Arcturus Therapeutics Holdings Inc (ARCT) 2025 Q2 法說會逐字稿

Please stand by. Your program is about to begin. Good day everyone, and welcome to the Arcturus Therapeutics second quarter 2025 earnings call. (Operator Instructions) Please note this call is being recorded and I will be standing by should you need any assistance.

請稍候。您的程式即將開始。大家好，歡迎參加 Arcturus Therapeutics 2025 年第二季財報電話會議。（操作員指示）請注意，此通話正在錄音，如果您需要任何協助，我將隨時待命。

It is now my pleasure to turn the conference over to Neda Safarzadeh, Vice President, Head of investor Relations, Public Relations Marketing. Please go ahead.

現在我很高興將會議交給副總裁、投資者關係主管、公共關係行銷主管 Neda Safarzadeh。請繼續。

Thank you, operator. Good afternoon and welcome to Arcturus Therapeutics quarterly financial update and pipeline progress call. Today's call will be led by Joe Payne, our President and CEO, and Andy Sassine, our CFO. Dr. Pad Chivukula, our CSO and COO, will join them for the Q&A session.

謝謝您，接線生。下午好，歡迎參加 Arcturus Therapeutics 季度財務更新和管道進度電話會議。今天的電話會議將由我們的總裁兼執行長喬·佩恩 (Joe Payne) 和首席財務長安迪·薩辛 (Andy Sassine) 主持。我們的首席策略長兼營運長 Pad Chivukula 博士將參加問答環節。

Before we begin, I would like to remind everyone that the statements made during this call regarding matters that are not historical facts are forward looking statements between the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

在我們開始之前，我想提醒大家，本次電話會議中關於非歷史事實的陳述屬於 1995 年《私人證券訴訟改革法案》安全港條款之間的前瞻性陳述。

Forward-looking statements are not guarantees of performance. They involve known and unknown risks, uncertainties, and assumptions that may cause actual results, performance, and achievements to differ materially from those expressed or implied by this statement. Please see the forward-looking statement disclaimer on the company's press release issued earlier today, as well as the risk factor section in our most recent Form 10-K and in subsequent filings with the SEC. In addition, any forward-looking statements represent our views only as of the date such a statements are made. Arcturus specifically disclaims any obligation to update such statements.

前瞻性陳述並不保證業績。它們涉及已知和未知的風險、不確定性和假設，可能導致實際結果、表現和成就與本聲明明示或暗示的結果、表現和成就有重大差異。請參閱本公司今天稍早發布的新聞稿中的前瞻性聲明免責聲明，以及我們最新的 10-K 表格和隨後向美國證券交易委員會提交的文件中的風險因素部分。此外，任何前瞻性陳述僅代表我們做出該陳述之日的觀點。Arcturus 明確否認有更新此類聲明的義務。

And with that, I will now turn the call over to Joe.

現在，我將把電話轉給喬。

Thank you, Neda. It's good to be with you again, everybody. I will begin with our ARCT-032 program. This is our messenger RNA therapeutic candidate for cystic fibrosis.

謝謝你，Neda。很高興能再次和大家在一起。我將從我們的 ARCT-032 計劃開始。這是我們用於治療囊性纖維化的信使 RNA 候選治療藥物。

Arcturus is advancing enrollment of adult CF participants in the open label Phase 2 multiple ascending dose CF study with daily inhaled treatments of ARCT-032 over a period of 28 days. There is serious unmet medical need in the CF community, especially with those that do not qualify or benefit from CFTR modulator therapy. Our present Phase 2 trial is focused on enrolling subjects that do not benefit from modulators, including Class 1 or null CF participants.

Arcturus 正在推進開放標籤 2 期多劑量遞增 CF 研究的成年 CF 患者招募，該研究為期 28 天，每天接受 ARCT-032 吸入治療。CF 群體存在嚴重的未滿足的醫療需求，特別是那些不符合或無法從 CFTR 調節劑療法中受益的人。我們目前的第二階段試驗重點是招募那些無法從調節劑中受益的受試者，包括 1 類或無 CF 參與者。

We have completed the enrollment and dosing of all three participants in the 5 milligram cohort. After a safety review, we were permitted to proceed with enrolling the second cohort at the 10 milligram dose level. All six CF participants in this second cohort are expected to complete dosing in early September.

我們已經完成了 5 毫克組所有三名參與者的招募和給藥。經過安全審查後，我們獲準繼續招募第二批劑量為 10 毫克的患者。第二批 CF 患者全部六名預計將於 9 月初完成給藥。

Each participant in the second cohort receives 280 milligram of ARCT-032 over the span of 28 days. And dosing at this level for 28 consecutive days is differentiating. And it's attributed to our modification, design, and proprietary purification of our mRNA drug substance and to the novel chemical features of our optimized LUNAR delivery technology.

第二組的每位參與者在 28 天內接受 280 毫克 ARCT-032。連續 28 天以這種水平給藥是有區別的。這歸功於我們對 mRNA 藥物物質的修改、設計和專有純化，以及我們優化的 LUNAR 遞送技術的新穎化學特性。

The company expects to provide Phase 2 in term data from these first nine enrolled participants next month in September 2025, and we expect to complete enrollment for this study as planned by year end. Arcturus anticipates meetings with the FDA and regulatory agencies in the first half of 2026 to discuss the Phase 2 data and plans for pivotal trials, including the enrollment of adolescent and pediatric participants followed by Phase 3 initiation in 2026.

公司預計在2025年9月下個月提供首批9名入組參與者的第二階段臨床數據，我們預計將在年底前按計劃完成這項研究的入組工作。Arcturus 預計將於 2026 年上半年與 FDA 和監管機構舉行會議，討論第 2 階段數據和關鍵試驗計劃，包括招募青少年和兒科參與者，隨後於 2026 年啟動第 3 階段。

I'll now move on to our ARCT-810 program. This is our messenger RNA therapeutic candidate for ornithine transcarbamylase or OTC deficiency. In June, the company along with key opinion leaders announced positive interim data from two Phase 2 multiple dose studies conducted in the OTC program.

我現在要繼續討論我們的 ARCT-810 計畫。這是我們針對鳥氨酸轉氨甲酰酶或 OTC 缺乏症的信使 RNA 治療候選藥物。6 月，該公司與關鍵意見領袖共同宣布了 OTC 計畫進行的兩項 2 期多劑量研究的積極中期數據。

In each study and in the combined analysis of both Phase 2 studies, decreases in glutamine levels to within normal range were observed following multiple ARCT-810 administrations to participants who remained on their standard of care therapy. Mean ammonia levels were stable within the normal range following at least two doses of ARCT-810 and remained stable for approximately 28 days after completion of dosing.

在每項研究以及兩項 2 期研究的綜合分析中，對繼續接受標準治療的參與者多次使用 ARCT-810 後，觀察到谷氨酰胺水平下降至正常範圍內。服用至少兩劑 ARCT-810 後，平均氨水水平穩定在正常範圍內，並在服藥完成後約 28 天內保持穩定。

During the treatment phase and follow up, two out of three participants in the Phase 2 US study showed increases in relative ureogenesis function to levels observed in asymptomatic OTC deficient patients as measured by a newly developed and optimized 15 and ureogenesis assay.

在治療階段和追蹤期間，透過新開發和優化的 15 和尿液生成測定法測量，美國第 2 階段研究中的三分之二的參與者的相對尿液生成功能增加至無症狀 OTC 缺陷患者的水平。

The remaining participant demonstrated increased 15 and [centrum line] enrichment. The data taken together suggest improvement of urea cycle function in all three participants. This orthogonal support of data adds further confidence to the glutamine normalization data that we observed.

其餘參與者則表現出 15 和 [中線] 富集增加。綜合數據顯示三名參與者的尿素循環功能均已改善。這種正交數據支持進一步增強了我們觀察到的谷氨酰胺標準化數據的信心。

ARCT -810 was generally safe and well tolerated and single dose Phase 1/1B and multi-dose Phase 2 studies comprising 40 participants to date and including 20 OTC deficient participants. The company is preparing for meetings with the US FDA and other regulatory agencies to discuss the clinical significance of the observed biomarker changes in relation to the design of the Phase 3 pivotal trial and pediatric studies. Phase 3 biomarker and trial design alignment with the FDA and other regulatory agencies is expected in the first half of 2026.

ARCT-810 總體上是安全的，耐受性良好，單劑量 1/1B 期和多劑量 2 期研究迄今已涉及 40 名參與者，其中包括 20 名 OTC 缺乏的參與者。該公司正在準備與美國 FDA 和其他監管機構舉行會議，討論觀察到的生物標記變化對於 3 期關鍵試驗和兒科研究設計的臨床意義。預計將於 2026 年上半年與 FDA 和其他監管機構進行第 3 階段生物標記和試驗設計的協調。

I will now provide regulatory updates to our partnered COVID-19 vaccine, also known as KOSTAIVEF. A marketing authorization application to the United Kingdom's MHRA was filed by CSL, our partner, with an approval expected next month.

我現在將提供有關我們合作的 COVID-19 疫苗（也稱為 KOSTAIVEF）的監管更新。我們的合作夥伴 CSL 已向英國 MHRA 提交了上市許可申請，​​預計下個月獲得批准。

Moving to Japan, MDA applications were filed by Meiji Seika Pharma to the PMDA for the two-dose lipolyzed vaccine presentation and for the upcoming season's COVID variant update with anticipated approvals this fall.

在日本，明治製果製藥公司向 PMDA 提交了 MDA 申請，用於展示兩劑脂解疫苗和下一季的 COVID 變體更新，預計今年秋季獲得批准。

US BLA filing to the FDA remains on track for September, with an approval decision expected in 2026. And moving on to ARCT-2138. This is our next generation star seasonal flu vaccine candidate. Under our collaboration with CSL Seqirus, we conducted a Phase 1 study in 100 young adults and 35 older adults.

美國向 FDA 提交的 BLA 申請仍將於 9 月按計劃進行，預計 2026 年做出批准決定。繼續討論 ARCT-2138。這是我們的下一代明星季節性流感疫苗候選疫苗。我們與 CSL Seqirus 合作，對 100 名年輕人和 35 名老年人進行了第一階段研究。

All tested dose levels of ARCT-2138 were immunogenic against all four influenza strains as measured by a hemagglutinin inhibition assay in both age groups, demonstrating a modest dose response within that range of the tested doses. ARCT-2138 also induced anti-amino dose, antibody responses at all tested dose levels against all four influenza strains.

透過對兩個年齡組進行血凝素抑制試驗測量，所有測試劑量水平的 ARCT-2138 均對所有四種流感病毒株具有免疫原性，表明在測試劑量範圍內具有適度的劑量反應。ARCT-2138 在所有測試劑量水平下也針對所有四種流感病毒株誘導抗氨基劑量抗體反應。

The frequencies of unsolicited adverse events and medically attended adverse events were similar to comparator vaccines. No major safety concerns were raised from the study results.

未經請求的不良事件和需要醫療處理的不良事件的發生頻率與對照疫苗相似。研究結果並未引發重大安全問題。

Overall, the study showed the potential of our next generation star vaccine encoding eight antigens to induce an immune response in both young and older adults with a dose as low as 2 micro gram and was tolerable up to 20 micro gram.

總體而言，該研究表明，我們的下一代明星疫苗編碼了八種抗原，可以在年輕人和老年人中誘導免疫反應，劑量低至 2 微克，最高可達 20 微克。

Now, moving on to ARCT-2304. This is our next gen star vaccine candidate for Pandemic A/H5N1 Influenza virus, also known as the bird flu. In April, Arcturus received US FDA fast track designation for ARCT-2304. This is the program contracted with and funded by BARDA. This contract was highlighted by the HHS in their recent press release as a program that was not impacted by their new budget and vaccine policy.

現在，繼續討論 ARCT-2304。這是我們針對大流行性甲型 H5N1 流感病毒（也稱為禽流感）的下一代明星候選疫苗。今年 4 月，Arcturus 的 ARCT-2304 獲得了美國 FDA 的快速通道認證。這是與 BARDA 簽約並由其資助的項目。美國衛生與公眾服務部在最近的新聞稿中強調，這項合約是一項不受其新預算和疫苗政策影響的項目。

We've completed recruitment of 212 adults, including 80 participants over the age of 60 years old in a randomized placebo-controlled Phase 1 trial being conducted here in the US. All three tested dose levels, 1.5 micrograms, and 12 micrograms in the Phase 1 BARDA funded study were well tolerated, with the majority of reported solicited AEs being mild to moderate and short-lived.

我們已經完成了 212 名成年人的招募，其中包括 80 名 60 歲以上的參與者，該參與者將在美國進行一項隨機安慰劑對照的 1 期試驗。在 BARDA 資助的第一階段研究中，測試的所有三個劑量水平（1.5 微克和 12 微克）均具有良好的耐受性，報告的大多數不良反應均為輕度至中度且持續時間短暫。

No safety concerns were raised from the available clinical data. The results from this ongoing Phase 1 study are expected later this year. And before passing the call on to our CFO, we're very pleased to announce that Arcturus has appointed Dr. Moncef Slaoui as Chairman of the Board, which became effective as of July 1, 2025.

從現有的臨床數據來看，沒有出現安全問題。這項正在進行的第一階段研究的結果預計將於今年稍後公佈。在將電話轉交給我們的財務長之前，我們非常高興地宣布，Arcturus 已任命 Moncef Slaoui 博士為董事會主席，該任命自 2025 年 7 月 1 日起生效。

And with that, I'll now pass the call to Andy.

現在我將把電話轉給安迪。

Thank you, Joe, and good afternoon, everyone. The press release issued earlier today includes financial statements for the second quarter of 2025 and provides a summary and analysis of year over year performance. Please also reference our most recent Form 10-Q for more details on the financial performance.

謝謝你，喬，大家下午好。今天稍早發布的新聞稿包括 2025 年第二季的財務報表，並提供了同比業績的總結和分析。有關財務業績的更多詳細信息，請參閱我們最新的 10-Q 表。

As we announced on our last quarterly call in May, our restructuring plan is in the final stages of implementation as we continue to consolidate operation. We have streamlined our internal pipeline to focus on our OTC and cystic fibrosis program, which enabled us to extend our runway into 2028.

正如我們在 5 月的上次季度電話會議上宣布的那樣，隨著我們繼續鞏固運營，我們的重組計劃正處於實施的最後階段。我們精簡了內部管道，專注於 OTC 和囊性纖維化項目，這使我們能夠將業務延伸至 2028 年。

As I provide a summary of our financial results for the second quarter of 2025, please take note of the significant reduction in year over year and sequential operating expenses. Revenue for the three and six months ended June 30th, 2025 with $28.58 million respectively, representing decreases of $22.30 million dollars compared to the same period in 2024.

當我提供 2025 年第二季財務績效摘要時，請注意同比和連續營運費用的大幅減少。截至 2025 年 6 月 30 日的三個月和六個月的收入分別為 2,858 萬美元，與 2024 年同期相比減少 2,230 萬美元。

The declines were primarily driven by lower revenues from the CSL collaboration, reflecting lower supply agreement activity and amortization of the upfront payment as KOSTAIVE progresses toward global commercialization.

下降的主要原因是與 CSL 合作的收入減少，這反映出隨著 KOSTAIVE 走向全球商業化，供應協議活動減少以及預付款攤提減少。

Total operating expenses for the three months ended June 30, 2025 were $40 million compared with $71 million for the three months ended June 30, 2024. Total operating expenses for the six months ended June 30, 2025 were $86 million compared to $139 million in the prior year.

截至 2025 年 6 月 30 日的三個月的總營運費用為 4,000 萬美元，而截至 2024 年 6 月 30 日的三個月的總營運費用為 7,100 萬美元。截至 2025 年 6 月 30 日的六個月的總營運費用為 8,600 萬美元，而上一年為 1.39 億美元。

Research and development expenses were $29.6 million for the three months ended June 30th, 2025, compared with 58.7 million in the prior year. A significant decrease was primarily driven by lower manufacturing costs for our COVID, flu, and cystic fibrosis program and reduced clinical trial expenses for COVID and OTC.

截至 2025 年 6 月 30 日的三個月，研發費用為 2,960 萬美元，去年同期為 5,870 萬美元。大幅下降的主要原因是我們的 COVID、流感和囊性纖維化項目的製造成本降低以及 COVID 和 OTC 的臨床試驗費用減少。

Lower payroll and employee benefits also contributed to the decrease, which were partially offset by higher clinical costs for the CF following the ramp up of Phase 1 trials in 2025. Research and development expenses were $64.5 million for the six months ended June 30th, 2025 compared to $112.2 million in the prior year.

薪資和員工福利的降低也導致了這一下降，但隨著 2025 年第一階段試驗的增加，CF 臨床成本的增加部分抵消了這一下降。截至 2025 年 6 月 30 日的六個月，研發費用為 6,450 萬美元，而前一年為 1.122 億美元。

The decrease was primarily driven by lower manufacturing and clinical costs for the KOSTAIVE program, reflecting the program's transition from the development to commercial phase. Additional decreases resulted from lower payroll and benefit expenses and reduced facilities and equipment costs. These reductions were partially offset by higher clinical expenses for the cystic fibrosis program.

下降的主要原因是 KOSTAIVE 計劃的製造和臨床成本降低，反映了該計劃從開發階段向商業階段的過渡。其他減少是由於工資和福利支出減少以及設施和設備成本降低。這些減少的部分被囊性纖維化計畫的臨床成本增加所抵消。

General and administrative expenses were $10.3 million and $21.7 million for the three and six months ended June 30, 2025 respectively. Compared with $12.3 million and $27.2 million in the comparable period last year. The decreases in both periods were primarily due to reduced share-based compensation expense, as well as reduced head count and employee benefits. We expect general and administrative expenses to continue to decrease slightly during the next 12 months.

截至 2025 年 6 月 30 日的三個月及六個月的一般及行政費用分別為 1,030 萬美元及 2,170 萬美元。而去年同期分別為 1,230 萬美元和 2,720 萬美元。這兩個時期的下降主要是由於股權激勵費用減少以及員工人數和員工福利減少。我們預計未來 12 個月內一般及行政開支將繼續小幅下降。

With the three months ended June 30, 2025, our tourists reported a net loss of approximately $9.2 million or $0.34 per diluted share. Compared with a net loss of $17.2 million or $0.64 per diluted share in the three months into June 30, 2024.

截至 2025 年 6 月 30 日的三個月，我們的遊客報告淨虧損約為 920 萬美元，即每股攤薄虧損 0.34 美元。相比之下，截至 2024 年 6 月 30 日的三個月內，淨虧損為 1,720 萬美元，即每股虧損 0.64 美元。

Cash, Cash equivalents and restricted cash were $253.4 million as of June 30, 2025 and $293.9 million on December 31, 2024. Based on the current pipeline and the reallocation of resources to the cystic fibrosis and OTC programs, the cash run rate remains extended into 2028.

截至 2025 年 6 月 30 日，現金、現金等價物及受限現金為 2.534 億美元，截至 2024 年 12 月 31 日，現金、現金等價物及受限現金為 2.939 億美元。根據目前的研發線以及對囊性纖維化和非處方藥項目的資源重新分配，現金運行率將持續到 2028 年。

In summary, the company remains in a strong financial position and had the cash runway needed to achieve multiple near-term value creating milestones for both the therapeutic program. We look forward to an exciting second half of 2025 with upcoming clinical data readouts from both our therapeutics and vaccine programs.

總而言之，該公司仍然保持著強勁的財務狀況，並擁有實現治療計劃的多個近期價值創造里程碑所需的現金流。我們期待 2025 年下半年的激動人心，屆時我們將獲得治療和疫苗計畫的臨床數據。

I will now pass the call back to Joe.

我現在將把電話轉回給喬。

Thanks, Andy. Arcturus had a productive quarter, making excellent progress across our mRNA therapeutics and vaccines pipeline. We look forward to sharing two cohorts of Phase 2 CF data in September, and with that, let's turn the time over to the operator for questions.

謝謝，安迪。Arcturus 本季業績豐碩，我們的 mRNA 療法和疫苗產品線取得了顯著進展。我們期待在 9 月分享兩組第 2 階段 CF 數據，然後，讓我們將時間交給操作員來回答問題。

(Operator Instructions)

（操作員指示）

Lili Nsongo, Leerink Partners.

莉莉‧恩松戈 (Lili Nsongo)，Leerink 合夥人。

Hi, good afternoon. Thank you for taking my question. This is to CF related questions. So as we get closer to the readout, can you maybe give us a reassurance to how you think about the bar for success there and, in terms of the patients that have already been enrolled, could you give us a little more granularity in terms of the ratio of modular eligible to non-eligible patients? Thank you.

嗨，下午好。感謝您回答我的問題。這是與 CF 相關的問題。因此，當我們接近讀數時，您能否向我們保證您如何看待那裡的成功標準，就已經登記的患者而言，您能否在模組化合格患者與不合格患者的比例方面給我們提供更詳細的信息？謝謝。

Hey Lili, thanks for the questions. Yeah, just a refresher for the historical precedent for cystic fibrosis is all through modulators with respect to regulatory engagement. And what they've established is a 3% threshold would be sufficient to advance this and further and develop now. I do remind people that modulators are small molecules they're systemically distributed throughout the entire body, and the class of subjects there or participants are typically delta 508s. So in contrast, Arcturus is developing an inhaled messenger RNA therapeutic that's topically delivered to the bronchial epithelial cells, and we're also engaging the most challenging group within the CF community, and that's the Class 1 subjects or modulator non-responders.

嘿，莉莉，謝謝你的提問。是的，回顧一下囊性纖維化的歷史先例，它都是透過調節劑進行監管參與的。他們設立的 3% 門檻足以推動這項進程並進一步發展。我確實提醒人們，調節劑是小分子，它們系統地分佈在整個身體中，而那裡的受試者或參與者的類別通常是 delta 508。相較之下，Arcturus 正在開發一種吸入式信使 RNA 療法，該療法局部輸送到支氣管上皮細胞，而且我們也在與 CF 社區中最具挑戰性的群體接觸，即 1 類受試者或調節劑無反應者。

But having said that, the short answer to your question is, comes from the regulatory agency. The FDA has said that, if you establish safety and tolerability and a positive measurable FEV then that would be a significant development to allow us to proceed.

但話雖如此，對你的問題的簡短回答是，來自監管機構。FDA 表示，如果確定了安全性和耐受性，並且 FEV 呈陽性且可測量，那麼這將是一個重大進展，可以讓我們繼續進行。

And so what does that mean? Well, we'll find out, but, clearly if we can establish safe and tolerable medicines with a positive FEV, then we'll be able to proceed further into development. This would be a big breakthrough for the modulator non-responders. But there is a legacy expectation from the modulator space of a, 2.5%, 3% threshold that's required. So that will likely play a role in the discussions with the regulatory agency.

那麼這意味著什麼呢？好吧，我們會找到答案，但是，顯然如果我們能夠開發出安全且可耐受的陽性 FEV 藥物，那麼我們就能進一步進行開發。對於調節劑無反應者來說這將是一個巨大的突破。但調製器空間的傳統期望是需要 2.5%、3% 的閾值。因此，這可能會在與監管機構的討論中發揮作用。

With respect to your second question, you were asking about what percentage, I believe, or maybe explain further the distribution of modulator nonresponders in in this trial so far, and I can help address that question. I would say a strong majority of these subjects, these nine subjects to date, have our Class 1 subjects. We do have representation of modulator that are not Class 1 but a solid or strong majority of them are Class 1.

關於您的第二個問題，我認為您問的是迄今為止在本次試驗中對調節劑無反應者的百分比，或者可以進一步解釋一下該百分比的分佈情況，我可以幫助解答這個問題。我想說，迄今為止的這九個科目中的絕大多數都是我們的一級科目。我們確實有一些非 1 類調變器的代表，但其中絕大多數都是 1 類。

Thank you.

謝謝。

Thanks, Lili.

謝謝，莉莉。

Yasmeen Rahimi, Piper Sandler.

亞斯明·拉希米、派珀·桑德勒。

Good afternoon, team. Thank you so much for taking our questions and very much looking forward to the update in September. One CF related and one OTC related. Team, could you talk about the type of safety or efficacy? What do you see on a blinded basis, especially around the safety aspect of your product?

大家下午好。非常感謝您回答我們的問題，我們非常期待九月的更新。一個與​​ CF 相關，一個與 OTC 相關。團隊，您能談談安全性或有效性的類型嗎？您在盲測的基礎上看到了什麼，特別是關於產品的安全性方面？

And then the second one is, could you maybe elaborate as you're going to engage with the agency on pivotal design alignment of what work has been done between allowing the use of biomarkers as a registrational endpoint and could glutamate and be potentially used. Appreciate if we could elaborate on both of these questions and I'll jump back in the queue.

然後第二個問題是，您能否詳細說明一下，因為您將與該機構就關鍵的設計協調進行合作，即在允許使用生物標誌物作為註冊終點和谷氨酸的潛在用途之間已經做了哪些工作。如果我們能夠詳細闡述這兩個問題，我將不勝感激，我會重新回到隊列中。

All right. Thanks Yas. Good to hear from you. In terms of elaborating on the safety, so for the last few decades, the industry has been aggressively developing inhaled RNA therapeutics, but unfortunately they haven't succeeded, and the reason for their failure collectively is primarily attributed to toxicology and tolerability issues and toxicology stems from two -- in two areas. Either the lipids are too toxic, the delivery system itself, or the impurities in the mRNA drug substance can be a challenge with respect to toxicology and tolerability.

好的。謝謝 Yas。很高興收到你的來信。就安全性而言，過去幾十年來，業界一直在積極開發吸入式 RNA 療法，但不幸的是，它們並沒有成功，而它們失敗的原因主要歸咎於毒理學和耐受性問題，而毒理學源於兩個方面——兩個領域。無論是脂質毒性太大、輸送系統本身，還是 mRNA 藥物物質中的雜質，都可能對毒理學和耐受性造成挑戰。

And this is shown in the clinic through bronchospasms, so undesired inflammatory responses and febrile reactions, which are an undesired immune response or elevated fevers, for example. So inflammatory responses can typically be credited to or blamed for toxic lipids. And then on the febrile reaction side or undesired immune responses, those can be attributed to impurities in the mRNA construct.

這在臨床上表現為支氣管痙攣，即不良的發炎反應和發熱反應，例如不良的免疫反應或發燒。因此，發炎反應通常可歸因於或歸咎於有毒脂質。然後在發燒反應方面或不良免疫反應方面，這些可以歸因於 mRNA 構建體中的雜質。

And what Arcturus brought forward with this ARCT-032 is strong intellectual property and innovation on the delivery system that addresses this primary concern of accumulating toxic lipids and then on the -- we also have purification IP that we've been building and working on for over a decade now. That allows us to effectively purify the drug substance and remove the bad actors, these small double stranded and single stranded impurities that can cause these untoward and problematic febrile reactions or undesired immune responses.

Arcturus 透過 ARCT-032 帶來的是強大的智慧財產權和輸送系統創新，解決了累積有毒脂質這一主要問題，然後——我們還擁有十多年來一直在建造和研究的淨化 IP。這使我們能夠有效地淨化藥物物質並去除有害成分，這些小的雙鍊和單鏈雜質可能導致不良和有問題的發熱反應或不良的免疫反應。

And that's what we're bringing forward there is improvements in addressing what the field has had challenges with over the last couple decades. Shifting to OTC, what's been done so far with respect to glutamine socialization and familiarity with the regulatory agency as we've provided and with respect to our N15 ureagenesis essay as well, they're well versed and understand our strategy with respect to Phase 2. They are very well aware that we're collecting this data and they're interested in seeing it.

這就是我們所提出的，在解決該領域過去幾十年來所面臨的挑戰方面取得了進展。轉向 OTC，到目前為止，我們在麩醯胺酸社會化和熟悉監管機構方面所做的工作，以及我們的 N15 尿素生成論文，他們都非常熟悉並了解我們關於第二階段的策略。他們非常清楚我們正在收集這些數據，並且他們有興趣查看這些數據。

We've provided them papers to illustrate the impact of these potential biomarkers and the recent paper as well with respect to ureagenesis, we intend to meet with them, to share the recent Phase 2 data and throughout the coming months, whether that's in a Type C meeting or meetings is yet to be determined and we haven't communicated the detail of that strategy, but rest assured they are aware of what we're trying to do and achieving alignment with them is a key objective for this Program, and we would view it as a value catalyst actually or value add, if we can get alignment with the FDA and other regulatory agencies with respect to the Phase 3 trial. But I'll pause my comments there. Thank you for the questions.

我們向他們提供了論文來說明這些潛在生物標誌物的影響，以及有關尿素生成的最新論文，我們打算與他們會面，分享最近的第 2 階段數據，在接下來的幾個月裡，無論是在 C 類會議還是其他會議中，都尚未確定，我們還沒有傳達該策略的細節，但請放心，他們知道我們正在嘗試做什麼，與他們達成一致階段試驗達成一致，我們實際上會將其視為價值催化劑或增值。但我會暫停我的評論。謝謝您的提問。

Thank you so much.

太感謝了。

Seamus Fernandez, Guggenheim.

謝默斯·費爾南德斯，古根漢美術館。

Great. Thanks for the question. So I just wanted to confirm, that the highest dose data will be sort of fully represented out to 28 days, Joe. I just wanted to confirm that, the 10 milligram cohort and at least six patients' worth of data would be available out to 28 days. The second question, -- yeah, go ahead, Joe.

偉大的。謝謝你的提問。所以我只是想確認一下，最高劑量的數據在28天內是否能夠完整呈現，喬。我只是想確認一下，10毫克劑量組和至少6名患者的數據在28天內是否能夠完整呈現。第二個問題——是的，請說，喬。

No, yes. So the first question is, yes, absolutely 28 days online subjects, most of these would also have their day 56 data. We do collect FEV after 56 days, and then there's even two months follow ups after that. But with respect to the final subject, we'll just have 28 day data.

不，是的。所以第一個問題是，是的，絕對是 28 天的線上主題，其中大多數也會有他們第 56 天的資料。我們確實在 56 天後收集了 FEV，然後甚至還有兩個月的跟踪。但就最後一個主題而言，我們只有 28 天的數據。

And can you just remind us your -- how you would define kind of clinically meaningful? I think historically, thought leaders we've talked to have said, at least 3% on the low end, and but 5% would certainly be clinically meaningful from their perspective. Just wanted to get your thoughts around that, and if there's a bar or what FDA might be looking for in terms of what they would define as clinically meaningful as you had to meet with the agency in the first half of next year.

您能否提醒我們一下—您如何定義「臨床意義」？我認為，從歷史上看，我們採訪過的思想領袖都表示，最低比例至少 3%，但從他們的角度來看，5% 肯定具有臨床意義。只是想了解您的想法，以及是否存在一個標準，或者 FDA 可能會尋找什麼來定義具有臨床意義，因為您必須在明年上半年與該機構會面。

Yeah. I think 3% is reasonable. However, I just want to make sure it's clear that our program is not a modulator. It's not systemically administered to Delta 508. It's inhaled mRNA to a more challenging population where the unmet medical need is more severe and so that would be part of the conversation with the FDA.

是的。我認為3%是合理的。但是，我只是想確保我們的程式不是調製器。它沒有系統地管理 Delta 508。它將 mRNA 吸入到更具挑戰性的人群中，這些人群的未滿足醫療需求更為嚴重，因此這將成為與 FDA 對話的一部分。

And also taking into consideration the theoretical likelihood of the FEV elevating further as you extend the study for a longer period of time will be taken into consideration. And what do I mean by that is if you saw, 3% after 28 days, then the likelihood of you seeing even more than that in months two or three through extended dosing is theoretically very high.

並且也會考慮到隨著研究時間的延長，FEV 進一步升高的理論可能性。我的意思是，如果您在 28 天後看到了 3%，那麼透過延長劑量，您在第二或三個月內看到更多的可能性在理論上非常高。

So that would be viewed very positive even if you -- whatever the positive number is. So just to reiterate what I have said a few times for clarity, is the FDA just wants safety, tolerability, and any positive measurable FEV, given that this is a 28 day study, and that would indicate a lot of positive feelings and response and allow us to advance this further into development as you extend that study even further in Phase 3.

因此，無論這個正數是多少，這都會被視為非常正面的。因此，為了清楚起見，我再次重申我已經說過幾次的話，FDA 只是想要安全性、耐受性和任何可測量的陽性 FEV，因為這是一項為期 28 天的研究，這將表明很多積極的感覺和反應，並允許我們在第 3 階段進一步擴展該研究，從而進一步推進開發。

Okay, great. I'll jump back in the queue. Thanks so much.

好的，太好了。我會重新回到隊列中。非常感謝。

Yeah, just to add to Seamus, Joe's comment, keep in mind, Seamus that, this class of population unfortunately has a degradation of FEV over on an annual basis and consequently their life span is shortened and so an opportunity to increase it or stabilize it for this class of population would be quite remarkable and certainly offer them an opportunity to have an extension of life, so.

是的，補充 Seamus，Joe 的評論，Seamus，請記住，不幸的是，這類人群的 FEV 值逐年下降，因此他們的壽命縮短了，因此，如果能為這類人群增加或穩定 FEV 值，那將是相當了不起的，也無疑能為他們提供延長壽命的機會。

Myles Minter, William Blair.

邁爾斯·明特、威廉·布萊爾。

Hi, this is Jake on from Miles. Thanks so much for taking our question. I wanted to ask a couple more on CF. I was sort of wondering what the interest level was in patient enrollment after the Vertex and Moderna trial pause, whether you saw any difference in appetite for your trial and maybe sort of comment we'd love your comments on the reopening of that trial and whether you think they're going to be able to get over the safety issue. That was raised with the DSMB there. Thanks.

大家好，我是 Miles 的 Jake。非常感謝您回答我們的問題。我想再問幾個有關 CF 的問題。我有點想知道在 Vertex 和 Moderna 試驗暫停後，患者招募的興趣程度如何，您是否發現對試驗的興趣有任何變化，也許我們希望您對重新開​​始該試驗發表評論，以及您是否認為他們能夠克服安全問題。這是向那裡的 DSMB 提出的。謝謝。

Yeah. With respect to the first question, we have several sites open and recruiting subjects, and in the sites where there was overlap with competitors, if those competitors are no longer recruiting and yes that would directly help or impact our recruitment rate there, but only a small number of sites do we have overlap with our competitors. We're working closely with the CF Foundation and they've identified sites that have limited competition for us for recruitment. So from that perspective, no.

是的。關於第一個問題，我們有幾個開放的站點正在招募人員，在與競爭對手有重疊的站點，如果這些競爭對手不再招募，那將直接幫助或影響我們在那裡的招募率，但只有少數站點與我們的競爭對手有重疊。我們正在與 CF 基金會密切合作，他們已經確定了對我們來說招募競爭有限的站點。所以從這個角度來看，不是的。

With respect to of your other question it would be, I don't know, inappropriate for me to speculate on, what’s happening at, with our competitors like with the Vertex program, and I don't want to come across as callous, but we frankly don't care that much. When we started this process there was a half a dozen of these companies aggressively pursuing this and we've just been putting our head down and executing and working hard and here we are and I think we'll just keep doing that but we definitely have a different delivery technology than our competitors, a different IP estate around purifying, and I think those are areas of innovation and intellectual property that we tend to emphasize as points of differentiation with our competitors, and we'll leave it at that.

關於您的另一個問題，我不知道，我不適合猜測我們的競爭對手（例如 Vertex 計劃）的情況，我不想顯得冷酷無情，但坦率地說，我們並不太在意。當我們開始這個過程時，有六家公司正在積極追求這一目標，我們只是埋頭苦幹、努力執行，現在我們做到了，我想我們會繼續這樣做，但我們肯定擁有與競爭對手不同的交付技術，以及圍繞淨化的不同知識產權，我認為這些是我們傾向於強調的創新和知識產權領域，作為與競爭對手的區別點，我們就此打住。

Thank you.

謝謝。

Whitney Ijem, Canaccord.

惠特尼·伊傑姆 (Whitney Ijem)，Canaccord。

Hey guys, this is Angela Chan on for Whitney. We have two questions on CF. The first one is, do you intend to proceed to a higher dose cohort or do you plan to initiate the regulatory conversations based on these two cohorts? And then the second one, can you just remind us what your pre-clinical data has suggested at the comparable doses and the degree of dose response? So when we think about, the potentially 3% FEV1 benefit, is that something that you believe could be achieved with the lower dose?

大家好，我是 Angela Chan，代表 Whitney 發言。我們有兩個關於 CF 的問題。第一個問題是，您是否打算繼續進行更高劑量的隊列研究，或者您是否計劃根據這兩個隊列啟動監管對話？然後第二個問題，您能否提醒我們一下，您的臨床前數據在可比較劑量和劑量反應程度方面顯示了什麼？因此，當我們考慮潛在的 3% FEV1 益處時，您是否認為可以透過較低的劑量來實現這一目標？

Both good questions. First of all, the present Phase 2 trial design is a 12 subject trial and three doses where we have three subjects at 5 milligram followed by six subjects at 10 milligram dosing and then an additional three subjects at 15 milligram dosing. That's the present plan. We do have flexibility built into that plan because we -- this is what was initiated and approved upon, but we've just been executing according to that plan and the first two cohorts we've already discussed are kind of the 5 milligram is completed and the 10 milligram is also going to be completed, at least the dosing phase in early September, and we'll be able to communicate some of those in term data.

這兩個問題都很好。首先，目前的第二階段試驗設計是 12 名受試者試驗和 3 種劑量，其中 3 名受試者服用 5 毫克，然後 6 名受試者服用 10 毫克劑量，最後 3 名受試者服用 15 毫克劑量。這就是目前的計劃。我們的計劃確實具有靈活性，因為我們——這是啟動和批准的計劃，但我們只是按照該計劃執行，我們已經討論過的前兩個組是 5 毫克已經完成，10 毫克也將完成，至少在 9 月初的給藥階段，我們將能夠在學期數據中傳達其中的一些。

With respect to the dose response we -- you would expect that a dose response with a therapeutic like ours. However, we do want to reference the modulator community and the CFTR biochemistry that has not necessarily been observed in the modulator space. That was more of a threshold situation where you increase the dose until it worked, but then you doubled or tripled the doses and it didn't improve the efficacy further.

關於劑量反應，我們—您會期望像我們這樣的治療方法會產生劑量反應。然而，我們確實想參考調節器社群和在調節器空間中不一定觀察到的 CFTR 生物化學。這更像是一種閾值情況，你增加劑量直到它起作用，但隨後你將劑量增加一倍或三倍，卻沒有進一步提高療效。

So if, while we do expect a dose response with respect to our therapeutic if we don't see it that's also okay, because it may just be a threshold type response like you see with the modulators. And then did I address your question, Angela?

因此，如果我們確實期望對我們的治療有劑量反應，但如果我們沒有看到它，那也沒關係，因為它可能只是一種閾值類型的反應，就像你在調節劑中看到的那樣。那我回答你的問題了嗎，安琪拉？

Yeah, thank you.

是的，謝謝。

Thank you.

謝謝。

Pete Stavropoulos, Cantor Fitzgerald.

皮特·斯塔夫羅普洛斯，康托·菲茨傑拉德。

Hi, this is Sarah Medeiros on for Pete. Congrats on the progress and thanks for taking our questions. Now back to CF, I assume you'll be showing both absolute and relative changes for FEV. So how should we think about presentation and interpretation of the endpoint when taking into consideration the patient's baseline, for example, like a high versus a low FEV baseline, and then just to follow up, besides FEV, are there any other measurements that you could or will look at to enhance the investigators conviction in the program, including like quality of life?

大家好，我是 Sarah Medeiros，為 Pete 播報。恭喜您的進展並感謝您回答我們的問題。現在回到 CF，我假設您將顯示 FEV 的絕對變化和相對變化。那麼，當考慮到患者的基線時，我們應該如何思考終點的呈現和解釋，例如，高 FEV 基線與低 FEV 基線，然後進行後續跟進，除了 FEV 之外，還有其他測量方法可以或將要查看以增強研究人員對該計劃的信心，包括生活品質？

Okay, a lot there. Good question. In terms of the FEV data, and other lung programs and inhaled therapeutic programs look at area above the baseline as we measure FEV throughout the patient experience in the trial, we'll be looking at kind of area under the curve, and that'll be the best way to add the most weight and confidence in the data.

好的，有很多。好問題。就 FEV 數據而言，其他肺部項目和吸入治療項目會查看基線以上的面積，因為我們會在試驗的整個患者體驗過程中測量 FEV，我們會查看曲線下的面積，這將是增加數據權重和信心的最佳方式。

In terms of the baseline characteristics, I know that we we've included a broad range for formality purposes of 40% to 100% baseline, but it's more like in that 60% to 80% range for the strong majority of these nine subjects, so I'd say that would be more typical.

就基線特徵而言，我知道我們為了形式目的已經包含了 40% 到 100% 的基線範圍，但對於這九個科目中的絕大多數來說，更像是在 60% 到 80% 的範圍內，所以我認為這更典型。

And then you asked about additional -- in addition to FEV responses, we are asking these participants to include a questionnaire, and address answers there. There's about 20 questions, for example, on the respiratory module of the CF questionnaire. This is a well understood quality of life questionnaire that has been used in the modulator space and we're using the same thing there.

然後您詢問了其他問題——除了 FEV 回應之外，我們還要求這些參與者填寫一份問卷，並在其中給出答案。例如，CF 問卷的呼吸模組大約有 20 個問題。這是一個很好理解的生活品質問卷，已在調節器領域使用，我們在那裡使用相同的東西。

So as you think of it, just to elaborate this on this a little bit more. As I think it's helpful to think of someone who stops smoking, right, the first week and first month they feel better, but their lung function improves throughout, not just in the initial weeks in a month, but in two and three months. So there's continuous healing and continued lung function improvements. And so that's likely what we would expect with an inhaled therapeutic like Arcturus is in the first month that if it's working, that people would see some elevated lung function, feel a lot better, but that could continue on into months two and three. Okay.

所以，正如您所想的，我們只需對此進行更詳細的闡述。我認為想像戒菸的人會很有幫助，對吧，第一週和第一個月他們會感覺更好，但他們的肺功能會不斷改善，不僅是在一個月的最初幾週，而且在兩三個月內。因此，治療會持續進行，肺功能也會持續改善。因此，我們很可能對 Arcturus 等吸入療法抱有期望，如果在第一個月它有效，人們會看到肺功能有所提高，感覺好很多，但這種情況可能會持續到第二個月和第三個月。好的。

Thank you.

謝謝。

Tom Shrader, BTIG.

BTIG 的湯姆·施拉德 (Tom Shrader)。

Good afternoon. Thank you for taking my questions. I think I'll have some vaccine questions. Your US BLA for COVID, is that going to be for approval of an updated vaccine or would that be for the historical vaccine and so you would need for next year to update.

午安.感謝您回答我的問題。我想我會有一些關於疫苗的問題。您提交的美國 COVID 疫苗許可申請 (BLA) 是用於批准更新的疫苗，還是用於歷史疫苗，因此您需要在明年進行更新。

And then on the seasonal flu vaccine, that's obviously getting very interesting. Your thoughts on the interplay of the antigens, do you feel like you have to be as good on hemagglutinins protective antibodies if you have neuraminidase? Is that understood that neuraminidase could cover for some hemagglutinin? Thank you.

然後關於季節性流感疫苗，這顯然變得非常有趣。您對抗原交互作用的看法是，如果您有神經氨酸酶，您是否覺得必須對血凝素保護性抗體有同樣好的表現？是否可以理解為神經氨酸酶可以取代一些血凝素？謝謝。

A good question. Thanks, Tom. First of all, with respect to the US BLA, yeah, the initial strategy here is to approve the platform in the original multi-dose file presentation. It would be fully expected like in other areas in other countries and regulatory agencies that we've been interacting with that an updated, variant vaccine would be expected on an annual basis. And so yeah, this one that's getting approved is just basically to set the foundation for the platform and get that approved in the US.

好問題。謝謝，湯姆。首先，關於美國 BLA，是的，這裡的初步策略是在原始多劑量文件演示中批准該平台。正如我們一直與之互動的其他國家和監管機構的其他地區一樣，預計每年都會推出更新的變異疫苗。是的，這個獲得批准基本上是為了為平台奠定基礎並在美國獲得批准。

With respect to the -- answering your question on, it was a seasonal flu question with the interplay of antigens. Let's see what can I do there. We are sharing the outcome of the Phase 1 clinical study, it's an 8 valent, right? There's 8 antigens, including 4 HA and 4 NA antigens in the seasonal influenza vaccine, and we're going to evaluate the ability of this platform to induce a balanced immune response against multiple antigens without interference.

關於—回答您的問題，這是一個與抗原相互作用的季節性流感問題。讓我們看看我能做什麼。我們正在分享第一階段臨床研究的結果，它是8價，對嗎？季節性流感疫苗中有8種抗原，包括4種HA抗原和4種NA抗原，我們將評估該平台在不受干擾的情況下誘導針對多種抗原的平衡免疫反應的能力。

But the changes of the WHO and the US CDC recommendations on vaccine composition, where these sorts of antigens are no longer required, so it will require further development of the candidate, but that's probably, I don't know if I'm specifically addressing your question, but --

但是世界衛生組織和美國疾病管制與預防中心對疫苗成分的建議發生了變化，不再需要這些抗原，因此需要進一步開發候選疫苗，但這可能，我不知道我是否專門回答了你的問題，但是--

Well, I guess my really my question is, are your hemagglutinin levels as high as the high dose protein vaccine? Can you say that yet and then when that will be presented?

嗯，我想我真正的問題是，你的血凝素水平是否與高劑量蛋白疫苗一樣高？你能這麼說嗎？什麼時候會提出來？

Yes. So that's later this year. We'll be able to do what we've disclosed today is that we saw a nice dose responsive, immunogenicity against all four versions of the flu, right? So but with respect to details that will be forthcoming later this year.

是的。那是今年晚些時候的事。我們今天能夠做到的是，我們看到了針對所有四種流感病毒的良好的劑量反應性和免疫原性，對嗎？但有關細節將於今年稍後公佈。

Okay. Thank you.

好的。謝謝。

Yeah. Thank you, Tom.

是的。謝謝你，湯姆。

Yigal Nochomovitz, Citigroup.

花旗集團的 Yigal Nochomovitz。

Yeah. Hi, Joe and Andy, thank you for taking the questions. On CF, could you just comment on the timing of the end of Phase 2 meeting with the FDA? Am I correct that it's been delayed a bit relative to your initial projections? And if so, is that related to the comments you made regarding seeing continuous improvements in months two and three and potentially wanting to see additional boost on FEV1 beyond the first month that would present a stronger data package to present to the FDA. Thank you.

是的。嗨，喬和安迪，感謝你們回答這些問題。關於 CF，您能否評論一下與 FDA 進行的第二階段會議結束的時間？與您最初的預測相比，它確實稍微延遲了一點，對嗎？如果是這樣，這是否與您所說的在第二個月和第三個月看到持續改善，並可能希望在第一個月之後看到 FEV1 的額外提升，從而向 FDA 提供更強大的數據包有關。謝謝。

Yeah. We've indicated or guided that we'll be completing the Phase 2 trial enrollment process this year, with respect to the third cohort. But, shortly after then we'll have an engagement with the FDA if it's an end to Phase 2 meeting that would be great. But it's at that time that we would discuss with them what's required for a Phase 3 study.

是的。我們已經表示或指導，我們將在今年完成第三批患者的第二階段試驗招募過程。但是，不久後我們將與 FDA 接觸，如果第二階段會議結束那就太好了。但那時我們會與他們討論第三階段研究的要求。

I can only speculate, but we're not expecting to need any other additional trials to allow us to shift or transition to a pivotal trial, especially with adult subjects. So that's the expectation at this point is the end of Phase 2 meeting will be in the first half of next year and we'll be able to initiate Phase 3 as soon as possible in 2026 without the need or requirement to do in any additional trials.

我只能推測，但我們預計不需要任何其他額外的試驗來讓我們轉變或過渡到關鍵試驗，尤其是針對成年受試者。因此，目前的預期是，第二階段會議將在明年上半年結束，我們將能夠在 2026 年盡快啟動第三階段，而無需或要求進行任何額外的試驗。

And then just -- am I correct, this is the first time that you've actually specified the doses, the 5 and the 10, and is there a specific driver behind that relative to sharing the data only in September?

然後——我說得對嗎，這是您第一次真正指定劑量，5 和 10，這背後是否有一個特定的驅動因素，相對於僅在 9 月份共享數據？

No. People, it just allows us to speak more freely as we enter the September bank conference season and engage with investors so that they can now understand that this is a generous dose. Like, for example, previous attempts at inhaled mRNA therapeutics maxed out at 80 milligram per month, and we're now showing data at 280 milligram. So that's a big difference and if we elevate further to the 15 milligram dose cohort that's 420 milligram over four weeks. So we can now speak to and point to actual data that it is more meaningful, that's why.

不。各位，這讓我們在進入九月份銀行會議季時能夠更加自由地發言，並與投資者互動，以便他們現在能夠理解這是一筆慷慨的金額。例如，先前嘗試吸入式 mRNA 療法的最大劑量為每月 80 毫克，而我們現在顯示的數據為 280 毫克。所以這是一個很大的差異，如果我們進一步提高到 15 毫克劑量組，那麼四周內就是 420 毫克。所以我們現在可以說並指出實際數據更有意義，這就是原因。

Okay, that's helpful. And then on OTC, any later thoughts on the higher 0.7 mgs per kg? I know earlier in the summer we were debating that possibility. I'm wondering if you have any updates there. Thanks.

好的，這很有幫助。那麼關於 OTC，您對每公斤 0.7 毫克的較高劑量有什麼看法嗎？我知道今年夏天早些時候我們正在討論這種可能性。我想知道您是否有任何更新。謝謝。

Well, it's a good question. We don't have a definitive answer. There's reasons to proceed at 0.7 mgs per kg, and there's reasons to truncate the timeline and get this into Phase 3 more quickly. But right now I think it's a conservative reasonable, expectation that will elevate the dose and get some experience at 0.7 mgs per kilogram just to give more therapeutic index comfort to the regulatory agency. But we haven't officially guided that, but I think that's a conservative expectation.

嗯，這是個好問題。我們沒有明確的答案。我們有理由以每公斤 0.7 毫克的劑量進行，也有理由縮短時間表並更快地進入第三階段。但目前我認為保守合理，預期將提高劑量，並在每公斤 0.7 毫克的劑量下獲得一些經驗，以便為監管機構提供更多的治療指數舒適度。但我們還沒有正式給予指導，但我認為這是保守的預期。

Okay. Thanks, Joe.

好的。謝謝，喬。

Thanks, Yigal.

謝謝，伊加爾。

Yanan Zhu, Wells Fargo.

朱亞南，富國銀行。

Great. Thanks for taking our questions. Maybe still on the CF program, given there's no placebo arm, could you, talk about, what could we look into the data to get comfort in terms of discerning treatment effect versus placebo effects. Of course, if there's a dose response that'll be -- make things easier, but I'm not sure the sample size and also potential, as you have highlighted earlier, whether there might be one, but just given that background, can you elucidate on potential ways to analyze the data.

偉大的。感謝您回答我們的問題。也許仍在進行 CF 計劃，考慮到沒有安慰劑組，您能否談談，我們可以查看哪些數據以便在辨別治療效果與安慰劑效果方面獲得安慰。當然，如果有劑量反應，那將會使事情變得更容易，但我不確定樣本量和潛力，正如您之前強調的那樣，是否可能存在，但僅考慮到這個背景，您能否闡明分析數據的潛在方法。

Well, the opportunity to implement a placebo strategy will be in Phase 3, and that's still to be negotiated the details of that with the FDA, but there'll be plenty of opportunity to implement a placebo arm or a placebo strategy into Phase 3 if requested.

嗯，實施安慰劑策略的機會將在第 3 階段，具體細節仍有待與 FDA 協商，但如果有要求，將有足夠的機會在第 3 階段實施安慰劑組或安慰劑策略。

It is kind of self-controlling, these folks have been measuring their FEV for quite a while, and if -- we'll be leveraging their past experience as some sort of self-control. But with respect to the placebo arm, that's yet to be determined and will likely be included in a Phase 3 trial.

這是一種自我控制，這些人已經測量他們的 FEV 很長一段時間了，如果——我們將利用他們過去的經驗作為某種自我控制。但就安慰劑組而言，這仍有待確定，並可能納入第三階段試驗。

I remind people too that our Phase 1 trial did have 32 subjects in it already, so we have a pretty good experience already with our Phase 1 and then Phase 1 being another 7 subjects and then you add on these 9 to 12 subjects that we're going to be looking at in, Phase 2 by the end of this year will be over 50 subjects of experience with respect to safety.

我也提醒大家，我們的第一階段試驗已經有 32 名受試者了，所以我們在第一階段已經有了相當不錯的經驗，然後第一階段又有 7 名受試者，再加上我們將要研究的這 9 到 12 名受試者，到今年年底，第二階段將在安全方面有超過 50 名受試者的經驗。

But the shift of the attention from a regulatory perspective will now go to duration. So we only have 28 days of experience, right? That's the other purpose that the Phase 3 trial will fulfill is, an extended duration whether it's two, three, four, five or six months will be determined at a later time.

但從監管角度來看，注意力現在將轉移到持續時間。所以我們只有 28 天的經驗，對嗎？這是第三階段試驗將實現的另一個目的，延長的時間是兩週、三週、四週、五週或六個月將在稍後確定。

Great. Can I ask you a quick follow up? You mentioned that some patients are followed out to 56 days. Will there be FEV1, measurement in the off treatment period?

偉大的。我可以問你一個快速的後續問題嗎？您提到有些患者的追蹤時間長達 56 天。在停止治療期間是否會進行 FEV1 測量？

There's an FEV measurement at day 56, but not -- and then there's two months of follow up, but there's -- my understanding is on clinical trials got to work, but my recollection of that is that there's no further FEVs after day 56.

第 56 天進行了 FEV 測量，但沒有 — — 然後是兩個月的隨訪，但是 — — 我的理解是臨床試驗必須起作用，但我記得第 56 天後沒有進一步的 FEV。

I guess, the question is, would we see any, FEV1 data after the treatment period has ended, perhaps as a way to discern treatment effect.

我想，問題是，治療期結束後我們是否會看到任何 FEV1 數據，也許可以作為辨別治療效果的一種方式。

Yeah. Well, that's the reason why we're measuring day 56 because the treatment phase ends day 28. It'll be interesting to share, what happens to the FEV response, 28 days after the dosing has been suspended. So we will have to be able to share some insight there.

是的。嗯，這就是我們測量第 56 天的原因，因為治療階段在第 28 天結束。分享一下停止服藥 28 天後 FEV 反應會發生什麼變化將會很有趣。因此我們必須能夠分享一些見解。

Great. Sorry, if I may ask the last question, in terms of kinetics or onset of effect. Based on your understanding of the translation of the mRNA. And protein and getting into the play into place to start working. What's the sense of the onset of action and that kinetics. Thank you.

偉大的。抱歉，我可以問最後一個問題，關於動力學或起效時間的問題。根據您對 mRNA 翻譯的理解。蛋白質進入發揮作用的地方並開始發揮作用。作用的開始和動力學的意義是什麼。謝謝。

Yeah. The onset of action is relatively quick, right, in order to get the first cells that are available to be transected and introduce new CFTR into those cells. But upon subsequent administrations, we also see that even more cells will be impacted. And so the threshold of how many cells will need to be transected and delivered in mRNA that's in codes and expresses CFTR, how many of those cells will need to be impacted before we see a physiological response or FEV improvement is the question we're addressing.

是的。為了獲得第一個可供橫切的細胞並將新的 CFTR 引入這些細胞，行動開始得相對較快，對吧。但在後續的管理中，我們也發現更多的細胞會受到影響。因此，我們正在解決的問題是，需要橫切和遞送編碼和表達 CFTR 的 mRNA 的細胞數量閾值，需要影響多少個細胞才能看到生理反應或 FEV 改善。

And how long will that take? But for the cells that get our drug the impact is fairly quick in terms of the biochemistry, it's fairly fast. But, biologically that's a different question, just like how you -- how long will it take for the phlegm to clear after someone stops smoking, right? It's a good analogy, it might be weeks or months depending on the person and variable depending on how long they've been smoking, for example.

這需要多長時間？但對於接受我們藥物的細胞來說，從生物化學角度來看，影響相當快，相當快。但是，從生物學角度來說，這是一個不同的問題，就像你一樣——一個人停止吸煙後，痰需要多長時間才能清除，對嗎？這是一個很好的比喻，例如，它可能是幾週或幾個月，這取決於個人，並且取決於他們吸煙的時間長短。

Got it. Very helpful. Thank you.

知道了。非常有幫助。謝謝。

Yeah, thank you.

是的，謝謝。

Evan Wong, Guggenheim Securities.

古根漢證券公司的 Evan Wong。

Hey guys, just two quick follow ups from us at the time. First, with OTC just wondering when we may see full data there whether that includes the higher dose cohort or not, and then with influenza, I believe the trial includes a comparator arm or arms that based on age, any comments in terms of, I guess hemagglutinin response relative to comparator thanks.

嘿夥計們，我們當時只想快速跟進兩件事。首先，對於 OTC，我只是想知道我們何時可以看到完整的數據，無論是否包括較高劑量組，然後對於流感，我相信試驗包括基於年齡的對照組或對照組，對於血凝素反應相對於對照組的任何評論，謝謝。

Good question. With respect to the comparator data, the details of that will be forthcoming later this year or at least when CSL feels it's comfortable to publish that data. So they'll be providing guidance on the detailed data we just today we just mentioned some high level summary, it's difficult for us to guide when that detailed data comes out, with respect to how image you see relative to comparator, so I won't be able to comment on that. With respect to your first question, you asked a when question about OTC. Could you restate that because I missed it.

好問題。關於比較數據，其詳細資訊將於今年稍後公佈，或至少在 CSL 認為可以發布該數據時公佈。因此，他們將就我們今天剛剛提到的詳細數據提供指導，一些高層次的總結，當這些詳細數據出來時，我們很難就您相對於比較器看到的圖像提供指導，所以我無法對此發表評論。關於您的第一個問題，您問了一個關於 OTC 的問題。你能重述一遍嗎，因為我錯過了。

I'm just curious when we may have fuller data with [30C], program.

我只是好奇我們什麼時候可以獲得 [30C] 程式的更完整的數據。

Okay. Yeah, fuller data. Well, it depends, if we proceeded to the 0.7 mg per kg cohort or truncate the Phase 2 data as is because we've already shown that it works at 0.3 and 0.5. We may not proceed with 0.7, but if we do proceed with 0.7, then that will add a few months to the timeline. So once that decision is made, we'll be able to give more specific guidance as to the completion of the Phase 2 portion of that.

好的。是的，更完整的數據。嗯，這取決於我們是否繼續進行0.7毫克/公斤的隊列研究，或直接截斷第二階段的數據，因為我們已經證明0.3毫克和0.5毫克的劑量有效。我們可能不會繼續進行0.7毫克/公斤的劑量研究，但如果我們繼續進行0.7毫克/公斤的劑量研究，那麼時間表就會延長幾個月。因此，一旦做出決定，我們將能夠就第二階段的完成提供更具體的指導。

What we did guide in today's press releases is that, we are in parallel socializing the glutamine biomarker strategy and the N15 ureagenesis and it's very likely going to be a Type C meeting or two, and then in the first half of next year we'll be in a good position to have alignment with the FDA and that's what we're focusing on now but in the background and in parallel whether we do 0.7 milligram per kilogram or not depends on some advice and of course our board approval, et cetera.

我們在今天的新聞稿中確實指導了這一點，我們正在同時推廣谷氨酰胺生物標誌物策略和 N15 尿素生成，這很可能是一兩次 C 類會議，然後在明年上半年我們將處於與 FDA 保持一致的有利位置，這就是我們現在關注的重點，但在後台和並行中，我們是否達到每公斤 0.7 毫克的一些建議，當然還有我們的水平

Great. Thank you.

偉大的。謝謝。

Yeah. Thanks, Evan.

是的。謝謝，埃文。

Yale Jen, Laidlaw and Company.

耶魯仁萊德勞公司。

Good afternoon, and thanks for taking the questions. My first question also is on the CF. Now you revealed that you have 15 milligram that to for the next dose. Just curious, when you designed the study, was 15 milligram, basically just to push the highest dose you could test the safety and efficacy or any other considerations, and I have a follow-up.

下午好，感謝您回答問題。我的第一個問題也是關於 CF 的。現在您透露您有 15 毫克用於下一次劑量。只是好奇，當您設計這項研究時，劑量是 15 毫克，基本上只是為了推高最高劑量，您可以測試安全性和有效性或任何其他考慮因素，我會進行後續跟進。

Yeah. The 5 milligram, 10 milligram, 15 milligram dosing strategy was implemented and agreed upon by the FDA when we designed the Phase 2 trial, and it was based on our experience in the 39 subjects in the CF program. So we explored four dose levels all the way up to 27 milligrams in Phase 1, and then we looked at intermediate dose levels in the Phase 1B program. And what this -- and then the experience for the data we're collecting in the Phase 2B study right now is 5 milligram, 10 milligram, and 15 milligram, and these, were already decided and agreed upon a while ago.

是的。當我們設計第 2 階段試驗時，FDA 實施並同意了 5 毫克、10 毫克、15 毫克的給藥策略，這是基於我們在 CF 計劃中的 39 名受試者的經驗。因此，我們在第 1 階段探索了最高可達 27 毫克的四種劑量水平，然後在第 1B 階段計劃中研究了中間劑量水平。然後，我們目前在第 2B 階段研究中收集的數據經驗是 5 毫克、10 毫克和 15 毫克，這些已經是不久前決定並達成一致的。

Okay, great. One follow up here is that both for 032 or for 810 before you conduct the meetings with the FDA, should we anticipate one more data release of either one of those or what might be the sort of decision.

好的，太好了。這裡的一個後續問題是，在與 FDA 舉行會議之前，對於 032 或 810，我們是否應該預期其中任何一個的更多數據發布，或者可能做出什麼樣的決定。

Yeah. I think it makes sense for us to share additional data for both of these programs as we complete the Phase 2 trials respectively. So we did an interim data release with OTC and a presentation with KOLs in the end of June. I think it makes sense to share the data set when Phase 2 is completed and also provide clarity on the Phase 3 trial design once we have that clarity from our conversations with the regulatory agency. And then, same thing with the CF program.

是的。我認為，在我們分別完成第二階段試驗時，分享這兩個項目的額外數據是有意義的。因此，我們在 6 月底與 OTC 進行了中期數據發布，並與 KOL 進行了演示。我認為，在第 2 階段完成時共享資料集是有意義的，並且在我們與監管機構的對話獲得明確資訊後，也應該明確第 3 階段試驗的設計。然後，CF 程式也是同樣的事情。

So should we anticipate those toward the end of this year or maybe to 2026?

那麼我們是否應該預計在今年底或 2026 年實現這一目標？

For the OTC program.

對於 OTC 計劃。

Yeah, for either one of those additional data update.

是的，對於其中任何一個附加資料更新。

Yeah. Well, we mentioned that we'll be -- we expect to complete the Phase 2 study as presently planned for CF this year in 2025 with respect to OTC, it depends whether we include the 0.7 milligram kilogram cohort, a small number of people, whether we do that or not, and that hasn't been communicated externally yet. So it's today is not the day to do that.

是的。嗯，我們提到過，我們預計將於今年 2025 年完成目前針對 CF 的 OTC 第 2 階段研究，這取決於我們是否包括 0.7 毫克/公斤的隊列，少數人，我們是否這樣做，而這尚未對外公佈。所以今天不是做這件事的日子。

Okay, great. Thanks a lot.

好的，太好了。多謝。

Thank you. And we show no further questions at this time. I will now turn the call over to Joe, for closing remarks.

謝謝。目前我們沒有其他問題。現在我將把電話交給喬，請他做最後發言。

Hey, thanks everyone, for participating on the call. If there are any remaining questions don't hesitate to reach out to our team and we'll get back to you as soon as we can. Good afternoon, or good evening everybody.

嘿，謝謝大家參加電話會議。如果還有任何問題，請隨時聯絡我們的團隊，我們會盡快回覆您。大家下午好，或晚上好。

Thank you. And this does conclude today's program. Thank you for your participation. You may disconnect at any time.

謝謝。今天的節目到此結束。感謝您的參與。您可以隨時斷開連線。