VivoSim Labs Inc (VIVS) 2019 Q4 法說會逐字稿

Good day, and welcome to Organovo Holdings, Inc. Fiscal Fourth Quarter 2019 Earnings Conference Call. (Operator Instructions) Please note, this event is being recorded.

您好，歡迎來到 Organovo Holdings, Inc.2019 財年第四季財報電話會議。（操作員指示）請注意，此事件正在記錄中。

I would now like to turn the conference over to Steve Kunszabo, Investor Relations. Please go ahead.

現在，我想將會議交給投資者關係部門的史蒂夫·昆薩博 (Steve Kunszabo)。請繼續。

Good afternoon, and thanks for joining us. I'd like to welcome you to our fiscal fourth quarter 2019 earnings call.

下午好，感謝您加入我們。歡迎您參加我們的 2019 財年第四季財報電話會議。

On the call with us this afternoon are CEO, Taylor Crouch; and our CFO, Craig Kussman. Today's call will begin with a discussion of our 2019 fiscal fourth quarter results followed by Q&A.

今天下午與我們一起通話的有首席執行官泰勒克勞奇 (Taylor Crouch)；以及我們的財務長 Craig Kussman。今天的電話會議將首先討論我們的 2019 財年第四季業績，然後進行問答。

Before I turn things over to Taylor, I'd like to caution all participants that our call this afternoon may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.

在我將事情交給泰勒之前，我想提醒所有參與者，我們今天下午的電話會議可能包含《1995 年私人證券訴訟改革法案》所定義的前瞻性陳述。

Forward-looking statements are statements that are not historical facts and include statements about our future expectations, plans and prospects. Such forward-looking statements are based upon our current beliefs and expectations and are subject to risks, which could cause actual results to differ from the forward-looking statements.

前瞻性陳述並非歷史事實的陳述，包括有關我們未來預期、計劃和前景的陳述。此類前瞻性陳述是基於我們目前的信念和期望，並受風險影響，可能導致實際結果與前瞻性陳述不同。

Such risks are more fully discussed in our filings with the Securities and Exchange Commission. We're also in the process of completing our audit for fiscal 2019. Accordingly, financial statement amounts discussed on our call today are subject to change upon completion of our audit. We expect to file our 10-K and annual report in the first week of June.

我們向美國證券交易委員會提交的文件中對此類風險進行了更詳細的討論。我們也正在完成 2019 財年的審計。因此，我們今天電話會議上討論的財務報表金額在審計完成後可能會發生變化。我們預計在六月第一週提交 10-K 和年度報告。

With that, let me turn things over to Taylor.

說完這些，讓我把話題交給泰勒。

Thanks, Steve, and good afternoon, everyone. We've a lot of ground to cover today as we have updated our clinical development goals for our liver therapeutic tissue program across the board. I'm going to jump right into the changes in our timeline for our first IND submission, the new challenges we have to address in the next 12 months, our key accomplishments and how we move forward.

謝謝，史蒂夫，大家下午好。今天我們有很多內容要講，因為我們已經全面更新了肝臟治療組織計畫的臨床發展目標。我將直接介紹我們第一次 IND 提交的時間表的變化、我們在未來 12 個月內必須應對的新挑戰、我們的主要成就以及我們未來的發展方式。

In short, we're pushing our key clinical development milestones out by a few quarters. We need to do more work to optimize our manufacturing processes and complete additional preclinical studies that generate consistent scientific data on the sustained functionality and therapeutic benefits of our liver tissue patch.

簡而言之，我們將關鍵臨床開發里程碑推遲了幾個季度。我們需要做更多的工作來優化我們的製造流程並完成額外的臨床前研究，以產生有關我們的肝組織貼片的持續功能和治療益處的一致的科學數據。

Our goal is to present data-rich analysis to the FDA as to how we harness this leading-edge capability to impact human disease. Our clinical strategy is expected to focus on initiating our Phase I trial in patients with end-stage liver disease. Subject to favorable outcomes in that trial, we intend to explore the benefits of NovoTissues in one or more inborn errors of metabolism disease areas such as Alpha-1-antitrypsin deficiency. We may also study our product as a bridge to transplant. All of these diseases represent high unmet need areas where we believe our liver patches may provide a meaningful benefit to patients.

我們的目標是向 FDA 提供數據豐富的分析，說明我們如何利用這種前沿能力來影響人類疾病。我們的臨床策略預計將集中於對終末期肝病患者啟動 I 期試驗。如果該試驗的結果令人滿意，我們打算探索 NovoTissues 在一種或多種先天性代謝疾病領域（例如 Alpha-1-抗胰蛋白酶缺乏症）中的益處。我們也可以研究我們的產品作為移植的橋樑。所有這些疾病都代表著尚未滿足的巨大需求，我們相信我們的肝貼片可以為患者帶來有意義的益處。

Based on our current planning, our expected pre-IND meeting with the FDA has shifted to calendar 2020, which also delays the start of our IND-enabling studies. Our IND submission and the first -- and the start of first-in-human trials are now both planned for calendar 2021. To achieve these critical objectives, we're devoting substantially all of our considerable effort and resources to our liver therapeutic tissue program.

根據我們目前的計劃，我們預計與 FDA 舉行的 IND 前會議已推遲至 2020 年，這也推遲了我們的 IND 支持研究的開始時間。我們的 IND 提交和首次人體試驗的開始都計劃於 2021 年進行。為了實現這些關鍵目標，我們將大部分的精力和資源投入到肝臟治療組織計畫中。

Let's dive into why we revised our plan and extended our preclinical testing window. Over the past several months, we've launched a large group of animal studies to further evaluate the capabilities of our liver tissue product. This project included experiments that implanted our patch into more than 500 rodents to investigate functionality, viability and surgical placement alternatives.

讓我們深入探討一下我們修改計劃並延長臨床前測試窗口的原因。在過去的幾個月裡，我們啟動了一項大規模的動物研究，以進一步評估我們的肝臟組織產品的能力。該項目包括將我們的貼片植入 500 多隻囓齒動物體內的實驗，以研究其功能性、可行性和手術放置替代方案。

While we made important progress and confirmed previously reported scientific data in some areas, we also concluded that additional development work needs to be done to enhance our manufacturing process and improve the duration and effectiveness of our tissues.

雖然我們取得了重要進展並在某些領域證實了先前報告的科學數據，但我們也得出結論，需要進行額外的開發工作以增強我們的製造流程並提高我們紙巾的使用壽命和有效性。

The primary challenge we're now facing is that the tissue patches in our latest studies have demonstrated a shorter duration and functionality than we saw in our earlier pilot studies. Specifically, the data from our current animal studies in rodents, which is primarily based on interim analyses, suggest that the human protein output of our bioprinted patches dropped significantly to nominal levels after about 1 month compared with up to 3 months in some of our earlier pilot studies.

我們現在面臨的主要挑戰是，我們最新研究中的組織貼片的持續時間和功能比我們在早期試點研究中看到的要短。具體而言，我們目前對囓齒動物進行的研究數據主要基於中期分析，表明我們的生物打印貼片的人體蛋白質產量在大約 1 個月後顯著下降至標稱水平，而在我們之前的一些試點研究中則長達 3 個月。

We've also observed a significant reduction in hepatocytes during this time frame. Despite these observations, we continue to see statistically meaningful reduction in toxic globules in our Alpha-1-antitrypsin rodent models all the way out to 90 days. The reduction of these toxic globules, which are a hallmark of the liver pathology in this disease, is consistent with our pilot studies.

我們也觀察到在此期間肝細胞顯著減少。儘管有這些觀察結果，我們仍然看到，在長達 90 天內，我們的 Alpha-1-抗胰蛋白酶囓齒動物模型中毒性球狀體有統計學意義的減少。這些毒性小球的減少是該疾病肝病理的標誌，這與我們的初步研究結果一致。

However, we need to do more work over the coming months to understand why we are seeing conflicting data and to improve the duration and functionality of our tissues. Bioprinted tissue engineering is at the leading edge of innovation in the regenerative medicine space, and all components and processes matter in creating a durable tissue that mimics key aspects of human biology. The challenges we face are not unique in this sector. In fact, they are very common. And we believe we are uniquely equipped to prepare our tissue platform for the rigors ahead.

然而，我們需要在接下來的幾個月裡做更多的工作來了解為什麼我們看到相互矛盾的數據，並改善我們組織的持續時間和功能。生物列印組織工程處於再生醫學領域創新的前沿，所有組件和流程對於創造模仿人體生物學關鍵方面的耐用組織都至關重要。我們面臨的挑戰並非該領域所獨有。事實上，它們非常常見。我們相信，我們擁有獨特的優勢，可以讓我們的組織平台做好迎接未來嚴峻考驗的準備。

To recap, we're extending our Chemistry Manufacturing and Controls or CMC development and preclinical testing with the aim of holding a pre-IND meeting with the FDA in calendar 2020. Following FDA feedback on our clinical strategy and manufacturing processes, we then plan to conduct our IND-enabling studies with the goal of an IND submission and the start of first-in-human trials in calendar 2021.

總而言之，我們正在擴展我們的化學製造和控製或 CMC 開發和臨床前測試，目標是在 2020 年與 FDA 舉行 IND 前會議。根據 FDA 對我們的臨床策略和製造流程的回饋，我們計劃進行 IND 支援研究，目標是在 2021 年提交 IND 並開始首次人體試驗。

I also want to highlight some important accomplishments on our platform. To name just a few, we've demonstrated the ability to deliver multiple patches of varying sizes in our animal models. We've taken early steps to scale up our patch sizes to what we target for human implantation and have begun to evaluate surgical techniques in a large animal study at a leading academic institution.

我還想強調一下我們平台上的一些重要成就。僅舉幾個例子，我們已經證明了在動物模型中提供多個不同大小的貼片的能力。我們已經採取早期措施將貼片尺寸擴大到適合人體植入的尺寸，並已開始在一家領先的學術機構的大型動物研究中評估手術技術。

We've explored different application methods for our NovoTissues and have had comparable results using both bioadhesives and sutures. We've successfully engrafted our therapeutic tissue onto fibrotic animal livers, an important step in evaluating the patch's versatility as we consider end-stage liver disease indications. Although definitive IND-enabling toxicology studies have not yet been performed, no adverse effects have been detected to date on liver enzymes or histology in well over 500 animals treated with our liver patches. This is quite important.

我們探索了 NovoTissues 的不同應用方法，並使用生物黏合劑和縫線獲得了可比較的結果。我們已成功將治療性組織移植到纖維化動物肝臟上，這是在考慮末期肝病適應症時評估貼片多功能性的重要一步。儘管尚未進行明確的 IND 毒理學研究，但迄今為止，在使用我們的肝貼片治療的 500 多隻動物中，尚未檢測到肝酵素或組織學的不良影響。這是相當重要的。

We continue to advance our operational capabilities to prepare our CMC plans. Assuming successful outcomes in our preclinical trials, our goal will be to implement clinical-scale manufacturing and quality processes well in advance of our first-in-human trials. These steps encompass a wide range of internal functions, including documentation, equipment and facilities optimization, process validation and the adoption of stringent manufacturing controls.

我們不斷提升我們的營運能力以製定我們的 CMC 計劃。假設我們的臨床前試驗成功，我們的目標是在首次人體試驗之前實施臨床規模的製造和品質流程。這些步驟涵蓋廣泛的內部功能，包括文件、設備和設施最佳化、流程驗證和採用嚴格的製造控制。

And finally, we continue to receive and process donated levers through our partnership with the International Institute for the Advancement of medicine, IIAM. You'll recall that IIAM is one of the world's leading organizations for the procurement of organs used in medical research and the development of therapeutic applications.

最後，我們透過與國際醫學促進研究所（IIAM）的合作，繼續接收和處理捐贈的槓桿。您會記得，IIAM 是世界上採購用於醫學研究和治療應用的器官的領先組織之一。

Our team of scientists at Samsara has collective experience, processing over 3,000 livers throughout their careers. This industry-leading expertise will serve as well as we continue to isolate and bank human cells and tissue to prepare for our first IND.

Samsara 的科學家團隊擁有豐富的集體經驗，在其職業生涯中處理過超過 3,000 個肝臟。這一行業領先的專業知識將有助於我們繼續分離和儲存人類細胞和組織，為我們的第一個 IND 做準備。

Before I wrap up, let me provide a quick update on the progress of many -- of our many partnerships in leading academic institutions. We continue to collaborate with organizations around the globe that are conducting proof-of-concept studies in 3D bioprinted tissues research areas, including the kidney, retina and vasculature.

在結束之前，請容我簡要介紹一下我們與眾多領先學術機構的合作進展。我們繼續與世界各地的組織合作，在 3D 生物列印組織研究領域（包括腎臟、視網膜和血管）進行概念驗證研究。

An excellent recent example of this work involves expanding our relationship with Professor Melissa Little at the Murdoch Children's Research Institute in Melbourne, Australia. With support from Stem Cells Australia and CSL Behring, we're working together to develop a 3D bioprinted stem cell-based therapeutic tissue for treating end-stage renal disease. We're proud to partner with these cutting-edge researchers and scientists to develop therapeutic gaps in areas of critical unmet need.

這項工作最近的一個很好的例子是擴大我們與澳洲墨爾本默多克兒童研究所的梅麗莎·利特爾教授的關係。在澳洲幹細胞協會和 CSL Behring 的支持下，我們正在合作開發一種基於 3D 生物列印幹細胞的治療組織，用於治療末期腎臟病。我們很榮幸能與這些前沿研究人員和科學家合作，共同探索尚未滿足的關鍵需求領域的治療空白。

In closing, we have a robust work plan ahead of us as we extend our preclinical testing window and continue to refine the timeline for our first IND submission. The clear priority in deploying significant financial and operational resources in the short term is to address these challenges and then to get into the clinic in calendar 2021.

最後，我們有一個強有力的工作計劃，因為我們延長了臨床前測試窗口，並繼續完善我們的第一個 IND 提交的時間表。短期內部署大量財務和營運資源的明顯優先事項是應對這些挑戰，然後在 2021 年進入臨床階段。

I look forward to updating you in the months ahead. With that, I'll turn it over to Craig for a more complete financial review.

我期待在未來幾個月內向您通報最新情況。說完這些，我將把它交給 Craig 進行更完整的財務審查。

Thanks, Taylor, and good afternoon, everyone. I'll start by reviewing our key operating and cash flow metrics for the fiscal fourth quarter and will then summarize our liquidity profile at-the-market or ATM financing activity and future capital requirements. I'll wrap up my comments with a quick recap of our income statement trends.

謝謝，泰勒，大家下午好。我將首先回顧我們第四財季的關鍵營運和現金流指標，然後總結我們的市場流動性狀況或 ATM 融資活動以及未來的資本需求。我將透過快速回顧我們的損益表趨勢來結束我的評論。

We recorded a fiscal fourth quarter net loss of $7 million, a $0.5 million improvement over the net loss we reported in the year ago quarter. Similarly, our net cash utilization shrunk to $5.1 million versus $5.7 million in the prior year period. The ongoing progress in these bottom line figures is primarily due to a 10% reduction in total expenses related to lower employee costs.

我們記錄的第四財季淨虧損為 700 萬美元，比去年同期報告的淨虧損減少了 50 萬美元。同樣，我們的淨現金利用率從去年同期的 570 萬美元縮減至 510 萬美元。這些底線數據的持續進步主要歸因於與員工成本降低相關的總支出減少了 10%。

At the end of March, we had a cash and cash equivalents balance of $36.5 million, which included net proceeds of $6.3 million from the issuance of 6.1 million shares of common stock in ATM offerings. Consistent with the strategy we've now outlined for several quarters, we'll continue to use our ATM facility opportunistically to extend the cash runway for the business.

截至三月底，我們的現金和現金等價物餘額為 3,650 萬美元，其中包括發行 610 萬股 A​​TM 普通股所得的 630 萬美元淨收益。按照我們目前製定的幾個季度的策略，我們將繼續適時使用 ATM 設施來延長業務的現金流。

We forecast a net cash utilization rate between $20 million and $22 million for fiscal year 2020, which is consistent with our burn rate in fiscal 2019 and also considers the increased R&D spend for our liver therapeutic tissue development program.

我們預測 2020 財年的淨現金使用率在 2,000 萬美元至 2,200 萬美元之間，這與我們 2019 財年的燒錢率一致，同時也考慮到了我們肝臟治療組織開發計劃的研發支出增加。

Overall, along with anticipated ATM usage, we believe we have sufficient funds to meet our operating and capital requirements through our forecasted IND submission in calendar 2021.

總體而言，加上預期的 ATM 使用量，我們相信我們有足夠的資金來滿足我們在 2021 年日曆中預測的 IND 提交的營運和資本需求。

Moving now to our income statement and focusing first on operating expenses. Research and development expenses were $4.4 million, an 11% year-over-year increase, largely resulting from higher lab supply costs related to preclinical work for our NovoTissues development program.

現在轉到我們的損益表，首先關注營運費用。研發費用為 440 萬美元，年成長 11%，主要由於與我們的 NovoTissues 開發計畫的臨床前工作相關的實驗室供應成本增加。

Selling, general and administrative expenses were $3.3 million during the fiscal fourth quarter, a 25% year-over-year reduction primarily due to lower employee costs.

第四財季的銷售、一般和行政費用為 330 萬美元，較去年同期減少 25%，主要原因是員工成本降低。

As we consider our expense trends over the next 12 months, there are 2 important items I'd like to highlight. First, we're planning for a modestly elevated level in R&D spending as we extend our preclinical testing window and capital challenges Taylor outlined related to the duration and functionality of our liver tissues. Second, we expect to more than offset the R&D expense increase with a meaningful reduction in SG&A costs resulting from the continued streamlining of our infrastructure.

當我們考慮未來 12 個月的支出趨勢時，我想強調兩個重要事項。首先，隨著我們延長臨床前測試窗口並應對泰勒所概述的與肝臟組織的持續時間和功能相關的資本挑戰，我們計劃適度提高研發支出。其次，我們預計，透過持續精簡基礎設施，銷售、一般及行政開支將大幅減少，進而抵銷研發費用的增加。

On the top line, Organovo posted fiscal fourth quarter total revenue of $0.7 million, which declined 38% from the prior year period. Total year-over-year revenue decreased, primarily due to fewer active contracts for liver tissue research services. It's worth reinforcing that in the short term, substantially all of our financial and operating resources are geared toward achieving the revised clinical development milestones for our implantable liver tissue.

營收方面，Organovo 公佈第四財季總營收為 70 萬美元，較去年同期下降 38%。總收入較去年同期下降，主要由於肝臟組織研究服務的有效合約減少。值得強調的是，在短期內，我們幾乎所有的財務和營運資源都將用於實現可植入肝組織的修訂臨床開發里程碑。

As a result, we continue to be increasingly selective about bringing on collaborative, revenue-generating agreements. We'll do so in a measured way where the scientific outcomes are complementary to our key goal of entering the clinics in calendar 2021. In consideration of these decisions, we expect that our revenue will continue to fluctuate and will most likely trend down as we allocate fewer resources to revenue-generating projects.

因此，我們在選擇合作和創收協議時會更加謹慎。我們將採取慎重的方式來進行這項工作，使科學成果與我們在 2021 年進入臨床的關鍵目標相輔相成。考慮到這些決定，我們預計我們的收入將繼續波動，並且由於我們為創收項目分配的資源減少，很可能會呈現下降趨勢。

In conclusion, we have a very busy 12 months ahead of us to bolster the scientific data for our liver therapeutic tissue program, with the most immediate goal being a successful pre-IND meeting with the FDA in calendar 2020. We're comfortable with our liquidity position for the next 18 months, and we'll continue to carefully manage our operating expenses. I look forward to sharing our progress over the next several quarters.

總而言之，未來 12 個月我們將非常忙碌，需要為我們的肝臟治療組織計劃增強科學數據，最直接的目標是在 2020 年與 FDA 成功舉行 IND 前會議。我們對未來 18 個月的流動性狀況感到滿意，並將繼續謹慎管理我們的營運費用。我期待在接下來的幾個季度分享我們的進展。

With that, I'll turn things back to the operator for the Q&A portion of this afternoon's call.

說完這些，我將把今天下午電話會議的問答部分交還給接線員。

(Operator Instructions) Our first question comes from Ed Arce with H.C. Wainwright.

(操作員指示) 我們的第一個問題來自 H.C. 的 Ed Arce。溫賴特。

I guess, I'll start, Taylor, with a sort of the crux of this call and why you're pushing back the timelines around the drops in the human protein that you've seen recently in some of those rodent model tests that you've done recently down to nominal levels at just 1 month instead of the 3 months previously. I'm wondering if you could share with us any more detail as to why do you think that's happening and how do you propose to get a handle on improving that back to where it was or perhaps better. And then, I guess, related to that, how does that tie into the manufacturing processes that you are seeking to improve?

泰勒，我想先談談這次通話的關鍵點，以及為什麼您要推遲最近在部分囓齒動物模型測試中觀察到的人類蛋白質下降的時間表，這些蛋白質在 1 個月內下降到名義水平，而不是之前的 3 個月。我想知道您是否可以與我們分享更多細節，說明您認為為什麼會發生這種情況，以及您建議如何控制以使情況恢復到原來的狀態或更好。然後，我想，與此相關的是，這與您想要改進的製造流程有何關聯？

Thanks, Ed, and this is Taylor. And clearly, you have a put your finger on the area that we're most closely focusing on at the moment. Just to start with a quick definition, when we refer to viability, we're talking about the ability to characterize the percent of living cells in our product. That's not something that's easily done, if at all, in living animal models. And so we need to come up with proxies for viability, which can be protein outputs, other measures or functional clues as to viability. And all of that requires some state-of-the-art development of measurement, techniques and validation in animals. So part of our work is just focus on -- focusing on getting better at measuring and standardizing around those measurements. That being said, we understand that when we put our human cell-derived patches under the service of rodent livers, this is a very unnatural environment for those patches. They are not receiving typical human growth factor signals or other cues that typically would lead the patches to respond in the ways we would expect to see once we reach humans. And so animal models are never a great translational model for what we're trying to do. And fortunately, the FDA understands that. That said, we certainly are concerned that some of our patches we see exhibiting viability and functionality out to 90 days or beyond, as we reported in the past in our pilot studies, but more recently, many of our patches are losing a significant degree of viability within 1 month of implantation. We believe that the process of manufacturing our patches can improve the starting viability and that the higher the viability we start with, perhaps the better the outcomes in terms of initial and enduring impact in our animals will be. And so what we're going to do is focus on the key steps of our manufacturing process that begin with isolating and nurturing and cryopreserving cells, taking those cells and incorporating them into bioinks and bioprinting, and then ultimately, the care and feeding of those patches up through release into animals. And fortunately, Organovo has a 10-year history leading the field in manufacturing and characterizing and manipulating tissues, and we believe that we will be able to look at each of these steps, tweak some of our processes and collectively result in higher starting viability, which we think should serve us well in our animals. Just as importantly, those processes that we'll be characterizing expanding upon and building upon will create a much stronger data-rich CMC package for submitting to the FDA at our pre-IND meeting. And if we think about -- our primary goal is to get to the best outcomes from our IND filing and to use our pre-IND dress rehearsal, if you will, prudently, ideally going in with the most data that we can bring and the most rigor built around our platform to lead to the best outcomes. And it was really the combination of creating this better dataset, helping to ideally reduce variability, improve marginally or significantly viability and then see whether that translates to a longer effect in animals. All of this, we believe, will stand us in much better shape once we go into the FDA, albeit unfortunately with the delays that we've mentioned in our timeline.

謝謝，艾德，這是泰勒。顯然，您已經指出了我們目前最關注的領域。首先簡單定義一下，當我們提到活力時，我們談論的是表徵產品中活細胞百分比的能力。在活體動物模型中，這並非一件容易做到的事。因此，我們需要提出生存力的代理指標，可以是蛋白質輸出、其他措施或生存力的功能線索。所有這些都需要在動物身上進行一些最先進的測量、技術和驗證。因此，我們的工作的一部分是關注——關注如何更好地進行測量並實現這些測量的標準化。話雖如此，我們知道，當我們將人類細胞衍生的貼片置於囓齒動物肝臟的服務之下時，這對這些貼片來說是一個非常不自然的環境。它們沒有接收到典型的人類生長因子訊號或其他線索，而這些訊號或其他線索通常會導致斑塊以我們在接觸人類後期望看到的方式做出反應。因此，動物模型對於我們嘗試做的事情來說永遠不是一個很好的轉換模型。幸運的是，FDA 了解這一點。儘管如此，我們確實擔心我們的一些貼片在 90 天或更長時間內仍能表現出活力和功能，正如我們過去的試點研究中所報告的那樣，但最近，我們的許多貼片在植入後 1 個月內就失去了相當程度的活力。我們相信，製造貼片的過程可以提高起始可行性，起始可行性越高，對動物的初始和持久影響的結果可能就越好。因此，我們要專注於製造過程的關鍵步驟，從分離、培育和冷凍保存細胞開始，取出這些細胞並將其整合到生物墨水和生物打印中，最後護理和餵養這些貼片，直至將其釋放到動物體內。幸運的是，Organovo 在組織製造、表徵和操作領域擁有 10 年的領先歷史，我們相信我們將能夠研究每一個步驟，調整我們的一些流程，並共同提高起始可行性，我們認為這應該對我們的動物有益。同樣重要的是，我們將要描述的、擴展和建構的那些流程將創建一個更強大的、數據豐富的 CMC 包，以便在我們的 IND 前會議上提交給 FDA。如果我們考慮一下——我們的主要目標是從我們的 IND 申請中獲得最佳結果，並利用我們的 IND 前彩排，如果你願意的話，謹慎地、理想地使用我們可以帶來的最多數據和圍繞我們的平台構建的最嚴謹的方法來獲得最好的結果。這實際上是創建更好的數據集的組合，有助於理想地減少變異性，略微或顯著地提高生存能力，然後觀察這是否會對動物產生更長期的影響。我們相信，一旦我們進入 FDA，所有這些都將使我們處於更好的狀態，儘管不幸的是，我們在時間表中提到了一些延誤。

Okay. Then maybe I'll just shift gears a little bit to sort of the target that you mentioned in your prepared remarks. Looking to ultimately enter your first trial in patients with end-stage liver disease, I was just curious around that choice, because it does seem to me that it could be, in some ways, analogous to the basket approach that you've described previously, given that there could be many etiologies behind the end-stage disease. And so perhaps you could discuss how you came to that decision and how it will help inform your choice from there into one or more inborn errors of metabolism?

好的。然後我可能要稍微轉換主題，談談您在準備好的發言中提到的目標。最終，您將在患有終末期肝病的患者中進行首次試驗，我只是對這個選擇感到好奇，因為在我看來，它在某些方面可能類似於您之前描述的籃子方法，因為終末期疾病的背後可能有很多病因。那麼也許您可以討論一下您是如何做出這個決定的，以及它將如何幫助您做出選擇，以應對一種或多種先天性代謝錯誤？

Sure. Thanks for that question. And indeed, we still view this basket approach concept as an opportunity for our platform. Our intention to enter the human trials in end-stage liver disease, first of all, recognizing that this first trial is a safety trail reflects the fact that we need to convince the FDA of the risk balance of subjecting patients to this experimental surgical implantation approach, trading off that risk with what we would hope to see is a very beneficial upside in this area of high-unmet need. The fact that end-stage liver disease are patients that are on the transplant list, have gotten to that list through a broad range of etiologies, including some of the target inborn error of that metabolism disease areas, such as Alpha-1-antitrypsin, should allow us to get some exposure to those patients right off the bat in our Phase I trial. And from the -- based on the results from that safety trial and any early indications of efficacy, then we can branch earlier into pursuing some of the specific diseases that land patients on this list and/or to continue to work in this critical patient area, providing a form of bridge to transplant, which would be addressing a huge unmet need that's kind of tailor-made for our functional patch strategy. So clearly, a basket that we can build off of from that first trial.

當然。謝謝你的提問。事實上，我們仍然將這種籃子方法概念視為我們平台的一個機會。我們打算進入末期肝病的人體試驗階段，首先，我們認識到這首次試驗是一次安全性試驗，這反映了我們需要讓 FDA 相信讓患者接受這種實驗性手術植入方法的風險平衡，我們希望看到的是，在這一尚未滿足的醫療需求領域，這種風險與這種風險之間的平衡會帶來非常有利的上升空間。事實是，末期肝病患者都是在移植名單上的，他們透過各種各樣的病因進入這個名單，包括一些目標先天性代謝疾病領域的錯誤，例如 Alpha-1-抗胰蛋白酶，這應該讓我們能夠在第一階段試驗中立即接觸到這些患者。根據該安全性試驗的結果和任何早期療效跡象，我們可以更早開始研究名單上的某些特定疾病，和/或繼續在這一關鍵患者領域開展工作，提供一種移植橋樑，這將解決一個巨大的未滿足的需求，這是我們的功能性貼片策略量身定制的。很顯然，我們可以從第一次試驗的基礎來建立一個籃子。

Okay. Great. Just perhaps one quick last one, if I may, before I jump in the queue. And this is probably best suited for Craig. You had mentioned the first week of June as your target for filing the 10-K. Is that -- just given that this is sort of an off quarter, is that sort of in line with normal guidelines on timing? Or is there any sort of delay or issue with preparing the audited financials?

好的。偉大的。如果可以的話，在我排隊之前，我可能只想快速說最後一句話。這可能最適合克雷格。您曾提到六月第一週是您提交 10-K 表格的目標。這是——只是考慮到這是一個淡季，這是否符合正常的時間指導方針？或在準備審計財務報表時是否有任何延誤或問題？

No, that's consistent with when we filed it in the past and corresponds to the timing of our long-standing scheduled Audit Committee meeting at the end of this month.

不，這與我們過去提交的文件一致，並且與我們本月底長期安排的審計委員會會議的時間相對應。

So -- yes. So really, what -- the only thing has changed is we thought it would be prudent to bring out this information of changed timelines and get that out to the market appropriately on time. The rest of our financial filings will follow the normal schedule.

所以——是的。所以實際上，唯一改變的是，我們認為明智的做法是及時發布有關改變時間表的資訊並將其適當地推向市場。我們其餘的財務文件將按照正常時間表進行。

Our next question comes from Matthew Cross with JonesTrading.

下一個問題來自 JonesTrading 的 Matthew Cross。

Sorry to hear about these new obstacles. I wanted to obviously address kind of the biggest issue here, which was just regarding tissue durability and kind of what's changed. So honing on things a little bit here, was this a result of additional work transplanting in new preclinical settings as well or just kind of greater sample sizes in the same settings? I guess, I'm effectively trying to assess whether these were concerns regarding a highly reproducible level of viability that just had an insufficient duration or if this was really kind of inconsistent viability in terms of, as you said, hepatocyte counts and protein output as you tested in a larger number of animals. I guess, how often are you seeing closer to a month in terms of viability versus the 90 days when you're looking at all of the samples now that you have, like you said, over 500?

很遺憾聽到這些新的障礙。我顯然想解決這裡最大的問題，即有關組織耐久性以及發生了什麼變化。因此，在這裡稍微分析一下，這是在新的臨床前環境中移植額外工作的結果嗎，還是只是在相同環境中樣本量更大？我想，我實際上是想評估這些是否是關於高度可重複的活力水平的擔憂，只是持續時間不夠，或者這是否真的是活力不一致，就如你所說的，肝細胞計數和蛋白質輸出在大量動物身上測試時的情況而言。我想，當您查看現在所有的樣本（就像您說的，超過 500 個）時，您看到存活率接近一個月而不是 90 天的頻率是多少？

Sure, Matt. Very good questions. The -- we have looked at similar models to those that we explored in our pilots, and we've also looked at some very different animal models. What we see in these statistically powered studies is a general observation that at least for the current batch of experiments, the durability seems to be shorter than the cases that we identified in our pilot studies. This could be a result of just better statistics. It could be a result of every time you start a new animal study, you're dealing with slight biological changes. And of course, we also expect that our manufacturing process continues to evolve, and perhaps there are things that we inadvertently tweaked in the wrong direction that we can identify and bring back on course. In the end, our goal is just to show the maximum duration possible in these animal models and to show it in a reproducible and rigorous way and then discuss with the FDA, the comment I made earlier on, which is no one really knows how long a human tissue construct should last in animals. We could argue before we ever implanted in animals that 7 days might have been a home run. The fact that we saw evidence out to 90 days -- and by the way, we still see functional evidence of globule clearing in the PiZ Alpha-1-antitrypsin model also out to 90 days. That was extremely exciting. We just want to hone down the variability in our animal models, tighten up and optimize as we can the package -- the CMC package and the starting viability. And then I think we've got a very tight package and message to go into the FDA with. And all of that made it seem prudent to delay our pre-IND meeting a couple of quarters just to strengthen and flesh out our database.

當然，馬特。非常好的問題。我們研究了與我們在試驗中探索的類似的模型，我們也研究了一些非常不同的動物模型。我們在這些具有統計學依據的研究中看到一個普遍的觀察結果：至少對於目前這一批實驗而言，其持久性似乎比我們在試驗研究中發現的情況要短。這可能只是統計數據改善的結果。這可能是因為每次開始一項新的動物研究時，你都要處理輕微的生物變化。當然，我們也期望我們的製造工藝能夠不斷發展，也許有些東西我們無意中朝著錯誤的方向上調整，但我們可以識別並回到正軌。最後，我們的目標只是在這些動物模型中展示盡可能長的持續時間，並以可重複和嚴格的方式展示它，然後與 FDA 討論我之前提出的評論，即沒有人真正知道人體組織構建體在動物體內應該持續多長時間。在將基因植入動物體內之前，我們可以爭辯說，7天可能已經足夠了。事實上，我們看到了長達 90 天的證據 — — 順便說一句，我們仍然看到 PiZ Alpha-1-抗胰蛋白酶模型中球狀物清除的功能性證據，也長達 90 天。那真是令人興奮極了。我們只是想降低動物模型的變異性，盡可能加強和優化包裝—CMC 包裝和起始可行性。然後我認為我們已經向 FDA 提交了一份非常嚴格的方案和資訊。所有這些都使得我們將 IND 前會議推遲幾個季度以加強和充實我們的資料庫似乎是明智之舉。

Okay. Got it. No, that's very helpful extra detail and it makes sense. Next one I had was just on whether you could provide any detail on the renal work you alluded to in your release and discussion here. I guess, what additional work has been done here so far? And then what was the impetus for revisiting that, as I know that had been more of a sideline focus alongside the liver in the past? And just related to that, could you provide a little bit more detail on how this [would] work in other organ applications, renal and otherwise, may impact you all from a cost perspective, if at all?

好的。知道了。不，這是非常有用的額外細節，而且很有意義。下一個問題是，您是否可以提供您在發布和討論中提到的腎臟工作的任何細節。我想，到目前為止這裡還完成了哪些額外的工作？那麼重新審視這個問題的動力是什麼呢？與此相關的是，您能否更詳細地介紹一下這項技術在其他器官應用（腎臟和其他器官應用）中的作用，以及從成本角度來看是否會對您產生影響？

Sure. So for starters, we've been in a longer-term collaboration with Melissa Little in Australia who is really recognized as one of the world leaders in stem cell-based kidney organoid development. And we're pleased to have progressed or expanded that relationship recently, and we'll be talking about that a little bit more in the future. The goal is to combine her stem cell-based technology with our deep platform understanding. Many of the exact same kinds of capabilities that we are fleshing out in our lead program in liver to see if we can jointly develop solutions that would be applicable to end-stage renal disease, which would open up a very important additional front in the pipeline. That's an aspirational goal. And so for the next 6 to 12 months, our primary focus will be almost entirely on our liver development program, as we've highlighted. And a lot of the preliminary work on the kidney will be taking place through our collaborators without tapping into significant resources or funds from the company.

當然。首先，我們與澳洲的 Melissa Little 進行了長期合作，她被公認為基於幹細胞的腎臟類器官開發領域的世界領導者之一。我們很高興最近這種關係有所進展和擴大，我們將來會進一步談論這個問題。目標是將她基於幹細胞的技術與我們對平台的深度理解結合起來。我們在肝臟領域的領先項目中充實了許多完全相同的功能，以查看我們是否可以共同開發適用於終末期腎病的解決方案，這將在研發過程中開闢一個非常重要的額外戰線。這是一個令人嚮往的目標。因此，正如我們所強調的，在接下來的 6 到 12 個月裡，我們的主要重點將幾乎完全放在我們的肝臟發育計劃上。腎臟的許多前期工作將透過我們的合作者進行，而無需利用公司的大量資源或資金。

This concludes our question-and-answer session as well as the conference. Thank you for attending today's presentation, and you may now disconnect.

我們的問答環節和會議到此結束。感謝您參加今天的演示，現在您可以斷開連接了。