Karyopharm Therapeutics Inc (KPTI) 2025 Q1 法說會逐字稿

Good afternoon. My name is Chloe, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics first-quarter 2025 financial results conference call. There will be a question-and-answer session to follow. Please be advised that this call is being recorded at the company's request. I would like to turn a call over to Brandon Strong, Senior Vice President, Investor Relations and Corporate Communications. Thank you. Please go ahead.

午安.我叫 Chloe，今天我將擔任您的會議主持人。現在，我歡迎大家參加 Karyopharm Therapeutics 2025 年第一季財務業績電話會議。接下來將會有一個問答環節。請注意，應公司要求，本次通話正在錄音。我想將電話轉給投資者關係和企業傳播部高級副總裁布蘭登·斯特朗 (Brandon Strong)。謝謝。請繼續。

Thank you, Chloe, and thank you all for joining us on today's conference call to discuss Karyopharm's first-quarter 2025 financial results and recent company progress. We issued a press release after the market closed, detailing our financial results for the first quarter of 2025. This release, along with a slide presentation that we will reference during today, are available on our website. For today's call, as seen on slide 2, I'm joined by Richard, Reshma Sohanya, and Lori, who'll provide an update on our results for the first quarter of 2025 and review new data that we are sharing for the first time today in Myelofibrosis.

謝謝你，Chloe，也謝謝大家參加今天的電話會議，討論 Karyopharm 2025 年第一季度的財務業績和公司近期進展。我們在股市收盤後發布了一份新聞稿，詳細介紹了我們 2025 年第一季的財務表現。此新聞稿以及我們今天將參考的幻燈片演示均可在我們的網站上找到。如投影片 2 所示，在今天的電話會議中，我與 Richard、Reshma Sohanya 和 Lori 一起，提供我們 2025 年第一季業績的最新情況，並審查我們今天在骨髓纖維化領域首次分享的新數據。

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995 as outlined on slide 3. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the risk factor section of our most recent Form 10-Q and 10-K on file with the SEC and in other filings that we may make with the SEC in the future.

在我們開始正式評論之前，我要提醒您，我們今天發表的各種言論均構成《1995 年私人證券訴訟改革法》安全港條款規定的前瞻性陳述，如幻燈片 3 所示。由於各種重要因素，實際結果可能與這些前瞻性陳述所示的結果有重大差異，包括我們向美國證券交易委員會提交的最新 10-Q 和 10-K 表格中的風險因素部分以及我們將來可能向美國證券交易委員會提交的其他文件中討論的因素。

Any forward-looking statements represent our views as of today only. 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 later date. I'll now turn the call over to Richard. Please turn to slide 4.

任何前瞻性陳述僅代表我們截至今天的觀點。雖然我們可能選擇在未來某個時間點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，即使我們的觀點改變。因此，您不應依賴這些前瞻性陳述來代表我們以後的觀點。我現在將電話轉給理查德。請翻到幻燈片 4。

Thank you, Brandon, and thank you all for joining us today for Karyopharm's Q1 2025 earnings call. As we continue to execute on our innovation and growth strategy, we are pleased that our Phase 3 SENTRY Trial in patients with JAKi-Naïve Myelofibrosis has passed its pre-specified futility analysis and continues as planned without modifications. We are very focused on completing enrollment in this trial while also advancing enrollment in our Phase 3 trial in Endometrial Cancer as outlined on slide 5. As we have discussed in the past, we have a profitable commercial organization in Multiple Myeloma that can be leveraged to drive rapid commercialization if we receive approval in additional disease areas. Turning to slide 6.

謝謝你，布蘭登，也謝謝大家今天參加 Karyopharm 2025 年第一季財報電話會議。隨著我們繼續執行創新和成長策略，我們很高興看到，針對 JAKi-Naï¯ve 骨髓纖維化患者開展的 3 期 SENTRY 試驗已通過預先指定的無效性分析，並按計劃繼續進行，無需修改。我們非常注重完成本次試驗的招募，同時也在推進子宮內膜癌 3 期試驗的招募，如幻燈片 5 中概述的那樣。正如我們過去所討論過的，我們在多發性骨髓瘤領域擁有一個盈利的商業組織，如果我們在其他疾病領域獲得批准，就可以利用該組織推動快速商業化。翻到幻燈片 6。

We are excited to share with you today new clinical data, which further strengthens our conviction and Selinexor's potential in combination with Ruxolitinib in JAKi-Naïve Myelofibrosis patients. The data that Reshma will take you through is Selinexor monotherapy data in a heavily pre-treated, hard to treat population from our randomized Phase 2 XPORT-MF-035 trial. The data are very encouraging because they continue to show Selinexor may have an impact across each of the four key hallmarks of the disease.

今天，我們很高興與您分享新的臨床數據，這進一步增強了我們的信念以及 Selinexor 與 Ruxolitinib 聯合治療 JAKi-Naïve 骨髓纖維化患者的潛力。Reshma 將向您介紹的數據是來自我們隨機 2 期 XPORT-MF-035 試驗的大量接受過預先治療且難以治療的人群的 Selinexor 單藥治療數據。這些數據非常令人鼓舞，因為它們繼續表明 Selinexor 可能對該疾病的四個主要特徵產生影響。

When combined with other clinical and preclinical data we have shared previously, this tells a consistent story which supports our belief that the combination of Selinexor plus Ruxolitinib has the potential to meaningfully improve patient outcomes and redefine the standard of care in Myelofibrosis. We look forward to sharing data with you from our Phase 3 SENTRY Trial, which is evaluating Selinexor in combination with Ruxolitinib toward the end of this year or in early 2026. We have now enrolled approximately 80% of the 350 patients that we are targeting for this study and expect to complete our targeted enrollment in the June-July time frame.

與我們先前分享的其他臨床和臨床前數據相結合，這講述了一個一致的故事，支持了我們的信念，即 Selinexor 和 Ruxolitinib 的組合有可能顯著改善患者的治療效果並重新定義骨髓纖維化的治療標準。我們期待與您分享我們的 3 期 SENTRY 試驗的數據，該試驗將在今年年底或 2026 年初評估 Selinexor 與 Ruxolitinib 的聯合治療效果。目前，我們已經招募了該研究目標患者 350 名中的約 80%，並預計在 6 月至 7 月期間完成目標招募。

As we think about our potential in Myelofibrosis, it is worth remembering how we got here, which is outlined on slide 7. We've been taking deliberate steps over many years to put us in the position we are in today. We continue to progress our Phase 3 SENTRY Trial faster than historical benchmarks while remaining incredibly focused on high quality clinical trial execution. As outlined on slide 8, leading key opinion leaders in Myelofibrosis, including Dr. Rampal from Memorial Sloan Kettering and Dr. Mascarenhas from Mount Sinai, continue to highlight the need for new treatment options for patients with my fibrosis and are encouraged by the strength of our Phase 1 combination data.

當我們思考我們在骨髓纖維化方面的潛力時，值得記住我們是如何走到這一步的，這在第 7 張幻燈片中有概述。多年來，我們一直在採取深思熟慮的措施，才達到今天的地位。我們繼續以比歷史基準更快的速度推進我們的 3 期 SENTRY 試驗，同時仍然高度重視高品質臨床試驗的執行。如投影片 8 所述，骨髓纖維化領域的主要意見領袖，包括紀念斯隆凱特琳癌症中心的 Rampal 博士和西奈山癌症中心的 Mascarenhas 博士，繼續強調對患有我這種纖維化的患者的新治療方案的需求，並對我們的 I 期組合數據的強勁表現感到鼓舞。

Finally, we continue to believe that the commercial opportunity in Myelofibrosis is transformational. As shown on slide 9, if approved, we believe that peak revenue for potential Selinexor or in Myelofibrosis is up to approximately $1 billion in the US alone. Based on our market research, including discussions with leading key opinion leaders on our Phase 1 data and the fact that we are looking to combine Selinexor with the existing standard of care, we believe that commercial uptake would be rapid. We are eager to see the outcome of Phase 3 trial and the potential opportunity ahead. Now, I'd like to turn the call over to Reshma.

最後，我們仍然相信骨髓纖維化的商業機會是變革性的。如投影片 9 所示，如果獲得批准，我們相信僅在美國，Selinexor 或骨髓纖維化的潛在高峰收入就高達約 10 億美元。根據我們的市場研究，包括與主要意見領袖就我們的第一階段數據進行的討論，以及我們希望將 Selinexor 與現有護理標準相結合的事實，我們相信商業化應用將會很快。我們迫切希望看到第三階段試驗的結果和未來的潛在機會。現在，我想把電話轉給 Reshma。

Thank you, Richard. Before I get into the new data, let's quickly review why we believe Selinexor as an XPO1 inhibitor is a rational mechanism to evaluate in patients with Myelofibrosis starting on slide 11.

謝謝你，理查。在我介紹新數據之前，讓我們從第 11 張投影片開始，快速回顧為什麼我們認為 Selinexor 作為 XPO1 抑制劑是評估骨髓纖維化患者的合理機制。

Selinexor prevents the nuclear export of various proteins and messenger RNA molecules, inhibiting both JAKi and non-JAKi pathways, the latter, which includes the nuclear localization and activation of P53, an important tumor suppressor in Myelofibrosis, given that approximately 95% of Myelofibrosis patients are P53 wild type. Let's start by reviewing the unmet need in JAKi-Naïve myelofibrosis on slide 12,

Selinexor 可阻止各種蛋白質和信使 RNA 分子的核輸出，抑制 JAKi 和非 JAKi 途徑，後者包括 P53 的核定位和激活，P53 是骨髓纖維化中的重要腫瘤抑制因子，因為大約 95% 的骨髓纖維化患者都是 P53 野生型。我們先回顧第 12 張投影片中 JAKi-Naïve 骨髓纖維化中未被滿足的需求，

Selinexor's potential to help patients with Myelofibrosis and our opportunity to redefine the standard of care as the first combination therapy. To set the stage, there has been a lack of new treatment options, given that the JAKi inhibitors are the only approved class of therapies. Ruxolitinib has been the standard of care for over 13 years. As the potential first combination therapy in Myelofibrosis, Selinexor plus Ruxolitinib would be a convenient all oral therapy that the Myelofibrosis community has clearly indicated interest in adopting given the rapid, deep, and durable spleen reductions and symptom improvement observed from the Phase 1 study. Let's now focus on the four key hallmarks in Myelofibrosis.

Selinexor 有助於治療骨髓纖維化患者，我們有機會將治療標準重新定義為首個聯合療法。首先，由於JAKi抑制劑是唯一核准的治療類型，因此缺乏新的治療選擇。魯索替尼已成為治療標準超過 13 年。作為骨髓纖維化的潛在首個聯合療法，Selinexor 加 Ruxolitinib 將是一種方便的全口服療法，鑑於第一階段研究觀察到的快速、深度和持久的脾臟縮小和症狀改善，骨髓纖維化社區已明確表示有興趣採用該療法。現在讓我們專注於骨髓纖維化的四個主要特徵。

First, let's look at spleen volume reduction. I think it's a helpful reminder that only approximately one-third of patients achieve a spleen volume reduction of greater than 35% with Ruxolitinib alone. As we have shared before, our Phase 1 data show that Selinexor plus Ruxolitinib more than doubles that SVR35 rate.

首先我們來看看脾臟體積減少。我認為這是一個有用的提醒，只有大約三分之一的患者僅使用魯索利替尼就能實現脾臟體積減少 35% 以上。正如我們之前分享的，我們的第 1 階段數據顯示，Selinexor 加上 Ruxolitinib 使 SVR35 率提高了一倍以上。

Second is symptom improvement. As a reminder, data from our phase one trial of Selinexor in combination with Ruxolitinib showed an average 18.5% improvement in absolute TSS at week 24, which suggests a meaningful improvement over the 11 to 14 point improvements achieved by patients on Ruxolitinib as observed in the Phase 3 manifest 2 and Transform 1 trials.

二是症狀改善。提醒一下，我們第一階段的 Selinexor 與 Ruxolitinib 聯合治療試驗的數據顯示，第 24 週的絕對 TSS 平均改善了 18.5%，這表明與使用 Ruxolitinib 的患者在第 3 階段 manifest 2 和 Transform 1 試驗中觀察到的 11 到 14 分的改善相比，有了改善的改善。

Third is hemoglobin stabilization and transfusion burden. The new data we will be reviewing today shows higher hemoglobin levels, lower transfusion burden, and much lower rates of all grade in Grade 3 plus anemia in patients randomized to Selinexor compared to physicians' choice, primarily JAKi inhibitors, including Ruxolitinib.

第三是血紅素穩定和輸血負擔。我們今天將要審查的新數據顯示，與醫生選擇的主要 JAKi 抑制劑（包括 Ruxolitinib）相比，隨機接受 Selinexor 治療的患者的血紅蛋白水平更高、輸血負擔更低、所有 3 級及貧血的發生率低得多。

Fourth is disease modification. There is minimal evidence of disease modification with JAKi inhibitors. The new monotherapy data shows substantial reduction in key cytokines that are critical to Myelofibrosis pathogenesis, symptom development, and anemia. We believe this data likely indicates that Selinexor is having an impact on the underlying disease, which enables both monotherapy as well as additive, if not potentially synergistic benefit when combined with other therapies, including Ruxolitinib. Turning to slide 13.

第四是疾病改良。JAKi 抑制劑對疾病改善的作用證據極小。新的單一療法數據顯示，對骨髓纖維化發病機制、症狀發展和貧血至關重要的關鍵細胞因子大幅減少。我們認為這些數據可能表明 Selinexor 正在對潛在疾病產生影響，這使得 Selinexor 既可以作為單一療法，也可以與包括 Ruxolitinib 在內的其他療法聯合使用，從而產生附加甚至潛在的協同效應。翻到第 13 張投影片。

Our XPORT-MF-035 trial is a randomized Phase 2 trial that is evaluating Selinexor monotherapy versus physician's choice. The study was designed to evaluate the efficacy and safety of Selinexor in a more heavily pre-treated Myelofibrosis population. Importantly, this trial allows for patients to cross over from physicians' choice to Selinexor if their spleen met predefined progression criteria. To be eligible for the trial, patients needed at least six months of prior exposure to a JAKi inhibitor. This trial was originally designed to randomize 112 patients. However, we stopped enrollment in 2023 to focus our resources on our ongoing Phase 3 SENTRY Trial.

我們的 XPORT-MF-035 試驗是一項隨機 2 期試驗，旨在評估 Selinexor 單一療法與醫生選擇的療法。該研究旨在評估 Selinexor 對接受過更多預先治療的骨髓纖維化族群的療效和安全性。重要的是，如果患者的脾臟符合預先定義的進展標準，這項試驗允許患者從醫生的選擇轉而使用 Selinexor。為了符合試驗資格，患者需要至少六個月接觸 JAKi 抑制劑。試驗最初設計隨機分配 112 名患者。然而，我們在 2023 年停止了招募，以便將資源集中在正在進行的 3 期 SENTRY 試驗上。

Slide 14 contains the baseline characteristics for the 24 patients that we enrolled in the trial. Keep in mind that this trial enrolled a very different patient population than the patients we are enrolling in our Phase 3 SENTRY Trial. Patients in this trial were heavily pre-treated with an average of 2 prior lines of therapy, with some patients having up to 4 lines of prior therapy. This is also a very frail, high-risk population. I would direct your attention to the fact that 17% of patients are triple negative and 21% are high risk. Furthermore, these patients are generally cytopenic with hemoglobin levels between 9 and 10. 5 of these patients were transfusion dependent prior to enrolling in the trial.

幻燈片 14 包含我們參加試驗的 24 名患者的基線特徵。請記住，本次試驗招募的患者群體與我們在 3 期 SENTRY 試驗中招募的患者群體非常不同。參與本次試驗的患者平均接受過 2 種療法，部分患者接受過多達 4 種療法。這也是一個非常虛弱、高風險的族群。我想提請您注意這樣一個事實：17% 的患者是三陰性，21% 的患者是高風險。此外，這些患者一般都患有血紅蛋白減少症，血紅素水平在 9 到 10 之間。其中 5 名患者在參加試驗之前依賴輸血。

Slide 15 contains the spleen volume reduction observed in this trial. We evaluated the maximum SVR experienced at any time in the efficacy of valuable populations. The 8 patients shown in blue were treated with physicians' choice. The patients represented by the solid green bars in the middle of the slide were randomized to Selinexor. The additional 5 patients in the textured green bars on the far right were patients that progressed on physicians' choice and crossed over to Selinexor.

投影片 15 包含本試驗觀察到的脾臟體積減少。我們評估了有價值人群在療效中隨時經歷的最大 SVR。藍色顯示的 8 名患者均由醫生選擇進行治療。幻燈片中間的實心綠色條代表的患者被隨機分配接受 Selinexor 治療。最右側帶有紋理的綠色條中的另外 5 名患者是根據醫生的選擇而進展並轉用 Selinexor 的患者。

As is clear on the slide, spleen volume reduction was greater in those patients that received Selinexor at any time compared to the group that received physicians' choice. In fact, all but one patient in the Selinexor arm achieved some degree of spleen volume reduction. Whereas only half of the patients in the physician's choice arm experienced a decrease in spleen volume, 38% of the valuable patients in the physician's choice arm achieved an SVR25 at any time, whereas 67% in the Selinexor arm, including patients that crossed over, achieved an SVR25. For SVR35 rates were more than double for Selinexor. 13% of patients in the physician's choice arm achieved this level of spleen volume reduction or greater compared to 33% in the Selinexor arm.

從幻燈片上可以清楚看出，與接受醫生選擇治療的組別相比，任何時間接受 Selinexor 治療的患者的脾臟體積減少幅度都更大。事實上，Selinexor 組除一名患者外，其餘所有患者的脾臟體積均有所縮小。儘管醫生選擇組中只有一半的患者脾臟體積減小，但醫生選擇組中 38% 的寶貴患者在任何時候都達到了 SVR25，而 Selinexor 組中 67% 的患者（包括交叉患者）達到了 SVR25。對於 SVR35，Selinexor 的利率是其兩倍以上。醫生選擇組有 13% 的患者達到了脾臟體積減少的程度或更高，而 Selinexor 組則為 33%。

Slide 16 contains a very compelling spider line graph that looks at the impact that Selinexor has on spleen size on patients that crossed over and thus had progressed on prior therapy. Of the 6 patients who crossed over from physicians' choice to Selinexor, 5 were valuable and are showed on the slide. 4 of these 5 patients received Ruxolitinib as a physician's choice prior to crossover. So in fact, the spider line graph really demonstrates Selinexor's effect on the spleen size in Ruxolitinib refractory patients.

投影片 16 包含一個非常引人注目的蜘蛛線圖，該圖顯示了 Selinexor 對交叉治療並在先前的治療中取得進展的患者的脾臟大小的影響。在 6 名從醫生選擇轉為使用 Selinexor 的患者中，有 5 名很有價值，並在幻燈片上顯示。這 5 名患者中有 4 名在交叉治療之前根據醫生的選擇接受了魯索利替尼治療。因此，事實上，蜘蛛線圖確實顯示了 Selinexor 對 Ruxolitinib 難治性患者脾臟大小的影響。

The first column, as represented by the y axis, represents the baseline spleen level for each patient. The second series of data points represents the maximum reduction of spleen volume on physicians' choice or Ruxolitinib. The third series of data points represent the spleen volume growth experienced at the time of progression. The fourth series of data points then represents spleen volume relative to baseline after the patient's crossover to Selinexor.

第一列（y 軸）代表每位患者的基線脾臟水準。第二組數據點代表醫師選擇或使用魯索利替尼後脾臟體積的最大減少量。第三組數據點代表病情進展時脾臟體積的成長。第四組數據點代表患者轉用 Selinexor 後脾臟體積相對於基線的變化。

The interpretation of these data are very clear. Each patient that crossed over to Selinexor demonstrated clear and meaningful reductions in their spleen volume after crossing over, likely indicating that Selinexor is targeting pathways beyond the jackstat pathway, enabling both monotherapy activity as well as additive, if not synergistic activity, when combined with Ruxolitinib.

這些數據的解釋非常清楚。每位接受 Selinexor 治療的患者在轉換治療方案後，脾臟體積都出現了明顯且有意義的減少，這可能表明 Selinexor 所針對的是 jackstat 通路以外的通路，與 Ruxolitinib 聯合使用時，既能發揮單一療法的活性，又能發揮附加活性（如果不是協同活性的話）。

Similar to spleen volume reduction, we also see meaningful symptom improvement with Selinexor monotherapy. As you see on slide 17, there was no improvement in symptoms for the patient's randomized physician's choice. In contrast, the seven efficacy of valuable patients randomized to Selinexor reported a 5.9% improvement in absolute TSS at week 24 and 29% achieved a TSS 50.

與脾臟體積減少類似，我們也看到 Selinexor 單一療法帶來症狀的顯著改善。正如您在幻燈片 17 上看到的，患者隨機選擇的醫生的症狀並沒有改善。相較之下，隨機接受 Selinexor 治療的 7 名有療效患者報告稱，第 24 週絕對 TSS 改善了 5.9%，29% 的患者達到了 TSS 50。

If you look at all patients treated with Selinexor, including those that crossed over, this group reported a 3.7% improvement in absolute TSS, and 18% achieved TSS 50 at week 24. Please note that all of these figures exclude the fatigue domain, which is consistent with how we are calculating absolute TSS in our Phase 3 SENTRY Trial. As we have previously discussed, we have aligned with FDA on this approach, and it is consistent with the comfort and (inaudible) trials that led to approvals for Ruxolitinib and the Fedratinib respectively. Turning to slide 18.

如果你觀察所有接受 Selinexor 治療的患者（包括那些交叉治療的患者），你會發現該組患者的絕對 TSS 改善了 3.7%，而 18% 的患者在第 24 週達到了 TSS 50。請注意，所有這些數字都不包括疲勞領域，這與我們在第 3 階段 SENTRY 試驗中計算絕對 TSS 的方式一致。正如我們之前所討論的，我們在這種方法上與 FDA 保持一致，並且它與分別導致 Ruxolitinib 和 Fedratinib 獲得批准的舒適度和（聽不清）試驗一致。翻到第 18 張投影片。

We show how hemoglobin levels changed over time. Patients randomized to Selinexor are shown in green. Patients on physicians' choice are shown in blue. Visually, you can see that hemoglobin levels are substantially higher in the Selinexor arm throughout the study duration. Let's take this a step further and look at transfusion burden as shown on slide 19.

我們展示了血紅蛋白水平隨時間的變化。隨機接受 Selinexor 治療的患者以綠色顯示。醫生選擇的患者以藍色顯示。從視覺上看，您可以看到在整個研究期間，Selinexor 組的血紅蛋白水平明顯更高。讓我們更進一步看看投影片 19 所示的輸血負擔。

Starting with the Swimmer's Plot on the left, we use the same colors from the prior slide. Patients randomized to Selinexor are in green. Patients randomized to physicians' choice are in blue, and patients that crossed over to Selinexor are shown in the yellow extensions at the end of the blue lines. The red dots represent transfusions. 5 patients were transfusion dependent at baseline, 3 in the physician's choice arm, and 2 in the Selinexor arm. Notably, patient 4112-003 in the Selinexor arm was transfusion dependent prior to randomization.

從左側的游泳者圖開始，我們使用與上一張幻燈片相同的顏色。隨機接受 Selinexor 治療的患者顯示為綠色。根據醫生的選擇隨機分配的患者顯示為藍色，而轉用 Selinexor 的患者則顯示為藍線末端的黃色延伸部分。紅點代表輸血。 5 名患者在基線時依賴輸血，其中 3 名來自醫生選擇組，2 名來自 Selinexor 組。值得注意的是，Selinexor 組的 4112-003 號患者在隨機分組之前依賴輸血。

Visually, you can see right away that patients that start on physicians' Choice receive many more transfusions. Why? It is likely because XPO1 inhibition is modifying the underlying disease and helping the patients produce more healthy bone marrow. We expect to be able to answer this question more definitively with the results from the Phase 3 SENTRY Trial. Now, we ask ourselves, why are we seeing higher hemoglobin levels and less transfusion. Let's look at slide 20, which outlines the Key Cytokines that are relevant in myelofibrosis.

從視覺上看，您可以立即看到，開始接受醫生選擇的患者接受了更多的輸血。為什麼？這可能是因為 XPO1 抑制正在改變潛在疾病並幫助患者產生更健康的骨髓。我們希望能夠透過第三階段 SENTRY 試驗的結果更明確地回答這個問題。現在，我們問自己，為什麼我們看到血紅蛋白水平更高而輸血更少。讓我們來看看第 20 張幻燈片，其中概述了與骨髓纖維化相關的關鍵細胞因子。

Starting with Myelofibrosis Pathogenesis, IL-6 and IL-8 are relevant to Malignant Mutated Clonal Expansion, Hepatosplenomegaly, and Bone Marrow Angiogenesis. IL-6 and IL-8 also affect constitutional symptoms and drive inflammation, as does TNF alpha. Anemia is affected by IL-6, Hepcidin, and TNF alpha, which plays a role in suppressing normal Hematopoiesis and also blocks iron availability. Please keep all of this in mind as we review slide 21.

從骨髓纖維化發病機制開始，IL-6 和 IL-8 與惡性突變克隆擴增、肝脾腫大和骨髓血管生成有關。IL-6 和 IL-8 也會影響全身症狀並引起炎症，TNF alpha 也是如此。貧血受到 IL-6、鐵調素和 TNF alpha 的影響，它們在抑制正常造血方面發揮作用，同時阻礙鐵的利用。當我們回顧第 21 張投影片時，請記住所有這些。

We obtained plasma samples at baseline, and again, at week 4, on a subset of the patients that participated in the trial, 5 from the Selinexor arm and 5 from the physician's choice arm. We plotted the Cytokine changes using a standard dendrogram plot. Blue and purple hues represent a decrease in Cytokines, red and peach hues represent an increase. The decreases are what we are looking for. As you look at the slide, please focus on the box in the middle of the screen. This is where the 4 Cytokines that are relevant to Myelofibrosis are shown. You'll see the arrows pointing to IL-6, IL-8, Hepcidin, and TNF alpha.

我們在基線時採集了血漿樣本，並在第 4 週再次採集了參與試驗的一部分患者的血漿樣本，其中 5 名來自 Selinexor 組，5 名來自醫生選擇組。我們使用標準樹狀圖繪製了細胞激素變化。藍色和紫色代表細胞激素減少，紅色和桃紅色代表細胞激素增加。我們所期待的正是這種減少。當您觀看幻燈片時，請注意螢幕中間的框框。這裡顯示了與骨髓纖維化相關的 4 種細胞因子。您會看到指向 IL-6、IL-8、Hepcidin 和 TNF alpha 的箭頭。

For these 4 key Cytokines, we are seeing clear reductions as early as week 4 in the Selinexor arm, while there are increases in the Cytokines in the physician's choice arm. In the blue box at the bottom, you can see the actual percentage changes, including a 37% median reduction in IL-8, 29% median reduction in IL-6, 25% median reduction in TNF alpha, and a 30% median reduction in Hepcidin for those patients in the Selinexor arm. In contrast, 3 of the 4 medians increased for the physician's choice arm. These data suggests that Selinexor is modifying the underlying disease, something that JAK inhibitors have not been able to adequately demonstrate. Let's now turn to the safety data on slide 22.

對於這 4 種關鍵細胞因子，我們早在第 4 週就看到 Selinexor 組的細胞因子明顯減少，而醫生選擇組的細胞因子增加。在底部的藍色框中，您可以看到實際的百分比變化，包括 Selinexor 組患者的 IL-8 中位數減少 37%，IL-6 中位數減少 29%，TNF alpha 中位數減少 25%，以及 Hepcidin 中位數減少 30%。相較之下，醫生選擇組的 4 個中位數中有 3 個增加了。這些數據表明 Selinexor 正在改變潛在的疾病，這是 JAK 抑制劑無法充分證明的。現在讓我們來看看第 22 張投影片上的安全資料。

Selinexor continues to demonstrate a manageable safety profile. Selinexor is similar to physicians' choice for both all Grade and Grade 3 plus TEAEs. In particular, nausea was only 33% in the Selinexor arm compared to physicians' choice. Similar rates of Thrombocytopenia were observed across the two arms. A notable exception is anemia, where both all Grade and Grade 3 plus anemia are meaningfully decreased in the Selinexor arm compared to physicians' choice, specifically all grade anemia with 25% in the Selinexor arm compared to 58% in the physician's choice arm in Grade 3 plus anemia with 17% in the Selinexor arm compared to 58% in the physician's choice arm.

Selinexor 繼續展現可控的安全性。對於所有 3 級和 3 級以上 TEAE，Selinexor 與醫生的選擇類似。具體來說，與醫生的選擇相比，Selinexor 組的噁心發生率僅為 33%。兩組觀察到的血小板減少症發生率相似。一個顯著的例外是貧血，與醫生選擇組相比，Selinexor 組的所有級別貧血和 3 級及以上貧血均顯著降低，具體而言，Selinexor 組的所有級別貧血為 25%，而醫生選擇組為 58%；3 級及以上貧血為 17%，而醫生選擇組為 58%。

These data are notable given that we are not only seeing higher hemoglobin levels and lower transfusion burdens, which I discussed on the prior slides, but also lower anemia AEs in our safety data, further suggestive of disease modification. Lastly, I'll note that none of the patients randomized to Selinexor discontinued treatment due to an adverse event. Turning to slide 23.

這些數據值得注意，因為我們不僅看到了更高的血紅蛋白水平和更低的輸血負擔（我在之前的幻燈片中討論過），而且我們的安全數據中的貧血不良事件也較低，進一步表明了疾病的改變。最後，我要指出的是，隨機接受 Selinexor 治療的患者中沒有一人因不良事件而停止治療。翻到第 23 張投影片。

We are pleased that our Phase 3 SENTRY Trial successfully passed its pre-specified futility analysis. The DSMB recommended that the study continue as planned without modification, following a review of safety and efficacy data in the first 61 patients, all of whom were followed for at least 24 weeks. In the study, we continue to make strong progress towards our goal of enrolling 350 patients. We expect to complete enrollment very shortly in the June July time frame.

我們很高興我們的第 3 階段 SENTRY 試驗成功通過了預先指定的無效性分析。在對前 61 名患者進行至少 24 週的追蹤後，DSMB 建議研究繼續按計劃進行，無需修改。在研究中，我們繼續朝著招募 350 名患者的目標取得重大進展。我們預計在六月至七月期間很快完成招生。

With the data that I just shared with Selinexor monotherapy and a hard to treat heavily pre-treated patient population, I'm very encouraged with the consistency that is being observed across our multiple clinical and preclinical data sets. These data continue to suggest that the combination of Selinexor plus Ruxolitinib has the potential to be clinically additive, if not synergistic, in a JAKi-Naïve patient population. Thus, leading to substantially higher SVR and TSS improvements as compared to each agent alone as observed in our Phase 1 combination study.

透過我剛剛分享的有關 Selinexor 單藥療法和難以治療的大量接受過預先治療的患者群體的數據，我對我們在多個臨床和臨床前數據集中觀察到的一致性感到非常鼓舞。這些數據繼續表明，對於 JAKi-Naïve 患者群體而言，Selinexor 與 Ruxolitinib 的組合具有臨床附加作用的潛力，甚至可能具有協同作用。因此，正如我們在第 1 階段組合研究中觀察到的，與單獨使用每種藥物相比，SVR 和 TSS 改善顯著提高。

Together with the hemoglobin stabilization and lower transfusion burden, as well as the potential for disease modification, the data continue to suggest that Selinexor is affecting each of the four key hallmarks of Myelofibrosis. We look forward to continuing to demonstrate this with the upcoming results from our Phase 3 SENTRY Trial and building upon Selinexor's well established safety profile with over 30,000 patients treated across multiple indications and the potential for patient convenience within all oral combination.

結合血紅蛋白穩定和較低的輸血負擔以及改變疾病的潛力，數據繼續顯示 Selinexor 正在影響骨髓纖維化的四個關鍵特徵。我們期待透過即將公佈的 3 期 SENTRY 試驗結果繼續證明這一點，並在 Selinexor 已建立的良好安全性基礎上，為超過 30,000 名接受多種適應症治療的患者提供服務，並有可能為所有口服組合中的患者帶來便利。

Now, let's shift our focus to Endometrial Cancer, where TP53 wild-type is such an important biomarker. As seen on slide 25, patients with both MMR proficient and TP53 wild-type tumors make up approximately 50% of all advanced or recurrent Endometrial Cancer cases, representing a very sizable group of patients. Selinexor primarily functions by blocking the export of TP53 from the nucleus to the cytoplasm. When TP53 accumulates in the nucleus, it leads to disrupted DNA repair processes, cell cycle arrest, and increased apoptosis. I remain encouraged with the potential of Selinexor to achieve clinically meaningful outcomes in the maintenance setting for patients TP53 wild-type Endometrial Cancer.

現在，讓我們將注意力轉移到子宮內膜癌，其中 TP53 野生型是一種重要的生物標記。如幻燈片 25 所示，同時患有 MMR 功能正常和 TP53 野生型腫瘤的患者佔所有晚期或復發性子宮內膜癌病例的約 50%，代表著一個非常龐大的患者群體。Selinexor 的主要作用是阻止 TP53 從細胞核輸出到細胞質。當 TP53 在細胞核中累積時，它會導致 DNA 修復過程中斷、細胞週期停滯和細胞凋亡增加。我仍然對 Selinexor 在 TP53 野生型子宮內膜癌患者的維持治療中取得具有臨床意義的結果的潛力感到鼓舞。

On slide 26, we outlined the study designed for our ongoing XPORT-EC-042 trial. Enrollment in the trial is progressing steadily, and we continue to expect to report topline data in the middle of 2026.

在第 26 張投影片上，我們概述了為正在進行的 XPORT-EC-042 試驗設計的研究。試驗的招募工作正在穩步推進，我們預計將在 2026 年中期報告頂線數據。

Lastly, our Phase 3 EMN29 SPD trial is outlined on slide 28. This trial aims to address the unmet need of patients with Multiple Myeloma by offering an all oral triplet treatment option that could also benefit those undergoing pre and post T cell engaging therapies. We expect to report top line data from this event-driven trial in the first half of 2026. I will now turn the call to Sohanya.

最後，我們的第 3 階段 EMN29 SPD 試驗概述於投影片 28。該試驗旨在透過提供全口服三重治療方案來解決多發性骨髓瘤患者未滿足的需求，該方案也可使接受治療前和治療後 T 細胞接合療法的患者受益。我們預計在 2026 年上半年報告此事件驅動試驗的頂線資料。現在我會把電話轉給 Sohanya。

Thank you, Reshma. On slide 30, I will discuss our commercial highlights for Q1 2025.

謝謝你，Reshma。在第 30 張投影片上，我將討論我們 2025 年第一季的商業亮點。

We delivered 5% demand growth in Q1 year over year, although net product revenue was $21.1 million and was adversely impacted by a $5 million increase in the product return reserve due to atypical returns of expired product, primarily 80-milligram and 100-milligram XPOVIO units. These higher dose units were purchased by clinics and hospitals following the 2020 approval of the XPOVIO 100-milligram triplet combination. The majority of XPOVIO that is prescribed today are 40-milligram and 60-milligram doses, and we expect product returns will be similar to historical levels in future quarters.

儘管淨產品收入為 2,110 萬美元，並且受到過期產品（主要是 80 毫克和 100 毫克 XPOVIO 單位）非正常退貨導致產品退貨儲備增加 500 萬美元的不利影響，但我們第一季的需求同比增長了 5%。繼 2020 年 XPOVIO 100 毫克三重療法獲得批准後，診所和醫院開始購買這些更高劑量的藥物。目前處方的 XPOVIO 大部分劑量為 40 毫克和 60 毫克，我們預計未來幾季的產品回報將與歷史水準相似。

As we look at the key drivers of demand in Q1, we delivered year-over-year growth in prescriptions across both academic and community settings of care, with the latter contributing to 60% of our sales. The Multiple Myeloma market remains highly competitive, and we're expecting additional new entrants this year. Within this market, XPOVIO is positioned in the community as a flexible therapy with a differentiated mechanism of action, oral convenient option following treatment with an anti CD38 therapy, as well as in patients who cannot access or fail a T cell engaging therapy.

當我們觀察第一季需求的主要驅動因素時，我們發現學術和社區護理環境中的處方量均同比增長，其中後者貢獻了我們銷售額的 60%。多發性骨髓瘤市場競爭依然激烈，我們預計今年將有更多新進者。在這個市場中，XPOVIO 的定位是一種靈活的治療方法，具有差異化的作用機制，是抗 CD38 療法治療後的便捷口服選擇，也適用於無法獲得 T 細胞介導療法或 T 細胞介導療法治療失敗的患者。

In the academic setting compared to last year, we're seeing increasing use of XPOVIO immediately before and following T cell therapies. We expect to continue to display resilience in a competitive Multiple Myeloma market, and in light of the atypical level of returns in the first quarter, we now expect to be tracking towards the lower end of our guidance range for net product revenue of $115 million to $130 million. Moving to slide 31.

與去年相比，在學術環境中，我們看到在 T 細胞治療之前和之後使用 XPOVIO 的情況越來越多。我們預計將在競爭激烈的多發性骨髓瘤市場中繼續展現韌性，鑑於第一季非典型的回報水平，我們現在預計淨產品收入將接近指導範圍的下限，即 1.15 億美元至 1.3 億美元。移至第 31 張投影片。

We continue to expand global patient access for Selinexor, which is translating into growth in royalty revenue from Menorini, Antigene and other international partners. Royalty revenue increased 57% to $1.7 million in the first quarter of 2025 compared to the first quarter of 2024, reflecting increasing global demand for XPOVIO and XPOVIO. As we now move to potential new indications, our commercial team is preparing for a very rapid launch in Myelofibrosis, if approved. As outlined on slide 32, we continue to believe that our peak annual revenue opportunity in the US alone is up to approximately a billion with additional royalty and milestone revenue globally.

我們繼續擴大 Selinexor 的全球患者可及性，這將轉化為來自 Menorini、Antigene 和其他國際合作夥伴的特許權使用費收入的成長。2025 年第一季的特許權使用費收入與 2024 年第一季相比成長 57%，達到 170 萬美元，反映出全球對 XPOVIO 和 XPOVIO 的需求不斷增長。隨著我們目前轉向潛在的新適應症，我們的商業團隊正在為骨髓纖維化領域（如果獲得批准）的快速上市做準備。正如第 32 張幻燈片中概述的那樣，我們仍然相信，僅在美國，我們的年收入峰值機會就高達約 10 億美元，並且在全球範圍內還有額外的特許權使用費和里程碑收入。

On slide 33, we outline why we believe we are so well positioned for a rapid launch in Myelofibrosis. As we have shared previously, 75% of the physicians that we surveyed say that they intend to adopt a combination therapy Myelofibrosis, if one becomes available. If Selinexor is approved in combination with Ruxolitinib, we could be the first combination therapy on the market. We would be in all oral therapy, which makes adoption much easier, especially in the community setting. On this point, there is an 80% overlap in the community between Myelofibrosis and Multiple Myeloma prescribers that our organization is already calling on, which enables us to drive a rapid launch and minimizes the upfront investment required for the launch.

在第 33 張投影片上，我們概述了為什麼我們相信我們有能力快速推出骨髓纖維化產品。正如我們之前所分享的，我們調查的 75% 的醫生表示，如果有聯合療法可用於治療骨髓纖維化，他們打算採用該療法。如果 Selinexor 與 Ruxolitinib 聯合治療獲得批准，我們可能會成為市場上首個聯合治療藥物。我們將進行全方位的口腔治療，這使得採用變得更加容易，特別是在社區環境中。在這一點上，我們組織已經在呼籲的骨髓纖維化和多發性骨髓瘤處方者在社區中有 80% 的重疊，這使我們能夠推動快速啟動並最大限度地減少啟動所需的前期投資。

Finally, in Endometrial Cancer, as shown on slide 34, we continue to believe that we have a significant opportunity in the TP53 wild-type PMMR patient population, which represents approximately 50% of advanced or recurrent Endometrial Cancer patients. Similar to what I outlined for Myelofibrosis, there's a large overlap between the potential community-based oncologists caring for Endometrial Cancer patients and those that we're already engaging with. Now, I'll turn the call over to Lori.

最後，對於子宮內膜癌，如幻燈片 34 所示，我們仍然相信，TP53 野生型 PMMR 患者群體具有重大機會，該群體約佔晚期或復發性子宮內膜癌患者的 50%。與我針對骨髓纖維化概述的情況類似，護理子宮內膜癌患者的潛在社區腫瘤學家與我們已經接觸的腫瘤學家之間存在很大的重疊。現在，我將把電話轉給 Lori。

Good afternoon, everyone, and thank you, Sohanya. Turning to our financials, since we issued a press release earlier today with the full financial results, I will focus on the highlights and reviewing our guidance for 2025 on slide 36.

大家下午好，謝謝你，Sohanya。談到我們的財務狀況，由於我們今天早些時候發布了一份包含完整財務業績的新聞稿，因此我將重點介紹其中的亮點，並在第 36 張幻燈片上回顧我們對 2025 年的指導。

Total revenue for the first quarter of 2025 was $30 million compared to $33.1 million for the first quarter of 2024. US XPOVIO net product revenue for the first quarter of 2025 was $21.1 million compared to $26 million for the first quarter of 2024. A decrease in net product revenue was due to an increase in the gross to net provision primarily related to the higher dose product returns recorded in the first quarter of 2025, resulting in a $5 million increase in the product return reserve compared to the first quarter of 2024. Related to this, the gross to net provisions for XPOVIO in the first quarter was 45% compared to 29.3% in the same period in 2024. We expect our gross net provisions will return to historic levels starting in the second quarter.

2025 年第一季的總收入為 3,000 萬美元，而 2024 年第一季的總收入為 3,310 萬美元。美國 XPOVIO 2025 年第一季的淨產品收入為 2,110 萬美元，而 2024 年第一季為 2,600 萬美元。淨產品收入減少是由於總撥備與淨撥備的增加，這主要與 2025 年第一季度記錄的較高劑量產品退貨有關，導致產品退貨儲備金與 2024 年第一季相比增加了 500 萬美元。與此相關，XPOVIO 第一季的總撥備與淨撥備比率為 45%，而 2024 年同期為 29.3%。我們預計，從第二季開始，我們的淨撥備總額將恢復到歷史水準。

R&D expenses for the first quarter of 2025 were $34.6 million compared to $35.4 million for the first quarter of 2024. The decrease with the reduction in headcount and contractors related to ongoing cost optimization initiatives, partially offset by increased clinical trial activity related to our pivotal Phase 3 study in Myelofibrosis. SG&A expenses for the first quarter of 2025 were $27.4 million compared to $29.5 million for the first quarter of 2024. The decrease was due to a reduction in headcount and contractors in connection with cost optimization efforts.

2025 年第一季的研發費用為 3,460 萬美元，而 2024 年第一季的研發費用為 3,540 萬美元。由於正在進行的成本優化計劃而導致員工數量和承包商減少，但部分被與我們在骨髓纖維化方面的關鍵性 3 期研究相關的臨床試驗活動的增加所抵消。2025 年第一季的銷售、一般及行政費用為 2,740 萬美元，而 2024 年第一季為 2,950 萬美元。減少的原因是，為了優化成本，員工和承包商的數量減少了。

We continue to be very diligent in allocating our resources and pipeline prioritization while striving to deliver additional cost savings in 2025 and continuing to advance our Phase 3 clinical trials and driving our commercial performance. We exited first quarter 2025 with cash, cash equivalents, restricted cash and investments of $70.3 million compared to $109.1 million as of December 31, 2024. As a reminder, cash burn is typically highest in the first quarter of each year.

我們將繼續非常勤奮地分配我們的資源和管道優先級，同時努力在 2025 年實現額外的成本節約，並繼續推進我們的 3 期臨床試驗並推動我們的商業表現。截至 2025 年第一季度，我們的現金、現金等價物、受限現金和投資為 7,030 萬美元，而截至 2024 年 12 月 31 日為 1.091 億美元。提醒一下，現金消耗通常在每年第一季最高。

Based on our current operating plans, our guidance for the full year of 2025 is as follows. Total revenue of $140 million to $155 million consisting of US XPOVIO net product revenue and license, royalty and milestone revenue expected to be earned from our partners, primarily Menarini and Antengene.

根據我們目前的營運計劃，我們對 2025 年全年的指導如下。總收入為 1.4 億美元至 1.55 億美元，包括美國 XPOVIO 淨產品收入以及預計從我們的合作夥伴（主要是 Menarini 和 Antengene）獲得的許可、特許權使用費和里程碑收入。

US XPOVIO net product revenue to be in the range of $115 million to $130 million. As a result of the atypical level returns in the first quarter, we now expect total revenue and net product revenue will be towards the lower end of these ranges. R&D and SG&A expenses to be in the range of $240 million to $255 million. And finally, we expect our existing cash equivalents and investments, the revenue we expect to generate from XPOVIO net product sales and other recent revenues, and ongoing discipline expense management will fund our planned operations into early Q1 2026.

美國 XPOVIO 淨產品收入將在 1.15 億美元至 1.3 億美元之間。由於第一季的回報率水準非典型性，我們現在預計總收入和淨產品收入將接近這些範圍的低端。研發和銷售、一般及行政費用在 2.4 億美元至 2.55 億美元之間。最後，我們預計我們現有的現金等價物和投資、我們預計從 XPOVIO 淨產品銷售額和其他近期收入中產生的收入以及持續的紀律費用管理將為我們計劃的運營提供資金，直至 2026 年第一季初。

This guidance does not include payment for the remaining 2025 convertible notes and our $25 million minimum liquidity covenant under our term loan. Considering the repayment of the 2025 convertible notes in the minimum liquidity covenant, we expect cash equivalents and investments will fund operations into early Q4 2025.

該指引不包括支付剩餘的 2025 年可轉換票據和我們定期貸款下的 2,500 萬美元最低流動性契約。考慮到最低流動性契約中 2025 年可轉換票據的償還，我們預計現金等價物和投資將為 2025 年第四季初的營運提供資金。

In closing, we are exploring various opportunities to extend our cash runway and our focus on the advancement of our Phase 3 clinical trials, driving commercial performance and continuing to be very diligent when allocating our resources. I will now turn the call back to Richard for some final thoughts.

最後，我們正在探索各種機會來延長我們的現金流，並將重點放在推進我們的第三階段臨床試驗、推動商業表現以及繼續非常勤勉地分配我們的資源。現在我將把電話轉回給理查德，請他發表一些最後的看法。

Turning to slide 38, as Lori mentioned, we are exploring various opportunities to extend our cash runway as we are focused on delivering the potentially transformational opportunity ahead of us in Myelofibrosis while also continuing to advance our Phase 3 trial in Endometrial Cancer and deliver solid commercial results.

翻到第 38 張幻燈片，正如 Lori 所提到的，我們正在探索各種機會來延長我們的現金流，因為我們專注於在骨髓纖維化領域提供潛在的轉型機會，同時繼續推進我們在子宮內膜癌方面的 3 期試驗並取得穩健的商業成果。

Myelofibrosis and Endometrial Cancer, depending on the outcome of the data, are both game-changing opportunities for patients, our organization, and our shareholders alike. We are working hard to unlock our innovation and growth strategy and are very excited by our growing body of data and what it can mean for patients with Myelofibrosis. Thank you again for joining us today, and I would now like to ask the operator to open the call up to the Q&A portion of today's call.

根據數據結果，骨髓纖維化和子宮內膜癌對患者、我們的組織和我們的股東來說都是改變遊戲規則的機會。我們正在努力解鎖我們的創新和成長策略，並對我們不斷增長的數據及其對骨髓纖維化患者的意義感到非常興奮。再次感謝您今天的參與，現在我想請接線生打開今天電話會議的問答部分。

(Operator Instructions)

（操作員指示）

Colleen Kusy, Baird.

科琳·庫西，貝爾德。

Hi, good afternoon. Thanks for taking our questions. Congrats on the continued progress and the new data. Thanks for all the updates. So on the futility analysis, can you talk about what that was based on and what the options were? Could the study have been upsized if the DSMB had suggested it?

嗨，下午好。感謝您回答我們的問題。恭喜您不斷取得進展並取得新數據。感謝所有的更新。那麼，關於無效性分析，您能談談其依據是什麼以及有哪些選擇嗎？如果 DSMB 建議的話，這項研究的規模可以擴大嗎？

Yeah, thanks, Colleen. I'll let Reshma go into the details of that from the futility analysis.

是的，謝謝，科琳。我會讓 Reshma 從無用性分析的角度來詳細說明這一點。

Yeah, thanks, Colleen for the question. So there was a futility analysis that was conducted earlier this year, and it was specifically based upon efficacy and safety that was observed in the first 61 patients, all of whom were followed for 24 weeks. For the efficacy, the DSMB had the unblinded data for both SVR35 in that cohort, as well as absolute TSS. Those efficacy analysis had pre-specified thresholds, essentially the thresholds amounted to no worsening for the combination relative to Ruxolitinib alone.

是的，謝謝科琳提出這個問題。因此，今年稍早進行了一項無效性分析，該分析專門基於對前 61 名患者觀察到的療效和安全性，所有患者都接受了 24 週的隨訪。對於療效，DSMB 擁有該隊列中 SVR35 以及絕對 TSS 的非盲數據。這些療效分析有預先指定的閾值，本質上這些閾值相當於組合治療相對於單獨使用魯索利替尼而言不會惡化。

For the safety, again, they were also provided the unblinded safety data from that cohort, and there was no pre-specified bars for that analysis that was really based upon their qualitative assessment of the totality of that safety data. As you noted, they passed the futility and recommended that the study just continues as planned as we are now doing, enrollment is now expected to complete in the June-July time frame.

為了確保安全性，他們再次獲得了該隊列的非盲安全性數據，並且沒有預先指定的分析標準，該分析實際上基於對全部安全性數據的定性評估。正如您所說，他們忽略了無用性，並建議研究按照我們現在的計劃繼續進行，預計招生將在 6 月至 7 月期間完成。

That's helpful, thanks. And then I believe in prior quarters you talked about a 2-point delta in average TSS, you know, being in a stat sig range for manifest to. But I think on your slide, you talk about the power and the primary points about a 4-point delta on TSS. So can you just talk about what you're expecting to need to hit on TSS for it to be a positive study?

這很有幫助，謝謝。然後我相信在前幾個季度中您談到了平均 TSS 的 2 點增量，您知道，這處於顯性的統計訊號範圍內。但我認為在您的幻燈片上，您討論了 TSS 的 4 點增量的力量和主要要點。那麼，您能否談談您認為需要對 TSS 進行哪些改進才能使其成為一項積極的研究？

Sure, so great question. So these are just our assumptions. So with 350 patients, we are assuming a delta of 4 across the two arms and a standard deviation of 12 for each of these two arms. Incorporating those assumptions, the overall power for hitting on absolute TSS is going to be greater than 80%. So these are just our assumptions and reality, as you know, the data can differ. We still maintain that a clinically meaningful outcome is just improvement for the combination, above and beyond what Ruxolitnib alone demonstrates. But again, that 4-point delta and standard deviation of 12 are just, again, the stat assumptions that drive the overall power.

當然，這個問題問得真好。這些只是我們的假設。因此，對於 350 名患者，我們假設兩組之間的差異為 4，且這兩組的標準差均為 12。結合這些假設，達到絕對 TSS 的總體功率將大於 80%。所以這些只是我們的假設和現實，如你所知，數據可能會有所不同。我們仍然堅持認為，具有臨床意義的結果只是組合療法的改善，超越了 Ruxolitnib 單獨療法所表現出的效果。但再次強調，4 點增量和 12 的標準差只是驅動整體力量的統計假設。

Got it. That's helpful. And if I can squeeze in one more quick one, the enrollment looks to be slightly behind schedule for the Phase 3 Myelofibrosis entry study. Can you speak to some of the enrollment dynamics you're seeing that's putting you kind of towards the end of the bottom half of the range? Thanks.

知道了。這很有幫助。如果我可以再擠出一點時間的話，第三階段骨髓纖維入門研究的招生似乎稍微落後於計劃。您能否談談您所看到的一些招生動態，這些動態使得您的招生人數處於範圍下半部的末端？謝謝。

Yeah, I think you (multiple speakers) Go ahead. Sorry.

是的，我認為你（多位發言者）請繼續。對不起。

Okay, yeah, sorry. We stepped over each other, but good question again, Colleen. Sort of like when we put together the enrollment cards, we were really looking at a lot of data, especially historical trials transform as well as manifest. We were getting a lot of information from the sites and really understanding sort of that competitive intensity or lack thereof that is occurring in the field of Myelofibrosis specifically in this patient population. I will admit sort of like what we've seen in the last sort of few months, especially in 2025, suggests that it's a little slower than expected. Things are still very robust, both from the screening as well as enrollment, but again, a little slower than what we had anticipated, which is what is driving that slight delay in the enrollment time frame.

好的，是的，抱歉。我們互相越過，但科琳，這又是一個好問題。有點像當我們整理入學卡時，我們實際上在查看大量數據，特別是歷史試驗轉變和表現。我們從這些站點獲取了大量信息，真正了解了骨髓纖維化領域（特別是這一患者群體）的競爭強度或缺乏競爭的情況。我承認，就像我們在過去幾個月看到的那樣，特別是在 2025 年，這表明它比預期的要慢。無論是從篩選還是從招生來看，情況都仍然非常強勁，但比我們預期的要慢一些，這就是導致招生時間略有延遲的原因。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特（Maury Raycroft），傑富瑞集團（Jefferies）。

Hi, this is Amy on from Maury. Thank you for taking our questions. We have two questions for the Myelofibrosis Phase 3 trials. The first one is can you talk about your assumptions to getting into the full enrollment in this June and July? Will you do a press release when you achieve the target enrollment? And also, can you talk more about the baseline characteristics of the patients today, or will you provide more colors on the baselines when the trial is fully enrolled? I have a quick follow up of this.

大家好，我是來自 Maury 的 Amy。感謝您回答我們的問題。我們對骨髓纖維化第 3 階段試驗有兩個問題。第一個問題是，您能否談談今年六月和七月實現全面招生的假設？當達到目標招生人數時，您會發布新聞稿嗎？另外，您今天能否詳細談談患者的基線特徵，或者當試驗完全招募完畢時，您是否會提供更多關於基線的顏色？我對此進行了快速跟進。

Yeah, I can take the first part of that. Our expectations and where we are now is really aligned with what Reshma talked to. We're 80% enrolled. We have visibility into the number of people in our screening and pre-screening process. So we expect to complete enrollment in the June-July time frame as Reshma shared. And when we do complete our targeted enrollment, yes, we will share that in a press release. Maybe for the second part of the question, I'll turn that over to Reshma for some of the baseline characteristics that we're seeing in the trial.

是的，我可以接受第一部分。我們的期望和現在的狀況與 Reshma 所說的完全一致。我們的入學率已達 80%。我們可以看到參與篩選和預篩選過程的人數。因此，正如 Reshma 所說，我們預計將在 6 月至 7 月期間完成招生。當我們完成目標招生後，我們會在新聞稿中分享這個消息。對於問題的第二部分，我將把它交給 Reshma，請她介紹我們在試驗中看到的一些基線特徵。

Yeah, sure. So for the baseline characteristics and then, again, this is just a quick snapshot. I mean, to your question, will we provide the baseline characteristics for the full population? Yeah, absolutely, and we anticipate being able to do so in the next few months after enrollment is completed. With that said, they just give a little bit of visibility.

是的，當然。因此，對於基線特徵，這只是一個快速快照。我的意思是，對於您的問題，我們會提供整個人口的基線特徵嗎？是的，當然可以，我們預計在招生完成後的幾個月內就能做到這一點。話雖如此，它們只是提供了一點點的可見性。

The patient population by and large is going to be similar to our Phase 1 trial. Again, these are going to be your JAKi-Naïve Myelofibrosis patients. All of the patients have to have a baseline platelet count above 100. With that said, they're a little less cytopenic than what we saw on our phase one so their baseline hemoglobins are slightly higher than what we saw in our Phase 1. Also, baseline platelet counts are slightly higher than what we saw in our Phase 1.

整體而言，患者群體與我們的第一階段試驗相似。再次強調，這些人將會是您的 JAKi-Naïve 骨髓纖維化患者。所有患者的基線血小板計數必須高於100。話雖如此，他們的細胞減少程度比我們在第一階段看到的要輕一些，所以他們的基線血紅蛋白比我們在第一階段看到的要略高。此外，基線血小板計數略高於我們在第一階段看到的水平。

Breakdown, by dips is very consistent with what you would expect for a JAKi-Naïve Myelofibrosis population. I think the one key difference is going to be baseline symptom scores. So in our Phase 1 population, we didn't have any requirement for that baseline TSS; in our Phase 3, we do. So patients do need to be symptomatic. We actually have a threshold. So overall, you are going to see higher baseline TSSs for this population, again, as compared to the Phase 1.

按下降趨勢細分的結果與 JAKi-Naïve 骨髓纖維化族群的預期結果非常一致。我認為一個關鍵的區別是基線症狀評分。因此，在我們的第 1 階段人群中，我們對基線 TSS 沒有任何要求；在第三階段，我們確實這麼做了。所以患者確實需要有症狀。我們其實有一個門檻。因此總體而言，與第一階段相比，您將再次看到該族群的基線 TSS 更高。

Thank you. That's very helpful. The follow up is can you talk a little about the -- if you see anything the patient compliance in the daily measurement of the TSS score, and how does that compare to your expectations and other Myelofibrrosis versus Phase 3 trials and what are -- yeah, that's it.

謝謝。這非常有幫助。接下來的問題是，您能否稍微談一談——如果您發現患者在每日測量 TSS 評分方面的依從性，以及這與您的預期以及其他骨髓纖維化與 3 期試驗相比如何——是的，就是這樣。

I can take that one as well. So compliance is really good, so this is something that we've been laser focused on from the very beginning of the trial. So you know, we use an e-pro vendor, an electronic PRO vendor who follows the data, alerts go out to the patients, we're notified if a patient doesn't happen to complete one of their daily TSSs. It just gives us visibility in terms of the data such that if a patient were to miss something, we're able to go ahead and talk to the site and ensure that that patient gets back on track. So overall, that compliance, we're really happy with that very high compliance on those daily TSS forms.

我也可以接受那個。因此依從性非常好，這也是我們從試驗一開始就一直在關注的事情。你知道，我們使用電子專業供應商，電子專業供應商會追蹤數據，向患者發出警報，如果患者沒有完成他們的每日 TSS 之一，我們就會收到通知。它只是讓我們在數據方面具有可視性，這樣如果患者錯過了什麼，我們就可以繼續與現場溝通並確保該患者回到正軌。因此，總體而言，我們對每日 TSS 表格的合規性非常滿意。

In terms of how that's comparing to other trials, I don't know. I'm not aware of any data regarding the compliance from other Phase 3 trials including manifest transform. Again, I got to say I'm very happy with where we are right now with our Phase 3.

至於這與其他試驗相比如何，我不知道。我不知道其他第 3 階段試驗（包括清單轉變）的依從性的任何數據。我再次表示，我對我們第三階段目前的進展感到非常滿意。

Ted Tenthoff, Piper Sandler.

泰德·坦索夫、派珀·桑德勒。

Great, thank you very much. Two questions, if I may. Firstly, when it comes to Multiple Myeloma, what really is driving utilization now? And what are some of the potential marketing synergies between the existing sales force and if we hopefully get positive minus 5 versus data, how would that sort of jumpstart your sales efforts in MS thanks?

太好了，非常感謝。請問我有兩個問題。首先，就多發性骨髓瘤而言，現在真正推動利用率的是什麼？那麼，現有銷售團隊之間有哪些潛在的行銷綜效呢？如果我們希望獲得正負 5 的數據，這將如何啟動您在 MS 的銷售工作？謝謝？

Yeah, thanks. And I'll take the second part of that and then I'll turn it back to Sohanya to take the first part. When you look at our existing commercialization capabilities and the alignment or synergy with Myelofibrosis, we have about 80% overlap, so a significant number of patients are seen in the community. We have strong capabilities across our commercial team, across our access team, across our global medical and scientific affairs teams. I think there's a really high level of synergy that would enable us to move forward rapidly with really minimal additional investments. And I'll turn to Sohanya to take the question on the first part about Multi Myeloma.

是的，謝謝。我將處理第二部分，然後將其交還給 Sohanya 處理第一部分。當您查看我們現有的商業化能力以及與骨髓纖維化的一致性或協同作用時，我們會發現我們有大約 80％ 的重疊，因此在社區中可以看到大量患者。我們的商業團隊、訪問團隊、全球醫療和科學事務團隊都擁有強大的能力。我認為，高度的協同效應將使我們能夠以最少的額外投資快速向前發展。現在請 Sohanya 來回答關於多發性骨髓瘤的第一部分的問題。

Thanks, Ted, for the question. So we were really pleased with the resilience of the team and ability to grow demand in an increasingly competitive marketplace year over year, so 5% growth in Q1. And as you look at sort of the underlying drivers of that growth, importantly, we were able to grow in the community setting as well as in the academic setting. If you kind of break it down into the two settings of care in the community setting, we continue to be used as a flexible combination therapy, a convenient oral about 50% to 60% of our patients are in that earlier line, second to fourth line setting, primarily treated in the community setting following an anti-CD 38 therapy. But also importantly, for patients that come to the community that either fail a T cell engaging therapy or just are not ineligible or don't have access to it.

謝謝泰德提出這個問題。因此，我們對團隊的韌性以及在競爭日益激烈的市場中逐年增長需求的能力感到非常滿意，因此第一季度實現了 5% 的成長。當你看到這種成長的根本驅動力時，重要的是，我們能夠在社區環境和學術環境中成長。如果將其分為社區環境中的兩種護理環境，我們將繼續採用靈活的聯合療法，一種方便的口服藥物，大約 50% 到 60% 的患者處於早期、第二到第四線環境中，主要在社區環境中接受抗 CD 38 治療。但同樣重要的是，對於那些來到社區的患者來說，他們要么無法接受 T 細胞介導療法治療，要么不符合治療條件，要么無法獲得治療。

Now, switching to the academic setting. We're positioning XPOVIO with our increasing body of evidence in that pre and post T cell engaging therapy setting, and we're seeing increasing use there which really led to the growth in the academic setting in Q1 year over year. Again, there -- it's a highly competitive landscape, as you know, but we continue to have a a unique positioning as a differentiated mechanism of action both in the community and academic settings.

現在，轉向學術環境。我們利用越來越多的證據來定位 XPOVIO 在 T 細胞介入治療前後的應用，並且我們看到該領域的使用率正在不斷提高，這確實導致了第一季學術領域的同比增長。再說一次，如你所知，這是一個競爭激烈的領域，但我們在社區和學術環境中繼續保持獨特的定位，成為一種差異化的行動機制。

And again, to reinforce to your second point what Richard mentioned. Obviously, a high level of synergy in the physicians we already call on, but our capability, our infrastructure that we have built in the past five years really sets us up well for a rapid launch in Myelofibrosis if approved.

再次強調理查德提到的第二點。顯然，我們已經與醫生們建立了高度的協同作用，但我們的能力，以及我們在過去五年中建立的基礎設施，確實為我們在獲得批准後迅速開展骨髓纖維化治療奠定了良好的基礎。

Peter Lawson, Barclays.

巴克萊銀行的彼得·勞森。

Hey, thanks so much for the question. Just on the returned products in 1Q, so that's $5 million. What's the normal run rate of returned product and there any further risks of revenue shortfall or return product in 2Q and 3Q that we should be thinking about?

嘿，非常感謝您的提問。光是第一季退回的產品就高達 500 萬美元。退貨產品的正常運作率是多少？第二季和第三季是否有收入短缺或退貨的進一步風險需要我們考慮？

Yeah, thanks, Peter. I'll -- at a high level, no, and I'll get Lori to go into the details. But I think as as Reshma and Lori both talked to this really is $5 million atypical impact from high dose returns and Lori, maybe you can just expand on that.

是的，謝謝，彼得。我會——從高層次上講，不，我會讓 Lori 詳細說明。但我認為，正如 Reshma 和 Lori 都談到的那樣，這確實是高劑量回報帶來的 500 萬美元非典型影響，Lori，也許你可以詳細說明一下。

Yes. Hi, Peter. So if you think about these returns, they were to support the Boston launch, which we talked about, which was really our sales in '21 and '22. So if you think about it, that's over $220 million in sales, and this impact was less than 2%. So if it when you -- and then when you look going forward, I think it's important to know that these atypical returns, these high doses, this is the expiry window that opened for these returns.

是的。你好，彼得。因此，如果您考慮這些回報，它們是為了支持我們談到的波士頓發布會，這實際上是我們在 21 年和 22 年的銷售額。如果你仔細想想，這可是超過 2.2 億美元的銷售額，但影響卻不到 2%。因此，如果當你——然後當你展望未來時，我認為重要的是要知道這些非典型回報，這些高劑量，這是為這些回報打開的到期窗口。

Going forward, as Sohanya mentioned, it translates more to the 40-milligram and the 60-milligram doses that we're seeing, so we don't expect this to carry on into future quarters. And so, we really do believe this is isolated to this quarter when this window opened, and relative to all of the sales, it still was below 2%. And then we expect going forward we'll continue to kind of get back to our more historic levels that we see for the doses more in the 40 milligram and 60 milligram.

展望未來，正如 Sohanya 所提到的，它更多地轉化為我們看到的 40 毫克和 60 毫克的劑量，因此我們預計這種情況不會持續到未來的幾個季度。因此，我們確實相信這只是本季度的例外，當這個視窗打開時，相對於所有銷售額，它仍然低於 2%。然後我們預計，未來我們將繼續回到更歷史性的水平，即 40 毫克和 60 毫克的劑量水平。

Okay, thank you. And sorry, you mentioned about extending the cash run away, different processes. What -- how are you thinking about prioritization between business development, equity raises, destructions?

好的，謝謝。抱歉，您提到了延長現金流失和不同的流程。您如何考慮業務發展、股權提升和破壞之間的優先順序？

So it's a very important question. How are we planning expanding our cash runway? I mean, we understand the importance of being well capitalized. And as Richard mentioned and I both mentioned on the call, we are exploring various alternatives to extend that cash runway. We'll continue to evaluate our cash runway and financial position basically how best can we deliver the Phase 3 clinical trials and get to these top line data readouts. But beyond this, I cannot really provide specific details at this time.

所以這是一個非常重要的問題。我們計劃如何擴大我們的現金流？我的意思是，我們了解充足資本的重要性。正如理查德和我都在電話中提到的那樣，我們正在探索各種替代方案來延長現金流。我們將繼續評估我們的現金流量和財務狀況，基本上如何才能最好地進行第三階段臨床試驗並獲得這些頂線數據讀數。但除此之外，我目前無法提供具體細節。

Jonathan Chang, Leerink Partners.

Jonathan Chang，Leerink Partners。

Hi, this is Albert Agustino dialing in from Jonathan Chang. Thanks for taking my question. Will you be able to give us reasons for confidence that you can still reach your revenue guidance? Thank you.

大家好，我是 Albert Agustino，來自 Jonathan Chang 的電話。感謝您回答我的問題。您能否給我們理由讓我們相信您仍能達到您的收入預期？謝謝。

Yeah, I think as you heard from Sohanya and you heard from Lori, we're guiding towards the lower end of our revenue guidance given the impact, this $5 million impact of our atypical, high dose returns. We heard with regards to our US business 5% demand growth year over year, we heard very strong growth from our global partners. So yes, we believe we're going to be seeing ourselves deliver in the lower end of our guidance from a global revenue perspective and from a US revenue perspective.

是的，我想正如你從 Sohanya 和 Lori 那裡聽到的那樣，考慮到我們非典型高劑量回報的 500 萬美元影響，我們正朝著收入預期的低端進行指導。我們聽說我們的美國業務需求年增 5%，我們的全球合作夥伴也表示成長非常強勁。所以是的，我們相信，從全球收入角度和美國收入角度來看，我們的業績將處於預期的低端。

(Operator Instructions)

（操作員指示）

Brian Abrahams, RBC Capital Markets.

加拿大皇家銀行資本市場 (RBC Capital Markets) 的 Brian Abrahams。

Hi, team, this is Kevin on for Brian. Thanks for taking our questions. Just had a follow up on the futility analysis. Can you remind us if this was pre-specified before the study expansion and co-primary endpoint change and if -- or if it was something maybe that the FDA was asking about with the protocol amendment. And then just speaking of FDA, have you had any further interactions with the agency in the meantime and just maybe how would you characterize those interactions? Thank you.

大家好，我是 Kevin，代替 Brian。感謝您回答我們的問題。剛剛對無效性分析進行了跟進。您能否提醒我們，這是否是在研究擴展和共同主要終點改變之前預先指定的，或者這是否是 FDA 在修改協議時詢問的內容。然後說到 FDA，您在此期間是否與該機構有進一步的互動？您如何描述這些互動？謝謝。

Yeah. Thank you, Kevin. I can take that one. So yes, this was pre-specified, and this futility analysis was part of the trial from the very beginning. So from the initial protocol, nothing that has happened either with the end points or even in the increase in the trial size from 300 to 350, prompted incorporation of that futility analysis.

是的。謝謝你，凱文。我可以接受那個。是的，這是預先指定的，而這種無效性分析從一開始就是試驗的一部分。因此，從最初的方案來看，無論是終點或試驗規模從 300 增加到 350，都沒有發生任何變化，促使納入無效性分析。

In terms of the FDA conversations, sort of like as we've mentioned in the past, the bulk of them are really around that end point change, specifically the change from TSS 50 to absolute TSS. No additional conversations, at this time, and we're just again looking forward to completing enrollment and providing top line results at the end of this year, beginning of '26.

就 FDA 的對話而言，就像我們過去提到的那樣，大部分對話實際上都圍繞著終點變化，特別是從 TSS 50 到絕對 TSS 的變化。目前還沒有其他對話，我們只是再次期待在今年年底、26 年初完成招生並提供最重要的結果。

Thank you. There are no further questions at this time. I will now hand the call back to Richard Paulson for any closing remarks.

謝謝。目前沒有其他問題。現在我將把電話轉回給理查德·保爾森，請他做最後發言。

Thank you, operator. And once again thank you, everyone, for joining us today. As you heard through the call, we're very focused and very excited about the transformational opportunity we have ahead of us in Myelofibrosis, very much in the near term as the team's focus on completing enrollment through June-July and reading up the top line data through the end of this year or early next year. The consistency we see in the strength of our data that Reshma shared again today in a difficult to treat, more severe patient population with multiple lines of therapy has continue to build our confidence and strength in the potential for Selinexor plus Ruxolitinib to become the new standard of care, pending positive data in JAKi-Naïve patients. So once again, thank you for joining us.

謝謝您，接線生。再次感謝大家今天的參加。正如您在電話會議中聽到的那樣，我們非常關注並且對我們在骨髓纖維化領域面臨的轉型機會感到非常興奮，因為團隊的重點是在 6 月至 7 月之前完成招生，並在今年年底或明年年初之前讀取頂線數據。Reshma 今天再次分享了我們在難以治療、病情較為嚴重且需要接受多種療法的患者群體中得出的數據，這些數據的強度與以往的一致，這繼續增強了我們的信心和力量，我們相信 Selinexor 聯合 Ruxolitinib 有潛力成為新的治療標準，但前提是 JAKi-Naïv 患者能夠獲得積極的數據。再次感謝您的參與。

Thank you and this concludes today's call. Thank you for participating. You me all disconnect.

謝謝，今天的通話到此結束。感謝您的參與。你們和我全部斷絕關係。