DiaMedica Therapeutics Inc (DMAC) 2023 Q3 法說會逐字稿

(audio in progress) 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. 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.

（音訊進行中）任何重播或文字記錄重讀的時間。 DiaMedica 不承擔任何更新其前瞻性聲明的責任。在準備好發言後，我們將開通電話提問。現在我想介紹一下今天電話會議的主持人，DiaMedica 總裁兼執行長 Rick Pauls 先生。保羅斯先生，您可以開始了，先生。

Thank you, Paul. Hello, everyone, and welcome to our third quarter conference call. I'm joined this morning by Scott Kellen, our Chief Financial Officer.

謝謝你，保羅。大家好，歡迎參加我們的第三季電話會議。今天早上我們的財務長 Scott Kellen 也加入了我的行列。

Before we begin this morning, I want to take a moment to welcome Dr. Ambarish Shah as our Chief Technology Officer. Dr. Shah has over 25 years of experience in advancing biopharmaceuticals from early stage to commercialization, where he has had key contributions to over 50 drugs and multiple successful drug approvals. He was previously the Vice President and Head of Global Vaccine Development at CSL Seqirus, where he is accountable for end-to-end chemistry, manufacturing, and control in the development of vaccines.

在今天早上開始之前，我想花一點時間歡迎 Ambarish Shah 博士擔任我們的技術長。 Shah 博士在推動生物製藥從早期階段到商業化方面擁有超過 25 年的經驗，其中他對 50 多種藥物做出了重要貢獻，並多次成功獲得藥物批准。他曾擔任 CSL Seqirus 的副總裁兼全球疫苗開發主管，負責疫苗開發的端對端化學、製造和控制。

Prior to that position, he was Executive Director, Head of Drug Product Development at Bristol-Myers Squib, formerly Celgene. His prior experience comprised increasingly impactful roles at AstraZeneca, formerly MedImmune; GlaxoSmithKline, formerly Human Genome Sciences; and Pfizer, formerly Wyeth.

在此之前，他曾擔任 Bristol-Myers Squib（原 Celgene）的執行董事兼藥品開發主管。他之前的經歷包括在阿斯特捷利康（AstraZeneca）（前身為 MedImmune）擔任越來越有影響力的職位；葛蘭素史克（GlaxoSmithKline），前身為人類基因組科學公司；輝瑞（Pfizer），原名惠氏（Wyeth）。

Ambarish consulted with us for five months before joining us in a permanent role. We are thrilled to have Ambarish as part of our team.

安巴里什在加入我們並擔任永久職位之前與我們進行了五個月的諮詢。我們很高興安巴里什成為我們團隊的一員。

Turning to our Phase 2 updates. As we've discussed, our clinical operations have been working tirelessly to assemble the team, update procedures, and prepare for the tools to properly support the physician investigators in the clinical study sites. During this time, we have also been speaking with study sites, key opinion leaders, industry experts, our Scientific Advisory Board, and our new interim Chief Medical Officer, Dr. [Duran Dubow], to ensure that the ReMEDy2 protocol is clear and executable as possible by study sites while generating the data required for the FDA and other regulatory bodies. More than that, we want to give DM199 greatest possible probability of clinical success.

轉向我們的第二階段更新。正如我們所討論的，我們的臨床操作部門一直在不懈地努力組建團隊、更新程序並準備工具，以便為臨床研究中心的醫師研究人員提供適當的支援。在此期間，我們還與研究中心、關鍵意見領袖、行業專家、我們的科學顧問委員會和我們新的臨時首席醫療官 [Duran Dubow] 博士進行了交談，以確保 ReMEDy2 協議清晰且可執行研究中心盡可能同時產生FDA 和其他監管機構所需的數據。更重要的是，我們希望給予 DM199 最大可能的臨床成功機率。

We will focus today on discussing these protocol amendments. In addition to issuing our quarterly earnings press release yesterday, we provided a slide deck presenting more detailed information. This information is available on both the DiaMedica website at www.diamedica.com and the SEC website, www.sec.gov.

今天我們將重點討論這些協議修正案。除了昨天發布季度收益新聞稿外，我們還提供了幻燈片，展示了更詳細的資訊。這些資訊可在 DiaMedica 網站 www.diamedica.com 和 SEC 網站 www.sec.gov 上取得。

The amendment protocols was submitted to the FDA in early October, and the FDA did not have any comments as of the end of the 30-day review period, which expired on November 3. Given this, we are able to and they're moving forward in conducting ReMEDy2 with this amended protocol. In its totality, we believe the amended protocol significantly increases our probability of achieving clinical success and will accelerate site activation.

修訂方案已於 10 月初提交給 FDA，截至 11 月 3 日到期的 30 天審查期結束時，FDA 沒有任何評論。鑑於此，我們能夠並且他們正在採取行動推進使用此修訂後的協議進行 ReMEDy2。總的來說，我們相信修訂後的方案顯著增加了我們實現臨床成功的可能性，並將加速站點啟動。

Furthermore, if we increase the performance improvement of DM199 versus placebo at the interim analysis, we can reduce the total required number of patients for the trial, which is our quickest and most cost-effective path to completing the trial and getting our drug to stroke patients, the most significant change in the protocol centered around the inclusion and exclusion criteria for the trial. Specifically, we modified the baseline National Institute of Health Stroke Scale, or NIHSS inclusions score to focus on a schematic strokes of moderate severity.

此外，如果我們在中期分析中提高DM199 相對於安慰劑的性能改進，我們就可以減少試驗所需的患者總數，這是我們完成試驗並使我們的藥物治療中風的最快且最具成本效益的途徑對於患者而言，方案中最顯著的變化集中在試驗的納入和排除標準。具體來說，我們修改了美國國立衛生研究院卒中量表或 NIHSS 納入評分的基線，以重點關注中等嚴重程度的示意性中風。

This is defined as patients presenting with a baseline NIHS score of 5 to 15. We conducted a post hoc review of a ReMEDy1 Phase 2 stroke trial, focusing on those participants that did not receive mechanical thrombectomy prior to enrollment in a ReMEDy1 trial. This is a subset of that trial that most closely aligns with the target patient population for the ReMEDy2 trial. In these patients, there was a 15% greater absolute improvement in participants reaching an excellent outcome, defined as a score of zero to one on a Modified Ranking Scale or MRS.

這被定義為基線 NIHS 評分為 5 至 15 分的患者。我們對 ReMEDy1 2 期中風試驗進行了事後審查，重點關注那些在參加 ReMEDy1 試驗之前未接受機械血栓切除術的參與者。這是該試驗的一個子集，與 ReMEDy2 試驗的目標患者群體最接近。在這些患者中，參與者的絕對改善提高了 15%，達到了優異的結果（定義為改良評分量表或 MRS 得分為 0 到 1）。

This group comprised of 45 participants, 25 active, and 21 placebo. These participants were enrolled based upon a baseline NIHSS score, of 6 to 24. Scores above 15 represent moderate to severe and severe strokes. When we look at the results from just a (technical difficulty) moderate severity strokes in this trial. Those in the NIHS scores of 6 to 15, which includes 34 participants, 19 on DM119 and 15 and placebo, the improvement in excellent outcomes increased to 18%.

該組由 45 名參與者組成，其中 25 名積極參與者和 21 名安慰劑參與者。這些參與者是根據 NIHSS 基線評分（6 至 24）入組的。評分高於 15 代表中度至重度和重度中風。當我們查看本次試驗中（技術難度）中等嚴重程度中風的結果。 NIHS 評分為 6 至 15 分的受試者（包括 34 名參與者，其中 19 名使用 DM119，15 名使用安慰劑）的優秀結果改善增加至 18%。

And if we go one step further and look at just the strokes with the baseline NIHSS score of 6 to 10, the improvement in excellent outcomes is even higher, where we had 35%, based on 26 participants, of which 14 were on DM199, and 12, placebo.

如果我們更進一步，僅觀察 NIHSS 基線評分為 6 至 10 分的中風，則優良結果的改善甚至更高，基於 26 名參與者（其中 14 名使用 DM199），我們的改善率為 35%， 12、安慰劑。

Let me add the caveat here and recognize that the post-hoc analysis includes a small number of patients, but is a key to point out there were no study participants in the non mechanical thrombectomy subgroup with a baseline score of 15 that achieved an excellent outcome and MRS of zero to one.

讓我在此補充一點，並認識到事後分析包括少數患者，但關鍵是要指出，基線評分為 15 的非機械血栓切除亞組中沒有研究參與者取得了優異的結果和MRS從0到1。

It is a high clinical bar to take a patient with a baseline NIHSS score above 15, a moderately severe stroke and expect many to get to an MRS score of zero to one. It is important to note the average NIHSS baseline in most kallikrein studies, this is the human urinary form of KLK1 in China ranged from 8 to 8.5. In contrast, ReMEDy1 was 10.9. By targeting some moderate strokes, we anticipate aligning more closely with the kallikrein range.

對於基線 NIHSS 評分高於 15 的患者來說，這是一個很高的臨床障礙，屬於中度嚴重中風，並且期望許多人的 MRS 評分為 0 到 1。值得注意的是，大多數激肽釋放酶研究中的平均 NIHSS 基線為 KLK1 在中國的人類尿型，範圍為 8 至 8.5。相比之下，ReMEDy1 為 10.9。透過針對一些中度的中風，我們預計與激肽釋放酶範圍更接近。

Just to tie things out, we're also including stroke patients, having a baseline NIHS score of five, which represents approximately 20% of all moderate strokes. As mentioned, we saw the highest treatment effect in the NIHS scores of 6 to 10, and by including NIHS scores of 5, we hope to capture more of these patients. Our new range of 5 to 15 also fall the alliance with official NIHS definition of moderate ischemic strokes.

為了弄清楚這一點，我們還包括中風患者，他們的 NIHS 基線評分為 5，約佔所有中度中風的 20%。如前所述，我們在 NIHS 評分為 6 至 10 分時看到了最高的治療效果，透過納入 NIHS 評分為 5 分的患者，我們希望能夠捕獲更多此類患者。我們的新範圍 5 至 15 也符合 NIHS 官方對中度缺血性中風的定義。

The net effect of the change in NIHS inclusion range does reduce the number of potentially eligible patients in the ReMEDy2 trial. However, we believe that by focusing on moderate strokes, we have the highest probability of clinical success in generating the largest possible improvement relative to placebo, the latter being important for both reducing the number of participants we need in the trial and generating greater statistical significance and perhaps equally as important, eventually driving commercial adoption and favorable pricing assumptions after the FDA marketing approval.

NIHS 納入範圍變化的淨效應確實減少了 ReMEDy2 試驗中潛在合格患者的數量。然而，我們相信，透過關注中度中風，我們在臨床上取得成功的可能性最高，相對於安慰劑而言，產生最大可能的改善，後者對於減少試驗中所需的參與者數量和產生更大的統計顯著性非常重要也許同樣重要的是，在 FDA 行銷批准後最終推動商業採用和有利的定價假設。

The second thing is you want to discuss is the exclusion of ischemia strokes occurring in the posterior circulation of the brain or PC strokes. These can be problematic strokes for clinical trials. The NIH Stroke Scale predominantly evaluates neurological deficits created by strokes are occurring in the interior or front circulation of the brain. As a result, PC strokes are often underscored by the NIH Stroke Scale.

第二件事是你要討論的是排除發生在大腦後循環的缺血性中風或PC中風。對於臨床試驗來說，這些可能是有問題的中風。 NIH 中風量表主要評估由發生在大腦內部或前部循環的中風引起的神經功能缺損。因此，NIH 中風量表經常強調 PC 中風。

Our Chief Business Officer, Dave, Wambeke was recently on a business development trip in China where he was able to capture greater perspective on the clinical use of kallikrein, the human urinary derived farmers, KLK1. In his various discussions, it became clear that PC strokes were excluded from the primary kallikrein studies, due to the issues with the NIH Stroke Scale properly evaluating these patients.

我們的首席商務官 Dave, Wambeke 最近在中國進行業務開發之旅，在那裡他能夠更深入地了解激肽釋放酶、人尿衍生農民 KLK1 的臨床應用。在他的各種討論中，很明顯，由於 NIH 中風量表在正確評估這些患者時存在問題，PC 中風被排除在主要激肽釋放酶研究之外。

Obviously, this issue has the potential to create uncontrollable variability in a clinical trial, which we prefer not to introduce in ReMEDy2. Here again, this may also reduce the number of eligible patients for the trial, but we expect the impact to the minimum. Only 20% of all strokes originate in the posterior circulation and approximately 70% of those have an NIHS score less than 5, meaning the vast majority of this already small pool of patients would not meet the bottom end of our baseline inclusion criteria.

顯然，這個問題有可能在臨床試驗中產生無法控制的變異性，我們不希望在 ReMEDy2 中引入這種變異。同樣，這也可能會減少符合試驗資格的患者數量，但我們預期影響會降至最低。所有中風中只有 20% 起源於後循環，其中約 70% 的 NIHS 評分低於 5，這意味著這部分患者中的絕大多數不符合我們基線納入標準的下限。

The last change I want to address is the one that has the least the potential to affect the overall timing of the trial, but it is more technical. It is our removal of the overwhelming efficacy assessment during the interim analysis. And interim assessment of efficacy comes with a penalty in the statistical analysis of the overall trial.

我要解決的最後一個變化是影響試驗整體時間的可能性最小的變化，但它更具技術性。這是我們在中期分析期間取消了壓倒性的功效評估。療效的中期評估會在整個試驗的統計分析中帶來懲罰。

This penalty is significantly larger than the penalty for re-estimating the sample size. By removing this penalty, we believe will further increase the possibility of study success. Additionally, from a practical perspective, our projected future enrollment rates suggest little benefit in conducting an interim analysis.

此懲罰明顯大於重新估計樣本量的懲罰。透過消除這種懲罰，我們相信將進一步增加研究成功的可能性。此外，從實際角度來看，我們預期的未來入學率顯示進行中期分析幾乎沒有好處。

It is key to remember that we will not stop enrolling patients once the 144th patient is recruited. During the period encompassing the enrollment of 144 patients through the 90 day follow-up and subsequent data analysis of the interim analysis, we anticipate enrollment nearing 240 patients. This 240 number represents the lower threshold of our re-estimated sample size range.

重要的是要記住，一旦招募了第 144 名患者，我們就不會停止招募患者。在 90 天的追蹤和隨後的中期分析數據分析期間，招募了 144 名患者，我們預計招募人數將接近 240 名。這個 240 數字代表我們重新估計的樣本量範圍的下限。

Should our interim results demonstrate overwhelming efficacy strong enough to warrant halting the study, we would likely already be at or very near that point. It is key to point out that we will not stop enrolling patients once the 144th patient is recruited. With now effective amended protocol that we believe gives us the highest probability of clinical success, our focus is solely on the site activation and patient recruitments.

如果我們的中期結果顯示出壓倒性的功效，足以證明我們需要停止這項研究，那麼我們很可能已經達到或非常接近那個點。需要指出的是，一旦招募了第 144 名患者，我們就不會停止招募患者。現在，我們相信有效的修訂方案為我們帶來了最高的臨床成功機率，我們的重點只是現場活化和病患招募。

Our team is energized and working closely with our global CROs. We have reached out to over 600 sites in 23 countries, and we are conducting extensive feasibility and site selection and narrowing down to what we believe will be the best sites for our trial, with a target still about 200 sites globally.

我們的團隊充滿活力，並與我們的全球 CRO 密切合作。我們已經接觸了 23 個國家/地區的 600 多個站點，我們正在進行廣泛的可行性和站點選擇，並縮小我們認為最適合我們試驗的站點，目標仍然是全球約 200 個站點。

Our protocol is also currently in review by the Canadian and Australian Stroke Consortiums. The first three sites of our trials are on track to be reactivated in November and December. then, 20 fast-track sites to be follow in the US. We are working with our CRO and scientific advisory board in the selection process.

我們的方案目前也正在接受加拿大和澳洲中風協會的審查。我們的前三個試驗地點預計將於 11 月和 12 月重新啟動。然後，美國將有 20 個快速通道網站跟進。我們正在與 CRO 和科學顧問委員會合作進行選擇過程。

The majority of US sites should be activated in the first half of 2024. We'll provide more information on the timing of sites at our next conference call.

大多數美國站點應在 2024 年上半年啟動。我們將在下次電話會議上提供有關站點時間表的更多資訊。

Also, as we discussed in our last earnings call, based upon enrollment rates in recent stroke trials and discussions with multiple CROs, we believe that full enrollment for the interim analysis can be completed in 2024. But ultimately, this will depend upon the actual enrollment rates.

此外，正如我們在上次財報電話會議中所討論的那樣，根據最近中風試驗的入組率以及與多個CRO 的討論，我們相信中期分析的全部入組可以在2024 年完成。但最終，這將取決於實際入組情況費率。

Before handing it over to Scott, I'd like to emphasize we have received significant interest from key opinion leaders and investigators. DM199 is designed to enhance collateral circulation, a method we consider superior to neuroprotectant and more like other established revascularization treatments like TPA and mechanical thrombectomy. They are also attracted to DM199's potential safety profile, particularly its lack of increased bleeding.

在將其交給斯科特之前，我想強調我們已經收到了關鍵意見領袖和調查人員的極大興趣。 DM199 旨在增強側支循環，我們認為這種方法優於神經保護劑，並且更像其他已建立的血管重建治療方法，如 TPA 和機械血栓切除術。他們也被 DM199 的潛在安全性所吸引，特別是它不會增加出血。

Additionally, we believe that revised trial design with a higher potential to demonstrate an improvement and excellent outcomes also contributes to this interest. We believe are at a pivotal moment in the treatment of ischemic stroke. Now at over a quarter century since approval of TPA for stroke. Our strategy represent a potential landmark advancement in stroke treatment since then.

此外，我們相信修訂後的試驗設計更有可能展示改進和優異的結果，也有助於這種興趣。我們相信，目前正處於治療缺血性中風的關鍵時刻。 TPA 被批准用於治療中風已有四分之一個世紀了。自那時以來，我們的策略代表了中風治療領域潛在的里程碑式進步。

I'd like to now turn the call to Scott Kellen to review this quarter's financial results.

我現在想打電話給斯科特·凱倫（Scott Kellen），讓他回顧本季的財務表現。

Thanks, Rick, and good morning, everyone, and thanks for being part of today's call. Our total cash, cash equivalents, and investments were $56.2 million at the end of Q3, up from $33.5 million as of December 31, 2022. This increase was due primarily to the $33.8 million of net proceeds from our June and April private placements conducted earlier this year, partially offset by cash used to fund operating activities during the nine months ended September 30, 2023.

謝謝瑞克，大家早安，謝謝您參加今天的電話會議。截至第三季末，我們的現金、現金等價物和投資總額為5,620 萬美元，高於截至2022 年12 月31 日的3,350 萬美元。這一增長主要是由於我們之前進行的6 月和4 月私募獲得了3,380 萬美元的淨收益今年，部分被截至 2023 年 9 月 30 日的九個月期間用於營運活動的現金所抵消。

Net cash used in operating activities for the nine months ended September 30, 2023, was $14.9 million compared to $8.7 million in the prior year period. The increase in cash usage relates primarily to increased net loss in the current year period over the prior year period and increased amortization of discounts on marketable securities, partially offset by non-cash share-based compensation and the effects of changes in operating assets and liabilities in the current year period.

截至 2023 年 9 月 30 日的九個月，經營活動使用的現金淨額為 1,490 萬美元，去年同期為 870 萬美元。現金使用量的增加主要與本年度淨虧損較上年同期增加以及有價證券折扣攤銷增加有關，但部分被非現金股份補償以及經營資產和負債變化的影響所抵消在本年度期間。

We believe that our current capital will support the clinical development of DM199 and our operations into 2026. Our research and development expenses increased to $3.3 million for the three months ended September 30, 2023, up from $1.6 million for the three months ended September 30, 2022.

我們相信，我們現有的資金將支持DM199 的臨床開發和我們到2026 年的營運。截至2023 年9 月30 日止三個月，我們的研發費用增加至330 萬美元，高於截至9 月30日止三個月的 160 萬美元。2022 年。

R&D expenses increased to $9.4 million for the nine months ended September 30, 2023, up from $5.6 million for the nine months ended September 30, 2022. The increase for the nine month comparison was driven primarily by costs incurred for the NU studies performed to address the recently lifted clinical hold on the company's ReMEDy2 AIS trial, cost incurred for the Phase 1c study, determining the DM199 blood concentration levels achieved with the IV dose of DM199 using PDC IV bags, and increased manufacturing and process development costs. Also contributing to the increase were higher personnel costs associated with expanding the clinical team.

截至2023年9月30日的九個月，研發費用從截至2022年9月30日的九個月的560萬美元增至940萬美元。這九個月的比較增長主要是由於為解決最近解除了該公司ReMEDy2 AIS 試驗的臨床擱置、1c 期研究產生的成本、使用PDC IV 袋確定DM199 IV 劑量所達到的DM199 血液濃度水平，以及增加的製造和製程開發成本。與擴大臨床團隊相關的人員成本增加也導致了這一成長。

These increases were partially offset by decreased costs incurred for the Phase 2/3 ReMEDy2 AIS trial, as activity was limited prior to the June 2023 lift of the clinical hold. Our general and administrative expenses were $1.9 million for the three months ended September 30, 2023, up from $1.5 million for the three months ended September 30, 2022.

這些增加被 2/3 期 ReMEDy2 AIS 試驗產生的成本下降部分抵消，因為在 2023 年 6 月臨床暫停解除之前活動受到限制。截至2023年9月30日止三個月，我們的一般及行政費用為190萬美元，高於截至2022年9月30日止三個月的150萬美元。

G&A expenses were $6 million for the nine months ended September 30, 2023, up from $4.5 million for the nine months ended September 30, 2022. To the increase for the nine month comparison was primarily due to increased legal fees incurred in connection with our lawsuit against PRA Netherlands and increased personnel costs incurred incurred in conjunction with expanding the team. Higher cost for patent prosecution and non-cash share-based compensation also contributed to the increase.

截至2023年9月30日止九個月的一般管理費用為600萬美元，高於截至2022年9月30日止九個月的450萬美元。這九個月比較的增加主要是由於與我們的訴訟有關的法律費用增加與 PRA 荷蘭隊的比賽以及因擴大團隊而產生的人員成本增加。專利申請和非現金股份補償成本的上升也導致了這種成長。

Before I turn you over to Rick, let me share that the hearing for the PRA lawsuit is currently still on track for December 7 of this year. PRA recently filed a counterclaim alleging that our enforcement of the April 2023 judgment affirming our ownership of all study records violated Dutch procedural loss. We disagree with their counter claim, and we don't currently anticipate that this will change the December 7 hearing date. We very much look forward to presenting our case against PRA.

在我把你交給 Rick 之前，讓我告訴大家，PRA 訴訟的聽證會目前仍在按計劃於今年 12 月 7 日舉行。 PRA 最近提出反訴，指控我們執行 2023 年 4 月的判決，確認我們對所有研究記錄的所有權，違反了荷蘭程序損失。我們不同意他們的反訴，我們目前預計這不會改變 12 月 7 日的聽證會日期。我們非常期待提出我們針對 PRA 的案件。

Now let me turn you back over to Rick.

現在讓我把你轉回給瑞克。

Thanks, Scott. With that, we would like to open the call for questions. Operator, if you could please open the lines for questions.

謝謝，斯科特。至此，我們想開始提問。接線員，如果可以的話，請打開提問線。

(Operator Instructions) Thomas Flaten, Lake Street Capital.

（操作員說明）Thomas Flaten，Lake Street Capital。

Good morning. Just a couple of quick questions, Rick. If you think about the total patients as a funnel, so you're excluding mechanical thrombectomy, TPA, so conservatively call that 20% of patients. Then you were moving about 20% of patients for the posture circulation. Can you just walk us through how that -- how you see that all working, especially if you include the NIHSS score as well?

早安.只是幾個簡單的問題，瑞克。如果您將患者總數視為一個漏斗，那麼您就排除了機械血栓切除術 (TPA)，因此保守地稱其為 20% 的患者。然後，您移動了大約 20% 的患者以進行體位循環。您能否向我們介紹一下這一切是如何運作的，特別是如果您還包括 NIHSS 分數的話？

Yeah, thanks, Thomas. So as we see this that -- bigger picture here is what's most important for us is getting to the -- we think that the greatest clinical effect with this drug. And so we think commercially, the larger Delta, we see some improvement of DM199 versus placebo. We think the greater commercial value.

是的，謝謝，托馬斯。因此，當我們看到這一點時——這裡的更大的前景對我們來說最重要的是——我們認為這種藥物的最大臨床效果。因此，我們認為在商業上，較大的 Delta，我們看到 DM199 相對於安慰劑有一些改進。我們認為商業價值較大。

And so as we're initially going to be targeting here, we anticipate initial label will be in the moderate severity stroke patients, which should be in a 35% to 40% of all strokes. And then commercially, though, as we talked to neurologists and commercial people, we think that if a patient has a mild or a moderate to severe strokes, then they most likely beginning in our treatment.

因此，正如我們最初的目標，我們預計最初的標籤將針對中度嚴重的中風患者，該患者應佔所有中風的 35% 至 40%。然而，在商業上，當我們與神經科醫生和商業人士交談時，我們認為如果患者患有輕度或中度至重度中風，那麼他們很可能開始接受我們的治療。

Got it. And then to get to the 144 patient enrollment by year end, how many sites do you need to have actively enrolling at your pacing to get to that number?

知道了。然後，為了在年底前達到 144 名患者註冊的目標，您需要有多少個網站以您的步調積極註冊才能達到這個數字？

So right now we're looking at and we're talking about up to a 100 sites. Really focusing on those steel first 75. So what we're looking at right now is about 40 in the US, potentially 10 in Australia, 10 in Canada, and then the remaining in Europe and other parts of the world. So as we are looking at the enrollment rate, that's the first assumption.

所以現在我們正在研究並討論多達 100 個站點。首先真正關注的是這些鋼鐵 75 個。所以我們現在關注的是美國大約 40 個，澳洲可能有 10 個，加拿大有 10 個，然後剩下的在歐洲和世界其他地區。因此，當我們考慮入學率時，這是第一個假設。

And then the second assumption is the patient to enrolment by site -- by month. So right now, what we're using as an enrollment rate target of 0.25. So having one patient per site every four months. And so this is based upon some of the analysis of some historical stroke trials.

第二個假設是病人按地點（按月）登記。現在，我們使用的入學率目標是 0.25。因此，每四個月每個站點就有一名患者。因此，這是基於對一些歷史中風試驗的一些分析。

We recently gone back and did an analysis of the last 20 or so stroke trials for acute ischemic stroke. Many of those were mechanical thrombectomy that a smaller treatment window and targeting a smaller patient population. And on average, there was an enrollment rate of 0.5. So about twice in terms of the rate that we're targeting. But there's still a lot of variables here that we just don't know.

我們最近回過頭來對最近 20 項左右的急性缺血性中風試驗進行了分析。其中許多是機械血栓切除術，治療窗口較小，針對的患者群體也較小。平均入學率為0.5。就我們目標速度而言，大約是兩倍。但這裡仍然有很多我們不知道的變數。

So even with these change is that we've made, we're still using the assumption of 0.25 enrollment rate and getting into the new year as we start to get some traction here. And we started in the first sites that will have better clarity of where that actual enrollment rates comes in at.

因此，即使我們做出了這些改變，我們仍然使用 0.25 入學率的假設，並進入新的一年，因為我們開始在這裡獲得一些牽引力。我們從第一個網站開始，這些網站將更清楚地了解實際入學率的情況。

Got it. And then one final one, if I might. Any reason that we shouldn't see the interim analysis readout in the second quarter of '25 if everything goes to plan?

知道了。如果可以的話，然後是最後一件事。如果一切按計畫進行，我們有什麼理由看不到 25 年第二季的中期分析結果？

No, that's the plan. And again, there's lots of variables. but I'm hoping here, I'm hoping that this enrollment rate is conservative. In the past, we had some challenges with COVID. Also part of these on protocol changes, there are some aspects in there that we had some -- that weren't quite clear. So with our new interim Chief Medical Officer in particular, helping us with just revising and just making the trial protocol more clear. And I think that's going to help with recruitment.

不，這就是計劃。再說一次，還有很多變數。但我希望這裡的入學率是保守的。過去，我們在新冠疫情方面遇到了一些挑戰。還有協議變更的一部分，我們有一些方面還不太清楚。因此，特別是我們新任臨時首席醫療官，幫助我們修改試驗方案並使試驗方案更加清晰。我認為這將有助於招聘。

Excellent. Appreciate taking the questions. Thank you.

出色的。感謝接受提問。謝謝。

Thanks, Thomas.

謝謝，托馬斯。

Alex Nowak from Craig-Hallum.

來自克雷格·哈勒姆的亞歷克斯·諾瓦克。

All right, great. Good morning, everyone. So the prior protocol made DM199 available only in one of mechanical thrombectomy wasn't given now it's based more on the interior circulation, but the goal still the same through reduced in mechanical thrombectomy patients. Is that correct?

好吧，太好了。大家，早安。因此，先前的方案使 DM199 僅適用於機械血栓切除術之一，現在它更多地基於內部循環，但透過減少機械血栓切除術患者的目標仍然相同。那是對的嗎？

So the plan still is to be excluding patients that were previously treated with mechanical thrombectomy and to exclude those patients that have a large vessel occlusion. And we believe that's about 20% of the strokes today that have a large vessel occlusion.

因此，該計劃仍然是排除先前接受過機械血栓切除術治療的患者以及排除那些有大血管閉塞的患者。我們相信，目前大約有 20% 的中風是由大血管閉塞引起的。

And now interior -- and then the interior circulations is being added on top of that?

現在是內部——然後在此基礎上添加內部循環？

Yeah. Alex, hey, this is Scott. As we were laying out the remarks, the NIHS score doesn't evaluate the posterior circulation strokes very well. And so the potential for getting miss scored patients into the trial -- scored low or high creates variability that we just don't want to introduce.

是的。亞歷克斯，嘿，這是史考特。正如我們所闡述的那樣，NIHS 評分並不能很好地評估後循環中風。因此，漏分患者進入試驗的可能性（得分低或高）會產生我們不想引入的變異性。

And keep in mind that of those 20% that PCS strokes, 70% generally present within an NIHS score of four or less. So the effect on the addressable patient population for ReMEDy2 is very minimal.

請記住，在 20% 的 PCS 中風患者中，70% 的 NIHS 評分通常為 4 分或更低。因此，ReMEDy2 對可尋址患者群體的影響非常小。

Okay. Got it. And then the assessment of the anterior versus posterior circulation, how quickly can that performance centers that just the real-time assessment? And then how many of ReMEDy1 were anterior?

好的。知道了。然後是前循環與後循環的評估，這種性能能夠以多快的速度集中於即時評估？那麼有多少 ReMEDy1 位於前部？

Yes, it's something that's a quick review by neurologists. We don't have the data in front of us from our ReMEDy1, but we can double check on that.

是的，這是神經科醫生快速審查的事情。我們面前沒有 ReMEDy1 的數據，但我們可以仔細檢查。

Okay. Understood. And then I just want to confirm -- so what will be reported now during the interim analysis? I understand you don't want to get the penalty. I just want to be clear on what we're going to see when that interim analysis heads.

好的。明白了。然後我只想確認一下——那麼在中期分析期間現在要報告什麼？我知道你不想受到處罰。我只是想弄清楚，當中期分析開始時我們會看到什麼。

Sure. So the interim analysis, if we're seeing a lack of efficacy, this study will be terminated for lack of efficacy. Otherwise, there'll be a resampling size between 240 and 728 patients. So the only thing has changed here is that we remove the option for stopping for overwhelming efficacy.

當然。所以中期分析，如果我們發現缺乏療效，這項研究將因缺乏療效而終止。否則，重新採樣的患者人數將在 240 至 728 名患者之間。所以這裡唯一改變的是我們刪除了為了壓倒性功效而停止的選項。

Got it. And there won't be any unblinding of the data we won't necessarily see excellent outcomes in the interim piece. We'll just either know it's either going to be stopped for lack of efficacy or study site need to be modified.

知道了。而且不會有任何數據揭盲，我們不一定會在中期作品中看到出色的結果。我們只會知道它要麼因缺乏療效而停止，要麼需要修改研究地點。

Yes, that's right. And we basically what drove this the change here as we're going through our forecasting and realizing that even if we achieve overwhelming efficacy at the interim analysis during that five month period from patient 144 is dosed in the interim analysis is conducted, we should be pretty close to that 240 patient anyways. In particular with not now expanding with our trial site of the US.

恩，那就對了。我們基本上是什麼推動了這裡的變化，因為我們正在進行預測並意識到，即使我們在中期分析中從患者 144 給藥的五個月期間取得了壓倒性的功效，我們也應該無論如何，與那240 名患者非常接近。特別是現在我們還沒有擴大我們在美國的試驗站點。

So we felt that there's no sense of taking that statistical penalty if effectively, we're going to be there anyways at that point in time.

因此，我們認為，如果有效的話，沒有必要採取統計懲罰，無論如何我們都會及時到達那裡。

Yeah, makes total sense. And then all these recommendations to the study change. Did they come internal? Did they come by KOLs that in the field or were they from the CRO?

是的，完全有道理。然後所有這些對研究的建議都會改變。他們是內部來的嗎？他們是來自現場的 KOL 還是來自 CRO？

So really good questions. They came really a combination. I mean, first off, Dave Wambeke, our Chief Business Officer was in China for a week in August. And speaking to the company that's currently marketing the kallikrein, the urine form of KLK1, speaking to several other pharmaceutical firms and related. And based upon that, he got some pretty clear feedback on some of these changes we've made like this posterial strokes, we'd be better targeting the moderates patient.

非常好的問題。他們確實是一個組合。我的意思是，首先，我們的首席商務官 Dave Wambeke 八月在中國待了一周。並與目前正在銷售激肽釋放酶（KLK1 的尿液形式）的公司進行了交談，並與其他幾家製藥公司及相關公司進行了交談。基於此，他對我們所做的一些改變（例如後中風）得到了一些非常明確的回饋，我們最好是針對溫和的患者。

So really leveraging the feedback, really in China in terms of patients that we believe will be better responders and then also having -- Duran Dubow, our interim Chief Medical Officer joining, taking another close looking at the protocol, getting some additional feedback here from the initial sites that we reached out to. So after coming off clinical hold, we reached out to numerous sites.

因此，真正利用這些回饋，真正在中國，就我們相信會有更好反應的患者而言，然後還有我們的臨時首席醫療官 Duran Dubow 加入，再次仔細研究該方案，從這裡獲得一些額外的反饋我們最初接觸的網站。因此，在結束臨床擱置後，我們聯繫了許多站點。

And there is a number of feedbacks to the protocol that we could be -- that could be done just to simplify and reducing some of the steps that we're perceived as complicated. And the point here right now, it's very important here that we make this protocol as simple as possible for the sites so that they are not looking at this protocol and feel that let's overcomplicate it.

我們可以對協議提出許多回饋——我們可以這樣做只是為了簡化和減少一些我們認為複雜的步驟。現在的重點是，我們讓網站的協議盡可能簡單，這樣他們就不會在看到這個協議時覺得我們把它變得過於複雜了，這一點非常重要。

So although this is taking a small delay here, I'd call it, but really very minor on terms of the big picture. So we see this as if we can increase the efficacy at the interim analysis by a few percentage than the previous protocol, that could really make the difference in not having to go to a larger total sample size. So ultimately, we feel this should reduce the total number of patients time and the costs from trial.

因此，儘管我認為這會帶來一點延遲，但從整體來看，這確實是非常小的延遲。因此，我們認為，與先前的方案相比，我們可以將中期分析的功效提高幾個百分點，這確實可以在不必採用更大的總樣本量的情況下產生差異。因此，最終，我們認為這應該會減少患者的總人數、時間和試驗成本。

All right. That makes sense. Appreciate the update. Thank you.

好的。這就說得通了。感謝更新。謝謝。

Yep. Thanks, Alex.

是的。謝謝，亞歷克斯。

Francois Brisebois, Oppenheimer.

弗朗索瓦·布里斯布瓦，奧本海默。

Hey, thanks for taking questions. So just a couple here. In terms of the moderate severity, can you help us understand -- I guess you're talking about the prevalence, but mechanistically, is there a rationale for this to make more sense here? And how do we get to feel comfortable that -- this won't -- having patients that are only moderately severe. Is it easy to gauge, choose moderate, and how do we feel comfortable that that will make enrollment quite a bit harder. Thank you.

嘿，謝謝你提出問題。所以這裡只有一對夫婦。就中等嚴重程度而言，您能否幫助我們理解——我猜您正在談論流行程度，但從機制上講，是否有一個更有意義的理由？我們如何對病情中等程度的患者感到放心（這不會）。是否容易衡量，選擇中等，以及我們如何感覺這會讓入學變得更加困難。謝謝。

Yes. So thanks, Frank. So the premise here is if you take a stroke patient that's come in -- and so first off, it's very clear. So the severity is scored by the NIHSS. So if the score is 5 to 15, that is a clear moderate severity stroke patient.

是的。所以謝謝，弗蘭克。所以這裡的前提是，如果你收治了一名中風患者——所以首先，這是非常清楚的。因此，嚴重程度由 NIHSS 進行評分。因此，如果評分為 5 至 15，則明確為中度嚴重中風患者。

And so we take a step back and we look at this, as a patient has a moderate to severe so above 15, the likelihood of that patient getting to a full recovery, an excellent outcome is not very high. And so as we take a step back and we look at this, and as we mentioned on the prepared remarks, from our Phase 2 trial, we didn't have a single pay patient on DM199 who came in with baseline above 15 that got to an excellent outcome.

因此，我們退後一步，考慮一下這一點，因為患者的病情為中度至重度，所以超過 15，該患者完全康復、獲得良好結果的可能性不是很高。因此，當我們退後一步並審視這一點時，正如我們在準備好的評論中提到的那樣，從我們的 2 期試驗中，我們沒有一個 DM199 的付費患者的基線高於 15一個很好的結果。

So I think what this does is just biases the opportunity here for a higher effect. And as we're looking at our Phase 2 data further, it's really in those patients that are -- frankly that were in the 6 to the 10 that we saw the greatest impact in getting to a full recovery compared to placebo. So we think these changes will ultimately show a greater effect and then furthermore, when we take a looking at the clinical use of the KLK1 in China, most of those trials are targeting a less severe -- so targeting more of a moderate severity stroke scale.

所以我認為這樣做只是偏向了這裡獲得更高效果的機會。當我們進一步查看第二階段數據時，坦白說，與安慰劑相比，我們看到對完全康復影響最大的患者確實是 6 到 10 名患者。因此，我們認為這些變化最終將顯示出更大的效果，此外，當我們觀察KLK1 在中國的臨床使用時，大多數試驗都針對不太嚴重的中風量表，因此更多針對中度嚴重的中風量表。

Okay, thanks. And then lastly, can you help us understand the potential outcomes of this lawsuit that's coming up here? Thank you.

好的謝謝。最後，您能幫助我們了解即將到來的這起訴訟的潛在結果嗎？謝謝。

Oh, sure, Frank. Hopefully the outcome is that we get access to our data, we get access to the study site, we're able to finally audit that study and confirm what the actual results were. I mean, first and foremost, we really really would like to get a final study report that's accurate and fileable.

哦，當然，弗蘭克。希望結果是我們能夠存取我們的數​​據，我們能夠訪問研究站點，我們能夠最終審查該研究並確認實際結果是什麼。我的意思是，首先也是最重要的，我們真的非常希望能獲得一份準確且可歸檔的最終研究報告。

Beyond that, we're going to ask -- we're asking for damages. That last proof of concept study that we believe was messed up would cost $6 million or $7 million to reperform today. So we're asking for that. We're asking for the some damages related to the license that -- an opportunity that DiaMedica had at the time that was basically undermined by the error reporting from PRA and we are taking a chance on lost value of the company as well.

除此之外，我們將要求賠償損失。我們認為最後一項概念驗證研究搞砸了，今天重新進行將花費 600 萬或 700 萬美元。所以我們要求這樣做。我們要求賠償與許可證相關的一些損失——DiaMedica 當時擁有的機會基本上被 PRA 的錯誤報告破壞了，我們也冒著公司價值損失的風險。

So all in, we're asking for as much as $75 million in damages and we'll see how much we can get through the court's process, again, provided that they have they reaffirmed their judgment from April that DiaMedica is the owner and the PRA has breached the agreement. Does that answer your question, Frank?

總而言之，我們要求賠償高達 7500 萬美元的損失，我們將再次看看我們能夠透過法院程序獲得多少賠償，前提是他們重申了 4 月份的判決，即 DiaMedica 是所有者，並且是PRA 違反了協議。這能回答你的問題嗎，法蘭克？

Yes, all set. Thank you.

是的，一切就緒。謝謝。

All right. Thanks, Frank.

好的。謝謝，弗蘭克。

And seeing no further questions, I'll turn the call back over to our host.

看到沒有更多問題，我會將電話轉回給我們的主持人。

All right, thanks, Paul. So the requirements that we discussed today in the inclusion criteria are intended to enhance ReMEDy2's probability of success on the primary endpoint, which also has the potential to reduce the total number of participants required to be enrolled in ReMEDy2 trial without significantly impacting the estimated enrollment rates.

好的，謝謝，保羅。因此，我們今天在納入標準中討論的要求旨在提高 ReMEDy2 在主要終點上成功的可能性，這也有可能減少 ReMEDy2 試驗所需的參與者總數，而不會顯著影響估計的入組率。

We'd like to thank everyone for joining us this morning and for your continued support. We are thrilled to be reengaged with clinical study sites and hope to be enrolling participants in. This concludes our call.

我們要感謝大家今天早上加入我們並感謝你們的持續支持。我們很高興能夠重新與臨床研究中心合作，並希望能夠招募參與者。我們的電話會議到此結束。

The meeting has now concluded. Thank you for joining, and have a pleasant day.

會議現已結束。感謝您的加入，祝您有個愉快的一天。