Apellis Pharmaceuticals Inc (APLS) 2023 Q4 法說會逐字稿

Good morning, ladies and gentlemen. Thank you for standing by, and welcome to the Apellis Pharmaceuticals Fourth Quarter 2023 Earnings Conference Call. (Operator Instructions) Please be advised today's conference is being recorded.

早安，女士們，先生們。感謝您的耐心等待，歡迎參加 Apellis Pharmaceuticals 2023 年第四季財報電話會議。 （操作員指示）請注意，今天的會議正在錄製中。

I would now hand the conference over to your speaker host, Meredith Kaya, Senior Vice President, Investor Relations & Strategic Finance. Please go ahead.

我現在將會議交給演講主持人、投資者關係和策略財務高級副總裁梅雷迪思·卡亞 (Meredith Kaya)。請繼續。

Good morning, and thank you for joining us to discuss Apellis' fourth quarter and full year 2023 financial results. With me on the call are: Co-Founder and Chief Executive Officer, Dr. Cedric Francois, Chief Operating Officer, Adam Townsend; Chief Medical Officer, Dr. Caroline Baumal; and Chief Financial Officer, Tim Sullivan.

早安，感謝您加入我們討論 Apellis 第四季和 2023 年全年財務表現。與我一起參加電話會議的有：共同創辦人兼執行長 Cedric Francois 博士、營運長 Adam Townsend；首席醫療官 Caroline Baumal 博士；和首席財務官蒂姆·沙利文。

Before we begin, let me point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties. And actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail.

在開始之前，請允許我指出，我們將根據我們當前的期望和信念做出前瞻性聲明。這些陳述存在一定的風險和不確定性。實際結果可能存在重大差異。我鼓勵您查閱我們向 SEC 提交的文件中討論的風險因素，以了解更多詳細資訊。

Now I'll turn the call over to Cedric.

現在我將把電話轉給塞德里克。

Thank you, Meredith, and thank you all for joining us this morning. As I reflect on this past year, I am extremely proud of our team and all of our achievements in 2023. Our two commercial products, SYFOVRE and EMPAVELI, are making meaningful differences for patients.

謝謝梅雷迪思，也謝謝大家今天早上加入我們。回顧過去的一年，我為我們的團隊以及我們在 2023 年取得的所有成就感到非常自豪。我們的兩種商業產品 SYFOVRE 和 EMPAVELI 正在為患者帶來有意義的改變。

The year ended with SYFOVRE in a very strong position. And we remain encouraged by the continuous uptick and high compliance rates for EMPAVELI in PNH. We also had multiple positive data readouts, including up to 3 years of efficacy and safety data from both of our approved therapies.

SYFOVRE 在這一年結束時處於非常有利的地位。我們仍然對 PNH 的 EMPAVELI 持續上升和高合規率感到鼓舞。我們還獲得了多個積極的數據讀數，包括我們批准的兩種療法長達 3 年的療效和安全性數據。

While 2023 certainly had its challenges, our accomplishments and our resilience position us well for continued execution in 2024 and to deliver on our mission for patients now and in the future. Let me share some details on this past year and our priorities for 2024.

雖然 2023 年確實面臨挑戰，但我們的成就和韌性使我們能夠在 2024 年繼續執行任務，並為現在和未來的患者履行我們的使命。讓我分享一些關於過去一年的細節以及我們 2024 年的優先事項。

Beginning with SYFOVRE. We recently celebrated SYFOVRE's 1-year approval anniversary. And what a year it has been. The launch had exceeded our expectations even with the unexpected challenges we faced last summer. More than 200,000 SYFOVRE doses have now been distributed to physician practices since launch through mid-February. And we estimate that approximately 215,000 SYFOVRE injections have been administered to patients through February, including our Phase III clinical trials.

從 SYFOVRE 開始。我們最近慶祝了 SYFOVRE 獲得批准一週年紀念。這是多麼美好的一年。儘管去年夏天我們遇到了意想不到的挑戰，但這次發布還是超出了我們的預期。自 2 月中旬推出以來，現已向醫師診所分發了超過 20 萬劑 SYFOVRE 劑量。我們估計，截至 2 月份，已向患者註射了約 215,000 支 SYFOVRE 注射劑，其中包括我們的 III 期臨床試驗。

These numbers underscore the retina community's confidence in the benefits of SYFOVRE and the central role it plays place in improving patients' lives. And importantly, based on these numbers, the risk of developing retinal vasculitis remains rare at an estimated rate of approximately 0.01% per injection.

這些數字強調了視網膜界對 SYFOVRE 的益處及其在改善患者生活方面發揮的核心作用的信心。重要的是，根據這些數字，發生視網膜血管炎的風險仍然很少，估計每次注射發生率約為 0.01%。

In the fourth quarter, we reported $114 million in SYFOVRE U.S. net product revenue. We achieved $275 million in SYFOVRE revenues for the full year. While we have experienced modest seasonality in the first quarter so far, SYFOVRE continues to show meaningful growth. And we look forward to bringing it to more and more patients throughout the year.

第四季度，我們報告 SYFOVRE 美國產品淨收入為 1.14 億美元。 SYFOVRE 全年營收達 2.75 億美元。儘管到目前為止，我們在第一季經歷了溫和的季節性因素，但 SYFOVRE 繼續顯示出有意義的成長。我們期待著全年將其帶給越來越多的患者。

In 2024, our priorities with SYFOVRE are to maximize access to patients in need in the U.S. and to bring SYFOVRE to patients with GA worldwide. Key to these are our commercial and medical activities, including building on the relationships we've already established in the retina community.

2024 年，我們與 SYFOVRE 的合作重點是最大限度地幫助美國有需要的患者，並將 SYFOVRE 帶給全球的 GA 患者。其中的關鍵是我們的商業和醫療活動，包括建立我們在視網膜界已經建立的關係。

Given our global expansion goal with SYFOVRE, let me comment on the European Union. As you know, we received a negative opinion by the Committee of Medicinal Products for Human Use, or CHMP, for the marketing application of SYFOVRE in the EU. While this is disappointing, we remain steadfast in our efforts, given the more than 2.5 million GA patients in need of treatment across Europe.

鑑於我們與 SYFOVRE 的全球擴張目標，讓我評論一下歐盟。如您所知，我們收到了人類使用藥物委員會（CHMP）對 SYFOVRE 在歐盟的營銷申請的負面意見。儘管這令人失望，但鑑於歐洲有超過 250 萬 GA 患者需要治療，我們仍然堅定不移地努力。

The feedback and support we have received for SYFOVRE from the physician and patient communities in Europe has been extraordinary. We have been informed of several letters sent to EMA from multiple European retina organizations, highlighting the need for new treatments and how important SYFOVRE would be for patients.

我們從歐洲醫生和患者社群收到的 SYFOVRE 的回饋和支持非常多。我們獲悉多個歐洲視網膜組織向 EMA 發送了幾封信，強調了對新治療方法的需求以及 SYFOVRE 對患者的重要性。

As such, we are initiating a reexamination of our application, which includes revising our dossier to ensure that key questions are addressed. We expect a final opinion in connection with this reexamination to be issued at an upcoming CHMP meeting in the second quarter. If positive, a decision by the European Commission is anticipated in the third quarter.

因此，我們正在開始重新審查我們的申請，其中包括修改我們的檔案以確保關鍵問題得到解決。我們預計與此複審有關的最終意見將在即將舉行的第二季 CHMP 會議上發布。如果是積極的，歐盟委員會預計將在第三季做出決定。

To be clear, and as we've said many times before, this is not going to be easy. It will be an uphill battle. And we do not know the likelihood of success at this stage. But we strongly believe in our data, including analyses that many experts agreed demonstrate a functional benefit with SYFOVRE treatment. And we will continue to work closely with the CHMP and the retina community throughout the process.

需要明確的是，正如我們之前多次說過的那樣，這並不容易。這將是一場艱苦的戰鬥。我們不知道現階段成功的可能性。但我們堅信我們的數據，包括許多專家一致認為 SYFOVRE 治療具有功能性益處的分析。我們將在整個過程中繼續與 CHMP 和視網膜界密切合作。

Turning to EMPAVELI. We generated $24 million in fourth quarter U.S. net product revenue and $91 million for the full year. The EMPAVELI injector, an innovative and first-of-its-kind, high-tech volume injector, was approved and launched last fall. We've been very pleased with the feedback and adoption so far.

轉向恩帕韋利。我們在美國第四季的產品淨收入為 2,400 萬美元，全年為 9,100 萬美元。 EMPAVELI 注射器是一款創新、同類首創的高科技容積注射器，於去年秋天獲得批准並推出。到目前為止，我們對回饋和採用感到非常滿意。

And in 2024, we will remain focused on maximizing our market position in PNH and also look forward to the Phase III data readout for systemic pegcetacoplan in C3G and IC-MPGN, two rare and debilitating kidney diseases. Our Phase III VALIANT study is fully enrolled. And we expect top line data from this study mid-year.

到 2024 年，我們將繼續專注於最大化我們在 PNH 的市場地位，並期待系統性 pegcetacoplan 在 C3G 和 IC-MPGN 這兩種罕見且令人衰弱的腎臟疾病中的 III 期數據讀出。我們的 III 期 VALIANT 研究已全部入組。我們預計這項研究將在年中公佈頂線數據。

Over the past couple of years, we've been very focused on our commercial products and new launches. But we have other exciting earlier-stage programs advancing. Let me shift to our fourth priority for 2024, which is to progress our early R&D pipeline with an eye to the long term.

在過去的幾年裡，我們一直非常專注於我們的商業產品和新產品的發布。但我們還有其他令人興奮的早期項目正在推進。讓我談談我們 2024 年的第四個優先事項，即著眼於長期發展我們的早期研發管道。

In addition to the EMPAVELI initiatives in C3G and IC-MPGN, we are focused on our siRNA program, APL-3007, which is now in a Phase I dose escalation study with data expected later this year. Additionally, we are advancing the gene testing program with Beam, on which we also expect to share more this year.

除了 C3G 和 IC-MPGN 方面的 EMPAVELI 計劃外，我們還專注於我們的 siRNA 項目 APL-3007，該項目目前正在進行 I 期劑量遞增研究，預計將於今年稍後獲得數據。此外，我們正在與 Beam 一起推進基因測試計劃，我們也預計今年將分享更多內容。

We are entering 2024 from a position of strength with an unwavering commitment to address unmet needs for patients and to create even greater value for our shareholders. And with that, I will now turn it over to Adam to discuss our commercial and medical affairs activity.

進入 2024 年，我們將堅定不移地致力於解決患者未滿足的需求，並為股東創造更大的價值。現在，我將把它交給 Adam 來討論我們的商業和醫療事務活動。

Thank you, Cedric. It was a big year commercially for Apellis with the launch of SYFOVRE in GA and the commercialization of EMPAVELI in PNH.

謝謝你，塞德里克。對 Apellis 來說，這是商業上重要的一年，SYFOVRE 在 GA 上市，EMPAVELI 在 PNH 商業化。

Starting with SYFOVRE. In the fourth quarter, we delivered approximately 62,000 doses to physician practices, including 55,000 commercial vials and 6,400 samples, generating $114 million in U.S. net product revenue. This strong growth underscores the rebound in weekly demand that began in August of 2023. Our execution was driven by meaningful engagement with our key stakeholders: physicians, patients and payers.

從 SYFOVRE 開始。第四季度，我們向醫生診所交付了約 62,000 劑疫苗，其中包括 55,000 個商業小瓶和 6,400 個樣品，為美國產品淨收入帶來了 1.14 億美元。這種強勁的成長凸顯了自 2023 年 8 月開始的每週需求的反彈。我們的執行是透過與我們的主要利害關係人（醫生、患者和付款人）進行有意義的接觸來推動的。

We continue to see weekly orders coming from both new and existing physician practices with a double-digit number of new sites ordering SYFOVRE every week since launch. Patients are motivated to seek treatment. And the vast majority of physicians are treating their patients with SYFOVRE every 6 to 8 weeks, reinforcing how much doctors and patients appreciate a more flexible dosing regimen. And we continue to have robust payer coverage.

我們繼續看到來自新的和現有的醫生診所的每週訂單，自 SYFOVRE 推出以來，每週訂購 SYFOVRE 的新網站數量都達到兩位數。患者有動力尋求治療。絕大多數醫師每 6 至 8 週就會使用 SYFOVRE 治療患者一次，這進一步證明了醫師和病患對更靈活的給藥方案的重視。我們繼續擁有強大的付款人覆蓋範圍。

We are encouraged by the demand growth we are seeing in the first quarter so far. January and February have been two of our biggest months since launch. However, as expected, we did see some seasonality in January as a result of Medicare recertifications as well as weather delays affecting doctor visits and product shipments. These seasonality trends are consistent with what has been seen with some of the anti-VEGF products in the wet AMD market.

迄今為止第一季的需求成長令我們感到鼓舞。一月和二月是我們自推出以來最重要的兩個月。然而，正如預期的那樣，由於醫療保險重新認證以及影響醫生就診和產品運輸的天氣延誤，我們確實在一月份看到了一些季節性。這些季節性趨勢與濕性 AMD 市場上一些抗 VEGF 產品的情況一致。

Today, SYFOVRE is the #1 chosen GA treatment with a current market share of approximately 90%. At launch, we estimated that there were 1 million patients with GA in the U.S. Now that treatments are available for GA patients, we are learning that this population may be even bigger than we expected with estimates suggesting there may be up to 1.5 million patients. Going forward, we expect to continue to build this market and maintain our market-leading position.

如今，SYFOVRE 已成為排名第一的 GA 治療方法，目前市佔率約為 90%。在發佈時，我們估計美國有 100 萬 GA 患者。現在 GA 患者可以獲得治療，我們了解到這個人群可能比我們預期的還要多，估計患者數量可能高達 150 萬。展望未來，我們預計將繼續建立這個市場並保持我們的市場領先地位。

We will be laser-focused on executing our strategy, highlighting the key advantages of SYFOVRE, which include: increasing effects over time with more than 40% reductions in GA lesion growth demonstrated in our GALE extension study; extensive experience with approximately 215,000 injections estimated to have been administered between our clinical trials and real-world experience; and more vision saved for patients, meaning treatment with SYFOVRE has been shown to preserve visual function longer in multiple post hoc analyses.

我們將集中精力執行我們的策略，強調 SYFOVRE 的主要優勢，其中包括： 隨著時間的推移，效果不斷增強，我們的 GALE 擴展研究表明 GA 病變生長減少了 40% 以上；豐富的經驗，根據我們的臨床試驗和實際經驗估計已進行了約 215,000 次注射；為患者挽救更多視力，這意味著在多項事後分析中，SYFOVRE 治療已被證明可以更長時間地保留視覺功能。

Now to EMPAVELI. The positive trends witnessed across the key leading indicators for this patient population have continued through the end of 2023. In the fourth quarter, EMPAVELI generated approximately $24 million in U.S. net product sales, resulting in a total of $91 million for the full year.

現在到恩帕韋利。該患者群體的主要領先指標的正面趨勢一直持續到 2023 年底。第四季度，EMPAVELI 在美國的產品淨銷售額約為 2,400 萬美元，全年銷售額總計 9,100 萬美元。

Notably, approximately 10% of demand in 2023 was from treatment-naive patients and compliance rates remain incredibly high at 97%. We also continue to have a very strong safety profile. We have over 1,400 patient years of systemic pegcetacoplan exposure and have had 0 cases of meningococcal infection and very low rates of thrombosis.

值得注意的是，到 2023 年，大約 10% 的需求來自未接受過治療的患者，而依從率仍高達 97%，令人難以置信。我們也繼續擁有非常強大的安全狀況。我們有超過 1,400 個病人年的系統性 pegcetacoplan 暴露，並且有 0 例腦膜炎雙球菌感染病例，血栓形成率非常低。

We are facing a more competitive market with the recent approval of an oral product in PNH. And I expect the convenience of a twice-a-day pill will be appealing for some patients. I previously commented on the positive feedback since approval of EMPAVELI injector. By simplifying administration and offering greater mobility, we believe the injector elevates the patient experience and fortifies our competitive position.

隨著 PNH 最近批准了一種口服產品，我們面臨著競爭更加激烈的市場。我預計一天兩次的藥丸的便利性會對一些患者有吸引力。我之前評論過 EMPAVELI 注射器獲得批准以來的正面回饋。透過簡化管理並提供更大的移動性，我們相信注射器可以提升患者體驗並鞏固我們的競爭地位。

Before I hand it over to Caroline, I'll close by saying that I am incredibly proud of both the SYFOVRE and EMPAVELI medical and commercial teams. They did an outstanding job throughout 2023, working night and day to bring these two medicines to physicians and patients in need.

在將其交給 Caroline 之前，我最後要說的是，我為 SYFOVRE 和 EMPAVELI 醫療和商業團隊感到無比自豪。他們在 2023 年表現出色，日以繼夜地將這兩種藥物帶給有需要的醫生和病人。

With that, let me turn the call over to Caroline.

接下來，讓我把電話轉給卡羅琳。

Thanks, Adam, and good morning, everyone. We had an active year within the medical community for both SYFOVRE and EMPAVELI.

謝謝亞當，大家早安。 SYFOVRE 和 EMPAVELI 在醫學界度過了活躍的一年。

In November, we presented data from our GALE extension study, which followed 3 years of continuous treatment with SYFOVRE, at the American Academy of Ophthalmology Annual Meeting. These data continue to show increasing effects over time with both monthly and every-other-month SYFOVRE dosing, a seminal feature of SYFOVRE's efficacy profile. As Adam just highlighted, SYFOVRE reduced GA lesion growth by more than 40% in patients with nonsubfoveal GA lesions in year 3 compared to projected sham. This is the largest treatment effect shown in GA to date.

11 月，我們在美國眼科學會年會上展示了 GALE 擴展研究的數據，該研究是在 SYFOVRE 連續治療 3 年後進行的。這些數據繼續顯示，隨著時間的推移，每月和每隔一個月 SYFOVRE 給藥的效果不斷增強，這是 SYFOVRE 功效概況的重要特徵。正如 Adam 剛剛強調的那樣，與預期的假手術相比，在第 3 年，SYFOVRE 將非中心凹下 GA 病變患者的 GA 病變生長減少了 40% 以上。這是迄今為止 GA 中顯示的最大治療效果。

2024 has already been a busy year so far in terms of medical meetings. Most recently, we were at the Macula Society, where we had a significant presence with three oral data presentations, including our GALE 36-month data; a matching-adjusted indirect comparison, or MAIC, analysis using our 24-month data; and post hoc microperimetry analysis demonstrating preservation of function in the retina following treatment with SYFOVRE.

就醫學會議而言，2024 年迄今已經是忙碌的一年。最近，我們在黃斑協會 (Macula Society) 上進行了三次口頭資料演示，其中包括我們的 GALE 36 個月資料；使用我們的 24 個月數據進行配對調整間接比較 (MAIC) 分析；事後微視野檢查分析證明 SYFOVRE 治療後視網膜功能得以保留。

Turning to EMPAVELI. We, along with our partner, Sobi, presented post hoc long-term efficacy and safety data on EMPAVELI at ASH Annual Meeting in December. These data showed that treatment with EMPAVELI can help PNH patients achieve rapid and sustained control of their disease over the long term. Furthermore, it is impressive that the majority of patients remain transfusion-free for up to 3 years, alleviating a significant and common disease burden for many patients living with PNH.

轉向恩帕韋利。我們與我們的合作夥伴 Sobi 在 12 月的 ASH 年會上展示了 EMPAVELI 的事後長期療效和安全性數據。這些數據表明，EMPAVELI 治療可以幫助 PNH 患者長期快速、持續地控制其疾病。此外，令人印象深刻的是，大多數患者在長達 3 年內保持不輸血，這減輕了許多 PNH 患者的重大且常見的疾病負擔。

Additionally, at Kidney Week, we had the opportunity to present new data from our Phase II NOBLE study, investigating pegcetacoplan for the treatment of post-transplant recurrence of C3G and IC-MPGN. C3G and IC-MPGN are diseases in which patients have a 50% chance of progressing to end-stage renal disease or kidney transplantation over the course of 5 to 10 years. Between these two indications, there are approximately 5,000 potential patients in the U.S. and up to 8,000 in Europe with no approved treatments available.

此外，在腎臟週上，我們有機會展示 II 期 NOBLE 研究的新數據，該研究調查了 pegcetacoplan 治療 C3G 和 IC-MPGN 移植後復發的效果。 C3G 和 IC-MPGN 是患者在 5 至 10 年內有 50% 的機會進展為末期腎病變或進行腎臟移植的疾病。在這兩種適應症之間，美國約有 5,000 名潛在患者，歐洲有多達 8,000 名患者沒有獲得批准的治療方法。

This year, we are looking forward to the top line data from our Phase III VALIANT study, which we expect mid-year. VALIANT enrolled 124 patients, split 50-50 between treatment and placebo, aged 12 and up, with C3G or primary IC-MPGN. It is the only study to include both native kidney patients and patients who have recurrent disease after receiving a kidney transplant.

今年，我們期待 III 期 VALIANT 研究的頂線數據，預計將在年中公佈。 VALIANT 招募了 124 名患有 C3G 或原發性 IC-MPGN 的患者，其中治療組和安慰劑組各佔 50-50 名，年齡在 12 歲及以上。這是唯一一項既包括天然腎臟病患者又包括接受腎臟移植後疾病復發的患者的研究。

Study participants were randomized to receive pegcetacoplan or placebo twice weekly for 26 weeks. Following this 26-week randomized controlled period, patients will proceed to a 26-week open-label phase in which all patients receive pegcetacoplan. The primary endpoint of the study is the reduction from baseline in urine protein to creatinine ratio, or UPCR, as compared to placebo at week 26.

研究參與者被隨機分配接受 pegcetacoplan 或安慰劑，每週兩次，持續 26 週。在這 26 週隨機對照期之後，患者將進入為期 26 週的開放標籤階段，所有患者均接受 pegcetacoplan 治療。研究的主要終點是第 26 週時與安慰劑相比，尿蛋白與肌酸酐比 (UPCR) 較基線降低。

I'd like to shift gears and comment on the CASCADE Phase III study evaluating the efficacy and safety of pegcetacoplan in patients with cold agglutinin disease, or CAD. As Sobi previously disclosed, the decision was made to end the study due to decreased medical need in the CAD space and a limited number of patients eligible for the study.

我想換個主題，對 CASCADE III 期研究發表評論，該研究評估了 pegcetacoplan 對冷凝集素病 (CAD) 患者的療效和安全性。正如 Sobi 先前所揭露的那樣，由於 CAD 領域的醫療需求減少以及符合該研究資格的患者數量有限，因此決定結束研究。

This is not due to any safety concerns. And the efficacy has not been evaluated due to the study being mapped. I'd like to express our gratitude to the CAD community for their support and collaboration. Sobi is working with study investigators to manage the next steps for those enrolled in the study with their welfare as the priority.

這並不是出於任何安全問題。由於研究正在繪製，因此尚未評估療效。我謹對 CAD 社群的支持和協作表示感謝。 Sobi 正在與研究人員合作，以他們的福利為優先考慮，為參與研究的人管理下一步。

Now I will turn the call over to Tim for a review of the financials. Tim?

現在我將把電話轉給蒂姆，以審查財務狀況。提姆？

Thank you, Caroline. I will provide a brief overview of our financials, and you can find additional details in the press release that we issued earlier this morning.

謝謝你，卡洛琳。我將簡要概述我們的財務狀況，您可以在我們今天早上發布的新聞稿中找到更多詳細資訊。

Total revenue for the fourth quarter and full year 2023 was $146 million and $397 million, respectively. Quarterly revenue consisted of $114 million in SYFOVRE and $24 million in EMPAVELI U.S. net product revenue and $8 million in additional licensing and other revenue associated with the Sobi collaboration. Full year revenue consists of $275 million in SYFOVRE and $91 million in EMPAVELI U.S. net product revenue and $30 million in additional licensing and other revenue associated with the Sobi collaboration.

2023 年第四季和全年的總收入分別為 1.46 億美元和 3.97 億美元。季度收入包括 1.14 億美元的 SYFOVRE 和 2,400 萬美元的 EMPAVELI 美國淨產品收入，以及 800 萬美元的額外許可和與 Sobi 合作相關的其他收入。全年收入包括 2.75 億美元的 SYFOVRE 和 9,100 萬美元的 EMPAVELI 美國淨產品收入，以及 3,000 萬美元的額外許可和與 Sobi 合作相關的其他收入。

Turning to the rest of the P&L. For the fourth quarter and full year, cost of sales was $20 million and $58.5 million, respectively. R&D expenses were $69 million and $354 million, respectively. G&A expenses were $142 million and $501 million, respectively. And we reported a net loss of $89 million and $529 million, respectively.

轉向損益表的其餘部分。第四季和全年的銷售成本分別為 2,000 萬美元和 5,850 萬美元。研發費用分別為 6,900 萬美元和 3.54 億美元。一般管理費用分別為 1.42 億美元和 5.01 億美元。我們報告的淨虧損分別為 8,900 萬美元和 5.29 億美元。

I'd like to point out a few items in our financial statements that will help in evaluating our business. First, we recorded accounts receivable of $206 million at year-end, which is primarily associated with payment terms that we provide to the SYFOVRE distributors. The accounts receivable line item has increased along with the increasing SYFOVRE sales and is in line with typical payment terms.

我想指出我們財務報表中的一些項目將有助於評估我們的業務。首先，我們在年底記錄了 2.06 億美元的應收帳款，這主要與我們向 SYFOVRE 經銷商提供的付款條件有關。應收帳款項目隨著 SYFOVRE 銷售額的增加而增加，並且符合典型的付款條件。

Second, as we shared previously, we are now categorizing the majority of medical affairs and certain other costs in G&A instead of in R&D. This represents an approximately $22 million shift from R&D to G&A in the fourth quarter and $41 million in the second half of 2023. No reclassifications were necessary for prior periods. However, it is important to note this shift when reviewing trends in our operating expenses.

其次，正如我們之前分享的那樣，我們現在將大部分醫療事務和某些其他成本歸類為一般管理費用，而不是研發費用。這意味著第四季大約有 2,200 萬美元從研發轉移到一般管理費用，2023 年下半年則有 4,100 萬美元。前期無需重新分類。然而，在審查我們的營運支出趨勢時，重要的是要注意這種轉變。

And finally, our operating expenses do not yet reflect the ongoing efficiencies that we expect from our restructuring last August due to severance and winding down of certain projects. As I said last quarter, we expect to realize these efficiencies beginning in 2024. And while I'm not going to get into detailed numbers, what I will say is that we expect our total operating expenses in 2024 to be less than our total expenses in 2023.

最後，由於某些項目的遣散和結束，我們的營運費用尚未反映我們去年八月重組所預期的持續效率。正如我上季度所說，我們預計從 2024 年開始實現這些效率。雖然我不會透露詳細數字，但我要說的是，我們預計 2024 年的總營運費用將低於我們的總費用2023年。

Turning to our balance sheet. As of December 31, 2023, we had $351 million in cash and cash equivalents. We continuously evaluate ways in which to further strengthen our financial position. And with that in mind, today, we announced that we entered into agreements to unwind approximately 80% of the capped call associated with the $425 million in convertible notes that we hold in treasury.

轉向我們的資產負債表。截至 2023 年 12 月 31 日，我們擁有 3.51 億美元的現金及現金等價物。我們不斷評估進一步加強我們財務狀況的方法。考慮到這一點，今天，我們宣布簽訂協議，解除與我們持有的 4.25 億美元可轉換票據相關的約 80% 的上限贖回權。

We expect total aggregate net cash proceeds to be up to $125 million, including approximately $100 million following this transaction and up to $25 million in additional net cash proceeds if we unwind the remaining capped call. The underlying transactions will be settled based on a 7-day averaging period beginning on, and including, February 27, 2024. As of December 31, 2023, the aggregate principal balance of the remaining convertible notes, net of unamortized issuance costs, was $93 million.

我們預計淨現金收益總額將高達 1.25 億美元，其中包括本次交易後的約 1 億美元，以及如果我們解除剩餘的上限看漲期權，則可獲得最多 2500 萬美元的額外淨現金收益。基礎交易將根據2024年2月27日（含）開始的7天平均期進行結算。截至2023年12月31日，剩餘可轉換票據的本金總額（扣除未攤銷發行成本）為93美元百萬。

We now believe that our cash and cash equivalents, combined with the cash generated from the capped call unwind and from sales of SYFOVRE and EMPAVELI, will be sufficient to fund our projected operating expenses and capital expenditures for the foreseeable future. That said, we will continue to evaluate opportunities to further optimize our balance sheet and maintain an appropriate cash balance at all times. We have multiple levers that are available to us. And as always, we will be incredibly thoughtful and opportunistic in any decision we make.

我們現在相信，我們的現金和現金等價物，加上上限看漲期權解除以及出售 SYFOVRE 和 EMPAVELI 所產生的現金，將足以為我們在可預見的未來預計的運營費用和資本支出提供資金。也就是說，我們將繼續評估進一步優化資產負債表並始終保持適當現金餘額的機會。我們有多種可用的槓桿。一如既往，我們在做出任何決定時都將深思熟慮並投機取巧。

I will now hand the call back over to Cedric for closing remarks. Cedric?

我現在將把電話轉回給塞德里克進行結束語。塞德里克？

Thanks, Tim. This was a strong finish to the year. We are building on our success and learnings, and the evidence of our ongoing strength continues to be seen in the numbers and feedback we are seeing. We are headed into the year with renewed energy and a huge focus in our goal of putting patients first and elevating the standard of care in all disease areas in which we work.

謝謝，蒂姆。這為這一年畫上了圓滿的句點。我們正在以我們的成功和經驗教訓為基礎，從我們看到的數字和回饋中繼續看到我們持續實力的證據。我們將以新的活力迎接新的一年，並高度重視將患者放在第一位並提高我們工作的所有疾病領域的護理標準的目標。

With this, we are determined to execute on our four key priorities: continuing to expand patient access to SYFOVRE in the U.S.; while also working to bring the therapy worldwide; maximizing EMPAVELI in PNH and then expanding in this new indication in C3G and IC-MPGN; and finally, progressing our early pipeline, including the siRNA program and our collaboration with Beam.

因此，我們決心執行我們的四個關鍵優先事項：繼續擴大美國患者使用 SYFOVRE 的機會；同時也致力於將這種療法推廣到全世界；在 PNH 中最大化 EMPAVELI，然後在 C3G 和 IC-MPGN 中擴展此新適應症；最後，推進我們的早期管道，包括 siRNA 計畫以及我們與 Beam 的合作。

As always, we are looking forward to sharing updates as they become available and continuing our efforts towards becoming the global leader in complement medicine.

一如既往，我們期待分享最新消息，並繼續努力成為補充醫學的全球領導者。

Let us now open the call for questions. Operator?

現在讓我們開始提問。操作員？

(Operator Instructions) Our first question comes from Jon Miller with Evercore.

（操作員說明）我們的第一個問題來自 Evercore 的 Jon Miller。

Congrats again on a great Q4 and a great reacceleration of the launch. I would love to start on the EU reexamination. Cedric, you mentioned that you're getting a lot of enthusiasm from patient groups, from docs in the EU. I would love to get a sense from you for how much impact that doc enthusiasm will have on the EU reexamination and maybe why that wasn't helpful in the first round. What's changed now that wasn't the truth in the first examination?

再次恭喜第四季的出色表現和發布的再次加速。我很想開始歐盟的重新審查。塞德里克，你提到你從歐盟的病人團體和醫生那裡得到了很大的熱情。我很想從您那裡了解這種文件熱情將對歐盟重新審查產生多大影響，以及為什麼這在第一輪中沒有幫助。現在有什麼變化，第一次檢查就不是事實了？

And then secondly, on the commercial launch, if -- even accounting for seasonality, is it fair to expect that Q1 will still be growing robustly relative to Q4? Do you expect that March orders will be making up for Medicare recertification delays in January and February?

其次，在商業發布方面，即使考慮到季節性，是否可以公平地預期第一季相對於第四季仍將強勁成長？您是否預計 3 月的訂單將彌補 1 月和 2 月的醫療保險重新認證延遲？

Thank you so much, Jon. So first of all, as it relates to the European Union. So these are -- these letters are letters that are not sent to us. They are sent to -- independently from us to the review organization and then we receive them via that route. So these are important letters of support. I think they highlight the unmet medical need. They highlight the support that physicians have for this product and their desire to make it available to their patients in Europe.

非常感謝你，喬恩。首先，因為它與歐盟有關。所以這些信不是寄給我們的。它們被獨立於我們發送到審核組織，然後我們透過該路徑接收它們。所以這些都是重要的支持信。我認為它們強調了未滿足的醫療需求。他們強調了醫生對該產品的支持以及他們希望將其提供給歐洲患者的願望。

Will it have an impact? That is really impossible to tell for us. As we've always mentioned, this will be an uphill battle. It is rare for these appeals to be successful. But of course, having the support from the patients and the physicians is important. Then as it relates to the commercial question, I will hand that over to Adam.

會有影響嗎？這對我們來說實在是無從說起。正如我們一直提到的，這將是一場艱苦的戰鬥。這些呼籲很少能成功。但當然，獲得患者和醫生的支持也很重要。然後涉及商業問題，我會把它交給亞當。

Yes. Jon, it's Adam. So yes, we did see seasonality impact January and the start of February. So that -- the vast majority of that was due to recertifications. And we also had a few weather delays. So interestingly, right, we did some homework. And the seasonality is always consistent. And we saw it with -- in our homework with some of the anti-VEGF products over the years.

是的。喬恩，是亞當。所以，是的，我們確實看到了一月和二月初的季節性影響。因此，其中絕大多數是由於重新認證造成的。我們也遇到了一些天氣延誤。有趣的是，我們做了一些功課。而且季節性總是一致的。多年來，我們在一些抗 VEGF 產品的作業中看到了這一點。

For example, I mean, we believe that EYLEA is not seeing growth above 5% in Q1 versus Q4 over approximately the last 10 years with several years resulting in a quarter-on-quarter decline in Q1, tends to be due to recertification seasonality and weather, et cetera, other demands.

例如，我的意思是，我們認為，在過去10 年左右的時間裡，EYLEA 第一季與第四季相比的成長並未超過5%，其中幾年導致第一季環比下降，這往往是由於重新認證的季節性和天氣等其他要求。

We have seen 2 of our biggest months since launch in January and February. And your question was do you expect to see that continue in March? We think we're through all of the recertifications. Hopefully, the weather stays friendly to us. So we continue to expect to see solid numbers in March as we move forward.

自推出以來，一月和二月是我們最大的兩個月。你的問題是你預計這種情況會在三月繼續下去嗎？我們認為我們已經完成了所有重新認證。希望天氣對我們保持友好。因此，隨著我們的前進，我們繼續期望在三月看到可靠的數字。

Makes sense. And maybe one for Tim, or I'll get back in the queue (inaudible)

說得通。也許給蒂姆一個，或者我會回到隊列中（聽不清楚）

Go ahead, Jon. Why don't you ask it quickly? I think that's easier.

繼續吧，喬恩。為什麼不快點問呢？我認為這更容易。

I was just going to ask, Tim, about the runway now through the foreseeable future. I remember at JPMorgan, you were saying that it was plausible you could reach profitability and be funded through the foreseeable future but that you might not want to do that. I would just want to get a sense for how that's changed since JPMorgan and whether you're really actively looking for ways to bolster cash positioning, give yourself a little bit more flexibility or if you think you've done that with these capped calls.

提姆，我只是想問一下現在和可預見的未來的跑道情況。我記得在摩根大通，您曾說過，您有可能實現盈利並在可預見的未來獲得融資，但您可能不想這樣做。我只是想了解自摩根大通以來情況發生了怎樣的變化，以及您是否真的在積極尋找加強現金頭寸的方法，給自己更多的靈活性，或者您是否認為自己已經通過這些上限看漲期權做到了這一點。

Well, so thanks, Jon. So look, the good news is with the capped call with $120 million to $125 million of essentially non-dilutive capital in addition to the $351 million we reported at year-end, that puts us in a great financial position. And as we mentioned, in our scenarios that we project that, that should get us to -- through without having to raise capital necessarily. I mean, it could be technically done.

嗯，謝謝，喬恩。因此，好消息是，除了我們年底報告的 3.51 億美元之外，還有 1.2 億至 1.25 億美元的基本非稀釋性資本上限，這使我們處於良好的財務狀況。正如我們所提到的，在我們預測的場景​​中，這應該能讓我們在不必籌集資金的情況下完成任務。我的意思是，這在技術上是可以做到的。

But we also have certain things like our SFJ liability, which -- that's $200 million in cash out the door over the next 2 years. That could put us in a position where we don't really have an ideal cash balance. So the good news is we're in a pretty strong position, and we have a lot of options available to us to opportunistically make sure we have a sufficient cash balance. That could be refinancing SFJ, that could be a number of things. So again, we'll be thoughtful and opportunistic as we always have been. And yes, that pretty much covers it.

但我們也有一些事情，例如我們的 SFJ 負債，也就是未來 2 年內 2 億美元的現金。這可能會讓我們陷入實際上沒有理想現金餘額的情況。因此，好消息是我們處於相當有利的地位，我們有很多選擇可以機會主義地確保我們有足夠的現金餘額。這可能是為 SFJ 再融資，可能有很多事情。因此，我們將一如既往地深思熟慮並抓住機會。是的，這幾乎涵蓋了它。

Our next question comes from Tazeen Ahmad with BofA Securities.

我們的下一個問題來自美國銀行證券公司的 Tazeen Ahmad。

Just a point of clarification, Adam. Are you expecting to see growth in 1Q relative to 4Q on samples? I just want to clarify, you did mention the EYLEA historics and wanted to make sure it's not going to be flat to down. And then secondly, I have a question on 3007. What are you expecting to show for this siRNA program? And what potential indications do you think it has promise in?

只是需要澄清一點，亞當。您是否預計第一季的樣品會比第四季有所成長？我只是想澄清一下，您確實提到了 EYLEA 的歷史，並想確保它不會持平或下降。其次，我有一個關於3007的問題。您希望透過這個siRNA計畫展示什麼？您認為它有哪些潛在的前景？

Tazeen, it's Adam. So yes, I mean, we continue to see growth in February, and we expect to continue to see growth in March moving forward. As I said, January and February were 2 of our biggest months since launch. You've also asked about samples. So we continue to provide samples to our U.S. physicians. And we expect to continue to do that, especially as we're still in what I would call the early phases of this launch.

塔津，是亞當。所以，是的，我的意思是，我們在 2 月繼續看到成長，我們預計在 3 月也將繼續看到成長。正如我所說，一月和二月是我們自推出以來最重要的兩個月。您也詢問了樣品。因此，我們繼續向我們的美國醫生提供樣本。我們希望繼續這樣做，特別是因為我們仍處於我所說的此次發布的早期階段。

Interestingly, we didn't see sampling increase in the first quarter, which I'll be honest, I thought it probably would as we were going through the recertifications. But sampling will continue to be there as we move forward. So hopefully, that answers your first question. And I'll hand over to Cedric.

有趣的是，我們沒有看到第一季的抽樣增加，老實說，我認為在我們進行重新認證時可能會增加。但隨著我們的前進，採樣將繼續存在。希望這能回答您的第一個問題。我將把工作交給塞德里克。

Thank you, Adam. So Tazeen, on 3007, so this is in the escalation phase in healthy subjects. It is the first of several things that are coming out of our -- out of the preclinical realm now, things that we're very excited about and we'll talk about more in the years to come as well.

謝謝你，亞當。 Tazeen，關於 3007，所以這在健康受試者中處於升級階段。這是我們現在從臨床前領域出來的幾件事中的第一件事，我們對此感到非常興奮，我們也會在未來幾年討論更多。

So what we're hoping to see there in the healthy volunteer phase is, of course, how much we can knock down C3 and how durable that will be in these subjects. The indications that we are going to pursue, we are for now keeping confidential. But we, of course, have what we believe is a very exciting development plan in store for that product.

因此，我們希望在健康志願者階段看到的當然是我們可以在多大程度上降低 C3 以及它在這些受試者中的持久性。我們將要追蹤的跡象目前處於保密狀態。當然，我們認為該產品有一個非常令人興奮的開發計劃。

Our next question comes from Anupam Rama with JPMorgan.

我們的下一個問題來自摩根大通的 Anupam Rama。

Adam, I wanted to ask you a quick question. What is driving your commentary about the GA population size in the U.S. being closer to 1.5 million versus, I think, what you've previously talked about is about 1 million patients?

亞當，我想問你一個簡單的問題。是什麼推動了您對美國 GA 人口規模接近 150 萬的評論，而我認為您之前談到的大約是 100 萬名患者？

Yes. Thanks, Anupam. So I'll answer, then I'll hand it to Caroline as well if she has any comments. So one thing we found with our interactions with physicians is one of our work prior to the launch was sizing an opportunity that was based on prevalence data but also having discussions prelaunch with physicians about how many patients that they think they have.

是的。謝謝，阿努帕姆。所以我會回答，如果她有任何意見，我也會交給卡洛琳。因此，我們在與醫生的互動中發現的一件事是，我們在發布之前的工作之一是根據患病率數據來確定機會，同時也在發布前與醫生討論他們認為自己有多少患者。

And one thing we found is when you're first-to-market launch, you'll find a lot of patients that weren't categorized as GA having GA because there was no treatments were lost to follow-up in terms of sitting with their optometrists or something like that. So we spent a large amount of effort to drive patients to go and get tested and check their vision at their optometrists. Then if they're diagnosed with GA, move into the clinic of a retina physician or an injecting physician.

我們發現的一件事是，當你首次向市場推出時，你會發現很多沒有被歸類為 GA 的患者患有 GA，因為沒有治療，因此失去了後續治療的機會他們的驗光師或類似的人。因此，我們花費了大量的精力來推動患者去驗光師那裡接受測試並檢查他們的視力。然後，如果他們被診斷患有 GA，請前往視網膜醫生或註射醫生的診所。

So in those interactions, we're starting to find that those patients that potentially were lost to follow-up have now been diagnosed with GA and are moving into the practices. So that's how we believe, based on those interactions, that the number is -- the market is bigger than we had first anticipated. Caroline, do you want to add anything from a doctor perspective?

因此，在這些互動中，我們開始發現那些可能失訪的患者現在已被診斷出患有 GA 並正在開始接受治療。因此，根據這些互動，我們相信這個數字是——市場比我們最初預期的要大。卡洛琳，你想從醫生的角度補充什麼嗎？

Sure. Thank you. I think that the GA story is getting out there not only to retina physicians and other eye care specialists but to patients. And this has really helped to drive it. The other thing is that now that we have a treatment, all of the patients that we've been seeing then have neovascular or wet AMD in one eye, we're looking more closely at their fellow eye and seeing, I think, that there's GA in those patients that have previously just been observed. So the number of patients seems to be greater and continues to be more in my practice.

當然。謝謝。我認為 GA 的故事不僅傳播給視網膜醫生和其他眼科護理專家，也傳播給患者。這確實有助於推動它。另一件事是，現在我們有了一種治療方法，我們所見過的所有患者的一隻眼睛都患有新生血管或濕性AMD，我們正在更仔細地觀察他們的另一隻眼睛，我認為，有之前剛觀察到的患者中存在 GA。因此，在我的實踐中，患者的數量似乎越來越多，而且還會繼續增加。

Our next question comes from Salveen Richter with Goldman Sachs.

我們的下一個問題來自高盛的 Salveen Richter。

This is Elizabeth on for Salveen. Two questions from us on the EU reexamination of the application of SYFOVRE. So first, you noted that you had revised the dossier to ensure key questions are addressed. Could you just speak to what was included in that revision?

這是薩爾文的伊麗莎白。我們就歐盟重新審查 SYFOVRE 的申請提出兩個問題。首先，您指出您已經修改了檔案以確保關鍵問題已解決。您能談談該修訂版中包含的內容嗎？

And then secondly, curious if the new rapporteurs have been identified? And if there's any color you could provide on them with respect to them providing potentially a new perspective compared to the first set of rapporteurs?

其次，好奇新報告員是否已經確定？與第一組報告員相比，您是否可以為他們提供任何顏色，以提供潛在的新視角？

Thank you, Elizabeth. Great to hear you. So on the revision, we don't provide that detail, first. But what's important is to educate, of course, to understand this disease of geographic atrophy and how that works as it relates to the functional endpoints. We have, as you mentioned, two new rapporteurs now. These are going to provide a very fresh view as to what we have presented. And we have new analyses available. We continue to generate data, as you know, in the GALE extension study as well.

謝謝你，伊麗莎白。很高興聽到你的聲音。因此，在修訂版上，我們首先不提供該細節。但當然，重要的是要進行教育，了解這種地理萎縮疾病以及它如何與功能終點相關。正如您所提到的，我們現在有兩位新報告員。這些將為我們所呈現的內容提供一個非常新鮮的視角。我們還有新的分析可用。如您所知，我們也在 GALE 擴展研究中繼續產生數據。

So look, we -- as we've always said, we believe that we have strong evidence, of course, not in a prespecified prospective trial but based on what we gathered throughout our very large dataset. And that is what we will now present to these new rapporteurs with more focus and by making some concessions maybe on the label but with a path forward, we hope.

所以，正如我們一直所說的那樣，我們相信我們擁有強有力的證據，當然，不是在預先指定的前瞻性試驗中，而是基於我們在非常大的數據集中收集到的證據。這就是我們現在將更加關注地向新報告員呈現的內容，並透過在標籤上做出一些讓步，但我們希望有前進的道路。

Our next question comes from Yigal Nochomovitz with Citigroup.

我們的下一個問題來自花旗集團的 Yigal Nochomovitz。

Cedric, I appreciate, as you pointed out, that it's not going to be easy for the CHMP reexamination, it's an uphill battle. You've mentioned the microperimetry data. You've shown us the post hoc BCBA data. There's another metric, which maybe you could talk about. I don't think you've discussed it before, the electroretinogram, the ERG.

Cedric，正如您所指出的，我欣賞 CHMP 的重新審查並不容易，這是一場艱苦的戰鬥。您提到了微視野測量數據。您已向我們展示了事後 BCBA 數據。還有另一個指標，也許你可以討論一下。我認為您之前沒有討論過視網膜電圖、ERG。

It's a very precise measure of electrical activity in the retina. Have you looked at that? Do you have any data there? Is that something that you could potentially include in the future that could support the claim that there is a functional benefit, even though you don't see it in the imaging or in the post hoc BCBA?

這是對視網膜電活動的非常精確的測量。你看過那個嗎？你那裡有數據嗎？即使您在成像或事後 BCBA 中沒有看到它，您將來是否可能會包含這些內容來支持功能性益處的主張？

Thank you so much, Yigal. So ERG, I will hand it over to Caroline to comment on that next. But it's not a type of examination that you could use to look at a functional response in geographic atrophy. Again, there's like a resolution problem with that from what I understand. But Caroline can talk about that more.

非常感謝你，伊格爾。 ERG，接下來我將把它交給 Caroline 來評論。但這並不是一種可以用來觀察地理萎縮的功能反應的檢查。再說一遍，據我了解，這似乎有解決問題。但卡羅琳可以更多地談論這一點。

What I think is important here is that the data that we have on microperimetry is very strong, right? And it's data that again the longer you treat patients, the more you see these benefits increase over time. And that is also reflected in the functional measurements that we have.

我認為這裡重要的是我們擁有的顯微視野測量數據非常可靠，對嗎？數據再次表明，治療患者的時間越長，這些益處就越會隨著時間的推移而增加。這也反映在我們的功能測量上。

So we will put all of that together in that package. We will consider on what we can do prospectively. That will take time, of course, for everybody in the future to continue to study this. But for now, I think we have a strong package with clear evidence that ERG is definitely not something that is part of that equation. Caroline, I don't know if you want to...

因此，我們將把所有這些都放在那個包中。我們將考慮未來可以做什麼。當然，這需要時間，大家以後繼續研究這件事。但就目前而言，我認為我們有一個強有力的方案，有明確的證據表明 ERG 絕對不是這個等式的一部分。卡洛琳，我不知道你願不願意...

Thank you. ERG is something that absolutely is used for clinical studies for inherited retinal diseases. It gives a growth response to function and is less used for something like geographic atrophy. But actually, our microperimetry data gives very similar sort of data to an ERG but in a more directed fashion.

謝謝。 ERG 絕對可用於遺傳性視網膜疾病的臨床研究。它對功能產生生長反應，較少用於地理萎縮等疾病。但實際上，我們的微視野測量數據提供的數據與 ERG 非常相似，但以更直接的方式提供。

I think the story of SYFOVRE is it's looking at the overall picture of what SYFOVRE has to add. And when we present this, it's very meaningful for doctors at meetings. We talk about the imaging parameters, how SYFOVRE reduces growth of GA, which alone in itself is highly meaningful. We talk about the AI parameters. And then we talk about all the functional data that we have, which is microperimetry, time to vision loss and other parameters that we've given at the clinical meetings.

我認為 SYFOVRE 的故事在於著眼於 SYFOVRE 必須添加的內容的整體情況。當我們在會議上展示這一點時，這對醫生來說非常有意義。我們談論成像參數，SYFOVRE如何減少GA的生長，這本身就非常有意義。我們談論AI參數。然後我們討論我們擁有的所有功能數據，即顯微視野檢查、視力喪失時間以及我們在臨床會議上給出的其他參數。

So I think that no one else has the amount of the robust microperimetry data that we have in such a large patient group. And it really speaks to physicians. And it's really just presenting the entire SYFOVRE story to the EMA and really educating the EMA on the story.

因此，我認為沒有人擁有我們在如此龐大的患者群體中擁有的可靠的微視野測量數據。這確實對醫生有幫助。它實際上只是向 EMA 展示整個 SYFOVRE 故事，並真正對 EMA 進行有關該故事的教育。

Okay. And then just one for Adam. You mentioned, Adam, the 90% share. Is that new starts? Or is that existing? Or is that everybody? Can you just split that out if possible?

好的。然後只給亞當一張。亞當，你提到了 90% 的份額。這是新的開始嗎？或者說是存在的？還是大家都是這樣？如果可能的話你能把它分開嗎？

Yes, that's -- thanks, Yigal. Yes, that's the total market share. So we're the #1 leading GA drug.

是的，那就是－－謝謝，伊格爾。是的，這就是總市場佔有率。所以我們是排名第一的 GA 藥物。

The next question comes from Steve Seedhouse with Raymond James.

下一個問題來自 Steve Seedhouse 和 Raymond James。

I wanted to ask about a couple of specific parameters as it pertains to the SYFOVRE launch. First, can you comment on patient persistence or discontinuation rates in the real world? Second, just the interval between doses, is it closer to 8 weeks or 6 weeks? What's the sort of average dose interval and then also net price or gross to net adjustment we should be thinking about as well?

我想問一些與 SYFOVRE 啟動相關的特定參數。首先，您能評論一下現實世界中患者的堅持率或停藥率嗎？第二，就服藥間隔而言，是接近8週還是6週？我們還應該考慮什麼樣的平均劑量間隔以及淨價格或總淨調整？

Thank you, Steve. Maybe, Caroline, you can briefly comment on what we've seen with discontinuation. And then Adam will talk about the pathology and the gross to net.

謝謝你，史蒂夫。卡羅琳，也許您可以簡要地評論一下我們所看到的停產。然後亞當將談論病理學和總的網絡。

Overall, from what I hear from physicians and what I've seen is that patients are highly motivated and actually, in some ways, are very comforted to know the exact number of injections that they might be receiving over a year and the following years. With anti-VEGFs, it's -- we often use treat-and-extend, so it can be a little more variable.

總體而言，從醫生那裡聽到的以及我所看到的情況是，患者的積極性很高，實際上，在某些方面，他們很高興知道他們一年內和接下來的幾年可能接受的確切注射次數。對於抗 VEGF 藥物，我們經常使用治療和延長治療，因此它的變化可能會更大一些。

But I think that the majority of physicians in the real world are dosing every 6 to 8 weeks with patients. And patients seem to be returning for their follow-ups. There was one group that looked at this, a large retina group, that found very high levels of (inaudible) patients.

但我認為現實世界中的大多數醫生每 6 至 8 週會對患者服藥一次。患者似乎正在返回進行隨訪。有一個小組正在研究這個問題，一個大型視網膜小組，發現了非常多的（聽不清楚）患者。

Yes. Just to build on that, too, Steve, it's Adam. We're still in the -- we just got past the first year. So it's still early in the launch. And we found that the vast majority of patients are really committed to receiving their treatment as Caroline just described beautifully.

是的。史蒂夫，也是以此為基礎，亞當。我們仍然處於——我們剛剛度過了第一年。所以現在還處於發布的早期階段。我們發現絕大多數患者確實致力於接受治療，正如卡羅琳剛剛描述的那樣。

So I think to the second part of your question, we are seeing the vast majority being every 6 to 8 weeks. It tends to skew closer to 6 weeks with that flexibility of every-other-month dosing. And that range allows physicians to move appointments around, particularly when weather impacts, et cetera, et cetera. So we truly believe that the every-other-month dosing, as we call it, 6 to 8 weeks, is a real, real competitive advantage for us and that the vast majority of patients are choosing that frequency. I'll hand the gross to net question over to Tim.

所以我認為對於你問題的第二部分，我們看到絕大多數是每 6 到 8 週一次。由於每隔一個月給藥一次的靈活性，它往往會偏向接近 6 週。這個範圍允許醫生改變預約時間，特別是在天氣影響等情況下。因此，我們堅信，每隔一個月給藥一次（我們稱之為 6 至 8 週）對我們來說是一個真正的競爭優勢，並且絕大多數患者都選擇這種頻率。我會將粗略的網路問題交給提姆。

Yes. Thanks, Adam. So in terms of gross to net, we don't guide on that. I think our previous guidance was something between 10% and 20%. But in our 10-K, we do have some pretty good disclosure over the past year in terms of the blended disclosure, both SYFOVRE and EMPAVELI. But it has chargebacks, discounts and fees laid out, government and other rebates and returns. And what you can see there is the provision related to sales in the current year that gets you kind of to the midpoint of that. That's on a historical basis. We don't say what that is going forward, but yes, sort of towards the middle.

是的。謝謝，亞當。因此，就總淨值而言，我們不提供指導。我認為我們之前的指導是 10% 到 20% 之間。但在我們的 10-K 中，我們在過去一年中確實在混合披露方面進行了一些相當不錯的披露，包括 SYFOVRE 和 EMPAVELI。但它有退款、折扣和費用、政府和其他回扣和回報。您可以看到與當年銷售相關的規定，可以讓您達到其中的中點。這是有歷史根據的。我們沒有透露未來會發生什麼，但是的，有點接近中間。

I just have one clarification because Adam mentioned, I think, sampling. You didn't see sampling increase in 1Q so far. I'm just curious, is that relative to 4Q or relative to what? Because in 4Q, it was down, I think, relative to -- like it was -- what you just reported, 6,400 relative to 10,000 in the prior quarter. So I'm just curious, what's the reference to -- what's the reference point for that comment?

我只想澄清一點，因為我認為 Adam 提到了抽樣。到目前為止，您還沒有看到第一季的抽樣增加。我只是好奇，這與 4Q 相關還是與什麼相關？因為在第四季度，我認為，相對於您剛剛報告的情況，它下降了 6,400 人，而上一季為 10,000 人。所以我只是好奇，該評論的參考點是什麼？

Yes. I was a little surprised, I'll be honest with you. Our assumption going -- this is the first January and February we've had, right, where recertifications were new to us. So our assumption prior to that was that some physicians would reach for a sample during this process. But I actually think that our sampling rate was relatively flat. It did not increase. It did not increase versus Q4 too dramatically. And I think that's because we were relatively efficient in getting through the reverification process.

是的。我有點驚訝，老實說。我們的假設是——這是我們經歷的第一個一月和二月，對吧，重新認證對我們來說是新鮮事。因此，我們先前的假設是，有些醫生會在過程中取得樣本。但我實際上認為我們的採樣率相對平坦。它沒有增加。與第四季度相比，它並沒有大幅增長。我認為這是因為我們在完成重新驗證過程方面相對有效。

So my assumption on something going up prior to those months turned out to be wrong. So I do expect sampling to continue. I do expect it to be -- continue to be flat quarter-on-quarter. As we drive new accounts to start, they tend to reach for less samples. And with our J-code, it's very easy for these accounts to get reimbursed for SYFOVRE. So hopefully, that answers your question.

因此，我對那幾個月之前發生的事情的假設被證明是錯誤的。所以我確實希望採樣能夠繼續下去。我確實預計季度環比將繼續持平。當我們推動新客戶啟動時，他們往往會獲得更少的樣本。透過我們的 J 代碼，這些帳戶可以輕鬆獲得 SYFOVRE 補償。希望這能回答你的問題。

Yes.

是的。

Our next question comes from Colleen Kusy with Baird.

我們的下一個問題來自科琳·庫西和貝爾德。

Congrats on the progress. A couple of commercial questions from us. What share of the patients on SYFOVRE today are receiving bilateral injections versus one injection or an injection in one eye?

祝賀取得的進展。我們提出了幾個商業問題。目前 SYFOVRE 上接受雙側注射的患者與單眼注射或單眼注射的患者比例是多少？

And then following up on Caroline's comment about patients with wet AMD, are you seeing those patients able to get their SYFOVRE and VEGF injections on the same day? Or are those injections typically being staggered?

然後跟進 Caroline 對濕性 AMD 患者的評論，您是否看到這些患者能夠在同一天接受 SYFOVRE 和 VEGF 注射？還是這些注射通常是交錯進行的？

Colleen, it's Adam. So yes, we were expecting bilateral treatment to be a core piece of our launch. And then obviously, during the rare episodes of vasculitis last year, we did see that bilateral usage slowed down. We are seeing a return to bilateral usage. We are seeing physicians change their approach in how they administer bilateral.

科琳，是亞當。所以，是的，我們期望雙邊治療成為我們推出的核心部分。顯然，在去年罕見的血管炎發作期間，我們確實看到雙邊使用速度減慢了。我們看到雙邊使用的回歸。我們看到醫生改變了雙側治療的方法。

They'll start potentially with one eye and they'll wait a little bit and see how that progresses and then they'll move to the second eye. So we are seeing bilateral usage increase. I think that's very positive as physicians start to really understand the benefit-risk profile of this drug and be able to have those conversations with patients. Anything, Caroline, you want to add on bilateral?

他們可能會從一隻眼睛開始，等一下，看看進展如何，然後他們會轉向第二隻眼睛。因此，我們看到雙邊使用量增加。我認為這是非常積極的，因為醫生開始真正了解這種藥物的獲益風險概況，並能夠與患者進行這些對話。卡洛琳，您想在雙邊方面補充什麼嗎？

I think it's very common to have patients have treatment with an anti-VEGF in one eye and if they need treatment with different products, including SYFOVRE, in the other eye to do that on the same day. But there's no generalizable formula to how retina doctors work. I will say one thing that retina doctors really like is flexibility. And fortunately, we have that in our label with this very flexible treatment interval between our label. So it can really be tapered to what works for your patient.

我認為，患者的一隻眼睛接受抗 VEGF 治療，而另一隻眼睛需要使用不同的產品（包括 SYFOVRE）治療，以便在同一天進行治療，這是很常見的情況。但視網膜醫生的工作方式並沒有通用的公式。我想說視網膜醫生真正喜歡的一件事是靈活性。幸運的是，我們的標籤中有這一點，標籤之間的治療間隔非常靈活。因此，確實可以根據患者的情況進行調整。

Our next question comes from Phil Nadeau with TD Cowen.

我們的下一個問題來自 Phil Nadeau 和 TD Cowen。

A couple on the U.S. market. First, over the summer, right after the vasculitis events were first found, I think you did a physician survey where you showed about 1/3 of physicians who stopped using SYFOVRE, 1/3 stopped using in new patients but continued patients and then 1/3, there was no change. Do you have a sense of how those numbers stand today? What proportion of physicians are still not using SYFOVRE versus what proportion have returned their use to normal? That's the first question.

美國市場上的一對夫婦。首先，整個夏天，就在首次發現血管炎事件之後，我認為您進行了一項醫生調查，其中顯示大約1/3 的醫生停止使用SYFOVRE，1/3 在新患者中停止使用，但繼續對患者使用，然後 1 /3，沒有變化。您知道這些數字今天的情況嗎？仍未使用 SYFOVRE 的醫師比例是多少，而已恢復正常使用的醫師比例是多少？這是第一個問題。

And then the second question, a follow-up to Yigal's. On the 90% share, what do you attribute that to? Is it the 2-year data that you have versus the 2-year data that IZERVAY has presented? Or is it execution issues? What do you think is enabling the 90% share that you currently have?

然後是第二個問題，是伊格爾問題的後續問題。對於90%的份額，您認為這歸因於什麼？是您擁有的 2 年數據還是 IZERVAY 提供的 2 年數據？還是執行力的問題？您認為是什麼讓您目前擁有 90% 的份額？

Phil, it's Adam. Thanks for the question. So yes, we haven't done any new research since the last wave of the, what I call, 1/3, 1/3, 1/3. One thing we have seen anecdotally is that each of those segments have started to use SYFOVRE again. So the segment that has stopped, we really spent time with those physicians. We were there. We were being incredibly transparent about these rare cases of vasculitis and we waited. And once those physicians were ready, we then stepped back up. And so we've started to see physicians that had stopped restart.

菲爾，是亞當。謝謝你的提問。所以，是的，自從上一波（我稱之為 1/3、1/3、1/3）以來，我們還沒有進行任何新的研究。我們聽說的一件事是，每個細分市場都已經開始再次使用 SYFOVRE。所以在已經停止的部分，我們確實花了時間和那些醫生在一起。我們去過那裡。我們對這些罕見的血管炎病例非常透明，我們等待著。一旦那些醫生準備好了，我們就退後一步。因此，我們開始看到停止復工的醫生。

Same for the segment of new patients only, again we've had a couple of physicians that I know of anecdotally that have said, "No, I've started new patients again based on the benefit-risk profile of the drug." And we continue to see growth in those accounts that did not stop. They continue to see the benefit of this drug. So whilst we don't have -- haven't done that wave of market research again, I do believe we're really impacting those three segments.

僅對於新患者部分而言也是如此，據我所知，我們有幾位醫生曾說過：“不，我根據藥物的獲益風險狀況再次開始接受新患者治療。”我們繼續看到這些帳戶的成長並沒有停止。他們繼續看到這種藥物的好處。因此，雖然我們沒有再次進行那波市場研究，但我確實相信我們確實正在影響這三個細分市場。

Now the second part of your question, the 90%, is -- I think it's down to a lot of things, right, continued strong execution from the team, particularly over the last few months. We've been incredibly transparent with the retina community. And I think we spend a lot of time building trust and confidence. Physicians now, I believe, truly see the benefits of our overall clinical profile. So this is long-term efficacy from GALE, real-world safety and over 200,000 doses since launch.

現在你問題的第二部分，即 90%，是——我認為這取決於很多事情，對吧，團隊持續強大的執行力，特別是在過去幾個月。我們對視網膜社區的透明度非常高。我認為我們花了很多時間來建立信任和信心。我相信，現在醫生們真正看到了我們整體臨床特徵的好處。這是 GALE 的長期功效、現實世界的安全性以及自上市以來超過 200,000 劑的效果。

Dosing flexibility, the vast majority of physicians, as I've said before, are leaning towards 6 to 8 weeks. We have strong payer coverage with our J-code from October 1. I think it's all of those things coming together. But the efficacy profile of this drug, I think, stands up high. And this is a drug you choose for its efficacy, the impact it can have on patients' vision moving forward. So we are laser-focused on communicating our benefit-risk and the benefit of this drug with physicians. And I think that will make a difference. Caroline, anything you want to add?

劑量彈性，正如我之前所說，絕大多數醫生傾向於 6 至 8 週。從 10 月 1 日起，我們的 J 代碼就為付款人提供了強大的覆蓋範圍。我認為這是所有這些事情的結合。但我認為這種藥物的療效很高。您選擇這種藥物是因為它的功效，以及它對患者未來視力的影響。因此，我們專注於與醫生溝通我們的獲益風險和該藥物的益處。我認為這會有所作為。卡洛琳，你還有什麼要補充的嗎？

I think it's like -- just to hone a little more on the efficacy story, the fact that we have the data from GALE with up to 3 years of data now that they really appreciate that this data is so thoughtful and also includes visual function with up to 42% reduction in GA lesion growth. That's something that's amazing. And the fact that every-other-month dosing into GALE in nonsubfoveal patients is so meaningful.

我認為這就像 - 只是為了進一步磨練功效故事，事實上我們擁有來自 GALE 長達 3 年的數據，現在他們真的很欣賞這些數據是如此周到，並且還包括視覺功​​能GA 病變生長減少高達42 %。這是一件令人驚奇的事。事實上，非中心凹下患者每隔一個月服用一次 GALE 是非常有意義的。

So the first thing for physicians is the efficacy story, the experience of the company and then their experience using the product. And that's sort of where doctors are getting that experience now. The initial patients who came in were with physicians who are in our clinical study, which was so large, and now we're reaching all the other physicians in the community.

因此，對醫生來說，首先要考慮的是功效故事、公司的經驗，然後是他們使用產品的經驗。這就是醫生現在獲得這種經驗的地方。最初進來的患者是參與我們臨床研究的醫生，研究規模非常大，現在我們正在聯繫社區中的所有其他醫生。

Our next question comes from Akash Tewari with Jefferies.

我們的下一個問題來自 Jefferies 的 Akash Tewari。

This is Ivy on for Akash. We just have two quick ones on SYFOVRE. So when we spoke to our team heading into (inaudible), you have felt confident that the long-term split between SYFOVRE and IZERVAY could be somewhere around like 70% and 30%. So given competitors have commented on their call that IZERVAY is currently taking 20% market share after 5 months of launch, how do you feel comfortable that you can maintain this 70-30 split in the long term? And then secondly, just quickly, why haven't you guided for SYFOVRE revenue for '24? And do you plan to guide in later quarters?

這是阿卡什的常春藤。我們在 SYFOVRE 上只有兩個快速的。因此，當我們與進入（聽不清楚）的團隊交談時，您確信 SYFOVRE 和 IZERVAY 之間的長期差距可能約為 70% 和 30% 左右。因此，考慮到競爭對手的評論稱，IZERVAY 目前在推出 5 個月後佔據了 20% 的市場份額，您對長期保持 70-30 的比例感到如何？其次，很快，為什麼你們沒有為 24 年 SYFOVRE 的收入提供指導？您打算在接下來的幾季提供指導嗎？

Thank you so much for that question. Adam?

非常感謝你提出這個問題。亞當？

Sure. Ivy, it's Adam. So yes, Astellas has said they have a 20% market share. But as I discussed previously, there are multiple ways you can estimate market share. Our assumption is that Astellas is using total vials shipped for a specific time period, so their last quarter versus our last quarter. What we do is we use real-world ECP injection data, which is a snapshot of the current market where physicians are ordering vials and using vials.

當然。艾薇，是亞當。所以，是的，安斯泰來表示他們擁有 20% 的市佔率。但正如我之前討論的，有多種方法可以估算市場份額。我們的假設是安斯泰來使用的是特定時間內運送的總瓶數，因此他們的上一個季度與我們的上一個季度相對。我們所做的是使用真實世界的 ECP 注射數據，這是當前市場的快照，醫生訂購藥瓶和使用藥瓶。

And we think this is actually a better way of analyzing market share. It actually counts injections rather than looking at vials shipped or revenue. And obviously, there's a total market analysis that we will do. So we're confident that we are the #1 GA drug out there. We also did a time-adjusted analysis of our launch versus the competitor's launch. And if you time-adjust so that you assume they both launch on the same day, ECP or physician demand for SYFOVRE was three times greater than that of IZERVAY in the first 4 months of launch. So that's an incredibly positive metric.

我們認為這實際上是分析市場份額的更好方法。它實際上計算注射次數，而不是查看裝運的小瓶或收入。顯然，我們將進行全面的市場分析。因此，我們有信心成為排名第一的 GA 藥物。我們也對我們的發布與競爭對手的發布進行了時間調整分析。如果你調整時間，假設它們都在同一天推出，那麼在推出的前 4 個月內，ECP 或醫生對 SYFOVRE 的需求是 IZERVAY 的三倍。所以這是一個非常正面的指標。

We also see that the majority of new patient starts continue to be on SYFOVRE. And just another point, right? Keep in mind that this market is much larger than we believed, from 1 million patients to 1.5 million. I think it can accommodate more than one product. But we truly believe that we are the #1 product. And we expect to maintain that leadership over time. So hopefully, that answers your question, Ivy. I think I'll hand it to Tim for the...

我們也發現，大多數新患者開始繼續使用 SYFOVRE。還有一點，對吧？請記住，這個市場比我們想像的要大得多，從 100 萬患者到 150 萬。我認為它可以容納不只一種產品。但我們堅信我們是排名第一的產品。我們希望隨著時間的推移保持這種領先地位。希望這能回答你的問題，艾維。我想我會把它交給蒂姆...

I'll take the guidance question. So obviously, after the past year, we felt we needed a little more time before we could guide effectively. And case in point, we've never been through a first quarter where we had recertifications or the like. So we're just going to take our time and make sure we understand the dynamics over the course of a full year. And we'll get back to you on when we plan to guide.

我將回答指導問題。顯然，在過去的一年之後，我們覺得我們需要更多的時間才能有效地進行指導。舉個例子，我們從來沒有在第一季進行過重新認證或類似的事情。因此，我們將花些時間確保我們了解一整年的動態。我們會在計劃指導時回覆您。

Our next question comes from Ellie Merle with UBS.

我們的下一個問題來自瑞銀集團的埃莉梅爾。

Congrats on all the progress. I just want to follow up on the quarter-over-quarter growth question asked earlier. You guys are seeing January and February as 2 of the strongest months since launch and the sampling rate did not increase. So shouldn't 1Q be higher than 4Q? I guess, how do we balance that with the seasonality commentary? Just want to clarify on that point.

祝賀所有的進步。我只想跟進之前提出的季度環比成長問題。你們認為一月和二月是自推出以來最強勁的兩個月，但取樣率並沒有增加。那麼1Q不應該高於4Q嗎？我想，我們如何平衡它與季節性評論？只是想澄清這一點。

And then just a second question, in terms of compliance and dosing frequency, are you seeing any trends and differences in compliance or dosing frequency at different types of sites such as private equity owned versus academic?

然後是第二個問題，就合規性和給藥頻率而言，您是否看到不同類型的網站（例如私募股權公司與學術機構）在合規性或給藥頻率方面有任何趨勢和差異？

Ellie, it's Adam. So yes, so we've been -- seasonality does impact drugs within this market. As I said, I used the analogs that we found from the anti-VEGFs. We did see recertifications happen a lot in January and week into February and impacted on the weather. We do believe that January and February are likely to be 2 of our largest months.

艾莉，是亞當。所以，是的，我們一直以來——季節性確實會影響這個市場中的藥品。正如我所說，我使用了我們從抗 VEGF 中發現的類似物。我們確實看到一月份和二月份的一周發生了很多重新認證的情況，並對天氣產生了影響。我們確實相信一月和二月可能是我們最大的兩個月。

So we're executing flawlessly and pushing to make Q1 as big as it possibly can by being incredibly thoughtful on how we interact with these physicians. So the team is flawlessly executing. I'm incredibly proud of them. And we're pushing incredibly hard as you would expect us to. We believe we have the #1 GA drug moving forward.

因此，我們正在完美執行，並透過對如何與這些醫生互動進行深思熟慮，努力使第一季盡可能大。所以團隊的執行力堪稱完美。我為他們感到無比驕傲。正如您所期望的那樣，我們正在非常努力地推動。我們相信，排名第一的 GA 藥物正在向前發展。

Compliance, as I said, it's a touch early for compliance. We tend to see the vast majority of patients being 6 to 8 weeks. And they seem to be very comfortable with that. We have not noticed any difference that I'm aware of between compliance at PE-backed practices versus non-PE-backed practices. We have a nice wide range of business rights.

合規性，正如我所說，對於合規性來說，這是一個早期的接觸。我們傾向於看到絕大多數患者的治療時間為 6 至 8 週。他們似乎對此感到非常滿意。據我所知，我們沒有註意到私募股權支持的實踐與非私募股權支持的實踐之間的合規性之間存在任何差異。我們擁有廣泛的商業權利。

So PE-backed practices are about 30% of our business and the rest, the remaining 70%, are independent practices and academic practices. To my knowledge, we haven't seen any differences in terms of compliance from those groups. As I said, we just exited the first year. I think as we get into years 2 and 3 of treatment with this drug, that's when physicians will have to have a conversation with their patients about compliance. But it's too early for them.

因此，私募股權支持的實踐約占我們業務的 30%，其餘的（剩餘的 70%）是獨立實踐和學術實踐。據我所知，我們沒有發現這些群體在合規性方面有任何差異。正如我所說，我們剛結束第一年。我認為當我們進入這種藥物治療的第二年和第三年時，醫生將不得不與患者就依從性進行對話。但對他們來說還為時過早。

Our next question comes from François Brisebois from Oppenheimer.

我們的下一個問題來自奧本海默的 François Brisebois。

This is Dan (inaudible) on for François Brisebois. Related to a question regarding the physician segments from the market research, now with the permanent J-code effective and the GALE extension readout, are you starting to see an impact within that 1/3 segment of physicians who are on the sidelines?

我是 François Brisebois 的丹（聽不清楚）。與市場研究中有關醫生細分市場的問題相關，現在隨著永久 J 代碼有效和 GALE 擴展讀數，您是否開始看到對 1/3 處於觀望狀態的醫生細分市場產生的影響？

Yes, thanks for the question. So yes, obviously, we haven't redone that market research, but we are starting to see an impact from physicians who are on the sideline, the J-code unlocked all of that. We continue -- it's my favorite metric. We continue to see double-digit new accounts sign up to use SYFOVRE every week since launch. That has continued. That tells you that these physicians are no longer on the sidelines that keep starting to -- want to start patients. I think that's an incredibly positive metric for us.

是的，謝謝你的提問。所以，是的，顯然，我們還沒有重新進行市場研究，但我們開始看到旁觀醫生的影響，J 碼解鎖了這一切。我們繼續下去——這是我最喜歡的指標。自 SYFOVRE 推出以來，我們每週都會看到兩位數的新帳戶註冊使用 SYFOVRE。這種情況一直持續著。這告訴你，這些醫生不再袖手旁觀，繼續想要開始治療病人。我認為這對我們來說是一個非常積極的指標。

So yes, whilst we haven't done the research anecdotally, we're hearing that those physicians who are on the sidelines have started to go. We do have some upside opportunity, too, right? So we have about 1,800 sites of care across the U.S. That's about 50% of our potential target list. So there's still an opportunity for growth for us to target that other half of the market. And we have some good plans to go and execute that, which we started in the first quarter and expect to move into the -- for the rest of the year. So hopefully, that answers your question.

所以，是的，雖然我們還沒有進行過有趣的研究，但我們聽說那些持觀望態度的醫生已經開始離開。我們也確實有一些上升的機會，對吧？因此，我們在美國擁有約 1,800 個護理站點，這大約占我們潛在目標清單的 50%。因此，我們仍然有機會瞄準另一半市場。我們有一些好的計劃來執行，我們從第一季開始實施，並預計在今年剩餘時間繼續實施。希望這能回答你的問題。

Our next question comes from Joseph Stringer with Needham.

我們的下一個問題來自約瑟夫·斯金格和李約瑟。

Just a quick one on potential switching dynamics, just curious if you could provide any metrics or data or even qualitative feedback that you're hearing so far on any switching dynamics between SYFOVRE and IZERVAY?

只是簡單介紹一下潛在的切換動態，只是好奇您是否可以提供迄今為止您聽到的有關 SYFOVRE 和 IZERVAY 之間任何切換動態的任何指標或數據，甚至定性反饋？

I think -- yes, thank you so much, really great to hear you. Look, that is a place where I think we are very well positioned as well. At the end of the day, where the metrics will stand out is the comparator between on efficacy as well as on safety, right, so -- and on the efficacy, quite frankly, the difference is quite stark, right? I mean, as mentioned before, on extrafoveal patients, up to 42% slowdown versus what has so far been reported as 14%, even though we don't know what it is exactly in the second year for our competing product.

我想——是的，非常感謝你，很高興聽到你的聲音。看，我認為我們在這方面也處於非常有利的位置。歸根結底，最引人注目的指標是功效和安全性之間的比較，對吧，所以——坦白說，在功效方面，差異非常明顯，對吧？我的意思是，如前所述，對於中心凹外患者，速度下降高達42%，而迄今為止報道的速度為14%，儘管我們不知道我們的競爭產品在第二年的具體情況是怎樣的。

And then maybe briefly on the safety, right? That risk can exist on the first injection of developing vasculitis, which is very rare, is something that we now firmly believe is caused by a pre-existing allergy towards polyethylene glycol, something that is shared between the products. And we have every reason to expect that both products in the future will have that risk, rare risk associated with it that will then have to be discussed with the patient when the treatment is planned. Adam, do you want to add something to that?

然後也許簡單地談談安全性，對吧？這種風險可能存在於第一次注射時出現的血管炎，這種情況非常罕見，我們現在堅信是由預先存在的對聚乙二醇過敏引起的，而這種過敏是產品之間共有的。我們有充分的理由預計，這兩種產品將來都會存在這種風險，與之相關的罕見風險，然後在計劃治療時必須與患者進行討論。亞當，你想添加一些東西嗎？

Yes. Joey, it's Adam. So yes, no surprise, right? During the rare cases of vasculitis last year, we did see some accounts switch. They switched primarily for safety. And we know where those accounts are. Now again, anecdotally, I have actually seen some physicians switch patients back. So I have seen and heard from my field teams that physicians switched from SYFOVRE to the competitor and then some of those patients were switched back.

是的。喬伊，是亞當。所以是的，不足為奇，對吧？在去年罕見的血管炎病例中，我們確實看到一些帳戶發生了變化。他們更換主要是為了安全。我們知道這些帳戶在哪裡。有趣的是，我實際上已經看到一些醫生將病人換回來。因此，我從我的現場團隊看到並聽到，醫生從 SYFOVRE 轉向競爭對手，然後其中一些患者又轉回來。

So switching does happen in this market. It definitely happened during the rare cases of vasculitis. But we believe in the profile, the efficacy and the safety and the benefit-risk of this drug. And we truly will be focused on making sure we communicate that profile to every physician in this market.

所以這個市場確實會轉變。這肯定發生在罕見的血管炎病例中。但我們相信這種藥物的概況、功效、安全性和獲益風險。我們確實將專注於確保將這一概況傳達給這個市場上的每位醫生。

Our next question comes from Derek Archila with Wells Fargo.

我們的下一個問題來自富國銀行的德里克·阿奇拉。

Just two on EMPAVELI. I guess, first, have you seen any impact from the launch of iptacopan in PNH? And I guess, how much upside do you think there is in the first line setting from the 10% you discussed today? And then just overall kind of commercial strategy for EMPAVELI and C3G and MPGN.

EMPAVELI 上只有兩個。我想，首先，您是否看到 iptacopan 在 PNH 推出的影響？我想，您認為第一線設定比您今天討論的 10% 有多少上升空間？然後是 EMPAVELI、C3G 和 MPGN 的整體商業策略。

Thank you so much, Derek, really great to hear you. Look, in PNH, we now have a very competitive situation, of course. And our expectations should be commensurate with that competitive situation. So while we don't guide, certainly, there will be pressure from this oral product. I think in general though that it is a great thing that there are now two products available to address the problem of extravascular hemolysis in these patients.

非常感謝你，德里克，很高興聽到你的聲音。當然，在 PNH，我們現在的競爭非常激烈。我們的期望應該與競爭情勢相適應。因此，雖然我們不進行指導，但這種口服產品肯定會帶來壓力。我認為總的來說，現在有兩種產品可以解決這些患者的血管外溶血問題，這是一件好事。

If we go back a couple of years, as you may recall, because you're already covering us, there was a notion that this was something affecting 7% of patients. That is not true. This is something that affects the overwhelming majority of these patients. And a big segment of patients can and will benefit from this.

如果我們回到幾年前，您可能還記得，因為您已經在報道我們，所以有人認為這會影響 7% 的患者。那不是真的。這影響著絕大多數患者。很大一部分患者可以而且將會從中受益。

And in that sense, raising the awareness around that, having Novartis by our side, will be helpful. As we've mentioned before, we're incredibly excited about what we can do in the kidney to the readout of the VALIANT trial this summer and what we will be able to do for the 5,000 patients with C3G and IC-MPGN that are in need. Adam, do you want to add something to that?

從這個意義上說，提高人們對此的認識，有諾華在我們身邊，將會有所幫助。正如我們之前提到的，我們對於今年夏天 VALIANT 試驗的結果，以及我們將為 5,000 名患有 C3G 和 IC-MPGN 的患者能夠做的事情感到非常興奮。需要。亞當，你想添加一些東西嗎？

Yes. You said it really well, Cedric, but just to add a few extra bits, right? So Derek, a twice-a-day oral will be appealing to PNH patients for sure. We should expect that. In fact, we've seen one or two patients switch from EMPAVELI to the twice-a-day oral, as you would expect. The vast majority of our patients are really committed to EMPAVELI. They see the benefits of the efficacy. They see the benefits of the safety profile. And with the auto injector, the EMPAVELI injector, we're really improving that convenience aspect of the drug. So we're going to be strongly competitive in the market. But an oral will have an impact.

是的。你說得很好，塞德里克，但只是添加一些額外的內容，對吧？因此，Derek，每天兩次口服藥物肯定會對 PNH 患者有吸引力。我們應該期待這一點。事實上，正如您所期望的那樣，我們已經看到一兩個患者從 EMPAVELI 改為每天兩次口服。我們的絕大多數患者都真正致力於 EMPAVELI。他們看到了功效的好處。他們看到了安全設定檔的好處。透過自動注射器 EMPAVELI 注射器，我們真正改善了藥物的便利性。因此，我們將在市場上具有很強的競爭力。但口頭上會有影響。

You asked about the first line segment, right? So I do expect -- we have 10%. I do expect that the oral will be used nicely within that first line segment. But I've been around the block a little bit. And every time there's a new entrant into the market and a conversation is had between a physician and a patient, it's an opportunity for EMPAVELI. So a patient has a conversation with a physician about starting on an oral or switching from ULTOMIRIS or SOLIRIS to an oral, that is an opportunity for us to make sure that EMPAVELI was in that consideration set. So switching opportunities become particularly important for us during this phase.

你問的是第一條線段，對吧？所以我確實預計——我們有 10%。我確實希望口語能在第一行段中得到很好的運用。但我已經在街區附近轉了一圈了。每當市場有新進者、醫生和患者之間進行對話時，這對 EMPAVELI 來說都是一個機會。因此，患者與醫生討論開始口服藥物或從 ULTOMIRIS 或 SOLIRIS 改為口服藥物，這對我們來說是一個機會，以確保 EMPAVELI 處於該考慮範圍內。所以這個階段轉換機會對我們來說就顯得特別重要。

And just an execution perspective on nephrology, so we obviously have a great medical affairs EMPAVELI team. We're starting to send that medical affairs team to the nephrology conferences. And they will be the face of the nephrology discussions that we have based on these conferences, et cetera, until we see some data mid-2024.

從腎臟病學的執行角度來看，我們顯然擁有一支出色的醫療事務 EMPAVELI 團隊。我們開始派遣醫療事務團隊參加腎臟科會議。他們將成為我們基於這些會議等進行的腎臟病學討論的代表，直到我們在 2024 年中期看到一些數據。

Our next question comes from Douglas Tsao with H.C. Wainwright.

我們的下一個問題來自 Douglas Tsao 和 H.C.溫賴特。

Just maybe as a follow-up on bilateral treatments, presumably, there was a slowdown during the vasculitis days. So should we think that relative to your sort of original expectations in terms of how big a part of the business it was, it is smaller? And are we starting to see sort of some of that catch-up? And so should we think about that as sort of some amount of pent-up demand of patients who are on SYFOVRE that are only getting one eye treated but eventually should most likely convert to bilateral treatment?

也許作為雙邊治療的後續行動，大概在血管炎期間出現了放緩。那麼，我們是否應該認為，相對於您最初的預期（即業務的一部分），它的規模較小？我們是否開始看到某種程度的追趕？因此，我們是否應該將其視為接受 SYFOVRE 治療的患者的某種被壓抑的需求，這些患者只接受一隻眼睛治療，但最終很可能會轉向雙眼治療？

I think that it's likely that physicians will -- once they are comfortable and patients have gotten past the first injection or so, then they will be using bilateral for patients just out of convenience for these patients to only have to come in once. So now that we have such a large number of vials that have been used and the robust patient experience to date, I think that we're approaching that.

我認為醫生很可能會——一旦他們感覺舒服並且患者已經通過了第一次注射左右，他們就會為患者使用雙側注射，只是為了方便這些患者只需要注射一次。因此，既然我們已經使用瞭如此大量的小瓶，並且迄今為止的患者體驗良好，我認為我們正在接近這一目標。

Yes. Doug, it's Adam, just to add. I think the bilateral usage was definitely impacted, as you said. I expect that to come back. But it's going to be time-delayed, right, as we start to communicate with all of these physicians. They've changed their practice on how they do bilateral injections, how the process of how they do it is different based on what happened last year. I don't think it impacts the opportunity. I think that's just the time delay as physicians get more comfortable.

是的。道格，我是亞當，補充。正如您所說，我認為雙邊使用肯定受到了影響。我希望那會回來。但當我們開始與所有這些醫生溝通時，這將會被延遲，對吧。根據去年發生的情況，他們改變了雙側注射的做法以及注射過程的差異。我認為這不會影響機會。我認為這只是醫生變得更舒服的時間延遲。

Yes. No, and I think my sort of question was is that when we think about a certain number of patients on SYFOVRE today, presumably a higher proportion are just having a single eye treated than you might have originally anticipated. But we should expect those to eventually catch up. So on a like -- we should see vials per patient increase relative to where we are.

是的。不，我想我的問題是，當我們考慮今天 SYFOVRE 上的一定數量的患者時，可能有比您最初預期的更高比例的單眼接受治療。但我們應該預期這些最終會迎頭趕上。因此，我們應該看到每位患者的藥瓶數量相對於我們現在的情況增加。

I think you should expect to see bilateral increase, yes, moving forward.

我認為你應該期待看到雙邊增長，是的，向前發展。

Our next question comes from Graig Suvannavejh with Mizuho Securities.

我們的下一個問題來自瑞穗證券的 Graig Suvannavejh。

Congratulations on the quarter. Just two, please. One, I might have missed this before. But just on the European reexamination process, could you just clarify for me whether as a company during this reexamination period whether you are able to submit additional data or new analyses? Or is it that the, call it, two new rapporteurs provide just a fresh view of the previous data that was included in the original dossier? So that's my first question.

恭喜本季。就兩個吧，拜託。第一，我以前可能錯過了這一點。但就歐洲複審過程而言，您能否向我澄清一下，作為一家公司，在復審期間您是否能夠提交額外的數據或新的分析？或者說，兩位新報告員只是對原始檔案中包含的先前數據提供了新的看法？這是我的第一個問題。

And then my second question, please, just a reminder on the safety profile of SYFOVRE. Has the rate of vasculitis changed in terms of either increasing or potentially decreasing? Or is it essentially the same?

然後是我的第二個問題，請提醒一下 SYFOVRE 的安全性。血管炎的發生率是否發生了增加或潛在減少的變化？或者本質上是一樣的？

Thank you so much, Graig. Great to hear you. First of all, on the European Union, so you are not allowed to include new data, but you are allowed to include new analyses, right? So that is something that we -- that our team has really done well. And again, especially the microperimetry data is really compelling. So we'll see what's going to happen. As we mentioned, it's an uphill battle, but one that we are excited to take on.

非常感謝你，格雷格。很高興聽到你的聲音。首先，在歐盟，所以你不能包含新的數據，但你可以包含新的分析，對吧？因此，我們的團隊確實做得很好。再說一遍，尤其是顯微視野測量數據確實令人信服。所以我們會看看會發生什麼。正如我們所提到的，這是一場艱苦的戰鬥，但我們很高興能夠參與這場戰鬥。

Then as it relates to the safety, the rate continues to be at 0.01%, where it has been since July. And of course, that stability provides a very good context for physicians to disclose to their patients when they speak with them as to what the risk in front of them is versus the benefit that it can get from being on treatment, so unchanged. Again, these cases are so rare that for a rate change to become manifest, we're going to have to wait quite a bit.

然後，由於與安全相關，利率自 7 月以來一直保持在 0.01%。當然，這種穩定性為醫生提供了一個非常好的背景，讓醫生在與患者交談時可以向患者透露他們面臨的風險與治療不變所帶來的好處。同樣，這些情況非常罕見，為了使利率變化變得明顯，我們將不得不等待相當長一段時間。

And I'm not showing any further questions at this time. I'd like to turn the call back over to Cedric for any closing remarks.

目前我不會提出任何進一步的問題。我想將電話轉回給塞德里克，讓其結束語。

Thank you so much, everyone, for joining. It is a great start to the year for us. And we look forward to sharing much more with all of you as the months come by. And for those of you available later today, we will be here to take questions and answer any further inquiries that you may have. Thank you.

非常感謝大家的加入。對我們來說，這是新的一年的良好開端。隨著時間的推移，我們期待與大家分享更多內容。對於今天晚些時候有空的各位，我們將在這裡回答您的問題並回答您可能有的任何進一步詢問。謝謝。

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.

女士們、先生們，今天的演講到此結束。您現在可以斷開連接，並度過美好的一天。