Karyopharm Therapeutics Inc (KPTI) 2024 Q3 法說會逐字稿

Good morning. My name is Jenny and I will be your conference operator today.

早安.我叫珍妮，今天我將擔任你們的會議操作員。

At this time, I would like to welcome everyone to Karyopharm Therapeutics third quarter, 2024 financial results conference call.

此時，我歡迎大家參加 Karyopharm Therapeutics 2024 年第三季財務業績電話會議。

There will be a question and answer session to follow. Please be advised that this call is being recorded at the company's request.

隨後將舉行問答環節。請注意，本次通話是應公司要求進行錄音的。

I would now like to turn the call over to Karyopharm, Senior Vice President, Investor Relations. Please go ahead.

我現在想將電話轉給投資者關係高級副總裁 Karyopharm。請繼續。

Thank you and thank you all for joining us on today's conference call to discuss Karyopharm Therapeutics third quarter, 2024 financial results and recent company progress. We issued a press release this morning detailing our financial results for the third quarter 2024. This release along with a slide presentation that we'll reference during our call today are available on our website. For today's call as seen on slide 2, I'm joined by Richard, Reshma, Sohanya and Mike who will provide an update on our results for the third quarter, 2024 and recent clinical development.

感謝大家參加今天的電話會議，討論 Karyopharm Therapeutics 2024 年第三季財務業績和公司近期進展。我們今天早上發布了一份新聞稿，詳細介紹了 2024 年第三季的財務表現。該新聞稿以及我們將在今天的電話會議中參考的幻燈片簡報可在我們的網站上取得。如投影片 2 所示，在今天的電話會議中，Richard、Reshma、Sohanya 和 Mike 也加入了我的行列，他們將提供我們 2024 年第三季的結果和最近的臨床開發的最新資訊。

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements, FLS for purposes of the safe harbor provisions under the private Securities Litigation Reform Act of 1,995. Outlined on slide 3 actual results may differ materially from those indicated by these FLS as a result of various important factors, including those discussed in the risk factors section of our most recent form 10-Q which is on file with the SEC and in other filings that we may make with the SEC in the future. Any FLS we present our views as of today only while we may elect to update these FLS 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 this FLS as representing our views as of any later date.

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前瞻性陳述，FLS 是為了 1,995 年《私人證券訴訟改革法案》中安全港條款的目的。由於各種重要因素的影響，投影片3 中概述的實際結果可能與這些FLS 所示的結果存在重大差異，這些因素包括我們向SEC 備案的最新10-Q 表格的風險因素部分中討論的因素以及其他文件中的內容我們將來可能會與 SEC 合作。對於任何 FLS，我們只在今天提出我們的觀點，而我們可能會選擇在未來某個時候更新這些 FLS。即使我們的觀點發生變化，我們也明確表示不承擔任何這樣做的義務。因此，您不應依賴本 FLS 來代表我們以後的觀點。

I will now turn the call over to Richard. Please turn to slide 4.

我現在將把電話轉給理查德。請翻到幻燈片 4。

Good morning. Thank you Elhan and thank you all for joining us today for Karyopharm Q3 2024 earnings call. Turning to slide 5. I want to begin with the exciting news that we shared last week regarding our phase three trial in Myelofibrosis, we announced a very favorable regulatory update as we are changing the co-primary endpoint of century to absolute TSS following productive discussions with the FDA.

早安.謝謝 Elhan，也謝謝大家今天參加我們的 Karyopharm 2024 年第三季財報電話會議。轉到投影片 5。首先，我想從我們上週分享的有關骨髓纖維化三期試驗的令人興奮的消息開始，我們宣布了一項非常有利的監管更新，在與FDA 進行富有成效的討論後，我們將世紀的共同主要終點改為絕對TSS。

Absolute TSS is supported by leading investigators and patient advocacy organization and increases our overall confidence in our trial.

Absolute TSS 得到了領先研究人員和患者倡導組織的支持，增強了我們對試驗的整體信心。

We remain on track to report top line data from century in the second half of next year. (Inaudible) unique mechanism of action, compelling data, our targeted approach to clinical development and ongoing disciplined cost management position us well to advance our prioritized late stage pipeline which may enable two transformative opportunities as we build on our Multiple myeloma foundation. With our existing commercialization capabilities, we are pleased to deliver our third consecutive quarter of net product revenue growth in the US and are on track to deliver revenue in the upper half of the guidance outlined at the start of the year.

我們仍有望在明年下半年報告本世紀的頂線數據。 （聽不清楚）獨特的行動機制、令人信服的數據、我們有針對性的臨床開發方法和持續嚴格的成本管理，使我們能夠很好地推進我們的優先後期管道，這可能會在我們建立多發性骨髓瘤基礎時帶來兩個變革機會。憑藉我們現有的商業化能力，我們很高興在美國實現連續第三個季度的淨產品收入成長，並有望實現年初概述的指導的上半部分。

Our established commercial organization is well set up to potentially drive successful and rapid launches in myelofibrosis and Endometrial cancer.

我們已建立的商業組織已建立良好的基礎，有可能推動骨髓纖維化和子宮內膜癌的成功和快速上市。

Turning to slide 6 in Myelofibrosis, If the data from our phase three century trial is supportive, we believe we will have the opportunity to transform the treatment paradigm by providing the first combination therapy in JAKi naïve Myelofibrosis.

轉向骨髓纖維化的幻燈片 6，如果我們三世紀試驗的數據是支持性的，我們相信我們將有機會透過提供第一個針對 JAKi naïve 骨髓纖維化的聯合療法來改變治療模式。

While Ruxolitinib alone has remained the standard of care for over a decade. Less than half of all patients achieve meaningful spleen reduction.

十多年來，魯索替尼一直是治療標準。不到一半的患者實現了有意義的脾臟縮小。

We believe that combination therapy with a novel mechanism of action like XPO1 one inhibition holds the key for driving rapid deep and durable responses for the vast majority of Myelofibrosis patients.

我們相信，採用 XPO1 one 抑制等新型作用機制的聯合療法是為絕大多數骨髓纖維化患者帶來快速、深度和持久反應的關鍵。

We continue to estimate that our annual us peak revenue opportunity of Myelofibrosis is approximately $1 billion in the multi billion dollar Myelofibrosis market. In Endometrial cancer, the opportunity remains substantial given the evolution in the molecular driven therapies.

我們繼續估計，在價值數十億美元的骨髓纖維化市場中，我們每年的骨髓纖維化高峰收入機會約為 10 億美元。鑑於分子驅動療法的發展，子宮內膜癌的機會仍然很大。

Our data in TP53 wild-type endometrial cancer offers the potential of a meaningful and unique mechanism in maintenance therapy for approximately half of all Endometrial cancer patients.

我們關於 TP53 野生型子宮內膜癌的數據為大約一半子宮內膜癌患者的維持治療提供了有意義且獨特的機制的潛力。

This represents approximately a billion dollars annual US peak revenue opportunity as well.

這也代表了美國每年約十億美元的最高收入機會。

Sohanya and Reshma will expand in detail on both these near term transformative opportunities.

Sohanya 和 Reshma 將詳細闡述這兩個近期變革機會。

Now, I'd like to turn the call over to Reshma who will give an update on our clinical programs. Reshma.

現在，我想將電話轉給 Reshma，她將介紹我們臨床計畫的最新情況。瑞詩瑪。

Thank you, Richard turning to slide 8. I want to highlight the unique potential of our promising late stage pipeline led by our three ongoing phase three studies.

謝謝理查德，請轉到幻燈片 8。我想強調我們的三項正在進行的三期研究主導的有前途的後期管道的獨特潛力。

Karyopharm has the potential to establish new standards of care in solid and hematologic malignancies building upon our foundation in Multiple myeloma while also optimizing the patient experience by incorporating substantially lower doses of Selinexor or in these studies. Beginning with Myelofibrosis on slide 10, Selinexor is a novel inhibitor of XCL1, that prevents the new export of various proteins and messenger RNA molecules. By doing so, it promotes the nuclear localization and activation of important tumor suppressor pathways such as TP53 while concurrently inhibiting the cytoplasmic activation of various proliferative and profibrotic pathways linked to myelofibrosis pathobiology. In addition of these multiple pathways position Selinexor is a unique potential therapeutic option in myelofibrosis.

Karyopharm 有潛力在多發性骨髓瘤的基礎上建立實體和血液惡性腫瘤的新護理標準，同時透過在這些研究中加入大幅降低劑量的 Selinexor 來優化患者體驗。從幻燈片 10 上的骨髓纖維化開始，Selinexor 是一種新型 XCL1 抑制劑，可阻止各種蛋白質和信使 RNA 分子的新輸出。透過這樣做，它促進重要腫瘤抑制途徑（如 TP53）的核定位和激活，同時抑制與骨髓纖維化病理學相關的各種增殖和促纖維化途徑的細胞質活化。除了這些多重途徑之外，Selinexor 是骨髓纖維化的獨特潛在治療選擇。

Before highlighting our important update to the coprimary endpoint relating to total symptom score, I will recap efficacy and safety data observed from the phase one trial, evaluating Selinexor four plus rallied inject inhibitor naive myelofibrosis patients. As outlined on slide, 11. Amongst the 14 patients who received Selinexor for 60 mg of rallied all evaluable patients achieved an SPR35 at any time and 79% of patients achieved SPR35 at week 24 in the ICT population. As you heard from some of the leading physicians in the space on our call last week, clean volume reduction is viewed as one of the most important factors by treating physicians. Given its correlation to overall survival, having nearly 80% of patients achieve SPR35 is viewed as very positive. Durability of response is also a key efficacy measure relevant to JAKi naïve patients. Our phase one data demonstrates a 100% probability of continuing response for both SPR35 and PS50 as shown on slide 12 over a median duration of follow up of 32 weeks and 51 weeks respectively.

在強調我們對與總症狀評分相關的共同主要終點的重要更新之前，我將回顧一下從第一階段試驗中觀察到的療效和安全性數據，評估Selinexor 4 加聯合注射抑製劑的初始骨髓纖維化患者。如投影片 11 所示。在 14 名接受 Selinexor 60 mg 治療的患者中，所有可評估的患者在任何時間都達到了 SPR35，並且在 ICT 族群中，79% 的患者在第 24 週達到了 SPR35。正如您上週在我們的電話會議上從該領域的一些領先醫生那裡聽到的那樣，治療醫生將清潔體積減少視為最重要的因素之一。鑑於其與總存活率的相關性，近 80% 的患者達到 SPR35 被認為是非常積極的。反應的持久性也是與未使用 JAKi 的患者相關的關鍵療效指標。我們的第一階段數據表明，SPR35 和 PS50 在中位數追蹤時間分別為 32 週和 51 週的情況下，持續緩解的可能性為 100%，如幻燈片 12 所示。

This is particularly meaningful as it suggests that once patients experience a response, they remain in response. On our call last week, one of the [KOLS] indicated that this is why he believes treatment Selinexor should be added to Ruxolitinib early on in the treatment journey. Given his view that deep responses early on are important and can improve outcomes for patients.

這是特別有意義的，因為它表明一旦患者經歷了反應，他們就會保持反應。在我們上週的電話會議上，其中一位 [KOLS] 表示，這就是為什麼他認為 Selinexor 應該在治療過程的早期添加到 Ruxolitinib 中。鑑於他認為早期的深度反應很重要，可以改善患者的治療結果。

According to slide 13, we were very pleased to announce last week that absolute total symptom score will replace TSS 50 as a coprimary endpoint in our century phase three trial in Myelofibrosis. Assessing the average improvement in symptoms over 24 weeks has contained support from the FDA investigators and patient advocacy groups and is a more sensitive method to assess symptom improvement in myelofibrosis.

根據幻燈片 13，我們上週非常高興地宣布，絕對總症狀評分將取代 TSS 50，作為我們世紀骨髓纖維化第三期試驗的共同主要終點。評估 24 週內症狀的平均改善得到了 FDA 研究人員和患者倡導團體的支持，是評估骨髓纖維化症狀改善的更敏感的方法。

The combination of Selinexor and rallied has demonstrated promising evidence of improvement in absolute total symptom scores in our phase one trial. And we look forward to utilizing this more comprehensive assessment of symptom improvement moving forward.

在我們的第一階段試驗中，Selinexor 和 ralled 的組合已經證明了絕對總症狀評分改善的有希望的證據。我們期待進一步利用這種更全面的症狀改善評估。

Building on our impressive SPR 35 results from our phase one trial. Changing our co primary end point to absolute TSS further increases our overall confidence in the century phase three trial. And we look forward to potentially addressing a tremendous unmet need in Myelofibrosis. With this combination. On slide 14, the de substant improvement with 60 mg of Selinexor plus Ruxolitinib in our phase one trial can be seen in comparison to historical data for Ruxolitinib monotherapy. The average reduction which signifies improvement absolute TSS of 18.5 points with our combination compared favorably to the average 11 to 14 point reduction that has been observed with Ruxolitinib in prior phase three clinical trials conducted by others. The rapid deep and durable findings observed with SPR35 is also observed with average TSS as seen on slide 15. These are new data we are presenting for the first time today specifically in our phase one trial, Selinexor plus Ruxolitinib demonstrated rapid deep and sustained improvements in average TSS. These rapid improvements in symptoms are seen as early as week four. Despite any side effects that the patients may experience from the treatment. These symptom improvements continue through week 24 demonstrating meaningful sustained symptom improvement for the entire six month duration, evaluated for the adverse events experienced. The most common were GI side effects such as nausea, anemia, thrombocytopenia and fatigue. And I think it is worth considering what we heard from our [KOLS] and GI side effects. Last week, these GI side effects are most common at the start of treatment only last approximately two cycles and can be effectively managed with antiemetics. Given this well documented profile, we believe patients and physicians can easily be educated around this profile, enabling patients to stay on treatment long term, which ultimately is what drives meaningful spleen reduction and symptom improvement. In summary slide, 16 highlights why the combination of Selinexor and Ruxolitinib has the potential to become the new standard of care if the combination is approved. And as we have heard at our recent call with Myelofibrosis physicians, the Myelofibrosis community wants to adopt combination therapies which quickly lead to deep and durable spleen reduction, symptom improvement.

以我們第一階段試驗令人印象深刻的 SPR 35 結果為基礎。將我們的共同主要終點更改為絕對 TSS 進一步增強了我們對世紀三期試驗的整體信心。我們期待有可能解決骨髓纖維化方面巨大的未滿足需求。有了這個組合。在投影片 14 上，與 Ruxolitinib 單藥治療的歷史數據相比，我們的一期試驗中 60 mg Selinexor 加 Ruxolitinib 的顯著改善可見。與其他人進行的先前三期臨床試驗中觀察到的 Ruxolitinib 平均 11 至 14 點降低相比，我們的組合的平均降低意味著絕對 TSS 改善了 18.5 點。使用 SPR35 觀察到的快速、深入和持久的發現也可以透過平均 TSS 觀察到，如幻燈片 15 所示。這些是我們今天首次提供的新數據，特別是在我們的一期試驗中，Selinexor 聯合 Ruxolitinib 證明了平均 TSS 的快速、深入和持續的改善。早在第四周就可以看到症狀的快速改善。儘管患者可能會因治療而出現任何副作用。這些症狀改善持續到第 24 週，顯示在整個六個月的持續時間內有意義的持續症狀改善，並對所經歷的不良事件進行了評估。最常見的是胃腸道副作用，如噁心、貧血、血小板減少和疲勞。我認為值得考慮我們從 [KOLS] 和胃腸道副作用中聽到的信息。上週，這些胃腸道副作用在治療開始時最常見，僅持續約兩個週期，並且可以透過止吐藥物有效控制。鑑於這種有據可查的概況，我們相信患者和醫生可以輕鬆地接受有關該概況的教育，使患者能夠長期接受治療，這最終是推動有意義的脾臟縮小和症狀改善的原因。在總結投影片中，16 強調了為什麼 Selinexor 和 Ruxolitinib 的組合如果獲得批准，有可能成為新的護理標準。正如我們在最近與骨髓纖維化醫生的電話會議中聽到的那樣，骨髓纖維化界希望採用聯合療法，以迅速實現深度和持久的脾臟縮小，症狀改善。

Selinexor potential in Myelofibrosis is strengthened by its well established safety profile as it has been administered to approximately 30,000 patients across multiple cancer indications. The low dose of 60 mg that is currently incorporated in the phase three trial suggests that Selinexor has the potential to be a tolerable convenient once weekly oral treatment, especially with the use of anti-metics during the first two cycles of treatment.

Selinexor 在骨髓纖維化方面的潛力因其完善的安全性而得到加強，因為它已被用於多種癌症適應症的約 30,000 名患者。目前納入第三階段試驗的 60 mg 低劑量表明，Selinexor 有潛力成為一種可耐受且方便的每週一次口服治療，特別是在前兩個治療週期中使用抗代謝藥物的情況下。

Turning to slide 17, we have increased confidence with the favorable changes made to the century trial. We've proactively increased the total sample size to approximately 350 patients to further increase the sensical powering.

轉向投影片 17，我們對世紀審判所做的有利改變增強了信心。我們主動將總樣本量增加到約 350 名患者，以進一步增強感官動力。

Given the strong enrollment, our expectations of topline data remain in the second half of 2025. Furthermore, the co-primary end point will change from TSS 50 to absolute TSS. The two co-primary end points of CR35 and absolute TSS will be tested sequentially. SPR35 will be evaluated first and if positive, the alpha will then be rolled down to absolute TSS.

鑑於入學人數強勁，我們對 2025 年下半年營收數據的預期仍為預期。此外，共同主要終點將從 TSS 50 更改為絕對 TSS。CR35 和絕對 TSS 的兩個共同主要終點將依序進行測試。首先將評估 SPR35，如果為正，則 alpha 將向下捲動至絕對 TSS。

Shifting focus to endometrial cancer On slide19, Selinexor primarily functions by blocking the export of P53 from the nucleus to the cytoplasm. When P53 accumulates in the nucleus, it leads to disrupted DNA repair processes, cell cycle arrest and increased apoptosis. This mechanism is underscored by the anti tumor effects in P53 dependent tumors specifically in endometrial cancer and has the potential to be the first novel oral maintenance therapy for patients with TP 53 wild type endometrial cancer as seen on slide 20. The P53 wild type status continues to increase in relevance throughout the treatment landscape for advanced and recurrent endometrial cancer. Recently, the FDA approved checkpoint inhibitors in combination with chemotherapy followed by maintenance therapy with checkpoint inhibitors for advanced recurrent endometrial cancer patients regardless of MMR status. However, the efficacy in patients with MMR proficient tumors is notably lower compared to those with MMR deficient tumors aligning with the mechanistic rationale for the effectiveness of checkpoint inhibitors in MMR deficient solid tumors. Notably patients with both MMR proficient and P53 wild type tumors make up approximately 50% of all advanced or recurrent Endometrial cancer cases.

將焦點轉移到子宮內膜癌 在幻燈片 19 上，Selinexor 的主要功能是阻斷 P53 從細胞核到細胞質的輸出。當 P53 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。這種機制在P53 依賴性腫瘤（特別是子宮內膜癌）中的抗腫瘤作用得到了強調，並且有可能成為TP 53 野生型子宮內膜癌患者的第一個新型口服維持療法，如幻燈片20 所示。P53 野生型狀態在晚期和復發性子宮內膜癌的整個治療領域中的相關性持續增加。最近，FDA 批准了檢查點抑制劑合併化療，隨後使用檢查點抑制劑維持治療晚期復發性子宮內膜癌患者，無論 MMR 狀態如何。然而，與 MMR 缺陷型腫瘤患者相比，MMR 缺陷型腫瘤患者的療效明顯較低，這與檢查點抑制劑在 MMR 缺陷型實體瘤中有效的機制原理一致。值得注意的是，同時患有 MMR 和 P53 野生型腫瘤的患者約佔所有晚期或復發性子宮內膜癌病例的 50%。

Only Slide 21 in the SIENDO trial exploratory subgroup data presented at ASCO revealed that Selinexor has the potential to provide promising outcomes for patients with P53 wild type endometrial cancer. Achieving a median P of 28.4 months compared to just 5.2 months for placebo translating to a hazard ratio of 0.44.

在 ASCO 上提交的 SIENDO 試驗探索性亞組數據中，只有幻燈片 21 顯示 Selinexor 有潛力為 P53 野生型子宮內膜癌患者提供有希望的結果。中位 P 為 28.4 個月，而安慰劑僅 5.2 個月，風險比為 0.44。

Looking more closely at the Mmr proficient subgroup. On slide 22 our ASCO data on SIENDO shows solex or demonstrates an encouraging signal of long term median ps benefit of 39.5 months.

更仔細地觀察 Mmr 熟練小組。在投影片 22 上，我們關於 SIENDO 的 ASCO 數據顯示了 solex 或展示了 39.5 個月的長期中位數 ps 效益的令人鼓舞的信號。

This was substantially higher than the 4.9 months observed placebo corresponding to a hazard ratio of 0.36.

這大大高於觀察到的 4.9 個月安慰劑，對應的風險比為 0.36。

Although we acknowledge the limitations of cross trial comparison, it's important to note that the PSS improvement with Selinexor in the subgroup exceeds the median overall survival achieved by checkpoint inhibitors and Mmr proficient patients emphasizing Selinexor substantial efficacy for these individuals. The updated safety data, endometrial cancer patients from the SIENDO trial is displayed on slide 23. It's important to note that the adverse events associated with Selinexor were generally manageable and well tolerated. nausea, vomiting and diarrhea were the most frequently observed adverse events regardless of grade. grade three plus treatment emergent events were infrequent with neutropenia, thrombocytopenia and nausea being the most common.

儘管我們承認交叉試驗比較的局限性，但值得注意的是，Selinexor 在亞組中的PSS 改善超過了檢查點抑製劑和Mmr 熟練患者所實現的中位總生存期，強調Selinexor 對這些個體具有顯著療效。SIENDO 試驗中子宮內膜癌患者的最新安全性數據顯示在投影片 23 上。值得注意的是，與 Selinexor 相關的不良事件通常是可控的且耐受性良好。無論程度如何，噁心、嘔吐和腹瀉是最常見的不良事件。第三級以上治療緊急事件並不常見，其中最常見的是嗜中性白血球減少症、血小板減少症和噁心。

Notably, the prophylactic dual antiemetics were not required during the standard trial. Whereas dual antiemetics are not only required in eco 42 for all of our phase three trials including cent, which is why we anticipate the safety profile from our phase three trials will be substantially improved. On slide 24 we remain on track for topline data readout for our pivotal X4 eco 42 phase three trial in early 2026. I remain encouraged with the potential of Selinexor source to achieve clinically meaningful outcomes in the maintenance setting for patients with P53 wild type endometrial cancer, especially those with MMR proficient tumor.

值得注意的是，標準試驗期間不需要預防性雙重止吐藥。然而，eco 42 不僅需要我們所有的第三階段試驗（包括 Cent）使用雙重止吐藥，這就是為什麼我們預計第三階段試驗的安全性將大幅改善。在投影片 24 上，我們仍在為 2026 年初關鍵的 X4 eco 42 第三階段試驗讀取頂線資料。我仍然對 Selinexor 來源在 P53 野生型子宮內膜癌患者（尤其是 MMR 腫瘤患者）的維持治療中取得具有臨床意義的結果的潛力感到鼓舞。

Lastly, our phase three EMN 29 TD trial is outlined on slide 26. This trial aims to address the unmet needs 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 therapy and build on the positive progression free survival data previously observed with SPD 40. As we noted on our second quarter earnings call. We have worked with the sponsor of the trial, the European Myeloma Network to amend the statistical analysis plan. We have a completed screening for the planned approximately 120 patients who will provide an updated timeline for top line data following regulatory feedback. We are very excited for what the future holds for Karyopharm working swiftly to progress Our three pivotal phase three programs fueled by increasingly compelling data, Selinexor could significantly benefit various patient populations facing unmet needs and also enhance our currently improved indications in multiple myeloma. I will now turn the call to Sohanya provide updates on our commercial results from this quarter.

最後，投影片 26 概述了我們的第三階段 EMN 29 TD 試驗。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，該方案也可以使那些接受T 細胞參與治療前後的患者受益，並建立在先前使用SPD 40 觀察到的積極無惡化存活數據的基礎上。正如我們在第二季財報電話會議上指出的那樣。我們與試驗主辦單位歐洲骨髓瘤網絡合作修改統計分析計畫。我們已完成對計劃約 120 名患者的篩檢，他們將根據監管回饋提供頂線數據的更新時間表。我們對Karyopharm 的未來感到非常興奮，我們正在迅速努力推進我們的三個關鍵的第三階段項目，這些項目在越來越令人信服的數據的推動下，Selinexor 可以顯著造福於面臨未滿足需求的各種患者群體，並增強我們目前改善的多發性骨髓瘤適應症。我現在將致電 Sohanya，提供本季商業業績的最新資訊。

Thank you, Reshma and Good morning. On slide 28, I'll discuss our commercial highlights for the third quarter of 2024. XPOVIO net product revenue was $29.5 million up 5% compared to our results in the second quarter. We are very pleased with our third consecutive quarter over quarter growth of XPOVIO revenues amidst a highly competitive marketplace and are well on track to deliver in the upper half of the guidance that we outlined at the start of the year.

謝謝你，瑞詩瑪，早安。在投影片 28 上，我將討論 2024 年第三季的商業亮點。XPOVIO 產品淨收入為 2,950 萬美元，較第二季的業績成長 5%。我們對 XPOVIO 收入在競爭激烈的市場中連續第三個季度環比增長感到非常滿意，並且有望實現我們年初概述的指導方針的上半部分。

In Q3 XPOVIO revenues were driven by double digit demand growth versus the prior quarter powered by an increase in refills and partially offset by an increase in gross to net. Largely due to a higher 340 B Book of Business.

第三季 XPOVIO 營收受到兩位數需求成長的推動，較上一季而言，需求成長是由補充品增加所推動的，但部分被毛淨額成長所抵消。很大程度是由於 340 B 的商業帳簿較高。

We achieved strong demand growth quarter over quarter in the community where XPOVIO tends to be used as a convenient oral and manageable option for patients as an earlier line of therapy. Or if the patients are unable to access a T cell therapy. We also delivered growth in demand in our academic setting as our use as a novel mechanism of action. Pre and post T cell therapies continues to increase with our team's strong execution, driving demand growth for XPOVIO year-to-date, we are confident in our ability to deliver on our revised full year 2024 US XPOVIO net product revenue guidance range of $110million to $115 million.

我們在社區中實現了逐季強勁的需求成長，在該社區中，XPOVIO 往往被用作患者的一種方便的口服且易於管理的選擇，作為早期治療方案。或如果患者無法接受 T 細胞治療。作為一種新穎的作用機制，我們也滿足了學術環境中需求的成長。隨著我們團隊強大的執行力，前後 T 細胞療法持續增長，推動 XPOVIO 的需求增長，今年迄今為止，我們有信心能夠實現修訂後的 2024 年全年美國 XPOVIO 淨產品收入指導範圍 1.1 億美元至1.15億美元。

Now I'd like to turn to slide 29 and shift our focus towards milestones accomplished outside of the US.

現在我想翻到第 29 張投影片，將我們的注意力轉向在美國以外實現的里程碑。

I am pleased with our momentum as we expand our global footprint with continued reimbursement and regulatory approvals for XPOVIO across the world.

我對我們的勢頭感到高興，因為我們透過在世界各地持續為 XPOVIO 提供報銷和監管批准來擴大我們的全球足跡。

In the third quarter, XPOVIO received reimbursement approvals in Italy and France and continued to expand its global footprint with additional regulatory approvals globally.

第三季度，XPOVIO 在義大利和法國獲得了報銷批准，並透過全球其他監管機構的批准繼續擴大其全球足跡。

Our commercial franchise continues to benefit an increasing number of multiple myeloma patients globally. And as a profitable business serves as a critical driver in funding our pipeline. with our dedicated commercialization team and partners We have the capabilities for strong launches in potential future indications.

我們的商業特許經營權繼續使全球越來越多的多發性骨髓瘤患者受益。作為一項盈利的業務，它是為我們的管道提供資金的關鍵驅動力。與我們專門的商業化團隊和合作夥伴一起，我們有能力在未來潛在的適應症中大力推出產品。

I'd like to now present in detail the potential market opportunity that we see for Selinexor or in myelofibrosis and Endometrial cancer. Each amounting to approximately a billion dollars in potential annual US peak revenues. Turning to slide 30 starting with Myelofibrosis as discussed by Reshma and on our call last week Selinexor has the opportunity to transform the frontline treatment paradigm In myelofibrosis. There are no drug classes other than jack inhibitors approved in the front line, which presents a unique opportunity for an efficacious and tolerable new drug with a novel mechanism of action to improve current standard of care.

我現在想詳細介紹我們在 Selinexor 或骨髓纖維化和子宮內膜癌方面看到的潛在市場機會。每一項都相當於美國年度最高收入的約十億美元。轉向幻燈片 30，從 Reshma 討論的骨髓纖維化開始，在我們上週的電話會議上，Selinexor 有機會改變骨髓纖維化的一線治療模式。除了傑克抑制劑之外，沒有其他藥物類別在一線獲得批准，這為開發有效且可耐受的新藥提供了獨特的機會，該新藥具有新穎的作用機制，可以改善當前的護理標準。

As we look at the myelofibrosis market In detail, there are roughly 7,000 estimated incidences in the US. About 6,000 of which are patients with intermediate to high risk myelofibrosis. Approximately three quarters of these patients with baseline platelet counts of 100 or above make up the target patient population for Selinexor combination therapy.

當我們詳細觀察骨髓纖維化市場時，美國約有 7,000 例骨髓纖維化發生率。其中約 6,000 名患者患有中度至高風險骨髓纖維化。這些患者中約四分之三的基線血小板計數為 100 或以上，構成 Selinexor 聯合治療的目標患者群體。

Third party market research conducted last year showed that 75% of physicians indicated their intent to adopt combination therapies as a frontline standard of care replacing Ruxolitinib monotherapy due to the potential of better efficacy with the combination.

去年進行的第三方市場研究表明，75% 的醫生表示他們打算採用聯合療法作為替代 Ruxolitinib 單藥療法的一線標準治療，因為聯合療法可能具有更好的療效。

The survey results also showed a strong perception from physicians on the product profile of Selinexor in combination with Ruxolitinib, we would anticipate strong demand at launch if approved. Given our data to date showing Selinexor ability to meaningfully improve spleen volume and symptom management when added to the current standard of care.

調查結果還顯示，醫生對 Selinexor 與 Ruxolitinib 組合的產品概況有強烈的看法，如果獲得批准，我們預計上市後需求強勁。鑑於我們迄今為止的數據顯示，當添加到目前的護理標準中時，Selinexor 能夠顯著改善脾臟體積和症狀管理。

Furthermore, we have an established commercial infrastructure in the hematology space and about 80% overlap in community-based physicians who treat multiple myeloma and myelofibrosis.

此外，我們在血液學領域擁有成熟的商業基礎設施，並且治療多發性骨髓瘤和骨髓纖維化的社區醫生大約有 80% 的重疊。

This gives us a tremendous opportunity to build a strong presence for selling next or in the multi billion myelofibrosis market with a potential annual US peak revenue opportunity of approximately a billion dollars.

這為我們提供了一個巨大的機會，可以在未來數十億的骨髓纖維化市場中建立強大的銷售地位，美國每年的峰值收入可能達到約 10 億美元。

Now, I'd like to shift your attention to Endometrial cancer on slide 31 which is an equally attractive opportunity for us. We are very encouraged by the potential to Selinexor to address a significant unmet need in key molecular subgroups. As we engage with key opinion leaders in this space, it is clear that they see the unmet need for a targeted treatment in unique molecular subgroups including TP 53 wild eye tumors.

現在，我想將您的注意力轉移到幻燈片 31 上的子宮內膜癌，這對我們來說是一個同樣有吸引力的機會。我們對 Selinexor 解決關鍵分子亞組中未滿足的重大需求的潛力感到非常鼓舞。當我們與該領域的關鍵意見領袖接觸時，很明顯，他們看到了包括 TP 53 野眼腫瘤在內的獨特分子亞組對標靶治療的需求尚未得到滿足。

While frontline treatment options are emerging rapidly, a clear net need remains in the P 53 wild type and specifically PMMR subgroup. Looking now at the potential market in more detail, endometrial cancer is the most common gynecologic cancer in the US. With about 17,000 expected incidences in 2032 approximately 80% of which is expected to be PMMR and 20% DMMR. About 10,000 advanced or recurrent endometrial cancer patients are expected to have P53 wild type status.

雖然一線治療方案正在迅速出現，但 P 53 野生型，特別是 PMMR 亞組仍有明顯的淨需求。現在更詳細地檢視潛在市場，子宮內膜癌是美國最常見的婦科癌症。預計 2032 年將發生約 17,000 起病例，其中約 80% 為 PMMR，20% 為 DMMR。預計約有 10,000 名晚期或復發性子宮內膜癌患者俱有 P53 野生型狀態。

With about two thirds of patients expected to respond to their frontline chemotherapy. Roughly over 6,000 patients would be eligible for Selinexor a potential novel and biomarker specific oral maintenance therapy.

大約三分之二的患者預計會對他們的第一線化療產生反應。大約 6,000 多名患者將有資格接受 Selinexor，這是一種潛在的新型生物標記特異性口腔維持療法。

In third party market research. When us physicians were shown multiple product profiles selling next door was the preferred regimen for 75% of patients with TP 53 wild type and PMMR status.

在第三方市場研究中。當我們的醫生看到隔壁銷售的多種產品簡介時，75% 的 TP 53 野生型和 PMMR 狀態患者的首選治療方案。

With our strong commercial presence in community accounts with XPOVIO, we expect to have roughly 80% overlap in community-based oncologists who treat multiple myeloma and endometrial cancer.

憑藉我們在 XPOVIO 社區帳戶中強大的商業影響力，我們預計治療多發性骨髓瘤和子宮內膜癌的社區腫瘤科醫生的重疊率約為 80%。

As a result, we expect a rapid potential launch of Selinexor and Endometrial cancer if approved with a potential annual us peak revenue opportunity of approximately a billion dollars.

因此，如果獲得批准，我們預計 Selinexor 和子宮內膜癌藥物可能會迅速上市，並帶來約 10 億美元的美國年度高峰收入機會。

Now, I'd like to turn the call over to Mike to give an update on our Q3 financial Results.

現在，我想將電話轉給麥克，介紹我們第三季財務業績的最新情況。

Good morning everyone and thank you Sohanya. Turning to our financials since we issued a press release earlier today with the full financial results, I will just focus on the highlights which are on slide. 33 total revenue for the third quarter of 2024 was $38.8 million compared to $36 million for the third quarter of 2023.

大家早安，謝謝 Sohanya。自從我們今天早些時候發布了包含完整財務業績的新聞稿以來，談到我們的財務狀況，我將只關注幻燈片上的亮點。 33 2024 年第三季的總收入為 3,880 萬美元，而 2023 年第三季的總收入為 3,600 萬美元。

Net us exposal revenue for the third quarter of 2024 was $29.5 million compared to $30.2 million for the third quarter of 2023. The gross to net discount for XPOVIO in the third quarter of 2024 was 31% as compared to 21% in the third quarter of 2023 and 29% in the second quarter 2024. This increase was driven by increased 340 B utilization and Medicare rebates. We expect GTN for the full year of 2024 to be approximately 30%.

2024 年第三季美國淨暴露收入為 2,950 萬美元，而 2023 年第三季為 3,020 萬美元。XPOVIO 2024 年第三季的毛淨折扣為 31%，而 2023 年第三季為 21%，2024 年第二季為 29%。這一增長是由 340 B 利用率增加和醫療保險回扣推動的。我們預計 2024 年全年的 GTN 約為 30%。

Our total expenses for the third quarter of 2024. We're down year over year by 3% due to ongoing head count reductions and other cost saving measures partly offset by our continued investment in our three ongoing phase III clinical trials.

我們 2024 年第三季的總支出。由於持續的人員減少和其他成本節約措施，我們的業績年減了 3%，但我們對三項正在進行的 III 期臨床試驗的持續投資部分抵消了這一影響。

R&D expenses for the third quarter of 2024 were $36.1 million compared to $35.6 million for the third quarter of 2023. The increase in R&D expenses was primarily attributable to higher clinical trial costs related to our ongoing pivotal phase III trial in myelofibrosis. SG&A expenses for the third quarter of 2024 were $27.6 million compared to $30.8 million for the third quarter of 2023. The decrease in SG&A expenses was primarily due to ongoing cost reduction initiatives and lower head count. Cash & cash equivalents, restricted cash and investments as of September 30th 2024 total $133.9 million compared to $192.4 million as of December 31st 2023.

2024 年第三季的研發費用為 3,610 萬美元，而 2023 年第三季的研發費用為 3,560 萬美元。研發費用的增加主要是因為與我​​們正在進行的骨髓纖維化關鍵 III 期試驗相關的臨床試驗成本增加。2024 年第三季的銷售、管理及行政費用為 2,760 萬美元，而 2023 年第三季為 3,080 萬美元。SG&A 費用的減少主要是由於持續的成本削減措施和員工人數減少。截至 2024 年 9 月 30 日，現金及現金等價物、限制性現金及投資總額為 1.339 億美元，而截至 2023 年 12 月 31 日為 1.924 億美元。

Based on our current operating plans, we are narrowing our guidance for the full year of 2024 as follows. Total revenue expects to be in the range of $145million to $155 million as compared to previous guidance of $145million to $169million US exposal. Net product revenue expected to be in the range of $110million to $115 million as compared to previous guidance of $105million to $120 million. R&D and SG&A expenses are expected to be in the range of $255million to $265 million, which includes approximately $20 million of estimated non-cash stock based compensation expense as compared to previous guidance of $250million to $265 million.

根據我們目前的營運計劃，我們將 2024 年全年的指導範圍縮小如下。總收入預計在 1.45 億美元至 1.55 億美元之間，而先前的美國暴露指引為 1.45 億美元至 1.69 億美元。產品淨收入預計在 1.1 億至 1.15 億美元之間，而先前的指引為 1.05 億至 1.2 億美元。研發和銷售、一般管理費用預計在 2.55 億美元至 2.65 億美元之間，其中包括約 2,000 萬美元的估計非現金股票補償費用，而先前的指引為 2.5 億美元至 2.65 億美元。

And finally, we expect our existing cash & cash equivalent and investments, the revenue we expect to generate from XPOVIO net product sales and other license revenues and ongoing discipline and expense management and cost saving measures will be sufficient to fund our planned operations into Q1 2026. Note that our cash flow does not include paying off the remaining 2025 convertible notes in our $25 million liquidity covered under the new term loan, taking into account the repayment of the 2025 convertible notes and the minimum liquidity covenant carried from specs of cash, cash equivalents and investments will be sufficient to fund its operations into the fourth quarter of 2025.

最後，我們預計我們現有的現金和現金等價物以及投資、我們預計從XPOVIO 產品淨銷售和其他許可收入以及持續的紀律和費用管理以及成本節約措施中產生的收入將足以為我們到2026 年第一季度的計劃運營提供資金。請注意，考慮到2025 年可轉換票據的償還以及現金、現金等價物規格所載的最低流動性契約，我們的現金流不包括償還新定期貸款涵蓋的2500 萬美元流動性中剩餘的2025 年可轉換票據投資將足以為其 2025 年第四季的營運提供資金。

We expect our 2025 operating expenses to be lower than 2024 we recognize the full year benefits of our ongoing cost saving initiatives.

我們預計 2025 年的營運費用將低於 2024 年，我們認識到我們持續的成本節約措施所帶來的全年效益。

In summary, we are focused on the advancement of our three phase III trials and driving commercial performance while continuing to be very diligent when allocating our resources.

總而言之，我們專注於推進三個 III 期試驗並推動商業業績，同時在分配我們的資源時繼續非常勤奮。

Before turning the call back to Richard, I'd like to extend my gratitude to everyone here at Karyopharm, our shareholders and everyone that I've had the opportunity to interact with in this role. I'm proud of helping to bring XPOVIO to the market and offering people with Multi myeloma a new therapeutic option. And I continue to believe the company has a very meaningful opportunities ahead, particularly in myelofibrosis and endometrial cancer. I'll now flip to slide 34 and turn the call over to Richard for some final thoughts, Richard.

在將電話轉回給 Richard 之前，我要向 Karyopharm 的每個人、我們的股東以及我在這個職位上有機會與之互動的每個人表示感謝。我很自豪能夠幫助將 XPOVIO 推向市場，並為多發性骨髓瘤患者提供新的治療選擇。我仍然相信該公司未來擁有非常有意義的機會，特別是在骨髓纖維化和子宮內膜癌方面。我現在將翻到幻燈片 34，然後將電話轉給理查德，讓他徵求一些最後的想法，理查德。

Thank you, Mike. It goes without saying that we are so grateful for your leadership and service to Karyopharm over the last 5.5 years, you've played a very important role in XPOVIO launch in the US, our partnership with Manin and the debt refinancing that we announced earlier this year. We wish you the best of luck in your new professional endeavors.

謝謝你，麥克。不用說，我們非常感謝您在過去 5.5 年裡對 Karyopharm 的領導和服務，您在 XPOVIO 在美國的推出、我們與 Manin 的合作以及我們今年早些時候宣布的債務再融資方面發揮了非常重要的作用年。我們祝福您在新的職業生涯中一切順利。

Now, as depicted on slide 35 several significant milestones are approaching for Karyopharm in the near future.

現在，如投影片 35 所示，Karyopharm 在不久的將來即將迎來幾個重要的里程碑。

We are excited about our innovation and growth strategy which offers transformative opportunities with our phase three clinical trials in myofibrosis and endometrial cancer. While building on our Multimyeloma Foundation, these trials have the potential to deliver new standards of care for patients and significantly advance our company as we work to deliver value for our shareholders. As we move forward, we will continue to work diligently towards unlocking the full potential of Selinexor and driving our next phase of growth.

我們對我們的創新和成長策略感到興奮，該策略為我們肌纖維化和子宮內膜癌的第三期臨床試驗提供了變革機會。在我們的多發性骨髓瘤基金會的基礎上，這些試驗有可能為患者提供新的護理標準，並在我們努力為股東創造價值的過程中顯著推動我們公司的發展。隨著我們的前進，我們將繼續努力釋放 Selinexor 的全部潛力並推動我們下一階段的成長。

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 operator.

再次感謝您今天加入我們。我現在想請接線生將通話打開到今天接線生的問答部分。

(Operator Instructions)

（操作員說明）

Brian Abrams from RBC capital Markets.

加拿大皇家銀行資本市場部的布萊恩‧艾布拉姆斯 (Brian Abrams)。

Oh, hi, good morning. Thanks for taking my questions and best wishes to Mike as well in his future endeavors. Two quick ones for me, I guess first on the the average total symptom score on slide 15 that you've shown obviously you know, pretty meaningful or a pretty notable reduction over that 24 week period. But I'm just wondering how the magnitude of that change is influencing your powering assumptions. And, and the reason I ask is I believe a collaborative and its original open label phase two study on top of RS showed at least a median absolute TSS improvement in that same 60% or so ballpark and then ended up sort of just being on the cusp of statistical significance in a 400 plus patient phase three. And then I guess, secondarily on TSS 50 is that still going to be a secondary endpoint in in in the phase III study? And is that something that you think the FDA will still be, you know, looking at, at least to even see some observe some trends there as potentially supportive of approval or as as the regulator have completely shifted to really only focusing on absolute.

哦，嗨，早安。感謝您提出我的問題並對邁克以及他未來的努力表示最良好的祝愿。對我來說兩個快速的，我想首先是幻燈片 15 上的平均總症狀評分，您顯然知道，在 24 週期間非常有意義或相當顯著的減少。但我只是想知道這種變化的幅度如何影響你的動力假設。而且，我問的原因是，我相信在RS 基礎上進行的一項合作及其最初的開放標籤第二階段研究顯示，至少在相同的60% 左右的範圍內至少有中位數絕對TSS 改善，然後最終有點只是在 400 多名患者的第三階段中具有統計顯著性的尖點。然後我想，其次，TSS 50 仍然是 III 期研究的次要終點嗎？你認為 FDA 仍然會關注這一點，至少會看到一些觀察到的一些趨勢，這些趨勢可能支持批准，或者監管機構已經完全轉向真正只關注絕對。

Thanks Brian for the question. This is in terms of average TSS that you noted on slide 15, yeah, I think those are very meaningful data. You know, I'll just reiterate as I did on our prepared remarks. You know, the what those data show over time is that the average TSS substantially improves starting as early as week 24. And then you can see as the patients progress from week 4 to 24 you continue to see this decrement all the way to that average 18.5 reduction that we've reported as part of the absolute TSS. So it really reinforces this meaningful improvement which again, is signified by a reduction in that TSS score. You know, when we look at our powering assumptions, what we're looking at is the delta across the two arms, right. So the average or the absolute TSS is an average assessment of the change in TSS from baseline to week 24. In the manifest data, you know, they observed an approximately two point difference across the two arms. It was not statistically significant. Our data suggests that we could observe something that is far higher, you know, well above two, if not, you know, double to four or above. So again, I think the data are strong, really shows a very meaningful improvement. When you translate the likelihood to a phase three, it really suggests that you can not only see statistical improved statistical significance in that absolute TSS but a clinically meaningful results as well in terms of your second question for TSS 50. So, you know, we are in a very enviable position to replace TSS 50 with absolute TSS. So the co primary end points again will be SPR 35 followed by absolute TSS. We will not be evaluating TSS 50. I think we are really seeing an evolution in terms of how we assess symptoms within a JAKi Naive space. I think everybody is in alignment and when I say everybody, I'm really talking about our Kols patient advocacy groups, certainly the regulatory agencies that absolute TSS which again looks at the average over time is probably the more sensitive in their comprehensive way to analyze these symptoms.

感謝布萊恩提出問題。這是您在投影片 15 中提到的平均 TSS，是的，我認為這些是非常有意義的數據。你知道，我只是重申我們準備好的發言。您知道，隨著時間的推移，這些數據顯示平均 TSS 早在第 24 週就開始大幅改善。然後您可以看到，隨著患者從第 4 週到第 24 週的進展，您會繼續看到這種下降，一直到我們報告的絕對 TSS 的一部分，平均下降 18.5。因此，它確實強化了這一有意義的改進，這再次透過 TSS 分數的降低來體現。你知道，當我們考慮我們的動力假設時，我們關注的是兩個手臂之間的增量，對吧。因此，平均或絕對 TSS 是從基線到第 24 週的 TSS 變化的平均評估。您知道，在清單資料中，他們觀察到兩隻手臂之間大約有兩點差異。這沒有統計意義。我們的數據表明，我們可以觀察到更高的東西，你知道，遠高於二，如果不是，你知道，兩倍到四或更高。再說一遍，我認為數據很強大，確實顯示出非常有意義的改進。當您將可能性轉化為第三階段時，它確實表明您不僅可以看到絕對 TSS 中統計顯著性的改善，而且還可以看到 TSS 50 的第二個問題具有臨床意義的結果。所以，你知道，我們處於非常令人羨慕的位置，可以用絕對 TSS 取代 TSS 50。因此，共同主要終點仍然是 SPR 35，然後是絕對 TSS。我們不會評估 TSS 50。我認為我們確實看到了 JAKi Naive 空間中評估症狀方式的演變。我認為每個人都是一致的，當我說每個人時，我實際上是在談論我們的Kols 患者倡導團體，當然還有監管機構，再次關註一段時間內的平均值的絕對TSS 可能在其綜合分析方式中更敏感這些症狀。

Really helpful. Thanks.

真的很有幫助。謝謝。

Edward White from HC Wainwright.

來自 HC Wainwright 的愛德華懷特 (Edward White)。

Good morning. Thanks for taking my questions. Congratulations on the new regulatory approvals outside of the US. I'm just wondering if you can give us an update of where you stand in the countries that we've already launched. How the launches are going and an outlook outside the US for 2025.

早安.感謝您回答我的問題。恭喜美國境外獲得新的監管批准。我只是想知道您是否可以向我們介紹您在我們已推出的國家/地區的最新情況。美國以外地區的發布進展如何以及 2025 年展望。

Thanks. I'll turn to Sohanya for that.

謝謝。為此我會向 Sohanya 求助。

We continue to see approvals for reimbursement as well as regulatory approvals in the past quarter. And, and we're very pleased with the global expansion of Selinexor or if you compare to some of the US launch experiences, they're starting in largely earlier lines of therapy versus you know, P to refractory. And that obviously they have some of the learnings in terms of anti-medics, side effect management and so as we look at, you know, 2025 will obviously provide a guidance on total revenues on the Q4, 2024 call. But with the ongoing reimbursement approval and launch this year, we anticipate royalties from X US selling next or revenues to increase in 2025. Now, in 2024 we achieved the majority of the major market reimbursement approvals. Therefore, we don't expect those to reoccur next year. Again, we'll provide more color on total revenue guidance on our Q4 2024 call.

我們在上個季度繼續看到報銷批准以及監管部門的批准。而且，我們對 Selinexor 的全球擴張感到非常滿意，或者如果你與美國的一些上市經驗進行比較，他們基本上是從早期的治療線開始的，而不是你知道的，P 到難治性的。顯然他們在抗醫療、副作用管理方面有一些經驗教訓，所以正如我們所見，2025 年顯然將為 2024 年第四季的電話會議提供總收入指導。但隨著今年報銷的持續批准和推出，我們預計 X US 下一步銷售的特許權使用費或收入將在 2025 年增加。現在，到 2024 年，我們獲得了大部分主要市場的報銷批准。因此，我們預計明年不會再發生這種情況。同樣，我們將在 2024 年第四季的電話會議上提供更多關於總收入指導的資訊。

Okay, thanks. And just to dig down into the end of each real market, you know, I just wanted to get your thoughts on some of the challenges of entering a maintenance therapy market versus, you know, a treatment market. And, and how the company is addressing that particular market on maintenance and, and getting patients to take the drug in a maintenance setting.

好的，謝謝。為了深入挖掘每個真實市場的盡頭，我只是想了解您對進入維持治療市場與治療市場所面臨的一些挑戰的看法。以及該公司如何應對特定的維持市場，以及如何讓患者在維持環境中服用藥物。

Yeah, we are thrilled about the opportunity to launch in endometrial cancer as a potential novel and biomarker specific oral maintenance only therapy for a couple of different reasons. I think as you've seen the the marketplace evolve rapidly, particularly in the past year, there continues to be a significant unmet need in specific molecular subgroups. And in our case, particularly focused on the TP53 wild type and PMMR sub group. And this is where our data as Rama has discussed is most compelling.

是的，出於多種不同的原因，我們很高興有機會在子宮內膜癌中推出一種潛在的新型和生物標記特異性口服維持療法。我認為正如您所看到的市場快速發展，特別是在過去的一年中，特定分子亞組的需求仍然存在巨大的未滿足的需求。在我們的案例中，特別關注 TP53 野生型和 PMMR 亞組。這就是拉瑪所討論的我們的數據最引人注目的地方。

Now, as we look at our product profile as a maintenance therapy, it is a highly compelling profile as supported by our market research. As I mentioned, when us physicians were shown multiple product profiles selling. So was the preferred regimen for a majority 75% of patients with TP53 wild type and PMMR status. So, you know, my belief is we have a potentially groundbreaking therapy in this maintenance space in a highly targeted subgroup with a compelling profile and a convenient oral therapy important to also reinforce. But as a commercial team, we have very strong overlap with treating physicians both in the multiple myeloma space and the Endometrial space in the community which enables us to hit the ground running with our messaging on day of approval. So, we're very excited about the potential opportunity to launch in this maintenance setting.

現在，當我們將我們的產品概況視為一種維持療法時，我們的市場研究支持它是一個非常引人注目的概況。正如我所提到的，當我們的醫生看到多種正在銷售的產品簡介時。對於大多數 75% 的 TP53 野生型和 PMMR 狀態患者來說，這也是首選方案。所以，你知道，我的信念是，我們在這個維護領域有一個潛在的突破性療法，在一個高度針對性的亞組中，具有令人信服的概況和方便的口服療法也很重要。但作為一個商業團隊，我們與社區中多發性骨髓瘤領域和子宮內膜領域的治療醫生有很強的重疊，這使我們能夠在批准之日立即開始我們的訊息傳遞。因此，我們對在此維護環境中啟動的潛在機會感到非常興奮。

Okay. Thanks for taking my questions.

好的。感謝您回答我的問題。

Peter Lawson from Barclays.

來自巴克萊銀行的彼得·勞森。

Great. Thanks so much. Thanks for taking the questions. I, I guess just initially on the the quarter, Sohanya, you've seen three quarters of quarter over quarter growth and if you can make any comments about any underlying trends there or anything that was different from the last couple of quarters for that quarter over quarter growth and kind of the mix between price and volume and then academic versus community settings. Thank You.

偉大的。非常感謝。感謝您提出問題。我想，Sohanya，在本季度一開始，您已經看到了三個季度的季度環比增長，您是否可以對那裡的任何潛在趨勢或該季度與前幾季度不同的任何內容髮表評論季度增長以及價格和數量之間的混合，然後是學術與社區環境。謝謝。

Thanks Peter for the question.

感謝彼得提出的問題。

We're very pleased with our three consecutive quarters of net revenue growth. Very proud of the team for the resilience and success they have demonstrated particularly in Q3 in driving double digit demand growth quarter over quarter. As we look at some of the dynamics here in terms of settings of care in the community setting, we achieved strong growth quarter over quarter. This remains the majority of our business. About 60% of our business came from the community setting or importantly in Q3 as well, we did see an uptick in demand in our academic setting as well quarter over quarter. And this is really driven by the body of evidence that we have worked hard to build in the past year around this concept of T cell fitness and selling export potential ability to preserve the immune environment with respect to T cell therapy. So, you know, as we look at this current year-to-date and our performance, our team is working hard to continue to drive demand and position exposal as a flexible combinable, manageable drug that allows for a class switch. Even though the the marketplace is highly competitive, it's clear that we are in a space where a multi mechanistic approach is increasingly needed for successful patient outcomes. And that's exactly where Selinexor comes in as a differentiated mechanism of action. So, again, very pleased with our performance this quarter, we've narrowed our guidance for the full year and feel confident in meeting that range.

我們對連續三個季度的淨收入成長感到非常滿意。對球隊所表現出的韌性和成功感到非常自豪，尤其是在第三季度，他們在推動需求季度環比增長兩位數方面。當我們觀察社區護理環境方面的一些動態時，我們實現了逐季度的強勁成長。這仍然是我們的大部分業務。我們大約 60% 的業務來自社區環境，重要的是在第三季度，我們確實看到學術環境的需求逐季上升。這實際上是由大量證據推動的，這些證據表明我們在過去一年中圍繞 T 細胞適應性概念努力建立，並銷售出口潛在能力，以保護 T 細胞治療的免疫環境。所以，你知道，當我們審視今年迄今為止的表現和我們的業績時，我們的團隊正在努力繼續推動需求，並將暴露定位為一種靈活的、可組合的、可管理的藥物，允許類別轉換。儘管市場競爭激烈，但很明顯，我們正處於一個越來越需要多機制方法才能獲得成功患者治療結果的領域。這正是 Selinexor 作為差異化作用機制的用武之地。因此，我們對本季的表現再次感到非常滿意，我們縮小了全年指導範圍，並對達到該範圍充滿信心。

Got it. Thank you. And then Reshma, just on the MMR proficient patients. Do you need any kind of alignment with the FDA around calling that out as a marker. And kind of how's, how's enrollment going there.

知道了。謝謝。然後是 Reshma，僅針對 MMR 熟練的患者。您是否需要與 FDA 就將其作為標記進行任何形式的協調？那裡的入學情況怎麼樣？

Yeah, thanks Peter. So, no, we don't largely because the patient population that we're targeting is TP 53 wild type and that P 53 wild type, I think the regulatory agencies and the FDA particularly really appreciate is going to include multiple molecular sub groups including MMR proficient. So, you know, tthere's no need to specifically call them out, you know, with that said, will we be looking at potential subgroups by MMR status. Yes, that's something that we will be, we will be considering in terms of enrollment. Enrollment is going well, we're certainly on track to report top line results in the early part of 2026. A lot of that is fueled by, again, just I think, strong enthusiasm for the data. You know, as we presented at ASCO and then, you know, again, had an opportunity to pre present very recently at IGCS in Dublin. Those data and specifically the benefit that Selinexor provides to TP 53 wild type is, you know, almost unprecedented, right? I mean, we are seeing in that TP 53 wild type subgroup of 28.4 month median PFS if you specifically look in that subgroup or both TP 53 wild type and MMR proficient again, that TFS now climbs to 40 months, which, you know, I mentioned earlier on the prepared remarks, you know, cross trial limitations aside exceeds the overall survival that you see with the checkpoint inhibitors. So strong enthusiasm about, you know, the trial largely due to the benefit that we are seeing with Selinexor and you know, the strong anticipation that these results are going to translate in our ongoing phase III.

是的，謝謝彼得。所以，不，我們不這樣做主要是因為我們的目標患者群體是 TP 53 野生型和 P 53 野生型，我認為監管機構和 FDA 特別真正欣賞的是將包括多個分子亞組，包括MMR 熟練。因此，您知道，沒有必要專門指出它們，您知道，話雖如此，我們是否會根據 MMR 狀態來研究潛在的亞群。是的，我們將在招生方面考慮這一點。註冊進展順利，我們肯定會在 2026 年初報告營收結果。我認為，這很大程度上是由對數據的強烈熱情所推動的。您知道，正如我們在 ASCO 上所展示的那樣，然後，您知道，最近又有機會在都柏林的 IGCS 上展示。這些數據，特別是 Selinexor 為 TP 53 野生型提供的益處，您知道，幾乎是前所未有的，對嗎？我的意思是，我們看到TP 53 野生型亞組的中位數PFS 為28.4 個月，如果您專門查看該亞組或再次精通TP 53 野生型和MMR，則TFS 現在攀升至40 個月，您知道，我前面在準備好的評論中提到，您知道，除了交叉試驗的局限性之外，超出了您使用檢查點抑製劑看到的總體生存率。您知道，對這項試驗如此強烈的熱情很大程度上是因為我們看到 Selinexor 帶來的好處，而且您知道，我們強烈期望這些結果將在我們正在進行的第三階段中得到體現。

Great. Thank you so much.

偉大的。太感謝了。

Maury Raycroft from Jefferies.

來自 Jefferies 的莫里雷克羅夫特 (Maury Raycroft)。

Hi, good morning. Thanks for taking the question. And I'll offer our best wishes to Mike as well next steps. I was going to ask one on the ongoing multiple myeloma SPD phase III study just if you could talk about the powering assumptions of the new trial design. What else do you need to align with regulatory agencies to get the go ahead there? And when do you anticipate you'll be able to clarify the time line today after the study?

嗨，早安。感謝您提出問題。我也會向麥克致以最良好的祝愿以及接下來的步驟。我想問一位正在進行的多發性骨髓瘤 SPD III 期研究，您能否談談新試驗設計的有力假設。您還需要與監管機構協調什麼才能取得進展？您預計今天研究結束後什麼時候能夠明確時間表？

Yeah, thanks so much Maury for the question. So, you know, what we were able to do is to really leverage the positively evolving data that we specifically observed with SPD 40. The media and PFF you know, as I mentioned previously, is substantially larger, longer than what we previously assumed. So that ability allows us to target not only a smaller number of total patients. And as you can see sort of like from earlier prepared remarks, we're now going to be targeting 120 patients as part of the ongoing trial. But it also allows us to reduce the total number of PFS events that's going to trigger that, you know, primary analysis for PFS without compromising any of the power that had already and built into the trial. So, you know, we don't specifically comment on our exact powering assumptions with that said in all of our phase three, we power, you know, above 80%. This trial is no different. So, you know, again, that ability is just based upon our, you know, our ability to leverage the positively evolving efficacy. in terms of alignment with the FDA So the updated enrollments, as well as the updated statistical assumptions were incorporated to an amendment. And that has been sent to the FDA. We expect you know, any kind of feedback to be coming in the next few weeks at that time. We will update, you know, our top line results milestones accordingly.

是的，非常感謝莫里的提問。所以，您知道，我們能夠做的是真正利用我們在 SPD 40 中特別觀察到的積極變化的數據。正如我之前提到的，你知道的媒體和 PFF 比我們之前假設的要大得多、長得多。因此，這種能力使我們不僅能夠瞄準較少數量的患者。正如您從先前準備好的評論中看到的那樣，我們現在將針對 120 名患者作為正在進行的試驗的一部分。但它也使我們能夠減少將觸發 PFS 初步分析的 PFS 事件總數，而不會損害試驗中已有的任何功能。所以，你知道，我們不會具體評論我們的確切供電假設，在我們的所有第三階段中，我們的供電率超過 80%。這次審判也不例外。所以，你知道，這種能力只是基於我們利用積極發展的功效的能力。因此，更新的註冊人數以及更新的統計假設都被納入了修正案。該訊息已發送至 FDA。我們希望您知道，任何類型的回饋都會在接下來的幾週內出現。您知道，我們將相應地更新我們的頂線業績里程碑。

Got it. Okay. And maybe one follow up. Just for the myelofibrosis study goes out to 24 weeks. Do patients continue on treatment? And, and what's the likelihood that you'll have to have a longer term follow up, potentially going out to 48 weeks?

知道了。好的。也許還有一個後續行動。光是骨髓纖維化研究就需要 24 週。患者是否繼續治療？而且，您需要長期追蹤（可能長達 48 週）的可能性有多大？

Yeah. So patients are going to continue on therapy well beyond 24 weeks. So the 24 week marks just indicates, you know, when that pr and the absolute TSS are going to be analyzed, patients are going to be continuing. We have multiple longitudinal end points that we are going to evaluate in including PFS overall survival in terms of long term end points. You know, right now, based upon our discussions with the regulatory agencies, the key endpoints that are going to drive regulatory decisions are again week 24 we'll have the opportunity to provide longer term data. But right now, we're really focused on that 24 week data for again, regulatory decision making.

是的。因此，患者將繼續接受治療超過 24 週。因此，24 週標記僅表明，您知道，當要分析 pr 和絕對 TSS 時，患者將繼續治療。我們有多個縱向終點，我們將對其進行評估，包括長期終點方面的 PFS 總存活期。您知道，現在，根據我們與監管機構的討論，推動監管決策的關鍵終點將在第 24 週再次出現，我們將有機會提供長期數據。但現在，我們真正關注的是 24 週的數據，以便再次做出監管決策。

Got it. Okay. Thanks for taking my questions.

知道了。好的。感謝您回答我的問題。

Thanks Maury.

謝謝莫里。

Thank you. There are no further questions at this time. Please proceed.

謝謝。目前沒有其他問題。請繼續。

Thank you operator and thank you everyone for joining us today. You know, as we mentioned as an organization, we are focused and excited about delivering our innovation and growth strategy which offers transformative opportunities with our phase III clinical trials and myofibrosis and endometrial cancer. As we build on our Multimyeloma foundation. these trials, we've heard the potential for them to really deliver new standards of care and significantly advance our company as we work to deliver value to shareholders. Once again, thank you for joining us today.

感謝營運商，也感謝大家今天加入我們。您知道，正如我們作為一個組織所提到的，我們專注於並興奮地實施我們的創新和成長策略，該策略為我們的 III 期臨床試驗以及肌纖維化和子宮內膜癌提供了變革機會。當我們建立多發性骨髓瘤基礎。透過這些試驗，我們了解到它們有可能真正提供新的護理標準，並在我們努力為股東創造價值的過程中顯著推動我們公司的發展。再次感謝您今天加入我們。

Thank you, ladies and gentlemen, the conference has now ended. Thank you all for joining you. May all disconnect your lines.

謝謝各位，女士們、先生們，會議現已結束。感謝大家的加入。願大家斷開你們的線路。