Amylyx Pharmaceuticals Inc (AMLX) 2023 Q1 法說會逐字稿

Good afternoon. My name is Debbie, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals First Quarter 2023 Earnings Conference Call. (Operator Instructions) Please be advised that this call is being recorded at the company's request.

下午好。我叫黛比，今天我將擔任你們的會議操作員。現在，我歡迎大家參加 Amylyx Pharmaceuticals 2023 年第一季度收益電話會議。 （操作員說明）請注意，本次通話是應公司要求進行錄音的。

I would now turn the call over to Lindsey Allen, Head, Investor Relations and Communications. Please proceed.

我現在將把電話轉給投資者關係和傳播主管林賽·艾倫 (Lindsey Allen)。請繼續。

Good afternoon, and thank you for joining us today to discuss our first quarter 2023 earnings. With me on the call are Josh Cohen and Justin Klee, our co-CEOs; Margaret Olinger, our Chief Commercial Officer; and Jim Frates, our Chief Financial Officer.

下午好，感謝您今天加入我們討論我們 2023 年第一季度的收益。與我一起參加電話會議的還有我們的聯合首席執行官喬什·科恩 (Josh Cohen) 和賈斯汀·克利 (Justin Klee)；瑪格麗特·奧林格 (Margaret Olinger)，我們的首席商務官；以及我們的首席財務官 Jim Frates。

Before we begin, I would like to remind everyone that any statements we make are information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans and expectations and are made pertinent to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectations with results to RELYVRIO and ALBRIOZA, statements regarding regulatory developments and the expected timing thereof, our business strategy and outlook and our expected financial performance. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements unless required by law.

在開始之前，我想提醒大家，我們所做的任何陳述都是在本次電話會議上提供的信息，不是歷史事實，而是基於我們當前的信念、計劃和期望的前瞻性陳述，並且與安全港相關。 1995 年《私人證券訴訟改革法案》的規定。這些聲明包括但不限於我們對 RELYVRIO 和 ALBRIOZA 的結果的預期、有關監管發展及其預期時間的聲明、我們的業務戰略和前景以及我們的預期財務業績。由於各種風險、不確定性和其他因素，包括我們最近向 SEC 提交的文件以及我們可能未來提交的任何其他文件中所述的因素，實際事件和結果可能與任何前瞻性陳述中明示或暗示的內容存在重大差異。與 SEC 合作。請您注意不要過分依賴這些前瞻性陳述，除非法律要求，Amylyx 不承擔更新此類陳述的義務。

Now I will turn the call over to Justin.

現在我將把電話轉給賈斯汀。

Thank you, Lindsey, and good afternoon. As everyone on this call knows, there is an enormous unmet need in ALS and other relentlessly progressive and fatal neurodegenerative diseases. It is our mission at Amylyx, to one day end the suffering caused by these diseases. Our treatment RELYVRIO enables us to make meaningful advances toward and continued investment in our mission.

謝謝你，林賽，下午好。正如本次電話會議上的每個人都知道的那樣，ALS 和其他不斷進展和致命的神經退行性疾​​病存在巨大的未滿足需求。 Amylyx 的使命是有一天結束這些疾病造成的痛苦。我們的治療 RELYVRIO 使我們能夠在我們的使命上取得有意義的進展並持續投資。

During the first quarter, we generated $71.4 million in net product revenues, reflecting the significant progress we continue to make toward our goal of ensuring every eligible person living with ALS has access to RELYVRIO. RELYVRIO is the first and only approved treatment for ALS that in a randomized placebo-controlled trial both met its prespecified primary outcomes, demonstrating a statistically significant benefit and function and showed a benefit on survival in a longer-term post-hoc analysis. These data suggest that ALS can, in fact, be treated.

第一季度，我們產生了 7140 萬美元的產品淨收入，這反映出我們在確保每個符合資格的 ALS 患者都能使用 RELYVRIO 的目標方面不斷取得重大進展。 RELYVRIO 是第一個也是唯一一個獲得批准的 ALS 治療方法，在一項隨機安慰劑對照試驗中，該治療方法均達到了預先設定的主要結果，顯示出具有統計學意義的益處和功能，並且在長期事後分析中顯示出對生存的益處。這些數據表明 ALS 事實上是可以治療的。

The full approval of RELYVRIO is an important step toward ALS, one day being a manageable disease. The ALS community has been waiting for meaningful treatment option since the disease was first characterized over 150 years ago, and we believe that RELYVRIO will eventually be a foundational therapy for ALS. In the first quarter, we saw a continued high level of interest from the ALS community in RELYVRIO, broadened insurance coverage and high levels of engagement with our Amylyx Care Team, also known as ACT. Just 2 quarters into launch, over 10% of the approximately 29,000 people living with ALS in the U.S., are now on RELYVRIO. Even with that success in our first 6 months, we have more to do. There remain many more thousands of people living with ALS in the U.S. and at least 200,000 people living with ALS globally. We are still in the early stages of our journey, and our team remains hard at work.

RELYVRIO 的全面批准是邁向 ALS 的重要一步，有一天，ALS 將成為一種可控制的疾病。自 150 多年前首次發現 ALS 疾病以來，ALS 社區一直在等待有意義的治療選擇，我們相信 RELYVRIO 最終將成為 ALS 的基礎療法。在第一季度，我們看到 ALS 社區對 RELYVRIO 的持續高興趣、擴大的保險範圍以及與我們的 Amylyx 護理團隊（也稱為 ACT）的高度互動。推出僅兩個季度，美國約 29,000 名 ALS 患者中超過 10% 正在使用 RELYVRIO。儘管我們在前 6 個月取得了成功，但我們還有更多工作要做。美國仍有數千名 ALS 患者，全球至少有 200,000 名 ALS 患者。我們仍處於旅程的早期階段，我們的團隊仍在努力工作。

Shifting to our plans internationally. We are diligently preparing to help bring our medicine to all eligible people living with ALS around the world. The regulatory review process in Europe remains ongoing, and we continue to expect an opinion from CHMP midyear and a decision at the earliest in Q3. Overall, we believe we have a strong scientific position that is supported broadly by the ALS medical and advocacy community and a capable team who is leading our process. We continue to prepare to execute a successful launch in the EU if approved. We are proud of our team's progress on advancing our mission.

轉向我們的國際計劃。我們正在努力準備，幫助將我們的藥物帶給世界各地所有符合資格的 ALS 患者。歐洲的監管審查流程仍在進行中，我們繼續期待 CHMP 在年中提出意見，並最早在第三季度做出決定。總體而言，我們相信我們擁有強大的科學地位，並得到 ALS 醫療和倡導界以及領導我們流程的有能力的團隊的廣泛支持。如果獲得批准，我們將繼續準備在歐盟成功啟動。我們為我們的團隊在推進我們的使命方面取得的進展感到自豪。

And now I'll turn the call over to Margaret to share a commercial update.

現在我將把電話轉給瑪格麗特，分享商業更新。

Thank you, Justin. As we enter the seventh month since our U.S. launch, we remain focused on 3 key priorities. The first is our effort to drive awareness and education about RELYVRIO among people living with ALS and clinicians. This includes educating that RELYVRIO is the first approved drug for adults with ALS to demonstrate a statistically significant benefit and function in a clinical trial as well as a benefit on survival in a longer-term post-hoc analysis.

謝謝你，賈斯汀。自我們在美國推出以來已進入第七個月，我們仍然專注於 3 個關鍵優先事項。首先是我們努力提高 ALS 患者和臨床醫生對 RELYVRIO 的認識和教育。這包括宣傳 RELYVRIO 是第一個批准用於治療 ALS 成人的藥物，在臨床試驗中證明具有統計學上顯著的益處和功能，並且在長期事後分析中證明對生存有益處。

Our efforts to drive awareness are yielding strong results. We are seeing continued interest and demand for RELYVRIO. As of March 31, there were roughly 3,000 people on RELYVRIO in the U.S., more than double the number of people on RELYVRIO at the start of the quarter. We are pleased that this many people have gained access to our important treatment. I think it's worth spending a minute to provide some additional context on the strength of our launch. While we knew there was pent-up demand, the fourth quarter and first quarter were still well ahead of our expectations. The rate of net patient adds has begun to moderate as expected. However, we still see significant demand from people living with ALS and physicians alike. Importantly, we still have plenty of room for growth, both at the top ALS Centers and the broader neurology community.

我們提高認識的努力正在取得顯著成果。我們看到對 RELYVRIO 的持續興趣和需求。截至 3 月 31 日，美國 RELYVRIO 約有 3,000 人，是本季度初 RELYVRIO 人數的兩倍多。我們很高興有這麼多人獲得了我們的重要治療。我認為值得花一點時間來提供一些有關我們發布的優勢的額外背景信息。儘管我們知道需求被壓抑，但第四季度和第一季度仍然遠遠超出了我們的預期。正如預期的那樣，淨患者增加率已開始放緩。然而，我們仍然看到 ALS 患者和醫生的巨大需求。重要的是，無論是在頂級 ALS 中心還是更廣泛的神經病學界，我們仍然有很大的發展空間。

Now let me run through a few metrics that show our progress but also the growth opportunities ahead of us. By the end of the first quarter, approximately 65% of the top 500 U.S. prescribers and approximately 95% of (inaudible) ALS Centers have prescribed RELYVRIO to at least one person since launch. Prescribing remains fairly concentrated with roughly 80 prescribers mostly at major ALS Centers, representing approximately half of all RELYVRIO prescriptions during the quarter. While we are encouraged with these data points, we see an opportunity for broader and deeper uptick at (inaudible) ALS Centers and the opportunity to continue to penetrate the group of top prescribers. Additionally, we believe we have a large untapped opportunity for additional growth outside of this group of top prescribers as we expand our outreach and education efforts more broadly.

現在讓我回顧一下一些指標，這些指標不僅顯示了我們的進步，也顯示了我們面前的增長機會。截至第一季度末，自推出以來，美國前 500 名處方醫生中約 65% 以及約 95%（聽不清）的 ALS 中心已為至少一人開出 RELYVRIO 處方。處方仍然相當集中，大約 80 名處方者大多在主要的 ALS 中心，約佔本季度所有 RELYVRIO 處方的一半。雖然我們對這些數據點感到鼓舞，但我們看到了（聽不清）ALS 中心有更廣泛、更深入增長的機會，以及繼續滲透到頂級處方醫生群體的機會。此外，我們相信，隨著我們更廣泛地擴大外展和教育工作，我們在這組頂級處方醫師之外還有大量未開發的額外增長機會。

Our second priority is engaging with payers to work towards our goal of ensuring that every eligible person who can benefit from RELYVRIO has access as quickly and efficiently as possible. At the end of the first quarter, U.S. insurers representing approximately 50% of covered lives have published formal coverage policies, including many of the key national and regional plans. The vast majority of these insurers provide broad access to RELYVRIO.

我們的第二個優先事項是與付款人合作，努力實現我們的目標，即確保每個可以從 RELYVRIO 中受益的合格人員都能盡快、高效地使用。截至第一季度末，代表約 50% 承保人壽的美國保險公司已經發布了正式的承保政策，其中包括許多重要的國家和地區計劃。這些保險公司中的絕大多數都提供廣泛的 RELYVRIO 服務。

For people living with ALS who go through the medical exception process, we are pleased that approximately 80% of prior authorization requests have been approved on the first admission. We continue to see a wide range of people living with ALS in terms of time since initial diagnosis, interested in and gaining access to RELYVRIO. Our team remains engaged with insurers across the country, and we continue to anticipate most plans will formalize their policies during the first half of this year.

對於經歷醫療例外流程的 ALS 患者，我們很高興大約 80% 的事先授權請求在首次入院時就獲得了批准。自初次診斷以來，我們不斷看到大量 ALS 患者對 RELYVRIO 感興趣並獲得使用權。我們的團隊仍然與全國各地的保險公司保持聯繫，我們仍然預計大多數計劃將在今年上半年正式確定其政策。

Our third priority is ensuring eligible people living with ALS have positive interactions through their treatment journey with RELYVRIO, and ALS Clinics have positive interactions with Amylyx. This includes facilitating an organized, clear process to get people prescribed RELYVRIO, access to the therapy as quickly as possible and optimizing peoples' experience accessing RELYVRIO as best we can. Our team is working expeditiously to get people living with ALS, who have been prescribed RELYVRIO on therapy. In the first quarter, on average, it took about 30 days between receiving an enrollment form and RELYVRIO being shipped, down from a little more than 45 days in the fourth quarter, and we expect to make additional progress on this metric in the second quarter with the benefit of more insurers having formal coverage decisions.

我們的第三個優先事項是確保符合條件的 ALS 患者在 RELYVRIO 的治療過程中能夠進行積極的互動，並且 ALS 診所與 Amylyx 能夠進行積極的互動。這包括促進一個有組織、清晰的流程，讓人們開出 RELYVRIO 處方，盡快獲得治療，並儘可能優化人們使用 RELYVRIO 的體驗。我們的團隊正在迅速努力幫助 ALS 患者接受 RELYVRIO 治療。第一季度，從收到報名表到 RELYVRIO 發貨平均需要 30 天左右的時間，而第四季度為 45 天多一點，我們預計第二季度在這一指標上將取得更多進展受益於更多保險公司做出正式的承保決定。

In the limited cases where access hasn't been granted (inaudible) our Interim Access Program and our Patient Assistance Program are available for eligible patients. In the first quarter, roughly 10% of people taking RELYVRIO, were part of these programs. We are pleased with the progress we've made so far on our goal to ensure that every eligible person living with ALS, has access to RELYVRIO, which we see as a potential foundational therapy in neurodegenerative disease.

在未獲得訪問權限的有限情況下（聽不清），我們的臨時訪問計劃和患者援助計劃適用於符合條件的患者。第一季度，大約 10% 服用 RELYVRIO 的人參與了這些計劃。我們對迄今為止在確保每個符合條件的 ALS 患者都能獲得 RELYVRIO 的目標方面取得的進展感到高興，我們認為 RELYVRIO 是神經退行性疾​​病的潛在基礎療法。

Our launch is off to a strong start, and it is our hope that eventually, RELYVRIO will become the most commonly used ALS medication. While we are clearly focused on the launch of RELYVRIO in the U.S., we also have a large opportunity internationally. ALS is a global disease, affecting more than 200,000 people worldwide. Interest in ALBRIOZA remains high in Canada, and we continue to negotiate public insurance coverage, consistent with the expected public time lines for coverage.

我們的推出有一個良好的開端，我們希望最終 RELYVRIO 將成為最常用的 ALS 藥物。雖然我們顯然專注於在美國推出 RELYVRIO，但我們在國際上也有很大的機會。 ALS 是一種全球性疾病，影響全球超過 200,000 人。加拿大對 ALBRIOZA 的興趣仍然很高，我們將繼續就公共保險承保範圍進行談判，與預期的公共承保時間線保持一致。

In addition, a few weeks ago, we appointed Masako Nakamura to lead our efforts in Asia Pacific and Latin America as we pursue additional opportunities to bring AMX0035 to as many people with ALS globally as possible. Masako Nakamura brings 30 years of commercial, general management and operational leadership experience in the biopharmaceutical industry with a strong track record of introducing rare disease therapies worldwide across multiple therapeutic areas. We are very pleased that she decided to join our team to further explore opportunities for AMX0035 access around the world.

此外，幾週前，我們任命 Masako Nakamura 領導我們在亞太地區和拉丁美洲的工作，我們正在尋求更多機會，將 AMX0035 帶給全球盡可能多的 ALS 患者。 Masako Nakamura 在生物製藥行業擁有 30 年的商業、綜合管理和運營領導經驗，在全球多個治療領域推出罕見疾病療法方面擁有良好的記錄。我們很高興她決定加入我們的團隊，進一步探索 AMX0035 在全球範圍內的訪問機會。

I will now turn the call over to Josh to provide an important update on our R&D pipeline.

我現在將把電話轉給喬什，以提供有關我們研發渠道的重要更新。

Thanks, Margaret. We are very pleased with how quickly we are bringing our important new treatment to people with ALS. Our top focus day-to-day remains the success of our commercial launches. These efforts enable the continued investment needed to bring RELYVRIO to more people living with ALS worldwide. They also enable the research and development needed to advance our pipeline in support of our mission. There's tremendous scientific interest among the neurodegenerative community to further investigate AMX0035 in other diseases. We have a positive randomized clinical trial data in ALS, encouraging biomarker data from the randomized Phase II PEGASUS study in Alzheimer's disease (inaudible) preclinical models demonstrating the effects of AMX0035 in reducing neuronal death.

謝謝，瑪格麗特。我們對能夠如此迅速地為 ALS 患者提供重要的新療法感到非常高興。我們日常的首要關注點仍然是商業發布的成功。這些努力使得我們能夠持續投資，將 RELYVRIO 帶給全世界更多的 ALS 患者。它們還支持推進我們的產品線所需的研究和開發，以支持我們的使命。神經退行性疾​​病界對進一步研究 AMX0035 在其他疾病中的作用有著巨大的科學興趣。我們在 ALS 方面擁有積極的隨機臨床試驗數據，來自阿爾茨海默病（聽不清）臨床前模型的隨機 II 期 PEGASUS 研究的令人鼓舞的生物標誌物數據，證明了 AMX0035 在減少神經元死亡方面的作用。

To prioritize which diseases to focus on, we look at the following criteria: clear unmet need, strong scientific rationale, existing and robust understanding of the natural history of disease, biomarkers to track treatment effects, adjacencies and synergies with ALS, potential to move directly into a Phase III pivotal study and interest and support from KOLs. We are excited to announce today our plans to initiate a global pivotal Phase III study with AMX0035 in progressive supranuclear palsy or PSP, a disease which meets all of these criteria.

為了優先關注哪些疾病，我們會考慮以下標準：明確的未滿足需求、強有力的科學依據、對疾病自然史的現有和深入了解、跟踪治療效果的生物標誌物、與 ALS 的鄰近性和協同作用、直接轉移的潛力進入第三階段關鍵研究以及 KOL 的興趣和支持。我們今天很高興地宣布，我們計劃啟動一項 AMX0035 治療進行性核上性麻痺 (PSP) 的全球關鍵 III 期研究，這種疾病符合所有這些標準。

For those of you who may not be familiar with PSP, it is a rare, progressive and fatal neurodegenerative disorder that affects body movements, walking with imbalance, speech and swallowing and eye movement. It is typically fatal within just 5 to 8 years. The estimated prevalence is 5 to 7 in 100,000 people worldwide, translating to between roughly 15,000 to 20,000 people in the United States. There are currently no disease-modifying treatments for PSP.

對於那些可能不熟悉 PSP 的人來說，這是一種罕見的進行性致命的神經退行性疾​​病，會影響身體運動、不平衡行走、言語和吞嚥以及眼球運動。它通常會在 5 到 8 年內致命。據估計，全世界每 10 萬人中就有 5 到 7 人患有此病，換算成美國大約有 15,000 到 20,000 人患有該病。目前尚無針對 PSP 的疾病緩解治療方法。

In addition to PSP meeting our criteria for a significant unmet need with a well-characterized natural history, there is also a strong scientific rationale for the potential use of AMX0035 in treating PSP. PSP is both the disease of rapid and significant neurodegeneration, and its pathology is characterized by significant tau protein deposition in affected regions of the brain. In the PEGASUS Alzheimer's study of AMX0035, AMX0035 treatment demonstrated a statistically significant lowering of both phospho-tau181 and total tau in the CSF of people living with Alzheimer's disease.

除了 PSP 滿足我們對未滿足的重大需求且具有充分錶徵的自然史的標準之外，AMX0035 潛在用於治療 PSP 也有強有力的科學依據。 PSP 是一種快速且顯著的神經退行性疾​​病，其病理學特徵是受影響的大腦區域有大量 tau 蛋白沉積。在 AMX0035 的 PEGASUS 阿爾茨海默氏症研究中，AMX0035 治療顯示阿爾茨海默氏症患者腦脊液中磷酸 tau181 和總 tau 的統計顯著降低。

AMX0035 is an oral, well-tolerated, FDA-approved medication for ALS, that has been shown preclinically to protect neurons against degeneration and clinical to lower tau, the hallmark protein of PSP. This has led to significant and strong support from key opinion leaders in PSP, and we are excited to work with them to test AMX0035 in a Phase III study, which I will now outline.

AMX0035 是一種經 FDA 批准的口服、耐受性良好的 ALS 治療藥物，臨床前已證明該藥物可保護神經元免受變性，臨床上可降低 PSP 的標誌蛋白 tau 蛋白。這得到了 PSP 關鍵意見領袖的大力支持，我們很高興與他們合作在 III 期研究中測試 AMX0035，我現在將概述該研究。

In designing and planning the study, we have collaborated with key global academic leaders, people living with PSP and advocacy groups working in this field. With an open IND in hand, we plan to enroll approximately 600 people in a randomized, placebo-controlled study, making this likely the largest PSP trial to date. We expect to have the study up and running by the end of this year. We are hopeful that we can provide a new treatment option, especially since there are currently no disease-modifying treatments available for this devastating disease. While we prepare to launch our pivotal Phase III study, we also remain hard at work in Wolfram syndrome.

在設計和規劃這項研究時，我們與全球主要學術領袖、PSP 患者以及該領域的倡導團體合作。有了開放式 IND 後，我們計劃招募約 600 人參與一項隨機、安慰劑對照研究，這可能是迄今為止規模最大的 PSP 試驗。我們預計該研究將在今年年底啟動並運行。我們希望能夠提供一種新的治療選擇，特別是因為目前還沒有針對這種毀滅性疾病的疾病緩解療法。在我們準備啟動關鍵的 III 期研究的同時，我們仍在努力研究 Wolfram 綜合徵。

Earlier this year, we announced HELIOS, a Phase II trial studying AMX0035 in Wolfram syndrome. This study is now enrolling participants. Wolfram syndrome is a disease that leads to multisystem failure, resulting in blindness, deafness, diabetes, ataxia, neurodegeneration and often death in early adulthood. Several papers characterize the disease is a prototypical disease of endoplasmic reticulum stress. And as we have discussed in the past, we believe AMX0035 plays a role in reducing ER stress. Data on AMX0035 in models of Wolfram syndrome were published in the Journal of Clinical Investigation Insight. We believe this study will provide key data to guide future studies and expect top line results from the study next year. Importantly, we are also investing in new ALS research to continue to transform how the disease is treated.

今年早些時候，我們宣布了 HELIOS，這是一項研究 AMX0035 治療 Wolfram 綜合徵的 II 期試驗。這項研究現在正在招募參與者。沃爾弗拉姆綜合徵是一種導致多系統衰竭的疾病，導致失明、耳聾、糖尿病、共濟失調、神經退行性變，甚至常常在成年早期死亡。幾篇論文描述該疾病是內質網應激的典型疾病。正如我們過去所討論的，我們相信 AMX0035 在減輕 ER 壓力方面發揮著作用。 Wolfram 綜合徵模型中 AMX0035 的數據發表在《Journal of Clinical Investigation Insight》上。我們相信這項研究將為指導未來的研究提供關鍵數據，並預計明年的研究結果。重要的是，我們還在投資新的 ALS 研究，以繼續改變該疾病的治療方式。

We believe that it is going to take a combination approach, targeting multiple cellular pathways implicating a disease pathogenesis to make ALS more and more manageable and ultimately, to find a cure. For this reason, we are investigating other therapies with different or potentially complementary pathways to treat ALS and other neurodegenerative diseases. This includes an antisense oligonucleotide called AMX0114 that our internal R&D team has developed. IND-enabling studies of AMX0114 are underway and progressing well. We continue to expect to build our pipeline, both through internal and external sources.

我們相信，將採取組合方法，針對涉及疾病發病機制的多種細胞途徑，使 ALS 變得越來越易於控制，並最終找到治療方法。因此，我們正在研究具有不同或潛在互補途徑的其他療法來治療 ALS 和其他神經退行性疾​​病。其中包括我們內部研發團隊開發的名為 AMX0114 的反義寡核苷酸。 AMX0114 的 IND 研究正在進行中，並且進展順利。我們繼續期望通過內部和外部來源建立我們的管道。

Before turning the call over to Jim, I wanted to share the PHOENIX, our Phase III study of AMX0035 in people with ALS, continues to progress as planned. In February, we announced that the study was fully enrolled with 664 participants. A reminder that there will be no interim data read-out, and we expect data on the primary outcome and several secondary outcomes in mid-2024. Overall survival data will take another year or more to mature and therefore, won't be available until at least mid-2025.

在將電話轉給 Jim 之前，我想分享一下 PHOENIX，我們在 ALS 患者中進行的 AMX0035 III 期研究，繼續按計劃取得進展。 2 月份，我們宣布該研究已全部入組，共有 664 名參與者。提醒您，不會有中期數據讀出，我們預計將在 2024 年中期公佈主要結局和若干次要結局的數據。總體生存數據還​​需要一年或更長時間才能成熟，因此至少要到 2025 年中期才能獲得。

I will now turn the call over to Jim to review our financial results for the first quarter.

我現在將電話轉給吉姆，以審查我們第一季度的財務業績。

Thanks, Josh. We're encouraged by the strong interest and demand we continue to see from the ALS community. From a financial point of view, our business is strong.

謝謝，喬什。我們不斷看到 ALS 社區的強烈興趣和需求，這讓我們深受鼓舞。從財務角度來看，我們的業務很強勁。

Net product revenue was $71.4 million for the quarter, compared to net product revenue of $21.9 million for the fourth quarter of 2022, with the vast majority of that revenue from the United States. Gross to net adjustments were approximately 16% in the quarter, consistent with our expectations in the 15% to 20% range.

本季度產品淨收入為 7140 萬美元，而 2022 年第四季度產品淨收入為 2190 萬美元，其中絕大多數收入來自美國。本季度毛淨調整約為 16%，與我們 15% 至 20% 的預期一致。

Inventory levels at the quarter end were as expected, with approximately 2 weeks of inventory in the channel at specialty pharmacies. Cost of sales were $5.3 million for the quarter and in the range of our expectations as sales volume grow. And for modeling purposes, keep in mind that roughly 10% of the people on RELYVRIO are receiving it for free through either our Interim Access Program or Patient Assistance Program.

季度末的庫存水平符合預期，專科藥房的渠道庫存量約為兩週。該季度的銷售成本為 530 萬美元，隨著銷量的增長，處於我們的預期範圍內。出於建模目的，請記住，RELYVRIO 上大約 10% 的人通過我們的臨時訪問計劃或患者援助計劃免費接收它。

Research and development expenses were $24.2 million for the quarter compared to $21.5 million for the same period in 2022. These costs were primarily driven by our Phase III PHOENIX study and added personnel as we support our programs. Starting in the second quarter, we expect R&D expenses will increase as we incur meaningful expenses to initiate our Phase III pivotal study in PSP. You should expect R&D expenses to increase this year in a range of $30 million to $40 million per quarter as we move through the remainder of the year.

本季度的研發費用為 2420 萬美元，而 2022 年同期為 2150 萬美元。這些成本主要是由我們的 III 期 PHOENIX 研究以及我們支持項目時增加的人員造成的。從第二季度開始，我們預計研發費用將會增加，因為我們會產生大量費用來啟動 PSP 的 III 期關鍵研究。隨著今年剩餘時間的推移，今年的研發費用預計每季度將增加 3000 萬至 4000 萬美元。

Selling, general and administrative expenses, or SG&A, were $44 million for the quarter compared to $26.3 million for the same period in 2022. We're investing in SG&A to support our strong commercial launch and expect our spend to settle in around $45 million per quarter for the remainder of the year. Overall, we're very pleased with our results this quarter, including achieving $1.6 million of net income, just 2 quarters into our launch.

本季度的銷售、一般和管理費用 (SG&A) 為 4400 萬美元，而 2022 年同期為 2630 萬美元。我們正在投資 SG&A 以支持我們強勁的商業發布，預計我們的支出將穩定在每季度 4500 萬美元左右。今年剩餘時間的季度。總體而言，我們對本季度的業績非常滿意，包括在推出後僅 2 個季度就實現了 160 萬美元的淨利潤。

I want to pause a moment on our overall financial results. With the strong demand for RELYVRIO driving near-term profitability ahead of our expectations, we want to reiterate our long-term financial goal. Driving top line revenue as RELYVRIO becomes standard of care, growing profitability for our investors and investing in a pipeline that has the potential to provide much-needed treatments for neurodegenerative diseases.

我想暫停一下我們的整體財務業績。由於對 RELYVRIO 的強勁需求推動近期盈利能力超出我們的預期，我們希望重申我們的長期財務目標。隨著 RELYVRIO 成為護理標準，我們將推動營收增長，為我們的投資者帶來更高的盈利能力，並投資於有潛力為神經退行性疾​​病提供急需治療的管道。

We're well positioned to build a profitable, financially strong organization for the long term. We ended the quarter with cash and short-term investments of $345.7 million and zero debt. So we're currently in a position to fund the programs we discussed today without the need to raise additional capital.

我們有能力建立一個長期盈利、財務實力雄厚的組織。本季度結束時，我們的現金和短期投資為 3.457 億美元，債務為零。因此，我們目前能夠為我們今天討論的項目提供資金，而無需籌集額外資金。

Finally, just a word on guidance. Last quarter, we gave some specific guidance on how the first quarter was going as we reported in mid-March. Since we're still early in the quarter, it's premature to provide a specific range of revenue guidance for the second quarter or for the full year at this time. The road ahead over the next few quarters is fairly simple, execute on the launch and execute on our clinical and pipeline development programs. I'm excited about the progress that we've made, and most importantly, our ability to have a positive impact on the lives of so many people living with ALS.

最後，簡單說一下指導。上個季度，我們對第一季度的進展情況給出了一些具體指導，正如我們在 3 月中旬報告的那樣。由於我們仍處於本季度初期，因此現在為第二季度或全年提供具體的收入指導範圍還為時過早。接下來幾個季度的前進道路相當簡單，即在啟動時執行並執行我們的臨床和管道開發計劃。我對我們所取得的進展感到興奮，最重要的是，我們有能力對這麼多 ALS 患者的生活產生積極影響。

With that, I'll turn the call over to Justin for some closing remarks.

接下來，我將把電話轉給賈斯汀，讓他做一些結束語。

Thanks, Jim, and thank you to everyone for joining us today. We covered a lot of exciting news. Our commercial ramp in the U.S. and Canada is proceeding very well, and we will know more on Europe later this year.

謝謝吉姆，也感謝大家今天加入我們。我們報導了很多令人興奮的消息。我們在美國和加拿大的商業擴張進展順利，今年晚些時候我們將對歐洲有更多了解。

We are expanding our clinical pipeline into PSP, a market that is likely as large as ALS with a product that has already been shown to have a favorable safety profile in another disease and that has a demonstrated effect on relevant biomarkers. And we achieved our first quarter of profitability in just the second quarter of our commercial launch in the U.S. We remain committed to our goal to help additional people with ALS and other relentlessly progressive neurodegenerative diseases, gain access to new therapies. Now we'd be happy to take your questions.

我們正在將我們的臨床管道擴展到 PSP，這個市場可能與 ALS 一樣大，其產品已被證明在另一種疾病中具有良好的安全性，並且對相關生物標誌物具有明顯的效果。我們在美國商業推出後的第二季度就實現了第一季度的盈利。我們仍然致力於實現我們的目標，幫助更多患有 ALS 和其他持續進行性神經退行性疾​​病的患者獲得新療法。現在我們很樂意回答您的問題。

Operator, please open the call up to Q&A.

接線員，請打開電話進行問答。

(Operator Instructions) The first question comes from (inaudible) with Bank of America.

（操作員說明）第一個問題來自（聽不清）美國銀行。

Great. This is (inaudible) on for Geoffrey Meacham. So I have 2 questions, please. The first one is, you mentioned that the rate of the pace has moderated (inaudible) going to perhaps the second quarter. Can you just provide more clarity on that? And my second question, just can you provide little more details with regard the payer discussions that you have and kind of what's your expectation for the remainder of the year?

偉大的。這是（聽不清）杰弗裡·米查姆的發言。所以我有兩個問題。第一個是，您提到節奏可能會放緩（聽不清），可能會持續到第二季​​度。您能否更清楚地說明這一點？我的第二個問題，您能否提供有關付款人討論的更多細節以及您對今年剩餘時間的期望是什麼？

Sure. So this is Margaret. Thank you very much for your question. And we continue to be incredibly pleased with our launch to date and more importantly, our ability to bring a new treatment option and hope to the ALS community, especially given that this is the first product to demonstrate in a clinical trial, a statistically significant benefit in both function and survival. So maybe if I could just reiterate a few key points. We ended the quarter with roughly 3,000 patients, again, double what we started with at the beginning of the quarter. And that's about 10% of the 29,000 patients living with ALS. So not surprisingly, our net patient adds can't double forever. So in Q2, we are expecting the number will be lower than what we delivered in Q4 and Q1. I think more importantly, we continue to see significant interest in demand for RELYVRIO, both from patients and HCP, and we have a tremendous opportunity for us to grow both in depth and breath at all the (inaudible) ALS Centers as well as the broader neurology community.

當然。這就是瑪格麗特。非常感謝您的提問。我們仍然對迄今為止的推出感到非常滿意，更重要的是，我們有能力為 ALS 社區帶來新的治療選擇和希望，特別是考慮到這是第一個在臨床試驗中證明的產品，具有統計上顯著的益處在功能和生存方面。所以也許我可以重申一些關鍵點。本季度末，我們的患者數量約為 3,000 名，再次是本季度初的兩倍。這大約佔 29,000 名 ALS 患者的 10%。因此，毫不奇怪，我們的淨患者補充道不可能永遠翻倍。因此，我們預計第二季度的數量將低於第四季度和第一季度的交付量。我認為更重要的是，我們繼續看到患者和 HCP 對 RELYVRIO 的需求表現出濃厚的興趣，並且我們有巨大的機會在所有（聽不清）ALS 中心以及更廣泛的領域進行深度和呼吸的發展神經病學界。

And then the second question was on payers. And again, we're very pleased with the progress we're making with payers with 50% of the covered lives to date, having a published policy, and we expect that to only get better over the first half of the year.

第二個問題是關於付款人的。再說一次，我們對迄今為止與 50% 的受保人的付款人取得的進展感到非常滿意，並製定了已發布的保單，我們預計這一情況只會在今年上半年有所改善。

The next question is from Michael DiFiore with Evercore.

下一個問題來自 Evercore 的 Michael DiFiore。

Congrats on the quarter. A few for me. The first question I have as a follow-up to the previous one. Now that more commercial payers have come on board and given the fact that you said that the rate of net patient adds is beginning to moderate. Could you perhaps provide any updated views on how big this initial (inaudible) of patients could be and how long it could last before you achieve a steady-state trajectory of new starts? That's my first question.

恭喜本季度。給我幾個。我的第一個問題是前一個問題的後續問題。現在，更多的商業付款人已經加入，並且考慮到您所說的淨患者增加率開始放緩。您能否就最初（聽不清）的患者規模以及在實現新開始的穩態軌蹟之前可以持續多長時間提供任何最新觀點？這是我的第一個問題。

And the second one is regarding the Phase III PHOENIX trial. You mentioned that the OS data is going to take at least a year more to read out and that it's a critical endpoint. So if we assume conditional approval in the EU based on CENTAUR and the statistically significant benefit on ALSFRS in PHOENIX, are you expecting EMA to still maintain their conditional approval until the OS data finally comes in? And could there be a scenario when full EU approval could be granted based on just positive ALSFRS data alone?

第二個是關於 PHOENIX III 期試驗。您提到操作系統數據至少需要一年的時間才能讀取，並且這是一個關鍵端點。因此，如果我們假設歐盟基於 CENTAUR 的有條件批准以及 PHOENIX 的 ALSFRS 的統計顯著效益，您是否期望 EMA 仍維持其有條件批准，直到 OS 數據最終到來？是否存在一種情況，僅根據積極的 ALSFRS 數據就可以獲得歐盟的全面批准？

Great. Thank you. This is Margaret again. Thanks for your question. Regarding the bolus, it's really too early to tell when the bolus will finish. But what I can say is that we know in Q4 and in Q1, we did see that high level of demand due to the pent-up demand that we had and they were quite frankly, even ahead of our expectations. So we have begun to see the rate in new patient adds moderate. But again, I want to reiterate, we have a tremendous opportunity for growth because even within the key accounts that we penetrated and just to remind you of some of the metrics, we said 95% of all the key ALS Centers have prescribed for at least one patient. Every account, you see one account, you see one account, right? It's a typical rare disease. So some accounts are highly penetrated and some accounts have a great deal of room ahead of us to penetrate and we really have just started to get out into the broader neurology community. So again, we see tremendous growth ahead of us to serve all the remaining patients that are depending on us.

偉大的。謝謝。這又是瑪格麗特。謝謝你的提問。關於推注，現在判斷推注何時完成還為時過早。但我可以說的是，我們知道在第四季度和第一季度，由於我們被壓抑的需求，我們確實看到了高水平的需求，坦率地說，甚至超出了我們的預期。因此，我們已經開始看到新患者的發病率適度增加。但我想再次重申，我們有巨大的增長機會，因為即使在我們滲透的關鍵客戶中，只是為了提醒您一些指標，我們說 95% 的所有關鍵 ALS 中心至少規定了一名患者。每個帳戶，您看到一個帳戶，您看到一個帳戶，對吧？這是一種典型的罕見病。因此，有些賬戶的滲透率很高，有些賬戶的滲透率還有很大的空間，我們確實剛剛開始進入更廣泛的神經病學社區。因此，我們再次看到，為所有依賴我們的剩餘患者提供服務，我們將面臨巨大的增長。

Yes. Mike, this is Justin. Thanks for the question. So first, just sort of baseline for everyone. So we continue to expect an opinion from the CHMP midyear and decision at the earliest in the third quarter. And in the meantime, our team is preparing for approval and launch. So in terms of the PHOENIX trial and how that could affect the conditional approval, so the way that the EMA (inaudible), we won't know if it's a conditional approval or full approval until we get the final decision. But in terms -- but our expectations is on the conditional marketing authorization. So the way that, that works is that you get approval, but with the condition that you do a follow-on study. And in this case, our expectation would be that it would be the PHOENIX trial. And then you have to renew that every single year until you meet the condition.

是的。邁克，這是賈斯汀。謝謝你的提問。首先，為每個人提供一個基線。因此，我們繼續期待 CHMP 年中提出意見，並最早在第三季度做出決定。與此同時，我們的團隊正在準備批准和啟動。因此，就 PHOENIX 試驗以及它如何影響有條件批准而言，以及 EMA（聽不清）的方式，在我們做出最終決定之前，我們不會知道這是有條件批准還是完全批准。但就條款而言，我們的期望是有條件的營銷授權。因此，有效的方法是您獲得批准，但條件是您需要進行後續研究。在這種情況下，我們的預期是 PHOENIX 試驗。然後你必須每年更新，直到滿足條件。

So then the question is, will we meet the condition depending on the ALSFRS functional results or the survival results. And that's really up to the regulators. What I will say, high level, though, is that if we have a functional benefit, if we have a survival benefit (inaudible) it's the best data anyone has seen in ALS. So I think either is a very positive situation. But ultimately, it's up to the CHMP and EMA.

那麼問題來了，我們是否滿足取決於ALSFRS功能結果或生存結果的條件。這實際上取決於監管機構。不過，我想說的是，如果我們有功能上的好處，如果我們有生存上的好處（聽不清），那麼這就是任何人在 ALS 中見過的最好的數據。所以我認為這兩者都是非常積極的情況。但最終，這取決於 CHMP 和 EMA。

The next question is from Corinne Jenkins with Goldman Sachs.

下一個問題來自高盛的科琳·詹金斯 (Corinne Jenkins)。

Maybe a couple from us. I guess, one, with more than 3,000 patients now on drug up from the 1,300, even understanding that there could be some moderation. How long are you thinking it will take you from here to get to the 10,000 patients you had stated as a target for being stable on therapy at steady state?

也許是我們當中的一對。我猜想，一是目前接受藥物治療的患者數量從 1,300 多人增加到了 3,000 多人，甚至了解到可能會有所節制。您認為您需要多長時間才能達到您所說的 10,000 名患者在穩定狀態下穩定治療的目標？

Maybe the second one for me is just given the clinical priorities that will be initiated. Do you expect to maintain profitability through the balance of the year? And then the final one, just could you talk through the rationale of moving straight into a large Phase III program in PSP without doing sort of like an earlier stage Phase II or otherwise, and help us understand the relevant clinical endpoints throughout indication.

也許對我來說第二個就是考慮將要啟動的臨床優先事項。您預計今年剩餘時間內保持盈利能力嗎？最後一個問題，您能否談談直接進入 PSP 大型 III 期項目而不進行類似早期 II 期或其他項目的基本原理，並幫助我們了解整個適應症的相關臨床終點。

Sure, Corinne. So I'll take the first question, and then I'll turn it over to Josh and Justin and probably Jim as well. So just -- we have not provided a time line on how long it will take us to achieve the 10,000 patients. Our goal of getting to the 10,000 patients really reflects our vision that RELYVRIO will become the most commonly used ALS medication, so basically standard of care. And we feel that that's very achievable, given it is the first product to demonstrate a benefit on both function and survival. I will tell you that right now, we are heavily focused on the launch execution with the goal of getting there as quickly as possible because patients are depending on us.

當然，科琳娜。所以我將回答第一個問題，然後我會將其交給喬什和賈斯汀，可能還有吉姆。所以，我們還沒有提供一個時間表來說明我們需要多長時間才能達到 10,000 名患者的目標。我們覆蓋 10,000 名患者的目標確實反映了我們的願景，即 RELYVRIO 將成為最常用的 ALS 藥物，因此基本上是護理標準。我們認為這是非常可以實現的，因為它是第一個在功能和生存方面都表現出優勢的產品。我要告訴你的是，現在我們主要專注於啟動執行，目標是盡快實現這一目標，因為患者依賴我們。

And maybe I'll turn it over to -- yes, go for it, Jim, sorry.

也許我會把它交給——是的，繼續吧，吉姆，抱歉。

Yes. Yes. Sorry, Josh. I'll take the next one on profitability. We decided not to guide at this stage, Corinne.So that will include also not guiding on profitability because essentially, obviously, that's guidance. But I think you all can see the math in terms of the hydraulics in our P&L. And as long as we can go revenue faster than we grow expenses, we'll be able to maintain that profitability. I think importantly for us, longer term, it just really highlights the opportunity we have in this business and how unique the ALS market is. And ultimately, I think we have to recognize it's the need of the patients that's driving this launch and the fact of the matter of the data that we have with RELYVRIO. So we're going to continue to focus on our long-term goals, as I tried to outline in the prepared remarks, making RELYVRIO the #1 ALS therapy, that's first and foremost, driving long-term profitability for our investors, right, because that's how we get to be a sustainable business long term.

是的。是的。對不起，喬什。下一篇我將討論盈利能力。 Corinne，我們決定在現階段不提供指導。因此，這也包括不提供盈利能力指導，因為本質上，顯然，這就是指導。但我想你們都可以在我們的損益表中看到液壓方面的數學原理。只要我們的收入增長速度快於支出增長速度，我們就能夠保持盈利能力。我認為對我們來說很重要的是，從長遠來看，它真正凸顯了我們在這項業務中擁有的機會以及 ALS 市場的獨特性。最終，我認為我們必須認識到，推動此次發布的是患者的需求，以及我們通過 RELYVRIO 獲得的數據的事實。因此，我們將繼續關注我們的長期目標，正如我在準備好的發言中試圖概述的那樣，使 RELYVRIO 成為排名第一的 ALS 療法，這首先是為我們的投資者帶來長期盈利能力，對吧，因為這就是我們如何成為一家長期可持續發展的企業。

And I think that's also another thing that differentiates us from a lot of other companies out there. We don't need to continue to go back to the market to fund our business because of how well the launch is going and the interest that we're seeing in the community.

我認為這也是我們與許多其他公司的不同之處。我們不需要繼續回到市場來為我們的業務提供資金，因為發布的進展情況以及我們在社區中看到的興趣。

But then also, we're going to invest in our pipeline because there's a real need in neurodegenerative diseases. And I think we can do all 3, which is what makes me so excited to be here at Amylyx at this time. Josh, back to you.

但我們也會投資我們的產品線，因為神經退行性疾​​病確實有需求。我認為我們可以做到這三點，這就是讓我此時來到 Amylyx 感到如此興奮的原因。喬什，回到你身邊。

Thanks, Jim. And so talking about PSP. So I think the first thing I can share is, over the last several years, we've gone through a process internally to try to select those indications that are highest priority for the company. And I outlined some of the things that we look at for that. But most importantly, PSP met all of the criteria that we were looking at for an indication to prioritize as a company, and we already have shown in a randomized placebo-controlled study data against what is thought to be the primary pathology of progressive supranuclear palsy. And so I think that's part of what's driving our excitement as well as the excitement we're hearing from the KOLs and the community about this indication (inaudible) there's also some preclinical data that's also supporting and making us excited here. But I think it's that constellation of factors that makes us really excited to go into this PSP study.

謝謝，吉姆。說到PSP。因此，我認為我可以分享的第一件事是，在過去幾年中，我們在內部經歷了一個流程，試圖選擇公司最優先考慮的那些適應症。我概述了我們為此考慮的一些事情。但最重要的是，PSP 滿足了我們作為一家公司優先考慮的適應症的所有標準，並且我們已經在一項隨機安慰劑對照研究中顯示了針對被認為是進行性核上性麻痺的主要病理學的數據。因此，我認為這是推動我們興奮的部分原因，也是我們從 KOL 和社區那裡聽到的關於這一跡象的興奮（聽不清），還有一些臨床前數據也支持並讓我們感到興奮。但我認為正是這一系列因素讓我們對這項 PSP 研究感到非常興奮。

The next question is from Neena Bitritto-Garg with Citi.

下一個問題來自花旗銀行的 Neena Bitritto-Garg。

Congrats on the update. So just in terms of trying to figure out this bolus. Can you talk a little bit about what you're seeing in terms of (inaudible) versus net adds. I'm just curious if you can talk about the trend you're seeing there. And then give us any color on duration of therapy so far or any dropouts that you're seeing, that would be great.

恭喜更新。所以只是想弄清楚這個丸劑。您能否談談您所看到的（聽不清）與淨增加方面的情況。我只是好奇你能否談談你在那裡看到的趨勢。然後給我們任何有關迄今為止治療持續時間或您所看到的任何退出的信息，那就太好了。

Yes. So we're not providing any guidance on the number of patients for the quarter. Again, I'll just go back to, we think our net patient adds, they can't double forever. So we'll be lower in Q2 than we've been able to deliver in Q4, Q1 because we believe that, that was the initial pent-up demand. Again, we don't know when that bolus will be over, so it's hard for us to really give any guidance on that.

是的。因此，我們不會提供有關本季度患者數量的任何指導。再說一遍，我想回到我們的網絡患者補充說，它們不可能永遠加倍。因此，我們第二季度的交付量將低於第四季度、第一季度的交付量，因為我們相信，這是最初被壓抑的需求。同樣，我們不知道該補充何時會結束，因此我們很難真正就此提供任何指導。

In terms of duration of treatment, it's really too early in the launch to give that. I mean the first patients who started on therapy were basically at the end of October, beginning in November. So they really haven't been on therapy long enough for us to give any clarification there.

就治療持續時間而言，現在就給出這個結論還為時過早。我的意思是，第一批開始治療的患者基本上是在十月底、十一月份開始的。所以他們接受治療的時間確實不夠長，我們無法對此做出任何澄清。

In terms of discontinuation rates, that's sort of similar as well. People just haven't been on therapy long enough. I can tell you that the general trends that we're seeing are kind of in line with what we saw with CENTAUR. Nothing is out of line there. And just as a reminder, with CENTAUR, we're seeing roughly about a 25% discontinuation rate at 6 months. So again, patients haven't really been on therapy for 6 months yet. So we're going to continue to monitor that very closely.

就停藥率而言，這也有點相似。人們只是接受治療的時間不夠長。我可以告訴你，我們看到的總體趨勢與我們在 CENTAUR 上看到的趨勢是一致的。那裡沒有什麼不正常的。提醒一下，對於 CENTAUR，我們看到 6 個月時大約有 25% 的停藥率。再說一遍，患者已經有 6 個月沒有真正接受治療了。因此，我們將繼續密切監視這一情況。

The next question is from Marc Goodman.

下一個問題來自馬克·古德曼。

Can you talk about the mechanism for AMX0114? And then second, just the data support the Wolfram study and the recent -- the rationale for moving there?

您能談談AMX0114的機制嗎？其次，只有數據支持 Wolfram 研究和最近的研究——搬到那裡的理由是什麼？

Sure. So first on AMX0114. So AMX0114 is an antisense oligonucleotide targeting calpain-2. So there's a pathway called Wallerian degeneration, that's been around since the 1850s, which is the pathway whereby a neuron will destroy its own axon in response to injury or stress. And that pathway over the last 150 years, the pharmacology has become pretty clear on what proteins need to be activated and otherwise for that axonal degeneration to occur. And what you'll find digging into Wallerian degeneration pathway is that calpain-2 is one of the key proteins involved in that. And then in addition, there's been preclinical studies with both kind of knock-in models and knock-out models that have shown that calpain-2 inhibition can be effective in several animal models of ALS.

當然。首先是 AMX0114。因此AMX0114是一種靶向calpain-2的反義寡核苷酸。因此，有一種稱為華勒變性的途徑，自 1850 年代以來就一直存在，通過這種途徑，神經元會因受傷或壓力而破壞自己的軸突。在過去 150 年裡，藥理學已經非常清楚地知道哪些蛋白質需要被激活，否則軸突變性就會發生。深入研究華勒變性途徑，您會發現 calpain-2 是其中涉及的關鍵蛋白質之一。此外，針對敲入模型和敲除模型的臨床前研究表明，calpain-2 抑制對多種 ALS 動物模型有效。

And then finally, there's a lot of evidence out there linking calpain-2 to different ALS biomarkers, including TDP-43. And then turning to Wolfram. So Wolfram, as we shared in the last conference call, is a space we've done at least 4 years of preclinical work together with Washington University and Dr. Fumihiko Urano there. And broadly, those experiments studied both cellular models of the disease as well as an animal model of the disease. Much of that data is published in the Journal of Clinical Investigation Insight. But broadly, what we saw was some degree of rescue of the phenotype, both in the cellular models as well as in the animal model. So I think that was the data that got us really excited to go forward there.

最後，有大量證據表明 calpain-2 與不同的 ALS 生物標誌物（包括 TDP-43）相關。然後轉向沃爾夫勒姆。因此，正如我們在上次電話會議中分享的那樣，Wolfram 是一個我們與華盛頓大學和那裡的 Fumihiko Urano 博士一起進行了至少 4 年臨床前工作的空間。從廣義上講，這些實驗研究了該疾病的細胞模型以及該疾病的動物模型。其中大部分數據發表在《臨床研究洞察雜誌》上。但總的來說，我們看到的是在細胞模型和動物模型中對錶型的某種程度的拯救。所以我認為正是這些數據讓我們非常興奮地繼續前進。

The next question is from Graig Suvannavejh with Mizuho Securities.

下一個問題來自瑞穗證券 (Mizuho Securities) 的 Graig Suvannavejh。

Congratulations on the quarterly results. I've got 2 questions, if I could. First is more commercially related, the second pipeline related. So on commercial, do you have any sense in these early days kind of how the drug is being used in patients? And by that, do you have a sense of distribution of its use, whether what percent is in monotherapy versus some combination setting versus a potential triple combination? Any thoughts there would be great. And then on the pipeline, I just had a question on the new Phase III PSP study. And maybe it's a twofold question. First, in light that there have been attempts in PSP in the past, one was with an anti-tau antibody. Is it really just the movement on markers that gives you confidence that it will be able to work in PSP? Is there some other elements? And then maybe the part B of that is, is the strategy more biomarker-driven in terms of kind of the momentum we're seeing in the neurodegenerative space and how FDA seems to be very open and receptive to biomarker-driven strategies?

祝賀季度業績。如果可以的話，我有兩個問題。第一個與商業相關，第二個與管道相關。那麼在商業方面，您對早期如何在患者身上使用該藥物有什麼了解嗎？由此，您是否了解其使用的分佈情況，無論是單一療法、某種組合療法還是潛在的三重組合療法的百分比是多少？任何想法都會很棒。然後在管道上，我剛剛對新的 III 期 PSP 研究有一個問題。也許這是一個雙重問題。首先，鑑於過去曾在 PSP 方面進行過嘗試，其中之一是使用抗 tau 抗體。難道真的只是標記上的移動讓你相信它能夠在 PSP 上運行嗎？還有其他一些元素嗎？那麼，也許其中的 B 部分是，就我們在神經退行性領域看到的勢頭而言，該策略是否更加由生物標誌物驅動，以及 FDA 似乎對生物標誌物驅動的策略非常開放和接受？

Yes. So I'll take your first question. I would say that regarding the use whether or not it's monotherapy or combination therapy, it's really a broad mix from single use of RELYVRIO to combination therapy with all 3 available products. And we're really seeing the utilization in a very broad patient population. So we continue to see patients that have been diagnosed with this disease for many years, get prescribed this drug as well as newly diagnosed patients. And we define newly diagnosed patients as patients who have been diagnosed in the last 6 months. I would say from an ease of access perspective, some physicians may start first with riluzole, and then they'll switch to or add RELYVRIO to riluzole just because again, it could take -- it was taking up to 30 days last quarter in Q1 for a patient to get access to the drug from the time to enrollment on average. And again, we expect that to continue to improve as more policies come on board.

是的。那麼我來回答你的第一個問題。我想說的是，無論是單一療法還是聯合療法，它實際上是一個廣泛的組合，從單一使用 RELYVRIO 到與所有 3 種可用產品的聯合療法。我們確實看到了它在非常廣泛的患者群體中的應用。因此，我們繼續看到多年來被診斷患有這種疾病的患者以及新診斷的患者都服用了這種藥物。我們將新確診患者定義為過去6個月內確診的患者。我想說，從易於使用的角度來看，一些醫生可能會首先使用利魯唑，然後他們會改用 RELYVRIO 或將 RELYVRIO 添加到利魯唑中，因為同樣，這可能需要 - 上個季度第一季度需要長達 30 天的時間患者從入組到平均獲得藥物的次數。再次，我們預計隨著更多政策的出台，這種情況將繼續改善。

And Graig, thanks for the question on PSP. This is Justin. And yes. I mean first, I would say, I think the PSP community and especially the key opinion leaders are really excited about this. I mean in RELYVRIO, we have an oral safe drug that's FDA-approved for another neurodegenerative disease.

Graig，謝謝你在 PSP 上提出的問題。這是賈斯汀。是的。我的意思是，首先，我認為 PSP 社區，尤其是關鍵意見領袖對此感到非常興奮。我的意思是，在 RELYVRIO 中，我們有一種口服安全藥物，已獲得 FDA 批准用於治療另一種神經退行性疾​​病。

And then in terms of the rationale for PSP, preclinically, we've shown that AMX0035 protects against neurodegeneration. PSP is a rapidly progressive neurodegenerative disease. And then clinically, we showed the very significant reductions in tau in our Alzheimer's study. And while, yes, there have been antibodies against tau that were unsuccessful in PSP. PSP is still a tauopathy. That's the canonical protein associated with it.

然後就 PSP 的基本原理而言，在臨床前，我們已經證明 AMX0035 可以預防神經退行性變。 PSP 是一種快速進展的神經退行性疾​​病。然後在臨床上，我們在阿爾茨海默病研究中發現 tau 蛋白顯著減少。當然，確實存在針對 tau 蛋白的抗體，但在 PSP 中並未成功。 PSP 仍然是一種 tau 蛋白病。這就是與之相關的典型蛋白質。

In terms of the study design, we're not going to get into that today. But I think it's really all of the above that makes us and probably more importantly, the key opinion leaders so excited about the study in PSP. So we'll continue to share more on that, but we're really excited about starting that study.

就研究設計而言，我們今天不打算討論這個問題。但我認為正是上述所有因素讓我們，也許更重要的是，關鍵意見領袖對 PSP 的研究如此興奮。因此，我們將繼續分享更多相關信息，但我們對開始這項研究感到非常興奮。

The last question comes from Ananda Ghosh with H.C. Wainwright.

最後一個問題來自 Ananda Ghosh 和 H.C.溫賴特。

Congrats on the quarter. I have 2 questions on PSP. The first one is, how similar is PSP with ALS concerning the downstream degeneration pathway? And the second is, we never got to hear about the mechanism with which AMX0035 impacts the tau in the -- in your Phase II trial, which is CENTAUR. Is there any insights?

恭喜本季度。我有兩個關於 PSP 的問題。第一個是，PSP 與 ALS 在下游變性途徑方面有何相似之處？第二是，我們從未聽說過 AMX0035 影響 tau 蛋白的機制——在你們的 II 期試驗中，即 CENTAUR。有什麼見解嗎？

Yes. So maybe first on PSP and ALS and their degenerative pathways. So I think for both of these diseases, there's still a lot of research into exactly all the etiology and pathology. I think our view and the literature, there's a lot of literature on this as well is that both diseases see significant cell death related to endoplasmic reticulum and mitochondrial related pathways, which is what we developed AMX0035 to target.

是的。所以也許首先是 PSP 和 ALS 及其退化途徑。所以我認為對於這兩種疾病，對於所有的病因學和病理學仍然有很多研究。我認為我們的觀點和文獻，也有很多這方面的文獻是，這兩種疾病都出現與內質網和線粒體相關途徑相關的顯著細胞死亡，這正是我們開發 AMX0035 的目標。

And then in terms of the pathways whereby AMX0035 may affect how -- so I think there's a lot of literature on the link between tau and endoplasmic reticulum stress. And so that's something that we've focused on there. But this change in tau, we've seen both in preclinical models, including ones that are published as well as in our Phase II Alzheimer's randomized placebo-controlled study. So we feel that that's a pretty robust and consistent finding.

然後就 AMX0035 可能影響的途徑而言，我認為有很多關於 tau 蛋白和內質網應激之間聯繫的文獻。這就是我們關注的重點。但 tau 蛋白的這種變化，我們在臨床前模型（包括已發表的模型）以及我們的 II 期阿爾茨海默病隨機安慰劑對照研究中都看到了。所以我們認為這是一個非常有力且一致的發現。

Thank you. There are no further questions at this time. I'll turn the call back to Mr. Klee for final comments.

謝謝。目前沒有其他問題。我會將電話轉回克利先生以徵求最終意見。

Thank you all very much for joining us this afternoon. We covered a lot of exciting news. Our commercial ramp in U.S. and Canada is proceeding really well. We're expanding into another clinical indication, which has a huge unmet need and has a market that is probably likely as large as ALS. And with the product, as we said, that's already been shown to be safe and well tolerated in a neurodegenerative disease as well as show quite significant reductions in tau. And maybe one other thing we only talked on briefly, but we achieved our first quarter of profitability in just the second quarter of commercial launch in the U.S., which we're really excited about. We're a mission-driven company. We have many more people to help and many more people to help around the world, both with ALS and we hope with other neurodegenerative diseases as well. Achieving profitability is what's going to allow us to have a sustainable business to keep moving forward and keep helping more and more people with neurodegenerative diseases. So thank you all very much for joining us and for your support, and we hope you have a great rest of your day.

非常感謝大家今天下午加入我們。我們報導了很多令人興奮的消息。我們在美國和加拿大的商業擴張進展順利。我們正在擴展到另一種臨床適應症，該適應症有巨大的未滿足需求，並且其市場可能與 ALS 一樣大。正如我們所說，該產品已被證明在神經退行性疾​​病中是安全的且具有良好的耐受性，並且 tau 蛋白顯著減少。也許我們只是簡單地談論了另一件事，但我們在美國商業推出的第二季度就實現了第一季度的盈利，對此我們感到非常興奮。我們是一家以使命為導向的公司。我們有更多的人需要幫助，世界各地有更多的人需要幫助，包括 ALS 患者，我們希望也能幫助其他神經退行性疾​​病患者。實現盈利將使我們能夠擁有可持續的業務，不斷前進並繼續幫助越來越多的神經退行性疾​​病患者。非常感謝大家的加入和支持，希望您度過愉快的一天。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連接。