Surrozen Inc (SRZN) 2022 Q4 法說會逐字稿

Good afternoon, and welcome to the Surrozen Corporate Update Conference Call. My name is Josh, and I will be your manager for this call. I will now turn the call over to Craig Parker, CEO of Surrozen to begin the call.

下午好，歡迎來到 Surrozen 公司更新電話會議。我叫 Josh，我將擔任這次電話會議的經理。我現在將電話轉給 Surrozen 的首席執行官克雷格帕克開始通話。

Thanks, Josh, and thank all of you for joining us today for this important corporate update. As Josh said, I'm Craig Parker, CEO of Surrozen. And with me today is Chuck Williams, the Chief Financial Officer at Surrozen. We'll be providing corporate and R&D pipeline updates today and will then address questions.

謝謝，喬希，感謝大家今天加入我們，了解這一重要的公司更新。正如 Josh 所說，我是 Surrozen 的首席執行官 Craig Parker。今天和我在一起的是 Surrozen 的首席財務官 Chuck Williams。我們今天將提供公司和研發管道更新，然後將解決問題。

Slide 2. I'll be making forward-looking statements. Please consult our SEC filings, in particular, our 2022 annual report on Form 10-K for a full discussion of our risk factors.

幻燈片 2。我將做出前瞻性陳述。請查閱我們向美國證券交易委員會提交的文件，特別是我們 2022 年 10-K 表年度報告，以全面討論我們的風險因素。

Slide 3. As some of you know, Surrozen is the preeminent innovator in using the Wnt pathway, the body's own physiologic mechanism for tissue repair to selectively stimulate tissue regeneration in a broad range of diseases. We do this through our proprietary platform and technologies that combine an understanding of Wnt pathway biology in specific disease settings with advanced antibody engineering techniques and proprietary antibody technologies. Our vision is to design and develop tissue selective antibodies that have the potential to regenerate tissue in many severe diseases. It's this targeted approach to Wnt modulation and the extremely broad potential therapeutic applications that distinguish our approach and our technologies. The ultimate clinical promise of our approach is disease-modifying benefit.

幻燈片 3。正如你們中的一些人所知，Surrozen 是使用 Wnt 通路的傑出創新者，Wnt 通路是人體自身的組織修復生理機制，可在多種疾病中選擇性地刺激組織再生。我們通過我們的專有平台和技術做到這一點，這些平台和技術結合了對特定疾病環境中 Wnt 通路生物學的理解與先進的抗體工程技術和專有抗體技術。我們的願景是設計和開發組織選擇性抗體，這些抗體有可能在許多嚴重疾病中再生組織。正是這種有針對性的 Wnt 調製方法和極其廣泛的潛在治療應用使我們的方法和技術脫穎而出。我們方法的最終臨床承諾是改善疾病的益處。

Wnt signaling plays an essential role in regulating many biological processes, including regenerative responses to tissue injury, and we see myriad opportunities to regenerate tissue for clinical benefit. We've invented several novel multivalent antibody-based approaches to selectively modulating Wnt signaling and have advanced to into the clinic. We believe that the Wnt pathway's broad physiologic role portends a role for Wnt therapeutics in a wide range of severe and acute diseases. Our approach overcomes a significant limitation to most regenerative medicine approaches that are limited by availability of donor tissue or long-term viability. We're currently focused on 2 key clinical areas: severe alcoholic hepatitis with our candidate SZN-043 and inflammatory bowel disease with our candidate SZN-1326.

Wnt 信號在調節許多生物過程中起著至關重要的作用，包括對組織損傷的再生反應，我們看到了無數的機會來再生組織以獲得臨床益處。我們發明了幾種基於多價抗體的新型方法來選擇性調節 Wnt 信號，並已進入臨床。我們相信 Wnt 通路廣泛的生理學作用預示著 Wnt 療法在廣泛的嚴重和急性疾病中的作用。我們的方法克服了大多數再生醫學方法的重大局限性，這些方法受到供體組織可用性或長期生存能力的限制。我們目前專注於 2 個關鍵臨床領域：嚴重酒精性肝炎的候選藥物 SZN-043 和炎症性腸病的候選藥物 SZN-1326。

Today, we'll provide you with corporate and pipeline updates, including anticipated time lines for our lead clinical programs, our prioritization efforts for the research pipeline, updates on our partnered program with Boehringer Ingelheim, and our expectations around cash runway as we look toward key inflection points in our lead programs. We'll also provide an overview of our initial evaluation of the transaminase elevations observed in the Phase Ia studies and our approach to advancing both lead programs. In November, we disclosed several adverse events observed in clinical trials that had commenced in 2022. One of the studies, the Phase I single ascending dose study for SZN-1326 was voluntarily paused pending further evaluation of Grade 3 transaminase or liver enzyme elevations. We're excited to be able to update you on progress for both SZN-043 and SZN-1326 Phase I clinical trials. Both are currently open to enrollment. For SZN-043, we've enrolled our first patient, and we'll provide more information later in the call.

今天，我們將為您提供公司和管道更新，包括我們主要臨床項目的預期時間表、我們對研究管道的優先排序工作、我們與勃林格殷格翰合作項目的更新，以及我們對現金跑道的預期，因為我們期待我們的主要計劃中的關鍵轉折點。我們還將概述我們對 Ia 期研究中觀察到的轉氨酶升高的初步評估，以及我們推進這兩個先導項目的方法。 11 月，我們披露了在 2022 年開始的臨床試驗中觀察到的幾項不良事件。其中一項研究，SZN-1326 的 I 期單劑量遞增研究自願暫停，等待進一步評估 3 級轉氨酶或肝酶升高。我們很高興能夠向您通報 SZN-043 和 SZN-1326 I 期臨床試驗的最新進展。兩者目前都可以註冊。對於 SZN-043，我們已經招募了第一位患者，我們將在稍後的電話會議中提供更多信息。

Slide 4. If Wnt biology is so promising, why has it taken decades to drug this pathway. There are many technical impediments. Wnt proteins themselves are insoluble, promiscuous and not manufacturable. So a typical recombinant native protein strategy is just not possible. Surrozen's platform technologies and strategies have helped us overcome all of these limitations. Our candidate molecules are full linked biospecific antibodies that have desirable drug-like properties such as solubility, stability and manufacturability. They're also highly targeted to tissue-specific receptors. Importantly, we're mimicking a normal physiologic response, so our antibodies in a selective way are able to do what Wnt pathway proteins do in all of our bodies in many tissues, either to maintain the tissue or respond to injury. The novelty and breakthrough nature of our work is validated by our strong publication record and high-impact peer-reviewed journals, including science, nature, cell chemical biology, nature scientific reports and nature communications.

Slide 4. 如果 Wnt 生物學如此有前途，為什麼要花幾十年的時間來對這種途徑進行藥物治療。有很多技術障礙。 Wnt 蛋白本身是不可溶的、混雜的並且不可製造。因此，典型的重組天然蛋白質策略是不可能的。 Surrozen 的平台技術和策略幫助我們克服了所有這些限制。我們的候選分子是完全連接的生物特異性抗體，具有理想的藥物樣特性，例如溶解度、穩定性和可製造性。它們還高度靶向組織特異性受體。重要的是，我們正在模仿正常的生理反應，因此我們的抗體能夠以選擇性的方式完成 Wnt 通路蛋白在我們所有身體的許多組織中所做的事情，以維持組織或對損傷做出反應。我們工作的新穎性和突破性得到了我們強大的出版記錄和高影響力的同行評審期刊的驗證，這些期刊包括《科學》、《自然》、《細胞化學生物學》、《自然科學報告》和《自然通訊》。

We have filed or licensed over 20 patent families related to our key discoveries involving the Wnt pathway and its modulation. We recently received notices of allowance from the United States Patent and Trademark Office for 2 patent families assigned to Surrozen related to the SZN-1326 program. We think the breadth of our scientific discoveries and related patent application and claims can establish a dominant position for us in the use of antibody therapeutics to modulate Wnt signaling.

我們已經申請或許可了 20 多項與我們涉及 Wnt 通路及其調製的關鍵發現相關的專利家族。我們最近收到了美國專利商標局關於分配給 Surrozen 的與 SZN-1326 計劃相關的 2 個專利家族的許可通知。我們認為我們的科學發現和相關專利申請和權利要求的廣度可以為我們在使用抗體療法來調節 Wnt 信號傳導方面確立主導地位。

Slide 5. Our proprietary technologies have led to 2 different lead programs that entered the clinic in 2022, the licensing of the lead development candidate, SZN-413 for treatment of retinal diseases to Boehringer Ingelheim in the fourth quarter of 2022 and a focus on 2 discovery pipeline programs for cornea and lacrimal gland. Our research programs focus on indications of high unmet need with no or few available treatments, including a group of ophthalmologic indications that we'll tell you more about.

幻燈片 5。我們的專有技術促成 2 個不同的先導項目於 2022 年進入臨床，2022 年第四季度，勃林格殷格翰獲得了用於治療視網膜疾病的先導開發候選藥物 SZN-413 的許可，並專注於 2發現角膜和淚腺管道程序。我們的研究計劃專注於高度未滿足需求且沒有或很少有可用治療的適應症，包括一組我們將告訴您更多的眼科適應症。

We're excited today to provide an update on advancing both of our clinical programs, SZN-043 and SZN-1326. Since our announcement in the fourth quarter of 2022 regarding transaminase elevations, we've completed numerous studies to understand the mechanism of transaminase elevation seen in this SZN-1326 programs and also at a lower grade in the SZN-043 program. We'll provide you with an overview of our efforts to date and clinical program plans.

今天，我們很高興能夠提供有關推進我們的兩個臨床項目 SZN-043 和 SZN-1326 的最新消息。自我們在 2022 年第四季度發布關於轉氨酶升高的公告以來，我們已經完成了大量研究，以了解此 SZN-1326 計劃以及 SZN-043 計劃中較低級別的轉氨酶升高的機制。我們將為您提供我們迄今為止的努力和臨床項目計劃的概述。

For SZN-043, we're really excited we've advanced to the second phase of the study in chronic liver disease patients following completion of dosing at 2 dose levels in healthy volunteers. For SZN-1326, we will progress our Phase I single ascending dose study at lower doses, pursuing a dosing strategy frequently applied to first-in-class antibodies referred to as MABEL or minimal anticipated biological effect level. Additionally, we will look forward to the opportunity to advance another development candidate in 2023 in collaboration with our partner, Boehringer Ingelheim, with the potential to identify the final Frizzled4 targeted development candidate by year-end, a milestone that would trigger a payment to Surrozen. Finally, we anticipate that our prioritization and restructuring will result in a cash runway into the second half of 2024, allowing us to achieve multiple key milestones and catalysts.

對於 SZN-043，我們非常興奮，在健康志願者完成 2 個劑量水平的給藥後，我們已經推進到慢性肝病患者研究的第二階段。對於 SZN-1326，我們將以較低劑量推進 I 期單次遞增劑量研究，尋求一種經常應用於一流抗體（稱為 MABEL 或最低預期生物學效應水平）的劑量策略。此外，我們期待有機會在 2023 年與我們的合作夥伴 Boehringer Ingelheim 合作推進另一個開發候選項目，並有可能在年底前確定最終的 Frizzled4 目標開發候選項目，這是一個里程碑，將觸發向 Surrozen 付款.最後，我們預計我們的優先級排序和重組將在 2024 年下半年形成一條現金跑道，使我們能夠實現多個關鍵里程碑和催化劑。

Slide 7. SZN-043 is our bispecific multivalent antibody that mimics the activity of R-spondin but importantly, is specifically targeted to hepatocytes via its ASGR1 binding. SZN-043 specifically activates Wnt signaling in the liver, resulting in hepatocyte proliferation, liver regeneration, improvement in liver function and reduction in fibrosis. We think the biological rationale and preclinical data that support the concept of activating Wnt signaling for the treatment of liver disease -- severe liver disease is compelling. We developed a data-driven clinical plan to align the molecule's pharmacology with specific disease pathologies and advance into clinical trials in 2022. As mentioned, we observed some mild-to-moderate adverse events in the first 2 dose cohorts, which we'll describe in more detail. Importantly, these observations did not impact our ability to advance into the next stage of the Phase I program in liver disease subjects. We'll describe our planned next steps and the significant opportunity in severe alcoholic hepatitis.

Slide 7. SZN-043 是我們的雙特異性多價抗體，它模擬 R-spondin 的活性，但重要的是，它通過其 ASGR1 結合特異性靶向肝細胞。 SZN-043 特異性激活肝臟中的 Wnt 信號，導致肝細胞增殖、肝臟再生、肝功能改善和纖維化減少。我們認為支持激活 Wnt 信號轉導治療肝病——嚴重肝病這一概念的生物學原理和臨床前數據是令人信服的。我們制定了一項數據驅動的臨床計劃，使分子的藥理學與特定疾病病理相一致，並在 2022 年進入臨床試驗。如前所述，我們在前 2 個劑量隊列中觀察到一些輕度至中度的不良事件，我們將對此進行描述更詳細。重要的是，這些觀察結果並未影響我們進入肝病受試者 I 期項目下一階段的能力。我們將描述我們計劃的下一步和嚴重酒精性肝炎的重要機會。

Slide 8. It's important to point out that our SWEETS antibody platform on which 043 is based allows for cell-specific targeting of the Wnt activating mechanism. SZN-043 utilizes a well-characterized hepatocyte-specific receptor, ASGR1 to target 043s activity to hepatocytes. Our SWEETS technology mimics the activity of a naturally occurring protein R-spondin. R-spondin's contribution to regeneration is well described, and we focused that its activity on hepatocytes with our technology. We've confirmed the cell-specific Wnt pathway effects of the molecule and our animal toxicology studies showed no adverse effects up to 125 milligrams per kilogram dose level.

幻燈片 8。必須指出，043 所基於的我們的 SWEETS 抗體平台允許 Wnt 激活機制的細胞特異性靶向。 SZN-043 利用一種充分錶徵的肝細胞特異性受體 ASGR1 將 043s 活性靶向肝細胞。我們的 SWEETS 技術模仿天然蛋白質 R-spondin 的活性。 R-spondin 對再生的貢獻得到了很好的描述，我們通過我們的技術將其重點放在肝細胞上。我們已經證實了該分子對細胞特異性 Wnt 通路的影響，我們的動物毒理學研究表明在高達 125 毫克/千克的劑量水平下沒有任何不良影響。

Let me explain why we think severe alcoholic hepatitis is the right indication for the molecule and for Surrozen. Alcoholic hepatitis is a severe clinical entity characterized by acute onset of jaundice and coagulopathy in patients with acute -- with alcohol use disorder. The incidence of alcoholic hepatitis is increasing over recent years. Short-term mortality of severe AH remains very high. 20% of patients with AH die within 30 days of admission to the hospital, and 30% die within 90 days due to hepatocyte loss and lack of sufficient regeneration to overcome that loss.

讓我解釋一下為什麼我們認為嚴重酒精性肝炎是該分子和 Surrozen 的正確適應症。酒精性肝炎是一種嚴重的臨床疾病，其特徵是患有急性酒精使用障礙的患者會出現黃疸和凝血病的急性發作。近年來，酒精性肝炎的發病率呈上升趨勢。嚴重 AH 的短期死亡率仍然很高。 20% 的 AH 患者在入院後 30 天內死亡，30% 在 90 天內死於肝細胞損失和缺乏足夠的再生來克服這種損失。

The medical management of alcoholic hepatitis has not evolved substantially in the last 2 decades with multiple potential therapeutic agents tested without success. There are no approved drugs indicated for severe alcoholic hepatitis. Corticosteroids remain the only established treatment for AH but are contraindicated in more than half the patients. Liver transplants often are denied due to alcoholism. And even if available, transplants are limited by donor organ availability, cost and limitations on medical centers with transplant capabilities. Hospitalization rates are very high in severe alcoholic hepatitis and represent about 130,000 hospitalizations per year.

酒精性肝炎的醫療管理在過去 20 年中沒有取得實質性進展，對多種潛在治療藥物進行了測試但均未成功。沒有批准的藥物適用於嚴重酒精性肝炎。皮質類固醇仍然是 AH 唯一確定的治療方法，但超過一半的患者禁用。肝臟移植常常因酗酒而被拒絕。即使可用，移植也受到供體器官可用性、成本和具有移植能力的醫療中心的限制。嚴重酒精性肝炎的住院率非常高，每年約有 130,000 人住院。

People with severe AH are typically admitted to the ICU. So this is an identifiable population with an extremely high unmet need. We are also aware that alcohol consumption increased by over 30% during the pandemic and hospitalizations also increased during the pandemic for alcoholic hepatitis. We think that the critical medical need in this population, the dearth of novel approaches and alignment of our mechanism with the disease pathophysiology is reinforced by an award to Surrozen of a several million dollar NIH grant for this program. Importantly, hepatocyte regeneration is known to correlate with improved survival.

患有嚴重 AH 的人通常會入住 ICU。因此，這是一個具有極高未滿足需求的可識別人群。我們還知道，在大流行期間飲酒量增加了 30% 以上，而在大流行期間因酒精性肝炎住院的人數也有所增加。我們認為，這一人群的關鍵醫療需求、新方法的缺乏以及我們的機制與疾病病理生理學的一致性，由於授予 Surrozen 數百萬美元的 NIH 資助而得到加強。重要的是，已知肝細胞再生與存活率提高相關。

Furthermore, we can utilize surrogates for response and survival, such as the Lille and MELD scores to assess early signs of clinical benefit. Both of these tools are using clinical practice to assess response to treatment, prognosis and eligibility for transplant. They are objective and are calculated using common laboratory tests like bilirubin. The Lille score at 7 days is a well-characterized marker of disease severity -- severity that is highly correlated with 90-day survival. We expect 90-day survival to be the approvable endpoint in a registration trial. Because of the disease severity and unmet medical need, we believe there's an opportunity for favorable regulatory treatment such as breakthrough designation and a potentially rapid approval pathway as seen in other grievous diseases.

此外，我們可以利用反應和生存的替代指標，例如 Lille 和 MELD 評分來評估臨床獲益的早期跡象。這兩種工具都使用臨床實踐來評估對治療的反應、預後和移植資格。它們是客觀的，是使用膽紅素等常見實驗室測試計算得出的。 7 天時的 Lille 評分是疾病嚴重程度的一個特徵明確的標誌——嚴重程度與 90 天存活率高度相關。我們預計 90 天生存期將成為註冊試驗中可批准的終點。由於疾病的嚴重性和未滿足的醫療需求，我們認為有機會獲得有利的監管治療，例如突破性指定和其他嚴重疾病中所見的潛在快速批准途徑。

Slide 9. We've published data from multiple rodent liver injury models demonstrating that SZN-043 rapidly proliferates mature hepatocytes resulting in functional improvements and a reduction in fibrosis. These publications and abstracts can be found in the Investors section of our corporate website. The efficacy of SZN-043 spans injury models specific to our initial indication of alcoholic hepatitis to models of fibrosis that could ultimately provide translation to additional liver indications in the future.

幻燈片 9。我們已經發布了多個囓齒動物肝損傷模型的數據，證明 SZN-043 可快速增殖成熟肝細胞，從而改善功能並減少纖維化。這些出版物和摘要可以在我們公司網站的投資者部分找到。 SZN-043 的功效涵蓋了特定於我們最初的酒精性肝炎適應症的損傷模型到纖維化模型，這些模型最終可以在未來轉化為其他肝臟適應症。

Slide 10. We're excited to have completed 2 cohorts of patients in the Phase I single ascending dose study in healthy volunteers, and we've enrolled our first patient with chronic liver disease. Following the outcome of the mild-to-moderate TA elevations in the first cohort of healthy volunteers treated at 3 milligrams per kilogram, we enrolled a second cohort in 6 healthy volunteers at a lower dose of 1 milligram per kilogram. We observed one case of mildly elevated Grade 1 transaminitis that also resolved spontaneously. Following completion of Cohort 2 in the Phase I SAD in healthy volunteers, we opened enrollment in the Phase I SAD in patients with chronic liver disease, and as I said, have enrolled our first patient.

幻燈片 10。我們很高興在健康志願者中完成了 I 期單次遞增劑量研究中的 2 個患者隊列，並且我們已經招募了第一位患有慢性肝病的患者。在第一組接受 3 毫克/千克治療的健康志願者出現輕度至中度 TA 升高的結果後，我們在 6 名健康志願者中招募了第二組，接受了 1 毫克/千克的較低劑量。我們觀察到一例輕度升高的 1 級轉氨酶炎也自發消退。在健康志願者完成 I 期 SAD 的第 2 期隊列後，我們開始招募慢性肝病患者的 I 期 SAD，正如我所說，我們已經招募了第一位患者。

We expect to enroll 4 subjects per dose group with an option to expand the cohort. We're proceeding with lower doses as our preclinical data indicates that damaged tissue may be more sensitive to the beneficial hepatocyte proliferation effects of SZN-043. Patients in Cohort 1 will be dosed at 0.5 milligrams per kilogram. Importantly, we anticipate having data from the Phase I single ascending dose in chronic liver disease patients by year-end 2023. Assuming acceptable safety, we anticipate moving into a Phase Ib clinical study in severe alcoholic hepatitis patients in 2024, with proof-of-concept data expected to be available in the second half of 2024.

我們希望每個劑量組招募 4 名受試者，並可選擇擴大隊列。我們正在使用較低劑量，因為我們的臨床前數據表明受損組織可能對 SZN-043 的有益肝細胞增殖作用更敏感。第 1 組患者的劑量為每公斤 0.5 毫克。重要的是，我們預計到 2023 年底將獲得慢性肝病患者 I 期單次遞增劑量的數據。假設安全性可接受，我們預計將在 2024 年進入嚴重酒精性肝炎患者的 Ib 期臨床研究，並證明-預計將於 2024 年下半年提供概念數據。

In summary, we believe that SZN-043's mechanism and preclinical data are ideally aligned with our initial target indication, and that SZN-043 has a well-defined clinical development and regulatory pathway. We look forward to advancing our understanding of the therapeutic potential of SZN-043 as we initiate treatment of subjects with chronic liver disease and ultimately, patients with severe alcoholic hepatitis.

總之，我們認為 SZN-043 的機制和臨床前數據與我們的初始目標適應症非常吻合，並且 SZN-043 具有明確的臨床開發和監管途徑。我們期待在我們開始治療慢性肝病患者並最終治療重度酒精性肝炎患者時，加深我們對 SZN-043 治療潛力的理解。

Slide 12. SZN-1326 is based on our SWAP technology, and we're developing SZN-1326 from moderate to severe inflammatory bowel disease. Based on a compelling effect in well-established rodent models of colitis, showing near complete healing of damaged intestinal epithelium, including reestablishment of the critical barrier function using 1 or -- just 1 or 2 doses of SZN-1326, we designed a clinical development plan leveraging the extensive experience of other biologic agents in IBD. In contrast to other biologics, though, our biology and preclinical data suggests we have an opportunity to directly drive mucosal healing or histologic remission.

Slide 12. SZN-1326 基於我們的 SWAP 技術，我們正在開發適用於中度至重度炎症性腸病的 SZN-1326。基於在成熟的囓齒動物結腸炎模型中的顯著效果，顯示受損腸上皮幾乎完全癒合，包括使用 1 或 - 僅 1 或 2 劑 SZN-1326 重建關鍵屏障功能，我們設計了臨床開發計劃利用其他生物製劑在 IBD 中的豐富經驗。然而，與其他生物製劑相比，我們的生物學和臨床前數據表明我們有機會直接推動粘膜癒合或組織學緩解。

In May 2022, we commenced dosing of SZN-1326 in a healthy volunteer Phase I single-ascending dose study. Several subjects in cohort 1 treated at 25 milligrams experienced asymptomatic liver transaminase elevations, including 2 subjects with Grade 3 ALT and AST elevations and 2 subjects with Grade 1 ALT elevations. There were no corresponding increases in total bilirubin nor any changes in other liver function markers and no other clinically significant laboratory abnormalities. The transaminase elevations resolved spontaneously in all subjects. No serious adverse events were observed during the study.

2022 年 5 月，我們開始在健康志願者 I 期單遞增劑量研究中對 SZN-1326 進行給藥。隊列 1 中幾名受試者在 25 毫克治療時出現無症狀肝轉氨酶升高，包括 2 名受試者有 3 級 ALT 和 AST 升高和 2 名受試者有 1 級 ALT 升高。總膽紅素沒有相應增加，其他肝功能標誌物也沒有任何變化，也沒有其他具有臨床意義的實驗室異常。轉氨酶升高在所有受試者中自發消退。研究期間未觀察到嚴重不良事件。

Although the protocol did not require that we halt the study, we announced a voluntary pause to enrollment in the Phase I healthy volunteer portion of the study in November following this observation -- following an observation of a grade 3 ALT elevation at a lower dose in order to give us an opportunity to analyze the clinical data. We have not observed transaminase elevations or any other adversities at doses up to 125 milligrams per kilogram in pilot or GLP toxicology studies. So these adverse events were unexpected and as such, could not be characterized with nonclinical data available at the time of the observed events. We've invested significantly in efforts to understand the mechanism of the TA elevations.

儘管協議不要求我們停止研究，但我們宣佈在 11 月自願暫停參加該研究的第一階段健康志願者部分，在此觀察之後——在觀察到較低劑量的 3 級 ALT 升高之後為了讓我們有機會分析臨床數據。在試點或 GLP 毒理學研究中，我們沒有觀察到轉氨酶升高或任何其他不利情況，劑量高達 125 毫克/千克。因此，這些不良事件是出乎意料的，因此無法用觀察到的事件發生時可用的非臨床數據來表徵。我們投入了大量精力來了解 TA 升高的機制。

Importantly, a better understanding of the nonclinical data and clinical data, combined with a modified dosing strategy, allows us now to proceed to dose additional healthy volunteers in the Phase I SAD portion of the study, which we expect to do in the next few weeks. Our initial rationale for dose levels for SZN-1326 was based on doses tested in multiple models of colitis, and the absence of any observed toxicities preclinically. Such a dosing strategy is informed by the NOAEL or no observed adverse effect level as well as other indicators of activities such as a therapeutically active dose. In light of the TA elevation observations, we're now pursuing a dose level strategy with SZN-1326 that, as I said, is commonly employed with agonistic antibodies for first-in-human studies and that's a MABEL or minimum anticipated biological effect level.

重要的是，更好地了解非臨床數據和臨床數據，結合修改後的劑量策略，我們現在可以在研究的 I 期 SAD 部分繼續對更多健康志願者進行劑量，我們預計將在接下來的幾週內完成.我們對 SZN-1326 劑量水平的最初基本原理是基於在多種結腸炎模型中測試的劑量，以及在臨床前沒有觀察到任何毒性。這種給藥策略由 NOAEL 或未觀察到的不良反應水平以及其他活動指標（如治療活性劑量）決定。鑑於 TA 升高觀察結果，我們現在正在尋求 SZN-1326 的劑量水平策略，正如我所說，它通常與激動性抗體一起用於首次人體研究，這是 MABEL 或最低預期生物學效應水平.

Slide 13. So I probably don't need to reinforce for all of you the remaining unmet need in this significant market. Initially, we're developing SZN-1326 for ulcerative colitis. Ulcerative colitis is a chronic immune-mediated inflammatory disease of the large intestine that's frequently associated with inflammation of the rectum, but also extends proximately to involve additional areas of the colon. Nearly 1 million individuals each in the U.S. and EU are affected. Peak incidence occurs between the ages of 15 and 45. Some patients with UC have persistent disease activity despite medical therapy. And 20% will develop at least one episode of acute severe ulcerative colitis requiring hospitalization.

幻燈片 13。因此，我可能不需要向大家強調這個重要市場中尚未滿足的需求。最初，我們正在開髮用於潰瘍性結腸炎的 SZN-1326。潰瘍性結腸炎是一種慢性免疫介導的大腸炎症性疾病，通常與直腸炎症有關，但也延伸至近端以累及結腸的其他區域。美國和歐盟各有近 100 萬人受到影響。發病高峰出現在 15 至 45 歲之間。一些 UC 患者儘管進行了藥物治療，但疾病活動仍持續存在。並且 20% 會發展為至少一次需要住院治療的急性重症潰瘍性結腸炎。

Importantly, although there are medical therapies on the market in development, there remains a significant unmet need in UC for the following. Rapid induction, as current anti-inflammatory biologics can take months to induce clinical remission. Improved efficacy, especially histologic remission as anti-inflammatory biologics achieved clinical remission in less than 50% of patients at 52 weeks, and low rates of histologic remission as low as 20%. Histologic remission has been associated with a better clinical course. Additional mechanisms of action -- as an additional unmet need as many patients fail first-line anti-inflammatory biologics and subsequently fail second and third-line therapies.

重要的是，儘管市場上有正在開發的藥物療法，但 UC 在以下方面仍然存在重大未滿足的需求。快速誘導，因為目前的抗炎生物製劑可能需要數月才能誘導臨床緩解。療效提高，尤其是組織學緩解，因為抗炎生物製劑在 52 週時只有不到 50% 的患者達到臨床緩解，組織學緩解率低至 20%。組織學緩解與更好的臨床過程相關。額外的作用機制——作為額外的未滿足需求，因為許多患者一線抗炎生物製劑失敗，隨後二線和三線治療失敗。

Slide 14. So what's the rationale for a Wnt mimetic in inflammatory bowel disease. A major component of the pathophysiology of IBD is an impaired epithelial barrier or gut wall, allowing for exposure of gut microbes to the gut immune system, resulting in inflammation. This inflammation further destroys the epithelial barrier. SZN-1326 can directly address this epithelial barrier dysfunction. It binds to intestinal stem cells in the colon crypt replacing Wnt ligands that in normal circumstances are produced by the stromal cells, but that's disrupted in IBD. This binding of 1326 leads to proliferation and differentiation of these cells as they move up and out of the colon crypt replacing the damaged epithelium and restoring the epithelial barrier. We've shown preclinical that this results in reduced inflammation and reduced disease activity.

幻燈片 14。那麼 Wnt 模擬物在炎症性腸病中的基本原理是什麼。 IBD 病理生理學的一個主要組成部分是上皮屏障或腸壁受損，使腸道微生物暴露於腸道免疫系統，從而導致炎症。這種炎症進一步破壞了上皮屏障。 SZN-1326 可以直接解決這種上皮屏障功能障礙。它與結腸隱窩中的腸幹細胞結合，取代正常情況下由基質細胞產生的 Wnt 配體，但在 IBD 中會被破壞。 1326 的這種結合導致這些細胞的增殖和分化，因為它們向上移動並移出結腸隱窩，替換受損的上皮細胞並恢復上皮屏障。我們已經在臨床前證明這會導致炎症減少和疾病活動減少。

Slide 15. In preclinical studies, we've demonstrated that 1326 restores Wnt signaling in the damaged intestine, repairs the damage colon epithelium, reduces inflammatory cytokines and reduces disease activity. We've also shown that this activity in preclinical models of colitis compares favorably to approved biologics and immunosuppressants. You can find abstracts related to some of this preclinical data on our website.

幻燈片 15。在臨床前研究中，我們已經證明 1326 可以恢復受損腸道中的 Wnt 信號，修復受損的結腸上皮細胞，減少炎症細胞因子並降低疾病活動度。我們還表明，這種在結腸炎臨床前模型中的活性優於批准的生物製劑和免疫抑製劑。您可以在我們的網站上找到與某些臨床前數據相關的摘要。

Slide 16. Over the last several months, we've identified several potential hypotheses for the transaminase elevations we've seen in the clinic and have established a rigorous science-based investigation plan. Our in-house expertise and capabilities have proved invaluable in expeditiously analyzing the available data and conducting additional experiments designed to specifically address key questions. Let me describe some of these activities, the data and our conclusions.

幻燈片 16。在過去的幾個月裡，我們已經確定了我們在臨床上看到的轉氨酶升高的幾個潛在假設，並製定了一個嚴格的基於科學的調查計劃。事實證明，我們的內部專業知識和能力在快速分析可用數據和開展旨在專門解決關鍵問題的額外實驗方面具有無可估量的價值。讓我描述其中的一些活動、數據和我們的結論。

We've established additional in vitro and in vivo systems, specifically employing human hepatocytes in order to most closely model human physiology. We've observed that our molecules do not have a direct toxic effect on human liver cells in multiple in vitro and in vivo experimental systems. We have not observed a direct effect on ALT or AST in vitro. And importantly, we have not seen any immune-mediated effects using multiple experimental settings, no cell death, no immune activation, no observed hepatocyte killing effect in any of our studies that we've undertaken over the last few months.

我們已經建立了額外的體外和體內系統，特別是使用人類肝細胞來最接近地模擬人類生理學。我們已經觀察到，我們的分子在多個體外和體內實驗系統中對人體肝細胞沒有直接的毒性作用。我們沒有在體外觀察到對 ALT 或 AST 的直接影響。重要的是，在我們過去幾個月進行的任何研究中，我們都沒有看到使用多個實驗設置的任何免疫介導的影響，沒有細胞死亡，沒有免疫激活，沒有觀察到肝細胞殺傷作用。

Although 043 and 1326 employ different receptor systems for activity, the downstream Wnt pathway effects are shared. We think the similarities and the patterns of transaminase elevations between the 2 molecules in light of their different pharmacokinetics is supportive of the hypothesis that activation of Wnt signaling and subsequent hepatocyte-driven liver regeneration is at least partially responsible for the transaminase effects. We'll continue to investigate additional models for applicability to understanding the mechanism of these TA elevations.

儘管 043 和 1326 採用不同的活性受體系統，但下游 Wnt 通路效應是共享的。我們認為，鑑於兩種分子不同的藥代動力學，它們之間轉氨酶升高的相似性和模式支持以下假設，即 Wnt 信號的激活和隨後的肝細胞驅動的肝再生至少對轉氨酶效應負有部分責任。我們將繼續研究其他模型以了解這些 TA 提昇機制的適用性。

I'll also remind you that this seems to be a liver-specific effect and many of our molecules would not be expected to affect liver cells based on either receptor targeting or route of administration. We'll be commencing dosing of SZN-1326 in the next cohort of healthy volunteers at a dose of 0.04 milligrams or 40 micrograms. Assuming acceptable safety in this and subsequent cohorts, we anticipate proceeding to doses up to at least 1 milligram. Following acceptable safety, we anticipate enrolling a proof-of-concept study in ulcerative colitis patients in 2024, with proof-of-concept data expected to be available in the second half of 2024.

我還要提醒您，這似乎是一種肝臟特異性作用，我們的許多分子預計不會根據受體靶向或給藥途徑影響肝細胞。我們將以 0.04 毫克或 40 微克的劑量開始在下一批健康志願者中服用 SZN-1326。假設此隊列和後續隊列的安全性可接受，我們預計會繼續使用高達至少 1 毫克的劑量。在可接受的安全性之後，我們預計在 2024 年對潰瘍性結腸炎患者進行概念驗證研究，概念驗證數據預計將在 2024 年下半年提供。

Slide 18. We have 3 research programs in late stages of lead optimization or candidate selection, 2 wholly owned by Surrozen and 1 partnered with Boehringer Ingelheim. As I mentioned, Wnt signaling plays a central role in tissue regeneration and Wnt responses cell types are found in tissues throughout the body. We believe this broad physiologic role portends a role for Wnt therapeutics in a wide range of severe and acute diseases. The role of Frizzled4-mediated signaling and blood vessels in the retina has been validated through human genetics, rodent models and our own and collaborators data and publications.

幻燈片 18。我們有 3 個處於領先優化或候選人選擇後期階段的研究項目，其中 2 個由 Surrozen 全資擁有，1 個與 Boehringer Ingelheim 合作。正如我提到的，Wnt 信號在組織再生中起著核心作用，Wnt 反應細胞類型存在於全身組織中。我們相信這種廣泛的生理作用預示著 Wnt 療法在廣泛的嚴重和急性疾病中的作用。 Frizzled4 介導的信號和血管在視網膜中的作用已通過人類遺傳學、囓齒動物模型以及我們自己和合作者的數據和出版物得到驗證。

We've shown that a Frizzled4 targeted SWAP, SZN-413 could fill a unique mechanistic role in the treatment of retinopathies by simultaneously addressing vascular leakage and retinal nonperfusion. In 2 different models of retinal injury, we've shown that SZN-413 could reverse multiple manifestations of retinal injury, including vascular leakage and areas in the retina that were not adequately vascularized and areas with characteristic pathologic neovascular tufts. This and other data stimulated interest from multiple parties in an SZN-413 partnership and led us to sign a collaboration agreement with Boehringer Ingelheim in October 2022.

我們已經證明，Frizzled4 靶向 SWAP，SZN-413 可以通過同時解決血管滲漏和視網膜非灌注問題，在視網膜病變的治療中發揮獨特的機製作用。在 2 種不同的視網膜損傷模型中，我們已經證明 SZN-413 可以逆轉視網膜損傷的多種表現，包括血管滲漏和視網膜中未充分血管化的區域以及具有特徵性病理性新生血管簇的區域。這一數據和其他數據激發了多方對 SZN-413 合作關係的興趣，並促使我們於 2022 年 10 月與勃林格殷格翰簽署了合作協議。

Slide 19. We also have a research program in regenerating cornea. Fuchs endothelial cell dystrophy is a disease characterized by corneal swelling and ultimately vision loss and discomfort caused by excessive loss of corneal endothelial cells. The cause of corneal endothelial cell loss is not well understood, but has a genetic component. Current therapies are limited to endothelial transplant or resection at late stages of the disease. There is a significant unmet need for therapies that mitigate disease progression and/or improve surgical efficacy. Our strategy for treating corneal disease is to specifically activate Wnt signaling in the tissue, regenerate corneal endothelial cells reduce corneal swelling and improve vision.

幻燈片 19。我們還有一個角膜再生研究項目。 Fuchs內皮細胞營養不良是一種以角膜腫脹為特徵的疾病，最終由於角膜內皮細胞過度丟失而導致視力喪失和不適。角膜內皮細胞丟失的原因尚不清楚，但具有遺傳成分。目前的治療僅限於疾病晚期的內皮移植或切除術。對減輕疾病進展和/或提高手術療效的療法存在顯著未滿足的需求。我們治療角膜疾病的策略是特異性激活組織中的Wnt信號，再生角膜內皮細胞，減少角膜腫脹，改善視力。

We've established a corneal research effort, including in vitro and in vivo models that to date have demonstrated the following: specific Frizzled receptors are expressed in corneal endothelium of both normal and Fuchs' human donors and can therefore be used in designing and targeting our SWAP molecules. We can observe Wnt activation through specific SWAPs that enhance proliferation of primary human, corneal endothelial cells in vitro. And we've established a corneal cryo injury model to measure the therapeutic effect of activating Wnt signaling in the corneal endothelium. In vivo Surrozen Wnt activating molecules are efficacious in reducing corneal thickness and improving opacity. The next step for our program is to optimize a lead molecule and select a development candidate.

我們已經建立了角膜研究工作，包括體外和體內模型，迄今為止已經證明了以下內容：特定的 Frizzled 受體在正常和 Fuchs 人類供體的角膜內皮中表達，因此可用於設計和靶向我們的交換分子。我們可以通過特定的 SWAP 觀察到 Wnt 激活，這些 SWAP 在體外增強原代人角膜內皮細胞的增殖。我們已經建立了角膜冷凍損傷模型來測量激活角膜內皮中 Wnt 信號的治療效果。體內 Surrozen Wnt 激活分子可有效減少角膜厚度和改善不透明度。我們計劃的下一步是優化先導分子並選擇開發候選者。

Slide 20. Well, let me tell you about another ophthalmologic program that we're excited about. We're pursuing a potential treatment for severe dry eye with our SWAP technology. Severe dry eye is characterized by atrophy of the tear producing glands in the eye and insufficient regeneration. The objective with the Wnt activating approach is to stimulate regeneration of the tear producing cells in the lacrimal gland and restore fluid secretion. We've established multiple lacrimal gland injury models in rodents, in which tear production is reduced. One using Intraleukin-1 alpha to promote inflammation-driven injury, the other, a lacrimal duct ligation model that results in necrosis to the gland. An important first mechanistic step in restoring tear production is to regenerate the tear-producing cells in the gland called the acinar cells.

幻燈片 20。好吧，讓我告訴你另一個讓我們興奮的眼科項目。我們正在尋求使用我們的 SWAP 技術治療嚴重干眼症的潛在方法。嚴重的干眼症的特徵是眼中的淚腺萎縮和再生不足。 Wnt 激活方法的目的是刺激淚腺中淚液生成細胞的再生並恢復液體分泌。我們已經在囓齒動物中建立了多個淚腺損傷模型，其中淚液產生減少。一個使用 Intraleukin-1 α 來促進炎症驅動的損傷，另一個是導致腺體壞死的淚道結紮模型。恢復淚液產生的一個重要的第一個機械步驟是再生腺體中稱為腺泡細胞的淚液產生細胞。

We've shown that a single injection of a SWAP molecule results in an increase in the weight of the lacrimal gland and a demonstrable proliferation of these acinar cells. So we're having a clear effect at the cellular level of increasing the number of target cells in the gland. In the IL-1a induced injury model, we've shown that SWAP molecules activate Wnt signaling in the tissue, which leads to an increase in tear secretion. The method for measuring tear secretion in this model is actually the same as that used in clinical trials of agents for dry eye, a phenol red thread. In this model, there's a statistically significant increase in tear production with SWAP molecules at days 2, 3 and 4. Similarly, in a duct ligation model of lacrimal gland injury, we've shown that treatment with the SWAP molecule restores tear production through activation of Wnt signaling and proliferation of acinar cells.

我們已經表明，單次注射 SWAP 分子會導致淚腺重量增加和這些腺泡細胞明顯增殖。所以我們在細胞水平上有明顯的效果，可以增加腺體中靶細胞的數量。在 IL-1a 誘導的損傷模型中，我們已經證明 SWAP 分子激活組織中的 Wnt 信號，從而導致淚液分泌增加。該模型中測量淚液分泌的方法實際上與乾眼症藥物酚紅線臨床試驗中使用的方法相同。在這個模型中，在第 2、3 和 4 天，使用 SWAP 分子產生的淚液在統計上顯著增加。同樣，在淚腺損傷的導管結紮模型中，我們已經證明使用 SWAP 分子治療通過激活恢復淚液產生Wnt 信號和腺泡細胞增殖。

Next step for the program is to optimize and finalize a lead molecule for development. We expect at least one of these programs to move forward into development in 2023, potentially in collaboration with a corporate partner. Both involve local administration of our antibodies to the affected tissue and therefore, would not be expected to have any potential liver exposure liabilities.

該計劃的下一步是優化和最終確定用於開發的先導分子。我們預計這些項目中至少有一個將在 2023 年推進開發，並有可能與企業合作夥伴合作。兩者都涉及將我們的抗體局部施用到受影響的組織，因此預計不會有任何潛在的肝臟暴露責任。

Slide 21, and I'm going to turn the slide over to Chuck.

幻燈片 21，我將把幻燈片交給 Chuck。

Thanks, Craig. So as Craig outlined, we've made significant progress with our programs over the last few months. And I wanted to highlight a few, the things that we've accomplished from a corporate and capital structure perspective to establish an even stronger foundation for continued future success.

謝謝，克雷格。因此，正如 Craig 概述的那樣，我們在過去幾個月的計劃中取得了重大進展。我想強調一些，我們從公司和資本結構的角度所取得的成就，為未來的持續成功奠定了更堅實的基礎。

So first, I wanted to highlight, we executed a partnership with Boehringer Ingelheim in the fourth quarter of 2022 to develop a Wnt agonist SZN-413 for the treatment of people with retinal diseases. We anticipate the potential to identify the lead Frizzled4 targeted Wnt agonist candidate by year-end 2023, would trigger a potential $10 million milestone payment. Secondly, we implemented a restructuring in Q1 of this year. Our efforts were focused on maximizing shareholder value by: one, aligning resources and R&D investments for the 2 lead clinical development programs with a focus on obtaining proof-of-concept data; two, prioritizing investment in the most advanced discovery preclinical programs, lacrimal and cornea; and thirdly, reducing operating expenses with the goal of maintaining a strong balance sheet.

首先，我想強調的是，我們在 2022 年第四季度與勃林格殷格翰建立了合作夥伴關係，以開髮用於治療視網膜疾病患者的 Wnt 激動劑 SZN-413。我們預計有可能在 2023 年底之前確定領先的 Frizzled4 靶向 Wnt 激動劑候選者，這將觸發潛在的 1000 萬美元里程碑付款。其次，我們在今年第一季度實施了重組。我們的工作重點是通過以下方式實現股東價值最大化：其一，為 2 個主要臨床開發項目調整資源和研發投資，重點是獲取概念驗證數據；第二，優先投資於最先進的發現臨床前項目，淚道和角膜；第三，減少運營費用，以保持強勁的資產負債表。

Following the corporate prioritization and restructuring activities, we anticipate a reduction in operating expenses, excluding noncash and nonrecurring charges of approximately 15% in 2023 compared to 2022. Cash, cash equivalents and marketable securities were approximately $76 million as of the end of 2022, and we expect our cash runway to last into the second half of 2024.

在公司優先排序和重組活動之後，我們預計與 2022 年相比，2023 年的運營費用（不包括非現金和非經常性費用）將減少約 15%。截至 2022 年底，現金、現金等價物和有價證券約為 7600 萬美元，並且我們預計我們的現金跑道將持續到 2024 年下半年。

Finally, I wanted to highlight in the fourth quarter of 2022, we entered into a securities purchase agreement with Continence. Given they decided that they were winding down their fund, they were an overhang on our stock, so we entered into an agreement to repurchase approximately 5.4 million shares of our common stock and approximately 1.3 million warrants for a purchase price of approximately $2.7 million. Following the repurchase, Continence no longer hold any shares of our common stock or warrants to purchase theirs in common stock.

最後，我想強調一下，在 2022 年第四季度，我們與 Continence 簽訂了證券購買協議。鑑於他們決定縮減基金規模，這對我們的股票構成了威脅，因此我們達成協議，以約 270 萬美元的購買價格回購約 540 萬股普通股和約 130 萬份認股權證。回購後，Continence 不再持有我們的任何普通股或認股權證以購買他們的普通股。

We're excited with the multiple opportunities that lie ahead of Surrozen in 2023 and 2024. We've shared some of our key milestones and catalysts through 2024 on this slide. We shared our thoughts on cash runway into the second half of '24 as we think about our key upcoming milestones and catalysts, and I'll briefly highlight a few of these.

我們對 Surrozen 在 2023 年和 2024 年面臨的多重機遇感到興奮。我們在這張幻燈片上分享了我們到 2024 年的一些關鍵里程碑和催化劑。在考慮我們即將到來的關鍵里程碑和催化劑時，我們分享了我們對 24 年下半年現金跑道的想法，我將簡要強調其中的一些。

First, for SZN-043, as Craig mentioned, we've enrolled the first patient for chronic liver disease and expect to have data by the end of the year, and plan to initiate a Phase Ib clinical trial in 2024 with potential proof-of-concept data in the second half of 2024. As it relates to 1326, we've opened enrollment for the Phase I in healthy volunteers, and we expect to be able to have data by the end of the year, and we'll initiate a Phase Ib trial in 2024 in UC patients and expect to have proof-of-concept data in the second half of '24.

首先，對於 SZN-043，正如 Craig 提到的，我們已經招募了第一位慢性肝病患者，預計將在年底前獲得數據，併計劃在 2024 年啟動 Ib 期臨床試驗，並可能證明-2024年下半年的概念數據，因為涉及到1326，我們已經開放了第一期健康志願者的招募，預計年底能有數據，我們會啟動2024 年在 UC 患者中進行 Ib 期試驗，預計在 24 年下半年獲得概念驗證數據。

As I've already mentioned, with SZN-413, which is partnered with Boehringer Ingelheim, we expect by the end of the year for them to nominate a candidate which will trigger a $10 million milestone payment, and as it relates to our research programs, we expect to nominate an additional program and/or partner that potential program.

正如我已經提到的，對於與勃林格殷格翰合作的 SZN-413，我們預計他們將在今年年底提名一名候選人，這將觸發 1000 萬美元的里程碑付款，因為它與我們的研究計劃有關，我們希望提名一個額外的項目和/或與該潛在項目合作。

So now I'd like to turn it back to the operator, and we'll open up the call for questions.

所以現在我想把它轉回接線員，我們將打開問題電話。

(Operator Instructions) Our first question comes from Dae Gon Ha with Stifel.

（操作員說明）我們的第一個問題來自 Stifel 的 Dae Gon Ha。

Congrats on all the progress. Good to hear things are back in motion on your side of the table. Maybe I'll just start with two before I hop back in the queue. Regarding the 043...

祝賀所有的進步。很高興聽到你身邊的事情又開始了。也許我會先從兩個開始，然後再回到隊列中。關於043...

I don't hear anything.

我什麼也沒聽到。

Hello. Can you guys hear me? Hello. Can you guys hear me now?

你好。你們能聽到我說話嗎？你好。你們現在能聽到我說話嗎？

Yes.

是的。

Congrats on all the progress. I wanted to ask two questions. One was more of a clarification for the 043 plan. Is there a change in the study plans? Because I thought the Phase I next study was in early cirrhotic patients, but now it seems like chronic liver disease. So was there a change? Or what was the, I guess, the nuance that I'm missing? And based on the liver transaminase observations, can you speak to your confidence or strategy to mitigate similar observations in more hepatically-impaired patients? And then I've got a follow-up.

祝賀所有的進步。我想問兩個問題。一個更像是對043計劃的澄清。學習計劃有變化嗎？因為我以為下一個I期研究是針對早期肝硬化患者，現在看來是慢性肝病。那麼有變化嗎？或者，我想，我遺漏的細微差別是什麼？根據肝轉氨酶的觀察結果，您能否談談您的信心或策略來減輕更多肝功能受損患者的類似觀察結果？然後我有一個後續行動。

Thanks for the questions, Dae Gon. So yes, you observed a nuance in what we think are the patients likely to be enrolled in the study. So the general objective of the study -- well, the primary objective of the study is unchanged, which is safety. We think that -- and cirrhotic patients are chronic liver disease patients. For many etiologies like patients with hep C, for example, cirrhosis is defined by in part a FibroScan score or transient elastography score of 7.5. We're taking patients with lower FibroScan scores. So they will certainly have chronic liver disease. They will have fibrosis. But whether they have frank cirrhosis, I think we'll just have to see. So that's the nuance in the description of the target population that you picked up on is they may have FibroScan scores that are low enough that they would not be considered to be cirrhotics yet, but they would certainly have fibrosis and have hepatic impairment.

謝謝你的問題，大坤。所以是的，您觀察到我們認為可能參加研究的患者存在細微差別。所以這項研究的總體目標——好吧，研究的主要目標沒有改變，那就是安全性。我們認為——肝硬化患者是慢性肝病患者。例如，對於許多病因，如丙肝患者，肝硬化的定義部分是 FibroScan 評分或瞬時彈性成像評分為 7.5。我們正在接受 FibroScan 評分較低的患者。所以他們肯定會得慢性肝病。他們會有纖維化。但他們是否患有明顯的肝硬化，我想我們只需要看看。所以這就是你所選擇的目標人群描述中的細微差別，他們可能有足夠低的 FibroScan 評分，以至於他們還不會被認為是肝硬化，但他們肯定會出現纖維化和肝損傷。

Got it. And what about the hepatically-impaired aspect? How might that be a potential complication for you guys? Or do you have strategies to mitigate that?

知道了。那麼肝功能受損的方面呢？這對你們來說可能是一個潛在的並發症嗎？或者您有緩解這種情況的策略嗎？

No. We have not identified a specific mechanism where one could mitigate, for example, by co-administering something else. And so I think, as I mentioned, we've observed that damaged tissue tends to be more sensitive. And so I think this is really going to come down to the dose response in disease tissue versus healthy tissue. So not -- there's no specific mechanistic strategy at this point based on the data that we've generated. But again, it's possible that at quite low doses, there's a regenerative response that doesn't bring with it some hepatocellular injury.

沒有。我們還沒有確定一種可以緩解的具體機制，例如，通過共同管理其他東西。所以我認為，正如我提到的，我們已經觀察到受損組織往往更敏感。所以我認為這真的要歸結為疾病組織與健康組織的劑量反應。所以不是——根據我們生成的數據，目前還沒有具體的機械策略。但同樣，在相當低的劑量下，可能會產生一種不會帶來一些肝細胞損傷的再生反應。

Okay. Regarding that MABEL aspect you were talking about, so if we think about your 1326 study, how many more dose cohorts are you going to be exploring? I think I heard you say starting with 0.04 but going up to 1 milligram dose. Have you clarified how many cohorts that would be? And kind of by extension, this notion of higher-than-expected exposure in humans versus animal studies. Is that also an effect for your 043 molecule as well?

好的。關於您所說的 MABEL 方面，所以如果我們考慮您的 1326 研究，您將探索多少個劑量組？我想我聽到你說從 0.04 開始但增加到 1 毫克劑量。你有沒有說明會有多少人？並且可以推而廣之，這種在人類與動物研究中的暴露高於預期的概念。這對你的 043 分子也有影響嗎？

Yes. We'll publish some of the pharmacokinetic data at some point for both molecules, but 043 was roughly in line with our PK projections from animals. We're -- Dae Gon, we're not going to disclose all the dosing cohorts, but it's a pretty typical dose level strategy. And we can continue to go above 1. And it's possible, for example, that we could go up to 2.5, where we've seen one of these events with a different route of administration. So one potential hypothesis, for example, is that Cmax may be a contributor. We don't have preclinical data suggesting that, but it's seen with other molecules, and we're giving the molecule IV. And we may ultimately want to test whether there's a difference at doses we've tested IV with the subcutaneous dose. So...

是的。我們將在某個時候發布這兩種分子的一些藥代動力學數據，但 043 大致符合我們對動物的 PK 預測。我們 - Dae Gon，我們不會透露所有劑量組，但這是一個非常典型的劑量水平策略。我們可以繼續超過 1。例如，我們有可能達到 2.5，我們已經看到其中一個事件具有不同的給藥途徑。因此，例如，一個潛在的假設是 Cmax 可能是一個貢獻者。我們沒有臨床前數據表明這一點，但它與其他分子一起出現，我們正在給分子 IV。我們可能最終想要測試我們測試過的劑量與皮下劑量是否存在差異。所以...

Our next question comes from Hannah Adeoye with JPMorgan.

我們的下一個問題來自摩根大通的 Hannah Adeoye。

It's Hannah on for Eric. Just a few from us. Have you commented on the half-life of 1326 before? And if so, are you able to speak to any of the expected dosing regimens or frequency for a multiple ascending dose study based on your preclinical and clinical findings thus far? I guess, generally, I'm trying to see what gives you comfort that the AEs you've observed initially...

埃里克是漢娜。就我們幾個。之前評論過1326的半衰期嗎？如果是這樣，您能否根據您迄今為止的臨床前和臨床發現，談談任何預期的給藥方案或多次遞增劑量研究的頻率？我想，一般來說，我想看看是什麼讓您對您最初觀察到的 AE 感到安慰......

Hannah, I couldn't hear that, I don't know if others could.

漢娜，我聽不到，我不知道其他人是否可以。

Okay. I can repeat. I was saying, have you guys commented on the half-life of 1326? And are you able to speak to any expected dosing regimens or frequencies for a multiple ascending dose study based on your preclinical and clinical findings thus far? Just trying to see if there's any data points to give you comfort that the AEs that you've observed thus far won't be seen over longer dosing intervals? Were you able to get that?

好的。我可以重複。我是說，你們評論過1326的半衰期嗎？根據您迄今為止的臨床前和臨床發現，您是否能夠說出任何預期的劑量遞增研究的給藥方案或頻率？只是想看看是否有任何數據點可以讓您放心，到目前為止您觀察到的 AE 不會在更長的給藥間隔內出現？你能得到嗎？

One moment, please, the conference will begin momentarily. Go ahead, Hannah.

請稍等，會議馬上就要開始了。去吧，漢娜。

Can you guys hear me now?

你們現在能聽到我說話嗎？

Yes.

是的。

Just was asking about the half-life of 1326 and your expected dosing regimen or frequencies for a multiple ascending dose study.

只是詢問 1326 的半衰期以及您預期的多次遞增劑量研究的給藥方案或頻率。

The half-life is about -- for 1326, you're asking, correct?

半衰期大約是——對於 1326，你問的對嗎？

Yes.

是的。

The half-life is about 5 days. Keep in mind, though, that because there are a number of Wnt pathway target genes that are activated when you activate the pathway, the biological effects could be longer lasting than the -- what you might anticipate from the half-life of the antibody. And so it's not a straightforward align the PK with the frequency of dosing. So we think this could be in every other week or perhaps even less frequent dosing regimen. We have not finalized that yet for the Phase Ib portion. And obviously, we want to see all the human PK data at different dose levels. That half life, by the way, was in primates for 5 days.

半衰期約為 5 天。但請記住，因為有許多 Wnt 通路靶基因在您激活該通路時被激活，所以生物學效應可能比抗體半衰期預期的更持久。因此，將 PK 與給藥頻率直接對齊並不是一件容易的事。所以我們認為這可能是每隔一周或更不頻繁的給藥方案。我們還沒有最終確定 Ib 階段的部分。顯然，我們希望看到不同劑量水平下的所有人類 PK 數據。順便說一句，靈長類動物的半衰期為 5 天。

(Operator Instructions) Our next question comes from Yatin Suneja with Guggenheim.

（操作員說明）我們的下一個問題來自古根海姆的 Yatin Suneja。

Can you guys hear me?

你們能聽到我說話嗎？

Yes, you're coming in loud and clear.

是的，你的聲音響亮而清晰。

I can't hear him.

我聽不見他的聲音。

Craig, can you hear me now? Once I get signal from the company I'll ask the question.

克雷格，你現在能聽到我說話嗎？一旦我收到公司的信號，我就會提出問題。

Craig, please give us the word when you can hear us?

克雷格，請在你能聽到我們的時候告訴我們？

I can hear you. I can't hear Yatin.

我可以聽見你。我聽不到雅婷。

Now? Hello? I think we are able to hear. I don't know because the other line is able to hear. Chuck, can you hear us?

現在？你好？我想我們能夠聽到。我不知道，因為另一條線路能夠聽到。查克，你能聽到我們嗎？

I can hear you. Craig, can you hear Yatin?

我可以聽見你。克雷格，你能聽到 Yatin 嗎？

No.

不。

You can hear me?

你能聽到我？

Yes. Can you translate the question?

是的。你能翻譯這個問題嗎？

Why don't we do that.

我們為什麼不那樣做。

Let me ask the question, Chuck, do your best in translating. So with regard to 043, I think you mentioned that you have confirmed target engagement. Can you characterize that for us? Was there a dose response? And how do you feel about 0.5 dose? Is that sufficient to elect either a clinical or a biological activity? That's one. And maybe a similar question for the other one because I don't think you said for 1326, anything on the target engagement.

讓我問這個問題，Chuck，盡力翻譯。所以關於043，我想你提到你已經確認了目標交戰。你能為我們描述一下嗎？有劑量反應嗎？你覺得 0.5 劑量怎麼樣？這足以選擇臨床或生物活動嗎？那是一個。也許另一個問題是類似的問題，因為我不認為你說的是 1326，任何關於目標參與的事情。

Yes. So Craig, can you hear me?

是的。克雷格，你能聽到我說話嗎？

Yes.

是的。

Question is we mentioned that we've confirmed target engagement and there was a dose response. So I think for -- Yatin is asking actually for both programs, for 043 specifically, how do we feel about 0.5 and the biological activity that we might see? And a similar question as it relates to 1326?

問題是我們提到我們已經確認目標參與並且有劑量反應。所以我認為 - Yatin 實際上要求兩個程序，特別是 043，我們對 0.5 和我們可能看到的生物活動有何看法？還有一個與 1326 相關的類似問題？

And Yatin, I can't hear you, so make sure you let Chuck or others know that you can hear me. So as you noted -- you can hear me, okay. As you've noted, we've confirmed target engagement with 043, at least targeting ASGR1 receptor through ALP elevation. So these are not adversities. These are ALP elevation that results from blocking ASGR1, which is a scavenger receptor in the liver that takes ALP out of the circulation. I think your question is really about what kind of doses have we seen activity in animal models? And are we in the range with 0.5? And while we've typically employed higher doses in animal models, we think we're in a range that could be a therapeutically active dose, and then I'll just also make the observation that obviously, given that we had not seen any of these adversities in other species, other species may not be that translatable for predicting a dose response. So we're in the range, and I wouldn't be overly concerned or focused on the exact dose in the mouse translating to humans since the translatability for tox has not been there.

Yatin，我聽不到你說話，所以一定要讓 Chuck 或其他人知道你能聽到我說話。所以正如你所說 - 你可以聽到我的聲音，好吧。正如您所指出的，我們已經確認了與 043 的目標接觸，至少通過 ALP 升高來瞄準 ASGR1 受體。所以這些都不是逆境。這些是由於阻斷 ASGR1 而導致的 ALP 升高，ASGR1 是肝臟中的一種清道夫受體，可將 ALP 帶出循環。我認為您的問題實際上是關於我們在動物模型中看到了什麼樣的劑量？我們在 0.5 的範圍內嗎？雖然我們通常在動物模型中使用更高的劑量，但我們認為我們處於一個可能具有治療活性劑量的範圍內，然後我也會進行觀察，顯然，鑑於我們沒有看到任何其他物種的這些逆境，其他物種可能無法預測劑量反應。所以我們在這個範圍內，我不會過分關注或關注小鼠轉化為人類的確切劑量，因為 tox 的可轉化性還不存在。

For 1326, we do not have a target engagement assay, so we'll take getting into UC patients and biopsying the tissue to identify whether we've activated Wnt signaling. So in that situation, in that setting, we have an assay for a Wnt target gene called Axin2 which we'll look for to confirm that we've activated the pathway.

對於 1326，我們沒有目標參與分析，因此我們將進入 UC 患者並對組織進行活檢以確定我們是否激活了 Wnt 信號。因此，在那種情況下，在那種情況下，我們對稱為 Axin2 的 Wnt 靶基因進行了檢測，我們將尋找它來確認我們已經激活了該通路。

Got it. Maybe one more question, Chuck, if you can translate. This is -- so I think it seems like at this point, we cannot rule out whether this is the phenomenon that you're seeing at least on the liver-related AEs, is it target-specific? We cannot rule that out. However, you are saying that these damaged tissues might be more sensitive. So can you help us understand is there any threshold effect at certain doses you might not see. I'm just curious like what gives you confidence...

知道了。也許還有一個問題，查克，如果你能翻譯。這是 - 所以我認為在這一點上，我們不能排除這是否是您至少在肝臟相關 AE 上看到的現象，它是否針對特定目標？我們不能排除這種可能性。但是，您是說這些受損組織可能更敏感。那麼您能否幫助我們了解在某些您可能看不到的劑量下是否存在任何閾值效應。我只是好奇是什麼給了你信心......

Chuck, I can't hear anyone still.

查克，我仍然聽不到任何人的聲音。

Yes, these damaged tissues are more sensitive.

是的，這些受損組織更敏感。

Craig, can you hear me?

克雷格，你能聽到我說話嗎？

Yes.

是的。

Okay. So he -- Yatin's question has to do with -- we can't -- at this point, you can't really rule out the liver issues are target-specific, and seeing that the damage might be more sensitive, is there any threshold effect at certain doses that we've seen or might see based on the data we've collected?

好的。所以他 - Yatin 的問題與 - 我們不能 - 在這一點上，你不能真正排除肝臟問題是針對特定目標的，並且看到損害可能更敏感，有沒有根據我們收集的數據，我們已經看到或可能看到的某些劑量的閾值效應？

So to answer the first part of your question, Yatin, this does seem to be a liver-specific effect while our SZN-1326 is targeting Frizzled5, which is enriched in the intestinal epithelium in ulcerative colitis patients. It is expressed on hepatocytes. So that would be consistent with an effect that's similar to 043, meaning they're both hitting liver to some extent. And I think, as to your -- the second question, I think, is what -- how do we find the therapeutic index? Is there -- what's the likelihood of finding a therapeutic index. And again, I think we have to be cautious about extrapolating too much from the animal models.

所以要回答你問題的第一部分，Yatin，這似乎確實是一種肝臟特異性效應，而我們的 SZN-1326 靶向的是 Frizzled5，它在潰瘍性結腸炎患者的腸上皮中富含。它在肝細胞上表達。因此，這將與類似於 043 的效果一致，這意味著它們都在某種程度上擊中了肝臟。我認為，關於你的——第二個問題，我想，是——我們如何找到治療指數？有沒有——找到治療指數的可能性有多大。再一次，我認為我們必須謹慎，不要從動物模型中推斷出太多。

As I've emphasized, I think the robust nature of the response in multiple different animal models for both molecules, the consistency of that response across experiments and across different types of injury, I think is very compelling evidence of the pharmacology and the biological rationale, but I wouldn't get too focused on the exact doses that we tested in animals. And I think if this is a Wnt-related effect related to regeneration, in the healthy liver, it may be, and I don't -- we don't have data to support this hypothesis right now, but it may be that the damaged liver, because there is some active regeneration ongoing will really just display the benefits of regeneration and not these bumps in transaminase, but we'll just have to see what the data says in humans. I don't think we have any preclinical data to exactly answer that question.

正如我所強調的，我認為這兩種分子在多種不同動物模型中反應的穩健性，這種反應在實驗和不同類型損傷中的一致性，我認為是藥理學和生物學原理的非常有說服力的證據，但我不會過於關注我們在動物身上測試的確切劑量。而且我認為如果這是與再生相關的 Wnt 相關效應，在健康的肝臟中，它可能是，而且我不知道 - 我們現在沒有數據支持這個假設，但可能是受損的肝臟，因為正在進行一些活躍的再生，實際上只會顯示再生的好處，而不是轉氨酶的這些顛簸，但我們只需要看看數據對人類的影響。我認為我們沒有任何臨床前數據可以準確回答這個問題。

Thank you. And this concludes the Q&A session. I'd now like to turn the call back over to Craig Parker for any closing remarks.

謝謝。問答環節到此結束。我現在想把電話轉回克雷格帕克，聽取任何結束語。

All right. Well, thanks, Josh, and thanks, Surrozen team for joining me, and thank you all for joining the call and for your interest. I apologize that we had a little bit of a phone game for me to be able to hear questions. But thank you again for your participation and look forward to hearing from you in the future.

好的。好吧，謝謝 Josh，也謝謝 Surrozen 團隊加入我的行列，感謝大家加入電話會議並表達您的興趣。很抱歉，我們有一些電話遊戲讓我能夠聽到問題。但再次感謝您的參與，並期待將來收到您的來信。

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.

謝謝。今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。