Spyre Therapeutics Inc (SYRE) 2018 Q4 法說會逐字稿

Greetings, and welcome to the fourth quarter 2018 corporate update and earnings call. (Operator Instructions) As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Mr. David Calusdian. Thank you, Mr. Calusdian. You may begin.

您好，歡迎參加 2018 年第四季公司更新及財報電話會議。（操作員指示）謹此提醒，本次會議正在錄製中。現在我想將會議交給東道主戴維·卡魯斯迪安先生。謝謝你，卡盧斯迪安先生。你可以開始了。

Well, welcome to Aeglea BioTherapeutics Corporate Update and Earnings Conference Call. After management's prepared remarks, they will be available to take your questions.

歡迎來到 Aeglea BioTherapeutics 公司最新動態與收益電話會議。管理層準備好發言後，他們將可以回答您的問題。

Before we begin, please note that today's call may include a number of forward-looking statements, including comments on the company's business strategy, strengths and priorities; the timing, plans and success of clinical trials and related data; the timing of announcements and updates relating to clinical trials and related data; the safety, therapeutic benefits and economic value of product candidates; the advancement of technologies and proprietary product candidates; regulatory pathways for development programs; the success of collaborations; the competitive landscape for product candidates; trends with respect to revenues, expenses and cash flows; the company's ability to fund research and development programs; and its ability to manage costs, along with the uses of cash and other matters. These forward-looking statements are based on assumptions that are subject to risks and uncertainties that could cause the company's actual results to differ significantly from those suggested by these statements. Given these risks and uncertainties, you should not place undue reliance on these forward-looking statements. Please refer to the company's Form 10-K, filed with the Securities and Exchange Commission on March 7, 2019, for some of the important risk factors that could cause its actual results to differ materially from expectations, including any forward-looking statements made on this call. Except as required by law, the company disclaims any obligation to publicly update or revise any forward-looking statements to account for or reflect events or circumstances that occur after this call. Also, please note that a presentation to accompany this call is available for download on the Events and Presentations page of the company's IR section of its website at www.aegleabio.com.

在我們開始之前，請注意，今天的電話會議可能包含一些前瞻性陳述，包括對公司業務策略、優勢和優先事項的評論；臨床試驗的時間、計劃和成功以及相關數據；與臨床試驗和相關數據相關的公告和更新的時間；候選產品的安全性、治療效果及經濟價值；技術和專有產品候選者的進步；發展計劃的監管途徑；合作的成功；產品候選者的競爭格局；收入、支出和現金流的趨勢；公司資助研發項目的能力；以及管理成本以及現金和其他事項的使用的能力。這些前瞻性陳述所基於的假設存在風險和不確定性，這些風險和不確定性可能導致公司的實際結果與這些陳述所建議的結果有顯著差異。鑑於這些風險和不確定性，您不應過度依賴這些前瞻性陳述。請參閱該公司於 2019 年 3 月 7 日向美國證券交易委員會提交的 10-K 表格，以了解可能導致其實際結果與預期存在重大差異的一些重要風險因素，包括關於這個電話。除法律要求外，本公司不承擔公開更新或修改任何前瞻性陳述以解釋或反映本次電話會議後發生的事件或情況的義務。另請注意，本次電話會議附帶的簡報可在該公司網站 www.aegleabio.com IR 部分的「活動和簡報」頁面下載。

I'll now turn the call over to Aeglea's Chief Executive Officer, Anthony Quinn. Dr. Quinn, please go ahead.

我現在將把電話轉給 Aeglea 的執行長 Anthony Quinn。奎因博士，請繼續。

Thank you, David, and good afternoon, everyone. Thank you for joining us. With me today are Charles York, our Chief Financial Officer; and Dr. Jim Wooldridge, our Chief Medical Officer. 2018 was a really successful year for Aeglea with substantial progress on a number of fronts and we've had a great start to 2019. In 2018, we made significant advances with our clinical programs for pegzilarginase in Arginase 1 Deficiency and oncology. We leveraged our unique drug-hunting capabilities to generate new pipeline programs for cystinuria and homocystinuria. We made significant progress in strengthening the company's balance sheet, which will allow us to continue to invest in our lead program and our pipeline.

謝謝大衛，大家下午好。感謝您加入我們。今天和我在一起的有我們的財務長查爾斯·約克 (Charles York)；以及我們的首席醫療官 Jim Wooldridge 博士。2018 年對 Aeglea 來說是非常成功的一年，在許多方面都取得了實質進展，我們為 2019 年有了一個良好的開端。2018 年，我們的聚乙二醇化酶治療精胺酸酶 1 缺乏症和腫瘤學的臨床計畫取得了重大進展。我們利用我們獨特的藥物搜尋能力來製定針對胱氨酸尿症和同型胱氨酸尿症的新管道計劃。我們在加強公司資產負債表方面取得了重大進展，這將使我們能夠繼續投資於我們的領先專案和管道。

As we look to 2019, the company is well positioned to advance both our programs and leverage our unique human enzyme design capabilities. We're continuing our investment in our lead product candidate, pegzilarginase; pipeline programs and accelerating our manufacturing activities. We've continued to build the team and our capabilities. We accelerated our plans to do our financing in 2019, and we closed an offering in February of this year, which resulted in total gross proceeds of $69 million, further strengthening our balance sheet and positioning us for success in 2019 and beyond.

展望 2019 年，該公司處於有利地位，可以推進我們的專案並利用我們獨特的人類酵素設計能力。我們將繼續投資我們的主要候選產品聚乙二醇化酶；管道計劃並加速我們的製造活動。我們繼續建立團隊和我們的能力。我們加快了 2019 年融資計劃，並於今年 2 月完成了發行，募集資金總額達 6,900 萬美元，進一步強化了我們的資產負債表，為我們在 2019 年及以後取得成功奠定了基礎。

We continued to build on the rapid progress we've made last year on our clinical experience with pegzilarginase in Arginase 1 Deficiency. The Phase I/II data continues to develop with 14 patients who have now completed 8 weeks of repeat dosing. We have an oral presentation at SIMD and will be providing an update on Phase I/II data at that meeting in Seattle, Washington in early April.

我們繼續以去年在聚乙二醇化酶治療精氨酸酶 1 缺乏症方面的臨床經驗取得的快速進展為基礎。I/II 期資料持續發展，14 名患者現已完成 8 週的重複給藥。我們在 SIMD 上進行了口頭報告，並將在 4 月初於華盛頓州西雅圖舉行的會議上提供 I/II 期數據的最新資訊。

As you all know, we have also been presenting studies on investigating the impact of arginine depletion with pegzilarginase in patients with advanced solid tumors. We have now completed enrollment in the single-agent expansion trials. We've also made good progress with our combination trial. Our early stage preclinical programs for homocystinuria and cystinuria, which address 2 more common rare diseases with significant unmet medical needs, also continued to advance forward with the initiation of the IND-enabling studies.

眾所周知，我們也一直在研究聚乙二醇精胺酸消耗對晚期實體腫瘤患者的影響。我們現已完成單藥擴展試驗的註冊。我們的組合試驗也取得了良好進展。我們針對同型半胱氨酸尿症和胱氨酸尿症的早期臨床前計畫也隨著 IND 支持研究的啟動而繼續推進，該計畫針對兩種更常見的罕見疾病，且醫療需求未得到滿足。

We're continuing to leverage our knowledge of biology, human metabolism and enzymology as we address diseases that have significant unmet medical needs. We're really excited about the opportunities ahead for our programs at Aeglea, and I'm very much looking forward to updating you on our progress as we move through 2019.

我們將繼續利用我們的生物學、人類新陳代謝和酵素學知識來解決醫療需求未被滿足的重大疾病。我們對 Aeglea 專案未來的機會感到非常興奮，我非常期待在 2019 年向您通報我們的最新進展。

I would now like to turn the call over to Jim, who will walk you through our 2018 achievements and also discuss our plans for 2019. Jim?

我現在想把電話轉給吉姆，他將向您介紹我們 2018 年的成就，並討論我們 2019 年的計劃。吉姆？

Thanks, Tony, and hello, everyone. As Tony mentioned, 2018 and the start of 2019 have been a productive and data-rich time at Aeglea in both rare disease and oncology. First, our -- with our lead investigational therapy, pegzilarginase for Arginase 1 Deficiency, we completed dosing on our Phase I/II clinical trial. Importantly, the data we generated in this study was clinical to and from the design of our pivotal Phase III PEACE trial.

謝謝托尼，大家好。正如 Tony 所提到的，2018 年和 2019 年初是 Aeglea 在罕見疾病和腫瘤學方面富有成效且數據豐富的時期。首先，我們主要的研究療法聚乙二醇精胺酸酶用於治療精胺酸酶 1 缺乏症，我們完成了 I/II 期臨床試驗的給藥。重要的是，我們在這項研究中產生的數據是我們關鍵的 III 期 PEACE 試驗設計的臨床數據。

While this was one of the biggest highlights, we also made important advances with our oncology trials in our pipeline molecules. In 2018, we completed enrollment to the single-agent Phase I trial in advanced solid tumors, including the cohort expansions in heavily pretreated patients with cutaneous melanoma, uveal melanoma and small cell lung cancer. In the fourth quarter, we presented interim clinical data at ESMO confirming the monotherapy safety profile and demonstrating antitumor activity with pegzilarginase in heavily pretreated patients with melanoma.

雖然這是最大的亮點之一，但我們在管道分子的腫瘤學試驗中也取得了重要進展。2018年，我們完成了晚期實體瘤單藥 I 期試驗的入組，包括對經過深度治療的皮膚黑色素瘤、葡萄膜黑色素瘤和小細胞肺癌患者進行隊列擴展。第四季度，我們在 ESMO 上提交了中期臨床數據，證實了單一療法的安全性，並證明了聚乙二醇化酶在經過大量治療的黑色素瘤患者中具有抗腫瘤活性。

In December, we also completed the Phase Ib dose-escalation trial of pegzilarginase in combination with KEYTRUDA and initiated enrollment into Phase II. This Phase II study is designed to assess safety and efficacy in patients with extensive disease small cell lung cancer, who relapsed to progress following platinum-based chemotherapy. From our Phase I trial, we confirmed the safety profile was consistent with prior pegzilarginase monotherapy observations and a recommended pegzilarginase Phase II dose of 0.27 milligrams per kilogram was selected in combination with KEYTRUDA. More importantly, we observed clinical activity in the 9 patients treated at this dose level, including stable disease in 3 at 9 weeks and 1 partial response. We expect top line data from this trial in the first half of 2020.

12月，我們也完成了pegzilarginase合併KEYTRUDA的Ib期劑量遞增試驗，並啟動了II期入組。這項 II 期研究旨在評估患有廣泛疾病的小細胞肺癌患者的安全性和有效性，這些患者在鉑類化療後復發並進展。從我們的 I 期試驗中，我們確認安全性與先前的聚乙二醇化酶單藥治療觀察結果一致，並選擇了建議的聚乙二醇化酶 II 期劑量 0.27 毫克/公斤，與 KEYTRUDA 聯合使用。更重要的是，我們觀察到以該劑量水平治療的 9 名患者的臨床活性，其中 3 名患者在 9 週內病情穩定，1 名患者出現部分緩解。我們預計該試驗將於 2020 年上半年獲得頂線數據。

We continued to be excited about progress with our pipeline. In October, we presented preclinical data on AEB4104, our new pipeline program for homocystinuria that has the potential to dramatically lower plasma homocysteine levels. In a preclinical model of homocystinuria, AEB4104 led to improvement of significant disease-related manifestations, including improved survival. Also, in October, we presented data at the American Society of Nephrology highlighting the discovery and activity of a novel cystine-degrading enzyme based on a human scaffold. In a preclinical model of cystinuria, our cystine-degrading candidate reduced plasma and urine cystine levels, inhibited crystal formation in urine and was accompanied by reduced kidney stone formation. We already started IND-enabling activities for both of these pipeline programs, and we look forward to bringing both programs toward the clinics in 2020.

我們繼續對管道的進展感到興奮。10 月，我們公佈了 AEB4104 的臨床前數據，這是我們治療同型半胱氨酸尿症的新管道項目，有可能顯著降低血漿同型半胱氨酸水平。在同型半胱氨酸尿症的臨床前模型中，AEB4104 改善了與疾病相關的顯著症狀，包括提高了存活率。此外，十月份，我們在美國腎臟病學會上發表了數據，強調了基於人體支架的新型胱胺酸降解酶的發現和活性。在胱胺酸尿症的臨床前模型中，我們的胱胺酸降解候選藥物降低了血漿和尿液中的胱胺酸水平，抑制了尿液中的結晶形成，並減少了腎結石的形成。我們已經開始為這兩個管道計畫啟動 IND 活動，我們期待在 2020 年將這兩個計畫推向臨床。

Turning now to pegzilarginase for Arginase 1 Deficiency. We announced in December the design of our global pivotal Phase III PEACE study, which we aligned a feedback from FDA and EMA. PEACE stands for Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints and is a global randomized and double-blind trial designed to assess the effects of pegzilarginase versus placebo over 24 weeks. So primary endpoint is plasma arginine reduction and secondary endpoints includes mobility and adaptive behavior as assessments of clinically meaningful effects in addition to safety and pharmacokinetics.

現在轉向聚乙二醇精氨酸酶來治療精氨酸酶 1 缺乏症。我們在 12 月宣布了全球關鍵 III 期 PEACE 研究的設計，我們根據 FDA 和 EMA 的回饋進行了調整。PEACE 代表 Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints，是一項全球隨機雙盲試驗，旨在評估 Pegzilarginase 與安慰劑在 24 週內的效果。因此，主要終點是血漿精氨酸減少，次要終點包括活動性和適應性行為，作為除安全性和藥物動力學之外的臨床有意義的影響的評估。

At the end of last year, we released guidance that we expect to dose the first patient on the PEACE trial in the second quarter of 2019. And we are on track to meet this milestone.

去年年底，我們發布了指導意見，預計將於 2019 年第二季度對 PEACE 試驗的第一位患者進行給藥。我們有望實現這一里程碑。

As we've discussed before, pegzilarginase is highly effective in reducing plasma arginine levels. Data from the Phase I/II studies support a weekly dose of 0.1 milligrams per kilogram, which should establish rapid control of plasma arginine in the PEACE trial. In the Phase I/II trial, reductions in plasma arginine levels were accompanied by improvements in important disease-related abnormalities after only 8 weeks of repeat dosing. Given the importance of good plasma arginine control, it's anticipated that the proportion of clinical responders will increase with longer treatment in that trial. Insights from standardized clinical assessments and feedbacks we've received from physicians and caregivers indicate that the assessments of mobility and adaptive behavior are ideally suited to capture the clinical benefits of pegzilarginase.

正如我們之前討論的，聚乙二醇精氨酸酶在降低血漿精氨酸水平方面非常有效。I/II 期研究的數據支持每週每公斤 0.1 毫克的劑量，這應該在 PEACE 試驗中建立對血漿精氨酸的快速控制。在 I/II 期試驗中，重複給藥僅 8 週後，血漿精胺酸水平降低，重要的疾病相關異常得到改善。鑑於良好的血漿精胺酸控制的重要性，預計臨床反應者的比例將隨著該試驗中治療時間的延長而增加。我們從醫生和護理人員那裡收到的標準化臨床評估和回饋的見解表明，對活動性和適應性行為的評估非常適合捕捉聚乙二醇化酶的臨床益處。

In summary, 2018 was a highly productive year and we look forward to a successful 2019 with initiation of the PEACE trial, advancing our combination study with KEYTRUDA in small cell lung cancer and bringing our 2 exciting pipeline programs closer to the clinics.

總而言之，2018 年是富有成效的一年，我們期待 2019 年取得成功，啟動 PEACE 試驗，推進我們與 KEYTRUDA 聯合治療小細胞肺癌的研究，並使我們的 2 個令人興奮的管道項目更接近臨床。

Furthermore, we are confident and excited with the PEACE trial design, and we expect the data from this trial will be sufficient to support marketing applications for pegzilarginase in Arginase 1 Deficiency.

此外，我們對 PEACE 試驗設計充滿信心和興奮，我們預計該試驗的數據將足以支持聚乙二醇精氨酸酶在精氨酸酶 1 缺乏症中的營銷應用。

With that, I'll turn the call over to Charles to discuss the financials.

這樣，我會將電話轉給查爾斯，討論財務問題。

Thanks, Jim, and good afternoon, everyone. As Anthony discussed earlier, we took important steps to strengthen our balance sheet already in 2019 by completing a $69 million financing in early February. The net proceeds, which came from new and existing investors, provide us with pro forma cash of approximately $139 million at December 31, 2018. More importantly, this capital is expected to provide Aeglea with cash runway through our PEACE pivotal trial readout in the first quarter of 2021.

謝謝吉姆，大家下午好。正如安東尼之前討論的那樣，我們在 2019 年就採取了重要措施來強化我們的資產負債表，並在 2 月初完成了 6900 萬美元的融資。截至 2018 年 12 月 31 日，來自新投資者和現有投資者的淨收益為我們提供了約 1.39 億美元的預計現金。更重要的是，這筆資金預計將透過我們在 2021 年第一季公佈的 PEACE 關鍵試驗結果為 Aeglea 提供現金跑道。

Regarding our 2018 financials, we continued to invest in key rare disease and cancer programs at Aeglea, which we believe will be the foundation of our long-term success. We recorded a net loss of $14.9 million or $0.62 per share in the fourth quarter of 2018 compared to a net loss of $6.5 million or $0.39 per share on $1.5 million of grant revenue in the fourth quarter of 2017. All 2018 and 2017 revenues at Aeglea were the result of our $19.8 million cancer research grant. That grant contract concluded in May of 2018 with the full $19.8 million of grant revenue recognized over the life of the award and the full cash balance received by year-end 2018.

關於我們 2018 年的財務狀況，我們繼續投資 Aeglea 的關鍵罕見疾病和癌症項目，我們相信這將成為我們長期成功的基礎。2018 年第四季，我們的淨虧損為 1,490 萬美元，即每股 0.62 美元，而 2017 年第四季的補助收入為 150 萬美元，淨虧損為 650 萬美元，即每股 0.39 美元。Aeglea 2018 年和 2017 年的所有收入均來自我們 1,980 萬美元的癌症研究補助金。該贈款合約於 2018 年 5 月簽訂，在贈款期限內確認了全額 1,980 萬美元的贈款收入，並於 2018 年底收到了全額現金餘額。

Operating expenses increased in 2018 given our strategy to drive forward with pegzilarginase in Arginase 1 Deficiency and concurrently develop additional product candidates.

鑑於我們的策略是推動聚乙二醇化酶治療精氨酸酶 1 缺乏症並同時開發其他候選產品，2018 年的營運費用增加。

Looking at R&D. Our fourth quarter 2018 R&D expense was $11.8 million versus $5.8 million in the fourth quarter of 2017.

著眼於研發。我們 2018 年第四季的研發費用為 1,180 萬美元，而 2017 年第四季為 580 萬美元。

And for G&A, our fourth quarter 2018 G&A expense was $3.5 million versus $2.3 million in the fourth quarter of 2017. The increase in operating expenses were primarily due to advancing the clinical development of our lead program, pegzilarginase; accelerate manufacturing and strengthening our product development capabilities.

對於一般管理費用，我們 2018 年第四季的一般管理費用為 350 萬美元，而 2017 年第四季為 230 萬美元。營運費用的增加主要是由於推進我們的主導計畫聚乙二醇化酶的臨床開發；加速製造並增強我們的產品開發能力。

During 2018, our expenses supported over enrolling our Phase I/II clinical trial in patients with Arginase 1 Deficiency, continuing our open label expansion trial in patients with Arginase 1 Deficiency, completing enrollment in our 3 solid tumor single-agent cohort expansion trials and completing enrollment in the Phase Ib combination trial in patients with small cell lung cancer.

2018 年期間，我們的費用支持了對精氨酸酶1 缺乏症患者進行I/II 期臨床試驗，繼續對精氨酸酶1 缺乏症患者進行開放標籤擴展試驗，完成3 個實體瘤單藥隊列擴展試驗的入組並完成入組小細胞肺癌患者的 Ib 期聯合試驗。

Now looking forward to 2019. We anticipate our burn will be in the range of $12 million to $15 million per quarter with the exception of the first quarter of 2019, where we anticipate our burn will be in the range of $15 million to $17 million, given our ramp in pipeline development and manufacturing activities for pegzilarginase in Arginase 1 Deficiency. And the pro forma cash of approximately $139 million at December 31, 2018, and extension of our cash runway through our PEACE pivotal trial readout in the first quarter of 2021 were important steps in strengthening our balance sheet.

現在期待2019年。我們預計每季的燒錢將在1200 萬美元至1500 萬美元之間，但2019 年第一季除外，考慮到我們在管道開發方面的增長，我們預計我們的燒錢將在1500 萬美元至1700萬美元之間以及針對精胺酸酶 1 缺乏症的聚乙二醇化酶的生產活動。截至 2018 年 12 月 31 日的預計現金約為 1.39 億美元，以及透過 2021 年第一季的 PEACE 關鍵試驗擴大我們的現金跑道，是加強我們資產負債表的重要步驟。

Additionally, the early data we've shared in homocystinuria and cystinuria continued to drive investment in both programs. We believe there is significant unmet medical need in both indications. And that we will benefit from a favorable market position where we own worldwide rights and most importantly, where we believe our assets are differentiated and compelling.

此外，我們在同型半胱氨酸尿症和胱氨酸尿症方面分享的早期數據繼續推動對這兩個項目的投資。我們認為這兩種適應症都存在大量未滿足的醫療需求。我們將受益於有利的市場地位，我們擁有全球權利，最重要的是，我們相信我們的資產具有差異化和引人注目的優勢。

I will now turn the call back over to Anthony for some final remarks.

現在我將把電話轉回給安東尼，讓他做最後的評論。

Thanks very much, Charles. So in closing, we believe we are really very well positioned to make meaningful progress towards our goal of providing transformative therapies to patients living with devastating diseases. And we're very appreciative of all the hard work of our employees and also importantly, the support that we get from patients, caregivers and investigators that are involved in our clinical trials. We're really excited by the multiple 2019 milestones ahead and very much looking forward to sharing these updates with you as we actually course through 2019.

非常感謝，查爾斯。因此，最後，我們相信我們確實處於有利位置，可以在向患有毀滅性疾病的患者提供變革性治療的目標方面取得有意義的進展。我們非常感謝員工的辛勤工作，更重要的是，我們從參與臨床試驗的患者、照護者和研究人員那裡得到的支持。我們對 2019 年即將到來的多個里程碑感到非常興奮，並且非常期待在 2019 年實際進程中與您分享這些更新。

We'll now open the call to questions. Operator, can you go ahead? Thank you.

我們現在開始提問。接線員，可以繼續嗎？謝謝。

(Operator Instructions) Our first question comes from the line of Josh Schimmer of Evercore ISI.

（操作員說明）我們的第一個問題來自 Evercore ISI 的 Josh Schimmer。

As the INDs for the cystinuria and homocystinuria programs approach, maybe you can give us a sense of how you expect each one of those to evolve? What the pivotal end points might look like? When you might be able to establish initial clinical proof of concept?

隨著胱胺酸尿症和高胱胺酸尿症項目 IND 的臨近，也許您可以讓我們了解一下您期望其中每一個項目如何發展？關鍵終點可能是什麼樣的？什麼時候能夠建立初步的臨床概念證明？

Okay. Josh, great, thanks for the question. So let me start with homocystinuria program. Obviously, we presented very exciting data at the end of last year showing that we have an enzyme at large homocysteine levels in a disease model that creates disease-related abnormalities and improved survival. So in homocystinuria -- and there's actually a lot of information linking homocysteine levels -- good control of homocysteine levels to control of the disease complications. So that's fairly well established. It's not a surrogate endpoint, and obviously, we're going to have to have some discussion with the regulatory authorities. But the evidence is available, it's pretty compelling about the importance of controlling homocysteine levels. It's a rare disease and we expect basically to go into the patient population, which means that we will get that readout of homocysteine modeling effects relatively early in the development program. What I really like about these models in the rare disease though is that the translatability of what you see in the animal model to what you're going to see in humans is very high. So we actually have a lot of confidence as we move forward with our homocystinuria program. So for cystinuria -- cystinuria actually is on the FDA's list of surrogate endpoints. So that's actually a great place to start. We've come up -- obviously, we've got a very novel approach. We've got some very compelling data showing by lowering plasma levels of cysteine, we lower urine levels, we inhibit crystallization, we inhibit stone formation and again, sampling highly translatable animal models, so therefore, we would expect, and the observation that we've seen in the model, high probability of seeing that as we carry over into humans. And obviously, we have given some guidance with our timelines. So for homocystinuria, we're guiding that we will actually anticipate having an IND filed in the first quarter of 2020 and then for cystinuria we're guiding the IND in the second half of 2020.

好的。喬什，太好了，謝謝你的提問。讓我從同型半胱氨酸尿症計劃開始。顯然，我們在去年年底提供了非常令人興奮的數據，表明我們在疾病模型中具有高同型半胱氨酸水平的酶，可以產生與疾病相關的異常並提高生存率。因此，在同型半胱氨酸尿症中，實際上有許多與同型半胱氨酸水平相關的資訊，良好控制同型半胱氨酸水平可以控制疾病併發症。所以這是相當確定的。這不是替代終點，顯然，我們必須與監管機構進行一些討論。但有證據表明，控制同型半胱氨酸水平的重要性非常令人信服。這是一種罕見的疾病，我們預計基本上會進入患者群體，這意味著我們將在開發計劃的相對早期階段獲得同型半胱氨酸建模效應的讀數。不過，我真正喜歡這些罕見疾病模型的地方在於，你在動物模型中看到的內容與你將在人類中看到的內容的可轉換性非常高。因此，當我們推進同型半胱氨酸尿症計劃時，我們實際上充滿信心。因此，對於胱胺酸尿症，胱胺酸尿症實際上已在 FDA 的替代終點清單中。所以這其實是一個很好的起點。顯然，我們已經提出了一種非常新穎的方法。我們得到了一些非常令人信服的數據，表明通過降低半胱氨酸的血漿水平，我們可以降低尿液水平，我們抑制結晶，我們抑制結石形成，並且再次採樣高度可轉化的動物模型，因此，我們期望，並觀察到我們我們已經在模型中看到，當我們將其應用到人類身上時，很有可能會看到這一點。顯然，我們已經就時間表提供了一些指導。因此，對於同型半胱氨酸尿症，我們預計將在 2020 年第一季提交 IND，然後對於胱胺酸尿症，我們將在 2020 年下半年提交 IND。

Our next question comes from the line of Matthew Luchini of BMO Capital Markets.

我們的下一個問題來自 BMO 資本市場的 Matthew Luchini。

This is Stephen on for Matthew. Could you give any color on responses from the SCLC cohort in the Phase I trial? Or maybe some timing on when we might see the data? And then because of the success of patient identification program for ARG1D, you guys said that the incidence may be greater than you initially thought. I was wondering if you had any update on that prevalence you thought there was.

這是史蒂芬替馬修發言。您能否對第一階段試驗中 SCLC 隊列的反應進行一些說明？或者也許我們什麼時候可以看到數據？然後因為ARG1D患者識別計畫的成功，你們說發病率可能比你們最初想像的還要高。我想知道您是否對您認為存在的流行率有任何更新。

Okay, so let's answer the questions in the order that you gave us. So I'm going to hand over to Jim and he will do the small cell lung cancer question.

好的，讓我們按照您給我們的順序回答問題。所以我會把任務交給吉姆，他將解決小細胞肺癌問題。

Yes -- so thanks for the question. Yes, so in patients with small cell lung cancer, we did not observe any responses, however, we did confirm the safety profile for the rest of the cohort. And we so we're really pleased that we are able to deliver that study as promised.

是的——謝謝你的提問。是的，因此在小細胞肺癌患者中，我們沒有觀察到任何反應，但是，我們確實確認了其餘隊列的安全性。我們非常高興能夠按照承諾進行這項研究。

And let me come back and talk about the Arginase 1 Deficiency population. So like any rare disease, the epidemiology is not particularly well understood. And we basically use an assessment that was done that used indirect data. So it used newborn screening data from some other urea cycle disorders. And then they extrapolated the number of arginase deficiency patients by considering the ratio of patients that were under followup with the urea cycle disorder consortium. We believe that gives us a solid base case, but it's likely to be on the conservative side and let me just remind you why we believe it's is on the conservative side. Arginase 1 Deficiency is different from other urea cycle disorders. There are actually very prominent neurological manifestations and less frequent hyperammonemic episodes. What that means is, there's actually a fairly high potential that arginase deficiency patients may not get the attention of metabolic physicians, so therefore would be underrepresented. So that's kind of where the number came from and with that number, we guided to at least 600 patients in the major addressable market. And a good analog is MPS VI. But what's really exciting me actually is that, look, everybody -- it's hard to find rare disease patients, we've already identified more than 170 patients with our efforts essentially confined largely to the U.S. and Europe. So 170 patients is more than 25% of the population we've guided to. And I know we're good at finding patients and we're continuing to get better. But I actually don't believe we're so good that we could have found 25% of the present population. So that's what speaks and gives us confidence that the number we initially guided to is on the conservative side. Does that help, Matt (sic) [Stephen]?

讓我回過頭來談談精胺酸酶 1 缺乏症族群。因此，與任何罕見疾病一樣，人們對流行病學的了解還不是特別透徹。我們基本上使用的是使用間接數據進行的評估。因此它使用了其他一些尿素循環障礙的新生兒篩檢數據。然後，他們透過考慮接受尿素循環障礙聯盟追蹤的患者比例，推斷出精胺酸酶缺乏症患者的數量。我們相信這給了我們一個堅實的基礎案例，但它可能是保守的，讓我提醒你為什麼我們認為它是保守的。精胺酸酶 1 缺乏症不同於其他尿素循環障礙。實際上有非常突出的神經系統表現和不太頻繁的高氨血症發作。這意味著，精胺酸酶缺乏症患者實際上很有可能得不到代謝醫師的關注，因此代表性不足。這就是這個數字的來源，透過這個數字，我們引導了主要目標市場中的至少 600 名患者。MPS VI 就是一個很好的模擬。但真正令我興奮的是，大家看，很難找到罕見疾病患者，我們已經發現了 170 多名患者，而我們的努力基本上主要局限於美國和歐洲。因此，170 名患者占我們指導人群的 25% 以上。我知道我們擅長尋找患者，而且我們正在不斷變得更好。但我其實不相信我們能強大到能夠找到目前人口的 25%。這就是讓我們相信我們最初指導的數字是保守的。這有幫助嗎，馬特（原文如此）[史蒂芬]？

Our next question comes from the line of Chad Messer of Needham & Company.

我們的下一個問題來自 Needham & Company 的 Chad Messer。

This is Gil on for Chad. Just a quick question. Could you remind us the reasoning behind the specific cancer types in the basket trial?

這是吉爾代表查德發言。只是一個簡單的問題。您能否提醒我們籃子試驗中特定癌症類型背後的原因？

Sure. Let's do that. So I'm going to ask Jim to walk you through the logic why we picked these particular tumor types. Jim?

當然。讓我們這樣做吧。因此，我將請吉姆向您介紹我們選擇這些特定腫瘤類型的邏輯。吉姆？

Yes, so thanks for the question, Gil. So as you recall, pegzilarginase is highly effective at depleting plasma arginine and some tumors are highly dependent on getting plasma arginine from the extracellular environment. And those cancers are driven by lack of expression of urea cycle enzyme called ASS1, argininosuccinate 1. And so the selection of our tumors with cutaneous melanoma, uveal melanoma and small cell lung cancer is the fact that each of those individual tumor types tends to have very low expression of ASS1 in a significant proportion of patients. And as you'll recall from our ESMO publication, not only do we show single-agent activity with 1 partial response in 8 stable diseases in the cutaneous and uveal melanoma cohorts, but we also saw a signal of more of that activity being concentrated in the ASS1 population.

是的，謝謝你的提問，吉爾。正如您所記得的，聚乙二醇精氨酸酶在消耗血漿精氨酸方面非常有效，並且一些腫瘤高度依賴於從細胞外環境中獲取血漿精氨酸。這些癌症是由尿素循環酶 ASS1、精氨琥珀酸 1 的表達缺乏引起的。的患者中ASS1 表現非常低。正如您從我們的ESMO 出版物中回想起的那樣，我們不僅在皮膚和葡萄膜黑色素瘤隊列中的8 種穩定疾病中顯示出具有1 種部分緩解的單藥活性，而且我們還看到了更多此活性集中在ASS1 群體。

Thank you very much for the clarifications. Could you give any additional color about any discussions going on with PRV for AEB?

非常感謝您的澄清。您能否對與 PRV 正在進行的 AEB 討論提供更多資訊？

Could you repeat the question, please?

請您重複一下這個問題好嗎？

I was asking about the potential for pediatric review voucher, if there is any additional color on it?

我問的是兒科檢查憑證的潛力，上面是否有其他顏色？

Yes, no, that's an important question. Yes, so we basically have rare pediatric disease designation, so the FDA has recognized that we have rare pediatric designation. The implications of that is that once we get approval with this drug, then we would be eligible for the -- we are eligible for the pediatric voucher, but the pediatric voucher is not given to you until you get approval of your drug.

是的，不，這是一個重要的問題。是的，所以我們基本上有罕見兒科疾病指定，因此 FDA 已經認可我們有罕見兒科疾病指定。這意味著，一旦我們獲得這種藥物的批准，那麼我們就有資格獲得——我們有資格獲得兒科優惠券，但在您獲得藥物批准之前，不會向您提供兒科優惠券。

(Operator Instructions) Our next question comes from the line of Matthew Cross of H.C. Wainwright (sic) [JonesTrading Institutional Services].

（操作員說明）我們的下一個問題來自 H.C. 的 Matthew Cross。溫賴特（原文如此）[瓊斯交易機構服務]。

Appreciate the update here. Had a couple of quick questions for you. So to start off, you mentioned completion of the Phase Ib, then moving into Phase II here. So couple of sub-questions in this one. First, given that the combination is proven pretty tolerable but responses are still pretty limited, how comfortable are you in the FDA with this 0.27 milligram per kilogram dose and not further escalating to test the limits of both safety and efficacy? And then the second part is, with no observed objective responses, but also no surprised safety signals compared to the monotherapy in small cell as Jim just reiterated, can you kind of recap your thinking on the rationale for moving toward into a Phase II without stronger signals at this point?

感謝這裡的更新。有幾個簡單的問題想問你。首先，您提到完成第一階段，然後進入第二階段。這其中有幾個子問題。首先，鑑於該組合已被證明具有相當的耐受性，但反應仍然相當有限，FDA 是否願意接受每公斤 0.27 毫克的劑量，而不進一步升級以測試安全性和有效性的極限？然後第二部分是，沒有觀察到客觀反應，但與吉姆剛才重申的小細胞單一療法相比，也沒有令人驚訝的安全信號，您能否回顧一下您對在沒有更強的情況下進入第二階段的基本原理的想法此時有訊號嗎？

Okay. Jim, do you want to take that one?

好的。吉姆，你想拿那個嗎？

Yes, let me start Tony, you can add some extra color if I miss anything. But I think -- first of all, just looking at our monotherapy Phase I, obviously, we tested 3 cohorts, and as I previously mentioned, we did actually report out on monotherapy activity with our uveal melanoma and cutaneous melanoma cohorts. And as you know, small cell lung cancer is a really rapidly moving disease. It's particularly in the relapsed setting. And so I think that's really important to keep in mind. When we did our Phase Ib study, we didn't actually observe any dose-limiting toxicities by protocol defined criteria. However, since our Phase I study in the other tumors actually demonstrated significant arginine depletion over a range of doses, we believe the tolerability would be actually quite a bit better at that 0.27 dose. And actually, this was both confirmed in the Phase I study and now it's what we're pulling through into our Phase II. So actually, we're looking pretty forward to capturing that.

是的，讓我開始吧，托尼，如果我錯過了什麼，你可以添加一些額外的顏色。但我認為，首先，看看我們的單一療法一期，顯然，我們測試了 3 個隊列，正如我之前提到的，我們實際上報告了葡萄膜黑色素瘤和皮膚黑色素瘤隊列的單一療法活動。如您所知，小細胞肺癌是一種發展迅速的疾病。尤其是在復發的情況下。所以我認為記住這一點非常重要。當我們進行 Ib 期研究時，我們實際上沒有根據方案定義的標準觀察到任何劑量限制毒性。然而，由於我們對其他腫瘤的 I 期研究實際上證明了在一定劑量範圍內精氨酸的顯著消耗，因此我們相信 0.27 劑量的耐受性實際上會更好。事實上，這一點在第一階段研究中都得到了證實，現在我們正在進入第二階段研究。所以實際上，我們非常期待捕捉到這一點。

Okay. And then just stepping back looking strategically, I just want to remind people, especially who may be new to the story, so when we started off with pegzilarginase, we had a human modified enhanced enzyme and enhanced arginase activity. We were looking at Arginase 1 Deficiency. And then there has been interest for some time about arginine depletion as an innovative approach for managing cancers. So obviously, what we're driving forward with pegzilarginase in Arginase 1 Deficiency, we're obviously starting a Phase III study, the approval in the rare disease is quick relative to oncology. As somebody mentioned earlier, we are eligible for the pediatric voucher. And obviously, there are other advantages within the orphan designation. And at the same time, we obviously are completing our activities in oncology. As Jim said, we have demonstrated single-agent activity and we've got compelling preclinical data showing that arginine depletion actually enhances the effect of various immuno-oncology approaches. We're actually looking at that in small cell cancer at the moment. And obviously, when we get our data, we will look at our data and then think carefully how best pegzilarginase fits in oncology space. But the good thing is we're actually driving forward in our rare disease program, so we complete momentum for our program.

好的。然後從戰略上退後一步，我只是想提醒人們，特別是那些可能對這個故事不熟悉的人，所以當我們開始使用聚乙二醇化酶時，我們有一種人類改良的增強酶和增強的精氨酸酶活性。我們正在研究精胺酸酶 1 缺乏症。一段時間以來，人們對精胺酸消耗作為治療癌症的創新方法產生了興趣。顯然，我們正在推動聚乙二醇化酶治療精氨酸酶 1 缺乏症，我們顯然正在開始一項 III 期研究，相對於腫瘤學而言，這種罕見疾病的批准速度很快。正如前面有人提到的，我們有資格獲得兒科優惠券。顯然，孤兒藥指定還有其他優點。同時，我們顯然正在完成我們在腫瘤學方面的活動。正如吉姆所說，我們已經證明了單藥活性，並且我們已經獲得了令人信服的臨床前數據，表明精氨酸消耗實際上增強了各種免疫腫瘤學方法的效果。目前我們實際上正在研究小細胞癌。顯然，當我們獲得數據時，我們會查看數據，然後仔細思考聚乙二醇化酶如何最好地適應腫瘤學領域。但好處是我們實際上正在推動我們的罕見疾病項目，因此我們完成了我們項目的動力。

Got it. Okay. Appreciate that color from both of you guys. And just -- do we expect to see that combination results sometime in the near future or in conference?

知道了。好的。欣賞你們倆的顏色。只是——我們是否期望在不久的將來或在會議上看到這種組合的結果？

Yes, so the -- yes, the combination results we've got to having in the first half of next year.

是的，所以——是的，我們必須在明年上半年得到綜合結果。

Go it. Okay. And then pivoting over to Arginase 1 Deficiency. I was curious how much of pricing for perpetual Arginase 1 Deficiency as we're looking ahead to hopefully completing the PEACE trial in 2020? How much do you think of pricing being tied to patient functional outcomes versus arginase reduction in the PEACE trial given that the FDA has given you the greenlight here to set arginase reduction in the surrogate in measuring efficacy here? Just given that this is kind of -- it's been kind of a tight ropewalk for pricing rare disease drugs at high enough levels to be profitable without any kind of regulatory or political pushback. Just trying to get your thinking on that given the allowance that the regulators are granting you?

去吧。好的。然後轉向精氨酸酶 1 缺乏症。我很好奇永久性精胺酸酶 1 缺乏症的定價是多少，因為我們希望在 2020 年完成 PEACE 試驗？鑑於 FDA 已批准您在衡量療效的替代品中設定精氨酸酶減少量，您認為 PEACE 試驗中的定價與患者功能結果與精氨酸酶減少量的關係有多大？考慮到這有點像——將罕見疾病藥物定價在足夠高的水平上，以便在沒有任何監管或政治阻力的情況下實現盈利。考慮到監管機構給您的津貼，只是想了解您對此的想法？

Yes, okay. So just -- look, this is a -- Arginase 1 Deficiency is a devastating disease. The kids are affected with this in early childhood. They kind of look like kids have cerebral palsy in terms of motor and mobility problems they have. But unlike kids with cerebral palsy, the neurological complications progress and patients die early. We haven't found many patients over the age of 50 and they end up with very severe, irreversible neurological complications and severe intellectual disability. So this is a devastating disease. Second thing is that as we know for a number of years the importance of plasma arginine control, if it had been easy to control plasma arginine, then there would have been a therapy by now. And I think what's very exciting about what we've been able to achieve is we have -- pegzilarginase is transformative in its ability to control plasma arginine levels. Now the final piece of the jigsaw is that what I am really excited about, this is a neurological disease. The fact that we've actually -- within 8 weeks of lowering plasma arginine levels, we are actually seeing these very impactful improvements in the patients in terms of their mobility and adaptive behavior. And it's very compelling. And obviously, that's one of the reasons why we have dosing for 6 months in the pivotal is so that we can actually look more at these clinical benefits that we're already seeing within 8 weeks. So the bottom line is I'm -- we're confident we're going to see clinical benefits. We've got plasma arginine reduction as the primary endpoint. We've actually powered the study to see a 40% difference between active and placebo, and we're confident that we will actually have that package. Now just to step back and remind you, pegvaliase, which is approved for phenylketonuria, which is obviously a recent drug that has been approved and obviously priced, that drug actually only lowers phenylalanine levels and in their clinical trial, they actually weren't able to demonstrate any clinical benefit. So it's kind of worthwhile looking at that in the context. But obviously, I'm very excited to see the clinical benefit we're seeing already. Agree?

是的，好的。所以，看，這是一種精氨酸酶 1 缺乏症，是一種毀滅性的疾病。孩子在幼兒期就會受到這種影響。從他們的運動和行動問題來看，他們看起來有點像是腦性麻痺的孩子。但與腦性麻痺兒童不同的是，神經系統併發症會惡化，患者會過早死亡。我們還沒有發現很多50歲以上的患者，他們最終會出現非常嚴重的、不可逆的神經系統併發症和嚴重的智力障礙。所以這是一種毀滅性的疾病。第二件事是，我們多年來都知道血漿精胺酸控制的重要性，如果很容易控制血漿精胺酸，那麼現在就會有一種治療方法。我認為我們所取得的成就非常令人興奮的是，聚乙二醇化酶在控制血漿精胺酸水平方面具有變革性的能力。現在拼圖的最後一塊是我真正興奮的，這是一種神經系統疾病。事實上，在降低血漿精胺酸水平的 8 週內，我們實際上看到患者在活動能力和適應性行為方面取得了非常有影響力的改善。這非常引人注目。顯然，這就是我們在關鍵時刻給藥 6 個月的原因之一，以便我們實際上可以更多地了解我們在 8 週內已經看到的這些臨床益處。所以最重要的是我——我們有信心我們會看到臨床效益。我們將血漿精胺酸減少作為主要終點。事實上，我們已經推動了這項研究，發現活性藥物和安慰劑之間有 40% 的差異，我們相信我們實際上會擁有該方案。現在退後一步提醒您，pegvaliase，它被批准用於苯酮尿症，這顯然是最近才被批准且明顯定價的藥物，該藥物實際上只能降低苯丙氨酸水平，在他們的臨床試驗中，他們實際上無法證明任何臨床益處。因此，在上下文中考慮這一點是值得的。但顯然，我很高興看到我們已經看到的臨床益處。同意？

Yes, I'm very much looking forward to it and see how things play out, and I appreciate that comparison for context.

是的，我非常期待它並看看事情會如何發展，並且我很欣賞這種背景比較。

(Operator Instructions) If there are no further questions over the portion of the conference, we will be concluding at this time. This concludes today's conference. Thank you for your participation. You may disconnect your lines at this time, and have a wonderful rest of your day.

（操作員指示）如果對會議的該部分沒有其他問題，我們將在此時結束。今天的會議到此結束。感謝您的參與。此時您可以斷開線路，享受美好的一天。