Milestone Pharmaceuticals Inc (MIST) 2019 Q2 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Milestone Pharmaceuticals midyear 2019 regulatory update call. As a reminder, this call is being recorded.

女士們、先生們，大家好，歡迎參加 Milestone Pharmaceuticals 2019 年中監管更新電話會議。提醒一下，本次通話正在錄音。

I would now like to introduce your host for today's conference, Eleanor Barisser.

現在我想介紹今天會議的主持人 Eleanor Barisser。

Thank you, operator. Good morning and thank you for joining us for our midyear regulatory update conference call. Delivering prepared remarks on today's call will be Joseph Oliveto, President and Chief Executive Officer. Joining Joe for the Q&A session will be Dr. Francis Plat, Chief Medical Officer; Lorenz Muller, Chief Commercial Officer; and Tim Maness, Vice President of Finance.

謝謝您，接線生。早安，感謝您參加我們的年中監管更新電話會議。總裁兼執行長約瑟夫·奧利維托 (Joseph Oliveto) 將在今天的電話會議上發表準備好的演講。首席醫療官 Francis Plat 博士將與 Joe 一起參加問答環節；商務長 Lorenz Muller；以及財務副總裁 Tim Maness。

Please note that the focus of today's call will be the etripamil program regulatory update announced this morning. For an overview of Milestone's second-quarter financial results, we ask that you please refer to this morning's press release or 10-Q filing.

請注意，今天電話會議的重點是今天上午宣布的 etripamil 計劃監管更新。如需了解 Milestone 第二季財務業績，請參閱今天上午的新聞稿或 10-Q 文件。

This is Milestone's first conference call since the closing of the Company's IPO in May. As such, the Milestone management team would like to inform investors of the Company's planned general practice of hosting conference calls in conjunction with key corporate updates, such as today's regulatory news, and not solely for the purpose of discussing quarterly financial results.

這是 Milestone 自 5 月公司首次公開發行 (IPO) 結束以來召開的首次電話會議。因此，Milestone 管理團隊希望告知投資者，公司計劃結合重要的公司更新（例如今天的監管新聞）召開電話會議，而不僅僅是為了討論季度財務表現。

Before we begin, I would like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the risk factors section of the Company's most recent quarterly report on Form 10-Q and other reports filed with the SEC.

在我們開始之前，我想提醒您，根據 1995 年《私人證券訴訟改革法案》的規定，本次電話會議中做出的任何非歷史性的陳述均被視為前瞻性陳述。由於各種重要因素，包括公司最新的 10-Q 表季度報告和向美國證券交易委員會提交的其他報告中風險因素部分所討論的因素，實際結果可能與這些聲明所示的結果存在重大差異。

Any forward-looking statements represent the Company's views as of today, August 13, 2019, only. For your convenience, an audio replay of today's call will also be available on our website shortly after the call.

任何前瞻性陳述僅代表本公司截至今天（2019 年 8 月 13 日）的觀點。為了您的方便，今天通話的音訊回放也將在通話結束後不久在我們的網站上提供。

With that, I would like to turn the call over to Milestone's CEO, Joseph Oliveto. Joe?

接下來，我想將電話轉給 Milestone 的執行長 Joseph Oliveto。喬？

Thank you, Eleanor, and thank you to everyone for joining us today. For those of you who may not be familiar with Milestone, the last few months have certainly been an exciting time for us.

謝謝你，埃莉諾，也謝謝大家今天的到來。對於那些可能不熟悉 Milestone 的人來說，過去幾個月對我們來說無疑是令人興奮的時光。

With the successful completion of our initial public offering in May, we are well on our way to delivering on our mission of bringing new treatments to patients living with episodic cardiovascular conditions. Our team has been initially focused on the indication known as paroxysmal supraventricular tachycardia, or PSVT.

隨著我們在五月成功完成首次公開募股，我們正在順利履行我們的使命，即為偶發性心血管疾病患者帶來新的治療方法。我們的團隊最初專注於陣發性室上性心搏過速（PSVT）這種疾病。

PSVT afflicts approximately 2 million people and results in at least 600,000 healthcare claims every year in the US alone. Patients experiencing a PSVT episode may feel palpitations, while heart rate increases dramatically, sometimes exceeding 200 beats per minute. The condition commonly causes great distress for patients and their family members and can result in emergency department visits or hospitalizations that add significant cost to our healthcare system.

在美國，PSVT 影響著約 200 萬人，每年導致至少 60 萬起醫療索賠。經歷 PSVT 發作的患者可能會感到心悸，同時心率急劇增加，有時會超過每分鐘 200 次。這種疾病通常會給患者及其家屬帶來極大的痛苦，並可能導致急診或住院治療，從而為我們的醫療保健系統增加大量成本。

Our lead candidate, etripamil, is a potent and short-acting calcium channel blocker that has the potential to become the first self-administered rapid onset nasal spray designed to terminate episodes of PSVT wherever and whenever the episodes occur. And without the needed oversight of the emergency department visits that currently available options require.

我們的主要候選藥物依替帕米是一種強效短效鈣通道阻斷劑，有可能成為首個自行給藥的速效鼻噴劑，旨在隨時隨地終止 PSVT 發作。並且沒有目前可用選項所需的對急診就診的監督。

Results from our Phase 2 trial showed that 87% of PSVT episodes were stopped within 15 minutes of using etripamil 70-milligram dose versus just 35% of placebo-treated patients. And it was these results that served as the foundation for our ongoing Phase 3 program.

我們第二階段試驗的結果顯示，使用 70 毫克劑量的依曲帕米後，87% 的 PSVT 發作在 15 分鐘內停止，而接受安慰劑治療的患者只有 35% 的 PSVT 發作停止。正是這些結果為我們正在進行的第三階段計劃奠定了基礎。

By way of background, our pivotal Phase 3 program of etripamil in PSVT consists of three distinct trials designed to support potential regulatory filings in the US and EU. These trials include one pivotal double-blind randomized efficacy trial known as 301 as well as two open-label safety studies, referred to as NODE-302 and NODE-303.

背景是，我們在 PSVT 中針對依曲帕米的關鍵 3 期計劃包括三項不同的試驗，旨在支持在美國和歐盟進行的潛在監管備案。這些試驗包括一項關鍵的雙盲隨機療效試驗（稱為 301）以及兩項開放標籤安全性研究（稱為 NODE-302 和 NODE-303）。

We recently held a productive meeting with the FDA to discuss several proposed changes which we view as potentially optimizing to our ongoing Phase 3 program. We are very pleased with the outcome of our interactions with the Agency, which I will be reviewing in today's call.

我們最近與 FDA 舉行了一次富有成效的會議，討論了幾項擬議的變更，我們認為這些變更可能會對我們正在進行的第三階段計劃進行最佳化。我們對與該機構互動的結果非常滿意，我將在今天的電話會議上回顧這一結果。

I'd like to start with the news regarding NODE-303. NODE-303 is our open-label safety trial which will primarily evaluate the safety and tolerability of etripamil 70 milligrams self-administered by the patient without medical supervision and similarly to how it is envisioned to be used commercially. The trial is a global study and will seek to assess up to 1,500 patient events in patients who did not participate in either of our other Phase 3 trials, NODE-301 or NODE-302.

我想先了解 NODE-303 的新聞。NODE-303 是我們的開放標籤安全性試驗，主要評估患者在沒有醫療監督的情況下自行服用 70 毫克依曲帕米的安全性和耐受性，以及與其預期的商業用途類似。該試驗是一項全球性研究，旨在評估未參加我們的其他 3 期試驗 NODE-301 或 NODE-302 的患者的多達 1,500 例患者事件。

Based on a review of the safety data to date from the ongoing Phase 3 trials, we approached the FDA requesting to initiate NODE-303 with two noteworthy protocol components. First, to allow the study to enroll a similarly broad patient population as the ongoing NODE-301 study, including in that population older patients as well as patients on concomitant beta blockers and calcium channel blockers.

根據對正在進行的 3 期試驗迄今為止的安全數據的審查，我們向 FDA 提出申請，要求啟動 NODE-303，並提出兩個值得注意的協議組成部分。首先，允許該研究招募與正在進行的 NODE-301 研究同樣廣泛的患者群體，其中包括老年患者以及同時服用β受體阻斷劑和鈣通道阻斷劑的患者。

And the second noteworthy protocol component was to allow patients to begin the study and treat their PSVT episodes whenever and wherever they occurred, and without the need for an in-office test dose of etripamil, which is currently used in NODE-301 study. We are pleased to report that we received agreement from the FDA to proceed with this study as requested. And we expect to begin enrolling patients in NODE-303 before the end of the year.

第二個值得注意的協議組成部分是允許患者隨時隨地開始研究並治療其 PSVT 發作，而無需在辦公室內使用目前在 NODE-301 研究中使用的依曲帕米測試劑量。我們很高興地報告，我們已獲得 FDA 的同意，並按照要求繼續進行這項研究。我們預計在今年底前開始招募 NODE-303 患者。

What is more, based on the Agency's early review of the Phase 3 interim safety data for assessing our NODE-303 request, the FDA has also expressed its willingness to consider an overall safety database of less than 1,500 PSVT patient events that they had previously guided us to and which matches the ICH guideline. We believe that this not only is indicative of etripamil's safety profile in the clinical setting so far, but could potentially result in reducing the overall size required of the NODE-303 trial to support an NDA filing.

此外，基於該機構對評估我們 NODE-303 請求的 3 期中期安全性數據的早期審查，FDA 還表示願意考慮一個包含少於 1,500 例 PSVT 患者事件的總體安全性數據庫，該數據庫與他們先前指導的一致，並且符合 ICH 指南。我們相信，這不僅表明了迄今為止依曲帕米在臨床環境中的安全性，而且有可能減少支持 NDA 申請所需的 NODE-303 試驗的總體規模。

While we are encouraged by this news, we also note that the program is still in the relatively early days with respect to the total safety database exposure. And as a result, we will continue to plan for sizing NODE-303 to enable the overall safety database of 1,500 patient events for the program. We look forward to providing further granularity on potentially reducing the size of NODE-303 and guidance on an NDA filing timeline as the exposure database continues to grow.

雖然我們對這一消息感到鼓舞，但我們也注意到，就整體安全資料庫暴露而言，該計劃仍處於相對早期階段。因此，我們將繼續規劃 NODE-303 的規模，以便為該計劃提供包含 1,500 起病患事件的整體安全資料庫。隨著暴露資料庫的不斷增長，我們期待進一步提供有關如何減少 NODE-303 的大小以及有關 NDA 歸檔時間表的指導。

Let me now turn to NODE-301. NODE-301 is our ongoing Phase 3 double-blind placebo-controlled trial evaluating the efficacy and safety of etripamil in terminating PSVT episodes in the outpatient setting. The FDA previously agreed that the trial could serve as a single efficacy study for potential approval and that remains our current plan.

現在我來談談 NODE-301。NODE-301 是我們正在進行的 3 期雙盲安慰劑對照試驗，旨在評估依曲帕米在門診終止 PSVT 發作的有效性和安全性。FDA 先前已同意該試驗可以作為單獨的功效研究以獲得批准，而這仍然是我們目前的計劃。

NODE-301 is designed as an event-driven trial. In this trial, we enroll and randomize up to 500 patients to receive either etripamil or placebo in a 2 to 1 ratio. We provide this study drug to the patients and send them home from the office prepared to treat their events when they occur. The study is completed when it reaches 100 confirmed PSVT events.

NODE-301 被設計為一個事件驅動的試驗。在本次試驗中，我們招募了多達 500 名患者，並以 2:1 的比例隨機分配接受依曲帕米或安慰劑治療。我們為患者提供這種研究藥物，並讓他們從辦公室回家，準備在發生事件時進行治療。當確認的 PSVT 事件達到 100 例時，研究即完成。

In addition to the 100 total event requirement, the powering of the study also requires a minimum number of events in each treatment arm: 50 for etripamil and 30 for placebo. Remember, it is randomized 2 to 1, hence the difference.

除了總共 100 個事件的要求外，研究的動力還要求每個治療組的最低事件數：依曲帕米為 50 個，安慰劑為 30 個。請記住，它是 2 比 1 隨機的，因此存在差異。

To avoid potential randomization imbalances, the study calls for an unblinded third-party statistician to review the data as the study approaches 100 events in order to ensure the minimum target number of events occur in each group. With this study tracking ahead of our initial projections, we took the opportunity of the planned FDA meeting to request an increase to the number of adjudicated events in NODE-301 from 100 events to 150 events, a change that addresses several goals.

為了避免潛在的隨機化不平衡，當研究接近 100 個事件時，研究要求一位未盲的第三方統計人員來審查數據，以確保每組發生的事件數達到最低目標值。由於這項研究的進展超出了我們最初的預測，我們藉計劃中的 FDA 會議的機會請求將 NODE-301 中裁定事件的數量從 100 個事件增加到 150 個事件，這一改變可以實現多個目標。

First, it eliminates the need for the unblinded third-party review of the data, which satisfies a previous request we received from the European Medicines Agency, or EMA, to remove this unblinded review. From a statistical standpoint, upsizing the trial to 150 events significantly decreases the chance of randomization imbalances impacting the study reaching the minimum number of events in each group. With this change, our program now allows us to align under both the FDA and EMA guidances.

首先，它消除了對資料進行非盲第三方審查的需要，這滿足了我們先前從歐洲藥品管理局（EMA）收到的取消此非盲審查的請求。從統計學角度來看，將試驗規模擴大到 150 個事件可顯著降低因隨機化不平衡而影響研究達到每組最低事件數的可能性。透過這項變化，我們的計劃現在允許我們遵守 FDA 和 EMA 的指導。

The second benefit is that upsizing the study allows us to collect more double-blind randomized data, which better enables subpopulation and pharmacoeconomic assessments, both of which will potentially enhance our understanding of etripamil's commercial profile. And lastly, upsizing the trial enhances its powering.

第二個好處是，擴大研究規模使我們能夠收集更多的雙盲隨機數據，從而更好地進行亞群和藥物經濟學評估，這兩者都有可能增強我們對依曲帕米商業概況的了解。最後，擴大試驗規模可增強其效力。

We also requested and received agreement from the FDA to continue collecting blinded results for patients who have been randomized in NODE-301 but have not yet experienced an event when the 150 events have accrued and the study is stopped. These additional event data will be collected between the time at which the study reaches 150 adjudicated events and until the majority of the remaining patients experience an event.

我們也請求並獲得 FDA 的同意，在累計 150 起事件並停止研究後，繼續收集已在 NODE-301 中隨機分組但尚未經歷事件的患者的盲法結果。這些額外的事件資料將在研究達到 150 個裁定事件後，直到大多數剩餘患者經歷事件期間收集。

These data will be analyzed separately as a secondary data set, which we will refer to as NODE-301B, B as in boy. The primary benefit of the 301B addition is the program's ability to generate further double-blind comparative data that will strengthen the safety database and add to subpopulation and pharmacoeconomic analyses and future potential publications and do so in an efficient manner.

這些數據將作為二級數據集進行單獨分析，我們將其稱為 NODE-301B，B 代表男孩。301B 附加項目的主要優勢在於，該項目能夠產生進一步的雙盲比較數據，從而加強安全數據庫，並豐富亞群和藥物經濟學分析以及未來的潛在出版物，並以高效的方式進行。

Stated more simply, we invested significant efforts in consenting and randomizing patients, packaging the drug for double-blind comparative data. And we thought, why not maximize the value of that work to support our eventual NDA filing and future publications?

更簡單地說，我們投入了大量精力來徵求患者同意並進行隨機分組，將藥物包裝起來以獲得雙盲比較數據。我們想，為什麼不最大限度地發揮這項工作的價值來支持我們最終的保密協議申請和未來的出版物呢？

As with NODE-301, any NODE-301B patient who successfully completes dosing of etripamil in a PSVT event will also be eligible to enroll in our open-label NODE-302 safety extension trial for the treatment of future events.

與 NODE-301 一樣，任何在 PSVT 事件中成功完成依曲帕米給藥的 NODE-301B 患者也將有資格參加我們的開放標籤 NODE-302 安全擴展試驗，以治療未來的事件。

Based on our progress and experience with the study, we believe that even with the study's increased size, a top-line NODE-301 study readout in the first half of 2020 is still expected. Importantly, while the NODE-301 study will be modestly more expensive than the original plan, there will be no meaningful impact to the total clinical program cost across all studies due to other efficiencies that are gained across the program.

根據我們在研究方面的進展和經驗，我們相信，即使研究規模擴大，我們仍有望在 2020 年上半年獲得 NODE-301 研究的頂線數據。重要的是，雖然 NODE-301 研究的成本將比原計劃略高，但由於整個計畫獲得了其他效率，因此所有研究的總臨床計畫成本不會產生重大影響。

Taken together, we are extremely pleased with the outcome of this meeting with the FDA and the progress of our pivotal program, all of which reflects on the hard work of our skilled and dedicated team. I would also like to thank the physicians and clinical study teams for all their hard work on the NODE-301 study to date. And of course, I'd like to especially thank the patients who have put their faith in the study and in Milestone.

總而言之，我們對與 FDA 會面的結果以及我們關鍵項目的進展感到非常滿意，這一切都體現了我們技術嫻熟、敬業精神的團隊的辛勤工作。我還要感謝醫生和臨床研究團隊迄今為止在 NODE-301 研究上所做的所有努力。當然，我要特別感謝那些信任這項研究和 Milestone 的患者。

We firmly believe we are well positioned for continued success in the execution of our etripamil pivotal program in PSVT and look forward to updating you on our continued progress in the coming months. Thank you all for your continued support as we work towards achieving our mission of bringing new treatments to patients living with episodic cardiovascular conditions.

我們堅信，我們有能力在 PSVT 中成功執行我們的 etripamil 關鍵項目，並期待在未來幾個月內向您通報我們的持續進展。感謝大家一直以來的支持，我們致力於實現我們的使命，為患有偶發性心血管疾病的患者帶來新的治療方法。

With that, I will close the prepared remarks and open up the call for questions.

至此，我將結束準備好的發言並開始提問。

(Operator Instructions) Chris Howerton, Jefferies.

(操作員指示) Chris Howerton，傑富瑞。

Hey, good morning. Thanks for the update and hope all is well with you guys. For the first question, I guess, just so I fully understand it, the initial plan was that you want to kind of make sure that you have the minimum event number for each arm. And the change in the upsizing essentially just gives you the confidence that you will meet that minimum number without a statistical adjudication. Is that the basic rationale?

嘿，早安。感謝您的更新，希望你們一切都好。對於第一個問題，我想，只是為了讓我完全理解它，最初的計劃是確保每個手臂都有最少的事件數。而規模擴大的變化本質上只是讓你有信心無需統計裁決就能達到最低數字。這就是基本原理嗎？

You got it, Chris. Exactly.

你明白了，克里斯。確切地。

Okay, got it, got it. And so when you think about the regulatory path in the EMA, will the NODE-301 trial serve as a single efficacy trial in that territory as well? Or is that still an open discussion with the EMA?

好的，知道了，知道了。那麼，當您考慮 EMA 中的監管路徑時，NODE-301 試驗是否也將成為該地區的單一功效試驗？或者這仍是與 EMA 的公開討論？

Great question, Chris. And yes, we were very pleased to hear from the EMA when we met with them that a single pivotal efficacy trial could serve as grounds for approval in European Union, as it does in the US with the FDA. So we are aligned on that point as well.

很好的問題，克里斯。是的，當我們與 EMA 會面時，我們非常高興地得知，單一關鍵療效試驗可以作為歐盟批准的依據，就像美國 FDA 批准一樣。因此我們在這一點上也是一致的。

Excellent, okay, great. And maybe just another one in terms of the conduct of the NODE-301 trial. And kind of any information or color you can give us around the event rate or the things that give you confidence that you will still be able to meet that deadline in the first half of next year for top-line results?

非常好，好的，非常好。就 NODE-301 試驗的實施而言，這或許只是另一個案例。您能否向我們提供有關事件發生率或讓您有信心在明年上半年的最後期限前取得營收業績的因素提供任何資訊或細節？

Right. Also a common question and a great question. We continue to have confidence, and we would obviously thought twice about making this change should our recruitment rates not have been there for our ongoing program.

正確的。這是一個常見的問題，也是一個很棒的問題。我們仍然有信心，如果我們正在進行的計劃的招聘率沒有達到預期，我們顯然會三思而後行做出這一改變。

But in fact, as you are well aware, Chris, and many of the investors are, we are changing the paradigm here. Going into our Phase 3 program, there was perhaps a little bit more uncertainty around our program than you might otherwise have for Phase 3 because we simply did not have other studies to point to, whether they were ours or others. There just haven't been anyone doing work in this area.

但事實上，克里斯，正如你和許多投資者所清楚的那樣，我們正在改變這種模式。進入我們的第三階段計劃時，我們的計劃可能比第三階段計劃有更多的不確定性，因為我們根本沒有其他研究可以參考，無論是我們的研究還是其他人的研究。只是還沒有人在這個區域工作。

So with that uncertainty, we went into this program with our best estimate. And now, with the randomization rates and event rates coming in, we are seeing that we are actually ahead of our initial projections and continue to have confidence that we will be able to deliver now the 150 events in the first half of 2020. Whereas before, we were thinking we were going to need that period of time to deliver the top-line data with only the 100 events. So it is because we are ahead of schedule on randomization and event rates that we are able to have that confidence.

因此，面對這種不確定性，我們以最好的估計啟動了該計劃。現在，隨著隨機化率和事件發生率的公佈，我們發現我們的目標實際上已經超出了最初的預測，我們有信心在 2020 年上半年實現 150 場事件。而之前，我們認為我們需要那段時間來提供僅包含 100 個事件的頂線資料。因此，正是因為我們在隨機化和事件發生率方面提前完成了計劃，我們才能夠有這樣的信心。

Awesome. Okay, well, great. And then maybe the other one. I think that I have some ideas, but I'd love to hear your thoughts as well is in terms of what the implications are for the 303 design modifications and the lack of the requirement for the test dose and potentially on the patient population. How does that change your view of the commercial opportunity if at all?

驚人的。好的，太好了。然後也許是另一個。我認為我有一些想法，但我也想聽聽您的想法，關於 303 設計修改以及缺乏測試劑量要求對患者群體有何影響。如果有的話，這會如何改變您對商業機會的看法？

Great question, Chris. I don't know if I would characterize it as changing our view but more confirming our view. Our product profile for etripamil has always been -- and etripamil is designed to be used with a moniker of safety to be used broadly by patients with PSVT events.

很好的問題，克里斯。我不知道我是否會將其描述為改變我們的觀點，但更多的是確認了我們的觀點。我們的依曲帕米產品簡介一直是－依曲帕米的設計初衷是安全，可供患有 PSVT 事件的患者廣泛使用。

And our profile does not have restrictions for any subgroups or any major subgroups. For example, we expect it to be utilized in elderly patients. We expect it to be utilized in patients that are taking other AV nodal blocking agents, such as calcium channel blockers or beta blockers.

且我們的個人資料對任何子群組或任何主要子群組沒有任何限制。例如，我們預計它可用於老年患者。我們期望它能夠用於服用其他 AV 結阻斷劑（例如鈣通道阻斷劑或β受體阻斷劑）的患者。

However, while we have that in our profile, we do need to confirm that in data. And I would say that this preliminary review of the interim data by the FDA gives us confidence that based on what we have seen so far, the drug is on the right path. Not seeing any particular issues with regard to those populations. So I would characterize it as we are on path to meet our profile rather than changing any views.

然而，雖然我們的資料中有這一點，但我們確實需要在數據中確認這一點。我想說，FDA 對中期數據的初步審查讓我們有信心，根據我們目前所看到的情況，藥物的前景是樂觀的。沒有發現與這些人群有關的任何特殊問題。因此，我認為我們正在走上符合我們形象的道路，而不是改變任何觀點。

Got it. Okay. All right. Well, thank you so much for the updates and look forward to the continued progress.

知道了。好的。好的。好吧，非常感謝您的更新，並期待繼續取得進展。

Ritu Baral, Cowen.

裡圖·巴拉爾（Ritu Baral），考恩。

Good morning, guys. Thanks for taking the question and the updates. If you had to rank order the reasons behind why the trial is enrolling faster than previously expected, if you had to rank order screening rates, randomization rates, and event rates, like what is the most important driving factor here?

大家早安。感謝您提出問題並提供最新消息。如果您必須對為什麼試驗招募速度比之前預期的更快的原因進行排序，如果您必須對篩選率、隨機化率和事件發生率進行排序，那麼這裡最重要的驅動因素是什麼？

Great question, Ritu, and you are hitting on a little bit of the uncertainty that we had going into this. We had a fair number of variables that we had to manage.

很好的問題，Ritu，你提到了我們在討論這個問題時所遇到的一些不確定性。我們必須管理相當多的變數。

I would say in general, the two drivers behind really us being ahead of schedule are -- and you mentioned screening rates. I would really characterize it as this test dose assessment and potential to screen out patients. And there, we are seeing very low screen-out rates from the test dose. Meaning that patients are tolerating the open-label drug quite well in the office and almost all of them are rolling into the double-blind randomized.

我想說，總的來說，真正讓我們提前完成計劃的兩個驅動因素是——你提到了篩檢率。我確實將其描述為測試劑量評估和篩檢患者的潛力。我們發現測試劑量的篩檢率非常低。這意味著患者在辦公室中對開放標籤藥物的耐受性非常好，幾乎所有患者都進入了雙盲隨機試驗。

And we had expectations that that screen-out rate would be a lot higher. So that is a major draw to us being able to --

我們原本預計篩選率會高很多。所以這對我們來說是一個很大的吸引力，能夠——

Sorry to interrupt. So should we assume that that was kind of like a low-single-digit screen failure rate for the test dose?

抱歉打擾了。那麼，我們是否應該假設，這有點像測試劑量的低個位數螢幕失敗率？

It is low-single digits.

它是低個位數。

Got it. Thanks. Sorry, keep going.

知道了。謝謝。抱歉，請繼續。

So that is one aspect that would be towards the top of the list. We are hitting on all cylinders on getting sites that are finding patients and finding the right patients. Meaning that patients are having episodes a little bit more frequently than we expected.

因此，這是應該列在清單首位的一個面向。我們正在全力以赴地尋找能夠發現患者的網站以及找到合適的患者。這意味著患者發病的頻率比我們預期的要高一些。

So for those of you who are close to the story, you know that we have done quite a bit of market research in this field. We estimate that patients have on average or a median number of about a handful to two handfuls of episodes per year; the median being in the range of six to eight.

對於那些熟悉這個故事的人來說，你們知道我們在這個領域做了相當多的市場調查。我們估計，患者每年發病的平均次數或中位數約為一把到兩把；中位數在六到八之間。

And we are actually finding when you think about that, you think about a patient having, for our study, maybe four events per year, of which we capture one. We are actually starting to have those events earlier and capturing those first events.

我們實際上發現，當您考慮到這一點時，您會發現，對於我們的研究而言，一個患者每年可能發生四次事件，而我們只會捕捉到其中一次。事實上，我們很早就開始舉辦這些活動，並捕捉這些最早的事件。

So it is a bit of execution play, where we are doing well. And we are seemingly getting the better patients that are having more events and quicker events. This is all as a result of hard work of our team and being on top of it. And really going to I think what are superstar sites that really get the protocol and are doing a good job helping us identify the correct patients.

因此，這在某種程度上是執行上的，我們在這方面做得很好。我們似乎得到了更好的治療，他們發生的事件更多，發生的速度更快。這一切都是我們團隊辛勤工作和堅持不懈的結果。我真正要思考的是，哪些超級明星網站真正掌握了協議，並且在幫助我們識別正確的患者方面做得很好。

And to confirm, your sort of patient interest, patient input rate is at least what you expected? Obviously, it has ramifications for patient prevalence.

並且確認，您的患者興趣、患者投入率至少是否達到您的預期？顯然，這對患者的盛行率有影響。

Yes, it is. It is better that what we expected in the sense that there are sites that are enrolling a lot of patients. We generally use averages and linear expectations because of all the variables at play and you can wrap yourself around the axle on this. But we do have sites obviously where we miss and haven't enrolled anyone, but the majority of our sites are enrolling patients, with some real superstar sites.

是的。從一些站點正在招募大量患者的角度來看，這比我們預期的要好。我們通常使用平均值和線性預期，因為其中涉及各種變量，你可以圍繞這個軸進行思考。但顯然我們漏掉了一些站點，沒有招募任何人，但我們的大多數站點都在招募患者，其中包括一些真正的超級明星站點。

Got it. And then the second question. You mentioned that upsizing the events gives you additional powering on some key subpopulation analysis and key pharmacoeconomic analyses. Can you give us a little more detail on the most important subpopulations and why? And which pharmacoeconomic analyses you were referring to in particular?

知道了。然後是第二個問題。您提到，擴大事件規模可以讓您對一些關鍵的亞群分析和關鍵的藥物經濟學分析獲得額外的支持。您能否向我們詳細介紹最重要的亞群以及原因？您具體提到了哪些藥物經濟學分析？

Right, great question. So the subpops that we typically think about and have on our minds here for this study are common across all studies. They are typical demographics. With regard to PSVT, we really would love to understand if there is age differences in terms of events and results. So in addition to age, there is gender.

好的，很好的問題。因此，我們在本研究中通常會考慮的和銘記在心的亞群體在所有研究中都是常見的。他們都是典型的人口統計學特徵。關於 PSVT，我們真的很想了解在事件和結果方面是否存在年齡差異。因此，除了年齡之外，還有性別。

We like to think about those patients that are on concomitant medications and other AV nodal blocking agents versus those that aren't. Identifying the subpopulations of PSVT, whether it is AVNRT or AVRT, will be interesting. And those are the subpopulations of interest, I would say.

我們喜歡思考那些正在服用同時用藥和其他房室結阻滯劑的患者與那些沒有服用同時用藥和其它房室結阻滯劑的患者。識別 PSVT 的亞群（無論是 AVNRT 還是 AVRT）將會很有趣。我想說，這些都是我們感興趣的亞群。

Again, exactly what it will mean for our drug, we are not sure. Maybe our hope is that it works equally well across. But it will be interesting to advance the field because there just simply is not much out there. And I think we aspire to be a leader in PSVT, and having a more robust study with more double-blind data will allow potential for greater populations in those subanalyses.

再說了，我們不確定這對我們的藥物到底意味著什麼。也許我們的希望是它能夠同樣發揮作用。但推動該領域的進步將會很有趣，因為目前該領域的研究成果並不多。我認為我們渴望成為 PSVT 領域的領導者，透過更多雙盲數據進行更穩健的研究將有可能在這些子分析中涵蓋更大的人群。

With regard to pharmacoeconomics, the study is not powered to show differences, so I just want to set expectations there. It had not been powered; even with an increase to 150, it is not powered to show differences. But we do feel that increasing to 150 as well as putting 301B on now and keeping that as double-blind randomized just gives us more chance of seeing signals.

關於藥物經濟學，研究無力顯示差異，所以我只是想在那裡設定期望。它尚未通電；即使增加到150，也無力顯示差異。但我們確實認為，現在增加到 150 以及引入 301B 並保持雙盲隨機化會讓我們有更多機會看到訊號。

The important ones we would look for there include interventions. Are there hospitalizations, are there trips to the emergency department, do they intervene with adenosine? Those are the big ones.

我們要尋找的重要內容包括介入措施。是否需要住院治療？這些都是大問題。

Would be also important to understand how patients feel about their use of the drug. So patient satisfaction questionnaires, which are embedded in our study, have a better chance with more double-blind randomized patients. Those are the main areas. Quality of life measures as well as real hard outcomes in terms of medical use of the system.

了解患者對使用該藥物的感受也很重要。因此，我們研究中嵌入的患者滿意度問卷在更多雙盲隨機患者中更有機會發揮作用。這些是主要領域。生活品質衡量標準以及系統醫療用途的實際成果。

Great. Thanks for taking all the questions. I will get back in the queue with my others.

偉大的。感謝您回答所有問題。我將和其他人一起回到隊列中。

Ted Tenthoff, Piper Jaffray.

泰德‧坦索夫 (Ted Tenthoff)，Piper Jaffray。

Great. Thank you very much and thanks for the updates. Joe, just want to make sure. Did you actually say what percentage of patients have been enrolled? And to this concept of kind of getting patients who have events earlier, remind me. Once they have one event, they go into the open-label study; it is not like they can be counted more than once in the 301, right? Thanks.

偉大的。非常感謝，感謝您的更新。喬，我只是想確認一下。您實際上有沒有說過已招募病患的比例是多少？讓我想起了這種讓早期發生過事件的患者參與的概念。一旦發生一項事件，他們就會進入開放標籤研究；在 301 中他們不可能被算上多次，對吧？謝謝。

Great questions, Ted, and I will take the second one first and confirm that you are correct. Once they have one event in 301, they are -- they get treated. We take their data and they are then out of the 301 study and they roll into the open-label extension called 302.

很好的問題，泰德，我將首先回答第二個問題並確認你是正確的。一旦他們在 301 中發生一次事件，他們就會得到治療。我們收集他們的數據，然後他們退出 301 研究，進入名為 302 的開放標籤擴展研究。

We collect further data on those patients, but it is not attributing to, if you will, the total safety data set in terms of one patient having two events counts once. So it is per patient, if you will.

我們收集了這些患者的進一步數據，但這並不意味著，就一個患者發生兩次事件只算一次的總安全數據集而言。所以如果你願意的話，這是針對每個病人的。

With regard to the percentage enrolled, we have not actually identified that or given details on that. I can say, though, and this was predefined with the FDA when we had our end of Phase 2 meeting that we would approach the FDA when about half of the 301 study was completed.

關於入學人數的百分比，我們實際上尚未確定或提供詳細資訊。不過，我可以說，這是在我們結束第 2 階段會議時與 FDA 預先確定的，即當 301 研究完成約一半時，我們就會與 FDA 聯繫。

So that will give the investors a feel as to where we are. We went to the FDA recently and we had about half the events under our belt, so about 50 events. So that would give a sense as to where we are without really getting into the details of specific numbers.

這將讓投資者了解我們的現狀。我們最近去了 FDA，已經完成了大約一半的活動，所以大約有 50 場活動。這樣就能讓我們了解目前的情況，無須真正了解具體數字的細節。

That's super helpful. I appreciate the additional color.

這非常有幫助。我很欣賞這額外的顏色。

Leland Gershell, Oppenheimer.

利蘭‧格謝爾 (Leland Gershell)、奧本海默。

Hey, good morning, Joe. Thanks for taking my questions and for the good update. I wanted to ask with the 301 data still on track for first half of next year, then the safety study seeming like that may go a bit faster, given your comments, just want to ask if you could maybe qualify for us a bit the NDA and approval timing following the 301 data with 303 filling in. If that could be moved up from prior expectations or how we should think about timelines until approval. Thanks.

嘿，早上好，喬。感謝您回答我的問題並提供有益的更新。我想問一下，由於 301 數據在明年上半年仍按計劃進行，因此安全性研究似乎可能會進行得更快一些，鑑於您的意見，我只想問一下，在 301 數據填寫完畢並準備好 303 數據之後，您是否可以為我們稍微確定一下保密協議 (NDA) 和批准時間。這是否可以高於先前的預期，或者我們應該如何考慮批准的時間表。謝謝。

Right. Outstanding question and one we are spending a lot of time on internally here, Leland. So here is how we are thinking about it. We have not provided guidance specifically to an NDA filing. We have guided our analysts and our investors that our expectation was that study 303 would run through 2021. That is with it needing to go to the full amount, however many patients that we would need in 303 to enable a total safety data set of around 1,500.

正確的。這是一個非常突出的問題，我們內部在這個問題上花了很多時間，利蘭。這就是我們對此的看法。我們沒有專門針對 NDA 申請提供指導。我們已經告知我們的分析師和投資者，我們預計 303 項研究將持續到 2021 年。這就是說，我們需要達到全部數量，但是 303 中需要多少患者才能形成大約 1,500 個總安全資料集。

So that was the guidance. That remains our guidance. Even though this is -- we are cautiously optimistic about the FDA willingness to consider something less than 1,500, we want to caution the investors that this is still pretty early in the game in terms of the amount of exposure we have had so far. So we are going to maintain that 303 still runs to the size needed to get us to 1,500 and that would run through 2021.

這就是指導。這仍然是我們的指導方針。儘管如此，我們對 FDA 願意考慮少於 1,500 個藥物持謹慎樂觀的態度，但我們想提醒投資者，就我們目前所接觸到的數量而言，這還處於相當早期的階段。因此，我們將堅持 303 仍能達到達到 1,500 所需的規模，並將持續到 2021 年。

Now, we will want to update the investors after we get 303 started and get some experience of 303 recruitment under our belt. 303 is in territories we have not experienced yet outside of North America. Both Europe and Latin America is where that study will be conducted, so we do want to get some experience there before we articulate more firm timelines on an NDA filing. And in general, just get more safety data under our belt before we can articulate what the size of the safety data set would be.

現在，在 303 啟動並累積一些 303 招募經驗後，我們將向投資者更新最新情況。303 位於北美以外我們尚未體驗過的地區。這項研究將在歐洲和拉丁美洲進行，因此我們希望在那裡獲得一些經驗，然後再明確 NDA 申請的時間表。一般來說，只有獲得更多的安全數據，我們才能清楚知道安全資料集的規模。

So we view those as coming out similarly. I don't have an exact time as when we would update you. But we will continue to assess the progress of the study and look to do it when we feel comfortable that we have our hands around both of those numbers.

因此我們認為這些都是類似的結果。我不知道我們何時會向您更新確切的時間。但我們將繼續評估研究的進展，並在我們確信掌握了這兩個數字後再進行研究。

Got you. And then just one more, if I may. As you are now going to expand the scope of the safety study and include elderly patients, older patients, patients who may be or have been more reluctant to, let's say, go for ablations and would prefer a pharmacologic intervention but who also may be on many more concomitant meds -- calcium channel blockers, other cardiac active medications -- if you could just again qualify for us what the picture looks like for those older patients in terms of what you see in terms of the meds they are coming on with that may also affect their cardiovascular system. Thanks.

明白了。如果可以的話，我再說一句。現在您要擴大安全性研究的範圍，將老年患者納入其中，這些老年患者可能不願意或曾經不願意接受消融治療，而是更願意接受藥物幹預，但也可能同時服用多種藥物，如鈣通道阻滯劑、其他心臟活性藥物，如果您能再次向我們說明一下這些老年患者的情況，他們服用的藥物也可能會影響他們的心血管系統。謝謝。

Right. So I will just reword a little bit of the question and then refer to my colleague, Francis, to articulate the concomitant meds that we are seeing with the elderly patients. But we are not opening up to more patients that are elderly or different patients. We have these patients already in NODE-301. We have elderly patients and we have a good percentage of our patients being elderly and/or those on concomitant medications.

正確的。因此，我將稍微重新表達這個問題，然後請我的同事法蘭西斯闡述我們在老年患者身上看到的伴隨用藥。但我們不會向更多老年患者或不同患者開放。我們的 NODE-301 中已經有這些患者了。我們有老年患者，其中很大一部分患者是老年人和/或正在服用同時用藥的患者。

The difference is now that given the data we have so far, we are comfortable and FDA is comfortable enrolling these patients without first testing them in the office. And the things we focus on most, as we do with every patient, is AV blocks and blood pressure drops. And we are just not seeing those in this population.

現在的不同之處在於，根據我們目前掌握的數據，我們感到放心，FDA 也放心招募這些患者，而無需先在辦公室對他們進行測試。正如我們對每個病人的治療一樣，我們最關注的是房室傳導阻滯和血壓下降。但我們在這個群體中卻沒有看到這些。

So just want to make sure everyone is on the same page. We are not really opening up to a broader population. We are maintaining the same population without the, if you will, training wheels or safeguards of the test dose. But Francis, can you comment on perhaps concomitant medications or more medications that the elderly may come with?

所以只是想確保每個人都了解同一觀點。我們實際上並沒有向更廣泛的民眾開放。我們維持著相同的人口數量，但是沒有（如果你願意的話）訓練輪或測試劑量的保障措施。但是弗朗西斯，您能否評論一下老年人可能服用的伴隨藥物或更多藥物？

Yes, certainly. The safety in 301 is overall very positive and the test dose actually went very well. And as we said, we have very few patients who were not randomized after the test dose, including those patients who are higher than 70 years old and have concomitant medication, especially beta blockers and/or calcium channel blockers.

是的，當然。301 的安全性總體來說非常好，並且測試劑量實際上效果很好。正如我們所說，我們有極少數患者在試驗劑量後沒有被隨機分配，其中包括年齡超過 70 歲且同時服用藥物的患者，尤其是β受體阻斷劑和/或鈣通道阻斷劑。

And when we take the overall safety, including the episode and the administration of the drug by the patients at home, we have no worrisome symptoms, no drop in blood pressure, and no concerns concerning arrhythmia and/or AV block. So basically, the safety is very positive for the overall population, including the elderly population with or without concomitant medication.

當我們考慮整體安全性時，包括發病和患者在家中服用藥物，我們沒有發現任何令人擔憂的症狀，沒有血壓下降，也不必擔心心律不整和/或房室傳導阻滯。因此基本上，對於總體人群，包括有或無同時用藥的老年人群，其安全性是非常積極的。

And Leland, I will just add lastly, the 301 study is representative, if you will, of also elderly patients having the host of other meds that we all know that they have. So there is no exclusions there; we are very open. And our goal here is really just to match how we expect this drug to be used commercially, which is with very few guardrails or exclusions.

最後，Leland，我只想補充一點，如果你願意的話，301 項研究也具有代表性，它表明老年患者也服用了我們都知道的大量其他藥物。所以不存在排除；我們非常開放。我們的目標實際上只是滿足我們對這種藥物商業用途的期望，幾乎沒有任何限製或排除。

Great. Thanks for the clarification. It's very helpful.

偉大的。感謝您的澄清。這非常有幫助。

(Operator Instructions) Ritu Baral.

（操作員指令） Ritu Baral。

Hey, guys. Thanks for taking the follow-up. One more trial conduct question. I know that you guys somewhere in the protocol will be adjudicating the patient events just to make sure that they are true PSVT events. Is that happening real-time or is that sort of adjudication of the true event something that happens after database lock? Remind me again.

嘿，大家好。感謝您的跟進。還有一個審判行為問題。我知道你們會在協議的某個地方對患者事件進行裁決，以確保它們是真正的 PSVT 事件。這是即時發生的嗎，還是對真實事件的裁決是在資料庫鎖定後發生的？再提醒我一下。

Yes, so it's in between. It is not real time; they are batched, if you will. And then when the adjudication committee comes together, they review a series of patients in a batched format and will update us as to whether those patients are truly characterizing their event and it is a true PSVT.

是的，所以它介於兩者之間。這不是實時的；如果你願意的話，它們是分批的。然後，當裁決委員會召開會議時，他們會分批審查一系列患者，並向我們通報這些患者是否真實描述了他們的事件，以及這是否是真正的 PSVT。

So we are down the path there. We are very happy with how these patients are characterizing their events. We do have some who mischaracterize or misdiagnose and it is not true PSVT. That is valuable for us because in the real world, that will happen. We want to see the safety on those patients.

所以我們沿著這條路走下去了。我們對這些病人對其事件的描述感到非常高興。我們確實有一些人錯誤描述或誤診，這不是真正的 PSVT。這對我們來說很有價值，因為在現實世界中，這會發生。我們希望看到這些患者的安全。

But we are again below our expectations and assumptions with how many are misdiagnosing. So that is actually another area that gets us to true PSVT events quicker than we had originally assumed.

但在誤診數量方面，我們再次低於我們的預期和假設。因此，這實際上是另一個讓我們比最初預想的更快地了解真正的 PSVT 事件的領域。

Got it. So basically by the time you lock the database and you count your events, you won't lose any events to classification of real or adjudication, put it that way.

知道了。因此，基本上，當您鎖定資料庫併計算事件時，您不會丟失任何事件來進行真實分類或裁決，就是這樣。

Correct. And that batching could be something that causes us to go -- in the past, would have caused us to go a little bit above 100 events. In this case, that batching may cause us to go a little bit above 150 events. We will try to have the committee meet a little bit more regularly as we get towards the end, but we are not worried if we go over by a couple events.

正確的。這種批次可能會導致我們 — — 在過去，會導致我們處理略超過 100 個事件。在這種情況下，批次處理可能會導致事件數量略超過 150 個。我們會嘗試在接近尾聲時讓委員會更定期地開會，但是我們並不擔心如果發生幾次活動而超出會議時間的情況。

Got it. And can you remind me, do you have any plans on changing the maximum number of doses in 302 and 303? I believe one of them is like 7 max and the other was 11 max. Any changes to that?

知道了。您能提醒我一下，您是否有計劃改變 302 和 303 中的最大劑量數？我相信其中一個最大是 7，另一個最大是 11。有什麼改變嗎？

We are not changing them. I will just provide the actual numbers. 302 enables up to 12 dosing events. And then NODE-303, which is the upcoming trial, open-label safety, we enable the patient to use the drug four times on four events.

我們不會改變它們。我僅提供實際數字。302 最多可實現 12 次加藥事件。然後是即將進行的 NODE-303 試驗，它具有開放標籤安全性，我們允許患者在四個事件中使用該藥物四次。

And then our expectation -- it is not that we don't want to keep providing the drug to patients, but the thought was four events would be an appropriate amount of data for the safety data set. There is no requirement, I will remind you, for repeat use in our data set. It is informative information for the Agency.

然後我們的期望——並不是我們不想繼續向患者提供藥物，而是認為四個事件對於安全資料集來說是合適的資料量。我要提醒你，我們的資料集不需要重複使用。這對該機構來說是很有幫助的資訊。

But after their four events, they have the opportunity to roll into -- our expectation being a means patient program where they will have access compassionately use.

但參加完四次活動後，他們就有機會進入——我們的期望是，他們可以懷著同情心參與一項患者援助計劃。

Got it. And then last question. Can you just confirm that Europe didn't have any other suggestions for the 301 trial design? Or are there potential other small protocol changes to either 301, 302, or 303 that they requested?

知道了。這是最後一個問題。你能否確認歐洲對301審判設計沒有其他建議？或者他們請求的 301、302 或 303 是否有可能進行其他小的協議更改？

The EU always has plenty of suggestions. I would classify them as not of the importance and rigor and definitiveness as this one. This one they were really focused on and hit on a few times. The other ones were taken account of and some incorporated into the protocol and some not. But we did not include every suggested change that the Europeans had.

歐盟總是有很多建議。我認為它們不具備與這篇一樣的重要性、嚴謹性和確定性。他們確實非常關注這一點，並且多次嘗試。其餘的都被考慮進去了，有些被納入了協議，有些則沒有。但我們並未採納歐洲人提出的所有變更建議。

But nothing that would jeopardize the acceptability of the current 301 study?

但沒有什麼會危及目前 301 研究的可接受性嗎？

That is our interpretation and expert review, yes.

是的，這是我們的解釋和專家評審。

Got it. Okay, thanks for taking the follow-up.

知道了。好的，感謝您的跟進。

I am currently showing no further questions at this time. I would like to turn the call back over to Joseph Oliveto for closing remarks.

我目前沒有其他問題。我想將電話轉回給約瑟夫·奧利維托 (Joseph Oliveto)，請他作最後發言。

Thank you very much, operator, and thank you to everyone again for taking the time out. We know it is earnings season. We know you are all busy, so really appreciate you guys following the story and continuing to support Milestone as we move forward here. Thank you very much. Have a great day.

非常感謝接線員，也再次感謝大家抽空。我們知道現在是獲利季節。我們知道你們都很忙，所以非常感謝你們關注這個故事並在我們前進的過程中繼續支持 Milestone。非常感謝。祝你有美好的一天。

Ladies and gentlemen, this concludes today's conference. Thank you for joining and have a wonderful day.

女士們、先生們，今天的會議到此結束。感謝您的加入並祝您有美好的一天。