Enliven Therapeutics Inc (ELVN) 2021 Q3 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Imara, Inc. Q3 earnings conference call and webcast. (Operator Instructions)

美好的一天，感謝您的支持。歡迎參加 Imara, Inc. 第三季度財報電話會議和網絡廣播。 （操作員說明）

I would now like to hand the conference over to your speaker today, Mike Gray. Please go ahead.

我現在想把會議交給今天的發言人邁克·格雷。請繼續。

Okay. Thank you, operator. Good morning, everyone, and welcome to Imara's third-quarter 2021 conference call. I'm joined this morning by Imara's President and CEO, Rahul Ballal.

好的。謝謝你，接線員。大家早上好，歡迎參加 Imara 2021 年第三季度電話會議。今天早上，Imara 總裁兼首席執行官 Rahul Ballal 也加入了我的行列。

Before we begin, I'd like to remind everyone that various statements we make during this conference call about the company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual events or results could differ materially from those expressed or implied by these forward-looking statements as a result of various important factors, including those set forth in the risk factors section of our most recent quarterly report on Form 10-Q that we filed with the SEC this morning, as well as any other filings that we may make with the SEC.

在開始之前，我想提醒大家，我們在本次電話會議中就公司未來的預期、計劃和前景所做的各種陳述均構成前瞻性陳述，以符合《私人證券訴訟改革法案》中的安全港條款的目的。 1995 年。由於各種重要因素的影響，實際事件或結果可能與這些前瞻性陳述中明示或暗示的事件或結果存在重大差異，包括我們最近的10-Q 表格季度報告的風險因素部分中列出的因素。今天早上向 SEC 提交的文件，以及我們可能向 SEC 提交的任何其他文件。

Any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today.

本次電話會議中所做的任何前瞻性陳述僅代表我們截至今天的觀點，不應被視為代表我們在任何後續日期的觀點。雖然我們可能選擇在未來某個時候更新這些前瞻性陳述，但我們明確表示不承擔任何這樣做的義務，即使我們的觀點發生變化。因此，您不應依賴這些前瞻性陳述來代表我們截至今天之後任何日期的觀點。

With that, I'll now turn the call over to Imara's President and CEO, Rahul Ballal, who will provide an overview of our third quarter and key recent accomplishments. I'll then return following Rahul's discussion to review our third-quarter financial results, and we'll then open the call for any questions. Rahul?

現在，我將把電話轉給 Imara 總裁兼首席執行官 Rahul Ballal，他將概述我們第三季度和最近取得的主要成就。然後，我將在拉胡爾討論後回來回顧我們的第三季度財務業績，然後我們將開始電話詢問任何問題。拉胡爾？

Thank you, Mike. Good morning, everyone, and thank you for joining today's call.

謝謝你，邁克。大家早上好，感謝您參加今天的電話會議。

The third quarter and recent weeks have been productive periods for Imara and specifically on IMR-687 which we'll also refer to in its generic name, tovinontrine. We are pleased to have made substantial progress in our ongoing Phase 2b trials, and we expect to report interim data from both our Ardent trial in sickle cell disease and Forte trial in beta-thalassemia this quarter. Furthermore, we have taken concrete steps to expand our development pipeline by continuing to work with tovinontrine in heart failure with preserved ejection fraction, or HFpEF, and announcing a new clinic-ready program in IMR-261, an oral Nrf2 activator.

第三季度和最近幾週對 Imara 來說是富有成效的時期，特別是 IMR-687，我們也將在其通用名稱 tovinontrine 中提及。我們很高興在正在進行的 2b 期試驗中取得了實質性進展，我們預計本季度將報告鐮狀細胞病 Ardent 試驗和 β 地中海貧血 Forte 試驗的中期數據。此外，我們還採取了具體措施來擴大我們的開發渠道，繼續使用 tovinontrine 治療射血分數保留的心力衰竭（HFpEF），並宣布了 IMR-261（一種口服 Nrf2 激活劑）的新臨床準備項目。

Beginning with sickle cell disease, and as we reported earlier this quarter, we have completed patient enrollment in our ongoing Ardent Phase 2b clinical trial with tovinontrine. We expect to report data from an interim analysis of this trial in approximately one-third of patients at 24 weeks during this quarter. The interim analysis will have a focus on safety dose and PD biomarkers, specifically HbF and F-cells.

從鐮狀細胞病開始，正如我們本季度早些時候報導的那樣，我們已經完成了正在進行的 Tovinontrine 2b 期 Ardent 臨床試驗的患者入組。我們預計將在本季度報告 24 週時對大約三分之一患者進行的這項試驗的中期分析數據。中期分析將重點關注安全劑量和 PD 生物標誌物，特別是 HbF 和 F 細胞。

In addition to this readout, we expect the primary analysis dataset in the first quarter of 2022. The primary analysis will focus on HbF and F-cells, as well as the effect of tovinontrine on the rate of vaso-occlusive crises, or VOCs, at 24 weeks. The Ardent study has been a global effort as we have enrolled approximately 115 subjects from across the world, including Europe, US, Middle East, and Africa. Our team has worked tirelessly on the conduct of this trial and are pleased to have important data readouts in the coming months.

除了此讀數之外，我們預計主要分析數據集將於 2022 年第一季度發布。主要分析將重點關注 HbF 和 F 細胞，以及 tovinontrin 對血管閉塞危機 (VOC) 發生率的影響， 24週時。 Ardent 研究是一項全球性的研究，我們招募了來自世界各地（包括歐洲、美國、中東和非洲）的約 115 名受試者。我們的團隊不知疲倦地進行這項試驗，並很高興在未來幾個月內獲得重要的數據讀數。

In addition to the Ardent trial readout this quarter, we look forward to reporting updated 12-month safety and VOC data from our Phase 2a open label extension, or OLE, trial of tovinontrine in adults with sickle cell disease at the American Society of Hematology Annual Meeting to be held December 11 to 14 this year.

除了本季度的Ardent 試驗結果外，我們還期待在美國血液學會年會上報告我們的2a 期開放標籤擴展(OLE) 試驗的最新12 個月安全性和VOC 數據，該試驗是托維農曲( tovinontrin) 治療成人鐮狀細胞病患者的試驗會議將於今年12月11日至14日舉行。

As a refresher, we reported final results from the Phase 2a parent trial as well as eight-month data from the OLE in June at the European Hematology Association Annual Congress. The parent study results indicate a well-tolerated safety profile, lower VOC rates, improved patient reported severity score, and variable biomarker results, including with respect to HbF. Importantly, VOC results for all 93 subjects enrolled in the Phase 2 trial demonstrated a 40% lower mean annualized VOC rate in the pool tovinontrine treated groups versus the pool placebo groups.

作為回顧，我們在 6 月份的歐洲血液學協會年會上報告了 2a 期母體試驗的最終結果以及 OLE 的八個月數據。母研究結果表明，安全性良好，VOC 率較低，患者報告的嚴重程度評分有所改善，生物標誌物結果（包括 HbF）也有所不同。重要的是，參加第 2 期試驗的所有 93 名受試者的 VOC 結果表明，與安慰劑組相比，tovinontrin 治療組的平均年化 VOC 率低 40%。

In addition, data from the parent study demonstrated a significant increase in the median time to first VOC as well as reduced rate of annualized VOC-related hospitalizations; in each case, when pool tovinontrine groups were compared to pool placebo groups. We're also encouraged to see patients in the OLE clinical trial continuing to benefit from lower annualized VOC rates. We believe that these continued VOC benefits in the OLE trial further support the findings from the 93-patient Phase 2a study.

此外，母研究的數據表明，首次 VOC 的中位時間顯著增加，並且每年與 VOC 相關的住院率降低；在每種情況下，當將聯合托維諾特里組與聯合安慰劑組進行比較時。我們還很高興看到 OLE 臨床試驗中的患者繼續受益於較低的年化 VOC 率。我們相信，OLE 試驗中 VOC 的持續益處進一步支持了 93 名患者 2a 期研究的結果。

Lastly, in addition to the positive VOC data in the OLE study, we're also pleased that 36%, or 4 of 11 patients in the OLE trial, had absolute HbF increases of more than 3% at the eight-month time point, while receiving 200 milligrams of tovinontrine. We believe the higher doses of tovinontrine have the potential to show even more robust HbF increases. Remember that the Ardent Phase 2b trial is currently dosing at up to 400 milligram daily, and is powered to show an HbF response rate of 35% in tovinontrine versus 5% on placebo at 24 weeks. We expect higher doses may further improve on that signal, which is why we're looking forward to reporting the interim data from the Ardent trial later this quarter.

最後，除了 OLE 研究中的陽性 VOC 數據外，我們還很高興看到 36%（即 OLE 試驗中 11 名患者中的 4 名）在 8 個月時間點的絕對 HbF 增加超過 3%，同時接受200毫克tovinontrin。我們相信較高劑量的 tovinontrin 有可能顯示出更強勁的 HbF 增加。請記住，Ardent 2b 期試驗目前的劑量為每天 400 毫克，並且在 24 週時顯示，tovinontrin 的 HbF 反應率為 35%，而安慰劑為 5%。我們預計更高的劑量可能會進一步改善該信號，這就是為什麼我們期待在本季度晚些時候報告 Ardent 試驗的中期數據。

Turning to our Forte Phase 2b clinical trial in beta-thalassemia. We also reached full enrollment in the transfusion-dependent, or TDT, cohort; are also seeing continued enrollment in the non-transfusion-dependent, or NTDT, cohort. We expect interim data from the TDT cohort this quarter, in which we plan to evaluate safety, transfusion burden, and PD biomarkers in approximately 30 patients at 24 weeks on study. Furthermore, we plan to conduct additional readouts for the full TDT cohort at 24 weeks in the first quarter of 2022, looking at similar data points at the interim analysis.

轉向我們針對 β 地中海貧血的 Forte 2b 期臨床試驗。我們還實現了輸血依賴（TDT）隊列的全部入組；還看到非輸血依賴性（NTDT）隊列的持續入組。我們預計本季度 TDT 隊列將獲得中期數據，我們計劃在研究 24 週時評估約 30 名患者的安全性、輸血負擔和 PD 生物標誌物。此外，我們計劃在 2022 年第一季度的 24 週時對整個 TDT 隊列進行額外的讀數，在中期分析中查看類似的數據點。

In addition to this important upcoming clinical data, we plan to present preclinical data in beta-thalassemia at the upcoming ASH annual meeting in December. We're looking forward to providing both of these updates in the coming weeks.

除了即將發布的重要臨床數據外，我們還計劃在 12 月即將召開的 ASH 年會上展示 β 地中海貧血的臨床前數據。我們期待在未來幾週內提供這兩項更新。

We are also selectively expanding our indication footprint to areas where PDE9 overexpression is implicated in serious diseases with high unmet needs. To that end, we've expanded our internal team and developed a protocol for a Phase 2 proof of concept study in heart failure with preserved ejection fraction, or HFpEF, with the help of our experienced cardiology clinical advisory board. We also expect to interact with the FDA Division of Cardiology and Nephrology this quarter. So collectively, we've made substantial progress, enabling the HFpEF program, with an eye towards the clinic in 2022.

我們還選擇性地將我們的適應症足跡擴大到 PDE9 過度表達與嚴重疾病相關且需求未得到滿足的領域。為此，我們擴大了內部團隊，並在經驗豐富的心髒病學臨床顧問委員會的幫助下，制定了射血分數保留型心力衰竭（HFpEF）第二階段概念驗證研究方案。我們還預計本季度與 FDA 心髒病學和腎病科進行互動。總的來說，我們已經取得了實質性進展，啟用了 HFpEF 項目，並著眼於 2022 年投入臨床。

Yesterday, we announced an oral presentation at the American Heart Association's Scientific Sessions, which is scheduled to take place later this week. Our abstract includes data in three preclinical mouse models of HFpEF, in which selective inhibition of PDE9 with tovinontrine was shown to reduce the median size of cardiomyocytes and lower plasma B-type and atrial natriuretic peptide levels.

昨天，我們宣佈在美國心臟協會的科學會議上進行口頭報告，該會議定於本週晚些時候舉行。我們的摘要包括三種 HFpEF 臨床前小鼠模型的數據，其中用 tovinontrin 選擇性抑制 PDE9 可減少心肌細胞的中值大小並降低血漿 B 型和心房鈉尿肽水平。

In addition, markers of renal dysfunction, including blood urea nitrogen and urine albumin-to-creatinine ratio, were lower in mice treated with tovinontrine compared to vehicle-treated mice in all models. Importantly, tovinontrine did not significantly change heart rate or blood pressure.

此外，在所有模型中，與媒介物治療的小鼠相比，用托維農曲治療的小鼠的腎功能障礙標誌物，包括血尿素氮和尿白蛋白與肌酐比值較低。重要的是，tovinontrin 不會顯著改變心率或血壓。

In summary, alongside independent literature on the potential value of PDE9 inhibition of HFpEF, as well as our own internally generated data, we believe tovinontrine may be a promising treatment option for patients with HFpEF.

總之，除了關於 PDE9 抑制 HFpEF 潛在價值的獨立文獻以及我們自己內部生成的數據之外，我們相信託維農曲可能是 HFpEF 患者有前途的治療選擇。

To lead clinical development of tovinontrine as a treatment for HFpEF, I'm also pleased to announce that Imara has appointed Toni Bransford, MD, as Vice President of Clinical Development. A seasoned cardiologist, Toni comes to Imara with 15 years of clinical development expertise within global pharmaceuticals, biotech, and clinical research organizations. Toni comes to Imara from Kaleido, where she led clinical research programs for multiple projects and oversaw translation of discovery programs.

為了領導托維農曲鹼治療 HFpEF 的臨床開發，我還很高興地宣布，Imara 已任命醫學博士托尼·布蘭斯福德 (Toni Bransford) 擔任臨床開發副總裁。 Toni 是一位經驗豐富的心髒病專家，來到 Imara 時擁有在全球製藥、生物技術和臨床研究組織中 15 年的臨床開發專業知識。 Toni 從 Kaleido 來到 Imara，在那裡她領導了多個項目的臨床研究項目並監督發現項目的翻譯。

Prior to her roles at Imara and Kaleido, Toni accumulated deep experience in the cardiovascular therapeutic area, including at Novartis, where she was the clinical lead for the HFpEF program conducting the Paramount and Paragon trials; was also responsible for leading regulatory authority interactions. We're delighted to have Dr. Bransford join our team to lead our HFpEF development efforts, working closely with our Chief Medical Officer, Ken Attie.

在就職於 Imara 和 Kaleido 之前，Toni 在心血管治療領域積累了豐富的經驗，包括在諾華 (Novartis) 擔任 HFpEF 項目的臨床負責人，進行 Paramount 和 Paragon 試驗；還負責領導監管機構的互動。我們很高興布蘭斯福德博士加入我們的團隊，與我們的首席醫療官 Ken Attie 密切合作，領導我們的 HFpEF 開發工作。

In addition to the progress we've made with tovinontrine, we are excited to announce IMR-261 as a new asset in our development pipeline. Briefly, IMR-261 is a clinic-ready, oral activator of nuclear factor erythroid 2--related factor 2, or Nrf2. In-vitro and in-vivo studies show that Nrf2 coordinates the expression of antioxidant genes in response to oxidative stress, regulates inflammation, inhibits the NF-kappaB pathway, and reactivates fetal hemoglobin, or HbF.

除了我們在 tovinontrine 方面取得的進展之外，我們很高興宣布 IMR-261 成為我們開發管道中的一項新資產。簡而言之，IMR-261 是一種可臨床使用的口服核因子紅細胞 2 相關因子 2（Nrf2）激活劑。體外和體內研究表明，Nrf2 協調抗氧化基因的表達以應對氧化應激，調節炎症，抑制 NF-kappaB 通路，並重新激活胎兒血紅蛋白 (HbF)。

IMR-261 was formerly known as CXA-10, and was previously evaluated by Complexa, Inc. in Phase 2 clinical trials for focal segmental glomerulosclerosis, FSGS, and pulmonary arterial hypertension, PAH. Independent medical literature suggests that Nrf2 activation could be relevant in a number of red blood cell diseases and disorders of hemoglobin.

IMR-261 以前稱為 CXA-10，之前由 Complexa, Inc. 在局灶節段性腎小球硬化症 (FSGS) 和肺動脈高壓 (PAH) 的 2 期臨床試驗中進行了評估。獨立醫學文獻表明，Nrf2 激活可能與許多紅細胞疾病和血紅蛋白紊亂有關。

And as a proof of principle, there's substantial preclinical data in sickle cell models with dimethyl fumarate, a known Nrf2 activator. Imara ran its own preclinical sickle cell disease models and found IMR-261 significantly increased HbF and F-cells, improved hemolytic markers, and decreased VOCs. In a preclinical beta-thalassemia model, IMR-261 increased hemoglobin and enabled red blood cell maturation.

作為原理證明，使用富馬酸二甲酯（一種已知的 Nrf2 激活劑）的鐮狀細胞模型中有大量臨床前數據。 Imara 運行了自己的臨床前鐮狀細胞病模型，發現 IMR-261 顯著增加了 HbF 和 F 細胞，改善了溶血標誌物，並減少了 VOC。在臨床前 β 地中海貧血模型中，IMR-261 增加血紅蛋白並使紅細胞成熟。

The IMR-261 data and submitted abstract was selected for an oral presentation at the upcoming ASH meeting, and Dr. Betty Pace, a leader in sickle cell research with DMF and Nrf2, is an author on this abstract. Since IMR-261 is a clinic-ready asset, we've initiated work toward drug product manufacturing as we explore potential clinical development paths. We look forward to providing updates on IMR-261 in 2022.

IMR-261 數據和提交的摘要被選為在即將召開的 ASH 會議上進行口頭報告，而 DMF 和 Nrf2 鐮狀細胞研究的領導者 Betty Pace 博士是該摘要的作者之一。由於 IMR-261 是一種可供臨床使用的資產，因此我們在探索潛在的臨床開發路徑時已啟動了藥品生產工作。我們期待在 2022 年提供 IMR-261 的更新。

In conclusion, we believe that the third quarter and first part of the fourth quarter have been productive periods for Imara on our core programs, expanding our indication opportunities, and developing a clinic-ready pipeline. We look forward to updating you on our further progress, including expected data readouts beginning later this quarter and in the first quarter of 2022.

總之，我們相信第三季度和第四季度上半年是 Imara 核心項目的富有成效的時期，擴大了我們的適應症機會，並開發了臨床就緒的管道。我們期待向您通報我們的進一步進展，包括從本季度末和 2022 年第一季度開始的預期數據讀數。

Thank you, and I'll turn the call back to Mike to review our financial results. Mike?

謝謝您，我會將電話轉回給邁克，以審查我們的財務業績。麥克風？

Thanks, Rahul. Our third-quarter 2021 results can be found in the press release that we issued this morning, which I'll summarize now. More details are also included in the 10-Q that we filed with the SEC earlier this morning.

謝謝，拉胡爾。我們的 2021 年第三季度業績可以在我們今天早上發布的新聞稿中找到，我現在對此進行總結。更多詳細信息也包含在我們今天早上向 SEC 提交的 10-Q 中。

Research and development expenses were $10.4 million for the third quarter of 2021 as compared to $9.5 million for the third quarter of 2020. The increase of $900,000 was primarily related to the development manufacturing of clinical materials, clinical research and oversight of the company's clinical trials, and investigator fees related to the development of tovinontrine, as well as increased personnel related and other R&D operating costs.

2021 年第三季度的研發費用為 1040 萬美元，而 2020 年第三季度的研發費用為 950 萬美元。增加的 90 萬美元主要與臨床材料的開發製造、臨床研究和公司臨床試驗的監督有關，與tovinontrine 開發相關的研究者費用，以及相關人員和其他研發運營成本的增加。

General and administrative expenses were $3.3 million for the third quarter of 2021 as compared to $3 million for the third quarter of 2020. The increase of $300,000 was primarily due to increased personnel related and other G&A operating costs.

2021 年第三季度的一般及管理費用為 330 萬美元，而 2020 年第三季度為 300 萬美元。增加 30 萬美元主要是由於人員相關費用和其他一般及行政管理運營成本增加。

Net loss attributable to common stockholders was $13.6 million, or $0.55 per share, for the third quarter of 2021 as compared to a net loss of $12.4 million, or $0.72 per share, for the third quarter of 2020.

2021 年第三季度歸屬於普通股股東的淨虧損為 1,360 萬美元，即每股 0.55 美元，而 2020 年第三季度的淨虧損為 1,240 萬美元，即每股 0.72 美元。

Cash, cash equivalents and investments were $102.8 million as of September 30, 2021, as compared to $88.2 million as of December 31, 2020. We believe this capital provides Imara with sufficient funds to enable us to fund our planned operations into the first quarter of 2023.

截至2021 年9 月30 日，現金、現金等價物和投資為1.028 億美元，而截至2020 年12 月31 日為8,820 萬美元。我們相信這筆資金為Imara 提供了足夠的資金，使我們能夠為第一季度的計劃運營提供資金2023 年。

That concludes our prepared remarks. Operator, could you please open the line for questions?

我們準備好的發言到此結束。接線員，您可以撥打電話詢問問題嗎？

(Operator Instructions) Yigal Nochomovitz, Citi.

（操作員指令）Yigal Nochomovitz，花旗銀行。

This is Carly on for Yigal. Thanks for taking our questions. We had two questions. First on the Nrf2 activator that you [explained], will you consider indications in kidney disease or are you focused on hemoglobin disorders?

這是伊格爾的卡莉。感謝您回答我們的問題。我們有兩個問題。首先，關於您[解釋的]Nrf2 激活劑，您會考慮腎臟疾病的適應症還是專注於血紅蛋白疾病？

And then second, on the Phase 2b study in sickle cell, you mentioned some of the details on the powering on fetal hemoglobin. Just curious what you can say about the powering on annualized VOC rate. And relatedly, are you stratifying patients based on the number of VOCs patients had in the year prior to the study? Thanks so much.

其次，關於鐮狀細胞的 2b 期研究，您提到了一些有關胎兒血紅蛋白供電的細節。只是好奇您對 VOC 年化率有何看法。與此相關，您是否根據研究前一年患者的 VOC 數量對患者進行分層？非常感謝。

Thank you. I'll take the first one and then hand it to our Chief Medical Officer, Ken, for the second question. So I think, as you know, a Nrf2 activation is implicated in a number of different diseases, including renal diseases. Our focus right now is rare cell disorders, red blood cell disorders, including hemoglobinopathy. So our first shot at a disease indication is really in that sphere. We are looking at associated and affiliated areas beyond sickle cell and beta cell. But for right now, our data is the strongest in those two indications.

謝謝。我將回答第一個問題，然後將其交給我們的首席醫療官 Ken，回答第二個問題。所以我認為，如您所知，Nrf2 激活與許多不同的疾病有關，包括腎臟疾病。我們現在的重點是罕見的細胞疾病、紅細胞疾病，包括血紅蛋白病。因此，我們針對疾病適應症的第一次嘗試確實是在這個領域。我們正在研究鐮狀細胞和β細胞以外的相關和附屬領域。但就目前而言，我們的數據在這兩個指標中是最強的。

I'll just note that, unlike renal diseases and PAH, which leverage Nrf2's antioxidant mechanism, the Nrf2 activators in sickle cell disease are actually specifically designed to induce and reactivate fetal hemoglobin. And so we like the specific mechanism around Nrf2 translocation to the nucleus, which actually creates the ability to reactivate fetal hemoglobin.

我只想指出，與利用 Nrf2 抗氧化機制的腎臟疾病和 PAH 不同，鐮狀細胞病中的 Nrf2 激活劑實際上是專門設計用於誘導和重新激活胎兒血紅蛋白的。因此，我們喜歡 Nrf2 易位到細胞核的具體機制，這實際上創造了重新激活胎兒血紅蛋白的能力。

So there are some mechanistic advantages to going into red cell disorders over some of the kidney indications that have been previously tried with this asset and certainly (technical difficulty)

因此，與之前使用該資產嘗試過的一些腎臟適應症相比，進入紅細胞疾病有一些機械上的優勢，當然（技術難度）

I'll turn it over to Ken to give you some color on the powering of the study, both the primary and secondaries.

我將把它交給 Ken，讓您了解這項研究的動力，包括主要研究和次要研究。

Yes. Thanks, Rahul. This is Ken Attie. We have powered the study primarily for the primary endpoint, which was an increase in hemoglobin F response rate for an increase of 3% or more from baseline. We haven't separately done power calculations for each of the secondary endpoints. Although we have now made annualized rate of VOCs, the key secondary endpoint. And based on our results from the Phase 2a study, we feel that we will probably be powered to show a difference similar to what we saw in the Phase 2a study with the number of patients from the Phase 2b study.

是的。謝謝，拉胡爾。這是肯·阿蒂。我們主要針對主要終點來推動這項研究，即血紅蛋白 F 反應率較基線提高 3% 或更多。我們還沒有單獨對每個次要端點進行功率計算。儘管我們現在已經將揮發性有機化合物的年化率作為關鍵的次要終點。根據 2a 期研究的結果，我們認為我們可能有能力顯示出與 2a 期研究中所見的差異與 2b 期研究中的患者數量相似的差異。

That study had several stratification factors, the current study, but it did not include the baseline VOC rate or the historical VOC rate. In order to get into this study, subjects had to have had initially 1 to 12 VOCs in the prior year. We revised the protocol to specify a minimum of 2 VOCs in the previous year. And so in our analysis plan -- statistical analysis plan, which we have finalized, we will be looking in both subjects with 1 to 12 VOCs in the prior year as well as 2 to 12 as a sensitivity analysis.

該研究有幾個分層因素，即當前的研究，但不包括基線 VOC 率或歷史 VOC 率。為了參與這項研究，受試者在前一年必須有 1 到 12 種揮發性有機化合物。我們在去年修訂了協議，規定至少 2 種 VOC。因此，在我們已最終確定的分析計劃（統計分析計劃）中，我們將研究前一年具有 1 至 12 種 VOC 的受試者以及 2 至 12 種 VOC 的受試者作為敏感性分析。

Okay, great. Thanks very much.

好的，太好了。非常感謝。

Thanks.

謝謝。

Joseph Schwartz, SVB Leerink.

約瑟夫·施瓦茨 (Joseph Schwartz)，SVB Leerink。

Hi, I'm [Joori], dialing for Joe. Thank you for taking our question. First, I guess I was wondering what could we expect to see when you present your 12-month VOC data from your ongoing Phase 2a OLE study that's presented at ASH. How many patients with data should we expect? And are there any differences we should expect from what you've presented so far from your OLE study?

嗨，我是 [Joori]，正在撥打 Joe 的電話。感謝您提出我們的問題。首先，我想我想知道當您展示 ASH 上正在進行的 2a 期 OLE 研究中的 12 個月 VOC 數據時，我們會看到什麼。我們應該期望有多少患者擁有數據？到目前為止，您在其他學習經歷研究中所呈現的內容與我們應該期待的有什麼不同嗎？

Sure. So I think -- thanks for the question, first of all. So I think our 12-month data for the OLE study will have kind of two nuances that the 8-month data did not. As you guys know, we have been doing annualized rates of VOC. So a patient that has been on the study for eight months, for example, is annualized out to 12 months. And so if the patient has had two VOCs in six months, they're annualized out to have four VOCs over the period of one year.

當然。所以我想——首先感謝你提出這個問題。因此，我認為 OLE 研究的 12 個月數據將具有 8 個月數據所沒有的兩個細微差別。如你們所知，我們一直在計算 VOC 的年化率。例如，一名接受研究 8 個月的患者的年化期限為 12 個月。因此，如果患者在六個月內出現了兩次 VOC，那麼他們在一年內就會出現四次 VOC。

The nice part about the data that we're going to present at ASH is now that we're looking at the 12-month endpoint, the annualization effort is minimal in the sense that most patients will have over 320 days on study. That will be approximately 20 patients. And so when we look at those VOC rates, we'll be, I think, comfortable in understanding what the yearly VOC rate is for those patients, as opposed to annualizing out data that was eight months and shorter. So I think that's going to be an advantage of that dataset.

我們將在 ASH 上展示的數據的好處在於，我們現在正在研究 12 個月的終點，年化工作量很小，因為大多數患者將有超過 320 天的研究時間。大約有 20 名患者。因此，當我們查看這些 VOC 發生率時，我認為我們會輕鬆了解這些患者的每年 VOC 發生率，而不是對八個月或更短時間的數據進行年度化。所以我認為這將是該數據集的一個優勢。

And then maybe just to finish that point, we'll obviously be showing what we've shown throughout the eight-month data set at EHA, which is HbF and F-cells, as well as these incremental reviews on VOCs.

然後也許只是為了完成這一點，我們顯然會展示我們在 EHA 的八個月數據集中所展示的內容，即 HbF 和 F 細胞，以及對 VOC 的增量審查。

I'll just end, though, we have safety data for all 26 subjects enrolled as of September 30, and, as Rahul mentioned, one-year data for approximately [20 subjects].

不過，我要結束的是，我們擁有截至 9 月 30 日登記的所有 26 名受試者的安全數據，並且正如 Rahul 提到的，大約 [20 名受試者] 的一年數據。

Okay, great. Thank you. And then our next question is on IMR-261. How did you decide on advancing IMR-216, and what are some challenges or gating factors you envision to getting this agent into the clinic?

好的，太好了。謝謝。我們的下一個問題是關於 IMR-261。您是如何決定推進 IMR-216 的？您認為將該藥物推向臨床有哪些挑戰或限制因素？

Yes. So we have followed the Nrf2 literature for quite some time. And as you guys may or may not know, there is actually quite a bit of detailed literature from Dr. Pace's lab at Augusta University on dimethyl fumarate and its ability to reactivate fetal hemoglobin, reduce NF-kappaB activation around those pathways, as well as be an antioxidant in general.

是的。所以我們關注 Nrf2 文獻已經有一段時間了。你們可能知道也可能不知道，奧古斯塔大學 Pace 博士的實驗室實際上有相當多關於富馬酸二甲酯及其重新激活胎兒血紅蛋白、減少這些途徑周圍 NF-kappaB 激活的能力以及一般而言是一種抗氧化劑。

And so as we look at programs that were available and ready for the clinic, we were lucky enough to stumble upon a program that had Phase 2 data, that was safe and well tolerated, that certainly did not have success in kidney indications, as we mentioned, in PAH, that had a unique perspective vis-a-vis dosing and regimen for a sickle cell study in the future.

因此，當我們查看可用並準備好用於臨床的項目時，我們很幸運地偶然發現了一個具有2 期數據的項目，該項目安全且耐受性良好，但在腎臟適應症方面肯定沒有取得成功，因為我們在 PAH 中提到，對於未來鐮狀細胞研究的劑量和治療方案具有獨特的視角。

And to be specific, those patients in the PAH and FSGS trials were dosed at a very low dose. They were not titrated up for a long time. And that company was able to complete a study prior to handing the asset over to us that showed you can increase the dose by two-fold to four-fold. And so we're starting from a much higher dose perspective.

具體來說，PAH 和 FSGS 試驗中的患者服用的劑量非常低。他們很長一段時間沒有滴定。該公司在將資產移交給我們之前完成了一項研究，表明您可以將劑量增加兩倍到四倍。因此，我們從更高劑量的角度開始。

We are starting from a mechanism that is, at least, preclinically well defined. And if you look at our ASH presentation, the fetal hemoglobin induction or reactivation is extremely robust. As an example, in the CD34 cell that many companies use to approximate fetal hemoglobin induction, we're seeing a seven-fold increase and a dose-dependent increase in fetal hemoglobin as an example.

我們從一種至少在臨床前明確定義的機制開始。如果您查看我們的 ASH 演示文稿，就會發現胎兒血紅蛋白的誘導或重新激活非常強勁。舉個例子，在許多公司用來近似胎兒血紅蛋白誘導的 CD34 細胞中，我們看到胎兒血紅蛋白增加了七倍，並且呈劑量依賴性增加。

Furthermore, in the Townes models, not only did we look at fetal hemoglobin induction, which was near threefold, we also looked at the reduction in VOC crises as shown by the TNF-alpha data. And so not only had we confirmed that the drug is active in a number of sickle cell models, we've done the same in beta-thalassemia. Then you add the existing literature for DMF that shows that this is in fact happening across the class and you get pretty excited about 261 as a clinic-ready asset for sickle cell disease.

此外，在 Townes 模型中，我們不僅觀察了胎兒血紅蛋白的誘導（接近三倍），還觀察了 TNF-α 數據顯示的 VOC 危機的減少。因此，我們不僅證實了該藥物在許多鐮狀細胞模型中具有活性，而且在β-地中海貧血中也做了同樣的研究。然後，您添加 DMF 的現有文獻，表明這種情況實際上正在整個類別中發生，並且您對 261 作為鐮狀細胞病的臨床就緒資產感到非常興奮。

You also noted the point about challenges. So anytime you receive a clinical asset from another company, drug product is certainly one of those in terms of expiry dates, in terms of getting drug substance to ultimately make drug product.

您還提到了有關挑戰的觀點。因此，每當您從另一家公司收到臨床資產時，就有效期而言，就獲得原料藥最終製造藥品而言，藥品肯定是其中之一。

So we've started that work on the drug substance, drug product side already. And as we've done that, we are in the process of evaluating a number of clinical paths to market for 261 since it already had an I&D for FSGS and PAH. We would foresee starting a clinical study in patients right away, and we'll certainly update external markets in 2022 about our path forward.

因此，我們已經開始在原料藥和藥品方面開展工作。正如我們所做的那樣，我們正在評估 261 的多種上市臨床路徑，因為它已經進行了 FSGS 和 PAH 的 I&D。我們預計將立即開始對患者進行臨床研究，並且我們肯定會在 2022 年向外部市場更新我們的前進道路。

Okay. Thank you very much.

好的。非常感謝。

Thanks.

謝謝。

(Operator Instructions) Matthew Harrison, Morgan Stanley.

（操作員指示）Matthew Harrison，摩根士丹利。

Good morning, everyone. This is Kostas on for Matthew. Congrats on the progress.

大家，早安。這是科斯塔斯替補馬修。祝賀取得的進展。

Two questions from us on 261. Can you talk a little bit about the doses you tested in mice and how these doses translate in humans and what the safety profile looks like under these doses in humans given you have available data? And secondly, how fast do you think the development pathway could potentially be given all the available data you have from Complexa? Thank you.

我們在261 上提出了兩個問題。您能否談談您在小鼠中測試的劑量以及這些劑量如何在人類中轉化以及鑑於您有可用數據，在人類中這些劑量下的安全性是什麼樣的？其次，您認為從 Complexa 獲得的所有可用數據的開發路徑可能有多快？謝謝。

Yes, Kostas. Good to hear from you, and thanks for the questions. So when we tested IMR-261 in our preclinical models, I had reference from the previous question about the study that Complexa did prior to handing the asset over to us.

是的，科斯塔斯。很高興收到你的來信，感謝你的提問。因此，當我們在臨床前模型中測試 IMR-261 時，我參考了上一個關於 Complexa 在將資產移交給我們之前所做的研究的問題。

To be brief, they study doses as high as 300 mg BID in the clinic in healthy volunteers, 600 mg total daily. And so we modeled that high dose that they tested as the dose in our preclinical models. So the doses for the Townes model, to be specific, are 37.5 mg per kg BID for a total of 75 mg per kg daily. That, if you look at the human equivalent dose, is right around the 300 mg BID.

簡而言之，他們在健康志願者的臨床中研究了高達 300 毫克 BID 的劑量，即每天總計 600 毫克。因此，我們將他們測試的高劑量建模為我們臨床前模型中的劑量。因此，湯斯模型的具體劑量為每公斤 37.5 毫克 BID，每天每公斤 75 毫克。如果您查看人體等效劑量，則約為 300 毫克 BID。

So we started with clinical data, and we downscaled to mice. So we knew, getting out of the preclinical, before we even started the preclinical experiments, that we could hit the dose in the clinic. So that is an advantage of getting a clinic-ready asset in this case.

所以我們從臨床數據開始，然後縮小到小鼠。因此，在我們開始臨床前實驗之前，我們就知道，在臨床前結束後，我們可以在臨床上達到劑量。因此，在這種情況下，這是獲得臨床就緒資產的優勢。

You talked a little bit about safety. We've gone through the data, and, at the doses that we just mentioned, the 300 mg BID, the healthy volunteer data, nausea, headache, and vomiting were the most commonly associated AEs, and overall the drug was well-tolerated with food.

您談到了一些關於安全的問題。我們查看了數據，在我們剛剛提到的劑量下，300 mg BID，健康志願者數據，噁心、頭痛和嘔吐是最常見的相關 AE，總體而言，該藥物具有良好的耐受性食物。

And so as you think about triangulating dose, efficacy in preclinical models, and obviously safety, we have, I think, done a good job of finding a dose forward for the clinic. Of course, drug product and drug substance remain a challenge for us in terms of getting that to the next stage and actually making the drug.

因此，當你考慮三角劑量、臨床前模型的療效以及明顯的安全性時，我認為我們在為臨床尋找劑量方面做得很好。當然，藥品和原料藥對於我們進入下一階段並實際製造藥物而言仍然是一個挑戰。

Thank you. And just one clarification, do you mean that you will be testing the 300 milligram BID in clinic? Or you haven't disclosed the dose yet?

謝謝。請澄清一點，您的意思是您將在臨床中測試 300 毫克 BID 嗎？或者你還沒有透露劑量？

We haven't disclosed any doses. I think your question was, do we feel comfortable with the preclinical data that it could translate to clinical doses of efficacy? I think the answer is yes. But as I said, we're still working through the clinical path forward [both of those], and ultimately indication.

我們尚未透露任何劑量。我認為你的問題是，我們對可以轉化為臨床劑量療效的臨床前數據感到滿意嗎？我認為答案是肯定的。但正如我所說，我們仍在努力探索臨床路徑（兩者）以及最終的適應症。

Perfect. Thank you very much. And if you could touch on the potential scenarios around the development pathway. How accelerated can it be potentially given the available data from Complexa? Thank you.

完美的。非常感謝。您能否談談開發路徑的潛在場景？考慮到 Complexa 的可用數據，它的加速速度有多大？謝謝。

Yes. So again, I think we are in the process of detailing a clinical development path forward, and we'll certainly update you over time. So we're not commenting on the timeline for that at this point. But I think maybe three organizing principles for us.

是的。再說一遍，我認為我們正在詳細制定臨床開發路徑，隨著時間的推移，我們肯定會向您通報最新情況。因此，我們目前不會對此時間表發表評論。但我認為我們可能遵循三個組織原則。

Number one, we're a clinical-stage company that knows how to do clinical trials. Number two, we really wanted a clinic-ready asset that could be put into the clinic near term. And number three, certainly, we understand the red cell -- rare red cell disorders and hemoglobinopathies quite well. So there's lots of different approaches that we're going to take to evaluating the best and fastest path forward.

第一，我們是一家臨床階段的公司，知道如何進行臨床試驗。第二，我們確實想要一種可以在短期內投入診所的臨床就緒資產。第三，當然，我們非常了解紅細胞——罕見的紅細胞疾病和血紅蛋白病。因此，我們將採取許多不同的方法來評估最佳和最快的前進道路。

But the fact that the drug has been tested in over 100 patients, the fact that there are two INDs open on this drug, and the fact that they've tested higher doses that could potentially be used by us, all sets up for a rapid path to clinic.

但事實上，該藥物已經在 100 多名患者中進行了測試，該藥物有兩個 IND 開放，並且他們已經測試了我們可能使用的更高劑量，所有這些都為快速通往診所的路徑。

Very helpful, thank you.

非常有幫助，謝謝。

Thanks for the questions, Kostas.

謝謝你的提問，科斯塔斯。

At this time, there are no further questions. I would now like to turn the call back over to management.

目前，沒有其他問題了。我現在想將電話轉回給管理層。

Thank you very much and appreciate your time today. Thank you for joining this morning's call. We're excited about the momentum that we have as a company from a variety of different angles that we've already talked about, and look forward to the upcoming data readouts. Everyone, stay healthy and safe and speak soon.

非常感謝並感謝您今天的寶貴時間。感謝您參加今天早上的電話會議。我們對我們作為一家公司從各個不同角度所擁有的勢頭感到興奮，並期待即將發布的數據。大家保持健康、安全並儘快發言。

This concludes today's conference call. Thank you for participating. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。