DiaMedica Therapeutics Inc (DMAC) 2022 Q4 法說會逐字稿

Good morning, ladies and gentlemen, and welcome to the DiaMedica Therapeutics ReMEDy2 Update Conference Call. An audio recording of the webcast will be available shortly after the call today on DiaMedica's website at www.diamedica.com in the Investor Relations section.

女士們先生們，早上好，歡迎參加 DiaMedica Therapeutics ReMEDy2 更新電話會議。今天電話會議後不久，將在 DiaMedica 網站 www.diamedica.com 的投資者關係部分提供網絡廣播的錄音。

Before the company proceeds with its remarks, please note that the company will be making forward-looking statements on today's call. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these statements.

在公司發表評論之前，請注意公司將在今天的電話會議上發表前瞻性陳述。這些陳述受風險和不確定因素的影響，這些風險和不確定性可能導致實際結果與這些陳述中預測的結果存在重大差異。

More information, including factors that could cause actual results to differ from projected results, appears in the section entitled Cautionary Note regarding forward-looking statements in the company's press release issued yesterday and under the heading Risk Factors in DiaMedica's most recent annual report on Form 10-K. DiaMedica's SEC filings are available at www.sec.gov and on its website.

更多信息，包括可能導致實際結果與預期結果不同的因素，請參見公司昨天發布的新聞稿中有關前瞻性陳述的警告性說明部分以及 DiaMedica 最新年度報告 Form 10 中的風險因素標題下-K。 DiaMedica 的 SEC 文件可在 www.sec.gov 及其網站上查閱。

Please also note that any comments made on today's call speak only as of today, March 29, 2023, and may no longer be accurate at the time of any replay or transcript rereading. DiaMedica disclaims any duty to update its forward-looking statements. Following the prepared remarks, we will open the phone lines for questions.

另請注意，在今天的電話會議上發表的任何評論僅在 2023 年 3 月 29 日今天發表，在重播或重讀文字記錄時可能不再準確。 DiaMedica 不承擔任何更新其前瞻性陳述的義務。在準備好的評論之後，我們將打開電話線進行提問。

I would now like to introduce your host for today's call, Mr. Rick Pauls, DiaMedica's President and Chief Executive Officer. Mr. Pauls, you may begin, sir.

我現在想介紹今天電話會議的主持人，DiaMedica 總裁兼首席執行官 Rick Pauls 先生。 Pauls 先生，您可以開始了，先生。

Thanks, Paul. Hello, everyone, and welcome to our fourth quarter con call. I'm joined this morning by Kirsten Gruis, our Chief Medical Officer; and Scott Kellen, our Chief Financial Officer. .

謝謝，保羅。大家好，歡迎來到我們的第四季度電話會議。今天早上，我們的首席醫療官 Kirsten Gruis 加入了我的行列；和我們的首席財務官 Scott Kellen。 .

I'd like to start off today's call by updating everyone on the status of our work to remove the clinical hold on our ReMEDy2 Phase II/III pivotal trial and our communications with the FDA as we approach what we believe will be the final resolution of the clinical hold. Recall that the hold was not caused by any issue with our drug product candidate, DM199, but was caused by the effects of switching to a new IV bag formulation in our ReMEDy2 trial.

在今天的電話會議開始之際，我想向大家介紹我們的工作狀態，以取消對我們的 ReMEDy2 II / III 期關鍵試驗的臨床擱置以及我們與 FDA 的溝通，因為我們認為這將是最終解決方案臨床舉行。回想一下，擱置不是由我們的候選藥物 DM199 的任何問題引起的，而是由於在我們的 ReMEDy2 試驗中改用新的 IV 袋配方的影響引起的。

In our prior ReMEDy1 Phase II trial, the IV bag made from polyolefin retained up to half of the DM199 drug. In our pivotal Phase II/III ReMEDy2 trial, we switched to the new PVC IV bag formulation, which does not retain any of the DM199, effectively delivering up to twice as much DM199 to study participants. We believe that this is what caused the transient clinically significant blood pressure drops or hypotension in those 3 participants.

在我們之前的 ReMEDy1 II 期試驗中，由聚烯烴製成的 IV 袋保留了多達一半的 DM199 藥物。在我們關鍵的 II/III 期 ReMEDy2 試驗中，我們改用新的 PVC IV 袋配方，它不保留任何 DM199，有效地向研究參與者提供高達兩倍的 DM199。我們認為這就是導致這 3 名參與者出現短暫的臨床顯著血壓下降或低血壓的原因。

In our initial safety studies, we identified hypotension as the dose-limiting tolerability for DM199. As a result, drops in blood pressure are consistent with the mechanism of action for DM199, and we believe that the hypotensive events at least indicate that DM199 is clearly active in patients.

在我們最初的安全性研究中，我們將低血壓確定為 DM199 的劑量限制耐受性。因此，血壓下降與 DM199 的作用機制一致，我們認為低血壓事件至少表明 DM199 在患者體內具有明顯的活性。

In the FDA's October continuable clinical hold letter, their most significant request was to expand our IV bag compatibility study to stimulate real-world usage, which is referred to as an in-use study. We had originally expected that we would need to request a Type A meeting with the FDA to discuss the requirements for the study. However, in December, we received written communication from the FDA which provided their expectations for our in-use study.

在 FDA 10 月份的持續臨床保留信中，他們最重要的要求是擴大我們的 IV 袋相容性研究以刺激現實世界的使用，這被稱為在用研究。我們最初預計我們需要要求與 FDA 召開 A 類會議來討論研究的要求。然而，在 12 月，我們收到了 FDA 的書面通信，其中提供了他們對我們在用研究的期望。

Since we're only entitled to one Type A meeting, we are pleased that this written communication saved us from having to use our Type A meeting for a discussion on the in-use study requirements. We incorporated the FDA's feedback into the study protocol and submitted the updated protocol to the FDA with a request for confirmation that the protocol would satisfy the requirements.

由於我們只有一次 A 類會議的資格，我們很高興這份書面交流使我們不必使用我們的 A 類會議來討論在用研究要求。我們將 FDA 的反饋納入研究方案，並向 FDA 提交了更新後的方案，並要求確認該方案滿足要求。

Last month, we received a follow-up notification indicating that the FDA believed that our in-use study protocol was reasonable. The in-use study is being conducted in 2 parts. Part 1 simulates actual use in the hospital with IV bag and the tubing using a pump to administer DM199. Part 2 test worst-case scenarios such as varying storage, duration, temperatures and light. The first part of the in-use study is complete, and we believe that the data from this part confirms the conclusion we reached in our prior testing.

上個月，我們收到了一份後續通知，表明 FDA 認為我們的在用研究方案是合理的。在用研究分兩部分進行。第 1 部分模擬在醫院中實際使用 IV 袋和使用泵管理 DM199 的管道。第 2 部分測試最壞情況，例如不同的存儲、持續時間、溫度和光線。在用研究的第一部分已經完成，我們相信這部分的數據證實了我們在之前的測試中得出的結論。

Specifically, it confirmed that up to approximately 50% of the DM199 was retained in the IV bags used in the ReMEDy1 as compared to the IV bags used in ReMEDy2 and supports our earlier proposed revision to the IV dose from ReMEDy2 from 1 to 0.5 micrograms per kg. These results have been submitted to the FDA along with a request for feedback and confirmation that we now have addressed all issues of the clinical hold once the Part 2 of the in-use study is submitted.

具體而言，它證實，與 ReMEDy2 中使用的靜脈輸液袋相比，ReMEDy1 中使用的靜脈輸液袋中保留了大約 50% 的 DM199，並支持我們早先提出的將 ReMEDy2 的靜脈注射劑量從 1 微克更改為 0.5 微克/公斤。這些結果已連同反饋請求和確認請求一起提交給 FDA，一旦提交使用中研究的第 2 部分，我們現在已經解決了臨床暫停的所有問題。

We are currently conducting Part 2 of the in-use study, and the results, once complete, will be submitted to the FDA, which we anticipate occurring in April. Note that Part 2 of the in-use study what we learned will likely only affect handling procedures for the IV dosing and not the dose rates.

我們目前正在進行在用研究的第 2 部分，一旦完成，結果將提交給 FDA，我們預計會在 4 月進行。請注意，我們在使用中研究的第 2 部分中學到的知識可能只會影響 IV 給藥的處理程序，而不影響劑量率。

Late last year and early this year, while we are awaiting feedback from the FDA on the in-use study protocol and preparing to run the in-use study, we developed a more sensitive assay for measuring KLK1 levels and enhance the consistency in our assay that measures the activity levels of KLK1. We'd also do this as the FDA had posed a question about our existing assay methods. While we believe our existing assays were reasonable, we decided to be prudent and ultimately less time consuming to complete this work and eliminate a risk that the FDA might have additional questions and further delay the resumption of ReMEDy2 trial.

去年底和今年年初，在我們等待 FDA 對在用研究方案的反饋並準備運行在用研究的同時，我們開發了一種更靈敏的檢測方法來測量 KLK1 水平並提高我們檢測方法的一致性測量 KLK1 的活動水平。我們也會這樣做，因為 FDA 對我們現有的檢測方法提出了問題。雖然我們認為我們現有的檢測是合理的，但我們決定謹慎並最終減少完成這項工作所花費的時間，並消除 FDA 可能有其他問題並進一步延遲恢復 ReMEDy2 試驗的風險。

The FDA had also asked whether trypsin could be a potential cause or contributor to the hypotensive events in ReMEDy2. This question likely stems from the use of trypsin in the manufacturing of the DM199 substance and trypsin by itself can cause drops in blood pressure.

FDA 還詢問胰蛋白酶是否可能是 ReMEDy2 中低血壓事件的潛在原因或促成因素。這個問題可能源於在製造 DM199 物質時使用了胰蛋白酶，而胰蛋白酶本身會導致血壓下降。

Early in 2022, as part of our ongoing manufacturing development program, we had initiated testing to that trypsin was fully removed from the DM199 during the manufacturing process. This testing confirmed that there is no or at least not detectable residue trypsin in DM199. In February, we submitted reports to the FDA confirming that trypsin was not measurable in DM199 and provided the update, validated methods, assays to the FDA for review.

2022 年初，作為我們正在進行的製造開發計劃的一部分，我們已開始測試胰蛋白酶在製造過程中已從 DM199 中完全去除。該測試證實在 DM199 中沒有或至少沒有檢測到殘餘胰蛋白酶。 2 月，我們向 FDA 提交了報告，確認在 DM199 中無法測量胰蛋白酶，並向 FDA 提供了更新、經過驗證的方法和檢測方法以供審查。

We recently received their feedback that the assays developed appear appropriate and our assessment of trypsin levels is also acceptable. At this point, I'm pleased to say that we believe we have a good ongoing dialogue with the FDA. We appreciate their engagement and we are confident that an end is in sight to our clinical hold. Note that the FDA has up to 30 days to review and respond to a Complete Response Letter, requesting the lifting of the clinical hold. Once we receive their response, we will provide an update on expected timing for getting ReMEDy2 restarted.

我們最近收到他們的反饋，即開發的檢測方法似乎合適，我們對胰蛋白酶水平的評估也是可以接受的。在這一點上，我很高興地說，我們相信我們與 FDA 正在進行良好的對話。我們感謝他們的參與，我們相信我們的臨床試驗即將結束。請注意，FDA 有最多 30 天的時間來審查和回复完整的回复函，請求解除臨床暫停。一旦我們收到他們的回复，我們將提供有關重啟 ReMEDy2 的預期時間的更新。

Yesterday, we also announced that we have initiated a Phase IC open-label, single-ascending dose study of the IV dosing of DM199 in the IV bags made from PVC used in the ReMEDy2 trial. This was not requested by the FDA, but as a proactive measure on our part decided before starting the in-use study.

昨天，我們還宣布我們已經啟動了一項 IC 期開放標籤、單次遞增劑量研究，研究 ReMEDy2 試驗中使用的 PVC 製成的靜脈輸液袋中 DM199 的靜脈給藥。這不是 FDA 的要求，而是作為我們在開始使用研究之前決定的一項主動措施。

We chose to do so for 2 primary reasons: First, if for some reason, the FDA is not satisfied that the results of the in-use study provided sufficient basis for adjusting the IV dose levels going forward in ReMEDy2, then the results of the Phase IC study will conclusively demonstrate the serum concentration levels of DM199 achieved with our proposed IV dose. The second reason has to do with driving confidence in the physician investigators. This study demonstrates our commitment to the patient safety. I mean I hope that will help us start strong when we resume enrollment in ReMEDy2. Enrollment in the Phase IC study began last week in the first 3 cohorts which gets us to 0.5 micrograms per kg dose level we've proposed to use going forward should be completed in April with preliminary data available in May.

我們選擇這樣做有兩個主要原因：首先，如果出於某種原因，FDA 不滿意在用研究的結果為調整 ReMEDy2 中未來的 IV 劑量水平提供了充分的基礎，那麼IC 期研究將最終證明我們建議的 IV 劑量所達到的 DM199 血清濃度水平。第二個原因與增強對醫師研究人員的信心有關。這項研究證明了我們對患者安全的承諾。我的意思是，我希望當我們恢復 ReMEDy2 的註冊時，這將幫助我們開始強大。上週開始的前 3 組 IC 期研究的註冊使我們達到了 0.5 微克/千克的劑量水平，我們建議在 4 月份完成，並在 5 月份提供初步數據。

I would like to also recognize and give a special thank you to our clinical team for getting this study designed, planned and initiated in a remarkably short period of time. We've learned a lot through this process. And as a result, DiaMedica will come out stronger and better prepared to resume trial activities once cleared by the FDA to do so.

我還要感謝並特別感謝我們的臨床團隊在非常短的時間內設計、計劃和啟動了這項研究。通過這個過程，我們學到了很多東西。因此，一旦獲得 FDA 的批准， DiaMedica 將變得更強大，準備更充分地恢復試驗活動。

This is also due in small part to some key additions to our management team in 2022. Dr. Kirsten Gruis, our Chief Medical Officer, is the Board certified neurologists with extensive experience in medical practice and drug development in bringing several drugs through FDA approval. Kirsten has also been instrumental in leading the response to the FDA and managing our FDA communications.

這在一定程度上也歸功於 2022 年我們管理團隊的一些重要補充。我們的首席醫療官 Kirsten Gruis 博士是董事會認證的神經科醫生，在醫療實踐和藥物開發方面擁有豐富的經驗，使多種藥物獲得 FDA 批准。 Kirsten 在領導對 FDA 的回應和管理我們與 FDA 的溝通方面也發揮了重要作用。

Dominic Cundari, our Chief Commercial Officer, you will recall, he managed the TPA franchise at Genentech for 30 years and came out of retirement to join DiaMedica because of his passion for the stroke community and the potential benefits of DM199.

Dominic Cundari，我們的首席商務官，你會記得，他在 Genentech 管理 TPA 特許經營權 30 年，由於他對中風社區的熱情和 DM199的潛在好處，他退休後加入 DiaMedica。

We also added significant late-phase clinical operation expertise with Julie Daves, our Senior Vice President of Clinical Development, Operations, bringing vast experience in clinical trial planning and execution and has a reputation for completing trials on time and under budget.

我們還與我們的臨床開發、運營高級副總裁 Julie Daves 一起增加了重要的後期臨床操作專業知識，帶來了臨床試驗規劃和執行方面的豐富經驗，並以按時和在預算內完成試驗而聞名。

In addition, at the Board level, we recently announced that Tanya Lewis has joined us. Tanya has extensive global regulatory expertise. This includes positions as Chief Development Officer, Chief Regulatory Officer and Chief Quality Officer. She has been involved with other clinical hold situations and has been responsible for several products making their way through the regulatory approval process with the FDA. It's a privilege to work with these individuals and the entire DiaMedica team.

此外，在董事會層面，我們最近宣布 Tanya Lewis 已加入我們。 Tanya 擁有廣泛的全球監管專業知識。這包括首席開發官、首席監管官和首席質量官等職位。她參與了其他臨床暫停情況，並負責通過 FDA 監管批准程序的幾種產品。與這些人和整個 DiaMedica 團隊一起工作是一種榮幸。

As you can tell here this morning, we look forward to getting out from under this clinical hold and resuming the development of DM199 to bring this important treatment to stroke patients. We see a bright horizon with the team we have built, and we will continue to grow as we move forward.

正如你今天早上在這裡所說的那樣，我們期待著擺脫這種臨床擱置，並恢復 DM199 的開發，為中風患者帶來這種重要的治療方法。我們看到了我們建立的團隊的光明前景，我們將在前進的過程中繼續成長。

One additional point that I'd like to make this morning. An important rationale for developing DM199, a synthetic form of the KLK1 protein, is the current usage of the KLK1 protein in China. As many of you know, in China, a form of the KLK1 protein is isolated from human urine, that product is called kallikrein and has been treating patients for over a decade now. In 2019, kallikrein was added to the National Reimbursement Medicines List. This spurred a dramatic increase in usage in China. There are more than 600,000 patients treated for stroke in 2021 alone.

今天早上我還想再說一點。開發 DM199（一種 KLK1 蛋白的合成形式）的一個重要理由是目前 KLK1 蛋白在中國的使用情況。正如你們許多人所知，在中國，一種形式的 KLK1 蛋白是從人體尿液中分離出來的，這種產品被稱為激肽釋放酶，十多年來一直在治療患者。 2019年，激肽釋放酶被列入國家醫保目錄。這刺激了中國使用量的急劇增加。僅 2021 年就有超過 600,000 名中風患者接受治療。

To put this into perspective, that's approximately 15% of the estimated 4 million annual strokes per year in China. This gives us extensive knowledge of the KLK1's clinical use and even more confidence that our recombinant form of the KLK1 therapy can bring this much-needed treatment to the U.S. and the rest of the world for patients who today do not have a treatment option.

從這個角度來看，這大約佔中國每年約 400 萬例中風的 15%。這使我們對 KLK1 的臨床用途有了廣泛的了解，並且更加相信我們的 KLK1 療法的重組形式可以為美國和世界其他地區的當今沒有治療選擇的患者帶來這種急需的治療。

I would like to now turn over the call to Scott Kellen to review the financial highlights.

我現在想把電話轉給 Scott Kellen，讓他審查財務亮點。

Thanks, Rick, and good morning, everyone. As Rick mentioned, we announced our full year 2022 financial results and filed our annual report on Form 10-K yesterday afternoon. These documents are both available on either the DiaMedica or the SEC websites.

謝謝，里克，大家早上好。正如里克所說，我們昨天下午公佈了 2022 年全年的財務業績，並提交了 10-K 表格的年度報告。這些文件均可在 DiaMedica 或 SEC 網站上獲得。

Starting with our balance sheet. As of December 31, 2022, our combined cash and investments totaled $33.5 million, down $2.6 million from $36.1 million as of the end of Q3 2022 and down $11.6 million from $45.1 million as of our prior year-end.

從我們的資產負債表開始。截至 2022 年 12 月 31 日，我們的現金和投資總額為 3350 萬美元，比 2022 年第三季度末的 3610 萬美元減少了 260 萬美元，比上年末的 4510 萬美元減少了 1160 萬美元。

Our 2022 cash usage was $11.6 million compared to $12.3 million in the prior year, and our cash usage was lower than planned due primarily to the halting of the enrollment in our ReMEDy2 trial. This should scale back up as we complete our response to the FDA and prepare for resuming enrollment. As Rick mentioned, we intend to provide an update on the timing for the resumption of the trial in the near future. We also reiterate that we believe our current cash will support the clinical development of DM199 and our operations into the fourth quarter of 2024.

我們 2022 年的現金使用量為 1160 萬美元，而上一年為 1230 萬美元，我們的現金使用量低於計劃，這主要是由於 ReMEDy2 試驗的註冊停止。隨著我們完成對 FDA 的回應並準備恢復註冊，這應該會擴大規模。正如 Rick 提到的，我們打算在不久的將來提供恢復試驗的最新時間。我們還重申，我們相信我們目前的現金將支持 DM199 的臨床開發和我們到 2024 年第四季度的運營。

Our research and development expenses decreased to $7.8 million for the year ended December 31, 2022, down from $8.8 million for the full year of 2021. This decrease was driven primarily by reduced costs incurred during 2022 for the wrap-up of our REDUX Phase II CKD trial and decreased nonclinical testing costs, a significant amount of which were incurred during 2021 in preparation for initiating the Phase II/III ReMEDy2 trial in 2022. These decreases were partially offset by increased personnel costs associated with expanding our R&D operations and increased manufacturing process development activities.

截至 2022 年 12 月 31 日止年度，我們的研發費用從 2021 年全年的 880 萬美元減少至 780 萬美元。這一減少主要是由於 2022 年 REDUX 第二階段總結所產生的成本減少所致CKD 試驗和降低的非臨床測試成本，其中很大一部分是在 2021 年發生的，以準備在 2022 年啟動 II / III 期 ReMEDy2 試驗。這些減少部分被與擴大研發業務和增加製造過程相關的人員成本增加所抵消發展活動。

Our general and administrative expenses were $6.2 million and $4.9 million for the years ended December 31, 2022 and 2021, respectively. This increase was primarily driven by increased directors and officers liability insurance, increased personnel and professional services costs to support our expanding clinical programs and increased legal fees for our lawsuit against PRA. These increases were partially offset by reduced noncash share-based compensation costs.

截至 2022 年 12 月 31 日和 2021 年 12 月 31 日止年度，我們的一般和行政費用分別為 620 萬美元和 490 萬美元。這一增長主要是由於董事和管理人員責任保險的增加、人員和專業服務成本的增加以支持我們不斷擴大的臨床項目以及我們針對 PRA 的訴訟的法律費用增加。這些增長部分被非現金股份補償成本的減少所抵消。

With that, let me turn the call back over to Rick.

有了這個，讓我把電話轉回里克。

Thanks, Scott. With that, we'd like to open the call for questions. Paul, if you could please introduce the first analyst.

謝謝，斯科特。有了這個，我們想打開問題的電話。保羅，如果可以請介紹第一位分析師。

(Operator Instructions) And our first question comes from Thomas Flaten of Lake Street Capital.

（操作員說明）我們的第一個問題來自 Lake Street Capital 的 Thomas Flaten。

Just a quick couple of questions on the Phase IC study. Was that protocol developed in conjunction with FDA? Or is this something you did completely independently as kind of a back pocket backup data set?

關於階段 IC 研究的幾個快速問題。該協議是與 FDA 聯合製定的嗎？或者這是你完全獨立做的事情，作為一種後袋備份數據集？

So I'll take that question. This is Kirsten. We've developed it independently the protocol in our -- what was your last response, to have in our back pocket. But we explained our situation to the sites and the local ethics board in terms of what we wanted to measure in that study.

所以我會回答這個問題。這是克爾斯滕。我們已經獨立開發了我們的協議——你最後的回應是什麼，放在我們的後兜里。但是我們根據我們想要在該研究中衡量的內容向網站和當地道德委員會解釋了我們的情況。

And then, Frank, then we can -- our previous Phase I trial that we did using the polyolefin bag, we basically are going to be able to compare that data with this new data and just confirm that we have the right dose range.

然後，弗蘭克，然後我們可以——我們之前使用聚烯烴袋進行的第一階段試驗，我們基本上將能夠將該數據與這個新數據進行比較，並確認我們有正確的劑量範圍。

Got it. And is there any risk that a normotensive patient would suffer a significant blood pressure drop outside of what you might see in a stroke patient?

知道了。血壓正常的患者是否存在中風患者血壓顯著下降的風險？

No. We wouldn't expect that because the prior Phase I that was done with the polyolefin bags that Rick mentioned, there were no problems with healthy volunteers who were normotensive having lowering of their blood pressure.

不，我們不希望因為之前的第一階段是用 Rick 提到的聚烯烴袋完成的，所以血壓正常的健康志願者沒有問題，血壓也降低了。

Got it. And then one final one. Rick, you mentioned that FDA has 30 days to respond to your final response. And if I'm reading the press release correctly, that response will go in, in April. So May would be the time line for a response on whether or not you've satisfied their outstanding questions?

知道了。然後是最後一個。 Rick，你提到 FDA 有 30 天的時間來回复你的最終回复。如果我沒有正確閱讀新聞稿，該回復將在 4 月份發布。那麼 5 月是回應您是否滿足了他們懸而未決的問題的時間線？

Yes. As soon as we have the Part 2 of the in-use study, and we're -- that's already initiated, there's few weeks for that study to be completed. So as soon as we have that completed, we'll submit and the FDA will then have up to 30 days.

是的。一旦我們有了使用中研究的第 2 部分，並且我們已經啟動，該研究將在幾週內完成。因此，一旦完成，我們就會提交，然後 FDA 將有最多 30 天的時間。

I think we're encouraged by the fact that over the last few months, we've had a good dialogue. We've been able to submit data along the way and then getting positive feedback. So I think this will be helpful instead of waiting to the end and submitting everything together.

我認為，過去幾個月我們進行了良好的對話，這讓我們感到鼓舞。我們已經能夠一路提交數據，然後獲得積極的反饋。所以我認為這比等到最後再一起提交所有內容更有幫助。

Our next question comes from Alex Nowak from Craig-Hallum Capital Group.

我們的下一個問題來自 Craig-Hallum Capital Group 的 Alex Nowak。

Okay. I think last call we had, I think there was -- I think, some strong confidence at the time that we weren't going to near the safety study in patient and now we're launching the Phase IC study. So was there something that you saw in the in-use study, anything in the FDA commentary that ultimately led you to say, we want to have this in our back pocket? Like what's changed here from the last call we had in October?

好的。我認為我們的最後一次通話，我認為當時有一些強烈的信心，我們不會接近患者的安全性研究，現在我們正在啟動 IC 期研究。那麼，您在使用研究中看到了什麼，FDA 評論中的任何內容最終讓您說，我們想把它放在我們的後兜里嗎？就像我們在 10 月份的最後一次通話相比這裡發生了什麼變化？

It's just for additional level of confidence, Alex. So we initiated the Phase IC. We started planning this well before even starting the in-use study. And so part of also the rationale is that when we were looking at some different scenarios, we actually were able to find a clinical site in Australia that had a slot open. That allowed us to get this study up and going quickly.

這只是為了增加信心，亞歷克斯。所以我們啟動了 Phase IC。我們甚至在開始使用中的研究之前就開始計劃好了。因此，部分原因還在於，當我們考慮一些不同的情況時，我們實際上能夠在澳大利亞找到一個有空位的臨床站點。這使我們能夠快速開展這項研究。

So at this point here, we anticipate to ideally having the results in early May. And while we didn't want to be in a situation that we run that in-use study and for some reason, we see something unexpected. And then we'd have to go back and run a Phase IC trial that could then put this out until this fall. So I think it was an important step here to giving us some comfort backup plan. And then importantly, it also helps with just providing some confidence for the sites that we're taking patient safety very, very importantly, and we'll give us just some additional data here to support this trial. And I think it's going to help with enrollment after the trials up and running.

因此，此時此刻，我們預計理想情況下會在 5 月初獲得結果。雖然我們不希望處於運行該使用中研究的情況，但出於某種原因，我們看到了一些意想不到的事情。然後我們必須回去進行 Phase IC 試驗，然後才能將其推遲到今年秋天。所以我認為這是為我們提供一些舒適的備用計劃的重要一步。然後重要的是，它還有助於為我們非常非常重要地對待患者安全的網站提供一些信心，我們將在這裡提供一些額外的數據來支持這項試驗。而且我認為這將有助於在試驗啟動和運行後進行註冊。

Okay. That all makes sense. And a question that I think still sits out there, did we know the correct dosage going into patients for the Phase II stroke study done in Australia going back a couple of years ago? So I mean I know we don't have it a clear answer on that, but what's the risk of the FDA even when you provide all this information back to them, they say, "Okay, fine, but we'd like you to do another Phase II study before relaunching this Phase II/Phase III study?"

好的。這一切都說得通。我認為仍然存在一個問題，我們是否知道幾年前在澳大利亞進行的 II 期中風研究中患者的正確劑量？所以我的意思是我知道我們對此沒有明確的答案，但即使你將所有這些信息提供給他們，FDA 的風險是什麼，他們說，“好吧，很好，但我們希望你在重新啟動此 II 期/III 期研究之前，是否進行另一項 II 期研究？”

Sure. So the initial Phase I study we did supports the Phase II for stroke. That study was really designed on the IV portion was to match the drug level. So the PK profile to what's been shown with the kallikrein, the human urinary form. So we did that with the polyolefin bag and then we went to our Phase II trial and we used the same bag.

當然。因此，我們所做的初始 I 期研究支持中風的 II 期研究。該研究實際上是在 IV 部分設計的，以匹配藥物水平。因此，PK 曲線與人類尿液形式的激肽釋放酶有關。所以我們用聚烯烴袋子做了那個，然後我們進行了 II 期試驗，我們使用了同一個袋子。

And so then what we discovered here is that, close to half of the drug was sticking. We went -- pivoted to the Phase II/III with a PVC bag. And effectively, we're overdosing by twofold. So we've now confirmed this in our 2 studies, the IV bag study we did last fall and then now with the in-use study. So we feel that for us and patient safety, we think we've identified the right range, but we're going to also have this data here in really a matter of weeks on -- from this additional Phase I trial that is ongoing.

然後我們在這裡發現的是，將近一半的藥物粘在一起了。我們去了——用 PVC 袋轉向 II/III 期。實際上，我們加倍過量。所以我們現在已經在我們的 2 項研究中證實了這一點，我們去年秋天進行的 IV 袋研究和現在的使用研究。所以我們覺得，為了我們和患者的安全，我們認為我們已經確定了正確的範圍，但我們也將在幾週後在這裡獲得這些數據——來自正在進行的額外 I 期試驗。

Okay. And walking through it like that, I think that makes sense. I think that should be a good argument to the FDA. Final question here. Once the clinical hold is lifted and maybe it's in the May-ish time frame, how quickly can you reactivate sites and start enrolling patients? Are you really starting from square one there? Or can you decide to activate or reactivate relatively quickly?

好的。像那樣走過它，我認為這是有道理的。我認為這應該是對 FDA 的一個很好的論據。最後一個問題在這裡。一旦解除臨床暫停並且可能在五月左右的時間範圍內，您可以多快重新激活網站並開始招募患者？你真的從那裡的第一個廣場開始嗎？還是您可以決定相對較快地激活或重新激活？

Yes. I mean before we had the clinical hold, I mean if you're looking at clinical trials like that, we had 15 sites. Really, we're going to do all we can to get that up and going. I think importantly, with having Kirsten and Julie of joining our team since last year, I think we're going to be in a lot better position here to get the study up. It's going to take a little bit of time, but I think importantly, after we get it up and running, we've been doing a lot of work since then and just getting all of our documents and materials cleaned up in really good shape. So as soon as we get off -- after we get off the clinical hold, we'll provide an update here in terms of some of the timing.

是的。我的意思是，在我們進行臨床試驗之前，我的意思是如果你正在研究這樣的臨床試驗，我們有 15 個站點。真的，我們將盡我們所能來實現它。我認為重要的是，自去年以來 Kirsten 和 Julie 加入了我們的團隊，我認為我們將在這方面處於更好的位置來開展研究。這需要一點時間，但我認為重要的是，在我們啟動並運行之後，我們一直在做很多工作，只是將我們所有的文件和材料清理得非常好。因此，一旦我們下車 - 在我們離開臨床暫停後，我們將在此處提供一些時間的更新。

And our final question comes from Francois Brisebois of Oppenheimer.

我們的最後一個問題來自 Oppenheimer 的 Francois Brisebois。

This is Dan on for Frank. Just a follow-up from the other 2 on the Phase IC study that's ongoing. Could you share some color on the doses that you're going to be using in the single ascending dose study? I believe the original Phase II -- the original plan for the ReMEDy2 was to use both 1 microgram per kilogram and 3 microgram per kilogram. So just in terms of what's the maximum dose that you're testing in this study?

這是弗蘭克的丹。只是其他 2 人對正在進行的 IC 階段研究的跟進。您能否分享您將在單次遞增劑量研究中使用的劑量的一些顏色？我相信最初的第二階段——ReMEDy2 的最初計劃是同時使用每公斤 1 微克和每公斤 3 微克。那麼就您在本研究中測試的最大劑量而言是多少？

Sure. So there's 2 doses. So the first is the IV dose that's being tested in the Phase IC. So maybe just to step back for a moment. So when a patient has a stroke, they come into the hospital and they will get the IV dose of DM199. So in our Phase IC, we're planning 3 initial doses of 0.1, 0.25 and 0.5 micrograms per kg. We believe that 0.5 will be the dose that we're using based upon the in-use data, the IV bag study and in our previous work.

當然。所以有2劑。所以第一個是在階段 IC 中測試的 IV 劑量。所以也許只是退後一步。因此，當患者中風時，他們會到醫院接受 DM199 的靜脈注射。因此，在我們的 IC 階段，我們計劃 3 種初始劑量，分別為每公斤 0.1、0.25 和 0.5 微克。我們相信 0.5 將是我們根據使用中的數據、IV 袋研究和我們之前的工作使用的劑量。

And then that's followed then clinically with subcu dosing, and that's at 3 micrograms per kg, and there's no change in that. So the subcu dosing occurs twice a week for 3 weeks and then they'll get 3 micrograms. And there's no impact on that dosing with this hold.

然後在臨床上進行亞劑量給藥，即每公斤 3 微克，並且沒有變化。因此，subcu 給藥每週兩次，持續 3 週，然後他們將獲得 3 微克。並且這種保留對劑量沒有影響。

And we have no further questions in queue. I'll turn the call back over to our host.

我們沒有其他問題要排隊了。我會把電話轉回我們的主持人。

All right. Again, we'd like to thank everyone for joining us this morning and for your continued support. The goal of bringing this important treatment to stroke patients as quickly as possible. We appreciate your interest in DiaMedica and your continued support. And this concludes our call today. Thank you.

好的。再次，我們要感謝大家今天早上加入我們以及您一直以來的支持。盡快為中風患者帶來這一重要治療的目標。感謝您對 DiaMedica 的關注和持續支持。我們今天的電話會議到此結束。謝謝。

That concludes today's conference call. Thank you for joining, and have a pleasant day.

今天的電話會議到此結束。感謝您的加入，祝您度過愉快的一天。