Regenxbio Inc (RGNX) 2024 Q4 法說會逐字稿

Welcome, everyone, to the fourth-quarter and year-end 2024 REGENXBIO earnings conference call. (Operator Instructions)

歡迎大家參加 REGENXBIO 2024 年第四季和年終財報電話會議。（操作員指示）

Please be advised that today's conference is being recorded. At this time I'd like to turn the conference over to Patrick Christmas, Chief Legal Officer of REGENXBIO. Please go ahead.

請注意，今天的會議正在錄音。現在，我想將會議交給 REGENXBIO 首席法律官 Patrick Christmas。請繼續。

Good afternoon and thank you for joining us today. Earlier this afternoon, REGENXBIO released financial and operating results for the fourth-quarter and year ending December 31, 2024. The press release is available on our website at www.regenxbio.com.

下午好，感謝您今天加入我們。今天下午早些時候，REGENXBIO 發布了截至 2024 年 12 月 31 日的第四季度和年度財務和營運業績。新聞稿可在我們的網站 www.regenxbio.com 上查閱。

Today's conference call will include forward-looking statements regarding our financial outlook, in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such aspect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning.

今天的電話會議將包括有關我們的財務前景以及監管和產品開發計劃的前瞻性聲明。這些前瞻性陳述受風險和不確定性的影響，可能導致實際結果與預測結果不同，並可透過方面、計劃、將、可能、預期、相信、應該、打算等詞語和其他類似含義的詞語來識別。

Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the risk factors in the management's discussion and analysis section of REGENXBIO's annual report on Form 10-K for the full year ended December 31, 2024, and Comparable Risk Factors sections of REGENXBIO's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website.

任何此類前瞻性陳述都不能保證未來的表現，並涉及一定的風險和不確定性。這些風險在 REGENXBIO 截至 2024 年 12 月 31 日的全年 10-K 表年度報告的管理層討論和分析部分的風險因素中以及 REGENXBIO 10-Q 表季度報告的可比較風險因素部分中有描述，這些報告已提交給美國證券交易委員會並可在美國證券交易委員會的網站上查閱。

Any information we provide on this conference call is provided only as of the date of this call, March 13, 2025, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise.

我們在本次電話會議上提供的任何資訊僅截至本次電話會議召開之日 2025 年 3 月 13 日，我們不承擔因新資訊、未來事件或其他原因而更新我們在本次電話會議上可能做出的任何前瞻性陳述的義務。

Please be advised that today's call is being recorded and webcast. In addition, to any unaudited or pro forma financial information that may be provided as preliminary and does not report to project financial positions or operating results of the company. Actual results may differ materially.

請注意，今天的通話將被錄音並進行網路直播。此外，任何未經審計或準備的財務資訊可能作為初步資訊提供，並未報告公司專案財務狀況或經營成果。實際結果可能存在重大差異。

I'll now turn the call to Curran Simpson, President and CEO of REGENXBIO. Curran.

現在我將電話轉給 REGENXBIO 總裁兼執行長 Curran Simpson。柯倫。

Thank you, Patrick, and thank you, everyone, for joining us today. 2025 is a transformational year for REGENXBIO, and we're off to an exciting start. We've submitted our first BLA and expect our first FDA approval in the fourth quarter for RGX-121, which is our treatment for boys with Hunter syndrome.

謝謝派崔克，也謝謝大家今天加入我們。 2025 年是 REGENXBIO 轉型的一年，我們迎來了一個令人興奮的開始。我們已經提交了第一份 BLA，並預計將於第四季度獲得 FDA 對 RGX-121 的首次批准，該藥物用於治療患有亨特綜合徵的男孩。

We will build on this momentum by advancing our diabetic retinopathy program into pivotal stage this year, then head into 2026 and 2027 with potential BLA filings for large opportunities, including RGX-202 for Duchenne Muscular Dystrophy, and ABBV-RGX-314 for Wet AMD.

我們將藉此勢頭，在今年將我們的糖尿病視網膜病變計畫推進到關鍵階段，然後進入 2026 年和 2027 年，為大型機會提交潛在的 BLA 申請，包括用於治療杜氏肌肉營養不良症的 RGX-202 和用於治療濕性 AMD 的 ABBV-RGX-314。

We are in a strong position as we prepare to launch multiple first or best-in-class gene therapies and have robust commercial capabilities and global partners. This is all with a view to sustainable profitability and is a result of 15-plus years of gene therapy leadership.

我們正準備推出多個首創或一流的基因療法，並擁有強大的商業能力和全球合作夥伴，因此我們處於有利地位。這一切都是為了實現永續獲利，也是 15 多年來基因療法領導地位的成果。

On today's call, I will review our recent business highlights and outline a vision for what we believe will be Catalyst rich years ahead. Then our Chief Medical Officer, Doctor Steve Pakola, will summarize our clinical progress before handing it over to Mitch Chan, Chief Financial Officer. Mitch will provide an overview of our financial results and share the many potential non-dilutive capital sources ahead. I'll then make some closing remarks before we open for Q&A.

在今天的電話會議上，我將回顧我們最近的業務亮點，並概述我們認為未來幾年催化劑豐富的願景。然後，我們的首席醫療官 Steve Pakola 醫生將總結我們的臨床進展，然後將其交給財務長 Mitch Chan。米奇將概述我們的財務表現並分享未來許多潛在的非稀釋性資本來源。在我們開始問答環節之前，我將做一些結束語。

Starting with our recent exciting news in MPS, we are thrilled to have completed the submission of the BLA for RGX-121 or clemidsogene lanparvovec under the accelerated approval pathway and partnered with Nippon Shinyaku for both of our MPS programs. This partnership marries our collective strengths. REGENXBIO's development and manufacturing expertise, with Nippon's experience in successfully commercializing rare-disease products.

從我們最近在 MPS 中令人興奮的消息開始，我們很高興在加速審批途徑下完成了 RGX-121 或 clemidsogene lanparvovec 的 BLA 提交，並與 Nippon Shinyaku 合作開展我們的兩個 MPS 專案。此次合作充分體現了我們共同的力量。REGENXBIO 的開發和製造專業知識，加上 Nippon 成功商業化罕見疾病產品的經驗。

Our teams are planning for potential approval of RGX-121 for MPS II in Q4 2025 and are working diligently to prepare for the commercial launch. Along with enabling access to these important medicines for patients in the US and Asia, this partnership is strategically insignificant to REGENXBIO.

我們的團隊正在計劃在 2025 年第四季度批准 RGX-121 用於 MPS II，並正在努力為商業發布做準備。除了讓美國和亞洲的患者能夠獲得這些重要藥物外，這種合作關係對 REGENXBIO 來說還具有重要的戰略意義。

As Mitch will share, this agreement provides meaningful potential milestones and revenue for us. The potential approval of RGX-121 also provides strategic value for the rest of our pipeline as we'd receive commercial licensure of our manufacturing facility prior to launching in our larger opportunities, including RGX-202 for Duchenne.

正如 Mitch 所說，這項協議為我們提供了有意義的潛在里程碑和收入。RGX-121 的潛在批准也為我們其餘的產品線提供了戰略價值，因為我們將在推出更大的機會（包括用於杜氏肌肉營養不良症的 RGX-202）之前獲得製造工廠的商業許可。

Moving to RGX-202, I am pleased to report that our pivotal study is advancing rapidly and that our unique second to market or fast-follower opportunity is on track for a mid-2026 BLA filing. Recent updates have indicated tremendous interest in the patient community for new treatments with RGX-202 as a valued option. Input from our growing investigator community supports our belief that RGX-202 has the potential to be a preferred and differentiated treatment option.

談到 RGX-202，我很高興地報告，我們的關鍵研究正在迅速推進，我們獨特的第二個市場或快速跟隨者機會預計將在 2026 年中期提交 BLA 申請。最近的更新表明，患者群體對以 RGX-202 為有價值的選擇的新療法表現出極大的興趣。我們不斷成長的研究人員社群的投入支持了我們的信念，即 RGX-202 有可能成為一種首選的差異化治療選擇。

I'll remind you that RGX-202 is the only investigational next generation, DMD gene therapy and pivotal study, and with both robust microdystrophin and functional data available. The pivotal trial of RGX-202 is rapidly enrolling approximately 30 ambulatory patients aged 1 and over. I'm pleased to share that this pivotal trial is nearly half enrolled, and we expect to complete enrollment this year.

我要提醒您，RGX-202 是唯一研究下一代 DMD 基因療法和關鍵研究，並且具有強大的微肌營養不良蛋白和功能數據。RGX-202 的關鍵試驗正在迅速招募約 30 名 1 歲及以上的門診患者。我很高興地告訴大家，這項關鍵試驗的受試者已接近一半，我們預計今年將完成受試者招募。

We are also on track to submit a BLA under the accelerated approval pathway by mid-2026. We expect more than half of the prevalent population to remain untreated through the next few years and this large population will need more than one treatment to serve all Duchenne patients. That's why we're confident in the rapid progress we've made thus far, and our path to delivering a potentially preferred gene therapy option.

我們還有望在 2026 年中期之前根據加速審批途徑提交 BLA。我們預計，未來幾年內，超過一半的患病人群仍未得到治療，而這一龐大的群體將需要不止一種治療方法來服務所有杜氏肌肉營養不良症患者。這就是為什麼我們對迄今為止的快速進展以及提供潛在優選基因治療方案的道路充滿信心。

Also, let me remind you that we are commercial ready when it comes to manufacturing 202. Our in-house, state of the art, suspension-based bioreactor process is currently producing 202 for our pivotal study. With industry leading purity levels of more than 80% forecasted. Our manufacturing innovation center can produce 2,500 doses of RGX-202 per year.

另外，讓我提醒您，我們在生產 202 方面已經做好了商業化的準備。我們內部最先進的懸浮生物反應器製程目前正在為我們的關鍵研究生產 202。預計純度水準將達到行業領先水準的 80% 以上。我們的製造創新中心每年可生產 2,500 劑 RGX-202。

As we continue to aggressively accelerate BLA enabling activities and commercial planning, we will share more meaningful updates. Specifically, we plan to share additional positive Phase 1, 2 biomarker data later this month at MDA. As well as updated Phase 1, 2 functional data in the first half of this year. With positive biomarker and functional data in hand, encouraging interactions with FDA and commercial ready manufacturing, we believe our second to market position in Duchenne remains strong.

隨著我們繼續積極加速 BLA 支援活動和商業規劃，我們將分享更多有意義的更新。具體來說，我們計劃本月稍後在 MDA 分享更多積極的第 1、2 階段生物標記數據。以及今年上半年更新的一、二期功能數據。憑藉著積極的生物標記和功能數據，以及與 FDA 的積極互動和商業化生產，我們相信我們在杜氏肌肉營養不良症領域的市場第二地位依然穩固。

Lastly, I will highlight a few updates on ABBV-RGX-314 or surabgene lomparvovec. This is our global AbbVie-partnered retinal franchise that is advancing in late-stage studies. As announced with AbbVie in January, data from the pivotal studies evaluating subretinal 314 in patients with wet AMD are expected in 2026. We expect a complete enrollment of both of these pivotal studies this year.

最後，我將重點介紹 ABBV-RGX-314 或 surabgene lomparvovec 的一些更新。這是我們與 AbbVie 合作的全球視網膜特許經營權，目前正在進行後期研究。正如今年 1 月與 AbbVie 共同宣布的那樣，評估濕性 AMD 患者視網膜下 314 的關鍵研究數據預計將於 2026 年公佈。我們預計這兩項關鍵研究今年都將完成全部報名。

In our diabetic retinopathy program evaluating in office suprachoroidal delivery of 314, we held a successful end of Phase 2 meeting with the FDA in the fourth quarter of 2024. We are now planning a pivotal program with AbbVie to support future global regulatory filings.

在我們的糖尿病視網膜病變計畫中，對 314 例門診脈絡膜上腔給藥進行了評估，我們於 2024 年第四季度與 FDA 成功舉行了第 2 階段會議。我們目前正與 AbbVie 合作規劃一項關鍵計劃，以支援未來的全球監管備案。

As we have said before, wet AMD and DR are very large commercial opportunities, and 314 represents a potential alternative for the patients losing vision with today's standard of care. Importantly, we will be entitled to additional milestone payments that are part of this $1.8 billion collaboration with AbbVie.

正如我們之前所說，濕性 AMD 和 DR 具有非常大的商業機會，而 314 為在當今標準治療下失去視力的患者提供了潛在的替代方案。重要的是，我們將有權獲得與 AbbVie 合作的 18 億美元中的額外里程碑付款。

In summary, we are excited for and well-positioned to deliver on the opportunities ahead of us to drive value for patients and shareholders.

總而言之，我們對眼前的機會感到興奮，並已做好準備，為病患和股東創造價值。

With that, I would now like to turn the call over to Steve for an update on our clinical programs. Steve.

說完這些，我現在想把電話轉給史蒂夫，讓他介紹我們的臨床計畫的最新情況。史蒂夫。

Thank you, Curran.

謝謝你，Curran。

I'll start with RGX-202, a potential one-time gene therapy for the treatment of Duchenne. RGF-202 is the only microdystrophin construct to include the C-Terminal domain, making it closest to naturally occurring dystrophin. In pre-clinical studies, microdystrophin with the CT domain was shown to better protect the muscle from contraction-induced damage associated with muscle breakdown in Duchenne.

我將從 RGX-202 開始，這是一種用於治療杜氏肌肉營養不良症的潛在一次性基因療法。RGF-202 是唯一包含 C 端結構域的微肌營養不良蛋白構建體，使其最接近天然存在的肌營養不良蛋白。在臨床前研究中，具有 CT 結構域的微肌營養不良蛋白已被證明能夠更好地保護肌肉免受杜氏肌肉營養不良症中肌肉分解相關的收縮引起的損傷。

In November, we announced the initiation of the pivotal phase of the AFFINITY DUCHENNE trial, evaluating 202 at a dose of 2e14 genome copies per kilogram in approximately 30 ambulatory patients aged 1 and older. We also reported positive safety and efficacy data from the Phase 1, 2 portion of the study. The data disclosed in November included positive functional outcomes from the first 5 participants in the Phase 1, 2 portion at 9 and 12 months. We also shared microdystrophin and other compelling biomarker data from 11 patients.

11 月，我們宣布啟動 AFFINITY DUCHENNE 試驗的關鍵階段，對約 30 名 1 歲及以上的門診患者以每公斤 2e14 個基因組拷貝的劑量對 202 進行評估。我們也報告了研究第 1 階段和第 2 階段的積極安全性和有效性數據。11 月揭露的數據包括第 1 階段、第 2 階段的前 5 名參與者在第 9 個月和第 12 個月取得的正向功能結果。我們也分享了 11 名患者的微肌營養不良蛋白和其他引人注目的生物標記數據。

In summary, the results showed 202 recipients exceeded external natural history controls and established benchmarks for clinical outcomes. Specifically, we observed functional improvements in all patients treated with dose level 1 and dose level 2 at 12 and 9 months respectively. Consistent robust expression, transduction and localization of our differentiated 202 microdystrophin in the muscle, and also a favorable safety profile observed at both those levels. There were no serious average events or AEs of special interest, which is truly outstanding in the landscape of Duchenne gene therapy.

總之，結果顯示 202 名接受者超越了外部自然史控制並為臨床結果建立了基準。具體來說，我們觀察到接受劑量等級 1 和劑量等級 2 治療的所有患者分別在 12 個月和 9 個月時功能均得到改善。我們的分化型 202 微肌營養不良蛋白在肌肉中具有持續強烈的表達、轉導和定位，並且在這兩個層面上都觀察到了良好的安全性。沒有發生嚴重的平均事件或特別值得關注的不良事件，這在杜氏基因治療領域確實非常突出。

As we've discussed, we've taken a thorough, proactive approach to safety, based on input and partnership with treating physicians and the patient community, as well as learnings from the field at large. Our immune-suppression regimen, including a short course of eculizumab, combined with our novel microdystrophin and leading product purity levels may be contributing to this positive safety profile.

正如我們所討論的，我們採取了全面、積極主動的安全措施，基於治療醫生和患者社區的意見和合作，以及整個領域的經驗。我們的免疫抑制方案（包括短期使用依庫珠單抗）與我們的新型微肌營養不良蛋白和領先的產品純度水平相結合，可能有助於實現這一積極的安全性。

These positive clinical results further strengthen our belief that 202 has the potential to serve as a best-in-class gene therapy for Duchenne muscular dystrophy. We look forward to sharing additional biomarker data at the MDA meeting in the coming days, including the first microdystrophin data from our cohort of patients under four years old.

這些正面的臨床結果進一步堅定了我們的信念，即 202 有可能成為杜氏肌肉營養不良症的最佳基因療法。我們期待在未來幾天的 MDA 會議上分享更多生物標記數據，包括來自我們四歲以下患者群體的首批微肌營養不良蛋白數據。

As Curran mentioned, the pivotal study is ongoing and advancing rapidly. The one- to three-age group represents a significant portion of the prevalent population of Duchenne patients, yet this group has no access to approved gene therapy. With pivotal enrollment nearly halfway completed, we look forward to continuing to work with physicians and the Duchenne community to complete enrollment this year and report topline data in the first half of 2026.

正如 Curran 所提到的，這項關鍵研究正在進行中，並且進展迅速。一至三歲年齡層的人口佔杜氏肌肉營養不良症患者總人口的很大一部分，但這群體無法獲得經批准的基因治療。關鍵招募工作已完成近一半，我們期待繼續與醫生和杜氏肌肉營養不良症社區合作，在今年完成招募，並在 2026 年上半年報告頂線數據。

Now on to our retina franchise, ABBV-RGX-314, which is being developed in collaboration with AbbVie to treat wet AMD and diabetic retinopathy, or DR. I'll start with 314 for DR being evaluated in the Phase 2 ALTITUDE trial using in-office suprachoroidal delivery.

現在介紹我們的視網膜特許經營權 ABBV-RGX-314，該產品正在與 AbbVie 合作開發，用於治療濕性 AMD 和糖尿病視網膜病變（DR）。我將從 314 開始，該 DR 正在第 2 階段 ALTITUDE 試驗中使用辦公室內脈絡膜上腔給藥進行評估。

Like wet AMD, DR is a progressive disease that causes vision loss, and ultimately blindness is not treated appropriately. It is a leading cause of blindness in working-age adults. As we've shared, we have completed our end of Phase 2 meeting with the FDA and are now working actively with AbbVie on plans for our Phase 3 clinical program. The program is expected to support global regulatory filing with the goal of preserving vision for millions.

與濕性 AMD 一樣，DR 是一種進行性疾病，會導致視力喪失，並且由於無法適當治療，最終會導致失明。它是工作年齡成年人失明的主要原因。正如我們所分享的，我們已經完成了與 FDA 的第二階段會議，目前正與 AbbVie 積極合作制定第三階段臨床計劃。該計劃預計將支持全球監管備案，目標是保護數百萬人的視力。

We previously expanded the broad, multi-indication global potential of 314 by initiating a new cohort in the ALTITUDE trial. This cohort is enrolling patients with Diabetic Macular Edema or DME, a vision threatening complications of diabetic eye disease.

我們先前透過在 ALTITUDE 試驗中啟動一個新的隊列，擴大了 314 的廣泛、多適應症全球潛力。該隊列招募患有糖尿病性黃斑水腫（DME）的患者，這是一種威脅視力的糖尿病眼部疾病併發症。

In Wet AMD, we are evaluating 314 via two different delivery forms, subretinal and suprachoroidal. Within subretinal, we have two ongoing pivotal trials, ATMOSPHERE and ASCENT, in the US, Europe, and Japan. These trials continue to progress well, as we announced in January, enrollment of both pivotal trials is expected to complete this year, and we expect to share topline data in 2026.

對於濕性 AMD，我們透過兩種不同的傳遞形式（視網膜下和脈絡膜上腔）對 314 進行評估。在視網膜下，我們在美國、歐洲和日本正在進行兩項關鍵試驗，ATMOSPHERE 和 ASCENT。這些試驗繼續進展順利，正如我們在一月份宣布的那樣，兩項關鍵試驗的招募預計將於今年完成，我們預計將在 2026 年分享頂線數據。

Overall, we continue to be encouraged by 314's progress. I'd like to particularly highlight the safety profile observed in our suprachoroidal program. In more than 180 patients treated in-office, we're seeing a differentiated safety profile, particularly in the setting of short-course, seven-week prophylactic steroid eye drops. A significantly shorter regimen than those used in other gene therapy trials. This continues to support the potential of 314 as a meaningful treatment option for patients and physicians.

總體而言，314 的進步繼續令我們感到鼓舞。我想特別強調我們在脈絡膜上腔工程中觀察到的安全性。在接受門診治療的 180 多名患者中，我們發現了不同的安全性特徵，特別是在短期、為期七週的預防性類固醇眼藥水的情況下。與其他基因治療試驗中使用的治療方案相比，此治療方案明顯較短。這繼續支持了 314 作為患者和醫生有意義的治療選擇的潛力。

Finally, on to our MPS programs. It's an incredibly exciting time for REGENXBIO and the Hunter Syndrome community with the submission of our BLA for RGX-121. This filing is based on data from the CAMPSIIT trial, which met its primary pivotal endpoint with high statistical significance.

最後，談談我們的 MPS 程序。隨著我們提交 RGX-121 的 BLA，對於 REGENXBIO 和亨特綜合徵社群來說，這是一個無比令人興奮的時刻。該文件基於 CAMPSIIT 試驗的數據，該試驗達到了其主要關鍵終點，具有很高的統計意義。

Patients treated with 121 achieve decreased CSF levels of heparan sulfate D2S6, a key biomarker of brain disease activity, to below maximum attenuated disease levels approaching normalization. Our BLA, using the accelerated approval pathway, is based on D2S6 as a surrogate endpoint reasonably likely to predict clinical benefits. We also previously reported that 80% of patients who received the pivotal dose discontinued enzyme replacement therapy or remain treatment naive, as well as neurodevelopmental skill acquisition, up to four years post-dosing.

接受 121 治療的患者腦脊髓液中的硫酸肝素 D2S6（腦疾病活動的關鍵生物標記）水平降低至接近正常化的最大減毒疾病水平以下。我們的 BLA 採用加速審批途徑，以 D2S6 作為合理預測臨床益處的替代終點。我們先前也報告稱，接受關鍵劑量治療的患者中有 80% 在服藥後長達四年內停止了酵素替代療法或仍處於未接受治療的狀態，並且無法獲得神經發育技能。

This is a meaningful update for patients and families whose only option today is weekly enzyme replacement therapy that does not address the neurocognitive decline of this disease. 121 is well-positioned to be the first gene therapy and one-time treatment for Hunter Syndrome that can address neurocognitive decline. We anticipate a potential FDA approval decision in the second half of 2025.

對於目前唯一的選擇是每週進行酵素替代療法但無法解決疾病的神經認知能力下降的患者和家屬來說，這是一個有意義的更新。 121 有望成為首個能夠解決神經認知能力下降問題的亨特氏症候群基因療法和一次性治療方法。我們預計 FDA 可能會在 2025 年下半年做出批准決定。

To conclude, we continue to make significant progress with data updates and trial progression across all programs in our pipeline. Lastly, I'd like to thank the patients, families, clinicians, and patient advocacy representatives who have been involved in and supported all of these trials.

總而言之，我們在所有專案的數據更新和試驗進展方面繼續取得重大進展。最後，我要感謝參與和支持所有這些試驗的患者、家屬、臨床醫生和患者權益代表。

With that, I'll turn the call over to Mitch to review our financial guidance. Mitch.

說完這些，我將把電話轉給米奇來審查我們的財務指導。米奇。

Thank you, Steve. REGENXBIO ended the quarter on December 31, 2024, with cash equivalents, and marketable securities of $245 million, compared to $314 million as of December 31, 2023. The decrease was primarily driven by cash used to fund operating activities during the 12 months ended December 31, 2024, partially offset by $131 million in net proceeds received from an upsized public offering of common stock and pre-funded warrants completed in March 2024.

謝謝你，史蒂夫。REGENXBIO 截至 2024 年 12 月 31 日的季度結束時，現金等價物和有價證券為 2.45 億美元，而截至 2023 年 12 月 31 日為 3.14 億美元。下降的主要原因是截至 2024 年 12 月 31 日的 12 個月期間用於資助經營活動的現金減少，但被 2024 年 3 月完成的普通股增發和預先出資認股權證所獲得的 1.31 億美元淨收益部分抵消。

R&D expenses were $209 million for the year ended December 31, 2024, compared to $232 million in 2023. The decrease was primarily attributable to decreases in head count and pre-clinical activities. We expect the balance in cash, cash equivalent and marketable securities of $245 million as of December 31, 2024, to fund our operations into the second half of 2026. This cash runway guidance is based on the company's current operational plans and excludes the impact of any future potential commercial revenue associated with RGX-121.

截至 2024 年 12 月 31 日止年度的研發費用為 2.09 億美元，而 2023 年為 2.32 億美元。減少的主要原因是員工數量和臨床前活動的減少。我們預計，截至 2024 年 12 月 31 日的現金、現金等價物和有價證券餘額為 2.45 億美元，可為我們的營運提供資金至 2026 年下半年。此現金流指引是基於公司目前的營運計劃，不包括與 RGX-121 相關的任何未來潛在商業收入的影響。

If we include additional non-diluted financing, we expect the cash runway to potentially extend meaningfully beyond 2026. For instance, some examples of our non-diluted financing options include our expected DR milestone payment from AbbVie, development milestone payments from Nippon Shinyaku, reversion of our so adjustment royalty income, and the potential monetization of our priority review voucher on RGX-121, if approved.

如果我們包括額外的非稀釋融資，我們預計現金流量可能會在 2026 年以後顯著延長。例如，我們的非稀釋融資選擇的一些例子包括我們預期從 AbbVie 獲得的 DR 里程碑付款、從 Nippon Shinyaku 獲得的開發里程碑付款、我們的 so 調整特許權使用費收入的回歸，以及如果獲得批准，我們對 RGX-121 的優先審查憑證的潛在貨幣化。

Collectively, we have many non-diluted financing optionality that could extend our cash runway well beyond the second half of 2026. In summary, we feel we are in a strong financial position as we near potential commercialization of three latest programs.

總的來說，我們擁有許多非稀釋融資選擇，可以將我們的現金流延長至 2026 年下半年以後。總而言之，隨著我們即將實現三個最新項目的商業化，我們認為我們的財務狀況良好。

With that, I would turn the call back to Curran to provide final thoughts.

有了這些，我會把電話轉回給 Curran，讓他提供最終的想法。

Thanks, Mitch. As you heard today, there's strong momentum across our pipeline as we advance towards key milestones. To recap, we have officially submitted our first BLA and closed an important partnership with Nippon Shinyaku for our NPS programs. We look forward to a potential FDA approval of RGX-121 this year.

謝謝，米奇。正如您今天所聽到的，隨著我們向關鍵里程碑邁進，我們的整個管道都呈現出強勁勢頭。總而言之，我們已經正式提交了第一份 BLA，並與日本新藥就我們的 NPS 計畫建立了重要的合作關係。我們期待 FDA 今年批准 RGX-121。

The pivotal study of RGX 202 is moving rapidly and we believe remains well positioned to potentially serve as the next and preferred gene therapy in Duchenne muscular dystrophy. We plan to share additional positive biomarker data later this month, followed by updated functional data in the first half of this year. And with enrollment nearly halfway through, we expect a complete enrollment of the pivotal study this year and share topline data in the first half of 2026.

RGX 202 的關鍵研究正在快速進展，我們相信它仍有可能成為杜氏肌肉營養不良症的下一個首選基因療法。我們計劃在本月稍後分享更多積極的生物標記數據，並在今年上半年分享更新的功能數據。目前招募工作已進行到接近一半，我們預計今年這項關鍵研究將完成招募工作，並在 2026 年上半年分享主要數據。

Our partnership with AbbVie is advancing towards multiple, large, global commercial opportunities. We expect the complete enrollment of two global pivotal trials for subretinal wet AMD and are working with AbbVie on a pivotal study in diabetic retinopathy in 2025.

我們與 AbbVie 的合作正朝著多個大型全球商業機會邁進。我們預計兩項針對視網膜下濕性 AMD 的全球關鍵試驗將完成招募，並正在與 AbbVie 合作於 2025 年開展一項針對糖尿病視網膜病變的關鍵研究。

As we look towards the next nine months and beyond, we are well-positioned to deliver on multiple, late-stage opportunities. Our programs are demonstrating beneficial differentiation against standard of care and available treatments. Each of our assets represent one-time treatments with the potential to transform the trajectory and management of disease for patients in need of new and better options. We look forward to sharing additional updates on our plans and achieving our critical milestones this year.

展望未來九個月及以後，我們已做好準備，抓住多個後期機會。我們的項目顯示出與標準護理和現有治療方法的有益差異。我們的每項資產都代表一次性治療，有可能為需要新的和更好的選擇的患者的疾病軌跡和管理改變。我們期待分享我們計劃的更多更新並在今年實現我們的關鍵里程碑。

With that, thanks for everyone for your time today. I'll turn the call over for questions. Operator.

最後，感謝大家今天抽出時間。我將把電話轉交給提問者。操作員。

(Operator Instructions)

（操作員指示）

Judah Frommer, Morgan Stanley. Judah, your line may be on mute.

猶大‧弗洛默，摩根士丹利。猶大，你的線路可能處於靜音狀態。

Hi, can you hear me now?

嗨，你現在聽得到我說話嗎？

Yes.

是的。

Thanks for taking the question. Hi, congrats on the progress here. Just one on cash runway and one clinical question. So I was hoping maybe you could delve a little deeper into the components of non-dilutive financing that are still available. And maybe you could give us kind of some internal insights into probabilities around realizing those we do get questions around the PRV and then anything that could get in the way of the AbbVie milestone coming through for DR.

感謝您回答這個問題。嗨，祝賀你取得進展。只有一個關於現金跑道和一個臨床問題。所以我希望您能更深入地研究仍然可用的非稀釋性融資組成部分。也許您可以為我們提供一些內部見解，讓我們了解實現這些目標的機率，我們確實對 PRV 有疑問，並且任何可能阻礙 AbbVie 實現 DR 里程碑的事情都有疑問。

And then just on the clinical side, another question we've been getting just expectations around potentially going to an ADCOM for 202 once you have the full data set. Thanks.

然後就在臨床方面，我們得到的另一個問題是，一旦您擁有完整的資料集，就有可能去 ADCOM 進行 202 的預期。謝謝。

Yes, thank you, Judith, for the question. So regarding non-dilutive options, as I kind of mentioned, it really comes in three different flavors. The first one is the DR milestone that we expect to receive in the second half of this year. That really is gated upon the first patient dose, and Steve and Curran could definitely speak to the clinical program timings and so forth. But that's really the potential risk to it. It, it's more of a timing issue than anything else because our expectation is that it will move forward.

是的，謝謝你，朱迪思，提出這個問題。因此，關於非稀釋性選擇權，正如我所提到的，它實際上有三種不同的類型。第一個是我們預計在今年下半年實現的 DR 里程碑。這確實取決於第一位患者的劑量，史蒂夫和柯倫肯定可以談談臨床計劃的時間安排等等。但這確實是它的潛在風險。這更多的是一個時間問題，因為我們期望它會向前推進。

Regarding the PRV, I think the question here is when do we receive a potential regulatory approval, because upon regulatory approval, that's when we're eligible to receive our priority review voucher, and we could then choose to monetize it at our discretion. So I think that's, I would say it's more of a regulatory approval risk than anything else which do not expect to have anyways at this moment in time.

關於 PRV，我認為這裡的問題是我們何時能獲得潛在的監管批准，因為一旦獲得監管批准，我們就有資格獲得優先審查憑證，然後我們可以自行選擇將其貨幣化。所以我認為，我認為這更多的是一種監管批准風險，而不是其他任何風險，目前還不指望有這種風險。

And the other non-dilutive financing option really is on the potential Zolgensma royalty stream that may revert back to us. Once we hit the HCR cap of $300 million that royalty stream does revert back to us. So again, it's hard to predict future revenues from Zolgensma given that it is promoted by a third party, Novartis here. But once that we reach the cap, that revenue stream will revert back to us, royalty revenue stream.

另一種非稀釋性融資選擇實際上是 Zolgensma 特許權使用費流，該特許權使用費流可能會返還給我們。一旦我們達到 3 億美元的 HCR 上限，特許權使用費流就會回饋給我們。因此，鑑於 Zolgensma 是由第三方（諾華）推廣的，因此很難預測其未來的收入。但一旦達到上限，收入流就會回到我們手中，也就是特許權使用費收入流。

Hi Judah, it's Curran. I can talk a little bit about just the PRV and probability of success. I think the fact that we've had a pre-BLA meeting with FDA reviewed the pivotal data really helps in terms of de-risking. They've seen the data, they've seen our approach, and while, of course, it's a regulatory review and that has risk associated with it like any, we feel like we're in a really good place, particularly because I think in over time, MPS II and therapies like ours have been referred to as perfect fits for an accelerated approval pathway.

你好，Judah，我是 Curran。我可以稍微談一下 PRV 和成功機率。我認為，我們與 FDA 舉行了 BLA 前會議並審查了關鍵數據，這確實有助於降低風險。他們已經看到了數據，看到了我們的方法，當然，這是一次監管審查，並且像任何審查一樣存在風險，但我們覺得我們處於一個非常好的位置，特別是因為我認為隨著時間的推移，MPS II 和像我們這樣的療法已經被認為非常適合加速審批途徑。

So I do expect this to be a high-probability event in terms of receiving both an approval and the PRV. And you know that's in line with all the discussions we've had with FDA. I'll let Steve comment a bit on DR, but I think the events that are occurring for DR now are really just regulatory discussions with AbbVie in the lead in terms of conducting those meetings.

因此我確實預計這將是獲得批准和 PRV 的高機率事件。您知道這與我們與 FDA 進行的所有討論一致。我會讓史蒂夫對 DR 發表一些評論，但我認為現在為 DR 發生的事件實際上只是與 AbbVie 就召開這些會議進行主導的監管討論。

We talked last fall about the end of Phase 2 meeting with FDA and related that that meeting was very positive in terms of our approach. And we've also discussed that they're also seeking regulatory advice XUS and that's an ongoing process, but we feel like two key things. The data is strong and so far, the feedback is strong. Again, pointing towards a positive movement towards the DR pivotal this year. Steve, I don't know if you have anything to add to that.

去年秋天，我們談到了與 FDA 進行的第二階段會議的結束，並表示該會議對我們的方法非常積極。我們也討論過，他們也在尋求 XUS 的監管建議，這是一個持續的過程，但我們覺得有兩件關鍵的事情。數據強勁，到目前為止，反饋也強勁。再次表明，今年 DR 的關鍵舉措將取得積極進展。史蒂夫，我不知道您是否還有什麼要補充的。

Sure. Hi, Judah. Yeah, I think, as Curran mentioned, we're very happy with the end of Phase 2 meeting with the FDA. AbbVie's always been very interested in global advancement and really getting access to 314 globally. That's one of the reasons we struck the deal with AbbVie. So not surprisingly for a global diabetic retinopathy plan. They do want to get EMA and feedback from Japan.

當然。你好，猶大。是的，我認為，正如 Curran 所提到的，我們對與 FDA 進行的第二階段會議的結束感到非常高興。AbbVie 一直對全球進步和真正在全球範圍內獲得 314 的權限非常感興趣。這就是我們與 AbbVie 達成交易的原因之一。因此，全球糖尿病視網膜病變計畫並不令人意外。他們確實希望獲得日本的 EMA 和回饋。

So those are some of the aspects that we want to tidy up those. And before we give any more details on the plan, but I think fortunately we have the benefit of precedent in treatment of diabetic retinopathy to know what to expect in terms of a regulatory path here. So we feel this is a pretty darn de-risked based on our regulatory discussions to date.

這些就是我們想要整理的一些面向。在我們提供有關該計劃的更多細節之前，但我認為幸運的是，我們有糖尿病視網膜病變治療的先例，可以知道這裡的監管途徑會發生什麼。因此，根據迄今為止的監管討論，我們認為這相當降低了風險。

You also, Judah, had a question on ADCOM probability, which I believe is probably related to 121 since we announced completion of the BLA submission. We don't know, it's not the kind of thing we can say with a 100% certainty either way. We, as of now, don't see a significant issue anywhere that would suggest one is needed.

Judah，你也對 ADCOM 機率有疑問，自從我們宣布完成 BLA 提交以來，我認為這可能與 121 有關。我們不知道，無論如何這都不是我們可以 100% 肯定的事情。到目前為止，我們還沒有發現任何地方有需要採取這項措施的重大問題。

If one comes our way, we'll be ready for it. So I think with any development program at this stage, you plan in case you may need it. If we have one, we'd be very confident with the discussions because of the compelling data we have and the different stakeholders that could be a part of getting across that benefit and the benefit risk for the product. But as of now we don't know.

如果有人來找我們，我們會做好準備。因此我認為，對於現階段的任何開發計劃，您都要做好萬全的準備，以防萬一。如果我們有這樣的計劃，我們會對討論非常有信心，因為我們有令人信服的數據，並且不同的利害關係人可以參與傳達該產品的利益和利益風險。但目前我們還不知道。

Thanks.

謝謝。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

Thank you for taking my questions. I apologize if this question already being asked. My phone got dropped, so I missed the previous question. So I have two questions. One is regarding the NBA update. Just wondering how many patient data from one to three year old should we expect, see, and also, giving the younger patient age, should we expect to see higher protein expression?

感謝您回答我的問題。如果這個問題已經被問到，我深感抱歉。我的手機掉在地上，所以我錯過了上一個問題。我有兩個問題。一個是關於NBA的最新消息。只是想知道我們應該預期看到多少一至三歲患者的數據，而且考慮到患者年齡較小，我們是否應該預期看到更高的蛋白質表現？

Related questions, any thoughts regarding lower age to zero, given, I think as so mentioned they will start a cohort between 0 and 18. And then my second question is regarding the ALTITUDE, DME cohort. Just wondering what will be the timing of data update and then in terms of also a number of patients and type of data you will share with us.

相關問題，關於將年齡降低到零的任何想法，鑑於，我認為正如所提到的，他們將在 0 到 18 歲之間開始一個隊列。我的第二個問題是關於 ALTITUDE、DME 佇列。我只是想知道數據更新的時間是什麼時候，以及您將與我們分享的患者數量和數據類型。

Great, I'll take the first one and then I'll let Steve answer the second one. So we're planning to update an MDA, likely one patient in the one to four cohort, in terms of their microdystrophin value. And I would suggest, based on the emerging database that we're gaining on age versus microdystrophin, that it's a fair expectation to expect a high number in terms of microdystrophin level.

太好了，我先回答第一個問題，然後讓史蒂夫回答第二個問題。因此，我們計劃更新 MDA，可能是 1 至 4 個隊列中的一名患者的微肌營養不良蛋白值。我認為，基於我們在年齡與微肌營養不良蛋白方面獲得的新興資料庫，對微肌營養不良蛋白水平的較高數字進行預期是合理的。

But obviously, we'll save that specific for the conference itself, but we're seeing a general trend that the younger patients will have higher microdystrophin numbers both in our study and other studies that we're able to see in the public domain.

但顯然，我們將把這個具體問題留到會議本身討論，但我們看到一種總體趨勢，即年輕患者的微肌營養不良蛋白數量更高，無論是在我們的研究中還是在公共領域中我們能夠看到的其他研究中都是如此。

Yeah, hi, Gena, thanks for the question. So ALTITUDE, our diabetic retinopathy study, where we've already shown very solid data in terms of diabetic retinopathy patients without DME, and that's why we're so excited with AbbVie to go into pivotal. You referred to the DME cohort, which we currently have enrolling. Enrollment is progressing quite nicely. We haven't given any guidance on when we would read out, but it's safe to say that when we do to your question of what you could look for the typical things that we've looked for in a wet AMD population but with different reference points of what you'd expect.

是的，你好，吉娜，謝謝你的提問。因此，我們在糖尿病視網膜病變研究 ALTITUDE 中已經獲得了沒有 DME 的糖尿病視網膜病變患者的非常可靠的數據，這就是為什麼我們如此興奮地與 AbbVie 一起進入關鍵階段。您提到了我們目前正在招募的 DME 隊列。招生工作進展順利。我們沒有給出任何關於何時讀出的指導，但可以肯定地說，當我們回答您的問題時，您可以尋找我們在濕性 AMD 人群中尋找的典型事物，但與您所期望的參考點不同。

So in DME you care about visual acuity and you also care about disease activity assessed by retinal thickness on OCT. And of course the third part of the triad is can you achieve good disease control and good visual acuity with a reduction in the need for injection, so basically treatment burden. So we would report on all three of those as well as safety.

因此，在 DME 中，您關心視力，也關心透過 OCT 上的視網膜厚度評估的疾病活動性。當然，三聯療法的第三部分是，能否實現良好的疾病控制和良好的視力，同時減少注射的需要，從而基本上減輕治療負擔。因此，我們會報告這三個方面以及安全性。

Thank you.

謝謝。

Mani Foroohar, Leerink.

Mani Foroohar，Leerink。

Hey, guys, you have Ryan on for Mani. Thanks for taking our question. So maybe just to can you talk about what you're seeing in terms of pace of enrollment for the DMD pivotal trial and whether you, expect this to accelerate as the year goes on as you activate new sites and share more data in the first half of the year.

嘿，夥計們，你們讓 Ryan 代替 Mani。感謝您回答我們的問題。因此，您能否談談您所看到的 DMD 關鍵試驗的招募速度，以及隨著您在上半年啟用新站點並分享更多數據，您是否預計這一速度會隨著時間的推移而加速。

And then maybe just on the younger patient enrollment within DMD, have you moved on to enrolling those patients in the pivotal trial yet, or are you still enrolling that separate cohort from the Phase 1, 2 trial? Thanks.

那麼也許只是在 DMD 中招募年輕患者，您是否已經開始招募這些患者參加關鍵試驗，或者您是否仍在招募來自第 1 階段、第 2 階段試驗的單獨隊列？謝謝。

Yeah. I think it's safe to say that we're seeing really encouraging enrollment in terms of the Duchenne study. And I think to the second part of -- and we know that from the screening logs and what we're seeing at sites as sites are activated that there's a significant number of -- there's a significant amount of interest in a significant number of patients that are going through screening.

是的。我認為可以肯定地說，就杜氏肌肉營養不良症研究而言，我們看到了確實令人鼓舞的入學人數。我認為第二部分是——我們從篩檢日誌和網站啟動時看到的情況知道，有相當多的人——對正在接受篩檢的患者有相當大的興趣。

And the second part is, yes, we do expect it to accelerate primarily because we're increasingly adding sites to the study. So the overall productivity of the study will just continue. So it'll be a nonlinear enrollment curve, if you will, and we're super optimistic about how, certainly meeting our guidance, which will be concluding enrollment, this year. But we're aiming to exceed that guidance by, beating that timeline significantly.

第二部分是，是的，我們確實預期它會加速，主要是因為我們正在不斷增加研究站點。因此，研究的整體成果將會持續下去。因此，如果你願意的話，這將是一個非線性的入學曲線，我們對於如何滿足我們的指導方針非常樂觀，今年將結束入學。但我們的目標是超越該指導方針，大大提前完成時間表。

The second question?

第二個問題？

The other interesting aspect, Ryan, is that it's not just increased sites, which certainly is going to help as we bring more sites on board. But we really saw a lot of interest after our November functional data update. We've heard from patient advocacy and investigators that there's a lot of families that have been waiting on the sidelines for a next gen gene therapy as long as they could see some functional data.

瑞安，另一個有趣的方面是，這不僅僅是增加了網站數量，這肯定會對我們吸引更多網站有所幫助。但我們在 11 月的功能數據更新後確實看到了許多興趣。我們從患者權益倡導者和研究人員那裡聽說，很多家庭一直在等待下一代基因療法，只要他們能看到一些功能數據。

So I think having the 9- and 12-month data has really bolstered our case across our clinic. So I think we're in a good shape there. You also asked about the younger patients, the one- to three-year-old age group. We look forward to providing the initial data in terms of microdystrophin in that age range.

因此我認為擁有 9 個月和 12 個月的數據確實增強了我們整個診所的案例。所以我認為我們的情況很好。您也詢問了年齡較小的患者，即一至三歲的年齡層。我們期待提供該年齡範圍內微肌營養不良蛋白的初步數據。

And we do know, by the way, harkening back to Gena's question that younger we have seen with other programs that you have higher-microdystrophin levels, and I think one of the massive unmet needs is in the older patients where you don't see with other programs high microdystrophin levels. So we're really excited about that. But we really want to treat broadly across the entire age range, and that's why we're enrolling not just the traditional four and up, but actually one year old and up.

順便說一句，回到 Gena 的問題，我們確實知道，在其他項目中，我們看到年輕患者的微肌營養不良蛋白水平更高，我認為，一個巨大的未滿足需求之一是在老年患者中，而在其他項目中，你不會看到老年患者的微肌營養不良蛋白水平較高。所以我們對此感到非常興奮。但我們確實希望對整個年齡層的患者進行廣泛治療，這就是為什麼我們不只招收傳統的四歲及以上患者，而是招收一歲及以上的患者。

To your question, any patients that come in now in that are one and above are going to count for a pivotal. So we are very excited to enroll across the age range that one to three years, four to seven, and also eight and older.

對於您的問題，現在來就診的任何一級及以上的患者都將被視為關鍵患者。因此，我們非常高興能夠招收 1 至 3 歲、4 至 7 歲以及 8 歲以上年齡層的學生。

And we're particularly interested in that cohort because as there's no approved therapy for patients in the one to four age category. So that's a key element of our pivotal plan, and we -- these patients will be included in that.

我們對這個族群特別感興趣，因為目前還沒有針對一至四歲年齡層患者的核准治療方法。這是我們關鍵計劃的關鍵要素，這些患者也將被納入其中。

Thanks, guys.

謝謝大家。

Luca Issi, RBC Capital Markets.

伊西 (Luca Issi)，加拿大皇家銀行資本市場部。

Oh, great. Thanks so much for taking our questions. This is Lisa on for Luca. Just on the DMD program, can you remind us if you are measuring cardiac endpoints like left ventricular injection fraction or cardiac biomarkers like troponin I as part of the AFFINITY study? And if so, could this be a meaningful way to differentiate your program further from Elavida's?

噢，太好了。非常感謝您回答我們的問題。這是 Lisa 為 Luca 表演的。僅在 DMD 計劃中，您能否提醒我們，作為 AFFINITY 研究的一部分，您是否正在測量心臟終點（如左心室注射分數）或心臟生物標記（如肌鈣蛋白 I）？如果是這樣，這是否可以成為一種有意義的方式，將您的程式與 Elavida 的程式進一步區分開來？

And I have one question on what AMD -- on the subretinal study. I'm just curious if you are considering maybe cutting the enrollment a bit short in order to accelerate the readout timelines. We know the wet AMD space is very competitive and there are also two long acting TKI. Studies that are also anticipated to read out in that same 2026-time frame and as we know, from the ISO's launch being first to market does matter. So any color here on DMD or the subretinal pivotals, that would be appreciated. Thanks so much.

我有一個關於 AMD 視網膜下研究的問題。我只是好奇您是否考慮縮短註冊時間以加快讀出時間。我們知道濕性 AMD 領域競爭非常激烈，而且還有兩種長效 TKI。預計這些研究也將在 2026 年的同一時間內完成，正如我們所知，從 ISO 推出之日起，率先進入市場確實很重要。因此，如果您能了解有關 DMD 或視網膜下樞軸點的任何顏色，我們將不勝感激。非常感謝。

Great thanks. I think I'll let Steve comment certainly on the retina discussion, but in terms of cardiac, Steve can describe what we're measuring in the clinic. But certainly from our preclinical data, when we looked at biodistribution in our early preclinical studies, we certainly have reason to expect good biodistribution not just to the peripheral muscle, but to the heart and to the lung section.

非常感謝。我想我會讓史蒂夫對視網膜討論發表評論，但就心臟而言，史蒂夫可以描述我們在臨床上測量的內容。但從我們的臨床前數據來看，當我們在早期臨床前研究中觀察生物分佈時，我們當然有理由期待良好的生物分佈，不僅在周邊肌肉，而且在心臟和肺部。

So that's represented well in studies that we did pre-clinically like the treadmill test for MDX mice. So I think in terms of do we expect our study to differentiate on that, of course that will come down to what we consider for cardiac a little bit longer term outcomes. We don't expect to see dramatic cardiac improvement in a four- or five-year-old, but over time that something will certainly be monitored. Maybe I'll let Steve cover how we're doing that.

因此，這在我們進行的臨床前研究（例如針對 MDX 小鼠的跑步機測試）中得到了很好的體現。因此，我認為，就我們是否期望我們的研究對此有所區分而言，當然這將取決於我們對心臟的長期結果的考慮。我們並不期望看到四、五歲兒童的心臟狀況有顯著改善，但隨著時間的推移，肯定會對這種情況進行監測。也許我會讓史蒂夫介紹一下我們是如何做到這一點的。

Sure. Hi Lisa. Yeah, for the reasons Curran mentioned, we feel very positive about the potential to have a benefit for Duchenne children not just based on skeletal muscle, but also the cardiac manifestations.

當然。你好，麗莎。是的，出於 Curran 提到的原因，我們非常看好杜氏肌肉營養不良症兒童的益處，不僅是骨骼肌，還有心臟表現。

I think one context to give is that these decreases or deterioration in cardiac function happen at an older age than the typical functional assessments that we look at in the younger age group. So it's really as the boys advance into the teen years that you see the unfortunate cardiac deterioration. So that's one of the reasons we're so excited that we're seeing very high and consistent microdystrophin expression in these older boys. So that also bolsters our confidence.

我認為一個背景是，心臟功能的下降或惡化發生在比我們在年輕年齡組中觀察到的典型功能評估更大的年齡。因此，當男孩們進入青少年時期時，你會看到不幸的心臟功能衰退。這就是我們如此興奮的原因之一，因為我們看到這些年齡較大的男孩體內有非常高且一致的微肌營養不良蛋白表現。這也增強了我們的信心。

So how can we look at this? Certainly ejection fraction, as you mentioned, is one of the measures you can look with echo, which isn't as accurate and sensitive as looking with MRI. So we do incorporate both of these, so we're going to have the ability to look at that. We do also look at troponin levels.

那我們該如何看待這個問題呢？當然，正如您所提到的，射血分數是可以透過迴聲觀察到的測量指標之一，但它不如 MRI 那樣準確和靈敏。因此，我們確實將這兩者結合起來，這樣我們就有能力審視這一點。我們也觀察肌鈣蛋白水平。

So again I think the key aspect is you're It's not going to be really meaningful to look at these while patients' cardiac function is normal. So in the traditional age groups up to 8, for example, and really it's going to be more once the patients get above 10, where you start to see abnormal ejection fractions, for example, where you can then monitor stability and more or less preventing worsening in these boys.

因此，我再次認為關鍵在於，當患者的心臟功能正常時，觀察這些並沒有什麼意義。因此，在傳統的 8 歲以下年齡組中，實際上，一旦患者年齡超過 10 歲，情況就會更加嚴重，例如，您會開始看到異常的射血分數，然後您可以監測穩定性併或多或少地防止這些男孩的病情惡化。

So the fact that we have patients already enrolled that are older, I think we're in a better position to monitor this over a long time, and we have patients already out 9 and 12 months and further as we go out further. But it's really something that takes more time for sure than a year, even if you're looking in the older-age group before you anticipate seeing a potential drug effect.

因此，事實上，我們已經招募了年齡較大的患者，我認為我們能夠更好地長期監測這種情況，而且隨著我們進一步推廣，我們已有患者出院 9 個月、12 個月甚至更久。但這確實需要一年多的時間，即使你關注的是老年人群體，你才能預期看到潛在的藥物效果。

Your other question about wet AMD and our pivotal trials for subretinal delivery, whether we'd consider cutting short the enrollment. We would not, and AbbVie would not as well. One of the key reasons we increased the size was to be able to go global. And you can imagine with a partner like AbbVie, we want to do things right, we don't want to skimp, especially when it comes to fully characterizing safety and efficacy.

您關於濕性 AMD 和我們視網膜下給藥關鍵試驗的另一個問題是，我們是否會考慮縮短入組時間。我們不會，AbbVie 也不會。我們擴大規模的一個主要原因是為了能夠走向全球。你可以想像，有了像 AbbVie 這樣的合作夥伴，我們希望把事情做好，我們不想偷工減料，特別是在充分描述安全性和有效性方面。

So this is a unique opportunity to compare to establish approved treatment regimens to really inform the clinical community, not just the regulatory bodies. So our view would not be to cut these short. And as Curran has summarized, we look forward to completing enrollment this year and being able to have results next year.

因此，這是一個獨特的機會，可以比較建立批准的治療方案，真正告知臨床界，而不僅僅是監管機構。因此我們的觀點是不要縮短這些時間。正如 Curran 所總結的那樣，我們期待今年完成招生並在明年取得成果。

And there is a lot of trial competition out there in the wet AMD space with, as you mentioned, some of the longer-acting TKIs. One of the things we're encouraged about is that this is really a paradigm shift. This is not a matter of incrementally increasing injection burden reduction from every two or every three months, every four or every six months. It's really being able to in a potentially a majority of patients prevent the need for injection. So we're seeing that as a strong differentiator and that's again why we are pleased that we're going to be able to complete enrollment this year.

正如您所提到的，在濕性 AMD 領域存在著許多針對一些長效 TKI 的試驗競爭。令我們感到鼓舞的事情之一是，這確實是一種範式轉移。這並不是每兩個月、每三個月、每四個月或每六個月逐步增加註射負擔減少的問題。它確實能夠讓大多數患者免於注射。因此，我們認為這是一個強大的差異化因素，這也是我們很高興今年能完成招生的原因。

One thing I would add to just we are certainly cognizant of timing and moving as quickly as we can to a BLA filing, and that's one reason that AbbVie, for example, will be doing the preparation and filing of the BLA. They have upwards of 700 people in their regulatory group and so these are -- it's a very large study and we're going to rely on AbbVie who has I think a great track record of speed to BLA from topline data. So that's something to follow in the next year. We're with you in terms of going as fast as possible, but as Steve mentioned, we want to do it the right way.

我想補充一點，我們當然清楚時機，並會盡快提交 BLA 文件，這也是 AbbVie 等公司準備和提交 BLA 的原因之一。他們的監管小組有 700 多人，所以這是一項非常大的研究，我們將依賴 AbbVie，我認為他們在從頂線數據到 BLA 的速度方面有著出色的記錄。這是明年要關注的事情。我們同意你們盡快採取行動，但正如史蒂夫所提到的，我們希望以正確的方式行事。

All right thanks so much for taking the questions.

好的，非常感謝您回答這些問題。

Annabel Samimy, Stifel.

安娜貝爾·薩米 (Annabel Samimy)，Stifel。

Hi, thanks for taking my questions. Just following on the regulatory discussions for DR. Are there any specific key areas of difference between the US and OUS regulators that we should be thinking about? I know that the pathway is pretty clear for the US. I'm curious about OUS.

你好，謝謝你回答我的問題。只是關注 DR 的監管討論。美國和澳洲監管機構之間是否存在一些具體的關鍵差異領域值得我們思考？我知道美國的道路非常清晰。我對 OUS 很好奇。

And then on DMD, and for the upcoming, not the Muscular Dystrophy Association, but the one where you're going to be disclosing functional data, will we be seeing just a follow up from patients we've already -- you've already disclosed, or will we see new patients of the 11 that had already been treated. And then finally for DMD, the 50% enrollment, can I just -- can you just clarify that this includes, whether this includes new patients that were enrolled into the pivotal, or does it also include the patients from the Phase 1, 2 study. Thanks.

然後關於 DMD，對於即將到來的，不是肌肉萎縮症協會，而是您將要披露功能數據的協會，我們是否只看到我們已經披露的患者的後續情況，還是我們會看到已經接受治療的 11 名新患者。最後，對於 DMD，50％ 的入組率，我能否 - 您能否澄清一下，這是否包括入組關鍵研究的新患者，還是也包括來自第 1 階段、第 2 階段研究的患者。謝謝。

Right, yeah, I'll take DMD first, and I think we'll let Steve comment on he's part of the joint development team with AbbVie that's conducting these regulatory meetings and can comment.

好的，是的，我首先要談論 DMD，我想我們會讓史蒂夫發表評論，他是 AbbVie 聯合開發團隊的成員，負責召開這些監管會議並可以發表評論。

For Duchenne, the data that we're speaking to around functional updates later this first half will be all of the above. So patients that we've already discussed at do dose level 2 that were at 9 months, moving out to 12, new patients that have not previously been reported in the dose level 2, Phase 1, 2 study, likely at 9 months, and then also long-term data on the dose level 1 patients. That'll be out at least to 18 months, depending on the timing, specific timing of the update.

對於杜氏肌肉營養不良症，我們在上半年後期圍繞功能更新討論的數據將是以上所有。因此，我們已經討論過的在 9 個月時接受 2 劑量水平治療的患者，將增加到 12 名，這些新患者之前在 2 劑量水平、第 1 階段、第 2 階段研究中沒有報告過，可能在 9 個月時，然後還有 1 劑量水平患者的長期數據。這將需要至少 18 個月，具體取決於更新的具體時間。

So that's what we're planning for. We don't have a specific number for new patients yet, but as you know from the past, there's seven patients total in that cohort, so we're just incrementally adding hopefully meaningful updates not patient by patient, enriching that data set as we go.

這就是我們的計劃。我們還沒有新患者的具體數字，但正如您過去所知，該群體中共有 7 名患者，因此我們只是逐步添加有意義的更新，而不是逐個患者地添加，從而豐富該數據集。

I think to the question of does the pivotal enrollment include new patients? The answer is yes. We have new patients that have been enrolled since we announced that we were recruiting for the pivotal trial and also some of the patients that were dosed, actually the majority of them that were dosed in the Phase 1, 2 study would also be eligible as part of the pivotal data set, and just recall that's an end of 30 that we're driving for to complete that study.

我認為關鍵的招募是否包含新患者？答案是肯定的。自從我們宣布招募關鍵試驗患者以來，我們已經招募了新的患者，並且一些已接受藥物治療的患者，實際上大多數在第 1 階段和第 2 階段研究中接受藥物治療的患者也有資格作為關鍵數據集的一部分，請記住，我們正在努力完成這項研究，為期 30 年。

Hi, Annabel. I'll take the first question now on diabetic retinopathy and the pivotal plan. As you mentioned, fortunately, there's a clear path from precedent of getting an indication for treatment of diabetic retinopathy from drugs like Lucentis and EYLEA, where what's been accepted and what's still accepted is use of the diabetic retinopathy severity scale, which has been clinically validated to predict bad outcomes for patients with diabetic retinopathy.

你好，安娜貝爾。我現在要回答有關糖尿病視網膜病變和關鍵計劃的第一個問題。正如您所說，幸運的是，從先例來看，使用 Lucentis 和 EYLEA 等藥物治療糖尿病視網膜病變已經有了明確的途徑，其中已經接受和仍然接受的是使用糖尿病視網膜病變嚴重程度量表，該量表已經過臨床驗證，可以預測糖尿病視網膜病變患者的不良後果。

And we know the path is there, but these drugs are not being used because of the significant treatment burden that's needed to keep the disease at bay. So that's important because that means it's still open the ability to use a negative control. So for example, in our case, the potential to use a sham control arm where we know that those patients don't magically get better, and in fact they on average get worse. So it allows us to power a study with the traditional one-year endpoint to look for a difference in active treatment compared to a negative control arm.

我們知道有辦法，但是這些藥物並沒有被使用，因為控制疾病需要很大的治療負擔。這很重要，因為這意味著仍然可以使用負面控制。例如，在我們的案例中，我們有可能使用假對照組，因為我們知道那些患者不會神奇地好轉，事實上他們的平均病情會惡化。因此，我們可以使用傳統的一年期終點來進行研究，以尋找積極治療與陰性對照組之間的差異。

There isn't that known precedent for Europe. So that's one of the reasons we want to work with the EMA and also in Japan. We think there's a very solid case for use of the diabetic retinopathy severity scale, and in fact, the more years that go by and the more studies that are done, we think that case gets stronger. And so we look forward to in the future giving an update on discussions that we've had with regulators around the world.

歐洲還沒有這樣的先例。這就是我們希望與 EMA 以及日本合作的原因之一。我們認為使用糖尿病視網膜病變嚴重程度量表的理由非常充分，事實上，隨著時間的推移和研究的增多，我們認為這種理由越來越充分。因此，我們期待未來能夠更新我們與世界各地監管機構的討論情況。

Thank you.

謝謝。

Brian Skorney, Baird. Brian, you may be on mute.

布萊恩·斯科尼，貝爾德。布萊恩，你可能靜音了。

You're right. I see now. Thanks for taking the question, everyone. You now submitted VLA for Hunter with CBER had discussions on physical program for DMD and planning a program for diabetic retinopathy. We get a lot of questions about continuity at CBER, given the change of guard at HHS and FDA, and I don't really know anyone who probably had more interaction than with CBER than you guys over the last couple of months.

你說得對。我明白了。謝謝大家回答這個問題。您現在已向 Hunter 提交了 VLA，並與 CBER 討論了 DMD 的物理治療計劃並製定了糖尿病視網膜病變的治療計劃。鑑於 HHS 和 FDA 的領導層變動，我們收到了很多關於 CBER 連續性的問題，而且在過去的幾個月裡，我真不知道有誰與 CBER 的互動比你們更多。

I just wonder, with Celia Wettens' departure a couple of weeks ago, if you can give us a sense as to how up to date your discussions with Wettens and OTP are, and if you're seeing significant change within the review division, the office of therapeutic products and how much that could potentially impact future gene therapy reviews.

我只是想知道，幾週前 Celia Wettens 已經離職，您能否告訴我們您與 Wettens 和 OTP 的討論是否及時，以及您是否看到審查部門、治療產品辦公室內部發生了重大變化，以及這些變化可能對未來的基因治療審查產生多大影響。

Yeah, I think our general comment is from our perspective it's business as usual in terms of the submissions that we're making. We're on a pretty frequent basis providing amendments to protocols, amendments to INDs, and those are -- we're getting questions back and forth on certain things. So we're really not seeing a significant difference either in timing of responses or availability of the teams.

是的，我認為我們的整體評論是從我們的角度來看，就我們所提交的意見而言，一切照常。我們經常對協議、IND 進行修訂，而且我們會就某些事情反覆提問。因此，我們確實沒有看到回應時間或團隊可用性方面的顯著差異。

And I think we were encouraged by some of the comments, especially on the rare-disease side around accelerated approval from Macare and you know just the overall sentiment. So to date, I think we feel, number one, that we've got really good connections and really good previous dialogue with the review team. The review team seems stable from what we can tell from those interactions and therefore we don't see any change in sort of the risk profile of our pending BLA now and ongoing discussions for Duchenne.

我認為我們受到了一些評論的鼓舞，特別是關於 Macare 加速批准的罕見疾病方面的評論，以及整體情緒。因此到目前為止，我認為，首先，我們與審查小組建立了良好的聯繫，並且進行了非常良好的對話。從這些互動中我們可以看出，審查團隊似乎很穩定，因此我們認為目前待決的 BLA 的風險狀況和正在進行的杜氏肌肉營養不良症討論沒有任何變化。

Alright, let me, if I can ask a follow up on DMD now that you're about 50% enrolled into the 202 pivotal. Can you give us any flavor as to how screening kind of goes? Are you seeing any particular favoritism by age or characteristics, in terms of patients looking at the screen?

好吧，現在您大約有 50% 的人參加了 202 關鍵課程，我可以問一下關於 DMD 的後續問題嗎？能告訴我們篩選過程是怎麼樣的嗎？就患者查看螢幕而言，您是否發現存在年齡或特徵方面的特殊偏好？

I mean in particular I wonder if like the availability of Alevitus and Alevitus’ data, but if it's sort of like, or four- to five-year-olds favoring coming in to be screened for gene therapy or because the data is strongest for Alevitus, do you see sort of in that age group do you see patients coming outside of that four- to five-year-old on a demand basis?

我特別想知道 Alevitus 和 Alevitus 數據的可用性，但如果是某種程度上，或者四到五歲的兒童傾向於來接受基因治療篩檢，或者因為 Alevitus 的數據最強，您是否看到在該年齡組中，是否會看到患者根據需求而來接受基因治療？

Yeah, I'll generally comment and then I'll let Steve maybe discuss because he does see the screening logs in more detail than I do. I mean, one of the reasons that we wanted to point to nearly half enrollment of the pivotal study is that in addition to that, our screening logs and patients testing for neutralizing antibodies, it's a significant number of people of patients being screened. And that just points to the strong interest we see from the patient community, and from the Duchenne patient advocacy groups as well that are supporting us.

是的，我通常會發表評論，然後讓史蒂夫討論，因為他確實比我更詳細地查看了篩選日誌。我的意思是，我們想要指出關鍵研究的入組人數接近一半的原因之一是，除此之外，還有我們的篩檢日誌和進行中和抗體檢測的患者，還有相當數量的患者正在接受篩檢。這表明，我們看到患者群體以及支持我們的杜氏肌肉營養不良症患者權益團體表現出濃厚的興趣。

Steve, I don't know if you want to comment. Are we seeing any difference in terms of the ages, or is it just a broad distribution?

史蒂夫，我不知道您是否想發表評論。我們看到年齡方面的差異了嗎，還是只是分佈廣泛？

I'd say it's a broad distribution, Brian. I think families across the age range have certainly different needs or different ways they'd look at evaluating different treatment options. I think that's where our differentiation comes into play. So I think certainly the microdystrophin levels that we're seeing, that's clear differentiation in the eight and older, as you mentioned, the four to seven and particularly the four to five. Is really the subset of patients where there's the most evidence for a Alevitus.

我想說它的分佈很廣泛，布萊恩。我認為不同年齡的家庭肯定有不同的需求，或以不同的方式評估不同的治療方案。我認為這就是我們的差異化發揮作用的地方。因此我認為，我們所看到的微肌營養不良蛋白水平在 8 歲以上的兒童中存在明顯差異，正如您所提到的，在 4 到 7 歲，特別是 4 到 5 歲之間。確實是有最多 Alevitus 證據的患者子集。

I think one aspect that is a differentiator across the spectrum is safety. So safety first, that's certainly how investigators think about it, and that's how patient families, of course, think about it. So we believe with various aspects of our program, both our proactive, immune-suppression-transient approach, our high-purity levels that are very differentiating.

我認為，在整個頻譜範圍內的一個區別因素是安全性。所以安全第一，這當然是研究人員的想法，當然也是病人家屬的想法。因此，我們相信，我們計劃的各個方面，包括我們的主動方法、免疫抑制瞬時方法、以及我們的高純度水平，都是非常有區別的。

And overall what we're seeing is very good safety. We have seen no SAEs, no AEs of special interest, so that includes no LFT elevations, no thrombocytopenia, and these are findings that have been seen in other programs. And with Alevitus, I think upwards of 40% have LFT elevation. So that's a clear differentiator that we think is important across the age range.

總體而言，我們看到的安全性非常好。我們沒有看到 SAE，沒有看到特別值得關注的 AE，因此包括沒有 LFT 升高，沒有血小板減少症，這些都是在其他項目中已經看到的發現。對於 Alevitus，我認為 40% 以上的患者肝功能檢查結果都會升高。所以，我們認為這是一個明顯的區別因素，對於各個年齡層的人來說都很重要。

Certainly in the three and under bucket, that's those are patients who do not have access to approved gene therapy in the US. One of the aspects we're excited about our program is some of the not just microdystrophin expression, but also vector genome copies per cell that we're actually seeing, which are much higher than has been reported by any other program.

當然，三種及以下的患者是無法在美國接受經批准的基因治療的患者。我們對我們的計畫感到興奮的方面之一是，我們實際上看到的不僅僅是微肌營養不良蛋白的表達，還有每個細胞的載體基因組拷貝數，這些拷貝數比任何其他項目報告的都要高得多。

So we think that gives added confidence when you think of that younger age group where there's still be some muscle cell division. So in short, in summary, we see good differentiation aspects that are compelling for doctors and patients' families to consider. And that's why we're confident we're going to get a widespread, which is a goal, given the broad patient population, we want to have safety and efficacy in.

因此，我們認為，當你想到仍然有一些肌肉細胞分裂的年輕年齡層時，這會給你額外的信心。簡而言之，總而言之，我們看到了很好的差異化方面，值得醫生和患者家屬考慮。這就是為什麼我們有信心獲得廣泛的應用，這是一個目標，考慮到廣泛的患者群體，我們希望獲得安全性和有效性。

I think particularly if you think about it, 95% of the prevalent market is still available for these studies. So I think that plus the focus on next generation therapies is really helping with enrollment. So we're excited where we are this early in the year, and I can guarantee we're pushing to go as quickly as we can on all fronts for the BLA submission.

我認為，特別是如果你仔細想想，95% 的主流市場仍然適合進行這些研究。因此我認為，對下一代療法的關注確實有助於招募新患者。因此，我們對今年年初所取得的進展感到非常興奮，我可以保證，我們將在各個方面盡快推進 BLA 提交。

Great, thank you.

太好了，謝謝。

Paul Choi, Goldman Sachs.

高盛的保羅·崔（Paul Choi）。

Oh thank you. Good afternoon and thanks for taking our questions. I want to ask on AFFINITY and how you're thinking about your post-trial or post-approval commitments and just your thoughts on the sort of requirements that I guess down the road for a confirmatory city or other regulatory requirements and just your thoughts there.

噢，謝謝。下午好，感謝您回答我們的問題。我想問 AFFINITY，您如何看待試驗後或批准後的承諾，以及您對未來確認城市或其他監管要求的要求的看法。

And second, based on the data you're seeing to date in the ambulatory population, I want to see if you -- what's the current appetite to potentially explore 202 in a non-ambulatory population at some point, even if it's an exploratory study, just your thoughts there would be great. Thank you for taking our questions.

其次，根據您迄今為止在門診人群中看到的數據，我想看看您是否有興趣在某個時候在非門診人群中探索 202，即使這是一項探索性研究，您的想法也很好。感謝您回答我們的問題。

Great, thanks. I think in terms of confirmatory study, we're going to have that discussion in more detail with FDA in terms of what's required. But I think in general, we intend to continue to enroll post-enrollment of our pivotal and equals 30 data set, towards the end of completing a confirmatory study as quickly as possible. And we'll have further discussions with FDA in our pre-BLA meeting about what exactly that will mean.

太好了，謝謝。我認為，就確認性研究而言，我們將與 FDA 就所需內容進行更詳細的討論。但我認為總的來說，我們打算繼續招募我們的關鍵和相當於 30 個資料集的後期人員，以盡快完成確認性研究。我們將在 BLA 前會議上與 FDA 進一步討論這到底意味著什麼。

I think a -- and the second question is. Remind me.

我認為──第二個問題是。提醒我。

So on non-ambulatory.

因此無法行走。

So we are considering (multiple speakers) we're certainly considering strongly, conducting studies in non-ambulatory patients. But right now, not at the expense of going as fast as possible for the ambulatory one and older patients that we're conducting as part of our clinical studies now. So it is definitely a consideration given the size of the prevalent market there, but we just don't want to use our sites for that purpose at this point, given that we want to close out our pivotal study as quickly as we can this year.

因此，我們正在考慮（多位發言者）我們當然正在認真考慮對無法行走的病人進行研究。但目前，我們正在進行臨床研究，但不能以犧牲門診患者和老年患者盡快康復為代價。因此，考慮到那裡普遍的市場規模，這肯定是一個考慮因素，但我們現在還不想將我們的網站用於此目的，因為我們希望今年盡快完成我們的關鍵研究。

Given the excellent microdystrophin levels and also functional results that we're seeing in eight and above, including a 12-year-old, it's an interesting dilemma really like Curran said, we got to focus on the population for our pivotal. But more and more once we showed that data, investigators and also patient advocacy are asking about non-ambulatory because it's quite logical given the results we've seen. So it's something we'll be looking at, but not acutely adding to the pivotal.

鑑於我們在 8 歲及以上（包括 12 歲）兒童中看到的優異的微肌營養不良蛋白水平和功能結果，這是一個有趣的難題，就像 Curran 所說的那樣，我們必須將重點放在關鍵人群上。但是，一旦我們展示了這些數據，研究人員和患者權益倡導者就會越來越多地詢問非步行性問題，因為根據我們所看到的結果，這是很合乎邏輯的。所以這是我們會關注的事情，但不會急於將其添加到關鍵內容中。

One thing I would add just to finish the question on planning for confirmatory study, we do have drug supply already prepared to cover both the pivotal study and a future confirmatory study based on some planning assumptions that we've made. So I think that's really important that we can seamlessly move into a confirmatory study with existing drug supply.

為了完成關於確認性研究計劃的問題，我想補充一點，根據我們所做的一些規劃假設，我們確實已經準備好了藥品供應，以涵蓋關鍵性研究和未來的確認性研究。因此我認為，利用現有的藥物供應無縫地進行確認性研究非常重要。

Ellie Merle, UBS.

瑞銀的艾莉·梅爾（Ellie Merle）。

Hey guys, thanks for taking the question. Just a little bit more on the functional data, specifically what should we be looking for at this upcoming, data update. And both of this update, but then thinking longer term, both from the pivotal study and then potential confirmatory. What do you think would be differentiating in terms of functional data?

嘿夥計們，謝謝你們回答這個問題。關於功能數據，我們具體應該在即將到來的數據更新中尋找什麼。這兩者都是更新，但從更長遠的角度來看，都是從關鍵研究和潛在的證實出發。您認為在功能數據方面會有什麼差異？

And then in terms of the pivotal study, I guess how do you plan to analyze some of this functional data? Do you have any stats protocol for say doing a natural history comparison? And if so, is this something that you've discussed at all with the FDA? Thanks.

然後就關鍵研究而言，我猜您打算如何分析這些功能數據？您是否有任何統計協議可以用於進行自然歷史比較？如果是的話，您是否與 FDA 討論過此事？謝謝。

Right, yeah, I'll cover just the general, specifics of the functional updates and then maybe I'll let Steve talk about the analysis of the data versus baseline and the external match controls that we're doing.

好的，是的，我將僅介紹功能更新的一般細節，然後也許我會讓史蒂夫談談我們正在進行的數據與基線的分析以及外部匹配控制。

I think in terms of the near-term functional data as I mentioned earlier, you should expect to see additional patients that were treated at dose level 2 in our Phase 1, Phase 1, 2 study. We'll be specific about the number of patients more around when their visits occur and when the data is updated. We'll also report 12-month data on patients that we previously reported. There were 2 at 9 months in that release.

我認為就我之前提到的近期功能數據而言，您應該會看到在我們的第 1 階段、第 1 階段、第 2 階段研究中接受劑量水平 2 治療的更多患者。我們將在患者就診時間和數據更新時具體說明患者人數。我們也將報告先前報告過的患者 12 個月的數據。在該版本中，9 個月時有 2 個。

And also, we will update patients dosed at dose level 1 that were at 12 months who are now likely out to about 18 months, maybe 2 years on some longer-term data, but of course that's not at the pivotal dose, so it'll be just informational at that point. So that that's what you should expect to see near term. And then over the course of the year, I would expect to see most of the data for all 7 patients that were dosed to dose level 2, out to 12 months, but that'll be much later in the year.

此外，我們將更新接受 12 個月劑量等級 1 治療的患者的數據，這些患者的長期數據現在可能已延長至約 18 個月，甚至可能是 2 年，但當然這不是關鍵劑量，因此屆時僅供參考。這就是您近期應該會看到的情況。然後，在一年的時間裡，我預計會看到所有 7 名接受劑量水平 2 治療的患者的大部分數據，持續 12 個月，但這將在今年稍後。

And then, and as far as what we see, or what we'll look at it will be the usual suspects, Ellie, as far as time function tests, so time to stand, 10 m walk, run, time to climb, and NSAA, which traditionally has been viewed as less sensitive than the time function test. But actually in our November update we saw encouraging results not just on the time function tests, but also on the NSAA. So we're excited to see if we can confirm those findings on longer follow up on the existing patients and then increase the sample of patients at dose level to what we see on those.

然後，就我們所看到的或我們將要看到的而言，這將是常見的嫌疑人，艾莉，就時間功能測試而言，站立時間、10 米步行、跑步、攀爬時間和 NSAA，傳統上被認為不如時間功能測試敏感。但實際上，在我們 11 月的更新中，我們不僅在時間功能測試中看到了令人鼓舞的結果，而且在 NSAA 中也看到了令人鼓舞的結果。因此，我們很高興看到我們是否可以透過對現有患者的長期追蹤來證實這些發現，然後將劑量水平的患者樣本增加到我們在這些患者身上看到的水平。

We'll continue to look at this the way we've done in the past, which is not just in isolation, but compared to matched external natural history controls. So that's really important given disease trajectory is different depending on age and baseline severity. So we match on all those factors to give greater confidence in terms of whether individual patients' trajectory is positive or not.

我們將繼續以過去的方式看待這個問題，不僅是孤立地進行，而且要與匹配的外部自然歷史控制進行比較。鑑於疾病軌跡隨年齡和基線嚴重程度的不同而不同，這一點非常重要。因此，我們會將所有這些因素進行匹配，以便更有信心地判斷個別患者的病情軌跡是否積極。

We have discussed this with the FDA, so this was certainly a part of the successful end of Phase 2 meeting that we held before starting pivotal, and we had no issues getting into the pivotal design.

我們已經與 FDA 討論過這個問題，所以這無疑是我們在開始關鍵階段之前舉行的第 2 階段會議成功結束的一部分，我們在進入關鍵設計時沒有遇到任何問題。

Cool, thanks.

太棒了，謝謝。

Sean McCutcheon, Raymond James.

肖恩麥卡琴、雷蒙德詹姆斯。

Hey guys, thanks for the question. One for me on NPDR, Steve, to your point, we've seen some reticence from patients. To receive anti-VEGF therapies due to that higher frequent injections. And you've shown some meaningful decreases in vision threatening events, up to 12 months in ALTITUDE at the higher dose, in line or better than the PANORAMA study of Flibercept. What do you view as the treatment durability at which we could start to see more utilization in NPDR and how do you view that as a thing for a gene therapy versus, say, a sustained release TKI? Thanks.

嘿夥計們，謝謝你的提問。史蒂夫，關於 NPDR，我想說的是，正如你所說，我們看到一些患者保持沉默。由於注射頻率較高，因此接受抗 VEGF 治療。並且，在 ALTITUDE 中，使用較高劑量長達 12 個月，視力威脅事件明顯減少，與 Flibercept 的 PANORAMA 研究結果一致或更好。您認為治療耐久性如何讓我們開始看到 NPDR 得到更多的利用，以及您如何看待基因療法與緩釋 TKI 相比有何不同？謝謝。

Sure, that's a great question, Sean, and I think that is the key observation that we've seen is that even though repeated anti-VEGF injections definitely work, it's just too much of a burden for patients and doctors to give injections indefinitely, because once you stop giving the injections, the severity comes back. So you're basically signing patients up who are currently asymptomatic to get injections the rest of their life, basically.

當然，肖恩，這是一個很好的問題，我認為我們看到的關鍵觀察是，儘管重複注射抗 VEGF 肯定有效，但無限期地註射對患者和醫生來說負擔太重，因為一旦停止注射，病情就會復發。因此，您基本上就是讓目前無症狀的患者終生接受注射。

And that's really the barrier also to even longer-durability TKIs since it's certainly better to only need an injection every six months or even every year. But if it's repeated injections, we see that as a major barrier and that's why we and AbbVie are so excited about the DR indication because of suprachoroidal in-office one time injection is really the way to address this massive unmet need.

這對於更持久的 TKI 來說也是一個真正的障礙，因為每六個月甚至每年只需注射一次肯定更好。但如果是重複注射，我們認為這是一個主要障礙，這就是為什麼我們和 AbbVie 對 DR 適應症如此興奮，因為脈絡膜上腔一次性注射確實是解決這一巨大未滿足需求的方法。

And that's why we're excited with the data that you referred to where we've shown an 89% reduction in vision threatening complications at a year. So that really was the impetus for us in AbbVie accelerating the end of Phase 2 planning and now that we have the positive outcome of that study. Now we're both excited to advance into pivotal this year.

這就是為什麼我們對您提到的數據感到興奮，我們發現一年內視力威脅併發症減少了 89%。因此，這確實是促使 AbbVie 加速完成第二階段計畫的動力，現在我們已經獲得了研究的正面成果。現在，我們都很興奮能夠進入關鍵的一年。

Thank you.

謝謝。

Alec Stranahan, Bank of America.

亞歷克·斯特拉納漢，美國銀行。

Hey, guys, thanks for taking our questions. May maybe two from us, both on DMD. Appreciate the updates on the pace of enrollment in AFFINITY DUCHENNE. I guess how long after completion of enrollment do you think we could see data? Would 12-week microdystrophin for the primary be enough maybe for the topline, or would you want to wait a bit longer for some of the other end points?

嘿，夥計們，感謝你們回答我們的問題。也許我們有兩個，都是 DMD 的。感謝您提供有關 AFFINITY DUCHENNE 招生進度的最新消息。我猜您認為完成註冊後多久我們才能看到資料？12 週的微肌營養不良蛋白對於主要研究來說是否足夠，或者您想等待更長時間才能獲得其他一些終點？

And second, I'm sure you guys are tracking the evolving commercial market and DMD pretty closely. I guess maybe following up on a previous question. What's your expectation around the market dynamic in say a year or two when you're a bit closer to approval. Any updated thinking around current supply and the addressable market at launch would be great. Thank you.

其次，我相信你們正在密切關注不斷發展的商業市場和 DMD。我想這也許可以回答之前的問題。當您距離批准更近一兩年時，您對市場動態有何預期？任何有關當前供應和發佈時可尋址市場的最新想法都很好。謝謝。

In terms of the second question I think I'll take first. I think one of the key aspects of our plan is that we think at least half of the prevalent market will still be available by 2027, which is what we're targeting for a potential approval. And if you look at the updated guidance now, we're pointing towards the mid-2026 BLA filing. So that that could lead to an approval, potential approval in early 2027, which I think is really important. And we're already planning how to address the market.

關於第二個問題，我想我先回答。我認為我們計劃的一個關鍵方面是，我們認為到 2027 年至少有一半的主流市場仍將可用，這正是我們獲得批准的目標。如果您現在查看更新後的指南，我們指的是 2026 年中期的 BLA 申請。因此這可能會導致批准，可能在 2027 年初獲得批准，我認為這非常重要。我們已經在計劃如何應對市場。

We'll be making our first lots that are eligible for commercial sales starting this fall, and we have the capability with our in-house manufacturing to stockpile a significant number of doses of had the launch. So assuming we can, establish a broad label, I would expect we're going to be very aggressive commercially in 2027 to take a significant amount of the prevalent population in terms of market.

從今年秋季開始，我們將生產首批符合商業銷售條件的疫苗，並且我們有能力透過內部生產儲存大量劑量以供上市。因此，假設我們能夠建立一個廣泛的品牌，我預計我們將在 2027 年在商業上非常積極，以佔據相當一部分市場。

And then, Alec, as far as your first question about when would we have actual results that we could disclose. The 12-week time point that is our accelerated approval end point time point for microdystrophin. So that's a very significant step, so we certainly would be coming out with that data, since that's really what's going to drive actually going ahead with the BLA submission by mid next year already, so. We'd also have safety at that time point as well, so I think that really puts us in a good position.

然後，亞歷克，關於你的第一個問題，我們什麼時候才能有可以揭露的實際結果。12 週的時間點是我們對微肌營養不良蛋白的加速核准終點時間點。這是非常重要的一步，所以我們肯定會公佈這些數據，因為這才是真正推動明年年中之前提交 BLA 的動力。我們在那個時間點也會很安全，所以我認為這確實讓我們處於有利地位。

I think if you think about what functional data would we have in hand at the time of filing, certainly the full Phase 1, 2 dose level 2 cohort would be past 12 months at that point. And a good proportion of the patients treated in the pivotal study will have at least 9 months, if not 12-month data. So we'll have a healthy level of functional data to accompany the primary endpoint of microdystrophin, at the time of filing and probably be able to update that somewhat at the 120-day safety update as well.

我認為，如果您考慮我們在提交申請時手頭上有哪些功能數據，那麼完整的第 1 階段、第 2 劑量級 2 隊列肯定將超過 12 個月。並且，在關鍵研究中接受治療的患者中，很大一部分將擁有至少 9 個月甚至 12 個月的數據。因此，在提交申請時，我們將擁有健康水平的功能數據來配合微肌營養不良蛋白的主要終點，並且可能能夠在 120 天的安全更新中對其進行一些更新。

Got it makes sense. Appreciate the color.

明白了，很有道理。欣賞色彩。

Yi Chen, H.C. Wainwright.

陳毅, H.C.溫賴特。

Oh, thank you for taking my question. Could you comment on Nippon Shinyaku's sales team presence in the US? How many of them will be promoting RGX-121? And do you expect to -- do you expect that any sales related milestone could be triggered within 12 months of commercial launch? Thank you.

哦，謝謝你回答我的問題。能評價一下日本新藥在美國的銷售團隊嗎？其中有多少人會推廣 RGX-121？您是否預計—您是否預計在商業發布後的 12 個月內能夠實現任何與銷售相關的里程碑？謝謝。

Didn't quite hear the first part. Could we repeat just the beginning of that question? I got it was a little bit muffled. Yeah, the audio is just a little rough.

沒聽清楚第一部分。我們能重複一下這個問題的開頭嗎？我覺得聲音有點沉悶。是的，音頻有點粗糙。

The sales ateam presence of the Nippon Shinyaku's US, how many of them will be promoting RGX-121?

日本新藥的美國銷售團隊中，有多少人會推廣RGX-121？

Okay. Yes, Nippon Shinyaku has a significant US presence in rare disease. They have an existing sales force that services their Duchenne launch and we expect that a majority of those that same team would be applied towards commercialization of RGX-121.

好的。是的，日本新藥在美國罕見疾病領域佔有重要地位。他們擁有一支現有的銷售隊伍，為杜氏肌肉營養不良症的推出提供服務，我們預計團隊中的大多數人將致力於 RGX-121 的商業化。

Given the timeline now that we've filed the BLA, we're pointing towards PDUFA date somewhere in Q4 of this year, and that would point to a launch either late this year or early next year, of course, and feel positive that the partnership with NS Pharma allows us to do that as rapidly as possible.

鑑於我們現在提交 BLA 的時間表，我們預計 PDUFA 日期將在今年第四季度的某個時候，當然，這意味著將在今年年底或明年年初推出產品，並且有信心與 NS Pharma 的合作使我們能夠盡快做到這一點。

Good alignment initially with them on site selection for commercial sale there are dosing centers that we've worked with clinically that we feel are obvious choices that have also previously handled commercial products. So more to follow as we go through the review process on the BLA.

最初在商業銷售地點的選擇上與他們進行了良好的協調，我們曾與一些劑量中心進行過臨床合作，我們認為這些劑量中心是顯而易見的選擇，這些中心以前也處理過商業產品。隨著我們對 BLA 的審查過程不斷推進，我們將推出更多內容。

In terms of achievement of sales milestones, the milestones, there are some that could be realized in the first year of sale. They're sort of staggered throughout the growth of the product. We haven't commented previously on what proportion that might be of the 700 million total potential milestones, but some of those could be realized in the first or second year of launch.

就實現銷售里程碑而言，有些里程碑可以在銷售的第一年實現。在產品的整個發展過程中，它們都是處於交錯狀態的。我們之前沒有評論過這個數字在 7 億潛在里程碑總數中所佔的比例，但其中一些可能會在推出的第一年或第二年實現。

Thank you.

謝謝。

I'm showing no further questions in queue at this time. This concludes today's conference call. Thank you for participating. You may now disconnect.

目前隊列中沒有其他問題。今天的電話會議到此結束。感謝您的參與。您現在可以斷開連線。