Aldeyra Therapeutics Inc (ALDX) 2022 Q4 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Aldeyra Therapeutics Full Year 2022 Financial Results Conference Call. (Operator Instructions)

女士們，先生們，感謝你們的支持，歡迎來到 Aldeyra Therapeutics 2022 年全年財務業績電話會議。 （操作員說明）

I would now like to hand the call over to -- the conference call over to Mr. Bruce Greenberg, the company's Interim Chief Financial Officer. Please go ahead, sir, Bruce Greenberg.

我現在想將電話會議轉交給公司的臨時首席財務官布魯斯·格林伯格先生。布魯斯·格林伯格先生，請繼續。

Thank you, and good morning, everyone. With me today is Dr. Todd Brady, our President and Chief Executive Officer. This morning, we issued a press release reporting recent corporate highlights and our financial results for the year ended December 31, 2022. A copy of the press release is available on the Investors & Media section of our website at www.aldeyra.com.

謝謝大家，早上好。今天和我在一起的是我們的總裁兼首席執行官 Todd Brady 博士。今天上午，我們發布了一份新聞稿，報告了最近的公司亮點和我們截至 2022 年 12 月 31 日止年度的財務業績。新聞稿的副本可在我們網站 www.aldeyra.com 的投資者與媒體部分獲取。

Please note that this morning's conference call contains forward-looking statements regarding future events and the future performance of Aldeyra. Forward-looking statements include, but are not limited to, statements regarding FDA review of our drug applications -- of our new drug applications, potential commercialization, the anticipated timing of initiation of results from our clinical trials, our projected cash runway, our possible or assumed future results of operations, expenses and financial position and potential growth opportunities.

請注意，今天上午的電話會議包含有關未來事件和 Aldeyra 未來業績的前瞻性陳述。前瞻性陳述包括但不限於關於 FDA 審查我們的藥物申請的陳述——我們的新藥申請、潛在的商業化、我們臨床試驗結果的預期啟動時間、我們預計的現金跑道、我們可能的或假設未來的經營業績、費用和財務狀況以及潛在的增長機會。

These statements are based on the information available to us today and reflect our current views concerning future events. They are based on assumptions and subject to risks and uncertainties, including the development, clinical and regulatory plans or expectations for Aldeyra's product candidates and systems-based approaches. The risk that result from clinical trials or portions of clinical trials may not accurately predict the results of future trials for the same or different indications and Aldeyra's continuing review and quality control analysis of clinical data.

這些聲明基於我們今天可獲得的信息，反映了我們目前對未來事件的看法。它們基於假設並受到風險和不確定性的影響，包括開發、臨床和監管計劃或對 Aldeyra 候選產品和基於系統的方法的期望。臨床試驗或部分臨床試驗產生的風險可能無法準確預測未來針對相同或不同適應症的試驗結果以及 Aldeyra 對臨床數據的持續審查和質量控制分析。

Aldeyra assumes no obligation to update these statements as circumstances change. Future events and actual results could differ materially from those projected in our forward-looking statements. Additional information concerning factors that could cause results to differ materially from our forward-looking statements are described in greater detail in our press release issued this morning and in our filings with the SEC.

Aldeyra 不承擔根據情況變化更新這些聲明的義務。未來事件和實際結果可能與我們前瞻性陳述中的預測存在重大差異。有關可能導致結果與我們的前瞻性陳述產生重大差異的因素的更多信息，在我們今天上午發布的新聞稿和我們向美國證券交易委員會提交的文件中有更詳細的描述。

I will now turn the call over to Dr. Brady.

我現在將電話轉給布雷迪博士。

Thank you, Bruce, and good morning, everyone, and thank you for joining us. Let me begin by recognizing the entire Aldeyra team as well as the clinical investigators and researchers and patients who have worked with us over the past year. The time and dedication you've invested to advance our strategic priorities in 2022 have resulted in 2 FDA accepted new drug applications, reproxalap for dry eye disease and ADX-2191, which was recently designated priority review for primary vitreoretinal lymphoma, a rare, aggressive, high-grade retinal cancer with no approved therapy.

謝謝你，布魯斯，大家早上好，感謝你加入我們。首先，我要感謝整個 Aldeyra 團隊以及在過去一年中與我們合作過的臨床研究人員、研究人員和患者。您為推進我們在 2022 年的戰略重點所投入的時間和奉獻精神使 FDA 接受了 2 項新藥申請，即用於乾眼病的瑞普沙普和 ADX-2191，ADX-2191 最近被指定用於原發性玻璃體視網膜淋巴瘤的優先審評，這是一種罕見的侵襲性，高級視網膜癌，沒有批准的治療方法。

We deeply appreciate your support in achieving a milestone that few companies of any size achieved this quarter and are proud to be actively working with the FDA to potentially bring 2 new therapies to patients as quickly as possible. These NDAs are catalysts for Aldeyra's future. They validate the novel platforms we've developed to treat both common and rare immune-mediated diseases characterized by inflammation. And they speak to the power of our drug discovery and development engine.

我們非常感謝您支持實現本季度幾乎沒有任何規模的公司實現的里程碑，並且很自豪能夠與 FDA 積極合作，盡快為患者帶來兩種新療法。這些 NDA 是 Aldeyra 未來的催化劑。他們驗證了我們開發的用於治療以炎症為特徵的常見和罕見免疫介導疾病的新型平台。他們談到了我們藥物發現和開發引擎的力量。

Building on this strong foundation, we are focused on advancing the next generation of our RASP modulation platform, ADX-629, ADX-246 and ADX-248 in 2023. For those of you that are new to Aldeyra, RASP are pro-inflammatory mediators that are elevated in ocular and systemic inflammatory disease, and thus represent therapeutic targets for immune modulation. Because RASP affects many proteins simultaneously, the RASP modulator platform represents a unique and novel pharmacologic approach. Unlike almost all drugs in use today, the platform is not designed to directly inhibit or activate a particular protein but instead selectively target a family of small molecules that in turn modulate the activity and structure of many proteins simultaneously.

在此堅實的基礎上，我們專注於在 2023 年推進我們的下一代 RASP 調製平台 ADX-629、ADX-246 和 ADX-248。對於那些剛接觸 Aldeyra 的人來說，RASP 是促炎介質在眼部和全身炎症性疾病中升高，因此代表免疫調節的治療目標。由於 RASP 同時影響許多蛋白質，RASP 調製器平台代表了一種獨特而新穎的藥理學方法。與當今使用的幾乎所有藥物不同，該平台並非設計用於直接抑製或激活特定蛋白質，而是選擇性地靶向一系列小分子，這些小分子反過來又同時調節許多蛋白質的活性和結構。

ADX-629, our first-in-class, orally administered RASP modulator product candidate is being evaluated in Phase II clinical trials in multiple systemic indications, including idiopathic nephrotic syndrome, which encompasses a broad group of renal inflammatory diseases, including minimal change disease and is characterized by edema, proteinuria and hypoalbuminemia. Sjogren-Larsson syndrome, an autosomal recessive neurocutaneous inborn error metabolism that prevents degradation of specific RASP and atopic dermatitis, a chronic hypersensitivity condition that is characterized by dry, itchy and inflamed skin.

ADX-629 是我們一流的口服 RASP 調節劑候選產品，目前正在多項系統適應症的 II 期臨床試驗中進行評估，包括特發性腎病綜合徵，它涵蓋了廣泛的腎臟炎症性疾病，包括微小病變和以水腫、蛋白尿和低白蛋白血症為特徵。 Sjogren-Larsson 綜合徵，一種常染色體隱性遺傳的神經皮膚先天性錯誤代謝，可防止特定 RASP 和特應性皮炎的降解，特應性皮炎是一種慢性超敏反應，其特徵是皮膚乾燥、發癢和發炎。

The ADX-629 clinical trials encompass a variety of clinical designs and are intended to develop to demonstrate activity across a range of diseases where RASP are implicated. Top line results from Sjogren-Larsson Syndrome as well as Part 1 of the atopic dermatitis and idiopathic nephrotic syndrome trials are expected in the second half of 2023.

ADX-629臨床試驗包括多種臨床設計，旨在開發以證明在涉及 RASP 的一系列疾病中的活性。 Sjogren-Larsson 綜合徵以及特應性皮炎和特發性腎病綜合徵試驗的第 1 部分的頂級結果預計將在 2023 年下半年公佈。

Our strategic approach is to identify multiple opportunities to establish the clinical relevance of ADX-629 in both common and rare diseases where the unmet medical need is significant. Toward this end, we also are conducting a multicenter randomized crossover Phase II clinical trial in approximately 50 patients with refractory or unexplained chronic cough. We expect to announce top line results from the trial in the first half of this year.

我們的戰略方法是確定多個機會，以確定 ADX-629 在未滿足醫療需求顯著的常見和罕見疾病中的臨床相關性。為此，我們還在大約 50 名難治性或不明原因的慢性咳嗽患者中進行多中心隨機交叉 II 期臨床試驗。我們預計將在今年上半年公佈試驗的最高結果。

Additionally, in 2023, we plan to initiate a Phase II trial in moderate alcohol-associated hepatitis. The decision to pursue this indication stems from the positive results we reported in December of a placebo-controlled Phase II Alcohol Challenge clinical trial, in which ADX-629 improved signs of alcohol intoxication. ADX-629 was superior to placebo in reducing dermal flushing, increasing Romberg test balance time and lowering levels of the ethanol RASP metabolite acetaldehyde following acute exposure to alcohol. We believe these results support the potential role of RASP modulation in treating alcohol liver -- alcohol-associated liver diseases, an indication for which there are few treatment options.

此外，我們計劃在 2023 年啟動針對中度酒精相關性肝炎的 II 期試驗。追求這一適應症的決定源於我們在 12 月報告的安慰劑對照 II 期酒精挑戰臨床試驗的積極結果，其中 ADX-629 改善了酒精中毒的跡象。 ADX-629 在減少皮膚潮紅、增加 Romberg 測試平衡時間和降低急性酒精暴露後乙醇 RASP 代謝物乙醛水平方面優於安慰劑。我們相信這些結果支持 RASP 調製在治療酒精肝中的潛在作用——酒精相關肝病是一種治療選擇很少的適應症。

ADX-629 has been administered to approximately 110 patients across multiple Phase I and Phase II clinical trials for up to 90 days. The drug has been observed to be generally well tolerated and has not resulted in any serious adverse events. We have invested thoughtfully and strategically to expand our RASP modulator pipeline. The newest product candidates, powered by our systems-based drug discovery and development engine, our ADX-246 and ADX-248. In the second half of 2023 or early 2024, we plan to initiate a Phase I/II clinical trial of orally administered ADX-246 for the treatment of systemic immune-mediated diseases and intravitreally injected ADX-248 for the treatment of geographic atrophy, a severe form of macular degeneration.

ADX-629已在多個 I 期和 II 期臨床試驗中對大約 110 名患者進行了長達 90 天的給藥。據觀察，該藥物通常具有良好的耐受性，並且未導致任何嚴重的不良事件。我們進行了深思熟慮和戰略性的投資，以擴展我們的 RASP 調製器管道。最新的候選產品，由我們基於系統的藥物發現和開發引擎 ADX-246 和 ADX-248 提供支持。 2023年下半年或2024年初，我們計劃啟動口服ADX-246治療全身免疫介導疾病和玻璃體內註射ADX-248治療地圖狀萎縮的I/II期臨床試驗，嚴重形式的黃斑變性。

With regard to ADX-2191, last week, we were thrilled to announce that the FDA accepted for priority review our NDA for the treatment of primary vitreoretinal lymphoma, also known as ocular lymphoma. The FDA had assigned a PDUFA date of June 21, 2023, 4 months from the acceptance of the NDA for review. The NDA is supported by a combination of more than 30 years of published literature on the safety and efficacy of methotrexate, the active ingredient of ADX-2191 for the treatment of ocular lymphoma. The submission is further supported by safety data from the recently completed Phase III GUARD trial of ADX-2191 in patients with proliferative vitreoretinopathy. An estimated 300 to 600 patients in the United States are diagnosed with ocular lymphoma each year. And the median survival for newly diagnosed patients is less than 5 years. If approved, we expect to launch ADX-2191 in the United States in the second half of this year, which would make ADX-2191, the first FDA-approved drug available for patients suffering from ocular lymphoma.

關於 ADX-2191，上週，我們很高興地宣布 FDA 接受優先審查我們用於治療原發性玻璃體視網膜淋巴瘤（也稱為眼淋巴瘤）的 NDA。 FDA 指定的 PDUFA 日期為 2023 年 6 月 21 日，即接受 NDA 審查後的 4 個月。 NDA 得到了 30 多年發表的關於甲氨蝶呤安全性和有效性的文獻的支持，甲氨蝶呤是 ADX-2191 用於治療眼部淋巴瘤的活性成分。最近完成的 ADX-2191 在增殖性玻璃體視網膜病變患者中進行的 III 期 GUARD 試驗的安全性數據進一步支持了該提交。據估計，美國每年有 300 至 600 名患者被診斷患有眼部淋巴瘤。新診斷患者的中位生存期不到 5 年。如果獲得批准，我們預計將於今年下半年在美國推出 ADX-2191，這將使 ADX-2191 成為 FDA 批准的第一個可用於眼部淋巴瘤患者的藥物。

ADX-2191 is also in development for 2 other retinal diseases without FDA-approved therapies. Proliferative vitreoretinopathy, a rare condition that is the leading cause of failure of retinal reattachment surgery and retinitis pigmentosa, a group of rare genetic eye diseases characterized by retinal cell death and loss of vision. We plan to conduct a Type C meeting mid-2023 with the FDA to discuss the completion of clinical development of ADX-2191 for the prevention of proliferative vitreoretinopathy. In addition, we plan to report top line results from the Phase II clinical trial of ADX-2191 in patients with retinitis pigmentosa in the first half of this year.

ADX-2191還在開發中，用於治療其他兩種未經 FDA 批准的治療方法的視網膜疾病。增殖性玻璃體視網膜病變是一種罕見病症，是視網膜復位手術失敗的主要原因，視網膜色素變性是一組以視網膜細胞死亡和視力喪失為特徵的罕見遺傳性眼病。我們計劃在 2023 年年中與 FDA 召開 C 類會議，討論 ADX-2191 用於預防增殖性玻璃體視網膜病變的臨床開發的完成情況。此外，我們計劃在今年上半年報告 ADX-2191 在色素性視網膜炎患者中進行的 II 期臨床試驗的主要結果。

With respect to reproxalap, the PDUFA date is November 23, 2023. We continue to engage in potential partnering discussions with multiple parties for reproxalap and are also preparing for commercialization internally. Our commercial preparations are designed to exploit the unparalleled rapid onset and breadth of activity observed in clinical trials of reproxalap in patients with dry eye disease. Last week, we reported top line results of the vehicle-controlled 12-month safety clinical trial for reproxalap in dry eye disease patients. Ocular safety was similar across reproxalap and vehicle treatment groups, and no treatment-emergent serious adverse events deemed at least possibly related to treatment were identified.

關於 reproxalap，PDUFA 日期是 2023 年 11 月 23 日。我們繼續與多方就 reproxalap 進行潛在的合作討論，同時也在為內部商業化做準備。我們的商業製劑旨在利用 reproxalap 在乾眼症患者的臨床試驗中觀察到的無與倫比的快速起效和廣泛的活性。上週，我們報告了瑞普列普在乾眼病患者中進行的為期 12 個月的車輛對照安全臨床試驗的主要結果。 reproxalap 和載體治療組的眼部安全性相似，並且沒有發現被認為至少可能與治療相關的治療中出現的嚴重不良事件。

What we believe to be particularly significant about the results is the potentially landmark evidence that visual acuity in patients treated with reproxalap was statistically superior to that in patients treated with vehicle. Visual acuity in the reproxalap group improved by approximately 37%, resulting in a P value of less than 0.0001. Coupled with demonstrated broad activity and rapid onset of action, a positive visual acuity data observed in the safety trial potentially further differentiate reproxalap in what we estimate is a $23 billion addressable market in the U.S.

我們認為對結果特別重要的是可能具有里程碑意義的證據表明，接受瑞普列普治療的患者的視力在統計學上優於接受載體治療的患者。 reproxalap 組的視力提高了約 37%，導致 P 值小於 0.0001。再加上廣泛的活性和快速起效，在安全試驗中觀察到的積極視力數據可能會進一步區分 reproxalap，我們估計在美國有 230 億美元的可尋址市場。

Now I'll turn the call back over to Bruce for the financial review.

現在我會把電話轉回 Bruce 進行財務審查。

Thanks, Todd. Let me begin with our liquidity profile. Cash, cash equivalents and marketable securities as of December 31, 2022, were $174.3 million. Based on our current operating plan, we believe that existing cash, cash equivalents and marketable securities will be sufficient to fund currently projected operating expenses into the second half of 2024. This includes the initial commercialization and launch plans for reproxalap and ADX-2191 if approved and continued early in late-stage development of our product candidates in ocular and systemic immune-mediated diseases.

謝謝，托德。讓我從我們的流動性狀況開始。截至 2022 年 12 月 31 日，現金、現金等價物和有價證券為 1.743 億美元。根據我們目前的運營計劃，我們認為現有現金、現金等價物和有價證券將足以支付目前預計到 2024 年下半年的運營費用。這包括 reproxalap 和 ADX-2191 的初步商業化和啟動計劃（如果獲得批准）並繼續早期開發我們在眼部和全身免疫介導疾病領域的候選產品。

Net loss for the year ended December 31, 2022, was $62.0 million or $1.06 per share compared with the net loss of $57.8 million or $1.07 per share for the same period in 2021. Losses have primarily resulted from the cost of our clinical trials and research and development programs, as well as from general and administrative expenses.

截至 2022 年 12 月 31 日止年度的淨虧損為 6200 萬美元或每股 1.06 美元，而 2021 年同期的淨虧損為 5780 萬美元或每股 1.07 美元。虧損主要來自我們的臨床試驗和研究成本和發展計劃，以及一般和行政費用。

Research and development expenses for the year ended December 31, 2022, were $47.3 million compared with $44.9 million for the same period in 2021. This increase was primarily related to an increase in drug product manufacturing expenditures, personnel costs, consulting expenditures and external preclinical development costs, which were partially offset by a decrease in external clinical development costs.

截至 2022 年 12 月 31 日止年度的研發費用為 4730 萬美元，而 2021 年同期為 4490 萬美元。這一增長主要與藥品製造支出、人員成本、諮詢支出和外部臨床前開發的增加有關成本，這部分被外部臨床開發成本的減少所抵消。

General and administrative expenses for the year ended December 31, 2022, were $15.4 million compared with $11.3 million for the same period in 2021. This increase was primarily related to higher consulting expenditures and higher personnel costs. Total operating expenses for the year ended December 31, 2022, were $62.7 million compared with total operating expenses of $56.2 million for the same period in 2021.

截至 2022 年 12 月 31 日止年度的一般和行政費用為 1540 萬美元，而 2021 年同期為 1130 萬美元。這一增長主要與諮詢支出增加和人員成本增加有關。截至 2022 年 12 月 31 日止年度的總運營費用為 6270 萬美元，而 2021 年同期的總運營費用為 5620 萬美元。

Now let me turn the call back to Dr. Brady for closing remarks.

現在讓我把電話轉回給布雷迪博士作結束語。

Thank you, Bruce. 2022 was a transformational year for Aldeyra highlighted by the achievement of key clinical and regulatory milestones across our drug development pipeline, including the submission of 2 new drug applications. That momentum continues in 2023 as we move closer to our goal of validation of our platforms for immune-mediated systemic and retinal diseases.

謝謝你，布魯斯。 2022 年是 Aldeyra 轉型的一年，突出體現在我們的藥物開發管道中實現了關鍵的臨床和監管里程碑，包括提交了 2 項新藥申請。隨著我們更接近驗證免疫介導的系統性疾病和視網膜疾病平台的目標，這種勢頭將在 2023 年繼續。

In our industry, success comes from forging one's own path based on evidence and science. That is precisely the course we are charting at Aldeyra. The development of reproxalap has created a strong foundation for our RASP modulation platform, which now features our orally administered candidate ADX-629 and 5 Phase II clinical trials representing varied designs and 2 new drug candidates poised to enter the clinic.

在我們的行業中，成功來自於在證據和科學的基礎上開闢自己的道路。這正是我們在 Aldeyra 制定的路線。 reproxalap 的開發為我們的 RASP 調製平台奠定了堅實的基礎，該平台現在包括我們的口服候選藥物 ADX-629 和代表不同設計的 5 項 II 期臨床試驗以及準備進入臨床的 2 種新候選藥物。

Through ADX-2191, we are creating a potential first-line therapy for rare retinal diseases without FDA-approved therapies, beginning with ocular lymphoma, proliferative vitreoretinopathy and retinitis pigmentosa, all indications for which our drug has received FDA's orphan drug designation.

通過 ADX-2191，我們正在為未經 FDA 批准的治療方法的罕見視網膜疾病創造潛在的一線治療方法，從眼淋巴瘤、增殖性玻璃體視網膜病變和色素性視網膜炎開始，我們的藥物已獲得 FDA 孤兒藥物指定的所有適應症。

And with that, we'll be happy to take your questions. Operator?

因此，我們很樂意回答您的問題。操作員？

(Operator Instructions) Our first question today comes from Marc Goodman of SVB Securities.

（操作員說明）我們今天的第一個問題來自 SVB 證券的馬克古德曼。

Todd, can you talk about the side effect profile that you've seen of the oral and how you think about that product and just the profile relative to what's on the market today? Obviously, the excitement is a broad spectrum oral. Just give us a sense of how you're thinking about it, what should we be looking for as far as just the profile, the side effect profile side?

托德，你能談談你看到的口服藥物的副作用概況以及你如何看待該產品以及與當今市場上的產品相關的概況嗎？顯然，興奮是一種廣譜口服。只是讓我們了解您是如何考慮它的，我們應該從側面尋找什麼，副作用側面？

Thanks, Marc. Very much appreciated, fireside chat we had together the other day. And thanks also for highlighting our oral RASP modulation pipeline. I would say broadly that inhibiting or activating single proteins tends to lead to toxicity. There's a reason why we have such proteins, is the reason why they are neither constitutively turned off or constitutively turned on and therein lies the value of RASP modulation. ADX-629, ADX-246, ADX-248, are all molecules that influence a family of mediators that in turn, influence a family of proteins. So we're not turning any protein on or off. We liken RASP modulation to a master volume knob where we're dialing down inflammation, say, from a 7 to a 2.

謝謝，馬克。非常感謝，前幾天我們一起進行了爐邊談話。也感謝您強調我們的口頭 RASP 調製管道。我會廣泛地說，抑製或激活單一蛋白質往往會導致毒性。我們有這樣的蛋白質是有原因的，這就是為什麼它們既沒有組成性關閉也沒有組成性開啟的原因，這就是 RASP 調製的價值所在。 ADX-629、ADX-246、ADX-248 都是影響介質家族的分子，而介質家族又反過來影響蛋白質家族。所以我們不會打開或關閉任何蛋白質。我們將 RASP 調製比作一個主音量旋鈕，我們可以在其中調低炎症，比如說，從 7 調到 2。

The value of that is safety and tolerability. Not only do we have breadth of activity, but we have drugs that aren't individually affecting proteins and therefore, should lead to less toxicity. We have seen that in trials observed to date, with ADX-629 we have very few side effects. As I mentioned in my prepared comments, we have no serious adverse events that have been deemed related to drug. So as we continue to test patients in other indications, I expect that safety profile will continue based on the mechanism of action of the drug.

其價值在於安全性和耐受性。我們不僅活動範圍廣，而且我們的藥物不會單獨影響蛋白質，因此應該會降低毒性。我們已經看到，在迄今為止觀察到的試驗中，ADX-629 的副作用很少。正如我在準備好的評論中提到的，我們沒有被認為與藥物有關的嚴重不良事件。因此，隨著我們繼續對其他適應症的患者進行測試，我預計安全性將繼續基於藥物的作用機制。

Our next question is from Yigal Nochomovitz from Citigroup.

我們的下一個問題來自花旗集團的 Yigal Nochomovitz。

Todd, with respect to the PDUFA for reproxalap, Yigal, obviously, that's filed. Could you comment to any extent on the partnering discussions there? And how does that has a clear target date for FDA approval? And then related to that, obviously, you have the second Phase III for AC coming up. I think in the past, you've indicated that it may not be necessary to file there given the extensive overlap between the AC and dry eye patient populations. I'm just wondering how are you thinking about that? Is it potentially a situation where the partners may want to see that data and then make a determination as to whether it'd be necessary to file in that second indication?

Todd，關於 reproxalap 的 PDUFA，顯然，Yigal 已經提交了。您能否對那裡的合作討論發表任何評論？以及如何為 FDA 批准制定明確的目標日期？然後與此相關的是，很明顯，AC 的第二階段 III 即將到來。我認為在過去，您曾表示，鑑於 AC 和乾眼症患者人群之間存在廣泛的重疊，可能沒有必要在那裡提交申請。我只是想知道你是怎麼想的？合作夥伴是否可能希望看到該數據，然後確定是否有必要在第二個指示中提交？

Happy to comment on partnering discussions and happy to comment on allergic conjunctivitis. As you know, the reproxalap NDA for dry eye disease has been accepted and thus, to some extent, regulatory risk has been removed at least as it relates to the FDA's review of that FDA (sic) [NDA]. As we've said before, we believe the NDA submission is the most comprehensive ever for a dry eye disease drug with 3 different signs and a variety of clinical trials that feature acute and chronic administration up to 12 weeks for efficacy and now 12 months for safety.

樂於就合作討論發表評論，樂於就過敏性結膜炎發表評論。如您所知，用於乾眼病的瑞普列普 NDA 已被接受，因此，在某種程度上，監管風險已被消除，至少因為它與 FDA 對該 FDA (sic) [NDA] 的審查有關。正如我們之前所說，我們認為 NDA 提交是有史以來最全面的干眼病藥物，具有 3 種不同的體徵和各種臨床試驗，其特點是急性和慢性給藥長達 12 週的療效，現在 12 個月安全。

All in all, the data continue to suggest that reproxalap is the only drug in development that can work quickly. And I think that's a major commercial differentiator. Also, as I announced in my prepared comments, reproxalap appears to be the only topically administered drug ever to demonstrate an improvement in chronic visual acuity, something that normally doesn't happen as we age over 12 months.

總而言之，數據繼續表明，reproxalap 是唯一一種可以快速起效的研發藥物。我認為這是一個主要的商業差異化因素。此外，正如我在準備好的評論中宣布的那樣，reproxalap 似乎是唯一一種能夠改善慢性視力的局部給藥藥物，這通常不會在我們超過 12 個月時發生。

Therefore, I would think that there are many potential partners that are interested in reproxalap. I can tell you that our partnering conversations are robust and as I mentioned in my prepared comments, involve multiple parties across a wide array of terms. I do expect that partners would want to be involved with reproxalap prior to label negotiations, which, in our case, I would expect to occur in the September to October time frame.

因此，我認為有很多潛在的合作夥伴對瑞普沙普感興趣。我可以告訴你，我們的合作對話非常穩健，正如我在準備好的評論中提到的那樣，涉及多方，涉及廣泛的術語。我確實希望合作夥伴希望在標籤談判之前參與 reproxalap，就我們而言，我希望在 9 月至 10 月的時間框架內進行。

Regarding allergic conjunctivitis, we continue to see that indication as a major differentiator for any dry eye disease drug. As you mentioned, there's a considerable overlap between dry eye disease and allergic conjunctivitis. And it's difficult for many health care providers to distinguish between those 2 diseases. Thus, a compound or a drug that can treat both of them simultaneously should be of considerable value.

關於過敏性結膜炎，我們繼續將該適應症視為任何干眼病藥物的主要區別因素。正如您提到的，乾眼症和過敏性結膜炎之間存在相當大的重疊。許多醫療保健提供者很難區分這兩種疾病。因此，能夠同時治療這兩者的化合物或藥物應該具有相當大的價值。

Our main goal at this point, Yigal, is to demonstrate the activity of reproxalap in allergic conjunctivitis. We have 2 published papers, 1 on Phase II trial, 1 on Phase III trial, the demonstrating activity of reproxalap in patients with allergic conjunctivitis across 2 different clinical trial models. The INVIGORATE-2 trial, which is our second allergen chamber trial that will be announced, as I mentioned in my prepared comments this morning, in the first half of this year. And I think pending the results of those trials, pending the partnership discussions of reproxalap, that we can then make a decision about the need to submit a new drug application for reproxalap in allergic conjunctivitis.

Yigal，我們在這一點上的主要目標是證明瑞普沙普在過敏性結膜炎中的活性。我們發表了 2 篇論文，其中 1 篇關於 II 期試驗，1 篇關於 III 期試驗，在 2 種不同的臨床試驗模型中證明了 reproxalap 在過敏性結膜炎患者中的活性。 INVIGORATE-2 試驗是我們將在今年上半年宣布的第二個過敏原試驗室試驗，正如我今天早上在準備好的評論中提到的那樣。我認為，在這些試驗的結果出來之前，在 reproxalap 的合作討論之前，我們可以決定是否需要提交 reproxalap 治療過敏性結膜炎的新藥申請。

Our next question comes from Justin Kim from Oppenheimer & Co.

我們的下一個問題來自 Oppenheimer & Co. 的 Justin Kim。

Congrats on all the progress. With reproxalap and 2191 sort of locked in for regulatory review over the course of the year, I just wanted to ask how you think about commercialization for these assets? How they sort of may differ? And how to think about the time line for investment for commercialization as sort of the review process progresses?

祝賀所有的進步。由於 reproxalap 和 2191 在這一年中被鎖定在監管審查中，我只想問你如何看待這些資產的商業化？它們有何不同？隨著審查過程的進展，如何考慮商業化投資的時間表？

Justin, thanks for the question. As Bruce mentioned in his prepared comments, we are well capitalized for initial launches for both compounds. There are certain synergies, particularly in the back office for launching both compounds. The sales efforts, though, are different. Reproxalap is obviously targeted towards optometrists and anterior segment ophthalmologists. ADX-2191 is targeted towards retinal surgeons, particularly those that treat the rare retinal diseases that relate to 2191.

賈斯汀，謝謝你的提問。正如布魯斯在他準備好的評論中提到的那樣，我們有足夠的資金來首次推出這兩種化合物。有一定的協同作用，特別是在後台啟動這兩種化合物。但是，銷售工作有所不同。 Reproxalap 顯然是針對驗光師和眼前節眼科醫生的。 ADX-2191面向視網膜外科醫生，尤其是那些治療與2191相關的罕見視網膜疾病的外科醫生。

I think that the breadth of sales activity and marketing activity regarding ADX-2191 is quite limited. And the reason I say that is because, a, retinal physicians are already using methotrexate to treat at least 2 of the diseases we've highlighted this morning. And b, there's a limited number of physicians that treat these diseases. I think there's something like 50 to 60 ocular oncologists in the United States. And therefore, I don't really consider ADX-21 to be a sales and marketing effort per se, but rather more of a market access effort, making physicians aware that compounding methotrexate, is no longer necessary and making physicians aware that ADX-2191 is in theory, clinically superior to compounded methotrexate because the volume is lower, the volume for injection is lower, the density is higher, all of that designed to reduce the side effects that you typically see with methotrexate injection into the eye, which is something called punctate keratitis.

我認為有關 ADX-2191 的銷售活動和營銷活動的範圍非常有限。我這麼說的原因是，a，視網膜醫生已經在使用甲氨蝶呤來治療我們今天早上強調的至少 2 種疾病。 b，治療這些疾病的醫生數量有限。我認為美國大約有 50 到 60 名眼腫瘤學家。因此，我並不真正認為 ADX-21 本身是一項銷售和營銷工作，而是更多的市場准入工作，讓醫生意識到復合甲氨蝶呤不再是必要的，並讓醫生意識到 ADX-2191理論上，臨床上優於復方甲氨蝶呤，因為體積更小，注射體積更小，密度更高，所有這些都旨在減少甲氨蝶呤注射到眼睛時通常會看到的副作用，這是稱為點狀角膜炎。

As we announced last year, as a result of the Phase III GUARD trial in proliferative vitreoretinopathy, the adverse events of keratitis was significantly lower than what one would expect with compounded methotrexate at least as has been published in the scientific literature. So I'm really quite thrilled about the commercial prospects of ADX-2191 for all those reasons, the advantages of the drug, combined with the fact that there's a targetable physician population, combined with the fact that there's no therapy approved for these indications.

正如我們去年宣布的那樣，作為增殖性玻璃體視網膜病變的 III 期 GUARD 試驗的結果，角膜炎的不良事件明顯低於人們對複合甲氨蝶呤的預期，至少科學文獻中已經發表了這一點。所以我對 ADX-2191 的商業前景感到非常興奮，因為所有這些原因，藥物的優勢，結合有目標醫生群體的事實，以及沒有批准用於這些適應症的治療的事實。

For reproxalap, one of the efforts we're pursuing internally is initial commercialization. You can expect that, that is a very thorough process that we will be prepared if necessary to launch internally. As I've said before, with mass-market drugs, it's not always optimal for small companies to launch. But in the ocular space, it is certainly feasible. We've seen it many times before. I think we're right on target to the extent that we need to do that, if we're unable to secure a partnering deal that's acceptable.

對於 reproxalap，我們在內部進行的努力之一是初步商業化。你可以預料到，這是一個非常徹底的過程，如果有必要，我們將準備好在內部啟動。正如我之前所說，對於大眾市場藥品，小公司推出並不總是最佳選擇。但是在眼空間，肯定是可行的。我們以前見過很多次。如果我們無法達成可接受的合作協議，我認為就我們需要這樣做的程度而言，我們的目標是正確的。

Okay. Great. Great. And maybe just then on the systemic RASP program. Can you just discuss 246 and its differentiation compared to 629? Just sort of any thoughts on indications that may be better suited for the sort of earlier stage asset with safety in tow?

好的。偉大的。偉大的。也許就在那時進行系統性 RASP 程序。您能談談 246 及其與 629 相比的區別嗎？關於可能更適合具有安全性的早期資產的跡象的任何想法？

Right. ADX-246 is our most potent RASP modulator yet. It is a direct product of our, the RASP modulator platform, which is really designed to select for new candidates that are effective RASP modulators, but also exhibit declines of pharmacokinetic properties we would desire for an orally administered drug.

正確的。 ADX-246 是我們迄今為止最強大的 RASP 調製器。它是我們 RASP 調製器平台的直接產品，該平台真正設計用於選擇作為有效 RASP 調製器的新候選者，但也表現出我們希望口服藥物的藥代動力學特性下降。

ADX-629, as you know, has been administered twice daily. There's the potential for 246 to be administered once daily. So not only is 246 more potent than 629, it also could have a more favorable dosage administration profile. 248 is similar, also a very potent RASP trap. But in this case, it will be formulated specifically for intravitreal injection for geographic atrophy and dark adaptation in patients with the dry form of AMD.

如您所知，ADX-629 每天給藥兩次。 246 有可能每天給藥一次。因此，246 不僅比 629 更有效，而且還可能具有更有利的給藥方式。 248 類似，也是一個非常強大的 RASP 陷阱。但在這種情況下，它將專門配製用於玻璃體內註射，用於乾性 AMD 患者的地理萎縮和暗適應。

Our next question is from Kelly Shi from Jefferies.

我們的下一個問題來自 Jefferies 的 Kelly Shi。

So I want to follow up on the 246. Todd, can you give us more color on the systemic immune-mediated diseases? Any details on specific indications you are pursuing? My second question is on the runway. I just want to confirm that the runway to second half 2024 includes both the launch plan for repro and 2191 and the projected revenue of both assets.

所以我想跟進 246。托德，你能給我們更多關於全身免疫介導疾病的顏色嗎？關於您正在尋求的具體適應症的任何細節？我的第二個問題是在跑道上。我只想確認到 2024 年下半年的跑道包括 repro 和 2191 的啟動計劃以及這兩種資產的預計收入。

And I think your 246 question relates to Justin's question about indications for 246. ADX-246 will initiate a Phase I clinical trial first. The idea there is to confirm safety and some of the pharmacokinetic advantages that I was highlighting in response to Justin's question. My expectation is that ADX-246 will inherit some of the indications where ADX-629 is being trialed today. Examples might include chronic cough or atopic dermatitis or alcohol-associated hepatitis.

我認為你的 246 問題與賈斯汀關於 246 適應症的問題有關。ADX-246 將首先啟動 I 期臨床試驗。那裡的想法是確認安全性和我在回答賈斯汀的問題時強調的一些藥代動力學優勢。我的期望是 ADX-246 將繼承 ADX-629 今天正在試用的一些適應症。例子可能包括慢性咳嗽或特應性皮炎或酒精相關性肝炎。

I think we need to see the results from the ADX-629 trial. And then to the extent there is activity we could consider then shifting molecules to 246, particularly for some of the mass market indication. I'd also expect that ADX-629 will remain on the orphan side of the equation. So as you know, we have 2 orphan indications that are being tested, currently one is idiopathic nephrotic syndrome and the other one is Sjogren-Larsson syndrome.

我認為我們需要看到 ADX-629 試驗的結果。然後在某種程度上我們可以考慮將分子轉移到 246，特別是對於一些大眾市場指示。我還希望 ADX-629 將保持在等式的孤立端。如您所知，我們有 2 個正在測試的孤兒適應症，目前一個是特發性腎病綜合徵，另一個是 Sjogren-Larsson 綜合徵。

Happy to briefly comment on cash and Bruce, feel free to fill in as well. But the guidance is very clear. We have cash into the second half of next year. That cash supports initial commercialization for both reproxalap and ADX-2191, and I hope the answers to the prior questions have given you a sense of how we're approaching those launches.

很高興簡要評論現金和布魯斯，也可以隨意填寫。但是指導非常明確。我們有現金進入明年下半年。這筆現金支持 reproxalap 和 ADX-2191 的初步商業化，我希望對先前問題的回答能讓您了解我們是如何接近這些發布的。

Yes. And I would just add that the forecast is conservative. It does not include any revenue nor does it include or expect any revenue from a license arrangement.

是的。我只想補充一點，預測是保守的。它不包括任何收入，也不包括或預期來自許可安排的任何收入。

Our next question is from Tom Shrader from BTIG.

我們的下一個問題來自 BTIG 的 Tom Shrader。

This is Sung on for Tom. So just 2 for us. So for ADX-2191, could you provide additional color on how the recent priority review for ocular lymphoma may help other indications such as PVR and retinitis pigmentosa? And for the second question, so for the visual acuity data, what will be the best strategy moving forward? Is this something you will try to include when you submit the safety data?

這是為湯姆而唱的。所以我們只有 2 個。那麼對於 ADX-2191，您能否提供更多顏色，說明最近對眼淋巴瘤的優先審查如何幫助其他適應症，如 PVR 和視網膜色素變性？對於第二個問題，對於視力數據，前進的最佳策略是什麼？這是您在提交安全數據時會嘗試包括的內容嗎？

Both of those are superb questions. Our regulatory strategy for ADX-2191 was quite intentional, and that is -- the idea is to get -- submit an NDA for ocular lymphoma first. The reason is that methotrexate, which is the active ingredient of 2191 is standard of care for treatment of ocular lymphoma. It's been injected in eyes for 30 years with acceptable safety and activity. .

這兩個都是極好的問題。我們對 ADX-2191 的監管策略是有意為之的，那就是——我們的想法是——首先提交一份針對眼淋巴瘤的 NDA。原因是作為 2191 活性成分的甲氨蝶呤是治療眼部淋巴瘤的標準護理。它已經在眼睛中註射了 30 年，安全性和活性都可以接受。 .

After that, subsequent NDA submissions or so-called supplemental NDAs, where the bar is somewhat lower because safety and the chemistry, manufacturing controls aspects of ADX-2191 have already been evaluated in the original NDA submission. That's why I highlighted this morning the safety results from the Phase III GUARD trial in proliferative vitreoretinopathy. Those are particularly important the lymphoma submission because the FDA always assesses not only activity but also safety. And in this case, we have a new formulation designed to be vitreous compatible with a lower volume and a higher density and so forth. And all that will be assessed from a safety standpoint as part of the lymphoma review.

之後，隨後的 NDA 提交或所謂的補充 NDA，其中的門檻有所降低，因為 ADX-2191 的安全性和化學、製造控制方面已經在原始 NDA 提交中進行了評估。這就是為什麼我今天早上強調了增殖性玻璃體視網膜病變 III 期 GUARD 試驗的安全性結果。這些對於淋巴瘤提交尤為重要，因為 FDA 總是不僅評估活性，而且評估安全性。在這種情況下，我們有一種新的配方，旨在與較低體積和較高密度等玻璃體相容。作為淋巴瘤審查的一部分，所有這些都將從安全的角度進行評估。

We were absolutely thrilled with the Phase III GUARD results in terms of safety. In terms of proliferative vitreoretinopathy, it appeared to be actually safer to administer methotrexate -- 2191 than it was not to administer 2191, which makes sense because methotrexate as a compound is anti-inflammatory and may mitigate some of the trauma associated with surgery. So by and large, I think we have a compelling submission for lymphoma based not only on the safety, but also on the activity from the scientific literature.

我們對 III 期 GUARD 在安全性方面的結果感到非常興奮。就增殖性玻璃體視網膜病變而言，服用甲氨蝶呤 - 2191 似乎比不服用 2191 更安全，這是有道理的，因為甲氨蝶呤作為一種化合物具有抗炎作用，可以減輕與手術相關的一些創傷。所以總的來說，我認為我們有一個令人信服的淋巴瘤提交，不僅基於安全性，還基於科學文獻的活性。

The visual acuity data was quite remarkable and unexpected from the 12-month safety trial of reproxalap. There is a 120-day update as part of a standard NDA review, which focuses on safety, in particular, obviously, the 12-month safety trial, the final data from the 12-month safety trial will be highlighted in that safety update, including the visual acuity data. What actually winds up in the label, I think, depends on negotiation with the FDA. But also we intend to publish the results of the safety trial. I think relative to other 12-month safety trials in dry eye disease, the visual acuity results are quite remarkable. And as I mentioned in my prepared comments, should stand to differentiate reproxalap from our potential competition in the dry eye space.

在為期 12 個月的 reproxalap 安全試驗中，視力數據非常出色且出乎意料。作為標準 NDA 審查的一部分，有一個 120 天的更新，重點是安全性，特別是，顯然，12 個月的安全試驗，12 個月安全試驗的最終數據將在該安全更新中突出顯示，包括視力數據。我認為，標籤中的實際內容取決於與 FDA 的協商。但我們也打算公佈安全試驗的結果。我認為相對於乾眼病的其他 12 個月安全性試驗，視力結果非常顯著。正如我在準備好的評論中提到的那樣，應該將 reproxalap 與我們在乾眼症領域的潛在競爭區分開來。

Our next question is from Catherine Novack from Jones Research.

我們的下一個問題來自 Jones Research 的 Catherine Novack。

Just wanted to kind of expand on the last question. Can you -- what was the change in visual acuity for the vehicle group in the safety study? And how clinically significant is this 37% improvement in (inaudible) seen in the treatment group?

只是想對最後一個問題進行擴展。你能——在安全研究中車輛組的視力有何變化？在治療組中看到的（聽不清）37% 的改善在臨床上有多大意義？

Both vehicle and drug improved vision from baseline, the improvement in the drug arm, the reproxalap arm was statistically significantly greater than that of vehicle. I think that speaks to a couple of phenomena. One is, dry eye patients are inflamed. There is edema or swelling in the cornea, which affects visual acuity. As we're treating these patients either with vehicle or drug we would expect that inflammation to improve. What's remarkable is, again, if you go back to other 12-month safety trials in dry disease, it's never been shown that either drug or vehicle can improve visual acuity.

賦形劑和藥物均從基線改善視力，藥物組的改善，reproxalap 組在統計學上顯著大於賦形劑。我認為這說明了一些現象。一是，乾眼症患者發炎了。角膜有水腫或腫脹，影響視力。當我們用載體或藥物治療這些患者時，我們預計炎症會有所改善。再次值得注意的是，如果您回顧其他為期 12 個月的干病安全性試驗，則從未表明藥物或載體可以提高視力。

And I think in this case, the improvement of visual acuity speaks to the activity of our drug product, that is the drug itself, reproxalap plus the vehicle in calming down the eye and potentially reducing that edema and improving inflammation broadly that facilitates an improvement in visual acuity. Most of these patients by design and enrollment, Catherine, have normal acuity. In other words, if patients have best corrected visual acuity, I think it's more than 2,100 or worse than 2,100. Now they're not enrolled for obvious reasons. So to see any change, any improvement in visual acuity in a group of patients that are essentially normal, I think, is quite remarkable.

我認為在這種情況下，視力的改善說明了我們的藥物產品的活性，即藥物本身，reproxalap 加上使眼睛平靜並可能減少水腫和廣泛改善炎症的載體，從而促進改善視力。凱瑟琳，根據設計和登記，這些患者中的大多數具有正常的敏銳度。換句話說，如果患者的最佳矯正視力，我認為是2100以上或者低於2100。現在他們因為明顯的原因沒有被錄取。因此，我認為，在一組基本正常的患者中看到任何變化，視力的任何改善，都是非常了不起的。

As I mentioned in response to another question, as we age over 12 months, you would expect to see visual acuity worsen slightly, particularly in the age group that is characteristic of dry eye disease, which is on average in your 60s. So all in all, I think these findings are quite remarkable. They're not something you would see with massively visually impaired populations. But here, any improvement, I think, speaks to the activity of the drug and frankly, there's little that's more clinically relevant in ocular disease than acuity. We have eyeballs to see. And if we see a little bit better, I think that speaks volumes for the activity of drug.

正如我在回答另一個問題時提到的那樣，隨著年齡超過 12 個月，您會發現視力會略有下降，尤其是在乾眼症特徵的年齡組，平均年齡為 60 多歲。所以總而言之，我認為這些發現非常了不起。它們不是您在大量視障人群中看到的東西。但在這裡，我認為任何改善都與藥物的活性有關，坦率地說，在眼部疾病中，沒有什麼比敏銳度更具有臨床相關性了。我們有眼球要看。如果我們看得好一點，我認為這說明了藥物的活性。

Got it. That's very helpful. And then one last question. I'm wondering if you can talk about the rationale for RASP modulators in geographic atrophy. We know that inflammation, oxidative stress, et cetera, have an implicated AMD. But at this point, most of the therapeutic approaches have focused on the complement cascade. So what led to the initiation of the study? And what do you think is differentiating about your approach?

知道了。這很有幫助。然後是最後一個問題。我想知道你是否可以談談 RASP 調製器在地理萎縮中的基本原理。我們知道炎症、氧化應激等與 AMD 相關。但在這一點上，大多數治療方法都集中在補體級聯反應上。那麼是什麼導致了這項研究的啟動呢？您認為您的方法與眾不同之處是什麼？

Well, I could talk about this one for an hour. We're particularly excited about geographic atrophy and dry AMD broadly as it relates to RASP modulation. It could be that we look backwards in time, decades from now and are somewhat embarrassed that we tried to treat a complicated inflammatory disease by targeting a single aspect of the complement cascade. RASP modulation is entirely different. As I mentioned in my prepared comments, the idea of RASP modulation is to influence a broad group of proteins and said another way, reduce inflammation from a variety of different fronts simultaneously, and that's exactly how RASP behave. They are broadly pro-inflammatory, they affect many different proteins, not just a single aspect of the complement cascade. That's part one of why we're excited about RASP modulation, geographic atrophy.

好吧，我可以用一個小時來談論這個。我們對廣泛的地理萎縮和乾性 AMD 特別興奮，因為它與 RASP 調製有關。可能是我們回顧過去，幾十年後，我們試圖通過針對補體級聯的單一方面來治療複雜的炎症性疾病，這讓我們有些尷尬。 RASP 調製完全不同。正如我在準備好的評論中提到的，RASP 調製的想法是影響廣泛的蛋白質組，換句話說，同時減少來自各種不同方面的炎症，這正是 RASP 的行為方式。它們具有廣泛的促炎作用，它們影響許多不同的蛋白質，而不僅僅是補體級聯的一個方面。這就是為什麼我們對 RASP 調製、地理萎縮感到興奮的部分原因之一。

Part two is characteristic of dry AMD and GA and related diseases such as Stargardt disease, is the accumulation of undigestible metabolites or macro molecules that build up in the back of the eye. These are the so-called drusen, which are comprised of a compound or a group of compounds called life of fusion, which are directly derived from RASP. So RASP are not only pro-inflammatory in GA, but they also lead to the accumulation of these macro molecules, which the retina is not capable of getting rid of.

第二部分是乾性 AMD 和 GA 以及相關疾病（如 Stargardt 病）的特徵，是無法消化的代謝物或大分子在眼後部積聚。這些就是所謂的玻璃膜疣，由一種或一組稱為融合生命的化合物組成，這些化合物直接來源於 RASP。因此，RASP 不僅在 GA 中具有促炎作用，而且還會導致這些大分子的積累，而視網膜無法清除這些大分子。

And what happens is, this accumulation of indigestible metabolites over time that lead to lipofuscin and drusen. So we have 2 mechanisms of RASP modulation, a broad anti-inflammatory approach, and I think it's very clear in the GA and dry AMD and Stargardt and related inflammation, but also the prevention of the formation of these metabolites that build up in the back of the eye as we age.

發生的事情是，隨著時間的推移，這種難以消化的代謝物積累會導致脂褐素和玻璃膜疣。所以我們有 2 種 RASP 調節機制，一種廣泛的抗炎方法，我認為這在 GA 和乾性 AMD 和 Stargardt 以及相關炎症中非常明顯，而且還可以防止這些代謝物在後面累積隨著年齡的增長。

We will now take our last question from Yale Jen from Laidlaw Company.

我們現在將接受來自 Laidlaw Company 的 Yale Jen 的最後一個問題。

In terms of INVIGORATE-2 study that you reported data this half, but could you give a little bit update in terms of the -- when the study started and what the current status of patient enrollment and others? And then I have a follow-up.

就 INVIGORATE-2 研究而言，你報告了這一半的數據，但你能否就研究開始的時間以及患者登記和其他方面的現狀提供一些更新？然後我有一個後續行動。

It wouldn't be an Aldeyra earnings call, if I didn't thank you for all your support over the years. It's just been an absolute pleasure. INVIGORATE-2, I think was started almost 2 years ago. And the reason I say that is because for allergen chamber trials, you cannot treat patients when there's pollen in the air. When there's ambient pollen, that ambient pollen confounds the activity you may or may not observe in the allergen chamber, and thus, most of these allergen chamber trials are run during the winter. So we had last year's winter season, we have this year's winter season. The reason why we're guiding this half for INVIGORATE-2 is that pollen will arrive again early spring, in the next month or 2. We will no longer be able to enroll patients and that enrollment we would expect will be complete relatively soon.

如果我不感謝您多年來的所有支持，那將不會是 Aldeyra 財報電話會議。這絕對是一種享受。 INVIGORATE-2，我想是大約 2 年前開始的。我之所以這麼說是因為對於過敏原室試驗，當空氣中有花粉時你不能治療病人。當有環境花粉時，環境花粉會混淆您在過敏原室中可能會或可能不會觀察到的活動，因此，大多數這些過敏原室試驗都是在冬季進行的。所以我們有去年的冬季，我們有今年的冬季。我們為 INVIGORATE-2 指導這一半的原因是花粉將在下個月或 2 個月的早春再次到達。我們將無法再招募患者，我們預計招募將很快完成。

As a reminder, the primary end point, really the only FDA-approved endpoint in ocular allergy is itching, that is a patient reported itching scale, typically 0 to 4. As you know, across the Phase III ALLEVIATE trial, across our Phase II allergen chamber trial, across the INVIGORATE allergen chamber trial, itching was significantly reduced relative to vehicle. And we've performed many analyses to confirm the clinical relevance of those findings. We hope to see the same thing in INVIGORATE-2. As far as we know, assuming positive data, INVIGORATE-2 would conclude our efficacy trials for allergic conjunctivitis.

提醒一下，主要終點，實際上是 FDA 批准的眼部過敏的唯一終點是瘙癢，即患者報告的瘙癢等級，通常為 0 到 4。如您所知，在 III 期緩解試驗中，在我們的 II 期中過敏原室試驗，在 INVIGORATE 過敏原室試驗中，相對於媒介物，瘙癢顯著減少。我們進行了許多分析來確認這些發現的臨床相關性。我們希望在 INVIGORATE-2 中看到同樣的東西。據我們所知，假設數據呈陽性，INVIGORATE-2 將結束我們對過敏性結膜炎的療效試驗。

Okay. Great. That's very helpful. Maybe one more here, which is for 2191, retinitis pigmentosa data readout. What should we anticipate from that data once you report it?

好的。偉大的。這很有幫助。也許這裡還有一個，用於 2191，視網膜色素變性數據讀數。一旦您報告了這些數據，我們應該期待什麼？

Well, thanks for highlighting retinitis pigmentosa. There are 3 major milestones for our company in this half. We just talked about INVIGORATE-2. I discussed chronic cough previously. And then retinitis pigmentosa is the third. What I think is remarkable about those 3 milestones as each milestone highlights a different aspect of our business. I'd like to think of Aldeyra in 3 parts, reproxalap being 1, ADX-2191 being 2 and the third being the oral pipeline and each of those aspects of our business that are representative of the milestones that we expect this half.

好吧，感謝您強調視網膜色素變性。我們公司在這半年有 3 個重要的里程碑。我們剛剛談到了 INVIGORATE-2。我之前討論過慢性咳嗽。然後是第三種視網膜色素變性。我認為這 3 個里程碑的非凡之處在於每個里程碑都突出了我們業務的不同方面。我想將 Aldeyra 分為三個部分，reproxalap 是 1，ADX-2191 是 2，第三個是口服管道，我們業務的每個方面都代表了我們預期的里程碑。

Retinitis pigmentosa is particularly interesting. It is the largest of the 3 indications we're currently testing with ADX-2191. To pick round numbers, one might think of roughly 400 incident patients with lymphoma, 4,000 incident patients with proliferative vitreoretinopathy and something like 40,000 incident patients with retinitis pigmentosa that relate to the particular mutations that appear to be sensitive to methotrexate administration.

視網膜色素變性特別有趣。這是我們目前使用 ADX-2191 測試的 3 種適應症中最大的一種。要選擇整數，人們可能會想到大約 400 名淋巴瘤患者、4,000 名增殖性玻璃體視網膜病變患者和大約 40,000 名視網膜色素變性患者，這些患者與似乎對甲氨蝶呤給藥敏感的特定突變有關。

The basis for using ADX-2191 and methotrexate in retinitis pigmentosa is cited in our clinical deck. There's been a remarkable series of experiments spanning many thousands of molecules in animal models of retinitis pigmentosa, the winner was methotrexate. And thus, investigators and many patients and certainly, the staff here at Aldeyra are excited about the potential for ADX-2191 in retinitis pigmentosa. This is an open-label trial. This is the first time methotrexate has been administered to retinitis pigmentosa patients. And we, as I mentioned, would expect to be able to announce results this half.

在我們的臨床平台中引用了在視網膜色素變性中使用 ADX-2191 和甲氨蝶呤的基礎。在色素性視網膜炎動物模型中進行了一系列跨越數千個分子的非凡實驗，獲勝者是甲氨蝶呤。因此，研究人員和許多患者，當然還有 Aldeyra 的工作人員對 ADX-2191 在視網膜色素變性中的潛力感到興奮。這是一項開放標籤試驗。這是甲氨蝶呤首次用於視網膜色素變性患者。正如我所提到的，我們希望能夠在下半年公佈結果。

Okay. Great. That's very helpful. And again, congrats for all these catalysts of this year.

好的。偉大的。這很有幫助。再次祝賀今年所有這些催化劑。

Exciting times, Yale. Thank you.

激動人心的時刻，耶魯。謝謝。

Thank you. I'll now turn the call back to Dr. Brady for closing comments.

謝謝。我現在將電話轉回 Brady 博士以徵求結束意見。

Thank you for joining us this morning. We are positioned for an exciting year in 2023. And as always, we look forward to bringing our novel therapies to patients with significant unmet medical need.

感謝您今天早上加入我們。我們計劃在 2023 年迎來激動人心的一年。一如既往，我們期待著將我們的新療法帶給醫療需求未得到滿足的患者。

Thank you, everyone, for joining today's call. You may now disconnect your lines and have a lovely day.

謝謝大家參加今天的電話會議。您現在可以斷開線路並度過愉快的一天。