Palvella Therapeutics Inc (PVLA) 2021 Q4 法說會逐字稿

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

您好，歡迎參加 Pieris Pharmaceuticals 年終收益電話會議。 （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 call over to Tom Bures, Chief Financial Officer. Thank you. You may begin.

我現在想將電話轉給財務長 Tom Bures。謝謝。你可以開始了。

Thank you. Good morning, everyone, and thank you for joining us for our year-end 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 Kaufmann, our Chief Scientific Officer; and Shane Olwill, our Chief Development Officer, 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 年底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 Kaufmann，我們的首席科學長；我們的首席開發長 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. 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。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'll 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 year-end earnings call. Last year was a busy year of execution for us. We entered into several collaborations, including the respiratory and ophthalmology collaboration with R&D leader Genentech and a collaboration to further expand our partnered 4-1BB bispecific pipeline. We also initiated multiple clinical trials, including first-in-human studies for our 4-1BB PD-L1 bispecific and we unveiled a new proprietary program in our respiratory franchise. All of these have set the stage for an exciting 2022.

謝謝湯姆，也謝謝大家今天參加我們的 2021 年年終財報電話會議。去年對我們來說是執行工作繁忙的一年。我們進行了多項合作，包括與研發領導者 Genentech 的呼吸和眼科合作，以及進一步擴大我們合作的 4-1BB 雙特異性管道的合作。我們還啟動了多項臨床試驗，包括針對 4-1BB PD-L1 雙特異性藥物的首次人體研究，並在我們的呼吸系統特許經營中推出了一項新的專有計劃。所有這些都為令人興奮的 2022 年奠定了基礎。

I would like to now take you through some of these highlights from last year and to discuss what to expect for this year. As many of you are aware, our lead respiratory program is PRS-060/AZD1402, an inhaled IL-4 receptor alpha inhibitor that we are developing alongside AstraZeneca for the treatment of moderate to severe asthma. The program is currently in a multicenter placebo-controlled Phase IIa study as a DPI formulation.

現在我想向您介紹去年的一些亮點，並討論今年的預期。正如你們許多人所知，我們的主要呼吸系統項目是PRS-060/AZD1402，這是一種吸入性IL-4 受體α 抑制劑，我們正在與阿斯特捷利康一起開發，用於治療中度至重度哮喘。該計畫目前正處於 DPI 製劑形式的多中心安慰劑對照 IIa 期研究。

Earlier this year, we announced the successful completion of Part 1a, or the safety portion of the 1 mg and the 3 mg dose cohorts in that study. In that portion of the study, 31 moderate asthmatics controlled on standard of care asthma therapy, which consists of medium dose ICS with LABA, were dosed twice daily over 4 weeks, randomized 1:1:1 across the 2 dose levels in the placebo arm.

今年早些時候，我們宣布成功完成第 1a 部分，即該研究中 1 毫克和 3 毫克劑量組的安全部分。在這部分研究中，31 名中度氣喘患者接受標準護理氣喘治療（包括中等劑量ICS 和LABA），在4 週內每天服用兩次，安慰劑組的2 個劑量水平按1:1:1 隨機給藥。

The safety review AstraZeneca conducted included measures such as incidents of adverse events, changes in laboratory markers, FEV1 and pharmacokinetics. Following a positive safety review, AstraZeneca is now enrolling the efficacy part of the study for the 1 and 3 milligram dose levels. In this portion of the study, moderate uncontrolled asthmatics on ICS/LABA with a blood eosinophil count of greater than or equal to 150 cells per microliter and a fractional exhaled nitric oxide or FeNO greater than or equal to 25 parts per billion at screening, are then randomized 1:1:1 across the 1 and 3 milligram dose cohorts in a placebo arm.

阿斯特捷利康進行的安全審查包括不良事件發生率、實驗室標記變化、FEV1 和藥物動力學等措施。經過積極的安全性審查後，阿斯特捷利康目前正在招募 1 毫克和 3 毫克劑量水平的功效部分研究。在這部分研究中，接受ICS/LABA 治療的中度未受控制的氣喘患者，在篩檢時血液嗜酸性粒細胞計數大於或等於150 個細胞/微升，呼出一氧化氮或FeNO 分數大於或等於十億分之25。然後將 1 毫克和 3 毫克劑量組以 1:1:1 隨機分配到安慰劑組。

We are looking at improvement of FEV1 at 4 weeks relative to placebo as the primary end point in this part of the study. In parallel, AstraZeneca is now enrolling the safety portion of the highest 10-milligram dose level, which is randomized 2:1 treatment to placebo. Although we have guided to top line Phase IIa data results from the study this year, we are actively evaluating feasibility of our study time lines in the current geopolitical environment, and we will update our guidance in the orderly course of business, if needed.

我們將 4 週時 FEV1 相對於安慰劑的改善作為這部分研究的主要終點。同時，阿斯特捷利康目前正在招募最高 10 毫克劑量水平的安全部分，該劑量以 2:1 的比例隨機分配給安慰劑。儘管我們已經指導了今年研究的 IIa 期數據結果，但我們正在積極評估研究時間表在當前地緣政治環境下的可行性，並且如果需要，我們將在有序的業務過程中更新我們的指導。

Looking forward, a positive readout from this study would be a trigger for the possibility of opting into co-development of PRS-060 with AstraZeneca. Within 30 days of the top line data from the study being made available to us, alongside a development plan in a proposed budget, we can choose to opt in the co-development of this program at 1 of 2 levels, neither of which includes an option exercise fee.

展望未來，這項研究的積極結果將觸發選擇與阿斯特捷利康共同開發 PRS-060 的可能性。在向我們提供研究的主要數據以及擬議預算中的開發計劃後 30 天內，我們可以選擇在 2 個級別中的一個級別共同開發該計劃，這兩個級別均不包括期權行使費。

At the first level, we would be responsible for 25% of the cost share with a predetermined cost cap. This presents one opportunity that when considering future development milestones would still cover a meaningful portion of our cost share and enable us to increase our share of potential sales milestones and royalties. At the second level, we would be responsible for 50% of the cost share without a cost cap. Although this opportunity would require more investments, it would enable us to receive an attractive gross margin share.

在第一級，我們將承擔 25% 的成本份額，並設定預定的成本上限。這提供了一個機會，在考慮未來的開發里程碑時，仍將涵蓋我們成本份額的很大一部分，並使我們能夠增加潛在銷售里程碑和特許權使用費的份額。在第二級，我們將承擔 50% 的成本份額，沒有成本上限。儘管這個機會需要更多的投資，但它將使我們能夠獲得有吸引力的毛利率份額。

If we choose not to participate in the ongoing co-development of PRS-060, we would continue to receive development milestones commensurate to those if we had opted in at 25%, although the royalties in the sales milestones would be lower than this first opt-in tier. As a reminder, beyond the co-development options and whether we choose to opt in to co-development at all, we will also have the option to co-commercialize this program in the United States.

如果我們選擇不參與正在進行的 PRS-060 聯合開發，我們將繼續收到與選擇參與 25% 的開發里程碑相當的開發里程碑，儘管銷售里程碑中的特許權使用費將低於第一個選擇- 在層中。提醒一下，除了共同開發選項以及我們是否選擇共同開發之外，我們還可以選擇在美國共同商業化該專案。

Beyond PRS-060, we are advancing 3 programs in collaboration with AstraZeneca. We jointly discontinued 1 of the 4 discovery stage programs in the collaboration for which AstraZeneca was not able to validate an exploratory target. We retained co-development and co-commercialization options for 2 of the 3 remaining active discovery programs in the collaboration.

除了 PRS-060 之外，我們還與阿斯特捷利康合作推進 3 個專案。我們共同終止了合作中 4 個發現階段專案中的 1 個，因為阿斯特捷利康無法驗證其探索性目標。我們為合作中剩餘的 3 個活躍發現專案中的 2 個保留了共同開發和共同商業化選項。

Now moving on to our most advanced fully proprietary respiratory asset, I want to briefly discuss our plans for PRS-220, which is an inhaled anticalin protein targeting CTGF, or connective tissue growth factor, for the treatment of idiopathic pulmonary fibrosis, IPF, that we unveiled last year. We reported encouraging preclinical data from the program last year. And this year, we anticipate initiating clinical development starting with a Phase 1 study in healthy volunteers.

現在轉向我們最先進的完全專有的呼吸資產，我想簡要討論一下我們的PRS-220 計劃，這是一種吸入抗託林蛋白，靶向CTGF（結締組織生長因子），用於治療特發性肺纖維化(IPF)，我們去年揭曉了。去年我們報告了該計畫令人鼓舞的臨床前數據。今年，我們預計將從健康志願者的第一階段研究開始啟動臨床開發。

When we announced the program last year, we also announced that we received a grant from the State of Bavaria in Germany for approximately $17 million to evaluate this program for post-COVID pulmonary fibrosis. This grant has since supported clinical readiness activities such as GLP tox and GMP manufacturing and will also apply to Phase 1 clinical development, making recent and near-term investments for this program very cost effective. Given the clinical validation of CTGF, in addition to the potential benefits of an inhaled antagonist to this target, we are excited about the opportunity this program offers.

當我們去年宣布該計畫時，我們也宣布獲得了德國巴伐利亞州約 1700 萬美元的撥款，用於評估該計畫針對新冠肺炎後肺纖維化的情況。這筆贈款此後支持了 GLP tox 和 GMP 製造等臨床準備活動，也將適用於一期臨床開發，使得該計劃的近期投資非常具有成本效益。鑑於 CTGF 的臨床驗證，除了吸入拮抗劑對該目標的潛在益處外，我們對該計劃提供的機會感到興奮。

And as a reminder, we also have an ongoing respiratory and ophthalmology collaboration ongoing with Genentech that we signed last year and as part of which we have initiated joint discovery activities for the 2 committed programs. We are enthusiastic about partnering with Genentech and hope to give more updates on that alliance as it progresses.

提醒一下，我們也與基因泰克公司進行了持續的呼吸和眼科合作，該合作是我們去年簽署的，作為合作的一部分，我們為這兩個承諾計畫啟動了聯合發現活動。我們熱衷於與基因泰克合作，並希望隨著聯盟的進展提供更多最新資訊。

Now, I'd like to give an update on our clinical immuno-oncology pipeline. We currently have 2 IO programs in clinical development. Our lead IO program is cinrebafusp alfa or PRS-343 or CINRA for short. CINRA is a proprietary 4-1BB/HER2 bispecific we are developing separately for HER2-high and HER2-low gastric cancer. In Phase 1 studies, the drug showed single-agent activity, biomarker data supportive of its mechanism of action and an acceptable safety profile. CINRA also showed activity in patients with immunologically cold tumors as well as those with HER2-low expressing tumors, both of which represent high unmet medical need.

現在，我想介紹一下我們的臨床免疫腫瘤學管道的最新情況。我們目前有 2 個 IO 專案處於臨床開發階段。我們主導的 IO 計畫是 cinrebafusp alfa 或 PRS-343 或簡稱 CINRA。 CINRA 是一種專有的 4-1BB/HER2 雙特異性藥物，我們正在分別針對 HER2 高和 HER2 低胃癌進行開發。在第一階段研究中，該藥物顯示出單藥活性、支持其作用機制的生物標記數據以及可接受的安全性。 CINRA 在免疫冷腫瘤患者以及 HER2 低表達腫瘤患者中也表現出活性，這兩種腫瘤都代表著高度未滿足的醫療需求。

Last month, we announced the dosing of the first patient in a Phase 2 study for this program. This study includes 2 20-patient arms. In the first arm, we are evaluating CINRA in combination with ramucirumab and paclitaxel in HER2-high gastric cancer patients. In the second arm, we are evaluating CINRA in combination with tucatinib in HER2-low gastric cancer patients. In both arms, the CINRA dose includes an 18 milligram per kilogram loading dose with a Q2 weekly 8-milligram per kilogram maintenance dose.

上個月，我們宣布了該計畫二期研究中第一位患者的給藥劑量。這項研究包括 2 組 20 名患者。在第一組中，我們正在評估 CINRA 與雷莫蘆單抗和紫杉醇聯合治療 HER2 高胃癌患者的情況。在第二組中，我們正在評估 CINRA 與 tucatinib 聯合治療 HER2 低胃癌患者。在兩組中，CINRA 劑量包括每公斤 18 毫克的負荷劑量和第二季度每週每公斤 8 毫克的維持劑量。

We expect to report data from the HER2-low arm later this year. And for the HER2-high arm, we expect to report data next year. As previously guided, we have set a high bar for our Go/No-Go criteria for both arms and objective response rate, or ORR, of at least 50% in the HER2-high arm and of at least 40% in the HER2-low arm. Of course, we will also be looking at duration of response and safety for both arms.

我們預計將在今年稍後報告 HER2-low 臂的數據。對於 HER2 高臂，我們預計明年將報告數據。如同先前的指導，我們為雙臂的通過/不通過標準和客觀緩解率 (ORR) 設定了很高的標準，HER2-高臂至少為 50%，HER2- 至少為 40%。低臂。當然，我們也會關注雙臂的反應持續時間和安全性。

Now, in addition to the CINRA Phase 2 trial, we also initiated the global open-label Phase 1/2 dose escalation study to evaluate the safety tolerability and preliminary evidence of antitumor activity of PRS-344, also known as S095012, a 4-1BB PD-L1 bispecific. We are currently evaluating PRS-344 in patients with advanced solid tumors whose cancer progressed on standard of care treatment. And we also recently published preclinical data for this program in the peer-reviewed journal Clinical Cancer Research.

現在，除了CINRA 2期試驗外，我們還啟動了全球開放標籤1/2期劑量遞增研究，以評估PRS-344（也稱為S095012）的安全耐受性和抗腫瘤活性的初步證據，PRS- 344是一種4- 1BB PD-L1 雙特異性。我們目前正在評估 PRS-344 在晚期實體瘤患者中的作用，這些患者的癌症在標準護理治療中出現進展。我們最近也在同行評審期刊《臨床癌症研究》上發表了該計畫的臨床前數據。

As a reminder, we have exclusive commercialization rights for PRS-344 in the United States and will receive royalties on ex-US sales for this program. Servier is also within the alliance continuing to develop PRS-352, which is an undisclosed Anticalin-based bispecific beyond 4-1BB.

提醒一下，我們擁有 PRS-344 在美國的獨家商業化權利，並將獲得該項目在美國以外地區銷售的特許權使用費。施維雅還在聯盟中繼續開發 PRS-352，這是一種未公開的基於 Anticalin 的超越 4-1BB 的雙特異性藥物。

I would like to end the IO update with a quick update on our other ongoing IO partnerships. Our collaboration with Seagen continues to progress, and we hope to have additional updates on those programs later this year. Additionally, Boston Pharmaceuticals continues the IND-enabling work necessary to progress PRS-342, the GPC3/4-1BB bispecific they licensed last year toward the clinic. It is rewarding to see the multitude of Pieris-sourced 4-1BB bispecifics that are in or soon have the potential to be in clinical development with a great roster of partners.

我想在 IO 更新結束時快速介紹我們其他正在進行的 IO 合作夥伴關係。我們與 Seagen 的合作繼續取得進展，我們希望在今年稍後對這些項目進行更多更新。此外，Boston Pharmaceuticals 也持續推動 PRS-342 所需的 IND 工作，PRS-342 是他們去年向臨床授權的 GPC3/4-1BB 雙特異性藥物。看到大量來自 Pieris 的 4-1BB 雙特異性抗體正在或很快有可能與眾多合作夥伴一起進行臨床開發，這是令人欣慰的。

This concludes my prepared remarks. And I would now like to hand the call back over to Tom.

我準備好的發言到此結束。我現在想把電話轉回給湯姆。

Thank you, Steve, and good morning again, everyone. Cash and cash equivalents totaled $117.8 million for the year ended December 31, 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 was due to cash received from new and existing collaboration agreements, including milestone achievements.

謝謝你，史蒂夫，大家早安。截至2021 年12 月31 日止年度的現金和現金等價物總額為1.178 億美元，而截至2020 年12 月31 日止年度的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合作協議，包括里程碑式的成就。

In addition, during 2021, the ATM program was utilized to raise a total of $38.5 million in net proceeds at an average price of $4.85 per share. These increases in cash were partially offset by cash used to fund operations in 2021. The year-end cash position also does not include the impact of the Bavarian government grant as those proceeds will be reimbursed for qualifying program costs that are incurred during the PRS-220 development period.

此外，2021 年期間，ATM 計劃以每股 4.85 美元的平均價格籌集了總計 3,850 萬美元的淨收益。這些現金成長被用於資助 2021 年營運的現金部分抵消。年終現金狀況也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 PRS 期間產生的合格計劃成本。220 開發期。

R&D expenses were $66.7 million for the year ended December 31, 2021, compared to $46.5 million for the year ended December 31, 2020. The ramp-up of R&D expenses relates to CMC activities required in advance of starting clinical trials, for which Steve noted the 2 IO trials started right around the end of the year, and we are planning the initiation of PRS-220 later this year. In addition, we incurred 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.

截至2021年12月31日止年度的研發費用為6,670萬美元，而截至2020年12月31日止年度的研發費用為4,650萬美元。研發費用的增加與開始臨床試驗前所需的CMC活動有關，史蒂夫指出兩項 IO 試驗於今年年底左右開始，我們計劃在今年稍後啟動 PRS-220。此外，我們也因 Cinrebafusp Alfa 產生了更高的臨床成本和更高的員工相關成本。這些增加部分被 PRS-060 較低的製造成本所抵消，而 PRS-060 的製造成本可全額補償。

G&A expenses were $16.5 million for the year ended December 31, 2021, compared to $16.7 million for the year ended December 31, 2020. We continue to leverage the capabilities of our G&A functions such that total G&A spending was consistent year-over-year.

截至2021 年12 月31 日止年度，一般及行政費用為1,650 萬美元，而截至2020 年12 月31 日止年度，一般及行政費用為1,670 萬美元。我們繼續利用G&A 職能部門的能力，使一般及行政費用總額與去年同期一致。

In 2021, higher fixed and variable compensation and higher insurance costs were offset by lower legal, accounting and project management costs. We also incurred lower office and building equipment costs as there were a number of one-time costs related to the move to the new R&D facility in Hallbergmoos, Germany in the prior year. For the year ended December 31, 2021, $3.7 million of other income was recorded for PRS-220 program costs that qualify for reimbursement under the Bavarian grant that was announced in June of 2021.

2021年，較高的固定和可變薪酬以及較高的保險成本被較低的法律、會計和專案管理成本所抵消。我們也降低了辦公室和建築設備成本，因為去年搬遷到德國哈爾伯格莫斯的新研發設施時產生了許多一次性成本。截至 2021 年 12 月 31 日的年度，PRS-220 計畫費用記錄了 370 萬美元的其他收入，這些收入有資格根據 2021 年 6 月宣布的巴伐利亞補助金進行報銷。

Net loss was $45.7 million or $0.71 loss per share for the year ended December 31, 2021, compared to a net loss of $37.2 million or $0.68 loss per share for the year ended December 31, 2020.

截至2021年12月31日止年度的淨虧損為4,570萬美元，即每股虧損0.71美元，而截至2020年12月31日止年度的淨虧損為3,720萬美元，即每股虧損0.68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 closing, I just want to say last year was characterized by heavy-lifting and execution that's necessary to set us up for an eventful 2022. We added new partners to our roster. We initiated new clinical trials and we maintained a healthy balance sheet. There is a clear focus on upcoming catalysts, including the Phase IIa data from PRS-060 later this year and our subsequent opt-in decision as well as our CINRA and PRS-344 readouts and our PRS-220 clinical initiation. I look forward to keeping you updated on those key inflection points as the year progresses.

謝謝你，湯姆。最後，我只想說，去年的特點是繁重的工作和執行力，這對我們迎接多事的 2022 年是必要的。我們在我們的名冊中添加了新的合作夥伴。我們啟動了新的臨床試驗，並維持了健康的資產負債表。我們明確關注即將推出的催化劑，包括今年稍後 PRS-060 的 IIa 期數據和我們隨後的選擇加入決定，以及我們的 CINRA 和 PRS-344 讀數以及我們的 PRS-220 臨床啟動。隨著這一年的進展，我期待著向您通報這些關鍵轉折點的最新情況。

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

感謝您今天加入我們，我們現在開始電話詢問您的問題。

(Operator Instructions) Our first questions come 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。

Let's start on PRS-060. It's the first time I think I've really heard you suggest that you might not opt in all the way or that maybe your body language there was feeling a little softer. Assuming the data is still good, how are you feeling about the 2 different levels of opt-in here? Are you still leaning towards a full option or what are the drivers of you maybe not going all the way there?

讓我們從 PRS-060 開始。這是我第一次真正聽到你建議你可能不會完全選擇，或者你的肢體語言感覺有點柔和。假設數據仍然良好，您對這裡的 2 個不同級別的選擇感覺如何？您是否仍然傾向於完整的選擇，或者是什麼驅動您可能沒有一路走下去？

And I think what we were able to start doing after aligning with AstraZeneca on the detail which we want to communicate around the opt-in contours, we've now been trying to educate investors on what the baseline value is on the royalty and milestone income should we not choose to opt in at all. And then as well as the contours of the 2 distinct opt-in decisions that we could make with our unfettered discretion in how those could be funded, whether through milestone streams or other means such as traditional equity financings.

我認為，在與阿斯特捷利康就我們想要圍繞選擇加入輪廓進行溝通的細節進行協調後，我們能夠開始做的事情是，我們現在一直在努力讓投資者了解特許權使用費和里程碑收入的基線價值是多少我們是否應該根本不選擇加入？然後，以及我們可以自由裁量權做出的兩個不同選擇決定的輪廓，決定如何提供資金，無論是透過里程碑流還是傳統股權融資等其他方式。

So I think data will be partly responsible for how much enthusiasm there is and how we would fund this. But I think it's good to go a little bit deeper and I'll turn it over to Tom to provide a little bit more color on why, for example, the first opt-in level of 25% is particularly attractive, and we're certainly not going to rule out the other one, but we want to make sure everyone understands the affordability of this in all cases.

因此，我認為數據將在一定程度上決定人們的熱情以及我們如何為其提供資金。但我認為更深入一點是很好的，我會將其交給 Tom，以提供更多資訊來解釋為什麼，例如，25% 的第一個選擇加入水平特別有吸引力，我們正在當然不會排除另一種，但我們希望確保每個人都了解在所有情況下的承受能力。

So I think in the different levels, right? So just to clarify, if we do nothing, we will get development milestones that are meaningful, so the traditional milestones you'd expect for the various phases of clinical development. And then, we get our sales milestone of royalties that we would normally get for any type of collaboration that is commercialized for a product.

所以我認為在不同的層面上，對嗎？因此，澄清一下，如果我們什麼都不做，我們將獲得有意義的開發里程碑，也就是您期望的臨床開發各個階段的傳統里程碑。然後，我們獲得了特許權使用費的銷售里程碑，我們通常會從產品商業化的任何類型的合作中獲得這種特許權使用費。

If we move on to the 25% co-development opt-in, here we think that this could be an attractive option for us because the development milestones are similar to those if we did nothing from the co-development opt-in. So at a 25% cost share, we would have sort of a significant offset from the ongoing development milestones. And here, then we have much greater potential upside on the sales milestones and royalties that we would be entitled to if we opted in to 25%. So we think that's, again, an attractive option. And again, the meaningfulness of the development milestones makes this something that we think we can really sort of look forward to in terms of our ongoing development and how we're planning for this.

如果我們繼續選擇 25% 的共同開發，我們認為這對我們來說可能是一個有吸引力的選擇，因為開發里程碑與我們不採取任何共同開發選擇的情況相似。因此，按照 25% 的成本分攤，我們將大大抵消正在進行的開發里程碑的影響。在這裡，如果我們選擇 25%，我們在銷售里程碑和特許權使用費方面有更大的潛在上升空間。所以我們認為這又是一個有吸引力的選擇。再說一次，開發里程碑的意義使我們認為，就我們正在進行的開發以及我們如何規劃這一點而言，我們確實可以期待這一點。

At the upside, we would have a 50% co-development share. Here, we would -- by doing that, there would be lower development milestones than in the first co-development scenario. But the upside would be the gross margin share that we would get on the commercial sales of the program, which again would even be a further step-up from the sales milestones and royalties that we would get. I think it goes without saying, obviously, that any of our decisions that we take are going to be based upon the data itself and how good those look post the Phase IIa results, right? That is going to be most meaningful to us.

從好的方面來說，我們將擁有 50% 的共同開發份額。在這裡，我們將 - 透過這樣做，開發里程碑將比第一個共同開發場景更低。但好處是我們將從該項目的商業銷售中獲得的毛利率份額，這甚至將比我們獲得的銷售里程碑和特許權使用費進一步提高。我認為，顯然，我們所做的任何決定都將基於數據本身以及 IIa 期結果後的效果如何，這是不言而喻的，對吧？這對我們來說是最有意義的。

And then, the other important piece of this component is, it's not just the data that we'll have and be able to communicate publicly but also a go-forward plan, and we'll have a budget. So it won't be like there will be a black box here. It will be very thoughtful and informative, and we'll be able to put an FP&A accordingly. So we're going to wait and see. And the good news is, I think, we feel pretty good about opting in, given how it's structured even at the lower rate. And if the data are there and the plan makes a lot of sense in the eyes of our investors, then the 50-50 would also be a very viable option, we believe, as well. So stay tuned.

然後，該組件的另一個重要部分是，這不僅僅是我們將擁有並能夠公開交流的數據，而且還有一個前進計劃，我們將有一個預算。所以這裡不會有黑盒子。這將是非常周到且資訊豐富的，我們將能夠相應地提出 FP&A。所以我們將拭目以待。我認為好消息是，考慮到即使在較低的費率下它的結構如何，我們對選擇加入感到非常滿意。如果有數據並且該計劃在我們的投資者眼中很有意義，那麼我們相信 50-50 也將是一個非常可行的選擇。所以請繼續關注。

The one other thing that I wanted to touch on is, I noticed your commentary on the geopolitical environment. Obviously you've got one site in the Ukraine on the PRS-060 study right now. And obviously we're all watching that situation very carefully, not just thinking about the fundamental impacts on companies obviously. But from the perspective of this trial, what are the circumstances here that would result in a meaningful impact to the time line given only one of your sites is in the Ukraine itself?

我想談的另一件事是，我注意到你對地緣政治環境的評論。顯然，您現在在烏克蘭有一個 PRS-060 研究地點。顯然，我們都在非常仔細地關注這種情況，而不僅僅是考慮對公司的根本影響。但從這次試驗的角度來看，考慮到你們的站點只有一個位於烏克蘭境內，哪些情況會對時間軸產生有意義的影響？

Yes. So we've used the Ukraine and Australia for the safety portions of the study. The safety portions are a little different nuanced over what we would use for the efficacy portion. And the Ukraine side had played a fair role, a fairly important role for us in the safety study. So we're also enrolling the safety portion, as we mentioned, and the highest cohort, the 10-milligram cohort in parallel to the 2 doses in the efficacy cohort. So depending on patient access in Ukraine, that could be something that would impact the safety timelines on the third cohort, but we're not changing anything today.

是的。因此，我們使用烏克蘭和澳洲來進行研究的安全部分。安全性部分與我們用於功效部分的部分略有不同。烏克蘭方面在我們的安全研究中發揮了公平、相當重要的作用。因此，正如我們所提到的，我們還招募了安全部分以及最高的隊列，即 10 毫克隊列，與功效隊列中的 2 個劑量平行。因此，根據烏克蘭患者的情況，這可能會影響第三組的安全時間表，但我們今天不會改變任何事情。

We're just letting investors know that we have used Ukraine and this terrible development notwithstanding, it does directly involve our program because we've used them a lot for the safety study. They are involved in the efficacy portion as well, as you know, on multiple sites. So there's certainly ways to navigate around that for the efficacy portions. So this is really just us in the good corporate housekeeping, letting investors know that this is something we're looking at. And AstraZeneca is going through very thoughtful discussions with the CRO to be able to reconfirm timelines. And if not, we will make an update in the orderly course of business, as we mentioned. So no changes today for sure.

我們只是讓投資者知道，我們已經使用了烏克蘭，儘管有這種可怕的發展，但它確實直接涉及我們的計劃，因為我們已經大量使用它們進行安全研究。如您所知，他們也參與了多個網站的功效部分。因此，肯定有一些方法可以解決功效部分的問題。因此，這實際上只是我們在做好企業內務管理方面的工作，讓投資人知道這是我們正在關注的事情。阿斯特捷利康正在與 CRO 進行非常深思熟慮的討論，以便能夠重新確認時間表。如果沒有，我們將在有序的業務過程中進行更新，正如我們所提到的。所以今天肯定不會有任何變化。

Our next questions come from the line of Matt Phipps with William Blair.

我們的下一個問題來自馬特·菲普斯和威廉·布萊爾的對話。

First on CINRA, just wanted to clarify that the update later this year in HER2-low, that would be from Part A of that kind of Simon 2-Stage design and, again, exceeding the target you guys have laid out, you had then just progressed to Part B to kind of confirm that or in a larger patient population.

首先關於 CINRA，只是想澄清今年晚些時候 HER2-low 的更新，這將來自那種 Simon 2 階段設計的 A 部分，並且再次超出了你們設定的目標，然後你們就完成了剛剛進展到B 部分以確認這一點或在更大的患者群體中進行驗證。

Essentially that's right. I mean, we set really high bars that we think would be meaningful if we achieve them into 20 patients. And we think that having the ability to -- if we have the ability to achieve and you hit that bar, a 40% ORR for HER2-low in 20 patients, we think that that will be regarded as very meaningful both in the eyes of the investment community and, in particular, in industry.

本質上是對的。我的意思是，我們設定了非常高的標準，我們認為如果我們在 20 名患者中實現這些目標將是有意義的。我們認為，如果我們有能力實現這一目標，即 20 名 HER2-low 患者的 ORR 達到 40%，我們認為這在雙方眼中都將被認為是非常有意義的。投資界，特別是工業界。

And so then that should open up a number of options for go forward. I think one natural progression is, of course, progressing forward after the 20 patients into broader expansion. But we'll, of course, look at the totality of the data and consider even partnering options at that stage as well. But that's the data readout for the end of the year, just to make it clear. That's what we're aiming for 20 patients ORR.

因此，這應該會為前進提供一些選擇。當然，我認為一種自然的進展是在 20 名患者進入更廣泛的擴展之後繼續前進。但我們當然會查看全部數據，甚至會考慮該階段的合作選擇。但這是年底的數據，只是為了說明這一點。這就是我們為 20 位患者實現 ORR 的目標。

You mentioned Seattle -- sorry, Seagen continue to progress an additional update later this year. Are those -- I know you can't take too much but disclose the targets or do you expect any milestones from the collaboration this year?

您提到了西雅圖 - 抱歉，Seagen 將在今年晚些時候繼續進行額外更新。我知道您不能接受太多，但請透露目標，或者您預計今年的合作會取得任何里程碑嗎？

So again, we have to align with our partners, and Seagen is a great partner, but we have to align with them before we can say more color than we would with a proprietary program. I can say, what we're really pleased with the progress that Seagen is making with the lead program, we look forward to providing updates which we anticipate we could provide later this year, there's still a lot of year in front of us. And the way we structured the deal, I can't remember [what was the firm], it was exactly public, but you can imagine that there are clinical milestones, and Tom might be able to share a little bit more color here.

再說一次，我們必須與我們的合作夥伴保持一致，Seagen 是一個很好的合作夥伴，但我們必須與他們保持一致，然後才能比專有程式提供更多的顏色。我可以說，我們對 Seagen 在主導項目上的進展感到非常滿意，我們期待著提供更新，預計我們可以在今年晚些時候提供，我們面前還有很多年。我們建立交易的方式，我不記得[這家公司是什麼]，它完全是公開的，但你可以想像有臨床里程碑，湯姆也許可以在這裡分享更多的色彩。

There are clinical entry milestones and subsequent development milestones that would -- one would expect from this. And I think at some point, there would be not just a communication of progress but also probably more color around the program itself. We have to align with Seagen and all that detail. And I don't know if Tom wants to add any more color here on the milestones.

人們可以從中期待一些臨床進入里程碑和後續開發里程碑。我認為在某些時候，不僅會傳達進展情況，而且可能會圍繞專案本身提供更多色彩。我們必須與 Seagen 以及所有細節保持一致。我不知道湯姆是否想在里程碑上添加更多色彩。

Steve, you're right. I mean, we would be entitled to milestones as they enter into the clinic and progress through that. So those are the things we would obviously look forward to not only just the development of the program, but some financial benefits from that as well.

史蒂夫，你是對的。我的意思是，當他們進入臨床並取得進展時，我們將有權獲得里程碑。因此，我們顯然不僅期待該計劃的發展，還期待從中獲得一些經濟利益。

And lastly, kind of following on Jon's first question. So you mentioned that Ukraine and Australia was coming from the safety portion of the trial. Does that mean there's -- maybe the real near-term risk is kind of the higher dose Part 1b or whatever getting that done or can that be all done now in Australia?

最後，回答喬恩的第一個問題。所以你提到烏克蘭和澳洲來自試驗的安全部分。這是否意味著——也許真正的近期風險是更高劑量的第 1b 部分或任何完成這項工作的風險，或者現在可以在澳洲完成這一切嗎？

I mean that's certainly one potential implication. Definitely we could rely on Australia. And I think the Australian situation last year, I think, was very different than it is right now around COVID. The country was practically locked down across various states for most of last year, and that certainly impacted the ability to recruit. And that's where Ukraine was meaningful. But now that COVID evolved and we're kind of getting back to normal in many jurisdictions, geographies, we feel that we could more effectively leverage Australia than maybe we had a year ago.

我的意思是，這肯定是一種潛在的影響。我們絕對可以信賴澳洲。我認為去年澳洲的情況與現在新冠疫情期間的情況非常不同。去年的大部分時間裡，該國各州實際上都處於封鎖狀態，這無疑影響了招募能力。這就是烏克蘭的意義。但現在，隨著新冠疫情的發展，我們在許多司法管轄區、地區都已恢復正常，我們認為我們可以比一年前更有效地利用澳洲。

(Operator Instructions) Our next questions come from the line of Roger Song with Jefferies.

（操作員說明）我們的下一個問題來自 Roger Song 和 Jefferies 的線路。

So just curious because of the co-development option already improved this gross margin sharing. Just -- can you just comment on the core commercialization options? So what will be the additional upside if you kind of decided to co-promote this PRS-060?

所以只是好奇，因為共同開發選項已經改善了毛利率共享。只是——您能評論一下核心商業化選項嗎？那麼，如果您決定共同推廣這款 PRS-060，會有哪些額外的好處呢？

I'm going to turn this over to Tom. Just say at the outset, there's not a lot more color we can provide on the co-co right now before aligning especially with AstraZeneca on a communication around that. But maybe Tom can provide just a bit more kind of color around what that entails versus the co-development option.

我要把這個交給湯姆。首先要說的是，在與阿斯特捷利康就這一問題進行溝通之前，我們現在無法為 co-co 提供更多的顏色。但也許湯姆可以提供比共同開發選項更多的色彩。

I think when we're looking at this, this is obviously something that's going to be a decision point that we have later, clearly once we're into Phase 3 and how we want to sort of think about commercialization of this alongside AstraZeneca, so -- where they potentially would be funding us for the co-commercialization.

我認為，當我們考慮這個問題時，這顯然將成為我們稍後的決策點，顯然一旦我們進入第三階段，以及我們想要如何考慮與阿斯特捷利康一起商業化，所以——他們可能會為我們的聯合商業化提供資金。

So it's sort of a nice option to have as we think about potentially being integrated from a biotech perspective, moving into the commercialization and sales aspects and being able to develop the sales force. But again, I think it's probably very early days in terms of us saying, that's something that we're giving a lot of thought. I think for right now, we want to focus on sort of the execution and looking forward to the co-development options that we have and how those can be meaningful for us as a company.

因此，當我們考慮從生物技術角度進行整合、進入商業化和銷售方面並能夠發展銷售團隊時，這是一個不錯的選擇。但同樣，我認為現在說我們正在認真考慮這一點可能還為時過早。我認為現在，我們希望專注於執行，並期待我們擁有的共同開發選項，以及這些選項如何對我們作為一家公司有意義。

And I would say, it's fair to also mention, Roger, that the economics that we've been talking about, as Tom shared around the 25% opt-in or the 50% opt-in. Those are fixed as a function of the co-development structure itself. The co-commercialization is really independent of that. That's really what is there to help facilitate us getting a foothold in the commercial spectrum, as Tom said, for integration. And I think, we would like to be able to explore that if we are co-developing and we would be able to do that we feel if we wanted to. But I think the key here, not to forget, is all the economics we mentioned are whether or not we do the co-commercialization option or not.

我想說，羅傑，公平地說，我們一直在談論的經濟學，正如湯姆分享的 25% 選擇加入或 50% 選擇加入一樣。這些是作為共同開發結構本身的功能而固定的。聯合商業化其實與此無關。正如湯姆所說，這確實有助於我們在商業領域站穩腳跟，進行整合。我認為，如果我們共同開發，我們希望能夠探索這一點，如果我們願意的話，我們將能夠做到我們所認為的那樣。但我認為這裡的關鍵是，不要忘記，我們提到的所有經濟學都是我們是否採取聯合商業化選項。

And so for the IO program, we all realized -- aware of the recent kind of next-generation HER2-targeted therapy, in particular ADC. So some kind of exciting news for the breast cancer, not necessarily gastric cancer, but curious your thoughts around the [ratio] from those targeted ADC versus your 4-1BB bispecific kind of HER2 (inaudible).

因此，對於 IO 計劃，我們都意識到 - 意識到最近出現的下一代 HER2 標靶療法，特別是 ADC。因此，關於乳癌（不一定是胃癌）的一些令人興奮的消息，但很好奇您對靶向 ADC 與 4-1BB 雙特異性 HER2 的[比率]的想法（聽不清）。

And Roger, are you referring to the HER2 low study, recent data from ADC in HER2-low?

Roger，您指的是 HER2 low 研究，也就是 ADC 在 HER2-low 方面的最新數據嗎？

Yes. HER2-low, yes.

是的。 HER2-低，是的。

Yes, it's good. So there's some really -- data that was announced from -- in HER2. I think that's really great for patients. And I think it doesn't change how we're thinking about the placement of a 4-1BB or immuno-oncology agent relative to either classic HER2-targeted therapies, whether an antibody or a TKI or now bringing a toxic payload with next-generation ADCs. And I think it goes back to the fundamentals of IO fundamentals of 4-1BB. We've talked about this in the past, but Shane's joining the call, and maybe he is probably the best scripted person to talk about this. And Shane can share in a couple of sentences, again, why we think that a 4-1BB agonist could have a major role within the treatment paradigm, alongside next-generation ADCs.

是，很好。因此，HER2 中確實有一些已公佈的數據。我認為這對患者來說真的很棒。我認為這並沒有改變我們對 4-1BB 或免疫腫瘤藥物相對於經典 HER2 標靶療法的放置的看法，無論是抗體還是 TKI，還是現在帶來有毒有效負載的下一個-一代 ADC。我認為這可以追溯到 4-1BB 的 IO 基本原理。我們過去曾討論過這個問題，但肖恩加入了電話會議，也許他可能是討論這個問題的最佳腳本人。 Shane 可以用幾句話再次分享為什麼我們認為 4-1BB 激動劑可以與下一代 ADC 一起在治療範例中發揮重要作用。

Shane, do you want to take that one?

謝恩，你想拿走那個嗎？

Roger, thanks for the question. So as Steve pointed out, there's fundamental differences in mechanism of action here. The fact that the HER2-low environment is being exploited by others now just shows the opportunities there. But in essence, from our perspective, nobody is taking advantage of a T cell targeted agent in this space. Our preclinical data and data coming out of our Phase 1 study showed us we can elicit a strong immune response based on quite low levels of HER2 expression. And how is that manifesting? It's manifesting by an induction of 4-1BB agonism. We believe that will lead to T cell expansion, NK cell expansion. And it will change the tumor microenvironment in favor of destroying that tumor.

羅傑，謝謝你的提問。正如史蒂夫指出的那樣，這裡的作用機制存在根本差異。事實上，HER2-low 環境現在正被其他人利用，這一事實恰恰表明了那裡存在的機會。但本質上，從我們的角度來看，沒有人在這個領域利用 T 細胞標靶藥物。我們的臨床前數據和第一階段研究的數據表明，我們可以基於相當低的 HER2 表達水平引發強烈的免疫反應。這是如何體現的？它表現為 4-1BB 激動的誘導。我們相信這會導致T細胞擴張、NK細胞擴張。它會改變腫瘤微環境，有利於破壞腫瘤。

From a 4-1BB perspective, you're going to elicit a memory response. You will -- that will lead to a durable impact. And we see that in the Phase 1 study as well. Those patients that responded to CINRA had a durable response. Another key facet here is the safety profile. So we have a very acceptable safety profile with CINRA, and that allows us to work as either a monotherapy or combined with other agents. And if you think about, for instance, ADCs, it's going to be pretty difficult to combine them with other agents. So we look forward to our Phase 2 data coming out of both the HER2-high and HER2-low arm asking very different biological questions, but it will give us a very strong position in terms of -- as a go-forward plan in both the HER2-low and HER2-high space.

從 4-1BB 的角度來看，你將引發記憶反應。你將會——這將帶來持久的影響。我們在第一階段研究中也看到了這一點。那些對 CINRA 有反應的患者俱有持久的反應。這裡的另一個關鍵方面是安全性。因此，CINRA 的安全性非常可接受，這使得我們可以作為單一療法或與其他藥物合併使用。例如，如果考慮 ADC，將它們與其他代理結合起來將非常困難。因此，我們期待 HER2-high 和 HER2-low 組的 2 期數據提出非常不同的生物學問題，但這將使我們在以下方面處於非常有利的地位 - 作為這兩個方面的前進計劃HER2-低和HER2-高空間。

There are no further questions at this time. I would like to turn the call back over to Steve Yoder for any closing comments.

目前沒有其他問題。我想將電話轉回史蒂夫·約德（Steve Yoder）以徵求結束意見。

All right. Thank you. No other comments other than to thank everyone again for your attention and for your continued support of Pieris. I want to wish everyone a great day. Thank you.

好的。謝謝。沒有其他評論，只是再次感謝大家對Pieris的關注和持續支持。我想祝大家有個愉快的一天。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。我們感謝您的參與。此時您可以斷開線路。享受你一天剩下的時間。