Belite Bio Inc (BLTE) 2024 Q1 法說會逐字稿

Hello, and thank you for joining us to discuss Belite Bio's first quarter 2024 financial results. Joining the call today are Dr. Tom Lin, Chairman and CEO of Belite Bio; Dr. Nathan Mata, Chief Scientific Officer; and Hao-Yuan Chuang, Chief Financial Officer.

您好，感謝您加入我們討論 Belite Bio 2024 年第一季的財務表現。今天參加電話會議的有 Belite Bio 董事長兼執行長 Tom Lin 博士； Nathan Mata 博士，首席科學官；以及財務長莊浩元。

Before we begin, let me point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. We encourage you to consult the Risk factors discussed in our SEC filings for additional detail. (Operator Instructions)

在我們開始之前，請允許我指出，我們將根據我們當前的期望和信念做出前瞻性的陳述。這些聲明受一定風險和不確定性的影響，實際結果可能有重大差異。我們鼓勵您查閱我們提交給美國證券交易委員會的文件中討論的風險因素以獲取更多詳細資訊。（操作員指示）

Now I'll turn the call over to Dr. Lin.

現在我將電話轉給林醫師。

Thank you, Judy. Thank you, everyone, for joining our reporting for the first quarter. I'm Tom Lin, CEO of Belite Bio. Joining me is our CSO, Nathan Mata; and CFO, Hao-Yuan.

謝謝你，朱迪。感謝大家參加我們第一季的報道。我是 Belite Bio 的執行長 Tom Lin。和我一起的還有我們的 CSO Nathan Mata；以及財務長郝元。

I'd like to start off with an overview. Tinlarebant is a novel, once-a-day oral tablet designed to bind to serum retinol binding protein, known as RBP4, as a means to specifically reduce retinol delivery to the eye. This approach is intended to slow or stop the formation of the toxic retinol-derived byproducts, which are generated in the visual cycle and are implicated in progression of Stargardt disease and Geographic Atrophy.

我想先做一個概述。Tinlarebant 是一種新型的每日一次口服藥片，旨在與血清視黃醇結合蛋白（RBP4）結合，以專門減少輸送到眼睛的視黃醇。這種方法旨在減緩或阻止視覺週期中產生的有毒視黃醇衍生副產物的形成，這些副產物與斯塔加特病和地圖狀萎縮的進展有關。

Belite Bio believes that early intervention directed at emerging retinol pathology, which is not mediated by inflammation, would be the best approach to potentially slow disease progression in Stargardt disease and GA. There is still a significant unmet need for both indications as currently there is no approved treatment for Stargardt disease, and there are currently no approved oral treatments for GA. And we're already in global Phase III trials for both indications.

Belite Bio 認為，針對新出現的視黃醇病理（不由發炎介導）的早期幹預將是減緩 Stargardt 病和 GA 病情進展的最佳方法。由於目前尚無核准用於治療 Stargardt 病的藥物，且目前尚無核准用於治療 GA 的口服藥物，因此這兩種適應症仍存在大量未滿足的需求。我們已經針對這兩種適應症進行了全球 III 期試驗。

So far, we have been granted fast-track designation, rare pediatric disease designation and orphan drug designation in US, EU and Japan. We have several patent families and with composition of matter patents lasting until 2040s. And with patent term extension and new patents to be filed, we will have patent protection past the 2040s.

目前，我們已獲得美國、歐盟和日本的快速通道資格、兒科罕見疾病資格和孤兒藥資格。我們擁有多個專利家族，其中物質組成專利將持續到 2040 年代。隨著專利期限的延長和新專利的提交，我們的專利保護將持續到 2040 年代以後。

For Stargardt indication, at ARVO last week, we presented further positive findings and treatment results from our end-of-Phase-II results, which our CSO will be presenting. The Phase III is already fully enrolled, and estimated interim readouts by end of 2024 or early 2025. We've also initiated a Phase II study in Stargardt, which will recruit Japanese patients that is required for NDA in Japan. For GA, dry AMD indication, we currently have about 100 subjects enrolled in our Phase III in GA.

對於 Stargardt 適應症，上週在 ARVO 上，我們展示了 II 期末期結果的進一步積極發現和治療結果，我們的 CSO 將展示這些結果。第三階段已全部完成招募，預計在 2024 年底或 2025 年初獲得中期讀數。我們也在 Stargardt 啟動了第二階段研究，該研究將招募日本 NDA 所需的日本患者。對於 GA、乾性 AMD 適應症，我們目前有大約 100 名受試者參加 GA 的 III 期臨床試驗。

And with this, I would like to pass it on to our CSO to give clinical and scientific update. Nathan?

藉此，我想將其傳遞給我們的 CSO，以提供臨床和科學更新。內森？

Thank you, Tom. And thank you, everyone, for attending. What we'd like to share with you today are some new analyses that we have from our open-label Phase II study in adolescent Stargardt disease. This trial enrolled 13 adolescents Stargardt subjects aged 12 to 18 years of age, and it was a two-year study in which patients took oral Tinlarebant 5 milligrams daily.

謝謝你，湯姆。感謝大家的出席。今天我們想與大家分享的是我們對青少年 Stargardt 病進行開放標籤 II 期研究的一些新分析。這項試驗招募了 13 名年齡在 12 至 18 歲之間的青少年 Stargardt 受試者，是一項為期兩年的研究，患者每天口服 5 毫克 Tinlarebant。

The first analysis I want to show you is a genetic analysis of all of our patients in the study. This has not previously been reported. You'll see for each subject, there are two entries. That's because there's an allele for each ABCA4 mutation. And so we're looking at two of them. And you can see 11 of 12 -- 11 of 13 subjects have severe biallelic mutations. This analysis, by the way, was conducted by Dr. Rando Allikmets, who is an identifier of the Stargardt gene, the ABCA4 gene.

我想向您展示的第一個分析是對研究中所有患者的基因分析。此前尚未有此類報道。您會看到每個主題都有兩個條目。這是因為每個 ABCA4 突變都有一個等位基因。因此我們正在研究其中的兩個。您可以看到 12 名受試者中有 11 名 - 13 名受試者中有 11 名患有嚴重的雙等位基因突變。順便說一下，這項分析是由 Rando Allikmets 博士進行的，他是 Stargardt 基因（ABCA4 基因）的識別者。

So the point here is that our cohort is very, very prominently affected with the severe mutations. There are only two subjects, subjects three and five, who have a moderate allele of ABCA4 on their mutations. It's important to note the way these genes are classified is through a score called the Combined Annotated Dependent Depletion score. In this analysis, scores above 20 are predicted to be among the 1% most deleterious. And you can see, all of our subjects, with the exception of those alleles on subject three and five, have scores well above 20. So this is a very severely affected cohort.

所以這裡的重點是，我們的群體受到嚴重突變的嚴重影響。僅有兩名受試者（受試者三和受試者五）的突變中含有中等程度的 ABCA4 等位基因。值得注意的是，這些基因的分類方式是透過稱為「組合註釋依賴性損耗評分」的評分來進行的。在該分析中，預計 20 以上的分數將屬於最有害的 1%。您可以看到，我們所有受試者（除了受試者三和受試者五上的等位基因外）的得分都遠高於 20。所以這是一個受到非常嚴重影響的群體。

The next analysis I'd like to show you is that, of these subjects, five of them, subjects one, three, four, 12 and 13, never spawned an atrophic lesion. This is important because in this particular study, subjects came in with only autofluorescent lesions at baseline. So we were monitoring the transition of the autofluorescent lesion to the atrophic lesion type. And then once the atrophic lesion formed, we measure the growth rate of that lesion. And we have previously reported a remarkably reduced growth rate in the overall population. Now we're showing you in those subjects that did not grow an atrophic lesion over 24 months, they had very severe mutations. So the absence of lesion growth in these subjects could not be attributed to benign or mild mutations.

我想向你們展示的下一個分析是，在這些受試者中，其中五個，即受試者一、三、四、12 和 13，從未出現萎縮性病變。這很重要，因為在這項特定的研究中，受試者在基線時僅存在自發性螢光病變。因此，我們正在監測自發性螢光病變向萎縮性病變類型的轉變。一旦萎縮性病變形成，我們就會測量該病變的生長率。我們之前曾報告過總人口成長率顯著下降。現在我們向您展示，在那些 24 個月內沒有出現萎縮性病變的受試者中，他們有非常嚴重的突變。因此，這些受試者的病變沒有生長不能歸因於良性或輕微的突變。

The next analysis is a very important one because it shows us that four subjects have the exact same allelic mutation. Subjects 9 and 10 are siblings. They are two brothers. You can see there, they have the exact same mutations across alleles. And subjects 12, 13 are brother/sister. They also have the very same mutations. The reason this is important is because other investigators have suggested that identical genetic mutations predict identical disease course. I can tell you right now that it's not what we're seeing in the Phase II study, and I'll show you some of that information right now.

下一個分析非常重要，因為它向我們展示了四個受試者俱有完全相同的等位基因突變。受試者 9 和 10 是兄弟姊妹。他們是兩兄弟。您可以看到，它們的等位基因突變完全相同。且受試者 12、13 是兄弟姊妹。它們也具有完全相同的突變。這很重要，因為其他研究人員已經提出相同的基因突變可以預測相同的疾病過程。我現在可以告訴你，這不是我們在第二階段研究中看到的情況，我現在將向你展示其中的一些資訊。

Here, we have the visual acuity analysis of all subjects before they came into the study, and they all have different disease duration. What we did is we looked at subjects that had bilateral vision loss, that is vision loss in each eye, over the period of time between the time they were diagnosed and the time before they came into the study. And what we found is there were six subjects who had a very severe bilateral vision loss of 10 letters per eye, a mean annual loss of 10 letters per eye.

在這裡，我們對所有受試者在進入研究之前的視力進行了分析，並且他們的患病持續時間各不相同。我們所做的是觀察患有雙側視力喪失（即每隻眼睛視力喪失）的受試者，觀察時間跨度是從他們被診斷出視力喪失到進入研究之前的一段時間。我們發現，有 6 位受試者雙側視力嚴重喪失，每隻眼睛視力喪失 10 個字母，平均每年每隻眼睛視力喪失 10 個字母。

That's significant because, well, for two reasons. One, it tells us that autofluorescent lesions in the fovea do, in fact, cause visual acuity loss. Remember, these subjects have not grown atrophic lesions yet. The other thing that's important is if you look at the sibling subjects again, 9, 10 and 12 and 13, you can see their visual acuity loss is very different. Subjects 9 and 10, again, are the two brothers. They have similar disease duration, but subject 10 lost vision, whereas his brother, subject 9, did not. Same thing for subjects 12 and 13. Subject 12 has an eight-year of disease duration, whereas the sister has only two years. Yet the sister with only two-year disease duration lost significant letters, whereas the brother did not. So these data tell us, in fact, that identical genetic mutations do not necessarily predict identical disease progression as so far as it pertains to visual acuity loss.

這很重要，因為有兩個原因。首先，它告訴我們中央凹的自發性螢光病變確實會導致視力喪失。請記住，這些受試者尚未出現萎縮性病變。另一件重要的事情是，如果你再次觀察兄弟姐妹，9、10、12 和 13 歲，你會發現他們的視力損失非常不同。受試者 9 和 10 再次是兩兄弟。他們的患病時間相似，但受試者 10 失去了視力，而他的兄弟受試者 9 沒有失去視力。科目 12 和 13 也一樣情況。受試者 12 患病已有 8 年，而其姐姐僅患病 2 年。然而，生病時間僅有兩年的姊姊遺失了重要的字母，而弟弟卻沒有。因此，這些數據實際上告訴我們，就視力喪失而言，相同的基因突變並不一定能預測相同的疾病進展。

This is an analysis of the visual acuity of all subjects on the left-hand side and then those six subjects shown on the right. I want to first say that in all subjects, over 24 months, the mean loss was only five letters. That is over the whole period of 24 months, all subjects lost only a mean of five letters over 24 months. So that's roughly 2.5 letters per year.

這是對左側所有受試者的視力分析，以及右側顯示的六位受試者的視力分析。首先我想說的是，在所有科目中，24 個月內，平均遺失的字母只有 5 個。也就是說，在整個 24 個月的時間裡，所有受試者平均只丟失了 5 個字母。所以每年大約有 2.5 封信。

Now if we just focus on the six subjects that came in losing 10 letters per year, we now see over 24 months, they've only lost about 3.8 letters, which is roughly about two letters per year. So we've taken the significant 10-letter per year loss down to two letters per year. That is a substantial preservation of visual acuity in these subjects.

現在，如果我們只專注於每年丟失 10 個字母的 6 個科目，我們會發現在 24 個月內，他們只丟失了大約 3.8 個字母，大約每年丟失 2 個字母。因此，我們將每年 10 封信的損失減少到每年 2 封信。這對這些受試者的視力來說是一種實質的保留。

The next analysis I'd like to show you is the lesion growth analysis. And it's important to note that these autofluorescent lesions convert to atrophic lesions. And a visual of that is shown on the graphic on the upper right-hand side. This is the actual lesion growth data from subject 10.

我想向您展示的下一個分析是病變生長分析。值得注意的是，這些自發性螢光病變會轉變為萎縮性病變。其視覺效果顯示在右上角的圖形上。這是來自受試者 10 的實際病灶生長數據。

You can see at baseline, there's this very large autofluorescent lesion, which is referred to as questionably decreased autofluorescence, or QDAF. Over time, atrophic lesions will be spawned within the autofluorescent lesions. The autofluorescent lesions are referred to as definitely decreased autofluorescent lesions. So here, we're looking at the transition of the autofluorescent lesion to the atrophic lesion type, and we're seeing if there's a proportionality between the decrease of the autofluorescence and the increase of the atrophic lesion size. And that graphic is shown on the lower left -- lower right-hand side.

您可以在基線看到，有一個非常大的自發性螢光病變，稱為可疑減少的自發性螢光，或 QDAF。隨著時間的推移，自發性螢光病變內會產生萎縮性病變。自發性螢光病變被稱為明顯減少的自發性螢光病變。因此，在這裡，我們正在觀察自發性螢光病變到萎縮性病變類型的轉變，並觀察自發性螢光的減少和萎縮性病變尺寸的增加之間是否存在比例。此圖形顯示在左下方和右下方。

As I said before, five of 12 subjects, 42%, never grew an atrophic lesion. We're not including subject 7 in the analysis because that subject was lost to follow at month 12. But in those subjects that did grow atrophic lesions, you can see a very clear correlation between the decrease of the autofluorescent area and the increase of the atrophic lesion area, showing that the atrophic lesion does grow certainly within the autofluorescent zone, but nowhere else. So we have confined the lesion growth to within this zone. And we know that lesion growth from prior analysis is significantly lower than in natural history.

正如我之前所說，12 名受試者中有 5 名（42%）從未出現萎縮性病變。我們沒有將受試者 7 納入分析，因為受試者在第 12 個月時失去追蹤。但在那些確實長有萎縮性病變的受試者中，你可以看到自發螢光區域的減少和萎縮性病變面積的增加之間存在非常明顯的相關性，表明萎縮性病變確實在自發螢光區內生長，但不在其他地方生長。因此我們將病變生長限制在這個區域內。我們從先前的分析得知，病灶的生長速度明顯低於自然史。

There's only one subject, subject five, that grew an atrophic lesion outside of initially identified autofluorescence area. And we believe that could be due to reading error of the image software, which I'll get to right now.

僅有一名受試者（受試者五）在最初確定的自發性螢光區域之外出現了萎縮性病變。我們認為這可能是由於影像軟體的讀取錯誤造成的，我現在就來解釋一下。

We typically use and most people use a software called the Heidelberg region finding software. This is a software that accompanies the imaging camera that allows ophthalmologists to grade lesions in the back of the eye -- retinal lesions. The problem with this software is that it is affected by human error. So humans have to actually look at the lesions and demarcate the zone of atrophy. And sometimes, readers don't agree. So you can have a case where you have a difference of opinion and it has to go to an arbitrator. So this can be a very time-consuming and error-prone process, but this is what is being used today.

我們通常使用並且大多數人都使用一種稱為海德堡區域查找軟體的軟體。這是與影像相機配對的軟體，可以幫助眼科醫師對眼球後部的病變—視網膜病變進行分級。該軟體的問題在於它容易受到人為錯誤的影響。因此，人類必須真正觀察病變並劃定萎縮區域。但有時，讀者並不同意。因此，如果你們意見相左，就必須提交仲裁。所以這可能是一個非常耗時且容易出錯的過程，但這就是今天正在使用的方法。

Our reading center has developed a new algorithm for reading lesions which does not rely on subjective reader bias. In fact, it uses a mathematical classification of lesions based on the proximity of the lesion and the density to that of the optic disc as well as healthy retinal tissue. And it focuses just on the 6-millimeter macular area, which is the most important to look at when you're talking about visual acuity loss. And as I said before, it's independent of reader bias. So it's looking at just pixel densities across the lesion area. And really all the reader is doing is getting the data back from the software and reporting whatever the computer algorithm provided.

我們的閱讀中心開發了一種新的閱讀損傷演算法，它不依賴主觀讀者偏見。事實上，它使用基於病變的接近程度和與視盤以及健康視網膜組織的密度對病變進行數學分類。它只關注 6 毫米的黃斑區域，這是談論視力喪失時需要關注的最重要的區域。正如我之前所說，它與讀者偏見無關。因此它僅觀察病變區域的像素密度。實際上，讀者所做的就是從軟體中獲取數據並報告電腦演算法提供的內容。

So I want to show you a reanalysis of our data using this particular image grading software. What we found, in fact, was that if we look within the macular area using this new grading algorithm, we find that there's 12 eyes of 8 subjects that did, in fact, have macular lesion involvement at baseline. And we monitor the lesion growth of the macular lesion of these patients over time. And you can see that on the left-hand side, the solid lines and dots show you the actual data from the lesion growth. And the dotted line shows you a third border polynomial fitted through the data so you can see the trend line.

所以我想向你們展示使用這個特定的圖像分級軟體對我們的數據進行的重新分析。事實上，我們發現，如果我們使用這種新的分級演算法觀察黃斑區域，我們會發現 8 名受試者的 12 隻眼睛在基線時確實患有黃斑部病變。並且我們會隨時監測這些患者的黃斑部病變的生長情況。您可以看到，在左側，實線和點顯示的是病灶生長的實際數據。虛線顯示了透過資料擬合的第三個邊界多項式，以便您可以看到趨勢線。

You can see it's very clear. The lesions do grow from baseline out to about month 16. But then starting from month 16 to month 24, there was absolutely no further growth of the lesion. And you can see on the right-hand side, the percentage involvement of the atrophy within that 6-millimeter macular zone. The 100% would indicate that all 6 millimeters of that zone are occupied by atrophy. As you can see here, our subjects are showing no more than a 7% encroachment of the atrophic lesion into the macula, and it's static from 16 to 24 months. So we're very pleased to report this data, and it is consistent with the stabilization of visual acuity that I showed you earlier.

你可以看到它非常清晰。病灶確實從基線開始生長到大約 16 個月。但從第 16 個月到第 24 個月，病灶不再進一步生長。您可以在右側看到 6 毫米黃斑區內萎縮的百分比。100% 表示該區域的所有 6 毫米均被萎縮佔據。正如您所看到的，我們的受試者的萎縮性病變侵入黃斑部的程度不超過 7%，並且在 16 至 24 個月內保持穩定。因此，我們很高興地報告這些數據，它與我之前向您展示的視力穩定性一致。

Finally, I want to talk a little bit about our Phase III study in Geographic Atrophy. It's important to note that the Phase III trial design in Stargardt disease and the Phase III trial design in Stargardt are very, very similar. They have the same dose. They have the same duration, two years, with the same interim analysis. There's the same 2:1 randomization. And of course, we're looking at all the same safety and efficacy assessments that we're looking at to judge an atrophic lesion growth and adverse events.

最後，我想談談我們對地理性萎縮的第三階段研究。值得注意的是，Stargardt 病的 III 期試驗設計和 Stargardt 的 III 期試驗設計非常非常相似。它們的劑量相同。它們的持續時間相同，均為兩年，並且具有相同的中期分析。同樣的，隨機性為 2:1。當然，我們正在研究所有相同的安全性和有效性評估，以判斷萎縮性病變的生長和不良事件。

There's only two differences in these studies. First, with the indication, GA instead of Stargardt; and then secondly, a higher predicted enrollment population for the GA study to reflect the higher prevalence of the disease in the population.

這些研究只有兩個不同之處。首先，在適應症上，GA 取代 Stargardt；其次，GA 研究的預測入選人群較高，以反映疾病在人群中的較高盛行率。

So with that, I'll turn it over to Hao-Yuan to discuss financials. Thank you.

因此，我將把主題交給郝元來討論財務問題。謝謝。

Thank you, Nathan. So in Q1 2024, we had R&D expenses of $6.8 million compared to $5.7 million in Q1 2023. The increase was primarily due to increase in expenses due to, first, conducting the DRAGON study; second, initiating the DRAGON II study; and third, wages and salaries due to our R&D team expansion and share-based compensation granted in the third quarter of 2023.

謝謝你，內森。因此，2024 年第一季度，我們的研發費用為 680 萬美元，而 2023 年第一季為 570 萬美元。增加的主要原因是費用增加，首先是因為開展 DRAGON 研究；第二，啟動DRAGON II研究；第三，由於我們2023年第三季研發團隊擴張和授予的股權激勵而產生的工資和薪金。

On G&A expenses, in Q1 2024, G&A expenses was $1.6 million compared to $1.2 million in Q1 2023. The increase was primarily due to increase in share-based compensation granted in the third quarter of 2023. On net loss, we had a net loss of $7.9 million in Q1 2024 compared to $6.9 million in Q1 2023.

在 G&A 費用方面，2024 年第一季的 G&A 費用為 160 萬美元，而 2023 年第一季為 120 萬美元。成長的主要原因是 2023 年第三季授予的股權激勵增加。就淨虧損而言，2024 年第一季我們的淨虧損為 790 萬美元，而 2023 年第一季為 690 萬美元。

In terms of cash, we had a total $95.5 million in cash and in investment, in short-term US Treasury bill in Q1 2024 as compared with $37.8 million in cash in Q1 2023. The increase was primarily due to last year's follow-on offering and an exercise of the warrants issue in the follow-on offering and our ATM offering. In Q1 2024, we raised $12.5 million on the exercise of the warrant issue in the follow-on offering and ATM offering. In addition, we raised additional $25 million from registered direct offering in April. We expect cash runway beyond 2026.

就現金而言，我們在 2024 年第一季的現金和短期美國國庫券投資總額為 9,550 萬美元，而 2023 年第一季的現金為 3,780 萬美元。成長主要歸因於去年的後續發行以及後續發行和 ATM 發行中認股權證的行使。2024 年第一季度，我們透過後續發行和 ATM 發行中的認股權證發行籌集了 1,250 萬美元。此外，我們在 4 月透過註冊直接發行額外籌集了 2,500 萬美元。我們預計現金流將持續到 2026 年以後。

Thank you. Back to you, Tom.

謝謝。回到你身邊，湯姆。

Thanks, Hao. I would like to conclude with the key milestones to expect for this year. We are still making good progress in the Phase III in GA. Many sites have been initiated and are enrolling subjects, and more sites will be initiated. Interim data for Phase III study in Stargardt disease is expected to be in December this year or early next year depending on data collection and when the DSMB can convene.

謝謝，郝。最後，我想談談今年值得期待的關鍵里程碑。我們在 GA 第三階段仍取得良好進展。許多站點已經啟動並正在招募受試者，並且還會啟動更多站點。預計 Stargardt 病 III 期研究的中期數據將在今年 12 月或明年年初公佈，具體取決於數據收集情況以及 DSMB 何時召開會議。

Thank you for participating, and we'll leave for -- leave some time for Q&A. Thank you.

感謝您的參與，我們將留出一些時間進行問答。謝謝。

(Operator Instructions)

（操作員指示）

Yi Chen, H.C. Wainwright.

陳毅, H.C.溫賴特。

With respect to the novel grading algorithm, is it being deployed in both DRAGON I and DRAGON II trials?

關於新穎的評分演算法，它是否正在 DRAGON I 和 DRAGON II 試驗中部署？

Yi, this is Nathan Mata. I'll answer the question. So we have not yet formally deployed the grading algorithm in either clinical study. We are going to speak with the FDA first about a validation process to determine how they would like us to proceed with this new algorithm in terms of demonstrating its robustness and reliability.

易，我是納森馬塔。我來回答這個問題。因此，我們尚未在任何一項臨床研究中正式部署分級演算法。我們將首先與 FDA 討論驗證流程，以確定他們希望我們如何推進這項新演算法，以證明其穩健性和可靠性。

That meeting will occur within the next month or so. But there is a chance -- there's every chance that, obviously, we can implement it before end of study and retrospectively grade the images once we have FDA's approval to use it as a formal grading analysis. It will always be combined with whatever -- or be compared to, I should say, with what we obtain with the Heidelberg region finding software.

該會議將在下個月左右舉行。但還是有機會的——顯然，我們可以在研究結束前實施它，並在獲得 FDA 批准將其用作正式分級分析後對圖像進行回顧性分級。它將始終與任何東西相結合——或者說，與我們透過海德堡地區查找軟體獲得的東西進行比較。

Okay. And to follow up with the DRAGON I and DRAGON II trials. Do you intend to enroll patients with at least some degree of atrophic lesion in both trials?

好的。並跟進 DRAGON I 和 DRAGON II 試驗。您是否打算在兩項試驗中招募至少有一定程度萎縮性病變的患者？

Yes. Yes. Certainly, for our Phase III studies, where the endpoint, of course, is slowing the growth of the atrophic lesions, Yi, all subjects will come in with some measure of atrophy at baseline. But again, as part of our differentiation, we are picking patients with smaller lesions at baseline because we believe that early intervention will be a more appropriate sort of approach for this particular disease, both diseases, GA and Stargardt.

是的。是的。當然，對於我們的 III 期研究，其終點當然是減緩萎縮性病變的生長，Yi，所有受試者在基線時都會出現一定程度的萎縮。但是，作為我們區分的一部分，我們選擇基線病變較小的患者，因為我們相信早期幹預對於這種特殊疾病（GA 和 Stargardt 兩種疾病）來說是一種更合適的方法。

Does that suggest that earlier-stage patients without atrophic lesion may not be a suitable population for the treatment?

這是否意味著沒有萎縮性病變的早期患者可能不適合接受治療？

That's not the case. The case is actually a more regulatory concern because the agency, FDA and even EMA, are not convinced that autofluorescent in and of itself is actually causing photoreceptor cell death or dysfunction, whereas atrophic lesions represent dead retina. And of course, that will lead to loss of vision. So until there's more clinical data to demonstrate that autofluorescence by itself is actually affecting photoreceptor function.

事實並非如此。該案例實際上是一個更具監管意義的問題，因為該機構、FDA 甚至 EMA 並不確信自發性螢光本身實際上會導致感光細胞死亡或功能障礙，而萎縮性病變則代表視網膜死亡。當然，這會導致視力喪失。因此，除非有更多臨床數據證明自發螢光本身確實會影響光感受器功能。

And we have some of that data, as I mentioned, in the presentation. We have these kids who have autofluorescent lesions at baseline. They don't have atrophy, many of them, but they're losing vision. So we'll need more data like that to convince the agency that, in fact, the autofluorescence is impacting photoreceptor function, then it would be a valid endpoint.

正如我在演示中提到的，我們有一些數據。我們有一些孩子在基線時患有自發性螢光病變。他們中的許多人並沒有出現萎縮症狀，但視力正在下降。因此，我們需要更多這樣的數據來讓該機構相信，事實上，自發螢光正在影響光感受器的功能，然後它才會是一個有效的終點。

But we've shown you here a slowing of the transition from the autofluorescent lesion to atrophic lesion. And then once the atrophic lesions are formed, a slowing of growth of those lesions. So we believe in both contexts, slowing the transition as well as slowing the growth of the atrophic lesions, this treatment approach is appearing to be effective at both of those different scenarios.

但我們在這裡向您展示了從自發性螢光病變到萎縮性病變的轉變速度減慢。一旦形成萎縮性病變，病變的生長就會減慢。因此，我們相信，在兩種情況下，減緩轉變以及減緩萎縮性病變的生長，這種治療方法似乎對這兩種不同情況都有效。

(Operator Instructions)

（操作員指示）

Marc Goodman, Leerink Partners.

馬克古德曼（Marc Goodman），Leerink Partners。

This is Basma on for Marc. We have a question regarding the interim readout. Can you remind us again of your regulatory plans if the interim is positive? And again, positive interim, does it mean that the separation between the treatment arm and the placebo arm has to be statistically significant? That's our first question. And we do have a follow-up question after this one.

這是巴斯瑪 (Basma) 為馬克 (Marc) 表演的。我們對臨時讀數有一個疑問。如果中期結果呈現正面趨勢，您能否再次提醒我們您的監管計劃？再次，積極的中期，是否意味著治療組和安慰劑組之間的分離必須具有統計意義？這是我們的第一個問題。在此之後我們還有一個後續問題。

Basma, this is Nathan. I'll answer the question. So the way the interim analysis will be handled, it will be independently assessed by our DSMB. Ourselves, on the sponsor side, will remain mass. So we will not know the treatment effect nor can we announce a particular treatment effect. The DSMB will do an analysis based upon a predefined statistical window that tells us whether or not we need to add patients. So if we don't need to add patients, there's a very good chance we've fallen within the statistical window in which the treatment effect would be consistent with what something the FDA would approve that is 20% or greater.

巴斯瑪，這是內森。我來回答這個問題。因此，中期分析的處理方式將由我們的 DSMB 進行獨立評估。我們自己，作為贊助商，將保持規模。所以我們不會知道治療效果，也不能宣布具體的治療效果。DSMB 將根據預先定義的統計視窗進行分析，告訴我們是否需要新增患者。因此，如果我們不需要增加患者，那麼很有可能我們已經落入統計視窗內，其中治療效果與 FDA 批准的 20% 或更高的效果一致。

If we are asked to add patients, that means we're not at that particular point yet. So we would be adding more patients to sort of increase the conditional power. I should mention that, that statistical analysis was developed when we find the enrollment at 90 subjects. We had since overenrolled the study at 104 subjects. So we actually already have a buffer of subjects that probably we won't need to add. So I'm pretty confident that number, that is the treatment effect number, will be consistent with our statistical window.

如果要求我們增加病人，那就意味著我們還沒有到達那個特定的階段。因此，我們會增加更多的患者，以增強條件力量。我應該提到，當我們發現入學人數達到 90 名時，就進行了統計分析。此後，我們的研究對象數量已超額達 104 名。因此，我們實際上已經擁有了一些可能不需要添加的主題的緩衝區。所以我非常有信心這個數字，也就是治療效果數字，將與我們的統計窗口一致。

There is an outcome where we are not in the statistical window, and it would be futile to add patients, but this is a nonbinding futility. So if we do get that outcome, we will still continue the trial to the end of two years because it is very likely that you could get a better treatment effect during the second year of study. So those are the three different outcomes. I hope that was clear for you, Basma.

有一種結果是我們不在統計窗口內，增加患者也是徒勞無功的，但這是一種不具約束力的徒勞。所以如果我們確實得到了這個結果，我們仍然會繼續試驗到兩年結束，因為很有可能在研究的第二年你就可以獲得更好的治療效果。這就是三種不同的結果。我希望你清楚這一點，巴斯瑪。

Right. So like you're not going to -- if -- okay, so my understanding now is that if there is a positive outcome, there is no change in plans? There's no change in the enrollment? And -- okay.

正確的。所以就像你不會——如果——好的，那麼我現在的理解是，如果有正面的結果，計劃就不會改變？招生沒有變化嗎？而且——好的。

Correct.

正確的。

Our follow-up question's regarding the five out of 12 patients with pathogenic variance that you showed that did not develop any atrophic lesions throughout the 24 months of the Phase II trial.

我們的後續問題是關於您所顯示的 12 名具有致病變異的患者中的 5 名，他們在 II 期試驗的 24 個月內沒有出現任何萎縮性病變。

Yes.

是的。

Can you remind us again, a patient with these kinds of variance based on that short history studies, how long does it take really to develop atrophic lesions from QDAF to DDAF, just to know the treatment effect -- to have a better understanding of the treatment effect.

您能否再次提醒我們，根據那項簡短的病史研究，對於具有這種差異的患者，從 QDAF 發展到 DDAF 的萎縮性病變真正需要多長時間，才能知道治療效果 - 更好地了解治療效果。

It really depends on their baseline status. So if you look at the baseline status of our subjects, the size of their autofluorescent lesions predicts growth within two years. That means it predicts atrophic lesion growth within two years. So the majority of subjects should have had atrophic lesion growth.

這實際上取決於他們的基線狀態。因此，如果你觀察我們受試者的基線狀態，他們的自發性螢光病變的大小可以預測兩年內的成長。這意味著它可以預測兩年內萎縮性病變的生長。因此大多數受試者應該會出現萎縮性病灶生長。

There's probably two subjects -- I can't identify them by number because I don't have the data in front of me. But I believe there was two that had relatively small areas of autofluorescent lesion, but it was encroaching the fovea. So they're still losing vision.

可能有兩個主題——我無法透過數字識別它們，因為我面前沒有數據。但我相信有兩個病例的自發性螢光病變面積相對較小，但卻侵襲了中央凹。所以他們的視力仍在喪失。

But the short answer is, in our cohort, it would have expected that the majority of subjects, at least 75% of subjects, would have converted by two years, would have converted to an atrophic lesion. So the fact that we're seeing 42% of subjects not convert is actually a very, very promising finding, in addition to actually slowing the growth of atrophic incident lesions once they are formed.

但簡短的回答是，在我們的隊列中，預計大多數受試者（至少 75％ 的受試者）會在兩年內轉變，轉變為萎縮性病變。因此，我們發現 42% 的受試者沒有轉變，這實際上是一個非常非常有希望的發現，此外，它實際上還減緩了萎縮性事件病變形成後的生長速度。

This now concludes our Q&A portion of the call. I would like to turn the call back over to Tom for final remarks.

本次電話會議的問答部分到此結束。我想將電話轉回給湯姆，請他做最後的評論。

Well, thank you, everyone, for joining this call and asking questions on the trial. Please look forward to more updates from us and as we're making good progress on both studies. Thank you very much, and we'll see you soon.

好吧，謝謝大家參加這次電話會議並詢問有關審判的問題。請期待我們的更多更新，因為我們在這兩項研究中都取得了良好的進展。非常感謝，我們很快就會再見。