BioMarin Pharmaceutical Inc (BMRN) 2024 Q4 法說會逐字稿

Ladies and gentlemen, thank you for standing by and welcome to the BioMarin Pharmaceuticals fourth quarter and full year's 2024 conference call. (Operator Instructions)

女士們，先生們，感謝大家的支持，歡迎參加 BioMarin Pharmaceuticals 2024 年第四季和全年電話會議。（操作員指令）

As a reminder, today's call is being recorded. I will now hand today's call over to Traci McCarty, Group Vice President, Investor Relations. Please go ahead.

提醒一下，今天的通話正在錄音。現在，我將今天的電話會議交給投資者關係集團副總裁 Traci McCarty。請繼續。

Thank you, operator. To remind you, this non-confidential presentation contains forward-looking statements about the business prospects of BioMarin's Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development.

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。

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. In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today.

結果可能會因 BioMarin 產品計劃的進展、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（例如 10-Q、10-K 和 8-K 報告）中詳述的因素而存在重大差異。此外，我們將在今天的電話會議中使用 G 規則中定義的非 GAAP 財務指標。

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 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.

這些非公認會計準則指標不應被孤立地視為根據美國公認會計準則編制的財務指標的替代品或優於這些指標，您可以在收益報告和收益介紹中找到與美國公認會計準則相關的對賬，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重點放在非公認會計準則財務指標。

On the call from BioMarin management today are Alexander Hardy, President and Chief Executive Officer; Brian Mueller, Chief Financial Officer; Cristin Hubbard, Chief Commercial Officer; and Greg Friberg, Chief R&D Officer. I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

今天參加 BioMarin 管理層電話會議的有總裁兼執行長亞歷山大哈迪 (Alexander Hardy)； Brian Mueller，財務長；克里斯汀‧哈伯德 (Cristin Hubbard)，首席商務官；以及首席研發長 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, Tracy, and good afternoon, everyone.

謝謝你，特蕾西，大家下午好。

Thank you for joining us today for our fourth-quarter 2024 results update. We are pleased to see BioMarin's new strategic vision starting to be realized, amplifying our financial performance, and creating value for shareholders, and most importantly, making a profound impact on the patients we serve.

感謝您今天加入我們的 2024 年第四季業績更新。我們很高興看到 BioMarin 的新策略願景開始實現，擴大了我們的財務業績，為股東創造了價值，最重要的是，對我們服務的患者產生了深遠的影響。

The specific initiatives introduced throughout 2024 include the prioritization of our most promising pipeline candidates, the reorganization of BioMarin's operating model now centered around business units, and the ongoing realization of the $500 million cost transformation program.

2024 年推出的具體舉措包括優先考慮我們最有前景的候選藥物、重組 BioMarin 以業務部門為中心的營運模式，以及持續實現 5 億美元的成本轉型計劃。

Combined, these initiatives give us a framework to achieve our ambitious need and long-term growth outlook. We are already producing positive results.

這些舉措共同為我們提供了實現雄心勃勃的需求和長期成長前景的框架。我們已取得了積極的成果。

Starting with our financial performance, 2024 was a year of record growth and profitability. We are pleased to share that full year 2024 exceeded market expectations across our guided items. Year over year, topline grew 18%. Non-GAAP operating margin expanded over 900 basis points, and non-GAAP diluted earnings per share increased 69%.

從我們的財務表現開始，2024 年是創紀錄的成長和獲利的一年。我們很高興地宣布，2024 年全年所有指導項目的表現都超出了市場預期。與去年同期相比，營業額成長了 18%。非公認會計準則營業利益率擴大超過 900 個基點，非公認會計準則每股稀釋收益成長 69%。

This financial strength puts us on the path of double-digit revenue growth in 2025 and enables our ongoing reinvestment in further innovation and growth.

這種財務實力使我們預計在 2025 年實現兩位數的收入成長，並使我們能夠持續對進一步的創新和成長進行再投資。

Our confidence is supported by BioMarin's increasingly profitable commercial portfolio. Leadership across skeletal conditions is anchored to global expansion, VOXZOGO for achondroplasia, which grew 56% year over year with plans to expand into hypochondroplasia in 2027, as well as four additional skeletal conditions should data be supportive.

BioMarin 日益盈利的商業組合增強了我們的信心。在骨骼疾病領域的領導地位依賴全球擴張，VOXZOGO 治療軟骨發育不全，年成長 56%，計畫在 2027 年擴展到軟骨發育不全症領域，另外如果數據支持，還將擴展到四種其他骨骼疾病領域。

Strengthened from our enzyme therapies, growing at 9% in the fourth quarter, year over year and now approaching $2 billion annual revenues, gives us confidence in our long-term outlook, high single digit CAGR on this business unit.

由於我們的酵素療法，第四季同比增長 9%，目前年收入接近 20 億美元，這讓我們對長期前景充滿信心，該業務部門的複合年增長率高達個位數。

The strategic prioritization of our pipeline last year resulted in the advancement BMN 351 for Duchenne Muscular Dystrophy; BMN 333, a long-acting CNP, two candidates that may provide highly differentiated treatment options for the conditions they address. We look forward to early clinical data results later this year for both candidates.

我們去年對產品線進行了策略優先排序，取得了用於治療杜氏肌肉營養不良症的 BMN 351 的進展； BMN 333 是一種長效 CNP，兩種候選藥物可能針對其針對的病症提供高度差異化的治療選擇。我們期待今年稍後獲得兩位候選人的早期臨床數據結果。

This year we plan to share results from our Phase 3 study with PALYNZIQ for adolescents. This potential age expansion represents an opportunity to provide 12- to 17-year-olds significant and sustained feed response, as well as unrestricted diet should data be supportive.

今年，我們計劃與 PALYNZIQ 分享針對青少年的第三階段研究的結果。這種潛在的年齡擴展代表著為 12 至 17 歲的青少年提供顯著且持續的進食反應以及不受限制的飲食的機會（如果數據支持的話）。

In summary, we're excited by the progress we're making at BioMarin. The strategic and operational decisions made last year yielding tangible results and allowing us to make an even greater impact for our patients, our employees, and our shareholders.

總而言之，我們對 BioMarin 的進展感到非常興奮。去年做出的策略和營運決策取得了切實的成果，並使我們能夠為患者、員工和股東帶來更大的影響。

Looking ahead in 2025, we expect to share clinical data from three of our advancing programs, drive double-digit global revenue growth, execute on our business development strategy, continue our journey towards delivering the mid- and long-term financial outlook provided at Investor Day last year.

展望 2025 年，我們希望分享我們三個推進項目的臨床數據，推動全球收入實現兩位數增長，執行我們的業務發展戰略，繼續朝著實現去年投資者日提供的中長期財務展望的目標邁進。

I would like to thank our employees around the world for their contributions in 2024. Look forward to the progress we will make together in 2025.

我要感謝我們全球員工在 2024 年所做的貢獻。期待2025年我們共同進步。

Thank you for your attention. I will now turn the call over to Brian to provide an overview of our financial highlights for the quarter.

感謝您的關注。現在，我將把電話轉給 Brian，讓他概述本季的財務亮點。

Thank you, Alexander. Please refer to today's press release for detailed fourth-quarter and full-year 2024 results, including reconciliations of GAAP to non-GAAP financial measures. All 2024 results will be available in our upcoming Form 10-K, 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 2024 年第四季和全年的詳細業績，包括 GAAP 與非 GAAP 財務指標的對帳。所有 2024 年的結果將在我們即將發布的 10-K 表中公佈，我們預計將在未來幾天提交該表格。

We are very pleased with BioMarin's execution in 2024, especially during a year of significant transformation.

我們對 BioMarin 在 2024 年的執行情況非常滿意，尤其是在重大轉型的一年。

Full-year total revenues grew 18% to $2.85 billion and set the stage for record results in 2025. Fourth quarter 2024 revenues increased 16% year over year to $747 million. Double-digit increases from VOXZOGO were a strong contributor to growth in the fourth quarter and full year.

全年總收入成長 18% 至 28.5 億美元，為 2025 年創紀錄的業績奠定了基礎。2024 年第四季營收年增 16% 至 7.47 億美元。兩位數VOXZOGO的成長對第四季和全年的成長起到了強勁推動作用。

Also contributing to record results in 2024, the enzyme therapy business totaled over $1.9 billion for the full year, a 12% increase versus the full year 2023, with consistent growth across BioMarin's marketed brands.

酵素療法業務全年總額超過 19 億美元，較 2023 年全年增長 12%，這也為 2024 年創下的業績做出了貢獻，BioMarin 旗下各品牌均實現了持續增長。

Moving to expenses for the full year 2024, non-GAAP R&D expense was slightly higher compared to the full year 2023, primarily due to spending on development of VOXZOGO and five new indications offset by a reduction in spend for deprioritized programs.

轉向 2024 年全年費用，非 GAAP 研發費用與 2023 年全年相比略高，主要原因是對 VOXZOGO 和五種新適應症的開發支出，但優先項目支出的減少抵消了這一影響。

In the fourth quarter of 2024, non-GAAP R&D expense was $159 million and lower compared to the same quarter in 2023, as the impact of discontinued programs was fully realized during the fourth quarter.

2024 年第四季度，非 GAAP 研發費用為 1.59 億美元，低於 2023 年同期，因為停止的專案的影響在第四季度已完全實現。

We expect that R&D expense will increase in 2025, as we ramp up our BMN 351, BMN 333, and VOXZOGO indication expansion studies.

我們預計，隨著我們增加 BMN 351、BMN 333 和 VOXZOGO 適應症擴展研究的力度，2025 年的研發費用將會增加。

For both the full year and fourth quarter of 2024, non-GAAP SG&A expense increased year over year, primarily due to a bad debt reserve, higher VOXZOGO commercialization expenses, and costs associated with our ERP implementation, partially offset by lower ROCTAVIAN spending.

2024 年全年和第四季度，非 GAAP 銷售、一般及行政開支同比增加，主要原因是壞帳準備金、VOXZOGO 商業化費用增加以及與我們的 ERP 實施相關的成本，但 ROCTAVIAN 支出減少部分抵消了這一影響。

Moving to profitability, we are pleased with the positive impact of BioMarin's strong revenue performance coupled with the ongoing progress of our cost transformation program outlined last year. As a result of this momentum, non-GAAP operating margin reached 28.6% for the full year 2024, an increase of 9.2 percentage points versus the full year 2023.

談到獲利能力，我們對 BioMarin 強勁的收入表現和我們去年概述的成本轉型計劃的持續進展產生的積極影響感到滿意。由於這股勢頭，2024 年全年非 GAAP 營業利潤率達到 28.6%，較 2023 年全年增長 9.2 個百分點。

Fourth quarter, non-GAAP operating margin of 31.1% was boosted by the benefit from the cost transformation initiatives, lower R&D spend related to discontinued programs, and profitability leverage from our strong revenue growth.

第四季度，非公認會計準則營業利潤率為 31.1%，這得益於成本轉型措施、與停止專案相關的研發支出降低以及強勁的收入成長所帶來的獲利能力槓桿。

In addition to significant revenue growth in 2024, BioMarin achieved its 2024 objective of accelerating profitability growth at meaningful and sustainable levels. On a full year, non-GAAP diluted earnings per share increased 69% to $3.52 and our Q4 non-GAAP diluted earnings per share increased 88% to $0.92.

除了 2024 年營收大幅成長外，BioMarin 還實現了 2024 年目標，即以有意義和可持續的水平加速獲利成長。全年來看，非 GAAP 稀釋每股盈餘成長 69% 至 3.52 美元，第四季非 GAAP 稀釋每股盈餘成長 88% 至 0.92 美元。

BioMarin's increasing profitability is also generating significant levels of operating cash flow, with $573 million of operating cash flow for the full year 2024, a 260% increase over the full year 2023, and further puts BioMarin on track to achieve our target of greater than $1.25 billion of operating cash flow in 2027.

BioMarin 不斷提高的盈利能力也產生了大量的營運現金流，2024 年全年經營現金流為 5.73 億美元，比 2023 年全年增長 260%，這也使 BioMarin 預計將實現 2027 年經營現金流超過 12.5 億美元的目標。

BioMarin's ability to generate meaningful, positive cash flows is a key enabler of our top capital allocation priority of investing in long-term revenue growth, both through our internal research and development investments and external innovation through our business development strategy.

BioMarin 產生有意義的正現金流的能力是我們首要資本配置重點投資於長期收入成長的關鍵因素，這包括透過內部研發投資和透過業務發展策略進行的外部創新。

Turning to our 2025 outlook and full year 2025 total revenues, we expect between $3.1 billion and $3.2 billion of total BioMarin revenue, which represents 10% growth compared to 2024. In 2025, strong growth is expected from VOXZOGO, VIMIZIM, PALYNZIQ, and BRINEURA, and we expect the majority of year-over-year revenue growth in the second half of the year, as growth in the business in the first half of the year translates to an increased revenue base in the second half of the year.

談到我們的 2025 年展望和 2025 年全年總收入，我們預計 BioMarin 的總收入將在 31 億美元至 32 億美元之間，與 2024 年相比成長 10%。2025 年，VOXZOGO、VIMIZIM、PALYNZIQ 和 BRINEURA 預計將實現強勁成長，我們預計大部分同比營收成長將出現在下半年，因為上半年業務的成長意味著下半年營收基數的增加。

In 2024, the enzyme therapy business benefited from unusually high ALDURAZYME contributions in the third quarter. Similarly, the NAGLAZYME demonstrated very strong growth and benefited from new patient additions as well as order timing.

2024年，酵素療法業務受惠於第三季異常高的ALDURAZYME貢獻。同樣，NAGLAZYME 也表現出非常強勁的成長勢頭，並受益於新患者的增加以及訂單時機的把握。

Due to these unique dynamics, we expect lower year-over-year growth rates for NAGLAZYME and ALDURAZYME in 2025.

由於這些獨特的動態，我們預計 2025 年 NAGLAZYME 和 ALDURAZYME 的年成長率將會下降。

Importantly, BioMarin's 2024 revenue performance and the expected growth in 2025 keep us on track for achieving our target of $4 billion of total revenues in 2027.

重要的是，BioMarin 2024 年的營收表現和 2025 年的預期成長使我們有望實現 2027 年 40 億美元總收入的目標。

VOXZOGO is expected to be a strong contributor to full-year 2025 total revenue growth, and we estimate it will contribute between $900 million and $950 million to 2025 total revenue.

VOXZOGO 預計將成為 2025 年全年總收入成長的強勁貢獻者，我們估計它將為 2025 年的總收入貢獻 9 億至 9.5 億美元。

Well, we are not changing our overall guidance structure of only guiding the total revenue. These directional insights are meant to provide a framework to align your expectations with ours.

嗯，我們不會改變僅指導總收入的整體指導結構。這些方向性的見解旨在提供一個框架，以使您的期望與我們的期望保持一致。

Moving to non-GAAP operating margin for the full year 2025, we are guiding to between 32% and 33%, which represents 3.9 percentage points of expansion at the midpoint versus the 2024 non-GAAP operating margin of 28.6%. Our guidance is supported by continued strong revenue growth along with the impact of the ongoing cost transformation initiatives.

對於 2025 年全年的非 GAAP 營業利潤率，我們預計在 32% 至 33% 之間，與 2024 年非 GAAP 營業利潤率 28.6% 相比，中間值增長 3.9 個百分點。持續強勁的收入成長以及持續的成本轉型措施的影響為我們的指引提供了支持。

While noting that 2025 also represents an important investment here for critical activities in our prioritized pipeline and sales and marketing to enable our long-term growth profile, based on the continued implementation of these activities in 2025, this is an important steppingstone towards the achievement of our target 40% non-GAAP operating margin next year.

雖然我們注意到 2025 年也是對我們優先考慮的產品線和銷售與行銷中的關鍵活動的一項重要投資，以實現我們的長期成長前景，但基於 2025 年這些活動的持續實施，這是實現我們明年 40% 非 GAAP 營業利潤率目標的重要基石。

Finally, for non-GAAP diluted earnings per share, we expect between $4.20-$4.40 per share for the full year 2025, which at the midpoint represents a two times topline growth rate over 2024, driving towards another expected year of leveraged profitability growth for BioMarin.

最後，對於非 GAAP 稀釋每股收益，我們預計 2025 年全年每股收益將在 4.20 美元至 4.40 美元之間，中間值代表 2024 年營收成長率的兩倍，推動 BioMarin 迎來另一個預期槓桿盈利增長的年份。

Building on our strong execution in 2024, we expect continued high performance as we benefit from BioMarin's revamped corporate strategy and operating model in 2025 and beyond.

基於我們在 2024 年的強勁執行力，我們預計將繼續保持優異的業績，因為我們將受益於 BioMarin 在 2025 年及以後改進的公司策略和營運模式。

I will now pass the call to Cristin to discuss the drivers of our commercial performance. Cristin?

現在我將把電話轉給克里斯汀，討論我們商業表現的驅動因素。克里斯汀？

Thank you, Brian. The team delivered strong growth in 2024, led by the continued global expansion of VOXZOGO, increasing PALYNZIQ penetration, and demand for enzyme replacement products, and we expect 2025 to build on this momentum.

謝謝你，布萊恩。該團隊在 2024 年實現了強勁成長，這得益於 VOXZOGO 的持續全球擴張、PALYNZIQ 滲透率的提高以及對酵素替代產品的需求，我們預計 2025 年將延續這一勢頭。

Record VOXZOGO results and 56% year-over-year growth for the full year were driven by strong demand globally, with a significant number of new patient starts in infants and young children.

VOXZOGO 創紀錄的業績和全年 56% 的同比增長得益於全球強勁的需求，其中大量嬰幼兒新患者開始接受治療。

In the United States, the expanding prescriber base and strong demand from families with children in the 0- to 5-year-old age cohort drove increased growth in 2024. Consistent with prior quarters, the majority of new patients starts in the US were for infants and young children under 5 years of age.

在美國，不斷擴大的處方基礎和 0 至 5 歲兒童家庭的強勁需求推動了 2024 年的成長。與前幾季一致，美國大多數新患者都是 5 歲以下的嬰兒和幼兒。

In international markets, we also saw significant VOXZOGO year-over-year growth throughout 2024. In deeply penetrated markets such as Germany, we focused on early diagnosis and treatment of the incident population.

在國際市場，我們也看到 VOXZOGO 在 2024 年同比增長顯著。在德國等深度滲透的市場，我們專注於發病人群的早期診斷和治療。

In markets with significant expansion potential, we are leveraging BioMarin's robust global footprint and commercial infrastructure to drive awareness and adoption in the eligible patient population.

在具有巨大擴張潛力的市場中，我們正在利用 BioMarin 強大的全球影響力和商業基礎設施來推動符合條件的患者群體的認知和採用。

To provide insight into these global dynamics, today we are providing the percentage of actual total VOXZOGO revenues split between the US and the combined contributions from outside the US or OUS.

為了深入了解這些全球動態，今天我們提供了 VOXZOGO 實際總收入在美國和美國或 OUS 以外地區的綜合貢獻中的分配百分比。

For full year 2024, of VOXZOGO total revenue of $735 million, 24% was from the US, and 76% was from all countries outside of the US.

2024 年全年，VOXZOGO 總收入為 7.35 億美元，其中 24% 來自美國，76% 來自美國以外的所有國家。

For fourth quarter 2024, of VOXZOGO total revenue of $208 million, 26% was from the US and 74% was from OUS.

2024 年第四季度，VOXZOGO 總營收為 2.08 億美元，其中 26% 來自美國，74% 來自 OUS。

Now moving to expansion strategies in 2025. In the United States, we look forward to realizing the growth opportunity ahead and building on the momentum of our growing prescriber base and continued demand from families with infants and younger children based on VOXZOGO's proven safety and efficacy profile.

現在轉向2025年的擴張策略。在美國，我們期待實現未來的成長機會，並基於 VOXZOGO 經過驗證的安全性和有效性，繼續保持不斷增長的處方基礎和嬰兒及幼兒家庭持續需求的勢頭。

Outside of the US and in our larger strategic markets such as Germany and Japan, we will continue to focus on early diagnosis and treatment of the incident population to drive treatment with VOXZOGO from infancy to provide maximum therapeutic benefits.

在美國以外以及在德國和日本等我們更大的戰略市場，我們將繼續專注於發病人群的早期診斷和治療，以推動從嬰兒期開始使用 VOXZOGO 進行治療，以提供最大的治療效益。

Now turning to growth strategies in other international markets, we intend to more deeply penetrate countries where VOXZOGO is already available and include patient starts in new countries that are added this year. By 2027, we are focused on increasing VOXZOGO access to more than 60 countries.

現在轉向其他國際市場的成長策略，我們打算更深入滲透 VOXZOGO 已經在提供的國家，並包括今年增加的新國家的患者。到 2027 年，我們致力於將 VOXZOGO 的存取權限擴展到 60 多個國家。

To facilitate these growth plans, we are investing in commercialization efforts, including but not limited to increased field personnel to enhance the referral and prescriber base, additional platforms to broaden reach, and the introduction of new initiatives to raise awareness and adoption of VOXZOGO treatment.

為了促進這些成長計劃，我們正在投資商業化努力，包括但不限於增加現場人員以增強轉診和處方基礎、增加平台以擴大覆蓋範圍，以及推出新舉措以提高人們對 VOXZOGO 治療的認識和採用。

Further supporting our expansion efforts, we are very pleased to see two publications highlighting the importance of early VOXZOGO treatment. Recently published international guidelines recommend early diagnosis, followed by early VOXZOGO treatment.

為了進一步支持我們的擴展工作，我們很高興看到兩份出版物強調了早期 VOXZOGO 治療的重要性。最近發布的國際指南建議早期診斷，然後進行早期 VOXZOGO 治療。

These guidelines were independently created to facilitate maximum clinical benefits for children with achondroplasia and to provide families confidence when choosing VOXZOGO treatment for infants and young children with achondroplasia.

這些指南是獨立制定的，目的是為軟骨發育不全兒童提供最大的臨床益處，並讓家庭在為軟骨發育不全的嬰幼兒選擇 VOXZOGO 治療時充滿信心。

Also, as published in the December issue of MED, VOXZOGO is the only treatment for achondroplasia to have demonstrated a statistically significant improvement in proportionality versus an untreated control arm after three years of follow-up.

此外，正如《MED》雜誌 12 月號所發表的那樣，VOXZOGO 是唯一一種經過三年隨訪後與未治療的對照組相比在比例方面顯示出統計學上顯著改善的軟骨發育不全治療方法。

We are confident that this will be another year of strong execution and record growth for VOXZOGO, the only approved treatment for infants and children with achondroplasia. At the same time, we are using our experience in achondroplasia to prepare for the 2027 launch of VOXZOGO for the treatment of hypochondroplasia should Phase 3 data be supportive.

我們相信，對於唯一獲準治療嬰兒和兒童軟骨發育不全症的藥物 VOXZOGO 來說，這又將是強勁執行和創紀錄成長的一年。同時，我們正在利用我們在軟骨發育不全方面的經驗，為 2027 年推出 VOXZOGO 治療軟骨發育不全做準備，如果第 3 階段的數據支持的話。

The commercial and medical team are creating programs to raise awareness and increase the diagnosis of hypochondroplasia, so we will be ready to provide VOXZOGO to those interested in treatment upon potential approval.

商業和醫療團隊正在製定計劃，以提高人們對軟骨發育不全的認識並增加對軟骨發育不全的診斷，因此我們將準備在獲得批准後向有興趣接受治療的人提供 VOXZOGO。

Now moving over to our enzyme therapies, global demand drove strong results across all of BioMarin's marketed products. Double-digit PALYNZIQ revenue growth in the quarter was the result of substantial patient uptake in the US and ongoing expansion in Japan.

現在轉向我們的酵素療法，全球需求推動了 BioMarin 所有行銷產品取得強勁業績。本季 PALYNZIQ 營收實現兩位數成長，這得益於美國患者的大量使用和日本市場的持續擴張。

In addition, we saw significant year-over-year growth in NAGLAZYME, VIMIZIM, and BRINEURA during the quarter, enabled by our ongoing efforts to find new patients and maintain treatment continuity for those on therapy.

此外，本季我們看到 NAGLAZYME、VIMIZIM 和 BRINEURA 的銷售量較去年同期顯著成長，這得益於我們不斷努力尋找新患者並維持接受治療患者的治療連續性。

We continue to make progress in finding and starting new patients with our enzyme replacement therapies. For instance, we have seen considerable success in certain regions where we have expanded our gene panel testing programs to help diagnose patients with MPS and CLN2.

我們在尋找和開始為新患者提供酵素替代療法方面不斷取得進展。例如，我們在某些​​地區取得了相當大的成功，在這些地區我們擴大了基因面板測試計劃，以幫助診斷 MPS 和 CLN2 患者。

For example, in Brazil, these initiatives have resulted in an increase in new diagnoses, and we expect to roll out these programs into multiple countries over the coming quarters. They're moving to PALYNZIQ with its highly differentiated profile and that it works across all PKU phenotypes, growth has been driven by new patient starts and reinitiation of treatment from adults with PKU.

例如，在巴西，這些措施已導致新診斷病例增加，我們預計未來幾季將這些計畫推廣到多個國家。他們正在轉向 PALYNZIQ，因為它具有高度差異化的特徵並且適用於所有 PKU 表型，其增長主要由新患者的開始治療和 PKU 成人患者的重新開始治療所推動。

We are also excited that adolescents with PKU may soon have access to the only substitute enzyme therapy that can deliver normal fee in an unrestricted diet.

我們也很高興患有苯酮尿症的青少年很快就能獲得唯一能夠在不受限制的飲食下恢復正常飲食的替代酵素療法。

With Phase 3 data coming mid-year, we look forward to potentially submitting our applications in the US and Europe in the second half of this year.

隨著第三階段數據將在年中公佈，我們期待在今年下半年向美國和歐洲提交申請。

In conclusion, I am very pleased with the team's execution in 2024 during a year of transformation across the organization.

總而言之，我對團隊在 2024 年整個組織轉型之年的表現感到非常滿意。

The transition to defined business units is resulting in higher focus, accountability, and performance, and we are already seeing the benefits of this operating model. We have set the stage for greater performance in 2025 and are on course to achieve our target of $4 billion of total revenues in 2027.

向明確的業務部門轉變帶來了更高的關注度、責任感和績效，我們已經看到了這種營運模式的好處。我們已經為 2025 年取得更大成績奠定了基礎，並有望實現 2027 年總收入 40 億美元的目標。

Thank you for your attention, and I'll now turn the call over to Greg to provide an R&D update. Greg?

謝謝您的關注，現在我將電話轉給 Greg，讓他提供研發更新資訊。格雷格？

Thank you, Cristin. We're making great progress across our pipeline. Starting with BMN 333, recall that in nonhuman primates, we achieve sustained free CNP exposures several fold higher than those demonstrated for other long-acting CNP agents. Our goal for BMN 333 is therefore to leverage this potential for greater exposure to deliver superior efficacy while maintaining an acceptable safety profile.

謝謝你，克里斯汀。我們的整個管道項目正在取得巨大進展。從 BMN 333 開始，回想一下，在非人類靈長類動物中，我們實現的持續遊離 CNP 暴露比其他長效 CNP 藥物高出幾倍。因此，我們對 BMN 333 的目標是利用這種潛力來獲得更大的曝光度，以提供卓越的療效，同時保持可接受的安全性。

As of today, our PK study in healthy volunteers is well underway, and we look forward to sharing topline data from the study in the second half of the year, with detailed data to be presented at a scientific congress in the first half of 2026.

截至今天，我們針對健康志願者的 PK 研究正在順利進行中，我們期待在今年下半年分享該研究的頂線數據，並在 2026 年上半年的科學大會上公佈詳細數據。

For BMN 351 and Duchenne's Muscular Dystrophy, our Phase 1/2 study is advancing with enrollment and dosing in the 9 mg/kg cohort. As previously shared, six boys were treated at the 6 mg/kg level, and we are eagerly awaiting the 25-week proof-of-concept biopsy data for this cohort, which we expect to present to the scientific congress in the second half of this year.

對於 BMN 351 和杜氏肌肉營養不良症，我們的 1/2 期研究正在進行中，並正在進行 9 mg/kg 劑量組的招募和給藥。正如之前所分享的，六名男孩接受了 6 毫克/公斤水平的治療，我們正熱切地等待這群人的 25 週概念驗證活檢數據，我們預計將在今年下半年向科學大會提交這些數據。

We believe these 25-week data will give us a clear line of sight as to whether our target of 10% dystrophin levels will be achievable at steady state in this 6 mg/kg cohort.

我們相信這些 25 週的數據將讓我們清楚地了解在這個 6 mg/kg 群體中，我們是否能夠在穩定狀態下實現 10% 肌肉營養​​不良蛋白水平的目標。

With VOXZOGO in additional skeletal conditions, we continue to advance our CANOPY clinical programs, our pivotal Phase 3 study in hypochondroplasia is rapidly recruiting, and we remain on track to complete enrollment to the treatment arms of the study in the first half of 2025.

隨著 VOXZOGO 在其他骨骼疾病領域的應用，我們將繼續推進我們的 CANOPY 臨床項目，我們針對軟骨發育不全的關鍵性 3 期研究正在快速招募患者，我們仍有望在 2025 年上半年完成該研究治療部門的招募。

Pivotal data from that program will be available in 2026, and a potential approval could come in 2027, assuming that data are supportive.

該計劃的關鍵數據將於 2026 年公佈，如果數據支持，則可能在 2027 年獲得批准。

Our two Phase 2 CANOPY studies, one in idiopathic short stature, and another encompassing Noonan's syndrome, Turner syndrome, and SHOX deficiency are screening and enrolling patients.

我們的兩項 2 期 CANOPY 研究（一項針對特發性矮小症）正在篩選和招募患者，另一項涵蓋努南氏症候群、特納氏症和 SHOX 缺乏症。

Moving to PALYNZIQ, our Phase 3 study in adolescence, aged 12 to 17, is on track for data readout to support US and European supplemental filings in the second half of the year.

談到 PALYNZIQ，我們針對 12 至 17 歲青少年進行的第三階段研究正在按計劃讀取數據，以支持今年下半年美國和歐洲的補充申請。

Recall, PALYNZIQ works across all PKU phenotypes, delivering potent phenylalanine reduction and can even afford some patients the potential for an unrestricted diet. We believe that this filing for adolescents could allow for patients and their families to manage the challenge of PKU and dietary restrictions from an early age, thereby supporting a smoother transition to independent adult living.

回想一下，PALYNZIQ 適用於所有 PKU 表型，可有效減少苯丙胺酸，甚至可以讓一些患者享受不受限制的飲食。我們相信，這項針對青少年的申請可以讓患者及其家人從小就應對苯酮尿症和飲食限制的挑戰，從而支持更順利地過渡到獨立的成年生活。

Finally, with BMN 349, an oral therapeutic for Alpha-1 antitrypsin deficiency associated liver disease, we are progressing well, having dosed the first cohort in the multiple ascending dose portion of the healthy volunteer study.

最後，對於 BMN 349（一種治療 Alpha-1 抗胰蛋白酶缺乏症相關肝病的口服藥物），我們取得了良好的進展，已經在健康志願者研究的多次遞增劑量部分中對第一批患者進行了給藥。

Following last year's strategic prioritization of the pipeline, the R&D organization is really hitting its stride, advancing our most high impact candidates, and we look forward to keeping you updated on our progress in the coming quarters.

繼去年對產品線進行策略優先排序之後，研發部門正在大步前進，推進我們最具影響力的候選人，我們期待在未來幾季向您通報我們的進展。

Thank you for your continued support, and we now open the call to your questions. Operator?

感謝您一直以來的支持，現在我們開始回答您的問題。操作員？

(Operator Instructions) Philip Nadeau, TD Cowen.

(操作員指示) Philip Nadeau，TD Cowen。

Good afternoon. Thanks for taking our question. We went to zero in on the VOXZOGO guidance. We're firmly expected to be $200 million year over year. That's healthy, but it is decelerating. Can you talk a bit more on where you expect that growth to come from, and in particular which territories and where they're currently reimbursed or new reimbursement, it will be coming this year and maybe more generally on the pushes and pulls, on the guidance what could cause performance to be better and what could cause it to fall short. Thanks.

午安.感謝您回答我們的問題。我們將注意力集中在 VOXZOGO 指導上。我們堅定地預計今年的銷售額將達到 2 億美元。這是健康的，但是正在減速。您能否再多談談您預計成長來自哪裡，特別是在哪些地區、目前在哪些地區可以報銷或新增報銷，這些增長將在今年實現，也許更普遍地說是推動和拉動因素，指導什麼可能導致業績更好，什麼可能導致業績不佳。謝謝。

Hi, Phil. This is Brian. Thanks for the question. I'll start and then, ask Cristin to provide some more color. So in terms of the overall guide, you accurately pointed out that, like close to $200 million of absolute [dollar] growth. It's still strong growth. What we're observing here as VOXZOGO global revenue gets to scale at close to [$0.75 billion], that there's some law of large numbers at play here.

你好，菲爾。這是布萊恩。謝謝你的提問。我先開始，然後請克里斯汀提供更多顏色。因此就整體指南而言，您準確地指出，絕對成長接近 2 億美元。它仍然保持強勁增長。我們觀察到，VOXZOGO 的全球收入接近 7.5 億美元，這其中存在著一些大數定律。

VOXZOGO grew 56% in 2024, which was impressive, but not sustainable on this increasing revenue base. Just a reminder that the multi-year compound annual growth rate that we're targeting for skeletal conditions through the long-term guidance in 2027 is greater than 25%, and with the growth of 56% last year, 25% as implied by the VOXZOGO range that we provided today and continued growth in the, well, maybe, low 20% going forward. Again, the growth rate will decrease over time as the base increases. We are on track for both the $4 billion and the 25%-plus CAGR.

VOXZOGO 在 2024 年成長了 56%，這令人印象深刻，但在這種不斷增長的收入基礎上是不可持續的。需要提醒的是，我們透過 2027 年的長期指導目標實現的骨骼疾病多年複合年增長率將超過 25%，加上去年 56% 的增長率，我們今天提供的 VOXZOGO 範圍暗示了 25% 的增長率，並且未來將繼續增長，嗯，可能在 20% 以下。再次，隨著基數的增加，成長率將隨著時間的推移而下降。我們正朝著 40 億美元和 25% 以上的複合年增長率邁進。

Yeah, maybe I'll add to that. Thanks so much for the questions, Phil. So to give you a sense of the geographies where much of the growth is coming from, I would say, I'll call it certainly the US as our largest single market opportunity, and I'll dig into a little bit of what we're doing there and to drive continued growth.

是的，也許我會補充這一點。非常感謝您提出這些問題，菲爾。因此，為了讓您了解大部分成長來自哪些地區，我想說，我肯定會將美國稱為我們最大的單一市場機會，我將深入了解我們在那裡所做的工作以及推動持續成長的方式。

We've also seen continued strong growth in our highly penetrated markets, Germany being a clear standout that we saw in 2024 and anticipate well into 2025 and beyond. And in our international markets, we're seeing growth around the globe. One of the bigger drivers being Brazil, which again will continue into 2025.

我們也看到，在我們高度滲透的市場中，德國的成長勢頭十分強勁，我們在 2024 年看到了這一表現，並預計這一趨勢將持續到 2025 年及以後。在我們的國際市場上，我們看到全球範圍內的成長。其中一個更大的推動因素是巴西，這一趨勢也將持續到 2025 年。

So currently, we're in 47 geographies, where we have commercialization efforts ongoing and expect to expand into over 60 by 2027. But to give you a little bit of a sense of the US, so as we had mentioned, that's currently about 25% of the revenue contribution, and we anticipate that contribution to grow as we are putting a lot of energy and effort into it, given that it is such a large market opportunity for us.

目前，我們已涵蓋 47 個地區，並正在進行商業化工作，預計到 2027 年將擴展到 60 多個地區。但為了讓大家對美國有一點了解，正如我們所提到的，這目前約佔收入貢獻的 25%，而且我們預計這一貢獻將會增加，因為我們在其中投入了大量的精力和努力，因為這對我們來說是一個巨大的市場機會。

So just as a reminder, in the US, there was a bit of a delay in terms of the timing of when infants had access to drugs, so it was initially indicated for 5 years and older. And only in the end of 2023, did we get the expansion into the younger 0 to 5 population.

所以需要提醒的是，在美國，嬰兒獲得藥物的時間有點延遲，所以最初適用於 5 歲及以上的嬰兒。直到 2023 年底，我們才實現了 0 至 5 歲年輕人口的擴張。

So what we're really seeing a lot of growth coming out is in new patients starts in that 0 to 5 age cohort, which is really exciting because that's well in line with the international consensus guidelines that have recently come out where really the goal for all treaters should be to diagnose early and then immediately upon diagnosis, treat with VOXZOGO. So we're excited to see that growth in that younger population.

因此，我們真正看到的是 0 至 5 歲年齡組的新患者數量大幅增長，這確實令人興奮，因為這與最近出台的國際共識指南相一致，即所有治療者的目標應該是儘早診斷，然後在診斷後立即使用 VOXZOGO 進行治療。因此我們很高興看到年輕人口的成長。

In addition to that, we're definitely working on expanding our prescriber base. So we're seeing that the biggest expansion in terms of growth of prescribers is in the pediatric endocrinologist, which is exactly a target area for us. And so, what we're doing to continue those types of efforts is we're investing more in commercialization, namely, in our field personnel, so out there driving both reach as well as depth -- so breadth and depth.

除此之外，我們正在努力擴大我們的處方人員基礎。因此，我們看到，就處方人員成長而言，成長最快的是兒科內分泌科醫生，這正是我們的目標領域。因此，為了繼續這些努力，我們正在對商業化進行更多投資，即對我們的現場人員進行更多投資，從而推動影響力和深度——廣度和深度。

We're also investing in platforms where we can ensure that we're getting the information out there to broader populations, namely in the pediatrician community where we want to ensure that we can drive referral patterns back to treaters. And then we're leveraging, our continued footprint outside the US to build on this growth trajectory.

我們也對平台進行了投資，以確保我們能夠將訊息傳播給更廣泛的人群，特別是在兒科醫生社區，我們希望確保能夠將轉診模式回饋給治療者。然後，我們將利用我們在美國以外的持續影響力來鞏固這一成長軌跡。

So I'd say we're really focused not only in the US, but of course in some of our -- in our international markets, and we see a lot of wind behind our sails, in particular with both the international guidelines I've already mentioned and importantly our new BU model where we're really being able to drive that level of focus and accountability and do the right pushes and pulls as we see them.

所以我想說，我們真正關注的不僅僅是美國，當然還有我們的一些國際市場，我們看到了巨大的發展勢頭，特別是我已經提到的國際指導方針，以及更重要的我們新的業務單元模式，我們真正能夠推動這種程度的關注和問責，並根據我們看到的情況採取正確的推動和拉動措施。

Jessica Fye, JP Morgan.

傑西卡‧菲伊 (Jessica Fye)，摩根大通 (JP Morgan)。

Hey guys, good afternoon. Thanks for taking my question. I was wondering if you could spend a little more time talking about your priorities for business development. For example, should we think of BioMarin as more focused on bringing in pipeline assets versus commercial assets to leverage your global footprint and what's your appetite for clinical risk.

大家下午好。感謝您回答我的問題。我想知道您是否可以花多一點時間談談您的業務發展重點。例如，我們是否應該認為 BioMarin 更注重引入管道資產而不是商業資產，以利用您的全球影響力以及您對臨床風險的承受能力。

And maybe just a quick follow up anything you would call out quarter-over-quarter or year-over-year for the first quarter, in the enzyme business like any international ordering patterns to think about there. Thank you.

也許只是快速跟進第一季酵素業務中每季或每年發生的任何變化，例如任何需要考慮的國際訂購模式。謝謝。

Brian, do you want to start with the last question and then I'll handle business development?

布萊恩，你想先問最後一個問題，然後我來處理業務發展嗎？

Yeah. Of course. Thanks for the question, Jess.

是的。當然。謝謝你的提問，傑西。

I wouldn't point to specific known ordering patterns granted, we're just midway through the quarter here and, as you know, our diversified global business, especially across the different enzyme therapy brands, is subject to some of that. A large single payer, [bullish] order pattern dynamic from time to time. So nothing is specifically to point to there, but since you mentioned the quarters, I will point out, as I mentioned in the prepared remarks, we do expect our growth in 2025 to be weighted to the second half of the year.

我不會指出已知的具體訂購模式，我們正處於本季度的中期，而且如您所知，我們多元化的全球業務，特別是跨不同酶療法品牌的業務，都受到其中的一些影響。大型單一付款人，[看漲]訂單模式不時動態。因此沒有什麼特別指向那裡，但是既然你提到了季度，我要指出，正如我在準備好的評論中提到的那樣，我們確實預計 2025 年的增長將集中在下半年。

So whether it be the enzyme therapies or VOXZOGO, we're just ramping up on the ambitious plan that Cristin just talked about for 2025 here in the first part of the year, so we expect our growth to be weighted to the -- to Q3 and Q4. Thanks.

因此，無論是酵素療法還是 VOXZOGO，我們都在加快實施克里斯汀在今年上半年談到的 2025 年雄心勃勃的計劃，因此我們預計我們的成長將集中在第三季和第四季。謝謝。

Thanks, Brian. Hey Jess, thanks very much for the question. With regard to business development, yeah, we're very excited about the role that business development can play to add to what is already a pretty compelling work over the coming years.

謝謝，布萊恩。嘿，傑西，非常感謝你提問。關於業務發展，是的，我們對業務發展在未來幾年所能發揮的作用感到非常興奮，這將為我們已經非常引人注目的工作增添新的色彩。

Last year, as you know, it was about setting the strategy for the company and clarifying where we wanted to play in terms of the business development space, making sure we've got the right business development team in place, the capabilities in place, and then obviously, these strong financial results are producing more strategic flexibility for us.

如您所知，去年我們制定了公司策略，明確了我們在業務發展領域的定位，確保我們擁有合適的業務發展團隊和能力，顯然，強勁的財務表現為我們帶來了更多的戰略靈活性。

And, we're very excited about, what we're seeing from the business development standpoint. We -- the JPMorgan meeting -- we had 155 meetings at JPMorgan. It's a reflection of the recognition of the strengths of BioMarin from a research, development, manufacturing, and commercialization, and specifically on the commercialization, what we hear from potential partners is our ability to commercialize across the globe.

並且，我們對從業務發展角度看到的情況感到非常興奮。我們 — — 摩根大通會議 — — 我們在摩根大通舉行了 155 次會議。這反映了對 BioMarin 在研究、開發、製造和商業化方面優勢的認可，特別是在商業化方面，我們從潛在合作夥伴那裡聽說了我們在全球範圍內實現商業化的能力。

And we're now in the process of looking at these various assets. You asked what stage these assets are at. We're looking at a range of stages. We're looking at pre-clinical assets and also clinical assets. Again, we expect to be able to strengthen our outlook for growth into the -- into longer term.

我們現在正在審查這些不同的資產。你問這些資產處於什麼階段。我們正在研究一系列階段。我們正在研究臨床前資產和臨床資產。再次，我們希望能夠加強我們的長期成長前景。

Salveen Richter, Goldman Sachs.

高盛的薩爾文·里希特（Salveen Richter）。

Hi, thanks for taking your question and congrats on the progress. This is Tommy on for Salveen. Wondering if we can get your thoughts on the durability and safety of the growth hormone and CNP combo. Is this something that you may be interested in with 333? And just to follow up on 333, for the data, could you just frame what you're looking for and help us understand them, any metrics to guide the translation here to AGV and later studies. Thank you.

你好，感謝您的提問，並祝賀您的進展。這是 Salveen 的 Tommy。想知道您是否可以了解您對生長激素和 CNP 組合的耐用性和安全性的看法。您對 333 有興趣嗎？只是為了跟進 333，對於數據，您能否概括出您正在尋找的內容並幫助我們理解它們，是否有任何指標可以指導此處轉化為 AGV 和後續研究。謝謝。

Yeah, this is Greg Friberg. Thank you, Salveen. Let me take the second question first. So I believe your question was about the PK study with 333 and what we're expecting to see.

是的，這是 Greg Friberg。謝謝你，薩爾文。我先回答第二個問題。所以我相信您的問題是關於 333 的 PK 研究以及我們期望看到的結果。

Again, that is a healthy volunteer study. So what we're hoping to see is purely PK in that regard. We'll be looking at the native species of BMN 333 as well as free CNP, and we're hoping to see several fold increases in terms of reaching sustained levels similar to the cynomolgus monkey model that we were referring to.

再次強調，這是一項健康志願者研究。因此我們希望看到的是純粹的 PK。我們將研究 BMN 333 的本土物種以及遊離 CNP，我們希望看到數倍的增加，達到與我們所指的食蟹猴模型相似的持續水平。

We believe that several fold increases, whether it's an AUC or times above sustained threshold, but that'll give us a chance again to try to recapitulate what we've seen in the animal models, which is a significantly greater growth dynamic in their long bones. With regard to the first question, can you just repeat the question for me? My apologies. I missed the nuance of the first question.

我們認為，無論是 AUC 還是超過持續閾值的次數都會增加幾倍，但這將給我們再次機會嘗試重現我們在動物模型中看到的情況，即它們的長骨的生長動力顯著增強。關於第一個問題，您能再重複一次嗎？我很抱歉。我沒理解第一個問題的細微差別。

The growth hormone.

生長激素。

Thank you. With regard to the growth hormone combination, our goal is to develop a single agent CNP drug that delivers not only best-in-class growth for patients, but also the kind of convenience and safety that we think, that the market demands. In addition to the challenges of two high-priced therapies, we think that trying to optimize the agents that we have available to us are our goal. Certainly, as data evolves, we can, again, as we always do, re-evaluate that strategy, but as of now, our goal is to have a single agent therapy that's both convenient and efficacious for patients with achondroplasia.

謝謝。關於生長激素組合，我們的目標是開發單一藥物CNP藥物，不僅為患者提供一流的生長效果，還能提供我們認為的市場所需的便利性和安全性。除了兩種高價療法的挑戰之外，我們認為嘗試優化我們現有的藥物也是我們的目標。當然，隨著數據的發展，我們可以像往常一樣再次重新評估該策略，但截至目前，我們的目標是找到一種對軟骨發育不全患者既方便又有效的單一藥物治療方法。

Your next question is from the line of Coy Kaseov with Evercore ISI.

您的下一個問題來自 Evercore ISI 的 Coy Kaseov。

Hey, good afternoon, guys. Thanks for taking the question, Greg, maybe another one for you on the DMD program. I believe you've mentioned that steady state dystrophin levels and treated patients are attained at about the 1 year mark. So when you mentioned this 10% goal, is that your expectation for the week 25 biopsies or should they be somewhere below that?

嘿，大家下午好。感謝您回答這個問題，Greg，也許我還有一個關於 DMD 計劃的問題可以問您。我相信您已經提到過，接受治療的患者在約 1 年後即可達到穩定的肌肉營養不良蛋白水平。那麼，當您提到這個 10% 的目標時，這是您對第 25 週活檢的期望嗎？

Thank you.

謝謝。

Yeah, thanks for the question, and it's an important point to make. We, of course, we've picked a chemical backbone, a non-morphulinno backbone that has a slower in, slower efficacy, delivery.

是的，感謝您的提問，這是一個重要的觀點。當然，我們選擇了一種化學主鏈，一種非嗎啉主鏈，它的傳輸速度和功效都比較慢。

What that affords us is the opportunity again, to open a therapeutic window, which has been challenging in this space. We also engineered the molecule again to have some other factors that we think will cause significantly higher dystrophin expression once we reach steady state.

這為我們再次提供了機會，打開了一扇治療之窗，這在該領域一直是一個挑戰。我們也再次對分子進行了設計，使其具有一些其他因素，我們認為一旦達到穩定狀態，這些因素將導致肌肉營養不良蛋白的表達顯著提高。

The week 25 data will give us a line of sight. That's the word I would use for that. We have a very clear model of what success looks like, and that is something that again, we think that once we have data from multiple time points at the 25 week moment that we'll be able to have a pretty clear idea of what we're going to be seeing out of the year.

第 25 週的數據將為我們提供視線。這就是我要使用的字。我們有一個非常清晰的成功模型，我們認為，一旦我們獲得了 25 週內多個時間點的數據，我們就能非常清楚地了解這一年將會取得什麼成果。

Of course we would ultimately want to demonstrate that with actual data, but the 25 week time point is going to give us a very solid read on our model of where we're headed and whether we're able to reach that. I'll just add that there's one other nuance here. Which is we're talking about the 6 mg per kilogram dose level, and we are going up in the dose as well.

當然，我們最終希望用實際數據來證明這一點，但 25 週的時間點將為我們提供有關我們的模型的非常可靠的解讀，讓我們了解我們的發展方向以及我們是否能夠實現這一目標。我只想補充一點，這裡還有一個細微差別。也就是說，我們討論的是每公斤 6 毫克的劑量水平，而且我們也在增加劑量。

So we're in a 9 mg cohort right now and again there are opportunities potentially to go higher. This is a field where of course we we want the lowest efficacious dose to be the one that we bring forward, and we're hopeful again that 6 mg is going to be able to give us a very clear indication of whether we're on that track for 10% or not.

因此，我們現在處於 9 毫克的隊列，並且還存在進一步上升的機會。在這個領域，我們當然希望最低有效劑量是我們提出的劑量，我們再次希望 6 毫克能為我們提供非常明確的跡象，表明我們是否正在朝著 10% 的目標前進。

Christopher Raymond with Piper Sandler.

克里斯多福·雷蒙德和派珀·桑德勒。

Thanks. Two questions just on the ERT business, you guys have, I think for some time now talked about being able to select, sort of the demand higher on harmonizing diagnostic protocols, I think across all geographies.

謝謝。關於 ERT 業務的兩個問題，我認為你們已經討論了一段時間，能夠選擇，對協調診斷協議的需求更高，我認為在所有地區都是如此。

I know this print was helped along by some government buy-ins, and I heard you, Brian, on your commentary on '25 being sort of back and loaded in terms of growth, but Any sort of color you can give us to the mix of, contribution from this diagnostic harmonization, is this something that's, where are we, I guess, in terms of maybe which ending in terms of being able to affect that that change. And then on 351 data timing, maybe splitting hairs a bit, but the press release says data second half, the slides say mid-'25.

我知道這份印刷品得到了一些政府的支持，布萊恩，我聽到了你對 25 年在增長方面落後的評論，但你能給我們提供任何關於這種診斷協調的貢獻的詳細信息嗎？然後關於 351 數據的時間，可能有點吹毛求疵，但新聞稿上說的是後半部的數據，幻燈片上說的是 25 年中期的數據。

Is this, are you indicating maybe you'll be top lining the data in mid-'25 and then presenting the full data at a conference later, any sort of color that would be great. Thanks.

這是，您是否表示也許您會在 25 年中期對數據進行排序，然後在稍後的會議上展示完整的數據，任何一種顏色都會很棒。謝謝。

Yeah, this is Greg Freiber. Thanks. Just to clarify, it of course is the middle two quarters of the year.

是的，這是 Greg Freiber。謝謝。需要澄清的是，這當然是一年中間兩個季度。

So again, you can read into that what they're both correct statements. We will be presenting it publicly in totality at a at a scientific congress in the early second half of the year.

因此，您再一次可以看出，它們都是正確的陳述。我們將在今年下半年初的科學大會上公開展示它的全部內容。

And hi, Chris, this is Cristin Hubbard, and to answer your question a little bit about the kind of the diagnostic component, so broadly speaking, when we think about a lot of the efforts that are being put out in our new BU model in particular across enzyme therapies, we are most certainly in particular. For MPS and CLN2, really looking at various activities that we can run across, different countries in the world around really understanding what diagnostic tools we can put into certain countries and really help with the diagnosis of both NPS and CLN2.

嗨，克里斯，我是克里斯汀·哈伯德，我來回答一下你關於診斷組件類型的問題，廣義上講，當我們考慮到我們在新的 BU 模型中所做的大量努力，特別是在酶療法方面，我們肯定是特別的。對於 MPS 和 CLN2，真正研究我們可以遇到的各種活動，世界不同國家真正了解我們可以將哪些診斷工具應用到某些國家，並真正幫助診斷 NPS 和 CLN2。

So we've seen great progress already. We're using both gene panels. We're looking at cascade screening, which is basically looking at a family tree and seeing if there's MPS or CLN2 in the family tree, and ensuring that we're getting the right patients identified so that we can then help start to get them onto therapy. And so we've done this very successfully, for instance, in Brazil and anticipate we will continue to push on these efforts in a select subgroup of countries where we know that this could be really meaningful. So that's certainly -- that's certainly a part of the BU strategy. But I'd also like to talk a little bit about PKU because we're expecting a significant amount of growth coming out of PKU.

我們已經看到了巨大的進展。我們正在使用這兩種基因組。我們正在研究級聯篩檢，基本上就是查看家譜並查看家譜中是否有 MPS 或 CLN2，並確保我們能夠識別出正確的患者，這樣我們就可以幫助他們開始接受治療。因此，我們在巴西等國家做得非常成功，我們預計將繼續在我們知道這可能真正有意義的部分國家推動這些努力。所以這當然是 BU 策略的一部分。但我還想談一談北大，因為我們預計北大將實現顯著的成長。

As you saw with our year over year growth with Pa and Zika alone, we put up 17% growth there and expect that to continue in double digit growth into 2025. And at the end of the day, this was really driven by the efforts largely in the US and Japan to to help get new patients identified. And then importantly, and keep them on therapy. So really have adherence programs that keep them on the right dose. And then importantly finding patients that have discontinued so that they can restart.

正如您所看到的，僅在 Pa 和 Zika 病毒方面的同比增長就達到了 17%，並且預計到 2025 年將繼續保持兩位數的增長。歸根結底，這實際上主要是由美國和日本為幫助識別新患者所做的努力所推動的。然後重要的是，讓他們繼續接受治療。因此確實需要有堅持計劃來讓他們服用正確的劑量。然後重要的是找到已停止治療的患者，以便他們可以重新開始治療。

And so we're seeing great progress with this. And really what we're hearing is that this is in large part because of the differentiated profile of pai, that it works across all PKAU phenotypes. You have the, potential for normal C levels and importantly, the potential for an unrestricted diet. So I think we'll, we've seen great progress there and we'll expect it to continue.

因此我們看到這方面取得了巨大進展。而我們真正聽到的是，這在很大程度上是因為 pai 的差異化特徵，它適用於所有 PKAU 表型。您有潛力達到正常的維生素 C 水平，更重要的是，您有潛力實現不受限制的飲食。所以我認為，我們會看到那裡取得巨大進展，並且我們期待這種進展能夠繼續下去。

Gena Wang with Barclays.

巴克萊銀行的 Gena Wang。

Thank you for taking my questions. I will ask one regarding the IT, for your CMT franchise. I know you mentioned that you already, started processing Europe. Maybe if you can provide some update there and also your strategy in the US. And then the second question is regarding the 349 AATD, you can complete that and also start mad. In the last year, maybe show us what you are looking for, regarding the data update.

感謝您回答我的問題。我將詢問一個有關 IT 的問題，關於您的 CMT 特許經營權。我知道您提到您已經開始處理歐洲問題。也許您能提供一些最新進展以及您在美國的策略。第二個問題是關於 349 AATD，您可以完成它並開始瘋狂。在過去的一年裡，也許可以向我們展示您正在尋找的有關數據更新的內容。

Thanks very much, Jeanie, for your questions, Alexander. I'll handle the the IP questions and then hand it over to Greg.

非常感謝你的提問，珍妮，亞歷山大。我會處理 IP 問題，然後將其交給 Greg。

So, in essence, I mean, we stay, as we said in January, that we've initiated action against to send this in the unified court in Munich.

因此，從本質上講，正如我們在一月份所說的那樣，我們已經採取行動，將此案提交給慕尼黑統一法院。

We have no further updates to provide on European IP action. It's underway. It's in process, and we expect at the moment, to receive a decision in the next 12 to 15 months. Should there be, an update, we will, of course, provide that to you in due course.

我們沒有關於歐洲知識產權行動的進一步更新資訊。正在進行中。該程序正在進行中，我們目前預計將在未來 12 到 15 個月內收到決定。如果有更新，我們當然會及時向您提供。

As regards the United States, if and when we see conduct that we believe infringes our intellectual property in the US or elsewhere, we will take appropriate action time to defend against infringement. So those are the the updates basically as we go, we'll continue to keep us updated as this unfolds, but we're we're We're following through on our commitment to defend our intellectual property and our innovation. Over to you Greg

對於美國，如果我們發現我們認為侵犯我們在美國或其他地方的智慧財產權的行為，我們將採取適當的行動來防止侵權。所以這些基本上就是我們的更新內容，我們會隨著事態的發展繼續更新，但我們正在履行捍衛我們的智慧財產權和創新的承諾。交給你了，格雷格

Yeah thanks Gena. I love talking about BMN 349, a molecule for those who aren't familiar for alpha 1 antitrypsin deficiency related liver disease. So this is a small molecule. It will be titratable. It, has the potential to bind to Z protein as it's created in patients who have alpha one antitrypsin deficiency. By doing so, it decreases that Z protein's ability to misfold and form. Polymers in the liver, which lead to fibrosis and ultimately in some patients, liver failure.

是的，謝謝 Gena。我喜歡談論 BMN 349，對於不熟悉 α1 抗胰蛋白酶缺乏相關肝病的人來說，這是一種分子。這是一個小分子。它是可滴定的。它具有與 Z 蛋白結合的潛力，因為它是在患有 α 一抗胰蛋白酶缺乏症的患者體內產生的。這樣做就降低了 Z 蛋白錯誤折疊和形成的能力。肝臟中的聚合物會導致纖維化，並最終導致某些患者肝衰竭。

The oral therapy, is one that also, because it's titratable and because it has about a 100, 150-fold, a differential between how it binds to the Z protein versus the native M protein, it has the potential to be used in patients who are not just homozygous, Z, alpha 1 antitrypsin, but heterozygous.

口服療法也是一種可滴定療法，因為它與 Z 蛋白的結合與與天然 M 蛋白的結合有大約 100 到 150 倍的差異，所以它有可能用於不僅是純合子 Z、α1 抗胰蛋白酶的患者，而且是雜合子的患者。

As well, and the implication here is, of course, we're running a healthy volunteer study, multiple ascending doses, the usual PK, of course, along with safety profile will be looked at very closely from that. But there is a nuance in these protocols where a handful of patients, both with the MZ as well as the Z-phenotypes, excuse me, genotypes are going to, potentially, they are going to be able to be enrolled.

當然，這裡的含義是，我們正在進行一項健康志願者研究，多次增加劑量，當然，通常的 PK 以及安全性概況將受到非常密切的關注。但這些協議中有一個細微差別，少數具有 MZ 和 Z 表型（對不起，是基因型）的患者都有可能被納入。

And though, again, these are limited duration studies, we may get some insights into the pharmacodynamics of circulating Z protein and circulating the polymers as well. So fingers crossed, that study is open for enrollment again for the handful of patients as well as for healthy volunteers right now, and we're plowing forward, working with regulators around the globe also to clarify what the path forward both for Z as well as M genotypes would be for a molecule that can accomplish what I've described.

儘管這些都是有限時間的研究，我們還是可以對循環 Z 蛋白和循環聚合物的藥效學有所了解。所以，讓我們祈禱吧，這項研究現在再次開放給少數患者和健康志願者進行招募，我們正在努力推進，並與全球監管機構合作，以明確 Z 基因型和 M 基因型未來的發展方向，以便開發出能夠實現我所描述的目的的分子。

Paul Matteis Stifel, Nicolaus & Company, Incorporated

Paul Matteis Stifel，Nicolaus＆Company，Incorporated

Hey there, thanks for taking our question. This is Julian on for Paul. Just curious if you'd be able to share a little bit more color on what you learned from the two biopsies that you did in the DMD study.

嘿，感謝您回答我們的問題。這是朱利安 (Julian) 代替保羅 (Paul)。我只是好奇您是否可以分享更多關於您從 DMD 研究中進行的兩次活檢中了解到的信息。

And since they were at a relatively early time point, just curious, what were you looking for exactly in order to be confident in your assumptions and goals for this 10% dystrophin goal that you've laid out.

而且由於他們處於相對較早的時間點，只是好奇，您究竟在尋找什麼，以便對您提出的 10％ 肌營養不良蛋白目標的假設和目標充滿信心。

Thank you.

謝謝。

Yeah, thank you, Julian. This is Greg Freiberg again, and I think you said it nicely.

是的，謝謝你，朱利安。我又是 Greg Freiberg，我認為你說得很好。

These were two biopsies done of the muscles of boys who had been treated at the 6 mg per kilogram cohort for just 12 weeks, 12 to 13 weeks. And so in that regard, if you have an S-shaped curve in terms of what we would expect in terms of over time and protein expression, we were not at the steep part of the curve yet.

這是對接受每公斤 6 毫克劑量治療僅 12 週（12 至 13 週）的男孩的肌肉進行的兩次活檢。因此從這方面來看，如果就我們預期的隨時間和蛋白質表現而言，您有一條 S 形曲線，則我們尚未到達曲線的陡峭部分。

So there is a limited amount that one can say mathematically, but I will tell you that directionally we wanted to ask a couple of really key questions. One was whether or not our assumptions with the modeling would translate into humans. Are we able to get the drug into the muscle and and we could quantify it as well. And the answer there was yes.

因此，從數學角度來說，我們能說的內容是有限的，但我可以告訴你，我們想從方向上提出幾個非常關鍵的問題。一是我們對建模的假設是否能轉化為人類的假設。我們能否將藥物注入肌肉？答案是肯定的。

The second question would be, we are targeting a novel spice variant. Again, the goal here is to produce not micro dystrophin but near full length dystrophin. And so from that standpoint, we were able to see that the gene product was being produced in the cells of these boys.

第二個問題是，我們的目標是開發一種新型的香料變種。再次強調，這裡的目標不是生產微型肌肉營養不良蛋白，而是生產接近全長的肌肉營養不良蛋白。因此從這個角度來看，我們能夠看到這些男孩的細胞中產生了基因產物。

And finally, of course, the end, at least the end of the biomarker story would be to measure that near full length dystrophin, and were able to measure that, consistent with with our models. And so in that regard, we're hopeful again, that this 25 week data is going to be very helpful at giving us a line of sight for, whether or not that 10% target is going to be achievable.

最後，當然，至少生物標記故事的結束是測量接近全長的肌肉營養不良蛋白，並且能夠根據我們的模型進行測量。因此在這方面，我們再次充滿希望，這 25 週的數據將非常有助於我們了解是否可以實現 10% 的目標。

I would say that pertinent negatives were taken off the table that had never been tested in humans before. And though it's just two patients and though it's early, that gives us, a good line of sight that when we hit '25 weeks, this is going to be useful information.

我想說的是，之前從未在人體上進行過測試的相關負面因素已被排除。儘管只有兩名患者，而且為時過早，但這為我們提供了一個很好的視角，即當我們達到 25 週時，這將是有用的信息。

Akash Tewari with Jeffrey.

Akash Tewari 和 Jeffrey。

Hey, thanks so much. Maybe just on BD. I mean, if you think about [Infograib], there is, this kind of potential of an oral therapy that has similar, if not a better efficacy than Voxogo. And I think for a lot of investors, that's a big reason why they have difficulty modeling the terminal value on Voxogo.

嘿，非常感謝。也許僅在 BD 上。我的意思是，如果你考慮 [Infograib]，它就有可能成為一種口服療法，其療效與 Voxogo 相似，甚至更好。我認為對許多投資者來說，這是他們難以在 Voxogo 上模擬終值的重要原因。

There are companies like Relay, which, have assets that have the same mechanism as [Infragraib], and I think they're looking for strategic options. What's the appetite for BioMarin to kind of have their own infragratina-like approach in achondroplasia? Is your team very confident that CNP is the only way forward, or is there a potential that, you could be looking to in license one of these assets?

像 Relay 這樣的公司擁有與 [Infragraib] 相同機制的資產，我認為他們正在尋找策略選擇。BioMarin 對在軟骨發育不全症方面採用自己的類似 infragratina 的方法有何興趣？您的團隊是否非常有信心 CNP 是唯一的前進方向，或者您有可能尋求許可其中一種資產？

Thank you.

謝謝。

Thank you for the question, Akash. Our business development focus is really around genetically defined conditions. We're certainly interested in, leadership positions that we're establishing in skeletal conditions, and that we already have, in enzyme therapies. So that is a somewhat of a, an overlay to our business development, activities.

謝謝你的提問，阿卡什。我們的業務發展重點實際上是圍繞基因定義的條件。我們當然對我們在骨骼疾病領域建立的領導地位以及我們在酶療法領域已經建立的領導地位很感興趣。所以這在某種程度上是我們業務發展和活動的覆蓋。

But we're very comfortable right now with our leadership vision. With the indications in development for VOXZOGO , which is really exciting in so much that CNP can reach those indications like ISS and Noonan's and Turner's shocks, which is not a possibility, as for HGFR, and, in these sorts of disease states, efficacy is very important, but so is safety.

但我們目前對我們的領導願景非常滿意。隨著 VOXZOGO 適應症的開發，這真的令人興奮，因為 CNP 可以達到像 ISS 以及努南和特納休克這樣的適應症，而對於 HGFR 來說這是不可能的，而且，在這些疾病狀態下，療效非常重要，但安全性也同樣重要。

And the CNP profile of safety in CNP and treating from from infancy is absolutely critical and it's a, that's a hurdle, a high hurdle that any FGFR is going to have to establish and produce a significant amount of evidence to really, I think, reassure both physicians and caregivers.

CNP 的安全性以及從嬰兒期開始的治療絕對至關重要，這是一個障礙，任何 FGFR 都必須建立並提供大量證據才能真正讓醫生和護理人員放心。

So it's a high bar. Right now we're focused on CNP. We think that at the moment is the path to, sustained leadership in skeletal conditions.

所以這是一個很高的標準。目前我們專注於 CNP。我們認為，這是目前在骨骼狀況方面持續發揮領導作用的道路。

Eliana Merle UBS Investment Bank

Eliana Merle 瑞銀投資銀行

Hey guys, thanks so much for taking the question. So for VOXZOGO , do you expect the mix of US and ex US revenues to remain stable, or do you see the contribution from ex US increasing over '25 and '26? And then in the US, I guess what's the proportion of eligible patients with achondroplasia who are not currently treated? And I guess for those patients, why do you think this is? Is it that the patients aren't, currently under care by the right prescribers, or do you expect less penetration in the older patients? I guess what do you see sort of longer term as the potential for uptake and penetration into this population? Thanks.

嘿夥計們，非常感謝你們回答這個問題。那麼對於 VOXZOGO 而言，您是否預期美國和美國以外地區的收入組合將保持穩定，或者您認為美國以外地區的貢獻在 25 年和 26 年會增加？那麼在美國，我猜目前未接受治療的軟骨發育不全症患者的比例是多少？我想對於那些病人來說，您認為這是為什麼呢？是因為目前患者沒有得到正確的醫師的治療，還是您認為老年患者的治療滲透率會較低？我想，您認為從長遠來看，該技術在這些人群中的應用和滲透潛力有多大？謝謝。

So thank you so much for the question. I think that, first, to the first question in terms of the contribution of the US being at roughly 25% today, we definitely see that increasing over time, as our overall portfolio, the contribution from ex US is about two-third. It's split two-third and one-third in the US, and so we certainly anticipate the US contribution increasing over time as we continue our growth trajectory in the United States specifically.

非常感謝您提出這個問題。我認為，首先，對於第一個問題，就美國的貢獻而言，目前約為 25%，我們肯定會看到，隨著時間的推移，這一比例會增加，因為在我們的整體投資組合中，來自美國以外的貢獻約為三分之二。其中三分之二在美國，三分之一在美國，因此隨著我們在美國繼續保持成長軌跡，我們預期美國的貢獻肯定會隨著時間的推移而增加。

Now, in terms of your question around patients not treated, I mean, I do want to come back to the fact that where we are seeing the bulk majority of new patients starts is in the 0 to 5 population today. That, of course, was not the case when we were first launched. We launched in the 5 plus year old cohort, and so, of course, that was where the bulk of our patients were.

現在，關於您關於未接受治療的患者的問題，我的意思是，我確實想回到這樣一個事實：我們看到當今絕大多數新患者都是在 0 到 5 歲的人群中。當然，我們剛推出時並非如此。我們的首批患者是 5 歲以上的人群，因此，我們的大部分患者當然都集中在這個年齡層。

So the rough split today, if you just look at how many patients are on treatment and the rough split, it skews more. For the 0 to 5, but that's a timing component. So really new patient starts we're really targeting the youngest patients. And in terms of patients not treated, the why, I mean, I think that there's a probably a myriad of reasons that that we could conclude.

因此，如果您只看今天的粗略分配情況，有多少患者正在接受治療以及粗略的分配情況，就會發現偏差更大。對於 0 到 5，但這是一個時間組件。因此，對於新的患者，我們真正瞄準的是那些最年輕的患者。就未接受治療的患者而言，我認為我們可以得出無數個原因。

Some of it would be awareness, some of it would be knowing where the prescriber, the treater would actually be. They might be being treated in pediatric offices today, and that is precisely why we are really focused on. Ensuring that there is broad awareness of the treatment options, seeing that VOXZOGO was the first and the only treatment option for acroplasia. So we want awareness and then comfort with the treaters and prescribers.

有些是意識，有些是知道開處方的醫生和治療者實際上在哪裡。他們今天可能正在兒科診所接受治療，這正是我們真正關注的原因。確保廣泛了解治療方案，因為 VOXZOGO 是治療肢體畸形的第一個也是唯一的治療方案。因此，我們希望提高治療人員和處方人員的認識，並讓他們感到安心。

We want them to be very comfortable using it, and that's precisely what we're working on, and that is why we're increasing our commercialization efforts in the United States to ensure that. I know, Greg, you might have something to add. If if.

我們希望他們能夠非常舒適地使用它，這正是我們正在努力的目標，這也是我們在美國加強商業化以確保這一點的原因。我知道，格雷格，你可能有一些要補充。如果如果。

I could just add as well, I mean, it is of course a complex decision. That patients and their families go through with the, with their physicians, whether to treat or not treat. What we are focused on in the R&D organization is continuing to provide data, continuing to, build on, the data set that we have out there. Again, this is not just a story about one year average growth velocity, we want to publish our two, three, four year data. We have over 6,000 years, patient years of Safety data at this point. And again, these are infants. So again, that means something to those treaters.

我還可以補充一點，這當然是個複雜的決定。無論是否治療，患者及其家屬都要與醫師商討。我們研發機構的重點是繼續提供數據，繼續建構我們現有的數據集。再說一遍，這不僅僅是一個關於一年的平均成長速度的故事，我們還想發布兩年、三年、四年的數據。到目前為止，我們已有超過 6,000 年、耐心多年的安全資料。再次強調，這些都是嬰兒。所以，這對那些治療者來說意義重大。

And finally, this isn't just a story about AGV or even even final adult height by itself. The story, of course, is all about the wellness and health of these patients, and, we've recently published our proportionality data, at three years, that's statistically significant compared to control. Quality of life measures we've published these craniofacial frame and magnum again, you put all of this together and then of course seeing the community evolve and seeing the guidelines, the independent guidelines that were published, identify these patients, start them as early as possible, we're hoping that that starts to tip the balance with the comfort level when the physicians are in the office with these infants and their parents making these decisions.

最後，這不僅僅是一個關於 AGV 的故事，甚至不僅僅是一個關於成年人最終身高的故事。當然，這個故事都是關於這些患者的健康和保健，而且，我們最近發布了三年的比例數據，與對照組相比，這具有統計意義。我們已經發布了這些顱面框架和顱骨大小等生活品質測量數據，將所有這些數據放在一起，然後當然會看到社區的發展和指南的發布，這些獨立指南會識別這些患者，並儘早開始治療，我們希望當醫生在辦公室裡與這些嬰兒及其父母一起做出這些決定時，這會開始與舒適度保持平衡。

Kostas Biliouris with BMO Capital Markets.

BMO 資本市場的 Kostas Biliouris。

Hi everyone, thanks for taking our question and congrats on the strong numbers. Great to see that three-fourth of VOXZOGO sales coming from ex-US.

大家好，感謝您回答我們的問題，並對強勁的數據表示祝賀。很高興看到 VOXZOGO 的四分之三的銷售額來自美國以外。

Maybe one question follow up on Akash's question on BB in the in the (technical difficulty) liver and the lung manifestation of the disease, and these approaches already have clinical validation, early clinical validation.

也許有一個問題是針對 Akash 關於 BB 在肝臟和肺部疾病表現（技術難度）中的問題，這些方法已經經過臨床驗證，早期臨床驗證。

Given your interest in that space, would you consider different modalities to complement your pipeline modalities, or you prefer to go only with one modality in that disease?

鑑於您對該領域的興趣，您是否會考慮採用不同的方式來補充您的管道模式，或者您更願意在該疾病中只採用一種模式？

Thank you.

謝謝。

I believe we were talking about the alpha one antitrypsin patients, and I'm sorry, it broke out a little bit and the disparity between liver and lung. Is that?

我相信我們正在談論α一抗胰蛋白酶患者，很抱歉，它爆發了一點，肝臟和肺臟之間的差異。是嗎？

I was asking about RNA editing approaches in alpha ones inefficiency and whether you would have interest in, such a process to complement your approach in your pipeline.

我詢問的是 RNA 編輯方法在 alpha 1 中的效率問題，以及您是否有興趣使用這樣的流程來補充流程中的方法。

Well, with regard to BMN 349, you're correct, it's focused on the liver, and again, the challenges of trying to solve both the lung and the liver problems we've seen, across the industry. We've focused on a mechanism again that is liver focused. Now, presumably because of the difference between selectivity for M&Z protein, this would be a therapy that could be given in conjunction with enzyme replacement as well, which would address some of the lung challenges. As of this point, that's our approach from the R&D standpoint. And Alexander, anything that you want to add from a strategic,

嗯，關於 BMN 349，您說得對，它專注於肝臟，而且，我們在整個行業中都看到了試圖解決肺部和肝臟問題的挑戰。我們再次關注以肝臟為中心的機制。現在，大概是因為 M 和 Z 蛋白的選擇性不同，這種療法可以與酵素替代結合使用，從而解決一些肺部問題。到目前為止，這就是我們從研發角度採取的方法。亞歷山大，從策略角度來說，你想補充什麼，

Yeah, it's early days and we're very hopeful again that we're going to have a differentiated mechanism of action that might work quite nicely, in combination with other therapies like enzyme replacement, potentially others.

是的，現在還為時過早，我們再次充滿希望，我們將擁有一種差異化的作用機制，它可以與其他療法（如酵素替代療法）以及其他療法相結合，發揮良好的作用。

Mohit Bansal Wells Fargo Securities

Mohit Bansal 富國證券

Hi, this is Sadia Roman on for Mohead. Thanks for taking our question. Another question on DMD, so are there any biomarkers like slicing levels that would be presented this year that could help us understand how this, compared to other agents? And can you talk about how those biomarkers were tracking in that early data, and also your decision to go up to 9 megs per kg. To initiate that cohort, wondering if that was based on the analysis that you did on the 13 week data at 6 megs.

大家好，我是 Mohead 的 Sadia Roman。感謝您回答我們的問題。關於 DMD 的另一個問題是，今年是否會呈現任何像切片水平這樣的生物標記來幫助我們了解與其他藥物相比 DMD 的效果？您能否談談這些生物標記在早期數據中的追蹤情況，以及您決定將劑量增加到每公斤 9 兆微克的原因。為了啟動該群組，想知道這是否基於您對 6 兆位元組 13 週資料所做的分析。

Yeah, thank you.

是的，謝謝。

Yeah, thanks for the question. Let me take the second question first. The 9 mg cohort was a planned step, and there could be potentially another step as well. The trigger to open that was simply one from the data monitoring committee, the independent DMC, and again, nice to know that they again approved that, and that speaks to again the safety and the benefit that they were seeing. Your other question was with regard to other biomarkers.

是的，謝謝你的提問。我先回答第二個問題。9毫克劑量組是一個計劃好的舉措，並且可能會有另一個舉措。啟動該程序的觸發因素只是來自數據監測委員會，即獨立的 DMC，而且很高興得知他們再次批准了該程序，這再次說明了他們所看到的安全性和好處。您的另一個問題是關於其他生物標記。

We only looked at the muscle biopsy in those patients at 13 weeks, and I've shared with you what we've looked at in those. Of course, how you measure full length dystrophin, can be different, and we've seen that, again, whether you're looking at normalized values, which assay, suffice to say we're actually looking at multiple different assays for dystrophin levels, and we want, we'll be as transparent as possible when we review, when we present our data.

我們只觀察了這些患者 13 週時的肌肉切片情況，我已經與大家分享了我們所觀察的結果。當然，測量全長肌肉營養不良蛋白的方法可能有所不同，我們已經看到，無論您是在查看標準化值，還是查看哪種檢測方法，都可以說我們實際上是在查看肌營養不良蛋白水平的多種不同檢測方法，我們希望在審查和呈現數據時盡可能透明。

We'll want to make sure again that that totality of the data is represented in addition to the clinical and PK data that's available. So nothing else to share now, but we're absolutely looking, at a variety of not only biomarkers, but we are measuring functional levers in these patients as well. And our, of course, ultimate hope is that we're not just treating to increase dystrophin, but to make these boys' lives better and have them be more functional. So more to come, but nothing else to share at this point.

我們希望再次確保除了可用的臨床和 PK 數據之外，所有數據都能夠反映出來。所以現在沒有其他資訊可以分享，但我們絕對在關注各種生物標誌物，同時也在測量這些患者的功能槓桿。當然，我們最終的希望不僅僅是透過治療來增加肌肉營養不良蛋白，而是讓這些男孩的生活更美好，讓他們的功能更強。後續還有更多內容，但目前還沒有其他可分享的。

Olivia Brayer with Cantor Fitzgerald.

奧利維亞·布雷爾 (Olivia Brayer) 和康托·菲茨杰拉德 (Cantor Fitzgerald)。

Hi, good afternoon. Thank you for the question. How are you guys thinking about the level of growth that we might see from the enzyme business over these next couple of years? I know you've talked about a high single digit keger over the next 10 or so years, but what about for '25, '26, '27? And then any comments around what the margin expansion could look like for that enzyme franchise? Just especially considering, patients getting older and some of these medicines are weight-based.

嗨，下午好。感謝您的提問。你們如何看待未來幾年酵素業務的成長水準？我知道您已經談到未來 10 年左右啤酒銷售將保持高個位數，但是 25、26、27 年的情況如何？那麼對於該酵素特許經營的利潤擴張前景，您有何評論嗎？特別考慮到，患者年齡不斷增大，而有些藥物是基於體重的。

Thank you.

謝謝。

Yeah, thanks Livia for the question. This is Brian. I'll I'll handle that one.

是的，感謝 Livia 提出這個問題。這是布萊恩。我會處理那個。

So you commented on that high single digit CAGAR over the long term. That, that's also the goal for the mid-term as well and part of what supports the $4 billion in 2027. There's going to be different dynamics based on the brand, any particular brand from year to year.

所以你對長期的高個位數 CAGAR 進行了評論。這也是中期目標，也是 2027 年 40 億美元目標的部分支撐。根據品牌的不同，任何特定品牌每年都會有不同的動態。

I mentioned, for example, this year Naglazyme had some of that additional buying in 2024, which, flattens out the growth rate a bit in 2025. Likewise for Aldurazyme, which Farmer revenue is not based on they're tied directly to and patient demand, but supply to San Rafael likewise we expect that to be more flat than 25/24. But over these next couple of years, high single digit across that, franchise is the goal.

我提到，例如，今年 Naglazyme 在 2024 年進行了一些額外購買，這使得 2025 年的成長率略微趨於平穩。對於 Aldurazyme 來說也是如此，其農民收入不是基於其與患者需求直接相關的，而是基於對聖拉斐爾的供應，同樣，我們預計其供應量將比 25/24 更加平穩。但在接下來的幾年裡，特許經營是我們的目標。

And within that. Within that, just a reminder, Cristen touched on it earlier, that the key driver is [palii]. We think we've got more market penetration to go there, healthy double digit growth in paliik, and then continued sustained growth in the enzyme business. And you're exactly right, you said margin, but then kind of talked about kind of some of the individual patient dynamics.

並且就在那之內。在此提醒一下，克里斯滕之前提到過，關鍵驅動因素是[帕里伊]。我們認為我們在那裡會擁有更大的市場滲透力，在帕利克市場會實現健康的兩位數成長，並且在酵素業務方面也會繼續保持持續的成長。您說得完全正確，您提到了邊緣，但隨後又談到了一些個別患者的動態。

I tumble, we don't disclose, business unit operating margin, and profitability at the business unit level, but, I'll share that both of the primary business units are, substantially profitable with, healthy operating margins well above our consolidated global operating margin which includes corporate costs and some allocated R&D for the pipeline. So, both franchises are generating substantial margin. And part of the sustainability and durability of that enzyme business is the patient dynamics. These patients are doing well. It's a weekly infusion for life, the enzyme therapies.

我不會透露業務部門的營業利潤率，以及業務部門層面的盈利能力，但我要說的是，兩個主要業務部門的盈利能力都相當強勁，營業利潤率遠高於我們的綜合全球營業利潤率，其中包括企業成本和一些分配給渠道的研發費用。因此，兩個特許經營權都產生了可觀的利潤。酵素業務的可持續性和持久性部分取決於患者的動態。這些病人狀況良好。這是每週一次的終生輸注，酵素療法。

And you mentioned the weight-based dosing, so that by all means is part of the durability of that franchise.

您提到了基於體重的劑量，所以這無疑是該特許經營持久性的一部分。

Alex Hammond with Wolver Research.

伍爾弗研究公司的亞歷克斯·哈蒙德（Alex Hammond）

Thanks for squeezing me in. Just quickly on VOXZOGO , can you provide any color on the expected degree of switch market dynamics following potential competitor launches? And just to follow up on that as well, can you kind of dimensionalize how those dynamics may differ across geographies as well as patient age groups?

謝謝你擠進我。在 VOXZOGO 上，您能否提供有關潛在競爭對手推出後交換器市場動態的預期程度的任何資訊？為了進一步跟進，您能否具體說明這些動態在不同地區以及不同患者年齡層之間有何差異？

Yeah, so thank you very much for the question. So, just to be very clear on our VOXZOGO numbers, I mean, competition has always been modeled into any of the assumptions we've put out there and so I just want to make that clear, not to mention. I think, competitive landscape is not a bad thing. I think honestly like raising the the awareness around this disease and the fact there's treatments around it is always a good thing.

是的，非常感謝您的提問。所以，為了非常清楚地了解我們的 VOXZOGO 數字，我的意思是，競爭一直被建模到我們提出的任何假設中，所以我只想說清楚，更不用說。我認為，競爭格局並不是一件壞事。我認為，提高人們對這種疾病的認識以及了解其治療方法始終是一件好事。

But to speak specifically about where we think we will, continue our leadership position, in particular in Achondroplasia, I think that there's multiple dynamics here. You could talk about certainly the notion of the potential for switching. From VOXZOGO to another compound should it become available, and we do believe that there's going to be some stickiness to being on VOXZOGO so that it's almost kind of like a start and stay paradigm that we're really looking to achieve.

但具體來說，我們認為我們將在哪些方面繼續保持領導地位，特別是在軟骨發育不全領域，我認為這裡有多個動力。您當然可以談談轉換潛力的概念。從 VOXZOGO 到另一種化合物（如果它可用的話），我們確實相信 VOXZOGO 會有一定的黏性，因此它幾乎有點像我們真正想要實現的開始和保持範例。

We know that, what we hear in the real world and do market research is that when patients and caregivers and their ACPs are seeing a positive experience, the barrier to switch becomes much higher because if they Trusted compound.it's working in that patient and so switching there that adds an element of risk that some will not choose to take.

我們知道，我們在現實世界中聽到的和做的市場調查是，當患者、護理人員和他們的 ACP 看到積極的體驗時，轉換的障礙就會變得更高，因為如果他們信任化合物，它就會在該患者身上起作用，因此在那裡轉換會增加一些人不會選擇承擔的風險。

Not to mention this is, VOXZOGO is a very trusted, it'll, it's a very trusted compound at this point in time. We have over 6,000 patient years of safety and efficacy data that is growing and and we're building on that body of evidence that goes well beyond height but really talking about the overall health of these patients.

更不用說，VOXZOGO 是一種非常值得信賴的化合物，目前它是一種非常值得信賴的化合物。我們擁有超過 6,000 名患者多年的安全性和有效性數據，而且這些數據還在不斷增加，我們正在以這些證據為基礎，不僅關注身高，還真正關注這些患者的整體健康狀況。

Not to mention just thinking of the experience, we have a high compliance rate, so we see on average about 95% compliance rates across the globe that is both in the US as well as outside the US, which is really important that we continue to build on that and that we leverage that.

更不用說僅從經驗來看，我們的合規率很高，因此我們看到全球範圍內平均合規率約為 95%，無論是在美國還是美國以外，這對於我們繼續在此基礎上發展和利用這一點非常重要。

Now thinking, I've talked a lot about what's happening in the US, but to remind you, 68% of the total addressable patient population lives outside of the US. And so these markets where we have an entrenched global footprint and a lot of experience in understanding the local dynamics. Those markets. This is an area where we really think that BioMarin has a strategic advantage in so much as we have this global footprint where we know a lot of those patients are going to be. So we really do see a lot of stickiness to our business over time both in the United States as well as ex US, and we really look forward to building on this leadership position.

現在想想，我已經談了很多關於美國發生的事情，但提醒一下，68% 的總可尋址患者群體居住在美國境外。在這些市場中，我們擁有根深蒂固的全球影響力，並且在了解當地動態方面擁有豐富的經驗。那些市場。我們確實認為 BioMarin 在這一領域具有戰略優勢，因為我們的業務遍布全球，我們知道許多患者都會在這裡。因此，我們確實看到，隨著時間的推移，我們的業務無論是在美國還是美國以外地區都具有很大的黏性，我們非常期待鞏固這一領導地位。

Thank you. This does include today's Q&A portion of today's call. This also comes to the conclusion of today's presentation. We thank you for joining. I will now have today's call over to the CEO for any closing remarks.

謝謝。這確實包括今天電話會議的問答部分。今天的演講也到此結束。感謝您的加入。現在，我將今天的電話會議轉交給首席執行官，請他做最後發言。

Thank you, operator, and thank you all for joining us today and thank you for your interest in BioMarin, as you've heard, the strategic and operational decisions that made made last year and yielding tangible results and enabling ongoing reinvestment in innovation and growth to make even greater impact on all of our stakeholders.

謝謝運營商，感謝大家今天的加入我們，感謝你們對 BioMarin 的關注，正如你們所聽到的，我們去年做出的戰略和運營決策取得了切實的成果，並持續對創新和增長進行再投資，對我們所有的利益相關者產生更大的影響。

We expect continued high performance as we benefit from BioMarin revamped corporate strategy and operating model in 2025 and beyond, and look forward to keeping you all apprised of our progress.

受惠於 BioMarin 在 2025 年及以後改進的公司策略和營運模式，我們期待繼續保持優異的業績，並期待向大家通報我們的進展。

Thank you so much and have a great day.

非常感謝，祝您有愉快的一天。

This concludes today's call. Thank you for joining. You may now disconnect your lines.

今天的電話會議到此結束。感謝您的加入。現在您可以斷開線路了。