BioMarin Pharmaceutical Inc (BMRN) 2025 Q2 法說會逐字稿

Good afternoon. My name is Audra, and I will be your conference operator today. At this time, I would like to welcome everyone to the BioMarin Pharmaceutical second quarter 2025 conference call. Today's conference is being recorded. (Operator Instructions)

午安.我叫奧德拉，今天我將擔任您的會議主持人。現在，我歡迎大家參加 BioMarin Pharmaceutical 2025 年第二季電話會議。今天的會議正在錄製中。（操作員指示）

At this time while I turn the conference over to Traci McCarty, Investor Relations at BioMarin. Please go ahead.

現在我將會議交給 BioMarin 投資者關係部門的 Traci McCarty。請繼續。

Thank you, operator. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market, and developments by competitors, and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

謝謝您，接線生。提醒您，本非機密簡報包含有關 BioMarin Pharmaceutical Inc. 業務前景的前瞻性陳述，包括對 BioMarin 的財務業績、商業產品以及不同治療研究和開發領域的潛在未來產品的預期。由於 BioMarin 產品項目的進展、監管機構的行動、資本的可用性、醫藥市場的未來行動、競爭對手的發展以及 BioMarin 向美國證券交易委員會提交的文件（如 10-Q、10-K 和 8-K 報告）中詳述的因素，結果可能會有顯著差異。

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with US GAAP, and you can find the related reconciliations to US GAAP in the earnings press release and earnings presentation, both of which are available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

此外，我們將在今天的電話會議中使用 G 條例中定義的非 GAAP 財務指標。這些非公認會計準則 (non-GAAP) 指標不應被視為與按照美國公認會計準則 (US GAAP) 編制的財務指標分離的替代指標或優於這些指標，您可以在收益新聞稿和收益報告中找到與美國公認會計準則 (US GAAP) 相關的對賬，這兩者都可以在我們網站的投資者關係部分找到。請注意，除非另有說明，我們對今天電話會議的評論將集中於非公認會計準則財務指標。

Introducing the BioMarin management team today on the call, we have Alexander Hardy, President and Chief Executive Officer; Brian Mueller, Executive Vice President, Chief Financial Officer; Cristin Hubbard, Executive Vice President, Chief Commercial Officer; and Greg Friberg, Executive Vice President, Chief R&D Officer. I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

今天在電話會議上介紹 BioMarin 管理團隊，我們有總裁兼執行長 Alexander Hardy、執行副總裁兼財務長 Brian Mueller、執行副總裁兼首席商務長 Cristin Hubbard 和執行副總裁兼首席研發長 Greg Friberg。現在我將把電話轉給 BioMarin 總裁兼執行長亞歷山大哈迪 (Alexander Hardy)。

Thank you, Traci, and thank you all for joining us today for BioMarin's second quarter update. Now moving to slide 6. We were very pleased with our Q2 performance across all aspects of the business, including strong growth, exciting progress across the pipeline, and delivery of our business development strategy.

謝謝你，Traci，也謝謝大家今天參加 BioMarin 第二季更新。現在轉到投影片 6。我們對第二季度業務各方面的表現非常滿意，包括強勁的成長、整個管道的令人振奮的進展以及業務發展策略的實現。

Starting with our strong growth in the second quarter. Leveraging our business unit structure to drive focus and accountability, BioMarin achieved double digit year over year revenue growth and significant profitability expansion.

從第二季的強勁成長開始。利用我們的業務部門結構來推動重點和責任，BioMarin 實現了兩位數的同比收入增長和顯著的盈利能力擴張。

Turning to pipeline progress, I'm excited to share that BMN 333, BioMarin's long-acting therapy for children with achondroplasia, achieved our target profile. Our goal is for BMN 333 to demonstrate superiority to VOXZOGO and set a new standard for the treatment of achondroplasia.

談到管道進展，我很高興地告訴大家，BMN 333（BioMarin 用於治療兒童軟骨發育不全的長效療法）達到了我們的目標。我們的目標是讓 BMN 333 展現出優於 VOXZOGO 的優勢，並為軟骨發育不全的治療樹立新的標準。

We plan to advance the program to the next stage of development and expect to begin a registrational Phase 2/3 study in the first half of next year. Greg will provide additional details in a few moments.

我們計劃將該項目推進到下一階段的開發，並預計在明年上半年開始註冊第 2/3 階段研究。格雷格稍後將提供更多詳細資訊。

Moving to our business development strategy, we successfully completed the acquisition of Inozyme on July 1, broadening our enzyme therapies portfolio. We executed the transaction with precision and focus, moving from agreement to close in less than two months.

在我們的業務發展策略方面，我們於 7 月 1 日成功完成對 Inozyme 的收購，擴大了我們的酵素療法產品組合。我們精準而專注地執行了交易，從達成協議到完成交易僅花了不到兩個月的時間。

A lead program, BMN 401, formerly known as INZ-701, is a treatment for ENPP1 deficiency, a condition with high unmet need and no approved treatment options. And we look forward to the pivotal data readout from this program in the first half of 2026. Greg will provide an update on some anticipated milestones with BMN 401.

一項主要項目 BMN 401（以前稱為 INZ-701）用於治療 ENPP1 缺乏症，這種疾病存在大量未滿足的需求，且沒有批准的治療方案。我們期待在 2026 年上半年讀取該計劃的關鍵數據。Greg 將提供有關 BMN 401 的一些預期里程碑的最新消息。

Moving to slide 7, our outlook for the remainder of 2025. Building on the strong momentum so far, we will continue to execute on our 2025 priorities with urgency to deliver value to our stakeholders. Looking ahead and building on the momentum, we expect continued strong growth throughout the remainder of 2025, leading us to increase our full year guidance for total revenues, non-GAAP operating margin, and earnings per share.

轉到幻燈片 7，我們對 2025 年剩餘時間的展望。基於迄今為止的強勁勢頭，我們將繼續緊急執行我們的 2025 年優先事項，為我們的利害關係人創造價值。展望未來，我們預計在 2025 年剩餘時間內將繼續保持強勁成長，這將促使我們提高全年總收入、非 GAAP 營業利潤率和每股收益的預期。

We are progressing our pipeline as announced today with BMN 333 advancing. BMN 401 pivotal data expected to read out next year, and a number of other updates anticipated over the coming quarters. And building on the Inozyme acquisition, we plan to continue to augment our portfolio with strategic business development transactions to diversify our growth strategy.

正如今天所宣布的，我們正在推進我們的管道建設，BMN 333 正在推進中。BMN 401 關鍵數據預計將於明年公佈，並且預計未來幾季還會公佈許多其他更新。在收購 Inozyme 的基礎上，我們計劃繼續透過策略性業務發展交易來擴大我們的產品組合，以實現我們的成長策略多元化。

In conclusion, with the first half of the year now complete, I'm pleased with our progress and remain enthusiastic about our potential to deliver for patients, employees, and our shareholders through the remainder of 2025 and beyond. Thank you for your attention. I will now turn the call over to Brian to provide our financial highlights for the quarter. Brian?

總而言之，今年上半年已經過去，我對我們的進展感到滿意，並對我們在 2025 年剩餘時間及以後為患者、員工和股東提供服務的潛力充滿熱情。感謝您的關注。現在我將把電話轉給 Brian，讓他提供本季的財務亮點。布賴恩？

Thank you, Alexander. Please refer to today's press release for detailed second-quarter 2025 results, including reconciliations of GAAP to non-GAAP financial measures. All 2025 results will be available in our upcoming Form 10-Q, which we expect to file in the coming days.

謝謝你，亞歷山大。請參閱今天的新聞稿，以了解 2025 年第二季的詳細業績，包括 GAAP 與非 GAAP 財務指標的對帳。所有 2025 年的結果將在我們即將發布的 10-Q 表中公佈，我們預計將在未來幾天內提交該表格。

Now moving to slide 9 and starting with revenue, we were very pleased with our strong performance in the second quarter of 2025. Total revenues grew 16% in the quarter and 15% in the first half of 2025 compared to the same periods in 2024. These results were driven by the underlying strength in global demand, and new patient starts across the portfolio. Looking ahead, BioMarin is positioned for continued growth in the second half of this year.

現在轉到第 9 張投影片，從營收開始，我們對 2025 年第二季的強勁表現感到非常滿意。與 2024 年同期相比，本季總營收成長了 16%，2025 年上半年總營收成長了 15%。這些結果是由全球需求的潛在強度以及整個投資組合中新患者的開始所推動的。展望未來，BioMarin 預計在今年下半年繼續成長。

Revenue highlights in the second quarter include VOXZOGO revenue increasing 20% year over year to $221 million, fueled primarily by the ongoing success of the product's global expansion. Midway through the year, as I previously noted, we expect second half VOXZOGO revenue to be higher than the first half, and further, we expect second half revenue to be weighted to Q4 due to both the impact of our strategic skeletal conditions business unit initiatives and order timing outside of the US. Therefore, with better line of sight into the dynamics in the US and outside of the US for the remainder of the year, we are targeting full year VOXZOGO revenue of between $900 million and $935 million.

第二季的營收亮點包括 VOXZOGO 營收年增 20% 至 2.21 億美元，這主要得益於該產品全球擴張的持續成功。正如我之前提到的，我們預計今年中期 VOXZOGO 的收入將高於上半年，此外，我們預計下半年的收入將集中在第四季度，這既受到我們戰略骨骼疾病業務部門舉措的影響，也受到美國以外訂單時間的影響。因此，透過更了解今年剩餘時間美國國內和國外的動態，我們預計 VOXZOGO 全年營收將在 9 億美元至 9.35 億美元之間。

Enzyme therapies revenue rose 15% year over year to $555 million, reflective of both strong demand and order timing from regions across the globe. With PALYNZIQ, we continue to see strong year over year growth, with Q2 marking two consecutive quarters of 20% growth. VIMIZIM was also a strong contributor to second quarter growth, increasing 21% year over year.

酵素療法營收年增 15% 至 5.55 億美元，反映出全球各地的強勁需求和訂單時機。憑藉 PALYNZIQ，我們繼續看到強勁的同比成長，第二季連續兩季實現 20% 的成長率。VIMIZIM 也是第二季成長的重要貢獻者，年增 21%。

Roctavian revenue was $9 million in the second quarter, led by contributions from the United States and Italy. All of these factors contributing to our strong Q2 revenues give us confidence to bring up the lower end of full year 2025 total revenue guidance to $3.125 billion, with the midpoint of our guidance range representing double digit year over year growth.

Roctavian 第二季的營收為 900 萬美元，主要來自美國和義大利的貢獻。所有這些促成我們第二季強勁收入的因素使我們有信心將 2025 年全年總收入預期的下限提高至 31.25 億美元，而預期範圍的中點代表著同比增長兩位數。

Now moving to slide 10 and operating expenses in the second quarter of 2025, non-GAAP R&D expense in the second quarter was lower compared to Q2 2024, benefiting from focused R&D investment in prioritized assets following last year's strategic portfolio review. Non-GAAP SG&A increased in Q2 year over year, mostly due to our investments in the company's enterprise resource planning system implementation and business unit strategic initiatives.

現在轉到第 10 張投影片和 2025 年第二季的營運費用，第二季的非 GAAP 研發費用與 2024 年第二季相比有所降低，這得益於去年策略投資組合審查後對優先資產的重點研發投資。非公認會計準則銷售、一般及行政費用在第二季度同比增長，主要由於我們對公司企業資源規劃系統實施和業務部門戰略舉措的投資。

As mentioned in our first quarter update, we expect both non-GAAP R&D and SG&A expense to increase over the second half of 2025 due to our historical spend patterns, incremental operating expenses related to the Inozyme acquisition, and continued advancement of our clinical programs and commercial initiatives. These investments include R&D expense for VOXZOGO and new indications and BMN 333, as well as expansion of commercial initiatives in our skeletal conditions and enzyme therapies business units.

正如我們在第一季更新中提到的那樣，由於我們的歷史支出模式、與 Inozyme 收購相關的增量營運費用以及我們臨床項目和商業計劃的持續推進，我們預計非 GAAP 研發和銷售、一般及行政費用將在 2025 年下半年增加。這些投資包括 VOXZOGO 及其新適應症和 BMN 333 的研發費用，以及我們骨骼疾病和酵素療法業務部門的商業計劃擴展。

Non-GAAP operating margin expanded significantly in the second quarter as compared to Q2 2024, driven by strong performance across the P&L, including underlying revenue growth and current operating expense trends. We anticipate that higher operating expenses in the second half of 2025 to support our business unit initiatives will decrease second half operating margin as compared to the first half of the year.

與 2024 年第二季相比，第二季非公認會計準則營業利潤率大幅擴大，這得益於損益表的強勁表現，包括基礎收入成長和當前營運費用趨勢。我們預計，為支持我們業務部門的計劃，2025 年下半年的營運費用將增加，與上半年相比，下半年的營運利潤率將有所下降。

Further, as just outlined, with revenue being back weighted to Q4, together with the expense timing, we expect profitability to be lower in Q3 as compared to Q4. All in all, continued strong revenue performance and underlying cost discipline enables us to raise full year 2025 non-GAAP operating margin guidance to between 33% and 34%.

此外，正如剛才概述的那樣，由於收入被回溯到第四季度，再加上費用時間，我們預計第三季的獲利能力將低於第四季。總而言之，持續強勁的收入表現和基本的成本控制使我們能夠將 2025 年全年非 GAAP 營業利潤率預期提高到 33% 至 34% 之間。

Now moving to slide 11 to highlight BioMarin's increasing profitability and operating cash flow. The bottom line continues to outpace top line growth at an impressive rate. In the second quarter, non-GAAP diluted earnings per share of $1.44 increased at more than 3 times the rate of revenue growth, reflecting the flow through of strong operating margin performance to the bottom line.

現在轉到第 11 張投影片，重點介紹 BioMarin 不斷成長的獲利能力和營運現金流。利潤成長速度持續以驚人的速度超過營收成長速度。第二季度，非公認會計準則每股攤薄收益為 1.44 美元，增幅是收入成長率的 3 倍多，反映出強勁的營業利潤率表現已轉化為利潤。

Looking through the remainder of 2025 and as with operating margins, we do expect increasing business unit investments to result in lower earnings per share in the second half of the year as compared to the first half, with a decrease concentrated to the third quarter due to timing.

展望 2025 年剩餘時間，與營業利潤率一樣，我們預計業務部門投資的增加將導致下半年每股收益低於上半年，並且由於時間原因，下降將集中在第三季度。

Supported by the strong first half performance, we are raising full year 2025 non-GAAP earnings per share guidance to between $4.40 and $4.55. In addition, BioMarin's increasing profitability continues to generate significant operating cash flow, reaching $185 million in Q2, a 55% increase versus the same period in 2024. Increasing operating cash flow is expected to continue going forward in support of our innovation expansion opportunities and future growth.

受上半年強勁業績的支撐，我們將2025年全年非公認會計準則每股收益預期上調至4.40美元至4.55美元之間。此外，BioMarin不斷提升的獲利能力持續產生可觀的營運現金流，第二季達到1.85億美元，較2024年同期成長55%。預計未來經營現金流將持續增加，以支持我們的創新擴張機會和未來成長。

Now moving to slide 12 and to summarize, we are pleased with our financial performance across the business in the second quarter. And today's full year 2025 guidance update reflect our expectation of continued strong growth and value creation for shareholders. Separately, with the Inozyme acquisition completed on July 1, we expect to account for the transaction as an asset purchase and record the impact of the acquired in-process research and development, or IPR&D expense, in our financial results in the third quarter of 2025. Today's guidance updates do not yet reflect the IPR&D, and we will update full year guidance when we report Q3 as the transaction is reported.

現在轉到投影片 12，總結一下，我們對第二季整個業務的財務表現感到滿意。今天發布的 2025 年全年指引更新反映了我們對持續強勁成長和為股東創造價值的預期。另外，隨著 7 月 1 日完成對 Inozyme 的收購，我們預計將該交易記為資產購買，並在 2025 年第三季的財務業績中記錄收購的在研研發或 IPR&D 費用的影響。今天的指導更新尚未反映 IPR&D，我們將在報告第三季交易時更新全年指引。

Thank you for your attention, and I will now turn the call over to Cristin for an update on commercial activities in the quarter. Cristin?

感謝您的關注，現在我將把電話轉給克里斯汀，以了解本季商業活動的最新情況。克里斯汀？

Thank you, Brian. Now moving to slide 14, I'd like to acknowledge the contributions from across the global teams that led to this strong second quarter performance from BioMarin's portfolio of eight innovative therapies.

謝謝你，布萊恩。現在轉到第 14 張投影片，我想感謝全球團隊的貢獻，這些貢獻使得 BioMarin 的八種創新療法組合在第二季度表現強勁。

Starting with VOXZOGO, 20% year over year revenue growth in the second quarter across a combined 51 countries was supported by new patient starts, as well as strong treatment adherence. We were pleased to see strong uptake in the 0 to 4 year old cohort in the US.

從 VOXZOGO 開始，第二季在 51 個國家的營收年增 20%，這得益於新患者的開始使用以及強大的治療依從性。我們很高興看到美國 0 至 4 歲兒童族群的強勁成長。

New initiatives in the US, including increasing the field force, as well as investments in digital promotion to drive VOXZOGO expansion, are working. As a result, we doubled the number of leads generated year-to-date, year over year, which translated to an increase in net new US patients.

美國的新舉措正在發揮作用，包括增加現場力量以及投資數位推廣以推動 VOXZOGO 擴張。結果，我們年初至今產生的銷售線索數量與去年同期相比增加了一倍，這意味著美國新增患者數量淨增加。

With these initiatives firmly in place, we expect US patient uptake over the remainder of the year to be strong, while noting that the revenue results from these initiatives will be realized over the coming quarters. Now outside the US, VOXZOGO expansion came from deeper penetration into existing countries, as well as good adherence from children on therapy with incremental contributions from newly added countries. In summary, we are pleased to expect VOXZOGO full-year 2025 revenue growth of 25% year over year at the midpoint.

隨著這些舉措的落實，我們預計今年剩餘時間內美國患者的接受度將保持強勁，同時注意到這些舉措帶來的收入成果將在未來幾季實現。現在，VOXZOGO 已在美國以外地區實現擴張，這得益於其對現有國家的深入滲透，以及兒童接受治療的良好依從性以及來自新增國家的增量貢獻。總而言之，我們很高興地預計 VOXZOGO 2025 年全年營收將年增 25%。

Now moving to slide 15 and turning to hypochondroplasia, the next indication we are studying for VOXZOGO treatment. Hypochondroplasia is a rare skeletal condition characterized by impaired bone growth, leading to disproportionate short stature, along with a wide range of medical complications and functional challenges.

現在翻到第 15 張幻燈片，討論軟骨發育不全，這是我們正在研究的 VOXZOGO 治療的下一個適應症。軟骨發育不全是一種罕見的骨骼疾病，其特徵是骨骼生長受損，導致身材矮小，並伴隨多種醫療併發症和功能障礙。

The comorbidities are highly varied and can look like any combination of disproportionality, macrocephaly, ear, nose, throat, and musculoskeletal related issues. Because hypochondroplasia is a clinically and genetically heterogeneous condition, it may be diagnosed late or not at all. Unfortunately, there is significant unmet need as the condition has no approved treatments except for growth hormone in Japan. People with hypochondroplasia can face significant health burdens and reduced quality of life.

合併症多種多樣，可以是比例失調、大頭畸形、耳、鼻、喉和肌肉骨骼相關問題的任意組合。由於軟骨發育不全是一種臨床和遺傳異質性疾病，因此可能診斷較晚或根本無法診斷。不幸的是，由於日本除了生長激素外沒有其他核准的治療方法，因此存在大量未滿足的需求。患有軟骨發育不良的人會面臨嚴重的健康負擔和生活品質下降。

To date, data from Dr. Andrew Dauber's investigator sponsored study has provided encouraging proof of concept results with VOXZOGO and hypochondroplasia. Enrollment pace in BioMarin's pivotal study exceeded internal expectations, giving us a good indication of demand for the treatment of this condition.

迄今為止，由 Andrew Dauber 博士發起的研究數據已為 VOXZOGO 和軟骨發育不全症提供了令人鼓舞的概念驗證結果。BioMarin 關鍵研究的入組速度超出了內部預期，這很好地表明了對這種疾病治療的需求。

We are leveraging our established capabilities to raise awareness of the upcoming Phase 3 hypochondroplasia data set which we plan to share in the first half of 2026 to support a potential launch in 2027. And at this stage we are actively engaging with the medical community to advance education on disease awareness and management through strategic partnerships with healthcare professionals, including achondroplasia thought leaders, advocacy groups, and academic institutions. We aim to improve early diagnosis in hypochondroplasia to shape future treatment decision making with VOXZOGO.

我們正在利用現有的能力來提高人們對即將到來的第 3 階段軟骨發育不全數據集的認識，我們計劃在 2026 年上半年分享該數據集，以支持 2027 年的潛在發布。目前，我們正在積極與醫學界合作，透過與醫療保健專業人士（包括軟骨發育不全思想領袖、倡導團體和學術機構）建立策略合作夥伴關係，推動疾病意識和管理教育。我們的目標是改善軟骨發育不全的早期診斷，以便透過 VOXZOGO 制定未來的治療決策。

Now moving to slide 16 and our enzyme therapies business unit. In the second quarter, combined products delivered 15% growth year over year. PALYNZIQ's strength in the quarter was driven by greater numbers of patients titrating to their daily maintenance dose and strong adherence.

現在轉到幻燈片 16 和我們的酵素療法業務部門。第二季度，綜合產品年增15%。PALYNZIQ 在本季的強勁表現得益於越來越多的患者按時達到每日維持劑量並堅持服用。

Incremental new patient starts were encouraging in the quarter, and we look forward to them achieving their maintenance dosing over the coming quarters to realize the full benefits of PALYNZIQ. And if approved, we look forward to the opportunity to make PALYNZIQ available to adolescents in the US and Europe based on its demonstrated ability to lower Phe into the normal range and allow for an unrestricted diet, even in people with the most severe form of PKU. We believe these two attributes will be particularly transformational for those preparing to transition into adulthood.

本季新增患者的開始令人鼓舞，我們期待他們在未來幾季內實現維持劑量，以充分享受 PALYNZIQ 的益處。如果獲得批准，我們預期有機會讓美國和歐洲的青少年也能使用 PALYNZIQ，因為它已被證明能夠將 Phe 降低到正常範圍內，並且允許不受限制的飲食，即使是患有最嚴重形式的 PKU 的人也是如此。我們相信，對於那些準備步入成年期的人來說，這兩種特質將具有特別的轉變作用。

VIMIZIM was also a strong performer during the quarter, growing 21% in year over year revenues and benefiting from ongoing patient demand globally, as well as the timing of large orders in certain regions. Across enzyme therapies, we expect strong trends to continue through the second half of 2025, despite potential quarter to quarter fluctuations due to order timing as we've observed historically.

VIMIZIM 在本季也表現強勁，營收年增 21%，受益於全球持續的患者需求以及某些地區大額訂單的時機。在酵素療法領域，儘管我們過去觀察到訂單時間可能導致季度間波動，但我們預計強勁趨勢將持續到 2025 年下半年。

In summary, the team delivered another quarter of strong performance across the globe. Despite the significant macro challenges many companies in our sector are facing, the essential nature of our medicines, our strong patient support programs, and BioMarin's global reach keep these important therapies available for the people who need them. I want to thank the team for their continued commitment and perseverance. I'll now turn the call over to Greg for an update on R&D progress in the quarter. Greg?

總而言之，該團隊在全球範圍內又取得了一個季度的強勁表現。儘管我們行業中的許多公司都面臨著巨大的宏觀挑戰，但我們藥品的本質、我們強大的患者支持計劃以及 BioMarin 的全球影響力使這些重要的療法能夠為有需要的人所用。我要感謝團隊的持續承諾和堅持。現在我將把電話轉給格雷格，以了解本季研發進展的最新情況。格雷格？

Thank you, Cristin. Now moving to slide 18. We're very pleased to share the first clinical update on BMN 333, BioMarin's long-acting CNP candidate for the treatment of achondroplasia. Today we announced that we have observed encouraging PK results from our healthy volunteer study where BMN 333 demonstrated free CNP levels more than 3 times greater than the AUC levels reported for another long-acting CNP as described in the British Journal of Clinical Pharmacology from June 2022. This profile represents a potential best-in-class molecule, with the opportunity to drive even greater improvements in growth parameters versus available therapies, and by extension, to further improved measures of health and wellness in children with achondroplasia.

謝謝你，克里斯汀。現在翻到第 18 張投影片。我們非常高興地分享 BMN 333 的首個臨床更新，BMN 333 是 BioMarin 用於治療軟骨發育不全的長效 CNP 候選藥物。今天，我們宣布，我們在健康志願者研究中觀察到了令人鼓舞的 PK 結果，其中 BMN 333 的遊離 CNP 水平比 2022 年 6 月《英國臨床藥理學雜誌》報道的另一種長效 CNP 的 AUC 水平高出 3 倍以上。該概況代表了一種潛在的同類最佳分子，與現有療法相比，它有機會推動生長參數的更大改善，進而進一步改善軟骨發育不全兒童的健康和保健指標。

Our own pre-clinical data, along with publicly available dose response data for long-acting CNP agents, suggests that additional growth should be achievable with greater CNP exposures. We believe that safely achieving these PK results with BMN 333 means we have the right agent in hand to immediately test this hypothesis.

我們自己的臨床前數據以及公開的長效 CNP 藥物劑量反應數據表明，隨著 CNP 暴露量的增加，應該可以實現額外的增長。我們相信，使用 BMN 333 安全地實現這些 PK 結果意味著我們擁有合適的藥物來立即檢驗這一假設。

Based on these results, we're planning to initiate the dose finding arm of our Phase 2/3 registration enabling program in the first half of 2026 with a targeted approval in 2030 should the data be supportive. The Phase 1 study continues as planned with ongoing monitoring of safety and pharmacokinetics at our sixth and final planned cohort.

基於這些結果，我們計劃在 2026 年上半年啟動 2/3 期註冊授權計畫的劑量探索部分，如果數據支持，則計劃在 2030 年獲得批准。第一階段研究按計劃繼續進行，並持續監測我們計劃的第六個也是最後一個隊列的安全性和藥物動力學。

We anticipate sharing this full data set publicly at a conference in the first half of next year. We're very encouraged by these results thus far and will continue to look for opportunities to accelerate the program.

我們預計在明年上半年的會議上公開分享這套完整的數據集。到目前為止，這些結果讓我們感到非常鼓舞，並將繼續尋找機會加速該計劃。

On slide 19, moving to our next regulatory filing, we're on track to submit applications to support an age extension for PALYNZIQ to include adolescents with the US and EU applications planned for the second half of this year. Recall that our PALYNZIQ adolescent study, similar to our previous adult study, required participants to have sustained Phe levels greater than 600 micromole per liter, despite available dietary and pharmacologic treatment. This is a more severe population than those in which the BH4 analogs have been routinely used.

在第 19 張投影片上，前往我們的下一份監管文件，我們正按計劃提交申請，以支持將 PALYNZIQ 的年齡延長至包括青少年，美國和歐盟的申請計劃於今年下半年提交。回想一下，我們的 PALYNZIQ 青少年研究與我們先前的成人研究類似，要求參與者的 Phe 水平維持在每公升 600 微摩爾以上，儘管可以進行飲食和藥物治療。與常規使用 BH4 類似物的族群相比，此族群的病情更為嚴重。

Beyond simple Phe lowering, the promise of PALYNZIQ is that it may offer adolescents the potential to consume more native protein during their formative years and to decrease or eliminate the need for medical food. We plan to share the complete data from our adolescent study at a scientific congress in the second half of this year, and we look forward to the possibility of expanding the PALYNZIQ label into adolescence with potential approvals in 2026.

除了簡單地降低 Phe 水平之外，PALYNZIQ 的前景還在於，它可以讓青少年在成長過程中攝取更多的天然蛋白質，從而減少或消除對醫療食品的需求。我們計劃在今年下半年的科學會議上分享我們青少年研究的完整數據，並期待將 PALYNZIQ 標籤擴展到青少年，並可能在 2026 年獲得批准。

On slide 20, now turning to another Phase 3 asset, we're very pleased that the Inozyme acquisition was closed so rapidly, allowing us to carry forward BMN 401 for the treatment of ENPP1 deficiency. ENPP1 deficiency is a rare, serious, and progressive genetic condition that can affect blood vessels, soft tissues, and bones in infants, in children, and in adults.

在投影片 20 上，現在轉向另一項第 3 階段資產，我們非常高興 Inozyme 的收購能夠如此迅速地完成，這使我們能夠繼續使用 BMN 401 來治療 ENPP1 缺乏症。ENPP1 缺乏症是一種罕見、嚴重且進行性的遺傳疾病，可影響嬰兒、兒童和成人的血管、軟組織和骨骼。

BMN 401 has the potential to be the first genetically targeted medicine for ENPP1 deficiency. We look forward to sharing a first look at the pivotal data from the ENERGY 3 study in 1- to 12-year-old in the first half of 2026 and to progressing clinical development in other age groups once we finalize the integration and determine the most efficient paths forward. In addition to this initial focus on ENPP1 deficiency, we are already evaluating other potential indications with BMN 401, and we will share more details as they become available.

BMN 401 有可能成為第一個針對 ENPP1 缺乏症的基因標靶藥物。我們期待在 2026 年上半年首次分享針對 1 至 12 歲兒童的 ENERGY 3 研究的關鍵數據，並在完成整合並確定最有效的前進路徑後推進其他年齡組的臨床開發。除了最初關注的 ENPP1 缺乏症之外，我們還在評估 BMN 401 的其他潛在適應症，並將在獲得更多細節後分享。

Finally, on slide 21, here is a snapshot of a few highlights expected across our pipeline through the next six quarters. Following today's healthy volunteer PK update for BMN 333, we look forward to the start of our Phase 2/3 study in the first half of next year. Also in the first half of 2026, we'll be sharing pivotal VOXZOGO data in hypochondroplasia with submissions planned in the second half of 2026 to support a potential approval and launch in 2027.

最後，第 21 張投影片簡要介紹了未來六個季度我們預計會出現的一些亮點。繼今天對 BMN 333 的健康志願者進行 PK 更新之後，我們期待明年上半年開始第 2/3 階段研究。此外，在 2026 年上半年，我們將分享軟骨發育不全的關鍵 VOXZOGO 數據，並計劃在 2026 年下半年提交數據，以支持 2027 年的潛在批准和推出。

We plan to submit our PALYNZIQ adolescent data before the year's end in support of potential launches in the US and Europe in 2026. BMN 401, as already mentioned, is expected to read out the ENERGY 3 study in the first half of 2026 in 1 to 12 year olds, followed by a potential regulatory submission in that age group in the second half of next year with the goal of launching in 2027.

我們計劃在今年年底前提交我們的 PALYNZIQ 青少年數據，以支持 2026 年在美國和歐洲的潛在發布。如前所述，BMN 401 預計將於 2026 年上半年針對 1 至 12 歲的兒童進行 ENERGY 3 研究，隨後於明年下半年針對該年齡組提交潛在的監管意見，目標是於 2027 年推出。

With BMN 351 for the treatment of Duchenne muscular dystrophy, our study is progressing as planned. In addition to previously discussed 6 and 9 mg per kilogram cohorts which have fully enrolled, the study data monitoring committee recently approved escalation to a third preplanned cohort of 12 mg per kilogram, which should complete enrollment by the end of the year.

使用 BMN 351 治療杜氏肌肉營養不良症，我們的研究正在按計劃進行。除了先前討論過的已全部入組的 6 毫克/公斤和 9 毫克/公斤隊列之外，研究數據監測委員會最近批准升級到第三個預先計劃的 12 毫克/公斤隊列，該隊列應在今年年底前完成入組。

We remain on track to share a more detailed clinical update by the end of this year. BMN 349 for alpha-1 antitrypsin deficiency is also progressing in the clinic, and we're planning a Phase 2 study start in the first half of 2026. In summary, we have a number of exciting readouts and regulatory filings on the horizon, and we look forward to sharing updates as they progress over the coming months. I want to thank you for your attention today. We will now open the call to your questions. Operator.

我們將在今年年底前分享更詳細的臨床更新。用於治療 α-1 抗胰蛋白酶缺乏症的 BMN 349 也在臨床上取得進展，我們計劃在 2026 年上半年開始進行第 2 階段研究。總而言之，我們即將發布一系列令人興奮的數據和監管文件，我們期待在未來幾個月分享最新進展。我想感謝大家今天的關注。我們現在開始回答你們的問題。操作員。

Paul Matteis, Stifel.

保羅·馬泰斯（Paul Matteis），Stifel。

Great. Thanks so much and congratulations on the quarter. I had a couple of questions on BMN 333. I just wanted to clarify that the computing program you're referring to is TransCon. CNP is related to the comparison to AUC data. And then as it relates to the data itself, can you just confirm the safety profile that you're targeting and whether or not increased exposure is running into any increased risk of hypertension or other side effects. Thanks so much.

偉大的。非常感謝，並祝賀本季取得佳績。我對 BMN 333 有幾個疑問。我只是想澄清一下，您所指的計算程序是 TransCon。CNP 與 AUC 資料的比較相關。然後，由於它與數據本身相關，您能否確認您所針對的安全性概況，以及增加暴露是否會增加高血壓或其他副作用的風險。非常感謝。

So Paulie, this is Greg Freiberg. I can confirm that the agent you're referring to is in that reference that we commented there. With regard to the profile we're seeing with BMN 333 from a safety standpoint, absolutely nothing unexpected though. We have to remember this is a healthy volunteer study. It's in adults, not in children.

保利，這是格雷格·弗賴伯格。我可以確認您所指的經紀人就在我們在那裡評論的參考資料中。從安全角度來看，就 BMN 333 的概況而言，絕對沒有任何意外。我們必須記住這是一項健康志願者研究。它存在於成人中，而不存在於兒童中。

That being said, nothing unexpected. And again, we also look at the genetic data in this disease where, from the standpoint of patients who either have inborn mutations that cause them to have high CNP levels or activated receptors, nature has shown us that those patients, the only problems that they tend to have in their lifetime is that, number one, they're quite tall and they are skeletal complications of being over 7 feet tall. But reassuringly those patients don't have challenges in other organ systems. So again, we're hopeful that that read through will again be recapitulated when we pharmacologically go to higher levels of CNP.

話雖如此，但並沒有什麼意外。再次，我們也會研究這種疾病的基因數據，從那些因先天突變而導致 CNP 水平高或受體激活的患者的角度來看，大自然向我們表明，這些患者一生中唯一的問題就是，第一，他們身材很高，身高超過 7 英尺會出現骨骼並發症。但令人放心的是，這些患者的其他器官系統並沒有出現問題。因此，我們再次希望，當我們從藥理學角度達到更高水平的 CNP 時，這種解讀將再次重現。

Cory Kasimov, Evercore ISI.

Cory Kasimov，Evercore ISI。

Good afternoon, guys. Thanks for taking the question and great to see the continued execution and the preliminary 333 data. On the achondroplasia front, I'd be interested in your thoughts on the evolving competitive landscape here, with the recent data showing a long-acting CNP in combination with growth hormone and how you think that could impact the market down the road. Thank you.

大家下午好。感謝您提出這個問題，很高興看到持續的執行和初步的 333 數據。在軟骨發育不全方面，我很想知道您對這裡不斷變化的競爭格局的看法，最近的數據顯示長效 CNP 與生長激素的結合，以及您認為這將如何影響未來的市場。謝謝。

Thanks, Cory. This is Greg Freiberg again. I'll take a stab at that. When the early data for the growth hormone combinations card turned over, it was not surprising to see that there was added growth at a very early time point when growth hormone was added to CNP.

謝謝，科里。我又是 Greg Freiberg。我會嘗試一下。當生長激素組合卡的早期數據翻轉時，毫不奇怪地發現，當生長激素添加到 CNP 時，在很早的時間點就出現了增加的生長。

Being able to achieve small or at least short-term increases has never been the problem with growth hormone. On the contrary, it's been whether or not those accelerations of growth can persist over time. Of course, achondroplasia is a condition which is not growth hormone deficient. And long term follow up of these patients, particularly, even the Japanese patients where it's approved in Japan, have only shown a couple of centimeters in increase in final adult height.

能夠實現小幅或至少短期的成長從來都不是生長激素的問題。相反，問題在於這些成長加速是否能夠持續下去。當然，軟骨發育不全並不是一種生長激素缺乏的疾病。對這些患者進行長期跟踪，特別是在日本獲得批准的日本患者，結果顯示其成年身高僅增加了幾厘米。

Similarly, the kind of evidence beyond growth that we're seeing with CNP, affecting facial morphology, looking at tibial bowing, all of these, evidence of improving the patient's well-being and health, those haven't been as profoundly documented with growth hormones.

同樣，我們在 CNP 中看到的除了生長之外的證據，包括影響面部形態、觀察脛骨彎曲等，所有這些改善患者幸福感和健康的證據，在生長激素中還沒有得到如此深入的記錄。

So, the question with the growth hormone combination, there are a few of them. One would be, is this something that's achievable over time. Secondarily, do we see mechanisms that accelerate bone age. Do we see those. You won't see those in the first six months. So we'll want to, as a, I think as a field, we'll want to see additional data before the story is written as to whether that combination will add anything significant for patients with achondroplasia.

因此，關於生長激素組合的問題，有幾個。其中一個問題是，這是否可以隨著時間的推移而實現。其次，我們是否看到了加速骨齡的機制。我們看到那些了嗎？在前六個月你不會看到這些。因此，我認為，作為一個領域，我們希望在撰寫報告之前看到更多數據，以確定這種組合是否會為軟骨發育不全患者帶來任何重大益處。

That's helpful. Thank you, Greg.

這很有幫助。謝謝你，格雷格。

Salveen Richter, Goldman Sachs

薩爾文·里克特，高盛

Thanks for taking our question. This is [Tommy] on for Salveen. Just on the VOXZOGO guidance, which was slightly adjusted, could you lay out the contributions of the various factors if you think about ex-US order timing, demand, and your US expansion initiatives? Thank you.

感謝您回答我們的問題。我是 Salveen 的 [Tommy]。僅就略微調整過的 VOXZOGO 指導而言，如果您考慮美國以外的訂單時間、需求和美國擴張計劃，您能否列出各種因素的貢獻？謝謝。

Yeah, thank you so much for the question, Tommy. So as we had mentioned, we are expecting higher revenues in the second half relative to the first half of the quarter. And really when we think about it throughout the quarter, this is primarily due to some of the shifting of large OUS orders that we see -- that we expected later in the quarter that'll shift out a little bit. Some into the beginning of 2026 as well, which will therefore kind of bring down the number a little bit.

是的，非常感謝你的提問，湯米。正如我們所提到的，我們預計下半年的收入將高於上半年。實際上，當我們思考整個季度的情況時，這主要是由於我們看到的一些大型 OUS 訂單發生了變化——我們預計本季度後期這些訂單會略有變化。有些也會持續到 2026 年初，因此這會使數字稍微下降。

Not to mention, we are coming closer with only five months to go in the year. And we just have a much better sense of kind of what we're trending toward and what we can forecast throughout the year. So what we did, as you see, is we brought down the top end of the range from $950 to $935, but I want to emphasize that that still represents 25% year over year growth.

更不用說，今年只剩下五個月的時間了。我們對未來的發展趨勢以及全年的預測有了更好的了解。因此，如您所見，我們所做的就是將價格範圍的上限從 950 美元降至 935 美元，但我想強調的是，這仍然代表著同比增長 25%。

Jessica Fye, JPMorgan

潔西卡費伊（Jessica Fye），摩根大通

Hello. This is Adam on for Jess. Thank you for taking our question. I just wanted to ask, can you walk us through when we should expect the next updates from the ITC proceedings? Thank you.

你好。這是亞當為傑西表演的。感謝您回答我們的問題。我只是想問一下，您能否告訴我們何時可以期待 ITC 訴訟的下一次更新？謝謝。

Yes, thanks very much for the question. With regard to the ITC update, we're expecting that has been publicly communicated that we're going to see the initial determination on the beginning of June, actually June 8, 2026. And then a completion date, the target date for the completion of the investigation, the ITC, of October 8, 2026. So, those are the time frames that have been publicly communicated. There is a possibility of a summary determination for that time, but these are very much what has been communicated by the ITC at this point.

是的，非常感謝您的提問。關於 ITC 的更新，我們預計已公開宣布我們將在 6 月初（實際上是 2026 年 6 月 8 日）看到初步裁決。然後是完成日期，即 ITC 完成調查的目標日期，即 2026 年 10 月 8 日。所以，這些都是已經公開傳達的時間框架。屆時有可能做出簡易裁定，但目前 ITC 所傳達的訊息基本上都是這些。

Akash Tewari, Jefferies.

Akash Tewari，傑富瑞。

Hey, thanks so much. Can you just give us a little more detail about the design of that 333 superiority trial? Because when I look at the VOXZOGO Phase 3, you had about 55 patients per arm. You're 90% power to get a 1.75% average growth velocity delta.

嘿，非常感謝。您能否向我們詳細介紹一下 333 優效性試驗的設計？因為當我查看 VOXZOGO 第 3 階段時，每組大約有 55 名患者。您有 90% 的力量來獲得 1.75% 的平均成長速度增量。

I feel like if you have the same powering per arm and you're going for superiority, you're probably looking at like a 0.8 to 1 centimeter improvement between 333 and VOXZOGO for that trial to hit on superiority. Is that the right way to think about efficacy? And like what gives you the confidence you can do that?

我覺得如果每隻手臂的力量相同並且想要獲得優勢，那麼你可能會看到 333 和 VOXZOGO 之間有 0.8 到 1 厘米的改進，以便在試驗中獲得優勢。這是思考功效的正確方式嗎？是什麼讓您有信心做到這一點？

And then maybe number two, can you talk about the potential to pursue maybe beyond weekly dosing with the profile that you showed in healthy volunteers? Thank you.

然後也許第二個問題，您能否談談根據您在健康志願者身上展示的情況，是否可能在每週劑量之外進行研究？謝謝。

Thanks, Akash. Just dissecting your questions one by one. From the standpoint of the Phase 3 study, we're not going to go into details on powering today, but we do have confidence that this is biologically a very reasonable hypothesis to test.

謝謝，阿卡什。只是逐一剖析你的問題。從第三階段研究的角度來看，我們今天不會詳細討論動力問題，但我們確實有信心，從生物學角度來看，這是一個非常合理的假設。

Of course we have the preclinical data and the mice where again in terms of attributable growth, we were able to almost double the amount of skeletal growth that we saw in those models using the kind of doses with BMN 333 that we've now been able to show, at least in a single dose study are safe in humans.

當然，我們有臨床前數據，就可歸因生長而言，我們能夠使使用 BMN 333 劑量的小鼠模型中的骨骼生長量幾乎翻倍，我們現在能夠證明，至少在單劑量研究中，它對人類是安全的。

Similarly, we've mentioned the human genetic data on the safety side. We also know that those individuals born with activating mutations in the pathway, they grow quite substantially, almost to 7 feet tall or farther. But finally, if we look at the available data that's published for another long-acting CNP agent, marching upwards to the highest dose, there is proportionately an increasing amount of growth at each step along the way. By being able to then, in our minds, continue that curve upwards with increased exposure, we feel we confidently have the right molecule to test that hypothesis with BMN 333.

同樣，我們在安全方面提到了人類基因數據。我們也知道，那些出生時通路中發生激活突變的個體，他們的身高會長得相當高，幾乎可以達到 7 英尺或更高。但最後，如果我們查看針對另一種長效 CNP 藥物發布的可用數據，並逐步提高到最高劑量，則會發現沿途每一步的增長量都在成比例地增加。然後，在我們的腦海中，隨著暴露量的增加，這條曲線繼續向上延伸，我們感覺到我們有信心找到正確的分子來用 BMN 333 來檢驗這個假設。

I'll just add that, we have -- we mentioned we're in our sixth cohort right now. We've completed five, and two of them have met our criteria. So again, we feel like we have on the PK side quite a bit of headroom and feeling very good about the results that we've seen.

我只想補充一點，我們提過，我們現在已經是第六批了。我們已經完成了五個，其中兩個符合我們的標準。因此，我們再次感覺到我們在 PK 方面有相當大的發展空間，並且對我們所看到的結果感到非常滿意。

With regard to the amount of attributable growth that we're going to look for in the comparative effectiveness study, what I would add is that we certainly have talked to patients, we've talked to physicians, we've talked to their caregivers. And again, we've come up with an amount that we think again would be meaningfully differentiated in the marketplace. And I would be remiss if I didn't add that this, while this is a story where we talk about growth and talk about the number of centimeters, we also want to pull through too, of course, the markers of health and wellness. Spinal stenosis, of course, is something that we're following very closely.

關於我們將在比較有效性研究中尋找的可歸因增長量，我想補充的是，我們當然已經與患者、醫生和他們的護理人員進行了交談。我們再次提出了一個數額，我們認為這個數額在市場上將具有顯著的差異化。如果我不補充這一點，那我就太失職了，雖然這是一個我們談論成長和厘米數的故事，但我們當然也希望實現健康和保健的標誌。當然，脊椎狹窄症是我們正在密切關注的。

The additional skeletal facial morphometry studies, all of those we would be measuring and we would hope to see meaningful improvements in the quality of life of these patients -- these individuals who have this condition.

我們將對額外的骨骼面部形態測量研究進行測量，並希望看到這些患有這種疾病的患者的生活品質得到有意義的改善。

So you know with that regard, we'll be sharing more information over time on the study design. I'll just simply add that from -- as you can extrapolate from some of the AUC comments I made, we would have the opportunity, if desired, to consider less frequent intervals than weekly. The question becomes which parameter do you want to prioritize? And for us, increasing efficacy, increasing the ability to drive health and wellness in the patients is what we're prioritizing at this point.

因此，您知道，在這方面，我們將隨著時間的推移分享更多有關研究設計的資訊。我只是簡單地補充一點——正如您可以從我所做的一些 AUC 評論中推斷的那樣，如果願意的話，我們將有機會考慮比每週更少的間隔。問題變成了您想要優先考慮哪個參數？對我們來說，提高療效、增強促進患者健康和保健的能力是我們目前的首要任務。

Joseph Schwartz, Leerink Partners.

Leerink Partners 的 Joseph Schwartz。

Hi, I'm Joori Park dialing in for Joe. Thank you for taking our questions. I know you're working on BMN 333 with the goal to launch in 2030. But in the meantime, how predictive is your low discontinuation rates for VOXZOGO in an environment where there is no competition? How do you think about the discontinuation rates when there are other options, including once weekly or once daily or a pull prior to the availability of BMN 333?

大家好，我是喬裡‧帕克 (Joori Park)。感謝您回答我們的問題。我知道您正在研究 BMN 333，目標是在 2030 年發射。但同時，在沒有競爭的環境中，您對 VOXZOGO 的低停產率的預測有多大？當有其他選擇時，您如何看待停藥率，包括每週一次或每天一次或在 BMN 333 上市前提貨？

Yeah, thank you so much for the question. This is Cristin Hubbard from Commercial. And just to speak to the adherence rates that we know today, we continue to see that the vast majority of children that are on therapy really do adhere to their daily dosing. And this is true across the globe. And we are really expecting that many of the new initiatives that we've started will continue to ensure this high compliance going forward.

是的，非常感謝您的提問。我是商業部門的克莉絲汀·哈伯德。就我們今天所知的依從率而言，我們繼續看到絕大多數接受治療的兒童確實堅持每日服藥。全球範圍內都是如此。我們真誠地期望，我們啟動的許多新措施將繼續確保未來的高合規性。

Now I will say that this is something that we've invested in in terms of patient support programming. We think it is incredibly important that patients do adhere to their therapy, and so we've definitely put some support programming in place that will aim at driving adherence and really ensuring that we have an improved experience, in particular in some of those more high-risk populations. We're truly seeing strong results in terms of adherence.

現在我要說的是，這是我們在患者支持計劃方面所投資的。我們認為患者堅持治療非常重要，因此我們確實制定了一些支持計劃，旨在提高依從性並真正確保我們獲得更好的體驗，特別是在一些高風險人群中。我們確實在堅持方面看到了顯著的成果。

And I do think that this is something that is one of BioMarin's core strengths at large across our portfolio. It's truly about finding patients through diagnostic efforts. It's about starting patients on treatment. And then importantly, it is really important that we keep patients on therapy because we know this is the most important thing for long-term outcomes. That's what we're investing in and continue to do so.

我確實認為這是 BioMarin 整個產品組合的核心優勢之一。這實際上是透過診斷努力來尋找患者。這是關於開始對患者進行治療。然後重要的是，讓患者繼續接受治療非常重要，因為我們知道這對長期結果來說是最重要的。這就是我們正在投資並將繼續投資的領域。

Shawn Lemon, Morgan Stanley.

摩根士丹利的肖恩·萊蒙。

Good afternoon, everyone, and thank you for taking my question. Hope everyone's well. Just thinking a little forward to your $4 billion revenue aspirations in 2027, I think it is. Just wondering how important other indications for VOXZOGO are to that and what sort of contribution do you think they might make. And, even going beyond hypochondroplasia, indications such as Noonan and Turner, when might we expect those? Thank you.

大家下午好，謝謝大家回答我的問題。希望大家一切安好。只是稍微展望一下您在 2027 年實現 40 億美元收入的願望，我認為是的。只是想知道 VOXZOGO 的其他適應症對此有多重要，以及您認為它們可能會做出什麼樣的貢獻。而且，甚至超越軟骨發育不良的範疇，出現像努南和特納這樣的症狀，我們什麼時候可以期待這些症狀呢？謝謝。

Hi Sean, this is Brian Mueller. Thanks for the question. I'll take that one. So first, some remarks on the $4 billion dollar revenue target in 2027. Given the many developments since we unveiled our new corporate strategy and 2027 guidance of $4 billion last year, we are taking a full account of the latest information and plan to provide an update on our 2027 revenue guidance and our long-term targets by the end of this year.

你好，肖恩，我是布萊恩穆勒。謝謝你的提問。我要那個。首先，我想談談 2027 年 40 億美元的營收目標。鑑於自去年我們公佈新的公司戰略和 2027 年 40 億美元目標以來取得的諸多進展，我們正在充分考慮最新信息，併計劃在今年年底前提供有關 2027 年收入目標和長期目標的最新信息。

So, stay tuned on that. We will revert shortly. I would answer the other part of your question that in the previous guidance, hypochondroplasia was the only indication expansion for VOXZOGO that was launching in that 2027 window so that there's a modest contribution from hypochondroplasia in that original number. Thank you.

因此，請繼續關注。我們將很快恢復。我想回答你問題的另一部分，在先前的指南中，軟骨發育不良是 VOXZOGO 的唯一適應症擴展，它將在 2027 年窗口期推出，因此軟骨發育不良在原始數字中佔有適度的貢獻。謝謝。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

Thank you for taking my questions. I also will ask about the 333 program. So Greg, you said that now you already dosed the six cohorts. What are your thoughts when you're going to the patient population? Is the aim to maintain area under the curve over 3 times, any upper limit you will be looking for regarding the safety?

感謝您回答我的問題。我也會詢問有關 333 計劃的問題。格雷格，你說現在已經給六個隊列下藥了。當您走向患者群體時，您有什麼想法？目標是將曲線下面積維持在 3 倍以上，對於安全性，您會尋求任何上限嗎？

And then, if you can remind us, the VOXZOGO low dose, high dose, what was the area under the curve comparison? We do understand the CMAX could be very different. But when you look at the area under the curve, what was the difference between the low dose and the high dose of VOXZOGO?

然後，如果您可以提醒我們，VOXZOGO 低劑量、高劑量的曲線下面積比較是多少？我們確實知道 CMAX 可能會大不相同。但是當您查看曲線下的面積時，VOXZOGO 的低劑量和高劑量之間有什麼區別？

Thanks, Gena. And let me take those in order. With regard to the data we have in hand for 333, we feel that it's going to give us a totality of evidence that'll allow us to pick, relatively speaking, a low, a medium, and a high dose. At least several of those will be, again, at this 3x or above is what we're anticipating. Picking those final doses will require us to finish the study and do the formal pharmacokinetic analysis.

謝謝，吉娜。讓我按順序來處理它們。關於我們掌握的 333 數據，我們認為它將為我們提供全面的證據，讓我們能夠相對選擇低劑量、中劑量和高劑量。我們預計其中至少有幾個將達到 3 倍或更高。選擇最終劑量需要我們完成研究並進行正式的藥物動力學分析。

As we mentioned, this sixth cohort, while recruited, hasn't completed in terms of its data collection. So that is ongoing. And with regard to the original VOXZOGO studies, the AUCs, because the half-life was 30 minutes to 60 minutes, as you note, the calculations of the AUC in terms of precision, we don't have a whole lot of confidence that comparing the 15 to the 30, for example, is going to give us all that meaningful data.

正如我們所提到的，第六批人員雖然已經招募，但資料收集工作尚未完成。這仍在進行中。至於原始 VOXZOGO 研究的 AUC，因為半衰期為 30 分鐘到 60 分鐘，正如您所說，就 AUC 的精確度而言，我們不太相信將 15 與 30 進行比較會為我們帶來所有有意義的數據。

But those numbers were much lower than the AUCs that we're seeing with the long-acting, which has a half-life on the order of days instead of a half-life on the order of minutes, in the 30 to 60 minutes. Beyond that, I can't give you any more details in terms of the numerics, but if you have any specific questions afterwards, I'll be happy to follow up with you offline.

但這些數字比我們在長效藥物中看到的 AUC 低得多，長效藥物的半衰期以天為單位，而不是以分鐘為單位，在 30 到 60 分鐘內。除此之外，我無法向您提供有關數字的更多細節，但如果您之後有任何具體問題，我很樂意離線跟進您。

Ellie Merle, UBS.

瑞銀的艾莉·梅爾（Ellie Merle）。

Hey, this is Jasmine on for Elle. Thanks so much for taking your question. Just another one on 333, trying to understand what the 3 times greater AUC reading means. From your preclinical work, can you give any more color on what this level of CNP exposure translates to in terms of growth?

嘿，我是 Elle 節目中的 Jasmine。非常感謝您回答這個問題。這只是 333 上的另一個，試圖理解 3 倍更大的 AUC 讀數意味著什麼。從您的臨床前工作來看，您能否進一步說明這種程度的 CNP 暴露對生長有何影響？

And then secondly, given the data that you've now seen, how does this impact your thinking on prioritizing 333 versus VOXZOGO for other growth disorders going forward? Thanks.

其次，根據您現在看到的數據，這對您今後在其他生長障礙治療中優先使用 333 還是 VOXZOGO 有何影響？謝謝。

Thanks for the question. With regard to the 3x growth, at least from a numeric standpoint, the preclinical model is probably the best, because again, there's a case where actually we were able to recapitulate this sort of increase in exposure.

謝謝你的提問。對於 3 倍的成長，至少從數字的角度來看，臨床前模型可能是最好的，因為再次，實際上我們能夠重現這種暴露的增加。

So the control animals were treated with a very healthy dose of VOXZOGO. And again, all of the growth that that could deliver, followed by increasing titrating doses of 333. And what we saw was at roughly what we're projecting are a 3x margin compared to, again, what's been published for other long-acting programs, that we were able to unlock additional growth.

因此，對照組動物接受了非常健康劑量的 VOXZOGO 治療。再次，所有可能的增長，隨後是 333 的滴定劑量的增加。我們看到的是，與其他長效項目相比，我們預期的利潤率大約是 3 倍，我們能夠釋放額外的成長。

And so the 3x again is what we see as a meaningful difference in exposure compared to what was seen before. And in the animal models again, we know that there's additional growth there. The question's going to be just how much is there.

因此，我們再次看到 3 倍與之前相比曝光度有顯著差異。而我們再次在動物模型中發現那裡有額外的生長。問題只是有多少。

What we know for sure is that we have what we believe to be the right agent in hand to test that hypothesis. We believe that we're going to be able to test multiple doses at that threshold or higher in the dose ranging Phase 2. And that before certainly the initiation of the comparative effectiveness study, we're going to have a good handle on how much growth is there to be at.

我們可以肯定的是，我們手中有我們認為正確的試劑來檢驗這個假設。我們相信，我們將能夠在第 2 階段的劑量範圍內測試該閾值或更高的多劑量。在開始比較有效性研究之前，我們將很好地掌握成長幅度。

That being said, it is an unanswered question. The preclinical, the genetic, and the data from other long-acting CNPs can only get us so far. And so having the right agent to test is the next step. And we're thrilled to be moving forward.

話雖如此，這仍是一個尚未解答的問題。臨床前、遺傳學和其他長效 CNP 的數據只能幫助我們到目前為止。因此，下一步就是找到合適的代理進行測試。我們很高興能夠繼續前進。

We're excited about 333 beyond just achondroplasia. We're putting together our hypochondroplasia plan as we speak. All of the additional indications do require us to do a dose ranging study, so doing that as quickly as possible is the key to unlock that.

我們對 333 的興奮不僅僅在於軟骨發育不全。我們正在製定軟骨發育不良症治療計劃。所有其他適應症都要求我們進行劑量範圍研究，因此盡快進行研究是解決這個問題的關鍵。

And again, having that arrow in our quiver is also going to allow us to think about additional indications where we might want a best-in-class long-acting CNP agent. And again, that's what we're hopeful that we have in BMN 333.

再次強調，有了這支箭，我們就可以考慮其他適應症，在這些適應症中我們可能需要一流的長效 CNP 藥物。再次強調，這正是我們對 BMN 333 所抱持的希望。

Olivia Brayer, Cantor Fitzgerald.

奧莉維亞·布雷爾，費茲傑拉領唱者。

Hey, good afternoon, guys. Thank you for the question. Can you give us an update on where you are with the citizen petition? Have you had any back-and-forth dialogue with the agency. And maybe just any comments on how confident you are that there will be action taken by the FDA here?

嘿，大家下午好。謝謝你的提問。您能否向我們介紹一下公民請願活動的進展？您是否與該機構進行過反覆對話？您是否對 FDA 採取行動的信心有多大？

And then just wanted to follow up on some of the comments made around the long-term guidance metrics. Is there something in particular that you're waiting to hear about before having better visibility into what those numbers could look like? Thank you.

然後只是想跟進一些關於長期指導指標的評論。在更好地了解這些數字可能會是什麼樣子之前，您是否在等待了解一些特別的事情？謝謝。

Thanks very much for the questions. I'll take the first one. This is Alexander. So with regards to the citizen petition, we have submitted that to the FDA. The FDA is, during the review process for the competing molecule, with regard to determining the validity of our orphan drug mentioned.

非常感謝您的提問。我要第一個。這是亞歷山大。因此，關於公民請願，我們已經將其提交給 FDA。FDA 在對競爭分子進行審查的過程中，正在確定我們提到的孤兒藥的有效性。

So we do not expect to hear anything from the FDA until the PDUFA. As you know, that is November 30. So that's all the information we have to share right now on the situation with regard to the petition. Now I'll hand it over to Brian to handle the second part of your question.

因此，在 PDUFA 頒布之前，我們預計不會收到 FDA 的任何消息。如你所知，那是 11 月 30 日。這就是我們現在要分享的有關請願書情況的所有資訊。現在我將把時間交給 Brian 來處理您問題的第二部分。

Yeah, thanks, Olivia. Well, on the $4 billion in 2027, there's not a specific event that we're waiting to pass before we give that updated view. It really is just working through our collective refreshed view across everything that's changed over the last year.

是的，謝謝，奧莉維亞。嗯，關於 2027 年的 40 億美元，我們並沒有等待某個特定事件發生後再給予更新的觀點。這實際上只是透過我們對過去一年發生的所有變化的集體更新的看法來實現的。

There's puts and takes. We're considering recent trends and market research across our portfolio. We've completed the enzyme acquisition this quarter. And of course, the VOXZOGO IP litigation is still ongoing. So, we're working through that and once we do, we'll share the perspective.

有得有失。我們正在考慮我們投資組合的最新趨勢和市場研究。我們本季完成了酵素的收購。當然，VOXZOGO 智慧財產權訴訟仍在進行中。所以，我們正在努力解決這個問題，一旦解決，我們就會分享觀點。

Kostas Biliouris, BMO Capital Markets.

Kostas Biliouris，BMO 資本市場。

Thanks for taking our question and congrats on the progress. Maybe some more color on some comments you made earlier. On the 3x difference between AUC, can you please clarify how exactly you performed the comparison? Was it 3x-- at least 3X across doses you compared or only in the highest dose or only in some doses?

感謝您回答我們的問題，並祝賀取得的進展。也許您之前所做的一些評論會更加詳細。關於 AUC 之間的 3 倍差異，您能否澄清一下您究竟是如何進行比較的？您比較的劑量是 3 倍——至少 3 倍，還是僅比較最高劑量或僅比較某些劑量？

And the follow-up is on Cmax. Does Cmax matter at all here, maybe for safety or efficacy, and how does your Cmax compare with TransCon CNP? Thank you.

後續研究關注的是 Cmax。Cmax 在這裡重要嗎，也許是為了安全性或功效，以及您的 Cmax 與 TransCon CNP 相比如何？謝謝。

Thanks for the question. With regard to the ongoing study, just to repeat something I said that I might have gone through too quickly, we've completed and analyzed five escalation cohorts. It's a healthy volunteer single dose study. And two of those cohorts already have met our AUC criteria of being greater than 3x.

謝謝你的提問。關於正在進行的研究，我只是想重複我可能說得太快了的事情，我們已經完成並分析了五個升級隊列。這是一項健康志願者單劑量研究。其中兩個群組已經滿足我們的 AUC 標準，即大於 3 倍。

That is greater than 3x the AUC, which is published in. And we put the reference in our slides for the other long-acting CNP agent that's been discussed. From that standpoint, again, we have a sixth cohort that's running right now. All of these have been avoiding the kind of CMAX ranges where with VOXZOGO, we knew that we started to see a very predictable effect on the vasculature, which was a drop in blood pressure and some tachycardia in patients.

比發表的 AUC 大 3 倍。我們在幻燈片中加入了對已討論過的其他長效 CNP 藥物的參考。從這個角度來看，我們現在有第六個佇列正在運行。所有這些都避免了 CMAX 範圍，使用 VOXZOGO 時，我們知道我們開始看到對血管非常可預測的影響，即患者血壓下降和心動過速。

That is Cmax that is well understood from the preclinical models and from our own experience, and we're still almost tenfold away from that with regard to what we're seeing. Nothing is for free, and of course as your AUC goes up, so does your Cmax. And so from that standpoint, the Cmax, we predict, will be greater than the other long-acting CNP out there.

這是從臨床前模型和我們自己的經驗中很好理解的 Cmax，但就我們所看到的而言，我們距離這個數字還有近十倍的差距。沒有什麼是免費的，當然隨著您的 AUC 上升，您的 Cmax 也會上升。因此，從這個角度來看，我們預測 Cmax 將高於其他長效 CNP。

The question is, is that problematic? And so far it has not been problematic. We're moving forward, and again this is why we will, in patients, do a dose ranging of a high, medium, and low. That's a relative term, but a high, medium, and low dose of BMN 333 moving forward in order to test not only what kind of growth and effects on health and wellness that we can see, but also to make sure that that is safe in those patients.

問題是，這有問題嗎？到目前為止還沒有出現問題。我們正在不斷進步，這就是為什麼我們會對患者進行高、中、低劑量範圍的治療。這是一個相對術語，但 BMN 333 的高、中、低劑量正在繼續推進，不僅是為了測試我們能夠看到什麼樣的增長和對健康和保健的影響，也是為了確保這些患者是安全的。

Jason Gerberry, Bank of America.

美國銀行的 Jason Gerberry。

Hey guys. Thanks for taking my question. Wanted to follow up on the HCH opportunity and the commentary about getting to the patient earlier. I guess we observed with ACH or achondroplasia that getting the below five indication was really key commercially in a number of geographies. And with HCH, at least in the prior Phase 2 work, I think the average age was about six years of age or enrollment criteria is three years.

嘿，大家好。感謝您回答我的問題。想要跟進 HCH 機會和有關更早接觸患者的評論。我想，我們觀察到，對於 ACH 或軟骨發育不全症來說，在許多地區獲得以下五種指徵在商業上確實很關鍵。對於 HCH，至少在之前的第 2 階段工作中，我認為平均年齡約為 6 歲，或入學標準為 3 歲。

So I just wonder, given it's a milder disease, the motivation to treat and sort of the risk, I guess from a patient perspective, that they're going to come on later in life and may not get the sort of lifetime benefit that they see in HCH. So just wondering if you can maybe expound upon some of those efforts and how you see that evolving. Thanks.

所以我只是想知道，鑑於這是一種較輕微的疾病，治療的動力和風險，我想從患者的角度來看，他們會在以後的生活中發病，並且可能無法獲得他們在 HCH 中看到的那種終生益處。所以我只是想了解一下您是否可以闡述其中的一些努力以及您如何看待這些努力的發展。謝謝。

So I'll start. Thank you very much for the question, Jason. And so I'll start a little bit about the opportunity because you're absolutely right that these patients do tend to get diagnosed later. It doesn't mean that there isn't a large unmet need in these patients. And I'd mention a little bit on the prepared remarks. And that is that you have comorbidities that we see, disproportionality, being a big one, macrocephaly, ENT issues, and musculoskeletal issues.

那我就開始了。非常感謝您的提問，傑森。因此，我將稍微談一下這個機會，因為您說得完全正確，這些患者確實往往會在較晚的時候才得到診斷。這並不意味著這些患者沒有大量未滿足的需求。我想稍微提一下準備好的發言稿。那就是，我們看到你有合併症，不成比例，這是一個很大的問題，大頭畸形，耳鼻喉問題和肌肉骨骼問題。

And what we know is that, as we see in achondroplasia, the earlier that you can treat patients, the better. And so we are very focused on leveraging much of our relationships, our infrastructure to ensure that we are educating on the unmet need that is here in hypochondroplasia, and importantly, that we can encourage diagnosis as soon as possible.

我們知道，正如我們在軟骨發育不全症中所看到的那樣，越早治療患者，效果就越好。因此，我們非常注重利用我們的大量關係和基礎設施來確保我們能夠對軟骨發育不全症中尚未滿足的需求進行教育，更重要的是，我們可以鼓勵盡快進行診斷。

Given that this is both clinically and genetically a heterogeneous condition, it's important that we educate on the importance of diagnosis. And that's precisely what we are focused on now as we await the Phase 3 data.

鑑於這在臨床和遺傳上都是一種異質性疾病，我們必須教育人們了解診斷的重要性。這正是我們在等待第三階段數據時所關注的。

Yeah. And I would just add that the study is for ages 3 to 18. So again, given the current state of diagnosis, we believe again that will serve a good number of patients. There is an infant study that's ongoing as well that will need to continue to enroll, and that will be delivering its data at a later time point.

是的。我還要補充一點，這項研究針對的是 3 歲至 18 歲的人。因此，鑑於目前的診斷狀況，我們再次相信這將為大量患者提供幫助。還有一項正在進行的嬰兒研究需要繼續招募，並將在稍後的時間點提供其數據。

But the bigger question that you bring up is again making sure that we do our part to not only measure but also report to the world the healthcare burdens that these patients and their families are experiencing. And we began that process. We published some abstracts, continuing to do work again, healthcare utilization, resources required by countries in order to care for these folks.

但您提出的更大問題是，再次確保我們盡自己的一份力量，不僅衡量而且向世界報告這些患者及其家人正在經歷的醫療負擔。我們開始了這個過程。我們發表了一些摘要，繼續開展工作，醫療保健利用，以及各國照顧這些人所需的資源。

But that will be an important part of the process here to continue to again create not only a data set and the label, but also an urgency to treat based on what these patients are experiencing in the real world.

但這將是此處流程的重要部分，不僅要繼續創建資料集和標籤，還要根據這些患者在現實世界中的經驗來緊急治療。

Alex Hammond, Wolfe Research.

沃爾夫研究公司的亞歷克斯·哈蒙德。

Thanks for taking my question. Just a few on VOXZOGO. So BioMarin has mentioned investing more in clinical coordinators to reduce the time needed to see a specialist. What's the average time from prescription that we're seeing currently and where do you aspire to be? And then on increasing prescribed referrals from pediatricians to endocrinologists, how is that strategy progressing?

感謝您回答我的問題。VOXZOGO 上只有少數。因此，BioMarin 提到要增加對臨床協調員的投資，以減少看專科醫生所需的時間。我們目前看到的處方平均耗時是多少？您希望達到什麼水準？那麼，關於增加兒科醫生向內分泌科醫生的處方轉診，該策略進展如何？

Yeah. Thank you very much for the question. And I can say that what we are focused on is certainly reducing the time it takes from diagnosis to get patients on treatment, which can take on the order of months to do. I do want to give a little bit of color in terms of where we're seeing the growth right now, which I think is really important. And where we saw -- again we saw strong uptake that continued into the second quarter. And what we saw is that this was especially in our youngest patients.

是的。非常感謝您的提問。我可以說，我們關注的重點肯定是縮短從診斷到患者接受治療所需的時間，這可能需要數月的時間。我確實想就我們目前看到的成長情況給出一些說明，我認為這非常重要。我們再次看到強勁的成長勢頭，並且這種勢頭持續到了第二季。我們發現，這種情況尤其發生在我們最年輕的患者身上。

So our biggest cohort that grew in the quarter over quarter was 0- to 2-year-olds. And this is really important because this is expected to be the only approved treatment in this age group. But we also saw strong growth in the 2- to 4-year-olds. And I think that this is really important because we're out there really trying to emphasize the importance and this is true when we saw the consensus guidelines as well in terms of early treatment so that we can ensure the maximum benefit of the therapy.

因此，我們本季成長最快的族群是 0 至 2 歲的兒童。這非常重要，因為這有望成為該年齡層中唯一獲批准的治療方法。但我們也看到2至4歲兒童的強勁成長。我認為這一點非常重要，因為我們確實在努力強調其重要性，當我們看到早期治療的共識指南時也是如此，這樣我們才能確保治療的最大益處。

Now in terms of how we are driving, as you've mentioned, referrals from pediatricians into treaters, whether those be pediatric endocrinologists primarily but also geneticists, that has been a successful strategy so far. We are seeing many of those new initiatives that are really taking place and taking off. And that was in part where we saw the growth being driven in the second quarter. So we expect that to continue over the quarters to come.

現在就我們如何推動而言，正如您所提到的，將兒科醫生的轉診給治療師，無論主要是兒科內分泌學家還是遺傳學家，到目前為止這都是一個成功的策略。我們看到許多新措施正在真正實施並取得進展。這在一定程度上是我們在第二季度看到的成長動力。因此我們預計這種情況在未來幾季將持續下去。

And what we saw is when we look at the treater base in terms of where we're seeing growth in treaters, it's actually happening across all treater types. So we're seeing growth in geneticists, in endocrinologists, and in pediatricians. So we're very happy with the results so far and anticipate continued investment in these areas.

我們看到，當我們從治療師數量增長的角度來觀察治療師群體時，所有類型的治療師都在出現這種增長。因此，我們看到遺傳學家、內分泌學家和兒科醫生的數量正在增加。因此，我們對目前的結果非常滿意，並期待繼續在這些領域進行投資。

Ellen Horste, TD Cowen.

艾倫·霍斯特（Ellen Horste），考恩（Cowen）TD。

Thanks for hearing my question and congrats on the exciting quarter. Regarding BMN 401, I'm wondering what success looks like for the ENERGY 3 trial, including potential functional endpoints that might be required for approval outside the US. And then if you can remind us how many patients have been identified so far and what's involved with identifying the 2,000 to 2,500 prevalence you estimate in your territory. Thanks.

感謝您聽取我的問題，並祝賀本季取得如此令人振奮的成績。關於 BMN 401，我想知道 ENERGY 3 試驗的成功程度如何，包括可能需要在美國境外獲得批准的潛在功能終點。然後，您能否提醒我們，到目前為止已經確認了多少名患者，以及確認您所在地區估計的 2,000 到 2,500 名患病者需要做些什麼。謝謝。

This is Greg Freiberg. Just taking that first question first. With the 401 card that's turning over. For those who aren't as familiar, this is the ENERGY 3 study. So this is in the children. And as opposed to infants or adolescents and adults, we'll be turning the card over in the first half of next year.

我是格雷格‧弗賴伯格。先回答第一個問題。隨著 401 卡的翻轉。對於那些不太熟悉的人來說，這是 ENERGY 3 研究。這就是孩子們的情況。與嬰兒、青少年和成年人相比，我們將在明年上半年翻開卡片。

And the success has two categories here. Those have been mortalized as co-primary endpoints in Europe, as you noted. And those are not only normalizing the pyrophosphate levels, which is a sign again of biochemical normalization, but also functional endpoints. And in this case it's the radiologic index that's noted -- that again is looking at the quality of bone in these children that still have their growth plates open.

這裡的成功分為兩類。正如您所說，這些在歐洲已被視為共同主要終點。這些不僅使焦磷酸鹽水平正常化，這再次表明生化正常化，而且也是功能終點。在這種情況下，要注意放射學指數——再次觀察這些兒童的骨骼質量，因為這些兒童的生長板仍然開放。

We have clear agreements with the Europeans as to what those functionality endpoints mean. And we're continuing to work with the FDA and other regulators to work through, again, the details of those. But it is a combination of both pyrophosphate as well as functional endpoints, as you point out.

我們與歐洲人就這些功能端點的含義達成了明確的協議。我們將繼續與 FDA 和其他監管機構合作，再次解決這些問題的細節。但正如您所指出的，它是焦磷酸鹽和功能終點的組合。

And we'll be measuring pain and some others in the protocol as well, but that's what's been agreed upon with the European regulators. To answer the second question, with regard to the number of patients, I'm going to hand it off to Cristin.

我們還將在協議中測量疼痛和其他一些因素，但這是與歐洲監管機構達成的一致意見。回答第二個問題，關於患者人數，我將把它交給克莉絲汀。

Thanks so much, Greg. So as you referred to, you're absolutely right in that in terms of the overall target patient population, addressable patient population, we do estimate that the range will be on the order of 2,000 to 2,500 patients.

非常感謝，格雷格。正如您所說，您說得完全正確，就總體目標患者群體、可尋址患者群體而言，我們確實估計該範圍將在 2,000 到 2,500 名患者左右。

Now I want to be very clear that the literature on this is very disparate and there's very high ranges. This is our current estimate in terms of what we believe the prevalence to be, as well as our ability to ensure that we get diagnosis of these patients.

現在我想非常清楚地表明，關於這方面的文獻非常多樣化，而且範圍非常廣。這是我們目前對盛行率的估計，以及我們確保對這些患者進行診斷的能力。

Now Inozyme had already identified over 600 patients. And we are carrying on much of the work that they were doing as we've taken this on. And they have had great work and great success in building KOL networks that have been highly successful in finding these patients. But we believe that we can expand on that.

目前，Inozyme 已識別出超過 600 名患者。我們在接手這項工作的同時，也繼續進行他們之前所做的大部分工作。他們在建立 KOL 網路方面做出了巨大努力並取得了巨大成功，這些網路在尋找這些患者方面非常成功。但我們相信我們可以進一步擴大這一點。

Again, going back to it being a core strength of ours, and that is investing in diagnostic efforts to ensure that we're diagnosing and finding these patients. It's also really useful that this will slot right into our enzyme therapy business unit where it's highly complementary to the relationships and the established networks that we have today.

再次回到我們的核心優勢，那就是投資診斷工作以確保我們能夠診斷並找到這些患者。這也非常有用，因為它可以直接融入我們的酵素療法業務部門，與我們今天擁有的關係和已建立的網絡高度互補。

So the specialties that we now treat ENPP1 deficiency are certainly include, but are not limited to, the treaters that we already call on. And that would be geneticists and endocrinologists. So we're very much leveraging our infrastructure and networks therein to ensure that we can properly find these patients and then hopefully, should the data turn out to be positive, get these patients on therapy as soon as possible.

因此，我們現在治療 ENPP1 缺乏症的專科當然包括但不限於我們已經聯繫過的治療師。那就是遺傳學家和內分泌學家。因此，我們充分利用我們的基礎設施和網絡，以確保我們能夠正確找到這些患者，然後希望，如果數據結果是積極的，這些患者能夠盡快接受治療。

Alison Bratzel, Piper Sandler.

艾莉森‧布拉澤爾，派珀‧桑德勒。

Good afternoon and thanks for taking the question. Another one on BMN 333. Just a clarification. And I'm sorry if I missed it, but can you help us better understand what exactly is gating to initiation of the dose ranging portion of the registration trial?

下午好，感謝您回答這個問題。BMN 333 上還有另一個。只是澄清一下。如果我錯過了，我很抱歉，但是您能否幫助我們更好地理解註冊試驗的劑量範圍部分啟動的門控到底是什麼？

And I think you've received FDA alignment for the Phase 2/3 plans, but could you just talk to your confidence in achieving regulatory alignment ex-US and timing there? Thank you.

我認為您已經獲得了 FDA 對第 2/3 階段計劃的批准，但您能否談談您對在美國以外實現監管批准和時間表的信心？謝謝。

Thanks for the question, and I'm very excited to share that we have regulatory alignment with multiple players around the globe at this point. And so the gating factor is, of course, completion of the current Phase 1 study. It's very typical for healthy volunteer studies actually to study doses sometimes that are higher than what you'd study, again giving you some PK buffer in Phase 2. And in that regard, having that complete data set is a requirement before we move forward.

感謝您的提問，我很高興地告訴大家，我們目前已經與全球多家企業達成了監管共識。因此，關鍵因素當然是完成目前第一階段的研究。對於健康志願者研究來說，研究劑量有時實際上會高於您所研究的劑量，這很典型，這再次為您在第 2 階段提供一些 PK 緩衝。在這方面，擁有完整的資料集是我們繼續前進的必要條件。

I'll also add though that we are moving very quickly. We're in the midst of protocol, not only writing, but we're very far along in that process. And really the next steps will be to initiate the study in the first half of next year. So if there is a gating factor, it's completion of the sixth cohort of the PK profile. But that is more of a formality in order to be able to again convince regulators and patients that again we have the data set in hand to justify moving forward in all of the doses that we've proposed. So more to come, but in that regard we're thrilled to be able to be moving to this next step for the dose ranging of 333.

我還要補充一點，我們的進展非常快。我們正在製定協議，不僅是寫作，而且我們已經在這個過程中走了很遠。下一步實際上是在明年上半年啟動這項研究。因此，如果存在一個限制因素，那就是完成 PK 概況的第六個隊列。但這更多的是一種形式，為了能夠再次讓監管機構和患者相信，我們手中有數據集，可以證明我們提出的所有劑量都是合理的。因此還有更多內容，但在這方面，我們很高興能夠進入下一步，劑量範圍為 333。

And that concludes the Q&A portion of today's call. I will now turn it back to BioMarin's President and CEO Alexander Hardy.

今天電話會議的問答部分到此結束。現在我將把話題交還給 BioMarin 總裁兼執行長亞歷山大哈迪 (Alexander Hardy)。

Thank you, operator, and thank you all again for joining us today. We're proud of the strong execution in the first half of this year, energized by the opportunities ahead.

謝謝接線員，再次感謝大家今天加入我們。我們為今年上半年的強勁執行力感到自豪，並為未來的機會注入活力。

Continued momentum across our commercial pipeline business development efforts. We believe BioMarin is well positioned to deliver significant value creation, patients, employees, and our shareholders through the remainder of 2025 and beyond. We look forward to updating you on our progress in the quarters to come. Thank you very much.

我們的商業管道業務發展努力持續保持強勁勢頭。我們相信，BioMarin 已做好準備，在 2025 年剩餘時間及以後為患者、員工和股東創造巨大價值。我們期待在未來幾季向您通報我們的進展。非常感謝。

And this concludes today's conference call. Thank you for your participation. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連線。