Palvella Therapeutics Inc (PVLA) 2021 Q1 法說會逐字稿

Greetings, and welcome to Pieris Pharmaceuticals Q1 Earnings Call. (Operator Instructions) As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Tom Bures, Vice President, Finance. Please go ahead.

您好，歡迎參加 Pieris Pharmaceuticals 第一季財報電話會議。 （操作員指示）謹此提醒，本次會議正在錄製中。現在我想將會議交給主持人、財務副總裁 Tom Bures。請繼續。

Thank you. Good morning, everyone, and thank you for joining us for our first quarter 2021 conference call and corporate update. On the call today, we have Steve Yoder, our President and CEO, who will provide a corporate overview and outlook on our pipeline; Hitto Kaufmann, our Chief Scientific Officer; and Shane Olwill, our Head of Translational Science, who will be available for Q&A. You can access the press release released this morning on the Investor Relations page of our website at www.pieris.com.

謝謝。大家早安，感謝您參加我們的 2021 年第一季電話會議和公司最新動態。在今天的電話會議上，我們的總裁兼執行長 Steve Yoder 將提供公司概況和對我們管道的展望； Hitto Kaufmann，我們的首席科學長；我們的轉化科學主管 Shane Olwill 將出席問答環節。您可以在我們網站 www.pieris.com 的投資者關係頁面上造訪今天早上發布的新聞稿。

Before we begin, I'd like to caution that comments made during this conference call may contain forward-looking statements involving risks and uncertainties regarding the operations and future results of operations of Pieris, including statements relating to the timing and progress of our clinical trials and preclinical programs, our partnerships and our financial position, and actual results or events may differ materially from those expressed or implied by such forward-looking statements.

在我們開始之前，我想提醒您，本次電話會議期間發表的評論可能包含涉及 Pieris 營運和未來營運結果的風險和不確定性的前瞻性陳述，包括與我們臨床試驗的時間和進展有關的陳述和臨床前計劃、我們的合作夥伴關係和我們的財務狀況以及實際結果或事件可能與此類前瞻性陳述明示或暗示的內容有重大差異。

Factors that might cause such differences are described in our filings with the SEC including our annual, quarterly and current reports. The information being presented is only accurate as of today, and Pieris undertakes no obligation to update any statements to reflect future events or circumstances.

我們向 SEC 提交的文件（包括我們的年度報告、季度報告和當前報告）中描述了可能導致此類差異的因素。所提供的資訊僅截至今日準確，Pieris 不承擔更新任何聲明以反映未來事件或情況的義務。

I will now turn the call over to Steve.

我現在將把電話轉給史蒂夫。

Well, thank you, Tom, and thank you to everyone for joining us today for our 2021 first quarter earnings call. The last few months have been very productive and marked by significant accomplishments as we advanced our proprietary and partner pipeline and leveraged existing and new alliances to materially bolster our balance sheet.

好吧，謝謝你，湯姆，也謝謝大家今天參加我們的 2021 年第一季財報電話會議。過去的幾個月非常富有成效，並取得了重大成就，因為我們推進了我們的專有和合作夥伴管道，並利用現有和新的聯盟來實質地增強我們的資產負債表。

Putting the past few weeks into perspective, we have generated USD 46 million in cash flow through milestone achievement, equity investments by partners, AstraZeneca and Seagen and the addition of a new partner, while also securing drug supply for a key combination study for our most advanced IO asset. We can and will continue to use partnerships and the power of nondilutive funding mechanisms to reach significant corporate inflection points.

回顧過去幾週，透過里程碑式的成就、合作夥伴阿斯特捷利康和Seagen 的股權投資以及新合作夥伴的增加，我們已經產生了4,600 萬美元的現金流，同時也確保了我們最重要的一項關鍵組合研究的藥物供應。高級 IO 資產。我們可以而且將會繼續利用夥伴關係和非稀釋性融資機制的力量來達到重要的企業轉折點。

Pieris is the proprietor of a class of next-generation therapeutic polypeptides called Anticalins, and we are focusing the development of Anticalins in 2 areas: one, inhaled delivery for respiratory disease; and two, bispecifics in immuno-oncology. I will first share some exciting updates from our respiratory pipeline, and I'm pleased to begin by announcing that patient dosing with PRS-060 has begun in the first part of a global Phase IIa study. PRS-060 is an IL-4 receptor alpha antagonist we are developing for moderate-to-severe asthma in collaboration with AstraZeneca, and it's our lead respiratory program.

Pieris 是一類名為Anticalins 的下一代治療性多肽的所有者，我們將Anticalins 的開發重點放在兩個領域：一是用於呼吸道疾病的吸入給藥；二是用於治療呼吸系統疾病的藥物。第二，免疫腫瘤學中的雙特異性。我將首先分享我們呼吸管道的一些令人興奮的更新，我很高興首先宣布 PRS-060 的患者給藥已在全球 IIa 期研究的第一部分開始。 PRS-060 是一種 IL-4 受體 α 拮抗劑，我們正在與阿斯特捷利康合作開發用於中度至重度氣喘的藥物，這是我們主要的呼吸系統項目。

The first part of this 2-part study is evaluating the safety and pharmacokinetics of the dry powder formulation of 060 in moderate asthmatics controlled on standard of care asthma therapy over 4 weeks. The second part of the study will then evaluate the efficacy, safety and pharmacokinetics of PRS-060 in moderate uncontrolled asthmatics over 4 weeks. The primary endpoint of the study will be FEV1 improvement compared to placebo.

這項由兩部分組成的研究的第一部分是評估 060 乾粉製劑在接受標準氣喘護理治療 4 週以上的中度氣喘患者中的安全性和藥物動力學。研究的第二部分將評估 PRS-060 在 4 週內對未控制的中度氣喘患者的療效、安全性和藥物動力學。研究的主要終點是與安慰劑相比 FEV1 的改善。

Last quarter, we announced the achievement of a $13 million milestone payment in connection with the initiation of this clinical study alongside a $10 million equity investment from AstraZeneca in connection with the restructuring of certain financial terms for PRS-060 in a manner that does not impact the overall value split of the asset between Pieris and AstraZeneca. We are pleased with AstraZeneca's commitment to this program and to this collaboration more broadly, which also includes 4 discovery stage programs that are currently under active collaboration. In addition to our partnered respiratory programs, we are also developing a number of proprietary programs and look forward to sharing additional details, including IND plans for one of these respiratory programs later this year.

上季度，我們宣布實現了與啟動這項臨床研究相關的 1300 萬美元里程碑付款，同時阿斯特捷利康以不影響 PRS-060 某些財務條款重組的方式進行了 1000 萬美元股權投資。 Pieris 和 Ask利康之間資產的總體價值分配。我們對阿斯特捷利康對該計畫以及更廣泛的合作的承諾感到高興，其中還包括目前正在積極合作的 4 個發現階段計畫。除了我們合作的呼吸項目外，我們還正在開發一些專有項目，並期待分享更多細節，包括今年稍後針對其中一個呼吸項目的 IND 計劃。

Looking beyond our respiratory franchise, I would now like to discuss the progress we have made in our immuno-oncology pipeline. Our immuno-oncology pipeline is concentrated around our expertise in 4-1BB based bispecifics. We remain enthusiastic about 4-1BB as a target which is an immune cell co-stimulatory receptor that is overexpressed on activated T cells and natural killer cells in particular and whose activation drives improved metabolic fitness of these cells. We have designed our 4-1BB-based bispecifics with the objective of agonizing 4-1BB locally to leverage its benefits while overcoming systemic and off-target side effects that have plagued systemically active 4-1BB agonist. We were the first company to bring a 4-1BB base bispecific into the clinic, which is now progressing into Phase II, and we have a number of 4-1BB-based bispecific programs following that lead.

除了我們的呼吸系統業務之外，我現在想討論我們在免疫腫瘤學管道方面的進展。我們的免疫腫瘤學管道集中在基於 4-1BB 的雙特異性藥物方面的專業知識。我們仍然對 4-1BB 作為靶點充滿熱情，它是一種免疫細胞共刺激受體，在活化的 T 細胞和自然殺手細胞上過度表達，尤其是其活化可改善這些細胞的代謝適應性。我們設計了基於 4-1BB 的雙特異性藥物，其目標是局部抑制 4-1BB，以利用其益處，同時克服困擾全身活性 4-1BB 激動劑的系統性和脫靶副作用。我們是第一家將 4-1BB 基礎雙特異性藥物引入臨床的公司，目前正進入第二階段，我們有許多基於 4-1BB 基礎雙特異性藥物的計畫緊隨其後。

Cinrebafusp alfa, also known as PRS-343 or Cinre is our lead 4-1BB clinical program. Cinre is a 4-1BB HER2 bispecific that we have tested in 2 Phase I studies. Last month, we presented clinical data update from the Phase I monotherapy study of Cinre at AACR, disclosing additional clinical benefit at the highest dose, including an additional confirmed durable partial response, 3 additional patients with stable diseases best response and overall durable benefit. Cinre has shown a clear dose response and a 4-1BB-driven mode of action and clinical benefit was observed in patients with cold tumors as well as those with HER2-low expressing tumors.

Cinrebafusp alfa，也稱為 PRS-343 或 Cinre，是我們領先的 4-1BB 臨床計畫。 Cinre 是一種 4-1BB HER2 雙特異性藥物，我們在 2 項 I 期研究中進行了測試。上個月，我們在AACR 上公佈了Cinre 單藥治療I 期研究的臨床數據更新，披露了最高劑量下的額外臨床獲益，包括額外確認的持久部​​分緩解、另外3 名具有穩定疾病最佳緩解的患者以及整體持久獲益。 Cinre 顯示出明顯的劑量反應和 4-1BB 驅動的作用模式，並且在冷腫瘤以及 HER2 低表達腫瘤患者中觀察到臨床益處。

Cinre has shown an acceptable safety profile at all doses tested with no dose-limiting toxicities. These findings provide the rationale for advancing this asset into a Phase II trial in HER2 expressing gastric cancer, a tumor type that continues to drive benefit from immunomodulatory therapies, as recently demonstrated by the KEYNOTE 811 clinical study outcome, which led to the approval of pembrolizumab when added to the first-line standard of care, trastuzumab and chemotherapy. The dose-dependent activity we are seeing with Cinre supports our recommended Phase II dose, which consists of a 2-cycle loading dose at 18 milligrams per kilogram on a Q2 weekly regimen, followed by an 8 mg per kilogram Q2 weekly regimen in subsequent cycles.

Cinre 在所有測試劑量下均表現出可接受的安全性，沒有劑量限制性毒性。這些發現為將這項資產推進到表達HER2 的胃癌的II 期試驗提供了理論基礎，正如最近KEYNOTE 811 臨床研究結果所證明的那樣，這種腫瘤類型將繼續從免疫調節療法中獲益，該結果導致派姆單抗獲得批准當添加到一線標準治療、曲妥珠單抗和化療中。我們在Cinre 上看到的劑量依賴性活動支持我們推薦的II 期劑量，其中包括在Q2 每周方案中採用18 毫克/公斤的2 個週期負荷劑量，然後在後續週期中採用8 毫克/公斤Q2每周方案。

As a reminder, the Phase II study will be a 2-arm study. The first arm will evaluate Cinre in HER2-high gastric cancer in combination with ramucirumab and paclitaxel with Lilly supplying ramucirumab at no cost to Pieris as part of a trial collaboration agreement. We expect to begin enrolling this 20-patient study arm later this summer, focusing on the U.S. and South Korea, where gastric cancer has a high prevalence. We are setting a high bar for go/no-go in our planned interim analysis of this study to ensure that we remain competitive with the evolving treatment landscape, and we'll be looking at a composite of efficacy measures, including durability and safety in addition to objective response rate or ORR.

提醒一下，第二階段研究將是一項雙臂研究。第一組將評估 Cinre 與 ramucirumab 和紫杉醇聯合治療 HER2 高胃癌的效果，作為試驗合作協議的一部分，禮來公司將免費向 Pieris 提供 ramucirumab。我們預計今年夏天晚些時候開始招募這個由 20 名患者組成的研究小組，重點關注胃癌發病率較高的美國和韓國。我們在計劃對這項研究進行的中期分析中為通過/不通過設定了很高的標準，以確保我們在不斷變化的治療領域中保持競爭力，並且我們將考慮綜合療效措施，包括耐久性和安全性除了客觀緩解率或 ORR 之外。

We are setting the ORR target at a minimum of 50% at this interim analysis, which is higher than the 28% ORR benchmark established by ramucirumab and paclitaxel and takes into consideration potential emerging standard of care, and it's a bar we believe we can achieve given the activity we have observed with Cinre to date and the complementary mode of action in this combination. We believe that setting stringent criteria for advancement of our proprietary assets will help to ensure prudent and judicious use of our corporate resources, and that achieving these criteria can translate into meaningful value for patients and shareholders.

在本次中期分析中，我們將ORR 目標設定為至少50%，高於雷莫蘆單抗和紫杉醇所製定的28% ORR 基準，並考慮到潛在的新興護理標準，這是我們相信我們能夠實現的目標鑑於我們迄今為止觀察到的 Cinre 活動以及該組合中的互補作用模式。我們相信，為我們的專有資產的發展制定嚴格的標準將有助於確保審慎和明智地使用我們的公司資源，並且實現這些標準可以為患者和股東轉化為有意義的價值。

The second arm of the study will enroll 20 patients with HER2-low gastric cancer and will evaluate Cinre in combination with tucatinib, which will be supplied by our partner, Seagen, at no cost to Pieris. In addition to the data we generated collaboratively with Seagen that showed synergy between tucatinib and Cinre in enhancing the 4-1BB mediated immune cell activation, the data we presented at this year's AACR conference also support that Cinre is active in the HER2-low tumor setting as we observed clinical benefit in multiple HER2-low patients receiving Cinre as a monotherapy, coupled with the pharmacodynamic data that demonstrate 4-1BB agonism in these HER2-low patients.

研究的第二部分將招募 20 名 HER2 低胃癌患者，並將評估 Cinre 與 tucatinib 的組合，後者將由我們的合作夥伴 Seagen 提供，Pieris 免費。我們與 Seagen 合作產生的數據顯示了 tucatinib 和 Cinre 在增強 4-1BB 介導的免疫細胞活化方面的協同作用，我們在今年 AACR 會議上公佈的數據也支持 Cinre 在 HER2 低腫瘤環境中發揮作用我們觀察到多名HER2 低患者接受Cinre 作為單一療法的臨床獲益，再加上藥效學數據證明這些HER2 低患者中4-1BB 具有激動作用。

We believe it is encouraging that when paired with tucatinib, Cinre may show clinical benefit in a setting where many other HER2-targeting drugs have shown only minimal activity. HER2-low gastric cancer, therefore, presents a high unmet medical need and is a sizable market opportunity. And as in the HER2-high arm of this study, we are setting a high bar for success for the HER2-low arm, looking at the same composite of efficacy measures, including durability and safety in addition to ORR.

我們相信，令人鼓舞的是，當與 tucatinib 配合使用時，Cinre 可能會在許多其他 HER2 標靶藥物僅顯示出最小活性的情況下顯示出臨床益處。因此，HER2 低的胃癌存在著高度未滿足的醫療需求，並且是一個巨大的市場機會。與本研究的 HER2 高組一樣，我們為 HER2 低組的成功設定了很高的標準，著眼於相同的療效指標組合，包括 ORR 以外的耐久性和安全性。

Here, we believe that achieving at least a 40% ORR would be a significant improvement over the 28% ORR demonstrated by standard of care, ramucirumab and paclitaxel, in light of the marginal activity of other agents tested in this setting. We are excited to study this novel combination regimen with Seagen who made a USD 13 million strategic equity investment in Pieris in collaboration and in connection with the amendment of our existing immuno-oncology collaboration agreement last quarter.

在這裡，我們認為，鑑於在此環境中測試的其他藥物的邊際活性，實現至少 40% 的 ORR 將比護理標準、雷莫蘆單抗和紫杉醇所證明的 28% ORR 顯著改善。我們很高興與 Seagen 一起研究這種新穎的聯合治療方案，Seagen 與上季度我們現有的免疫腫瘤學合作協議的修訂合作，對 Pieris 進行了 1300 萬美元的戰略股權投資。

As we are making the necessary preparations for the start of the Phase II study of Cinre, we are also working hard alongside our partner, Servier, in anticipation of advancing PRS-344, which is a 4-1BB/PD-L1 bispecific into Phase I later this year. Last month, we also presented preclinical data for 344 at AACR demonstrating superiority to the combination of PD-L1 and 4-1BB targeting molecules. As a reminder, we hold exclusive commercialization rights for PRS-344 in the United States and will receive royalties on ex U.S. sales by Servier for this program. Servier is also responsible for further development of PRS-352, an undisclosed immuno-oncology bispecific that is also part of our collaboration.

在我們為 Cinre II 期研究的開始做必要的準備的同時，我們也與我們的合作夥伴施維雅一起努力，期待將 4-1BB/PD-L1 雙特異性藥物 PRS-344 推進到臨床階段。我今年晚些時候。上個月，我們也在 AACR 上展示了 344 的臨床前數據，證明了 PD-L1 和 4-1BB 標靶分子組合的優越性。謹此提醒，我們擁有 PRS-344 在美國的獨家商業化權利，並將獲得施維雅在美國以外銷售該項目的特許權使用費。施維雅也負責 PRS-352 的進一步開發，這是一種未公開的免疫腫瘤雙特異性藥物，也是我們合作的一部分。

Finally, we also recently entered into a license and collaboration agreement granting Boston Pharmaceuticals exclusive worldwide rights to PRS-342, a preclinical 4-1BB GPC3 immuno-oncology bispecific. Under the terms of that agreement, Pieris received an upfront payment of $10 million and is further entitled to receive up to around USD 350 million in milestone payments, tiered royalties up to low double digits on sales of the treatment, if successfully approved and commercialized, and a share of certain subsequent sublicensing revenue. Pieris will collaborate with Boston Pharmaceuticals to advance the program towards an IND submission. Boston Pharmaceuticals has a strong leadership team and proven track record of developing a broad range of assets, including oncology, and we look forward to the advancement of this novel next-generation bispecific, which follows in the localized 4-1BB agonism mode of action of Cinre.

最後，我們最近還簽訂了一項許可和合作協議，授予 Boston Pharmaceuticals PRS-342（一種臨床前 4-1BB GPC3 免疫腫瘤雙特異性藥物）的全球獨家權利。根據該協議的條款，Pieris 獲得了1000 萬美元的預付款，如果成功獲得批准並商業化，Pieris 還將有權獲得高達約3.5 億美元的里程碑付款，以及治療銷售的分層特許權使用費高達低兩位數，以及某些後續再授權收入的份額。 Pieris 將與波士頓製藥公司合作，推進該專案的 IND 提交。波士頓製藥公司擁有強大的領導團隊和開發包括腫瘤學在內的廣泛資產的良好記錄，我們期待這種新型下一代雙特異性藥物的進步，它遵循局部 4-1BB 激動作用模式辛雷。

So in conclusion, with our focused investments in Cinrebafusp alfa and our partnerships with Servier, Seagen and Boston Pharmaceuticals, we have placed our immuno-oncology bispecifics pipeline on solid footing, and we look forward to the progression of multiple assets into the clinical stage beyond Cinre, driven by material ongoing investments by these partners.

因此，總而言之，透過我們對Cinrebafusp alfa 的重點投資以及與Servier、Seagen 和Boston Pharmaceuticals 的合作，我們已經為我們的免疫腫瘤雙特異性藥物管道奠定了堅實的基礎，我們期待多種資產進入臨床階段，超越Cinre，由這些合作夥伴持續進行的實質投資所推動。

This concludes my prepared remarks, and I would now like to hand the call back over to Tom to guide you through our first quarter 2021 financial results. Over to you, Tom.

我準備好的演講到此結束，現在我想將電話轉回給 Tom，以引導您了解我們 2021 年第一季的財務表現。交給你了，湯姆。

Thanks, Steve, and good morning again, everyone. Cash and cash equivalents totaled $66.8 million for the quarter ended March 31, 2021 compared to a cash and cash equivalents balance of $70.4 million for the quarter ended December 31, 2020. The increase was due to the USD 13 million received from Seagen in March 2021, offset by our operating cash needs. The quarter end cash balance excludes both $23 million received from AstraZeneca in April and $10 million to be received from Boston Pharmaceuticals.

謝謝史蒂夫，大家早安。截至2021 年3 月31 日的季度現金和現金等價物總額為6,680 萬美元，而截至2020 年12 月31 日的季度現金和現金等價物餘額為7,040 萬美元。增加的原因是2021 年3 月從Seagen 收到1,300 萬美元，被我們的營運現金需求所抵銷。季末現金餘額不包括 4 月從阿斯特捷利康收到的 2,300 萬美元和從波士頓製藥公司收到的 1,000 萬美元。

On a pro forma basis, quarter end cash and cash equivalents would have been approximately $100 million, which ensures that we are well positioned to execute on our strategic plans into 2023. R&D expenses were $16.6 million for the quarter ended March 31, 2021 compared to $12.8 million for the quarter ended March 31, 2020. The increase reflects higher spending on preclinical activities for our proprietary respiratory pipeline and manufacturing costs for our immuno-oncology programs, while maintaining flat spending on other nonproject-related R&D costs.

按預計，季度末現金和現金等價物約為 1 億美元，這確保我們有能力執行 2023 年的戰略計劃。截至 2021 年 3 月 31 日的季度研發費用為 1,660 萬美元，而截至2020 年3 月31日的季度為1280 萬美元。這一增長反映了我們專有呼吸管道的臨床前活動支出和免疫腫瘤項目的製造成本增加，同時保持其他非項目相關研發成本的支出不變。

G&A expenses were $4.1 million for the quarter ended March 31, 2021 compared to $4.4 million for the quarter ended March 31, 2020. This decrease reflects more onetime costs incurred in 2020 related to the move to our new R&D facility in Hallbergmoos, Germany, partially offset by higher consulting expenses in the current quarter.

截至2021 年3 月31 日的季度的一般管理費用為410 萬美元，而截至2020 年3 月31 日的季度的一般管理費用為440 萬美元。這一下降反映了2020 年與搬遷至德國哈爾與伯格莫斯的新研發設施相關的一次性成本增加，部分原因是被本季較高的諮詢費用所抵銷。

Net loss was $4.2 million or a $0.07 loss per share for the quarter ended March 31, 2021 compared to a net loss of $3.6 million or a $0.07 loss per share for the quarter ended March 31, 2020.

截至 2021 年 3 月 31 日的季度淨虧損為 420 萬美元，即每股虧損 0.07 美元，而截至 2020 年 3 月 31 日的季度淨虧損為 360 萬美元，即每股虧損 0.07 美元。

With that, I'll turn the call back over to you, Steve.

這樣，我會將電話轉回給你，史蒂夫。

Thanks, Tom. And as I trust, you all would agree, these last few months have been a productive time at Pieris, particularly with respect to our leveraging of new and existing partnerships, and we look forward to building on our momentum. Thanks to our business development activities, we have added USD 46 million to our balance sheet through a mix of nondilutive funding and focused strategic equity stakes from 2 existing partners. We remain committed to this business model. We look forward to keeping you updated on our progress as we drive towards achieving key inflection points throughout the year.

謝謝，湯姆。我相信，你們都會同意，過去幾個月是 Pieris 富有成效的時期，特別是在我們利用新的和現有的合作夥伴關係方面，我們期待著繼續鞏固我們的勢頭。由於我們的業務發展活動，我們透過非稀釋性融資和 2 個現有合作夥伴的重點策略股權相結合，為我們的資產負債表增加了 4,600 萬美元。我們仍然致力於這種商業模式。在我們努力實現全年關鍵拐點的過程中，我們期待向您通報我們的最新進展。

I want to thank you for joining us on the call today, and we would now like to open the call to your questions.

我要感謝您今天加入我們的電話會議，現在我們將開始回答您的問題。

(Operator Instructions) Our first question today is from Umer Raffat of Evercore.

（操作員說明）我們今天的第一個問題來自 Evercore 的 Umer Raffat。

I have a few today, if I may. One, for the asthma trial, would you have an internal readout of the Part 1? I know clin trial says that will be an unblinded review. So I'm just trying to understand, can we talk to you about Part 1, perhaps even if it's not a press release? And also, would you be able to announce that you're now formally progressing to Part 2? And that dose level 3 was included, would that be a formal announcement? Should we expect that or not? And perhaps also if you could spell out for us, what is that bar that you have to clear to include that third dose and to move to Phase III? And finally, just quickly, if you could remind us the choice of site selection. I noticed it's Australia and the Ukraine site, and I'm trying to understand if we should expect U.S. sites to be up as well when you get to Part 2.

如果可以的話，我今天有一些。第一，對於氣喘試驗，您可以獲得第 1 部分的內部讀數嗎？我知道臨床試驗說這會是一次非盲審。所以我只是想了解一下，我們能否與您討論第 1 部分，即使這不是新聞稿？另外，您能宣布您現在正式進入第 2 部分嗎？而且還包括了 3 級劑量，這算是正式宣布嗎？我們是否應該期待這一點？也許您也可以為我們說明一下，您必須清除的障礙是什麼才能包括第三劑並進入第三階段？最後，請盡快提醒我們選址的選擇。我注意到這是澳洲和烏克蘭的網站，我試圖了解當您進入第 2 部分時，我們是否應該期望美國網站也能上線。

Umer, thanks for the questions, all focused on 060 clinical study design, and that's great. I can try to take all those one at a time. So yes, as you noted, Umer, there's 2 parts to the study, there's the part 1 efficacy phase, which is up to 3 -- safety phase, sorry, which is up to 3 doses. And then there is the part 2 efficacy phase, which would look at FEV1 as the primary endpoint. We have not disclosed specific communication planning for the progression from Part 1 into Part 2. But as I had mentioned before, it's my personal desire, and assuming AstraZeneca is fine with that, I assume that they will be, is that we intend to be able to announce when we have or that we have progressed from Part 1 into Part 2, which I would anticipate pending enrollment as planned that, that would be sometime later this year. So that's something that we hope to be able to talk about even though I would not expect a formal press release around any data disclosures, but then we could talk about that for sure.

Umer，謝謝你提出的問題，所有問題都集中在 060 臨床研究設計上，這很好。我可以嘗試一次拿走所有這些。所以，是的，正如您所指出的，Umer，該研究分為 2 個部分，第 1 部分是功效階段，最多為 3 階段——安全階段，抱歉，最多為 3 劑。然後是第 2 部分療效階段，該階段將 FEV1 作為主要終點。我們還沒有透露從第 1 部分進展到第 2 部分的具體溝通計劃。但正如我之前提到的，這是我個人的願望，假設阿斯特捷利康對此表示同意，我認為他們會的，我們打算能夠宣布我們何時從第1 部分進展到第2 部分，我預計這將按計劃進行，這將在今年稍後的某個時候進行。因此，這是我們希望能夠討論的事情，儘管我不希望就任何數據披露發布正式新聞稿，但我們肯定可以討論這一點。

As far as the doses that would be used in the Part 1 as a progression to Part 2, there is a certain amount of staging that is allowed such that if one were to clear the first 2 doses, one could then move into the efficacy phase rather than wait for all 3. So that's some nuances in design that we still will consider, but we don't necessarily have to clear all 3 doses before moving into the efficacy phase at the lower doses.

就第 1 部分中使用的劑量（作為第 2 部分的進展）而言，允許一定量的分期，這樣，如果要清除前 2 個劑量，則可以進入功效階段而不是等待所有3 個劑量。因此，我們仍會考慮設計中的一些細微差別，但在進入較低劑量的功效階段之前，我們不一定必須清除所有3 個劑量。

And then as far as the sites, as you noted, we are currently leveraging efficiency and regulatory interactions and site readiness. We've been very, very accustomed to working in Australia with Phase I and Phase Ib with PRS-060. So we're focused there and also in the Ukraine. And we're looking at multiple additional geographies and several other sites. It's a global study. We haven't disclosed the specific strategy in the U.S. yet, but certainly, interactions with the FDA are certainly contemplated before too long.

然後就網站而言，正如您所指出的，我們目前正在利用效率和監管互動以及網站準備。我們非常非常習慣在澳洲進行 PRS-060 的 I 期和 Ib 期工作。所以我們的重點是那裡以及烏克蘭。我們正在考慮多個其他地區和其他幾個站點。這是一項全球性研究。我們尚未透露在美國的具體策略，但可以肯定的是，不久之後肯定會考慮與 FDA 互動。

The next question is from Matt Phipps of William Blair.

下一個問題來自威廉布萊爾的馬特菲普斯。

Congrats on the business development activity in the quarter. I guess where -- given where you guys have gotten with Cinre and the data generated with really this first 4-1BB bispecific and now it's becoming a pretty competitive space. Just looking for a bigger picture on how you can leverage that info into the rest of your pipeline? And then specifically for kind of the PD-L1 group of these bispecifics, we've had a couple of other companies start to give some disclosures around their programs. Wondering what you might have taken from that, that can help with the development of 344 in combination with obviously what you've learned from Cinre.

恭喜本季的業務發展活動。我猜想，考慮到你們已經透過 Cinre 取得了進展，並且透過第一個 4-1BB 雙特異性抗體產生了數據，現在它正在成為一個相當有競爭力的領域。只是想了解如何將這些資訊應用到管道的其餘部分嗎？然後，特別是針對這些雙特異性藥物的 PD-L1 組，我們已經有其他幾家公司開始圍繞他們的專案進行一些披露。想知道您可能從中得到了什麼，這可以幫助您結合從 Cinre 學到的知識來開發 344。

Sure, Matt. Thanks so much. There's a lot of things we could talk through there. I mean, firstly, what do the data from Cinre speak to the opportunity with Cinre itself in the gastric cancer space, in particular, and we can talk about that. Then you also mentioned the broader learnings of Cinre throughout the rest of our pipeline and then specifically looking at the PD-L1/4-1BB bispecific approach where there are a number of other programs that have recently moved into clinical stage and some of them already reported some initial data.

當然，馬特。非常感謝。我們可以在那裡討論很多事情。我的意思是，首先，Cinre 的數據特別說明了 Cinre 本身在胃癌領域的機會，我們可以討論這一點。然後您還提到了 Cinre 在我們管道的其餘部分中的更廣泛的學習，然後特別關注了 PD-L1/4-1BB 雙特異性方法，其中有許多其他項目最近已進入臨床階段，其中一些項目已經報告了一些初步數據。

So I can just frame that at a high level, and then I'd like for Shane to go through that in a little bit more detail. And when we first think about the Cinre, for Cinre's sake, looking at the opportunity in HER2-expressing tumors, let's not forget that we have what I think is pretty compelling, impressive single-agent activity, coupled with a very good safety and tolerability profile, and I don't want that to get lost on people, because 4-1BB agonism can be a very sharp knife. And we've seen that coupled with the dose response. And I think a great set of PD correlates that will help us to -- have helped us to zero in on what we think is a very thoughtful RP2D.

所以我可以從高層次來闡述這一點，然後我希望肖恩能夠更詳細地闡述這一點。當我們第一次考慮Cinre 時，看在Cinre 的份上，看看在表達HER2 的腫瘤中的機會，我們不要忘記，我們擁有我認為非常引人注目、令人印象深刻的單藥活性，以及非常好的安全性和耐受性我不想讓人們迷失這一點，因為 4-1BB 的對抗可能是一把非常鋒利的刀。我們已經看到了這一點與劑量反應的結合。我認為一組很棒的 PD 相關性將幫助我們——幫助我們將我們認為非常周到的 RP2D 歸零。

And when we consider the single-agent activity, the relevance of immunotherapies in gastric cancer and the ability to play in both the HER2-high space and the HER2-low space, the latter being far less dynamic than the HER2 positive space, we really like those nuances of bringing a 4-1BB bispecific into this field. And if you think about the biology at stake, this is the only, to our knowledge, the only HER2 engaging agent that leverages the adoptive immune space. It also brings innate immunity to it with NK cells, but compared to bispecifics, compared to novel payloads, compared to macrophage biology, this is different. And if we think about what 4-1BB does, which is it drives the improved metabolic fitness of T cells and immune cells in general, this is something we think could lead to meaningful differentiated opportunity.

當我們考慮單藥活性、胃癌免疫療法的相關性以及在 HER2 高空間和 HER2 低空間中發揮作用的能力時，後者的動態遠不如 HER2 陽性空間，我們真的就像將4-1BB 雙特異性引入該領域的細微差別一樣。如果你考慮一下所面臨的生物學問題，就我們所知，這是唯一一種利用過繼免疫空間的 HER2 結合劑。它也給它帶來了NK細胞的先天免疫，但與雙特異性相比，與新穎的有效負載相比，與巨噬細胞生物學相比，這是不同的。如果我們思考 4-1BB 的作用，即它總體上改善 T 細胞和免疫細胞的代謝適應性，我們認為這可能會帶來有意義的差異化機會。

And there will be learnings from this into how we think about positioning the 4-1BB/PD-L1-based bispecific as well as, I think, helping Boston Pharmaceuticals on the positioning of the GPC3 4-1BB bispecific. So Shane can maybe go a little bit deeper on some of the nuances in HER2-high and HER2-low, including the bars that we announced today on ORR as well as why we feel really enthusiastic about our specific 4-1BB/PD-L1 bispecific, which we've really put a lot of thought into designing for potentially best-in-class opportunity there. So I'm going to hand it over to Shane to go a little bit deeper.

我們將從中學到如何定位基於 4-1BB/PD-L1 的雙特異性抗體，以及幫助波士頓製藥公司定位 GPC3 4-1BB 雙特異性抗體。因此，Shane 或許可以更深入地探討 HER2-high 和 HER2-low 中的一些細微差別，包括我們今天在 ORR 上宣布的條形圖，以及為什麼我們對特定的 4-1BB/PD-L1 感到非常熱情雙特異性，我們確實花了很多心思來設計它，以獲得潛在的同類最佳機會。所以我要把它交給 Shane 更深入地探討。

Thanks, Steve. And thanks, Matt, for the question. So maybe just going back to your question in terms of what do we see in 4-1BB that excites us and how can we leverage what we see with Cinre to really help position those other programs we're bringing through. So with regard to what we see with Cinre, the power of 4-1BB is very evident in our clinical trial. As you know, it was a translation heavy trial where we mandated paired biopsies that allowed us to take a look into the tumor microenvironment and see what was happening. And we see a really nice dose-dependent increase in CD8 T cells. As Steve said, this is, to our mind, the only HER2-targeted agent that is shown to be driving expansion of T cells in the tumor microenvironment.

謝謝，史蒂夫。謝謝馬特提出的問題。所以也許回到你的問題，我們在 4-1BB 中看到什麼讓我們興奮，以及我們如何利用我們在 Cinre 中看到的東西來真正幫助定位我們正在推出的其他項目。因此，就我們在 Cinre 中看到的情況而言，4-1BB 的功效在我們的臨床試驗中非常明顯。如您所知，這是一項繁重的翻譯試驗，我們要求進行配對活檢，使我們能夠了解腫瘤微環境並了解發生了什麼。我們看到 CD8 T 細胞出現了非常好的劑量依賴性增加。正如 Steve 所說，在我們看來，這是唯一能夠驅動腫瘤微環境中 T 細胞擴增的 HER2 標靶藥物。

We also have developed a very useful biomarker in soluble 4-1BB, which can be tracked in the blood of patients, and that demonstrates target engagement and our 4-1BB mechanism of action. And what's very important is those PD correlates are also correlating with clinical benefits. So we're seeing patients benefit, expansion of CD8 T cells and the expansion of 4-1BB gaining clinical benefit from our agent. As Steve said, the monotherapy activity is, to our mind, very compelling. And what's also compelling is that we're driving that 4-1BB agonism in a HER2-low setting as well. And that has really allowed us to go for this 2 armed gastric cancer study. So in terms of the first arm there, we will combine with ramucirumab paclitaxel. We've set an ORR of 50% or greater, and we believe that's achievable based on that very unique mechanism of action, which will complement the debulking of the chemotherapy and the vascular normalization that will come with ramucirumab.

我們還開發了一種非常有用的可溶性 4-1BB 生物標誌物，可以在患者的血液中進行追踪，並證明目標參與和我們的 4-1BB 作用機制。非常重要的是，這些 PD 相關因素也與臨床效益有關。因此，我們看到患者受益，CD8 T 細胞的擴增和 4-1BB 的擴增從我們的藥物中獲得臨床益處。正如史蒂夫所說，在我們看來，單一療法活動非常引人注目。同樣引人注目的是，我們也在 HER2 低的環境中驅動 4-1BB 激動。這確實讓我們能夠進行這項 2 組胃癌研究。因此，就第一組而言，我們將與雷莫蘆單抗紫杉醇結合。我們設定了 50% 或更高的 ORR，我們相信基於這種非常獨特的作用機制，這是可以實現的，這將補充雷莫蘆單抗帶來的化療減滅和血管正常化作用。

In terms of what else have we learned from this study, well, we've learned that we can combine with tucatinib in a meaningful way with a preclinical data set showing that we can drive strong 4-1BB agonism off of fairly low HER2 receptor density. And when we look forward into the other studies, we're certainly bringing all of that biomarker data with us. We know what to expect from a tumor microenvironment perspective. We know that we can drive the NK population. We can drive cytotoxic T cells. And therefore, it has allowed us with regard to PRS-344 to set up a very nice biomarker strategy there as well.

就我們從這項研究中學到的其他知識而言，我們已經了解到，我們可以以有意義的方式與tucatinib 結合，臨床前數據集顯示我們可以在相當低的HER2 受體密度下驅動強4- 1BB 激動作用。當我們展望其他研究時，我們肯定會帶來所有生物標記數據。我們知道從腫瘤微環境的角度來看會發生什麼事。我們知道我們可以驅趕 NK 人口。我們可以驅動細胞毒性 T 細胞。因此，它使我們能夠針對 PRS-344 建立一個非常好的生物標記策略。

In terms of how are they -- how are we feeling at Pieris? What others are doing? Well, certainly, we feel that 4-1BB is very relevant, and the data coming out from competitor trials is also confirming that. So we will use all of the data that we've generated, all the knowledge we have of 4-1BB to have a smart design there. But in terms of PD-L1/4-1BB, in particular, we've certainly developed a molecule which we believe has a compelling activity profile based on what we shared at AACR this year, and we look forward to taking that into the clinic later this year. As Steve said, we've also got the Boston Pharmaceuticals collaboration, where we'll bring the 4-1BB GPC3 molecule forward. All of the biomarker assays we've set up for Cinre are certainly relevant there, and we'll collaborate very closely with Boston Pharma to ensure that, that clinical trial design takes full advantage of them.

就他們而言——我們在 Pieris 的感覺如何？其他人在做什麼？嗯，當然，我們認為 4-1BB 非常相關，來自競爭對手試驗的數據也證實了這一點。因此，我們將使用我們產生的所有數據以及我們擁有的 4-1BB 的所有知識來進行智慧設計。但特別是就PD-L1/4-1BB 而言，我們確實開發了一種分子，根據我們今年在AACR 上分享的內容，我們相信該分子具有令人信服的活性特徵，我們期待著將其帶入臨床今年稍晚。正如 Steve 所說，我們也與 Boston Pharmaceuticals 進行了合作，我們將推動 4-1BB GPC3 分子的發展。我們為 Cinre 建立的所有生物標記測定當然都與那裡相關，我們將與 Boston Pharma 密切合作，以確保臨床試驗設計充分利用它們。

Can I ask -- just 1 follow up. We've had, I think, at least 2 competitors in the PD-L1/4-1BB space have to pick a recommended Phase II dose kind of below what you would expect to saturate the PD-L1 receptor or at least fully inhibit that pathway. Do you think 344 will be able to overcome that? Or do you think it's okay to kind of fall in the middle dose range on the PD-L1 side?

我可以問一下嗎——只需 1 次跟進。我認為，PD-L1/4-1BB 領域至少有 2 個競爭對手必須選擇建議的 II 期劑量，該劑量低於您期望的使 PD-L1 受體飽和或至少完全抑制該劑量的劑量途徑。你認為344能夠克服這個問題嗎？或者您認為 PD-L1 劑量落在中間劑量範圍內可以嗎？

Yes. So to your question on the forwards, the recommended Phase II dose of the competitor molecules and the safety profiles that they have observed in the clinic, we certainly have to be aware of the fact that a PD-L1/4-1BB bispecific is going to be very potent. We see it preclinically. It drives T cells into a proliferative burst and also really changes their phenotype. So it's going to be a very powerful bispecific.

是的。因此，對於您關於前進方向的問題、競爭對手分子的建議 II 期劑量以及他們在臨床中觀察到的安全性概況，我們當然必須意識到 PD-L1/4-1BB 雙特異性藥物即將上市的事實非常有效。我們在臨床前看到了這一點。它可以驅動 T 細胞增殖並真正改變它們的表型。所以它將是一個非常強大的雙特異性抗體。

In terms of our molecule, we certainly have gone with a moderate affinity 4-1BB agonist, which we feel is appropriate for activating the pathway. We have to wait for the clinic to read out to see where -- what that plays out like from a safety perspective. In terms of do you need to saturate the checkpoint arm here, well, preclinical data would suggest not. Preclinical data would suggest that you can get very strong activation of the T cell compartment without saturating the checkpoint arm. So I would say that there's opportunities to go forward without saturating that arm in terms of therapeutic window. There may be small nuances between different people's approaches, but in essence, we have to let that readout in the clinic.

就我們的分子而言，我們當然選擇了中等親和力的 4-1BB 激動劑，我們認為它適合激活該通路。我們必須等待診所讀出結果，看看從安全角度來看，情況會如何。就是否需要使檢查點臂飽和而言，臨床前數據顯示不需要。臨床前數據表明，您可以在不使檢查點臂飽和的情況下獲得 T 細胞室的非常強的活化。所以我想說，在治療窗口方面，有機會繼續前進，而不會使該手臂飽和。不同人的方法之間可能存在細微差別，但本質上，我們必須在臨床上體現出來。

There are no additional questions at this time. I would like to turn the call back to Steve Yoder for closing remarks.

目前沒有其他問題。我想將電話轉回給史蒂夫·約德（Steve Yoder），讓他發表結束語。

Okay. Well, I just want to thank everyone again for your attention and for your continued support of Pieris. I wish you all a great day. Thank you for participating today.

好的。好吧，我想再次感謝大家對 Pieris 的關注和持續支持。祝大家有個愉快的一天。感謝您今天的參與。

This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.

今天的會議到此結束。此時您可以斷開線路。感謝您的參與。