Abeona Therapeutics Inc (ABEO) 2023 Q1 法說會逐字稿

Greetings. Welcome to the Abeona Therapeutics First Quarter '23 Portfolio Update Conference Call. (Operator Instructions) Please note, this conference is being recorded. I will now turn the conference over to your host, Greg Gin, Vice President of Investor Relations and Corporate Communications. You may begin.

問候。歡迎參加 Abeona Therapeutics 第一季度 '23 投資組合更新電話會議。 （操作員說明）請注意，本次會議正在錄製中。現在我將會議交給東道主投資者關係和企業傳播副總裁格雷格·金 (Greg Gin)。你可以開始了。

Thank you, Holly. Good morning, everyone. I would like to welcome and thank everyone for joining us on our portfolio update conference call. Our objective today is to share additional new positive data from our EB-101 and AAV ophthalmology programs recently presented at scientific congresses. The press release is announcing the data at the ISID and ASGCT meetings are available on our website at www.abeonatherapeutics.com. Before we start, I would like to note that remarks made during today's call may contain projections and forward-looking statements.

謝謝你，霍莉。大家，早安。我謹歡迎並感謝大家加入我們的投資組合更新電話會議。我們今天的目標是分享我們最近在科學大會上提出的 EB-101 和 AAV 眼科項目的更多新積極數據。該新聞稿宣布 ISID 和 ASGCT 會議的數據可在我們的網站 www.abeonatherapeutics.com 上獲取。在我們開始之前，我想指出，今天的電話會議中發表的言論可能包含預測和前瞻性陳述。

Forward-looking statements are made pursuant to the safe harbor provisions of the federal securities laws. These forward-looking statements are based on current expectations and are subject to change, and actual results may differ materially from those expressed or implied in the forward-looking statements. Various factors that could cause actual results to differ include, but are not limited to, those identified under the Risk Factors section in our Form 10-K and periodic reports filed with the SEC.

前瞻性陳述是根據聯邦證券法的安全港條款做出的。這些前瞻性陳述基於當前的預期，可能會發生變化，實際結果可能與前瞻性陳述中明示或暗示的結果存在重大差異。可能導致實際結果有所不同的各種因素包括但不限於我們的 10-K 表格和向 SEC 提交的定期報告中的風險因素部分中確定的因素。

These documents are available on our website at www.abeonatherapeutics.com. On the call today are Dr. Vish Seshadri, Chief Executive Officer, who will give some opening remarks. Dr. Dmitriy Grachev, Chief Medical Officer, who will review the new VIITAL Study data that we presented at ISID and Dr. Brian Kevany, Chief Technical Officer, who will review the animal proof-of-concept data from our AAV ophthalmology program presented at ASGCT last week.

這些文件可在我們的網站 www.abeonatherapeutics.com 上獲取。首席執行官 Vish Seshadri 博士出席了今天的電話會議，他將致開幕詞。首席醫療官 Dmitriy Grachev 博士將審查我們在 ISID 上提出的新 VIITAL 研究數據，首席技術官 Brian Kevany 博士將審查我們在 ISID 上提出的 AAV 眼科項目的動物概念驗證數據。上週 ASGCT。

After the prepared remarks, joining us for the Q&A session will be Joe Vazzano, Chief Financial Officer; and Dr. Madhav Vasanthavada, Vice President, Business Development. And with that, I will now turn the call over to Vish Seshadri to kick it off. Vish?

在準備好的發言結束後，首席財務官喬·瓦扎諾 (Joe Vazzano) 將加入我們的問答環節；以及業務開發副總裁 Madhav Vasanthavada 博士。現在，我將把電話轉給 Vish Seshadri 來啟動。維什？

Thank you, Greg. Good morning, everybody, and thank you for joining us this morning. I want to start today by saying last week was a great advancement for the epidermolysis bullosa, or EB, community, I want to congratulate Crystal Biotech, the EB patient community, researchers and regulators for bringing the first genetic therapeutic option to tackle this debilitating disease as more therapies come to market, we anticipate increased awareness about therapeutic options in the EB space and also improved diagnosis and genotyping for this painful disease.

謝謝你，格雷格。大家早上好，感謝您今天早上加入我們。今天開始，我想說上週對於大皰性表皮鬆解症（EB）社區來說是一個巨大的進步，我要祝賀 Crystal Biotech、EB 患者社區、研究人員和監管機構帶來了第一個基因治療選擇來解決這種使人衰弱的疾病隨著越來越多的療法進入市場，我們預計人們對 EB 領域治療選擇的認識將會提高，並且這種痛苦疾病的診斷和基因分型也會得到改善。

Recessive Dystrophic EB, or RDEB, is a connective tissue disorder in which both copies of the gene for collagen VII are mutated and dysfunctional resulting in the lack of connectivity between the outer and inner layers of the skin. Patients with RDEB face a lifelong struggle with fragile skin that easily tears and blisters with most patients developing large painful wounds that remain unhealed, often covering a significant proportion of their body.

隱性營養不良性 EB（RDEB）是一種結締組織疾病，其中 VII 型膠原蛋白基因的兩個拷貝均發生突變且功能失調，導致皮膚外層​​和內層之間缺乏連接。 RDEB 患者終生都在與脆弱的皮膚作鬥爭，這些皮膚很容易撕裂和起水泡，大多數患者會出現大而疼痛的傷口，無法癒合，通常覆蓋了身體的很大一部分。

Recently published Natural History data in RDEB analyzing 251 RDEB wounds describe the 2 distinct types of RDEB wounds. On the top are chronic open RDEB wounds, while on the bottom are the recurrent wounds. On the right, the spider plots show chronic wounds rarely show 50% or greater wound healing, while the recurrent wounds frequently hear even completely and open again.

最近發表的 RDEB 自然歷史數據分析了 251 個 RDEB 傷口，描述了 2 種不同類型的 RDEB 傷口。頂部是慢性開放性 RDEB 傷口，底部是複發性傷口。在右側，蜘蛛圖顯示慢性傷口很少顯示 50% 或更高的傷口癒合，而復發性傷口經常甚至完全癒合併再次開放。

Furthermore, at ISID this year, a prospective study was presented by the team at Stanford, that further corroborated this distinction between large chronic wounds and recurrent wounds. We are excited to advance EB-101 as a potential therapy that could deliver years of sustained wound healing and proven pain relief after a onetime treatment cycle for a large chronic RDEB wounds.

此外，在今年的 ISID 上，斯坦福大學團隊提出了一項前瞻性研究，進一步證實了大型慢性傷口和復發性傷口之間的區別。我們很高興將 EB-101 作為一種潛在的療法來推進，它可以在大面積慢性 RDEB 傷口的一次性治療週期後提供多年的持續傷口癒合和經證實的疼痛緩解。

These are pictures of the patients in our VIITAL study with large chronic wound on the upper left side, you can see the large area coverage and wound healing that were achieved with 3 EB-101 sheets applied in a quilt-like fashion. On the far right, Tatooed wounds were scored as greater than 75% healed. Although the wound looks nearly completely healed to the naked eye, they were scored at 75% plus healed because without picking the cross, the yellow crust that you see there, the physician is unable to confirm complete healing.

這些是我們的 VIITAL 研究中左上方有大面積慢性傷口的患者的照片，您可以看到使用 3 塊 EB-101 床單以被子般的方式實現的大面積覆蓋和傷口癒合。在最右邊，紋身傷口的癒合率超過 75%。雖然肉眼看來傷口幾乎完全癒合，但傷口的癒合率卻達到了 75% 以上，因為如果不挑十字，也就是你看到的黃色痂皮，醫生就無法確認完全癒合。

That speaks to the stringent criteria in our scoring for complete wound closure. Over the next 2 slides, I'll discuss the molecular basis for how EB-101 delivers wound healing in a sustained fashion. EB-101 works by durably restoring functional collagen VII expression to RDEB keratinocytes. Keratinocytes are sourced from patients' skin biopsy, grown in cell culture and transduced with a corrected copy of the COL7A1 gene through a retroviral vector. The transduced keratinocytes are further cultured into epidermal sheets that are transplanted onto open wounds of patients to secure instantaneous closure.

這說明了我們對傷口完全閉合評分的嚴格標準。在接下來的兩張幻燈片中，我將討論 EB-101 如何以持續的方式實現傷口癒合的分子基礎。 EB-101 的作用是持久恢復 RDEB 角質形成細胞的功能性 VII 型膠原蛋白表達。角質形成細胞來自患者的皮膚活檢，在細胞培養物中生長，並通過逆轉錄病毒載體轉導正確的 COL7A1 基因副本。轉導的角質形成細胞進一步培養成表皮片，移植到患者的開放性傷口上以確保瞬時閉合。

The scientific rationale for EB-101's durable benefit is that the transgene encoding functional collagen 7A1 integrates into the host genome and is therefore maintained stably as cells divide and form epidermal sheets in our manufacturing process. Furthermore, immunohistochemistry of skin biopsies from EB-101 treated sites demonstrates sustained collagen expression for up to 24 months.

EB-101 持久益處的科學原理是，編碼功能性膠原蛋白 7A1 的轉基因整合到宿主基因組中，因此在我們的製造過程中細胞分裂和形成表皮片時保持穩定。此外，EB-101 治療部位皮膚活檢的免疫組織化學顯示膠原蛋白持續表達長達 24 個月。

And in fact, we have unpublished data for up to 36 months those green lines that you see indicate collagen 7A1 staining and the white arrows point to the epidermal junction. This is the rationale for the compelling durability with EB-101 as observed in our Phase I/IIa study at the mean follow-up of 5.9 years and a maximum of 8 years. The results show that majority of EB-101 treated wounds showed sustained healing when pain reduction after a onetime treatment. I'd now like to turn the call over to our Chief Medical Officer, Dr. Dmitriy Grachev, who will review the results that were presented at ISID.

事實上，我們有長達 36 個月的未發表數據，您看到的那些綠線表示膠原蛋白 7A1 染色，白色箭頭指向表皮連接處。這就是 EB-101 令人信服的耐久性的基本原理，正如我們在 I/IIa 期研究中觀察到的，平均隨訪時間為 5.9 年，最長為 8 年。結果表明，大多數 EB-101 治療的傷口在一次性治療後疼痛減輕時表現出持續癒合。我現在想將電話轉給我們的首席醫療官 Dmitriy Grachev 博士，他將審查 ISID 上提交的結果。

Thank you, Vish. First, I would like to express my excitement about data presented at International Societies for Investigated Dermatology meetings or ISID Dr. Jean Tang, Professor of Dermatology Stanford and principal instigator of the VIITAL study, presented the data during oral session at ISID and data were also featured in separate poster presentation.

謝謝你，維什。首先，我想對在國際皮膚病學研究學會會議或 ISID 上提出的數據表示興奮。斯坦福大學皮膚病學教授、VIITAL 研究的主要發起人 Jean Tang 博士在 ISID 口頭會議上提出了這些數據，並且數據也被在單獨的海報展示中出現。

The results presented at ISID show that EB-101 improved wound healing and pain reduction at 6, 12 and 24 weeks compared to control wounds following onetime application of EB-101. Furthermore, EB-101 demonstrated improvement in patient reported and caregiver reported outcomes for each and blistering severity. Before reviewing the results, I want to provide a brief summary of the trial design for VIITAL.

ISID 上公佈的結果顯示，與一次性使用 EB-101 後的對照傷口相比，EB-101 在 6、12 和 24 週時改善了傷口癒合並減輕了疼痛。此外，EB-101 證明了患者報告和護理人員報告的每種情況和起泡嚴重程度的結果都有所改善。在審查結果之前，我想簡要總結一下 VIITAL 的試驗設計。

VIITAL was designed to investigate the efficacy, safety and tolerability of EB-101 in approximately 36 large chronic wound pairs in 10 to 15 patients with a minimum age of 6 years. Our study was randomized and controlled. Each patient had a minimum 2 large chronic wounds selected with each randomized treated wounds being paired with the controlled wound simulant size, years that wound remain chronically open and anatomical location to the extent possible with the same patients.

VIITAL 旨在研究 EB-101 在 10 至 15 名年齡至少為 6 歲的患者的約 36 對大型慢性傷口中的療效、安全性和耐受性。我們的研究是隨機和對照的。每個患者至少選擇 2 個大的慢性傷口，每個隨機治療的傷口與受控傷口模擬尺寸、傷口保持長期開放的年數和解剖位置盡可能與相同患者配對。

In VIITAL, we define large chronic wounds as wounds that have greater than 20 square centimeters of surface area and remain open for a minimum 6 months although many were open for years. We aligned with FDA on the study endpoints and statistical analysis plan. Given that EB-101 is targeting large chronic wounds, remember, the hardest to treat wounds that remain open for years because they cannot self-heal. We align on the co-primary endpoint of greater than or equal to 50% wound healing and the second co-primary endpoint of pain reduction as additional measure of clinical benefit. Specifically, the co-primary end points were; first, the proportion of RDEB wound sites with greater than equal to 50% of healing from baseline, comparing randomized treated with match control wound size at 6 months' time point as determined by direct investigator assessment; and second, pain reduction associated with wound dressing change assessed by the mean difference in score of the Wong-Baker FACES scale between randomized treated and [meg-control] wounds at 6-month standpoint as reported by the patient.

在 VIITAL 中，我們將大型慢性傷口定義為表面積大於 20 平方厘米且開放時間至少 6 個月的傷口，儘管許多傷口已開放數年。我們與 FDA 在研究終點和統計分析計劃上保持一致。鑑於 EB-101 的目標是大面積慢性傷口，請記住，最難治療的傷口是多年開放的傷口，因為它們無法自愈。我們將傷口癒合率大於或等於 50% 的共同主要終點和疼痛減輕的第二個共同主要終點作為臨床效益的額外衡量標準。具體來說，共同主要終點是：首先，RDEB 傷口部位自基線癒合率大於等於 50% 的比例，將隨機治療與 6 個月時間點的匹配對照傷口大小進行比較（由直接研究者評估確定）；其次，根據患者報告的 6 個月標準，通過隨機治療傷口和 [meg 對照] 傷口之間的 Wong-Baker FACES 量表評分的平均差異來評估與傷口敷料更換相關的疼痛減輕。

This is the first pivotal study, this patient reported pain as a co-primary endpoint. The secondary endpoint was the proportion of RDEB wound sites with complete wound healing from baseline, campaign randomized treated with meg-control wound size at weeks 12 and 24. Exploratory endpoints included additional assessment for wound healing and pain reduction as well as assessment for each severity and blistering.

這是第一項關鍵研究，該患者報告疼痛作為共同主要終點。次要終點是 RDEB 傷口部位相對於基線完全癒合的比例，在第 12 周和第 24 週時使用巨噬細胞對照傷口大小進行隨機治療。探索性終點包括對傷口癒合和疼痛減輕的額外評估以及對每種嚴重程度的評估和起泡。

We reviewed the baseline characteristics during the VIITAL top line results call and I won't go into details here. I'm just to remind you of the large size and severe pain associated with the wound included in VIITAL. Median body surface area of randomized wounds treated with EB-101 per patient was 160 square centimeters with the range of 80,000 to 200 square centimeters. To clarify, average treated wounds is 40 square centimeters, exactly the size of the graph.

我們在 VIITAL 頂線結果電話會議期間審查了基線特徵，我不會在這裡詳細介紹。我只是提醒您 VIITAL 中的傷口面積較大且疼痛劇烈。每位患者接受 EB-101 治療的隨機傷口的中位體表面積為 160 平方厘米，範圍為 80,000 至 200 平方厘米。需要澄清的是，平均治療的傷口為 40 平方厘米，正好是圖表的大小。

For large chronic areas that exceed 40 square centimeters, multiple grafts could be applied to quilt like fashion, in which case the area covered by the each graft is considered distant wound. In a wound area was less than 40 square centimeters, debridement was required to prepare the wound bed to feed the graft. On the contrary, control wounds were not debrided. Median wound duration of randomized treated wounds that is months that the wound had remained chronically open was 60 months or 5 years. The control wounds had very similar wound durations.

對於超過40平方厘米的大面積慢性病區，可以將多個移植物應用到被子狀時裝中，在這種情況下，每個移植物覆蓋的區域被認為是遠處傷口。在傷口面積小於40平方厘米的情況下，需要進行清創以準備傷口床以餵養移植物。相反，對照傷口沒有被清創。隨機治療傷口的中位傷口持續時間（即傷口長期保持開放的月份）為 60 個月或 5 年。對照傷口的傷口持續時間非常相似。

Now we can turn to the results. To help you follow the charts and graphs, EB-101 treatment -- treated wounds are in blue and controlled wounds and gray. Wound healing was observed at the earliest standpoint assessed, which was 6 weeks and was sustained at all subsequent time points including 24 weeks. Consistent with wound healing, statistically significant pain reduction was seen in early standpoint assessed, which was 6 weeks and sustained at all subsequent time points including 24 weeks.

現在我們可以看看結果了。為了幫助您遵循圖表和圖形，EB-101 治療——已治療的傷口為藍色，受控制的傷口為灰色。在評估的最早時間點即 6 週觀察到傷口癒合，並在隨後的所有時間點（包括 24 週）持續癒合。與傷口癒合一致，在 6 週的早期評估中觀察到統計學上顯著的疼痛減輕，並且在包括 24 週在內的所有後續時間點上持續存在。

Pain assessment by caregivers showed great improvement in pain scores for EB-101 treated wounds with 46% of caregivers categorizing wounds as much improved or very much improved at week 24 from baseline for EB-101 treated wounds compared to 0% for the control wounds. In addition, at home pain severity assessment using Wong-Baker FACES scale showed significant pain reduction with EB-101 treatment as early as week 3.

護理人員的疼痛評估顯示，EB-101 治療傷口的疼痛評分有了很大改善，46% 的護理人員將 EB-101 治療傷口在第 24 週時的傷口分類為與基線相比有很大改善或非常改善，而對照傷口的這一比例為 0%。此外，使用 Wong-Baker FACES 量表進行的家庭疼痛嚴重程度評估顯示，早在第 3 週，EB-101 治療的疼痛就顯著減輕。

Pain was also assessed using Patient-Reported Outcomes Measurement Information System called PROMISE with a significantly greater improvement in pain quality sensory score achieved with EB-101 treatment. In addition to significantly reducing pain, patient reported and care giver reported outcomes related to each and blistering showed significantly greater improvement with EB-101 treatment.

還使用名為 PROMISE 的患者報告結果測量信息系統對疼痛進行了評估，通過 EB-101 治療，疼痛質量感覺評分有了顯著改善。除了顯著減輕疼痛之外，患者報告和護理人員報告的與每個相關的結果和水皰顯示，EB-101 治療有顯著更大的改善。

As a reminder, each for -- other patient is a significant factor that impacts quality of life and increases risk of trauma, blistering and infection. Now let's review safety and tolerability. EB-101 was shown to be safe and well tolerated with no serious treatment-related adverse events observed in VIITAL, consistent this past clinical trial experience.

提醒一下，對於其他患者來說，每一個都是影響生活質量並增加創傷、水泡和感染風險的重要因素。現在讓我們回顧一下安全性和耐受性。 EB-101被證明是安全的且耐受性良好，在 VIITAL 中沒有觀察到與治療相關的嚴重不良事件，這與過去的臨床試驗經驗一致。

In conclusion, VIITAL demonstrated positive pivotal study results and a favorable risk-benefit profile for EB-101 in patients with RDEB. Back to you, Vish.

總之，VIITAL 展示了 EB-101 在 RDEB 患者中的積極關鍵研究結果和有利的風險效益狀況。回到你身邊，維什。

Thank you, Dmitriy. We've made significant progress towards BLA submission and are marching towards commercialization. We had previously mentioned, one of the key milestones was to complete 3 consecutive process performance qualification, or PPQ runs, to demonstrate our validated process and readiness for commercial production.

謝謝你，德米特里。我們在 BLA 提交方面取得了重大進展，並正在邁向商業化。我們之前提到過，關鍵里程碑之一是完成連續 3 次工藝性能鑑定或 PPQ 運行，以證明我們經過驗證的工藝和商業生產的準備情況。

We're excited to share that today, we have completed this important step for both the retroviral vector manufacturing and EB-101 drug product manufacturing, which was the last critical piece of data we had to generate to complete the CMC module for the BLA submission. We announced in our first quarter 2023 results press release that we had submitted a pre-BLA meeting request with the FDA.

我們很高興今天與大家分享，我們已經完成了逆轉錄病毒載體製造和 EB-101 藥品製造的這一重要步驟，這是我們為完成 BLA 提交的 CMC 模塊而必須生成的最後一個關鍵數據。我們在 2023 年第一季度業績新聞稿中宣布，我們已向 FDA 提交了 BLA 前會議請求。

The FDA has since accepted our request and the pre-BLA meeting is scheduled on July 10, 2023 to discuss the format, content and acceptability of the anticipated BLA application. Based on this meeting date, we are on track for the anticipated BLA submission in early third quarter of 2023. Based on the anticipated timing of BLA submission, we expect potential BLA approvals in late first quarter or early second quarter of 2024. If the BLA is approved, we anticipate being granted the priority review voucher, which can be used to receive expedited review by the FDA of a subsequent marketing application for a different product or sold to another company, prior PRVs have been sold to other biopharma companies for approximately $100 million.

FDA 此後接受了我們的請求，並定於 2023 年 7 月 10 日召開 BLA 前會議，討論預期 BLA 申請的格式、內容和可接受性。根據本次會議日期，我們預計將在 2023 年第三季度初提交 BLA。根據 BLA 提交的預期時間，我們預計 BLA 可能會在 2024 年第一季度末或第二季度初獲得批准。如果 BLA獲得批准後，我們預計將獲得優先審查憑證，該憑證可用於接受 FDA 對不同產品的後續營銷申請或出售給另一家公司的快速審查，之前的 PRV 已以大約 100 美元的價格出售給其他生物製藥公司百萬。

As part of our commercial planning for EB-101, we continue to engage with stakeholders across the health care system including public and private payers and health care providers to better understand market access and pricing for EB-101. We are encouraged by the initial feedback from these stakeholders and feedback that we have received from patient advocates and organizations, which collectively support positive coverage decisions and pricing in line with the value of a onetime treatment that delivers wound healing and pain reduction for years.

作為 EB-101 商業規劃的一部分，我們繼續與整個醫療保健系統的利益相關者（包括公共和私人付款人和醫療保健提供者）合作，以更好地了解 EB-101 的市場准入和定價。這些利益相關者的初步反饋以及我們從患者倡導者和組織收到的反饋令我們感到鼓舞，他們共同支持積極的承保決策和定價，符合一次性治療的價值，可實現傷口癒合和多年減輕疼痛。

Based on our initial discussion, payers view RDEB as a disease with very high unmet need and believe EB-101 has a well differentiated profile with durable clinical benefit for the treated wounds. Also, given the ultra-rare prevalence of our debt, payers view EB-101 will have a limited overall budget impact and have indicated high willingness to cover EB-101 with favorable access policies giving us confidence in its potential. Now let's turn to our preclinical ophthalmology programs. We presented animal proof-of-concept data at ASGCT for investigative AAV-based gene therapies for Stargardt disease, X-linked retinitis and autosomal dominant optic atrophy.

根據我們的初步討論，付款人將 RDEB 視為一種需求未得到滿足的疾病，並相信 EB-101 具有良好的差異化特徵，可為治療的傷口帶來持久的臨床益處。此外，鑑於我們的債務極其罕見，付款人認為 EB-101 對總體預算的影響有限，並表示非常願意以優惠的准入政策覆蓋 EB-101，這讓我們對其潛力充滿信心。現在讓我們轉向我們的臨床前眼科項目。我們在 ASGCT 上展示了針對 Stargardt 病、X 連鎖視網膜炎和常染色體顯性視神經萎縮的基於 AAV 的基因療法的動物概念驗證數據。

The preclinical proof-of-concept data provides early evidence of the potential of our proprietary AAV capsid and gene construct to express the recombinant protein in target tissues and rescue mutant phenotype in mouse disease models. I'd now like to turn the call over to our Chief Technical Officer, Dr. Brian Kevany, who will review the results presented at ASGCT.

臨床前概念驗證數據提供了早期證據，證明我們專有的 AAV 衣殼和基因構建體在靶組織中表達重組蛋白並在小鼠疾病模型中拯救突變表型的潛力。我現在想將電話轉給我們的首席技術官 Brian Kevany 博士，他將審核 ASGCT 上公佈的結果。

Thank you, Vish. We are excited by the broad potential for treating serious eye diseases with the new AAV-based therapies using novel AAV capsids from our in-licensed AIM capsid library and internal research. At ASGCT, we presented 3 posters highlighting encouraging findings from animal proof-of-concept experiments from our AAV ophthalmology program. The first poster presented featured ABO-504, a novel approach to treating Stargardt disease, the most common form of juvenile inherited macular dystrophy. Autosomal recessive starter disease is caused by mutations in the ABCA4 gene, preventing the removal of toxic substances from photoreceptor cells that result in photoreceptor cell death and progressive vision loss.

謝謝你，維什。我們對基於 AAV 的新型療法使用來自我們許可的 AIM 衣殼庫和內部研究的新型 AAV 衣殼治療嚴重眼部疾病的廣泛潛力感到興奮。在 ASGCT 上，我們展示了 3 張海報，重點介紹了 AAV 眼科項目的動物概念驗證實驗的令人鼓舞的發現。第一張海報展示了 ABO-504，這是一種治療 Stargardt 病的新方法，Stargardt 病是青少年遺傳性黃斑營養不良的最常見形式。常染色體隱性遺傳病是由 ABCA4 基因突變引起的，該基因突變阻止感光細胞去除有毒物質，從而導致感光細胞死亡和進行性視力喪失。

Our proprietary strategy is designed to efficiently reconstitute the full length ABCA4 gene which is too large to fit in a standard AAV genome by implementing a dual AAV vector strategy utilizing the Cre-lox fee recombinase system. The data at ASGCT provides compelling evidence that 2 independent AAV vectors utilizing Cre recombinase can efficiently reconstitute the ABCA4 gene, leading to full length ABCA4 protein expression.

我們的專有策略旨在通過利用 Cre-lox 費重組酶系統實施雙 AAV 載體策略，有效地重建全長 ABCA4 基因，該基因太大而無法適應標準 AAV 基因組。 ASGCT 的數據提供了令人信服的證據，證明利用 Cre 重組酶的 2 個獨立的 AAV 載體可以有效地重建 ABCA4 基因，從而導致全長 ABCA4 蛋白表達。

Key conclusions presented include in vivo Cre mediate recombination yields full length ABCA4 using our dual AAV vector system, recombinant human ABCA4 is detected and properly localized to photoreceptor outer segments within one month of treatment. Our results show that Cre mediated recombination of dual AAV vectors is safe and effective in delivering an expression of full-length human AVC (inaudible) in a knockout mouse model, paving the way for a novel therapeutic approach for treating Stargardt disease.

提出的關鍵結論包括使用我們的雙 AAV 載體系統體內 Cre 介導重組產生全長 ABCA4，在治療一個月內檢測到重組人 ABCA4 並正確定位到光感受器外節。我們的結果表明，Cre 介導的雙 AAV 載體重組在敲除小鼠模型中安全有效地表達全長人 AVC（聽不清），為治療 Stargardt 病的新治療方法鋪平了道路。

Further studies will evaluate ABCA4 expression on accumulation of lipofuscin in a mouse model of Stargardt disease. Additionally, we believe our dual vector approach using Cre-lox can also be adapted for other therapies in which AAV-based delivery of large genes is desired. Our second poster presented at ASGCT featured ABO-503, a novel gene therapy approach for the treatment of X-linked retinoschisis, or XLRS, the most common form of inherited macular dystrophy in males. XLRS patients present in the first decade of life with cavities developing between retinal layers leading to discontinuity within the retinal circuitry, photoreceptor degeneration and vision loss.

進一步的研究將評估 Stargardt 病小鼠模型中 ABCA4 表達對脂褐素積累的影響。此外，我們相信我們使用 Cre-lox 的雙載體方法也可以適用於需要基於 AAV 的大基因遞送的其他療法。我們在 ASGCT 上展示的第二張海報展示了 ABO-503，這是一種用於治療 X 連鎖視網膜劈裂症 (XLRS) 的新型基因治療方法，XLRS 是男性遺傳性黃斑營養不良的最常見形式。 XLRS 患者在生命的第一個十年中出現視網膜層之間形成空洞，導致視網膜迴路內的不連續性、光感受器變性和視力喪失。

ABO-503 is composed of a functional human RS1 package in the novel AIM capsid AAV204 that effectively targets photoreceptors and restores RS1 expression. ABO-503 will be administered via a para retinal injection that will provide an improved safety profile for treatment of XLRS in which targeting and photoreceptors is desired, but where disease renders the retinas susceptible to damage from more invasive approaches.

ABO-503由新型AIM衣殼AAV204中的功能性人類RS1包組成，可有效靶向光感受器並恢復RS1表達。 ABO-503 將通過視網膜旁注射進行給藥，這將為 XLRS 的治療提供改進的安全性，其中需要靶向和光感受器，但疾病使視網膜容易受到更具侵入性方法的損害。

The data presented at ASGCT demonstrated robust RS1 expression in the retina improved cone photoreceptor density and overall photoreceptor cell survival as well as the restoration of the outer retina architecture. Treatment with ABO-503 in Newton mice was associated with photoreceptor preservation and improved retinal function.

ASGCT 上提供的數據表明，視網膜中 RS1 的強勁表​​達提高了視錐細胞密度和整體感光細胞存活率，並恢復了外視網膜結構。對牛頓小鼠進行 ABO-503 治療與光感受器保存和視網膜功能改善相關。

These results support further development of ABO-503 for the treatment of XLRS. Our third poster presentation at ASGCT featured an investigative AAV gene therapy for autosomal dominant optic atrophy, or ADOA, a form of vision loss associated with loss of retinal ganglion cells or RGCs, residing in the inner retina caused by mutations in the OPA1 gene. The candidate vector is composed of the human OPA1 gene packaged in the AIM Capsid-AAV204 discussed previously.

這些結果支持進一步開發 ABO-503 用於治療 XLRS。我們在 ASGCT 上的第三張海報展示以針對常染色體顯性視神經萎縮（ADOA）的研究性 AAV 基因療法為特色，ADOA 是一種與視網膜神經節細胞或 RGC 損失相關的視力喪失形式，位於視網膜內層，由 OPA1 基因突變引起。候選載體由包裝在前面討論的 AIM Capsid-AAV204 中的人類 OPA1 基因組成。

The proximity of RGCs to the vitreous cavity make them an attractive target for gene therapy delivered by a pararetinal dosing route. The data presented confirmed expression of OPA1 in both cell culture and retinas of dosed wild type and disease model animals, improvements in photoreceptor outer nuclear layer thickness and optokinetic responses were observed with our OPA1 gene therapy candidate in a 10-month proof-of-concept study designed to test the functional consequences of OPA1 restoration in mouse retinas following an intravitreal injection.

RGC 靠近玻璃體腔，使其成為通過視網膜旁給藥途徑進行基因治療的有吸引力的靶點。數據證實了 OPA1 在野生型和疾病模型動物的細胞培養物和視網膜中的表達，在 10 個月的概念驗證中，我們的 OPA1 基因治療候選藥物觀察到光感受器外核層厚度和光動反應的改善研究旨在測試玻璃體內註射後 OPA1 恢復對小鼠視網膜的功能影響。

Initial efficacy results suggest an improvement in retinal signaling to the brain and improved visual acuity and treated Newton life. These benefits support further development of our OPA1 gene therapy candidate. Back to you, Vish.

初步療效結果表明，視網膜向大腦發出的信號得到了改善，視力也得到了改善，牛頓的壽命也得到了改善。這些益處支持我們的 OPA1 基因療法候選藥物的進一步開發。回到你身邊，維什。

Thank you, Brian. We're looking forward to pre-IND meetings with the FDA for 2 of our programs taking place this quarter. With that, I'll turn the call back over to Ali for the Q&A section.

謝謝你，布萊恩。我們期待本季度與 FDA 就我們的 2 個項目舉行 IND 前會議。這樣，我會將電話轉回給 Ali 進行問答部分。

(Operator Instructions) Our first question is coming from Maury Raycroft at Jefferies.

（操作員說明）我們的第一個問題來自 Jefferies 的 Maury Raycroft。

Congrats on the updates and thanks for the presentation today. We saw Krystal's VYJUVEK was approved with a relatively broad label. Do you expect the same based on your conversations with the agency, including patient profile type of wounds, et cetera? Maybe if you can talk a little bit about what you're expecting the label.

祝賀您的更新並感謝您今天的演講。我們看到Krystal的VYJUVEK被批准了一個相對廣泛的標籤。根據您與該機構的對話，包括患者概況、傷口類型等，您是否期望得到同樣的結果？也許你可以談談你對這個標籤的期望。

Thank you, Maurice, for the question. Regarding the indication and the patient types, I want to reiterate that VIITAL, our pivotal study has treated RDEB patients or recessive dystrophic EB. And we have inclusion criteria that focus on large and chronic wounds. It's very early in the BLA process to comment on how broad or restrictive the label would be given, of course, the high unmet need, and this is an ongoing dialogue that's going to be there with the agency. So Unfortunately, I cannot give you a definitive answer, but what I can assure is the types of wounds that we have generated evidence for.

謝謝莫里斯提出的問題。關於適應症和患者類型，我想重申，我們的關鍵研究 VIITAL 已經治療了 RDEB 患者或隱性營養不良 EB。我們的納入標準主要針對大面積和慢性傷口。在 BLA 流程的早期階段，就該標籤的廣泛性或限制性進行評論還為時過早，當然，未滿足的需求很高，這是將與該機構進行的持續對話。不幸的是，我無法給你一個明確的答案，但我可以保證的是我們已經生成證據的傷口類型。

Got it. That makes sense. And you mentioned that initial feedback from stakeholders across the health care system has been positive. Maybe if you can talk a little bit about how you're anticipating pricing could work out with VYJUVEK having a list price of about $630,000. I guess how does that inform how you're thinking about pricing?

知道了。這就說得通了。您提到整個醫療保健系統的利益相關者的初步反饋是積極的。也許如果您能談談您對定價的預期，VYJUVEK 的標價約為 630,000 美元。我想這對您如何考慮定價有什麼影響？

Certainly can talk about that. I will turn the call over to Madhav Vasanthavada, who is leading a lot of our discussions with important stakeholders like both payers as well as hospital administrators, where there's a clear appreciation for the value proposition of a onetime treatment that can give you years of benefit without having to treat the same wound again. So Madhav, if you can throw light on the differentiation and how we have discussed about pricing, please?

當然可以談論這一點。我會將電話轉給 Madhav Vasanthavada，他正在領導我們與付款人和醫院管理人員等重要利益相關者進行大量討論，他們對一次性治療的價值主張有明確的讚賞，這種治療可以給您帶來多年的好處無需再次治療同一傷口。 Madhav，您能否闡明一下差異化以及我們如何討論定價？

Sure, Vish. Maury, thanks for the question. Yes, we find VYJUVEK launch price now to be very insightful in how we will go about with pricing. Earlier in the year, we had conducted payer research, mostly blinded research with nearly a dozen payer groups across commercial, Medicare, Medicaid. And it was very encouraging to hear when we discussed the clinical profiles of both all the investigation therapies, including B-VEC as well as for EB-101 that the payers really find the clinical profile for EB-101 to be very transformational given the wound healing profile, pain reduction and durable.

當然，維什。莫里，謝謝你的提問。是的，我們發現 VYJUVEK 現在的發布價格對於我們如何定價非常有洞察力。今年早些時候，我們進行了付款人研究，大部分是對商業、醫療保險、醫療補助等近十幾個付款人團體進行的盲法研究。當我們討論包括 B-VEC 和 EB-101 在內的所有研究療法的臨床概況時，聽到付款人確實發現 EB-101 的臨床概況對於傷口而言非常具有變革性，這令人非常鼓舞癒合輪廓、減少疼痛且持久。

And at that time, we had placed a few different scenarios as to what if the entry price for VYJUVEK would be? And how would that compare with potential price and price elasticity for EB-101, which is all very encouraging. And now that we have learned what the pricing for VYJUVEK is, we will be in a much better position to be able to place pricing for EB-101 to making sure that there is no access hurdles to patients. But at the same time, we are also capturing the value for the innovation and the durable effects that EB-101 will be able to bring. So all in all, I think the price elasticity maintains. And given the profile that we now have, we'll be in a better position to be able to place a price for a launch price for EB-101. Does that help shed?

當時，我們設定了幾種不同的場景，如果 VYJUVEK 的入門價格會怎樣？與 EB-101 的潛在價格和價格彈性相比如何，這一切都非常令人鼓舞。現在我們已經了解了 VYJUVEK 的定價，我們將能夠更好地為 EB-101 定價，以確保患者不存在使用障礙。但與此同時，我們也正在捕捉 EB-101 能夠帶來的創新價值和持久影響。總而言之，我認為價格彈性保持不變。鑑於我們現在掌握的情況，我們將能夠更好地為 EB-101 的上市價格定價。這有助於脫毛嗎？

Yes, that's helpful. It makes sense with understanding the value proposition. And maybe last question, and then I'll hop back in the queue. The gene therapy data from ASGCT looks good. Just wondering if you could talk a little bit more about how you're prioritizing those 3 different opportunities. And should we think of Stargardt what the 504 program as being the lead? Or how should we think about that?

是的，這很有幫助。了解價值主張是有意義的。也許是最後一個問題，然後我會跳回到隊列中。 ASGCT 的基因治療數據看起來不錯。只是想知道您是否可以多談談您如何優先考慮這 3 個不同的機會。我們是否應該將 Stargardt 視為 504 計劃的主導者？或者說我們應該如何思考這個問題？

Sure. I can talk a little bit about it and then turn it over to Brian for any additional thoughts. Right now, we have compelling preclinical data from these disease models in mice that showed the expression of the gene as you may be aware, there's high unmet need in all 3 of those indications. We have chosen those indications specifically based on many other investigational therapies are able to make inroads and have hit some challenges along the way. And we're encouraged to see that Stargardt of course, the most talked about among the 3 were able to uniquely address the size of the ABCA4 gene and produce that in the correct tissue. In terms of prioritization and how we resource these programs, Maury, it's going to be -- we have a lot of dialogue going on.

當然。我可以談談它，然後將其轉交給布萊恩以獲取任何其他想法。目前，我們從小鼠的這些疾病模型中獲得了令人信服的臨床前數據，這些數據顯示了該基因的表達，正如您可能知道的那樣，所有這 3 種適應症都有很高的未滿足需求。我們專門基於許多其他研究療法能夠取得進展並在此過程中遇到了一些挑戰而選擇了這些適應症。當然，我們很高興看到 Stargardt（這 3 者中最受關注的）能夠獨特地解決 ABCA4 基因的大小並在正確的組織中產生它。在優先順序以及我們如何為這些計劃提供資源方面，莫里，我們將進行很多對話。

We're looking at various different sources of funding, non-dilutive as well and even some potential government funds, and these are programs that are all equally high in unmet need. And so it's not really going to be an either/or it's just going to be a matter of when. And such events will be further discussed in our upcoming calls as we make more progress and also get a little bit more clarity on other nuances from our dialogue with the agency because that tells us -- I mean, are we going to be helped to having NHP data? Or can we have other types of animal studies, which will make it much quicker to develop these drugs. So there's a lot of other pieces to the equation, which will further inform our prioritization.

我們正在研究各種不同的資金來源，包括非稀釋資金，甚至一些潛在的政府資金，這些項目的未滿足需求同樣很高。因此，這並不是一個非此即彼的問題，而只是時間問題。隨著我們取得更多進展，並從與該機構的對話中更清楚地了解其他細微差別，此類事件將在我們即將舉行的電話會議中進一步討論，因為這告訴我們 - 我的意思是，我們是否會得到幫助國民健康保險數據？或者我們可以進行其他類型的動物研究，這將使開發這些藥物的速度更快。因此，這個方程還有很多其他部分，這將進一步確定我們的優先級。

Your next question is coming from Kristen Kluska at Cantor Fitzgerald.

您的下一個問題來自 Cantor Fitzgerald 的 Kristen Kluska。

Congrats on both of these recent data sets. The first question I had was related to the ophthalmology portfolio. So we haven't seen as many dual AAV vector strategies yet in gene therapy. I know it's something that others have talked about for some time. So maybe the first part of the question is just understanding what you think is differentiated about your construct that led to the successful findings at this preclinical stage. And then the latter half of that question is just, frankly, looking at the dual AAV vector landscape, what are the expectations on how you would expect this to translate into human studies. And I guess the key things to look out for, given the difference between the models.

祝賀這兩個最近的數據集。我的第一個問題與眼科投資組合有關。因此，我們在基因治療中尚未看到如此多的雙 AAV 載體策略。我知道這是其他人已經談論了一段時間的事情。因此，也許問題的第一部分只是了解您認為您的構造有何不同之處，從而在臨床前階段取得了成功的發現。坦率地說，這個問題的後半部分只是看看雙 AAV 載體景觀，您對如何將其轉化為人類研究有何期望。考慮到模型之間的差異，我猜想需要注意的關鍵事項。

I'm going to turn it over to the expert on AAV and Ophthalmology, which will be Dr. Brian Kevany, but I think before that, I'd just say that we do have -- thank you for this question specifically because there are certain mechanistic elements of why we think we can be successful where some other approaches of getting full linked ABCA4 other methods fail in the past. So Brian, can you please throw some light on our unique gene constructs and the dual AAV system, please?

我將把它交給 AAV 和眼科專家，即 Brian Kevany 博士，但我想在此之前，我只想說我們確實有 - 特別感謝您提出這個問題，因為有某些機制因素解釋了為什麼我們認為我們可以成功，而過去一些其他獲得完全鏈接的 ABCA4 方法卻失敗了。 Brian，您能介紹一下我們獨特的基因構造和雙 AAV 系統嗎？

Of course, yes. Thanks, Kristen. Yes. So I think there have been a number of strategies that have been tried, both in dual AAV vectors as well as mini genes for ABCA4. And while those programs have been going on for a number of years, we haven't seen a lot of movement. So I think we were encouraged by our ability to do this and push into a field that is still struggling to get construct that provides full length ABCA4.

當然，是的。謝謝，克里斯汀。是的。因此，我認為已經嘗試過多種策略，包括雙 AAV 載體以及 ABCA4 的迷你基因。雖然這些計劃已經進行了很多年，但我們還沒有看到太多進展。因此，我認為我們有能力做到這一點並進入一個仍在努力獲得提供全長 ABCA4 的結構的領域，這讓我們感到鼓舞。

As far as how we differentiate from others, the Cre recombinase system is one of the most efficient recombination systems known in nature. And we're trying to take advantage of that as part of developing this therapy. So I think that is the one place where we differentiate from others where they're using things like homologous recombination and intains where the efficiency of recombination may not be as high as what we're seeing with the Cre recombinase system.

就我們與其他重組酶的區別而言，Cre 重組酶系統是自然界已知的最有效的重組系統之一。我們正在嘗試利用這一點作為開發這種療法的一部分。所以我認為這是我們與其他人不同的地方，他們使用同源重組之類的東西，並且重組效率可能不如我們在 Cre 重組酶系統中看到的那麼高。

So I think the major differentiating point for us is less about the [dual AVs] and more about the actual mechanistic aspects of the therapy that we're trying to develop here. And Kristen, could you repeat your second part of your question?

因此，我認為我們的主要區別點不是 [雙 AV]，而是我們在這裡嘗試開發的療法的實際機制方面。克里斯汀，你能重複一下你問題的第二部分嗎？

The second part of the question was just essentially on how you think it's going to translate into human studies. And I guess, what are the key things to consider the risks of course, going from the different models outside of what you normally expect.

問題的第二部分本質上是關於你認為它將如何轉化為人類研究。我想，當然，從您通常預期之外的不同模型中考慮風險的關鍵因素是什麼。

Sure. Yes. I mean I don't anticipate any significant differences. I mean the advantage here is we're approaching this with a subretinal delivery for the Stargardt program. For those that aren't aware, this is a relatively very specific injection that occurs between the photoreceptors and the retinal pigment epithelium. This directed injection keeps the vector very close to the site of action and does not get diluted out as if you were providing it as an intravenous or other types of injections. So I think the aspects of that keep it somewhat similar to between -- as we're moving between, say, mouse to a larger animal model during IND-enabling studies and then beyond into the human studies.

當然。是的。我的意思是我預計不會有任何重大差異。我的意思是，這裡的優勢是我們正在通過 Stargardt 計劃的視網膜下遞送來解決這個問題。對於那些不知道的人來說，這是發生在光感受器和視網膜色素上皮之間的相對非常特殊的注射。這種定向注射使載體非常接近作用部位，並且不會像靜脈注射或其他類型注射那樣被稀釋。因此，我認為這在某種程度上保持了兩者之間的相似性——例如，在 IND 啟用研究期間，我們正在從小鼠模型轉移到更大的動物模型，然後再進入人類研究。

So I think the translation from, say, the large animal to the human studies is going to be relatively smooth because of the injection volume will be exactly the same between the large animal model and the human. We'll be using a lot of the -- exactly the same type of dosing. So I think that sort of translation from large to humans is going to be relatively seamless. Yes.

因此，我認為從大型動物研究到人類研究的轉化將相對順利，因為大型動物模型和人類之間的注射量將完全相同。我們將使用很多完全相同類型的劑量。所以我認為從大到人類的這種翻譯將是相對無縫的。是的。

And then for the autosomal dominant optic atrophy study that you presented on, you have the bullet here that visual acuity assessments demonstrate function recovery. I think with a lot of the AAV ophthalmology gene therapy trials, the goal essentially is to show slowing down of disease progression rather than reversal. So I guess I'm just kind of interested in the context of that comment. And maybe how you think about this clinically and understand a lot of it is going to have to do with age of intervention. And these different diseases progress at different rates, but what the underlying goal you're essentially looking at will be.

然後，對於您提出的常染色體顯性視神經萎縮研究，這裡的重點是視力評估證明功能恢復。我認為許多 AAV 眼科基因治療試驗的目標本質上是顯示疾病進展的減慢而不是逆轉。所以我想我只是對該評論的背景感興趣。也許你在臨床上如何看待這個問題並理解其中很多內容與乾預年齡有關。這些不同的疾病以不同的速度發展，但您本質上關注的根本目標是什麼。

Yes. So visual acuity in mice is something that we've studied with this animal study and looking at preservation or improvement of visual acuity over time. So these animals, as they age, the mutant animals age, they start to lose their ability to have high acuity vision. This treatment was provided very early on in the disease progression prior to any degradation of that visual acuity. So it really was a prevention of that development. And visual acuity is a difficult thing to study in humans because it's something that takes a long time to develop.

是的。因此，我們通過這項動物研究來研究小鼠的視敏度，並觀察隨著時間的推移視敏度的保持或提高。所以這些動物，隨著年齡的增長，突變動物的年齡，他們開始失去高視力的能力。在疾病進展的早期，在視力出現任何下降之前就提供了這種治療。所以這確實是對這種發展的阻止。人類的視敏度是一件很難研究的事情，因為它需要很長時間才能發展。

We've seen a number of failures in the industry where visual acuity was the primary endpoint for their trial. And because of the slow progression of these diseases and specifically visual acuity, it tends to be a bit of a blunt instrument for looking at therapeutic benefit. So I think as part of our discussions with the agency, we're going to be looking at understanding how primary endpoint decisions are made to better capture a therapeutic benefit.

我們已經看到了該行業的許多失敗案例，其中視力是其試驗的主要終點。由於這些疾病的進展緩慢，特別是視力，它往往是觀察治療效果的一個生硬工具。因此，我認為，作為我們與該機構討論的一部分，我們將了解如何做出主要終點決策，以更好地獲得治療益處。

This is a very hot topic at ASGCT last week, specifically in ocular but in general, over the rare disease space about understanding meaningful endpoints that capture therapeutic benefit that may not be the ones that are available right now. So I think as we start to talk to regulators, we'll have a better sense of how we want to approach end points and make sure that we're capturing that benefit that is probably there but may not be captured by something like visual acuity.

這是上週 ASGCT 上的一個非常熱門的話題，特別是在眼科領域，但總體而言，在罕見疾病領域，了解有意義的終點，這些終點可能無法獲得目前無法獲得的治療益處。因此，我認為，當我們開始與監管機構交談時，我們將更好地了解我們希望如何接近終點，並確保我們正在捕捉可能存在但可能無法通過視力等手段捕捉到的好處。

Yes. And if I may just add to that, Kristen, also what we're going to be looking at is for any monogenic disease where we have a gene therapy our goal is to treat early enough that the disease symptoms don't appear or you preserve your eye function, right? But in terms of clinical development, it's going to be, the first priority would be prevention or cessation of deterioration of visual acuity. But of course, the bigger goal is also to see can you reverse disease that's already happened because it's a prevalent pool of patients with forgone disease.

是的。如果我可以補充一點，克里斯汀，我們還將關注的是我們進行基因治療的任何單基因疾病，我們的目標是儘早治療，以便疾病症狀不會出現或保留你的眼睛功能對嗎？但就臨床開發而言，首要任務是預防或停止視力下降。但當然，更大的目標也是看看你能否逆轉已經發生的疾病，因為這是一個普遍存在的已放棄疾病的患者群體。

So we're going to be looking to test all types of populations, maybe those that start at around 20 to 60 level of vision and maybe for those subjects where visual function may have deteriorated even more, can you reverse that, right? So we're going to be investigating clinically for all those signals -- and of course, the long-term goal is to prevent such deterioration from happening in the first place.

因此，我們將尋求測試所有類型的人群，也許是那些視力水平在 20 到 60 左右的人群，也許是那些視覺功能可能惡化得更嚴重的受試者，你能扭轉這種情況嗎？因此，我們將對所有這些信號進行臨床調查——當然，長期目標是首先防止這種惡化的發生。

Great. And then last question for me related to ARDA. ISID 2 key new findings, we're just understanding the effects at an earlier point of valuation and then also around some of these other secondary end points. So since you presented these data, I wanted to hear as you have all these discussions with thought leaders, how important these 2 components are. And I know in the past, we've talked about looking at understanding pain reductions correlated with wound healing, but now you have a number of other data points to support these notions.

偉大的。我的最後一個問題與 ARDA 有關。 ISID 2 的關鍵新發現，我們只是了解早期估值點的影響，以及其他一些次要終點的影響。因此，自從您提供了這些數據以來，當您與思想領袖進行所有這些討論時，我想听聽這兩個組成部分有多重要。我知道過去我們討論過了解與傷口癒合相關的疼痛減輕，但現在您有許多其他數據點來支持這些概念。

I'll take that. So just to kind of highlight what's the delta of data that we presented at ISID, which wasn't in the top line, right? The top line focused on the 6-month endpoint because that's the regulatory endpoint timing, whereas what we presented at ISID is, number one, how quickly do we see these effects, right? So you saw that 6 weeks, 12 weeks, 24 weeks. In fact, even 3 weeks where there wasn't a patient's visit to do a physician assessment where they're reporting, they're maintaining their diaries and writing down the pain levels and itch levels and things like that, and caregivers are scoring as well.

我會接受的。所以只是為了強調一下我們在 ISID 上提供的數據增量是多少，這不在頂行中，對吧？最上面一行重點關注 6 個月終點，因為這是監管終點時間，而我們在 ISID 上提出的第一點是，我們多久才能看到這些影響，對吧？所以你看到了 6 週、12 週、24 週。事實上，即使三週內沒有患者來訪進行醫生評估，他們也會記錄日記並寫下疼痛程度和瘙癢程度等類似信息，護理人員的評分為出色地。

We're seeing that the clinical benefit sets in early, and we've seen an example of even 3 weeks, which is pretty much soon -- a couple of weeks after they discharged and went home, right? And at every time point, you can see the same kind of benefit between treated wounds and untreated wounds, that effect has sustained.

我們看到臨床獲益很早就開始出現，我們甚至看到了 3 週的例子，這幾乎是很快的——他們出院回家後幾週，對吧？在每個時間點，您都可以看到已治療的傷口和未治療的傷口之間具有相同的益處，並且這種效果持續存在。

So that's key, and that's important to note. The second is also -- we have previously presented the correlation between the wound healing level and pain reduction. That's also very encouraging to see that it's not a one time point that's showing that it's very consistent over the time course post treatment.

所以這是關鍵，也是值得注意的。第二個也是——我們之前已經介紹了傷口癒合水平和疼痛減輕之間的相關性。這也非常令人鼓舞，因為這不是一個單一的時間點，表明它在治療後的時間過程中非常一致。

And that's -- those are the -- some of the new data points that were discussed, and we've had a lot of discussions with KOLs. And this is going to be very important in further building on the value proposition. And as Dr. Dmitriy Grachev presented, we had Itch data that's also showing a dramatic improvement for treated versus untreated. And as you heard, Itch can also be a risk factor for further blistering and trauma.

這就是——這些是——我們討論過的一些新數據點，我們與 KOL 進行了很多討論。這對於進一步構建價值主張非常重要。正如德米特里·格拉喬夫 (Dmitriy Grachev) 博士介紹的那樣，我們的瘙癢數據也顯示出治療組與未治療組相比有了顯著改善。正如您所聽到的，瘙癢也可能是進一步起泡和創傷的危險因素。

And that's something that we're encouraged to see. So this is going to be a holistic view of what is the benefit fragment. And beyond all what the KOLs, Opine and what we see as data points, what's encouraging to us is those patients who went through VIITAL are coming back in our current ongoing study, which is a source for our manufacturing runs that we conducted PPQ.

我們很高興看到這一點。因此，這將是對利益片段的整體看法。除了 KOL、Opine 和我們所看到的數據點之外，令我們感到鼓舞的是那些經歷過 VIITAL 的患者正在回到我們當前正在進行的研究中，這是我們進行 PPQ 的生產運行的來源。

And they've all lined up and they're asking for their control wounds to be treated and things like that. That's for us the ultimate a source of confidence and conviction that this is something that patients really value I hope that answered your question, Kristen?

他們都排成一排，要求治療他們的控制性傷口之類的事情。這對我們來說是最終的信心和信念的源泉，相信這是患者真正重視的東西，我希望這回答了你的問題，克里斯汀？

(Operator Instructions) Your next question for today is coming from Jim Molloy at Alliance Global Partners.

（操作員說明）今天您的下一個問題來自 Alliance Global Partners 的 Jim Molloy。

I just want to follow up on a question earlier, obviously, a competitive (inaudible) approval. And I think on their call, they're talking about the $630,000 a year about $485,000 a year after U.S. government discounts and I think they're saying about 1,100 target patients, not to hold you to a competitor's numbers, but how do those change up or down, your guys' estimates for where you think pricing can come in and size of the market given sort of their -- what they've put out there publicly as their estimates?

我只是想跟進早些時候的一個問題，顯然是競爭性（聽不清）的批准。我認為在他們的電話中，他們談論的是每年 630,000 美元，在美國政府折扣後每年約 485,000 美元，我認為他們談論的是大約 1,100 名目標患者，不是為了讓你遵守競爭對手的數字，但這些會如何改變上升還是下降，你們對定價的估計以及市場規模的估計——他們公開發布了他們的估計？

Thank you for the question, Jim. We did take note of what their pricing is, Jim. But at this point in time, as Madhav mentioned, we're encouraged by the value that the various stakeholders are placing in these types of gene therapies. I would reiterate that what we thought a year ago maybe in terms of what pricing we were considering. And then post VIITAL results, clearly, having seen the results in the best case scenario of clinical profile play out, we're definitely relooking at pricing in a different way.

謝謝你的提問，吉姆。吉姆，我們確實注意到了他們的定價。但在這個時候，正如 Madhav 提到的，我們對各個利益相關者對這些類型的基因療法的重視感到鼓舞。我想重申一下，我們一年前的想法可能是我們正在考慮的定價。然後發布 VIITAL 結果，顯然，在看到臨床概況的最佳情況下的結果後，我們肯定會以不同的方式重新考慮定價。

Now what we don't know is many details about the label for VYJUVEK is #1, it's very broad. It includes all of dystrophic EB, whereas we're currently looking at -- our clinical evidence is focused on recessive dystrophic EB, which is, let's say, half of the DEB. And so it's really an apples-to-oranges comparison because RDEB is a smaller -- it's a relatively rarer narrower disease space.

現在我們不知道的是有關 VYJUVEK 標籤的許多細節是#1，它非常廣泛。它包括所有營養不良型 EB，而我們目前正在研究的臨床證據集中在隱性營養不良型 EB，也就是說，DEB 的一半。所以這實際上是一個蘋果與橘子的比較，因為 RDEB 較小——它是一種相對罕見的狹窄疾病空間。

And the value proposition is different as well. I mean, it's -- on the one hand, you have a redoseable gene therapy. On the other hand, we have -- for a given wound, a onetime treatment that gives you years of benefit and not having to retreat soon enough, right? So that's something we will definitely take into account.

而且價值主張也不同。我的意思是，一方面，你有一種可重複劑量的基因療法。另一方面，對於特定的傷口，我們有一次性治療，可以給你帶來多年的好處，而且不必很快撤退，對嗎？所以這是我們肯定會考慮的事情。

I don't want to comment anything about exact price points and things like that because we have to do our homework on how the estimated pricing per year works out and what happens in the real world because sometimes we make these estimates and then the real world turns out. So there is some time and homework for us to do before we come up.

我不想對確切的價格點和類似的事情發表任何評論，因為我們必須做功課，了解每年的估計定價如何計算以及現實世界中發生的情況，因為有時我們先進行這些估計，然後再進行現實世界事實證明。所以我們上來之前還有一些時間和功課要做。

But I want to reassure that we will be responsible corporate citizens and make sure that patients will get access to our therapies because that's our guiding principle here.

但我想向大家保證，我們將成為負責任的企業公民，並確保患者能夠獲得我們的治療，因為這是我們的指導原則。

Outstanding. And then on the pre-BLA, anything that we should tip potentially coming out of the pre-BLA? I imagine it's a fairly -- it should be a fairly straightforward meeting then right into BLA. And then a follow-up would be again, given the competitor's approval, has this changed your thinking on self-launch for potentially partnering?

傑出的。然後，關於預 BLA，我們應該提示預 BLA 中可能出現的任何內容嗎？我想這應該是一次相當簡單的會議，然後就進入 BLA。然後後續會再一次，考慮到競爭對手的認可，這是否改變了您對自我推出潛在合作夥伴的想法？

Thanks, Jim. So the first question that you asked on the pre-BLA, it's every BLA submission, given the complexity of our therapies, the therapeutic space, limited experience that we have in these disease areas, it behooves us to have the pre-BLA meeting to make sure that we have everything that warrants a submission, there's no deficiency.

謝謝，吉姆。因此，您就 BLA 預審提出的第一個問題是每一份 BLA 提交，考慮到我們療法的複雜性、治療空間以及我們在這些疾病領域的有限經驗，我們有必要召開 BLA 預審會議來確保我們擁有所有需要提交的內容，沒有任何缺陷。

So that's kind of a -- but the pre-BLA meeting itself is that former step that you have. However, I just want to assure that it's not like we have complete silence with the agency and suddenly appearing for one; meeting on July 10, we have -- we've been having a lot of interaction with the agency, even as we speak. There's also a series of informal meetings and exchange.

所以這有點——但 BLA 之前的會議本身就是您所採取的前一步。然而，我只是想保證，我們並不是與該機構完全保持沉默，然後突然出現的。在 7 月 10 日的會議上，我們一直在與該機構進行大量互動，甚至在我們講話的時候。還有一系列非正式會議和交流。

So this will be like the final culmination step saying we scored everything that we needed to. We're going to make put the dossier in front of you, right? So that is what the pre-BLA meeting is, and we're confident we should be in time because, as I mentioned, that the biggest piece of work that we had to finish was the PPQ runs, and we completed those 3 consecutive manufacturing runs successfully.

所以這就像最後的高潮步驟，說我們取得了我們需要的一切。我們會把檔案放在你面前，對嗎？這就是 BLA 前的會議，我們有信心我們應該及時召開，因為正如我提到的，我們必須完成的最大工作是 PPQ 運行，並且我們完成了這 3 個連續的製造運行成功。

And what's significant about that is it's not just that we had to meet the release criteria for EB-101 drug products, but also all the various process parameters have to fall within the prespecified range to show the robustness of our process and we're happy to report that all those parameters met the goal and where we have everything we need to pull together the package. So that's for the pre-BLA and that submission work stream itself.

重要的是，我們不僅必須滿足 EB-101 藥品的放行標準，而且所有各種工藝參數都必須落在預先指定的範圍內，以顯示我們工藝的穩健性，我們很高興報告所有這些參數都達到了目標，並且我們擁有整合包所需的一切。這就是 BLA 前和提交工作流本身。

Your second question was about partnering and commercialization. And this is a rare disease. We have -- the focus for us is more on the delivery of our therapy in the centers where we're going to administer this and lesser on sales and marketing and full demand because we're going to be working closely with the advocacy groups, the patient communities. So there's a typical launch scenario here that the focus is going to be on how do we deliver what the patient services that's going to be needed.

你的第二個問題是關於合作和商業化。而且這是一種罕見的疾病。我們的重點更多地放在我們將要管理的中心提供治療，而不是銷售和營銷以及充分需求，因為我們將與倡導團體密切合作，患者社區。因此，這裡有一個典型的啟動場景，重點是我們如何提供患者所需的服務。

So given that, the profile of a partner, if we get a partner is going to be a very different profile than a typical large pharma kind of partnership. And so we're open to that. At the same time, we're also looking at how do we retain the value we've created? And is there options where we should be ready because we don't want to wait forever to make a partnership deal while those types of conversations are still ongoing, we want to score certain pieces of launch readiness in our hands already, which is why we started to do the payer research and stuff and talk to the stakeholders and get ready one step at a time.

因此，考慮到這一點，如果我們找到一個合作夥伴，合作夥伴的概況將與典型的大型製藥公司的合作夥伴關係截然不同。所以我們對此持開放態度。與此同時，我們也在考慮如何保留我們所創造的價值？我們是否應該做好準備，因為我們不想在這些類型的對話仍在進行時永遠等待達成合作夥伴協議，我們希望已經做好了某些啟動準備工作，這就是為什麼我們開始進行付款人研究等工作，並與利益相關者交談，一步一步做好準備。

And of course, that is only going to pick up more steam once we're through the BLA submission, which is kind of the 800-pound gorilla in the world right now. So, I hope that gives you some sense of how we are looking at commercialization as the next step. So the second half of this year is going to have a lot of that conversation coming up to lime light.

當然，只有當我們完成 BLA 提交後，這種情況才會變得更加強勁，BLA 相當於目前世界上 800 磅重的大猩猩。因此，我希望這能讓您了解我們如何看待下一步的商業化。因此，今年下半年將會有很多這樣的對話成為人們關注的焦點。

We have reached the end of the question-and-answer session, and I will now turn the call over to Vishwas for closing remarks.

問答環節已經結束，我現在將會議轉交給維什瓦斯，他將致閉幕詞。

Thank you. In closing, I want to thank our shareholders and other stakeholders who have listened to this call, and we will talk to you again soon. Thank you.

謝謝。最後，我要感謝聆聽本次電話會議的股東和其他利益相關者，我們很快將再次與您交談。謝謝。

This concludes today's conference, and you may disconnect your lines at this time. Thank you for your participation.

今天的會議到此結束，此時您可以掛斷電話了。感謝您的參與。