BioCryst Pharmaceuticals Inc (BCRX) 2025 Q1 法說會逐字稿

Good day and welcome to the BioCryst first quarter 2025 earnings conference call. (Operator Instructions) Please note that this event is being recorded.

大家好，歡迎參加 BioCryst 2025 年第一季財報電話會議。（操作員指示）請注意，此事件正在被記錄。

I would now like to turn the conference over to John Bluth with investor relations with BioCryst. Please go ahead.

現在，我想將會議交給 BioCryst 投資者關係部門的 John Bluth。請繼續。

Thank you. Good morning and welcome to BioCryst's first quarter 2025 corporate update and financial results conference call. Today's press release and accompanying slides are available on our website. Participating with me today are CEO, Jon Stonehouse; Chief Commercial Officer, Charlie Gayer; and Chief R&D Officer, Dr. Helen Thackray. Following our remarks, we'll answer your questions.

謝謝。早安，歡迎參加 BioCryst 2025 年第一季公司更新與財務績效電話會議。今天的新聞稿和隨附的幻燈片可在我們的網站上查閱。今天與我一起參加的還有執行長 Jon Stonehouse；首席商務長 Charlie Gayer；以及首席研發長 Helen Thackray 博士。在我們發言之後，我們將回答您的問題。

Today's conference call will contain forward-looking statements, including those statements regarding future results, unaudited and forward-looking financial information, as well as the company's future performance and/or achievements. These statements are subject to known and unknown risks and uncertainties, which may cause their actual results, performance, or achievements to be materially different from any future results or performance expressed or implied in this presentation. You should not place undue reliance on these forward-looking statements.

今天的電話會議將包含前瞻性陳述，包括有關未來業績、未經審計和前瞻性財務資訊以及公司未來業績和/或成就的陳述。這些陳述受已知和未知的風險和不確定性的影響，這可能導致其實際結果、表現或成就與本簡報中表達或暗示的任何未來結果或表現有重大差異。您不應過度依賴這些前瞻性陳述。

For additional information, including a detailed discussion of our risk factors, please refer to the company documents followed with the Securities and Exchange Commission, which can be accessed on our website. In addition, today's conference call includes non-GAAP financial measures. For reconciliation of these non-gap measures against the most directly comparable GAAP financial measure, please refer to the earnings release posted in the press releases section of our investor relations website at www.bioCryst.com.

如需更多信息，包括我們的風險因素的詳細討論，請參閱公司向美國證券交易委員會提交的文件，該文件可在我們的網站上查閱。此外，今天的電話會議還包括非公認會計準則財務指標。有關這些非差距指標與最直接可比較的 GAAP 財務指標的對賬，請參閱我們投資者關係網站 www.bioCryst.com 新聞稿部分發布的收益報告。

I'd now like to turn the call over to Jon Stonehouse.

現在我想把電話轉給喬恩‧斯通豪斯。

Thank you, John. We've started 2025 with another quarter of outstanding performance, as you will hear from Charlie in more detail. The US commercial team made tremendous progress in moving patients on ORLADEYO from free drug to paid at a much faster rate than we expected.

謝謝你，約翰。我們以另一個季度的出色表現開啟了 2025 年，查理將為您詳細介紹這一點。美國商業團隊在將 ORLADEYO 患者從免費藥物轉變為付費藥物方面取得了巨大進展，其速度比我們預期的要快得多。

The result is quarterly revenue of $134 million. This improvement in the paid rate impacts revenue performance in Q1, but also through the rest of the year, leading us to raise annual revenue guidance for ORLADEYO to between $580 million and $600 million which is 33% to 37% growth over last year.

結果是季度收入為 1.34 億美元。支付率的提高不僅影響了第一季的營收表現，也影響了今年剩餘時間的營收表現，因此我們將 ORLADEYO 的年度營收預期上調至 5.8 億美元至 6 億美元之間，比去年成長 33% 至 37%。

Our improved revenue growth significantly increases our margins and has also accelerated our cash flow and profitability goal by a year. We now expect to be profitable on a full-year basis this year. This increased financial strength and the positive cash flow it generates enabled us to pay down $75 million of our debt in April while continuing to invest in and advance our pipeline.

我們的收入成長顯著提高了我們的利潤率，並且使我們的現金流和獲利目標提前了一年。我們現在預計今年全年將獲利。財務實力的增強和由此產生的正現金流使我們能夠在 4 月償還 7500 萬美元的債務，同時繼續投資和推進我們的管道建設。

In addition, we are now moving into ORLADEYO revenue levels, where we no longer pay a royalty on sales above $550 million and we're getting closer to our peak sales for ORLADEYO of $1 million.

此外，我們現在正進入 ORLADEYO 的收入水平，我們不再為超過 5.5 億美元的銷售額支付特許權使用費，而且我們正接近 ORLADEYO 100 萬美元的峰值銷售額。

In the current environment of uncertainty, having a company with growing sustainable revenue and advancing pipeline and financial strength to be profitable, pay down debt, and be independent of the markets is hard to find in our industry. But that's exactly what we have at BioCryst.

在當前不確定的環境下，在我們的行業中很難找到一家擁有不斷增長的可持續收入、不斷推進的管道和財務實力、能夠盈利、償還債務並獨立於市場的公司。但這正是 BioCryst 所擁有的。

With that, I'll turn it over to Charlie to discuss our fantastic first quarter results. Charlie?

接下來，我將把時間交給查理來討論我們出色的第一季業績。查理？

Thanks, John. The launch trajectory for ORLADEYO has been consistently strong for the past four years, but the first quarter of 2025 was our best yet because of the combination of great demand generation and amazing progress helping patients gain access to therapy.

謝謝，約翰。過去四年來，ORLADEYO 的上市軌跡一直保持強勁，但 2025 年第一季是我們迄今為止最好的成績，因為巨大的需求產生和幫助患者獲得治療的驚人進展相結合。

As we described previously, US patient demand in 2024 matched the first year of the launch. Our team continued this momentum as first quarter new prescriptions slightly exceeded our best quarter from last year.

正如我們之前所述，2024 年美國患者的需求與推出該藥物的第一年相當。我們的團隊延續了這一勢頭，第一季的新處方量略微超過了去年最好的一個季度。

In addition, our latest patient survey showed that regardless of their current treatment status, the percentage of USHA patients who strongly prefer oral prophylaxis grew to 70%, up from 51% in 2023, as you can see on slide 7 in today's presentation. And HAE treaters are increasingly convinced that ORLADEYO is very effective and convenient for patients based on their individual experience and the rapidly expanding body of real-world evidence that they have seen.

此外，我們最新的患者調查顯示，無論目前的治療狀況如何，強烈傾向於口腔預防的 USHA 患者比例從 2023 年的 51% 增長到 70%，正如您在今天簡報的第 7 張幻燈片中看到的那樣。並且，根據 HAE 治療者的個人經驗以及他們所見的迅速擴展的真實世界證據，他們越來越相信 ORLADEYO 對患者非常有效且方便。

ORLADEYO is becoming their treatment of choice. What really drove Q1 performance though was a 10 percentage point jump in the rate of paid patients in the US over where we ended 2024. We expected that level of improvement to take three years. We did it in four months.

ORLADEYO 正在成為他們首選的治療方法。然而，真正推動第一季業績的是美國付費患者比例較 2024 年底上升了 10 個百分點。我們預計達到這一水平的改善需要三年時間。我們花了四個月的時間完成了它。

The Inflation Reduction Act drove about two-third of the improvement because the IRA is achieving its intent of helping Medicare patients afford their prescription co-payments. Medicare patients were not only able to afford their ORLADEYO prescriptions, but they were able to do so earlier in the quarter than expected. And we also continue to make great progress among the roughly 60% of ORLADEYO patients who have commercial insurance.

《通貨膨脹削減法案》推動了約三分之二的改善，因為 IRA 實現了其幫助醫療保險患者負擔處方共同支付費用的目的。醫療保險患者不僅能夠負擔得起 ORLADEYO 處方藥，而且能夠比預期更早地負擔得起。我們在約 60% 擁有商業保險的 ORLADEYO 患者中也繼續取得了巨大進展。

The paid rate in that segment increased to 84% as we further improved our ability to convert patients from long-term free product to paid product. By the end of April, we were nearly through the reauthorization season and approximately 84% of all established patients on ORLADEYO were receiving paid therapy.

隨著我們進一步提高將患者從長期免費產品轉化為付費產品的能力，該部分的付費率上升至 84%。截至 4 月底，我們已基本度過重新授權期，ORLADEYO 約 84% 的老患者正在接受付費治療。

That's close to our long-term goal of 85% on the path to $800 million in US revenue, a rate we forecast it would take at least three years to hit. This acceleration and paid rate improvement means a lot more revenue this year, allowing us to increase guidance significantly as John noted.

這接近我們在美國實現 8 億美元收入的長期目標的 85%，我們預測至少需要三年時間才能達到這一目標。正如約翰所說，這種加速和支付率的提高意味著今年的收入將大大增加，使我們能夠大幅提高指導。

But it also positions us to capture more ORLADEYO revenue over the next several years as our patient base continues to grow. In other words, we're still on a path to a billion dollars in global revenue in 2029, and the path is now even more profitable.

但隨著我們的患者群體不斷增長，它也使我們能夠在未來幾年內獲得更多的 ORLADEYO 收入。換句話說，我們仍有望在 2029 年實現全球 10 億美元的收入，而且現在的獲利能力更強。

As we look to the second quarter, our very strong first quarter means that the typical revenue jump in Q2 will still be the largest quarterly increase for the year, but less pronounced than in prior years, in the range of $10 million to $12 million. Slide 5 shows visually how we expect this year to look different.

展望第二季度，我們第一季的業績非常強勁，這意味著第二季度的典型營收成長仍將是今年最大的季度增幅，但增幅不如前幾年明顯，在 1,000 萬美元至 1,200 萬美元之間。幻燈片 5 直觀地展示了我們預期今年將有何不同。

We anticipate this pattern shift because we captured more revenue opportunity per patient in Q1, so the Q2 increase will move closer to the underlying patient growth trend. I'll provide a bit more color to explain.

我們預計這種模式會發生轉變，因為我們在第一季度抓住了更多的每位患者的收入機會，因此第二季度的成長將更接近潛在的患者成長趨勢。我將提供更多細節來解釋。

As I mentioned earlier, patients move to paid status more quickly than expected in Q1, which means we gave away less free product. Our team also continued to improve growth to net, which in Q1 allowed us to keep it closer to the lower end of our typical range of 15% to 20% when in prior years it was closer to 20% in the first quarter.

正如我之前提到的，患者在第一季轉為付費狀態的速度比預期要快，這意味著我們贈送的免費產品減少了。我們的團隊也繼續提高淨成長率，這使我們能夠在第一季將其保持在我們通常的 15% 至 20% 範圍的低端，而前幾年第一季的成長率接近 20%。

We expect growth to net to improve throughout the rest of the year, but more gradually so that the full-year average will be right around 15%. Our great execution to start the year and accelerated ORLADEYO outlook for the rest of 2025 come at an exciting time because our clinical pipeline is nearing important early milestones. The path to another differentiated rare disease product like ORLADEYO could soon be increasingly clear.

我們預計今年剩餘時間內經濟成長將有所改善，但速度將更加緩慢，因​​此全年平均成長率將在 15% 左右。我們今年年初的出色執行以及 2025 年剩餘時間 ORLADEYO 前景的加速到來正值激動人心的時刻，因為我們的臨床管線即將達到重要的早期里程碑。通往另一種類似 ORLADEYO 的差異化罕見疾病產品的道路可能很快就會變得越來越清晰。

I'll turn it over to Helen to describe our progress.

我將把這個交給海倫來描述我們的進展。

Thank you, Charlie. Good morning. Today, I'm pleased to share an update on recent significant milestones for our pipeline programs. First, we've submitted our pediatric NDA for ORLADEYO to FDA, introducing an oral granule formulation for patients aged 2 to 11, with additional filings in Europe, Japan, and Canada also this year.

謝謝你，查理。早安.今天，我很高興與大家分享我們管道項目近期取得的重要里程碑的最新消息。首先，我們已向 FDA 提交了 ORLADEYO 的兒科 NDA，為 2 至 11 歲患者推出口服顆粒劑型，今年也將在歐洲、日本和加拿大提交額外申請。

This would be a significant advance in the treatment of children with HAE as it would be the first targeted oral prophylactic therapy for this age group.

這將是 HAE 兒童治療的重大進步，因為這將是針對該年齡層的第一個有針對性的口服預防療法。

Next, I'm pleased to report that we received authorization to initiate patient enrollment for both of the pipeline programs following ORLADEYO. BCX17725 in Netherton syndrome and of oral stat in diabetic macular edema, which is an important step on our path to having initial clinical data in patients for both programs by the end of the year.

接下來，我很高興地報告，我們獲得了授權，可以啟動 ORLADEYO 之後兩個管道項目的患者招募。BCX17725 在治療 Netherton 症候群和糖尿病黃斑水腫方面的療效，這是我們在今年年底前獲得這兩個計畫患者的初步臨床數據的重要一步。

Today I'll focus on the Netherton syndrome program in detail and provide more information about the trial design, what we're looking for, and what to expect by the end of the year.

今天，我將詳細介紹 Netherton 綜合徵項目，並提供有關試驗設計、我們正在尋找的內容以及年底預期結果的更多資訊。

First, I'll describe why we're so excited about the potential for 17725 as a transformative treatment for people living with Netherton's syndrome. This is a devastating illness. Its consequences are very serious and lead to lifelong impacts on health and well-being.

首先，我將描述為什麼我們對 17725 作為 Netherton 綜合徵患者的變革性治療方法的潛力如此興奮。這是一種毀滅性的疾病。其後果非常嚴重，會對健康和福祉造成終身影響。

We've heard from patients that the lack of treatment leads them to withdraw from medical care. We recently heard exactly the same feedback from our clinical site investigators. Just as it's been for other rare diseases like HAE, we expect introducing a new potential treatment that could revolutionize care, will attract patients back into the care system and into clinical trials.

我們聽到患者說，由於缺乏治療，他們放棄醫療。我們最近從臨床現場研究人員那裡聽到了完全相同的回饋。正如 HAE 等其他罕見疾病一樣，我們期望引入一種可以徹底改變醫療保健的新潛在治療方法，吸引患者重返醫療保健系統並參與臨床試驗。

We designed 17725 to address the fundamental pathology that causes Netherton syndrome. Every aspect of which is ultimately caused by a genetically determined lack of an essential skin protein called SPINK5, also known as LEKTI. Normally, this protein stops cells in the outer layer of the skin from prematurely separating from the cells below. It achieves this by controlling the activity of key kallikrein, KLK5, which digests bridging proteins that glue the outer layer of skin cells together.

我們設計了 17725 來解決導致 Netherton 綜合徵的基本病理。這一切最終都是由於基因決定的缺乏一種名為 SPINK5（也稱為 LEKTI）的必需皮膚蛋白造成的。正常情況下，這種蛋白質會阻止皮膚外層的細胞過早地與下面的細胞分離。它透過控制關鍵激肽釋放酶 KLK5 的活性來實現這一點，激肽釋放酶 KLK5 可以消化將皮膚細胞外層粘合在一起的橋接蛋白。

In Netherton syndrome, there is no breaking mechanism for this because KLK5 is continuously on, and so skin cells quickly separate and are lost. What that causes is a massive disruption of the essential barrier functions of the skin, which normally keeps warmth and moisture inside and microorganisms outside but not in Netherton syndrome.

在 Netherton 症候群中，由於 KLK5 持續處於開啟狀態，因此沒有打破這種現象的機制，因此皮膚細胞會迅速分離並失去。這會導致皮膚基本屏障功能的嚴重破壞，皮膚通常可以保持皮膚內部的溫暖和水分，並將微生物阻擋在外面，但在 Netherton 綜合徵中卻不是這樣。

And in addition, KLK5 directly activates the rest of the kallikrein cascade in the skin via KLK7 and KLK14. Through cascading pathologic, inflammatory, and allergic pathways, the effect is magnified down into the deeper skin and tissue layers, ultimately also resulting in systemic inflammatory and atopic effects like asthma and food allergies.

此外，KLK5 透過 KLK7 和 KLK14 直接活化皮膚中其餘的激肽釋放酶級聯。透過級聯病理、發炎和過敏途徑，這種影響被放大到更深的皮膚和組織層，最終也會導致全身性發炎和特異性影響，如氣喘和食物過敏。

All this stems from one faulty gene, leading to the lack of one protein, SPINK5, the regulator for KLK5. This means KLK 5 is the key pharmacologic target in this disease because it's the pinnacle protein, the one at the very top of the cascade that drives the whole process as we see in slide 13 in today's presentation.

這一切都源自於一個缺陷基因，導致缺乏一種蛋白質，即 SPINK5，即 KLK5 的調節劑。這意味著 KLK 5 是這種疾病的關鍵藥理學靶點，因為它是頂級蛋白質，是驅動整個過程的級聯最頂端的蛋白質，正如我們在今天的簡報的第 13 張幻燈片中看到的那樣。

Our scientists engineered 17725 to replace the function of that missing protein in its control of KLK5. So we have tremendous confidence in the target and the pharmacologic approach we are taking based on the significant experience of our scientists and many others who have published their clinical and preclinical work.

我們的科學家設計了 17725 來取代缺失的蛋白質在控制 KLK5 中的功能。因此，基於我們的科學家和許多其他發表過臨床和臨床前研究成果的人的豐富經驗，我們對我們所採取的目標和藥理學方法充滿信心。

A big challenge with a protein therapeutic in this disease is to get enough drug into the epidermis and have it stay put. The epidermis or the outer layer of the skin is where it needs to act. So to give us the best chance of success, our scientists designed this molecule with far greater potency compared to the natural inhibitor and very high affinity or stickiness for KLK5. These features give us the best chance to minimize the dose necessary and make every molecule that finds the target count by binding tightly and blocking KLK5.

對於這種疾病，蛋白質治療的一大挑戰是讓足夠的藥物進入表皮並使其停留在原處。表皮或皮膚的外層是它需要發揮作用的地方。因此，為了給我們帶來最大的成功機會，我們的科學家設計了這種分子，其效力比天然抑制劑強得多，並且對 KLK5 具有非常高的親和力或黏性。這些特性使我們有最大的機會最大限度地減少必要的劑量，並透過緊密結合和阻斷 KLK5 來使每個找到目標的分子都發揮作用。

Today, we're reporting that the IND has cleared in the US for enrolling patients with Netherton syndrome into our Phase 1 trial. This clinical trial is set up to tell us quickly whether we've met our objectives and design of the drug. The trial plan is outlined on slide 14.

今天，我們報告，美國已批准 IND 招募患有 Netherton 綜合徵的患者參加我們的第一階段試驗。這次臨床試驗的目的是快速告訴我們是否達到了藥物的目標和設計。試驗計劃概述在第 14 張投影片中。

We're currently dosing healthy volunteers to evaluate basic information on exposure and safety, and we're now identifying sites in both the US and Australia for the patient arm of the study. Patients will be given four weeks of treatment and about two months of continuing evaluation beyond that.

我們目前正在對健康志願者進行劑量評估，以了解暴露和安全性的基本信息，並且我們正在美國和澳大利亞確定研究患者組的地點。患者將接受四週的治療，之後也將接受約兩個月的持續評估。

Building on this, we also plan to expand the trial later in the year to evaluate a longer 12-week course of treatment as we learn more about the drug. Cohort size will be small, as we expect to gain a significant amount of information from just a handful of patients and perhaps from every patient.

在此基礎上，隨著我們對該藥物的了解越來越多，我們還計劃在今年稍後擴大試驗，以評估更長的 12 週療程。隊列規模將會很小，因為我們希望從少數患者甚至每個患者身上獲得大量資訊。

To best inform the design of future trials and to provide early insights into the therapeutic potential of 17725, we need to understand how the drug behaves in patients living with Netherton syndrome.

為了更好地指導未來試驗的設計並儘早了解 17725 的治療潛力，我們需要了解該藥物在患有 Netherton 綜合徵的患者中的表現。

To do this, we'll be looking at drug levels in the epidermis both by using adhesive tape to collect skin epidermal cell samples and with small skin biopsies. We would be thrilled to see the presence of 17725 in those samples and normal levels of skin kallikrein enzymatic activity achieved in patients who have Netherton syndrome, which would provide a strong signal of the potential for clinical efficacy.

為此，我們將透過使用膠帶收集皮膚表皮細胞樣本和進行小塊皮膚活檢來觀察表皮中的藥物含量。我們很高興看到這些樣本中存在 17725，並且患有 Netherton 綜合徵的患者皮膚激肽釋放酶活性達到正常水平，這將為臨床療效的潛力提供強烈的信號。

In addition, we'll be looking at clinical impact. If we don't see clinical benefit at a studied dose level and dosing is safe, we intend to progress to higher doses. If we do see clinical benefit, as indicated by improvement in measures such as itch score, and physician global assessment of severity will have excellent information to inform dose selection for a future pivotal program and even higher confidence in the opportunity for 17725 to be a truly disease modifying therapy for people living with Netherton syndrome.

此外，我們還將研究臨床影響。如果我們在研究的劑量水平下沒有看到臨床益處且劑量是安全的，我們打算提高劑量。如果我們確實看到了臨床益處，例如搔癢評分等指標的改善以及醫生對嚴重程度的整體評估，我們將獲得極好的信息來指導未來關鍵項目的劑量選擇，並且更有信心 17725 有機會成為 Netherton 綜合徵患者真正的疾病改良療法。

Although it's always a challenge to conduct clinical trials in rare diseases, we have plenty of experience with this, and we're very encouraged by the clear enthusiasm for our trial that we heard during our recent clinical site visits. We look forward to sharing our initial phase one trial data in patients with Netherton syndrome by year end.

儘管進行罕見疾病臨床試驗始終是一項挑戰，但我們在這方面擁有豐富的經驗，而且我們在最近的臨床現場訪問中聽到的對試驗的明顯熱情讓我們感到非常鼓舞。我們期待在年底前分享我們對患有 Netherton 綜合徵的患者的第一階段初步試驗數據。

And now I'll hand the call back to John for a financial review.

現在我將把電話交還給約翰進行財務審查。

Thanks, Helen. We are exiting the first quarter in a great financial position with stronger than expected revenue growth, increasing full-year revenue guidance, accelerating full-year profitability to this year, and last month we've reduced our outstanding debt.

謝謝，海倫。我們第一季的財務狀況非常好，營收成長超出預期，全年營收預期上調，全年獲利能力加快，上個月我們也減少了未償債務。

Well, you can find our detailed first-quarter financials in today's press release. I'd like to draw your attention to a few items.

好吧，您可以在今天的新聞稿中找到我們第一季的詳細財務狀況。我想提請您注意以下幾點。

Total revenue for the quarter came in at $145.5 million, 134.2 million dollars of which came from ORLADEYO. Of that ORLADEYO total revenue, $120.2 million or 89.5% is coming from the US.

本季總營收為 1.455 億美元，其中 1.342 億美元來自 ORLADEYO。ORLADEYO 的總收入中，有 1.202 億美元（89.5%）來自美國。

Operating expenses, excluding stock-based compensation, were $102.9 million for the quarter, up from $93.6 million in the same quarter last year. This was primarily driven by an increase in commercial expense to support our growing ORLADEYO revenue, our newly launched regions like Spain and Italy, and expanded international operations, including global commercial support activities across finance, HR, IT, and supply chains.

本季營運費用（不含股票薪酬）為 1.029 億美元，高於去年同期的 9,360 萬美元。這主要是由於商業費用的增加，以支持我們不斷增長的 ORLADEYO 收入、我們新推出的西班牙和義大利等地區以及擴大的國際業務，包括跨財務、人力資源、IT 和供應鏈的全球商業支援活動。

Operating profit for the first quarter of 2025 was $21.2 million and net income was slightly positive. Cash at the end of the quarter was $317 million. As a result of the significant and durable improvements to revenue that Charlie discussed, we are revising our revenue guidance by $45 million to $50 million above our prior guidance. And which represents, as I mentioned before, a 33% to 37% growth over last year.

2025年第一季營業利潤為2,120萬美元，淨收入略為正值。本季末的現金為3.17億美元。由於查理談到的收入顯著且持久的改善，我們將收入預期上調 4500 萬至 5000 萬美元，比之前的預期高出一倍。正如我之前提到的，這比去年增長了 33% 至 37%。

We now expect non-GAAP operating expense for the year to be $440 million to $450 million a $15 million increase over our prior guidance driven by expenses supporting our commercial growth and an increase in COGS as sales of RAPIVAB increased.

我們現在預計本年度非 GAAP 營業費用為 4.4 億美元至 4.5 億美元，比我們之前的指導增加 1500 萬美元，這主要是由於支持我們商業增長的費用以及 RAPIVAB 銷售額增加導致的 COGS 增加。

The result of this strong revenue performance combined with our continued focus on disciplined capital allocation is that we now expect to be profitable for the full year on a net income and positive cash flow basis this year. This is one year earlier than we previously planned.

強勁的收入表現加上我們持續專注於嚴格的資本配置，使得我們預計今年全年淨收入和現金流將實現盈利。這比我們之前計劃的提前了一年。

Further, based on this improved financial strength, in April, we made a paydown of $75 million on our debt with Pharmacon and reduced our outstanding debt to $249 million. As a result, we expect to save approximately $23 million in interest payments over the life of the debt net of the early pre-payment penalty.

此外，基於財務實力的增強，我們於 4 月償還了 Pharmacon 的 7,500 萬美元債務，並將未償債務減少至 2.49 億美元。因此，我們預計在債務期間內扣除提前還款罰金後可節省約 2,300 萬美元的利息支出。

I am immensely proud of the continued focus of our employees who are delivering meaningful improvements in patients' lives both today and in the future.

我為我們員工的持續專注感到無比自豪，他們正在為患者現在和將來的生活帶來有意義的改善。

Our commercial and support teams are driving access and usage of ORLADEYO, and our R&D team is advancing our pipeline to address challenges in new disease areas where patients are underserved. Financially, we are driving revenue growth and are well on our way to $1 billion at peak, efficiently allocating capital and R&D to create sustainable and long-term revenue growth, accelerating our profitability, and reducing our outstanding debt.

我們的商業和支援團隊正在推動 ORLADEYO 的訪問和使用，我們的研發團隊正在推動我們的產品線，以應對患者服務不足的新疾病領域的挑戰。在財務方面，我們正在推動收入成長，並有望達到 10 億美元的峰值，有效分配資本和研發以創造可持續的長期收入成長，加速獲利能力並減少未償債務。

We have never been in a stronger financial position, and I am excited for how this sets us up for a very bright future.

我們的財務狀況從未如此強勁，我很高興這將為我們帶來非常光明的未來。

Operator, we are now ready for your questions.

接線員，我們現在可以回答您的問題了。

Thank you. We will now begin the question-and-answer session. (Operator Instructions)

謝謝。我們現在開始問答環節。（操作員指示）

Steven Seedhouse, Cantor.

史蒂文·西德豪斯（Steven Seedhouse），領唱。

Good morning. Thanks so much for taking the question. Just looking ahead to another potential tailwind for ORLADEYO, which is the pediatric launch. Do you have a sense of how many pediatric HAE patients are on Takhzyro today in the US, and do you think you'll mainly be switching children from Takhzyro or can you sort of quantify how many patients maybe just don't want a needle, but would be new starts, opportunities for ORLADEYO prophylaxis altogether?

早安.非常感謝您回答這個問題。展望 ORLADEYO 的另一個潛在順風，即兒科產品的推出。您是否知道目前美國有多少兒童 HAE 患者正在使用 Takhzyro，您是否認為主要會讓兒童放棄使用 Takhzyro，或者您能否量化有多少患者可能只是不想打針，但希望開始使用 ORLADEYO 進行預防治療？

Charlie, you want to take that one?

查理，你想拿那個嗎？

Sure, we certainly do expect pediatrics to be a tailwind for us. And just as a reminder, any future revenues for pediatrics are not included in our $800 million in the US or billion dollar global peak sales.

當然，我們確實希望兒科能帶給我們順風。需要提醒的是，兒科的任何未來收入都不包括在我們在美國 8 億美元或全球 10 億美元的高峰銷售額中。

To answer your question, I don't know exactly how much, how many patients are on Takhzyro. We do think that there are about 500 patients -- pediatric patients in the US, and at least 200 of whom could be appropriate for prophylactic therapy. But once an oral is available, we actually think that that could grow.

回答你的問題，我不知道到底有多少病人在服用 Takhzyro。我們確實認為，美國有大約 500 名兒科患者，其中至少有 200 名適合接受預防性治療。但我們確實認為，一旦口服藥物問世，這個數字就會成長。

And so I think our -- where we'll get patients is a mix of those switching from injectable therapies like Takhzyro, but we also think that the whole landscape for treating kids under age 12 could change. And that more kids could start prophylaxis at a younger age to prevent attacks and really change the course of their life with the condition and an oral therapy really makes that happen because I would say there's literally no preference for an injectable for children, so we think we'll be very well positioned. We're excited about it.

因此我認為，我們的患者既包括那些從 Takhzyro 等注射療法轉換過來的患者，也包括那些從 Takhzyro 等注射療法轉換過來的患者，但我們也認為，治療 12 歲以下兒童的整個前景可能會發生變化。而且更多的孩子可以在更小的年齡就開始預防疾病，從而防止發作，並真正改變他們的生活軌跡，而口服療法確實可以實現這一點，因為我想說，對於兒童來說，注射劑幾乎沒有偏好，所以我們認為我們處於非常有利的位置。我們對此感到很興奮。

Yeah, I would add that when you consider that you can just sprinkle our medicine, the granules, onto some soft food or into a glass of water versus the trauma of sticking a needle into a toddler, we should be the market leader. There's no doubt in doubt in our minds that that's going to be the case, and I think the other thing that Charlie's referenced in the past is this halo effect.

是的，我想補充一點，當你考慮到你可以將我們的藥物顆粒撒在一些軟食或一杯水中，而不必將針頭扎進幼兒體內時，我們就應該是市場領導者。我們心中毫無疑問會是這種情況，我認為查理過去提到的另一件事就是光環效應。

We still have some top HAE physicians that haven't started switching patients and we know they have pediatric patients, and there's no reason for them to not start using our drug for pediatric patients. And when they see how well it works, our expectation is that that's going to expand their usage. So we're really excited about this. We haven't put any hard numbers on it yet publicly, but we're really excited about it.

我們仍有一些頂級 HAE 醫生尚未開始轉換患者，我們知道他們有兒科患者，他們沒有理由不開始對兒科患者使用我們的藥物。當他們看到它的效果如此好時，我們期望它能夠擴大他們的使用範圍。所以我們對此感到非常興奮。我們還沒有公開任何確切的數字，但我們對此感到非常興奮。

Great. Just also on DME program, so it looks like you're guiding for data this year. I'd be just curious if you could frame, what you would do as a successful outcome for that first read out, given the precedent data, given your, obviously, the novel delivery method. Just what are you hoping hoping to see there in the first group of patients?

偉大的。同樣也涉及 DME 計劃，因此看起來您今年正在指導數據。我只是好奇，您是否可以設想一下，在有先例數據和顯然新穎的交付方法的情況下，第一次讀出的成功結果會是什麼樣子。您到底希望在第一批患者身上看到什麼？

Yeah, so we'll have our first patients on drugs, as I said, we have authorization to proceed with enrolling patients in that trial. And what we're looking for is the obvious safety and tolerability, but more importantly to your question, we're looking for the effect on the thickness of the retina, the edema in the retina. So we'll be able to in those first patients watch over several months of exposure to assess that retinal thickness and whether that is changing.

是的，我們將會讓第一批患者接受該藥物治療，正如我所說，我們有權繼續招募患者參加該試驗。我們尋求的是明顯的安全性和耐受性，但對於您的問題更重要的是，我們尋求對視網膜厚度、視網膜水腫的影響。因此，我們將能夠對首批患者進行數月的觀察，以評估其視網膜厚度及其是否有變化。

We do expect it will take a little bit of time to change, but not very long, and I point to some of our preclinical data that shows that in a VEGF dependent model, the use of oral stat as a plasma kallikrein inhibitor, has a result on leakage of the vessels very quickly within six days. So just to say that a readout that we'll be watching this year will be that retinal edema, retinal thickness, and we'll be observing in the first few patients by the end of the year.

我們確實預計改變需要一點時間，但不會太久，我指出我們的一些臨床前數據表明，在 VEGF 依賴模型中，使用口服 stat 作為血漿激肽釋放酶抑製劑，會在六天內很快導致血管滲漏。所以說，我們今年將要觀察的讀數是視網膜水腫、視網膜厚度，我們將在今年年底前對前幾名患者進行觀察。

Yeah, normally we don't get super excited about SAD studies, but this is in patients, and what we've seen in rabbits is that when you give a single dose, you still have a really high concentration out to six months. So a single dose of this drug in DME patients could tell us a lot. And so, we're excited to see what we see at the end of the year.

是的，通常我們不會對 SAD 研究感到非常興奮，但這是針對患者的研究，我們在兔子身上看到的是，當你給予單劑量時，在六個月內你仍然會有非常高的濃度。因此，糖尿病性黃斑水腫 (DME) 患者服用一次該藥物就能了解許多資訊。因此，我們很高興看到年底的成果。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特（Maury Raycroft），傑富瑞集團（Jefferies）。

Hi, good morning. Congrats on the update today and thanks for taking my questions. Wondering if we could just talk more about getting patients onto pay drug and, what you did there that worked better than expected, and should we expect the rate to be maintained or improved upon going forward or what are some of the drivers you're focused on that could cause the rate to decrease again over time?

嗨，早安。恭喜今天的更新，感謝您回答我的問題。想知道我們是否可以更多地談論如何讓患者使用付費藥物，以及您所做的工作是否比預期效果更好，我們是否應該預期該比率在未來會保持或提高，或者您關注的一些驅動因素可能導致該比率隨著時間的推移再次下降？

Sure, Maury. The number one thing that we did, and we've talked about this before is we've over the last couple of years made investments in our team to make sure that we're really prepared and really expert in this reauthorization process, and we've gotten better every year, and we knew that there was this potential tailwind with Medicare this year.

當然，莫里。我們所做的最重要的事情，我們之前也討論過這一點，就是在過去幾年中我們對我們的團隊進行了投資，以確保我們做好了充分的準備並且真正熟練地掌握這個重新授權流程，而且我們每年都在進步，我們知道今年醫療保險可能會帶來順風。

We also knew there was more space that we could improve in the very important commercial segment. And so I would just say that the team has just reached a level of excellence that allowed them to execute this year, and we're looking forward to further improvements going forward.

我們也知道，在非常重要的商業領域，我們還有很大的進步空間。因此，我只想說，團隊已經達到了讓他們在今年完成任務的卓越水平，我們期待未來能取得進一步的進步。

What we would expect the rest of this year is that the rate will stay about the same, maybe decrease a little bit, because the rest of the year our paid rate is driven more by new prescriptions as opposed to reauthorizations. But where we ended Q1, where we ended April, becomes the floor for what I would expect in the future, and I'm very confident we'll reach our 85% goal. We'll reach it ahead of when we expected to originally, and we'll be looking to exceed it if we can.

我們預計今年剩餘時間的費率將保持不變，甚至可能略有下降，因為今年剩餘時間我們的支付費率更多地取決於新處方，而不是重新授權。但是，我們在第一季結束時，也就是在四月結束時，達到了我對未來預期的底線，我非常有信心我們將實現 85% 的目標。我們將比最初預期的時間提前實現這一目標，如果可以的話，我們將努力超越這一目標。

Yeah, the other thing I'd say is, you should take a look at that slide that Charlie referred to around the pattern of revenue this year. It's different, right? So we pulled forward revenue that would usually be a big bump from first quarter to second quarter into the first quarter, so you're going to see less of a bump.

是的，我想說的另一件事是，你應該看看查理提到的今年收入模式的幻燈片。這很不一樣，對吧？因此，我們將通常會從第一季大幅增加到第二季度的營收提前到第一季度，這樣你會看到較小的成長。

I think the other thing though that's exciting is that the underlying growth continues to be really strong and so, that's where we're going to see incremental improvement over the course of the year and we're really excited to share that with you.

我認為另一件令人興奮的事情是，潛在的成長繼續保持強勁，因此，我們將在今年看到逐步的改善，我們非常高興與你們分享這一點。

Got it. That's helpful. And maybe just as a follow up, if you could just provide more specifics on what you did to improve gross to that in first quarter and what you're doing to better improve that over the course of the year as well.

知道了。這很有幫助。也許只是作為後續問題，如果您可以提供更多具體信息，說明您在第一季度採取了哪些措施來提高總銷售額，以及您在今年將採取哪些措施來更好地提高銷售額。

Yeah, so a couple things, Maury. One big impact was just the fact that we got so many more Medicare patients paid, and that changed the overall gross to net mix. The other thing is the team's just been really focused at every little detail that can make a difference, such as how much co-payment assistance do we give to a commercial patient and we've made some adjustments there that have improved gross to net.

是的，有幾件事，莫里。一個很大的影響就是我們為更多的醫療保險患者支付了費用，這改變了整體的毛利與淨利的比率。另一件事是，團隊真正關注的是每一個可能產生影響的小細節，例如，我們向商業患者提供多少共同支付援助，並且我們對此進行了一些調整，從而提高了毛收入與淨收入。

So the team is being very disciplined, not just about getting patients paid, helping new patients come on board, but the team is very focused on maximizing the opportunity in all segments and so I'm really pleased that we made that kind of a progress in the first quarter, and I think that will be durable through the rest of the year.

因此，團隊非常自律，不僅要讓患者獲得報酬，幫助新患者加入，而且團隊非常注重最大限度地利用各個領域的機會，所以我很高興我們在第一季度取得了這樣的進展，我認為這將持續到今年剩餘時間。

Jessica Fye, JPMorgan.

潔西卡費伊（Jessica Fye），摩根大通。

Hey guys, good morning. Thanks for taking the question. I was curious, more specific to the guidance bump for ORLADEYO, can you quantify how much of that increase is related to part redesign and a higher proportion of paid patients through that kind of mechanism versus higher-than-expected demand versus just execution dealing with the coverage re-offs at the start of the year.

大家好，早安。感謝您回答這個問題。我很好奇，更具體地說，對於 ORLADEYO 的指導性增長，您能否量化其中有多少增長與部分重新設計有關，以及通過這種機制增加付費患者的比例，還是高於預期的需求，還是僅僅執行處理年初的覆蓋範圍重新取消。

And second question, just with profitability pulled forward here, how does that impact how you think about investing in the business and I guess more specifically could that allow you to accelerate any development plans for your earlier stage pipeline? Thank you.

第二個問題是，隨著獲利能力的提前，這對您對投資業務的看法有何影響？更具體地說，這是否可以讓您加速早期階段的開發計畫？謝謝。

So I can take the first part of that. As I mentioned in my remarks, of the 10% improvement in paid rate, about two-thirds of that was related to the IRA helping patients afford their co-pay. So that's great. But what I'm really excited about is how much progress we made in the 60% of patients who are on commercial insurance where we improved by close to 5% over where we ended last year ending up at 84%. So that that was the other third of that improvement.

所以我可以講一下第一部分。正如我在演講中提到的那樣，在支付率提高 10% 的過程中，大約三分之二與 IRA 幫助患者支付共同支付費用有關。這太棒了。但真正讓我興奮的是，我們在 60% 享受商業保險的患者方面取得了很大進展，與去年年底的 84% 相比，提高了近 5%。這就是改進的另外三分之一。

Clearly in terms of raising our guidance for the year, that increase in paid rate overall was the number one factor, but we have an underlying patient growth year over year close to 20% and as I mentioned, we had one of our best years ever last year. And in the first quarter we were a little bit better than that and so that underlying demand is what's going to drive this brand going forward.

顯然，就提高今年的指導方針而言，整體支付率的提高是首要因素，但我們的潛在患者數量同比增長接近 20%，正如我所提到的，去年是我們有史以來最好的一年。我們在第一季的表現比這要好一些，所以潛在的需求將推動這個品牌向前發展。

And then John, you want to answer --?

那麼約翰，你想回答--？

Yeah, I'll take the profitability. So yeah, it's territory we haven't been in before and are really excited to be in it. The programs are fully funded already to go as fast as we possibly can, and I'm -- I think the teams have done a great job of figuring out how to get the programs to move as quickly as possible.

是的，我會追求獲利。是的，這是我們以前從未涉足過的領域，我們對此感到非常興奮。這些專案已經獲得了充足的資金，以便我們能夠盡快推進，而且我認為團隊已經出色地完成了工作，找到了讓這些專案盡快推進的方法。

And then in terms of what are we investing, I think we gave you a pretty good clue by paying -- making a paydown of $75 million of the Pharmacon debt, cleaning up the balance sheet, not having to pay significant amounts of interest over time is something that, we'll continue to look at as cash flow comes into the company.

然後就我們的投資而言，我想我們透過支付給了你一個很好的線索——償還 7500 萬美元的 Pharmacon 債務，清理資產負債表，不必隨著時間的推移支付大量利息，我們會在現金流進入公司時繼續關注這些事情。

Operator, I think we can go to the next question.

接線員，我想我們可以進入下一個問題了。

Brian Abrahams, RBC Capital Markets.

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

Hi, everyone, this is Nevin on for Brian. Congrats on the quarter and thanks for taking the questions. So just following up from some of the prior questions so. Given that you're on around 84% pay drug and also that you're on the lower end of your gross to net range for the year, does this potentially indicate that there was a dip in the total patients that were on ORLADEYO and like how do you see that kind of evolving into the rest of the year?

大家好，我是 Nevin，代表 Brian 發言。恭喜本季取得佳績，感謝您回答問題。所以只是跟進一些之前的問題。鑑於您支付的藥物費用約為 84%，而且您今年的毛收入與淨收入處於較低水平，這是否可能表明 ORLADEYO 的患者總數有所下降，您認為這種情況會如何發展到今年剩餘時間？

Well, I can tell you that there wasn't a dip in patients on ORLADEYO. So maybe I'm not quite understanding your question, Nevin. We've had extremely consistent demand. So, again, last year we had as many new patients starts as we did in the first year of the launch, and then we did a little bit better than that in the first quarter.

嗯，我可以告訴你，奧拉迪約醫院的病人數量並沒有減少。所以也許我不太理解你的問題，內文。我們的需求一直都非常穩定。因此，去年我們接收的新患者數量與推出服務的第一年一樣多，而且第一季我們的表現比第一季略好一些。

The retention rate of patients has also been extremely consistent the last couple of years where anybody who starts on ORLADEYO, we get about 60% of those patients to stay on therapy through the first year and then very few drop off after that.

過去幾年中，患者的保留率也一直非常穩定，任何開始接受 ORLADEYO 治療的患者，大約有 60% 會在第一年繼續接受治療，之後很少有患者放棄治療。

So what we're seeing in patient demand is as strong, if not stronger than we've ever seen it. And then you add on top the paid rate and the improved growth to net, it just means that we're more profitable. And so we still see reaching a billion dollars in 2029, but the path to get there every year with that underlying demand is just going to be more profitable than we previously expected. So it's a great position to be in.

因此，我們看到患者的需求與以往一樣強勁，甚至比以往任何時候都更強勁。然後將支付率和改善的淨成長率添加到淨收入中，這意味著我們的利潤更高。因此，我們仍然認為 2029 年該數字將達到 10 億美元，但隨著這一潛在需求的增加，每年實現這一目標的路徑將比我們之前預期的更有利可圖。所以這是一個很好的位置。

Yeah, I think, Nevin, that I don't know if you're referring to that slide of the pattern of sales, which because of the fast change in free drug to pay, the pattern's different than previous years, and it'll probably go back to the same pattern as previous years next year, but there is nothing that is slowing down. And you know we're really excited about the underlying demand and continuing, and there's more patients to get quite frankly. I mean, I think the last update Charlie said is around 3,000 patients.

是的，我認為，內文，我不知道您是否指的是銷售模式的下滑，由於免費藥品付費的快速變化，這種模式與前幾年不同，明年可能會回到與前幾年相同的模式，但沒有任何放緩的跡象。你知道，我們對潛在的需求和持續的需求感到非常興奮，坦白說，我們會有更多的病人。我的意思是，我認為查理說的最新更新是約有 3,000 名患者。

3,000 at the end of last year.

去年年底為3000。

Yeah, and there's 10,000 available, so there's plenty more to get, so no signs of slowing down. Just a change in pattern.

是的，目前有 10,000 個可用，因此還有很多可供獲取，因此沒有放緩的跡象。只是模式上的改變。

Got it. And then I guess on the uptick in patients that you're seeing for preference for oral prophylactic, what do you think is kind of driving that underlying dynamic there? Have rates of maybe needle phobia changed or is it just a convenience factor that's being appreciated more say kind of the more maturing launch of ORLADEYO and convenience of that offers.

知道了。然後我想，您看到患者對口服預防藥物的偏好增加，您認為是什麼推動了這種潛在的動態？針頭恐懼症的發生率是否有所變化，或者這是否只是一個更便利的因素，比如說 ORLADEYO 的更成熟推出及其提供的便利。

Thanks for that question. I think what we've known since before launch that fundamentally the great majority of patients prefer oral therapy to injectable, but what's really important to patients is that they get control of their HAE attacks, so they'll never sacrifice efficacy for convenience.

謝謝你的提問。我認為我們在產品上市之前就知道，從根本上來說，絕大多數患者更喜歡口服療法而不是注射療法，但對患者來說真正重要的是他們能夠控制自己的 HAE 發作，因此他們永遠不會為了方便而犧牲療效。

But now four plus years into the launch, what they're seeing is with all of our efforts is with ORLADEYO you can have both. You can have great efficacy. You can have convenience. And so the patients have seen it themselves. They've heard from their peers. It's a very connected community within HAE.

但現在，距離推出已有四年多了，他們看到的是，透過我們所有的努力，有了 ORLADEYO，您就可以同時擁有這兩者。您可以獲得很大的功效。您可以享受便利。病人也親眼目睹了這一切。他們聽到了同行的聲音。HAE 內部是一個聯繫非常緊密的社區。

And then their healthcare providers are just that much more confident, which always is a critical factor that the physicians have confidence in a drug. And so you put all this together with the efforts that we've made from a sales and marketing perspective, it's natural that patients underlying preferences is coming out, and I think that's why we've seen it grow by about 20% over the last couple of years, and I wouldn't be surprised if it continues to grow.

然後他們的醫療保健提供者就會更加有信心，這始終是醫生對藥物有信心的關鍵因素。因此，如果將所有這些與我們在銷售和行銷方面所做的努力結合起來，那麼患者的潛在偏好自然就會顯現出來，我認為這就是我們在過去幾年中看到其增長了約 20% 的原因，如果它繼續增長，我不會感到驚訝。

I think it was around a year ago we told you -- Charlie told you that there was a momentum change and that there was a confidence build up and that was because more and more physicians were having positive experiences with their patients. Patients talk and doctors talk about other patients to their patients, saying, I have a patient that does really well on early day, you might want to consider trying it. And so it's that confidence in the product that I think is reflected in the market research.

我想大約一年前我們告訴過你——查理告訴你，情況正在發生變化，信心也在增強，這是因為越來越多的醫生在與患者相處時有了積極的體驗。病人和醫生都向自己的病人談論其他病人，說「我有一個病人在早期表現得很好，你可能要考慮試一試」。所以我認為市場調查反映出了對產品的信心。

Great, thank you all so much and congrats again on the quarter.

太好了，非常感謝大家，再次恭喜本季取得的成績。

Stacey Ku, TD Cowen.

史黛西·庫 (Stacey Ku)，考恩 (Cowen) TD。

Thanks so much for taking your questions and congratulations on the really impressive quarter. So first, as we think about these additional patient additions and strong patient demand, you've previously added around 60 prescribers per quarter. What are your expectations for this year? And then some follow ups on Netherton, are you able to make any disclosures on the Phase 1 early SAD, MAD results? Are you able to disclose anything at this point in time, or can you narrow the timelines for any updates in other terms? And then I have a follow up on Netherton.

非常感謝您回答問題，並祝賀您取得了令人印象深刻的季度成績。首先，當我們考慮這些額外的患者增加和強勁的患者需求時，您之前每季增加了約 60 名處方者。您對今年有什麼期望？然後是關於 Netherton 的一些後續問題，您能否揭露第一階段早期 SAD、MAD 結果？現在您能透露任何消息嗎？或者您能否以其他方式縮短更新的時間表？然後我會跟進 Netherton 的情況。

Okay, I'll start with the healthcare providers. Good memory, Stacy. Last year, we actually averaged 61 new healthcare prescribers for ORLADEYO per quarter. It was 62 in 2023, and in Q1 we had 59, so it's incredible consistency at this stage in the launch that we're still convincing new prescribers. Our team will always go out and find new prescribers.

好的，我將從醫療保健提供者開始。記憶力真好，史黛西。去年，我們平均每季為 ORLADEYO 新增 61 位醫療處方人員。2023 年這一數字為 62，而第一季我們有 59 個，因此在推出的這個階段，我們仍然能夠說服新的處方者，這真是令人難以置信的一致性。我們的團隊會不斷出去尋找新的處方者。

The other thing though is, and John touched on this earlier, but we've made progress in the Tier 1 physician, so 81% of those doctors have now prescribed, and we're seeing more and more physicians become repeat prescribers and even some returning -- who prescribed some years ago, now returning now that they better understand the product. So the physician dynamics are excellent along with the overall patient dynamics.

不過，另一件事是，約翰之前提到過這一點，但我們在一級醫生方面取得了進展，因此現在有 81％ 的醫生都開過處方，而且我們看到越來越多的醫生成為重複開處方者，甚至有些醫生是回頭客——他們幾年前開過處方，現在因為他們對產品有了更好的了解而再次回來。因此，醫師的動態和整體患者動態一樣出色。

And then Helen, you might want to talk about how we're thinking about packaging all the data towards the end of the year.

然後海倫，你可能想談談我們如何考慮在年底前打包所有數據。

Yeah. So in terms of the results on the SAD, MAD, Stacy, we've been following that trial. We have its intent with initial safety and PK data. We have the confidence now from that to open the dosing in patients, so you should see that as a sign of generally what we're seeing. And then what's most important, and we've -- I've been clear about looking for the skin outcomes in patients, what's most important is what happens in patients.

是的。因此，就 SAD、MAD、Stacy 的結果而言，我們一直在關注該試驗。我們的目標是獲得初始安全性和 PK 資料。我們現在有信心為患者開放劑量，因此您應該將其視為我們所看到的整體情況的標誌。然後最重要的是，我們已經——我已經明確要尋找患者的皮膚結果，最重要的是患者身上發生了什麼事。

So we'll bundle it all together. It'll be by the end of the year. It will have the updates from the healthy volunteer data, but then more importantly that outcome in patients and are we at the dose that gets to skin healing.

因此我們將把它們全部捆綁在一起。預計到年底。它將獲得來自健康志願者的更新數據，但更重要的是患者的結果以及我們是否達到了皮膚癒合的劑量。

So in healthy volunteers, no news is good news.

因此，對於健康志工來說，沒有消息就是好消息。

Okay, wonderful. Well, I guess that leads to my follow-up about Netherton. I know you've talked about kind of the early interactions with investigators and the activation of sites. But maybe nuance Part 4 of the Phase I study, it sounds like you're getting at least some sense of safety. Could you broaden the POC in younger patients? Or are you mainly seeing into adults? Thank you.

好的，太棒了。好吧，我想這就引出了我對 Netherton 的後續關注。我知道您談到了與調查人員的早期互動以及站點的激活。但也許第一階段研究的第四部分的細微差別，聽起來你至少獲得了一些安全感。您能擴大年輕患者的 POC 嗎？或者您主要關注的是成年人？謝謝。

So Part 4 is the extension of treatment. It is designed so that it's additional patients. So what we're hearing at the sites, it's -- we're hearing clear enthusiasm. We're hearing that a potent KLK5 inhibitor that could target at the top of the cascade is something that physicians want to try in their patients with Netherton syndrome. It will be the first few patients who are on that Part 3.

因此第 4 部分是治療的延伸。它的設計目的是為了讓更多的患者能夠接受。因此，我們在現場聽到的是——我們聽到的是明顯的熱情。我們聽說，醫生們想在患有 Netherton 症候群的患者身上嘗試一種能夠針對級聯頂端的強效 KLK5 抑制劑。這將是第 3 部分的前幾名患者。

And then we're sort of continuing. We'll open Part 4 and continue and broaden enrollment to get a longer-term exposure. I would think of them as sort of going together rather than being separate. And the result is, by the end of the year, we'll have patients on, we think, both sections with a longer-term follow-up on those who have been dosed in Part 3 and then more recent follow-up in those dosed in Part 4.

然後我們繼續。我們將開啟第 4 部分並繼續擴大招生範圍以獲得更長期的曝光。我認為它們是一起的，而不是分開的。結果是，到今年年底，我們認為兩個部分的患者都會得到治療，對在第 3 部分接受治療的患者進行長期隨訪，然後對在第 4 部分接受治療的患者進行近期隨訪。

I think one other thing, Stacy, that I'm certainly learning as we learn more about this community and both the physicians and the patients is there are some significant differences from HAE, right? There's no therapies in place. The organization for advocacy isn't nearly as advanced as HAE was. So those are challenges in finding patients. But the flip side is the hope we're offering these patients is off the charts, right?

史黛西，我想，隨著我們對這個社區以及醫生和患者的了解越來越多，我肯定了解到的另一件事是，它們與 HAE 存在一些顯著差異，對嗎？目前尚無有效的治療方法。該倡導組織遠不如 HAE 先進。所以這些都是尋找病人的挑戰。但另一方面，我們帶給這些病人的希望是超乎尋常的，對嗎？

They were hopeless or they have been hopeless and coping because they have nothing to treat the underlying cause of their disease. And when we start talking to patients and tell them what we're trying to work on, I mean, it brings them to tears. And so that's powerful. And so if we can find these patients, and I'm confident we will, and this drug gets to the skin, we've got something really powerful to help them and give them hope.

他們感到絕望，或一直感到絕望，因為他們無法治療疾病的根本原因。當我們開始與患者交談並告訴他們我們正在努力做什麼時，他們會感動得流淚。這非常強大。所以，如果我們能找到這些病人，我相信我們會的，而且這種藥物能夠到達皮膚，我們就有非常強大的力量來幫助他們，給他們帶來希望。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

I have two questions. I think I joined a little bit late, so if already discussed, and I heard some of the answers, if already discussed, I apologize. So for your paid rate, truly very impressive, like 10% -- over 10% increase from, say, last quarter, 73.5%, now improved to 84%. You did comment when you answered numerous questions answer various parts. But can you help us understand like what make it like in such a short time that has such a big improvement?

我有兩個問題。我想我加入得有點晚了，所以如果已經討論過了，而且我聽到了一些答案，如果已經討論過了，我很抱歉。因此，對於您的支付率而言，確實非常令人印象深刻，例如增加了 10% - 比上一季的 73.5% 增加了 10% 以上，現在提高到了 84%。當您回答眾多問題的各個部分時，您確實發表了評論。但是您能幫助我們理解為什麼在這麼短的時間內會有這麼大的進步嗎？

Can you walk us through the actual process what you did make it possible in short time, see such a high increase regarding the pay rate? And then the second question is regarding the DME. So you will have patient data later this year. Could you give us some benchmark you are looking for that you will consider that will be encouraging to move forward?

您能否向我們介紹一下實際過程，您是如何做到在短時間內實現這一目標並實現工資率如此高的增長的？第二個問題是關於 DME 的。因此您將在今年稍後獲得患者數據。您能否為我們提供一些您正在尋找的基準，您認為這些基準將鼓勵我們繼續前進？

Yeah. Hey, Charlie, maybe I'll start first on this first one, and then you can answer the rest. I want to remind everybody that when the Medicare negative thing happened, it snapped the other direction very quickly, like within a quarter. So this is a snapback, but I'll let Charlie explain it in more detail.

是的。嘿，查理，也許我應該先回答這個問題，然後你再回答其餘的問題。我想提醒大家，當醫療保險的負面影響發生時，它會很快地轉向另一個方向，例如在一個季度內。所以這是一個反擊，但我會讓查理更詳細地解釋它。

Yeah. So again, Gena, one thing I explained is about two-thirds of the improvement was Medicare. And as Jon said, that was a quick snapback, but it was because our team prepared. And so the snapback is -- and I've always said this, that Medicare plans approve ORLADEYO at the highest rate amongst all the insurers that we see. It was just an affordability thing for patients.

是的。所以，吉娜，我再次解釋的一件事是，大約三分之二的改善來自於醫療保險。正如喬恩所說，那是一次快速的反擊，但這是因為我們的團隊已經準備好了。因此，反彈是——我一直這麼說，醫療保險計劃批准 ORLADEYO 的比例在我們看到的所有保險公司中是最高的。這只是患者負擔得起的事情。

So it's great that IRA is helping patients afford. And our paid rate amongst the 20% of Medicare -- of our patients who are in Medicare is now 89%. So that kind of underlines what I've just said about it being the top segment for approvals.

因此，IRA 能夠幫助患者負擔得起治療費用，這真是太好了。在 20% 享有醫療保險的患者中，我們的付費率現已達到 89%。所以這強調了我剛才所說的它是獲得批准的最高部分。

The other piece, though, is the team really prepared on the commercial side. And one of the preparations is we have all this long-term real-world evidence. So what we know about the drug and the efficacy today is very different from what we knew four years ago.

但另一方面，團隊在商業方面確實做好了準備。其中一項準備就是我們擁有所有這些長期的現實世界證據。因此，我們今天對該藥物及其功效的了解與四年前有很大不同。

And so the team is able to use that more proactively with payers, and it's convincing more and more payers that this is a very effective drug, and therefore, they're choosing to pay for it for the patients. That's where I think we can still make progress, but it's about the data, the preparation and then also the intended impact of the IRA coming through.

因此，該團隊能夠更積極地與付款人合作，並讓越來越多的付款人相信這是一種非常有效的藥物，因此，他們選擇為患者支付費用。我認為我們仍然可以在這方面取得進展，但這與數據、準備以及 IRA 的預期影響有關。

The other thing before I turn it over to Helen on the DME is back when patients were struggling to make their co-pay, we made a very conscious decision to give them free drug. And we kept the patients and we actually gained patients as a result of that strategy. So then when the affordability got back to normal, those patients snapped back quickly. And I think strategically, that was, in hindsight, a good move to make.

在我把 DME 交給海倫之前，我還要說一件事，當病人難以支付共同費用時，我們做出了一個非常明智的決定，為他們提供免費藥物。透過這項策略，我們保留了患者，並且實際上獲得了患者。因此，當負擔能力恢復正常時，這些患者就會迅速回來。我認為，從策略角度來看，這是一個很好的舉措。

Helen, do you want to talk about DME?

海倫，你想談談 DME 嗎？

Yeah. So because we have authorization now to dose in patients, this is a big milestone for this program. We are looking this year to have exposure and experience with a few patients with that single dose. As Jon mentioned earlier, this is a drug with long durability of exposure. And we're looking for that the outcome, the retinal edema lessening, reduction in the size of the retinal thickness. We're looking for that, and we'll be looking for that for the end of the year.

是的。因此，由於我們現在有權對患者進行給藥，這對該計劃來說是一個重要的里程碑。我們希望今年能透過單一劑量療法讓少數患者獲得治療體驗。正如喬恩之前提到的，這是一種具有較長暴露持久性的藥物。我們期望的結果是視網膜水腫減輕，視網膜厚度減少。我們正在尋找這一點，並且我們將在今年年底之前尋找這一點。

In terms of what then is the benchmark to move forward, we're looking for a really big effect. We're looking for a clear and uncontroversial reduction in edema that would then tell us that we have a dose level that's got the exposure necessary to have that effect. If we don't see that, we will increase the dose. So we'll either see a very significant reduction in edema and know that we have a dose we can take forward or we'll not have achieved that yet, and we'll expect to increase the dose until we do.

就未來發展的基準而言，我們期待看到真正巨大的效果。我們正在尋找一種明顯且無爭議的水腫減少現象，從而告訴我們所採用的劑量水平是否達到了達到該效果所需的程度。如果我們沒有看到這種情況，我們將增加劑量。因此，我們要么看到水腫明顯減少，並知道我們有一個可以繼續服用的劑量，要么我們還沒有實現這一目標，並且我們期望增加劑量，直到我們實現這一目標。

Yeah. I think we've always said we're looking for signals of activity and starting to get a sense around dose. And that's exactly what Helen said. When you have three patients per cohort, there's a limited amount of information that you can get. But I think if we can see some sort of effect and duration of effect that gives us encouragement, nobody else with the kallikrein inhibitor has done that yet, right? And so that would be very exciting for the program.

是的。我想我們一直說我們正在尋找活動訊號並開始了解劑量。這正是海倫所說的。當每個隊列有三名患者時，您能獲得的資訊量是有限的。但我認為，如果我們能夠看到某種讓我們感到鼓舞的效果和持續時間，那麼其他使用激肽釋放酶抑制劑的人還沒有做到這一點，對嗎？這對於該計劃來說將是非常令人興奮的。

Sorry, if I can follow up. So how many micron reduction you will consider clear and uncontroversial?

抱歉，如果我可以跟進的話。那麼您認為減少多少微米才是明確且無爭議的呢？

So I would use the -- within the literature for what is generally accepted as something that's going to be predictive of likely response in visual acuity. I can't give you a number today, but I can tell you, we're looking for an uncontroversial difference. So not something that's small.

因此，我會使用文獻中普遍接受的可以預測視力可能反應的指標。我今天無法給你一個數字，但我可以告訴你，我們正在尋找一個無爭議的差異。所以這不是什麼小事。

Laura Chico, Wedbush Securities.

勞拉‧奇科（Laura Chico），韋德布希證券公司。

First one is just going back to the pediatric formulation for ORLADEYO. Can you just remind us on maybe some of the time lines after a pediatric launch arrives? Would there be a lag in deployment to the channel upon approval, just getting material out for supply? And then as we're thinking about the cadence of uptake in the pediatric population versus the adult, just kind of curious what dynamics we should be thinking about that might impact that uptake a little bit differently than what we've seen in the adults? And I have just one quick follow-up.

首先要回顧一下 ORLADEYO 的兒科配方。您能否提醒我們兒科產品上市後的一些時間表？批准後部署到通路是否會出現滯後，只是將材料發出去供應？然後，當我們思考兒科族群與成年人的吸收節奏時，只是有點好奇我們應該考慮哪些動態因素可能會對這種吸收產生與我們在成年人身上看到的略有不同的影響？我還有一個簡短的後續問題。

Sure. We will try to make the lag as small as possible. When we launched capsules back in 2020, it was only two weeks from approval to being in the channel. That was amazing. I don't know if we'll go quite that fast, but we're looking to get it out as quickly as possible. The other thing we'll do is prepare our team to begin promoting right away. And I think that's even more important because it will take a little time for kids to come in and visit their physicians.

當然。我們將盡力使滯後盡可能小。當我們在 2020 年推出膠囊時，從批准到進入渠道僅用了兩週。太棒了。我不知道我們是否會進展得這麼快，但我們希望盡快將其推出。我們要做的另一件事是讓我們的團隊做好準備，立即開始推廣。我認為這更重要，因為孩子們來拜訪醫生需要一點時間。

The uptake dynamics, I alluded to some of this a little bit earlier. I think the biggest difference is that prophylaxis really hasn't been the standard of care for kids under 12. The historical conventional wisdom is that kids become symptomatic mainly around puberty. I think what we saw in our clinical trial is for many of these kids, that is very not true.

關於吸收動力學，我之前稍微提到過一些。我認為最大的區別是預防治療實際上並不是 12 歲以下兒童的標準治療方法。歷史上的傳統觀點認為，孩子主要在青春期出現症狀。我認為，我們在臨床試驗中看到的情況對許多孩子來說，情況並非如此。

Many of these kids were -- in fact, I think the average age of symptoms was age 2. And so changing the way the whole treatment paradigm for children. If you could prevent attacks so that patients could avoid that fear, so parents could avoid that fear. It could really change the course of a kid's life living with HAE. And so I think that will be the biggest change.

事實上，我認為這些孩子中有很多出現症狀的平均年齡是 2 歲。從而改變整個兒童治療模式。如果你能預防發作，那麼病人就能避免這種恐懼，父母也能避免這種恐懼。它確實可以改變患有 HAE 的孩子的生活軌跡。所以我認為這將是最大的改變。

And as Jon and I both said earlier, I think an oral formulation is going to be the natural choice for that starting prophylaxis with the kids. So we'll see how quickly it goes, but we're hearing a lot of enthusiasm from both health care providers and the patient community for the change that I'm describing.

正如喬恩和我之前所說的那樣，我認為口服製劑將成為兒童開始預防的自然選擇。因此，我們將觀察進展速度，但我們聽到醫療保健提供者和患者群體對我所描述的變化表現出極大的熱情。

Yeah. And Laura, I'd add one thing. One of the things we learned with adults is it takes longer than you think. And so that's why we're not getting out over our skis here on giving you guidance on the uptake because we just don't know yet. We're confident that we will be the market leader because we believe we have a formulation that is way more acceptable to little kids than injectable. But the pattern to get there is it's just too early to predict.

是的。蘿拉，我想補充一點。我們從成年人身上學到的一件事是，事情需要的時間比你想像的還要長。這就是為什麼我們不會在這裡向您提供有關吸收的指導，因為我們還不知道。我們有信心成為市場領導者，因為我們相信我們的配方比注射劑更容易被小孩子接受。但現在預測實現這一目標的模式還為時過早。

And then one quick follow-up on Netherton. Can you remind us the dosing range you're going to be starting with for 17725? And then I just wanted to clarify, I know you mentioned advancing later to 12-week dosing, but what is the actual trigger for that? Is that dependent on accruing sufficient 4-week data in the initial cohorts? Any clarity there would be helpful.

然後對 Netherton 進行一次快速跟進。您能否提醒我們 17725 的起始劑量範圍？然後我只是想澄清一下，我知道您提到將劑量延長至 12 週，但實際觸發因素是什麼？這是否取決於在初始隊列中累積足夠的 4 週數據？任何澄清都會有幫助。

Yeah, sure. So in terms of the dosing range, we have experienced with a fairly broad dosing range now in healthy volunteers, and we'll be dosing patients somewhere in the middle of that range. it's 6 milligrams is the dose for patients in that initial part of Part 3. There isn't a trigger so much for the Part 4, 12 weeks. It's more that we'll learn about the dose level.

是的，當然。因此，就劑量範圍而言，我們現在在健康志願者中已經經歷了相當廣泛的劑量範圍，我們將在該範圍的中間位置為患者提供劑量。 6毫克是第 3 部分初始階段患者的劑量。第 4 部分（12 週）沒有太多觸發條件。我們將進一步了解劑量水平。

We'll learn about whether we see initial effects quickly in Part 3. And from that, we'll understand if we need to start with the same dose or dose escalate quickly in Part 4. It's more that there'll be sort of dosing initially in Part 3, learning from that as we initiate Part 4, both going in parallel with ongoing observations over time. So as I said earlier, it's more like a continuous sort of set of 2 trials, 2 arms that go together.

我們將在第 3 部分中了解是否能快速看到初步效果。由此，我們將了解是否需要從相同劑量開始或在第 4 部分快速增加劑量。更重要的是，我們在第 3 部分最初會進行某種劑量給藥，並在開始第 4 部分時從中學習，兩者都會隨著時間的推移與持續的觀察同時進行。所以正如我之前所說的，它更像是一組連續的 2 次試驗，2 個並行的分支。

Yeah. And if the drug works, we'll have an ability to keep patients on drug.

是的。如果這種藥物有效，我們就有能力讓患者繼續服用該藥物。

Liisa Bayko, Evercore ISI.

Liisa Bayko，Evercore ISI。

Congratulations on a strong quarter. Two parts to my question. First is, I just want to make sure I understand that the paid rate improvement that you saw, you've talked about it kind of being like a switch that flips on. Is there any chance that flips back? Can you talk about the sustainability of this paid rate improvement as we head into next year and future years?

恭喜本季業績強勁。我的問題分為兩部分。首先，我只是想確保我理解您所看到的付費費率的提高，您說過它就像一個打開的開關。有沒有可能逆轉？您能否談談明年及未來幾年工資率提高的可持續性？

And then part TWO is really, can you talk about the patients on treatment today? And then walk us through the kind of remaining pool of patients out there, at least in the US, who have not yet tried ORLADEYO and your plans to kind of increase utilization there?

第二部分是，您能談談今天接受治療的患者嗎？然後請您向我們介紹一下至少在美國還有哪些患者尚未嘗試過 ORLADEYO，您計劃在那裡提高其利用率嗎？

Sure. Thanks, Liisa. The paid rate I believe will be very sustainable. Based on the evidence that we've shown for ORLADEYO, it's really changing our conversations with payers. And so I think that 84% is kind of our new floor as we look forward over time. The patients on therapy.

當然。謝謝，莉莎。我相信支付率將會非常可持續。根據我們為 ORLADEYO 展示的證據，它確實改變了我們與付款人的對話。因此，我認為，隨著時間的推移，84% 是我們新的底線。正在接受治療的患者。

So as I mentioned earlier, at the end of last year, 3,000 patients in the US had tried out of a pool of about 10,000. Launch to date, 52% of our patients have switched from other prophylaxis. About 30% -- just over 30% have switched from acute only and the remaining 16%, 18%, whatever it is, our patients best we can tell, were naive to therapy.

正如我之前提到的，截至去年年底，美國約有 10,000 名患者，其中 3,000 名嘗試了該療法。截至目前，已有 52% 的患者從其他預防措施轉為使用其他預防措施。約 30% — — 略高於 30% 的患者從急性治療轉為接受治療，而剩下的 16%、18% 的患者，無論他們是什麼，據我們所知，都是未接受過治療。

And so that last piece I'm excited about because what it shows is that this is a market that is still growing. We've known that the market for prophylaxis has been growing over time, but we're finding new patients out there, and they're coming to prophylaxis. And so we have at least another 7,000 or so patients who have not yet experienced ORLADEYO, and many of them will be appropriate for prophylaxis.

所以我對最後一點感到很興奮，因為它表明這個市場仍在成長。我們知道預防市場一直在成長，但我們也發現了新的患者，他們也開始尋求預防治療。因此，我們至少還有另外 7,000 名左右的患者尚未接受過 ORLADEYO 治療，其中許多人適合進行預防性治療。

You combine that with the 70% preference for oral prophylaxis that we discussed in the call today and the growing health care provider enthusiasm and the fact that we're getting paid at such a high rate, it just increases confidence overall, and I think will continue to drive ORLADEYO going forward.

結合我們今天在電話會議上討論的 70% 對口腔預防的偏好，以及日益增長的醫療保健提供者的熱情，以及我們獲得如此高報酬的事實，這總體上增強了信心，我認為這將繼續推動 ORLADEYO 向前發展。

Yeah. And if you think about it, at the end of the fifth year since we got approval, we're at about a third of the patients that have tried it, and we're at $580 million to $600 million, we are definitely on our path to $1 billion.

是的。如果你仔細想想，自從我們獲得批准以來的第五年末，大約有三分之一的患者嘗試過這種療法，我們的收入達到了 5.8 億到 6 億美元，我們肯定正在朝著 10 億美元邁進。

Serge Belanger, Needham & Company.

塞爾日·貝朗格（Serge Belanger），Needham & Company。

Congrats on the nice quarter. A couple of ORLADEYO questions for Charlie. Now that you've reached your target for paid rate of 85%. Should we expect continued improvements on that number? Is there more to do on the commercial or Medicare side?

恭喜本季取得良好成績。ORLADEYO 向 Charlie 提出了幾個問題。現在您已經達到 85% 的付費率目標了。我們是否應該期待這個數字繼續改善？在商業或醫療保險方面還有更多工作要做嗎？

And then just a follow-up on the patient add questions. It sounds like 1Q was one of your best quarters ever in terms of new patient adds. Just curious if you're noticing a trend on where these patients are coming from, if it's still 50% prophy and 30% acute? Or is that mix changing with this new batch of new patient adds?

然後只是對患者進行後續跟進並提出問題。聽起來，就新增患者數量而言，第一季是您有史以來最好的季度之一。只是好奇，您是否注意到這些患者的來源趨勢，是否仍是 50% 為預防性，30% 為急性性？或者說，隨著這群新病人的到來，這種組合會改變嗎？

Sure. Thanks, Serge. Yeah, I think we're almost to our long-term goal of 85%, a little more room there. But what we'll do is we'll probably up that number. We'll keep striving to get better. I mentioned just a minute ago that in the Medicare segment, that's 20% of our patients, the paid rate is now 89%. And so that shows that we can improve past the 85%, and we'll do everything we can to keep getting better. I don't expect another big tailwind like we had this year, but it's just now going to be incremental improvements.

當然。謝謝，塞爾吉。是的，我認為我們幾乎已經達到了 85% 的長期目標，還有更多的空間。但我們可能會提高這個數字。我們會繼續努力變得更好。我剛才提到，在醫療保險領域，我們的 20% 患者，支付率現在是 89%。這表明我們可以超越 85%，並且我們將竭盡全力繼續進步。我並不期望出現像今年那樣的巨大順風，但現在情況將逐漸改善。

In the first quarter, yes, fundamentally, the patient base was very similar to what we've seen since the beginning of launch. The other thing I'd add is the mix of prescribers that I haven't completely discussed today. But in the first quarter, 55% of the prescriptions were from our top tier of doctors, those physicians that we know treat about 50% of all HAE patients. And then the other 45% came from everyone else.

是的，從根本上來說，第一季的患者群體與我們自推出以來所看到的情況非常相似。我要補充的另一件事是今天我還沒有完全討論過的處方人員的組合。但在第一季度，55% 的處方來自我們的頂尖醫生，我們知道這些醫生治療了大約 50% 的 HAE 患者。其餘 45% 來自其他人。

So really balanced across the board. I mentioned earlier, we had 59 new prescribers in the quarter. And so we just keep capturing more opportunity, and we keep capturing it from all the different segments, which gives us that extra confidence in the sustainability of this growth over the next several years.

因此，各方面確實都保持平衡。我之前提到過，本季我們有 59 位新開處方者。因此，我們只是不斷抓住更多的機會，並不斷從各個不同的領域抓住機會，這讓我們對未來幾年的成長永續性更有信心。

Jon Wolleben, Citizens.

喬恩‧沃勒本（Jon Wolleben），公民。

A couple on Netherton for me. Can you remind us of your preclinical tox work that you've completed so far? And then, Helen, when you talk about seeing a clinical impact determining dosing higher, what metrics will you be looking at? And what's your bar internally to determine whether or not you're in a sufficient spot in terms of efficacy?

對我來說，Netherton 上有一對夫婦。您能否提醒我們您迄今為止完成的臨床前毒理學工作？然後，海倫，當您談到看到臨床影響決定更高的劑量時，您會關注哪些指標？那麼，您內部的標準是什麼來決定您在功效方面是否達到了足夠的水平？

Yeah, sure. So preclinical tox, so this is the biologics protein therapeutic. There's a fairly standard safety profile for protein therapeutics, and we're seeing a very consistent profile with that. I think the other thing to look at with preclinical tox is we have the authorization now to proceed not only in healthy volunteers, but also in patients, and that includes authorization in the US and Australia. So just indicative of the range of confidence coming from the preclinical tox data.

是的，當然。因此，臨床前毒性，這是生物製劑蛋白質治療。蛋白質療法具有相當標準的安全性，我們看到了非常一致的安全性。我認為臨床前毒性研究需要關注的另一件事是，我們現在不僅有權在健康志願者身上進行研究，而且還有權在患者身上進行研究，其中包括在美國和澳洲的授權。因此，這僅表明了來自臨床前毒性數據的置信範圍。

Yeah. And Helen, I would add, we have an open IND, and we have the ability to dose in Part 3 up to 4 weeks and Part 4 up to 12 weeks. So that gives you some sense of the duration of tox and the like.

是的。海倫，我想補充一下，我們有一個開放的 IND，我們有能力在第 3 部分進行長達 4 週的給藥，在第 4 部分進行長達 12 週的給藥。這樣您就可以了解毒性的持續時間等。

Right. So standard toxicology to support that. In terms of the clinical impact, so what we're looking for is really normalization of the skin. So that means we're assessing by how the patient feels about their skin, is their itch still, and we want to see the itch really go away. We're looking also at a physician assessment of the skin and the severity index for thickening and scaling of the skin.

正確的。因此標準毒理學支持這一點。就臨床影響而言，我們真正尋求的是皮膚的正常化。這意味著我們要根據患者對皮膚的感覺來評估他們的搔癢是否仍然存在，並且我們希望看到搔癢真的消失。我們也正在關注醫生對皮膚的評估以及皮膚增厚和脫屑的嚴重程度指數。

And so we're looking for that redness to go down and for the scaling to stop. I expect that we'll see some of that initially. I expect that it will probably improve over time. And if we need to dose up to get to healing, meaning normal looking skin and patient not reporting itch, then we'll dose up to that.

因此，我們希望紅腫能夠消退，並且脫屑現象能夠停止。我希望我們最初能看到一些這樣的情況。我預計隨著時間的推移情況可能會有所改善。如果我們需要增加劑量才能達到治癒效果，即皮膚看起來正常且患者不會報告搔癢，那麼我們就會增加劑量。

How many patients per cohort can patients in Part 3 be included in Part 4? And then how do you think about the time-dependent nature of these improvements?

每個隊列中第 3 部分的患者可以納入第 4 部分嗎？那麼您如何看待這些改進的時間依賴性？

Part 3 is smaller than Part 4. We could see what we need to see in single-digit patients. So it's going to be fewer than 10 in Part 3. Part 4 will be slightly larger, but this is still an ultra-rare disease and every patient will inform whether we're at the dose and seeing what we need.

第 3 部分比第 4 部分小。我們可以在個位數患者身上看到我們需要看到的東西。因此第 3 部分的數量將少於 10。第 4 部分會稍微大一些，但這仍然是一種極為罕見的疾病，每個患者都會告知我們是否服用了適當的劑量以及是否看到了我們需要的東西。

So it will be larger, but not much larger in Part 4, maybe more than 10. In terms of the time dependency, we just don't know. We do know that the -- we expect the skin turnover in Netherton syndrome to be about 2 weeks. We do know that we would expect healing to occur as the skin is turning over.

所以它會更大，但在第 4 部分不會大很多，可能超過 10。就時間依賴性而言，我們還不知道。我們確實知道——我們預計 Netherton 綜合徵的皮膚更新時間約為 2 週。我們確實知道，隨著皮膚的更新，癒合就會發生。

So we may be seeing clinical signs as quickly as 4 or 8 weeks in this. We also may be seeing continuing improvement in healing of the skin because the inflammatory components take a little bit longer to heal. But our goal is to see whether we are getting that initial quick result in the short term, 4- to 8-week time frame after end of dosing and then observe over time as we continue to expand to Part 4 and be able to dose patients for a longer period of time.

因此，我們可能最快在 4 或 8 週內就會看到臨床症狀。我們也可能看到皮膚癒合情況的持續改善，因為發炎成分需要更長的時間才能癒合。但我們的目標是觀察我們是否能在短期內（服藥結束後 4 至 8 週的時間範圍內）獲得初步的快速效果，然後隨著我們繼續擴展到第 4 部分並能夠為患者進行更長時間的服藥而進行持續觀察。

This concludes our question-and-answer session. I would now like to turn the conference back over to Mr. Stonehouse for closing remarks.

我們的問答環節到此結束。現在我想將會議交還給斯通豪斯先生，請他致閉幕詞。

Thank you. So I mean, it was a great quarter. I don't know what else to say. And I'll repeat what I said earlier, I am immensely proud of the employees of BioCryst for delivering the results of this quarter. But count on us to continue to be executing. We're not going to rest on our laurels. There's a lot more to do, a lot more to deliver over the course of the year, and you can count on us for continuing to work as hard as we can to do that. So thank you for your interest, and we'll keep you updated along the way. Have a great day.

謝謝。所以我的意思是，這是一個很棒的季度。我不知道還能說什麼。我重複我之前說過的話，我為 BioCryst 員工本季的表現感到無比自豪。但請相信我們將繼續執行。我們不會滿足於現狀。今年還有很多事情要做，還有很多事情要完成，你可以相信我們將繼續盡最大努力實現這些目標。感謝您的關注，我們隨時向您通報最新情況。祝你有美好的一天。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連線。