Palvella Therapeutics Inc (PVLA) 2021 Q3 法說會逐字稿

Greetings, and welcome to the Pieris Pharmaceuticals, Inc. Q3 Earnings Call. (Operator Instructions) As a reminder, this conference is being recorded.

您好，歡迎參加 Pieris Pharmaceuticals, Inc. 第三季財報電話會議。 （操作員指示）謹此提醒，本次會議正在錄製中。

I would now like to turn the conference over to your host, Mr. Tom Bures, CFO. Please go ahead, sir.

現在我想將會議交給房東、財務長 Tom Bures 先生。請繼續，先生。

Good morning, everyone, and thank you for joining us for our third 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; Tim Demuth, our Chief Medical Officer; Hitto Kaufman, our Chief Scientific Officer; and Shane Olwill, our Chief Development Officer, all of whom 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.

大家早安，感謝您參加我們的 2021 年第三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； Tim Demuth，我們的首席醫療官； Hitto Kaufman，我們的首席科學長；我們的首席開發長 Shane Olwill 都將出席問答環節。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. 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.

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以及我們的財務狀況和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。我們向 SEC 提交的文件中描述了可能導致此類差異的因素，包括我們的年度報告、季度報告和當前報告。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。

Thank you, Tom, and thank you to everyone for joining us today for our 2021 third quarter earnings call. I am pleased to report that as we continue to advance a very exciting pipeline on our own and together with our several great alliance partners, we ended the quarter with a healthy balance sheet of over USD 125 million, which Tom will discuss in greater detail later and which will get us through key milestones next year. Among the most important of these milestones is the top line data from the entire Phase IIa study of PRS-060/AZD1402, an inhaled dry powder formulation IL-4 receptor alpha inhibitor, we are jointly developing with AstraZeneca for the treatment of moderate-to-severe asthma. Dosing has been completed in Part Ia of the global Phase IIa study of PRS-060. The objective of Part I is to evaluate the safety and pharmacokinetics of the dry powder formulation in moderate asthmatics controlled on standard of care over 4 weeks. Data unblinding and review will now follow, the outcome of which we will publicly disclose gaining progression to the second part of the study, where efficacy will be assessed in moderate uncontrolled asthmatics. In Part II of the study, AstraZeneca will evaluate the efficacy, safety and pharmacokinetics of 060 over 4 weeks in moderate uncontrolled asthmatics having a T2 endotype, with the primary endpoint being FEV1 improvement compared to placebo. Upon reporting the top line results of the entire Phase IIa study next year, we will have the options to codevelop and separately co-commercialize PRS-060 in the United States.

謝謝湯姆，也謝謝大家今天參加我們的 2021 年第三季財報電話會議。我很高興地向大家報告，隨著我們繼續獨自推進一條非常令人興奮的管道，並與我們的幾個偉大的聯盟合作夥伴一起，我們在本季度結束時擁有超過1.25 億美元的健康資產負債表，湯姆稍後將更詳細地討論這一點這將使我們在明年實現關鍵的里程碑。其中最重要的里程碑是PRS-060/AZD1402 整個IIa 期研究的頂線數據，PRS-060/AZD1402 是一種吸入乾粉製劑IL-4 受體α 抑制劑，我們與阿斯特捷利康共同開發，用於治療中度至- 嚴重氣喘。 PRS-060 全球 IIa 期研究的 Ia 部分已完成給藥。第一部分的目的是評估乾粉製劑在 4 週以上標準護理控制下的中度氣喘患者的安全性和藥物動力學。接下來將進行數據揭盲和審查，我們將公開披露研究第二部分的進展情況，其中的結果將在中度不受控制的氣喘患者中評估療效。在研究的第二部分中，阿斯特捷利康將評估060 在4 週內對具有T2 內型的中度未控制氣喘患者的療效、安全性和藥物動力學，主要終點是與安慰劑相比FEV1 的改善。明年報告整個 IIa 期研究的主要結果後，我們將可以選擇在美國共同開發和單獨共同商業化 PRS-060。

Beyond PRS-060, we continue to advance 4 early-stage programs that we are working on together with AstraZeneca. Another respiratory pipeline catalyst we are looking forward to next year is initiating clinical development for our recently announced fully proprietary respiratory program, PRS-220, an inhaled anticalin protein targeting CTGF, or connective tissue growth factor, for the treatment of idiopathic pulmonary fibrosis. We reported preclinical data for the program at the European Respiratory Society International Congress in September, providing the rationale and supportive data for the advantages of a local intervention against CTGF such as with PRS-220. Data presented on the drug-like properties for PRS-220 demonstrated its suitability for delivery to the lungs via nebulization, the intended administration route. Additionally, the data showed that in head-to-head preclinical studies, PRS-220 achieved greater target engagement and more efficient mitigation of lung fibrosis than pamrevlumab a systemically administered monoclonal antibody against the same target and which has provided clinical validation via a randomized Phase IIa study in IPF patients. These data support our thesis that a CTGF inhibitor locally administered through inhalation like PRS-220 may be a superior approach to a systemically administered antagonist.

除了 PRS-060 之外，我們還繼續推進與阿斯特捷利康合作的 4 個早期專案。我們期待明年推出的另一個呼吸管道催化劑是啟動我們最近宣布的完全專有呼吸計劃PRS-220 的臨床開發，PRS-220 是一種吸入抗託林蛋白，靶向CTGF 或結締組織生長因子，用於治療特發性肺纖維化。我們在 9 月的歐洲呼吸學會國際大會上報告了該計畫的臨床前數據，為 PRS-220 等針對 CTGF 的局部幹預措施的優勢提供了理由和支持數據。 PRS-220 的類似藥物特性的數據證明了其適合透過霧化（預期的給藥途徑）輸送到肺部。此外，數據顯示，在頭對頭的臨床前研究中，PRS-220 比pamrevlumab 實現了更大的標靶參與和更有效的肺纖維化緩解，pamrevlumab 是針對同一標靶的全身給藥單株抗體，並透過隨機階段提供了臨床驗證IPF 患者的 IIa 研究。這些數據支持我們的論點，即透過吸入局部施用的 CTGF 抑制劑（如 PRS-220）可能是比全身施用拮抗劑更好的方法。

We will also be evaluating this program for post-COVID pulmonary fibrosis with the support of a grant approximating USD 17 million from the state of Bavaria in Germany. The grant will support clinical readiness activities and initial clinical development for the program, including GLP tox studies, GMP manufacturing and Phase I clinical development.

我們還將在德國巴伐利亞州提供的約 1700 萬美元贈款的支持下，評估該針對新冠肺炎後肺纖維化的計畫。這筆贈款將支持該計畫的臨床準備活動和初步臨床開發，包括 GLP 毒物研究、GMP 製造和 I 期臨床開發。

Before moving on to our immuno-oncology pipeline, I would also briefly like to mention the progress of the Genentech collaboration we signed earlier this year. We have now initiated joint discovery activities for the 2 committed programs, 1 in respiratory and 1 in ophthalmology, as part of the collaboration to discover, develop and commercialize locally delivered therapies that leverage our proprietary Anticalin platform. We are excited to be working with an industry leader, Genentech, on these programs, and we look forward to giving additional updates on their progress in due course.

在繼續我們的免疫腫瘤學管道之前，我還想簡要提及我們今年早些時候簽署的基因泰克合作的進展。我們現在已經啟動了2 個承諾項目的聯合發現活動，其中1 個是呼吸科項目，1 個是眼科項目，作為合作的一部分，利用我們專有的Anticalin 平台發現、開發和商業化本地交付的療法。我們很高興能與行業領導者基因泰克公司在這些項目上合作，我們期待在適當的時候提供有關其進展的更多最新資訊。

With that, I would now like to give an update on our immuno-oncology pipeline, beginning with cinrebafusp alfa. As a reminder, cinra, also known as PRS-343, is a 4-1BB/HER2 bispecific that we are currently developing for HER2-high and HER2-low gastric cancer and which is entering Phase II. The Phase II study design is comprised of 220 patient arms, 1 with HER2-high patients and 1 with HER2-low patients. The HER2-high arm will evaluate cinra in combination with the current standard of care regimen, ramucirumab and paclitaxel, to be supported by a drug supply agreement with Lilly, the ramucirumab, while the HER2-low arm will evaluate cinra in combination with tucatinib, a small molecule inhibitor of HER2 and HER3, to be supported by a drug supply agreement with Seagen for tucatinib. As previously reported, we plan to report initial efficacy data from the HER2-low arm next year, for which we are setting a bar of at least 40% objective response rate, or ORR, which is significantly higher than the 28% benchmark established by the standard of care. In addition to ORR, we will be evaluating duration of response, disease control rate and safety.

說到這裡，我現在想介紹我們的免疫腫瘤學管道的最新情況，從 cinrebafusp alfa 開始。提醒一下，cinra，也稱為 PRS-343，是一種 4-1BB/HER2 雙特異性藥物，我們目前正在開髮用於 HER2 高和 HER2 低胃癌，並已進入 II 期。 II 期研究設計由 220 名患者組成，其中 1 名 HER2 高患者，1 名 HER2 低患者。 HER2-高臂將評估cinra 與當前標準治療方案、雷莫蘆單抗和紫杉醇的結合，並得到與禮來公司簽訂的藥物供應協議的支持，雷莫蘆單抗，而HER2-低臂將評估cinra 與tucatinib 的組合， HER2 和 HER3 的小分子抑制劑，將得到與 Seagen 的 tucatinib 藥物供應協議的支持。如同先前所報導的，我們計劃明年報告 HER2 低臂的初步療效數據，為此我們設定了至少 40% 的客觀緩解率（ORR），這明顯高於 28% 的基準護理標準。除了 ORR 之外，我們還將評估緩解持續時間、疾病控制率和安全性。

For the HER2-high arm, given the evolving treatment landscape, we have recently made a strategic decision to focus enrollment on a more homogenous patient population, namely those patients who have progressed after just one line of therapy. Given this change, we now expect to report data from this arm in 2023, which includes ORR, duration of response, disease control rate as well as safety and tolerability. As we have previously guided, the bar for our go/no-go criteria for this HER2-high arm is a composite of measures, including an ORR of at least 50%. We and our advisers believe that a 50% response rate with a good durability and attractive safety profile would represent an important option for patients with HER2-high gastric cancer.

對於 HER2 高臂，考慮到不斷變化的治療前景，我們最近做出了一項策略決定，將招募重點放在更同質的患者群體上，即那些僅經過一種治療後出現進展的患者。鑑於這一變化，我們現在預計在 2023 年報告該組的數據，其中包括 ORR、緩解持續時間、疾病控制率以及安全性和耐受性。正如我們之前所指導的，我們對 HER2 高臂的通過/不通過標準是綜合衡量標準，包括至少 50% 的 ORR。我們和我們的顧問相信，50% 的緩解率、良好的耐久性和有吸引力的安全性將成為 HER2 高胃癌患者的重要選擇。

Turning to our next I-O program. We are nearing dosing of the first patient in the Phase I/II study of PRS-344 or S095012, a 4-1BB/PD-L1 bispecific, and we have received regulatory clearance to conduct the study in a number of jurisdictions. The global open-label dose escalation study will evaluate the safety, tolerability and preliminary evidence of antitumor activity in patients with advanced solid tumors whose cancer progressed on standard of care treatment. Pieris holds full U.S. rights for this program in collaboration with Servier who holds ex-U.S. rights.

轉向我們的下一個 I-O 計劃。我們即將對PRS-344 或S095012（一種4-1BB/PD-L1 雙特異性藥物）的I/II 期研究中的第一位患者進行給藥，並且我們已獲得監管部門的批准，可以在多個司法管轄區進行該研究。全球開放標籤劑量遞增研究將評估在標準護理治療下癌症進展的晚期實體瘤患者的安全性、耐受性和抗腫瘤活性的初步證據。 Pieris 與 Servier 合作，擁有該計畫在美國的全部權利，而 Servier 擁有前美國的權利。權利。

And lastly, as part of our immuno-oncology update, I'm pleased to announce that we have initiated the second program within the bispecific immuno-oncology collaboration with Seagen, a program that includes a co-promotion option for Pieris in the United States. Furthermore, Seagen is continuing to develop the first program, an undisclosed anticalin-based bispecific.

最後，作為我們免疫腫瘤學更新的一部分，我很高興地宣布，我們已經啟動了與 Seagen 的雙特異性免疫腫瘤學合作中的第二個項目，該項目包括 Pieris 在美國的聯合推廣選項。此外，Seagen 正在繼續開發第一個程序，這是一個未公開的基於抗替卡林的雙特異性程序。

I would now like to hand the call back over to Tom, whom I would also like to congratulate on his recent promotion to Chief Financial Officer. Tom oversees all financial matters and capital markets-related activities at the company, including treasury, tax, financial planning, procurement and investor relations.

現在我想把電話轉給湯姆，我還要祝賀他最近晉升為財務長。湯姆負責監督公司的所有財務事務和資本市場相關活動，包括財務、稅務、財務規劃、採購和投資者關係。

And lastly, I would also like to congratulate Ahmed Mousa on his recent promotion to Chief Business Officer. In his new role, Ahmed will head business development and portfolio strategy in addition to serving as General Counsel and Boston Site Head.

最後，我還要祝賀艾哈邁德·穆薩 (Ahmed Mousa) 最近晉升為首席商務官。在新職位上，艾哈邁德除了擔任總法律顧問和波士頓網站負責人外，還將負責業務開發和投資組合策略。

Tom, please go ahead.

湯姆，請繼續。

Thank you, Steve, and good morning again, everyone. Cash and cash equivalents totaled $125.1 million for the quarter ended September 30, 2021, compared to a cash and cash equivalents balance of $70.4 million for the year ended December 31, 2020. The increase since December 2020 is due to cash received from new and existing collaboration agreements including milestone achievements, along with our use of the ATM program. The increase was partially offset by cash used to fund our operations for the first 9 months of 2021. The September 30 cash balance does not include the impact of the Bavarian government grant as those proceeds will be reimbursed for qualifying PRS-220 program costs incurred over the IND-enabling and early clinical development period. In the third quarter ended September 30, 2021, we sold 4.6 million shares for gross proceeds of $24 million under our ATM program at an average stock price of $5.27.

謝謝你，史蒂夫，大家早安。截至2021 年9 月30 日的季度現金和現金等價物總額為1.251 億美元，而截至2020 年12 月31 日的年度現金和現金等價物餘額為7,040 萬美元。自2020 年12 月以來的增加是由於從新的和現有的業務收到的現金合作協議包括里程碑式的成就以及我們對 ATM 程序的使用。這一增長被用於2021 年前9 個月營運的現金部分抵消。9 月30 日的現金餘額不包括巴伐利亞政府補助金的影響，因為這些收益將用於償還2021 年前9 個月發生的合格PRS-220 計劃成本。IND 啟用和早期臨床開發階段。截至 2021 年 9 月 30 日的第三季度，我們根據 ATM 計劃出售了 460 萬股股票，總收益為 2,400 萬美元，平均股價為 5.27 美元。

R&D expenses were $18.9 million for the quarter ended September 30, 2021, compared to $11.8 million for the quarter ended September 30, 2020. The increase in spending reflects higher spending on preclinical and manufacturing activities for PRS-220, an increase in manufacturing costs across multiple immuno-oncology programs, higher clinical costs on cinrebafusp alfa and higher employee-related costs. These increases were partially offset by lower manufacturing costs on PRS-060 which are fully reimbursable by AstraZeneca.

截至2021 年9 月30 日的季度研發費用為1,890 萬美元，而截至2020 年9 月30 日的季度研發費用為1,180 萬美元。支出的增加反映了PRS-220 臨床前和製造活動的支出增加，以及整個生產成本的增加。多個免疫腫瘤學課程、cinrebafusp alfa 更高的臨床成本以及更高的員工相關成本。這些成長部分被 PRS-060 較低的製造成本所抵消，阿斯特捷利康可全額補償該成本。

Moving on to G&A expenses. We incurred $4.1 million for both quarters ended September 30, 2021 and 2020. There were no significant changes in the categories of spending, as we continue to efficiently leverage our G&A functions and spending to support the overall company needs. For the quarter ended September 30, 2021, $1.8 million of other income was recorded for PRS-220 program costs that qualified for reimbursement under the Bavarian grant, which was previously announced in June 2021. And finally, net loss was $16.5 million or a loss of $0.24 per share for the quarter ended September 30, 2021, compared to a net loss of $14.3 million or a $0.26 loss per share for the quarter ended September 30, 2020.

接下來是一般行政費用。截至 2021 年 9 月 30 日和 2020 年的兩個季度，我們的支出均為 410 萬美元。支出類別沒有重大變化，因為我們繼續有效地利用我們的 G&A 職能和支出來支持公司的整體需求。截至2021 年9 月30 日的季度，PRS-220 計畫成本記錄了180 萬美元的其他收入，這些收入符合巴伐利亞補助金的報銷資格，該補助金此前於2021 年6 月宣布。最後，淨虧損為1,650 萬美元或虧損截至 2021 年 9 月 30 日的季度每股虧損 0.24 美元，而截至 2020 年 9 月 30 日的季度淨虧損 1,430 萬美元，即每股虧損 0.26 美元。

With that, I will turn the call back over to Steve.

這樣，我會將電話轉回給史蒂夫。

Thank you, Tom. In conclusion, I just want to say that this year has been an eventful one for us so far, filled with new partnerships, new programs and overall advancement of several compelling therapeutic programs, and we look forward to executing on additional key goals before year-end. I'm looking forward to continuing clinical execution on our lead immuno-oncology and respiratory programs and to sharing our progress with you next year.

謝謝你，湯姆。總之，我只想說，今年對我們來說是不平凡的一年，充滿了新的合作夥伴關係、新的計畫以及幾個引人注目的治療計畫的整體進展，我們期待著在這一年之前實現更多的關鍵目標——結尾。我期待明年繼續進行我們領先的免疫腫瘤學和呼吸系統計畫的臨床執行，並與您分享我們的進展。

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

感謝您今天加入我們的電話會議，我們現在開始電話會議，回答您的問題。

(Operator Instructions) Our first question comes from the line of Jonathan Miller with Evercore.

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

I just have a couple here. I think I'm obviously very excited to hear the results from part 1 of the 060 Phase IIa, but I want to get some more clarity on what we should be expecting from communication of that safety portion. I think investor expectations are already for a tolerable profile. So what should we be expecting from that release that gets us comfortable while we wait for part 2 in the eventual patient population?

我這裡只有一對。我想我顯然很高興聽到 060 Phase IIa 第 1 部分的結果，但我想更清楚地了解我們應該從該安全部分的溝通中期待什麼。我認為投資者的期望已經是可以接受的。那麼，在我們等待最終患者群體的第二部分時，我們應該對這個讓我們感到舒適的版本有何期待呢？

Secondly, it's very nice to see the 220 preclinical data. I thought there were some very interesting things in the U.S. presentation, but what are your latest thoughts on the early clinical development path here and especially time line? When could we start to get a sense for differentiation versus the systemic antibody in humans?

其次，很高興看到220個臨床前數據。我認為美國的演示中有一些非常有趣的事情，但是您對這裡的早期臨床開發路徑，特別是時間軸的最新想法是什麼？我們什麼時候才能開始了解人類與全身抗體的分化？

Great. Thanks, Jon. Steve here. I'll try to take a cut at the first question and then also maybe frame the second question before handing it over to more depth to Shane.

偉大的。謝謝，喬恩。史蒂夫在這裡。我會嘗試對第一個問題進行刪減，然後也可能框架第二個問題，然後再將其更深入地交給Shane。

So on PRS-060 safety gate from Part Ia into the efficacy part 2 of the Phase IIa study, I think it's good just to look where we are and what we're going to need to go through. So we noted that we completed dosing of the first 2 doses and placebo in the safety part, additional safety part, where the goal there is to assess safety, tolerability and pharmacokinetics. So as this is a blinded study, there's an unblinding process and then the data calling and data review and then a review within AstraZeneca governance, in particular. So there will be a time for committees to meet and review the data and then conclude whether or not to move forward into the Phase IIa portion or the efficacy portion of the study. So we will be working closely with AZ to go through that process. And what we are going to plan to do, as we have guided previously, is we will be announcing that we're going through the gate into the efficacy portion, but we won't be announcing any data per se. The data that we will first present for this trial will be the full top line data from the complete study, so the safety part and the efficacy part, which we're still guiding will be next year. So I would say, look for some sort of an announcement that would then note that we're progressing. And that's something that we will align officially on with AstraZeneca as we move into year-end here. And we're looking forward to doing that as soon as we can. And we haven't guided on specific weeks or anything like that, but it's in the process now given that the dosing has completed and we just got to go through the motions of unblinding review and reporting. Does that address your question?

因此，關於 PRS-060 從 Ia 部分到 IIa 期研究功效第 2 部分的安全門，我認為最好看看我們現在所處的位置以及我們需要經歷什麼。因此，我們注意到，我們在安全部分、附加安全部分完成了前 2 劑和安慰劑的給藥，目標是評估安全性、耐受性和藥物動力學。因此，由於這是一項盲法研究，因此有一個揭盲過程，然後是資料調用和資料審查，然後是阿斯特捷利康治理內部的審查。因此，委員會將有時間開會並審查數據，然後決定是否繼續進入 IIa 期研究部分或療效部分。因此，我們將與 AZ 密切合作來完成這一過程。正如我們之前所指導的那樣，我們計劃要做的是我們將宣布我們將進入功效部分，但我們不會宣布任何數據本身。我們將首先為此試驗提供的數據將是完整研究的完整頂線數據，因此我們仍在指導的安全性部分和有效性部分將在明年進行。所以我想說，尋找某種公告來表明我們正在取得進展。當我們進入年底時，我們將與阿斯特捷利康正式達成協議。我們期待盡快做到這一點。我們還沒有提供具體的幾週或類似的指導，但鑑於劑量已經完成，我們現在正在處理中，我們只需完成非盲審和報告的議案。這能解決你的問題嗎？

That makes perfect sense. And on 220?

這是完全有道理的。那麼220呢？

Yes. So on 220, we already put I think forth -- just to remind everyone, our R&D strategy is to address clinically validated targets in nuanced ways over what are normally ostensibly validations from monoclonal antibodies. And as we did that with PRS-060, vis-a-vis dupilumab, we believe we're able to start doing that again with the IPF approach with CTGF antagonist against pamrevlumab. We've already shown superior target engagement. We've already shown the benefits through drug trafficking in preclinical studies over pamrevlumab in a number of studies that we presented at ERS. So the way this will ultimately pan out, of course, is in the clinical setting, but we will continue to avail ourselves to techniques that will show preclinically the potential benefits of a local approach. And so we're going to continue, as we prepare for clinical development, we're going to also look at other preclinical and translational and mechanistic ways to reinforce why not only a local approach is the right way to go, but also that specifically against pamrevlumab that we have a benefit. And so that's what we tend to generate. That's what we intend to disclose in due course, as we work towards early clinical development with this program.

是的。因此，在 220 上，我們已經提出了我的想法——只是為了提醒大家，我們的研發策略是以細緻入微的方式解決臨床驗證的目標，而不是通常表面上透過單株抗體進行的驗證。正如我們對 PRS-060 與 dupilumab 所做的那樣，我們相信我們能夠透過針對 pamrevlumab 的 CTGF 拮抗劑的 IPF 方法再次開始這樣做。我們已經展現了卓越的目標參與。在 ERS ​​上發表的多項研究中，我們已經在臨床前研究中展示了透過毒品販運相對於 pamrevlumab 的益處。當然，最終實現這一目標的方式是在臨床環境中，但我們將繼續利用技術，在臨床前顯示局部方法的潛在益處。因此，當我們為臨床開發做準備時，我們將繼續研究其他臨床前、轉化和機械方法，以強調為什麼局部方法不僅是正確的方法，而且還特別是相對於 pamrevlumab，我們有一個優勢。這就是我們傾向於產生的。這就是我們打算在適當的時候披露的內容，因為我們致力於該專案的早期臨床開發。

Shane, I maybe said already everything that there is to say there, but I would give you a chance to comment if you want to add anything else in terms of how we specifically plan to articulate beyond what we've done, benefits over systemic and also, in particular, benefits over pamrevlumab.

肖恩，我可能已經說了所有要說的事情，但如果您想添加任何其他內容，我會給您一個評論的機會，例如我們具體計劃如何闡明我們已經所做的事情之外的內容、相對於系統性的好處和還特別優於 pamrevlumab。

Thanks, Dave. And Jon, thanks for the question. So just in terms of the question, Jon, how are we going to demonstrate a differentiation from pamrevlumab, and then from an early clinical perspective, how should we see data flowing out? The differentiation over pamrevlumab, as Steve said, is based on the fact that we feel we've got better target engagement for CTGF. We feel the route administration facilitates better target saturation and really coverage of that target. And also, of course, you've got a better convenience for the patients.

謝謝，戴夫。喬恩，謝謝你的提問。那麼就問題而言，Jon，我們如何證明與 pamrevlumab 的差異，然後從早期臨床的角度來看，我們應該如何看待數據流出？正如 Steve 所說，與 pamrevlumab 的差異化是基於這樣一個事實：我們認為我們對 CTGF 具有更好的標靶參與度。我們認為路線管理有助於更好的目標飽和度和對該目標的真正覆蓋。當然，您也為患者提供了更好的便利。

In terms of the preclinical evaluation of that, as you said, we did share data this year at ERS. We'll continue to characterize that, showing our ability to deliver our drug to the right areas of the lung. And there's a number of preclinical models and methods we can utilize to clarify that and further characterize it in parallel to our IND-enabling activities.

就臨床前評估而言，正如您所說，我們今年確實在 ERS ​​上分享了數據。我們將繼續描述這一點，以展示我們將藥物輸送到肺部正確區域的能力。我們可以利用許多臨床前模型和方法來闡明這一點，並在我們的 IND 支持活動的同時進一步表徵它。

In terms of the clinic, there's going to be some standard components to this. Initially, in the clinic, we have to look at safety tolerability and then start to drive towards those registrational endpoints. And one of the things that has made us very excited about CTGF as a target is the clarity of the reduction in -- decline in lung function that was observed with pamrevlumab from their Phase IIb study. So there's real markers from -- in terms of what we want to see in the clinic. And there's some standard components that we have to get through, of course, initially. And as we get closer to that date, the initiation of our clinical trials will certainly give more color on how we're approaching it. And in essence, we'll aim to get to that meaningful readout in as quicker manner as possible.

就診所而言，這將有一些標準組成部分。最初，在臨床上，我們必須考慮安全耐受性，然後開始朝著這些註冊終點邁進。讓我們對 CTGF 作為目標感到非常興奮的事情之一是，在 IIb 期研究中使用 pamrevlumab 觀察到肺功能明顯減少。因此，就我們希望在診所看到的情況而言，存在真正的標記。當然，一開始我們必須完成一些標準組件。隨著我們越來越接近那個日期，我們臨床試驗的啟動肯定會為我們如何接近它帶來更多的色彩。從本質上講，我們的目標是盡可能快速地獲得有意義的讀數。

Your next question comes from the line of Roger Song with Jefferies.

你的下一個問題來自 Roger Song 和 Jefferies 的對話。

Great. So maybe 3 from me, 2 for 060. So I think, Steve, you just mentioned you already completed the enrollment for 2 doses, if I remember that correctly. You kind of said you will kind of dose up to 3 dose levels. And just curious if the sort of dose still in place, you will do that later? Or is that something already you think the 2 doses is enough for the Phase II?

偉大的。所以可能是我的 3 劑，2 劑代表 060。所以我想，史蒂夫，你剛剛提到你已經完成了 2 劑的登記，如果我沒記錯的話。你說過你會服用最多 3 個劑量水平。只是好奇這種劑量是否仍然有效，您稍後會這樣做嗎？或者您已經認為 2 劑疫苗對於第二階段來說就足夠了？

The second part of the 060 is understanding you're conducting additional Phase I MAD study and AstraZeneca also doing the DPI study as well. Just curious when we will kind of -- we should expect some data from those 2 studies?

060 的第二部分是了解您正在進行額外的 I 期 MAD 研究，阿斯特捷利康也在進行 DPI 研究。只是好奇我們什麼時候會——我們應該期待這兩項研究的一些數據？

Yes. Thanks, Roger. So your first question was, I think, the sequence of cohorts across both part 1 and part 2. And so by design, what AstraZeneca and Pieris had aligned on was that the placebo group and then the first 2 doses, so the low and the mid dose, would be randomized at once and then be gating through the initiation of the efficacy portion in the part 2, which would then run in parallel to the third and the highest dose in the safety part. And then after completion of the low and the mid dose and the efficacy part, assuming that the data justified going into the high dose and the efficacy part, that would also, following all of that, would complete and our guidance remains top line data next year for all of those patients who are enrolled in the study, both safety and efficacy. So hopefully, that answers your question in terms of how things are sequenced and staged.

是的。謝謝，羅傑。因此，我認為你的第一個問題是第1 部分和第2 部分的隊列順序。因此，按照設計，阿斯特捷利康和Pieris 的一致性是安慰劑組，然後是前2 個劑量，因此低劑量和中間劑量將立即隨機化，然後透過第 2 部分中的功效部分的啟動進行選通，然後與安全部分中的第三個和最高劑量並行運行。然後，在完成低劑量和中劑量以及功效部分後，假設數據證明進入高劑量和功效部分是合理的，那麼在所有這些之後，這也將完成，我們的指導仍然是接下來的頂線數據對於所有參與研究的患者來說，無論是安全性或有效性。希望這能回答您關於事物如何排序和上演的問題。

And the second question you asked was around the data availability from the additional MAD work that we had done, I think, in the nebulized formulation in the Phase I study, where we enrolled pheno-high mild controlled asthmatics and then any DPI bridging work that AstraZeneca had done in order to get a better read on PK in the bridge from nebulized formulation to DPI. We're working on manuscript drafting and submission and the finalization process, therefore, of those together with AstraZeneca. So our intention is that these data will come out in the form of more comprehensive peer-reviewed publications in due course. It's all part of the review process. And so we will -- you'll know whenever they're published. But that's all in process. Both of those have separate studies, separate manuscripts.

你問的第二個問題是關於我們在 I 期研究的霧化製劑中所做的額外 MAD 工作的數據可用性，其中我們招募了表型高的輕度控制性哮喘患者，然後是任何 DPI 橋接工作阿斯特捷利康所做的一切是為了更了解從霧化製劑到DPI 的橋樑中的PK。因此，我們正在與阿斯特捷利康一起致力於稿件起草、提交以及最終確定過程。因此，我們的目的是這些數據將在適當的時候以更全面的同行評審出版物的形式發布。這都是審查過程的一部分。所以我們會——只要它們發布，你就會知道。但這一切都在進行中。兩者都有各自的研究、各自的手稿。

That's great. Okay. My last question is related to 343. Just very interesting, you mentioned this kind of evolving landscape and you slightly changed the HER2-high population. Just curious -- just remind us what's the key differences for the kind of HER2-high population. Also, you mentioned KOL, I think the 50% ORR and the reasonable DOR should be very meaningful for this population. Maybe just provide some clarity around the DOR, what kind of a DOR you're expecting for this population?

那太棒了。好的。我的最後一個問題與 343 有關。非常有趣，您提到了這種不斷變化的景觀，並且您稍微改變了 HER2 高人群。只是好奇 - 請提醒我們 HER2 高人群的主要區別是什麼。另外，你提到了KOL，我認為50%的ORR和合理的DOR對這個族群來說應該是非常有意義的。也許只是對 DOR 進行一些澄清，您期望該人群獲得什麼樣的 DOR？

Sure. Thanks, Roger. I think it's good just to contextualize again cinra in terms of what it is and isn't relative to HER2 engagers. And so remember, we think of this as primarily a 4-1BB immuno-oncology T-cell agonist or immuno-agonist that uses 4-1BB primarily as a hook and a cluster mediator. And based on the data that we generated preclinically and clinically, we do see a great opportunity for this program to be tested in HER2 low and separately in HER2 high. And we're reiterating today the rationale for HER2 low, given that there's just been a dearth of progress in there. And the second-line standard of care has been as such for quite some time. And at a 28% ORR, we think we can show a meaningful benefit by going for our targeted bogey of 40%.

當然。謝謝，羅傑。我認為最好再次將 cinra 置於上下文中，了解它與 HER2 參與者相關的內容以及與 HER2 參與者無關的內容。因此請記住，我們認為這主要是一種 4-1BB 免疫腫瘤學 T 細胞激動劑或免疫激動劑，主要使用 4-1BB 作為鉤子和簇介體。根據我們在臨床前和臨床中產生的數據，我們確實看到了該程序在 HER2 低水平和 HER2 高水平中分別進行測試的絕佳機會。今天我們重申 HER2 低的理由，因為這方面缺乏進展。二線護理標準已經存在相當長一段時間了。在 ORR 為 28% 的情況下，我們認為透過實現 40% 的目標柏忌可以顯示出有意義的好處。

Now HER2 high, because of all the HER2 antagonists and HER2 disrupters in the space that uses HER2, it's been primarily as the mediator for disease intervention, there are a number of other players in that space, and it's a very dynamic space, as you probably all are aware. So even though this is primarily cinra an I-O agent, we do contend with the other HER2-engaging modalities that are in development. And so as we looked at the HER2 landscape in a HER2-high setting, we still think that in the second line, we do offer something that is, number one, very different than other engagers that are out there. And number two, setting a bar of 50% ORR, plus with the intended durable benefit of an immunotherapy, we still think that, that composite remains very relevant. Now the difference in the last year or so is the nature of evolving standard of care and how that would impact the types of patients that we can get in various geographies. And as part of Tim, coming in as our Chief Medical Officer, we had over the last couple of months some really good discussions with him and with advisers and we've concluded that making this adjustment to second line is the right way to go here, second line only. And I think it will be good, maybe Tim can share in his few words or his own words, what he thinks is right to do here and why we've now tightened or focused the enrollment to second-line only.

現在 HER2 很高，因為使用 HER2 的領域中存在所有 HER2 拮抗劑和 HER2 幹擾劑，它主要作為疾病幹預的中介，該領域還有許多其他參與者，這是一個非常動態的領域，就像你一樣也許所有人都知道。因此，儘管這主要是一種 I-O 藥物，但我們確實與正在開發的其​​他 HER2 接合方式競爭。因此，當我們在 HER2 高設定中查看 HER2 景觀時，我們仍然認為在第二行中，我們確實提供了與其他參與者非常不同的東西。第二，設定 50% ORR 的標準，加上免疫療法預期的持久益處，我們仍然認為，該複合材料仍然非常相關。現在，過去一年左右的差異在於不斷發展的護理標準的性質，以及這將如何影響我們在不同地區所能獲得的患者類型。作為蒂姆的一部分，作為我們的首席醫療官，我們在過去的幾個月裡與他和顧問進行了一些非常好的討論，我們得出的結論是，對二線進行調整是正確的方法，僅第二行。我認為這會很好，也許蒂姆可以用他的幾句話或他自己的話來分享，他認為在這裡做的事情是正確的，以及為什麼我們現在只收緊或集中於二線招生。

Thanks, Steve. And thanks, Roger, for the question. Great question. So yes, obviously, gastric cancer is a heterogeneous population to begin with. We know that as a general principle in oncology, patients have less of a response rate with later lines of treatment. And so when we have those KOL interactions and really dove deep into the data, we realized we would benefit the program and our decision-making down the road by really tightening up the population, that is to really focus the HER2 high on the second-line population where we have the most robust benchmark data. Steve just mentioned the RAINBOW publication. Obviously, that's 28% response rate. You asked about the duration of response. With RAINBOW, of course, it's published at 4.4 months. So we would anticipate a significant benefit when we add cinra to ram/pac over that, and that is confirmed with our investigators as well. And I think we have reason to believe that we will be able to deliver that based on the Phase I data that we've shown at AACR this year, and that's shown before at (inaudible). So yes, just to conclude, cinra has a very different mechanism of action. It's envisioned to be an option for second-line patients. It's an evolving landscape, and we are adapting our strategy to this ever-evolving landscape.

謝謝，史蒂夫。謝謝羅傑提出這個問題。很好的問題。所以，是的，顯然，胃癌一開始就是一個異質性族群。我們知道，作為腫瘤學的一般原則，患者對後續治療的反應率較低。因此，當我們與 KOL 互動並真正深入研究數據時，我們意識到，透過真正收緊人口，我們將使該計劃和我們的決策受益，即將 HER2 高值真正集中在第二個方面——我們擁有最可靠的基準數據的人口線。史蒂夫剛剛提到了 RAINBOW 出版物。顯然，回覆率為 28%。您詢問了回應的持續時間。當然，《RAINBOW》的發佈時間為 4.4 個月。因此，當我們將 cinra 添加到 ram/pac 中時，我們預計會帶來顯著的好處，這也得到了我們的研究人員的證實。我認為我們有理由相信，我們將能夠根據今年在 AACR 上展示的第一階段數據來實現這一目標，並且之前在（聽不清楚）上展示過這一點。所以，是的，只是得出結論，cinra 有一個非常不同的作用機制。預計它將成為二線患者的一種選擇。這是一個不斷變化的格局，我們正在調整我們的策略以適應這個不斷變化的格局。

(Operator Instructions) Our next question comes from the line of Matt Phipps with William Blair.

（操作員說明）我們的下一個問題來自馬特·菲普斯和威廉·布萊爾的對話。

So on 060, you mentioned dosing is done. Is the kind of blinded data in-house? There's also a 4-week follow-up period. So just wondering on timing, if we still in to wait for that 4-week follow-up period before they will do any unblinding. And then will you let us know when that third dose in the Phase Ib completes the safety portion? And then lastly on 060 for the Phase II data we get next year, is that all 3 doses or at least it would be the first 2 doses?

所以在 060 上，你提到劑量已經完成。這種盲數據是內部的嗎？還有 4 週的追蹤期。所以只是想知道時間，我們是否還要等待 4 週的追蹤期，然後他們才會進行揭盲。然後，您能否告知我們 Ib 期第三劑疫苗何時完成安全部分？最後關於 060，我們明年獲得的 II 期數據是全部 3 劑還是至少是前 2 劑？

Right. Yes. So thanks, Matt, for the questions. So your first question was getting into timing on the announcement of passing through the gate based on the fact that we've announced both -- or all patients have been dosed in the Part Ia and that there is a 30-day follow-up period. I don't know, Tim, you want to comment on the aspects of the review process from on out. But again, we're not guiding on a specific date. And remember, no data.

正確的。是的。謝謝馬特提出的問題。所以你的第一個問題是根據我們已經宣布的事實——或者所有患者都已在 Ia 部分中接受了給藥並且有 30 天的隨訪期——來了解宣布通過大門的時間。提姆，我不知道您是否想對審核過程的各個方面進行評論。但同樣，我們不會指導具體日期。請記住，沒有數據。

And then we'll come back to your question on Phase IIa top line in a second.

然後我們將立即回到您關於 IIa 期頂線的問題。

Thanks, Matt, for the question. Great question. So yes, as Steve pointed out, there is a 4-week safety follow-up period for the patients enrolled in the study. And there will actually be -- well, first of all, as Steve mentioned, we completed enrollment of the first part of the study. The data is in-house. It's being analyzed, as we speak, in a blinded fashion. There will be a Safety Review Committee held -- coming up. And the 4-week follow-up data will be available later on to complete the data set for this first part of the study. So efficacy, safety available for all patients right now. Follow-up data will come very soon.

謝謝馬特提出的問題。很好的問題。所以，是的，正如 Steve 指出的那樣，參與研究的患者有 4 週的安全追蹤期。實際上，首先，正如史蒂夫所提到的，我們完成了研究第一部分的註冊。數據是內部的。正如我們所說，它正在以盲目的方式進行分析。即將召開安全審查委員會。稍後將提供 4 週的追蹤數據，以完成研究第一部分的數據集。因此，現在所有患者都可以獲得療效和安全性。後續數據很快就會出來。

And Matt, just to add a little color on your final question. So the Part Ib of the safety study would be that third and highest dose, which will, as I mentioned earlier, from Jon's question, I think was it will run in parallel to the first 2 doses in the efficacy part. I think our current plan was not to announce any results from the Part 1b of the 2-part study and just to bulk everything together in the Phase IIa top line of the entire study. And again, just to make it crystal clear, the objective is that the top line, which we intend to disclose next year, will include the entirety of the study, right, so everything. And AZ, of course, will be able to power the enrollment to match the -- with the number of sites, number of jurisdictions to meet that expectation. And that is currently the plan, is that we would dose in efficacy that which passes safety.

馬特，只是為了給你的最後一個問題添加一點色彩。因此，安全性研究的 Ib 部分將是第三次也是最高劑量，正如我之前提到的，根據 Jon 的問題，我認為它將與功效部分的前 2 劑並行進行。我認為我們目前的計劃是不公佈 2 部分研究的 1b 部分的任何結果，而只是將整個研究的 IIa 階段的所有內容集中在一起。再說一次，為了說清楚，我們的目標是，我們打算明年披露的頂線將包括整個研究，對吧，所以一切。當然，AZ 將能夠透過站點數量、司法管轄區數量來支持註冊，以滿足這一期望。這就是目前的計劃，我們將有效地劑量通過安全性。

Yes. Okay. On 343, it seems like if I was reading -- or understanding correctly that this second line focuses for the chemo combo and HER2 high alone. Is the tucatinib combo for HER2 low strictly second line as well? Or is that the -- or that one still a little bit broader?

是的。好的。在 343 上，似乎我正在閱讀或正確理解第二行只關注化療組合和 HER2 高。用於 HER2 低的圖卡替尼組合是否也是嚴格的二線藥物？還是——或者那個範圍更廣一些？

Yes, it's a great question. I'll turn that over to Tim. I think this is because of the dearth of emerging standard of care, that one is far more manageable than HER2 high, but we'll let Tim comment on that.

是的，這是一個很好的問題。我會把它交給蒂姆。我認為這是因為缺乏新興的護理標準，該標準比 HER2 高水平更容易管理，但我們會讓 Tim 對此發表評論。

Yes. Thanks, Steve. Yes, indeed, the HER2-high population, obviously, it's a very competitive space, new entries on a regular basis. Pretty low, arguably and speaking with a lot of external consultants in the eastern part of the world as well as in the western part, is equally, some might argue even higher unmet medical needs. So there is not much outstart for patients even in clinical trials beyond the approved chemotherapy regimen. So it's not even an established second-line therapy, let alone a third line. So at this point, we feel that it is most pragmatic to have a second line-plus indication for the HER2-low population, while at the same time, as we discussed earlier, really tightening the criteria for the HER2 high part of the study.

是的。謝謝，史蒂夫。是的，確實，HER2 高人群，顯然，這是一個競爭非常激烈的領域，定期有新條目出現。可以說，相當低，並且與世界東部和西部的許多外部顧問交談，有些人可能會認為未滿足的醫療需求甚至更高。因此，即使在核准的化療方案之外的臨床試驗中，患者也沒有太多的起步空間。因此，它甚至不是既定的二線療法，更不用說第三線了。因此，在這一點上，我們認為對 HER2 低人群設置二線+適應症是最務實的，同時，正如我們之前討論的那樣，真正收緊研究中 HER2 高部分的標準。

Great. And last quick one. So 344, congrats on getting a couple approvals to start trials there in countries. Are you waiting for an IND clearance in the U.S. to start that trial? Or will that start ex U.S.?

偉大的。最後一個快點。第 344 章您是否正在等待美國的 IND 批准來開始試驗？或者這會從美國開始嗎？

We haven't guided on specific jurisdictions. I think what we did say in the past, and we'll just refer back to that, is that we learned a lot from our initial escalation in the U.S. with cinra. And of course, that has allowed us to calculate our engagement with FDA accordingly as we look for the most efficient way to escalate. But given the competitive nature of the space, we haven't yet disclosed which jurisdictions we have gone into, but that will come out in ct.gov filings and other regulatory filings in due course.

我們尚未針對特定司法管轄區提供指導。我認為我們過去確實說過，我們將回顧一下，我們從最初在美國與 cinra 的升級中學到了很多。當然，這使我們能夠在尋找最有效的升級方式時相應地計算與 FDA 的合作。但考慮到該領域的競爭性質，我們尚未透露我們已進入哪些司法管轄區，但這些資訊將在適當的時候在 ct.gov 備案文件和其他監管備案文件中公佈。

Ladies and gentlemen, we have reached the end of the question-and-answer session, and I would like to turn the call back to Mr. Stephen Yoder for closing remarks.

女士們、先生們，問答環節已經結束，我想請史蒂芬‧約德先生做結束語。

All right. Thanks, Hector. And nothing to add other than to thank everyone again for your attention today and for your continued support of Pieris. Have a great day.

好的。謝謝，赫克托。除了再次感謝大家今天的關注以及對 Pieris 的持續支持之外，沒有什麼可補充的。祝你有美好的一天。

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

今天的會議到此結束。此時您可以斷開線路。感謝大家的參與。