BioMarin Pharmaceutical Inc (BMRN) 2023 Q1 法說會逐字稿

Welcome to the BioMarin Pharmaceuticals First Quarter Investor Update Call. Hosting the conference call today from BioMarin is Traci McCarty, Group Vice President, Investor Relations. Please go ahead, Traci.

歡迎來到 BioMarin Pharmaceuticals 第一季度投資者更新電話會議。 BioMarin 負責投資者關係的集團副總裁 Traci McCarty 主持了今天的電話會議。請繼續，Traci。

Thank you, Ross, and thank you all for joining us today. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical, including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development.

謝謝你，羅斯，感謝大家今天加入我們。提醒您，這份非機密報告包含有關 BioMarin Pharmaceutical 業務前景的前瞻性陳述，包括對 BioMarin 的財務業績、商業產品和治療研發不同領域的潛在未來產品的預期。

Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authority, 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.

結果可能存在重大差異，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述的那些因素，例如 10- Q、10-K 和 8-K 報告。

On the call today from BioMarin's management team are JJ Bienaimé, Chairman and Chief Executive Officer; Jeff Ajer, Executive Vice President and Chief Commercial Officer; Hank Fuchs, President, Worldwide Research and Development; Greg Guyer, Executive Vice President, Chief Technical Officer; and Brian Mueller, Executive Vice President and Chief Financial Officer.

今天接到 BioMarin 管理團隊電話的是董事長兼首席執行官 JJ Bienaimé；執行副總裁兼首席商務官 Jeff Ajer；全球研發總裁 Hank Fuchs； Greg Guyer，執行副總裁兼首席技術官；執行副總裁兼首席財務官 Brian Mueller。

I will now turn the call over to our Chairman and CEO, JJ Bienaime.

我現在將把電話轉給我們的董事長兼首席執行官 JJ Bienaime。

Thank you, Traci, and good afternoon, everyone. Thank you for joining us today. So we are very pleased with BioMarin's progress in the first quarter as more families gain access to Voxzogo as well as or our other essential medicines. Our financial performance in the quarter was strong, especially in light of ongoing macroeconomic challenges across the globe.

謝謝 Traci，大家下午好。感謝您今天加入我們。因此，隨著越來越多的家庭獲得 Voxzogo 以及我們的其他基本藥物，我們對 BioMarin 在第一季度取得的進展感到非常滿意。我們在本季度的財務表現強勁，尤其是考慮到全球範圍內持續存在的宏觀經濟挑戰。

15% growth of the top line and 15% non-GAAP income growth on the bottom line puts BioMarin firmly on track to achieving our 2023 financial goals. These results included $88 million in Voxzogo revenues and strong Q1 profitability of $51 million on a GAAP basis, and all this is from our fully owned portfolio of commercial products.

15% 的收入增長和 15% 的非 GAAP 收入增長使 BioMarin 堅定地走上了實現我們 2023 年財務目標的軌道。這些結果包括 Voxzogo 的 8800 萬美元收入和 GAAP 基礎上 5100 萬美元的強勁第一季度盈利能力，所有這些都來自我們完全擁有的商業產品組合。

With Q1 total revenues coming in at just under $600 million, we are on the path to achieving our 2023 objectives of double-digit revenue growth and significant operating leverage, driving approximately 30% growth in bottom line profitability in 2023, as communicated in February. We are very pleased with the continued cadence of Voxzogo uptake worldwide. Voxzogo is now being used in around 1,500 patients in 35 different geographies, and we have seen significant growth of Voxzogo in Japan since approval there.

隨著第一季度總收入略低於 6 億美元，我們正在實現 2023 年兩位數收入增長和顯著運營槓桿的目標，推動 2023 年底線盈利能力增長約 30%，正如 2 月份所傳達的那樣。我們對 Voxzogo 在全球範圍內的持續使用節奏感到非常高興。 Voxzogo 目前正在 35 個不同地區的約 1,500 名患者中使用，自從日本獲得批准以來，我們已經看到 Voxzogo 在日本的顯著增長。

And as a result, we are raising again our 2023 full year guidance midpoint by $50 million at the midpoint level based on increasing expectations for the brand. Based on the still very limited market penetration, we believe Voxzogo is on its way to become a blockbuster.

因此，基於對品牌不斷增長的期望，我們再次將 2023 年全年指導中點提高 5000 萬美元。基於仍然非常有限的市場滲透率，我們相信 Voxzogo 正在成為重磅炸彈。

Turning to Roctavian in Europe today, we have begun working directly with a single national German insurance fund, or GKV, on a final federal German prices and therefore, we will not pursue any additional Outcomes Based Agreements with sub-insurance, which are the German, most of the regional 6-month at this time. We believe that the highly innovative profile of Roctavian offers an attractive treatment option for those people with severe hemophilia A interested in an efficacious alternative to chronic therapy.

談到今天在歐洲的 Roctavian，我們已經開始直接與單一的德國國家保險基金 (GKV) 合作，確定最終的德國聯邦價格，因此，我們不會尋求與子保險簽訂任何額外的基於結果的協議，這是德國的，大部分地區此時為6月。我們相信，Roctavian 的高度創新特性為那些對慢性治療的有效替代方案感興趣的嚴重血友病 A 患者提供了一個有吸引力的治療選擇。

We believe that working directly with a primary health insurance provider in Germany, which we expect will cover Roctavian treatment with a onetime payment and with us an outcome based fund will facilitate access. We also believe the German health care system will recognize our payment value based on the transformational efficacy observed in a majority of participants across our extensive development program with Roctavian.

我們相信直接與德國的主要健康保險提供者合作，我們預計這將通過一次性付款涵蓋 Roctavian 治療，並且與我們一起建立基於結果的基金將有助於獲得。我們還相信，德國醫療保健系統將根據在我們與 Roctavian 的廣泛發展計劃中觀察到的大多數參與者的轉化功效來認可我們的支付價值。

Our initial interactions with the GKV have been positive, and we anticipate a final German reimbursement price that would be representative of the full value Roctavian is delivering to patients, especially based on our recent 3-year update of our Phase III trial. Over the long term, we don't expect today's updates to impact our expectations for Roctavian as we continue to hear feedback from German hematologists that they are ready to treat despite some of the challenges, BioMarin has experienced with German regional 6-months reimbursement in the very short term.

我們與 GKV 的初步互動是積極的，我們預計德國的最終報銷價格將代表 Roctavian 為患者提供的全部價值，特別是基於我們最近 3 年更新的 III 期試驗。從長遠來看，我們預計今天的更新不會影響我們對 Roctavian 的期望，因為我們繼續聽到德國血液學家的反饋，儘管存在一些挑戰，他們已準備好治療，BioMarin 在德國地區 6 個月的報銷中經歷了非常短期。

So we are pleased to share that other markets in Europe and outside of Europe are actively pursuing access to Roctavian, which Jeff will review in a moment. With the U.S. PDUFA action date only 2 months away, we are optimistic cautiously, of course, for what lies ahead in the second half of the year. The commercial team is working hard to prepare for another successful product launch.

因此，我們很高興地分享歐洲和歐洲以外的其他市場正在積極尋求獲得 Roctavian 的機會，Jeff 稍後將對此進行審查。距離美國 PDUFA 行動日期僅剩 2 個月，我們當然對下半年的前景持謹慎樂觀態度。商業團隊正在努力為另一次成功的產品發布做準備。

And as we communicated during our Q4 conference call a couple of months ago, in the United States, roughly 300 patients from the bleeding disorders community have engaged with BioMarin directly to learn more about Roctavian, which is a very positive sign. So we believe 2023 is the year of Roctavian, and we are looking forward to continued progress ahead in both Europe, the U.S. and the rest of the world.

正如我們在幾個月前的第四季度電話會議上交流的那樣，在美國，大約 300 名來自出血性疾病社區的患者直接與 BioMarin 接觸，以了解更多關於 Roctavian 的信息，這是一個非常積極的跡象。因此，我們相信 2023 年是 Roctavian 年，我們期待在歐洲、美國和世界其他地區繼續取得進展。

So in summary, we are very pleased with BioMarin's performance in the first quarter and our outlook for the remainder of the year. The momentum behind Voxzogo continues driving record financial results. We are making good progress on the European launch of Roctavian, and we look forward to the outcome of the June 30 PDUFA milestone. In the U.S., we are ready. So importantly, we have made the transition to an earnings growth story, a unique accomplishment in our industry, and we thank you for your continued support.

因此，總而言之，我們對 BioMarin 第一季度的表現以及我們對今年剩餘時間的展望感到非常滿意。 Voxzogo 背後的動力繼續推動創紀錄的財務業績。我們在歐洲推出 Roctavian 方面取得了良好進展，我們期待著 6 月 30 日 PDUFA 里程碑的成果。在美國，我們已經準備好了。非常重要的是，我們已經實現了盈利增長的轉變，這是我們行業中獨一無二的成就，我們感謝您一直以來的支持。

I will now turn the call over to Jeff to discuss the commercial business update. Jeff?

我現在將電話轉給傑夫討論商業業務更新。傑夫？

Thank you, JJ. I'm very pleased with our record-breaking performance in the first quarter, resulting in $596 million in total revenues and representing 15% growth year-over-year, including KUVAN and 19% growth excluding KUVAN. Solid contributions from our enzyme products resulted in year-over-year growth of approximately 5%, which is in line, given anticipated seasonality and ordering patterns for certain brands.

謝謝你，傑傑。我對我們在第一季度創紀錄的業績感到非常滿意，總收入達到 5.96 億美元，同比增長 15%，包括 KUVAN 在內，增長 19%，不包括 KUVAN。考慮到某些品牌的預期季節性和訂購模式，我們酶產品的堅實貢獻導致同比增長約 5%，這符合預期。

Overall, the enzyme product revenue base is tracking as expected, and we anticipate it will provide meaningful contributions to BioMarin's full year total revenues this year. Turning to Voxzogo. As underscored by our guidance increase today, we are very pleased with the continued acceleration of growth. Today, we raise full year Voxzogo revenue guidance to between $380 million and $430 million, a $50 million increase at the midpoint and representing 140% growth over 2022.

總體而言，酶產品收入基礎符合預期，我們預計它將為 BioMarin 今年的全年總收入做出有意義的貢獻。轉向 Voxzogo。正如我們今天的指導增長所強調的那樣，我們對增長的持續加速感到非常高興。今天，我們將 Voxzogo 的全年收入預期提高到 3.8 億美元至 4.3 億美元之間，中點增加了 5000 萬美元，比 2022 年增長了 140%。

At the end of the first quarter, approximately 1,500 children with achondroplasia in 35 different markets were being treated with Voxzogo within the currently approved age ranges. Uptake to date represents 9% penetration of indicated patients in BioMarin's commercial footprint, highlighting the significant growth potential that remains. This includes Europe for children 2 years old and older, the United States for children 5 years old and older, and in Japan, where Voxzogo is approved with no age restrictions.

在第一季度末，35 個不同市場的大約 1,500 名軟骨發育不全兒童在目前批准的年齡範圍內接受了 Voxzogo 治療。迄今為止，在 BioMarin 的商業足跡中，指定患者的吸收率達到 9%，突顯出仍然存在的巨大增長潛力。這包括適用於 2 歲及以上兒童的歐洲、適用於 5 歲及以上兒童的美國，以及在日本批准 Voxzogo 且沒有年齡限制的國家。

Japan was a key driver of growth due in part to the availability of Voxzogo treatment for children of all ages. We also saw significant contributions in the quarter from Europe, United States and certain markets in the Latin American regions. Looking ahead for the remainder of 2023, we expect growth across markets with continued uptake in existing markets and expansion into new markets. We do look forward to learning in the coming months if European and U.S. health authorities are supportive of extending access to Voxzogo to younger children which would make it available to more than 1,000 additional children in those markets. Taken together, we continue to believe that Voxzogo has the potential to be our first $1 billion brand.

日本是增長的主要驅動力，部分原因是所有年齡段的兒童都可以使用 Voxzogo 治療。我們還看到歐洲、美國和拉丁美洲地區某些市場在本季度做出了重大貢獻。展望 2023 年剩餘時間，我們預計隨著現有市場的持續增長和向新市場的擴張，整個市場都將實現增長。我們確實期待在未來幾個月內了解歐洲和美國衛生當局是否支持將 Voxzogo 的使用範圍擴大到年幼的兒童，這將使這些市場中的 1,000 多名額外兒童可以使用它。總而言之，我們仍然相信 Voxzogo 有潛力成為我們第一個價值 10 億美元的品牌。

Turning now to Roctavian. To remind you, upon European approval of Roctavian late last year, our plan was to quickly facilitate access for patients in Germany through the use of Outcomes Based Agreements. At the time of approval, the prepricing window in Germany was 12 months, but was changed to 6-month in January. With a 12-month prepricing window at the time of launch, it made sense to pursue OBAs with the goal of facilitating access to Roctavian prior to final federal reimbursement.

現在轉向羅克塔維安。提醒您，去年年底歐洲批准 Roctavian 後，我們的計劃是通過使用基於結果的協議快速促進德國患者的使用。在批准時，德國的定價前窗口為 12 個月，但在 1 月份改為 6 個月。在推出時有 12 個月的預定價窗口，追求 OBA 的目標是在最終聯邦報銷之前促進獲得 Roctavian 是有意義的。

Now that we are already working with GKV on a final federal price for Roctavian, we will not pursue additional OBAs, as JJ shared. A reminder, GKV is the umbrella entity that is responsible for health insurance to approximately 90% of the German population, and we believe this path will facilitate the broadest access. While we work to finalize a German price with GKV, reimbursement for people treated with Roctavian is possible under Named Patient authorizations through individual insurers.

既然我們已經在與 GKV 就 Roctavian 的最終聯邦價格進行合作，我們將不會尋求額外的 OBA，正如 JJ 所分享的那樣。提醒一下，GKV 是負責為大約 90% 的德國人口提供健康保險的傘式實體，我們相信這條道路將促進最廣泛的訪問。在我們努力與 GKV 敲定德國價格的同時，在指定患者授權下，可以通過個別保險公司報銷接受 Roctavian 治療的人。

Those sales would be subject to the final price once it has been established. Patients treated under executed OBAs will benefit from the terms of that OBA at least until the German price is finalized. As JJ shared, we expect the GKV negotiations to yield the price for Roctavian that incorporates durability and other benefits that would be paid in a onetime upfront payment and without bespoke Outcomes Based Agreements.

一旦確定，這些銷售將以最終價格為準。根據執行的 OBA 接受治療的患者將至少在德國價格最終確定之前受益於該 OBA 的條款。正如 JJ 所分享的那樣，我們預計 GKV 談判將為 Roctavian 提供包含耐用性和其他利益的價格，這些利益將在一次性預付款中支付，並且沒有定制的基於結果的協議。

Turning to CDx testing in Germany. We are pleased to see a significant pipeline of patients building as more tests are in motion. As of the most recent data, 18 people had been screened for AAV5 seropositivity, an important eligibility criteria for treatment with Roctavian. We expect that our first treated patient in Germany will be sourced from this pool in the second quarter. And while not all patients tested will be eligible and choose treatment with Roctavian, we are encouraged by the level of interest from patients in Germany.

轉向德國的 CDx 測試。我們很高興看到隨著更多測試的進行，大量患者正在建立。根據最新數據，18 人接受了 AAV5 血清陽性篩查，這是 Roctavian 治療的重要資格標準。我們預計我們在德國的第一位接受治療的患者將在第二季度從這個池中採購。雖然並非所有接受測試的患者都符合條件並選擇 Roctavian 治療，但我們對德國患者的興趣程度感到鼓舞。

Beyond Germany, our applications seeking price and reimbursement approvals as well as other launch preparation activities are making progress in both France and Italy, where we expect negotiations to conclude by Q4 of this year. In Italy, we were pleased that Roctavian was recently awarded conditional innovation designation, a positive signal that should facilitate pricing and reimbursement.

在德國之外，我們尋求價格和報銷批准的申請以及其他啟動準備活動正在法國和意大利取得進展，我們預計談判將在今年第四季度結束。在意大利，我們很高興 Roctavian 最近獲得了有條件的創新稱號，這是一個促進定價和報銷的積極信號。

We are also encouraged by early interest in Roctavian in other markets, including Argentina and Saudi Arabia, where we have the potential to provide access to Roctavian through Named Patient authorizations. We are aware of 11 completed CDx tests in Argentina and a recent prescription for Roctavian treatment. Taken together, we are pleased with the progress we are seeing outside of the United States, especially noting some key differences in reimbursement and launch dynamics between the U.S. and other markets.

我們也對其他市場（包括阿根廷和沙特阿拉伯）對 Roctavian 的早期興趣感到鼓舞，我們有可能通過指定患者授權提供對 Roctavian 的訪問。我們知道在阿根廷有 11 項完整的 CDx 測試和最近的 Roctavian 治療處方。總而言之，我們對在美國以外看到的進展感到高興，特別是注意到美國和其他市場在報銷和啟動動態方面的一些關鍵差異。

Touching briefly on some of the differences that we believe will positively impact the Roctavian U.S. launch upon a potential approval in June. First, we intend to implement a single warranty, which will allow us to offer a uniform agreement to all purchasers in the U.S., avoiding the need to negotiate bespoke contracts.

簡要談談我們認為將在 6 月獲得批准後對 Roctavian 美國上市產生積極影響的一些差異。首先，我們打算實施單一保修，這將使我們能夠向美國的所有購買者提供統一的協議，避免談判定制合同的需要。

Next, we plan to leverage the value-based assessment from the Institute for Clinical and Economic Review or ICER, which noted that Roctavian was a dominant treatment with substantial cost savings, along with projected gains and quality adjusted life years at $2.5 million per onetime treatment. ICER's conclusion of value is consistent with the results from payer research conducted recently in the U.S. As in prior launches, we believe it will be possible to navigate reimbursement approvals following approval for individual patients on the basis of medical exception until coverage policies are issued.

接下來，我們計劃利用臨床和經濟評論研究所或 ICER 的基於價值的評估，該評估指出 Roctavian 是一種主要的治療方法，可以節省大量成本，預計收益和質量調整生命年為每次治療 250 萬美元. ICER 的價值結論與最近在美國進行的付款人研究的結果一致。與之前的發布一樣，我們認為，在保險政策發布之前，有可能根據醫療例外情況批准個別患者的報銷批准。

Finally, in Europe, we are not promoted to promote -- we are not permitted to promote Roctavian directly to patients, so many people with severe hemophilia A only learn of it during their annual or semiannual check-ins with their hematologists. In the U.S., in contrast, we intend to use all channels available to raise awareness of Roctavian. That is a good segue to our update on U.S. commercial preparedness. Our teams have worked with treatment centers to ensure site readiness, conducted discussions with payers, worked through a refinement of our warranty and our promotional campaign is ready.

最後，在歐洲，我們沒有被推廣到推廣——我們不允許直接向患者推廣 Roctavian，因此許多患有嚴重血友病 A 的人只是在每年或每半年與他們的血液學家進行一次檢查時才知道它。相比之下，在美國，我們打算使用所有可用的渠道來提高對 Roctavian 的認識。這是我們對美國商業準備情況更新的一個很好的續集。我們的團隊與治療中心合作以確保現場準備就緒，與付款人進行討論，完善我們的保修，我們的促銷活動也已準備就緒。

The supply of demand has been manufactured, we stand ready to go upon potential approval. We have identified and are focused on a relatively small number of the largest and most capable hemophilia treatment centers to be ready to treat with Roctavian in the U.S. at or shortly after launch. We understand the value of and are committed to hemophilia treatment centers being the site of treatment for Roctavian for the reasons of appropriate patient selection, post-treatment follow-up and monitoring and more generally due to the complexity of hemophilia management.

需求的供應已經製造，我們隨時準備接受潛在的批准。我們已經確定並專注於相對較少的最大和最有能力的血友病治療中心，準備在美國推出 Roctavian 時或推出後不久進行治療。我們了解血友病治療中心的價值，並致力於將血友病治療中心作為 Roctavian 的治療場所，這是出於適當的患者選擇、治療後隨訪和監測的原因，更普遍的原因是血友病管理的複雜性。

In conclusion, we are off to a strong start in 2023, delivering record-breaking results in the first quarter underscores demand for our essential medicines. Based on the challenges faced securing additional OBAs in the quarter to facilitate patient access to Roctavian and the updated U.S. PDUFA action date from March to June, we have lowered full year 2023 Roctavian guidance to between $50 million and $150 million.

總之，我們在 2023 年開局良好，第一季度取得了創紀錄的業績，凸顯了對我們基本藥物的需求。基於在本季度確保更多 OBA 以促進患者獲得 Roctavian 所面臨的挑戰以及更新的美國 PDUFA 行動日期為 3 月至 6 月，我們已將 2023 年全年 Roctavian 指導下調至 5000 萬至 1.5 億美元。

Thank you for your attention. And I will now turn the call over to Hank to provide an R&D update. Hank?

感謝您的關注。我現在將把電話轉給 Hank 以提供研發更新。漢克？

Thanks, Jeff, and thank you all for joining us today. BioMarin's worldwide R&D organization has gratified to see the enthusiasm from families interested in benefiting from Voxzogo treatment for their children with achondroplasia. In the coming months, we look forward to learning the outcome of our request to potentially expand the label, both in Europe and in the United States, to offer the possibility of treatment to children of all ages where Voxzogo is currently available.

謝謝，傑夫，感謝大家今天加入我們。 BioMarin 的全球研發組織很高興看到有興趣從 Voxzogo 治療他們患有軟骨發育不全的孩子中受益的家庭的熱情。在接下來的幾個月裡，我們期待了解我們在歐洲和美國可能擴大標籤的請求的結果，以便為目前 Voxzogo 可用的所有年齡段的兒童提供治療的可能性。

Also, later in 2023 with Voxzogo, we look forward to results from the investigator-sponsored trial evaluating Voxzogo's potential to treat other genetic forms of short stature, including, for example, hypochondroplasia, mutations in the NPR2 gene and Noonan syndrome, just to name a few. We are also engaged in active discussions with top authorities concerning the opportunity to leverage Voxzogo, a natural regulator bone growth, and these other conditions characterized by impaired bone growth.

此外，在 2023 年晚些時候與 Voxzogo 一起，我們期待研究者贊助的試驗的結果，該試驗評估 Voxzogo 治療其他遺傳形式的身材矮小的潛力，包括例如軟骨發育不全、NPR2 基因突變和 Noonan 綜合徵，僅舉幾例一些。我們還與最高當局積極討論利用 Voxzogo 的機會，Voxzogo 是一種天然的骨骼生長調節劑，以及其他以骨骼生長受損為特徵的疾病。

Moving to Roctavian. As we announced in March, the United States Food and Drug Administration extended their review of the Biologics License Application for Roctavian. As anticipated, the FDA determined that the submission of the 3-year data analysis from the ongoing Phase III Generic 1 study, as requested by the agency, constituted a major amendment due to the substantial amount of additional data and set a new PDUFA target action date of June 30, 2023. We continue to engage with the agency and look forward to our June 30 PDUFA action date.

搬到羅克塔維安。正如我們在 3 月份宣布的那樣，美國食品和藥物管理局延長了對 Roctavian 的生物製品許可申請的審查。正如預期的那樣，FDA 確定，根據該機構的要求，提交正在進行的 III 期通用 1 研究的 3 年數據分析構成了一項重大修正案，因為有大量額外數據並設定了新的 PDUFA 目標行動日期為 2023 年 6 月 30 日。我們繼續與該機構合作，並期待我們的 6 月 30 日 PDUFA 行動日期。

Briefly on the earlier stage pipeline, we shared a few incremental updates in our press release today on BMN 255 for hyperoxaluria in chronic liver disease. BMN 331 gene therapy for hereditary angioedema and BMN 349 for alpha-1 antitrypsin deficiency. We look forward to providing updates across our advancing development pipeline at our R&D Day in New York on September 12.

簡要介紹早期管道，我們在今天的新聞稿中分享了一些關於 BMN 255 治療慢性肝病高草酸尿症的增量更新。 BMN 331 基因治療遺傳性血管性水腫和 BMN 349 治療 α-1 抗胰蛋白酶缺乏症。我們期待在 9 月 12 日於紐約舉行的研發日上提供我們推進開發管道的最新信息。

Starting with BMN 255, we have concluded the multi-ascending dose in the healthy volunteer study. In January, we shared early data that demonstrated a rapid and potent increase in plasma glycolate following treatment with BMN 255. Oral daily dosing at all tested levels for 14 days was safe and showed sustained elevations in plasma glycolate, which is predicted to have a profound reduction in oxalate excretion in patients.

從 BMN 255 開始，我們已經結束了健康志願者研究中的多次遞增劑量。 1 月，我們分享了早期數據，這些數據表明在使用 BMN 255 治療後血漿乙醇酸迅速而有效地增加。在所有測試水平下每天口服給藥 14 天是安全的，並顯示血漿乙醇酸持續升高，預計這將產生深遠的影響減少患者的草酸鹽排泄。

Based on these early signals, we now plan to initiate and enroll an expanded study in patients with chronic liver disease and hyperoxaluria later in 2023. We believe the availability of a potent orally bioavailable small molecule like BMN 255 may be able to significantly reduce disease and treatment burden in patients with -- in a patient population with significant unmet need.

基於這些早期信號，我們現在計劃在 2023 年晚些時候啟動並招募一項針對慢性肝病和高草酸尿症患者的擴展研究。我們相信，像 BMN 255 這樣的有效口服生物可利用小分子的可用性可能能夠顯著減少疾病和患者的治療負擔——在有大量未滿足需求的患者群體中。

Turning to our next gene therapy, BMN 331 for hereditary angioedema, which is like hemophilia in the sense that it poses a chronic lifelong burden of therapy due to the risk of breakthrough attacks that are extremely burdensome and potentially life threatening. The disease is due to genetically determined loss of the key protein regulating the inflammatory cascade responsible to these attacks.

轉向我們的下一個基因療法，用於遺傳性血管性水腫的 BMN 331，它就像血友病一樣，由於突破性發作的風險極其沉重且可能危及生命，因此它會造成長期的終生治療負擔。該疾病是由於遺傳決定的關鍵蛋白質丟失，該關鍵蛋白質調節導致這些攻擊的炎症級聯反應。

The available therapies on the market have confirmed the effectiveness of replacement much like in the case of replacement Factor VIII therapy in hemophilia. We've shown in 3 studies with BMN 331 gene therapy that in (inaudible) and non-human primates that a similar dose to that employed in clinical studies of Roctavian can provide ample and constant expression of C1 inhibitor within the therapeutic [rating] patients.

市場上可用的療法已經證實了替代療法的有效性，就像在血友病中替代凝血因子 VIII 療法一樣。我們在 BMN 331 基因療法的 3 項研究中表明，在（聽不清）和非人類靈長類動物中，與 Roctavian 臨床研究中使用的劑量相似的劑量可以在治療 [評級] 患者中提供 C1 抑製劑的充足和恆定表達.

We expect to continuously express levels of protein will provide improvements in the disease course of hereditary angioedema over existing therapies. In March, the second sentinel patient was dosed safely at 6e13vg per kilo following an encouraging response from the first participant, who demonstrated an early increase in C1 inhibitor that may ultimately be therapeutically relevant, and this is exciting.

我們預計持續表達的蛋白質水平將比現有療法改善遺傳性血管性水腫的病程。 3 月，第二名哨兵患者以每公斤 6e13vg 的劑量安全給藥，這是在第一名參與者的令人鼓舞的反應之後，他證明 C1 抑製劑的早期增加可能最終與治療相關，這令人興奮。

With BMN 349 for alpha-1 antitrypsin deficiency, preclinical studies have demonstrated oral bioavailability in a small molecule that potentially sequesters the mutant protein preventing polymerization in the liver cells that drive progressive liver disease form of the illness. In preclinical studies, BMN 349 is titratable to effect with rapid onset and high potency. Preclinical results have strong implications for potential improvement of our current management, particularly for severe liver disease requiring rapid action.

使用 BMN 349 治療 alpha-1 抗胰蛋白酶缺乏症，臨床前研究表明小分子的口服生物利用度可能會隔離突變蛋白，防止肝細胞聚合，從而導致進行性肝病。在臨床前研究中，BMN 349 可滴定至起效快且效力高。臨床前結果對我們當前管理的潛在改進具有重要意義，特別是對於需要迅速採取行動的嚴重肝病。

IND-enabling studies are underway, and BioMarin is close to submit an IND for BMN 349 in the second half of the year. Stay tuned for updates on these as well as 351 for Duchenne muscular dystrophy and BMN 293 for myosin-binding protein C3 hypertrophic cardiomyopathy at R&D Day in New York in September.

支持 IND 的研究正在進行中，BioMarin 即將在今年下半年提交 BMN 349 的 IND。請繼續關注 9 月紐約研發日的這些更新以及針對杜氏肌營養不良症的 351 和針對肌球蛋白結合蛋白 C3 肥厚性心肌病的 BMN 293。

Thank you all for your continued support. And I will now turn the call over to Brian to update financial results in the quarter. Brian?

感謝大家一直以來的支持。我現在將電話轉給布賴恩，以更新本季度的財務業績。布萊恩？

Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the first quarter of 2023. Since JJ and Jeff spoke to our revenue performance for the quarter and future revenue outlook, I will primarily focus on the remainder of our P&L and other key financial updates this quarter. As usual, all results will be available in our upcoming Form 10-Q, which we are on track to file by the end of this week.

謝謝你，漢克。請參閱今天總結我們 2023 年第一季度財務業績的新聞稿。由於 JJ 和 Jeff 談到了我們本季度的收入表現和未來的收入前景，我將主要關注我們剩餘的損益表和其他關鍵信息本季度的財務更新。與往常一樣，所有結果都將在我們即將發布的 10-Q 表格中提供，我們有望在本週末之前提交該表格。

We referred to last year as a transformational year for BioMarin with the growing base business of enzyme products plus the successful launch of Voxzogo, together with operating expense control, driving meaningful GAAP net income and a foundation for our financial growth strategy into the future. We are pleased that the strong start of the business in the first quarter of 2023 is supportive of our 2023 and long-term objectives of substantial revenue growth, margin expansion and increasing earnings.

我們將去年稱為 BioMarin 的轉型年，酶產品基礎業務的增長加上 Voxzogo 的成功推出，加上運營費用控制，推動了有意義的 GAAP 淨收入，並為我們未來的財務增長戰略奠定了基礎。我們很高興業務在 2023 年第一季度的強勁開局支持了我們 2023 年和長期目標，即收入大幅增長、利潤率擴張和收益增加。

BioMarin's $596 million of total revenue in the first quarter of 2023 is an increase of 15% compared to the first quarter of 2022. Regarding our revenue outlook for the rest of 2023, Jeff commented on the increase to our 2023 Voxzogo revenue guidance and decrease to our 2023 Roctavian revenue guidance, which offset each other in aggregate, resulting in no change to our total revenue guidance for 2023, which is annual growth of 16% at the midpoint.

BioMarin 在 2023 年第一季度的總收入為 5.96 億美元，與 2022 年第一季度相比增長了 15%。關於我們對 2023 年剩餘時間的收入展望，Jeff 評論了我們 2023 年 Voxzogo 收入指導的增加和減少到我們 2023 年的 Roctavian 收入指引相互抵消，導致我們 2023 年的總收入指引沒有變化，即中點的年增長率為 16%。

Across the rest of the P&L, Q1 2023 gross margin was 78.8%, which is an improvement of 1.3% as compared to the first quarter of 2022. R&D expense in 2023 started at a moderate rate in the first quarter, which was expected given the planned increase in R&D investment in our early-stage pipeline and the life cycle management development efforts for Roctavian and Voxzogo that we expect to ramp up over the course of this year.

在其餘損益表中，2023 年第一季度的毛利率為 78.8%，與 2022 年第一季度相比提高了 1.3%。2023 年第一季度的研發費用以溫和的速度開始，這是預期的，因為計劃增加對我們早期管道的研發投資，以及我們預計將在今年增加的 Roctavian 和 Voxzogo 的生命週期管理開發工作。

SG&A expense in the first quarter of 2023 of $223 million increased as compared to $195 million in the first quarter of 2022, which is in line with expectations as we continue to invest in the global Voxzogo commercialization, the EU Roctavian launch and the commercial launch preparations for Roctavian in the U.S. Back to the bottom line, we delivered on our commitment to profitability with the $51 million of GAAP net income in Q1 2023 and $116 million of non-GAAP income, which sets up BioMarin well to achieve our full year 2023 profitability objective.

與 2022 年第一季度的 1.95 億美元相比，2023 年第一季度的 SG&A 費用增加了 2.23 億美元，這符合預期，因為我們繼續投資於全球 Voxzogo 商業化、歐盟 Roctavian 上市和商業上市準備工作對於美國的 Roctavian 回到底線，我們兌現了盈利承諾，2023 年第一季度 GAAP 淨收入為 5100 萬美元，非 GAAP 收入為 1.16 億美元，這為 BioMarin 實現 2023 年全年盈利奠定了良好基礎客觀的。

GAAP net income decreased in Q1 year-over-year. However, it is important to note that GAAP net income in the first quarter of last year included the gain on the sale of the priority review voucher received in connection with the U.S. approval of Voxzogo, which was approximately $89 million after income tax.

GAAP 淨收入在第一季度同比下降。然而，值得注意的是，去年第一季度的 GAAP 淨收入包括出售與美國批准 Voxzogo 有關的優先審評憑證的收益，稅後約為 8900 萬美元。

Today, we reaffirmed our 2023 GAAP and non-GAAP income guidance of $155 million to $205 million and $360 million to $410 million, respectively. Total cash and investments in the first quarter of 2023 was close to $1.5 billion, which decreased during the quarter due to some milestone payments, the timing of accounts receivable collections and known seasonality of operating accrual net pay down.

今天，我們重申 2023 年 GAAP 和非 GAAP 收入指引分別為 1.55 億美元至 2.05 億美元和 3.6 億美元至 4.1 億美元。 2023 年第一季度的現金和投資總額接近 15 億美元，由於一些里程碑付款、應收賬款收款的時間安排以及運營應計淨付款減少的已知季節性，本季度現金和投資總額有所下降。

As we believe these cash flow timing events were front loaded to the beginning of the year, we expect to resume positive cash flows over the course of 2023. In closing, we are pleased to observe a solid start to 2023 and are keenly focused on maximizing the potential of the global Voxzogo and European Roctavian commercial launches, measured operating expense investments and the resulting leverage profitability growth that we anticipate for the full year and beyond.

由於我們認為這些現金流時間事件在年初就已提前完成，因此我們預計將在 2023 年恢復正現金流。最後，我們很高興看到 2023 年開局良好，並熱切關注最大限度地提高全球 Voxzogo 和歐洲 Roctavian 商業發布的潛力、可衡量的運營費用投資以及由此產生的我們預計全年及以後的槓桿盈利能力增長。

Thank you all for your attention, and we'll now open up the call for your questions. Operator?

感謝大家的關注，我們現在將打開您的問題電話。操作員？

(Operator Instructions) And our first question comes from Salveen Richter from Goldman Sachs.

（操作員說明）我們的第一個問題來自高盛的 Salveen Richter。

Can you provide more detail here on how the GKV facilitate discussions on the final price and any impact on this price given that additional OBAs will not be pursued? And then in the interim, do you expect patients to actually be treated through either Named Patient authorizations or the one finalized OBE? Or is it really just GKV here?

您能否在此處提供更多詳細信息，說明 GKV 如何促進最終價格的討論以及在不追求額外 OBA 的情況下對該價格的任何影響？然後在此期間，您是否希望通過指定患者授權或最終確定的 OBE 實際治療患者？或者這裡真的只是 GKV？

Salveen, I will be happy to take that one on. So the GKV process that we've described here that takes essentially 12 months to get to a final reimbursement price and broad reimbursement access, this is normal. So this is the same process that we've gone through for all of our previous brands.

Salveen，我很樂意接受那個。因此，我們在這裡描述的 GKV 流程基本上需要 12 個月才能達到最終報銷價格和廣泛的報銷渠道，這是正常的。所以這與我們之前所有品牌所經歷的過程相同。

I think 12 months from approval, not 12 months from today.

我認為從批准起 12 個月，而不是從今天起 12 個月。

Yes, 12 months from our price listing, which was September 15 of last year. So we're very familiar with that process. And we are pretty deep into that process by now. So we submit a full price and reimbursement dossier. We did in the fall of last year, that takes a while to get processed by -- with GKV. We've had our first meeting to review that. There's usually a series of 4 meetings and reviews before we get to a final answer.

是的，從我們去年 9 月 15 日的價目表算起 12 個月。所以我們對這個過程非常熟悉。到目前為止，我們已經深入到這個過程中了。因此，我們提交了全價和報銷檔案。我們在去年秋天做了，這需要一段時間才能通過 GKV 進行處理。我們已經召開了第一次會議來審查它。在我們得出最終答案之前，通常會有一系列的 4 次會議和審查。

We think that, that first meeting was set up a very favorable tone, including testimony from key positions in Germany on behalf of Roctavian. So that's kind of the process. What's different with Roctavian than our other brands is our other brands have all entered into a situation where there is no existing standard of care.

我們認為，第一次會議的基調非常有利，包括來自德國關鍵職位代表羅克塔維安的證詞。這就是一個過程。 Roctavian 與我們其他品牌的不同之處在於，我們的其他品牌都陷入了沒有現有護理標準的境地。

In the case of hemophilia, we knew that we are launching into a situation where there was an existing, indeed an evolving standard of care. And so our strategy was to contract with subnational insurer umbrella organizations, what we're calling sub-insurers here to put Outcomes Based Agreements in place, get agreement on preliminary price to facilitate rapid uptake of Roctavian.

在血友病的案例中，我們知道我們正在進入一個存在現有的、確實是不斷發展的護理標準的情況。因此，我們的策略是與地方保險公司傘式組織簽訂合同，我們在這裡稱之為子保險公司，以製定基於結果的協議，就初步價格達成協議，以促進 Roctavian 的快速採用。

When we launch, we believe that the prepricing period in Germany as it has been for years and years would be 12 months. So what changed? The first thing that changed is, late last year, there was new legislation that changed the 12-month to 6-month prepricing period. And that's new. While some people saw that coming, as we did, what's new about that is nobody really knows how the parties will behave at the end of the 6-month prepricing period and before we have final price and reimbursement approval from GKV.

當我們推出時，我們相信德國多年來的定價前期將是 12 個月。那麼改變了什麼？首先發生變化的是，去年年底，新立法將 12 個月的預定價期改為 6 個月。這是新的。雖然有些人和我們一樣看到了這一點，但沒有人真正知道各方在 6 個月的預定價期結束時以及在我們獲得 GKV 的最終價格和報銷批准之前將如何表現。

The second thing that changed according to our plan was we saw more than we were expecting from the sub-insurer groups to engage in finding a path forward and defining OBAs, which are new for Roctavian. So now that we are in well into discussions on a final price and reimbursement arrangement that covers essentially all of Germany, we think it just does not make sense any longer to pursue additional Outcomes Based Agreements with those so-called subnational insurers.

根據我們的計劃發生變化的第二件事是，我們從子保險公司團體那裡看到的比我們預期的更多，他們參與尋找前進的道路和定義 OBA，這對 Roctavian 來說是新的。因此，既然我們正在就基本上涵蓋整個德國的最終價格和報銷安排進行深入討論，我們認為與那些所謂的地方保險公司簽訂額外的基於結果的協議已經沒有意義了。

Instead, we think we've got some patients covered under an existing Outcomes Based Agreements, it covers a part of the population. And we know that patients can be submitted through their health insurer for essentially a one-off or a Named Patient approval while we work to get the final price and reimbursement. Sorry for all the detail, but you did ask for it.

相反，我們認為現有的基於結果的協議涵蓋了一些患者，它涵蓋了一部分人口。我們知道，在我們努力獲得最終價格和報銷的同時，患者可以通過他們的健康保險公司提交，以獲得基本上一次性或指定患者的批准。抱歉所有細節，但你確實要求過。

And our next question comes from Geoff Meacham from Bank of America.

我們的下一個問題來自美國銀行的 Geoff Meacham。

I just have 2 quick ones on Roctavian. So I guess, to follow up on Germany: So do you have to go back to square one and communication of kind of cost-benefit to GKV? And I guess, was the 6 months of OBA negotiation a total waste here? And then secondly, in the U.S., just commercially, what's left to help streamline access and reimbursement, obviously aside from formal FDA approval?

我在 Roctavian 上只有 2 個快速的。所以我想，跟進德國：那麼你是否必須回到第一個問題並向 GKV 傳達某種成本效益？我想，OBA 談判的 6 個月是否完全浪費了？其次，在美國，就商業而言，除了正式的 FDA 批准之外，還有什麼可以幫助簡化獲取和報銷？

Yes. So thanks for the questions, Geoff. So to reiterate: Right after we submitted our price and got that listed in September 15 of last year, shortly after that, we submitted, as we always do for our brands, to the GKV a full price and reimbursement dossier. And as I noted in the last question, it takes 4, 5, 6 months for GKV to get to the point where they're ready to enter negotiations with us because it is an intensive dossier to review. The work that we did with the so-called subnational insurers was not a complete waste of time. Indeed we achieved proof of principle with getting one major insurer signed up. So patients under that insurance group have the benefit of that outcomes-based agreement. And so I think that's -- as I described also in the previous question, that's where we're at. We're more than 6 months in. We're well underway with getting to a final federal reimbursement price. And that price, when it's set, will be retroactive to any patients that are treated from March 15 on, when the prepricing period ended.

是的。謝謝你的問題，傑夫。所以重申一下：在我們提交價格並於去年 9 月 15 日上市後不久，我們像往常一樣為我們的品牌提交了全價和報銷檔案。正如我在上一個問題中指出的那樣，GKV 需要 4、5、6 個月才能達到他們準備好與我們進行談判的地步，因為這是一份需要審查的密集檔案。我們與所謂的地方保險公司開展的工作並非完全是在浪費時間。事實上，我們通過讓一家大型保險公司簽約來實現了原則證明。因此，該保險集團下的患者可以從該基於結果的協議中受益。所以我認為這就是——正如我在上一個問題中所描述的那樣，這就是我們所處的位置。我們已經超過 6 個月了。我們正在順利確定最終的聯邦報銷價格。這個價格一旦確定，將對從 3 月 15 日起接受治療的任何患者都有追溯力，當時定價期結束。

U.S.? U.S. pharma...

我們。？美國藥...

U.S. is a completely different situation. So as we've disclosed, we have a warranty agreement that does not require to be negotiated one payer by one payer. It's a uniform agreement that we intend to offer to all purchasers of Roctavian, so that cuts down on the time associated with doing bespoke agreements. That's the first piece. And then the second piece is, similar to our other launches in the United States, we know that it is possible to navigate individual payer approvals for patients that are submitted as a part of a medical exception process and while coverage policies are in process of being issued. And you know, because you follow other launches, that coverage policies can take anywhere from 1 to 9 or 12 months to get issued, variable by payer. So that's how we plan to navigate that process immediately following launch.

美國是完全不同的情況。因此，正如我們所披露的那樣，我們有一份保修協議，不需要由一個付款人與一個付款人協商。這是我們打算向 Roctavian 的所有購買者提供的統一協議，這樣可以減少與定制協議相關的時間。那是第一塊。然後第二部分是，類似於我們在美國推出的其他產品，我們知道可以為作為醫療例外流程的一部分提交的患者進行個人付款人批准，同時承保政策正在製定中發布。而且你知道，因為你關注其他發布，覆蓋政策可能需要 1 到 9 或 12 個月才能發布，具體取決於付款人。這就是我們計劃在發布後立即導航該過程的方式。

And our next question comes from Chris Raymond from Piper Sandler.

我們的下一個問題來自 Piper Sandler 的 Chris Raymond。

If I can ask another Roctavian question. So just curious. You guys highlighted 18 patients have undergone antibody testing. I think, last quarter, that number was 10, so it doesn't seem like you're seeing necessarily, in Germany anyway, an inflection higher or sort of an acceleration. Maybe just talk about that dynamic. Is that also subject to any reimbursement barriers that you didn't anticipate? And then maybe on the guidance change: Changing, cutting top and bottom by $50 million, it's -- yes, I know you weren't expecting $50 million in Q1. And I know your original plan didn't hinge on a March U.S. approval, but maybe can you talk about how much of this reduction is driven by the sort of the resistance you're seeing in Germany versus maybe a reassessment of the U.S. opportunity?

如果我可以問另一個 Roctavian 問題。所以只是好奇。你們強調了 18 名患者接受了抗體檢測。我認為，上個季度，這個數字是 10，所以看起來你不一定會看到，無論如何，在德國，拐點更高或某種加速。也許只是談論那種動態。這是否也受到您沒有預料到的任何報銷障礙的影響？然後可能是關於指導變化：改變，削減最高和最低 5000 萬美元，是的，我知道你沒想到第一季度會有 5000 萬美元。我知道你最初的計劃並不取決於 3 月份美國的批准，但也許你能談談這種減少有多少是由你在德國看到的阻力推動的，而不是對美國機會的重新評估？

So let me start out. And I'll ask Brian or JJ to round out anything I missed, Chris. First, with respect to the CDx test completed, you're right. It was 2 months ago actually that we reported that we had 10 patients that had been submitted for CDx testing. So you could look at that and say, over the past 2 months, we've seen an additional 8; and I can tell you, because I review the situation with the team every week, already have additional patients in motion this week. So what I'm seeing is the development of a patient pipeline. And it was slow to get started. It was, for sure, impacted by patient awareness or the lack of patient awareness immediately following approval and our ability to influence patient awareness in Germany; the cadence of when patients come in to see their hematologists for hemophilia guidance, which is anywhere from every 3 months to every 12 months. And that cadence of patient visits to hemophilia treatment centers didn't change just because Roctavian was approved, so I would say that, that building of the patient funnel and all of the things that are happening underneath the top of that funnel are really encouraging to me. I'm seeing movement literally every week now and that movement every week that I'm seeing is picking up pace, so I'm pretty encouraged by that. In terms of guidance, guidance was impacted for Roctavian by the pace of -- the pace and timing of getting first patient treated, which is different than we were expecting at the beginning of the year; and the change of the PDUFA date in the United States from the end of March to end of June.

所以讓我開始吧。 Chris，我會請 Brian 或 JJ 補充我遺漏的任何內容。首先，關於已完成的 CDx 測試，您是對的。實際上是在 2 個月前，我們報告說我們有 10 名患者已提交進行 CDx 測試。所以你可以看看那個，然後說，在過去的 2 個月裡，我們又看到了 8 個；我可以告訴你，因為我每週都會和團隊一起回顧情況，這週已經有更多的病人在行動。所以我看到的是患者管道的發展。而且上手很慢。當然，它受到患者意識或批准後立即缺乏患者意識以及我們影響德國患者意識的能力的影響；患者來找他們的血液科醫生尋求血友病指導的節奏，從每 3 個月到每 12 個月不等。患者到血友病治療中心就診的節奏並沒有因為 Roctavian 獲得批准而改變，所以我要說的是，患者漏斗的構建以及漏斗頂部下方發生的所有事情確實令人鼓舞我。我現在每週都能看到運動，而且我看到的每週運動都在加快步伐，所以我對此感到非常鼓舞。在指導方面，Roctavian 的指導受到首位患者接受治療的速度和時間的影響，這與我們年初的預期不同；以及美國PDUFA日期從3月底改到6月底。

That's right. This is Brian. Thanks, Chris. Just to supplement that: We noted that the high end of the previous range accounted for the current March PDUFA. And so just a reminder, with -- or with what was the March PDUFA at the time. Just a reminder that, while that's a 3-month shift with a product like Roctavian that we expect to ramp up in terms of revenue over time, that 3-month shift from a revenue standpoint actually causes us to lose the -- what would have been the last quarter of revenue in 2023, so -- and likely the largest quarter. And then on the bottom end, you're right. There is a combining effect of the challenges in Germany, so we've tried to account for all scenarios in the revised guidance.

這是正確的。這是布萊恩。謝謝，克里斯。只是補充一下：我們注意到之前範圍的高端佔當前 3 月 PDUFA。所以只是提醒一下，或者說當時的三月 PDUFA 是什麼。提醒一下，雖然像 Roctavian 這樣的產品需要 3 個月的轉變，我們預計隨著時間的推移收入會增加，但從收入的角度來看，這 3 個月的轉變實際上導致我們失去了——本來會有什麼是 2023 年最後一個季度的收入，所以 - 可能是最大的一個季度。然後在底端，你是對的。德國面臨的挑戰會產生綜合影響，因此我們試圖在修訂後的指南中考慮所有情況。

And our next question comes from Phil Nadeau from TD Cowen.

我們的下一個問題來自 TD Cowen 的 Phil Nadeau。

One more question on Germany. I guess it's still unclear to us why those patients who have gone through CDx testing have not gone on therapy. I think you've been very clear about the price -- or the reimbursement negotiation process, but you've also suggested that there are patients who are covered through one OBA or named patient use, so for those patients who have gone through CDx testing, why have they not been treated yet? What's the bottleneck there? Is it a concern about time to reimbursement? Do the physicians have some other concern? Kind of what's preventing that for you? And then secondarily, I think you said in your prepared remarks you do expect the first patient to be treated in Q2. What gives you confidence in that given that no one was treated in Q1?

還有一個關於德國的問題。我想我們仍然不清楚為什麼那些經過 CDx 測試的患者沒有接受治療。我認為您對價格或報銷談判過程已經非常清楚，但您還建議有些患者通過一個 OBA 或指定患者使用，所以對於那些已經過 CDx 測試的患者，為什麼他們還沒有得到治療？那裡的瓶頸是什麼？是否擔心報銷時間？醫生們還有其他顧慮嗎？是什麼阻止了你？其次，我想你在準備好的發言中說過，你確實希望第一位患者在第二季度接受治療。鑑於第 1 季度沒有人接受治療，是什麼讓您對此充滿信心？

Phil, I'll start with that one and see if JJ wants to round out with any comments. So what's going on between CDx testing and treatment? The first thing is CDx testing is one of a couple of eligibility criteria. So it's an important one and it's probably the biggest piece to get done. There is also liver health testing that's an eligibility criteria. It is possible. It's likely, highly likely, that anybody that's going through the process of CDx testing is interested in potential treatment with Roctavian. As has been described to me by some of the German physicians, the cadence of decision-making may not just hinge on a positive or a negative CDx test. It's possible, but as described to me, patients go back. They confer with their family. Sometimes they have additional questions for their treating physician. Sometimes they come back for additional appointments to discuss and be counseled on Roctavian as a treatment option, so I think it's an important but not the only part in the process of what I might term the purchase decision of a patient for Roctavian.

Phil，我將從那個開始，看看 JJ 是否想發表任何評論。那麼 CDx 測試和治療之間發生了什麼？首先是 CDx 測試是幾個資格標準之一。所以這是一個重要的部分，而且可能是要完成的最大部分。還有肝臟健康測試，這是一個資格標準。有可能的。很可能，非常有可能，任何正在經歷 CDx 測試過程的人都對 Roctavian 的潛在治療感興趣。正如一些德國醫生向我描述的那樣，決策的節奏可能不僅僅取決於 CDx 測試的陽性或陰性。這是可能的，但正如我所描述的，患者會回去。他們與家人商量。有時他們會向主治醫生提出其他問題。有時他們會回來進行額外的預約，討論 Roctavian 作為一種治療選擇並接受諮詢，所以我認為這是一個重要但不是唯一的部分，我可以稱之為患者購買 Roctavian 的決定過程。

And then the second question, what gives us confidence in first patient tested in Q2? So in the previous questions, I was describing that we've got a patient funnel now that is 18 and growing. And if you said, well, emergence of a patient at the top of the funnel is defined by sending sample in for CDx testing -- and then I just described maybe some of the other steps along the way, additional liver testing, conferring with family, thinking a big decision over, maybe coming back in to the clinic for further counseling. Those patients are working down the funnel that leads to the purchase decision. And as I said in the previous question, every week, I see updates and movement in Germany. And the pace of those movement is picking up all the time, so that's what gives me confidence that we will have shortly a first or more than 1 patient coming out of the bottom of that funnel for treatment.

然後是第二個問題，是什麼讓我們對第二季度測試的第一位患者充滿信心？所以在前面的問題中，我描述了我們現在有一個 18 歲的患者漏斗，而且還在不斷增長。如果你說，好吧，漏斗頂部患者的出現是通過發送樣本進行 CDx 測試來定義的——然後我只是描述了可能沿途的其他一些步驟，額外的肝臟測試，與家人商量，考慮一個重大決定，也許回到診所接受進一步諮詢。這些患者正在沿著導致購買決定的漏斗前進。正如我在上一個問題中所說，每週，我都會看到德國的更新和動態。而且這些運動的步伐一直在加快，所以這讓我有信心，我們很快就會有第一名或不止一名患者從漏斗底部出來接受治療。

And maybe just to add [kind of] to what Jeff said. I mean, first of all, [taking about a year to get reimbursement] in Germany -- in competitive markets is the norm, so there is nothing that's surprising here. Again we thought with an OBA we would be able to get usage a little faster, but obviously it's been difficult. So we did sign an OBA agreement mainly with one payer that only represents about 10% of the German lives -- or covered lives. So 10% of 18 patients will be like 1.8 patients. So it's not that surprising because the other patients basically are not covered by an existing OBA. So for the other patients who are dependent upon a different insurance company -- in Germany, physicians are personally liable financially for prescribing a treatment or a procedure that is not -- where they don't have coverage from -- their [sick folks]. And obviously here we're talking about $1 million or so [cost] of therapy, so obviously you understand why physicians want to double and triple check that their -- the health insurance company of the patients will cover the procedure before they move forward. I think all this is being debugged and it's going to be happening. [So in truth, this is why now], based on the growing pipeline of patients, that we believe that we're going to get a patient treated at least in the Q2 of this year in Germany. And then there are patients [potentially] we can talk about in the rest of the world.

也許只是為了 [有點] 添加 Jeff 所說的話。我的意思是，首先，[需要大約一年的時間才能獲得報銷]在德國——在競爭激烈的市場中是常態，所以這裡沒有什麼令人驚訝的。我們再次認為通過 OBA 我們能夠更快地獲得使用，但顯然這很困難。因此，我們確實主要與一個付款人簽署了一項 OBA 協議，該付款人僅代表大約 10% 的德國人的生命——或覆蓋的生命。所以 18 名患者中的 10% 就像 1.8 名患者。所以這並不奇怪，因為其他患者基本上不在現有 OBA 的覆蓋範圍內。因此，對於依賴不同保險公司的其他患者 - 在德國，醫生對開出的治療或程序不承擔經濟責任 - 他們沒有保險 - 他們的 [sick folks] .很明顯，我們在這裡談論的是 100 萬美元左右的治療 [費用]，所以很明顯你明白為什麼醫生想要雙重和三次檢查他們的 - 患者的健康保險公司將在他們繼續之前支付該程序。我認為所有這些都在調試中，並且將會發生。 [所以事實上，這就是為什麼現在]，基於不斷增長的患者管道，我們相信我們至少會在今年第二季度在德國讓一名患者接受治療。然後我們可以在世界其他地方談論 [潛在] 患者。

And then the other thing that Jeff forgot to mention is regarding what happened in the past few months since we gave the previous update of about 10 patients that have been screened for AAV5. In Germany, they take -- I understand they take Easter holidays very seriously. So for 2 weeks in early April, there wasn't much activity going on anywhere in the medical [field] in Germany. So that also explains, but it looks like, since we passed Easter, it looks like things are picking up again in terms of [AAV] test screening, so which is very positive.

然後 Jeff 忘記提及的另一件事是關於自從我們上次更新約 10 名接受 AAV5 篩查的患者以來過去幾個月發生的事情。在德國，他們——我知道他們非常重視復活節假期。因此，在 4 月初的兩週內，德國醫療 [領域] 的任何地方都沒有太多活動。所以這也解釋了，但看起來，自從我們過了復活節，就 [AAV] 測試篩選而言，情況似乎又開始好轉，所以這是非常積極的。

And our next question comes from Jessica Fye from JPMorgan. .

我們的下一個問題來自摩根大通的 Jessica Fye。 .

I have one more on Roctavian and then another on Voxzogo. So I think you mentioned you expect the first German patient to get Roctavian in the second quarter, but maybe more broadly, can you just help us understand your expectations for Roctavian uptake in Germany between now and September when you get that final reimbursement? I guess, like, apart from a patient here and there, does this update about not pursuing OBAs mean that we should expect very modest uptake in Germany until the fall? And then separately, on Voxzogo, can your -- can you share your latest thinking about the most likely path to approval for settings like hypochondroplasia?

我還有一個關於 Roctavian 的，然後另一個是關於 Voxzogo 的。所以我想你提到你希望第一位德國患者在第二季度獲得 Roctavian，但也許更廣泛地說，你能幫助我們了解你對從現在到 9 月獲得最終報銷時在德國使用 Roctavian 的期望嗎？我想，就像，除了這里和那裡的病人，這種關於不追求 OBA 的更新是否意味著我們應該期望德國在秋天之前的接受度非常低？然後分別在 Voxzogo 上，您能否分享您對最可能批准軟骨發育不良等設置的途徑的最新想法？

I'll take the first part of that, Jessica. So relative to the subject of uptake, I started out by saying our plan was to facilitate early and more rapid uptake for Roctavian with these outcomes-based agreements. We tried that, yes. And I think it was a good plan, but things didn't work out according to that plan, so I think we're resetting expectations about the pace of uptake; the -- certainly the timing of first [uptake], which I think is likely in Q2 of this year. And as JJ noted in the script, the fact that we're deemphasizing or deprioritizing those outcomes-based agreements in favor of the full federal process probably means that we'll have slower uptake until we get that price finalized. It doesn't mean that we won't have any uptake, because we've got one agreement in place. And there is a process for physicians to submit patients that they want to treat to their insurer for individual review. So that's kind of our qualitative expectation there. I'll turn it over to Hank for the Voxzogo question.

我來做第一部分，傑西卡。因此，關於吸收的主題，我首先說我們的計劃是通過這些基於結果的協議促進 Roctavian 的早期和更快速的吸收。我們試過了，是的。我認為這是一個很好的計劃，但事情並沒有按照該計劃進行，所以我認為我們正在重新設定對吸收速度的預期； - 當然是第一次 [uptake] 的時間，我認為這很可能在今年第二季度。正如 JJ 在劇本中指出的那樣，我們正在淡化或取消那些基於結果的協議以支持完整的聯邦程序這一事實可能意味著在我們最終確定價格之前我們的接受速度會變慢。這並不意味著我們不會接受，因為我們已經達成了一項協議。醫生有一個流程可以將他們想要治療的患者提交給他們的保險公司進行單獨審查。所以這就是我們在那裡的定性期望。關於 Voxzogo 問題，我會轉交給 Hank。

Path to hypochondroplasia, other new indications for Voxzogo, a pretty exciting question [and time] because of Voxzogo's tremendous activity as a natural regulator of bone growth and because of the unmet need of individuals who have severe impairments in bone growth resulting in health outcomes -- poor health outcomes. And the path includes both generating some additional pilot data, which we've shared a little bit of, but we're generating more of that data to increase our and your confidence in the potential for Roctavian -- for Voxzogo to add value for patients with skeletal impairments and also dialogue with health authorities around requirements for registration. As far as our next steps with stakeholders, probably the next real meaningful update you will get from us about the back-and-forth that we're having with health authorities is going to be when we finalize our plans. And we can tell you what the trial is going to look like; when it's going to start; how many patients are going to be involved; what the end points are going to be; what, if any, are our comparators or concomitant medications in the trial. So a pretty exciting time, and stay tuned. We're well underway.

軟骨發育不全的途徑，Voxzogo 的其他新適應症，這是一個非常令人興奮的問題 [和時間]，因為 Voxzogo 作為骨骼生長的天然調節劑具有巨大的活性，並且由於骨骼生長嚴重受損導致健康結果的個體的需求未得到滿足 - - 健康狀況不佳。該路徑包括生成一些額外的試點數據，我們已經分享了一些，但我們正在生成更多的數據，以增加我們和您對 Roctavian 潛力的信心——讓 Voxzogo 為患者增加價值有骨骼損傷，並與衛生當局就註冊要求進行對話。至於我們與利益相關者的下一步行動，您可能會從我們那裡得到關於我們與衛生當局的來回交流的下一個真正有意義的更新，這將是在我們最終確定我們的計劃時。我們可以告訴您審判會是什麼樣子；什麼時候開始；將涉及多少患者；終點是什麼；如果有的話，我們在試驗中的比較劑或伴隨藥物是什麼。這是一個非常激動人心的時刻，敬請期待。我們進展順利。

And our next question comes from Akash Tewari from Jefferies.

我們的下一個問題來自 Jefferies 的 Akash Tewari。

Just on the upcoming [double] readout, is there a potential the FDA may require you to run a trial head-to-head versus growth hormone? And kind of what's your confidence that vosoritide's efficacy won't drop off as we go to 1 year and beyond? Obviously that didn't occur with achondroplasia, but with these new [growth-side] disorders, that's a question that does come up. And then I also noticed you had 11 patients in Argentina screened for AAV5 antibodies. Can you walk us through a reasonable launch time frame and price expectations for markets outside of the U.S. and EU5?

就在即將到來的 [double] 讀數中，FDA 是否有可能要求您進行與生長激素的頭對頭試驗？您對 vosoritide 的療效在 1 年及以後不會下降的信心如何？顯然，軟骨發育不全不會發生這種情況，但對於這些新的 [生長方面] 疾病，確實會出現這個問題。然後我還注意到你們在阿根廷對 11 名患者進行了 AAV5 抗體篩查。您能否為我們介紹一個合理的發佈時間框架和對美國和歐盟 5 國以外市場的價格預期？

I'll start, Akash, your one question [of -- actually that had about 5 subparts], but I may not get them all. But one is what will be expected of us in regard to durability demonstration for non-achondroplasia indications. And another part of your question is will the agency require comparators, for example, with growth hormone. And I think the answers to both of those questions are a little bit TBD in the sense that we are in discussions with the agency. And as I said, we'll tell you what sort of the resolution of all that is in regard to more specifically the answer to your question by specific type of indication, but I think you also put your finger on the head of the -- a finger on the actual pulse of what the issues to address are. And I think one of the really exciting things about Voxzogo as a natural regulator of bone growth is that, even in a severe skeletal dysplasia like achondroplasia, we were actually able to demonstrate sufficient durability to satisfy the agency, the FDA, that at least the changes that we saw in AGV were in fact reasonably likely to predict a long-term accumulation of a clinically meaningful height benefit. So I think that is a good platform you referenced that -- I also think the issue about growth hormone is that, outside of growth hormone deficiencies, there isn't great evidence about accumulated benefit of growth hormone as regard -- well, there is -- let me qualify that. There is a lot of evidence about the accumulated height benefit of growth hormone in nongrowth hormone deficiency syndromes. It's not very compelling evidence. That is to say that there isn't much of a height gain in regard to what growth hormones can do for children who don't have growth hormone deficiency. So I think you take all of that together and these are going to be the kinds of discussions that we have with the agency to chart the path forward for new indications for Voxzogo. It's not without complications, but I think the settler for all of this is a medication like a -- like Voxzogo that has the property of being a natural regulator of bone growth.

阿卡什，我將開始你的一個問題 [實際上它有大約 5 個子部分]，但我可能無法全部回答。但一個是我們對非軟骨發育不全適應症的耐久性示範的期望。你問題的另一部分是該機構是否需要比較劑，例如生長激素。我認為這兩個問題的答案都有點待定，因為我們正在與該機構進行討論。正如我所說，我們會通過特定類型的指示告訴你所有關於更具體地回答你的問題的解決方案，但我認為你也把你的手指放在了 -把握要解決的問題的實際脈搏。我認為 Voxzogo 作為骨骼生長的天然調節劑，真正令人興奮的事情之一是，即使在軟骨發育不全等嚴重的骨骼發育不良中，我們實際上也能夠證明足夠的耐久性來滿足 FDA 的要求，至少我們在 AGV 中看到的變化實際上很可能預測具有臨床意義的身高收益的長期積累。所以我認為這是你提到的一個很好的平台——我也認為關於生長激素的問題是，除了生長激素缺乏之外，沒有很好的證據表明生長激素的累積益處——嗯，有- 讓我限定一下。有很多證據表明生長激素對非生長激素缺乏症的累積身高有益。這不是很有說服力的證據。也就是說，對於沒有生長激素缺乏症的兒童，生長激素對身高的影響不大。所以我認為你把所有這些放在一起，這些將是我們與該機構進行的那種討論，以規劃 Voxzogo 新適應症的前進道路。這並非沒有並發症，但我認為所有這一切的定居者是一種藥物，就像 Voxzogo 一樣，它具有骨骼生長的天然調節劑的特性。

And your second question, Akash, about what's the significance or what do we read into those 11 CDx tests in Argentina. I would say, in the general sense, named patient sales, in the absence of or even prior -- just prior to a registration, is an important part of our commercial picture overall. Witness, for example, the rapid uptake across our commercial footprint with Voxzogo, some of which but not all of which is in markets where we have registrations. We don't tend to talk about those markets a lot in detail because they tend to be smaller and come at a slower pace than, for example, the major markets in Europe, Japan or the United States, but they're important overall. And I think Argentina, with early signals of patient movement, a first prescription, is a good representation of what we might expect also in other markets and where we get going, one patient at a time, on a named patient basis. We also mentioned that Saudi Arabia, which is also an -- usually an early mover like Argentina on a named patient sales basis, is -- we also are underway. And there's interest in Roctavian in that market, so what we're trying to do here is highlight the fact that, beyond where we have very specific plans like in Germany, France and Italy that I've mentioned, there is movement in those other important named patient sales markets.

你的第二個問題，Akash，關於阿根廷的 11 項 CDx 測試的重要性或我們讀到了什麼。我會說，在一般意義上，在沒有或什至之前 - 就在註冊之前，命名患者銷售是我們整體商業圖景的重要組成部分。例如，見證我們在 Voxzogo 的商業足跡中的迅速普及，其中一些但不是全部都在我們註冊的市場中。我們不傾向於詳細討論這些市場，因為與歐洲、日本或美國等主要市場相比，它們往往規模較小且發展速度較慢，但總體而言它們很重要。而且我認為，阿根廷有患者移動的早期信號，第一個處方，很好地代表了我們在其他市場和我們前進的地方也可能期望的，一次一個患者，在指定患者的基礎上。我們還提到，沙特阿拉伯也是——通常是像阿根廷這樣的先行者，在指定的患者銷售基礎上——我們也在進行中。那個市場對 Roctavian 很感興趣，所以我們在這裡要做的是強調一個事實，即除了我提到的德國、法國和意大利等我們有非常具體的計劃之外，其他市場也有進展重要的指定患者銷售市場。

And our next question comes from Joseph Schwartz from SVB Securities.

我們的下一個問題來自 SVB 證券公司的 Joseph Schwartz。

I have a question on Roctavian -- I'm Joori, dialing in for Joe. How is the process with the single public insurance funds in France and Italy going? And can you provide any more color around your expectations to secure reimbursement and access to Roctavian later in 2023?

我有一個關於 Roctavian 的問題——我是 Joori，撥入 Joe 的電話。法國和意大利單一公共保險基金的進程如何？您能否就您的期望提供更多顏色，以確保在 2023 年晚些時候獲得報銷和使用 Roctavian？

So the process in each of France and Italy, which in our commercial footprint and with our kind of capabilities, is always a close follower to Germany in terms of timing and prioritization. Those markets essentially take a year, sometimes longer, to get price and reimbursement approval. And right -- I mentioned, as soon as we got our price listed in Germany, we submitted the full price and reimbursement dossier there and got the process going last fall. Right after we did that with Germany, we were submitting in the fall of last year for France and Italy, so both of those processes are ongoing. There is no guarantee as there is in Germany that you'll conclude in 12 months, but we're on track in both of those markets. And we think it's likely that we'll be at the end of that process by the fall of next year. And in the script, we mentioned...

因此，在我們的商業足跡和我們的能力範圍內，法國和意大利的流程在時間安排和優先級方面始終緊隨德國。這些市場基本上需要一年，有時甚至更長的時間才能獲得價格和報銷批准。是的——我提到過，一旦我們在德國列出了我們的價格，我們就在那裡提交了全價和報銷檔案，並在去年秋天開始了這個過程。在我們對德國這樣做之後，我們在去年秋天為法國和意大利提交了申請，所以這兩個過程都在進行中。不能像在德國那樣保證您會在 12 個月內得出結論，但我們在這兩個市場都走上了正軌。我們認為我們很可能會在明年秋天結束這一過程。在劇本中，我們提到...

(inaudible).

（聽不清）。

This year. (inaudible). Sorry. And we mentioned in the script that in Italy -- and this is breaking news. It's -- it just happened last week, that we were granted conditionally innovative status for Roctavian, which doesn't confer anything specific but is in the general sense a positive signal to how the -- how AIFA is looking at Roctavian in Italy, as an example.

今年。 （聽不清）。對不起。我們在劇本中提到在意大利——這是突發新聞。這是——上周剛剛發生的事情，我們獲得了 Roctavian 的有條件創新地位，這並沒有賦予任何具體的東西，但在一般意義上是一個積極的信號，表明 AIFA 如何看待意大利的 Roctavian，因為一個例子。

And our next question comes from Gena Wang from Barclays.

我們的下一個問題來自巴克萊銀行的 Gena Wang。

I wanted to ask about Roctavian again. For the 18 patients that complete the antibody testing, how many of these were eligible? Also, in Europe, since now you are pursuing directly with GKV without pursuing outcome-based agreements with sub-insurance, does that mean your price will be much lower than EUR 1.5 million that you previously discussed?

我想再問問羅克塔維安的事。完成抗體檢測的18位患者中，有多少符合條件？另外，在歐洲，由於現在您直接與 GKV 尋求而不與子保險尋求基於結果的協議，這是否意味著您的價格將遠低於您之前討論的 150 萬歐元？

And then lastly, very quickly, regarding the U.S., can you discuss on hemophilia A patient under 340B program? And how does that mechanism impact the Roctavian initial launch?

最後，很快，關於美國，您能否討論 340B 計劃下的血友病 A 患者？該機制如何影響 Roctavian 的首次發射？

Thank you, Gena, for those questions. Let me start with the 18 CDx tested and percentage that are eligible. So first thing to note is CDx testing is one eligibility test. Liver health is the second. Relative to the AAV5 seropositive or negative status, the best thing that we can do to guide our expectations on that is the publication from our seroprevalence study in hemophilia A. And in that study, which was published, the overall seropositivity rate for AAV5 in Germany was 35%. So that's guiding our expectations on the percent of patients that would be eligible based on AAV5 seronegativity. Relative to the GKV price negotiations and what we had guided to as net price of about EUR 1.5 million, which was last fall, we think it is likely. Based on what the GKV is statutorily allowed to do, we think it's likely that they will not be putting into the agreement an outcomes-based component or a pay-over-time component, but nothing is certain until we get done with that process. But you're right. In that particular case, we think that the price negotiations with GKV would incorporate all of the aspects of value of Roctavian, including durability, for example, so we think that the final price would model in how GKV is looking at durability of Roctavian over time.

謝謝 Gena，提出這些問題。讓我從經過測試的 18 個 CDx 和符合條件的百分比開始。所以首先要注意的是 CDx 測試是一項資格測試。肝臟健康是其次。相對於 AAV5 血清反應陽性或陰性狀態，我們能做的最好的事情就是發表我們在血友病 A 中的血清陽性率研究。在發表的那項研究中，德國 AAV5 的總體血清陽性率為 35%。因此，這指導了我們對基於 AAV5 血清陰性的符合條件的患者百分比的期望。相對於去年秋天的 GKV 價格談判和我們指導的約 150 萬歐元的淨價，我們認為這是有可能的。根據 GKV 被法定允許做的事情，我們認為他們很可能不會在協議中加入基於結果的部分或按時間付費的部分，但在我們完成該過程之前，一切都不確定。但你是對的。在這種情況下，我們認為與 GKV 的價格談判將包含 Roctavian 價值的所有方面，例如耐久性，因此我們認為最終價格將模擬 GKV 如何看待 Roctavian 隨著時間的推移的耐久性.

And then relative to the 340B question in the United States. In our script remarks, we mentioned that we're committed to this HTC model of treatment and follow-up. Hemophilia treatment centers or HTCs in the United States are granted 340B eligibility. That's a way of kind of funding the work -- the important work that they do to care for hemophilia patients, so we think all or substantially all of our revenue in the United States would be subject to the 340B discount.

然後是相對於美國的340B問題。在我們的劇本評論中，我們提到我們致力於這種 HTC 治療和跟進模式。美國的血友病治療中心或 HTC 被授予 340B 資格。這是一種為工作提供資金的方式——他們為照顧血友病患者所做的重要工作，所以我們認為我們在美國的全部或幾乎所有收入都將受到 340B 折扣的影響。

So then what's your opinion as to what that's going to do to the launch? I mean, in some respects, it's positive for us at least.

那麼你對這將對發射產生什麼影響有什麼看法？我的意思是，在某些方面，這至少對我們是積極的。

Yes. We think that's very positive. So as I mentioned, the reason for being for HTCs to have access to the 340B discount is to have a source of revenue to fund their important operations. And as Roctavian would likely be eligible for those 340B discounts for all or essentially all of their patients, that's revenue that would accrue to those HTCs to fund their operations. And that revenue would happen at the time of treatment versus, for example, revenue that they might be getting from supplying factor replacement products which they would see over time. And by the way, important point to note is the HTCs see a revenue component from factor replacement therapy only for a small proportion of their patients on average, so we think that this is actually maybe a motivating factor for treatment with Roctavian in the U.S.

是的。我們認為這是非常積極的。因此，正如我提到的，HTC 獲得 340B 折扣的原因是有收入來源來為其重要運營提供資金。由於 Roctavian 可能有資格為所有或基本上所有患者享受 340B 折扣，因此這些 HTC 將獲得這些收入來為其運營提供資金。這種收入將在治療時發生，例如，他們可能會從供應他們會隨著時間推移看到的因子替代產品中獲得收入。順便說一句，需要注意的重要一點是，HTC 認為平均只有一小部分患者從因子替代療法中獲得收入，因此我們認為這實際上可能是在美國使用 Roctavian 進行治療的一個激勵因素。

And our next question comes from Tim Lugo from William Blair.

我們的下一個問題來自威廉布萊爾的蒂姆盧戈。

You mentioned Voxzogo is on its way to becoming the first blockbuster for the company. Will these other non-achondroplasia indications add to the market? And kind of how much? And can you also update us, maybe I missed this, on converting the accelerated approval to a full approval?

你提到 Voxzogo 正在成為公司的第一個重磅炸彈。這些其他非軟骨發育不全的適應症會增加市場嗎？多少？您是否也可以向我們更新有關將加速批准轉換為完全批准的信息，也許我錯過了這一點？

Maybe I'll start. And then Jeff can provide more info. I mean, as -- I think as we made in the prepared remarks, I think in Jeff's remarks, we only have penetrated about less than 10% of the market right now for Voxzogo achondroplasia worldwide, so obviously [we can get past it]. And we are on a run rate already of $450,000 -- or $450 million or so, so obviously, in the achon market alone there is a lot of room to grow. And we can easily pass $1 billion in revenues in achon alone, so obviously, other indications are going to [make it, the part], even larger, but that's kind of my first comment to your questions. Jeff?

也許我會開始。然後 Jeff 可以提供更多信息。我的意思是——我認為正如我們在準備好的發言中所做的那樣，我認為在 Jeff 的發言中，我們目前在全球範圍內只滲透了不到 10% 的 Voxzogo 軟骨發育不全市場，所以很明顯 [我們可以克服它] .而且我們的運行率已經達到 450,000 美元 - 或者 4.5 億美元左右，所以很明顯，僅在 achon 市場就有很大的增長空間。我們可以很容易地僅在 achon 就超過 10 億美元的收入，所以很明顯，其他跡象會 [make it, the part]，甚至更大，但這是我對你的問題的第一個評論。傑夫？

Nothing to add. Thanks, JJ. And then there was the question of accelerated to full approval...

沒什麼可補充的。謝謝，JJ。然後是加速到完全批准的問題......

Nothing new to report there. It's publish post-marketing requirement. And the specifics of the timing for that, we've kept those relatively proprietary, so stay tuned.

那裡沒有什麼新的報導。它是發布後營銷要求。以及具體的時間安排，我們保留了那些相對專有的內容，敬請期待。

And our next question comes from Paul Matteis from Stifel.

我們的下一個問題來自 Stifel 的 Paul Matteis。

Surprised it took a long time to get a question on the FDA with Roctavian, but I thought I'd just throw it in there. You should be only a handful of weeks away from labeling discussions. I'm just curious if you could update us on the cadence of your discussions and how everything is going. And then if you do get approval in June, do you think these reimbursement warranties could be agreed upon and then placed quickly enough to generate meaningful revenues for Roctavian in the U.S. in 3Q?

很驚訝花了很長時間才得到 Roctavian 關於 FDA 的問題，但我想我只是把它扔在那裡。距離標籤討論應該只有幾週的時間了。我只是想知道您是否可以向我們介紹您討論的節奏以及一切進展情況。然後，如果您確實在 6 月獲得批准，您是否認為可以就這些報銷保證達成一致，然後足夠快地安排，以便在第三季度為美國的 Roctavian 產生可觀的收入？

Thanks, Paul, for the question. I won't get into the specifics of the back-and-forth, but I would say that, as a general matter, the things that we expect to be having at this stage of the review appear to be happening; and I think that gives us optimism. I think we've also expressed some caution there because we don't have perfect visibility into everything going on in the agency and exactly where senior management and the people who signed the letters are, but we're optimistic.

保羅，謝謝你提出這個問題。我不會詳細說明來回的細節，但我想說的是，總的來說，我們期望在審查的這個階段發生的事情似乎正在發生；我認為這讓我們感到樂觀。我認為我們在那裡也表達了一些謹慎，因為我們無法完全了解該機構發生的一切，也無法完全了解高級管理人員和簽署信件的人的確切位置，但我們很樂觀。

Relative to the warranty, Paul. The nature of the warranty is that it is uniform. It is nonnegotiable. It is available to all purchasers and essentially we don't have to negotiate. The purchaser essentially gets that warranty with purchase, so the timing is relatively trivial.

相對於保修，保羅。保修的性質是統一的。這是沒有商量餘地的。它適用於所有購買者，基本上我們不需要談判。購買者基本上在購買時獲得了保修，因此時間相對微不足道。

No timing.

沒有時間。

No timing, yes.

沒有時間，是的。

No delay...

沒有延遲...

No delay.

沒有延遲。

And our next question comes from Robyn Karnauskas from Truist Securities.

我們的下一個問題來自 Truist Securities 的 Robyn Karnauskas。

So just to clarify. For Roctavian, since you're not doing OBAs anymore, can you give us some sense of what price we should be using, since that's been the fixation of a lot of us for Europe, and how to think about that? And then second, for Voxzogo, you're averaging now like 400 patients a quarter. You mentioned a lot of expansion, new indications, geographic. Should we think of it more consistent or choppy?

所以只是為了澄清。對於 Roctavian，既然你不再做 OBA，你能告訴我們應該使用什麼價格，因為這是我們很多人對歐洲的固定價格，以及如何考慮這一點？其次，對於 Voxzogo，你現在平均每個季度有 400 名患者。你提到了很多擴張、新適應症、地理。我們應該認為它更一致還是起伏不定？

[Roctavian]...

[羅克塔維亞]...

Let me start off with the price component. We've guided roughly, last fall, to net price expectations in Europe. How we get [there is] different whether there's an outcomes-based agreement or no outcomes-based agreement. And that's figured into the value of -- the durability, which is figured into the value of the upfront price, but the over -- where we wind up should not be materially different from either path.

讓我從價格部分開始。去年秋天，我們粗略地指導了歐洲的淨價格預期。無論是否有基於結果的協議，我們如何達成 [有] 是不同的。這被計入了——耐用性的價值，它被計入了前期價格的價值，但結束了——我們結束的地方不應該與任何一條路徑有實質性的不同。

One of the reasons why we decided to focus on the GKV and [national price] is because we assumed that it's very likely there will not be an OBA with the federal -- their German federal governments. And then so these prices might be a little lower than what we would potentially have had with an OBA, but the net price will be about the same based on the fact that there is no -- that we don't have to reimburse the payers based on [Roctavian] patients going back to [probably] therapy after 3, 4 or 5 years. So [net-net], we don't anticipate. And based on our interactions with the GKV, so far, yes, it looks pretty promising. And we actually don't anticipate any substantial -- as Jeff said, any substantial difference with this approach.

我們決定關注 GKV 和 [國家價格] 的原因之一是因為我們假設很可能不會與聯邦 - 他們的德國聯邦政府建立 OBA。然後，這些價格可能會比我們使用 OBA 可能獲得的價格低一點，但基於沒有 - 我們不必償還付款人的事實，淨價將大致相同基於 [Roctavian] 患者在 3、4 或 5 年後返回 [可能] 治療。所以 [net-net]，我們沒有預料到。根據我們與 GKV 的互動，到目前為止，是的，它看起來很有希望。正如傑夫所說，我們實際上預計這種方法不會有任何實質性差異。

And then relative to your question about the cadence of Voxzogo patient uptake, it's within kind of a band. It's actually been pretty steady these last few quarters. Underneath that steady uptake, there's a lot of individual market dynamics going on, but it comes on pretty smooth. I would suggest, when modeling forward, that you work from our revenue guidance that we've updated most recently and acknowledging that we've had a lot of updates to those revenue guidance [we've] -- in a positive direction, but yes, I'd fall back to that.

然後相對於你關於 Voxzogo 患者吸收節奏的問題，它在某種範圍內。在過去的幾個季度裡，它實際上非常穩定。在這種穩定的增長之下，有很多個別的市場動態在發生，但進展非常順利。我建議，在進行前向建模時，您可以根據我們最近更新的收入指南進行工作，並承認我們已經對這些收入指南進行了很多更新 [我們已經] - 朝著積極的方向，但是是的，我會回到那個。

And that is all the time we have for questions today. I would like to turn the call back to BioMarin's CEO, JJ Bienaimé, for closing remarks.

這就是我們今天所有的提問時間。我想將電話轉回給 BioMarin 的首席執行官 JJ Bienaimé，請他發表結束語。

So in conclusion. We are very pleased with [BioMarin] progress in the first quarter and the continued successful launch of Voxzogo around the world. The importance of our medicines to the people who rely on them is clear. And while sometimes the development path forward is not always clear cut, we will continue to push that in the interest of our patients.

所以總而言之。我們對 [BioMarin] 第一季度的進展以及 Voxzogo 在全球的持續成功推出感到非常高興。我們的藥物對依賴它們的人的重要性是顯而易見的。雖然有時前進的道路並不總是明確的，但我們會為了患者的利益繼續推動它。

Thank you for your support. And have a good rest of the day.

感謝您的支持。好好休息一天。

The host has ended this call. Goodbye.

主持人已結束本次通話。再見。