BioMarin Pharmaceutical Inc (BMRN) 2024 Q3 法說會逐字稿

Thank you for standing by. My name is Bary, and I will be your conference operator today. At this time, I would like to welcome everyone to the BioMarin Pharmaceuticals third-quarter 2024 conference call. (Operator Instructions) I would now like to turn the call over to Tracy McCarty, Group Vice President of Investor Relations. You may begin.

謝謝你的支持。我叫巴里，今天我將擔任你們的會議操作員。此時此刻，我歡迎大家參加 BioMarin Pharmaceuticals 2024 年第三季電話會議。（操作員說明）我現在想將電話轉給投資者關係集團副總裁 Tracy McCarty。你可以開始了。

Thank you, operator. To remind you, this nonconfidential 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. 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.

謝謝你，接線生。提醒您，本非機密簡報包含有關 BioMarin 製藥公司業務前景的前瞻性陳述，包括對 BioMarin 的財務業績、商業產品以及治療研究和開發不同領域的未來潛在產品的預期。結果可能會存在重大差異，具體取決於BioMarin 產品計劃的進展、監管機構的行動、資本的可用性、製藥市場的未來行動和競爭對手的發展，以及BioMarin 向美國證券交易委員會提交的文件中詳細說明的因素，例如10 -Q、10-K 和 8-K 報告。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。

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. On the call from BioMarin management today are 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 Guyer, Executive Vice President, Worldwide R&D. I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

這些非公認會計原則措施不應孤立地視為替代或優於根據美國公認會計原則編制的財務措施，並且您可以在收益發布和收益演示中找到與美國公認會計原則相關的調節表，兩者均可取得在我們網站的投資者關係部分。今天，BioMarin 管理層的總裁兼首席執行官 Alexander Hardy 接聽了電話； Brian Mueller，執行副總裁兼財務長； Cristin Hubbard，執行副總裁兼首席商務長； Greg Guyer，全球研發執行副總裁。我現在將把電話轉給 BioMarin 總裁兼執行長 Alexander Hardy。

Thank you, Traci, and good afternoon, everyone. Thank you for joining us today for our third quarter 2024 earnings call. The strategic and operational decisions we have made over the last nine months are driving strong performance, and I'm pleased to report another quarter of record financial results with revenues reaching $746 million, marking a robust 28% increase compared to the same period in 2023. As outlined at Investor Day, we are implementing our new corporate strategy focused on innovation, growth and value commitment.

謝謝你，崔西，大家下午好。感謝您今天參加我們的 2024 年第三季財報電話會議。我們在過去九個月中做出的策略和營運決策正在推動強勁的業績，我很高興地報告又一個季度創紀錄的財務業績，收入達到 7.46 億美元，與 2023 年同期相比強勁增長 28% 。正如投資者日所概述的，我們正在實施新的企業策略，重點是創新、成長和價值承諾。

During the quarter, we made significant progress on each of these pillars, resulting in strong performance. We are structuring the company around new business units in skeletal conditions, enzyme therapies and Roctavian to drive accountability, deliver strong revenue growth and improve efficiency while reaching a growing number of patients around the world. We have set this company on the path to stronger performance, and these results are evidence of our progress. Today, I'm also delighted to welcome Greg Guyer and [James Sabre] to BioMarin.

本季度，我們在每個支柱上都取得了重大進展，並取得了強勁的業績。我們正在圍繞骨骼疾病、酶療法和 Roctavian 等新業務部門建立公司，以推動問責制、實現強勁的收入成長並提高效率，同時覆蓋全球越來越多的患者。我們已經讓這家公司走上了業績更強勁的道路，這些結果證明了我們的進步。今天，我也很高興歡迎 Greg Guyer 和 [James Sabre] 來到 BioMarin。

With Greg and James in role and the addition of Cristin Hubbard earlier this year, we have incredible strength and depth in our leadership team with the right combination of scientific and business acumen. I'm confident that with these leaders in place, we are positioned to deliver the new strategy and innovate across all aspects of our business. Greg and Cristin will provide their updates on the call in a moment. Moving to the results in the quarter. Strong financial performance was driven by a 50% revenue growth in Voxzogo for the treatment of achondroplasia.

隨著格雷格和詹姆斯的加入以及今年早些時候克里斯汀·哈伯德的加入，我們的領導團隊擁有令人難以置信的實力和深度，以及科學和商業頭腦的正確結合。我相信，有了這些領導者的到位，我們就有能力實施新策略並在業務的各個方面進行創新。格雷格和克里斯汀稍後將提供電話會議的最新情況。轉向本季的業績。強勁的財務表現得益於用於治療軟骨發育不全的 Voxzogo 收入成長 50%。

This growth was supported by a significant level of new patient starts, driven by increased penetration in the US and new geographies that leveraged our broad geographic footprint and capabilities. The growth is also being driven by our expanded indication into infants and the increasing evidence of Voxzogo benefits to the health of patients beyond height. As our global launch of October for achondroplasia continues to gain momentum worldwide, we are confident in our sustained leadership across our skeletal conditions franchise over the long term. Our proven capabilities of diagnosing, treating, facilitating market access and building the achondroplasia therapeutic area provide BioMarin the unique ability to sustainably lead this global market.

這一增長得益於大量新患者的啟動，這是由於美國滲透率的提高以及利用我們廣泛的地理足跡和能力的新地區的推動。我們擴大了嬰兒適應症，以及越來越多的證據表明 Voxzogo 對身高以外患者的健康有益，也推動了這種成長。隨著我們 10 月針對軟骨發育不全症的全球推出繼續在全球範圍內獲得動力，我們對我們在骨骼疾病特許經營領域的長期持續領導地位充滿信心。我們在診斷、治療、促進市場准入和建立軟骨發育不全治療領域的成熟能力為 BioMarin 提供了可持續領導全球市場的獨特能力。

The five key reasons supporting our confidence in growing and maintaining the achondroplasia market are; first, a potential five-year commercial lead, including the largest database in achondroplasia of long-term durable efficacy and greater than 6,000 aacent years of safety. And an emerging data set on benefits beyond height, including quality of life. Second, global approvals from infancy and our plans to continue to deeply penetrate this market segment along with complicated potential switch market dynamics. The US and EU markets comprised approximately 32% of the global total addressable patient population and then for the majority, 68% is more insulated from midterm competitive threats because of our global capabilities and market leadership.

支持我們對發展和維持軟骨發育不全市場充滿信心的五個關鍵原因是：首先，潛在的五年商業領先優勢，包括最大的軟骨發育不全資料庫，具有長期持久的功效和超過 6,000 年的安全性。還有一個關於身高之外的好處的新興數據集，包括生活品質。其次，全球的批准從起步階段開始，我們計劃繼續深入滲透這個細分市場，以及複雜的潛在開關市場動態。美國和歐盟市場約佔全球可尋址患者總數的 32%，而對大多數患者而言，由於我們的全球能力和市場領導地位，其中 68% 更能免受中期競爭威脅。

Third, our global commercial, medical and market access capabilities plus over 20 years, as just described. Fourth, the prioritization and acceleration of BMN 333, a long-acting CNP that leverages the same CNP as Voxzogo. And fifth, our plans to vigorously defend our intellectual property. In summary, we maintain our confidence in the long-term growth potential of our skeletal conditions franchise. Beyond skeletal conditions, our global enzyme therapies portfolio continued to perform well and grow in the third quarter with 27% revenue growth in Q3 and 13% year-to-date growth.

第三，我們的全球商業、醫療和市場進入能力加上20多年，正如剛才所描述的。第四，BMN 333 的優先順序和加速，這是一種長效 CNP，利用與 Voxzogo 相同的 CNP。第五，我們計劃大力捍衛我們的智慧財產權。總之，我們對骨骼疾病專營權的長期成長潛力保持信心。除了骨骼疾病外，我們的全球酵素療法產品組合持續表現良好，並在第三季實現成長，第三季營收成長 27%，今年迄今成長 13%。

Q3 enzyme therapy revenue benefited from increased Aldurazyme revenue as we delivered a substantial amount of product to Sanofi during the quarter. Excluding the Aldurazyme revenue, the enzyme therapies still grew at close to 10% year-to-date. We're starting to deploy the new initiatives outlined at Investor Day and these, together with a focus from the business unit structure give us confidence that we can grow this portfolio even faster than historical rates. We're pleased today to raise full year guidance at the midpoint for all items driven by a strong ongoing execution and focus on performance.

第三季酵素療法收入受益於 Aldurazyme 收入的增加，因為我們在本季向賽諾菲交付了大量產品。排除 Aldurazyme 的收入，酵素療法今年迄今仍以接近 10% 的速度成長。我們開始部署投資者日概述的新舉措，這些舉措以及業務部門結構的重點讓我們相信，我們可以比歷史速度更快地發展該投資組合。今天，我們很高興在強勁的持續執行力和對績效的關注的推動下，提高所有專案的全年指引。

Alongside record revenues, we have driven considerable profitability expansion with year-to-date non-GAAP EPS growing more than three times faster than revenue. As a result of our focused cost transformation program and leverage revenue growth we continue to drive substantial expansion of our operating margin. Our strong financial performance reinforces our confidence in reaching our midterm and long-term outlook provided at Investor Day. Today, we are reaffirming our long-term guidance and outlook, which include achieving approximately $4 billion in total revenues by 2027, reaching 40% non-GAAP operating margin starting in 2026 and growing to the low mid-40% range over time, generating more than $1.25 billion in operating cash flow per year starting in 2027.

除了創紀錄的收入外，我們還推動了盈利能力的大幅增長，年初至今的非公認會計原則每股收益的增長速度是收入的三倍多。由於我們專注於成本轉型計劃和利用收入成長，我們繼續推動營業利潤率的大幅擴張。我們強勁的財務表現增強了我們對實現投資者日所提供的中長期前景的信心。今天，我們重申我們的長期指導和展望，其中包括到2027 年實現約40 億美元的總收入，從2026 年開始達到40% 的非GAAP 營業利潤率，並隨著時間的推移增長到40% 左右的範圍，產生從 2027 年開始，每年營運現金流超過 12.5 億美元。

Targeting a mid-teen compound annual growth rate for total revenues through 2034. Developing potential treatments for skeletal conditions that represent greater than $5 billion revenue opportunity over time. And as a reminder, this $5 billion opportunity assumes only a very modest penetration into the skeletal conditions indications. In summary, our third quarter performance highlights the ongoing execution of our corporate strategy under BioMarin's new operational plan to achieve sustained and significant returns.

目標是到 2034 年總收入實現中位數的年複合成長率。開發潛在的骨骼疾病治療方法，隨著時間的推移，這將帶來超過 50 億美元的收入機會。提醒一下，這個價值 50 億美元的機會假設對骨骼疾病適應症的滲透非常有限。總之，我們第三季的業績凸顯了我們在 BioMarin 新營運計畫下持續執行的企業策略，以實現持續且顯著的回報。

These results should demonstrate our commitment to superior performance resulting from our laser focus on making an impact on the life of each patient we serve. I would like to thank our employees around the world for all of the work they've done during the third quarter to contribute to this progress and to their commitment to continuing to evolve the way we work to support the new strategy. 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.

這些結果應該證明我們對卓越績效的承諾，因為我們專注於對我們所服務的每位患者的生活產生影響。我要感謝我們世界各地的員工在第三季為實現這一進展所做的所有工作，並感謝他們致力於繼續改進我們的工作方式以支持新策略。感謝您的關注。我現在將把電話轉給布萊恩，概述我們本季的財務亮點。

Thank you, Alexander. Please refer to today's press release summarizing our financial results for full details on the third quarter of 2024, including reconciliations of GAAP to non-GAAP financial measures. All third quarter 2024 results will be available in our upcoming Form 10-Q, which we expect to file in the coming days. As Alexander just shared, our record-setting performance that generated $746 million of total revenue, drove robust growth year-over-year. Voxzogo was a key driver of revenue growth increasing 54% year-over-year and reaching $190 million in the third quarter.

謝謝你，亞歷山大。請參閱今天總結我們財務業績的新聞稿，了解 2024 年第三季度的完整詳細信息，包括 GAAP 與非 GAAP 財務指標的調節表。2024 年第三季的所有結果都將在我們即將發布的 10-Q 表格中提供，我們預計將在未來幾天內提交。正如 Alexander 剛剛分享的那樣，我們創紀錄的業績創造了 7.46 億美元的總收入，推動了同比的強勁增長。Voxzogo 是營收成長的主要推動力，第三季營收年增 54%，達到 1.9 億美元。

Please recall that Q2 Voxzogo revenues benefited from order timing of approximately $20 million and this timing dynamic negatively impacted Q3 revenues. Turning to our enzyme therapies, which include Vimizim, Naglazyme, Aldurazyme, Brineura and Palynziq, this portfolio contributed $509 million of combined net product revenues in the third quarter, representing a 27% year-over-year increase. Aldurazyme was a large driver of revenue growth primarily due to the timing of order fulfillment to Sanofi as we recognize revenues when the product is released and control is transferred to Sanofi, who is responsible for selling Aldurazyme into the market. We estimate that the impact of timing on Aldurazyme revenue in Q3 is approximately $20 million to $30 million.

請記住，Voxzogo 第二季度的收入受益於約 2000 萬美元的訂單時間，而這種時間動態對第三季的收入產生了負面影響。談到我們的酵素療法，包括 Vimizim、Naglazyme、Aldurazyme、Brineura 和 Palynziq，該產品組合在第三季度貢獻了 5.09 億美元的合併淨產品收入，同比增長 27%。Aldurazyme 是營收成長的主要動力，主要是由於賽諾菲訂單履行的時間安排，因為我們在產品發布且控制權轉移給負責將 Aldurazyme 銷售到市場的賽諾菲時確認收入。我們估計，時間安排對 Aldurazyme 第三季營收的影響約為 2,000 萬至 3,000 萬美元。

Naglazyme grew 21% year-over-year. demonstrating increasing demand and benefiting from some order timing. Palynziq revenues increased 15% year-over-year, driven by the strong patient uptake in the US, our largest market for Palynziq. Looking ahead, we are confident in the continued strong commercial performance of our portfolio, driven by Voxzogo and the enzyme therapy. As a result, we are narrowing our full year 2024 revenue guidance to between $2.79 billion and $2.825 billion, thereby raising the midpoint representing approximately 16% year-over-year growth at the midpoint.

Naglazyme 年成長 21%。表明需求不斷增長並從某些訂單時機中受益。Palynziq 營收年增 15%，這得益於 Palynziq 最大市場美國患者的強勁需求。展望未來，在 Voxzogo 和酵素療法的推動下，我們對我們的產品組合持續強勁的商業表現充滿信心。因此，我們將 2024 年全年營收指引縮小至 27.9 億美元至 28.25 億美元之間，從而提高中點，即中點年增約 16%。

From an operating expense standpoint, GAAP R&D expense was $185 million in the third quarter and GAAP SG&A expense was $253 million. SG&A expense on a GAAP basis includes $45 million of restructuring expenses that we adjust out of non-GAAP income. And after that adjustment, SG&A expense decreased slightly year-over-year, with R&D expense also declining year-over-year. Overall operating expenses are in a transition phase and trended lower in Q3 as we start to realize the savings from the various portfolio and organizational actions taken this year.

從營運費用的角度來看，第三季 GAAP 研發費用為 1.85 億美元，GAAP SG&A 費用為 2.53 億美元。銷售及管理費用以 GAAP 計算的費用包括 4,500 萬美元的重組費用，我們從非 GAAP 收入中調整了這些費用。調整後，SG&A 費用較去年同期略有下降，研發費用也較去年同期下降。隨著我們開始意識到今年採取的各種投資組合和組織行動的節省，整體營運費用處於過渡階段，並在第三季度呈下降趨勢。

We expect operating expenses to begin to increase going forward as we accelerate our commercial growth strategies and advance the R&D pipeline, albeit at a significantly lower expense growth rate than revenue growth which will drive operating margin improvement over time. BioMarin has executed well in 2024. Our Q3 GAAP diluted earnings per share increased 162% over Q3 last year to $0.55 in the quarter. Our Q3 non-GAAP diluted earnings per share nearly doubled compared to Q3 2023 totaling $0.91 in the quarter.

我們預計，隨著我們加速商業成長策略並推動研發管道，未來營運支出將開始增加，儘管費用成長率明顯低於收入成長，這將隨著時間的推移推動營運利潤率的提高。BioMarin 在 2024 年表現良好。我們第三季的 GAAP 攤薄每股收益比去年第三季成長 162%，達到 0.55 美元。與 2023 年第三季相比，我們第三季的非 GAAP 攤薄每股收益幾乎翻了一番，本季總計 0.91 美元。

We achieved a non-GAAP operating margin of 28% for the third quarter, driven by a combination of robust revenue growth and our commitment to operational efficiency. It is important to note that these results have been achieved during a year of significant transformation for the company, including the previously mentioned portfolio prioritization decisions and the ongoing execution of BioMarin's enterprise-wide reorganization. BioMarin's strong execution on profitability in Q3 2024 also generated significant operating cash flows totaling $221 million in Q3, an increase of 63% compared to the third quarter of last year. We also settled the $495 million of convertible debt maturity and cash during Q3 as planned.

在強勁的收入成長和我們對營運效率的承諾的共同推動下，我們第三季的非公認會計原則營運利潤率達到了 28%。值得注意的是，這些成果是在公司重大轉型的一年中取得的，包括前面提到的投資組合優先決策和 BioMarin 企業範圍重組的持續執行。BioMarin 在 2024 年第三季的獲利能力方面表現出色，在第三季也產生了總計 2.21 億美元的大量營運現金流，與去年第三季相比成長了 63%。我們還按計劃在第三季結算了 4.95 億美元的可轉換債務到期和現金。

This was the first time that BioMarin managed the convertible debt maturity without issuing a new convertible instrument, thereby retiring approximately 4 million potentially diluted shares and returning that value to shareholders. Total cash and investments at the end of Q3 2024 were approximately $1.5 billion. And we concluded the quarter with the balance sheet and an even stronger position as we continue on the trajectory to generate increasing operating cash flow into the future. As mentioned, given our strong year-to-date execution, we've raised our guidance at the midpoint across all items for 2024.

這是 BioMarin 首次在不發行新的可轉換工具的情況下管理可轉換債務到期日，從而退出約 400 萬股可能被稀釋的股票，並將該價值返還給股東。截至 2024 年第三季末，現金和投資總額約為 15 億美元。我們在本季結束時獲得了資產負債表和更強勁的地位，因為我們繼續走在未來產生不斷增加的營運現金流的軌道上。如前所述，鑑於我們今年迄今的強勁執行力，我們將 2024 年所有項目的指導上調至中點。

In addition to the aforementioned revenue guidance raise, we now guide to a non-GAAP operating margin of 26.5% to 27.5% representing a 7.6 percentage point expansion at the midpoint versus 2023. We have also increased our non-GAAP diluted earnings per share guidance to between $3.25 and $3.35 aligning with our goal to grow profitability faster than revenues. While we are expecting year-over-year revenue and profitability growth in the fourth quarter of 2024. It is important to reiterate that Q3 benefited from the Aldurazyme timing previously forecasted in Q4.

除了上述收入指引上調外，我們現在的非 GAAP 營業利潤率指引為 26.5% 至 27.5%，較 2023 年中位數成長 7.6 個百分點。我們也將非 GAAP 攤薄每股收益指引提高至 3.25 美元至 3.35 美元，符合我們獲利成長速度快於營收成長的目標。我們預計 2024 年第四季的營收和獲利能力將年增。需要重申的是，第三季受益於先前在第四季預測的 Aldurazyme 時機。

And to my comments a moment ago on operating expenses, we expect higher operating expenses in Q4 versus Q3 2024 also in line with historical Q4 trends. As a reminder, BioMarin's dynamic global business continues to experience quarter-to-quarter fluctuations and we point to our full year guidance and annual results as the best measures of our performance and growth. In summary, as we implement the revamp strategy, we drove strong results for the third quarter and year-to-date. This performance, along with our increased guidance for the year and reaffirmation of BioMarin's long-term outlook underscore our confidence in delivering high growth and superior returns in 2024 and beyond.

根據我剛才關於營運費用的評論，我們預計 2024 年第四季的營運費用將高於第三季度，這也符合第四季的歷史趨勢。謹此提醒，BioMarin 充滿活力的全球業務繼續經歷季度波動，我們將全年指導和年度業績作為衡量我們業績和成長的最佳指標。總之，隨著我們實施改革策略，我們在第三季和年初至今取得了強勁的業績。這一業績，加上我們增加的年度指引以及對 BioMarin 長期前景的重申，突顯了我們對在 2024 年及以後實現高成長和卓越回報的信心。

I will now turn the call to Cristin to discuss the commercial dynamics behind our strong quarterly performance. Cristin?

我現在將致電克里斯汀，討論我們強勁的季度業績背後的商業動態。克里斯汀？

Thank you, Brian. As you have heard, we are proud of our commercial performance, demonstrating continued momentum in the third quarter. The Voxzogo results underscore the significant opportunity ahead in achondroplasia where we have identified a Total Addressable Patient population or TAP of 24,000 patients across BioMarin's global commercial presence. To provide some context on our expanding global leadership in achondroplasia, we've been pleased with the number of new patient starts, especially for the youngest patients who can benefit most from the longer Voxzogo treatment. Supportive of this benefit we expect that new global guidelines will soon be published based on early real-world experience in clinical practice that recommends children with achondroplasia be referred as soon as diagnosis is suspected to enable early initiation of treatment.

謝謝你，布萊恩。正如您所聽到的，我們對我們的商業業績感到自豪，展示了第三季的持續成長勢頭。Voxzogo 結果強調了軟骨發育不全領域未來的重大機遇，我們已經在 BioMarin 的全球商業存在中確定了 24,000 名患者的總可尋址患者群體或 TAP。為了說明我們在軟骨發育不全領域不斷擴大的全球領導地位，我們對新患者開始治療的數量感到滿意，特別是對於最年輕的患者來說，他們可以從較長的 Voxzogo 治療中受益最多。為了支持這項益處，我們預計新的全球指南將很快根據臨床實踐中的早期實際經驗發布，建議一旦懷疑患有軟骨發育不全的兒童就應立即轉診，以便儘早開始治療。

These guidelines reinforce our belief that beginning treatment soon after diagnosis provides the optimal outcome for children with achondroplasia, including for benefits beyond height in the comorbidity associated with the condition. Now, since Voxzogo's approval in 2021, we've been extremely gratified to be able to provide families with the only approved therapy that treats the underlying cause of a achondroplasia. Through our ongoing global expansion, supported by a growing dossier of supportive safety and efficacy data, we aspire to reach every family interested in Voxzogo therapy. As we expand our global leadership in achondroplasia, we're pleased with the momentum behind Voxzogo awareness.

這些指南強化了我們的信念，即診斷後立即開始治療可為軟骨發育不全兒童提供最佳結果，包括與該疾病相關的合併症的除身高以外的益處。現在，自 Voxzogo 在 2021 年獲得批准以來，我們非常高興能夠為家庭提供唯一經批准的治療軟骨發育不全根本原因的療法。透過我們持續的全球擴張，在越來越多的支持性安全性和有效性數據的支持下，我們渴望惠及每一個對 Voxzogo 療法感興趣的家庭。隨著我們擴大在軟骨發育不全領域的全球領導地位，我們對 Voxzogo 意識背後的勢頭感到高興。

We have continued to add significant levels of new commercial patients with over 3,800 children being treated with Voxzogo worldwide at the end of the third quarter of 2024, compared to over 2,300 children as of the same period last year. This represents approximately 65% growth year-over-year. Our global commercial operations are yielding significant new patient starts, including in Europe, the Middle East and Latin America. We're committed to leveraging our global commercial capabilities to expand Voxzogo into more than 20 additional markets by 2027.

我們持續大幅增加新的商業患者，截至 2024 年第三季末，全球有超過 3,800 名兒童接受 Voxzogo 治療，而去年同期有超過 2,300 名兒童。這意味著同比增長約 65%。我們的全球商業營運正在產生大量新患者，包括在歐洲、中東和拉丁美洲。我們致力於利用我們的全球商業能力，到 2027 年將 Voxzogo 擴展到另外 20 多個市場。

We estimate that approximately 90% of the global achondroplasia total addressable patient population is outside of the US, which considering BioMarin's ability to leverage its established global commercial footprint is a significant competitive advantage. Moving to dynamics in the United States. We are seeing robust patient growth across all ages with the majority of new patient starts during the quarter from children under five years old. The expanded Voxzogo age label from infancy approved late last year in the US continues to be a major driver of new patient starts. And finally, on Voxzogo, consistent with BioMarin's prior product launches, Voxzogo has now reached a level of global commercialization where it's appropriate to focus on revenue rather than patient numbers as the key metric of growth.

我們估計，全球軟骨發育不全患者總數中約 90% 位於美國境外，考慮到 BioMarin 利用其已建立的全球商業足跡的能力，這是一個重大的競爭優勢。轉向美國的動態。我們看到各個年齡層的患者均出現強勁增長，本季大多數新患者都是五歲以下兒童。去年年底，美國批准了從嬰兒期開始的擴大的 Voxzogo 年齡標籤，這仍然是新患者開始使用的主要推動力。最後，在 Voxzogo 上，與 BioMarin 先前發布的產品一致，Voxzogo 現在已經達到了全球商業化的水平，適合關注收入而不是患者數量作為成長的關鍵指標。

As we launch into dozens of countries across multiple continents, patient-level data by country becomes unreliable or even unavailable. So as a result, with Voxzogo reaching its third full year of its global launch, this is the last quarter in which we will share quarterly patient growth. We will move forward using revenues as the key performance indicator. Now, turning to our enzyme therapies. 27% revenue growth during the quarter was driven by robust demand across the portfolio.

當我們進入多個大洲的數十個國家/地區時，各國的患者層級數據變得不可靠甚至不可用。因此，隨著 Voxzogo 在全球推出的第三個完整年頭，這是我們將分享季度患者成長的最後一個季度。我們將繼續使用收入作為關鍵績效指標。現在，轉向我們的酵素療法。該季度營收成長 27% 是由整個投資組合的強勁需求推動的。

While Q3 benefited from order timing dynamics, particularly for Aldurazyme. We also saw strong patient uptake across the brands that BioMarin commercializes, especially in Palynziq. New patient additions in the US and a strong ongoing launch in Japan drove 15% year-over-year revenue growth in Palynziq during the quarter. Looking forward, we expect continuing growth of the enzyme therapy portfolio as we implement new initiatives over the coming quarters outlined in Investor Day.

第三季受惠於訂單時間動態，尤其是 Aldurazyme。我們也看到 BioMarin 商業化的品牌的患者接受度很高，尤其是在 Palynziq。美國新增患者以及日本市場的持續推出推動 Palynziq 本季營收年增 15%。展望未來，隨著我們在投資者日概述的未來幾季實施新舉措，我們預計酵素療法組合將持續成長。

A few examples include focused investments in high-yield patient finding initiatives, selective geographic expansion and patient support programs enabling long-term adherence to therapies. We believe these additional initiatives will drive long-term compound annual growth rate in the high single digits for the enzyme therapies. In our Roctavian business, we generated $7 million in revenue during the quarter, supported by three new patient starts in Italy and three in the US. Recall that Roctavian price is weight based, so revenue per patient can fluctuate accordingly.

一些例子包括對高收益患者尋找計劃的集中投資、選擇性地理擴張和患者支持計劃，以實現長期堅持治療。我們相信，這些額外舉措將推動酵素療法的長期複合年增長率達到高個位數。在我們的 Roctavian 業務中，本季我們創造了 700 萬美元的收入，這得益於義大利的 3 個新患者啟動計畫和美國的 3 個新患者啟動計畫。回想一下，Roctavian 的價格是基於體重的，因此每位患者的收入可能會相應波動。

So to add color to the three countries we are focused on, let's start with the US. The US sites that have dosed patients have increased confidence in their ability to successfully negotiate single-case agreements and reimbursement. In Italy, patients have been treated across multiple regions thus far and going forward as new sites are added across the country, we expect to see increased patient uptake. And in Germany, we continue to work with additional sub insurers to facilitate access for patients, and we will provide further updates when we have progress to share.

因此，為了為我們關注的三個國家增添色彩，我們先從美國開始。為患者註射藥物的美國站點對其成功談判單例協議和報銷的能力信心增強。在義大利，到目前為止，患者已在多個地區接受治療，隨著全國各地新站點的增加，我們預計患者接受率將會增加。在德國，我們繼續與其他子保險公司合作，為患者提供便利，當我們有進展可分享時，我們將提供進一步的更新。

So in conclusion, our strong commercial performance in the third quarter, combined with the promising outlook for the remainder of 2024 has enabled us to raise our full year revenue guidance. We are excited about the opportunities ahead and are confident in our ability to deliver exceptional value to our patients and stakeholders around the world. Thank you so much for your attention. I'll now turn the call over to Greg to provide an R&D update. Greg?

總而言之，我們第三季強勁的商業表現，加上 2024 年剩餘時間的樂觀前景，使我們能夠提高全年營收指引。我們對未來的機會感到興奮，並對我們為世界各地的患者和利害關係人提供卓越價值的能力充滿信心。非常感謝您的關注。我現在將把電話轉給格雷格，以提供研發最新資訊。格雷格？

Thank you, Cristin. I'm happy to speak with you on my first quarterly results call since joining the company in September. Since joining as the lead for worldwide R&D, I've been energized by the team's commitment to innovation and their emphasis on execution. I look forward to leading this organization as we target 11 high-impact launches by 2034. These include two by 2027, those being Voxzogo for hypochondroplasia and Palynziq for adolescents.

謝謝你，克里斯汀。我很高興在 9 月加入公司以來的第一次季度業績電話會議上與您交談。自從加入作為全球研發負責人以來，我一直被團隊對創新的承諾和對執行的重視所激勵。我期待著領導這個組織，我們的目標是到 2034 年推出 11 項高影響力的產品。其中包括到 2027 年的兩個，即用於治療軟骨發育不全的 Voxzogo 和青少年的 Palynziq。

A few activities to highlight from the quarter. I'm pleased to announce that our pipeline is progressing well, including our Canopy clinical program evaluating the expanded potential of Voxzogo in children with hypochondroplasia and with other genetic skeletal conditions. For hypochondroplasia, we completed the enrollment target for the Phase III eligible patients in our observational study. After six months of observation, we anticipate that these very patients will feed directly into our Phase 3 Voxzogo Interventional Study to complete its enrollment in the first half of 2025.

本季需要重點介紹的一些活動。我很高興地宣布，我們的產品線進展順利，包括我們的 Canopy 臨床項目，該項目評估了 Voxzogo 在患有軟骨發育不全和其他遺傳性骨骼疾病的兒童中的擴大潛力。對於軟骨發育不全，我們在觀察性研究中完成了 III 期合格患者的入組目標。經過六個月的觀察，我們預計這些患者將直接進入我們的 3 期 Voxzogo 介入研究，並於 2025 年上半年完成入組。

We can, therefore, reaffirm our expectation for pivotal data for the hypochondroplasia Phase 3 program in 2026 and an approval in 2027 if those data are supportive. Our Phase 2 Canopy studies including one in idiopathic short stature and the second basket study in Noonan Syndrome, Turner Syndrome and SHOX deficiency, each remain on track. Looking forward to advancing these programs and we expect Phase 2 data readouts in 2026. At the 16th Annual International Skeletal Dysplasia Society Meeting in September, BioMarin and our external research partners contributed to eight presentations, including four orals, discussing the value of Voxzogo in the burden of illness in achondroplasia and related disorders.

因此，我們可以重申我們對 2026 年軟骨發育不全第 3 期計畫關鍵數據的期望，如果這些數據具有支持性，那麼我們將在 2027 年獲得批准。我們的 Canopy 2 期研究包括一項針對特發性身材矮小的研究，以及另一項針對努南症候群、特納氏症和 SHOX 缺陷症的籃子研究，每項研究均仍在正常進行中。期待推進這些計劃，我們預計第 2 階段的數據將於 2026 年讀出。在9 月舉行的第16 屆國際骨骼發育不良協會年度會議上，BioMarin 和我們的外部研究合作夥伴發表了8 場演講，其中包括4 場口頭演講，討論了Voxzogo 在軟骨發育不全及相關疾病的疾病負擔方面的價值。

These data included showing that children with achondroplasia treated with Voxzogo experienced meaningful improvements beyond height, such as gains in health-related quality of life and maintained bone strength while increasing bone length. Researchers also presented encouraging data from ongoing investigator-led studies in children with other genetic skeletal conditions. These included hypochondroplasia, Noonan Syndrome and with genetic variants often associated with idiopathic short stature, such as aggrecan deficiency and heterozygous NPR2 mutations. Our Phase 3 program with Palynziq and adolescents aged 12 to 17 has completed enrollment and is expected to read out in the first half of 2025.

這些數據顯示，接受 Voxzogo 治療的軟骨發育不全兒童在身高之外獲得了有意義的改善，例如健康相關生活品質的提高以及在增加骨長度的同時保持骨強度。研究人員還提供了由研究者主導的針對患有其他遺傳性骨骼疾病的兒童正在進行的研究的令人鼓舞的數據。其中包括軟骨發育不全、努南氏症候群以及通常與特發性身材矮小相關的遺傳變異，例如聚集蛋白聚醣缺陷和雜合 NPR2 突變。我們針對 Palynziq 和 12 至 17 歲青少年的第 3 階段計劃已完成註冊，預計將於 2025 年上半年宣讀。

This will allow for a potential supplemental NDA filing midyear 2025. We believe this supplement for adolescents could offer patients and their families the opportunity to address the burden of fetal ketonuria as well as the dietary restrictions early on and thus facilitate an easier transition to independent adult living. With our earlier stage pipeline, I am pleased to share that BMN 351 for Duchenne's Muscular Dystrophy, a potential best-in-class therapy has completed enrollment of our first cohort 6 patients with initial proof-of-concept data expected internally in quarter two of 2025, this will be in the form of muscle dystrophin levels after 25 weeks of dosing. With BMN 349 an oral therapeutic for alpha-1 antitrypsin deficiency associated liver disease. We have completed the single ascending dose study in healthy volunteers and expect to begin the multiple-ascending dose study by the end of the year.

這將允許在 2025 年年中提交補充 NDA 申請。我們相信，這種針對青少年的補充劑可以為患者及其家人提供機會，以解決胎兒酮尿症的負擔以及早期的飲食限制，從而促進更容易過渡到獨立的成年生活。透過我們的早期產品線，我很高興地與大家分享，用於治療杜興氏肌肉營養不良症的BMN 351，一種潛在的同類最佳療法，已經完成了我們第一批6 名患者的入組，初步概念驗證數據預計將在2020 年第二季度內部完成。BMN 349 是一種口服療法，用於治療 α-1 抗胰蛋白酶缺乏相關的肝臟疾病。我們已經完成了在健康志願者中進行的單次劑量遞增研究，並預計在今年年底開始進行多次劑量遞增研究。

Finally, I'm happy to share that BioMarin's long-acting C-Type naturetic peptide BMN 333 remains on track for initiation of the first-in-human study in early 2025. I look forward to future opportunities to communicate our progress across the R&D organization over the coming quarters and to personally meeting many of you at an upcoming investor event. Thank you for your continued support, and we will now open the call to your questions. Operator?

最後，我很高興地告訴大家，BioMarin 的長效 C 型天然勝肽 BMN 333 仍有望在 2025 年初啟動首次人體研究。我期待著未來有機會在未來幾季交流我們整個研發組織的進展，並在即將舉行的投資者活動中親自會見你們中的許多人。感謝您一直以來的支持，我們現在將開始電話解答您的問題。操作員？

(Operator Instructions) Phil Nadeau, TD Cowen.

（操作員說明）Phil Nadeau，TD Cowen。

Just two for us, one on Voxzogo and one on. On Voxzogo, you noted that patient starts were primarily among the patients under the age of five here in the US. What does that say about the maturity of the launch in the US? Are we approaching a period where new patients start to largely be an incident population?

我們只有兩份，一份在 Voxzogo 上，另一份在 Voxzogo 上。在 Voxzogo 上，您指出，開始治療的患者主要是美國五歲以下的患者。這說明了在美國推出的成熟度​​如何？我們是否正在接近新患者開始成為主要發病族群的時期？

Or is there still a lot of the prevalent population out there that's untreated in the US and could go on therapy? The second, on business development, James, welcome. Congrats on the new position and great article and BioSentry over the weekend. Curious, based on the presentation, you noted you want to target deals less than $1.5 billion. What phase of development would be ideal for BioMarin at this stage in the pipeline's maturity?

或者在美國還有很多未接受治療的流行人群可以繼續治療？第二，關於業務發展，詹姆斯，歡迎。恭喜週末獲得新職位、精彩文章和 BioSentry。奇怪的是，根據演示文稿，您指出您希望目標交易金額低於 15 億美元。在管道成熟的現階段，什麼階段的開發對 BioMarin 來說是理想的？

Yes, I'll take the first question. Thanks so much for it. So with regard to Voxzogo growth well into our third year the launch. You mentioned the callout on the age of being treated. So that is true that with the label expansion that we had in the US only last year, we are seeing the majority of new patient starts in the zero to five-year-old age group.

是的，我將回答第一個問題。非常感謝。因此，Voxzogo 的成長已經進入了我們推出的第三年。您提到了接受治療年齡的標註。確實如此，隨著我們去年在美國進行的標籤擴展，我們看到大多數新患者都是從零到五歲的年齡組開始的。

So that is more for the maturity of when that what the label has expanded in the US. In other markets where we have really high penetration in some of our early strategic markets where we have patient level data, we're seeing that many of the new starts are in the zero to two population. So to your point, that's where we really do start to see that incident market be created where we have higher penetration.

因此，這更多是因為該品牌在美國擴張的成熟度。在其他市場中，我們在一些早期策略市場的滲透率非常高，我們擁有患者層級的數據，我們發現許多新啟動的人群都是零到兩歲的人群。因此，就您的觀點而言，這就是我們真正開始看到在我們具有更高滲透率的地方創建事件市場的地方。

Phil, this is Alexander. I'll take the question on the business development. James is not on the Q&A today. With regard to business development, we will be focusing, as you say, on transactions less than $1.5 billion in transaction size. We'll have two areas of focus that James will be prioritizing.

菲爾，這是亞歷山大。我將回答有關業務發展的問題。詹姆斯今天沒有參加問答。至於業務發展，正如你所說，我們將專注於交易規模小於15億美元的交易。詹姆斯將優先考慮兩個重點領域。

One is really leveraging our scientific right to win our development, regulatory, manufacturing and commercial footprint across the globe in approximately 80 countries to identify potential deals. He's also working with research in terms of identifying earlier transactions in our pipeline to bolster our early research efforts and pipeline. So those are the two focuses that James has. He's just in his first month in the role, and you'll hear more from him in the future.

一是真正利用我們的科學權利贏得我們在全球約 80 個國家的開發、監管、製造和商業足跡，以確定潛在的交易。他還致力於研究確定我們管道中的早期交易，以支持我們的早期研究工作和管道。所以這是詹姆斯的兩個重點。他剛上任第一個月，以後你會聽到更多他的消息。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

Could you just walk through the development strategy here for BMN 333 and how quickly you can move into other indications beyond achondroplasia with the long-acting CNP? And then separately, with regard to your IP strategy here in the context of Ascendis and the long-acting CNP, just help us understand where you stand on your IP and just the strategy on the forward here with regard to your franchise?

您能否在此簡單介紹 BMN 333 的開發策略，以及利用長效 CNP 進入軟骨發育不全以外的其他適應症的速度有多快？然後，分別考慮您在 Ascendis 和長期發揮作用的 CNP 背景下的智慧財產權策略，請幫助我們了解您在智慧財產權方面的立場，以及關於您的特許經營權的未來策略？

Thanks, Salveen. This is Greg Guyer. I'll take the first question. With regard to BMN 333, of course, we're quite excited to be able to bring that at patients, and we should be entering the clinic early next year. The strategy behind the molecule, of course, is to elongate the half life, and we're confident that the linker technology and the binding technology, again, are tried and true, and we'll be able to do that.

謝謝，薩爾文。這是格雷格·蓋爾。我來回答第一個問題。當然，對於 BMN 333，我們非常高興能夠將其帶給患者，我們應該會在明年初進入臨床。當然，該分子背後的策略是延長半衰期，我們相信連接技術和結合技術再次經過嘗試並且是真實的，我們將能夠做到這一點。

What that can afford, of course, is one of two things. The less exciting would be less frequent administration. But the more exciting aspect is the one I just want to focus on for a moment, which is if you can change the PK profile of this near native CNP and you can increase the delivery of that hormone into the body in a safe way, then we could think about actually increasing not only the pharmacokinetic exposure to CNP but also the pharmacodynamic effect in our preclinical models would suggest that there is more to be gained there with regard to activity and bone lengthening.

當然，它所能承受的只是兩件事之一。不太令人興奮的是管理頻率較低。但更令人興奮的方面是我想暫時關注的一個方面，那就是如果你可以改變這種接近天然的 CNP 的 PK 特徵，並且可以以安全的方式增加該激素進入體內的輸送，那麼我們可以考慮實際上不僅增加CNP 的藥物動力學暴露，而且增加臨床前模型中的藥效學效應，這表明在活性和骨延長方面還有更多收穫。

And the first set of data is going to give us a lot of important clues as to whether or not the PK profile is playing out the way that we had anticipated. That's data that we should have in-house next year. The healthy volunteer study is going to give us a good read on that PK profile. Depending upon the results there, we could go in a variety of directions. We do believe, as you point out nicely that this is a pathway that should be able to address genetic skeletal disorders beyond simply achondroplasia and hypochondroplasia, and the teams are working very diligently to come up with scenarios if that profile plays out the way that we believe it may to accelerate that approval.

第一組數據將為我們提供許多重要線索，讓我們了解 PK 情況是否按照我們預期的方式進行。這是我們明年應該擁有的內部數據。健康志願者研究將使我們更了解 PK 概況。根據那裡的結果，我們可以朝不同的方向發展。我們確實相信，正如您很好地指出的那樣，這是一條應該能夠解決遺傳性骨骼疾病的途徑，而不僅僅是軟骨發育不全和軟骨發育不全，並且團隊正在非常努力地工作，以提出如果該情況按照我們的方式進行的話。

More to come there. But I think you've highlighted very nicely that there are opportunities here to accelerate the program, and we'll be looking for those actively.

還會有更多的事情發生。但我認為你很好地強調了這裡有加速該計劃的機會，我們將積極尋找這些機會。

And Salveen, with regard to your question around IP, I'm not going to elaborate further on IP beyond what we said on Investor Day, I simply put we're confident in the intellectual property we have, and we plan to vigorously defend our intellectual property.

And Salveen, with regard to your question around IP, I'm not going to elaborate further on IP beyond what we said on Investor Day, I simply put we're confident in the intellectual property we have, and we plan to vigorously defend our智慧財產.

Jessica Fye, JPMorgan.

潔西卡法耶，摩根大通。

First, on the P&L, COGS looks elevated this quarter. The press release makes mention of the impact of Roctavian inventory reserves. How big was that? And would gross margin have been in line with more recent quarters without that effect?

首先，從損益表來看，本季的銷貨成本看起來有所上升。新聞稿提到了 Roctavian 庫存儲備的影響。那有多大？如果沒有這種影響，毛利率是否會與最近幾季保持一致？

And then maybe following up on Salveen's question for 333. I think you've talked about single ascending dose data in 2025. Is it possible we could get a full dose data next year as well? Or if not, should we think of that in 2016?

然後可能會跟進 Salveen 的 333 問題。我想您已經談到了 2025 年的單次劑量遞增數據。明年我們是否也可以獲得完整的劑量數據？或者如果沒有，我們是否應該在 2016 年考慮這一點？

Hi, Jess, this is Brian, I'll take the first question on COGS and margin. Good pickup. Cost of goods sold here in Q3 '24 at about 25% of revenue and a 75% gross margin. That is a click down from where we've been trending close to 80%. Two things going on there this quarter. First is that Bolus of Aldurazyme revenue that we had that we commented on in the prepared remarks.

嗨，傑西，我是布萊恩，我將回答關於銷貨成本和利潤的第一個問題。很好的接機。2024 年第三季這裡銷售的商品成本約佔營收的 25%，毛利率為 75%。這比我們的趨勢趨勢接近 80% 有所下降。本季發生了兩件事。首先是我們在準備好的評論中評論過的 Aldurazyme 收入的 Bolus。

So Aldurazyme revenue, again, Sanofi is responsible for marketing to third parties. We recognize revenue when we supply bulk inventory to Sanofi as delivered and control is transferred. So I had a number of lots delivered in Q3. And because we're recognizing roughly half of the Aldurazyme revenue according to the revenue split with Sanofi, that means that Aldurazyme is our lowest margin product, roughly half or less of the gross margin we earn across the rest of the portfolio.

因此，Aldurazyme 的收入再次由賽諾菲負責向第三方行銷。當我們向賽諾菲提供已交付的大宗庫存且控制權轉移時，我們確認收入。所以我在第三季交付了許多批次。因為我們根據與賽諾菲的收入分成確認了大約一半的 Aldurazyme 收入，這意味著 Aldurazyme 是我們利潤率最低的產品，大約是我們在其他產品組合中賺取的毛利率的一半或更少。

So high rate of Aldurazyme revenue, lower gross margin, that's going to be dilutive to margins in the quarter.

Aldurazyme 的收入如此之高，但毛利率較低，這將稀釋本季的利潤率。

And then secondly, we did have some inventory reserves here in Q3 mostly related to some gene therapy raw materials that because we paused Roctavian manufacturing, we took a reserve on before they expire And nothing else going on. Those two items account for roughly 5%, which would put us close to the 80% -- 79%, 80% that we've been tracking to this year.

其次，我們在第三季確實有一些庫存儲備，主要與一些基因治療原料有關，因為我們暫停了 Roctavian 的生產，我們在它們到期之前保留了儲備，沒有其他情況發生。這兩項約佔 5%，這將使我們接近今年我們一直追蹤的 80% - 79%、80%。

This is one or the other?

這是其中之一還是另一個？

No, roughly half and half between those two.

不，兩者之間大約各佔一半。

And Jessica, with regard to BMN 333, the single ascending dose study, of course, is in healthy volunteers. Right now, what we're committing to in 2025 is that, that is the PK data that we'll have in-house. Of course, the data we are very eager to gather would be in patients and would be to see dose ranging and multiple ascending doses. As of right now, what we're committed to publicly is the 2025 data point, and we'll keep you updated as we move along.

傑西卡，關於 BMN 333，單次劑量遞增研究當然是在健康志願者中進行的。目前，我們在 2025 年承諾的是，這就是我們將擁有的內部 PK 數據。當然，我們非常渴望收集患者的數據，並了解劑量範圍和多次遞增劑量。截至目前，我們公開承諾的是 2025 年數據點，我們將隨時向您通報最新情況。

Paul Matteis, Stifel.

保羅馬蒂斯，斯蒂菲爾。

Great. As it relates to your reiteration of guidance, I think the inference that many analysts and investors have made that if you're willing to or I guess, confident in reiterating your guidance in the face of made some surprising increased competition in achondroplasia. You must have thought originally that your guidance issued at the Investor Day was fairly conservative. Is that the right inference? And if so, on what points did you feel like your initial guidance was conservative? Around what points do you feel like the Street is missing the big picture on your long-term vision around the size of these markets and your penetration?

偉大的。由於這與您重申指導意見有關，我認為許多分析師和投資者都做出了這樣的推論：如果您願意或我猜，面對軟骨發育不全領域令人驚訝的競爭加劇，有信心重申您的指導意見。您最初一定認為您在投資人日發布的指引相當保守。這是正確的推論嗎？如果是這樣，您認為最初的指導在哪些方面是保守的？您認為華爾街在哪些方面忽略了您對這些市場規模和滲透率的長期願景？

Thanks, Paul. This is Brian. I'll start and then Alexander has anything more to add. We would not describe the long-term guidance as conservative. What we have said is that when the new competitor data showed up, which was different than what most of us had seen leading up to that announcement. We took that additional data, went back and worked it through our model.

謝謝，保羅。這是布萊恩.我先開始，然後亞歷山大還有什麼要補充的。我們不會將長期指導描述為保守。我們所說的是，當新的競爭對手數據出現時，這與我們大多數人在宣布消息之前所看到的不同。我們獲取了額外的數據，然後返回並透過我們的模型進行處理。

We shared on Investor Day that our long-term revenue guidance did already have a competition assumption. We didn't go into detail, but fair to say it was based on data available to the world at the time, which was not that most recent data. And so when we went back and reworked our assumptions around both competitive share as well as, frankly, other levers available to us across the portfolio and within Voxzogo, we were able to absorb and confidently reaffirm the long-term guidance. So again, we would not call it conservative, but we are confident in where we landed after that follow-on analysis.

我們在投資者日表示，我們的長期收入指引確實已經有了競爭假設。我們沒有詳細說明，但公平地說，它是基於當時世界上可用的數據，而不是最新的數據。因此，當我們回過頭來圍繞競爭份額以及坦率地說，我們在整個投資組合和 Voxzogo 內可用的其他槓桿重新制定我們的假設時，我們能夠吸收並自信地重申長期指導。再說一遍，我們不會稱之為保守，但我們對後續分析後的結果充滿信心。

Thanks very much, Brian. What I would add, Paul, is if you for the period into the longer term, beyond the '27, we're talking about and we're reaffirming our targeting mid-teen CAGR and the 5 billion potential for skeletal conditions. Obviously, that very much factors in also the tap in these further indications beyond achondroplasia. And just to reiterate, we resumed very modest penetration levels in forecast that underpin that outlook.

非常感謝，布萊恩。保羅，我要補充的是，如果你從長遠來看，在 27 世紀之後，我們正在討論並重申我們的目標是青少年複合年增長率和 50 億骨骼疾病的潛力。顯然，這在很大程度上也影響了軟骨發育不全以外的其他適應症的表現。重申一下，我們在預測中恢復了非常溫和的滲透率水平，這支撐了這一前景。

And additional competitors should they declare a development plan in those indications. They will be contributing to the growth of those markets, which we would share with them in some proportion. And then the last thing I would say is, of course, all of this excludes intellectual property and our confidence in our intellectual property position, which I've already talked it.

其他競爭對手應該宣布針對這些適應症的開發計劃。他們將為這些市場的成長做出貢獻，我們將與他們分享一定比例的份額。我要說的最後一件事當然是，所有這些都排除了智慧財產權和我們對智慧財產權地位的信心，我已經談到了這一點。

Eli Merle, UBS.

伊萊·梅爾，瑞銀集團。

Can you give us a bit more color on what's driving the increase in the ERT business growth? And I guess your confidence that this can continue to grow in the high single digits for years to come. I think you mentioned some initiatives you're working on, if you can maybe elaborate a bit more on what those entail?

您能給我們詳細介紹一下推動 ERT 業務成長的因素嗎？我猜你有信心在未來幾年內這一數字可以繼續以高個位數成長。我想您提到了您正在進行的一些舉措，您能否詳細說明一下這些舉措的含義？

Hi Eli, thanks for the question, it's Cristin. So yes, great question on our ERT business. So as we had said at Investor Day and stand firm behind we anticipate high single-digit growth for the years to come in that business. And primarily driven right now there are a lot coming from the Palynziq market or the business there that you saw in the numbers, we have 15% growth in Palynziq and a lot of that is being driven primarily in the US market, where we are seeing really great uptake not only for new patient starts that see the highly beneficial impact that Palynziq can have both from an efficacy and lowering fee levels as well as a liberalization on their diet.

嗨，伊萊，謝謝你的提問，我是克莉絲汀。是的，這是一個關於我們 ERT 業務的好問題。因此，正如我們在投資者日所說並堅定支持，我們預計該業務在未來幾年將實現高個位數成長。現在主要是由 Palynziq 市場或您在數位中看到的業務驅動的，我們在 Palynziq 增長了 15％，其中許多主要是在美國市場驅動的，我們看到真正的巨大吸收不僅對於新患者來說，他們看到Palynziq 可以從功效、降低費用水平以及飲食自由化方面產生非常有益的影響。

So they don't need to do medical nutrition. That's driving a lot of new patient starts, but we're also focused on picking up on any patients who have discontinued therapy. And so we're seeing really great uptake there, so that's the Palynziq business. But on the MPS CLN2 areas and our global footprint of over 80 countries, approximately 80 countries, what we're seeing there is that we're putting some new initiatives into place, which, as you had alluded to, I mentioned at Investor Day, and what those are, are looking at high-yield diagnostic efforts in markets where we think we can really move the needle as well as some adherence programs in a few select markets and expansion into new geographies where we think that the access marketplace is in the right place for us to move forward.

所以他們不需要做醫學營養。這推動了許多新患者開始接受治療，但我們也專注於接診任何已停止治療的患者。所以我們看到那裡的吸收率非常高，這就是 Palynziq 業務。但在 MPS CLN2 領域以及我們在 80 多個國家（大約 80 個國家）的全球足跡中，我們看到我們正在實施一些新舉措，正如您所提到的，我在投資者日提到以及這些是什麼，正在關注我們認為我們可以真正推動發展的市場中的高收益診斷工作，以及在一些選定市場中的一些堅持計劃，以及擴展到我們認為進入市場所在的新地區。 。

Those are the initiatives that we've mentioned we're going to start, but because of the nascent stage of those initiatives, we don't have an update to give on those yet, but we'll commit to further showing the progress that we're making in those. I've seen early data that are looking very good, but we will be updating you in the future. Not to mention, as we've talked a lot about, we are moving as well in transforming the business into business unit models, which we believe that, that alone will really help us to drive the urgency, the accountability and the real clarity of where we can move our resources in a quick way. So we'll be reporting on that in the earnings calls and investor days to come.

這些是我們提到的我們將要啟動的舉措，但由於這些舉措還處於初期階段，我們還沒有更新這些舉措，但我們將致力於進一步展示所取得的進展我們正在做這些。我已經看到了看起來非常好的早期數據，但我們將在將來為您更新。更不用說，正如我們已經談論過的那樣，我們也在將業務轉變為業務單元模型，我們相信，僅此一項就將真正幫助我們提高業務的緊迫性、責任感和真正的清晰度。在這裡快速轉移我們的資源。因此，我們將在未來的財報電話會議和投資者日中對此進行報告。

Cory Kasimov, Evercore.

科里·卡西莫夫，Evercore。

Just two for me as well. So for Voxzogo, can you comment as to how many patients from your original Phase 3 trial have now reached their full adult height? And then just a clarification on the DMD program. You noted that you're going to have the data in-house in Q2. Is that going to be publicly shared at that time as well? I just wasn't sure when you said it was going to be internal.

我也只有兩個。那麼對於 Voxzogo，您能否評論一下您最初的 3 期試驗中有多少患者現在已經達到了成年身高？然後是對 DMD 計劃的澄清。您指出，您將在第二季擁有內部數據。到時候也會公開分享嗎？我只是不確定你什麼時候會說這將是內部的。

Thanks, Cory. This is Greg. For the first question, we are tracking those patients from the Phase 3 program very vigorously. We're not going to release numbers with regard to how many patients have reached final adult height. Clearly, that is an endpoint that regulators are very interested in, and that is part of our commitment for post-marketing requirements to provide that data at a reasonable time. Part of the challenge, of course, is that these patients reach that final adult height in different timing based on what age they were when they entered the study. But suffice to say, we're, of course, following that very closely and continue to make progress year-to-year.

謝謝，科里。這是格雷格。對於第一個問題，我們正在非常積極地追蹤第三階段專案的患者。我們不會公佈有多少患者達到最終成年身高的數字。顯然，這是監管機構非常感興趣的端點，也是我們對上市後要求在合理時間提供該數據的承諾的一部分。當然，部分挑戰在於，這些患者根據他們進入研究時的年齡，在不同的時間達到最終的成年身高。但可以說的是，我們當然會非常密切地關注這一點，並繼續逐年取得進展。

With regard to the Duchenne Muscular Dystrophy program, yes, we're very excited that we will have muscle dystrophin data from the first six patients in-house midyear. We'll be looking at that. And just to take a step back for those who aren't quite as familiar, this is a molecule that's engineered to increase dystrophin levels in the muscle to levels that are dramatically higher than what we've seen with other molecules in the space. And there's a variety of engineering levers that were pulled to try to accomplish that.

關於杜氏肌肉營養不良症項目，是的，我們非常興奮，我們將在年中獲得前六名內部患者的肌肉營養不良蛋白數據。我們會關注這一點。對於那些不太熟悉的人來說，這是一種經過設計的分子，可以將肌肉中的肌肉營養不良蛋白水平提高到比我們在太空中看到的其他分子高得多的水平。為了實現這一目標，人們使用了各種工程槓桿。

But the most important of which is addressing a novel binding domain in the nucleic acid that at least the preclinical models results in 30%, 40%, 50% dystrophin levels in the rodent models at a much higher rate than what we've seen with other molecules that we both synthesized and those that are available. So that data from the first cohort is going to give us a line of sight on whether or not we can hit our target. Our target is a 10% level or higher at steady state in the muscle of these boys who are on the study. Now it's important to remember that steady state actually is not at 25 weeks. It may be later than that.

但其中最重要的是解決核酸中的一個新的結合域，至少臨床前模型在囓齒動物模型中導致 30%、40%、50% 的肌肉營養不良蛋白水平比我們所看到的要高得多我們合成的和可用的其他分子。因此，第一批數據將使我們了解是否能夠實現目標。我們的目標是參與研究的這些男孩的肌肉在穩定狀態下達到 10% 或更高的水平。現在重要的是要記住，穩定狀態實際上並不是在 25 週時。可能會晚點。

But we've done some modeling, and I think with our 13-week data and our 26-week biopsies, we'll have a good read by midyear where we're headed. Depending on what that data is, it may be worthy of release, it may be giving us information that also tells us that we need to adjust the dose but we will certainly be revealing that data when we feel that it's of a sufficient quality and volume that it would be meaningful to release. Beyond that, not much more to add at this point.

但我們已經做了一些建模，我認為透過我們 13 週的數據和 26 週的活檢，我們將在年中之前對我們的發展方向有一個很好的了解。根據數據的內容，它可能值得發布，它可能為我們提供的資訊也告訴我們需要調整劑量，但當我們認為數據的品質和數量足夠時，我們肯定會披露這些數據釋放是有意義的。除此之外，目前無需添加更多內容。

Kostas Biliouris, BMO Capital Markets.

Kostas Biliouris，BMO 資本市場。

Hello, everyone. Congrats on the quarter. Two quick from us, one on Voxzogo and one on Palynziq. On Voxzogo follow-up from a question before. Can you remind us what is the status of the transition to full approval from accelerated approval and what this may mean for the regulatory pathway of competitors that are behind you in development?

大家好。恭喜本季。我們很快就收到了兩份，一份在 Voxzogo，一份在 Palynziq。關於 Voxzogo 之前問題的後續。您能否提醒我們，從加速批准過渡到全面批准的情況如何？

And the second question on Palynziq is any thoughts around competitive positioning given that some oral agents may enter the market in 2025?

Palynziq 的第二個問題是，考慮到一些口服製劑可能會在 2025 年進入市場，對競爭定位有何想法？

Thank you Kostas, this is Greg again. Why don't I take a stab at those two. With respect to Voxzogo, we are committed to measuring final adult height on our patients who were on our clinical study, our pivotal study, and we have that agreement with regulatory authorities. Beyond saying that we're vigorously collecting that data and looking forward to reaching the critical mass that the regulators are interested in.

謝謝科斯塔斯，我又是格雷格。我為什麼不去刺殺那兩個人呢？就 Voxzogo 而言，我們致力於測量參與我們臨床研究（我們的關鍵研究）的患者的最終成年身高，並且我們與監管機構達成了這項協議。除此之外，我們正在積極收集這些數據，並期待達到監管機構感興趣的臨界質量。

I don't have much else to add. Of course, regulators with regard to full and accelerated approval, they always have their ability to use their judgment to decide when new agents come along. So we're very much focused on our own agent and being able to convert that to full approval for the good of, of course, the patients who are treated with. With regard to Palynziq, the PKU space is one that BioMarin has a fortunate position to be able to serve these patients for almost 20 years now.

我沒有太多要補充的了。當然，監管機構對於全面和加速批准，他們總是有能力運用自己的判斷來決定何時出現新的代理人。因此，我們非常關注我們自己的藥物，並能夠將其轉化為完全批准，當然，這也是為了接受治療的患者的利益。就 Palynziq 而言，BioMarin 很幸運能夠在 PKU 領域為這些患者提供服務近 20 年。

And in that time, we've learned quite a bit about the space, about the patients, about the treating physicians and about what the needs of this group are. The big picture here is that these are a very heterogeneous group of patients. They have different ages. They have different needs. We know from the clinical studies that they respond differently to the therapies that are available.

在那段時間裡，我們對這個空間、病人、治療醫生以及這個群體的需求有了很多了解。整體情況是，這些患者是一群非常異質的患者。他們有不同的年齡。他們有不同的需求。我們從臨床研究得知，它們對現有療法的反應不同。

And because of that, we see the addition of new agents to this field actually is being good for patients. It will give physicians more arrows in their quiver. Not every patient has created equal a Palynziq patient, for example. These are patients in our pivotal study that had fee levels that were over 1,000, for example.

正因為如此，我們看到在這一領域添加新藥物實際上對患者有好處。它將為醫生的箭袋裡提供更多的箭。例如，並非每個患者都創造出與 Palynziq 患者相同的水平。例如，在我們的關鍵研究中，這些患者的費用水準超過 1,000。

And this is a molecule that if you look at the treatment guidelines that are out there, the Palynziq patient, the goal of that patient is to be able to reduce the fee levels as low as possible. And I believe the quote in many of the guidelines is with a normalized diet. That is a very different patient than perhaps the BH4, analogs may be able to address. That being said, it's a good thing for patients that they have multiple different options, and we're anticipating that these are the kind of advances that patient's need.

這是一個分子，如果你看看現有的治療指南，Palynziq 患者，該患者的目標是能夠盡可能降低費用水平。我相信許多指南中的引用都是針對正常化的飲食。這是一個與 BH4 類似物能夠解決的患者截然不同的患者。話雖如此，對於患者來說，他們有多種不同的選擇是一件好事，我們預期這些正是患者所需的進步。

In fact, we're developing a next-generation Palynziq because we believe that we can help build upon that profile as well. So that standpoint, I think the only other objective data that's out there, there was an FDA ruling recently. One of the oral agents that was filed was given a standard review. By definition, they use two criteria when they define that.

事實上，我們正​​在開發下一代 Palynziq，因為我們相信我們也可以幫助建立這項配置。因此，從這個角度來看，我認為唯一存在的其他客觀數據是 FDA 最近的一項裁決。其中一種已提交的口服藥物已接受標準審查。根據定義，他們在定義時使用兩個標準。

One is that, is this a serious illness. We believe that PK is a serious illness by their definition. The other criteria they use is did this new applicant meet the criteria for a significant improvement in efficacy and safety compared to available therapies. They obviously chose to give a standard review. So I think from an objective standpoint, that speaks for itself.

一是，這是一個大病嗎？我們認為，根據他們的定義，PK 是一種嚴重的疾病。他們使用的另一個標準是這位新申請人是否符合與現有療法相比功效和安全性顯著改善的標準。他們顯然選擇了標準審查。所以我認為從客觀的角度來看，這是不言而喻的。

Joe Schwartz.

喬·施瓦茨。

I have a question on 333 and also 390. So at your Investor Day, I think you projected that 333 could come to market in 2030. But since your CNP patent expires in that year, that doesn't seem to give you much time to convert people to your own long-acting before generics arrive and then you'll probably also have a couple of branded competitors by then. So I'm just wondering if you can talk about the practical benefit of 333 is expected to be on the business?

我有一個關於 333 和 390 的問題。因此，在您的投資者日，我認為您預計 333 可能會在 2030 年上市。但由於你的 CNP 專利在那一年到期，在仿製藥到來之前，你似乎沒有太多時間讓人們轉向你自己的長效藥物，到那時你可能還會有幾個品牌競爭對手。所以我想知道您是否可以談談333預計對業務帶來的實際好處？

And then likewise, you noted there that your next gen Palynziq with a novel PEG could expand the PKU market a lot, but the development path you laid out suggested it would take about 10 years to get it to market. I know PEGPAL took that long, but I'm just wondering why should it take that long for BMN 390.

同樣，您在那裡指出，具有新型 PEG 的下一代 Palynziq 可以極大地擴大 PKU 市場，但您制定的發展路徑表明，需要大約 10 年才能將其推向市場。我知道 PEGPAL 花了那麼長時間，但我只是想知道為什麼 BMN 390 需要那麼長時間。

Thanks, Joe. I'm going to hand it off to Alexander first.

謝謝，喬。我先把它交給亞歷山大。

Just wanted to just start off with the first part of your question with regard to 333 and the rationale given the patent on the Voxzogo. Actually, we estimate our patents, our IP will last to the mid-2030s, therefore, giving us plenty of time after the launch of 333 to convert the market over. Again, as you well know, Joe, the target product profile here is for a product that's more efficacious as well as offering the convenience of weekly dosing. We think that is a sort of proposition that's required to move patients off Voxzogo.

只是想從您關於 333 的問題的第一部分以及 Voxzogo 專利的基本原理開始。實際上，我們估計我們的專利、我們的IP將持續到2030年代中期，因此，在333推出後給我們足夠的時間來轉換市場。喬，正如您所知，這裡的目標產品簡介是更有效且提供每週給藥便利的產品。我們認為這是讓患者遠離 Voxzogo 所必需的一種主張。

The hierarchy needs of both physicians and caregivers is, first and foremost, efficacy, safety, and then only if those are improved its convenience, seem to be important. So we're very focused on that. And if we're successful with that product profile with this time frame, we believe we can convert our business from Voxzogo. And now I hand it over to Greg for the rest of your question.

醫生和護理人員的層次需求首先是功效、安全性，然後只有當這些都得到改善時，其便利性似乎才重要。所以我們非常關注這一點。如果我們在這個時間範圍內成功地實現了該產品簡介，我們相信我們可以將 Voxzogo 的業務轉變為我們的業務。現在我把你剩下的問題交給格雷格。

Thanks, Alexander. With regard to BMN 390. I would just comment that we're very early in its development. We're pleased that we'll be able to file an IND targeting next year. The dates that you laid out indeed represent similar development time lines to the predecessor molecules.

謝謝，亞歷山大。關於 BMN 390。我只想評論說我們還處於開發的早期階段。我們很高興明年能夠提交 IND 目標。您列出的日期確實代表了與前身分子類似的開發時間軸。

I would think of those as the upper error bar. We're going to be working very diligently not only has the profile reveals itself, but also as we learn more in the marketplace of developing Palynziq as well to look for opportunities to accelerate that development.

我將其視為上部誤差線。我們將非常努力地工作，不僅要讓資料顯示出來，而且隨著我們在開發 Palynziq 的市場中了解更多，我們也會尋找加速開發的機會。

Akash Tewari, Jefferies.

阿卡什·特瓦里，杰弗里斯。

Can you talk about the dynamics between total patient adds and incremental revs for Voxzogo? You had 300 patient adds from Q2 to Q3. You had a modest $7 million increase in revs. I know there was a $20 million stocking benefit. But number one, is 300 patient adds a reasonable assumption going forward for Voxzogo growth in Aecon.

您能談談 Voxzogo 的總病患增加量和增量轉速之間的動態嗎？從第二季到第三季度，您新增了 300 名患者。您的轉速小幅增加了 700 萬美元。我知道有 2000 萬美元的庫存福利。但第一，300 名患者為 Voxzogo 在 Aecon 的未來成長提供了合理的假設。

And then number two, how should we think about reps per patient evolving as you expand into international populations? And then just on Ascendis and IP, how aggressive is your team willing to be here? Should we be thinking about some type of royalty payment? Or is the angle BioMarin going to pursue it's going to be a preliminary injunction, and you're aiming to stop attendance from launching the product altogether. How should we think about how aggressive you'll be on IP?

第二，當你擴展到國際人群時，我們該如何考慮每個患者代表的變化？然後就 Ascendis 和 IP 而言，您的團隊願意有多積極進取？我們應該考慮某種類型的特許權使用費嗎？或者 BioMarin 尋求的角度是初步禁令，而您的目標是完全阻止出席者推出產品。我們應該如何考慮您在智慧財產權方面的積極性？

I'll start with your first question, Akash, about the incremental patient adds and really the question about Voxzogo growth. So we have about 3,800 infant children's as of Q3, excuse me, which had a pretty big jump versus last year in this period, which is 2,300 patients. That's 54% growth in revenues and 65% in patient adds. Now interestingly, I think you asked the question does that seem like the right number? Is that strong growth?

我將從你的第一個問題開始，Akash，關於增量患者的增加，以及關於 Voxzogo 成長的問題。抱歉，截至第三季度，我們約有 3,800 名嬰兒，與去年同期的 2,300 名患者相比，有相當大的跳躍。這意味著收入增加了 54%，患者數量增加了 65%。有趣的是，我認為您問了這個數字是否正確？這是強勁的成長嗎？

And I will say that we are tracking exactly the plan on where we think we should be in terms of the growth of this product, well into our launch. Now what I think is important is to reiterate where we think we're going from here, and that is that we have said at Investor Day and still stands strong behind our projected CAGR of 25% growth for Voxzogo through 2027. And really, the reason to believe and the reason that we're confident in the ability to deliver on that, which we do think is strong growth for a for a product at this stage in its life cycle, is really in and around the totality of the data that we have in the 6,000-plus patient years of efficacy and safety. And the notion that we have a really broad age label, which as we're seeing in new patient starts, this is really important because we know that treating early is absolutely critical.

我要說的是，我們正在準確地追蹤我們認為在該產品的成長方面應該達到的計劃，直到我們推出為止。現在我認為重要的是重申我們認為我們今後的發展方向，那就是我們在投資者日所說的，並且仍然堅定地支持我們預計 Voxzogo 到 2027 年複合年增長率為 25% 的目標。事實上，我們相信的理由以及我們對實現這一目標的能力充滿信心的原因，我們確實認為，對於產品在其生命週期的這個階段來說，這是強勁的增長，這確實是在整體之中和周圍。我們有一個非常廣泛的年齡標籤的概念，正如我們在新患者中看到的那樣，這非常重要，因為我們知道早期治療絕對至關重要。

It's also in our ability to be in a very broad geographical reach. We talk about our 80 countries that we're in, we've already started with Voxzogo 144, and we intend to expand to another 20 or greater countries by 2027. And this really is basing it on our expertise in our commercialization, our medical and our market access capabilities. And we're seeing that we're able to grow this expansion at a pace that we feel is very not only strong, but that we can continue in the years to come. So I just want to reiterate that strong CAGR into 2027.

這也在於我們有能力涵蓋非常廣泛的地理範圍。我們談到我們所在的 80 個國家/地區，我們已經從 Voxzogo 144 個國家開始，並打算在 2027 年擴展到另外 20 個或更多國家。這實際上是基於我們在商業化、醫療和市場准入能力方面的專業知識。我們看到，我們能夠以我們認為不僅強勁而且可以在未來幾年繼續進行的擴張速度進行擴張。因此，我只想重申 2027 年的強勁複合年增長率。

Just on your question on IP. I'm afraid I'm not going to elaborate further on our IP strategy or how this might play out. We'll keep you informed as and when we take action. But that is what we can share at this point.

就你關於智慧財產權的問題。恐怕我不會進一步詳細說明我們的知識產權策略或這可能如何實施。當我們採取行動時，我們會及時通知您。但這就是我們現在可以分享的。

Chris Raymond, Piper Sandler.

克里斯·雷蒙德，派珀·桑德勒。

Just on the clinical premise behind BMN 333, I hear you guys talk about improved PK and PD with a long-acting CNP that could drive better growth metrics. But I get this question from investors. Maybe walk through the differences between 333 and TransCon CNP? If we haven't seen a discernible growth benefit from that asset, why mechanistically would 333 be different?

就 BMN 333 背後的臨床前提而言，我聽到你們談論長效 CNP 可以改善 PK 和 PD，從而推動更好的生長指標。但我從投資者那裡得到了這個問題。也許可以了解一下 333 和 TransCon CNP 之間的差異？如果我們沒有看到該資產帶來明顯的成長效益，為什麼從機制上講 333 會有所不同？

Thanks, Chris. This is Greg. Let me take a stab at that. First and foremost, we are targeting a free CNP level that is higher than not only what Voxzogo can deliver from a time of a threshold AUC standpoint, but higher than published data for agents external to BioMarin as well. So in the preclinical models, that suggests if you can increase that 50%, 100%, that there are discernible changes in AGV in those animal models.

謝謝，克里斯。這是格雷格。讓我來嘗試一下。首先也是最重要的，我們的目標是免費 CNP 水平，該水平不僅高於 Voxzogo 從閾值 AUC 角度來看可以提供的水平，而且也高於 BioMarin 外部藥物的已發布數據。因此，在臨床前模型中，這表明如果可以增加 50%、100%，那麼這些動物模型中的 AGV 就會發生明顯的變化。

Now the premise, of course, assumes that, that can be done safely. Again, our preclinical package suggests that, that is the case. But then that is an experiment that we do need to test in the clinic with those ranging studies in patients. the totality of evidence here is going to be something that absolutely is key. We still believe that Voxzogo is an agent that not only is first-in-class, but has the best-in-class evidence package.

當然，現在的前提是假設可以安全地完成。我們的臨床前方案再次表明，情況確實如此。但這是一項我們確實需要在臨床上透過對患者進行的一系列研究進行測試的實驗。這裡的全部證據絕對是關鍵。我們仍然相信 Voxzogo 是一款不僅是一流的藥物，而且還擁有一流的證據包。

There's a variety of reasons why we believe that. It's beyond just the 6,000 patients of data. It also it really touches on the durability of data. It's not just a single year AGV or proportionality. We see out to seven years of consistent data there. By building on that data, both with regard to growth velocity as well as the basket of data, which is evidence beyond just growth, the wellness and health of these patients.

我們相信這一點的原因有很多。這不僅僅是 6,000 名患者的數據。它也確實涉及到數據的持久性。這不僅僅是一年的AGV或比例。我們在那裡看到了七年的一致數據。透過建立在這些數據的基礎上，無論是生長速度還是一攬子數據，這些數據都是這些患者的生長、健康和健康以外的證據。

We think that if we can take that molecule and increase the exposure, if we can do it in a safe way, that, that will translate not just into increased growth velocity, but also we're going to start seeing benefits on the health and wellness of patients. And of course, there's a variety of those measures that we will continue to publish on not only for Voxzogo, but also for the new agent.

我們認為，如果我們能夠採用該分子並增加暴露量，如果我們能夠以安全的方式做到這一點，那麼，這不僅會轉化為生長速度的加快，而且我們將開始看到對健康和健康的益處。當然，我們將繼續發佈各種措施，不僅針對 Voxzogo，也針對新代理商。

Mohit Bansal, Wells Fargo.

莫希特·班薩爾，富國銀行。

Two, if I may ask. What is your base case assumption around the length of trial for BMN 333 at this point? Is it a two-year controlled trial or one-year controlled trial? I'm asking because if there's any room to expedite it and then maybe launching before 2030 here. Number two, it does seem like Naglazyme has done really well compared to what we have seen in prior years year-over-year basis.

兩個，請容許我問一下。目前，您對 BMN 333 試驗長度的基本案例假設是什麼？是兩年對照試驗還是一年對照試驗？我問這個問題是因為是否有任何加快進程的空間，然後可能會在 2030 年之前啟動。第二，與我們前幾年所看到的逐年相比，Naglazyme 的表現確實非常好。

So can you talk a little bit about the strategy and what has helped here? And how should we think about the product going forward?

那麼您能談談這個策略以及它的幫助嗎？我們應該如何考慮該產品的未來發展？

So thanks, Mohit, for the question. For the Phase 3 study, the development plan for BMN 333, of course, there's two variables in play here. Any study, of course, needs to recruit the set of patients and the effect size that we would be targeting would absolutely drive not only the number of patients we need, but the amount of time that we take to recruit those patients. The profile is going to, again, reveal itself incrementally.

謝謝莫希特提出的問題。對於第三階段研究，即 BMN 333 的開發計劃，當然，這裡有兩個變數在起作用。當然，任何研究都需要招募一組患者，而我們的目標效應大小絕對不僅會影響我們需要的患者數量，還會影響我們招募這些患者所需的時間。個人資料將再次逐漸顯現出來。

I think the PK will be the first step. But if we believe that this is a molecule that can deliver much higher CNP exposure in the patients. And if we believe that, that translates into effect sizes, that would indeed change the endpoints that we'd look for in a Phase 3. There are far too many permutations to be able to go into additional details at this point of what the Phase III study might look like or might not look like.

我認為PK將是第一步。但如果我們相信這種分子可以為患者帶來更高的 CNP 暴露。如果我們相信這一點，這會轉化為效應大小，那確實會改變我們在第三階段尋找的終點。目前，有太多的排列無法詳細說明 III 期研究可能會是什麼樣子或可能不是什麼樣子。

But inherent in your question is, can this be accelerated? I believe there are scenarios where if the profile plays out the way that we're anticipating that we will have the chance to try to accelerate those time frames. No promises today, but it's something we're actively looking at. And urgency to get to patients is one of our absolute core values here at BioMarin.

但你的問題本質上是，這可以加速嗎？我相信在某些情況下，如果設定檔按照我們預期的方式進行，我們將有機會嘗試加快這些時間框架。今天沒有任何承諾，但這是我們正在積極關注的事情。迫切需要幫助患者是 BioMarin 的絕對核心價值之一。

And we understand that if we have a molecule that's delivering something more valuable than even our own product, we would want to bring that as quickly as we can.

我們知道，如果我們有一種分子能夠提供比我們自己的產品更有價值的東西，我們會希望盡快推出它。

Mohit, this is Brian. I'll take the Naglazyme question. Appreciate the question. Naglazyme did have a great quarter. We did include in the prepared remarks, just to be clear, that Naglazyme did benefit from some timing that 21% growth in the quarter did have some timing in there, but nothing where we would isolate a single country order like we have in the past.

莫希特，這是布萊恩。我將回答 Naglazyme 問題。感謝這個問題。Naglazyme 確實有一個出色的季度。我們確實在準備好的評論中加入了這一內容，只是為了明確起見，Naglazyme 確實受益於本季度 21% 的增長確實有一些時機，但我們不會像過去那樣孤立單個國家/地區的訂單。

I think what you're seeing with Naglazyme over time on the market for nearly 20 years, is just a good case example of how we talk about the durability of this enzyme therapy portfolio and the durable growth potential this market is nearly fully penetrated, but this is a weekly infusion for life. Patients are doing well, being into adulthood, gaining weight, weight-based dosing. And it's the epitome of this franchise and how we see it growing going forward.

我認為，隨著Naglazyme 在市場上近20 年的發展，您所看到的只是一個很好的案例，說明了我們如何談論這種酶療法產品組合的耐久性以及該市場幾乎完全滲透的持久增長潛力，但是這是終生每週一次的輸注。患者狀況良好，已進入成年期，體重增加，基於體重的劑量。這是這個系列的縮影，也是我們如何看待它未來發展的縮影。

But I'd also point to when we talk about some of the new initiatives and the promise of this business unit structure that Cristin touched on earlier, those aren't yet implemented. Those are all incremental for the future. That's what drives us the believe we can be more aspirational with the long-term enzyme therapy growth rate.

但我還想指出，當我們談論克里斯汀之前提到的一些新舉措和業務部門結構的承諾時，這些舉措尚未實施。這些都是未來增量的。這促使我們相信我們可以對酵素療法的長期成長率抱有更大的期望。

John Wang, Barclays.

約翰王，巴克萊銀行。

So I would just ask one question regarding the BMN 333. Greg, you did mention that you wanted to have a better efficacy hopefully, with a better exposure. But based on the Voxzogo dose escalation study, there it seems there was a ceiling effect regarding the efficacy. And so we will make you confident that could be with a higher dose or high exposure that can translate to better efficacy.

所以我只想問一個關於 BMN 333 的問題。格雷格，你確實提到你希望透過更好的曝光來獲得更好的功效。但根據 Voxzogo 劑量遞增研究，療效似乎存在上限效應。因此，我們會讓您相信，更高的劑量或更高的暴露量可以轉化為更好的功效。

And then related questions, I think, based on the Investor Day that one slide shared with investors we did see like the exposure plus concentration almost in the like two log or three log magnitude improvement compared to, say, Voxzogo or even TransCon CNP. And within that, frequency of dosing? Would that be also a very important component that you were taken into consideration?

然後是相關問題，我認為，根據投資者日與投資者分享的一張幻燈片，我們確實看到，與Voxzogo 甚至TransCon CNP 相比，暴露加集中度幾乎達到了兩個對數或三個對數的幅度改善。其中，給藥頻率？這是否也是您考慮的一個非常重要的組成部分？

Thanks, the your questions with regard, why don't I think first Investor Day figure. With a molecule like BMN 333, there are two species, of course, that we need to be talking about when we look at PK. One will be the native molecule. That will include the linker technology, the binding technology and so forth.

謝謝，關於你的問題，我為什麼不先考慮投資者日的數據。對於像 BMN 333 這樣的分子，當我們考慮 PK 時，當然需要討論兩個物種。一種是天然分子。這將包括連接技術、結合技術等等。

And I believe that's what was shown in investor, a much higher molecular weight. So again, if you're comparing the units, they will look somewhat differently. From a pull-through, what we, of course, care about is the liberated, and we, of course, from our preclinical data in humans will be measuring very closely. That profile of free CNP and we do believe that we can safely and in a way that has a different shape to the PK curve.

我相信這就是投資人所展現的，更高的分子量。因此，如果您比較這些單位，它們看起來會有所不同。從拉通中，我們當然關心的是解放，當然，我們將根據人類的臨床前數據進行非常密切的測量。自由 CNP 的輪廓，我們確實相信我們可以安全地以一種與 PK 曲線形狀不同的方式。

So it would rather than be a software tooth pattern of a shorter half-life molecule, would be able to increase AUC, again, increased time above threshold we believe not only can we increase the exposure of CNP there, but do so in a way we could see physiologic differences as compared to Voxzogo in the way that it was given.

因此，它不會是較短半衰期分子的軟體齒模式，而是能夠增加 AUC，再次增加高於閾值的時間，我們相信我們不僅可以增加 CNP 在那裡的暴露，而且可以以某種方式這樣做我們可以看到與Voxzogo 的給藥方式相比，生理上的差異。

I think of this similar to other peptides where insulin, for example, is one that when given in its native form versus in a variety of constructs, you can see different biologic effects from the shapes of the curve that are more than just described by, say, Cmax or AUC alone. And so we're absolutely excited to test this in patients. We're going into the clinic in the very early next year. And we should have a good read on both the molecule, BMN 333 pharmacokinetics as well as free CNP in rapid order. So that will have that data in-house midyear.

我認為這與其他勝肽類似，例如，當以天然形式與各種結構相比，胰島素是一種勝肽，您可以從曲線的形狀中看到不同的生物效應，而不僅僅是以下描述的：比方說，單獨的 Cmax 或 AUC。因此，我們非常高興能夠在患者身上進行測試。我們將於明年初進入診所。我們應該快速閱讀該分子、BMN 333 藥物動力學以及遊離 CNP。這樣年中就會有這些數據在內部。

And at this time, I will turn the call back over to CEO, Alexander Hardy for closing remarks.

此時，我會將電話轉回執行長亞歷山大哈迪 (Alexander Hardy) 進行總結發言。

Thank you, operator, and thank you all for joining us today. As you've heard, we have the team in place this quarter now to deliver on our new corporate strategy that you heard about at Investor Day, focused on innovation, growth and value commitment. And we've made significant progress on each of these. Today's strong quarterly performance highlights the ongoing implementation of this strategy under BioMarin's new operational plan to achieve sustained and significant returns for the benefit of all stakeholders.

謝謝運營商，也謝謝大家今天加入我們。正如您所聽說的，我們的團隊現已在本季度就位，以實施您在投資者日上聽到的新企業策略，重點關注創新、成長和價值承諾。我們在每一個方面都取得了重大進展。現今強勁的季度業績凸顯了 BioMarin 在新營運計畫下持續實施此策略，以實現持續且顯著的回報，造福所有利害關係人。

We're looking forward to keeping you apprised as we continue to execute on these plans. Thank you very much for your attention, and good day.

我們期待在我們繼續執行這些計劃的過程中隨時向您通報情況。非常感謝您的關注，祝您有美好的一天。

This does conclude today's conference call. You may now disconnect.

今天的電話會議到此結束。您現在可以斷開連線。