Vir Biotechnology Inc (VIR) 2023 Q4 法說會逐字稿

Hello. Welcome to Vir Biotechnology's fourth-quarter and full-year 2023 financial results and business update call. As a reminder, this conference call is being recorded. (Operator Instructions) After the speakers' presentation, there will be a question-and-answer session.

你好。歡迎參加 Vir Biotechnology 2023 年第四季和全年財務業績和業務更新電話會議。謹此提醒，本次電話會議正在錄音中。（操作員說明） 演講者演講結束後，將進行問答環節。

I will now turn the call over to Sasha Damouni Ellis, Executive Vice President, Chief Corporate Affairs Officer. You may begin, Ms. Damouni Ellis.

我現在將把電話轉給執行副總裁兼首席企業事務官 Sasha Damouni Ellis。你可以開始了，達穆尼·艾利斯女士。

Thank you, and good afternoon. With me today are Dr. Marianne De Backer, Chief Executive Officer; Dr. Phil Pang, Chief Medical Officer; and Sung Lee, Chief Financial Officer.

謝謝你，下午好。今天與我在一起的有執行長 Marianne De Backer 博士； Phil Pang 博士，首席醫療官；和財務長李成。

Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under the securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by such forward-looking statements. These risks and uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including Forms 10-K, 10-Q, and 8-K.

在開始之前，我想提醒大家，我們今天發表的一些聲明屬於證券法規定的前瞻性聲明。這些前瞻性陳述涉及重大風險和不確定性，可能導致我們的臨床開發計畫、未來結果、績效或成就與此類前瞻性陳述明示或暗示的內容有顯著差異。這些風險和不確定性以及與我們業務相關的風險在公司向美國證券交易委員會提交的報告中進行了描述，包括表格 10-K、10-Q 和 8-K。

I will now turn the call over to our CEO, Marianne De Backer.

我現在將把電話轉給我們的執行長 Marianne De Backer。

Thank you, Sasha. Good afternoon to everyone on the webcast and thank you all for joining us today. Before we discuss the tremendous progress we made in 2023 and what's ahead in 2024, I want to touch on the announcement we made earlier this week that Phil Pang, our Chief Medical Officer, has decided to step down at the end of March to spend more time with his family. We have initiated a search for his successor. I want to sincerely thank Phil for his leadership. He leaves a strong clinical development team in place, positioning us well for continued success, and I wish him the very best.

謝謝你，薩沙。網路廣播中的大家下午好，感謝大家今天加入我們。在我們討論 2023 年取得的巨大進展以及 2024 年的前景之前，我想談談我們本週早些時候發布的公告，即我們的首席醫療官 Phil Pang 決定於 3 月底辭職，以投入更多資金和家人相處的時間。我們已開始尋找他的繼任者。我要真誠地感謝菲爾的領導。他留下了一支強大的臨床開發團隊，為我們的持續成功做好了準備，我祝他一切順利。

Stepping in as Interim Chief Medical Officer is Dr. Carey Hwang, currently Vir's Senior Vice President, Clinical Research.

現任 Vir 臨床研究資深副總裁 Carey Hwang 博士接任臨時首席醫療官。

As I reflect on 2023, I'm proud of the clinical progress we have made towards developing a potential treatment for patients with chronic hepatitis delta, a potential functional cure for the millions living with chronic hepatitis B as well as a differentiated approach to preventing HIV. Our priority is to deliver on our mid-stage clinical pipeline while also refocusing our research and early pipeline to programs beyond infectious disease. We anticipate significant data readouts this year, which build off last year's progress across all our clinical programs.

回顧 2023 年，我為我們在開發針對慢性丁型肝炎患者的潛在治療方法、針對數百萬慢性乙型肝炎患者的潛在功能性治愈方法以及預防艾滋病毒的差異化方法方面取得的臨床進展感到自豪。我們的首要任務是交付我們的中期臨床管道，同時將我們的研究和早期管道重新集中到傳染病以外的項目。我們預計今年將公佈大量數據，這是我們所有臨床計畫去年取得進展的基礎。

Specifically, already in the first quarter, we anticipate completing the enrollment of approximately 60 participants across two cohorts in SOLSTICE, our Phase 2 hepatitis delta trial. We attribute this rapid rate of enrollment to the positive clinician and patient interest following the initial data we reported at AASLD last year.

具體來說，我們預計在第一季就完成 SOLSTICE（我們的 2 期三角洲試驗）兩個隊列中約 60 名參與者的入組。我們將這種快速的入組率歸因於我們去年在 AASLD 報告的初步數據後臨床醫生和患者的積極興趣。

In the second quarter, we plan to share early virologic and safety data on a subset of these participants. It is important to appreciate that there is a significant underserved patient population in need of a safe, highly efficacious, and convenience therapy for treating hepatitis delta.

在第二季度，我們計劃分享部分參與者的早期病毒學和安全性數據。重要的是要認識到，有大量服務不足的患者群體需要安全、高效和方便的治療方法來治療丁型肝炎。

We estimate that there are at least 12 million people diagnosed with this disease and an estimated 60 million or more undiagnosed globally. We aim to develop a best-in-cost treatment, which we believe will drive increased diagnosis rates and position Vir to become the leader in hepatitis delta. To position us for success, we are collaborating with patient advocacy groups and policymakers to improve surveillance and screening.

我們估計，全球至少有 1200 萬人被診斷出患有這種疾病，估計有 6000 萬人或更多人未確診。我們的目標是開發一種成本最佳的治療方法，我們相信這將提高診斷率，並使 Vir 成為丁型肝炎領域的領導者。為了使我們成功，我們正在與患者權益團體和政策制定者合作，以改善監測和篩檢。

In addition, crucial work is ongoing to understand who and where delta patients are. These efforts will support a targeted, rapid, and successful commercial launch in the future.

此外，了解三角洲患者的身份和地點的重要工作正在進行中。這些努力將支持未來有針對性、快速且成功的商業發布。

Switching gears, I will now discuss our functional cure program for chronic hepatitis B, another area of high unmet medical need. Based on the data reported in our ongoing Phase 2 trial thus far, we believe our two therapeutic candidates, tobevibart and elebsiran has the potential to play a critical role in delivering high functional cure rates for chronic hepatitis B patients. We look forward to reporting end-of-treatment data from the MARCH Part B trial at a major medical congress in the fourth quarter.

換個話題，我現在將討論我們針對慢性B型肝炎的功能性治療計劃，這是另一個醫療需求未被滿足的領域。根據我們迄今為止正在進行的 2 期試驗報告的數據，我們相信我們的兩種候選治療藥物 tobevibart 和 elebsiran 有潛力在為慢性乙型肝炎患者提供高功能治癒率方面發揮關鍵作用。我們期待在第四季度的一次重要醫學大會上報告 MARCH B 部分試驗的治療結束數據。

Finally, in the second half of the year, we are looking forward to sharing initial immunologic proof-of-concept data for VIR-1388, an HIV T cell vaccine candidate currently being evaluated in a Phase 1 trial. If the data supports the validity of the platform, it could be a springboard for other indications, including our preclinical therapeutic vaccine for control of pre-cancerous lesions and HPV cancers.

最後，在今年下半年，我們期待分享 VIR-1388 的初始免疫學概念驗證數據，VIR-1388 是一種 HIV T 細胞候選疫苗，目前正在一期試驗中進行評估。如果數據支持該平台的有效性，它可能成為其他適應症的跳板，包括我們用於控制癌前病變和 HPV 癌症的臨床前治療疫苗。

Switching to research. We continue to advance antibody therapeutics optimized for increased likelihood of development success, thanks to our proprietary platform powered by AI and machine learning. Our focus is on prophylactic antibodies for influenza A and B, RSV/MPV, and COVID-19. In addition, we are developing a cocktail of broadly neutralizing antibodies for an HIV cure. We look forward to sharing more about these programs and the timing of potential IND submission during the year.

轉向研究。由於我們由人工智慧和機器學習支援的專有平台，我們繼續推進優化的抗體療法，以增加開發成功的可能性。我們的重點是甲型和乙型流感、RSV/MPV 和 COVID-19 的預防性抗體。此外，我們正在開發一種廣泛中和抗體的混合物，用於治療愛滋病毒。我們期待分享有關這些計劃的更多資訊以及年內可能提交 IND 的時間。

On February 21, Vir and GSK terminated our collaboration to research, develop, and commercialize our monoclonal antibodies targeting the influenza of virus under our Definitive Collaboration Agreement that we established in May of 2021. Vir retains sole rights to continue advancing our investigational therapies for influenza. With that in mind, we are actively pursuing external partnership opportunities for our next-generation influenza A and B antibodies and ADCs. Meanwhile, our respiratory collaboration with GSK continues.

2 月 21 日，Vir 和 GSK 根據我們於 2021 年 5 月簽訂的最終合作協議終止了我們針對流感病毒的單株抗體的研究、開發和商業化。Vir 保留繼續推進我們的流感研究療法的獨家權利。考慮到這一點，我們正在積極尋求下一代甲型和乙型流感抗體及 ADC 的外部合作機會。同時，我們與 GSK 的呼吸系統合作仍在繼續。

Turning to our cash and investments. Our financial strength allows us to fund our clinical programs through major inflection points while enabling the flexibility to invest in external innovation opportunities. In evaluating external innovation, we are thoughtful, selective, and strategic with a focus on opportunities capable of augmenting our pipeline and platforms.

轉向我們的現金和投資。我們的財務實力使我們能夠在重大拐點為我們的臨床項目提供資金，同時能夠靈活地投資外部創新機會。在評估外部創新時，我們深思熟慮、選擇性和策略性，重點關注能夠擴大我們的管道和平台的機會。

To recap, we are preparing for a transformational year at Vir, anticipating critical value inflection points in our programs focused on chronic hepatitis delta, hepatitis B, and HIV.

回顧一下，我們正在為 Vir 的轉型年做準備，預計我們專注於慢性丁型肝炎、乙型肝炎和愛滋病毒的計畫將出現關鍵價值轉折點。

With that, I'll now turn the call over to Phil.

現在，我將把電話轉給菲爾。

Thank you, Marianne. I want to begin by thanking you, the Board, and all of my dear colleagues for what has been an honor and privilege to serve as Vir's Chief Medical Officer. Vir has been a family to me as well as an all-consuming passion for the last seven-plus years. I have full confidence in Vir's future and the ability of our promising clinical programs to impact the lives of millions of patients.

謝謝你，瑪麗安。首先，我要感謝你們、董事會和所有親愛的同事，讓我榮幸地擔任 Vir 的首席醫療官。在過去的七年多里，Vir 一直是我的家人，也是我全心投入的熱情。我對 Vir 的未來以及我們充滿前景的臨床計畫影響數百萬患者生活的能力充滿信心。

Moving on to that pipeline. I'll begin by summarizing the initial results from our Phase 2 SOLSTICE trial, which is on hepatitis delta that was shared in a late-breaker presentation at AASLD last year and discussed earlier this year. The SOLSTICE trial is evaluating tobevibart alone and in combination with elebsiran as a potential chronic treatment for patients living with chronic hepatitis delta.

繼續該管道。首先，我將總結我們 2 期 SOLSTICE 試驗的初步結果，該試驗是關於丁型肝炎的，該結果在去年 AASLD 的最新報告中分享，並在今年早些時候進行了討論。SOLSTICE 試驗正在評估托貝巴特單獨使用以及與 elebsiran 聯合使用作為慢性丁型肝炎患者的潛在慢性治療方法。

Tobevibart is our investigational neutralizing monoclonal antibody, which has been engineered for enhanced immune engagement. Elebsiran is an investigational HBV-targeted siRNA that reduces hepatitis B surface antigen, which is the protein that the delta virus needs for its life cycle.

Tobevibart 是我們在研的中和單株抗體，經過精心設計，可增強免疫參與。Elebsiran 是一種研究中的 HBV 靶向 siRNA，可減少乙型肝炎表面抗原，而乙型肝炎表面抗原是 δ 病毒生命週期所需的蛋白質。

In our initial data, we observed extraordinarily rapid declines in HDV RNA. Five out of six participants had undetectable HDV RNA and six out of six were below the lower limit of quantification within 12 weeks of starting combination therapy. Of note, two out of six also achieved ALT normalization.

在我們的初始數據中，我們觀察到 HDV RNA 異常快速下降。在開始聯合治療的 12 週內，六名參與者中的五名 HDV RNA 檢測不到，六分之六的水平低於定量下限。值得注意的是，六分之二的人也實現了 ALT 正常化。

While participant numbers are small, these data were recognized by several hepatologists as one of the most exciting advancements shared at the AASLD conference in 2023. That excitement has meaningfully translated into our ability to rapidly enroll patients both with and without cirrhosis ahead of schedule in our SOLSTICE study.

雖然參與者人數很少，但這些數據被幾位肝病學家認為是 2023 年 AASLD 會議上分享的最令人興奮的進展之一。這種興奮有意義地轉化為我們能夠提前快速招募患有和不患有肝硬化的患者參加我們的 SOLSTICE 研究。

As a reminder, our stated goal is to enroll approximately 60 participants in SOLSTICE by the end of the first quarter. These participants are being enrolled into two groups. The first group is receiving tobevibart monotherapy every two weeks and a second group is receiving tobevibart plus elebsiran combination therapy every four weeks.

提醒一下，我們的既定目標是在第一季末之前招募大約 60 名 SOLSTICE 參與者。這些參與者被分成兩組。第一組每兩週接受託貝巴特單藥治療，第二組每四周接受託貝巴特加 elebsiran 合併治療。

As of early February, greater than 90% of participants have been dosed. Notably, of the 55 participants who have already been dosed, 24 of them or 44% have compensated cirrhosis. We plan to share initial data on a subset of these participants in the second quarter, specifically, 15 participants per regimen at 12 weeks and 10 participants per regimen at 24 weeks. Should these data be supported, we intend to discuss with regulators on a potential path to registration in the third quarter.

截至 2 月初，超過 90% 的參與者已接受注射。值得注意的是，在接受給藥的 55 名參與者中，其中 24 人（即 44%）出現了代償性肝硬化。我們計劃在第二季分享這些參與者的一部分的初始數據，具體來說，12 週時每個方案 15 名參與者，24 週時每個方案 10 名參與者。如果這些數據得到支持，我們打算與監管機構討論第三季註冊的潛在途徑。

Switching to our Phase 2 program for chronic hepatitis B, our preliminary data suggests that when elebsiran was given with pegylated interferon alfa for up to 48 weeks, approximately 26% of participants achieved hepatitis B surface antigen loss at the end of treatment, and 16% maintained hepatitis B surface antigen loss 24 weeks after the end of therapy.

轉向我們針對慢性乙型肝炎的2 期計劃，我們的初步數據表明，當elebsiran 與聚乙二醇幹擾素α 一起服用長達48 週時，大約26% 的參與者在治療結束時實現了乙型肝炎表面抗原喪失，16% 的參與者在治療結束時實現了乙型肝炎表面抗原喪失。治療結束後24週仍維持乙型肝炎表面抗原喪失。

Again, although the number of participants treated was small, this was the first sign that our siRNA may have a potential impact on functional cure rates beyond what is possible with peginterferon alone. In a subsequent trial, when adding tobevibart to a regimen of elebsiran alone or elebsiran plus peginterferon, we observed an almost threefold increase in end of treatment response rates after only 24 weeks of treatment.

同樣，儘管接受治療的參與者數量很少，但這是第一個跡象，表明我們的 siRNA 對功能性治癒率的潛在影響可能超出單獨使用聚乙二醇幹擾素所能達到的效果。在隨後的試驗中，當托貝巴特添加到單獨的 elebsiran 或 elebsiran 加聚乙二醇幹擾素的治療方案中時，我們觀察到僅治療 24 週後治療結束反應率幾乎增加了三倍。

These data were the first indication of the potentially important role of an HBV-directed antibody in hepatitis B functional cure. These data are encouraging, and we look forward to sharing end-of-treatment data from the MARCH Part B trial, which is evaluating 48 weeks of the doublet and triplet regimens in the fourth quarter. This will be followed by post-treatment data in the first half of 2025, which will allow us to assess functional cure rates.

這些數據首次顯示了針對乙型肝炎病毒的抗體在乙型肝炎功能性治癒中具有潛在的重要作用。這些數據令人鼓舞，我們期待分享 MARCH B 部分試驗的治療結束數據，該試驗正在第四季度評估 48 週的雙聯和三聯療法。隨後將在 2025 年上半年提供治療後數據，這將使我們能夠評估功能性治癒率。

Turning to what we anticipate will enter the clinic next. VIR-7229 is a next-generation COVID antibody with increased potency, breadth, and resistance to viral escape thanks to AI engineering and optimization. We expect to file a health authority application to support a Phase 1 trial later this year. The development of VIR-7229 through the end of Phase 1 is supported by BARDA. We look forward to continuing to share our progress over the coming quarters and during an R&D Day planned for the end of this year.

轉向我們預計接下來將進入診所的產品。VIR-7229 是新一代新冠病毒抗體，得益於人工智慧工程和優化，其效力、廣度和抗病毒逃脫能力均得到增強。我們預計將在今年稍後向衛生當局提交申請以支持第一階段試驗。VIR-7229 的開發直至第一階段結束均得到 BARDA 的支持。我們期待在未來幾季以及計劃於今年年底舉行的研發日期間繼續分享我們的進展。

I will now turn the call over to Sung.

我現在將電話轉給宋。

Thank you, Phil. We're pleased to share our financial results for the fourth quarter of 2023 and the full year. Total revenues in the fourth quarter of 2023 were $16.8 million compared to $49.4 million for the same period in 2022. Total revenues for the full year of 2023 were $86.2 million compared to $1.62 billion in 2022. The primary driver for the year-over-year decline is lower collaboration revenues from sotrovimab.

謝謝你，菲爾。我們很高興分享 2023 年第四季和全年的財務表現。2023 年第四季的總收入為 1,680 萬美元，而 2022 年第四季的總收入為 4,940 萬美元。2023 年全年總收入為 8,620 萬美元，而 2022 年為 16.2 億美元。年比下降的主要驅動因素是 sotrovimab 的合作收入下降。

We do not anticipate any meaningful collaboration revenue from sotrovimab in the future. And this line item could make a negative contribution to our top line due to the ongoing required investments to support the marketing authorization of sotrovimab, which our partner GSK leads the efforts in.

我們預計未來 sotrovimab 不會產生任何有意義的合作收入。由於需要持續進行投資以支持 sotrovimab 的營銷授權（我們的合作夥伴葛蘭素史克領導了這項工作），因此該項目可能會對我們的營收產生負面貢獻。

Turning to operating expenses. Cost of revenue for the full year of 2023 was $2.8 million compared to $146.3 million in 2022. The year-over-year decline was driven by lower third-party royalties owed on sotrovimab sales. R&D expenses in the fourth quarter of 2023 were $111.9 million compared to $155.2 million in the same period in 2022.

轉向營運費用。2023 年全年的收入成本為 280 萬美元，而 2022 年為 1.463 億美元。年比下降的原因是 sotrovimab 銷售所欠的第三方特許權使用費較低。2023 年第四季的研發費用為 1.119 億美元，而 2022 年同期為 1.552 億美元。

The decrease was primarily driven by the wind down of the Phase 2 Flu study of VIR-2482 in the fourth quarter of 2023. Included in the R&D expense for the fourth quarter of 2023 is a severance charge of $2.6 million related to the workforce reduction announced in December 2023.

這一下降主要是由於 VIR-2482 的 2 期流感研究於 2023 年第四季結束。2023 年第四季的研發費用中包括與 2023 年 12 月宣布的裁員相關的 260 萬美元遣散費。

R&D expenses for the full year of 2023 were $589.7 million compared to $474.6 million in 2022. The year-over-year increase was primarily driven by the Phase 2 flu trial evaluating VIR-2482 and related manufacturing costs, and to a lesser extent, the advancement of our hepatitis delta and hepatitis B programs.

2023 年全年研發費用為 5.897 億美元，而 2022 年為 4.746 億美元。同比增長主要是由評估 VIR-2482 和相關製造成本的 2 期流感試驗推動的，在較小程度上是由我們的丁型肝炎和乙型肝炎項目的進展推動的。

SG&A expenses in the fourth quarter of 2023 were $43.1 million compared to $38.7 million for the same period in 2022. The increase was primarily driven by higher personnel costs and a severance charge of $1.9 million related to the workforce reduction announced in December of 2023. SG&A expenses for the full year of 2023 were $178 million compared to $161.8 million in 2022. The year-over-year increase was primarily driven by higher personnel costs.

2023 年第四季的銷售、管理及行政費用為 4,310 萬美元，而 2022 年同期為 3,870 萬美元。這一增長主要是由於人事成本上升以及與 2023 年 12 月宣布的裁員相關的 190 萬美元遣散費所致。2023 年全年的 SG&A 費用為 1.78 億美元，而 2022 年為 1.618 億美元。年比成長主要是由於人員成本上升所致。

For the fourth quarter of 2023, we reported a consolidated net loss of $116 million compared to a net loss of $101.6 million for the same period in 2022. For the full year of 2023, we reported a consolidated net loss of $615.1 million compared to a net income of $515.8 million in 2022.

2023 年第四季度，我們報告的綜合淨虧損為 1.16 億美元，而 2022 年同期的淨虧損為 1.016 億美元。2023 年全年，我們的綜合淨虧損為 6.151 億美元，而 2022 年的淨利潤為 5.158 億美元。

Moving to the balance sheet. Cash, cash equivalents and investments declined by $108 million quarter over quarter, and we finished the fourth quarter of 2023 with $1.63 billion.

轉向資產負債表。現金、現金等價物和投資環比下降 1.08 億美元，2023 年第四季結束時現金、現金等價物和投資為 16.3 億美元。

Turning to the financial guidance for 2024. We anticipate that the GAAP combined R&D and SG&A expense will be in the range of $650 million to $680 million. Included in this range are non-cash stock-based compensation expense in the range of $105 million to $115 million and restructuring charges for the closing of two R&D sites previously announced in December 2023 in the range of $25 million to $35 million.

轉向 2024 年的財務指引。我們預計，以 GAAP 計算，研發和銷售、一般管理費用總計將在 6.5 億至 6.8 億美元之間。此範圍包括 1.05 億至 1.15 億美元的非現金股票補償費用，以及先前於 2023 年 12 月宣布的關閉兩個研發基地的重組費用，金額為 2,500 萬至 3,500 萬美元。

The restructuring expenses are primarily non-cash. When excluding the non-cash stock-based compensation and restructuring expenses from the GAAP combined R&D and SG&A expense range, the resulting range is $500 million to $550 million, which represents an 18% year-over-year decline at the midpoint.

重組費用主要為非現金。當從 GAAP 合併研發和 SG&A 費用範圍中排除非現金股票薪酬和重組費用時，得出的範圍為 5 億美元至 5.5 億美元，中點年減 18%。

The expected year-over-year decline is driven primarily by, first, the absence of expenses from the Phase 2 flu trial evaluating VIR-2482 and related manufacturing cost in 2024, partially offset by the ramp-up of our hepatitis delta and hepatitis B programs in 2024; and second, the cost optimization measures taken in 2023. Approximately 3% to 4% of the GAAP combined R&D and SG&A expense will be funded by grants.

預期年減的主要原因是，首先，2024 年評估 VIR-2482 的 2 期流感試驗和相關製造成本缺乏費用，部分被我們的 Delta 和 B 型肝炎的增加所抵消2024 年計劃；二是2023年採取的成本優化措施。GAAP 研發和銷售、一般管理費用合計中約 3% 至 4% 將透過補助提供資金。

It's important to remember that these grants are recognized as revenue in our income statement. The combined GAAP R&D and SG&A expense guidance does not include the effect of GAAP adjustments caused by events that may occur subsequent to the publication of this guidance, including but not limited to, business development activities, litigations, in-process R&D impairments, and changes in the fair value of contingent considerations.

重要的是要記住，這些補助金在我們的損益表中被確認為收入。合併後的 GAAP 研發和 SG&A 費用指南不包括本指南發布後可能發生的事件引起的 GAAP 調整的影響，這些事件包括但不限於業務開發活動、訴訟、過程中的研發減損和變更或有代價的公允價值。

Our financial strength allows us to advance the Phase 2 hepatitis delta and hepatitis B program through multiple milestones, invest in our core antibody platform, and provide flexibility to evaluate external innovation. We will continue to have a disciplined approach to capital allocation and expense management.

我們的財務實力使我們能夠透過多個里程碑推進 Delta 型肝炎和乙型肝炎專案的第二階段，投資於我們的核心抗體平台，並提供評估外部創新的靈活性。我們將繼續採取嚴格的資本配置和費用管理方法。

I will now turn the call back to Sasha.

我現在將電話轉回給薩莎。

Thank you, Sung. We will now start the Q&A section. Please limit questions to two per person so that we are able to get to all of our covering analysts. Operator, please open up the line for questions.

謝謝你，宋。我們現在開始問答部分。請將問題限制為每人兩個，以便我們能夠聯繫到所有涵蓋的分析師。接線員，請開通提問線。

(Operator Instructions) Paul Choi, Goldman Sachs.

（操作員指示）Paul Choi，高盛。

Everyone can hear me? Hello?

大家都能聽到我說話嗎？你好？

Yes.

是的。

Hi. This is Khalil calling in for Paul. Thanks so much for taking our question. I guess we'd like to ask about the tobevirbart/elebsiran combination cohort without peginterferon alfa in MARCH Part B at 24 weeks. Is that slightly higher efficacy observed in the cohort without interferon, something you expect to see repeated in the 48-week data? And what would that mean for interferon's place in a future pivotal study?

你好。我是卡里勒來找保羅。非常感謝您提出我們的問題。我想我們想詢問 3 月 B 部分 24 週時不含聚乙二醇幹擾素 α 的托貝韋巴特 / elebsiran 組合隊列的情況。在沒有乾擾素的隊列中觀察到的療效是否稍高一些，您希望在 48 週的數據中看到這一點？這對於幹擾素在未來關鍵研究中的地位意味著什麼？

Thank you for that question, Paul. I will ask our CMO, Phil Pang, to give you deeper insights into that.

謝謝你提出這個問題，保羅。我將請我們的首席行銷長 Phil Pang 為您提供更深入的見解。

Thank you. Yeah. So I that remember the numbers from the 24-week end-of-treatment data that we showed with the doublet and the triplet are still small numbers. So I would not look much into the fact that the median of the doublet was slightly different from the triplet at 24 weeks.

謝謝。是的。所以我記得我們用雙聯體和三聯體顯示的 24 週治療結束數據中的數字仍然很小。因此，我不會過多關注 24 週時雙聯體的中位數與三聯體的中位數略有不同這一事實。

I think that really what we're looking forward to seeing what happens, as you know, after 48 weeks of the doublet and triplet. So I would say the jury's still out as to what those results are going to be, which we will share with you in the fourth quarter.

我認為這確實是我們所期待的，正如你所知，在 48 週的雙胞胎和三胞胎之後會發生什麼。因此，我想說的是，對於這些結果將是什麼，尚無定論，我們將在第四季度與您分享。

And I think that leaves open whether or not interferon will be required. And if it is, I think it will require a slightly higher functional cure rate given the known side effects of interferon. But I think again, for patients and for providers, it always comes down to risk benefit. And I think that if we can show a transformational increase in functional cure rates such as 30% or more, this is something that will be very important tool for clinicians.

我認為是否需要幹擾素尚不確定。如果是這樣，考慮到干擾素的已知副作用，我認為需要稍高的功能治癒率。但我再次認為，對於患者和提供者來說，這總是歸結為風險效益。我認為，如果我們能夠實現功能性治癒率的轉變，例如 30% 或更高，這對臨床醫生來說將是非常重要的工具。

Got it. Thank you so much. And I guess quick follow-up relating to the pipeline in general, could you just give like a potential timeline as to when the company will select a front runner antibody candidates to enter the clinic? And any color on what would drive that decision of choosing one.

知道了。太感謝了。我想總體上與管道有關的快速跟進，您能否給出一個可能的時間表，說明公司何時選擇領先的抗體候選者進入診所？以及任何有助於做出選擇決定的顏色。

So just to provide a little clarity, we have a number of candidates entering the clinic in the near term. And that's sort of regardless of platform, whether it's an antibody or a T cell vaccine. And really what we're always looking for is obviously something that is differentiated and something that we believe can make an impact on patients' lives. So those three candidates are VIR-7229, the next-generation COVID antibody I spoke about earlier with its increased breadth and potency, thanks to our AI engineering platform.

因此，為了澄清一點，我們有一些候選人在短期內進入診所。這與平台無關，無論是抗體或 T 細胞疫苗。事實上，我們一直在尋找的顯然是與眾不同的東西，我們相信它可以對患者的生活產生影響。這三個候選藥物是 VIR-7229，這是我之前談到的下一代新冠抗體，由於我們的人工智慧工程平台，它的廣度和效力都得到了增強。

That also includes VIR-2981, our neuraminidase targeting monoclonal antibody, which is differentiated on three levels: one, it targets both flu A and B; it's more potent than 2482; and has a derisk mechanism of action by targeting the neuraminidase enzyme.

其中還包括 VIR-2981，我們的神經氨酸酶靶向單株抗體，它在三個層面上有所不同：一是它同時針對甲型流感和乙型流感；它比 2482 更有效；並具有針對神經氨酸酶的無風險作用機制。

And third, we're very excited about VIR-1949, which is a potential therapeutic T cell vaccine that builds on our human cytomegalovirus vaccine vector platform and target pre-cancerous HPV lesions. But I do want to say and stress that, of course, the first two candidates, 7229 and 2981, we are planning to execute with a partner given the scale of development necessary.

第三，我們對 VIR-1949 感到非常興奮，它是一種潛在的治療性 T 細胞疫苗，建立在我們的人類鉅細胞病毒疫苗載體平台之上，針對癌前 HPV 病變。但我確實想說並強調，考慮到必要的開發規模，我們計劃與合作夥伴一起執行前兩個候選者 7229 和 2981。

Right. All right. Thank you so much.

正確的。好的。太感謝了。

Thank you, Khalil

謝謝你，卡里爾

Gena Wang, Barclays.

王吉娜，巴克萊銀行。

This is Yi on Gena. Thank you so much for taking our question. So first of all, for Phil, best wishes for your next journey. And for Marianne, with Phil's departure and now you have focus on infectious disease, oncology, and immunology, what do you think will be the ideal candidate for your next CMO?

這是伊·吉納。非常感謝您提出我們的問題。首先，謹向菲爾祝福你的下一次旅程一切順利。對於 Marianne 來說，隨著 Phil 的離開，您現在專注於傳染病、腫瘤學和免疫學，您認為下一位 CMO 的理想人選是什麼？

And for your HDV, could you share your data expectation that you're going to share in the second quarter? And also, did you hear some initial regulatory feedback on the approval path? And lastly, for your earlier stage pipeline, how do you select the lead antibody candidates and what will drive those decisions? Thank you.

對於 HDV，您能否分享一下您將在第二季分享的數據預期？另外，您是否聽到了有關審批路徑的一些初步監管回饋？最後，對於您的早期管道，您如何選擇先導抗體候選物以及什麼將推動這些決策？謝謝。

Thank you very much, Gena. I will start with your first question related to a successor to Phil and what we are looking for in the next CMO. First of all, what is going to be really critical is for someone to have a proven track record in advancing therapies really through Phase 3 and having experience bringing therapeutics all the way to market.

非常感謝你，吉娜。我將從你的第一個問題開始，涉及菲爾的繼任者以及我們在下一個首席行銷長中尋找什麼。首先，真正關鍵的是某人在推進療法真正進入第三階段方面擁有可靠的記錄，並且擁有將療法一路推向市場的經驗。

Needless to say, we have already initiated a search for a successor. And I must say also, since the news have gone out this week, we have received a flood of inquiries. But obviously, we will be very selective in what the profile of that candidate needs to be.

不用說，我們已經開始尋找繼任者。我還必須說，自從本週消息傳出以來，我們收到了大量詢問。但顯然，我們會對候選人的個人資料進行嚴格篩選。

We're also looking for someone who has a really in-depth understanding of the evolving regulatory landscape, deep insights in how to use data and big data for insights into clinical development. So there's a number of things here that need to come together.

我們也正在尋找對不斷變化的監管環境有真正深入了解的人，對如何使用數據和大數據深入了解臨床開發有深刻的見解。因此，這裡有很多事情需要結合在一起。

And as Phil pointed out, we have a very talented leadership team here in our clinical group. So we are also looking for someone who can lead such a team of very talented developers for success, especially focused on our hepatitis B and hepatitis delta programs.

正如菲爾指出的那樣，我們的臨床團隊擁有一支非常有才華的領導團隊。因此，我們也在尋找能夠領導這樣一支非常有才華的開發人員團隊取得成功的人，特別是專注於我們的B型肝炎和丁型肝炎專案的人。

Now switching to your second question, Gena, I understood that was related to hepatitis delta and what data we are expecting in the second quarter. So I will ask Phil to give you more color on that.

現在轉向你的第二個問題，Gena，我知道這與丁型肝炎以及我們預計第二季的數據有關。所以我會請菲爾給你更多關於這一點的資訊。

Yeah. Thank you, Marianne. So with regard to the data in Q2 around hepatitis delta, to step back first, as we shared both at the conference earlier this year as well as the AASLD, what we showed was data on six patients. And that data, we think, is quite transformative, but it is only six patients. So what we're looking for in Q2 is really to answer three questions. The first is, what happens when we dose more patients with our combination therapy, will we be able to repeat that type of data? Number 2, what will happen when we dose patients who have compensated cirrhosis? And three, what will happen with the long-term durability of those initial six patients?

是的。謝謝你，瑪麗安。因此，關於第二季度圍繞丁型肝炎的數據，首先退一步，正如我們在今年早些時候的會議以及 AASLD 上分享的那樣，我們展示的是 6 名患者的數據。我們認為這些數據具有很大的變革性，但它只有六名患者。因此，我們在第二季度尋找的實際上是回答三個問題。第一個問題是，當我們對更多患者進行聯合治療時會發生什麼，我們是否能夠重複此類數據？第二，當我們給代償性肝硬化患者服用藥物時會發生什麼事？第三，最初六名患者的長期耐受性會如何？

So I think we're excited and looking forward to that data. I think you also asked a question about regulatory feedback. And I just wanted to reiterate what we have said earlier this year, which is that the next step will be to take that data if positive and put it in front of regulators in the third quarter in an attempt to discuss a path to registration. So that's sort of the path as we see it coming from here on out.

所以我認為我們對這些數據感到興奮和期待。我想你也問了一個關於監管回饋的問題。我只是想重申我們今年早些時候所說的，那就是下一步將採取積極的數據，並在第三季度將其提交給監管機構，試圖討論註冊途徑。這就是我們從現在開始看到的路徑。

Yes. And we're not -- related to your third question, which was related to our early-stage pipeline, I think that's still in answering question, as Phil already laid out. We really have three candidates that can enter the clinic for in the next 12 months to 24 months. It's VIR-7229, VIR-2981, VIR-1949. And so each of those are really progressing very well, and we will be providing more data and informational timing during the course of this year.

是的。我們與你的第三個問題無關，這與我們的早期管道有關，我認為這仍在回答問題，正如菲爾已經提出的那樣。我們確實有三位候選人可以在未來 12 個月到 24 個月內進入診所。它是 VIR-7229、VIR-2981、VIR-1949。因此，每一項都進展順利，我們將在今年提供更多數據和資訊時間。

Roanna Ruiz, Leerink Partners.

羅安娜·魯伊斯 (Roanna Ruiz)，Leerink 合夥人。

Hi. Good afternoon. This is Nik Gasic on for Roanna. Thanks for taking our questions. Just first on HDV. Could you provide a little more color around how large the market opportunity is in HDV currently? And also, could you discuss what a possible accelerated approval pathway could look like for tobevibart and elebsiran in HDV? And then I have a quick follow-up.

你好。午安.我是尼克·加西克 (Nik Gasic)，代表羅安娜 (Roanna) 出場。感謝您回答我們的問題。首先是 HDV。您能否就目前 HDV 的市場機會有多大提供更多資訊？另外，您能否討論一下 Tobevibart 和 elebsiran 在 HDV 中可能的加速審批途徑是什麼樣的？然後我會進行快速跟進。

Okay. Thank you, [Josh]. Let me maybe begin with reminding everyone that delta is the most severe form of hepatitis. And as you know, I mean people that are co-infected with delta progress to liver cancer 4 times faster and 2 times faster to death. So there's a tremendous unmet need here. I think it's the first point that I would like to make.

好的。謝謝你，[喬許]。首先我要提醒大家，三角洲是最嚴重的肝炎。如你所知，我的意思是，同時感染 Delta 的人罹患肝癌的速度要快 4 倍，死亡速度快 2 倍。所以這裡有一個巨大的未滿足的需求。我想這是我想說的第一點。

And then looking at the prevalence, we estimate that there are about 100,000 patients in the United States and over 200,000 patients in the EU5 alone. And we do believe that this is likely a growth underestimate given that diagnosis is really not optimal at this moment in time.

然後看看盛行率，我們估計美國約有 10 萬名患者，光是歐盟五國就有超過 20 萬名患者。我們確實認為，鑑於目前的診斷確實不是最佳的，這可能是對成長的低估。

So you can assume that even if you were to access only a modest portion of this population and if you think about pricing that would reflect really the clinical benefit of a potential transformative therapy, taking that together, we are confident that you would already be looking at a very large and significant market opportunity.

因此，您可以假設，即使您只接觸到這一人群中的一小部分，並且如果您考慮的定價將真正反映潛在變革療法的臨床益處，綜合考慮，我們相信您已經在尋找一個非常大且重要的市場機會。

And obviously, we believe that the combination regimen that we have of tobevibart and elebsiran represents the potential of such a transformative therapy based on the data that we have shown thus far, and of course, in a limited set of patients, but still very impressive data.

顯然，我們相信，根據我們迄今為止所顯示的數據，我們的托貝巴特和埃來布西蘭的聯合方案代表了這種變革性療法的潛力，當然，在有限的一組患者中，但仍然非常令人印象深刻數據。

And with regard to an accelerated approval, if I'll take that one, Marianne?

至於加速批准，我是否會接受，瑪麗安？

Yes, please go ahead, Phil.

是的，請繼續，菲爾。

I think that as we often like to say in the development space, data changes everything and more data is always better. So I think that when we think about accelerated approval, or a rapid path to approval, what's in our favor is the fact that the unmet need, as Marianne has described, is undoubtable, right?

我認為，正如我們在開發領域經常喜歡說的那樣，數據改變一切，而且數據越多越好。因此，我認為，當我們考慮加速批准或快速獲得批准的途徑時，對我們有利的是，正如瑪麗安所描述的那樣，未滿足的需求是不容置疑的，對吧？

There are hundreds of thousands of patients worldwide who would benefit from a chronic suppressive therapy for delta. And the fact that there is a lack of good options for many of them is also clear. So I think that, that all favors a rapid path in the setting of the right data.

全球有數十萬名患者將受益於 Delta 的長期抑制治療。事實上，他們中的許多人缺乏好的選擇也是顯而易見的。所以我認為，這一切都有利於快速設定正確的數據。

On the other hand, of course, our program is still early, and we're really waiting for our chance to get in front of regulators and our anticipated goalpost is Q3. And by then, we'll have a subset of data, which we've talked about previously, which we will share in Q2, which is 30 participants through week 12 and 20 participants through week 24 in our two regimens that we are exploring. And to remind you of that, that is the combination of tobevibart and elebsiran every four weeks versus just tobevibart every two weeks.

當然，另一方面，我們的計劃還處於早期階段，我們確實在等待向監管機構提交申請的機會，而我們的預期目標是第三季。到那時，我們將獲得我們之前討論過的數據子集，我們將在第二季度分享這些數據，在我們正在探索的兩種方案中，第12 周有30 名參與者，第24 周有20名參與者。提醒您的是，這是每四週一次的托貝巴特和 elebsiran 的組合，而不是每兩週一次的托貝巴特。

Thank you, Phil. Josh, did you have an additional question?

謝謝你，菲爾。喬什，您還有其他問題嗎？

Yes. Sorry, this is Nik. Just wanted to follow up on HDV. Curious what signals you're hoping to see in the upcoming additional data from SOLSTICE and maybe what are some of the gating factors for moving this program into the Phase 3? I guess like what would regulators really want to see in this data to support maybe going into the Phase 3?

是的。抱歉，這是尼克。只是想跟進 HDV。好奇您希望在 SOLSTICE 即將發布的附加資料中看到什麼訊號，以及將該計劃移至第 3 階段的一些限制因素是什麼？我想監管機構真正希望在這些數據中看到什麼來支持可能進入第三階段？

Sorry, Josh, are you referring to hepatitis B or delta?

抱歉，喬什，您指的是B型肝炎還是丁型肝炎？

I can take that one, Marianne. So I think -- thank you, Nik. So as I said earlier, I think it's really a question of getting in front of them with the -- so to answer your first question, there are three things we're looking for in the data. The first thing we're looking for in the data is does it repeat what we've seen with the original six patients; second, what will happen when we dose patients who have compensated cirrhosis; and third, how durable it will be.

我可以接受那個，瑪麗安。所以我想——謝謝你，尼克。正如我之前所說，我認為這實際上是一個在他們面前提出問題的問題——因此，為了回答你的第一個問題，我們正在數據中尋找三件事。我們在數據中尋找的第一件事是它是否重複我們在最初的六名患者身上看到的情況；其次，當我們給代償性肝硬化患者服用藥物時會發生什麼事？第三，它的耐用程度。

I think that all of that data in terms of numbers will matter to the regulators and be able to reassure them that six patients -- the data on the six patients is not sort of a one-off, but actually something that really is as transformative as we believe it to be.

我認為所有這些數位數據對監管機構來說都很重要，並且能夠讓他們放心，六名患者——這六名患者的數據不是一次性的，而是真正具有變革性的東西正如我們所相信的那樣。

So in terms of gating factors, I can only speak more generally, but once we have the opportunity to sit down with regulators in the third quarter, which is our anticipated goal, we'll be able to discuss with them, one, what the comparator arm would be; two, what the size of the safety database needs to be; and three, what kind of particular endpoints they would be most interested in that they believe would be demonstrative of transformative efficacy.

因此，就限制因素而言，我只能更籠統地說，但是一旦我們有機會在第三季度與監管機構坐下來（這是我們的預期目標），我們將能夠與他們討論，第一，比較器臂將是；二、安全資料庫的大小需要是多少；第三，他們最感興趣的是哪些特定的終點，他們認為這些終點可以證明改變的功效。

So that's what we're going to be talking about. And then, of course, it's a matter of execution. I will say that, of course, we are planning for success in terms of both trial planning and regulatory interactions. And so we'll continue to do so because this is our most important clinical program and it's first out of the gate.

這就是我們要討論的內容。當然，這是執行的問題。我想說，當然，我們正在計劃在試驗規劃和監管互動方面取得成功。因此，我們將繼續這樣做，因為這是我們最重要的臨床計劃，也是第一個啟動的項目。

Yeah. So just to maybe add and repeat that, already in the second quarter, we will be seeing 12-week data on 30 participants across the two regimens and then 20 participants for the 24 weeks. So that will give us already a lot of insights into the data.

是的。因此，也許要補充並重複一遍，在第二季度，我們將看到 30 名參與者採用兩種方案的 12 週數據，然後是 20 名參與者 24 週的數據。這將使我們對數據有很多了解。

Okay. Thank you.

好的。謝謝。

Eva Privitera, TD Cowen.

伊娃·普里維特拉，TD·考恩。

Hey, good afternoon and thank you for taking our questions. Just a couple from us. On the HDV SOLSTICE trial, there was some ALT elevations seen with 2218 monotherapy, which came down with the combo. What's the mechanism for that? And what are the kinetics for achieving ALT normalization with suppressing viral RNA?

嘿，下午好，感謝您回答我們的問題。只有我們幾個人。在 HDV SOLSTICE 試驗中，2218 單一療法出現了一些 ALT 升高，而聯合療法則降低了這一水平。其機制是什麼？透過抑制病毒 RNA 來實現 ALT 正常化的動力學是什麼？

I'll take that one, Eva. So thank you for the question. I think that it's important to remember that the number of patients dosed with 2218 or elebsiran monotherapy is small, but we did see a couple of patients who did show an ALT signal. This replicates what we've seen with other siRNA therapy in hepatitis delta patients in a larger study, known as REEF-D, almost 70% of patients did see an ALT signal in patients receiving siRNA who had delta.

我要那個，伊娃。謝謝你的提問。我認為重要的是要記住，接受 2218 或 elebsiran 單藥治療的患者數量很少，但我們確實看到一些患者確實顯示出 ALT 訊號。這重複了我們在一項名為REEF-D 的大型研究中在Delta 型肝炎患者中使用其他siRNA 療法所看到的情況，幾乎70% 的患者在接受siRNA 的Delta 型肝炎患者中確實看到了ALT訊號.

But it's important to remember that when they gave an siRNA and when we've given our siRNA to hepatitis B patients, we have not seen this. So it does not appear to be something intrinsic to the drug, but some interaction between the drug and the hepatitis delta virus itself. So with that in mind, when you look at the data closely, it seems to suggest that on treatment with an siRNA, there is a paradoxical increase in HDV RNA after some duration of therapy. If that is the driving force behind the ALT signal, then it would make sense that driving that HDV RNA down further and preventing the infection of new hepatocytes would be key.

但重要的是要記住，當他們給予 siRNA 時以及當我們向乙型肝炎患者給予 siRNA 時，我們還沒有看到這種情況。因此，這似乎不是該藥物固有的東西，而是該藥物與丁型肝炎病毒本身之間的某種相互作用。因此，考慮到這一點，當您仔細查看數據時，似乎表明在使用 siRNA 治療時，經過一段時間的治療後，HDV RNA 會出現矛盾的增加。如果這是 ALT 訊號背後的驅動力，那麼進一步降低 HDV RNA 並防止新肝細胞感染就成為關鍵。

And that's exactly what we're intending to do with our monoclonal antibody tobevibart, or VIR-3434. So the idea there is that any kind of fluctuation you would see in HDV RNA that might be driving an ALT signal would be prevented by having a neutralizing antibody like tobevibart. And so far, of course, the numbers are very small, of the six patients, we did not see any ALT elevations unlike the 70% of ALT elevation seen with siRNA monotherapy by another company. And so that's the thing we'll be looking forward to seeing as to what will happen when we dose these next 30 patients in the combination arm.

這正是我們打算用單株抗體 tobevibart（即 VIR-3434）來實現的目標。因此，我們的想法是，HDV RNA 中出現的任何可能驅動 ALT 訊號的波動都可以透過使用托貝巴特 (tobevibart) 等中和抗體來預防。當然，到目前為止，在 6 名患者中，這個數字非常小，我們沒有看到任何 ALT 升高，這與另一家公司使用 siRNA 單一療法觀察到 70% 的 ALT 升高不同。因此，當我們對聯合組中接下來的 30 名患者進行給藥時，我們將期待看到會發生什麼。

So to summarize, the mechanism is still not clear, but there are early signals that it is due to the changes in the HDV RNA and there are early signals that 3434 or tobevibart can solve for that.

總而言之，其機制仍不清楚，但有早期訊號表明這是由於 HDV RNA 的變化所致，並且 3434 或 tobevibart 可以解決這一問題。

Perfect. Thank you. And another question on the HBV MARCH trial. You've previously shown that high antibody titers were predictive of sustained surface antigen loss. Do you expect to present antibody titer data at the 48 weeks end of treatment data in Q4?

完美的。謝謝。還有一個關於 HBV MARCH 試驗的問題。您之前已經證明，高抗體滴度可以預測持續的表面抗原流失。您是否預計在第 4 季提供治療數據 48 週結束時的抗體滴度數據？

So we have not yet guided to whether or not we will be sharing anti-HBs data along with the actual surface antigen loss, but we will be doing everything we can to provide as much clarity on our results at that time. So stay tuned.

因此，我們尚未決定是否會與實際表面抗原損失一起共享抗 HBs 數據，但我們將盡一切努力提供盡可能清晰的結果。所以請繼續關注。

Perfect. Thank you.

完美的。謝謝。

Patrick Trucchio, H.C. Wainwright.

特魯基奧 (Patrick Trucchio)，H.C.溫賴特。

Congrats on all the progress. I have a couple of follow-up questions on SOLSTICE program. So just first, a clarification around the next data readouts. I'm wondering, first, should we expect the next update -- or when should we expect the next update on the patient cohort data reported at AASLD 2023, specifically the proportion who achieved ALT normalization, which I understand can take longer than achieving HDV RNA below lower limit of quantification as well as assessment of the durability of the virologic response?

祝賀所有的進展。我有幾個關於 SOLSTICE 計劃的後續問題。首先，對下一個數據讀數進行澄清。我想知道，首先，我們是否應該期待下一次更新，或者我們應該何時期待AASLD 2023 上報告的患者隊列數據的下一次更新，特別是實現ALT 正常化的比例，我知道這可能比實現HDV 需要較長的時間RNA 低於定量下限以及病毒學反應持久性的評估？

I'm wondering if that update may be part of this data that's coming in the second quarter or if maybe we would see the next cut there later this year in the fourth quarter.

我想知道該更新是否可能是第二季即將發布的數據的一部分，或者我們是否會在今年稍後的第四季度看到下一次削減。

And then secondly, I'm wondering how we should think about the 44% of patients having compensated cirrhosis. Is this a proportion of patients with compensated cirrhosis consistent with what would be expected in real-world setting for patients with chronic HDV or how did you decide on that proportion?

其次，我想知道我們應該如何看待 44% 的代償性肝硬化患者。這個代償性肝硬化患者的比例是否與現實世界中慢性 HDV 患者的預期一致，或者您是如何決定這個比例的？

And then how should we think about these key endpoints like HBV RNA and normalization of ALT and as well the safety profile of the combination regimen in these patients with or without compensated cirrhosis?

那麼我們應該如何考慮這些關鍵終點，如 HBV RNA 和 ALT 正常化，以及這些有或沒有代償性肝硬化患者的聯合治療方案的安全性？

All right. Well, Patrick, you're going to challenge my memory to make sure I remember all those questions. But let me start with the compensated cirrhosis question and move on to the endpoint question, and then finish with the durability question.

好的。好吧，派崔克，你要挑戰我的記憶力，以確保我記住所有這些問題。但讓我從代償性肝硬化問題開始，然後轉到終點問題，然後以耐久性問題結束。

So with regard to the compensated cirrhosis, it is, the epidemiology on hepatitis delta patients and how many of them have compensated cirrhosis is not entirely clear, but it is certainly a large proportion, probably somewhere between 30% to 50%. That was not the reason why we ended up at 44%.

那麼關於代償性肝硬化，就是說，丁型肝炎患者的流行病學情況，有多少人是代償性肝硬化，還不完全清楚，但是比例肯定是很大的，大概在30%到50 %之間。這並不是我們最終達到 44% 的原因。

As you can imagine, when you're enrolling in this trial, we actually targeted around 50%, but you want to move also the trial enrollment as fast as possible. So right now, as I said in my prepared remarks, there's about 90% of the trial has been enrolled. That's why it's at 44%. I expect that number to go up because the only patients left in screening are all cirrhotic -- are all patients with cirrhosis.

正如您可以想像的那樣，當您註冊此試用時，我們實際上的目標是 50% 左右，但您也希望盡快轉移試用註冊。所以現在，正如我在準備好的演講中所說，大約 90% 的試驗已經完成。這就是為什麼它是 44%。我預計這個數字會上升，因為剩下的篩檢患者都是肝硬化患者——都是肝硬化患者。

So we'll probably get 44% or maybe even 48% or somewhere around there. But what we really wanted to do was to get at least 10 to 15 patients with cirrhosis per cohort to be able to understand what the kinetics of viral decline is and ensure that there's no obvious safety signals. So that's how the 44% is just sort of the result of where we are in enrollment.

所以我們可能會得到 44% 甚至 48% 或附近的某個地方。但我們真正想做的是讓每個隊列中至少 10 到 15 名肝硬化患者能夠了解病毒下降的動力學是什麼，並確保沒有明顯的安全訊號。這就是 44% 是我們招生狀況的結果。

With regard to the endpoints, I think it is important to remember that how we think about the endpoints is both historical as well as forward-looking. So there are a few possibilities for the primary endpoint that I want to share with you.

關於終點，我認為重要的是要記住，我們對終點的看法既是歷史性的，也是前瞻性的。因此，我想與您分享主要終點的幾種可能性。

The first, of course, is the endpoint that was used by bulevirtide, which was a combined virologic and biochemical endpoint. Specifically, that virologic endpoint allowed either a 2-log decline or getting to the limit of detection virologically and then also requiring ALT normalization.

當然，第一個是 bulevirtide 使用的終點，它是病毒學和生化終點的組合。具體來說，該病毒學終點允許 2 個對數下降或達到病毒學檢測極限，然後還需要 ALT 正常化。

But I think when you speak to physicians, providers, and virologists, what they'll say is, they're not sure what a 2-log decline actually means. For example, if you go from 7 logs to 5 logs, you still have 100,000 copies of the virus in your blood per milliliter. And that obviously does not sound good. So we think, as well as clinicians, that getting to undetectable or below the limit of quantification would be strongly preferred.

但我認為，當你與醫生、提供者和病毒學家交談時，他們會說，他們不確定 2 個對數下降實際上意味著什麼。例如，如果從 7 個日誌變為 5 個日誌，則每毫升血液中仍含有 100,000 個病毒副本。這顯然聽起來不太好。因此，我們以及臨床醫生認為，達到不可檢測或低於量化限度的水平將是強烈首選。

So then you can imagine a forward-looking endpoint, and I think this is the likely possibility, of requiring patients to get to the lower limit of detection or the lower limit of qualification and ALT normalization without allowing patients to achieve just a 2-log decline in viral load.

那麼你可以想像一個前瞻性終點，我認為這是可能的可能性，要求患者達到檢測下限或資格和 ALT 正常化下限，而不讓患者僅達到 2-log病毒載量下降。

That would set a gold standard that I think we could definitely show a meaningful benefit on because it would require everyone to at the first instance, get to the lower limit of quantification where we would have a possible advantage over the standard of care. So I think those are some of the color I can provide for you around the primary endpoint.

這將設定一個黃金標準，我認為我們絕對可以顯示出有意義的好處，因為它要求每個人首先達到量化的下限，這樣我們就可能比護理標準更有優勢。所以我認為這些是我可以為您提供的圍繞主要終點的一些顏色。

And then as far as your third question around durability, I would say that we have actually not guided to the follow-up on those six patients. But as we're going to have nearly 20 participants at 24 weeks, we'll be able to share their kinetics of both viral load decline and ALT changes, which I think will be informative. And we will look into sharing the six patient follow-up data as well in a future guidance call.

至於你關於耐久性的第三個問題，我想說的是，我們其實沒有指導對這六名患者進行追蹤。但由於 24 週時我們將有近 20 名參與者，我們將能夠分享他們的病毒量下降和 ALT 變化的動力學，我認為這將提供豐富的資訊。我們還將考慮在未來的指導電話會議中分享六名患者的追蹤數據。

Great. That's very helpful. Thanks so much.

偉大的。這非常有幫助。非常感謝。

Eric Joseph, JPMorgan.

艾瑞克‧約瑟夫，摩根大通。

(technical difficulty) or to have the program, what do you expect to be the ultimate treatment duration or kind of paradigm here with the tobe/ele combination? Do you expect it to be finite therapy or chronic treatment? And if it is the former finite interval, I guess how much off-treatment observation do you think you would hope to have going into discussions with regulators?

（技術難度）或有該計劃，您期望使用 tobe/ele 組合的最終治療持續時間或範例是什麼？您希望它是有限療法還是長期治療？如果是前一個有限間隔，我想您認為您希望與監管機構進行討論多少治療結束觀察？

So Eric, sorry, the beginning of your question was a little bit difficult to understand.

艾瑞克，抱歉，你問題的開頭有點難以理解。

Is the -- in hepatitis delta, is the expected treatment algorithm going to be finite therapy or chronic therapy? If it's finite therapy, how much treatment follow-up do you think you would have going into initial discussions with regulators?

對於三角型肝炎，預期的治療演算法是有限療法還是慢性療法？如果是有限治療，您認為您需要與監管機構進行初步討論嗎？

Thank you, Eric. Yes, what we are aiming to achieve here is a chronic treatment regimen for hepatitis delta patients. Do you want to comment further, Phil?

謝謝你，埃里克。是的，我們的目標是為丁型肝炎患者提供長期治療方案。菲爾，你想進一步評論嗎？

Yeah. So with that -- in that framework of chronic viral suppressive therapy, as we currently know it, for example, for other viruses like HIV and for hepatitis B, there is no need for a follow-up therapy as there is not a finite duration therapy. I think one of the questions that can come up is, are we going to be following these patients for 24 or 48 weeks? And of course, we'll follow for both, but the question will be with regulators, is there any precedent for earlier data and there is with bulevirtide, and that's another discussion we'll be having with regulators.

是的。因此，在我們目前所知的慢性病毒抑制治療的框架中，例如，對於愛滋病毒和B型肝炎等其他病毒，不需要後續治療，因為沒有有限的持續時間治療。我認為可能出現的問題之一是，我們要追蹤這些患者 24 週還是 48 週？當然，我們會關注這兩個方面，但問題在於監管機構，早期數據是否有先例，bulevirtide 是否有先例，這是我們將與監管機構進行的另一項討論。

Anything you can share about the tolerability profile in -- among patients receiving the upfront combo regimen in the Q2 cohort?

關於第二季度隊列中接受前期聯合治療方案的患者的耐受性概況，您有什麼可以分享的嗎？

Yeah. So I think that certainly, we're looking forward to the Q2 data from our SOLSTICE trial and the patients who have started what we call de novo or immediately on combination therapy without lead-in. And what we've said is that we'll have about 30 participants between the two arms actually, between mono and combo at week 12 and 20 participants at week 24. So you divide that into 15 of the patients will be through week 12 and 10 participants through week 24 in the combination arm, and we're looking forward to being able to share that data in Q2.

是的。所以我認為，我們當然期待 SOLSTICE 試驗的第二季數據，以及那些已經開始我們所謂的從頭治療或立即開始聯合治療而無需導入的患者。我們說過的是，實際上，在第 12 週，兩組之間將有大約 30 名參與者，在單藥和組合之間，在第 24 週有 20 名參與者。因此，您將其分為聯合組中第 12 週的 15 名患者和第 24 週的 10 名參與者，我們期待能夠在第二季度分享這些數據。

Okay. Thanks for taking the question.

好的。感謝您提出問題。

Thanks, Eric.

謝謝，埃里克。

Alec Stranahan, Bank of America.

亞歷克·斯特拉納漢，美國銀行。

Hey, guys. Thanks for taking our question. Just a couple from us. You've mentioned in the past about expanding beyond infectious disease into say, immunology, et cetera. Are there any areas of immunology or targets such as say in 20 that you see as particularly interesting? And would you say within your core competencies regarding antibodies in siRNA or would you be more maybe technology-agnostic?

大家好。感謝您提出我們的問題。只有我們幾個人。您過去曾提到要從傳染病擴展到免疫學等領域。您認為有哪些免疫學領域或目標（例如 20）特別有趣嗎？您會說在您關於 siRNA 抗體的核心能力範圍內，或者您會更不了解技術？

And one question on how you plan to allocate your $1.6 billion roughly in cash. Maybe if you could break down percent spend on pipeline development, discovery, clinical trials, and investments in your AI and machine learning capabilities versus, say, dry powder for investing in external innovation, that'd be great. Thanks.

還有一個問題是關於您計劃如何大致分配 16 億美元現金。也許如果你能將管道開發、發現、臨床試驗以及人工智慧和機器學習能力投資的支出百分比與外部創新投資的乾粉支出進行細分，那就太好了。謝謝。

Okay. Thank you, Alec. Yeah. I mean since its inception, Vir has really been a leader in immunology and of course, initially focused only on really targeting infectious diseases. But what we're really doing now is broadening that vision to, we call it powering the immune system, which is really giving patients the ability to power their immune system to either fight infection, fight cancer. And we do it in two fundamental ways through our powerful antibody therapeutics, which we generate through AI engineering.

好的。謝謝你，亞歷克。是的。我的意思是，自成立以來，Vir 確實是免疫學領域的領導者，當然，最初只專注於真正針對傳染病。但我們現在真正要做的是將這個願景擴大到，我們稱之為增強免疫系統，這實際上使患者能夠增強免疫系統的能力，以抵抗感染，抵抗癌症。我們透過人工智慧工程產生強大的抗體療法，以兩種基本方式做到這一點。

And then secondly, through generating unique T cell responses in vivo with our T cell-based viral vector platform. So the type of expansion that we're looking at, Alec, is really rooted in our strength as a company and where we have deep expertise, and that is in immunology, virology, and oncology.

其次，透過我們基於 T 細胞的病毒載體平台在體內產生獨特的 T 細胞反應。因此，亞歷克，我們正在考慮的擴張類型確實植根於我們作為一家公司的實力以及我們擁有深厚的專業知識，即免疫學、病毒學和腫瘤學。

So we are looking at expanding into viral-associated diseases and then indeed immune targeting such as in cancer. And we will be sharing more information on our early programs in that area towards the end of the year when we will be holding an R&D Day.

因此，我們正在考慮擴展到病毒相關疾病，然後實際上是免疫靶向，例如癌症。我們將在年底舉辦研發日活動，分享更多有關該領域早期專案的資訊。

So with that, I'll maybe ask Sung to comment on our cash position and breakdown.

因此，我可能會請宋對我們的現金狀況和細分發表評論。

Yeah. So Alec, thanks for that question. So with regard to our $1.6 billion in cash and cash equivalents, the majority of this will be dedicated to the ongoing clinical stage programs of hepatitis delta and hepatitis B. Of course, we have to take this one year at a time as we have important data readouts in both of those programs this year. So obviously, we're rooting for success and that would dictate the capital allocation for subsequent years.

是的。亞歷克，謝謝你提出這個問題。因此，就我們的16 億美元現金和現金等價物而言，其中大部分將專門用於正在進行的丁型肝炎和乙型肝炎臨床階段項目。當然，我們必須一年一次地進行這一項目，因為我們有重要的今年這兩個項目的數據讀出。顯然，我們正在為成功而奮鬥，這將決定接下來幾年的資本配置。

But when you look at the immediate year 2024, we've provided guidance of R&D and SG&A expense combined. It's fair to think that more than half of that is dedicated to the development programs, primarily hepatitis delta and hepatitis B. There's amounts that will be invested to in our antibody platform. And as Marianne said in her prepared comments, we'll be very opportunistic about tapping into external innovation where it makes sense, but we'll be very prudent about that.

但當您展望 2024 年時，我們提供了研發和 SG&A 費用相結合的指導。公平地說，其中一半以上專門用於開發項目，主要是丁型肝炎和乙型肝炎。我們的抗體平台將投資大量資金。正如瑪麗安在她準備好的評論中所說，我們將非常機會主義地利用有意義的外部創新，但我們對此將非常謹慎。

Appreciate the color. Thank you.

欣賞顏色。謝謝。

Thanks, Alec.

謝謝，亞歷克。

Joseph Stringer, Needham & Company.

約瑟夫‧斯金格，李約瑟公司。

Hi. Thanks for taking our questions. Just a follow-up question on the delta readout in the second quarter. I just wanted to focus on the cirrhotic patients. Clearly, safety will be key, but do you anticipate that it would be more challenging to show a treatment effect in these patients relative to the non-cirrhotic patients? And how important from a commercial perspective would it be to show a clinical effect in these patients?

你好。感謝您回答我們的問題。只是關於第二季度增量讀數的後續問題。我只是想關注肝硬化患者。顯然，安全性是關鍵，但您是否預期相對於非肝硬化患者，在這些患者中顯示治療效果更具挑戰性？從商業角度來看，在這些患者中顯示臨床效果有多重要？

Thank you, Joey. I'll take that one if that's all right, Marianne. So in terms of cirrhosis, first off, I want to just provide a little clarity. We need to distinguish between patients who have what we call compensated cirrhosis and patients who have decompensated cirrhosis. Decompensated patients are obviously much more fragile and have a high one-year mortality.

謝謝你，喬伊。如果可以的話我就買那個，瑪麗安。因此，就肝硬化而言，首先，我想澄清一點。我們需要區分代償性肝硬化患者和失代償性肝硬化患者。失代償的患者顯然更加脆弱，且一年死亡率很高。

So I think really, we need to -- we are focused on getting our drugs to patients as fast as possible or our drug candidates to patients as fast as possible. And that will include both compensated cirrhosis -- patients with compensated cirrhosis as well as those who are non-cirrhotic.

所以我認為，我們確實需要——我們專注於盡快將我們的藥物提供給患者，或盡快將我們的候選藥物提供給患者。這將包括代償性肝硬化—代償性肝硬化患者以及非肝硬化患者。

We think that the -- as I said earlier, I think the compensated cirrhosis patients are approximately 30% to 50% of patients currently living with hepatitis delta. That number is obviously a little bit biased simply because those with compensated cirrhosis are more likely to present to a clinician.

我們認為，正如我之前所說，代償性肝硬化患者大約佔目前患有丁型肝炎的患者的 30% 至 50%。這個數字顯然有點偏差，因為那些患有代償性肝硬化的人更有可能出現在臨床醫生面前。

In terms of whether or not we expect the efficacy to be any different, I don't see any biological reason why we would expect a different result in cirrhotic patients compared to non-cirrhotic patients from a viral efficacy perspective.

至於我們是否期望療效有任何不同，我看不出有任何生物學原因可以解釋為什麼從病毒功效的角度來看，我們會期望肝硬化患者與非肝硬化患者有不同的結果。

From a safety perspective, there's also not any reason to believe that they would be a significant safety signal. I do want to point out that we did do a hepatic impairment study in decompensated child-pugh turcotte B patients or CPT B patients, and there was no evidence to date of a clinically significant change in PK or safety in that small study. So I think that there's, again, no reason to believe there's a concern, but that's why we do the clinical trials. And that's why we're looking forward to seeing what that data looks like in Q2.

從安全角度來看，也沒有任何理由相信它們會是重要的安全訊號。我確實想指出，我們確實在失代償的child-pugh turcotte B 患者或CPT B 患者中進行了一項肝損傷研究，並且迄今為止沒有證據表明該小型研究中PK 或安全性出現臨床顯著變化。因此，我認為沒有理由相信存在擔憂，但這就是我們進行臨床試驗的原因。這就是為什麼我們期待看到第二季的數據。

Great. Very helpful. Thanks for taking our questions.

偉大的。很有幫助。感謝您回答我們的問題。

Thank you, Joey.

謝謝你，喬伊。

Okay. Thank you, Joey.

好的。謝謝你，喬伊。

Mike Ulz, Morgan Stanley.

麥克烏爾茲，摩根士丹利。

Hey, guys. Thanks for taking the question. Maybe just a follow-up for Sung. Thanks for giving clarity on how to think about OpEx spend this year. But maybe if I could push you a little bit. As we think about moving beyond 2024, maybe give us a sense of how to think about it trend-wise. Should we be thinking more flattish spend or should we be thinking sort of an upward trend? I know a lot will depend on kind of what happens with some of these readouts here. But any comments there would be helpful. Thanks.

大家好。感謝您提出問題。也許只是宋的後續行動。感謝您闡明如何思考今年的營運支出。但也許我可以稍微推動一下你。當我們思考 2024 年後的發展時，或許能讓我們了解如何從趨勢角度思考它。我們應該考慮更平淡的支出還是應該考慮某種上升趨勢？我知道很大程度上取決於這裡的一些讀數會發生什麼。但任何評論都會有幫助。謝謝。

Thanks for the question, Mike. So kind of going back to what I said before, the bulk of the capital allocation, if we continue to demonstrate successful data with hepatitis delta and hepatitis B programs as we have over the last 18 months, that would garner the lion's share of capital allocation.

謝謝你的提問，麥克。回到我之前所說的，大部分資本配置，如果我們繼續像過去 18 個月那樣展示丁型肝炎和乙型肝炎項目的成功數據，那將獲得大部分資本配置。

So moving beyond 2024, we would expect hepatitis delta and hepatitis B studies to continue to ramp up. They're still in Phase 2. As we get into Phase 3, both of these studies would peak, but that peak would not be reached in 2025. The peak would most likely be reached somewhere in the second half of 2026 to 2027 time frame as things progress.

因此，2024 年之後，我們預計丁型肝炎和乙型肝炎研究將繼續增加。他們仍處於第二階段。當我們進入第三階段時，這兩項研究都將達到頂峰，但該頂峰不會在 2025 年達到。隨著事情的進展，高峰很可能會在 2026 年下半年到 2027 年的某個時間段達到。

But again, we have to really take this one year at a time because it's dependent on data. I might just add though, when you look at the guidance for 2024, we put a lot of information out there to help you think about not only GAAP operating expenses, excluding cost of sales, but also how to think about cash utilization from our guidance range because we've provided you with important non-cash items. So both on an OpEx basis and cash utilization basis, we would be significantly lower than 2023, which we would consider a peak year driven by the flu study and related manufacturing.

但同樣，我們必須一次一年地進行一次，因為它依賴數據。不過，我可能只是補充一下，當您查看2024 年的指導時，我們提供了大量信息，不僅可以幫助您考慮GAAP 運營費用（不包括銷售成本），還可以幫助您考慮如何從我們的指導中考慮現金利用率範圍，因為我們為您提供了重要的非現金物品。因此，無論是在營運支出還是現金利用率的基礎上，我們都將大大低於 2023 年，我們認為 2023 年是流感研究和相關製造業推動的高峰年。

And I'll just round out my statement by saying, on an operating expense basis, when you exclude the non-cash significant items, we would expect to be down 18% year over year, which is significant. And again, from all the cost optimization efforts undertaken last year and coming off the peak of the flu investment last year as well.

我想總結我的聲明，在營運費用的基礎上，當你排除非現金重大項目時，我們預計會比去年同期下降 18%，這很重要。再次，從去年進行的所有成本優化工作以及去年流感投資的高峰來看。

All right. That's helpful. Thank you.

好的。這很有幫助。謝謝。

There are no further questions at this time. I will now turn the call over to Marianne De Backer for closing remarks.

目前沒有其他問題。現在我將把電話轉給瑪麗安·德·巴克 (Marianne De Backer) 作結束語。

Okay. Thank you, operator. So to close, we are eagerly anticipating on multiple data catalysts that really in our mind holds a great promise for patient impact and for value creation. And we are well on our way, as we said, powering the immune system to transform lives. Thank you all for joining us today. And operator, you may end the call. Thank you.

好的。謝謝你，接線生。因此，最後，我們熱切期待多種數據催化劑的出現，在我們看來，這些催化劑確實對病人影響和價值創造有著巨大的希望。正如我們所說，我們正在為免疫系統提供動力以改變生活。感謝大家今天加入我們。接線員，您可以結束通話了。謝謝。

This concludes today's call. You may now disconnect.

今天的電話會議到此結束。您現在可以斷開連線。