BioMarin Pharmaceutical Inc (BMRN) 2024 Q1 法說會逐字稿

Good afternoon. My name is Audra, and I will be your conference operator today. At this time, I would like to welcome everyone to the BioMarin Pharmaceutical First Quarter 2024 Conference Call.

午安.我叫奧德拉，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 Pharmaceutical 2024 年第一季電話會議。

Today's conference is being recorded. (Operator Instructions)

今天的會議正在錄製中。 （操作員說明）

At this time, I'd like to turn the conference over to Traci McCarty, Group Vice President, Investor Relations. Please go ahead.

這次，我想將會議交給投資人關係集團副總裁 Traci McCarty。請繼續。

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

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、商業產品以及治療研究和開發不同領域的潛在未來產品的預期。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。

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are available in the Investor Relations section of our website.

此外，我們將在今天的電話會議中使用 G 條例中定義的非 GAAP 財務指標。這些非公認會計原則措施不應孤立地考慮，作為根據美國公認會計原則準備的財務措施的替代品或優於根據美國公認會計原則準備的財務措施，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，這兩者都是可在我們網站的投資者關係部分找到。

On the call from BioMarin management today are Alexander Hardy, President and Chief Executive Officer; Hank Fuchs, President of Worldwide R&D; and Bert Brian Mueller, Executive Vice President, Chief Financial Officer. Jeff Ajer, Executive Vice President, Chief Commercial Officer; and Greg Guyer, Executive Vice President, Chief Technical Officer, are here with us to answer questions during the Q&A portion of the call.

今天，BioMarin 管理層的總裁兼首席執行官 Alexander Hardy 接聽了電話； Hank Fuchs，全球研發總裁；以及執行副總裁兼財務長伯特·布萊恩·穆勒 (Bert Brian Mueller)。 Jeff Ajer，執行副總裁兼商務長；執行副總裁兼首席技術長 Greg Guyer 在電話問答部分與我們一起回答問題。

I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

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 all for joining us today. In addition to strong financial results, we made significant progress in the quarter developing the components of BioMarin's new corporate vision and strategy, all in the interest of positively impacting patients' lives while creating value for shareholders, and with a number of strategic initiatives ongoing to finalize these components to be communicated at Investor Day, which we have now set for September 4. We are pleased to share the first chapter update today, the results from our strategic assessment BioMarin's R&D portfolio.

謝謝你，崔西，大家下午好。感謝大家今天加入我們。除了強勁的財務業績外，我們在本季度開發BioMarin 新企業願景和策略的組成部分方面取得了重大進展，所有這些都是為了積極影響患者的生活，同時為股東創造價值，並且正在進行多項策略舉措最終確定這些內容，並在投資者日進行溝通，我們現在將其定於 9 月 4 日。

As innovation is fueled BioMarin's success to date, we undertook a prioritization of our overall portfolio from early to life cycle stage assets. The goal of this assessment was to accelerate the delivery of those assets, which add the greatest value to all of our stakeholders and align with the time lines for our strategic growth plans. We added a commercial lens early in the portfolio review process to ensure that return on investment, resource allocation, patient impact were all thoroughly considered. As a result, we chose to accelerate 3 assets that we believe offer the most transformative potential for patients and value creation for shareholders. We are also discontinuing 4 programs that did not meet our new higher bar for continued development.

由於創新推動了 BioMarin 迄今為止的成功，我們對從早期資產到生命週期階段資產的整體投資組合進行了優先排序。此次評估的目標是加快這些資產的交付，為我們所有利害關係人增加最大價值，並與我們策略成長計畫的時間表保持一致。我們在投資組合審查過程的早期添加了商業視角，以確保投資回報、資源分配、患者影響都得到徹底考慮。因此，我們選擇加速推進 3 項資產，我們相信這些資產能夠為患者提供最具變革性的潛力，並為股東創造價值。我們也終止了 4 個未達到新的更高持續開發標準的專案。

Moving briefly to progress made in the quarter on our 4 strategic priorities outlined in January. Beginning with our opportunity to accelerate and maximize our Voxzogo, we made significant progress during the quarter with 74% revenue growth year-over-year and more than 500 additional children receiving therapy in the first quarter. Voxzogo in achondroplasia continues towards blockbuster status. The majority of new U.S. prescriptions in the quarter were for children under the age of 5, an important trend since FDA's age expansion approval last quarter, albeit we continue to see expansion in the over 5 population as well. Global access to Voxzogo from infancy is having a significant impact on rapid uptake as families pursue maximum therapeutic benefit by starting treatment early.

簡要介紹本季在 1 月概述的 4 項策略重點方面取得的進展。從加速和最大化 Voxzogo 的機會開始，我們在本季度取得了重大進展，收入同比增長了 74%，第一季又有 500 多名兒童接受治療。 Voxzogo 治療軟骨發育不全繼續走向重磅炸彈地位。本季度美國大部分新處方藥都是針對 5 歲以下兒童，這是自 FDA 上季度批准擴大年齡範圍以來的一個重要趨勢，儘管我們繼續看到 5 歲以上人群的擴張。隨著家庭透過儘早開始治療來追求最大的治療效益，從嬰兒期開始在全球範圍內使用 Voxzogo 對快速吸收產生了重大影響。

In the United States, we continue to observe an increase in the breadth and depth of our prescriber base as real world experience drives confidence in Voxzogo's extensive safety and efficacy profile. Leveraging our established leadership in achondroplasia, we also made important strides in our plans to expand the multiple other growth-related conditions. Our pivotal program with Voxzogo for the treatment of children with hypochondroplasia will begin the treatment study midyear with a target of completing enrollment by the first half of 2025.

在美國，我們繼續觀察到我們的處方者基礎的廣度和深度不斷增加，因為現實世界的經驗增強了人們對 Voxzogo 廣泛的安全性和有效性的信心。利用我們在軟骨發育不全領域既定的領導地位，我們在擴大多種其他生長相關疾病的計劃方面也取得了重要進展。我們與 Voxzogo 合作治療軟骨發育不全兒童的關鍵計畫將於年中開始治療研究，目標是在 2025 年上半年完成入組。

Based on ongoing discussions with global health authorities on study protocols with Voxzogo, idiopathic short stature and multiple genetic short stature pathway conditions. We expect to begin enrollment in these programs later this year. The momentum we are seeing with Voxzogo in achondroplasia supports our belief that CNP can potentially unlock clinical benefit for children across a number of growth-related conditions for many years to come. Hank will share a perspective on the opportunities ahead with Voxzogo based on strong proof-of-concept in indications beyond achondroplasia as well as the potential for longer-acting formulations.

基於與全球衛生當局就 Voxzogo、特發性身材矮小和多種遺傳性身材矮小途徑病症的研究方案進行的持續討論。我們預計將在今年稍後開始註冊這些項目。我們在 Voxzogo 治療軟骨發育不全方面看到的勢頭支持了我們的信念，即 CNP 有可能在未來許多年為兒童帶來許多與生長相關的疾病的臨床益處。 Hank 將基於軟骨發育不全以外的適應症的強有力的概念驗證以及長效製劑的潛力，分享對 Voxzogo 未來機會的看法。

The second priority, establishing the Roctavian opportunity continues to be complex. With pricing and reimbursement established in the United States, Germany and Italy, aligning the required steps leading to patient treatment continues to pose different challenges. For example, while the Roctavian National German price was established and published in December, the sub insurers have inserted new barriers to reimbursement. In the U.S., the complexity of local site reimbursement contracting continues to be an obstacle. We remain confident in the clinical profile of Roctavian and we're pleased with the Roctavian update at the TH SNA meeting, showing durable hemostatic efficacy, improved quality of life and no safety signals at 4 years.

第二個優先事項，即建立羅克塔維亞機會仍然很複雜。隨著美國、德國和義大利制定了定價和報銷制度，調整病患治療所需的步驟繼續帶來不同的挑戰。例如，雖然 Roctavian National 德國價格在 12 月制定並公佈，但子保險公司設置了新的報銷障礙。在美國，當地現場報銷合約的複雜性仍然是一個障礙。我們對 Roctavian 的臨床概況仍然充滿信心，我們對 Roctavian 在 TH SNA 會議上的更新感到滿意，它顯示出持久的止血功效，改善了生活質量，並且 4 年沒有安全信號。

With respect to the additional Roctavian development programs, we are proceeding with Roctavian development in Japan and in the prior inhibitor population and of course, other programs until we observe more meaningful Roctavian commercial uptake. We recognize the importance of allocating our resources to the highest value-creating opportunities. And with the current levels of Roctavian investments and continued challenges with commercial uptake, we plan to communicate our evaluation criteria for Roctavian in terms of its place in our portfolio and related timing for potential next steps at the Investor Day in September.

關於額外的 Roctavian 開發項目，我們正在日本和先前的抑制劑群體中繼續進行 Roctavian 開發，當然還有其他項目，直到我們觀察到更有意義的 Roctavian 商業應用。我們認識到將資源分配給創造最高價值的機會的重要性。鑑於 Roctavian 的當前投資水準和商業應用的持續挑戰，我們計劃在 9 月的投資者日上傳達我們對 Roctavian 的評估標準，包括其在我們投資組合中的地位以及潛在後續步驟的相關時間安排。

The third priority is our focus on the most productive R&D assets. And as already mentioned, I'm pleased we have completed the initial chapter of that work. Beyond our refresh pipeline, centered around 3 key assets to be accelerated, we're in a strong position to leverage external innovation in conjunction with our internal capabilities to fortify our mid- and longer-term pipeline. At Investor Day, we will also share more about our innovation strategy and plans and how they fit into our capital allocation and internal external portfolio innovation strategies.

第三個優先事項是我們關注最俱生產力的研發資產。正如已經提到的，我很高興我們已經完成了這項工作的第一章。除了以要加速的 3 個關鍵資產為中心的更新管道之外，我們還處於有利地位，可以利用外部創新與我們的內部能力相結合，以加強我們的中長期管道。在投資者日，我們也將分享更多我們的創新策略和計劃，以及它們如何融入我們的資本配置和內部外部投資組合創新策略。

Lastly, our fourth priority to increase profitability faster than originally planned. As demonstrated by our first quarter results, we're tracking well towards achieving this priority. As I complete my first quarter as CEO, I hope it's evident that we're taking decisive and thoughtful action to realize our priorities, all designed to align with our broader operational and cost transformation strategies to be shared at Investor Day. Our full year 2024 guidance reflects double-digit revenue growth non-GAAP operating margin expansion and non-GAAP earnings per share growing faster than revenues. These full year guidance items allow you to track our financial progress as we transform BioMarin's operating model to produce the best outcomes for the patients we serve, our employees and our shareholders.

最後，我們的第四個優先事項是比原計劃更快地提高獲利能力。正如我們第一季的業績所證明的那樣，我們在實現這一優先事項方面進展順利。當我擔任執行長的第一季結束時，我希望我們正在採取果斷和深思熟慮的行動來實現我們的優先事項，所有這些都是為了與我們將在投資者日分享的更廣泛的運營和成本轉型策略保持一致。我們的 2024 年全年指引反映了兩位數的營收成長（非 GAAP 營業利潤率擴張）以及非 GAAP 每股盈餘的成長快於營收的成長。這些全年指導專案使您能夠追蹤我們的財務進展，因為我們轉變 BioMarin 的營運模式，為我們服務的患者、員工和股東創造最佳結果。

So in summary, we are making tangible progress across the enterprise to reshape BioMarin's corporate vision and strategy. This is an enormous body of work that remains in process. But as you can see from our first quarter updates, we're working with a sense of urgency on this, and we are making definitive progress. We're excited to continue this work over the coming months with the goal of sharing our vision for a successful future with you at Investor Day on September 4 in New York. Thank you for your attention.

總而言之，我們正在整個企業取得實際進展，以重塑 BioMarin 的企業願景和策略。這是一項仍在進行中的龐大工作。但正如您從我們第一季的更新中看到的那樣，我們對此充滿緊迫感，並且正在取得明確的進展。我們很高興在未來幾個月繼續這項工作，目標是在 9 月 4 日紐約投資者日與您分享我們對成功未來的願景。感謝您的關注。

I will now turn the call over to Hank to provide an update on key R&D highlights.

我現在將把電話轉給漢克，以提供關鍵研發亮點的最新情況。

Thank you, Alexander, and good afternoon, everyone. The R&D team is energized by the more focused approach, decisions and clarity on the path forward to advancing the highest potential programs following our portfolio review. As a leading innovative and scaled biopharma company is more important than ever that we invest R&D resources in medicines that benefit the greatest number of patients. We move forward with an evaluation framework that will provide a high bar for consistent assessment of programs to determine if they fit in our burgeoning portfolio strategy.

謝謝你，亞歷山大，大家下午好。在我們的投資組合審查之後，研發團隊因更專注的方法、決策和明確的前進道路而充滿活力，以推進最具潛力的項目。作為一家領先的創新和規模化生物製藥公司，我們比以往任何時候都更加重要的是，我們將研發資源投入到造福最多患者的藥物上。我們推進一個評估框架，該框架將為專案的一致評估提供高標準，以確定它們是否適合我們新興的投資組合策略。

Briefly on the 3 programs that we chose to accelerate and starting with BMN 351 for the treatment of Duchenne muscular dystrophy. BNM 351 is the potential best-in-class antisense oligonucleotides designed to restore full-length dystrophin expression to more than 10% of normal at steady state. The next-generation skipping oligo -- this next-generation skipping oligo has the potential to convert patients phenotypes from progressive functional loss to durably preserve strength and function if data are supportive. BMN 351 is differentiated from other antisense oligos based on optimized chemistry and a unique slice enhancer target site, which together result in significantly improved potency for restoring dystrophin expression. It is also differentiated from gene therapy as BMN 351 produces near full-length dystrophin rather than the truncated microdystrophin produced via gene therapy. And BMN 351 can be administered chronically. For this reason, we believe the potential clinical benefit of BMN 351 over currently approved gene therapies and other treatments represents high value to patients and families living with this debilitating condition.

簡單介紹我們選擇加速的 3 個項目，並從 BMN 351 開始治療杜氏肌肉營養不良症。 BNM 351 是潛在的同類最佳反義寡核苷酸，旨在將全長肌營養不良蛋白表達恢復到穩定狀態下正常表達的 10% 以上。下一代跳躍寡核苷酸—如果數據支持的話，這種下一代跳躍寡核苷酸有可能將患者的表型從進行性功能喪失轉變為持久保留力量和功能。 BMN 351 與其他反義寡核苷酸的差異在於優化的化學成分和獨特的切片增強子標靶位點，這兩者共同導致恢復肌營養不良蛋白表現的效力顯著提高。它也與基因療法不同，因為 BMN 351 產生接近全長的肌肉營養不良蛋白，而不是透過基因療法產生的截短的微小肌肉營養不良蛋白。 BMN 351 可以長期服用。因此，我們相信 BMN 351 相對於目前核准的基因療法和其他治療方法的潛在臨床益處對於患有這種衰弱疾病的患者和家庭來說具有很高的價值。

The 52-week clinical proof-of-concept study with BMN 351 is actively recruiting patients and will include 18 boys with Duchenne muscular dystrophy with the potential to expand enrollment as needed and is designed to assess both dystrophin levels and functional measures. Also accelerating BMN 349 is a potential first oral therapeutic for the treatment of alpha-1 antitrypsin deficiency liver disease with the ability to address genotypes beyond PiZZ based on preferential binding to the Z protein with potential transformative effects on reversing fibrosis and preventing end-stage liver disease. There is a large addressable market and we aim to differentiate ourselves from the competition based on specificity for the Z AAT allele and the ability to titrate to effect. This first-in-human study in healthy volunteers remains ongoing.

這項為期52 週的BMN 351 臨床概念驗證研究正在積極招募患者，將包括18 名患有杜氏肌肉營養不良症的男孩，並有可能根據需要擴大招募範圍，旨在評估肌肉營養不良蛋白水平和功能指標。 Also accelerating BMN 349 is a potential first oral therapeutic for the treatment of alpha-1 antitrypsin deficiency liver disease with the ability to address genotypes beyond PiZZ based on preferential binding to the Z protein with potential transformative effects on reversing fibrosis and preventing end-stage liver疾病.有一個巨大的潛在市場，我們的目標是根據 Z AAT 等位基因的特異性和滴定效果的能力，使自己在競爭中脫穎而出。這項針對健康志願者的首次人體研究仍在進行中。

BMN 333, our long-acting formulation of CNP is designed to optimize and expand the reach of treatment for our portfolio of growth disorders by providing treatment optionality by a less frequent dosing and potentially improving the patient and caregiver experience, leveraging our current leadership in treating achondroplasia and anticipated expansion into other growth-related conditions, including hypochondroplasia, idiopathic short stature and multiple genetic short state pathway conditions, we believe offering multiple treatment options will help families interested in safe and effective medicines to treat rare skeletal disorders. BMN 333 is completing IND-enabling studies and is slated to enter the clinic in early 2025.

BMN 333 是我們的CNP 長效製劑，旨在優化和擴大我們生長障礙組合的治療範圍，透過減少給藥頻率提供治療選擇，並有可能改善患者和護理人員的體驗，利用我們目前在治療方面的領先地位軟骨發育不全以及預期擴展到其他生長相關疾病，包括軟骨發育不全、特發性身材矮小和多種遺傳性短態通路疾病，我們相信提供多種治療選擇將有助於對治療罕見骨骼疾病的安全有效藥物感興趣的家庭。 BMN 333 正在完成 IND 支持研究，預計 2025 年初進入臨床。

Finally, for BMN 293, our gene therapy for hypertrophic cardiomyopathy, we are completing activities to advance it towards the clinic, while we wait additional supportive information, and we'll share our next update with you at Investor Day. We look forward to accelerating our prioritized programs as they hold the highest promise for patients and align with the timing of our strategic growth plans. The programs that did not meet the criteria for advancement, mostly earlier stage, are listed in our press release and will wind down over the coming quarters. There were no safety signals observed across the discontinued programs. We are working with sites now where applicable to continue monitoring patient safety per protocol as a top priority and we would like to thank all the patients who participated in these studies, the investigators sites and other health care providers. Having the inability to focus on our priority programs in terms of resources and strategy that will enable us to -- that will enable the highest probability and most rapid outcome for patients who may benefit. We will share more on time lines for each at Investor Day.

最後，對於 BMN 293（我們針對肥厚型心肌病變的基因療法），我們正在完成將其推向臨床的活動，同時等待更多支持信息，我們將在投資者日與您分享我們的下一次更新。我們期待加快我們的優先項目，因為它們為患者帶來最高的希望，並與我們策略成長計畫的時機保持一致。不符合晉升標準的計劃（大部分是早期階段）已列在我們的新聞稿中，並將在未來幾季逐步結束。在已停止的項目中沒有觀察到安全性訊號。我們現在正在與適用的地點合作，將繼續監測每個方案的患者安全作為首要任務，我們要感謝所有參與這些​​研究的患者、研究人員地點和其他醫療保健提供者。我們無法在資源和策略方面專注於我們的優先計劃，而這些計劃將使我們能夠為可能受益的患者帶來最高的可能性和最快的結果。我們將在投資者日分享更多關於每個項目的時間表。

Touching briefly on other encouraging clinical updates validating our plans to expand Voxzogo's reach to address a variety of growth related conditions, we were pleased to see Dr. Dauber's 1-year update from his hypochondroplasia study demonstrating a 1.8-centimeter improvement in annualized growth velocity at the American College of Medical Genetics. Our registration study in hypochondroplasia is progressing well with the treatment study enrollment planned for midyear. We are targeting approval in 2027, subject to enrollment and data results. I was also pleased to preview Dr. Dauber's abstract to be shared at the Pediatric Endocrine Society's website including very encouraging data from his study addressing both ISS and pathway conditions. This first presentation of data at 12 months treatment with Voxzogo in Noonan and ISS conditions showed positive efficacy results in all subgroups. It was well tolerated with a similar safety profile to previous reports in patients with achondroplasia.

簡要談及其他令人鼓舞的臨床更新，這些更新驗證了我們擴大Voxzogo 的覆蓋範圍以解決各種生長相關疾病的計劃，我們很高興看到Dauber 博士的軟骨發育不全研究的1 年更新表明年化生長速度提高了1.8 公分美國醫學遺傳學學院。我們在軟骨發育不全的登記研究進展順利，並計劃於年中進行治療研究入組。我們的目標是在 2027 年獲得批准，具體取決於註冊情況和數據結果。我還很高興預覽 Dauber 博士的摘要，該摘要將在兒科內分泌學會的網站上分享，其中包括他針對 ISS 和通路狀況的研究中非常令人鼓舞的數據。首次公佈的 Voxzogo 在 Noonan 和 ISS 條件下治療 12 個月的數據在所有亞組中均顯示出積極的療效結果。它具有良好的耐受性，其安全性與先前針對軟骨發育不全患者的報告相似。

These data are supportive of our thinking around the role CNP may play in benefiting patients across a variety of growth-related conditions. We are still in discussions on study design for multiple genetic short stature pathway conditions and expect to have a more detailed update on the second quarter call and are still expecting to begin that study in the second half of the year.

這些數據支持了我們關於 CNP 在使各種生長相關疾病的患者受益方面可能發揮的作用的想法。我們仍在討論多種遺傳性身材矮小途徑條件的研究設計，並預計在第二季度電話會議上獲得更詳細的更新，並仍預計在今年下半年開始研究。

On BioMarin's clinical program in idiopathic short stature, we held productive discussions with the U.S. FDA and on this program and have aligned on plans to support approval in new condition -- new indication. Based on the feedback, we plan to start the clinical development program in ISS in the second half of this year. We expect our first study protocol in ISS to be posted to clinicaltrials.gov in the next few weeks and will include the following agreed-upon elements. The study will be a placebo-controlled Phase II study and patients who will be naive to human growth hormone treatment, and we use the primary endpoint of annualized growth velocity determined at 6 months to determine the therapeutic dose levels. Patients will be randomized to 1 of 5 study cohorts, 1 of 3 different doses of Voxzogo, including doses that are both higher and lower than the commercial dose in achondroplasia, placebo or human growth hormone.

關於 BioMarin 特發性身材矮小症的臨床項目，我們與美國 FDA 就該項目進行了富有成效的討論，並已就支持新病症（新適應症）批准的計劃達成一致。根據回饋，我們計劃今年下半年在ISS啟動臨床開發專案。我們預計 ISS 的第一個研究方案將在未來幾週內發佈到 ClinicalTrials.gov，並將包括以下商定的要素。該研究將是一項安慰劑對照的 II 期研究，患者將首次接受過人類生長激素治療，我們使用 6 個月時確定的年化生長速度的主要終點來確定治療劑量水平。患者將被隨機分配到 5 個研究隊列中的 1 個、3 個不同劑量的 Voxzogo 中的 1 個，包括高於和低於軟骨發育不全商業劑量、安慰劑或人類生長激素的劑量。

We have made a lot of progress with the FDA in designing the development path for ISS and intend to refine the design of our Phase III program as data emerge from the Phase II program, including the results of dose selection from the planned study. In conclusion, we are pleased with our rapid progress building out BioMarin's leadership in multiple growth-related conditions and we look forward to updating you on our progress with these clinical programs in the coming months.

我們與 FDA 在設計 ISS 的開發路徑方面取得了很大進展，並打算隨著 II 期專案的數據（包括計劃研究的劑量選擇結果）的出現，完善我們 III 期專案的設計。總而言之，我們對 BioMarin 在多種生長相關疾病中建立領導地位的快速進展感到高興，我們期待在未來幾個月向您通報我們在這些臨床項目方面的最新進展。

Thank you for your attention, and I'll now turn the call over to Brian for our financial updates.

感謝您的關注，我現在將電話轉給布萊恩，以了解我們的財務最新情況。

Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the first quarter of 2024, including reconciliations of GAAP to non-GAAP financial measures. All first quarter 2024 results will be available in our upcoming Form 10-Q, which we expect to file in the coming days.

謝謝你，漢克。請參閱今天總結我們財務業績的新聞稿，了解 2024 年第一季度的完整詳細信息，包括 GAAP 與非 GAAP 財務指標的調節表。 2024 年第一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。

In the first quarter of 2024, BioMarin generated record total revenue of $649 million, representing 9% year-over-year growth, 13% on a constant currency basis driven by continued strong demand for Voxzogo. Our base portfolio of products, including Kuvan, contributed $484 million of net product revenues in the first quarter. Looking more closely at net product revenue in the first quarter, Voxzogo revenues of $153 million represented 74% year-over-year growth. That level of growth was despite the supply constraint on Voxzogo discussed last year and expected to continue through the second quarter of this year. Our plan for supply to satisfy the forecasted commercial demand around the middle of this year remains intact. 21% revenue growth of Palynziq in the first quarter demonstrated continued momentum for the only biologic approved for the treatment of PKU, offset by lower Kuvan revenues as expected.

2024 年第一季度，BioMarin 的總營收達到創紀錄的 6.49 億美元，年成長 9%，在 Voxzogo 持續強勁需求的推動下，以固定匯率計算成長 13%。我們的基礎產品組合（包括 Kuvan）在第一季貢獻了 4.84 億美元的淨產品收入。更仔細觀察第一季的淨產品收入，Voxzogo 收入為 1.53 億美元，年增 74%。儘管去年討論了 Voxzogo 的供應限制，但這種成長水準預計將持續到今年第二季。我們為滿足今年年中預測的商業需求而提供的供應計劃保持不變。 Palynziq 第一季營收成長了 21%，這表明該藥物是唯一被批准用於治療 PKU 的生物製劑，其成長勢頭持續強勁，但正如預期的 Kuvan 收入下降所抵消。

And within Naglazyme and Aldurazyme contributions in the first quarter, we're not surprising given the usual variable global ordering patterns for those brands. Importantly, we continue to observe commercial patient growth in these brands that we expect will drive sustainable revenue growth over time despite the quarterly order timing.

鑑於 Naglazyme 和 Aldurazyme 在第一季的貢獻，考慮到這些品牌通常變化的全球訂購模式，我們並不感到驚訝。重要的是，我們繼續觀察這些品牌的商業患者成長，儘管按季度訂購，但我們預計這些品牌將隨著時間的推移推動可持續的收入成長。

GAAP R&D expenses in the first quarter were $205 million, an increase of $33 million year-over-year primarily due to increased early-stage research activities as well as increased activity in our clinical programs. GAAP SG&A expense in the first quarter was $226 million, representing a year-over-year increase of $15 million, driven by the continued support of the global Voxzogo market expansion as well as corporate expenses in the quarter. This financial performance in Q1 drove an operating margin of 13.6% on a GAAP basis and 23.8% on a non-GAAP basis.

第一季 GAAP 研發費用為 2.05 億美元，較去年同期增加 3,300 萬美元，主要是由於早期研究活動的增加以及臨床項目活動的增加。第一季 GAAP SG&A 費用為 2.26 億美元，年增 1,500 萬美元，得益於本季全球 Voxzogo 市場擴張以及企業費用的持續支持。第一季的財務業績使以 GAAP 計算的營業利潤率達到 13.6%，以非 GAAP 計算的營業利潤率達到 23.8%。

Moving to the bottom line. GAAP net income for the first quarter was $89 million, an increase of $38 million year-over-year and representing GAAP diluted earnings per share of $0.47. Non-GAAP income for the first quarter was $140 million, representing non-GAAP diluted earnings per share of $0.71 and growth of 18% over the same period in 2023. The R&D prioritization decisions made in the first quarter will positively impact non-GAAP diluted earnings per share in 2024 due to now lower levels of expected R&D expense in the second half of 2024 versus prior guidance.

移動到底線。第一季 GAAP 淨利為 8,900 萬美元，年增 3,800 萬美元，相當於 GAAP 攤薄後每股收益 0.47 美元。第一季非GAAP 營收為1.4 億美元，相當於非GAAP 稀釋後每股收益0.71 美元，較2023 年同期成長18%。產生正面影響由於目前 2024 年下半年的預期研發費用水準低於先前的指導，因此 2024 年每股收益將下降。

We estimate that the discontinuation of the 4 programs announced today will result in a reduction of between $50 million to $60 million in R&D expense in 2024. And as Alexander and Hank mentioned, we are prioritizing 3 of our pipeline assets as well as the Voxzogo indication expansion. And we identified opportunities to accelerate the development of those assets this year. Therefore, there is a planned offsetting increase in 2024 R&D expenses of approximately $15 million to $20 million, which together with the planned reductions, we extract will result in lower projected R&D expense for the full year of between $35 million to $40 million.

我們估計，今天宣布的 4 個項目的終止將導致 2024 年研發費用減少 5,000 萬至 6,000 萬美元。今年我們發現了加速這些資產開發的機會。因此，計劃在 2024 年抵消增加約 1500 萬至 2000 萬美元的研發費用，再加上計劃的削減，我們將導致全年預計研發費用降低 3500 萬至 4000 萬美元。

Those anticipated net R&D spend reductions in 2024 are driving an expected increase to our non-GAAP operating margin guidance to 24% to 25%. And an increase to our full year non-GAAP diluted earnings per share guidance to between $2.75 to $2.95 per share. Noteworthy is that we are maintaining our prior projections for the full year, except for the changes in R&D, including total revenue guidance, which remains the same as communicated in February. Also, this update does not include the impact of any further potential strategic business decisions and potential future cost efficiencies to be discussed at Investor Day.

這些預期的 2024 年淨研發支出削減將推動我們的非 GAAP 營運利潤率預期提高至 24% 至 25%。我們將全年非 GAAP 攤薄每股盈餘指引提高至每股 2.75 美元至 2.95 美元。值得注意的是，我們維持先前對全年的預測，但研發方面的變化除外，包括總收入指導，與 2 月公佈的相同。此外，本次更新不包括投資者日討論的任何進一步潛在策略性業務決策和潛在未來成本效率的影響。

As we look forward to Q2 2024, we continue to anticipate limited revenue growth in Q2 versus Q1 due to the timing orders -- timing of orders for the enzyme products and similarly for Voxzogo, while we manage through the supply constraint. We expect higher operating expenses in Q2 versus Q1 due to normal quarterly business dynamics, our various 2024 strategic initiatives and the timing of expenses.

展望2024 年第二季度，我們繼續預計第二季度與第一季相比收入增長有限，原因是訂單時間——酶產品的訂單時間以及Voxzogo 的訂單時間，而我們在應對供應限制的情況下進行管理。由於正常的季度業務動態、我們的各種 2024 年策略性舉措和支出時間安排，我們預計第二季的營運支出將高於第一季。

With all this in mind, we expect limited total revenue growth in Q2 versus Q1, and we expect non-GAAP operating margin and EPS to be lower in Q2 than in Q1. In the second half of '24, we anticipate more meaningful revenue growth as we expect of Voxzogo supply constraints to be resolved. From an expense point of view, we expect all of the reduced R&D for the discontinued programs announced today to begin to be realized in the beginning of Q3 through the end of the year.

考慮到所有這些，我們預計第二季的總收入成長較第一季有限，並且我們預計第二季的非公認會計原則營業利潤率和每股收益將低於第一季。在 2024 年下半年，我們預計收入將出現更有意義的成長，因為我們預計 Voxzogo 的供應限制將得到解決。從費用的角度來看，我們預計今天宣布的已終止項目的所有減少的研發費用將在第三季初到年底開始實現。

Lastly, while we plan to share our updated capital allocation strategy at Investor Day regarding our $495 million of convertible notes maturing in August of this year, we plan to leverage our strong cash position and expected operating cash flow to repay the notes with available cash. Furthermore, given the settlement structure of the notes, we are planning for a share neutral outcome should the notes be in the money at maturity with the goal of returning value to shareholders by avoiding the potential dilution associated with the 4 million underlying shares.

最後，雖然我們計劃在投資者日分享關於今年 8 月到期的 4.95 億美元可轉換票據的最新資本配置策略，但我們計劃利用我們強大的現金狀況和預期營運現金流來用可用現金償還票據。此外，考慮到票據的結算結構，如果票據到期時處於貨幣狀態，我們正在計劃實現股份中立的結果，目的是透過避免與 400 萬股相關股票相關的潛在稀釋來向股東回報價值。

As we move into our next chapter of BioMarin, we are executing on our growth strategy with impressive performance driven by Voxzogo in achondroplasia in our pursuit of new indications, a durable and growing enzyme products business and an increased focus on streamlining the business through cost structure transformation and operating model efficiencies. Together, this presents an opportunity to drive meaningful improvements in our financial performance and sustainable shareholder value creation.

隨著我們進入BioMarin 的下一個篇章，我們正在執行我們的成長策略，在軟骨發育不全領域的Voxzogo 的推動下取得了令人印象深刻的業績，我們追求新的適應症、持久且不斷增長的酶產品業務，並更重視透過成本結構簡化業務轉型和營運模式效率。總之，這提供了一個推動我們的財務表現和永續股東價值創造有意義的改善的機會。

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

感謝您一直以來的支持，我們現在將開放電話解答您的問題。操作員？

(Operator Instructions) We'll go first to Phil Nadeau at TD Cowen.

（操作員指示）我們先去找 TD Cowen 的 Phil Nadeau。

Just wanted to follow up on your comments on Roctavian. Can you give us some sense of what you need to see to support continued investment in the Roctavian program? Or maybe asked another way, what would you have to see over the next several months in order to decide to out-license Roctavian or curtailed future investments there?

只是想跟進您對羅克塔維安的評論。您能否告訴我們一些您需要看到什麼來支持對 Roctavian 計劃的持續投資？或者換個方式問，在接下來的幾個月裡，您會看到什麼，才能決定放棄 Roctavian 的許可或減少在那裡的未來投資？

Thanks very much for the question, Phil. As you heard today, our focus from the R&D side is to allocate assets to the highest value and clearly, we have a high level of current of Roctavian investments and continued challenges with commercial uptake. What we're saying today is that at Investor Day, we will communicate our evaluation criteria, and the timing for that evaluation criteria at Investor Day on the fourth of September. The possible outcomes of that, I'll just elucidate; one would be that we see the uptake, the ramp starting to happen in a meaningful way, and that would be a state of course approach would be the outcome.

非常感謝你的提問，菲爾。正如您今天所聽到的，我們研發方面的重點是將資產分配到最高價值，顯然，我們目前對 Roctavian 的投資水平很高，並且在商業應用方面面臨持續的挑戰。我們今天要說的是，在投資者日，我們將傳達我們的評估標準，以及在 9 月 4 日投資者日上實施該評估標準的時間。我將解釋一下可能的結果；一個是我們看到人們的接受，開始以有意義的方式成長，這將是一種狀態，當然方法將是結果。

The second would be, we see a lower potential for the asset and a path towards a reasonable return on investment by rightsizing the level of investment across the organization from an R&D, medical affairs and commercial standpoint. And thirdly, the third possible outcome would be, we remove it from our portfolio, and we divest the asset. So we're not ready yet to share the evaluation criteria or when valuation criteria timing would be, but we will provide more information on this at Investor Day.

第二個是，我們看到該資產的潛力較低，並且透過從研發、醫療事務和商業的角度調整整個組織的投資水準來實現合理的投資回報。第三，第三種可能的結果是，我們將其從我們的投資組合中刪除，並剝離該資產。因此，我們尚未準備好分享評估標準或評估標準的時間，但我們將在投資者日提供更多相關資訊。

I just wanted to also highlight that even as we speak right now, we've really focused our strategy and execution with Roctavian. We're focused on the site level pull-through of the patients in the 3 major commercial markets where reimbursement established, United States, Germany and Italy. We have focused our life cycle management activities. So the ongoing studies, ones where we feel that there is a high potential, which is the prior inhibitor population, the registration in Japan. And we will continue to drive towards an evaluation and communicate more at Investor Day. Thank you, Phil.

我還想強調，即使我們現在說話，我們也確實將我們的策略和執行重點放在了 Roctavian 身上。我們專注於美國、德國和義大利這三個已建立報銷的主要商業市場中患者的站點級拉動。我們專注於生命週期管理活動。因此，正在進行的研究，我們認為有很大潛力的研究，即先前的抑制劑群體，在日本的註冊。我們將繼續推動評估並在投資者日進行更多溝通。謝謝你，菲爾。

We'll go next to Geoff Meacham at Bank of America.

接下來我們將前往美國銀行的傑夫‧米查姆 (Geoff Meacham)。

I know you've talked about label expansion for Voxzogo being of the highest important strategically. I guess the question is, in the near term, what are the next steps in optimizing the current formulation for Voxzogo? I wasn't sure what the cadence of data coming up is for that.

我知道您曾說過 Voxzogo 的品牌擴張具有最重要的策略意義。我想問題是，在短期內，優化 Voxzogo 目前配方的下一步是什麼？我不確定數據的出現頻率是多少。

Yes. Geoff, Hank here. So big picture, absolutely, your question started in the right direction, which is all of the activities that are underway to expand our CNP franchise into as many areas where there's potentially transformative medical benefit for children with statural impairments, not least of which is entering into a Phase III registration-enabling trial in hypochondroplasia and as I delineated we're now well underway in terms of idiopathic short stature. And we're really making great progress with our long-acting formulation.

是的。傑夫，漢克在這裡。這麼大的圖景，絕對，你的問題是從正確的方向開始的，這就是我們正在進行的所有活動，目的是將我們的CNP 特許經營權擴展到盡可能多的領域，這些領域對患有體態障礙的兒童有潛在的變革性醫療益處，尤其是正在進入一項針對軟骨發育不全的 III 期註冊試驗，正如我所描述的，我們現在在特發性身材矮小方面進展順利。我們的長效配方確實取得了巨大進展。

So in the category of additional presentations to delight patients, we have a lot of stuff that's also going on internally that for proprietary reasons, we won't detail until we're ready to get a little further along. But suffice it to say that we have a lot of confidence in the future of the CNP franchise, a number of different opportunities for treating and transforming the lives of patients and a number of different approaches to take to give families as many good choices they can have for treating their children.

因此，在讓患者高興的額外演示方面，我們還有很多內部正在進行的內容，出於專有原因，在我們準備好進一步了解之前，我們不會詳細說明。但我只想說，我們對 CNP 特許經營權的未來充滿信心，對治療和改變患者生活的許多不同機會以及為家庭提供盡可能多的良好選擇而採取的許多不同方法充滿信心有用於治療他們的孩子。

We'll move next to Salveen Richter at Goldman Sachs.

我們將接任高盛的 Salveen Richter。

On the strategic review here across the pipeline (inaudible) levers for lowering OpEx from this line? And how are you thinking separately about the mid- to late-stage pipeline in this context? And be the that may need to be done to sort of essentially add to the revenue pipeline on the board.

在整個管道（聽不清楚）的策略審查中，有哪些槓桿可以降低這條線的營運支出？在這種背景下，您如何單獨考慮中後期管道？這可能需要做才能從本質上增加董事會的收入管道。

Salveen, this is Brian. You broke up for just a second when you mentioned the line item you were asking about. Would you mind repeating which one?

薩爾文，這是布萊恩。當你提到你所詢問的訂單項目時，你們就分手了。您介意重複哪一個嗎？

Sure. The R&D line item.

當然。研發項目。

Yes, R&D, thanks. So as you noted, starting with your question, thank you, by the way. The strategic review is looking at both strategy and operations and efficiency, and we'll be eager to share details at Investor Day. But big picture, similar to the margin expansion narrative just enhanced now that we talked about in the past. It starts with a bit of core leverage of what we've built over the last many years, specific to R&D, full end-to-end, early-stage research, clinical regulatory to medical affairs, leveraging that engine, and then next, we'll be streamlining the business and cost transformation.

是的，研發，謝謝。正如您所指出的，從您的問題開始，順便說一句，謝謝您。策略審查著眼於策略、營運和效率，我們將渴望在投資者日分享詳細資訊。但從大局來看，類似我們過去談到的利潤擴張敘事只是增強。它從我們過去多年建立的一些核心槓桿開始，具體到研發、完整的端到端、早期研究、醫療事務的臨床監管、利用該引擎，然後下一步，我們將簡化業務和成本轉型。

So doing that same work but more efficiently. And then third, as you're seeing today is prioritizing the work on the right assets. So those 3 things, we believe, will provide leverage. We'll share more details on what the specific levers are and the tools around cost transformation and business efficiency at Investor Day, but those are the 3 big levers.

因此，做同樣的工作但效率更高。第三，正如您今天所看到的，優先考慮正確資產的工作。因此，我們相信，這三件事將提供槓桿作用。我們將在投資者日分享更多有關具體槓桿以及圍繞成本轉型和業務效率的工具的詳細信息，但這些是三大槓桿。

I'll hand it over to Hank on the pipeline question.

我會將管道問題交給漢克。

Yes, Salveen, the portfolio evaluation that we undertook was actually it started as a planned activity. But I think what's new this year because we've been doing it annually every -- so every -- for the last several years. But what was new, I think, this year was a higher degree of rigor and a higher bar set and a tighter commercial input, as Alexander mentioned, as well. And I have to comment that I'm very pleased about that tighter commercial connection starting under Jeff and looking forward to Kristin joining, where we'll really be able to have the opportunity to look at assets which are both important and transformational to patients, but also valuable to BioMarin as an organization.

是的，Salveen，我們進行的投資組合評估實際上是作為一項計劃活動開始的。但我認為今年有什麼新鮮事，因為過去幾年我們每年都會這樣做。但我認為，今年的新變化是更高程度的嚴格性、更高的標準以及更嚴格的商業投入，正如亞歷山大所提到的。我必須說，我對傑夫領導下的更緊密的商業聯繫感到非常高興，並期待克里斯汀的加入，在那裡我們將真正有機會看到對患者來說既重要又具有變革性的資產，而且對BioMarin 作為一個組織也很有價值。

What didn't change in any of this review is this notion that we're going to do what we can to make a big difference in people's lives. We're going to leverage good biology to find those assets that we believe are highly likely to work. Increasingly, what we've been doing is tying the timing considerations of our portfolio to our emerging growth strategy, which kind of leaves on the last piece of your question over -- I'll turn it over to Alexander to talk about your comments about the rest of the pipeline and potentially making room for later stage or other assets.

這篇評論沒有改變的是我們將盡我們所能為人們的生活帶來巨大改變的觀念。我們將利用良好的生物學特性來尋找那些我們認為極有可能發揮作用的資產。我們一直在做的事情越來越多地將我們投資組合的時機考慮與我們的新興增長戰略聯繫起來，這會留下你問題的最後一部分——我將把它交給亞歷山大來談談你的評論管道的其餘部分，並可能為後期或其他資產騰出空間。

Yes. Thanks very much, Hank. Thank you, Salveen, for the question. Yes, I mean, we are -- we have a real commitment to innovation at BioMarin, and we're excited about what we see in our early pipeline. We're excited about the 3 assets that we are advertising to accelerate and we're extremely excited about the Voxzogo life cycle management, which we're really excited at this call to be able to share some really significant progress, I think, as you heard in Hank's comments. But we also see that going forward, in terms of meeting our ambitions for sustained growth into the long, long term, we see a role for external innovation.

是的。非常感謝，漢克。謝謝薩爾文提出的問題。是的，我的意思是，我們對 BioMarin 的創新有真正的承諾，我們對我們在早期管道中看到的東西感到興奮。我們對我們正在宣傳加速的 3 項資產感到興奮，我們對 Voxzogo 生命週期管理感到非常興奮，我們對這次電話會議感到非常興奮，能夠分享一些真正重大的進展，我認為，你在漢克的評論中聽到了。但我們也看到，展望未來，在實現我們長期持續成長的雄心壯志方面，我們看到了外部創新的作用。

In the past, that's been very successful for us from an early research standpoint. We now see that there's an opportunity by dialing in on assets that could augment our existing portfolio that leverage our distinctiveness, i.e., what we know and we know we do well, better than others, that we should be more open to those sorts of opportunities. I would just stress that our guidance at the moment for this year does not reflect any incremental BD activity. We will share more -- and you'll have to keep history of saying this, we'll share more at Investor Day about our plans in the space. But in the interim, we've got no plans right now to transact major BD but we do see a growing role for this in the future.

過去，從早期研究的角度來看，這對我們來說非常成功。我們現在看到，有一個機會，可以透過撥入資產來擴大我們現有的投資組合，從而利用我們的獨特性，即我們所知道的，我們知道我們做得比其他人更好，我們應該對這些機會更加開放。我想強調的是，我們目前對今年的指導並不反映任何增量 BD 活動。我們將分享更多——你必須記住這句話的歷史，我們將在投資者日分享更多關於我們在該領域的計劃。但在此期間，我們目前還沒有交易主要 BD 的計劃，但我們確實看到未來這方面的作用越來越大。

We'll take our next question from Chris Raymond at Piper Sandler.

我們將回答 Piper Sandler 的 Chris Raymond 提出的下一個問題。

So just on the leverage you guys highlighted here. The focus today is all on the R&D pipeline. But I guess I wanted to ask on another important line item, which is SG&A. BioMarin's historical spending as a percent of revenue has been pretty meaningfully above that of your large-cap peers. And I know the last few, if you hasn't dropped yet with respect to all the transformation you're affecting here, Alexander. But any sort of thoughts there in terms of the potential in terms of having maybe a more in-line SG&A line item.

所以，就你們在這裡強調的槓桿作用而言。今天的焦點全部集中在研發管線。但我想我想問另一個重要的項目，即SG&A。 BioMarin 的歷史支出佔收入的百分比明顯高於大型同業。我知道最後幾個，如果你還沒有放棄你在這裡影響的所有轉變，亞歷山大。但對於可能擁有更符合 SG&A 行專案的潛力，有任何想法。

Chris, this is Brian Mueller. Thank you for the question. I'll start just to give you a little more color on the line item. And then maybe hand it over to Alexander as he thinks about the opportunity. So I might reference back to the comments I gave in response to Salveen's question on R&D, it does start with leverage. So importantly, as you know, in order for us to get to the $2 billion plus in revenue, mostly through the base enzyme products business where we sell in almost 80 markets, very diverse, complicated global sales and marketing, supply chain and related supporting infrastructure. That's the level of operational capability that we built over the last decade. And basically, over the last couple of years and now going forward, we're growing into it and making that machine work. It's that same infrastructure that's launching Voxzogo that's driving a lot of the margin improvement that you're seeing last year and this year. It will be that same infrastructure that launches future products (inaudible) grows the business from here. So it does start with leveraging what we built, recognizing that, that was a significant investment in the last few years.

克里斯，這是布萊恩·穆勒。感謝你的提問。我將首先為您提供更多關於訂單項目的顏色。然後，當亞歷山大考慮這個機會時，也許會將其交給他。所以我可能會參考我在回答Salveen關於研發的問題時給出的評論，它確實從槓桿開始。重要的是，如您所知，為了讓我們實現20 億美元以上的收入，主要是透過我們在近80 個市場銷售的基礎酵素產品業務，非常多樣化、複雜的全球銷售和行銷、供應鏈和相關支援基礎設施。這就是我們在過去十年中建立的營運能力水準。基本上，在過去的幾年以及現在的未來，我們正在不斷成長並讓這台機器運作起來。正是推出 Voxzogo 的基礎設施推動了去年和今年利潤率的大幅提高。推出未來產品（聽不清楚）的基礎設施將從這裡發展業務。因此，它確實從利用我們所建造的東西開始，並認識到這是過去幾年的一項重大投資。

And then next, what we're doing is streamlining it. Again, our focus over the last several years has been that organic capability growth. We're now focused on optimizing the business and prioritizing. We're also making sure we're reallocating resources, not just to the right places organizationally and globally but in the right brands. Voxzogo with this growth we've seen and its future potential deserves more resource allocation. How can we continue to sustain this robust launch? And for the mature brands, is there an opportunity to be more efficient there and recognize that while they're still growing, they may not require the same level of investment that they did over the years.

接下來，我們正在做的是簡化它。同樣，過去幾年我們的重點是有機能力成長。我們現在專注於優化業務並確定優先順序。我們還確保重新分配資源，不僅在組織和全球範圍內分配到正確的位置，而且分配到正確的品牌。我們看到 Voxzogo 的成長及其未來潛力值得更多的資源分配。我們如何才能繼續維持這強勁的推出？對於成熟的品牌來說，是否有機會提高效率，並認識到雖然它們仍在增長，但它們可能不需要與多年來相同水平的投資。

So that's the approach. Alexander, you comment on the opportunity?

這就是方法。亞歷山大，您對這個機會有何評論？

Yes. Thanks very much, Brian. Thanks for the question, Chris. Yes. I mean I've been really impressed by the potential leverage we have with our footprint in 70 countries and the capabilities we have globally. So building off the leverage, just like we've done with R&D, we're considering how to really leverage the capabilities we've got to have a greater impact and to be more efficient. And that's one of the work streams that we have is cost transformation. It's looking at all the line items on our P&L to say how can we now optimize that.

是的。非常感謝，布萊恩。謝謝你的提問，克里斯。是的。我的意思是，我們在 70 個國家的足跡以及我們在全球擁有的能力所具有的潛在影響力給我留下了深刻的印象。因此，就像我們在研發方面所做的那樣，我們正在考慮如何真正利用我們所擁有的能力來產生更大的影響並提高效率。我們的工作流程之一就是成本轉型。它會查看損益表上的所有行項目，以說明我們現在如何對其進行最佳化。

So you can expect to hear more from us at an Investor Day about our specific plans on the G&A line, on the on the sales and marketing line and additional efficiency in how we do research and development. This will all be rolled up into the long-term guidance that we'll be providing and our path to significantly improved margins, which, as we've said, at the start of this year was one of our priorities. So more details to come, but it's certainly one of the areas of focus for us.

因此，您可以期待在投資者日聽到我們更多有關我們在一般管理費用、銷售和營銷方面的具體計劃以及我們如何進行研發的額外效率的信息。這一切都將納入我們將提供的長期指導以及我們顯著提高利潤率的道路，正如我們所說，這是我們今年年初的優先事項之一。更多細節即將公佈，但這無疑是我們關注的領域之一。

We'll take our next question from Akash Tewari at Jefferies.

我們將回答傑富瑞 (Jefferies) 的 Akash Tewari 提出的下一個問題。

This is Amy on for Akash. So first, what's driving the difference between the reported Voxzogo demand increase and the revenue increase from the numbers? It seems like the demand is up more than sales from a quarter-over-quarter basis, would really appreciate any color on how to reconciliate this? And then also, if we can sneak in one more. Is there an increased appetite to divest the gene therapy franchise? And can you outline how much spend this makes up currently on OpEx?

這是艾米為阿卡什主持的節目。首先，是什麼導致了報告的 Voxzogo 需求成長與數位收入成長之間的差異？似乎需求的環比成長超過了銷售額的成長，真的很想知道如何協調這一點嗎？還有，如果我們能再偷偷溜進去一次。剝離基因治療特許經營權的意願是否增強？您能否概述一下目前這在營運支出上的支出有多少？

Thanks for the question, Amy. This is Brian. I'll start and Jeff has any other color to add. I think what you're starting to see on the Voxzogo line is consequences of its robust growth globally and a number of significant markets now online. Whereby we've got two things going on. One, some order timing. We've seen that trend over the years with the enzyme business. We're seeing a bit of larger for those for those markets that place less frequent, larger orders. We're seeing some Voxzogo revenue impacted by basic order timing. Two is the timing of patient additions any -- at being a chronic therapy any new patient additions for Voxzogo, especially in, say, the second half of the quarter are going to be less revenue generating than patients that were on drug the entire quarter. So that's another dynamic that could just draw the disconnect that you mentioned.

謝謝你的提問，艾米。這是布萊恩。我先開始，傑夫還有其他顏色要加。我認為您在 Voxzogo 系列上開始看到的是其在全球範圍內強勁增長以及許多重要線上市場的結果。由此我們發生了兩件事。一、一些訂單時間。多年來我們在酵素業務中看到了這種趨勢。我們發現那些訂單頻率較低、訂單量較大的市場的訂單量會較大。我們發現 Voxzogo 的一些收入受到基本訂單時間的影響。二是患者增加的時間——作為一種長期療法，Voxzogo 的任何新患者增加，特別是在本季度下半年，產生的收入將低於整個季度服用藥物的患者。所以這是另一種動態，可能會導致你提到的脫節。

And then perhaps to the first point, there's some unique aspects right now with the supply constraint. We are managing through the supply constraint by managing orders at the specific market and SKU level. And that's going to throw the trends off a little bit. You might recall back in Q4 where we reported revenues over our guidance, not because we overperformed on patient additions but because some additional supply became available, and so we shipped it into the market. So we'll ask you to stay tuned. We're trying to provide the right metrics in terms of patients and ask you to follow revenues to watch those trends. It's a great question but it is dynamic. And Jeff give me a thumbs up, so we're covered.

也許對於第一點，目前的供應限制存在一些獨特的面向。我們透過管理特定市場和 SKU 層級的訂單來應對供應限制。這會稍微偏離趨勢。您可能還記得在第四季度，我們報告的收入超出了我們的指導，不是因為我們在患者增加方面表現出色，而是因為有一些額外的供應可用，因此我們將其運送到市場。因此，我們請您繼續關注。我們正在努力提供有關患者的正確指標，並要求您追蹤收入以觀察這些趨勢。這是一個很好的問題，但它是動態的。傑夫對我豎起大拇指，這樣我們就放心了。

And gene -- there was a gene therapy question, whether the divestiture is an option.

還有基因——有一個基因治療問題，剝離是否是一種選擇。

Yes. Thanks for the question on Roctavian divestment. As I mentioned before, our focus right now is making sure that we really establish what the Roctavian opportunity is, and we really focused our strategy around that. I talked already about the possible outcomes of our assessment. And one of them could be that we remove it from the portfolio and divest, that is not our focus right now. We are not engaging with people around the divestment of Roctavian. Our focus is really on establishing the opportunity right now. But should we remove it from the portfolio we will absolutely look at the options around divesting it.

是的。感謝您提出有關羅克塔維安撤資的問題。正如我之前提到的，我們現在的重點是確保我們真正確定 Roctavian 的機會是什麼，我們的策略也真正圍繞著這一點。我已經談到了我們評估的可能結果。其中之一可能是我們將其從投資組合中刪除並剝離，這不是我們現在的重點。我們不會與有關羅克塔維安撤資事宜的人士接觸。我們現在的重點其實是創造機會。但如果我們將其從投資組合中刪除，我們絕對會考慮剝離它的選擇。

We'll go next to Jessica Fye at JPMorgan.

接下來我們將採訪摩根大通的傑西卡·菲伊。

On the pipeline, can you talk a little more about the long-acting CNP product you're prioritizing? What's the half-life there and the dosing frequency you're contemplating? And then just a quick one on BMN 293, the gene therapy for hypertrophic cardiomyopathy. Is that one staying or going, I don't know if I caught it in the list?

在管道方面，您能多談談您優先考慮的長效 CNP 產品嗎？您正在考慮的半衰期和給藥頻率是多少？然後簡單介紹 BMN 293，一種肥厚型心肌病變的基因療法。那個是留下還是離開，不知道我是否在清單中發現了它？

Jess, long-acting, we have every reason to believe that the dosing interval there could be as long as weekly. But obviously, that's going to be informed by early human clinical trials to actually measure what that dosing frequency is going to be. On 293, that's a program we want to gather a little bit more information. We recently learned that there is a population of patients with C3 deficiency in hypertrophic cardiomyopathy who are very severely affected with really poor outcomes as measured, for example, by short time to left ventricular assist devices or mortality. And we are actively working with investigators to understand better how findable those patients are and how interested and motivated those patients are. And finally, whether there's a regulatory pathway to a faster approval by virtue of the severity of their condition.

Jess，長效的，我們有充分的理由相信那裡的給藥間隔可能長達每週一次。但顯然，這將透過早期人體臨床試驗來實際測量給藥頻率。在 293 上，我們想要收集更多資訊。我們最近了解到，肥厚型心肌病變中有一群患有 C3 缺乏症的患者，他們受到的影響非常嚴重，結果非常差，例如左心室輔助裝置安裝時間短或死亡率。我們正在積極與研究人員合作，以更好地了解這些患者的可找到性以及這些患者的興趣和積極性。最後，是否有監管途徑可以根據病情的嚴重程度來加快批准速度。

As we learned, the more significant the medical, the unmet need is, the more motivation there can be for the uptake of these novel disruptive types of therapy. So that's the additional information we're gathering and we'll keep you informed as to decisions that we make about further advancement of 293.

據我們了解，未滿足的醫療需求越重要，採用這些新型破壞性療法的動力就越大。這就是我們正在收集的額外信息，我們將隨時向您通報我們就進一步推進 293 所做的決定。

We'll go next to Joseph Schwartz at Leerink Partners.

接下來我們將採訪Leerink Partners 的約瑟夫·施瓦茨(Joseph Schwartz)。

I was wondering, can we infer anything from the amount of savings that you expect to realize as a result of the strategic portfolio assessment of R&D programs, which you announced today about the amount of operating expense savings, which might be realized as a result of the remainder of the strategic and operating assessment, which is ongoing. Can you give us any insight into the relative degree of operating expense savings, which might remain to be realized relative to what you announced today, even if it's just a general order of magnitude?

我想知道，我們能否從您期望透過研發計劃的戰略組合評估實現的節省金額中推斷出任何信息，您今天宣布了有關運營費用節省的金額，這可能是由於以下原因實現的：戰略和運營評估的其餘部分正在進行中。您能否向我們介紹一下營運費用節省的相對程度，相對於您今天宣布的內容，這可能仍有待實現，即使這只是一般的數量級？

Yes. Thanks a lot, Joe. It's a really good question. Given we talked today about the financial impact of what was a discrete clear eye view on the portfolio. The financial repercussions and the net reduced R&D were a consequence of that portfolio review, not the purpose. And that -- and -- from there, I would not make an inference on what the future potential savings are for 2 reasons. This was a review, top to bottom of the current portfolio. And again, a consequence but also the strategic review and the remaining optimization of the business is work in process. So we'll have to put that latter part in the category of stay tuned for Investor Day to hear both the strategy, both top-level business strategy, operational excellent strategy, long-term guidance. And we'll get color on all the line items, how we'll plan to be more efficient on cost. But the heart of your question, I would not make that influence today.

是的。非常感謝，喬。這是一個非常好的問題。鑑於我們今天討論了對投資組合的離散清晰視角的財務影響。財務影響和研發淨減少是投資組合審查的結果，而不是目的。從那時起，我不會對未來潛在的節省量做出推斷，原因有二。這是對目前投資組合從上到下的回顧。同樣，結果以及戰略審查和剩餘的業務優化正在進行中。因此，我們必須將後半部分放在敬請關注投資者日的類別中，以聽取策略、頂級業務策略、卓越營運策略和長期指導。我們將在所有訂單項目上顯示顏色，說明我們將如何規劃更有效地降低成本。但你問題的核心是，我今天不會產生這種影響。

Our next question comes from Gena Wang at Barclays.

我們的下一個問題來自巴克萊銀行的 Gena Wang。

I have one regarding Roctavian revenue of $0.8 million in the quarter. We also, together with, I believe, many investors did due diligence regarding exactly how many patients got treated in the first quarter. So based on our due diligence, we understand that Germany actually there's no patient got treated and as some investors they are due diligent believe there a few patients got treated in the U.S. So the question here is $0.8 million, can you remind us where that revenue is from? And also at what point the timing for you to recognize revenue as well as pay for performance, the warrant at what point you booked this? My understanding previously was gross to net but I just want to make sure.

我有一個關於 Roctavian 本季收入 80 萬美元的資訊。我相信，我們也與許多投資者一起對第一季到底有多少患者得到了治療進行了盡職調查。因此，根據我們的盡職調查，我們了解到德國實際上沒有患者得到治療，而一些盡職盡責的投資者認為美國有一些患者得到了治療。收入在哪裡嗎？另外，您在什麼時候確認收入以及按績效支付工資，您在什麼時候預訂了權證？我之前的理解很粗糙，但我只是想確定一下。

Gena, jeff here. Yes, we are aware and have heard of some survey or due diligence work by yourself and others, but without knowing the methodology and so forth of the survey results we can't really speak to them specifically. We can speak to our revenues. So in the press release, it was noted that first patient was treated in Italy, and the revenue that you see in Q1 is tied to that first patient in Italy. Revenue recognition varies a little bit by market. But essentially, Gena, we can tell when product is shipped to patients, we're scoring revenue right around that treatment of patients. And so if your question is, is it likely that there's been a bunch of patients treated, and we're not seeing that in our prepared remarks or revenue, I think the answer is no.

吉納，傑夫在這裡。是的，我們知道並聽說過您自己和其他人進行的一些調查或盡職調查工作，但在不了解調查結果的方法等的情況下，我們無法真正與他們具體交談。我們可以談談我們的收入。因此，在新聞稿中，有人指出，第一位患者在義大利接受治療，您在第一季看到的收入與義大利的第一位患者相關。收入確認因市場而異。但本質上，Gena，我們可以知道產品何時運送給患者，我們就圍繞患者的治療獲得收入。因此，如果您的問題是，是否有可能已經有一堆患者接受了治療，而我們在準備好的評論或收入中沒有看到這一點，我認為答案是否定的。

And maybe Brian could make some further remarks about revenue recognition.

也許布賴恩可以就收入確認發表一些進一步的評論。

Yes, I think you've got it right, Jeff. Thank you. maybe just noting the nuance in Italy is that Italy happens to be a market where title transfer and revenue recognition occurs before the actual dosing of the patient. Hence, the March revenue and the first week of April treatment. I'll share that in other key markets like the U.S. and Germany, the revenue recognition and title transfer is much closer, if not at the point of infusion.

是的，我認為你說得對，傑夫。謝謝。也許只是注意到義大利的細微差別是，義大利恰好是一個所有權轉讓和收入確認發生在患者實際用藥之前的市場。因此，三月份的收入和四月份的第一周的治療。我將分享的是，在美國和德國等其他主要市場，即使不是在註入時，收入確認和所有權轉移也要接近得多。

We'll go next to Ellie Merle at UBS.

接下來我們將採訪瑞銀集團的 Ellie Merle。

Can you help us understand how you're thinking about the relative size of the opportunities between ISS and genetic short stature pathways? And also as well as the level of clinical risk or clinical validation from the data that you've seen from these the date between the two of these planned studies and just help us understand how you're thinking about the biology and confidence in activity in ISS as well as the genetic for factor pathways?

您能否幫助我們了解您如何看待 ISS 與遺傳性身材矮小途徑之間機會的相對大小？以及您從這些計劃中的兩項研究之間的數據中看到的臨床風險或臨床驗證水平，這只是幫助我們了解您對生物學的看法以及對活動的信心ISS 以及因子途徑的遺傳？

Maybe I'll start on the R&D science piece and then I'll look for help from Alexander on the market sizing kinds of pieces. Although I can say a little bit about things like epidemiology. But from an R&D perspective, our confidence that CNP is going to work in conditions beyond hypochondroplasia is driven by genetics, and we've talked about where patients who had humans who have gain of function mutations in the CNP pathway or taller than their predicted final adult it would be in patients who have negative mutations are shorter. So these are human, if you will, proof of concepts about exposure. There are also individuals who are extremely toll to have gain-of-function mutations in NPR2 or who are -- or in its receptor.

也許我會從研發科學作品開始，然後我會向亞歷山大尋求有關市場規模的協助。雖然我可以說一點流行病學之類的東西。但從研發的角度來看，我們對CNP 將在軟骨發育不全以外的情況下發揮作用的信心是由遺傳學驅動的，我們已經討論過，那些患有CNP 途徑功能獲得性突變或高於預期最終身高的患者成年後，攜帶陰性突變的患者的體重會更短。所以，如果你願意的話，這些都是人類關於暴露概念的證明。也有一些人因 NPR2 或其受體發生功能獲得性突變而造成嚴重後果。

So a lot of biological data but what's new now is we're days away from Dr. Dauber presenting his first 12-month cohort of using Voxzogo to treat patients with either pathway conditions, in his case, Noonan syndrome or with things that were formerly known as idiopathic short stature because that term got coined before sequencing helped us to understand that specific mutations could be accountable for what was formerly known as idiopathic short stature and had an opportunity as has the Food and Drug Administration to review those emerging data, which led them and us to conclude that there is a great prospect for benefit with vosoritide and the treatment of these relatively more common conditions.

生物學數據很多，但現在的新情況是，距離Dauber 博士展示他的第一個12 個月隊列，使用Voxzogo 治療患有任何途徑疾病的患者，在他的例子中，是努南綜合症或以前患有的疾病被稱為特發性身材矮小，因為這個術語是在測序之前創造的，幫助我們理解特定的突變可能是以前稱為特發性身材矮小的原因，食品和藥物管理局有機會審查這些新出現的數據，這導致了他們和我們得出的結論是，vosoritide 以及治療這些相對較常見的病症有很大的獲益前景。

So you've heard me talk about idiopathic short stature in terms of the volume of people who are available. It's something like 2 standard deviations below average stature encompasses 2.5% of the basically the human population. So we're talking about some is a fairly large potential indication.

所以你已經聽過我會根據可用人數來談論特發性身材矮小。大約有 2.5% 的人口低於平均身高 2 個標準差。所以我們談論的是一些相當大的潛在跡象。

I don't know if Alexander you want to add anything more about that.

我不知道亞歷山大您是否想補充更多相關內容。

In terms of the size of the future indications. JPMorgan, we talked about how the indications beyond achondroplasia, so hypochondroplasia, ISS, Noonan's, Turner's, SHOX, in total, represent about 600,000 patients compared to the total global addressable population for any achondroplasia of 21,000. We're obviously going to be and I just want to highlight this that we're going to be going for a more severe patient population in, for example, idiopathic short stature editions. And you'll see -- if you go on clinical trials it's actually posted today, you'll see the design of our Phase II study in ISS.

從未來的規模來看。摩根大通，我們討論了軟骨發育不全以外的適應症，因此軟骨發育不全、ISS、Noonan's、Turner's、SHOX 總共代表約 600,000 名患者，而全球軟骨發育不全的可尋址人群總數為 21,000 人。顯然我們會，我只是想強調這一點，我們將針對更嚴重的患者群體，例如特發性身材矮小版本。你會看到——如果你繼續今天發布的臨床試驗，你會看到我們在 ISS 的 II 期研究的設計。

So we'll share more at Investor Day about the TAMs for all the different indications. They represent significant multiyear growth potentials for Voxzogo. And it's really exciting to see and being able to share today not just the R&D prioritization but the progress we're making with Voxzogo, not just the uptake, which is really exciting to see in achondroplasia globally with growth accelerating, but we've had really productive conversations with regulatory authorities. We have definite plans now solidified, heard from the feedback from the FDA on ISS. We have clarity now of the duration of the study, endpoints comparator. We have a very clear path forward in multiple of these indications and an opportunity to bring Voxzogo to so many more patients around the world.

因此，我們將在投資者日分享更多有關所有不同適應症的 TAM 的資訊。它們代表了 Voxzogo 多年的巨大成長潛力。今天看到並能夠分享的不僅是研發優先順序，還有我們在Voxzogo 上取得的進展，而不僅僅是吸收，這真的很令人興奮，看到全球軟骨發育不全症的增長加速，這真的很令人興奮，但我們已經與監管機構進行真正有成效的對話。從 FDA 對 ISS 的回饋中得知，我們現在已經有了明確的計劃。我們現在已經清楚了研究的持續時間和終點比較器。我們在多個適應症方面都有非常明確的前進道路，並且有機會將 Voxzogo 帶給世界各地更多的患者。

We'll go next to Paul Matteis at Stifel.

我們將前往 Stifel 的 Paul Matteis 旁邊。

I was curious what the management team's current thinking is on the various competitors are in achondroplasia given that we're going to get data from a couple this year. And as you think about potentially -- and I don't know if it's exactly potentially giving margins guidance or commentary aspirations at the Investor Day, it feels like whether or not there is competition in achondroplasia is a key variable. So I would love your perspective on that.

我很好奇管理團隊目前對軟骨發育不全的各個競爭對手的看法如何，因為我們今年將從幾個競爭對手那裡獲得數據。當你考慮潛在的情況時——我不知道它是否確實有可能在投資者日提供利潤指導或評論願望，感覺軟骨發育不全是否存在競爭是一個關鍵變量。所以我很喜歡你對此的看法。

Yes. Thanks very much for the question. Paul, I really do appreciate it. Overall, we're feeling very good about where we are in achondroplasia and now with the path forward in all these other indications starting to become really quite clear from us -- for us. Demand and the feedback from families is excellent. We see really good assistance and adherence to Voxzogo. And we're really -- every day that we're on the market, clearly, we now have over 3,000 patients now on Voxzogo. We're really establishing a safety and efficacy profile that gives a lot of confidence to physicians to prescribe the product and also family members and parents, children, now infants beginning treatment.

是的。非常感謝您的提問。保羅，我真的很感激。總的來說，我們對軟骨發育不全的現狀感覺非常好，現在所有其他跡象的前進道路開始變得非常清晰——對我們來說。家庭的需求和回饋非常好。我們看到了對 Voxzogo 的良好幫助和遵守。顯然，我們每天在市場上的每一天，現在都有超過 3,000 名患者在使用 Voxzogo。我們確實正在建立一個安全性和有效性概況，這給醫生開出該產品的處方以及家庭成員和父母、兒童（現在是開始治療的嬰兒）帶來了很大的信心。

I think from our perspective, we've done extensive market research, we really understand these disease states. And it's really very clear that the most important thing for patients and caregivers and equivocally is safety and efficacy, and they will not sacrifice that for convenience. I was reviewing with the team, some of the market research, and I'll just give you a couple of examples. A caregiver said, weekly or oral would need to be within 5% or less the efficacy of Voxzogo, where I wouldn't consider it. Safety is an absolute and the physician said, my #1 priority for novel therapy is safety and efficacy that won't be sacrificed for something more convenient. So whilst we believe with BMN 333, we're excited about it. The TPP for that is for it to be at least as effective and safe as Voxzogo with the potential for, as Hank mentioned, more convenient dosing. But we believe that Voxzogo is well set up to be a very robust competitor to any potential new entrants.

我認為從我們的角度來看，我們已經做了廣泛的市場研究，我們真正了解這些疾病狀態。很明顯，對於患者和照護者來說，最重要的是安全性和有效性，他們不會為了方便而犧牲這一點。我正在與團隊一起審查一些市場研究，我只想給大家舉幾個例子。一位護理人員說，每週或口服 Voxzogo 的功效需要在 5% 或更低的範圍內，但我不會考慮。安全性是絕對的，醫生說，我對新療法的第一要務是安全性和有效性，不會為了更方便的東西而犧牲安全性和有效性。因此，雖然我們相信 BMN 333，但我們對此感到興奮。 TPP 的目標是它至少與 Voxzogo 一樣有效和安全，正如 Hank 所提到的那樣，具有更方便給藥的潛力。但我們相信，對於任何潛在的新進者來說，Voxzogo 已經做好了成為強而有力的競爭對手的準備。

Our next question comes from Mohit Bansal at Wells Fargo.

我們的下一個問題來自富國銀行的 Mohit Bansal。

And staying on the competitive theme, I think one of your competitors is also testing a longer-acting CNP in combination with growth hormones in achondroplasia. How do you think about the rationale there? And do you think you could do something like something similar for Voxzogo? And then the related question is, in the ISS trial that has been posted, it seems like you are testing against growth hormones. Is there a rationale to test it in combination with growth hormones as well in that indication?

繼續保持競爭主題，我認為你們的一位競爭對手也在測試一種長效 CNP 與生長激素聯合治療軟骨發育不全的情況。您如何看待其中的原理？你認為你可以為 Voxzogo 做類似的事情嗎？然後相關的問題是，在已經發布的國際太空站試驗中，似乎您正在測試生長激素。在該適應症中是否有理由將其與生長激素聯合測試？

Yes, Mohit. The efficacy of Voxzogo in achondroplasia restores growth to a fairly physiologic level, over 90% of average stature growth. So it's hard to beat that in terms of efficacy. And so a little tough to rationalize combination therapy to do better than basically normal. I think the most important thing to be doing with Voxzogo as regards to improving long-term outcomes is to start therapy earlier, which was why we were so keen to have label extension into almost every market in the world where Voxzogo is available to almost from infancy because that's where you can make a big difference in the overall outcome. And again, probably doesn't necessarily warrant the addition of another therapy, it warrants starting therapy as soon as the condition is understood. And I think same story for ISS. We need to look at the data that comes out next month from Dr. Dauber to gauge how much of a stature of improvement we get and whether there is any room for improvement, but I wouldn't anticipate that being a key consideration.

是的，莫希特。 Voxzogo 對軟骨發育不全的療效使生長恢復到相當生理的水平，超過平均身高生長的 90%。因此，就功效而言，很難擊敗它。因此，要使聯合療法合理化以使其比基本正常療法更好有點困難。我認為，就改善長期結果而言，使用 Voxzogo 做的最重要的事情是儘早開始治療，這就是為什麼我們如此熱衷於將標籤擴展到世界上幾乎所有可以使用 Voxzogo 的市場。你可以對整體結果產生重大影響的時期。再說一遍，可能不一定需要添加另一種治療方法，但需要在了解病情後立即開始治療。我認為國際太空站也有同樣的情況。我們需要查看道伯博士下個月發布的數據，以衡量我們取得了多大程度的改進以及是否有改進的空間，但我不認為這是一個關鍵的考慮因素。

Finally, in the Phase II study you mentioned, the inclusion of the growth hormone arm is really purely for internal reference so that we have a sense of through randomization, what the sort of apples-to-apples comparison might be. As Alexander just mentioned and I believe I steered us in the direction of, we do have agreement from the Food and Drug Administration on some really cardinally -- cardinal important points of the design of the Phase III program, just to recapitulate them, we've agreed on the target patient population that is growth hormone naive. We've agreed on the endpoint, 52 weeks annualized growth velocity as improvement. And most importantly, we've agreed with the agency that placebo can be an appropriate comparator for the registration. So we're well underway. We don't believe that we need to add other therapies into the armamentarium to augment the effect of vosoritide because it's doing just fine by itself.

最後，在你提到的二期研究中，納入生長激素組實際上純粹是為了內部參考，以便我們透過隨機化來了解可能進行的同類比較。正如亞歷山大剛才提到的，我相信我引導我們朝著這個方向前進，我們確實與食品和藥物管理局就第三階段計劃設計的一些真正基本的重要要點達成了一致，只是為了重述它們，我們'我們就未使用生長激素的目標患者群體達成一致。我們已就終點達成一致，即 52 週年化成長率作為改善。最重要的是，我們已與該機構達成一致，即安慰劑可以作為註冊的合適比較器。所以我們進展順利。我們認為我們不需要在醫療設備中添加其他療法來增強沃索立肽的效果，因為它本身就效果很好。

We'll go next to Vikram Purohit at Morgan Stanley.

接下來我們將採訪摩根士丹利的維克拉姆‧普羅希特 (Vikram Purohit)。

So we had a follow-up on Roctavian. So you obviously discussed some of the reimbursement and market access challenges. The product is seen here to date. But looking forward, could you speak about some of the strategies you're putting in place now to help with the -- I guess, the operational lift of the franchise? And how many months or quarters would you expect it to take for some of the challenges to be a bit less of a variable in the product trajectory, assuming the franchise stays in-house with BioMarin?

所以我們對羅克塔維安進行了後續行動。因此，您顯然討論了一些報銷和市場准入挑戰。迄今為止，該產品已在此處看到。但展望未來，您能否談談您現在正在實施的一些策略，以幫助提升特許經營權的營運？假設特許經營權仍由 BioMarin 內部管理，您預計需要多少個月或幾季才能使產品軌跡中的一些挑戰變得不那麼重要？

Thank you for the question. This is Jeff. I'll field that one. As Alexander mentioned earlier, we're really focused on patient pull-through in the markets where we have reimbursement approvals. So a reminder, that's the U.S., Germany and Italy. Patient pull-through is really the last mile but we've experienced the challenges with. So we think that establishing proof-of-concept in pulling those patients through that last mile and getting them treated is what we need to do on a going-forward basis. How long that will take undetermined. Alexander already mentioned that at Investor Day early September, criteria will be laid out for what that looks like.

感謝你的提問。這是傑夫。我會派出那個。正如亞歷山大之前提到的，我們真正關注的是在我們獲得報銷批准的市場中的患者拉動。提醒一下，這是美國、德國和義大利。病人的拉通確實是最後一英里，但我們已經經歷了挑戰。因此，我們認為，建立概念驗證，幫助這些患者度過最後一英里並為他們提供治療，是我們未來需要做的事情。需要多長時間尚未確定。亞歷山大已經提到，在九月初的投資者日，將會制定標準。

And the other thing I would comment on is, in Europe, in most cases, the commercialization starts with the price and reimbursement approval. We got the GBA approval listed in December of last year, 4 months ago. In Italy, that was 3 months ago. So one way of looking at the situation, at least in Europe, as I say, perhaps the clock started ticking 3 to 4 months ago in those 2 target markets and -- so thinking about how long that might take during the course of this year could be instructive.

我要評論的另一件事是，在歐洲，在大多數情況下，商業化是從價格和報銷批准開始的。去年12月，也就是4個月前，我們就獲得了GBA的核准上市。在義大利，那是三個月前的事了。因此，從一個角度來看，至少在歐洲，正如我所說，這兩個目標市場的時鐘可能在 3 到 4 個月前開始計時，因此請考慮今年可能需要多長時間可能具有啟發性。

We'll move next to Tim Lugo at William Blair.

我們將搬到威廉布萊爾的蒂姆盧戈旁邊。

This is Lachlan on for Tim. So you've identified Voxzogo as a strategic priority and have obviously made a lot of progress on the development front in new indications. But is there anything you're doing on the commercial front there, too? Because I noticed you obviously added a much larger number of patients this quarter than last quarter. So I was curious if that's sort of a result of any direct initiatives or actions you've taken or just the maturing markets and increasing supply.

這是拉克蘭替提姆發言。因此，您已將 Voxzogo 確定為戰略重點，並且顯然在新適應症的開發方面取得了巨大進展。但你們在商業方面也做了什麼嗎？因為我注意到本季明顯比上個季度增加了更多患者。所以我很好奇這是否是你們採取的任何直接舉措或行動的結果，或者只是市場的成熟和供應的增加。

Yes, we're very -- thanks very much for the question. We're really happy with the progress on Voxzogo. I mean it is one of the priorities we set out we described has tremendous potential in achondroplasia as we talked about extensively in other diseases. So right now, it's in achondroplasia and that ramp is accelerated. We added 500 patients in the first quarter compared to adding 300 patients in the fourth quarter of last year. So we're seeing that growth actually accelerating. This is driven very much by the 0 to 5 (inaudible) to use the product from birth, which is now in many, many geographies around the world. And it's good to see that, that growth is actually consistent across the major markets. The U.S. actually driving the most growth, which is great to see because this is where we didn't have the same ramp. We're now seeing that.

是的，我們非常——非常感謝你提出這個問題。我們對 Voxzogo 的進展感到非常滿意。我的意思是，正如我們在其他疾病中廣泛討論的那樣，這是我們所描述的在軟骨發育不全方面具有巨大潛力的優先事項之一。所以現在，它處於軟骨發育不全狀態，而且加速了。我們在第一季增加了 500 名患者，而去年第四季增加了 300 名患者。所以我們看到成長實際上在加速。這在很大程度上是由 0 到 5（聽不清楚）從出生起就使用該產品所驅動的，現在該產品已在世界各地許多許多地區使用。很高興看到，主要市場的成長實際上是一致的。美國實際上推動了最大的成長，這是很高興看到的，因為這是我們沒有相同成長的地方。我們現在看到了這一點。

And I think the 0 to 5 and the team is really focused on that as well as the other things that we've been doing, we're seeing bearing fruit, which is really focusing on the pediatric. Analogist making sure we've got referral pathways, the setting up the skeletal dysplasia clinics, which are going to be very important, not just for achondroplasia but also for the subsequent indications. So the team is really driving on all cylinders in more geographies. It's one thing that actually I do want to say, which is with regard to supply, we mentioned in our prepared remarks that we will be hitting supply levels, which we'll be able to meet demand in the middle of this year but we have really good news to share with regard to the maximum supply available this year.

我認為 0 到 5 和團隊確實專注於這一點以及我們一直在做的其他事情，我們看到了成果，這真正關注的是兒科。類比學家確保我們有轉診途徑，建立骨骼發育不良診所，這將非常重要，不僅對於軟骨發育不全，而且對於隨後的適應症也非常重要。因此，該團隊確實在更多地區全力以赴。實際上我想說的一件事是，關於供應，我們在準備好的發言中提到，我們將達到供應水平，我們將能夠在今年年中滿足需求，但我們有關於今年的最大供應量，確實是個好消息。

So in January at the JPMorgan conference, we shared our supply plan for Voxzogo, which is obviously very, very critical, especially as we accelerate our life cycle funds and ambitions for this product. We are now going to be able to supply by the end of this year, 8,000 patients supplies work of Voxzogo. If you remember from January, that's what we said that we would achieve by the end of 2025. So the team here in manufacturing has moved this us up by 1 year and this continues to give us confidence that even as we ramp up demand for Voxzogo, by the end of this year, we're going to be able to meet that demand.

因此，在一月份的摩根大通會議上，我們分享了我們對 Voxzogo 的供應計劃，這顯然非常非常關鍵，特別是當我們加快我們對該產品的生命週期資金和雄心壯志時。我們現在將能夠在今年年底前為 8,000 名患者提供 Voxzogo 的工作。如果您還記得 1 月的情況，這就是我們所說的 2025 年底要實現的目標。到今年年底，我們將能夠滿足這項需求。

And that is all the time we have for Q&A today. I will turn it back to Alexander Hardy.

這就是我們今天問答的全部時間。我會把它轉回亞歷山大·哈代。

Well, thank you all for joining us today. I hope you've heard and it came across that how hard this team and all the teams across BioMarin are working right now to shape the future corporate and R&D strategy for BioMarin. We're setting very ambitious long-term financial targets and we're starting to deliver on them. We've got a real sense of urgency. I think that comes across and we're really looking forward to sharing our vision with you and our full plans with you all in New York Investor Day on September 4.

好的，謝謝大家今天加入我們。我希望您已經聽說並了解這個團隊以及 BioMarin 的所有團隊現在正在多麼努力地制定 BioMarin 未來的企業和研發策略。我們正在製定非常雄心勃勃的長期財務目標，我們正在開始實現這些目標。我們有一種真正的緊迫感。我認為這一點已經得到體現，我們非常期待在 9 月 4 日的紐約投資者日與大家分享我們的願景以及我們的完整計劃。

Meantime, thank you very much for your attention. I wish you all a wonderful evening. Take care.

同時，非常感謝您的關注。祝大家有個美好的夜晚。小心。

And that does conclude today's conference call. Again, thank you for your participation. You may now disconnect.

今天的電話會議到此結束。再次感謝您的參與。您現在可以斷開連線。