Design Therapeutics Inc (DSGN) 2023 Q4 法說會逐字稿

Good afternoon and welcome to Design's conference call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session after the prepared remarks. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Dr. Sean Jeffries, Chief Operating Officer of Design Therapeutics. You may begin.

下午好，歡迎參加 Design 的電話會議。此時，所有參與者都處於只聽模式。準備好的發言後將進行問答環節。請注意，本次通話是應公司要求進行錄音的。我現在想將電話轉給 Design Therapeutics 首席營運長 Sean Jeffries 博士。你可以開始了。

Welcome and thank you for joining us today. Earlier, we issued a press release outlining our fourth quarter and full year 2023 financial results and updates across our portfolio of GeneTAC small molecule genomic medicines. The slides that we'll be using today during today's call will be available, along with the recording of this call, in the investor section of our website at designtx.com. I'm Sean Jeffries, Chief Operating Officer of Design, and I'm joined today on the call by our Chairman and CEO, Dr. Pratik Shah.

歡迎並感謝您今天加入我們。早些時候，我們發布了一份新聞稿，概述了我們第四季度和 2023 年全年的財務業績以及我們 GeneTAC 小分子基因組藥物組合的最新情況。我們將在今天的電話會議中使用的幻燈片以及本次電話會議的錄音將在我們網站 designtx.com 的投資者部分提供。我是設計部首席營運長肖恩·傑弗里斯 (Sean Jeffries)，今天我們的董事長兼首席執行官普拉蒂克·沙阿 (Pratik Shah) 博士也加入了我的電話會議。

During this call, we will use forward-looking statements related to our current expectations and plans, including our program development plans, which are subject to risk and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recently filed Form 10-K. These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. We take no obligation to publicly update any forward-looking statements. With that, I'd like to turn the call over to Dr. Shah.

在本次電話會議中，我們將使用與我們目前的預期和計劃相關的前瞻性陳述，包括我們的專案開發計劃，這些陳述存在風險和不確定性。由於各種重要因素，包括我們最近提交的表格 10-K 的風險因素部分中所述的因素，實際結果可能會存在重大差異。這些陳述代表了我們截至本次電話會議的觀點，不應被視為代表我們在未來任何日期的觀點。我們沒有義務公開更新任何前瞻性陳述。說到這裡，我想把電話轉給沙阿醫生。

Thank you, Dr. Jeffries, and good afternoon, everyone. I'm excited to present Design Therapeutics’ first significant update for 2024. What makes this company unique and compelling is that we have discovered a new class of small molecules that are designed to dial up or dial down the expression of an individual gene in the genome. When you think about the role of individual genes and disease, there are many monogenic disorders where the single gene that causes the disease is well established.

謝謝杰弗里斯博士，大家下午好。我很高興向大家介紹 Design Therapeutics 2024 年的第一個重大更新。這家公司的獨特之處和引人注目之處在於，我們發現了一類新型小分子，旨在提高或降低基因組中單一基因的表達。當您考慮單一基因和疾病的作用時，您會發現許多單基因疾病，其中導致疾病的單一基因已得到充分證實。

Our vision is to develop small molecules that can provide a restorative therapy and work with the patient's natural genome to help cells read the genes in a manner that restores cellular health, despite the presence of the mutations. We are working on at least four major such disorders: Friedreich ataxia, Fuchs endothelial corneal dystrophy, Huntington’s Disease, and myotonic dystrophy. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class. I'm Pratik Shah and I serve as the CEO.

我們的願景是開發能夠提供恢復性治療的小分子，並與患者的自然基因組一起工作，幫助細胞以恢復細胞健康的方式讀取基因，儘管存在突變。我們正在研究至少四種主要的此類疾病：弗里德賴希共濟失調、福克斯內皮性角膜營養不良、亨廷頓病和強直性肌肉營養不良。我們在這些領域追求的每個項目都有可能成為同類第一或同類最佳。我是 Pratik Shah，擔任執行長。

I was previously Chairman of Synthorx, which is now part of Sanofi as a result of $2.5 billion acquisition, and prior to that, I was CEO of Auspex Pharmaceuticals, which was acquired for $3.5 billion. There, we had discovered and developed AUSTEDO, which is now doing over $1 billion in annual revenue, and I'm joined by an accomplished and capable leadership team at Design, including Dr. Sean Jeffries, our Chief Operating Officer; and Dr. Jae Kim, our Chief Medical Officer. Design's genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases. In addition, we have a five-year operating runway, which enables us to generate clinical proof of concept on up to four programs. Success in any one of these programs has the potential to generate enormous value for patients and shareholders.

我之前曾擔任Synthorx 的董事長，該公司因25 億美元的收購而現已成為賽諾菲的一部分，在此之前，我曾擔任Auspex Pharmaceuticals 的首席執行官，該公司被以35 億美元的價格收購。在那裡，我們發現並開發了 AUSTEDO，該公司現在的年收入超過 10 億美元，我的設計團隊中有一支卓有成效且有能力的領導團隊，其中包括我們的營運長 Sean Jeffries 博士；以及我們的首席醫療官 Jae Kim 博士。Design 的基因組醫學平台有潛力超越基因編輯和基因療法等治療這些疾病的競爭方式。此外，我們還有一個為期五年的營運跑道，使我們能夠為多達四個項目產生臨床概念驗證。這些項目中任何一項的成功都有可能為患者和股東創造巨大的價值。

Each of our programs is pursuing the treatment of monogenic diseases where the single gene root cause is know. And our therapeutic strategy is to restore the normal gene expression state of this known single gene driver. Each of our programs has a first or best in class profile, which has highly differentiating features, and each of these are substantial market opportunities. Friedreich Ataxia, or FA, is a debilitating neuromuscular disorder with hypertrophic cardiomyopathy as the primary cause of death.

我們的每個計畫都致力於治療已知單基因根本原因的單基因疾病。我們的治療策略是恢復這個已知的單基因驅動器的正常基因表現狀態。我們的每個項目都擁有一流或一流的概況，具有高度差異化的功能，並且每一個都是巨大的市場機會。弗里德賴希共濟失調（FA）是一種使人衰弱的神經肌肉疾病，肥厚性心肌病變是主要的死亡原因。

It's caused by a GAA repeat mutation in the Frataxin gene, which is broadly expressed in the body. The goal of our genomic medicine is to increase levels of endogenous RITUXAN and address the monogenic cause of FA. We will address the background in greater detail later in the presentation. We had taken our lead molecule, DT216, for Friedreich Ataxia into clinical trials in 2022 and ‘23, and confirmed that DT-216 can increase the level of frataxin RNA expression in patients with FA.

它是由 Frataxin 基因中的 GAA 重複突變引起的，該基因在體內廣泛表達。我們基因組醫學的目標是提高內源性 RITUXAN 的水平並解決 FA 的單基因原因。我們將在稍後的演示中更詳細地介紹背景。我們已於 2022 年和 2023 年將治療 Friedreich Ataxia 的先導分子 DT216 納入臨床試驗，並證實 DT-216 可以增加 FA 患者的 frataxin RNA 表現量。

We also learned about limitations to the prior formulation in human studies. Today, we would like to announce a new drug product using the same DT-216 drug substance as before. We refer to this new drug product as DT-216P2, which we believe has properties that resolve these prior barriers to progressing DT-216 further into development. The market opportunity for a systemic therapy that can restore endogenous rituxan levels remains large and unaffected by progress by others in the field.

我們也了解了人類研究中先前公式的局限性。今天，我們想宣布一款使用與之前相同的 DT-216 原料藥的新藥品。我們將這種新藥產品稱為 DT-216P2，我們相信它具有解決這些先前阻礙 DT-216 進一步開發的障礙的特性。能夠恢復內源性利妥昔單抗水平的全身療法的市場機會仍然很大，並且不受該領域其他進展的影響。

The prior DT-216 drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile, and therefore, drug levels in the plasma were low after only a few hours. The orange curve shows the pharmacokinetics of the prior DT-216 drug product in non-human primates. In green, is the PK of DT-216P2, which has a shorter alpha phase and a more rapid transition to the beta phase, and therefore, a substantial increase in drug levels over a much longer period of time. Due to this increase in exposure, lower levels of administered drug are needed to achieve these desired profiles.

先前的 DT-216 藥品在稱為 α 相的時期及其暴露曲線中從血漿中快速消除，因此僅幾個小時後血漿中的藥物水平就很低。橙色曲線顯示了先前的 DT-216 藥物在非人靈長類動物中的藥物動力學。綠色是 DT-216P2 的 PK，它的 α 相較短，向 β 相的轉變更快，因此藥物水平在更長的時間內大幅增加。由於暴露量的增加，需要較低水平的給藥藥物來實現這些所需的分佈。

In addition, a favorable injection site reaction profile has been seen with the new drug product in nonclinical studies. With this new advance, we are back on a path to continue further development of DT-216 for patients with FA. In the time since our last update, we have also advanced the GeneTAC platform and have refined our strategy and priorities for the programs. Our FECD program data have now been reviewed by the FDA, resulting in an IND cleared to proceed.

此外，在非臨床研究中，此新藥產品具有良好的注射部位反應特性。憑藉這一新進展，我們又回到了繼續進一步開發針對 FA 患者的 DT-216 的道路上。自上次更新以來，我們也改進了 GeneTAC 平台，並完善了我們的計畫策略和優先事項。我們的 FECD 專案數據現已由 FDA 審查，從而獲得 IND 批准繼續進行。

As a result, we plan to initiate Phase 1 development for DT-168 this year. We have also decided to conduct an observational study in patients with FECD, prior to conducting an investigational drug treatment trial in patients. We are also announcing for the first time our Huntington's disease program, where we have identified small molecule candidates that exhibit allele selective reduction of Mutant Huntington expression, considered an ideal, although elusive profile, for molecules that could be reasonably advanced as systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting allele selective inhibition of Mutant DMPK, which is the root cause of myotonic dystrophy, with what we believe are best-in-class foci reduction and splicing restoration data.

因此，我們計劃今年啟動 DT-168 的第一階段開發。我們也決定在對 FECD 患者進行研究性藥物治療試驗之前，對 FECD 患者進行一項觀察性研究。我們還首次宣布我們的亨廷頓病計劃，其中我們已經鑑定出表現出等位基因選擇性降低突變亨廷頓表達的小分子候選物，這被認為是理想的，儘管難以捉摸的概況，對於可以通過系統施用和廣泛應用而合理推進的分子分配化合物。同樣，我們已經鑑定出對突變 DMPK 表現出等位基因選擇性抑制的化合物，這是強直性肌肉營養不良的根本原因，我們認為這是同類最佳的病灶減少和剪接恢復數據。

We aim to advance both HD and DM1 programs to declare development candidates. Gene editing and gene therapy have understandably captured the imagination of humankind. Ever since we learned that mutations in single genes cause disease, there has been a desire to edit the genome in some fashion to restore normal cellular health. Other approaches have also emerged that try to get at the root cause of monogenic diseases; however, if gene tech molecules work in patients, there would be little doubt that they represent the best option in genomic medicine, since GeneTAC molecules when systemically administered, can distribute widely to a broad set of tissues in the target cells broadly to affect the desired outcome without altering a patient's natural genome.

我們的目標是推進 HD 和 DM1 計劃以宣布開發候選者。基因編輯和基因療法激發了人類的想像力，這是可以理解的。自從我們了解到單一基因的突變會導致疾病以來，人們一直希望以某種方式編輯基因組以恢復正常的細胞健康。其他方法也出現了，試圖找出單基因疾病的根本原因。然而，如果基因技術分子在患者身上發揮作用，毫無疑問它們代表了基因組醫學的最佳選擇，因為GeneTAC 分子在全身給藥時，可以廣泛分佈到目標細胞的廣泛組織中，從而影響所需的效果。在不改變患者自然基因組的情況下獲得結果。

Furthermore, investments into new platform companies often suffer from frequent rounds of dilution due to the necessary high R&D burn rates that often require investors to time their investment decisions with great care. Design’s approach is more cost effective, making an investment decision for a longer horizon potentially quite attractive. The advantage of GeneTAC molecules become more apparent when you consider how much smaller these molecules are than those of competing modalities, which further explains the broad distribution properties. Also, by restoring endogenous gene expression, like in FA, the gene products are entirely normal and under normal physiologic control.

此外，由於必要的高研發消耗率，對新平台公司的投資經常會遭受頻繁的稀釋，這通常要求投資者非常謹慎地選擇投資決策。設計方法更具成本效益，使得長期投資決策可能非常有吸引力。當您考慮到這些分子比競爭模式的分子小得多時，GeneTAC 分子的優勢就變得更加明顯，這進一步解釋了廣泛的分佈特性。此外，透過恢復內源基因表現（如 FA），基因產物完全正常且處於正常的生理控制之下。

The mechanism of action of these GeneTAC molecules, which drive these remarkable observations are shown in this animation that I'll walk you through: first, we start with FA. FA is caused by low levels of frataxin, which is a protein that's systemically expressed in the body. So if you look inside the cell and inside the nucleus, the frataxin gene has a GAA repeat expansion shown in red, which causes the RNA polymerase to slow down through this region and produce low levels of frataxin premium RNA, and therefore low levels of express translated protein, and that's what drives the dysfunction. GeneTAC candidates are hetero bifunctional small molecules, where one end of the molecule has been designed to specifically recognize the GAA expanded repeats.

這些 GeneTAC 分子的作用機制驅動了這些非凡的觀察結果，如我將引導您完成的動畫所示：首先，我們從 FA 開始。FA 是由 frataxin 水平低引起的，frataxin 是一種在體內全身表達的蛋白質。因此，如果您觀察細胞內部和細胞核內部，會發現frataxin 基因有一個以紅色顯示的GAA 重複擴增，這會導致RNA 聚合酶減慢通過該區域的速度，並產生低水平的frataxin 優質RNA，因此表達水平較低翻譯蛋白質，這就是導致功能障礙的原因。GeneTAC 候選物是異質雙功能小分子，其中分子的一端被設計用於特異性識別 GAA 擴展重複序列。

When this compound is administered systemically, it distributes widely, gets into the cell, gets into the nucleus, and then recognizes the GAA repeat expansions by binding to the minor groove of intact double stranded DNA in the frataxin gene. And the other end of the molecule recruits a transcriptional elongation complex. The presence of these transcriptional elongation complexes enables the RNA grim race to now rapidly read through the repeat region, and therefore, produce normal levels of the frataxin pre mRNA. Because the repeat expansion is in an intron, that portion of the RNA is just spliced out normally to produce normal levels of intact full length endogenous mRNA, which produces normal endogenous frataxin protein, with all of its natural isoforms under the native regulatory control.

當這種化合物全身給藥時，它會廣泛分佈，進入細胞，進入細胞核，然後透過與 frataxin 基因中完整雙股 DNA 的小溝結合來識別 GAA 重複序列擴展。分子的另一端招募轉錄延伸複合物。這些轉錄延伸複合物的存在使得 RNA grim 種族能夠快速讀取重複區域，從而產生正常水平的 frataxin 前 mRNA。因為重複擴增在內含子中，所以該部分RNA 被正常剪接以產生正常水平的完整全長內源mRNA，從而產生正常的內源frataxin 蛋白，其所有天然亞型均處於天然調節控制之下。

This restores frataxin levels, and therefore, cellular health. Now, for the other side of the platform, long repeat expansions in non coding regions of genes are shown in red in the upper half. This is the case in diseases like Fuchs endothelial corneal dystrophy and myotonic dystrophy. Repeat expansions in coding regions of genes are shown in the lower half in red, as is the case in Huntington’s disease, and it only takes one allele to cause the disease.

這可以恢復 frataxin 水平，從而恢復細胞健康。現在，對於平台的另一側，基因非編碼區域的長重複擴展在上半部顯示為紅色。福克斯內皮性角膜營養不良和強直性肌肉營養不良等疾病就是這種情況。基因編碼區的重複擴增在下半部以紅色顯示，就像亨丁頓舞蹈症的情況一樣，只需要一個等位基因就能引起這種疾病。

So patient has one wild type allele shown in the strand without the red, and a mutant allele shown in the strand with the red expanded regions. Now, in the upper half, this mutant allele is transcribed by RNA polymerase to create RNA, which then folds over on itself, causes tangles and sequesters MBNL proteins. This causes nuclear foci and [sliceosteopathy] and other cellular dysfunction. Now in the lower half, the RNA is transcribed and then translated by ribosomes to make toxic mutant proteins.

因此，患者俱有在沒有紅色的鏈中顯示的一種野生型等位基因，以及在具有紅色擴展區域的鏈中顯示的突變等位基因。現在，在上半部分，這個突變等位基因被 RNA 聚合酶轉錄以產生 RNA，然後 RNA 會自行折疊，導致纏結並隔離 MBNL 蛋白。這會導致核病灶和[切片骨病變]和其他細胞功能障礙。現在，在下半部分，RNA 被轉錄，然後由核醣體翻譯，產生有毒的突變蛋白。

These proteins cause toxic aggregates, as is the case in mutant huntington protein causing huntington’s disease. GeneTAC molecules selectively target these abnormal alleles at the repeat expansions shown in red, and they dial down transcription of toxic mutant gene products, and thereby, restore cellular health. The wild type alleles continue to function normally. This slide summarizes the mechanism of action that we've just reviewed in the animation.

這些蛋白質會導致有毒聚集物，就像導致亨廷頓氏舞蹈症的突變亨廷頓蛋白一樣。GeneTAC 分子在紅色所示的重複擴增中選擇性地靶向這些異常等位基因，並降低有毒突變基因產物的轉錄，從而恢復細胞健康。野生型等位基因繼續正常發揮作用。這張投影片總結了我們剛剛在動畫中回顧的作用機制。

And now, for a deeper dive into our FA program, the root cause of FA lies in the single gene frataxin. It's the reduction in frataxin expression that causes the dysfunction, whether it's in the C&S, musculoskeletal tissues, cardiac hypertrophy, or metabolic problems that patients face. When we look at frataxin levels in (technical difficulty) healthy individuals, carriers and patients. We see that carriers have approximately half the level of their frataxin is indicated by the black line representing the group average, carriers do not have FA and have no disease burden.

現在，為了更深入地研究我們的 FA 項目，FA 的根本原因在於單基因 frataxin。frataxin 表現的減少導致了功能障礙，無論是在 C&S、肌肉骨骼組織、心臟肥大或患者面臨的代謝問題中。當我們觀察（技術難度）健康個體、攜帶者和患者中的 frataxin 水平。我們看到，攜帶者的 frataxin 水平大約是群體平均水平的一半，由代表組平均值的黑線表示，攜帶者沒有 FA，也沒有疾病負擔。

FA patients have a quarter to a fifth of normal frataxin levels on average. Of course, around every mean is a distribution, and there may be individuals who are above or below the mean, and different individuals might require different levels of restoration to get back into the normal zone, which is somewhere near carrier levels. And that is the therapeutic goal, which is thought to be about a doubling. Now, most of the general population has less than 34 GA repeats in their frataxin gene, but someone with FA has 400 or over a 1,000, and these repeats reduce the level of normal frataxin, and it turns out, you can measure this reduction with a blood test.

FA 患者的 frataxin 水準平均為正常水準的四分之一到五分之一。當然，每個平均值周圍都有一個分佈，可能有人高於或低於平均值，不同的人可能需要不同程度的恢復才能回到正常區域，即接近運營商水平的地方。這就是治療目標，被認為是翻倍。現在，大多數普通人群的 frataxin 基因中的 GA 重複序列少於 34 個，但患有 FA 的人有 400 個或超過 1,000 個，這些重複序列降低了正常 frataxin 的水平，事實證明，你可以用驗血。

What's shown on the top right is a result of a PCR test conducted on blood cells from patients. You can see in the gray bar on the graph that RNA levels are low in patient cells, when compared with frataxin from an unaffected sibling who has two normal copies of the frataxin gene. You can imagine our excitement when we were able to observe that when cells from patients are incubated with GeneTAC molecules, there's a restoration of frataxin to normal levels in a dose dependent fashion. And when cells from unaffected siblings are incubated with the compounds, the frataxin levels remain unaltered.

右上方顯示的是患者血球進行 PCR 檢測的結果。您可以在圖中的灰色條中看到，與具有兩個正常 frataxin 基因拷貝的未受影響兄弟姐妹的 frataxin 相比，患者細胞中的 RNA 水平較低。當我們能夠觀察到當來自患者的細胞與 GeneTAC 分子一起孵育時，frataxin 以劑量依賴性方式恢復到正常水平時，您可以想像我們的興奮。當未受影響的兄弟姐妹的細胞與這些化合物一起孵育時，frataxin 水平保持不變。

This is exactly what one would wish for an FA, a medicine that restores natural levels of the single gene product that causes all of these problems. And that's what's so exciting about Design, is we have an opportunity to provide a restorative therapy of natural frataxin from the patient's own genes, and to do it with a small molecule. Now, we've seen that this effect is observed in a wide variety of cell types tested. Shown here is the result of treating terminally differentiated neurons taken from patient-derived IPS cells.

這正是人們對 FA 的期望，FA 是一種能夠恢復導致所有這些問題的單基因產物的自然水平的藥物。這就是設計令人興奮的地方，我們有機會提供來自患者自身基因的天然 frataxin 的恢復療法，並使用小分子來實現。現在，我們發現在多種測試的細胞類型中都觀察到了這種效應。這裡顯示的是對取自患者的 IPS 細胞的終末分化神經元進行治療的結果。

On the left, is an increase in frataxin RNA, and on the right is an increase in frataxin protein, which follows a few days later and has a long half-life of several days. DT-216 was taken into clinical trials in patients with FA in 2022 and ‘23, with a prior formulation and the trial design is shown here. We learned from the human studies that the duration of adequate levels of exposure of DT-216 was much shorter than expected. While we knew that the drug was short-lived in plasma, human studies showed by muscle biopsy that it was also short-lived in tissue, and that what you observe in plasma is predictive of what is observed in tissue.

左邊是 frataxin RNA 的增加，右邊是 frataxin 蛋白的增加，幾天後出現增加，半衰期長達數天。DT-216 於 2022 年和 23 年在 FA 患者中進行了臨床試驗，採用先前的配方，試驗設計如下所示。我們從人體研究中了解到，足夠的 DT-216 暴露持續時間比預期短得多。雖然我們知道該藥物在血漿中的壽命很短，但透過肌肉活檢進行的人體研究表明，它在組織中的壽命也很短，並且在血漿中觀察到的情況可以預測在組織中觀察到的情況。

The tissue levels from human muscle biopsies were approximately only eight to 10 nanomolar at day two, and the drug was almost gone with levels of one nanomolar by day seven. Well, despite that, there was a clear increase in frataxin expression observed in treated patients in a dose dependent fashion with one patient frataxin level, going to clinically normal carrier levels as shown in the right. However, the effect was transient because the drug exposure was transient, so we needed to develop a new drug product that could sustain this drug exposure. While the drug was generally well tolerated, there were injection site thrombophlebitis events observed, which limited the frequency and levels of dosing with the prior product candidate.

第二天，人體肌肉活檢的組織水平大約僅為 8 至 10 納摩爾，到第七天，藥物水平幾乎消失為 1 奈摩爾。好吧，儘管如此，在接受治療的患者中觀察到 frataxin 表達以劑量依賴性方式明顯增加，其中一名患者 frataxin 水平達到臨床正常載體水平，如右圖所示。然而，由於藥物暴露是短暫的，所以效果是短暫的，因此我們需要開發一種可以維持這種藥物暴露的新藥品。雖然該藥物整體耐受性良好，但觀察到注射部位血栓性靜脈炎事件，這限制了先前候選產品的給藥頻率和水平。

Nonclinical studies showed that these reactions were attributable to the formulation excipients in the drug product. We have now conducted new non GLP animal studies with DT-216P2, which lead us to believe that these issues have now been solved and we can progress to confirmatory GLP studies to get back into the clinic. Furthermore, this new drug product appears suitable for IV administration, compatible with injections or infusions, peripheral or central, and also appears suitable for a subcutaneous route of administration. As we showed in the beginning, the new drug product, DT-216P2, has a much more sustained exposure profile, as seen in the single dose ID PK curve from non-human primates.

非臨床研究表明，這些反應可歸因於藥品中的配方賦形劑。我們現在已經用 DT-216P2 進行了新的非 GLP 動物研究，這使我們相信這些問題現在已得到解決，我們可以進行驗證性 GLP 研究以重返臨床。此外，這種新藥物產品似乎適合靜脈注射給藥，與週邊或中樞注射或輸注相容，也似乎適合皮下給藥途徑。正如我們在開始時所展示的，新藥品 DT-216P2 具有更持久的暴露曲線，如非人靈長類動物的單劑量 ID PK 曲線所示。

You can see between day one and day seven, the levels are 10 to perhaps a hundred-fold higher than the prior drug product, even with a quarter to approximately a tenth of the reference dose. This is because of a shorter alpha phase and the elimination half-life between the prior and new drug products are very similar. This profile has been achieved by using a proprietary and novel excipient in the formulation. DT-216P2 also has a sustained exposure profile when administered by subcutaneous route of administration, as shown on the right slide.

您可以看到，在第一天到第七天之間，即使使用參考劑量的四分之一到大約十分之一，其水平也比之前的藥品高 10 到 100 倍。這是因為先前的藥物產品和新的藥物產品之間的α相較短且消除半衰期非常相似。這種特性是透過在配方中使用專有的新型賦形劑來實現的。當透過皮下給藥途徑給藥時，DT-216P2 還具有持續的暴露曲線，如右幻燈片所示。

This profile has a blunted CMAX and a sustained exposure with low peak to trough level fluctuations. We have flexibility in both root of administration as well as frequency of dosing, as seen here with both a daily or weekly subcutaneous injection in non-human primates. In the clinical trial, we observed that the tissue level as measured by muscle biopsy was in line with the plasma exposure, and this is typical of a small molecule drug. The new drug product also shows that the tissue levels, as measured by muscle biopsy in non-human primates, is in line with plasma exposures, providing comfort that the extended profile seen in plasma will provide the desired extended profile in tissues.

此曲線具有鈍化的 CMAX 和持續暴露，且峰谷水平波動較低。我們在給藥方式和給藥頻率方面都具有靈活性，正如這裡在非人類靈長類動物中每天或每週皮下注射所看到的那樣。在臨床試驗中，我們觀察到透過肌肉活檢測量的組織水平與血漿暴露量一致，這是小分子藥物的典型特徵。該新藥產品還表明，透過非人靈長類動物的肌肉活檢測量的組織水平與血漿暴露一致，這讓人確信血漿中看到的擴展輪廓將在組織中提供所需的擴展輪廓。

Repeat dose studies done in non GLP assessments have also been encouraging and the program will be proceeding to GLP studies, which are planned to be completed by the end of this year to support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies, our plan is now to conduct a Phase 1 clinical trial in healthy volunteers, so as to confirm the pharmacokinetics and also to confirm injection site tolerability. This will also help us in choosing a dosing root and dosing frequency for longer term studies. Subsequent trials will be in FA patients, which we plan to conduct to determine safety, tolerability, and the effect of treatment on endogenous frataxin levels.

在非 GLP 評估中進行的重複劑量研究也令人鼓舞，該計劃將繼續進行 GLP 研究，並計劃於今年年底完成，以支持 2025 年患者的給藥。鑑於臨床前研究中發現的非常不同的 PK 特徵，我們現在計劃在健康志願者中進行一期臨床試驗，以確認藥物動力學並確認注射部位的耐受性。這也將幫助我們為長期研究選擇給予根和給藥頻率。後續試驗將在 FA 患者中進行，我們計劃進行以確定安全性、耐受性以及治療對內源性 frataxin 水平的影響。

Skyclarys is now approved for the treatment of FA and its update confirms that this is a large market opportunity. Since Skyclarys does not affect frataxin level, we believe this approval has no appreciable impact on the potential opportunity for DT-216. As we've discussed before, GeneTAC small molecules have several potential advantages over any other genomic medicine modalities. Now, in case you see any literature reports of possible effects of other molecules on frataxin expression, we show here that GeneTAC molecules restore frataxin in a more substantial way than anything else reported in the literature, which is not surprising given its direct and elegant mechanism of action.

Skyclarys 現已獲批用於治療 FA，其更新證實這是一個巨大的市場機會。由於 Skyclarys 不影響 frataxin 水平，我們認為此批准對 DT-216 的潛在機會沒有明顯影響。正如我們之前討論的，GeneTAC 小分子比任何其他基因組醫學模式具有幾個潛在優勢。現在，如果您看到其他分子對frataxin 表達可能產生影響的任何文獻報道，我們在此表明 GeneTAC 分子以比文獻中報道的任何其他分子更實質性的方式恢復frataxin，鑑於其直接而優雅的機制，這並不奇怪的行動。

Fuchs Endothelial Corneal Dystrophy, or FECD is a degenerative disease of the cornea that's been known for over a hundred years. The literature widely cites that this disease affects 4% of all adult Americans over the age of 40. Only in the last decade though, has it been shown that approximately 70% to 80% of these adults get the condition due to inheriting a monogenic repeat, CTG expansion in the TCF4 gene. Based on the current census, this works out to approximately 4.6 million to 5.3 million US FECD patients.

福克斯內皮性角膜營養不良（FECD）是一種角膜退化性疾病，人們已經知道一百多年了。文獻廣泛指出，40 歲以上的美國成年人中有 4% 患有這種疾病。然而，直到最近十年，才顯示大約 70% 到 80% 的成年人患有這種疾病是由於繼承了 TCF4 基因中的單基因重複（CTG 擴增）。根據目前的人口普查，美國約有 460 萬至 530 萬 FECD 患者。

There are no approved disease modifying prescription drugs for FECD, and treatment is restricted to things like hypertonic saline drops to try and dehydrate the cornea. Eventually, a small fraction of patients get a corneal transplant surgery, which there are about 18,000 to 30,000 corneal transplant surgeries done in the United States annually, and that's a very small fraction and represented by the red figure. Most patients, unfortunately, quietly suffer from declining visual quality. On the right is a photoshop image composed by a patient to communicate her loss of visual quality in late stage Fuchs.

目前還沒有批准用於 FECD 的疾病緩解處方藥，治療僅限於高滲透壓鹽水滴劑等藥物，以嘗試使角膜脫水。最終，一小部分患者接受了角膜移植手術，美國每年大約進行18,000至30,000例角膜移植手術，這是一個非常小的部分，以紅色數字表示。不幸的是，大多數患者都默默地遭受視覺品質下降的困擾。右側是由一位患者製作的 Photoshop 影像，旨在表達她在 Fuchs 晚期時視覺品質的喪失。

The analogy is sometimes that of a foggy and rainy windshield, resulting in loss of low contrast, visual acuity, glare, and contrast sensitivity. And we have heard from a number of clinicians who see these patients that, if there was anything that slowed progression and was well tolerated, they would treat everyone, even patients who were presymptomatic. FECD is caused by dysfunction in the cells of the endothelial monolayer of the cornea, and these cells have a role in maintaining a dehydrated stroma to keep the cornea free of extracellular matrix deposits. These cells are slowly lost over time due to the disease, and they're sick because of the TCF4 mutation, which is the CTG repeat expansion in the non-coding region of the gene.

有時，這就像有霧和下雨的擋風玻璃，導致低對比、視力、眩光和對比敏感度的損失。我們從許多看過這些患者的臨床醫生那裡得知，如果有任何東西可以減緩病情進展並且耐受性良好，他們就會治療所有人，甚至是出現症狀前的患者。FECD 是由角膜單層內皮細胞功能障礙引起的，這些細胞在維持脫水基質以保持角膜無細胞外基質沉積物方面發揮作用。隨著時間的推移，這些細胞會因疾病而慢慢消失，它們生病是因為 TCF4 突變，即基因非編碼區的 CTG 重複擴增。

This inherited mutation can be detected by means of a blood test. So how can one develop a therapy for this? By helping restore cellular health to the endothelial layer, and this cell dysfunction arises from this single inherited mutant allele. The polymerase reads the mutant allele and makes an RNA containing these repeats, the RNA folds over on itself, creates tangles, and you can see them.

這種遺傳性突變可以透過血液檢查來檢測。那麼如何開發一種治療方法呢？透過幫助恢復內皮層的細胞健康，這種細胞功能障礙是由這種單一遺傳突變等位基因引起的。聚合酶讀取突變等位基因並產生包含這些重複序列的 RNA，RNA 會自行折疊，形成纏結，你可以看到它們。

You can stain for them. These tangles sequester MBNL splice proteins and cause missplicing of a number of downstream genes, which then drive cellular dysfunction. We have designed GeneTACs to bind and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic TCF4 mutant RNA. This slide shows the effectiveness of the GeneTAC molecule.

你可以給它們染色。這些纏結會隔離 MBNL 剪接蛋白並導致許多下游基因的錯誤剪接，從而導致細胞功能障礙。我們設計了 GeneTAC 來結合併識別突變等位基因中的這些長 CTG 重複區域，並阻止有毒 TCF4 突變 RNA 的產生。這張幻燈片顯示了 GeneTAC 分子的有效性。

Recall, I said that you could stain for these mutant foci. They're shown in the above panel in the middle section as dots that light up, with a fluorescently labeled probe inside the nucleus of endothelial cells taken directly from discarded cornea of patients who've undergone surgery. On the lower panel, we observed that these foci largely go away when these patient corneal cells are treated with DT-168. The compound has low nanomalar potency, as shown in the dose response curve on the right.

回想一下，我說過你可以對這些突變病灶進行染色。它們在上圖中的中間部分顯示為發光的點，內皮細胞核內有螢光標記的探針，該探針直接取自接受手術的患者廢棄的角膜。在下圖中，我們觀察到，當這些患者角膜細胞接受 DT-168 處理後，這些病灶大部分消失。該化合物具有較低的奈米效力，如右側的劑量反應曲線所示。

This slide shows the results of assay for wild type TCF4 transcripts from patient cells as shown here. Drug treatment has no effect on the wild type TCF4 expression. This is an allele selective inhibition, which is highly desirable. This slide looks at missplicing that occurs in a variety of downstream genes at baseline and light green, and with drug treatment as mutant TCF4 expression is dialed down, and sequestered splicing proteins are released, downstream normal splicing is restored, leading to a treatment of the cellular dysfunction.

這張幻燈片顯示了患者細胞野生型 TCF4 轉錄物的測定結果，如下所示。藥物治療對野生型TCF4表現沒有影響。這是非常理想的等位基因選擇性抑制。這張幻燈片著眼於基線和淺綠色的各種下游基因中發生的錯誤剪接，透過藥物治療，突變體 TCF4 表達下降，隔離的剪接蛋白被釋放，下游正常剪接得到恢復，從而治療細胞功能障礙。

Not only do we see an allele selective effect, which is the desired product profile, we have also been able to formulate this to be suitably delivered as an eye drop. All the required nonclinical safety studies have been conducted and reviewed by the FDA, resulting in an IND that's been cleared. We plan to initiate Phase 1 development for DT-168 in 2024. We now need to determine the impact of this type of treatment on the progression of this degenerative corneal disease.

我們不僅看到了等位基因選擇性效應（這是所需的產品特徵），而且還能夠將其配製為合適的滴眼劑。所有必需的非臨床安全性研究均已由 FDA 進行和審查，從而獲得了 IND 的批准。我們計劃於 2024 年啟動 DT-168 的第一階段開發。我們現在需要確定這種治療對這種退化性角膜疾病進展的影響。

And for that purpose, we need to gain experience with various possible endpoints and patient characteristics. Therefore, prior to jumping into an interventional trial in patients, we believe the correct strategy for clinical development is to first run an observational study with patients diagnosed with Fuchs, who have a genetically confirmed TCF4 expansion mutation. We have begun enrollment in such a trial and plan to recruit 200 patients during the year, and plan to follow them for two years. This will enable us to understand the patient characteristics and endpoints that allow us to measure the dysfunction and progression in these patients.

為此，我們需要獲得各種可能的終點和患者特徵的經驗。因此，在對患者進行介入試驗之前，我們認為臨床開發的正確策略是首先對診斷為 Fuchs 且具有基因證實的 TCF4 擴展突變的患者進行觀察性研究。我們已經開始參加這樣的試驗，計劃年內招募 200 名患者，並計劃對他們進行兩年的追蹤。這將使我們能夠了解患者的特徵和終點，使我們能夠測量這些患者的功能障礙和進展。

Once we have gathered sufficient data to measure disease progression and the performance of various endpoints, we will then focus on an interventional treatment trial. These endpoints include measures of visual quality, anterior eye tomography, and also microscopic visualization of the corneal endothelium. We are revealing for the first time our program for Huntington's disease. As you know, HD is a devastating neurodegenerative disease caused by an exonic repeat expansion in the Huntington gene.

一旦我們收集了足夠的數據來衡量疾病進展和各種終點的表現，我們將專注於介入治療試驗。這些終點包括視覺品質、前眼斷層掃描以及角膜內皮顯微可視化的測量。我們首次公佈我們的亨廷頓舞蹈症治療方案。如你所知，HD 是一種毀滅性的神經退化性疾病，由亨廷頓基因的外顯子重複擴增引起。

A longstanding objective in the field has been for there to be a selective inhibition of the mutant Huntington allele, with a molecule that can distribute widely to the effect cells, and this has been a very elusive profile to achieve. Here is data looking at the effect of one of our two candidate molecules on wild type and Mutant Huntington, RNA from treated patient fibroblast cells. The left panel shows data from a normal onset HD genotype and the right panel, the effect on an early onset HD genotype, which contains a longer repeat expansion. We observe an allele selective inhibition of Mutant Huntington RNA.

這個領域的一個長期目標是用一種可以廣泛分佈到效應細胞的分子來選擇性抑制突變亨廷頓等位基因，而這是一個非常難以實現的目標。以下數據考察了我們的兩種候選分子之一對野生型和突變型亨廷頓（來自接受治療的患者成纖維細胞的 RNA）的影響。左圖顯示了正常發病 HD 基因型的數據，右圖顯示了對早發 HD 基因型的影響，其中包含較長的重複擴增。我們觀察到突變亨廷頓 RNA 的等位基因選擇性抑制。

The effect is even more pronounced in the early onset genotype. This is particularly encouraging because regardless of the genotype, it is known that the repeats undergo somatic expansion of various lengths in different neurons over time. And this data suggests that the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CAG repeats. This slide shows that the RNA effect shown earlier, translated to the expected effect on mutant Huntington protein.

這種效應在早發性基因型中更為明顯。這是特別令人鼓舞的，因為無論基因型如何，眾所周知，隨著時間的推移，不同神經元中的重複序列會經歷不同長度的體細胞擴張。這些數據表明，該化合物將對這些細胞產生更深遠的影響，這些細胞的 CAG 重複體經歷了更長的體細胞擴張。這張幻燈片顯示了先前顯示的 RNA 效應，轉化為對突變亨廷頓蛋白的預期效應。

The above panel shows that Mutant Huntington selective antibodies able to detect mutant protein disappearing with increasing concentrations of drug. The middle panel uses an antibody that detects both wild type and Mutant Huntington, and you can see an expected reduction due to the mutant protein being reduced. Now, the size of these proteins are hard to resolve in the normal onset genotype in the left panel gels, but in the early onset genotypes, the mutant and wild type proteins are different enough in size to actually show up as two bands on the middle panel on the right side. This is the RNA inhibition data from candidate two, showing a similar allele selective inhibition, and this is the protein inhibition data from candidate two, also showing an effect as expected from the RNA inhibition.

上圖顯示突變亨廷頓選擇性抗體能夠檢測隨著藥物濃度增加而消失的突變蛋白。中間面板使用可檢測野生型和突變亨廷頓蛋白的抗體，您可以看到由於突變蛋白減少而導致的預期減少。現在，在左圖凝膠的正常發病基因型中，這些蛋白質的大小很難解析，但在早期發病基因型中，突變型和野生型蛋白質的大小差異很大，實際上在中間顯示為兩條帶面板位於右側。這是候選物二的RNA抑制數據，顯示出類似的等位基因選擇性抑制，這是候選物二的蛋白質抑制數據，也顯示了RNA抑制所預期的效果。

We expect to choose one of these compounds to move forward with as a development candidate, once further testing is conducted. Having seen these exciting profiles, we are encouraged at the preliminary non-GLP tolerability of these molecules in both rodents and non-human primates. We've conducted pharmacology assessments of these molecules and have selected a widely used Q-175DN pharmacodynamic mouse model to a SaaS PD. We observe in this study that with systemic administration, there is an over 50% reduction of mutant Huntington RNA and protein in the striatum of mice, which supports the idea that this compound is able to get into the brain and get into the cells, and have the intended effect with systemic administration.

一旦進行進一步的測試，我們希望選擇其中一種化合物作為開發候選化合物。在看到這些令人興奮的概況後，我們對這些分子在囓齒動物和非人類靈長類動物中的初步非 GLP 耐受性感到鼓舞。我們對這些分子進行了藥理學評估，並選擇了廣泛使用的 Q-175DN 藥效學小鼠模型作為 SaaS PD。我們在這項研究中觀察到，透過全身給藥，小鼠紋狀體中突變型亨廷頓 RNA 和蛋白質減少了 50% 以上，這支持了這種化合物能夠進入大腦並進入細胞的觀點，並且全身給藥可達到預期效果。

We are very encouraged to see this in vivo confirmation of the activity seen in cells derived from patients. If this pans out, HD GeneTAC molecules hold the potential of selectively reducing mutant Huntington with a widespread distribution profile and systemic administration regardless of the patient's HD genotype. This would be a best-in-class profile. Our next milestone for the program is to choose a development candidate.

我們非常高興地看到來自患者的細胞中所見活性的體內證實。如果這結果成功，HD GeneTAC 分子具有選擇性減少突變亨廷頓蛋白的潛力，無論患者的 HD 基因型如何，其分佈範圍廣泛，並且可以全身給藥。這將是一流的配置文件。我們該計劃的下一個里程碑是選擇一名開發候選人。

We are also working on a program in myotonic dystrophy. DM1 is caused by a CTG repeat in the DMPK gene in the three prime untranslated region. Much like the FECD story, mutant DMPK RNA form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best-in-class profile to have a selective inhibitor of mutant DMPK for the treatment of myotonic dystrophy that would distribute broadly in all affected tissues and cell types.

我們也正在研究強直性肌肉營養不良症的項目。DM1 是由三素非翻譯區 DMPK 基因的 CTG 重複引起的。與 FECD 的故事非常相似，突變的 DMPK RNA 形成毒性灶和下游剪接功能障礙。非常需要一種同類最佳的突變型 DMPK 選擇性抑制劑來治療強直性肌肉營養不良，該抑制劑將廣泛分佈於所有受影響的組織和細胞類型中。

This data shows that we have a GeneTAC molecule that reduce these toxic DMPK foci with low nanomolar potency. This is a splicing index from panel of splice genes with seven days of treatment from patient derived myotubes, showing that the DM1 foci reduction does have beneficial downstream effect on cellular health. The next milestone for this program is DC declaration. In summary, we have a promising new platform for genomic medicine that is meaningfully differentiated from other genomic medicine modalities.

這些數據表明，我們擁有一種 GeneTAC 分子，可以以低納摩爾效力減少這些有毒 DMPK 病灶。這是來自患者來源的肌管經過 7 天治療後的一組剪接基因的剪接指數，顯示 DM1 灶的減少確實對細胞健康產生有益的下游影響。該計劃的下一個里程碑是 DC 聲明。總之，我們擁有一個有前途的基因組醫學新平台，它與其他基因組醫學模式有顯著差異。

We have four drug programs, each in significant markets and with highly differentiated profiles. The first two of which are expected to be clinical stage next year. We ended 2023 with approximately $281 million, and this gives us a cash runway for the next five years. Pending future R&D results and ongoing strategic review, this cash runway would support generating clinical proof of concept data in up to four programs.

我們有四個藥物項目，每個項目都位於重要市場，並且具有高度差異化的特徵。其中前兩項預計將於明年進入臨床階段。截至 2023 年，我們的收入約為 2.81 億美元，這為我們未來五年提供了現金跑道。在等待未來的研發結果和正在進行的策略審查之前，這條現金跑道將支援在最多四個項目中產生臨床概念驗證數據。

We believe each of these programs has the potential to transform the treatment of these debilitating conditions, and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward and welcome you to participate in this journey and help us get to success. This concludes our prepared remarks and we'll now move to Q&A. Operator, (technical difficulty) please open the line for questions.

我們相信，這些項目中的每一個都有可能改變這些使人衰弱的疾病的治療方法，並且其中任何一個項目的成功都將為投資者創造巨大的價值。我們致力於推動這些分子向前發展，並歡迎您參與這趟旅程並幫助我們取得成功。我們準備好的演講到此結束，現在我們將進入問答環節。接線員，（技術難度）請開通線路提問。

(Operator Instructions) Joseph Schwartz, Leerink Partners.

（操作員說明）Joseph Schwartz，Leerink Partners。

Hi, thanks very much for the update. I was wondering if you could tell us more about the tissue distribution relative to the plasma distribution for DT-216P2 in all of the relevant tissue types for patients affected by FA? And then have you gone back and back tested the ISR profile for the original formulation of DT-216, as well as the new one? Thank you.

您好，非常感謝您的更新。我想知道您是否可以告訴我們更多有關受 FA 影響的患者的所有相關組織類型中 DT-216P2 相對於血漿分佈的組織分佈？然後，您是否反覆測試過 DT-216 原始配方以及新配方的 ISR 配置？謝謝。

Thank you, Joe, for that question. On the exposure profile, as a reminder, one of the major learnings from our prior clinical trial was that the levels of drug required in tissue are similar to the in vitro EC90. So that eight to 10 animal exposure that we saw in muscle in patients from the trial is something that sets a target. The prior drug product had this disconnect between the duration of plasma and tissue levels in animals.

謝謝喬提出這個問題。關於暴露情況，提醒一下，我們先前臨床試驗的主要經驗之一是組織中所需的藥物水平與體外 EC90 相似。因此，我們在試驗中看到患者肌肉中有 8 到 10 隻動物暴露，這就是設定的目標。先前的藥品在動物體內的血漿持續時間和組織水平之間存在這種脫節。

We did not observe any such disconnect in humans and the new drug product DT-216P2 is well behaved in that, even in animals, there's no longer a disconnect between plasma and tissue levels. And this is what you would expect with a small molecule drug. So if you reference slide 22, muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with our DT-216P2, where on the right, you see that in non-human primate studies, the plasma levels are much higher, and so are the tissue levels as shown by muscle biopsy from these NHPs.

我們沒有在人類中觀察到任何此類脫節，並且新藥品 DT-216P2 表現良好，即使在動物中，血漿和組織水平之間也不再存在脫節。這就是您對小分子藥物的期望。因此，如果您參考投影片 22，肌肉活檢顯示組織水平是透過血漿水平預測的。事實證明，我們的 DT-216P2 也是如此，在右側，您可以看到在非人類靈長類動物研究中，血漿水平要高得多，並且通過肌肉活檢顯示的組織水平也更高。NHP。

In addition, we have some additional confirmatory data in a rat distribution study, which we can show you in the subsequent slide here, that there's adequate levels of drugs seen in a broad set of tissues against that target level of eight to 10 animals that we require to see a biological effect. And so, once you exceed the threshold required for biological effect, there's no excessive pharmacology. So we feel that the exciting results we've seen with the plasma PK do also set us up well for good tissue distribution. On your other question about injection site reactions, non-clinical studies show that the injection site reactions were attributable to the excipients in the prior clinical formulation.

此外，我們在大鼠分佈研究中還有一些額外的驗證性數據，我們可以在接下來的幻燈片中向您展示，在廣泛的組織中發現了足夠的藥物水平，與我們在8 到10 只動物的目標水平相比。需要看到生物效應。因此，一旦超過了生物效應所需的閾值，就不存在過度的藥理作用。因此，我們認為，我們在血漿 PK 中看到的令人興奮的結果也確實為我們實現良好的組織分佈奠定了良好的基礎。關於注射部位反應的另一個問題，非臨床研究顯示注射部位反應可歸因於先前臨床製劑中的賦形劑。

And now the new non-GLP studies that we've conducted with DT-216P2 support the conclusion that this formulation has resolved the injection site issues and is suitable to progress into confirmatory GLP studies. And in fact, in one arm of the study, we've included daily injections over four weeks, which gives us further confidence that the injection site tolerability issues appear resolved.

現在，我們用 DT-216P2 進行的新的非 GLP 研究支持這樣的結論：該製劑已經解決了注射部位問題，並且適合進行驗證性 GLP 研究。事實上，在該研究的一個分支中，我們在四個星期內每天進行注射，這讓我們進一步相信注射部位的耐受性問題似乎已解決。

All right, thank you.

好吧。謝謝。

[Nevin], RBC Capital Markets.

[內文]，加拿大皇家銀行資本市場。

HI, everyone, this is Nevin on for Leo. Thank you for taking our questions. Just a couple from us. How are you thinking about designing your Phase 1 for DT-216P3? And then, if you show for tax and expression increases in patients, do you think that that might potentially open a path forward for accelerated approval given some of the latest understanding of the biology and the FDA's views on that? And then should we also expect similar patient numbers to the original SAT in that study? Thank you.

大家好，我是 Leo 的內文。感謝您接受我們的提問。只有我們幾個人。您如何考慮為 DT-216P3 設計第一階段？然後，如果你顯示患者的稅收和表達增加，考慮到對生物學的一些最新理解和 FDA 對此的看法，你認為這可能會為加速批准開闢一條道路嗎？那麼我們是否也應該預期研究中的患者數量與原始 SAT 相似？謝謝。

Okay, thank you for the question. With regard to the Phase 1 studies, because we see this remarkably different PK profile that hits all of the criteria that we were looking for, our approach here is to, first, conduct a Phase 1 PK study in healthy volunteers. And this is to confirm the encouraging PK profile of DT-216P2. Once we get data from that study, we then plan to conduct patient studies beginning in 2025. With regard to your next question on FDA and endpoints, I would say that the unmet need here is high.

好的，謝謝你的提問。關於第一階段研究，因為我們看到這種顯著不同的 PK 特徵符合我們正在尋找的所有標準，所以我們的方法是先在健康志願者中進行第一階段 PK 研究。這證實了DT-216P2令人鼓舞的PK特性。一旦我們從研究中獲得數據，我們計劃從 2025 年開始進行患者研究。關於您關於 FDA 和終點的下一個問題，我想說這裡未滿足的需求很高。

We don't have anything to add in terms of what the FDA may or may not require in the future. We've had productive engagement with the FDA previously and we'll continue to engage with the agency upon resumption of clinical studies.

對於 FDA 未來可能要求或不要求的內容，我們沒有任何補充。我們之前與 FDA 進行了富有成效的合作，在恢復臨床研究後我們將繼續與該機構合作。

Okay, thank you.

好的謝謝。

Laura Chico, Wedbush.

勞拉·奇科，韋德布希。

Sorry about that, thank you very much for taking the question. I believe you were also working in parallel on some new method development with respect to frataxin and detection on a protein level. I'm wondering if you can share any details on where that methodology stands at present and maybe timing to advance those efforts? And then I have one quick follow up.

抱歉，非常感謝您提出這個問題。我相信您也在同時開發一些有關 frataxin 和蛋白質水平檢測的新方法。我想知道您是否可以分享有關該方法目前的情況以及推進這些努力的時機的任何詳細資訊？然後我會進行快速跟進。

Thank you, Laura. We are dedicated to continuing to work on whatever improvements we can make in measurement of frataxin levels. We have robust assays that we've already used in prior clinical studies for measurement of frataxin RNA, and we continue to make improvements on our ability to reliably measure frataxin protein and possible changes and frataxin protein. And we will provide updates on that progress as we progress to the clinic.

謝謝你，勞拉。我們致力於繼續致力於在 frataxin 水平測量方面做出任何改進。我們擁有強大的檢測方法，已在先前的臨床研究中用於測量 frataxin RNA，我們將繼續改進可靠測量 frataxin 蛋白以及可能發生的變化和 frataxin 蛋白的能力。當我們進入臨床階段時，我們將提供有關進展的最新資訊。

Okay, thank you very much. And then just quickly with respect to Fuchs, and this may come out in your observational study, but I'm curious with AMD visual acuity measurements are pretty straightforward, but contrast that with something else like geographic atrophy and it's a little bit more challenging to characterize progression or loss of vision. So I'm curious, where does Fuchs shake out in that spectrum and any ideas in terms of measurements that you think might be most promising? Thank you.

好的，非常感謝。然後就 Fuchs 而言，這可能會在您的觀察研究中出現，但我很好奇 AMD 視力測量非常簡單，但與地理萎縮等其他東西相比，要測量它更具挑戰性描述視力進展或喪失的特徵。所以我很好奇，福克斯在這個範圍內表現如何，以及您認為最有前途的測量方面的任何想法？謝謝。

Thank you for the question. Yeah, we're conducting an observational study in patients with Fuchs, with a confirmed TCF4 mutation to better understand both patient characteristics, as well as the characteristics of the endpoints and disease progression. And those come in three different broad buckets: One is, a variety of measures of visual quality, and there are numerous reports in the literature of ways to measure the loss of visual quality in patients with Fuchs, and we'll be getting direct experience with those types of measures. Second is, measures of edema or fluid buildup in the cornea, because the endothelial cell layers' function is to dehydrate the stroma and keep the cornea clear.

感謝你的提問。是的，我們正在對已確認 TCF4 突變的 Fuchs 患者進行觀察性研究，以更好地了解患者特徵以及終點特徵和疾病進展。這些分為三個不同的大類：一是視覺品質的各種衡量標準，文獻中有大量關於衡量福克斯患者視覺品質損失的方法的報告，我們將獲得直接經驗通過這些類型的措施。其次是角膜水腫或液體積聚的措施，因為內皮細胞層的功能是使基質脫水並保持角膜清潔。

And there are ways in the clinic to measure this subclinical edema using anterior eye tomography, for example, so we're including those measures in the observational study. And third, as you've seen in the back of the eye in geographic atrophy, there are analogous or corresponding ways to directly visualize the corneal endothelium in patients using specialized microscopy. And so, we'll be including those measures as well. And that will give us a variety of tools to examine the characteristics of the patients and the disease progression.

例如，臨床上有一些方法可以使用前眼斷層掃描來測量這種亞臨床水腫，因此我們將這些測量納入觀察性研究中。第三，正如您在地圖樣萎縮的眼睛後部所看到的那樣，有類似或相應的方法可以使用專門的顯微鏡直接觀察患者的角膜內皮。因此，我們也將包括這些措施。這將為我們提供各種工具來檢查患者的特徵和疾病進展。

Thanks very much.

非常感謝。

Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call back over to Mr. Pratik Shah for any closing remarks.

謝謝。目前我在隊列中沒有顯示任何其他問題。我現在想將電話轉回給 Pratik Shah 先生，請他發表結束語。

Well, thank you, everyone, for joining us on today's call. We look forward to updating you as we continue to make exciting progress at Design.

好的，謝謝大家參加今天的電話會議。隨著我們在設計方面繼續取得令人興奮的進展，我們期待向您通報最新情況。

Thank you all for participating. This concludes today's program. You may now disconnect.

感謝大家的參與。今天的節目到此結束。您現在可以斷開連線。