Immunocore Holdings PLC (IMCR) 2022 Q4 法說會逐字稿

Greetings. Welcome to the Immunocore 2022 Financial Results and Business Update Call. (Operator Instructions) Please note, this conference is being recorded. I will now turn the conference over to your host, Clayton Robertson, Head of Investor Relations. Thank you. You may begin.

問候。歡迎參加 Immunocore 2022 年財務業績和業務更新電話會議。 （操作員說明）請注意，正在錄製此會議。我現在將會議轉交給您的主持人，投資者關係主管克萊頓·羅伯遜 (Clayton Robertson)。謝謝。你可以開始了。

Thank you, Daryl. Welcome to our Q4 and 2022 financial results call. Before we begin, I would like to remind you that this call will contain forward-looking statements within the meaning of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. These include expectations and plans concerning future events, prospects and performance, including with respect to commercialization, clinical development and trials, regulatory approvals and financial results. Actual events may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those disclosed in our filings with the SEC. And such statements represent our views only as of the date of this webcast and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update such statements.

謝謝你，達里爾。歡迎來到我們的第四季度和 2022 年財務業績電話會議。在我們開始之前，我想提醒您，本次電話會議將包含 1995 年《私人證券訴訟改革法案》安全港條款含義內的前瞻性陳述。這些包括對未來事件、前景和業績的預期和計劃，包括商業化、臨床開發和試驗、監管批准和財務結果。由於各種重要因素，包括我們向美國證券交易委員會提交的文件中披露的因素，實際事件可能與這些前瞻性陳述所指示的事件存在重大差異。此類聲明僅代表我們截至本次網絡廣播之日的觀點，不應被視為代表我們截至任何後續日期的觀點。我們特別聲明不承擔任何更新此類聲明的義務。

I'm now pleased to introduce Immunocore's CEO, Dr. Bahija Jallal.

我現在很高興地介紹 Immunocore 的首席執行官 Bahija Jallal 博士。

Thank you, Clay. Good morning and good afternoon, everyone. We're very happy to share an overview of our 2022 performance. With me today are Ralph Torbay, our Head of Commercial; Brian Di Donato, our Chief Financial Officer and Head of Strategy; and David Berman, our Head of Research and Development. We will be happy to take questions at the end.

謝謝你，克萊。大家早上好，下午好。我們很高興分享我們 2022 年業績的概覽。今天和我在一起的是我們的商務主管拉爾夫·托貝 (Ralph Torbay)；我們的首席財務官兼戰略主管 Brian Di Donato；和我們的研發主管 David Berman。我們很樂意在最後回答問題。

2022 was a momentous year, one that established Immunocore as the leader in TCR therapeutics. It is not every day that the company can achieve the first, which makes it even more meaningful to have delivered 3 first with the launch of KIMMTRAK. And we will not stop there. We will stay true to our mission to radically improve outcomes for patients with cancer, infectious disease and autoimmune conditions, and we're never satisfied with incremental benefit. And I'm extremely proud of how our teams had advanced this mission in 2022.

2022 年是重要的一年，這一年使 Immunocore 成為 TCR 療法的領導者。公司並非每天都能取得第一，這使得隨著 KIMMTRAK 的推出而獲得 3 個第一變得更加有意義。我們不會就此止步。我們將堅持我們的使命，從根本上改善癌症、傳染病和自身免疫性疾病患者的預後，我們永遠不會滿足於增量收益。我為我們的團隊在 2022 年如何推進這一使命感到非常自豪。

So let's take a look at the highlights from 2022. KIMMTRAK is the first and only approved treatment for unresectable or metastatic uveal melanoma. It is now approved in more than 30 countries, and we have treated more than 500 patients since the end of Phase 3 trial with KIMMTRAK. We have revenues of just over $140 million with 25% quarter-over-quarter growth. For a biotech of our size, what the team has achieved is amazing. Ralph will provide you with more details about our launch performance as well as our plans to launch in more countries and make KIMMTRAK available to even more patients.

那麼讓我們來看看 2022 年的亮點。KIMMTRAK 是第一個也是唯一一個被批准用於治療不可切除或轉移性葡萄膜黑色素瘤的藥物。它現已在 30 多個國家/地區獲得批准，自 KIMMTRAK 的 3 期試驗結束以來，我們已經治療了 500 多名患者。我們的收入剛剛超過 1.4 億美元，環比增長 25%。對於我們這樣規模的生物技術公司，該團隊取得的成就令人驚嘆。 Ralph 將為您提供有關我們的發布性能的更多詳細信息，以及我們在更多國家/地區推出並使 KIMMTRAK 可供更多患者使用的計劃。

Our research and development teams having successfully passed the (inaudible) KIMMTRAK to the commercial and medical teams have delivered substantial progress with our pipeline. Starting with tebentafusp, we are screening patients with advanced melanoma in Phase 2/3 trial. We presented initial data with our ImmTAC therapy targeting PRAME-A02 at ESMO, showing 3 things: RECIST responses, reduction in circulating tumor DNA across multiple solid tumors and most importantly, durability of response. Our focus now is increasing the trial footprint for the PRAME-A02 Phase 1/2 trial across multiple tumor types as well as in combination with standards of care. In addition, we have announced 3 new candidates in our pipeline. The first to expand our PRAME franchise with ImmTac therapies targeting PRAME-A24 and PRAME-A02 half-life extended.

我們的研發團隊已成功將（聽不清） KIMMTRAK 傳遞給商業和醫療團隊，我們的管道取得了實質性進展。從 tebentafusp 開始，我們正在 2/3 期試驗中篩查晚期黑色素瘤患者。我們在 ESMO 上展示了針對 PRAME-A02 的 ImmTAC 療法的初始數據，顯示了 3 件事：RECIST 反應、跨多個實體瘤的循環腫瘤 DNA 減少以及最重要的是反應的持久性。我們現在的重點是增加 PRAME-A02 1/2 期試驗在多種腫瘤類型中的試驗足跡，並結合護理標準。此外，我們還宣布了 3 名新候選人。第一個擴大我們的 PRAME 特許經營權的 ImmTac 療法針對 PRAME-A24 和 PRAME-A02 的半衰期延長。

The third one is an exciting one, is a first-in-class novel immunotherapy targeting PIWIL. PIWIL has the potential for patients with colorectal cancer and other GI tumors, which are so far insensitive to checkpoint inhibitors. Confirming further the potential of our ImmTac platform, we presented the first safety and pharmacodynamic activity with our ImmTac in HIV just last week at CROI. With this HIV candidate and our HBV therapy, we presented data last year, our aim is to evaluate their potential as a functional cure. As you can see, we had a very busy and productive 2022. We are well placed to deliver these ambitious goals with our projected financial runway taking us into 2026.

第三個是令人興奮的，是針對 PIWIL 的一流新型免疫療法。 PIWIL 有可能用於結直腸癌和其他 GI 腫瘤患者，這些患者迄今為止對檢查點抑製劑不敏感。為了進一步確認我們的 ImmTac 平台的潛力，我們上週在 CROI 展示了我們的 ImmTac 在 HIV 中的第一個安全性和藥效學活性。有了這個 HIV 候選者和我們的 HBV 療法，我們去年提交了數據，我們的目標是評估它們作為功能性治癒的潛力。正如您所看到的，我們度過了一個非常忙碌和富有成效的 2022 年。我們有能力實現這些雄心勃勃的目標，我們預計的財務跑道將帶我們進入 2026 年。

I will now hand it over to Ralph.

我現在將它交給拉爾夫。

Thank you, Bahija. I'm delighted to be here today to provide you with an update on what was a very successful launch year. Approvals in over 30 countries and the launch of KIMMTRAK, we have strongly delivered against the promise of radically improving outcomes for patients living with metastatic uveal melanoma. This has been recognized with KIMMTRAK inclusion into the ASCO and NCCN guidelines, recommending it as a standard of care for patients with mUM and through the prestigious innovative therapy award from (inaudible) in France and the best new drug award from script.

謝謝你，巴希亞。我很高興今天來到這裡，向您介紹非常成功的發布年的最新情況。在 30 多個國家獲得批准並推出 KIMMTRAK，我們堅決兌現了從根本上改善轉移性葡萄膜黑色素瘤患者預後的承諾。 KIMMTRAK 已被納入 ASCO 和 NCCN 指南，推薦將其作為 mUM 患者的護理標準，並獲得了法國（聽不清）享有盛譽的創新療法獎和劇本最佳新藥獎，這一點得到了認可。

Our teams have executed flawlessly launching KIMMTRAK just days after approval, achieving reimbursement in the U.S., Germany and France, transitioning all EAP patients to commercial supply within weeks and importantly, establishing KIMMTRAK as the most prescribed medicine for HLA-A02:01 positive metastatic tubulomynoloma patients across all countries that we've launched in. In 2022, we recognized $141 million in net sales of KIMMTRAK, primarily in 3 major countries. Our Q4 net sales of $51 million represents approximately a 25% quarter-over-quarter growth. This was driven by strong demand in the U.S., including a onetime increase in year-end stocking at our specialty distributors and single-digit demand growth in Germany and France.

我們的團隊在 KIMMTRAK 獲得批准幾天后就完美地啟動了，在美國、德國和法國實現了報銷，在數週內將所有 EAP 患者轉變為商業供應，重要的是，將 KIMMTRAK 確立為 HLA-A02:01 陽性轉移性腎小管肌瘤最常用的處方藥我們推出的所有國家/地區的患者。2022 年，我們確認 KIMMTRAK 的淨銷售額為 1.41 億美元，主要在 3 個主要國家/地區。我們第四季度的淨銷售額為 5100 萬美元，環比增長約 25%。這是由美國的強勁需求推動的，包括我們的專業經銷商的年終庫存一度增加，以及德國和法國的個位數需求增長。

Let's now look at our progress in the U.S. and what to expect moving forward. The outstanding execution by our U.S. team delivered KIMMTRAK to 240 new accounts in 2022. We believe these capture approximately 50% of the patient potential, and we plan to continue increasing the number of new accounts, especially in the community. Our focus on enabling first-line patients, we closed the year with 60% of KIMMTRAK share in first line, being treated closer to home is important for patients and the future of our therapy. At the end of 2022, 1 out of 2 patients were being treated in the community. I'm pleased to see the efficacy and tolerability of KIMMTRAK reported in our Phase 3 clinical trial playing out in the real-world setting. While it remains early to confirm the average duration of therapy, our commercial persistence models indicate that KIMMTRAK duration of therapy is tracking to a mean of around 9 months, which is broadly in line with our expectations.

現在讓我們看看我們在美國取得的進展以及對未來的期待。我們美國團隊出色的執行力在 2022 年將 KIMMTRAK 交付給了 240 個新客戶。我們相信這些佔據了大約 50% 的患者潛力，我們計劃繼續增加新客戶的數量，尤其是在社區中。我們專注於為一線患者提供支持，我們以 60% 的 KIMMTRAK 份額結束了這一年，在離家較近的地方接受治療對患者和我們治療的未來都很重要。到 2022 年底，每 2 名患者中就有 1 名在社區接受治療。我很高興看到 KIMMTRAK 在我們的 3 期臨床試驗中報告的療效和耐受性在現實環境中發揮作用。雖然現在確定平均治療持續時間還為時過早，但我們的商業持久性模型表明 KIMMTRAK 治療持續時間的平均持續時間約為 9 個月，這與我們的預期基本一致。

From an access perspective, our teams have done a tremendous job in securing formal policy coverage for over 90% of all potential patients in the U.S. And last year, we saw 99% of prescription covered. We continue to work hard towards our goal of supporting access for every single patient who needs KIMMTRAK to our KIMMTRAK Connect program.

從可及性的角度來看，我們的團隊在為美國 90% 以上的潛在患者確保正式政策覆蓋方面做了大量工作。去年，我們看到 99% 的處方藥得到了覆蓋。我們繼續努力實現我們的目標，即支持每位需要 KIMMTRAK 的患者訪問我們的 KIMMTRAK Connect 計劃。

Let's move on to Europe, where we've had a fantastic launch as well. With over 100 accounts treating patients with KIMMTRAK across Germany and France, we are capturing nearly all potential patients with mUM in these key markets. The European team are dedicating their efforts to increasing patients treated with KIMMTRAK in first line by working to expand our treatment footprint into office-based physicians in Germany and with [dermato-oncologist] in France. The clinical value of KIMMTRAK has been recognized in Germany by the GBA with a considerable added benefit rating. This is particularly important as KIMMTRAK becomes 1 of only 3 (inaudible) oncology products in the last 10 years to have received a strong rating, which will support our ongoing price negotiations. We expect to reach a negotiated price by the first half of the year. This negotiated price will apply retroactively and we have started accruing for this potential discount in our German net sales as of November 2022.

讓我們繼續前進到歐洲，我們也在那裡進行了精彩的發布。在德國和法國，我們有 100 多個客戶使用 KIMMTRAK 治療患者，我們正在捕獲這些主要市場中幾乎所有潛在的 mUM 患者。歐洲團隊正致力於通過努力將我們的治療足跡擴大到德國的辦公室醫生和法國的[皮膚腫瘤學家]，來增加一線接受 KIMMTRAK 治療的患者。 KIMMTRAK 的臨床價值已在德國獲得 GBA 的認可，並具有相當大的附加效益評級。這一點尤為重要，因為 KIMMTRAK 成為過去 10 年中僅有的 3 種（聽不清）腫瘤學產品中的一種，獲得了很高的評級，這將支持我們正在進行的價格談判。我們預計將在今年上半年達成協商價格。這一協商價格將追溯適用，我們已開始在 2022 年 11 月的德國淨銷售額中累積這一潛在折扣。

In France, we have received an ASMR rating of 3 and then SMR benefit of importance. With no restrictions and not relevant clinical comparators, this strong rating will enable us to begin pricing negotiations in the second half of 2023, with an agreement expected in the first half of 2024. 2022 was certainly a historic year for patients with mUM and for Immunocore. One year ago, we began delivering the amazing innovation that is KIMMTRAK to patients. Today, we have successfully launched in 3 countries, radically improved outcomes for more than 300 patients, and our early access program has benefited over 500 patients globally.

在法國，我們獲得了 3 的 ASMR 評級，然後是 SMR 重要性收益。由於沒有限制且沒有相關的臨床比較，這一強大的評級將使我們能夠在 2023 年下半年開始定價談判，預計將在 2024 年上半年達成協議。對於 mUM 患者和 Immunocore 來說，2022 年無疑是具有歷史意義的一年.一年前，我們開始向患者提供令人驚嘆的創新 KIMMTRAK。今天，我們已在 3 個國家成功推出，從根本上改善了 300 多名患者的預後，我們的早期訪問計劃已使全球 500 多名患者受益。

Looking ahead, we expect to launch KIMMTRAK in one major European country around midyear and in up to 5 additional countries by year-end. Across countries where reimbursement is not yet available, we continue to offer KIMMTRAK to nearly 200 patients through the EAP. We remain focused on our ambition of making KIMMTRAK available to over 1,000 patients by 2025.

展望未來，我們預計將在年中左右在一個主要歐洲國家推出 KIMMTRAK，並在年底前在多達 5 個其他國家推出。在尚未提供報銷的國家/地區，我們繼續通過 EAP 向近 200 名患者提供 KIMMTRAK。我們仍然專注於到 2025 年使 KIMMTRAK 可用於 1,000 多名患者的雄心壯志。

With that, I want to thank the team for an excellent 2022. Thank you for your support. And now I invite Brian to take you through our financial results.

有了這個，我要感謝團隊出色的 2022 年。感謝您的支持。現在我請 Brian 向您介紹我們的財務結果。

Thank you, Ralph. Today, we will focus on the financial highlights in the fourth quarter and year-end 2022 and provide some insights into 2023. Please refer to the press release we issued this morning and our SEC filing on Form 20-F later today for our full financial results. Comparisons discussed versus third quarter 2022 using U.S. dollar convenience rates unless otherwise stated.

謝謝你，拉爾夫。今天，我們將重點關注 2022 年第四季度和年底的財務亮點，並提供對 2023 年的一些見解。請參閱我們今天上午發布的新聞稿和我們今天晚些時候在美國證券交易委員會提交的 20-F 表格，了解我們的完整財務信息結果。除非另有說明，否則使用美元便利利率討論與 2022 年第三季度的比較。

On Slide 14, you see a summary of our financial results. I'm excited to report that our teams continue to execute and to deliver KIMMTRAK to patients in the United States, Germany and France, with the impressive site expansion and seamless reimbursement while continuing to expand our global early access program in new countries currently treating nearly 200 patients. In Q4, we increased vial sales in both the U.S. and Europe. Total fourth quarter net revenue, as Ralph mentioned, was $51.1 million when converted to U.S. dollars, an increase of 25% over Q3. In the U.S., we saw a 50% increase in Q4 net sales, in part due to some onetime year-end stocking and the year-end adjustment of gross to net, which produced 340B and Medicaid assumptions.

在幻燈片 14 上，您可以看到我們的財務業績摘要。我很高興地報告，我們的團隊繼續執行並向美國、德國和法國的患者提供 KIMMTRAK，站點擴展和無縫報銷令人印象深刻，同時繼續在目前治療近200 名患者。在第四季度，我們增加了美國和歐洲的藥瓶銷量。正如拉爾夫所說，第四季度總淨收入換算成美元後為 5110 萬美元，比第三季度增長 25%。在美國，我們看到第四季度淨銷售額增長了 50%，部分原因是一些一次性的年終庫存和年終毛額對淨額的調整，這產生了 340B 和醫療補助假設。

In Europe, even with an increase in vial sales, net revenues decreased to $12.2 million due to new reimbursement accruals for Germany, which started on November 1 and will continue until final pricing agreement expected in Q2. On the expense side, SG&A increased to $52.1 million in Q4, partly due to a currency loss of $50 million on U.S. dollar reserves when it's translated back to great British pounds. R&D expenses for the quarter increased to $32.8 million and are expected to marginally increase throughout 2023 as we expand and accelerate our clinical development portfolio. The company has capitalized with over $400 million in cash and cash equivalents at year-end. With projected KIMMTRAK revenue, this provides a runway into 2026 with the current development plans, including our new ImmTACs portfolio candidates.

在歐洲，即使小瓶銷售額有所增加，淨收入仍下降至 1220 萬美元，原因是德國的新報銷應計費用從 11 月 1 日開始，並將持續到預計在第二季度達成最終定價協議。在費用方面，SG&A 在第四季度增加到 5210 萬美元，部分原因是美元儲備在轉換回英鎊時損失了 5000 萬美元。本季度的研發費用增加到 3280 萬美元，隨著我們擴大和加速我們的臨床開發組合，預計整個 2023 年將略有增加。截至年底，該公司已投入超過 4 億美元的現金和現金等價物。根據 KIMMTRAK 的預計收入，這為當前的開發計劃（包括我們新的 ImmTACs 候選產品組合）提供了一條通往 2026 年的跑道。

Ralph has shared with you some of the key drivers for KIMMTRAK looking ahead. On Slide 15, it summarizes some of these insights as we head into 2023. In Europe, a key dynamic will be formal reimbursement agreement in Germany and France as well as the expected launch of commercial KIMMTRAK in one additional major European country by midyear, and we expected 5 additional new countries by year-end. In the U.S., one opportunity for growth is new community oncology accounts, which tend to be lower density than academic centers, which may lead to lower U.S. growth rates as we move into 2023.

拉爾夫與您分享了 KIMMTRAK 展望未來的一些關鍵驅動因素。在幻燈片 15 上，它總結了我們進入 2023 年時的一些見解。在歐洲，一個關鍵動態將是德國和法國的正式報銷協議以及預計到年中在另一個主要歐洲國家推出商業 KIMMTRAK，以及我們預計年底前還會有 5 個新國家。在美國，增長的一個機會是新的社區腫瘤賬戶，其密度往往低於學術中心，這可能會導致我們進入 2023 年時美國的增長率下降。

Globally, it's too still too early to know real-world ration of treatment. However, currently, we are approaching the 9 months observed in the clinical trials. Another consideration in the U.S. is the 2021 Refund Act. TAP requires drug manufacturers to rebate CMS for discarded drug events. Starting in Q4 2023, CMS may request a rebate of a portion of our CMS sales for KIMMTRAK. We plan to seek an exemption from CMS as we follow FDA and USP guidance regarding required fill to ensure patients safely and consistently receive 68 micrograms of KIMMTRAK.

在全球範圍內，現在了解真實世界的治療比例還為時過早。然而，目前，我們正在接近臨床試驗中觀察到的 9 個月。美國的另一個考慮因素是 2021 年退款法。 TAP 要求藥品製造商為廢棄藥品事件對 CMS 進行返還。從 2023 年第 4 季度開始，CMS 可能會要求退還我們用於 KIMMTRAK 的部分 CMS 銷售額。我們計劃尋求 CMS 的豁免，因為我們遵循 FDA 和 USP 關於所需填充的指導，以確保患者安全和持續地接受 68 微克 KIMMTRAK。

Given the number of moving revenue targets in 2023, it is still too early to accurately provide sales guidance for the year. The team and I are extremely pleased with the commercial team's execution and bringing KIMMTRAK to patients globally, and we look forward to continuing to health and support patients with metastatic uveal melanoma.

鑑於 2023 年收入目標的變動，現在準確提供全年銷售指引還為時過早。我和團隊對商業團隊的執行以及將 KIMMTRAK 帶給全球患者感到非常滿意，我們期待繼續保持健康並為轉移性葡萄膜黑色素瘤患者提供支持。

I will now turn the call over to David, who will review our portfolio updates. David?

我現在將電話轉給大衛，他將審查我們的投資組合更新。大衛？

Thank you very much, Brian. We are very proud to have brought KIMMTRAK as the first approved medicine for metastatic uveal melanoma. Gp100 which is the target of KIMMTRAK, is also expressed in other melanoma types, including cutaneous melanoma. All of the efficacy signals we observed in early trials for tebn in mUM are also replicated in cutaneous melanoma, and this gives us confidence to initiate a registrational program in previously treated cutaneous melanoma with a survival endpoint. The study is now screening patients, and we estimate the opportunity in this indication is 2x to 4x the size of uveal melanoma.

非常感謝你，布萊恩。我們非常自豪地將 KIMMTRAK 作為第一個被批准用於治療轉移性葡萄膜黑色素瘤的藥物。作為 KIMMTRAK 靶標的 Gp100 也在其他黑色素瘤類型中表達，包括皮膚黑色素瘤。我們在 mUM 的 tebn 早期試驗中觀察到的所有療效信號也在皮膚黑色素瘤中得到復制，這使我們有信心在先前治療過的具有生存終點的皮膚黑色素瘤中啟動註冊計劃。該研究目前正在篩查患者，我們估計該適應症的機會是葡萄膜黑色素瘤大小的 2 至 4 倍。

Gp100 is a melanoma specific target. And with PRAME, we have the opportunity to go to other solid tumors. And based on the strength of the Phase 1 data, we have invested in building a franchise around this target. The lead program, F106C targets a PRAME peptide presented by HLA-A02. At ESMO last year, we showed that F106C induced durable PRs in uveal melanoma, cutaneous melanoma and ovarian carcinoma. And our focus now is to expand the trial footprint globally and enrolled 4 monotherapy expansions as well as combinations. We expect to have efficacy data by the first half of '24.

Gp100 是黑色素瘤特異性靶點。有了 PRAME，我們就有機會去研究其他實體瘤。基於第一階段數據的優勢，我們圍繞這一目標投資建立了特許經營權。主導項目 F106C 以 HLA-A02 呈遞的 PRAME 肽為目標。在去年的 ESMO 上，我們發現 F106C 在葡萄膜黑色素瘤、皮膚黑色素瘤和卵巢癌中誘導了持久的 PR。我們現在的重點是在全球範圍內擴大試驗足跡，並招募了 4 種單一療法擴展和聯合療法。我們希望在 24 年上半年獲得療效數據。

In January, we announced that we will be bringing 2 new PRAME impacts to IND in the next 18 months. T119C targets a PRAME peptide presented by HLA-A24 and this will expand the potential addressable population by 30%. In Japan alone, for example, 60% of patients are positive for A24. P115C targets the same HLA-A02 peptide as the lead program that has an extended half-life. We know that our current platform with a standard half-life is very active with durable PRs in multiple solid tumors and for tebentafusp a dramatic survival benefit.

一月份，我們宣布我們將在未來 18 個月內為 IND 帶來 2 個新的 PRAME 影響。 T119C 以 HLA-A24 呈遞的 PRAME 肽為目標，這將使潛在的可尋址人群擴大 30%。例如，僅在日本，就有 60% 的患者呈 A24 陽性。 P115C 靶向與具有延長半衰期的先導程序相同的 HLA-A02 肽。我們知道，我們目前具有標準半衰期的平台非常活躍，在多種實體瘤中具有持久的 PR，並且對於 tebentafusp 具有顯著的生存益處。

Nevertheless, given our enthusiasm for PRAME, we are also investing in an HLA version, which could enhance patient convenience. Our discovery engine has a pipeline of unique targets where we will push the boundaries of using TCRs to unlock solid tumors. And here, I'm delighted to present a novel TCR target called PIWIL1. PIWIL1 have several features reminiscent of PRAME, one of which is that it's a negative prognostic marker, suggesting it has an important role in tumor progression. PIWIL1 has broad homogenous expression in about (inaudible) colorectal cancer patients.

儘管如此，鑑於我們對 PRAME 的熱情，我們還在投資 HLA 版本，這可以提高患者的便利性。我們的發現引擎擁有一系列獨特的目標，我們將在這些目標中突破使用 TCR 解鎖實體瘤的界限。在這裡，我很高興展示一個名為 PIWIL1 的新型 TCR 靶標。 PIWIL1 有幾個特徵讓人聯想到 PRAME，其中之一是它是一種陰性預後標誌物，表明它在腫瘤進展中具有重要作用。 PIWIL1 在大約（聽不清）結直腸癌患者中具有廣泛的同質表達。

And CRC historically has been insensitive to checkpoints, reminiscence of uveal melanoma. We believe the addressable population is 35,000 patients per year and an IND is planned for fourth quarter of this year. Our T cells scan for cancer, but they also scan for virally infected cells. And therefore, it was logical to apply our technology to attempt functional therapy HBV and HIV. Both have viral reservoirs where current therapy cannot remove or eliminate the residual virus. The goal of TCR by specifics are to eliminate these reservoirs.

而 CRC 歷來對檢查點不敏感，讓人聯想到葡萄膜黑色素瘤。我們認為可尋址人群為每年 35,000 名患者，計劃在今年第四季度進行 IND。我們的 T 細胞掃描癌症，但它們也掃描病毒感染的細胞。因此，將我們的技術應用於嘗試功能性治療 HBV 和 HIV 是合乎邏輯的。兩者都有病毒庫，目前的治療無法去除或消除殘留的病毒。 TCR 的具體目標是消除這些水庫。

113V, our HIV ImmTAC is potent at killing HIV infected CD4 T cells and works by recruiting the cytotoxic CD8 T cell to punch holes in the infected T cell. We opened a single ascending dose portion of the HIV trial last year and have had very strong enthusiasm in enrollment of people living with HIV who are stable on antiretroviral therapy. The primary objective was safety and to identify a dose for the multiple ascending dose portion. We identified 15 micrograms as a dose that was well tolerated with no clinical cytokine release syndrome, but induced IL-6 in the blood. We have found in our oncology programs that IL-6 is a sensitive downstream biomarker of T cell engagement and redirection and this consistency from oncology to infectious disease is striking for us and provides reason to move to the MAD.

113V，我們的 HIV ImmTAC 可有效殺死 HIV 感染的 CD4 T 細胞，並通過募集細胞毒性 CD8 T 細胞在受感染的 T 細胞上打孔來發揮作用。去年，我們啟動了 HIV 試驗的單次遞增劑量部分，並且非常熱衷於招募接受抗逆轉錄病毒治療穩定的 HIV 感染者。主要目標是安全性和確定多次遞增劑量部分的劑量。我們將 15 微克確定為耐受性良好且沒有臨床細胞因子釋放綜合徵但在血液中誘導 IL-6 的劑量。我們在我們的腫瘤學項目中發現，IL-6 是 T 細胞參與和重定向的敏感下游生物標誌物，這種從腫瘤學到傳染病的一致性對我們來說是驚人的，並提供了轉向 MAD 的理由。

We have now opened the MAD portion where participants living with HIV will receive 3 months of 113V on top of antiretroviral therapy. The primary endpoint of safety and to determine a Phase 2 dose, but we are very keen to also look at antiviral activity, including stopping the ImmTAC 113V and the antiretroviral treatment after 3 months to see if we can affect slow or decrease the kinetics and magnitude of HIV viral rebound. We believe this trial should provide early POC for a functional care.

我們現在已經開放了 MAD 部分，感染 HIV 的參與者將在抗逆轉錄病毒治療的基礎上接受 3 個月的 113V。安全性和確定 2 期劑量的主要終點，但我們也非常熱衷於研究抗病毒活性，包括停止 ImmTAC 113V 和 3 個月後的抗逆轉錄病毒治療，看看我們是否可以減緩或降低動力學和幅度HIV 病毒反彈。我們認為該試驗應該為功能性護理提供早期 POC。

I'll now hand back to Bahija.

我現在將交還給 Bahija。

Thank you, David, Brian, and thank you, Ralph. As you have heard, 2022 was an amazing and transformative year for the company. We have definitely written the next chapter in oncology treatment as we pioneered and now launched KIMMTRAK. This pipeline reflects the large potential that our ImmTAC platform can offer to patients across many cancer types, and as you just heard, also infectious diseases. Given the breadth and depth of our pipeline, we need to continually prioritize our portfolio candidates. You'll note that we have removed our ImmTAC candidate targeting MAGE-A4(AO2). We have opted out of our co-funding agreement with Genentech, given our focus on PRAME.

謝謝你，大衛，布賴恩，謝謝你，拉爾夫。如您所知，2022 年對公司來說是令人驚嘆和變革的一年。當我們率先推出 KIMMTRAK 時，我們無疑已經寫下了腫瘤治療的新篇章。這條管道反映了我們的 ImmTAC 平台可以為許多癌症類型的患者提供的巨大潛力，正如你剛剛聽到的，還有傳染病。鑑於我們管道的廣度和深度，我們需要不斷地優先考慮我們的投資組合候選人。您會注意到我們已經刪除了針對 MAGE-A4(AO2) 的 ImmTAC 候選藥物。鑑於我們專注於 PRAME，我們選擇退出與基因泰克的共同資助協議。

In the collaboration, we are eligible to receive development of commercial milestones if Genentech advances the MAGE-A4(A02) therapy. This is a robust pipeline based on which we will continue building Immunocore as the growing leader in TCR therapeutics. So officially, Immunocore is now a commercial stage biotech company. I'm very proud to report such revenues for Q4 and 2022 and a cash runway into 2026 that will allow us to continue delivering against our commitment as we have done to date. Our performance is even more significant in the context of what has been another challenging year for the biotech sector.

在合作中，如果 Genentech 推進 MAGE-A4（A02）療法，我們就有資格獲得商業里程碑的開發。這是一個強大的管道，我們將在此基礎上繼續打造 Immunocore 作為 TCR 治療領域日益增長的領導者。因此，Immunocore 現在正式成為一家商業階段的生物技術公司。我非常自豪地報告第四季度和 2022 年的收入以及到 2026 年的現金跑道，這將使我們能夠像迄今為止所做的那樣繼續兌現我們的承諾。在生物技術行業又一個充滿挑戰的一年的背景下，我們的表現更加顯著。

So as we wrap up our remarks, I'm excited for the year ahead. So if 2022 was a transformative year, 2023 will be a year expanding on those successes. Our priorities are clear. We are focused on launching and growing KIMMTRAK and enrolling the cutaneous melanoma trial. For our PRIME program, we are investing in increasing the site footprint and enrolling patients in multiple tumor types as well as in combination with standards of care. We are also expanding the PRAME franchise with an eye towards multiple INDs in the next 18 months. Also in oncology, we plan to file an IND for our first-in-class therapy targeting PIWIL1 later this year.

因此，當我們結束我們的發言時，我對來年感到興奮。因此，如果 2022 年是變革的一年，那麼 2023 年將是擴大這些成功的一年。我們的優先事項很明確。我們專注於啟動和發展 KIMMTRAK 並參與皮膚黑色素瘤試驗。對於我們的 PRIME 計劃，我們正在投資增加站點足跡並招募多種腫瘤類型的患者以及結合護理標準。我們還在擴大 PRAME 特許經營權，著眼於未來 18 個月內的多個 IND。同樣在腫瘤學方面，我們計劃在今年晚些時候為針對 PIWIL1 的一流療法提交 IND。

And infectious disease, we have finished a single ascending dose portion of the HIV trial and started the multiple ascending dose part to identify safety and also antiviral activity that could lead to a functional cure. Along the way, we will continue to focus on cost and cash discipline the way we have been every step of the way. So as we enter 2023, we do so with same drive, determination and sense of urgency to radically improve outcomes for patients.

在傳染病方面，我們已經完成了 HIV 試驗的單次遞增劑量部分，並開始了多次遞增劑量部分，以確定可能導致功能性治癒的安全性和抗病毒活性。在此過程中，我們將一如既往地繼續關注成本和現金紀律。因此，當我們進入 2023 年時，我們將以同樣的動力、決心和緊迫感這樣做，以從根本上改善患者的預後。

With that I want to thank every single employee at Immunocore. I want to thank you as our investors and shareholders for your support. But most importantly, I want to thank our patients and our -- and their families. And now I'll be happy with the team to take your questions, and we'll open the call for questions. Thank you.

我要感謝 Immunocore 的每一位員工。我要感謝您作為我們的投資者和股東的支持。但最重要的是，我要感謝我們的患者和我們——以及他們的家人。現在我很高興和團隊一起回答你的問題，我們將開始提問。謝謝。

(Operator Instructions) Our first question comes from the line of Michael Yee with Jefferies.

（操作員說明）我們的第一個問題來自 Michael Yee 與 Jefferies 的合作。

Congrats on a great year. 2 questions, On the KIMMTRAK sales in U.S., there was a very strong number there. And then you mentioned that there were some onetime positive impacts like gross to net and also some inventory. Could you just help us understand what the underlying number of demand there was in the fourth quarter, so that could help us get a good run rate going into 2023? And describe what you think the growth rate looks like throughout 2023 for the U.S.?

恭喜你度過了美好的一年。 2 個問題，關於 KIMMTRAK 在美國的銷售情況，那裡的數字非常強勁。然後你提到有一些一次性的積極影響，比如毛淨值和一些庫存。您能否幫助我們了解第四季度的潛在需求量，從而幫助我們在 2023 年獲得良好的運行率？並描述一下您認為美國整個 2023 年的增長率如何？

And then a question on PRAME, maybe for David. I know you're enrolling the Phase 2 or Phase 1 the expansion cohorts. Can you talk to us a little bit about how you think about the bar for lung cancer and the expectation for lung cancer, given what you've seen previously and to help right size us or what is good lung cancer data?

然後是關於 PRAME 的問題，可能是給大衛的。我知道您正在招募第 2 階段或第 1 階段的擴展隊列。你能和我們談談你如何看待肺癌的標準和對肺癌的預期嗎，考慮到你之前看到的情況，並幫助調整我們的規模或什麼是好的肺癌數據？

Thank you, Michael. Great questions. Brian, you'll take the first one and then David.

謝謝你，邁克爾。很好的問題。布賴恩，你選第一個，然後選戴維。

Yes. So Michael, some more specifics around those 2 increases in Q4. Together, they're about $5 million that we saw for increase in stocking and a reduction in gross to net, mostly 340 the assumptions that we use. We're probably a little bit conservative, so about $5 million. So the U.S. instead of being $38 million it was probably around $33 million in real end demand. So that's probably a pretty good number as we move into Q1 for benchmarking. And as we mentioned, as we have saturated or have now penetrated most of the academic centers, and we're moving in community growth, you should expect growth to be slower in 2023 in the U.S. The other dynamic is we'll have another month of German discount for Q1 versus Q4. So that will reduce it a little bit more as well from a benchmark perspective.

是的。所以邁克爾，關於第四季度這兩個增長的更多細節。我們看到庫存增加和毛淨減少的總和約為 500 萬美元，主要是我們使用的假設 340。我們可能有點保守，所以大約 500 萬美元。因此，美國的實際最終需求可能不是 3800 萬美元，而是大約 3300 萬美元。因此，當我們進入第一季度進行基準測試時，這可能是一個相當不錯的數字。正如我們所提到的，由於我們已經飽和或現在已經滲透到大多數學術中心，並且我們正在推動社區增長，你應該預計到 2023 年美國的增長會放緩。另一個動態是我們還有一個月德國第一季度與第四季度的折扣。所以從基準的角度來看，這也會減少一點。

Yes, Michael, I guess I would answer it in 2 ways. The first is that lung is a very complex tumor. So we need to study different populations. For example, the EGFR ALK mutation is historically IO insensitive. And of course, we're studying patients now who've also failed on checkpoints. So there's that lung complexity we need to take into account.

是的，邁克爾，我想我會用兩種方式回答。首先是肺是一種非常複雜的腫瘤。所以我們需要研究不同的人群。例如，EGFR ALK 突變歷來對 IO 不敏感。當然，我們現在正在研究在檢查點上也失敗的患者。所以我們需要考慮肺的複雜性。

But in terms of expectations of what we're looking for, I think I would look at it 2 ways. One is we're looking to get confidence that F106C is active in line. Is there any evidence of activity, i.e., ctDNA reductions? And then we're looking for confidence in RECIST endpoint. Is there the opportunity for response rate or PFS. And so I think those are the 2 levels of activity that we're looking at.

但就我們正在尋找的東西的期望而言，我想我會用兩種方式來看待它。一是我們希望獲得 F106C 在線激活的信心。是否有任何活動證據，即 ctDNA 減少？然後我們正在尋找對 RECIST 端點的信心。是否有響應率或 PFS 的機會。所以我認為這些是我們正在研究的兩個活動級別。

Our next questions come from the line of Jessica Fye with JPMorgan.

我們的下一個問題來自 JPMorgan 的 Jessica Fye。

This is Nick on for Jess. (inaudible) today, you mentioned that you're about 50%, 60% patients on therapy in the first-line study. How does that -- did that hold true across the U.S. or Europe? Or is one region more heavily weighted towards first line or second line versus the other?

這是傑西的尼克。 （聽不清）今天，你提到你大約有 50%、60% 的患者在一線研究中接受治療。那是如何 - 這在美國或歐洲是否適用？還是一個區域比另一個區域更偏向於一線或二線？

Great. Ralph, you can take that one.

偉大的。拉爾夫，你可以拿那個。

Nick, thank you for the question. So look, in the U.S., we are seeing 60% of the KIMMTRAK patients in first line. So the remainder of them are in second line plus. In Europe, specifically in Germany and France, we're seeing around 45%, and that's where we're focused on increasing because our focus is first line. That's where we see OS that's where we see the duration of therapy. We're focused on increasing that as high as we can get it.

尼克，謝謝你的提問。所以看，在美國，我們看到 60% 的 KIMMTRAK 患者在一線。所以他們中的其餘部分都在二線加上。在歐洲，特別是在德國和法國，我們看到大約 45%，這就是我們專注於增加的地方，因為我們的重點是第一線。這就是我們看到 OS 的地方，也就是我們看到治療持續時間的地方。我們專注於盡可能提高它。

Our next questions come from the line of Tyler Van Buren with Cowen.

我們的下一個問題來自 Tyler Van Buren 和 Cowen 的對話。

This is [Tara] on for Tyler. So when you say that the PRAME dose expansion data are expected by the first half of 2024, is there a chance that it could come later in 2023, maybe at ESMO or one of those conferences? And are there any other data updates this year that we can look forward to?

這是泰勒的[塔拉]。所以當你說 PRAME 劑量擴展數據預計在 2024 年上半年出現時，它是否有可能在 2023 年晚些時候出現，也許是在 ESMO 或其中一個會議上？以及今年還有哪些值得我們期待的數據更新？

Yes. It's really the -- our strategy was to invest early into expanding the footprint for the clinical footprint. I think that in any drug development, that's what takes the longest. And that's exactly what we want to focus the team on and that it's a pretty comprehensive program with multiple arms for the monotherapy plus the combination. So that's really the focus, and that's why we are going globally and we said we'll bring the data by the first half of 2024.

是的。這真的是 - 我們的戰略是儘早投資擴大臨床足蹟的足跡。我認為在任何藥物開發中，這都是需要最長的時間。這正是我們希望團隊關注的重點，這是一個非常全面的項目，有多個手臂用於單一療法和聯合療法。所以這才是真正的重點，這就是我們走向全球的原因，我們說我們將在 2024 年上半年之前提供數據。

Our next question comes from the line of Patrick Trucchio with H.C. Wainwright.

我們的下一個問題來自 Patrick Trucchio 和 H.C.溫賴特。

I actually have a follow-up question on the capital allocation focus. Specifically with KIMMTRAK revenues ramping, while multiple programs continue through development and these new programs emerge. I'm wondering if you can discuss the focus for capital allocation in the next year and beyond, particularly as it relates to balancing the focus on R&D and pipeline development with the potential eventual pivot to profitability. How do you balance these priorities? And when might the company achieve profitability?

我實際上有一個關於資本配置重點的後續問題。特別是隨著 KIMMTRAK 收入的增加，同時多個項目繼續開發，這些新項目不斷湧現。我想知道你是否可以討論明年及以後的資本配置重點，特別是因為它涉及平衡對研發和管道開發的重點與潛在的最終盈利能力。您如何平衡這些優先事項？公司什麼時候可以實現盈利？

Yes. Thank you. Thank you for the question. I'll start and then Brian. Really, our focus is expanding the pipeline. As you have seen, the pipeline is expanding, and that's exactly what we will be -- the dollars will go there. I think it's very important. We have some great assets. But Brian, do you want to comment on that as well?

是的。謝謝。感謝你的提問。我先開始，然後是 Brian。實際上，我們的重點是擴大渠道。正如你所看到的，管道正在擴大，而這正是我們將要做的——美元將流向那裡。我認為這非常重要。我們有一些很棒的資產。但是布賴恩，你也想對此發表評論嗎？

Yes. Great question, Patrick. If you look at our research expenses over the last 3 years, we've been pretty consistent in our research expenses, and we've been able to deliver these new ImmTAC molecules like well PIWIL, PRAME-A24, PRAME half-life extension with those research expenses. So we don't expect that to change dramatically. Well, what will change and will scale as you would expect, would be the development cost as we move and advanced PRAME. And it'll really be driven in the large part by how many large pivotal trials we need to run for PRAME. So that's where we're focused. We have those in the budget now. You'll notice that we did opt out of the co-development co-funding of MAGE as we focus on the PRAME expansion. And however, we still appreciate the collaboration with Genentech, and we'll still be in collaboration with them and be able to receive milestones and royalties from MAGE-A4 if they move that forward.

是的。好問題，帕特里克。如果你看看我們過去 3 年的研究費用，我們的研究費用一直非常穩定，我們已經能夠提供這些新的 ImmTAC 分子，如 PIWIL、PRAME-A24、PRAME 半衰期延長那些研究費用。所以我們不希望這種情況發生巨大變化。好吧，隨著我們移動和推進 PRAME，將會發生變化並會像您預期的那樣擴展的是開發成本。它實際上在很大程度上取決於我們需要為 PRAME 運行多少大型關鍵試驗。所以這就是我們關注的地方。我們現在在預算中有這些。你會注意到我們確實選擇退出 MAGE 的共同開發共同資助，因為我們專注於 PRAME 擴展。然而，我們仍然感謝與 Genentech 的合作，我們仍將與他們合作，如果他們向前推進，我們將能夠從 MAGE-A4 獲得里程碑和版稅。

Our next question comes from the line of Justin Kim with Oppenheimer.

我們的下一個問題來自 Justin Kim 和 Oppenheimer 的對話。

With regards to the median (inaudible) duration, does the team have any intake on how physicians are managing patients through situations of potential to the progression? And are there any tools to observationally compare how the experience might be additive to the clinical trial experience, perhaps benchmarking against HLA-A02 negative patient?

關於中位（聽不清）持續時間，團隊是否了解醫生如何通過可能進展的情況來管理患者？是否有任何工具可以觀察性地比較這些經驗如何添加到臨床試驗經驗中，也許是針對 HLA-A02 陰性患者的基準？

Great, Justin. I think Ralph you can talk about the DOT and where we are compared with clinical trials, go ahead.

太好了，賈斯汀。我想拉爾夫，你可以談談 DOT 以及我們與臨床試驗相比的地方，繼續。

Justin, look, it's really great when we launched a new medicine, and we see the experience in the clinical trial being replicated in the real world because that means that the safety and efficacy that we've seen in the clinical trial is true and physicians are able to really use the medicine the way that is intended. And the patients are seeing the benefit and physicians are seeing that the patients benefit.

賈斯汀，你看，當我們推出一種新藥時真的很棒，我們看到臨床試驗中的經驗在現實世界中被複製，因為這意味著我們在臨床試驗中看到的安全性和有效性是真實的，醫生們能夠真正按照預期的方式使用藥物。患者看到了好處，醫生看到患者受益。

So from a medium perspective, we're at 6 months. And from a mean, we're tracking to 9 months. And if you recall, that's what we saw exactly in the clinical trial. As that relates subset progression, we keep educating on that aspect or treatment beyond progression, we keep educating on that aspect. Of course, today, we see treatment patterns to -- very similar to what we're seeing in academic accounts, which is why we're also seeing this mean duration of treatment at tracking to 9 months.

所以從中等角度來看，我們已經 6 個月了。從平均值來看，我們追踪到 9 個月。如果你還記得，那正是我們在臨床試驗中看到的。由於這與子集進展有關，我們繼續在這方面進行教育或超越進展的治療，我們繼續在這方面進行教育。當然，今天，我們看到的治療模式與我們在學術報告中看到的非常相似，這就是為什麼我們也看到這種平均治療持續時間長達 9 個月。

Our next question comes from the line of Justin Zelin with BTIG.

我們的下一個問題來自 BTIG 的 Justin Zelin。

Maybe just a follow-up on the prior question just on duration of therapy. Do you expect that this duration of therapy, what kind of tick in the results seen thus far mirroring the clinical trials in the real world? Or do you think that it's possible that you could see extension with more follow-up here?

也許只是對先前關於治療持續時間的問題的跟進。您是否期望這種治療持續時間，迄今為止看到的結果與現實世界中的臨床試驗有何相似之處？或者您是否認為您可以在這裡看到更多跟進的擴展？

Go ahead.

前進。

So Justin, that's what we expect. We expect to see so far what we've seen in the clinical trial. And if you look at our clinical trial to a clinical trial, you see the median staying somewhat the same and then the mean growing not significantly, and that's driven mostly by the tale. So we do expect that the longer we're in the market, if physicians keep treating the way they're treating, we do expect the mean to be growing, not significantly, and I think you can use the clinical trial the benchmark to see where this is going.

賈斯汀，這就是我們所期望的。到目前為止，我們希望看到我們在臨床試驗中看到的結果。如果你看看我們的臨床試驗，你會發現中位數保持不變，然後平均值增長不顯著，這主要是由故事驅動的。所以我們確實預計我們進入市場的時間越長，如果醫生繼續按照他們的治療方式進行治療，我們確實預計均值會增長，但不會顯著增長，我認為你可以使用臨床試驗作為基準來查看這是怎麼回事。

Our next question comes from the line of Peter Lawson with Barclays.

我們的下一個問題來自巴克萊銀行的彼得勞森。

I guess more of a follow-up here, just around where you think that duration of treatment could eventually settle for KIMMTRAK? And the half-life extension, is that for patient convenience? Or do you think that could help with durability as well?

我想更多的是這裡的後續行動，就在您認為治療持續時間最終可以滿足 KIMMTRAK 的地方？半衰期延長，是為了方便病人嗎？或者你認為這也有助於提高耐用性嗎？

Yes. Great. I think Ralph you take the duration and maybe David on the half-life expected -- extension.

是的。偉大的。我認為 Ralph 你考慮了持續時間，也許 David 考慮了預期的半衰期 - 延長。

So I think the best answer I can give you is that we're going to be providing an update of our 3-year overall survival, which will include duration of therapy in PFS at an upcoming conference. So I invite you to take a look at that. So you can see where we expect the mean duration of treatment to go. David?

因此，我認為我能給你的最佳答案是，我們將在即將召開的會議上提供 3 年總生存期的更新，其中包括 PFS 的治療持續時間。所以我邀請你看一看。所以你可以看到我們期望的平均治療持續時間。大衛？

Yes. Peter, you know what's remarkable with KIMMTRAK with a plasma half-life of 8 hours, we saw survival benefit with a hazard ratio of 0.51. So we know that our current platform is, of course, very highly active. I think it's an open question about whether a half-life extension will have any improvement in efficacy or durability. We'll have to just be data driven on that.

是的。 Peter，你知道 KIMMTRAK 的血漿半衰期為 8 小時的顯著之處，我們看到了風險比為 0.51 的生存獲益。所以我們知道我們當前的平台當然非常活躍。我認為延長半衰期是否會對療效或耐久性有任何改善是一個懸而未決的問題。我們必須僅由數據驅動。

Our next question comes from the line of Jeff Hung with Morgan Stanley.

我們的下一個問題來自 Jeff Hung 與摩根士丹利的對話。

For advanced melanoma, can you talk about why you're using ctDNA in Phase 2? And how predictive do you think that is for survival endpoint in Phase 3? And then for PRAME, how do you think about treating multiple HLAs? And what needs to be done to get there?

對於晚期黑色素瘤，您能談談為什麼在第 2 階段使用 ctDNA 嗎？您認為這對第 3 階段的生存終點有多大的預測意義？然後對於 PRAME，您如何看待治療多個 HLA？需要做什麼才能到達那裡？

Right. Great question. David?

正確的。很好的問題。大衛？

So for the advanced melanoma, the dual endpoints for the Phase II are both ctDNA and overall survival. The reason we're doing ctDNA is because that gives us the earliest fastest read so that we can make the decisions for the Phase 3, i.e., drop one of the arms, repower it. We also designed it though, because ctDNA is not yet completely validated in cutaneous melanoma, we realize that. It's going to give us a directional look. We designed it also to have a survival look. We realized survival won't be mature at that point, but we will have enough power to get an estimate about whether survival is trending. So that's really the reason for the ctDNA.

因此，對於晚期黑色素瘤，II 期的雙重終點是 ctDNA 和總生存期。我們做 ctDNA 的原因是因為它給了我們最快的讀取速度，這樣我們就可以為第 3 階段做出決定，即放下一隻手臂，重新啟動它。我們也設計了它，因為 ctDNA 尚未在皮膚黑色素瘤中得到完全驗證，我們意識到這一點。它會給我們一個定向的外觀。我們將它設計成具有生存外觀。我們意識到生存在那個時候還不會成熟，但我們將有足夠的力量來估計生存是否有趨勢。所以這就是 ctDNA 的真正原因。

With regard to the second question, I think you're asking about different alleles for PRAME. Is that...

關於第二個問題，我想你問的是 PRAME 的不同等位基因。就是它...

Yes. (inaudible).

是的。 （聽不清）。

-- correct? Yes. So after A2, the most attractive HLA allele for PRAME A24, and that's why we announced that we are pursuing this HLA-A24. And we'll take the learnings from the HLA-A2 allele and apply it to A24 to make it develop faster. We estimate this will increase the opportunity 30% from a patient population opportunity.

- 正確的？是的。所以在 A2 之後，最有吸引力的 HLA 等位基因是 PRAME A24，這就是為什麼我們宣布我們正在追求這個 HLA-A24。我們將從 HLA-A2 等位基因中吸取教訓並將其應用於 A24 以使其發展更快。我們估計這將使患者群體的機會增加 30%。

Our next question comes from the line of Nick Gallo with Goldman Sachs.

我們的下一個問題來自 Nick Gallo 與 Goldman Sachs 的對話。

(technical difficulty)

（技術難度）

Looks like we lost Nick. I'm going to bring through the next questioner. Our next questions come from the line of Ahu Demir with Ladenburg Thalmann.

看來我們失去了尼克。我要請下一位提問者發言。我們的下一個問題來自 Ahu Demir 與 Ladenburg Thalmann 的對話。

Congrats on a good quarter and a year. My first question is on KIMMTRAK. Could you maybe provide more color on discontinuation rates and treatment beyond progression in the real world?

祝賀一個好的季度和一年。我的第一個問題是關於 KIMMTRAK。您能否提供更多有關停藥率和超越現實世界進展的治療的顏色？

Great. Thank you. Ralph, do you want to...

偉大的。謝謝。拉爾夫，你想...

Great question. So we are seeing the treatment discontinuations to be in line with what we expected in the clinical trial experience. In fact, we look at closely the reasons for discontinuation and they're really tracking very well. We're not seeing any surprises, which is always great to see when you go into the real world.

很好的問題。因此，我們看到治療中斷符合我們在臨床試驗經驗中的預期。事實上，我們仔細研究了停產的原因，他們確實跟踪得很好。我們沒有看到任何驚喜，當你進入現實世界時，看到這總是很棒的。

With regard to treatment beyond progression, what we do is we ask physicians, whether they are comfortable treating beyond progression. And then obviously, that's part of our conversations that we have from a medical affairs perspective with physicians. And so far, we are seeing that level of comfort. Of course, as we go into the community, more education needs to be had, and that's what we're focused on.

關於超越進展的治療，我們所做的是詢問醫生，他們是否願意接受超越進展的治療。然後很明顯，這是我們從醫療事務的角度與醫生進行的對話的一部分。到目前為止，我們看到了那種程度的舒適。當然，當我們進入社區時，需要接受更多的教育，而這正是我們關注的重點。

Yes. I think it's a really good point because in the academic centers, there -- the investigators are the ones who actually saw that there is benefit beyond progression. So I think there is more work to be done when we go into the community, but that's where the MSLs and the education and the science will come in.

是的。我認為這是一個非常好的觀點，因為在學術中心，研究人員是真正看到進步之外的好處的人。所以我認為當我們進入社區時還有更多工作要做，但這就是 MSL、教育和科學將發揮作用的地方。

There are no further questions at this time. I would now like to hand the call back over to Bahija Jallal for any closing remarks.

目前沒有其他問題。我現在想將電話轉回給 Bahija Jallal 以聽取任何結束語。

Yes. So thank you so much for your questions, and thank you for your support, and we're going to now close the call. Thank you.

是的。非常感謝您提出的問題，感謝您的支持，我們現在將結束電話會議。謝謝。

Thank you. This does conclude today's teleconference. We appreciate your participation. You may disconnect your lines at this time. Enjoy the rest of your day.

謝謝。今天的電話會議到此結束。感謝您的參與。此時您可以斷開線路。享受你剩下的一天。