE are expecting and working on updating their guidelines. We hope, of course, that they take this into consideration. Also remember right now patients have nothing to really treat their disease.

是的，所以我認為這些指導方針是值得期待的，當然他們一直在等待它的發布。我們知道，測試和 ARIKAYCE 正在期待並致力於更新他們的指南。當然，我們希望他們考慮到這一點。也要記住，目前患者沒有任何東西可以真正治療他們的疾病。

We're talking about patients who do respiratory therapy and if they have an infection, they're getting an antibiotic. It is nothing that currently truly impacts the progression of their disease or goes to the causation of their disease. And maybe one more comment that shows us also the interest just driven by patients themselves because we've measured who is actually looking at the publications that the New England.

我們談論的是接受呼吸治療的患者，如果他們感染了，就會服用抗生素。目前，這些都不能真正影響他們的疾病進展或導致他們的疾病。也許還有一條評論向我們展示了患者自身的興趣，因為我們已經測量了誰真正在看新英格蘭的出版物。

And we've seen an exorbitant high amount of over 60% that is coming from the public, so this is largely represented by patients interested family members and caregivers. We expect always the scientific community to be part of it, but patients who are strongly engaged and their representatives are looking at these publications and this data.

我們看到，超過 60% 的捐款來自公眾，這部分捐款主要來自病人、有興趣的家庭成員和照護者。我們始終期望科學界參與其中，但積極參與的患者及其代表正在關注這些出版物和數據。

Just to clarify quickly, do you expect a CT scan to be necessary for prescription and diagnosis there?

只是為了快速澄清一下，您是否認為那裡的處方和診斷需要進行 CT 掃描？

Yes, so just to be crystal clear, the definitive diagnosis of bronchiectasis is achieved with a high resolution CT scan and symptom evaluation by a pulmonologist. And so when we identify patients with two or more exacerbations who have a definitive diagnosis of bronchiectasis, all of those criteria are met in the numbers we've outlined.

是的，為了清楚起見，支氣管擴張的明確診斷是透過高解析度 CT 掃描和肺病專家的症狀評估來實現的。因此，當我們確定有兩次或兩次以上病情加重並確診為支氣管擴張的患者時，我們所列出的所有標準均已滿足。

What we've raised for awareness is that there are many more behind them who perhaps have COPD or asthma or some other comorbidity and also are experiencing exacerbations despite being on best available treatments for those conditions, and that suggests that they may also be suffering from bronchiectasis.

我們提高意識的是，在他們之後還有更多的人可能患有慢性阻塞性肺病或哮喘或其他合併症，儘管接受了針對這些疾病的最佳治療，但病情仍然惡化，這表明他們也可能患有支氣管擴張。

To Martina's point, in the absence of anything to treat these patients, there really hasn't been a strong motivation to get them a CT scan to definitively define and identify the diagnosis of bronchiectasis because there's nothing, they can do about it.

正如 Martina 所說，由於沒有任何方法可以治療這些患者，所以他們並沒有強烈的動機去讓他們進行 CT 掃描以明確定義和確定支氣管擴張的診斷，因為他們對此無能為力。

So with that potential arrival of this new medicine that will change that equation dramatically, and it's not uncommon to find when a disease that has a first ever treatment arrives that many more patients than were originally thought are part of the diagnosed group that eventually emerges.

因此，隨著這種新藥的潛在出現，它將極大地改變這一現狀，當一種首次治療的疾病出現時，我們會發現最終確診的患者數量比最初認為的要多得多，這並不罕見。

Thank you. Your next question comes from the line of Jessica Fye with JP Morgan. Your line is now open.

謝謝。您的下一個問題來自摩根大通的傑西卡·費伊 (Jessica Fye)。您的線路現已開通。

Hi, this is Nick on for Jess. Thanks for taking our questions. First, for the upcoming TPIP update, can you talk about how you're thinking about the relative importance of PVR versus six-minute walk? And then I know it doesn't sound like it, but can you just remind us if you're powered for six-minute walk in the phase 2 trial?

大家好，我是尼克，代表傑西。感謝您回答我們的問題。首先，對於即將發布的 TPIP 更新，您能談談您如何看待 PVR 與六分鐘步行的相對重要性嗎？然後我知道這聽起來不像，但是你能提醒我們在第二階段試驗中您是否有能力進行六分鐘的步行嗎？

Yeah, so the way we think about it is that the most definitive examination of this is the PVR measure, right? That's a direct measure of pulmonary vascular resistance. These patients typically expire as a result of right heart failure, so the ability to alleviate that pressure is very material. It's also an incredibly invasive measure, and so that's why it's not conducted commonly or widely.

是的，所以我們認為對此最明確的檢查是 PVR 測量，對嗎？這是肺血管阻力的直接測量值。這些患者通常因右心衰竭而死亡，因此減輕這種壓力的能力非常重要。這也是一種極具侵入性的措施，因此它並不常見或廣泛實施。

In the setting of the clinical trial and phase two in particular, you're often seeing it as the definitive measure for whether or not the drug is having an impact, and then people look to the correlate of six-minute walk tests and other biomarkers like NT-proBNP to capture the impact as a result of the treatment. So we think PVR is the most important measure.

在臨床試驗，尤其是第二階段的臨床試驗中，你通常會將其視為衡量藥物是否產生影響的決定性指標，然後人們會參考六分鐘步行測試和 NT-proBNP 等其他生物標誌物的相關性來捕捉治療產生的影響。因此我們認為 PVR 是最重要的衡量標準。

I think the agency and physicians would agree with that. And then we look at six-minute walk. As a less specific measure but still capturing the ultimate exercise capacity of patients as an ancillary benefit of the pulmonary vascular resistance improvement. So when we look at it in this context of this phase 2 study, we are not powered for statistical significance on six-minute walk test.

我認為機構和醫生都會同意這一點。然後我們看看六分鐘的步行。作為一種不太具體的措施，但仍可以捕捉患者的最終運動能力，作為肺血管阻力改善的輔助益處。因此，當我們從第二階段研究的角度來看這個問題時，我們無法對六分鐘步行測試得出統計意義。

However, we are hoping to see a trend somewhere in the 15 meter to 20 meter range, just as we expressed that we're hoping to see a placebo adjusted PDR reduction of 20% as the threshold for success for this trial. We are, it's our practice to put out these expectations before data is unblinded.

然而，我們希望看到 15 公尺到 20 公尺範圍內的某個趨勢，正如我們所表達的，我們希望看到安慰劑調整後的 PDR 減少 20% 作為本次試驗成功的門檻。我們的慣例是在資料揭曉之前提出這些預期。

Get them by stepping back and saying what would be a definitive way to prove that this medicine is impactful in a phase 2 setting that would impress physicians and regulators and market access participants.

讓他們退一步來看看，什麼是可以確定的方法來證明這種藥物在第二階段的環境中是有效的，從而給醫生、監管機構和市場准入參與者留下深刻印象。

And having done that work, these are the measures that we come back with, and we'll see where the trial comes out. It's been widely reported that the fact that this is a once a day is in and of itself a huge advance for these patients.

完成這些工作後，我們會採取這些措施，看看試驗結果如何。據廣泛報導，每天一次的治療本身對這些患者來說是一個巨大的進步。

Clearly we're not setting ourselves up to top tick the results because we're measuring a trough, but nonetheless, we think that's the right way to think about it through the lens of the patient, the physician, and the regulatory and market access communities. What will this drug really do for patients after they take it? And if we can capture that by an improvement of 20% or so placebo adjusted on PVR, that's a clear win.

顯然，我們不會為了達到最佳結果而努力，因為我們正在測量一個最低值，但儘管如此，我們認為這是從患者、醫生以及監管和市場准入社區的角度來看待這個問題的正確方法。患者服用此藥後究竟能產生什麼作用？如果我們能夠透過對 PVR 進行 20% 左右的安慰劑調整來捕捉這一改進，那顯然是一場勝利。

Thank you. Your next question comes from the line of Joe Schwartz with Leerink Partners. Your line is now open.

謝謝。您的下一個問題來自 Leerink Partners 的 Joe Schwartz。您的線路現已開通。

Great, thanks for taking my question and for the update. On forensic head, it was great to see the New England Journal of Medicine article recently. The accompanying editorial seemed to raise some questions about the magnitude of the benefit, and I'm just wondering how common is that opinion in the marketplace.

太好了，感謝您回答我的問題並提供最新消息。關於法醫頭部，最近看到《新英格蘭醫學雜誌》的文章真是太好了。隨附的社論似乎對收益的大小提出了一些疑問，我只是想知道這種觀點在市場上有多普遍。

And what does the company typically or what kind of company say when in order to educate folks on the importance of the benefit and how come we don't hear more about the severity of exacerbations as opposed to just the number of exacerbations?

為了讓人們了解福利的重要性，公司通常會說什麼，或說什麼樣的公司會說什麼，為什麼我們沒有聽到更多關於病情加重的嚴重程度，而不僅僅是病情加重的次數？

Yeah, so a number of points in there, Joe. The first is to understand that when the New England Journal has published the results from phase 2 and phase 3 for the same drug in the same condition, that's an extremely rare occurrence. I think in the last 25 years it's happened maybe five times in the respiratory field, and it's been for drugs like Dupixent and other extremely impactful medicines.

是的，喬，這裡面有很多要點。首先要明白的是，當《新英格蘭雜誌》發表相同藥物在相同條件下的第 2 階段和第 3 階段的結果時，這種情況極為罕見。我認為在過去的 25 年裡，呼吸領域可能發生過五次這樣的情況，而且都是針對 Dupixent 和其他極具影響力的藥物。

So we're excited about that. Coupled with that, to have two editorials associated with the publication is also equally rare, and it highlights the importance that the medical community puts on the arrival of this medicine, which is something that the editorial clearly called out this is the new kid on the block, as they said. It's important to go for a more nuanced look at what those editorials were saying and where they are coming from.

所以我們對此感到很興奮。除此之外，該出版物附有兩篇社論也同樣罕見，這凸顯了醫學界對這種藥物的重視，社論明確指出，正如他們所說，這是一種新生事物。更細緻地了解這些社論的內容和來源非常重要。

And so let me just take a moment to dwell on that. The reference to a macrolide as a potential use of therapy is not uncommon in the most restricted and rationed healthcare systems in the world. That was the lens through which they were examining this. It is not something we have encountered in any of our settings where we are planning on commercializing the drug.

所以請容許我花一點時間來詳細討論這個問題。在世界上限制最嚴格、配給最嚴格的醫療保健系統中，將大環內酯類藥物作為一種潛在的治療用途並不罕見。這就是他們審視此事的視角。在我們計劃將該藥物商業化的任何環境中，我們都沒有遇到過這種情況。

And it is not something that is common discussion. Clearly macrolides and other medicines are used for the treatment of bronchiectasis when patients develop infections, but macrolide use as a monotherapy is a really big no. And one of the challenges that emerges from that is the potential for resistance development. A macrolide and once that happens, that patient is in very serious trouble.

這不是一個常見的討論話題。顯然，當患者出現感染時，大環內酯類藥物和其他藥物可用於治療支氣管擴張，但大環內酯類藥物作為單一療法是絕對不行的。由此產生的挑戰之一就是產生抗藥性的可能性。大環內酯類藥物，一旦發生這種情況，患者就會陷入非常嚴重的困擾。

So you will hear mention of this in, health care ration communities. I think it was offered as something almost ancillary. We have not encountered it in any of our market access discussions, nor do we expect to, nor would you find it commonly.

因此，您會在醫療配給社區中聽到有關此內容的提及。我認為它幾乎是作為輔助的東西提供的。在我們的任何市場准入討論中，我們都沒有遇到過這種情況，我們也不期望遇到這種情況，您也不會經常發現這種情況。

In the medical community, but it is an interesting additional perspective, and I think the New England Journal prides itself in ensuring objectivity and third-party points of view are heard, and that's why we received the two editorials which, on balance, I would say were quite positive in terms of their endorsement of the arrival of this new and important medicine.

在醫學界，但這是一個有趣的額外視角，我認為《新英格蘭雜誌》以確保客觀性和第三方觀點被聽取為榮，這就是為什麼我們收到這兩篇社論，總的來說，我認為它們對這種新的重要藥物的到來給予了相當積極的支持。

Thank you. Your next question comes from the line of Vamil Divan with Guggenheim Securities. Your line is now open.

謝謝。您的下一個問題來自古根漢證券公司的 Vamil Divan。您的線路現已開通。

Hi, thank you. Yeah, this is Daniel on for Vamil. I have a couple questions on the next generation DPP1s. So, you mentioned that COPD and rheumatoid arthritis, there are potential indications to pursue. Maybe if you could describe in a little more detail the choice of highlighting these two indications in particular.

你好，謝謝。是的，這是丹尼爾 (Daniel) 代替瓦米爾 (Vamil)。我對下一代 DPP1 有幾個問題。所以，您提到 COPD 和類風濕性關節炎有潛在的適應症值得研究。也許您可以更詳細地描述特別強調這兩個跡象的選擇。

And if there is any, sort of hierarchy between those two for which you think would be a higher priority, whether due to commercial or scientific reasons and connected to that, maybe if you could dive into what properties you're looking for in the next generation DPP1. As compared to what you, have with the Brunswick kind of profile. Thank you.

如果您認為這兩者之間存在某種層次結構，並且該層次結構的優先順序更高，無論是出於商業原因還是科學原因，並且與此相關，那麼您可以深入了解您在下一代 DPP1 中尋找的屬性。與您擁有的 Brunswick 類型的資料相比。謝謝。

Sure, so I think the first thing that is important to convey is that our North Star is always the patient and the impact of the medicine on the patient. And while that may sound trite or ring a little hollow to people in this industry, it is truly something to which we align ourselves.

當然，所以我認為首先要傳達的重要一點是，我們的北極星始終是病人以及藥物對病人的影響。雖然對於這個行業的人來說這可能聽起來有些陳腔濫調或空洞，但這確實是我們所認同的。

And with that in mind, we look at these areas COPD, rheumatoid arthritis, and many others because we see an unmet medical need and we see this medicine as having a particularly impactful potential in those settings. We've done some early animal work in some of these, and so we know that DPP1 in that setting is effective. That raises our expectation and excitement and enthusiasm for what we may be able to do.

考慮到這一點，我們關注慢性阻塞性肺病、類風濕性關節炎等許多疾病領域，因為我們看到了未滿足的醫療需求，我們認為這種藥物在這些環境中具有特別大的潛力。我們已經對其中一些動物進行了早期研究，因此我們知道 DPP1 在那種環境下是有效的。這提高了我們對可能做的事情的期望、興奮和熱情。

Shortly after the Willow study was published, we began work on expanding the library of DPP-1 candidates, both from the point of view of protecting what we already have, but also to expand potential clinical use into new indications.

Willow 研究發表後不久，我們就開始著手擴大 DPP-1 候選藥物庫，不僅從保護現有藥物的角度，也從擴展潛在臨床用途的角度來擴大新適應症。

And so some of the molecules differ from brensocatib in ways that we hope will ultimately result in clinical benefit to patients in these different disease settings, and that is the primary driver of how we're going about their assessment, as they develop and as we learn more entering the clinic perhaps as early as next year, we certainly are going to be very excited about that because these are substantial indications and our goal is to have the biggest influence on the largest number of patients and that's why we targeted them.

因此，我們希望某些分子與 brensocatib 有所不同，最終將為不同疾病環境下的患者帶來臨床益處，這是我們進行評估的主要驅動力，隨著它們的發展以及我們了解更多信息並可能最早在明年進入臨床，我們肯定會對此感到非常興奮，因為這些都是實質性的適應症，我們的目標是對最多數量的患者產生最大的影響，這就是我們瞄準它們的原因。

Thank you. Your next question comes from the line of Ritu Baral with TD Cowen. Your line is now open.

謝謝。您的下一個問題來自 TD Cowen 的 Ritu Baral。您的線路現已開通。

Hi guys, thanks for taking the question. Apologies for any background noise. Will, can you address if there's any outstanding inspections on the brenso review to be done, whether it's domestic or international, and then I have a follow-up question on TPIP.

大家好，感謝你們回答這個問題。對於任何背景噪音，我們深表歉意。威爾，您能否回答布倫索審查中是否還有任何未完成的檢查需要完成，無論是國內檢查還是國際檢查，然後我有一個關於 TPIP 的後續問題。

So the short answer to your question or two is that the FDA reserve the right to inspect all the way up basically till the end of the approval. So we can't say definitively whether or not there's any more to come. I can only say definitively, as we mentioned in the comments, that we've had some inspections. We've had the mid-cycle review.

因此，對於您的兩個問題，簡短的回答是，FDA 保留全程檢查的權利，基本上直到批准結束。所以我們無法明確地說是否還會有更多。我只能明確地說，正如我們在評論中提到的，我們已經進行了一些檢查。我們已經進行了中期審查。

Everything is going according to plan. We couldn't be happier about the progress we're making, and that's being echoed in what we're seeing internationally in terms of the engagement both in the approval of the initial filing but also the engagement we're receiving from the regulators, almost on a daily basis as we sit here today. So nothing but thumbs up from our side at this point to report.

一切都按計劃進行。我們對所取得的進展感到非常高興，我們在國際上看到的參與也反映了這一點，不僅包括初始申請的批准，還包括我們今天坐在這裡幾乎每天都收到的來自監管機構的參與。因此，就目前而言，我們對此只有讚賞。

Were there any surprises in the mid-cycle review meeting and then on the TPIP side, what are your thoughts on either the phase redesign or the path forward in the event of divergent six-minute walk and PVR data, you clearly expressed the 15 to 20 on six-minute walk and then the 20 plus on PVR, but you know what if you have sort of extreme? What does that tell you about what you need to do with the phase 3?

在中期審查會議上是否有任何意外，然後在 TPIP 方面，如果六分鐘步行和 PVR 數據出現分歧，您對階段重新設計或前進的道路有何看法，您清楚地表達了六分鐘步行 15 到 20，然後 PVR 超過 20，但您知道如果出現極端情況會怎樣？這告訴您需要對第三階段做什麼？

Yeah, so on the mid-cycle review, no surprises. On the TPIP study, you do see divergence on occasion in these measures, and that's always something that is what gives us caution to otherwise interpreting the blended blinded data that has been positive as we as we've shared to date.

是的，因此在中期審查中，沒有什麼意外。在 TPIP 研究中，您確實偶爾會看到這些指標存在分歧，而這始終促使我們謹慎解讀迄今為止我們所分享的正向混合盲法資料。

But I'm not as concerned about that for a number of reasons. The primary one being that this is a known moiety, the underlying drug, the prostanoid class, the vasodilation it accomplishes is well established to be beneficial in both of these measures, and consequently we would expect that to be evident.

但由於多種原因，我對此並不擔心。主要原因是，這是一種已知的部分，其基礎藥物、前列腺素類、它所實現的血管舒張作用已被充分證實對這兩種措施都是有益的，因此我們期望這一點是顯而易見的。

If we see aberrations look very closely at the data. Many of you have heard the great story from the phase two of last year where we had a patient who had great PVR reduction and then had a terrible six-minute walk result, and it turned out that between the beginning and the end of the six-minute walk measure they had broken their leg.

如果我們發現異常，請仔細查看數據。你們中的許多人都聽說過去年第二階段的一個精彩故事，我們有一位患者，他的 PVR 大大減少，但六分鐘步行測試的結果卻很糟糕，結果發現，在六分鐘步行測試開始和結束之間，他的腿斷了。

So sometimes it is just something as simple as that. That can throw off results if it's a more broader trend where there's divergence, that would be very unexpected. So I would just say I think we feel good about where we are. We're going to know in about a month and once we've got that data in hand, we'll obviously share it and be very transparent with it because we think it's important for people to understand if we have enthusiasm where that's coming from.

所以有時候它就是如此簡單的事情。如果這是一個更廣泛的趨勢，存在分歧，這可能會影響結果，那將是非常出乎意料的。所以我只想說，我們對目前的狀況感到滿意。我們將在大約一個月內知道結果，一旦我們掌握了這些數據，我們顯然會分享它，並且非常透明，因為我們認為讓人們了解我們的熱情來自哪裡是很重要的。

Thank you. Your next question comes from the line of Jennifer Kim with Cantor Fitzgerald. Your line is now open.

謝謝。您的下一個問題來自 Cantor Fitzgerald 的 Jennifer Kim。您的線路現已開通。

Hi, thanks for taking my question. Congrats on the progress. Maybe just start, during your prepared remarks, you commented on expanding your US manufacturing footprint specifically for brenso and US. Can you just talk about timing?

你好，謝謝你回答我的問題。恭喜你取得進展。也許只是開始，在您準備好的演講中，您評論了擴大美國製造足跡，特別是針對布倫索和美國。能談談時間安排嗎？

So part of that is driven by how we managed to pull this through and as you know these things are not just as simple as flipping a switch and starting something up. There's qualification there's other elements of that, but the important point for people to understand is that this is a plan that has been underway for some time.

因此，部分原因在於我們如何設法實現這一目標，正如你所知，這些事情並不像按下開關並啟動某件事那麼簡單。其中還包含其他資格要求和其他因素，但人們需要理解的重要一點是，這個計劃已經進行了一段時間。

And so as we begin to implement it, we'll provide further updates, but as a point of departure, as Sara mentioned, our tariff exposure is de minimis by virtue of domiciling our US intellectual property in the US, coupled with the fact that our manufacturing base is already in some cases exclusively in the US in some for some of our programs. And for others that are important, we are already underway in establishing duplicative manufacturing capability in the US.

因此，當我們開始實施時，我們將提供進一步的更新，但作為出發點，正如 Sara 所提到的，由於我們的美國智慧財產權在美國註冊，再加上我們的製造基地在某些情況下已經完全在美國，我們的一些項目也在某些情況下，我們的關稅風險是最低的。對於其他重要領域，我們已經開始在美國建立複製製造能力。

Okay, that's helpful. And maybe a question on blinded blended data, maybe both for BiRCh for brenso and ARIKAYCE for ENCORE. I think ARIKAYCE, you said blinded blended data looks very similar to ARIKAYCE. Is that in terms of the individual components of the PRO and then on BiRCh, any update on what you've been seeing?

好的，這很有幫助。也許還有一個關於盲法混合數據的問題，也許是針對 brenso 的 BiRCh 和 ENCORE 的 ARIKAYCE。我認為 ARIKAYCE，您說的盲混合數據看起來與 ARIKAYCE 非常相似。這是關於 PRO 的各個元件以及 BiRCh 的，您所看到的任何更新嗎？

So on BiRCh and the ENCORE study, I'm going to turn it over to Martina for her comments.

因此，關於 BiRCh 和 ENCORE 研究，我將把它交給 Martina 來徵求她的意見。

Yeah, so for the ENCORE study we continue to look at blinded. What is the trend that we see in the PRO. It's the PRO, as we've aligned with the agency will be based on the QLB with eight questions. It's not looking at the individual components. It says we are blinded at this point, but what we see is consistency of what we have seen in ARIKAYCE.

是的，對於 ENCORE 研究，我們繼續採用盲法進行研究。我們在 PRO 中看到的趨勢是什麼。這是 PRO，因為我們已經與該機構達成一致，將基於 QLB 提出八個問題。它不是查看單一組件。它說我們在這一點上是盲目的，但我們所看到的與我們在 ARIKAYCE 中所看到的東西是一致的。

With regards to BiRCh, the same is true when you look at the primary endpoint in the BiRCh study is the sin of total symptom score. So this is also a questionnaire that patients fill out every day and over the treatment period you'll look at where what is the difference that you see here.

對於 BiRCh，當您查看 BiRCh 研究中的首要終點即總症狀評分時，情況也是如此。這也是一份患者每天填寫的問卷，在治療期間，您將觀察這裡有哪些差異。

Between baseline and the end of treatment, so we'll look and see is there anything that is unexpected or do we see a trend in the right direction, which is what we currently do.

在基線和治療結束之間，我們會觀察是否有任何意外情況，或者我們是否看到朝著正確方向的趨勢，這就是我們目前所做的。

There is a second PRO that that you are looking at and that is called the snob 22. This is often a very good correlator also to the total symptom score, and we're seeing that both of those continue to trend in the right direction and most importantly in the same direction.

您正在看的是第二個 PRO，它被稱為 snob 22。這通常也是整體症狀評分的一個非常好的相關因素，我們看到這兩者都繼續朝著正確的方向發展，最重要的是朝著同一個方向發展。

Thank you. Your next question comes from the line of Liisa Bayko with Evercore. Your line is now open.

謝謝。您的下一個問題來自 Evercore 的 Liisa Bayko。您的線路現已開通。

Hi, thanks for taking the question. I wonder if you could just walk us through this, so we have it kind of all straight. Number of patients with bronchiectasis, this is in the US, those with a CT scan, how many are under care and then how many have at least two exacerbations.

你好，謝謝你回答這個問題。我想知道您是否可以簡單介紹一下這一點，以便我們能夠理清一切。這是美國患有支氣管擴張症的患者人數，其中接受 CT 掃描的患者有多少人正在接受治療，有多少人病情至少加重兩次。

And when we think about that, just to just ask a little question on that, is that, would that be like in the last year or is that kind of on average in the prior years? Like, how do we think about that? But I'm just trying to kind of break down from top to bottom. When you launch, how many are actually in care with at least two exacerbations. Thanks.

當我們考慮這一點時，只想問一個小問題，那就是，這與去年的情況一樣嗎？還是與前幾年的平均一樣？比如，我們怎麼看待這個問題？但我只是想從上到下分解。當你啟動時，實際上有多少人至少有兩次病情加重。謝謝。

Sure. So just to be really clear, the numbers that we have put out into the ether, as it were, about patient numbers in the US are derived from ICD 10 coding for bronchiectasis, patients with two or more exacerbations in the last 12 months.

當然。因此，為了真正清楚起見，我們發布的有關美國患者數量的數字源自 ICD 10 對支氣管擴張的編碼，即過去 12 個月內病情加重兩次或兩次以上的患者。

So the entry criteria for our phase 3 study, which we anticipate will be the criteria for use at the market access level. We don't actually anticipate that that will necessarily be the label, but it doesn't really matter because the market access is what's going to control obviously access to the medicine.

因此，我們預期第三階段研究的准入標準將成為市場進入層面的使用標準。我們實際上並不認為這必然是標籤，但這並不重要，因為市場准入顯然將控製藥品的取得。

From that point of view, the roughly 500,000 patients in the US represents those that are diagnosed today with bronchiectasis, including a definitive CT scan of those, roughly half we estimate have had two or more exacerbations documented in the last 12 months, so entirely consistent with that market access criteria, and those are the patients that we'll be targeting out of the gate.

從這個角度來看，美國大約有 50 萬名患者被診斷出患有支氣管擴張症，其中包括經過確診的 CT 掃描的患者，我們估計其中大約有一半在過去 12 個月內出現過兩次或兩次以上的病情加重，因此完全符合市場准入標準，而這些患者正是我們一開始就瞄準的患者。

Okay, great thanks.

好的，非常感謝。

Thank you. Your next question comes from the line of Graig Suvannavejh with Mizuho Securities. Your line is now open. Okay.

謝謝。您的下一個問題來自瑞穗證券的 Graig Suvannavejh。您的線路現已開通。好的。

Okay. Thank you, thanks for taking my question. Congrats on the quarter and the progress. Wanted to get back to the brensocatib launch and the idea that you're going to try to affect a frictionless launch. You've given us great color on what's happening with patients.

好的。謝謝，感謝您回答我的問題。恭喜本季取得的進展。想要回到 brensocatib 發射以及您要嘗試影響無摩擦發射的想法。您向我們詳細講述了患者的情況。

Just remind us on the payer front, you provided some color how that's going, but could you provide a little bit more on, perhaps based maybe on latest market research like where pricing, where your head is on pricing and also just for our modeling purposes what we might be able to think about in terms of gross net.

只是提醒我們，在付款人方面，您提供了一些關於進展情況的信息，但您能否提供更多信息，也許基於最新的市場研究，例如定價，您對定價的看法，以及僅出於我們的建模目的，我們可以從淨毛利角度考慮什麼。

Thanks. Sure, so I'll turn pricing and gross nets over to Sara in a minute, but the frictionless launch ambition we have is just really a way to express the best possible practice for a commercial launch for any medicine. And what we're trying to do is ensure not only that the access to the medicine, once the appropriate patient has been identified.

謝謝。當然，我馬上就會把定價和總淨收入交給 Sara，但我們所擁有的無摩擦發布目標實際上只是一種表達任何藥物商業發布最佳實踐的方式。我們要做的不僅是確保在確定了合適的病人後，能夠獲得藥物。

It is smooth and easy that insurance will support that as quickly as is possible and that we can fulfill that to ensure that patient has the best possible experience on the medicine that obviously includes for a chronic medicine like this one reauthorization as well as upfront ease of access and so we are entering into select negotiations and contracting.

保險將盡快支持這一點，這很順利也很容易，我們可以實現這一點，以確保患者獲得最佳的藥物體驗，這顯然包括像這樣的慢性藥物的重新授權以及前期的便利性，因此我們正在進行選擇性談判和簽約。

To gain that access and to ensure that the prior authorization is one that is consistent and doesn't introduce any unnecessary onerous aspects to it like going back and pulling from the records the scan and the documentation of the exacerbations.

取得此存取權限並確保事先授權是一致的，並且不會引入任何不必要的繁瑣方面，例如返回並從記錄中提取病情加重的掃描和文件。

What we're looking for is a physician to simply attest to the existence of those, which is the appropriate way to address something like this. So with all that said, our discussions with the market access world have been very positive.

我們正在尋找一位醫生來證明這些問題的存在，這是解決此類問題的適當方法。總而言之，我們與市場准入領域的討論非常積極。

I think we continue to feel very good about the ranges we've expressed to the street in terms of price and no new information that would direct that any other way. I think this launch is going to go well based on those pre-approval discussions with market access which can now include detail from the actual phase 3 study.

我認為，我們對於向公眾表達的價格範圍仍然感到非常滿意，並且沒有任何新的資訊可以改變這種局面。我認為，根據與市場准入有關的預先批准討論，這次發布將會順利進行，現在可以包括實際第三階段研究的細節。

So in other words, we're having much more specific dialogue with the market access world. Here is what the medicine is going to provide. Here is what we propose, and we get to hear their reaction to that and ultimately we'll come to agreement with them as we get closer to launch. And we won't launch the actual announce the actual price just at the time of launch, but Sara, over to you for comments on price and gross the net.

換句話說，我們正在與市場准入領域進行更具體的對話。以下是該藥物將提供的作用。這是我們提出的建議，我們會聽取他們的反應，最終在發布前我們會與他們達成一致。我們不會在發佈時公佈實際價格，但是 Sara，請您就價格和淨利潤發表評論。

Yeah sure, thanks Graig for the question. I'll just remind the listeners that we have put out, a price range 40,000 to 96,000 based on, other products in the space. We've commented that we believe our price will be in the upper half of that range.

是的，感謝 Graig 提出這個問題。我只是想提醒聽眾，我們已經根據該領域的其他產品推出了 40,000 至 96,000 的價格範圍。我們曾表示，我們相信我們的價格將處於該範圍的上半部。

I do not expect that we provide any more narrow guidance on that until we launched on gross tone. We have again not provided formal guidance, but we have studied other specialty launches and what their gross to net has looked like, as well as the impact of IRA.

我認為，在我們推出整體基調之前，我們不會就此提供任何更狹隘的指導。我們再次沒有提供正式的指導，但我們研究了其他專業產品的推出及其總淨收入的情況，以及 IRA 的影響。

I'll remind folks that we are not subject to the small manufacturer sort of exception for brenso like we are air case because brenso isn't launched yet. We will need to pay for the 20% catastrophic coverage for the Medicare patients. We've commented we believe the breakdown will be pretty similar, so about 60% of patients we will believe will be on Medicare.

我要提醒大家，我們不受 brenso 小型製造商例外的約束，就像我們是空氣箱一樣，因為 brenso 尚未推出。我們需要為醫療保險患者支付 20% 的災難保險費用。我們曾表示，我們相信細分情況將非常相似，因此我們認為大約 60％ 的患者將享有醫療保險。

So off the bat, that's 12% on gross to net. And so, if you study all that and take that into account, somewhere between 25% and 35% seems reasonable based on precedent and analogs, but again not formal guidance. Hope that helps.

因此，首先，毛利率為 12%。因此，如果您研究所有這些並將其考慮在內，根據先例和類似情況，25％到35％之間的某個值似乎是合理的，但這仍然不是正式的指導。希望有幫助。

Thank you. Your next question comes from the line of Leonid Timashev with RBC. Your line is now open.

謝謝。您的下一個問題來自 RBC 的 Leonid Timashev。您的線路現已開通。

Hey guys, thanks for taking my question. I just wanted to ask on the HS trial, can you guys talk a little bit more about what the bar for the futility analysis is going to be? Is that just going to be any positive trend? Is there like a 20% difference that you'd like to see? And then ultimately just curious what you'd expect or would like to show relative to the jacks and the biologists and that indication. Thanks.

嘿夥計們，謝謝你們回答我的問題。我只是想問一下關於 HS 試驗的問題，你們能否再多談談無效性分析的標準是什麼？這僅僅是正面的趨勢嗎？您希望看到 20% 的差異嗎？最後，我只是好奇你期望或想要展示什麼，相對於傑克和生物學家以及那個跡象。謝謝。

Martina, do you want one?

瑪蒂娜，你想要一個嗎？

Yes, sure. So remember on the futility analysis of 100 patients, we're not looking for [AP value]. We're looking for a signal of efficacy. We're still determining from a statistical perspective exactly how that will look like for this phase 2 study.

是的，當然。所以記住，在對 100 名患者進行無效性分析時，我們不尋求[AP值]。我們正在尋找功效的訊號。我們仍在從統計學角度確定第二階段研究的具體情況。

What are looking at is the difference of the total abscess and nodule counts from baseline to the end of treatment. I think the study will tell us what we have in terms of the efficacy, and that will allow us to then plan for what is it that we can show and that we will plan for in phase 3.

所觀察的是從基線到治療結束時膿瘍和結節總數的差異。我認為這項研究將告訴我們在療效方面我們擁有什麼，這將使我們能夠規劃我們可以展示什麼以及我們將在第三階段製定計劃。

And just so you're clear, that 100 patient analysis that will be an unblinded analysis by an outside group of experts. We will not see that data, so there'll be no data shared with the market or with us for that matter. What we're simply going to hear is a thumbs up or a thumbs down.

為了讓您清楚，這 100 名患者的分析將由外部專家小組進行非盲分析。我們不會看到這些數據，因此不會與市場或我們分享任何數據。我們聽到的只是贊成或反對的聲音。

This trial should continue because see something going on there that could be positive or we don't see anything that's futile and shut it down, and that goes to the heart of our belief that we don't want patients on a medicine they're not going to receive benefit from and this has few animal models that are gold standard in terms of predictability.

這項試驗應該繼續下去，因為我們看到了一些可能具有積極意義的進展，或者我們沒有看到任何徒勞的事情，因此就停止了這項試驗，這符合我們的核心信念，即我們不希望患者服用他們不會從中受益的藥物，而且在可預測性方面，很少有動物模型可以作為黃金標準。

So our hope is that this medicine will show something and that first 100 patients will permit us to say so. And if that's the case, then we want to continue with all speed on the completion of that phase 2 trial from which we'll learn and derive how we're going to structure the phase 3 trial.

因此，我們希望這種藥物能夠發揮作用，而前 100 名患者能夠讓我們這麼說。如果情況確實如此，那麼我們希望盡快完成第二階段試驗，從中我們將了解並得出如何建立第三階段試驗。

In the end, we're anxious to see whether or not this medicine could be a complement to the other medicines that have been developed for the treatment of this condition.

最後，我們急切地想知道這種藥物是否可以作為治療這種疾病的其他藥物的補充。

Yeah, maybe just one thing to answer. So what we're looking for from a powering perspective really for this trial is that we are showing a 40% reduction. That's what we're aiming for versus placebo in the [AN count]. And I just want to remind everybody the [AN count] is not exactly the same as the high score, but it has 2/3 of the components of the high score, and that will inform how we're powering for phase 3.

是的，也許只需回答一件事。因此，從供電角度來看，我們這次試驗真正希望的是減少 40%。這就是我們的目標，而不是安慰劑[AN計數]。我只是想提醒大家，[AN 計數] 與高分並不完全相同，但它佔高分組成部分的 2/3，這將告訴我們如何為第三階段提供動力。

Thank you. Your next question comes from the line of Nicole Germino with Truist Securities. Your line is now open.

謝謝。您的下一個問題來自 Truist Securities 的 Nicole Germino。您的線路現已開通。

Hi, good morning. Congrats on the progress and thanks for taking the question. So just quickly, for CRS without nasal polyps, are you enriching for patients with higher neutrophil level or, patients were a lot more worse, and is there a minimum threshold or cutoff for NSP and blood, or is that something that you're looking for in the preset side subgroups that you'll be examining? I have a quick follow-up.

嗨，早安。恭喜您取得的進展並感謝您提出這個問題。因此，簡單來說，對於沒有鼻息肉的 CRS，您是否會針對中性粒細胞水平較高的患者進行富集，或者患者的病情要嚴重得多，並且 NSP 和血液是否有最低閾值或截止值，或者這是您在將要檢查的預設側亞組中尋找的東西？我有一個快速的後續行動。

So I'll ask Martina to take that question.

所以我請 Martina 來回答這個問題。

Yeah, so in the BiRCh study we're allowing patients to enroll up to 750 eosinophil counts. The reason we're cutting it off at this point is because if you go into very high eosinophil counts, the disease is most likely purely eosinophilic driven, and that's not the population that we're looking at.

是的，因此在 BiRCh 研究中，我們允許患者登記最多 750 個嗜酸性粒細胞計數。我們之所以在這裡將其切斷，是因為如果嗜酸性粒細胞計數非常高，那麼這種疾病很可能純粹是由嗜酸性粒細胞引起的，而這並不是我們所關注的人群。

However, patients below 300 as well as above 300 cap but below 750, both are enrolled in the trial. What we've seen in the ASPEN study, because we looked at these patients as well, is there was not really a difference between either of those patient populations. And in a blinded way, that is what we are currently seeing also in the BiRCh trial.

然而，低於 300 的患者以及高於 300 但低於 750 的患者均參加了試驗。由於我們也觀察了這些患者，因此我們在 ASPEN 研究中發現，這兩組患者之間並沒有真正的差異。並且，以盲測的方式，這也是我們目前在 BiRCh 試驗中看到的結果。

That is the reason why we have made the decision to look at the analysis of the intent to treat analysis. And there is no indication right now that we see that both these patients would be differently. So with capping patients at 750, you are really capturing the vast majority of patients with CRS without nasal polyps, and maybe just a short comment on how this endotype.

這就是我們決定研究意向治療分析的原因。目前沒有跡象顯示這兩名患者的情況會有所不同。因此，透過將患者數量限制在 750 人，您實際上就捕獲了絕大多數沒有鼻息肉的 CRS 患者，並且可能只是對這種內型的一個簡短評論。

So the mix between neutrophilic and eosinophilic disease works while in the majority of cases it's neutrophils that drive the disease. There is a mixed endotype where both neutrophil and eosinophils are part of the disease and right now, we will look at what BiRCh shows us in the nasal polyps and then we can then decide is there an opportunity to go potentially even in patients with nasal polyps.

因此，中性粒細胞疾病和嗜酸性粒細胞疾病的混合會起作用，而在大多數情況下，中性粒細胞會導致疾病。有一種混合內型，其中中性粒細胞和嗜酸性粒細胞都是疾病的一部分，現在，我們將看看 BiRCh 在鼻息肉中顯示的情況，然後我們可以決定是否有機會在患有鼻息肉的患者中進行治療。

Maybe just as a reminder if you look for an example that is similar in patients with severe asthma have a similar type where they have a mix between neutrophils and eosinophils, and that could be also a situation that we see in CRS overall.

也許只是提醒一下，如果您尋找一個類似的例子，患有嚴重氣喘的患者也有類似的類型，其中中性粒細胞和嗜酸性粒細胞混合在​​一起，這也可能是我們在 CRS 中整體看到的情況。

And just to highlight this, we originally thought you would see a distinction between higher or lower eosinophil counts, and so we stratified the trial across the numbers that Martina just mentioned, so patients below 750 but above 300, and those patients below 300 in terms of eosinophil counts.

為了強調這一點，我們原本以為您會看到嗜酸性粒細胞計數較高或較低之間的區別，因此我們根據 Martina 剛才提到的數字對試驗進行了分層，即嗜酸性粒細胞計數低於 750 但高於 300 的患者，以及嗜酸性粒細胞計數低於 300 的患者。

Because of the ASPEN analysis, which revealed that there was no difference in terms of impact on patients with those different eosinophil profiles, we've now removed that stratification from our statistical analysis plan that's been proposed, and that essentially increases the statistical power of the study on that end point.

由於 ASPEN 分析表明，對具有不同嗜酸性粒細胞特徵的患者的影響沒有差異，我們現在已經從提出的統計分析計劃中刪除了這種分層，這從本質上增加了該終點研究的統計能力。

Okay, great. Thanks so much for that. And then one quick clarification. So the two exacerbations and the CT scan, is that going to be on the label or is this more for a peer requirement?

好的，太好了。非常感謝。然後快速澄清一下。那麼兩次病情加重和 CT 掃描會出現在標籤上，還是更多的是同儕的要求？

So we don't anticipate it will be on the label and obviously we won't know until we see the label, but in our discussion that is not the direction we're traveling. However, we have always said that market access is going to align their approval pathway with what were the entry criteria of the phase 3 study, and so we're structuring all of our commercial efforts around that reality.

因此，我們預計它不會出現在標籤上，而且顯然，只有看到標籤我們才會知道，但在我們的討論中，這不是我們要走的方向。然而，我們一直表示，市場准入將使他們的審批途徑與第三階段研究的准入標準保持一致，因此我們正在圍繞這一現實構建我們所有的商業努力。

Yeah, maybe just to clarify, I think I heard you say two HRCT scans. The HRCT scan is just to diagnose the disease. The two pulmonary exacerbations is what we've studied.

是的，也許只是為了澄清一下，我想我聽到您說了兩次 HRCT 掃描。HRCT掃描只是為了診斷疾病。我們研究的是兩次肺部疾病惡化的情況。

Right. And those are examined, pardon me, those are documented separately from the CT scan.

正確的。那些檢查，請原諒，那些是與 CT 掃描分開記錄的。

Thank you. Your next question comes from the line of Maxwell Skor with Morgan Stanley. Your line is now open.

謝謝。您的下一個問題來自摩根士丹利的 Maxwell Skor。您的線路現已開通。

Great, thank you. Just a quick question on the TPIP readout in PAH. Could you remind me the rationale for measuring PVR versus baseline and how we should think about the potential placebo rates and also for the potential phase 3 trial, what do you consider to be a relevant primary endpoint? Will you potentially go with mortality or morbidity and mortality-based endpoint? Thank you.

太好了，謝謝。這只是關於 PAH 中的 TPIP 讀數的一個簡單問題。您能否提醒我測量 PVR 與基線的理由，以及我們應該如何考慮潛在的安慰劑率，以及對於潛在的 3 期試驗，您認為相關的主要終點是什麼？您是否有可能採用死亡率或發病率以及基於死亡率的終點？謝謝。

I ask Martina to address that.

我請 Martina 來解決這個問題。

Yeah, let me start with phase 3. So the registrational endpoint recognized is a six-minute walk distance. That's what we anticipate we will have a primary input also in phase 3. Yes, there is clinical worsening, and clinical worsening would be one of the things we consider as an endpoint. We right now look at the primary endpoint being the six-minute walk distance.

是的，讓我從第三階段開始。因此識別的註冊終點是步行六分鐘的距離。這就是我們預期在第三階段也將獲得的主要投入。是的，臨床情況確實在惡化，而臨床情況惡化是我們考慮的終點之一。我們現在關注的主要終點是六分鐘步行距離。

With regards to PVR, so you're measuring PDR at baseline and at the end of the study to basically see what is the reduction that you can achieve over the treatment period. In our trial, we are titrating up to a maximum of 640 micrograms. That titration goes over a three-week period.

關於 PVR，您需要在基線和研究結束時測量 PDR，以便基本上了解在治療期間可以實現的減少量。在我們的試驗中，我們滴定至最高 640 微克。此滴定過程持續三週。

The majority of the many patients have already reached the 640 micrograms, which is why in the open label study we're allowing a higher titration up to 1280 micrograms. We anticipate and plan for a higher up to 1280 in our phase 3 study. The exact design we will then determine based on the phase two readout.

大多數患者已經達到了 640 微克，這就是為什麼在開放標籤研究中我們允許更高的滴定水平，最高可達 1280 微克。我們預計併計劃在第三階段研究中將這一數字提高至 1280。我們將根據第二階段的讀數來確定具體的設計。

Thank you. And your next question comes from the line of Trung Huynh with UBS. Your line is now open.

謝謝。您的下一個問題來自瑞銀的 Trung Huynh。您的線路現已開通。

Thanks for the question. I have one and then just a clarification on TPIP. So. You announced your CCO departed the company late last month. Do you anticipate naming a permanent replacement ahead of brenso potential launch, and then the clarification on TPIP just in your prepared remarks, you said you're locking and cleaning at the moment.

謝謝你的提問。我有一個問題，然後只是對 TPIP 澄清。所以。您宣布您的首席文化長已於上個月底離職。您是否預計在布倫索 (brenso) 潛在發射之前任命一個永久的替代方案，然後在您準備好的發言中澄清 TPIP，您說您目前正在鎖定和清理。

Is there anything particularly unusual or complex about that database cleaning or analysis process? Your last patient week 16 visit with late March and you expect read out in June. That's three months. And should we expect anything with this data release? Thank you.

資料庫清理或分析過程有什麼特別不尋常或複雜的地方嗎？您最後一次就診的時間是 3 月底，第 16 週，預計 6 月出院。那是三個月。我們對這次數據發布有什麼期待嗎？謝謝。

Yeah, so in regard to the Chief Commercial Officer, that's a transition and a search that is underway. We're not in any rush. We have the benefit of continued access to Drayton during this time frame and also I'll remind everybody that we also have the benefit of our Chief Operating Officer who is the former Chief Commercial Officer of the company who is still working with us and so I feel like we are be in suspenders in terms of the capabilities we have on board right now.

是的，就首席商務官而言，這是一個過渡，並且正在尋找新的人選。我們並不著急。在這段時間內，我們可以繼續與 Drayton 合作，而且我還要提醒大家，我們還可以得益於我們的首席營運官，他是該公司的前首席商務官，目前仍在與我們合作，所以我覺得就我們目前擁有的能力而言，我們處於懸吊狀態。

And I'll also just emphasize our preparation for this commercial launch began two years ago, so we are unusual in that regard. Many of you had many questions about that during the two years before we saw the data, and I understand those questions, but now that the data has come out as strong as it has, everyone celebrates that early effort and early investment in the preparation for a successful launch.

我還要強調的是，我們為這次商業發布的準備工作兩年前就開始了，所以在這方面我們很不尋常。在我們看到數據之前的兩年裡，你們中的許多人對此有很多疑問，我理解這些疑問，但現在數據已經如此強勁，每個人都為成功發射的準備工作中的早期努力和早期投資感到高興。

And I think we're all going to be the beneficiaries of that, most importantly, the patients. The second question was with regard to TPIP and the data cleaning. All right, so the note I wrote here was registration. So one of the things we're doing with this TPIP data set as we do with all of our data sets now is we want them to be registrational quality.

我認為我們都將成為其中的受益者，最重要的是病人。第二個問題是關於TPIP和資料清理的。好的，我在這裡寫的註釋是註冊。因此，我們對這個 TPIP 資料集所做的一件事，就像我們現在對所有資料集所做的那樣，我們希望它們具有註冊品質。

What that means is you can produce top line results pretty quickly after you lock and clean a database, but we want to go back in and make sure that every single detail there is accounted for in every way so that it is prepared and ready for submission to the FDA and that requires an extra layer of scrutiny and quality control.

這意味著您可以在鎖定和清理資料庫後很快得到頂線結果，但我們希望回過頭來確保每個細節都得到妥善處理，以便做好準備並準備提交給 FDA，而這需要額外的審查和品質控制。

There is nothing about this database that we have seen that is aberrant or in any way problematic, and you should not interpret the time we're taking as being related to that on the contrary, I'll just remind everybody the original timeline for this was the second half of this year.

我們沒有發現該資料庫有任何異常或問題，您不應將我們所花費的時間解釋為與此有關，相反，我只是想提醒大家，這項計劃的原始時間表是今年下半年。

The trial was then accelerated once the blended blinded it to the treating physician community, and they began to come to us with patients that they wanted to put on the trial and now we're in a place where we're able to narrow down the release of the top line results to June of this year, which is at the front end of our original guidance of the middle of the year.

一旦混合療法對治療醫生群體盲法，試驗就會加速進行，他們開始帶著他們想要參加試驗的患者來找我們，現在我們可以將頂線結果的發佈時間縮小到今年 6 月，這是我們最初指導的年中前端。

So overall I would say this is moving very efficiently. The team is doing a fantastic job of getting the database ready not only for the release in terms of top line results to the street, but also equally importantly, if not more so, preparation for a registration or submission when that day comes.

所以總的來說，我認為這是非常有效的。團隊正在出色地準備資料庫，不僅為向街道發布最重要的結果做準備，而且同樣重要的是，為當天的註冊或提交做準備。

Thank you. Your final question comes from the line of Andy Chen with Wolfe Research. Your line is now open.

謝謝。您的最後一個問題來自 Wolfe Research 的 Andy Chen。您的線路現已開通。

Hi, this is Emma for Andy. Thanks for taking our question. Congrats on the quarter. Just a question from our side on your gene therapy program with the patient death reported, with Sarepta's, DMD gene therapy, has this influenced your development strategy at all? Thank you.

大家好，我是艾瑪，我是安迪。感謝您回答我們的問題。恭喜本季取得佳績。我們想問一下，關於你們的基因治療項目，據報道，Sarepta 的 DMD 基因治療出現了患者死亡的情況，這是否影響了你們的發展策略？謝謝。

So I appreciate the question. I think one of the things that we want to emphasize about these programs are that they sit in what we refer to as our fourth pillar. The entire scope of research that's underway at Insmed is well controlled from a capital investment point of view at less than 20% of our overall spend. It is nonetheless, I would describe it as extensive.

我很感謝你提出這個問題。我認為我們想要強調的關於這些計劃的一件事是，它們屬於我們所說的第四大支柱。從資本投資的角度來看，Insmed 正在進行的整個研究範圍都得到了很好的控制，不到我們總支出的 20%。儘管如此，我還是會將其描述為廣泛的。

We have advanced a number of different preclinical programs. We haven't commented on them publicly just because we think the right time for a company of our profile to. Those to your attention as they are entering the clinic.

我們已經推進了許多不同的臨床前計畫。我們沒有公開評論它們，只是因為我們認為對於我們這樣的公司來說現在是發表評論的正確時機。當他們進入診所時，請注意這些。

The strategy in particular with regard to gene therapy and as it relates to DMD is that we are using an intrathecal delivery approach that has several benefits, one of which is that it reduces the amount of drug that you actually have to deliver.

特別是關於基因療法以及與 DMD 相關的策略是，我們使用鞘內輸送方法，這種方法有幾個好處，其中之一就是它減少了實際需要輸送的藥物。

That is a clear safety benefit to patients. The other is that by virtue of it being an Intrathecal delivery, you're bypassing the first pass effect on the liver, which is typical. Where the strongest immune reactions occur and a lot of the viral delivery is frankly lost, so you have to overdose the patient to get past the liver's efficiency at removing a lot of that viral vector.

這對患者來說顯然是安全益處。另一個原因是，由於它是鞘內輸送，所以可以繞過肝臟的首過效應，這是很常見的。當最強烈的免疫反應發生時，大量的病毒載體就會流失，因此你必須給病人過量用藥，以超越肝臟清除大量病毒載體的效率。

What we've seen in the preclinical models is that this has resulted in a very good transduction throughout the musculoskeletal system, as well as the cardiac tissue. Quite remarkable given that it's intrathecally delivered. And I think that's going to, we think that's going to provide benefits from a safety point of view as well as an efficacy point of view.

我們在臨床前模型中看到，這導致了整個肌肉骨骼系統以及心臟組織的非常好的傳導。考慮到它是鞘內輸送的，這相當了不起。我認為這將從安全性和功效的角度帶來好處。

We'll see that as we begin to dose these patients just to remind everybody it's going to take a while for us to get patients on drugs and then we are going to be for purposes of safety titrating up slowly to ensure that we have that these patients get the appropriate dose and that we're putting safety first.

我們會看到，當我們開始給這些患者服藥時，只是為了提醒大家，我們需要一段時間才能讓患者服藥，然後為了安全起見，我們將慢慢增加劑量，以確保這些患者獲得適當的劑量，並且我們將安全放在第一位。

We have not seen anything that gives us any concern of the kind that you've seen at other places, and we certainly hope that we don't see any more of that for anyone, but I think one of the reasons we tried to take the extra time on our gene therapy program.

我們還沒有看到任何讓我們擔心的、像您在其他地方看到過的那樣的情況，我們當然希望不要再看到任何人出現這種情況，但我認為這就是我們試圖在基因治療項目上花費額外時間的原因之一。

It is because of those safety concerns that have appeared. CMC and our control over that is, I think, standard setting for the industry. I think as we look at the other gene therapies we're developing for things like ALS and Stargardt, those two are on track for getting into the clinic between now and sort of 18 months from now. And as those develop and they get in and we begin to see data, safety and efficacy, we'll be sure to share that with everybody.

正是因為這些安全隱憂才出現的。我認為，CMC 和我們對此的控制就是業界的標準制定。我認為，當我們研究針對 ALS 和 Stargardt 等疾病開發的其他基因療法時，這兩種療法預計將在現在和大約 18 個月內進入臨床階段。隨著這些技術的發展和應用，我們開始看到數據、安全性和有效性，我們一定會與大家分享。

Thank you. That is all the time that we have for question and answer today. On behalf of Insmed, I do thank you for your time. That does conclude today's call. You may now disconnect.

謝謝。今天我們的問答時間就到這裡。我代表 Insmed 感謝您抽出時間。今天的電話會議到此結束。您現在可以斷開連線。