Karyopharm Therapeutics Inc (KPTI) 2023 Q3 法說會逐字稿

Good morning. My name is [Dhruv], and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics third-Quarter 2023 financial results conference call. There will be a question and answer session to follow. Please be advised that this call is being recorded as the company's request. (Operator instructions).

早安.我的名字是 [Dhruv]，今天我將擔任你們的會議操作員。此時此刻，我歡迎大家參加 Karyopharm Therapeutics 2023 年第三季財務業績電話會議。隨後將舉行問答環節。請注意，本次通話是根據公司的要求進行錄音的。 （操作員說明）。

I would now like to turn the call over to Elhan Webb, Senior Vice President, Investor Relations.

我現在想將電話轉給投資者關係高級副總裁 Elhan Webb。

Thank you, and thank you all for joining us on today's conference call to discuss Karyopharm's third-Quarter 2023 financial results and recent company progress. We issued a press release this morning detailing our financial results for the third quarter 2023. This release, along with a slide presentation that we will reference during our call today are available on our website.

謝謝大家，也謝謝大家參加今天的電話會議，討論 Karyopharm 2023 年第三季的財務業績和公司最近的進展。我們今天早上發布了一份新聞稿，詳細介紹了 2023 年第三季度的財務業績。該新聞稿以及我們將在今天的電話會議中參考的幻燈片演示文稿可在我們的網站上獲取。

For today's call, as seen on slide 2, I am joined by Richard, Reshma, Sohanya and Mike, who will provide an update on our results for the third quarter and recent clinical developments. Before, we begin our formal comments, I will remind you that various remarks will make today constitute forward-looking statements, FLS for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995, as outline on slide 3.

如投影片 2 所示，Richard、Reshma、Sohanya 和 Mike 也參加了今天的電話會議，他們將介紹我們第三季的結果和最近的臨床進展的最新情況。在我們開始正式評論之前，我要提醒您，今天發表的各種言論均構成前瞻性陳述，FLS 出於 1995 年《私人證券訴訟改革法案》中安全港條款的目的，如幻燈片 3 所示。

Actual results may differ materially from those indicated by these FLS as a result of various important factors, including those discussing 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 represent 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 these FLS as representing our views as of emulator date. I will now turn the slide over to Richard. Please turn to slide 4.

由於各種重要因素的影響，實際結果可能與這些FLS 所示的結果有重大差異，包括討論我們最新的10-Q 表格中風險因素部分的內容，該表格已提交給SEC 以及我們可能提交的其他文件未來將與 SEC 合作。任何 FLS 僅代表我們今天的觀點。雖然我們可能選擇在未來某個時候更新這些 FLS，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 FLS 來代表我們截至模擬器日期的觀點。我現在將幻燈片交給理查。請翻到幻燈片 4。

Thank you, Elhan, good morning, everyone, and thank you for joining Karyopharm's Q3 2023 earnings call. Turning to slide 5, we are strongly positioned for our next stage of growth, driven by our focused and rapidly advancing mid and late-stage pipeline of innovative first-in-class oral selective inhibitors of nuclear export, their target XPO1, as well as a strong commercial organization that continues to positively impact the lives of multiple myeloma patients every day.

謝謝 Elhan，大家早安，謝謝您參加 Karyopharm 的 2023 年第三季財報電話會議。轉向幻燈片 5，在我們專注且快速推進的創新一流口服選擇性核輸出抑製劑、其目標 XPO1 以及中後期管道的推動下，我們為下一階段的增長做好了充分準備。一個強大的商業組織，每天繼續對多發性骨髓瘤患者的生活產生正面影響。

Our US and global commercial presence is on track to deliver $145 million to $160 million of annual total revenues in 2023, and provides us with the capabilities needed to launch in new indications, if approved, following the outcome of our three pivotal Phase 3 clinical trials. We have the opportunity to significantly improve standard of care for patients across these indications and we continue to generate compelling data, including impressive durability data observed with Selinexor 60 milligrams in combination with ruxolitinib in patients with myelofibrosis, as well as the substantial progression free survival observed in patients with TP53 wild-type endometrial cancer, which Reshma will expand upon shortly.

我們的美國和全球商業業務預計在 2023 年實現 1.45 億至 1.6 億美元的年總收入，並為我們提供在三項關鍵 3 期臨床試驗結果獲得批准後推出新適應症所需的能力。我們有機會顯著提高針對這些適應症的患者的護理標準，並且我們將繼續產生令人信服的數據，包括在骨髓纖維化患者中觀察到Selinexor 60 毫克與魯索替尼聯合治療所觀察到的令人印象深刻的耐久性數據，以及觀察到的顯著的無惡化存活期Reshma 將很快對 TP53 野生型子宮內膜癌患者進行擴展。

We are committed to deliver on the opportunities ahead of us and believe selinexor could generate approximately $2 billion of peak annual revenues in the US alone. With a cash runway through late 2025, we have the financial strength to deliver on key data readouts from our three Phase 3 studies. We will continue to be disciplined about our expense management, focusing our resources on our prioritized late-stage pipeline.

我們致力於抓住眼前的機遇，並相信 selinexor 僅在美國就可以產生約 20 億美元的高峰年收入。憑藉著 2025 年底的現金跑道，我們有足夠的財務實力來提供三項 3 期研究的關鍵數據讀數。我們將繼續嚴格費用管理，將資源集中在優先的後期管道上。

As we move to slide 6, presented here is an overview of the timing of the upcoming key data readouts, which we expect in 2024 and 2025, each of our ongoing Phase 3 clinical trials, if successful, represents an incredibly meaningful growth opportunity for our organization with the potential to deliver roughly $2 billion in annual peak revenues.

當我們轉到幻燈片6 時，此處概述了即將發布的關鍵數據讀數的時間安排，我們預計將在2024 年和2025 年進行，我們正在進行的每項3 期臨床試驗如果成功，將為我們帶來極其有意義的成長機會該組織有潛力提供約 20 億美元的年度高峰收入。

Our proven and established commercialization and a late stage development capabilities are focused on executing with our current label and a rapidly progressing these pivotal Phase 3 programs. And approval in just one of these in three indications is a transformational opportunity for Karyopharm and the clinical data ratio will review today continues to strengthen our confidence in each of these programs. With the potential for pivotal catalysts over the next two years and with the cash runway to deliver on each of these top line readouts, we are well positioned for our next stage of growth.

我們經過驗證和建立的商業化和後期開發能力專注於以我們當前的標籤執行並快速推進這些關鍵的第三階段專案。三種適應症中的一種的批准對 Karyopharm 來說是一個轉型機會，今天將審查的臨床數據比例將繼續增強我們對這些項目的信心。憑藉未來兩年關鍵催化劑的潛力，以及實現這些營收數據的現金跑道，我們為下一階段的成長做好了充分準備。

Moving to Slide 7, I would now like to turn the call over to Reshma to expand further on our clinical pipeline progress, Reshma.

轉到幻燈片 7，我現在想將電話轉給 Reshma，以進一步擴展我們的臨床管道進展，Reshma。

Thank you, Richard. Turning the slide 8, we have a very promising late stage pipeline with pivotal data readouts over the next two years. I will focus on our 3 Phase 3 trials, where our confidence only grows, given the positively evolving preclinical and clinical data that support each indication. Each of these trials could position selinexor to substantially change the treatment paradigms in each of these populations, if approved.

謝謝你，理查。翻到投影片 8，我們有一個非常有前途的後期管道，將在未來兩年內讀出關鍵數據。我將重點放在我們的 3 個 3 期試驗，鑑於支持每個適應症的積極發展的臨床前和臨床數據，我們的信心只會增強。如果獲得批准，這些試驗中的每一項都可以使 selinexor 顯著改變每個人群的治療模式。

Turning our attention first to myelofibrosis on slide 10. Treatment of JAKi naive myelofibrosis patients remains an area of high unmet need with more than 20,000 myelofibrosis patients in the US alone. Ruxolitinib remains the standard care for the majority of JAKi naive patients. However, there is an opportunity to improve benefit, given that the efficacy with ruxolitinib is limited with less than 50% of patients achieving an SVR35 and TSS50.

首先將我們的注意力轉向幻燈片 10 上的骨髓纖維化。JAKi 初治骨髓纖維化患者的治療仍然是一個高度未滿足需求的領域，僅在美國就有超過 20,000 名骨髓纖維化患者。魯索替尼仍然是大多數未經 JAKi 治療的患者的標準治療方法。然而，鑑於魯索替尼的療效有限，只有不到 50% 的患者達到 SVR35 和 TSS50，仍有機會提高益處。

We are evaluating the potential for selinexor in combination with ruxolitinib to provide benefit across all of the hallmarks of the disease, including spleen reduction, symptom improvement, disease modification and stabilization, if not improvement at cytopenias. On Slide 11, you see that XPO1 inhibition is a fundamental mechanism in myelofibrosis, given that it targets both JAKi and non-JAKi pathways, underscoring selinexor's additive or potentially synergistic activity when dosed in combination.

我們正在評估 selinexor 與 ruxolitinib 聯合使用的潛力，以在該疾病的所有特徵上提供益處，包括脾臟縮小、症狀改善、疾病緩解和穩定（如果不能改善血球減少）。在投影片 11 中，您會看到 XPO1 抑制是骨髓纖維化的基本機制，因為它同時針對 JAKi 和非 JAKi 途徑，這強調了 selinexor 聯合用藥時的累積或潛在協同活性。

Non-JAKi mechanisms include inhibition of NF-kB induction of Cell Cycle Arrest and p-53 driven cell death. Together, XPO1 inhibition increases malignant cell death, decreases malignant cell proliferation and reduces inflammation. We presented updated Phase 1 data at the ASCO conferences in June 2023, which can be seen on slide 12.

非 JAKi 機制包括抑制 NF-kB 誘導的細胞週期停滯和 p-53 驅動的細胞死亡。總之，XPO1 抑制會增加惡性細胞死亡、減少惡性細胞增生並減少發炎。我們在 2023 年 6 月的 ASCO 會議上展示了更新的第一階段數據，如投影片 12 所示。

These data show meaningful SVR35 and TSS50 improvement with 60 milligram selinexor, including a 79% SVR35 and 58% TSS50 at week 24 in the intent to treat populations. Importantly, amongst the evaluable patients, 100% achieved in SVR35 at any time. Today at the NPN Congress, data are being presented, including SVR response and TSS50 durability amongst the 11 out of 14 patients who achieved a 35% of greater spleen volume reduction at week 24 and the 7 out of 12 patients who achieved the TSS50 at the same time point.

這些數據顯示，60 毫克 selinexor 顯著改善了 SVR35 和 TSS50，包括在治療族群的第 24 週時 SVR35 和 TSS50 分別為 79% 和 58%。重要的是，在可評估的患者中，任何時候 100% 都達到了 SVR35。今天在NPN 大會上公佈了數據，包括第24 週時脾臟體積縮小了35% 的14 名患者中的11 名以及在第24 週時達到TSS50 的12 名患者中的7 名的SVR 反應和TSS50 持久性。同一時間點。

We are very encouraged by these data, given the impressive durability seen on slide 13 for both of these endpoints. As of August 1, 2023, none of the week 24, SVR35 responders dosed a selinexor 60 milligrams had observed radiographic progression. Note that the longest patient has been followed for 78 weeks, and the median duration of follow-up as of the data cut-off is 32 weeks.

鑑於幻燈片 13 中這兩個端點令人印象深刻的耐用性，我們對這些數據感到非常鼓舞。截至 2023 年 8 月 1 日，第 24 週，服用 60 毫克 selinexor 的 SVR35 應答者均未觀察到放射學進展。請注意，最長的患者追蹤時間為 78 週，截至數據截止時的中位追蹤時間為 32 週。

Similarly, none of the week 24, TSS50 responders had observed symptom progression with the longest follow-up of 64 weeks and a median duration of 51 weeks. While, I acknowledge the apparent limitations and cross trial comparisons, contrast these data to ruxolitinib alone, in which only approximately 70% of responses were ongoing at 78 weeks. Data for ruxolitinib PSS50 durability data beyond week 24 have not been provided.

同樣，在第 24 週，TSS50 應答者中沒有觀察到症狀進展，最長追蹤時間為 64 週，中位數持續時間為 51 週。雖然我承認存在明顯的局限性和交叉試驗比較，但將這些數據與單獨的魯索替尼進行對比，其中只有大約 70% 的反應在 78 週時持續存在。尚未提供 24 週後的魯索替尼 PSS50 耐久性資料。

These data add to the substantial benefit observed with week 24 SVR and TSS50 and highlight the substantial benefit that may be observed with this novel combination compared to ruxolitinib alone. Together, these data illustrates the rapid deep and now durable spleen and symptom improvement achieved with selinexor in combination with ruxolitinib and further demonstrate the potential for this combination to change treatment paradigms, project naive myelofibrosis patients.

這些數據增加了第 24 週 SVR 和 TSS50 觀察到的實質益處，並強調了與單獨使用魯索替尼相比，這種新型組合可能觀察到的實質益處。總而言之，這些數據說明了 selinexor 與魯索替尼組合實現了快速、持久的脾臟和症狀改善，並進一步證明了這種組合改變治療模式、預測初治骨髓纖維化患者的潛力。

This profile in conjunction with the subgroup analysis shown on slide 14, which depict SVR35 and TSS50 responses, despite treatment with suboptimal doses of ruxolitinib, which is suggestive of potential monotherapy activity, underscores our confidence in the ongoing Phase 3 study.

該概況與幻燈片14 中顯示的亞組分析相結合，顯示了SVR35 和TSS50 反應，儘管魯索替尼治療劑量不理想，表明潛在的單一療法活性，強調了我們對正在進行的3 期研究的信心。

As seen on slide 15, our Phase 3 study is evaluating the combination of selinexor 60 milligrams with ruxolitinib versus ruxolitinib alone in 306 JAKi naive myelofibrosis patients. This important trial in addition to the Phase 2 selinexor monotherapy trial that we are planning in treatment naive myelofibrosis patients with moderate Thrombocytopenia has the potential to entrench selinexor as a foundational therapy in approximately 90% of all treatment naive myelofibrosis patients.

如投影片 15 所示，我們的 3 期研究正在 306 名未經 JAKi 治療的骨髓纖維化患者中評估 selinexor 60 毫克與魯索替尼的組合與單用魯索替尼的比較。除了我們計劃在患有中度血小板減少症的初治骨髓纖維化患者中進行的2 期selinexor 單藥治療試驗之外，這項重要的試驗有可能鞏固selinexor 作為約90% 的所有初治骨髓纖維化患者的基礎治療的地位。

As we turn to slide 17, endometrial cancer is a key focus in our pipeline, given the high unmet need and the substantial benefit observed in patients whose tumors are P53 wild-type. Advanced and recurrent endometrial cancer is the most common form of gynecologic cancer in the United States with the current treatment landscape being driven by molecular classifications.

當我們轉向幻燈片 17 時，考慮到未滿足的需求很高以及在 P53 野生型腫瘤患者中觀察到的實質益處，子宮內膜癌是我們產品線中的一個重點關注點。晚期和復發性子宮內膜癌是美國最常見的婦科癌症，目前的治療模式是由分子分類所驅動的。

As a result, in MMR deficient patients who represent approximately 20% of all advanced recurrent endometrial cancer patients, the new FDA approved standard is just starlimab in combination with chemotherapy, followed by the starlimab maintenance. For MMR proficient patient, which represent the remaining 80% of advanced recurrent endometrial cancer checkpoint inhibitors are not approved. As such, the primary treatment option is chemotherapy, followed by watch-and-wait.

因此，對於佔所有晚期復發性子宮內膜癌患者約 20% 的 MMR 缺陷患者，FDA 批准的新標準是 starlimab 聯合化療，然後進行 starlimab 維持治療。對於 MMR 熟練的患者，代表剩餘 80% 的晚期復發性子宮內膜癌檢查點抑制劑未獲批准。因此，主要的治療選擇是化療，然後是觀察等待。

Importantly, wild type P53 is found in the majority of all advanced recurrent endometrial cancer, as seen on slide 18, taken together, patients whose tumors are both MMR proficient and P53 wild-type represent 40% to 55% of all advanced recurrent endometrial cancer patients. In the substantial population, the benefit observed with selinexor is considerable as seen on slide 19, given that a 68% decrease in the risk of disease progression or death corresponding to a hazard ratio of 0.32 and the median progression free survival that has not been reached was observed in this exploratory subgroup of patients from the C&R trial, as of March 30th, 2023, data cut off.

重要的是，野生型P53 存在於大多數晚期復發性子宮內膜癌中，如幻燈片18 所示，腫瘤同時具有MMR 功能且P53 野生型的患者佔所有晚期復發性子宮內膜癌的40%至55%患者。在大量人群中，如幻燈片 19 所示，使用 selinexor 觀察到的益處相當大，因為疾病進展或死亡的風險降低了 68%，對應的風險比為 0.32，且中位無進展生存期尚未達到截至2023 年3 月30 日，數據截止，在C&R 試驗的這一探索性患者亞群中觀察到了這一情況。

The progression free survival results observed in those patients who are P53 wild-type and MMR deficient are also noteworthy with a median PFS for selinexor 13.1 months and hazard ratio of 0.45. Further strengthening our rationale and P53 wild-type endometrial cancer are the preclinical data that were recently presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October.

在 P53 野生型和 MMR 缺陷的患者中觀察到的無惡化存活結果也值得注意，selinexor 的中位 PFS 為 13.1 個月，風險比為 0.45。最近在 10 月的 AACR-NCI-EORTC 國際分子標靶和癌症治療會議上發表的臨床前數據進一步強化了我們的理論基礎和 P53 野生型子宮內膜癌。

These data from endometrial cancer models further confirm the biology by demonstrating significantly better potency in P53 wild-type models as compared to P53 mutant models, further validating the design of the ongoing Phase 3 study, as shown on slide 20.

這些來自子宮內膜癌模型的數據透過證明P53 野生型模型與P53 突變型模型相比具有顯著更好的效力，進一步證實了生物學特性，進一步驗證了正在進行的3 期研究的設計，如幻燈片20 所示。

The EC-042 pivotal Phase 3 study is evaluating selinexor as a maintenance therapy in patients with TP53 wild-type advanced or recurrent endometrial cancer. The study will involve approximately 220 women, whose tumors are TP53 wild-type. Ultimately, this trial will enable the development of a companion diagnostic, and we anticipate the approval of a companion diagnostic would occur at the same time as selinexor, if approved.

EC-042 關鍵 3 期研究正在評估 selinexor 作為 TP53 野生型晚期或復發性子宮內膜癌患者的維持治療。該研究將涉及約 220 名女性，她們的腫瘤為 TP53 野生型。最終，該試驗將促進伴隨診斷的開發，如果獲得批准，我們預計伴隨診斷將與 selinexor 同時獲得批准。

The study is a collaboration between Karyopharm in [endgot], the European network for gynecological oncological trial group and GOG, the gynecology oncology group. [Endgot] in GOG include the top opinion leaders in gynecology oncology. Their participation in the ongoing Phase 3 study, further underscore the strength of the data observed in the P53 wild-type subgroups and the potential selinexor may have in providing a new standard of care to P53 wild-type endometrial cancer patients.

該研究是歐洲婦科腫瘤試驗組網路 [endgot] 的 Karyopharm 與婦科腫瘤組 GOG 之間的合作。 GOG 中的 [Endgot] 包括婦科腫瘤學領域的頂尖意見領袖。他們參與正在進行的 3 期研究，進一步強調了在 P53 野生型亞組中觀察到的數據的強度，以及 selinexor 可能為 P53 野生型子宮內膜癌患者提供新的護理標準的潛力。

Together, we are making strong progress and have been intensely focused on activating sites and enrolling patients. We are now expecting top line results in the first half of 2025, with the slight timing shift related to country-specific regulatory delays in a few European countries. As seen on slide 22, we are expanding our multiple myeloma franchise with the ongoing Phase 3 trial that is evaluating selinexor at the low dose of 40 milligrams in combination with a well-established backbone therapy as pomalidomide and dexamethasone.

我們共同取得了巨大進展，並一直專注於激活站點和招募患者。我們現在預計 2025 年上半年會出現頂線結果，但時間上會略有變化，這與一些歐洲國家特定國家的監管延遲有關。如幻燈片22 所示，我們正在透過正在進行的3 期試驗來擴大我們的多發性骨髓瘤特許經營範圍，該試驗正在評估40 毫克低劑量的selinexor 與成熟的骨幹療法（如泊馬度胺和地塞米松）的組合。

SPd, an all oral combination and evaluated after an anti-CD38 antibody has the potential to benefit a significant number of patients across the multiple myeloma journey. As seen on slide 23, the Phase 3 trials enrolling patients with relapsed refractory multiple myeloma, who have received an anti-CD38 antibody as our most recent therapy.

SPd 是一種全口服組合，並在抗 CD38 抗體後進行評估，有可能使大量多發性骨髓瘤患者受益。如幻燈片 23 所示，3 期試驗招募了復發難治性多發性骨髓瘤患者，他們接受了抗 CD38 抗體作為我們最新的治療方法。

Patients are randomized one-to-one to the oral regimen of selinexor, pomalidomide and dexamethasone or elotuzumab, pomalidomide and dexamethasone. The primary endpoint is progression free survival. The potential approval of this combination could lead to the only all oral potentially T-cell sparing regimen for patients with relapse refractory multiple myeloma, which is gaining increased importance, given the incorporation of T-cell therapies in the multiple myeloma treatment landscape.

患者被一對一隨機分配接受selinexor、泊馬度胺和地塞米鬆或埃羅妥珠單抗、泊馬度胺和地塞米鬆的口服方案。主要終點是無惡化存活期。該組合的潛在批准可能會為復發難治性多發性骨髓瘤患者帶來唯一的全口服潛在T 細胞保留方案，鑑於T 細胞療法納入多發性骨髓瘤治療領域，這一方案變得越來越重要。

As seen on slide 24, we are evaluating the effect of selinexor on the immune environment through preclinical trend relational and real-world data, as well as clinical trials. We recently announced a collaboration with BMS that will evaluate selinexor in combination with mezigdomide a novel CELMoD or cereblon E three ubiquitin ligase modulator in triple class exposed multiple myeloma patients.

如投影片 24 所示，我們正在透過臨床前趨勢關係和真實世界數據以及臨床試驗來評估 selinexor 對免疫環境的影響。我們最近宣布與 BMS 合作，將在三類暴露的多發性骨髓瘤患者中評估 selinexor 與 mezigdomide（一種新型 CELMoD 或 cereblon E 三泛素連接酶調節劑）的組合。

This combination has the potential to reverse T-cell resistance and builds upon the multiple selinexor combinations that have already demonstrated clinical benefit in multiple myeloma. In summary, we have near term late stage opportunities supported by compelling data in our rapidly advancing pipeline that will potentially benefit multiple cancer patient populations of high unmet need building on our approved indications.

該組合具有逆轉 T 細胞抗藥性的潛力，並建立在多種 selinexor 組合的基礎上，這些組合已在多發性骨髓瘤中表現出臨床益處。總而言之，我們在快速推進的管道中擁有令人信服的數據支持的近期後期機會，這將有可能使基於我們批准的適應症的高度未滿足需求的多個癌症患者群體受益。

With that, please turn to slide 25, and I will now hand it over to Sohanya for a review of our commercial performance for this quarter.

接下來，請翻到投影片 25，我現在將其交給 Sohanya，以審查我們本季的商業業績。

Thank you, Reshma, and good morning, everyone. On slide 26, I am pleased to present the progress we have made in our third quarter performance, as we delivered sequential growth in net product revenues over three consecutive quarters in 2023 in an increasingly competitive landscape and amidst high utilization of free drug through our patient assistance program.

謝謝你，瑞詩瑪，大家早安。在幻燈片26 上，我很高興介紹我們在第三季業績中取得的進展，在競爭日益激烈的環境中以及患者對免費藥物的高利用率的情況下，我們在2023 年連續三個季度實現了淨產品收入的環比增長援助計劃。

XPOVIO delivered $30.2 million in net sales in Q3 and when compared to Q3 of last year, net sales was adversely impacted by higher utilization of our patient assistance program due to the impact from Myeloma Foundation closures, as we have previously discussed. In the third quarter, two of the four main multiple myeloma foundations were open and continue to remain open.

XPOVIO 在第三季度實現了3020 萬美元的淨銷售額，與去年第三季度相比，正如我們之前所討論的，由於骨髓瘤基金會關閉的影響，我們的患者援助計劃利用率較高，從而對淨銷售額產生了不利影響。第三季度，四個主要的多發性骨髓瘤基金會中有兩個開放並繼續保持開放狀態。

As a result, new patients entering PAP have largely normalized, although we saw the refill impact of patients already in PAP earlier in the year. Total PAP utilization contributed to 9% of total demand in Q3 2023 versus 4% in Q3 2022. As we mentioned before, in 2024, due to the IRA related changes in the design of Medicare Part C, which will eliminate the patient burden up to 5% beneficiary coinsurance requirement, we expect significantly less need for Medicare Part D patients to utilize path for co-pay assistance.

因此，儘管我們看到了今年早些時候已經進入 PAP 的患者的補充影響，但進入 PAP 的新患者已基本恢復正常。 2023 年第三季度，PAP 總利用率佔總需求的9%，而2022 年第三季為4%。正如我們之前提到的，到2024 年，由於IRA 相關的Medicare C 部分設計發生變化，這將消除最多患者的負擔5% 的受益人共同保險要求，我們預計 Medicare D 部分患者利用共同支付援助途徑的需求將大大減少。

Additionally, net revenue was impacted by two points higher year-over-year gross-to-net in the third quarter, driven by increased Medicaid rebate and 340b discounts. Total demand year-over-year declined 3% when compared to Q3 of last year, which was our strongest quarter thus far. Total demand growth year-over-year for Q3 was negatively impacted by increased competition in the late lines in the academic setting.

此外，在醫療補助回扣和 340b 折扣增加的推動下，第三季淨收入年增了兩個百分點。與去年第三季相比，總需求年減 3%，這是我們迄今為止最強勁的季度。第三季總需求年增率受到學術環境後期競爭加劇的負面影響。

In the earlier line, we continue to make strong progress. In Q3 2023, XPOVIO new patient share mix was greater than 60% in the second to fourth line, which represents approximately 20% growth year-over-year. This shift in mix of patients continues to drive higher refill use as earlier-line patients tend to stay on therapy longer. Furthermore, our opportunity in the earlier line is enhanced by the elevation of XPOVIO in the NCCN guidelines to a category one and now preferred regimen in the lenalidomide refractory patient population in relapsed or refractory multiple myeloma.

在前期工作中，我們持續取得強勁進展。 2023 年第三季度，XPOVIO 在第二至第四線的新病患份額組合超過 60%，較去年同期成長約 20%。患者組合的這種轉變繼續推動補充藥物的使用量增加，因為較早就診的患者往往會接受更長時間的治療。此外，NCCN 指南中將 XPOVIO 提升為一類，目前是複發或難治性多發性骨髓瘤來那度胺難治性患者群體的首選方案，從而增強了我們在早期產品線中的機會。

This is meaningful in guiding treatment choices for physicians, particularly in the community as a patients progressing from regimens like, the Darzalex Revlimid Dexamethasone combination. In addition, new subgroup data was presented at the European Hematological Association from our Phase 3 BOSTON study, which showed that patients that are PI-naive are not previously exposed to a proteosome inhibitor and that are treated with XVD showed an approximately tripling of PFS, up 29.5 months versus the control arm VD of 9.7 months with a hazard ratio of 0.29.

這對於指導醫生的治療選擇具有重要意義，特別是在社區中，作為從 Darzalex Revlimid 地塞米松組合等治療方案中取得進展的患者。此外，歐洲血液學協會也向歐洲血液學協會提交了我們3 期BOSTON 研究的新亞組數據，該數據表明未接受過PI 治療的患者之前未接觸過蛋白酶體抑製劑，並且接受XVD 治療的患者的PFS 大約提高了三倍，與對照組 VD 9.7 個月相比，延長了 29.5 個月，風險比為 0.29。

Patients are increasingly treated with PI free regimens like the Darzalex Revlimid Dexamethasone combination in the frontline, which constitutes up to about 10% of frontline patients with this segment growing over time. At multiple myeloma patients are living longer with the emergence of new classes of therapy, XPOVIO represents an opportunity for these patients to be treated with an effective and novel class of therapy earlier in their treatment journey and allow for potential sequencing in the future with other classes of therapies.

越來越多的患者在一線接受無 PI 方案的治療，例如 Darzalex Revlimid 地塞米松組合，佔第一線患者的約 10%，並且隨著時間的推移，這群人不斷增長。隨著新療法的出現，多發性骨髓瘤患者的壽命越來越長，XPOVIO 為這些患者提供了一個機會，讓他們可以在治療過程的早期接受有效且新穎的療法，並允許將來與其他類別進行潛在的測序的療法。

Our commercialization team is laser focused on sharing our new data, guideline updates and leveraging the experience of our broad base of physicians that have used XPOVIO to drive further use and in earlier lines. All amidst and intensifying competitive landscape in the late lines. We reaffirm our US XPOVIO net revenue guidance of $110 million to $125 million in 2023.

我們的商業化團隊專注於分享我們的新數據、指南更新，並利用我們廣泛的醫生基礎的經驗，這些醫生已經使用 XPOVIO 來推動進一步的使用和早期的使用。一切都處於後期競爭格局的加劇之中。我們重申 2023 年美國 XPOVIO 淨收入指引為 1.1 億至 1.25 億美元。

Let's now turn to Slide 27 to review how we are distinctly positioning XPOVIO in the community and academic settings in an evolving landscape. In the community setting, while we do see competitive pressures in the late-line with some larger accounts, the majority of physicians in the community tend to treat earlier-line patients and are looking for agents that are effective, manageable and convenient.

現在讓我們轉向幻燈片 27，回顧我們如何在不斷發展的環境中在社區和學術環境中明確定位 XPOVIO。在社區環境中，雖然我們確實看到一些較大客戶的後線競爭壓力，但社區中的大多數醫生傾向於治療較早的患者，並正在尋找有效、可管理和方便的藥物。

We believe XPOVIO as a novel class that is an effective, manageable, easily combinable and a convenient oral therapy fit the needs of the community well. Furthermore, the NCCN has recently updated their guidelines to recommend switching classes of therapy that patients have not been exposed to previously versus recycling the anti CD-38 class, which occurs frequently in the community.

我們相信 XPOVIO 作為一種新穎的類別，是一種有效、易於管理、易於組合且方便的口服療法，非常適合社區的需求。此外，NCCN 最近更新了其指南，建議更換患者以前未接觸過的治療類別，而不是重複使用社區中經常發生的抗 CD-38 類別。

This update, combined with the elevation of XPOVIO in the NCCN guidelines, highlights the importance of changing the mechanism of action with a novel class like XPOVIO. A highly compelling new PI-naive, subgroup data further strengthens our positioning in the community in the second to fourth line. In the academic setting, where we are seeing the impact of competition from new approvals, including T-cell therapies, we continue to build the body of evidence to demonstrate how XPOVIO may be used as an optimal therapy with a novel mechanism of action pre or post T-cell therapies.

此次更新，結合 NCCN 指南中 XPOVIO 的提升，強調了用 XPOVIO 這樣的新型類改變作用機制的重要性。非常引人注目的新 PI 樸素亞組數據進一步加強了我們在第二至第四線社區中的定位。在學術環境中，我們看到了新批准（包括 T 細胞療法）競爭的影響，我們繼續建立大量證據來證明 XPOVIO 如何作為一種具有新穎作用機制的最佳治療方法T細胞療法後。

Also the opportunity to launch SPd, when approved at the lower dose of 40 milligrams could lead to the only all oral and potentially T-cell sparing regimen. In Q4, we remain focused on entrenching XPOVIO in the community, which represents about 60% of our business and driving earlier line growth. While we expect further intensification of the competitive landscape in the later lines.

此外，當以 40 毫克的較低劑量獲得批准時，推出 SPd 的機會可能會導致唯一的全口服和潛在的 T 細胞保留方案。在第四季度，我們仍然專注於鞏固 XPOVIO 在社群中的地位，該社群約占我們業務的 60%，並推動早期產品線的成長。但我們預期後期的競爭格局將進一步加劇。

In the mid to long term, we believe that the potential approval of SPd and further data generation around the T-cell fitness space with novel combination could unlock further benefit for myeloma patients with XPOVIO. Furthermore, Karyopharm has a tremendous opportunity for growth across multiple indications in the future, and we look forward to leveraging our strong commercialization team and capabilities and our deep relationships in the community and centers of excellence for these launches.

從中長期來看，我們相信 SPd 的潛在批准以及圍繞 T 細胞健康空間的新組合的進一步數據生成可以為 XPOVIO 的骨髓瘤患者帶來進一步的益處。此外，Karyopharm 未來在多個適應症方面擁有巨大的成長機會，我們期待利用我們強大的商業化團隊和能力以及我們在社區和卓越中心的深厚關係來完成這些發布。

These advance now to slide 28, and I will turn the call over to Mike.

這些現在前進到幻燈片 28，我將把電話轉給麥克。

Thank you, Sohanya. During 2023, we have further reduced our cost structure to focus resources on our pivotal Phase 3 trials, and in August, we reduced our workforce by approximately 20%, including contractors. These steps, further strengthen our financial position to invest in our three ongoing Phase 3 studies with top line data readouts expected within our cash runway.

謝謝你，索哈妮亞。 2023 年，我們進一步降低了成本結構，將資源集中在關鍵的第 3 階段試驗上，8 月份，我們減少了約 20% 的勞動力，其中包括承包商。這些步驟進一步加強了我們的財務狀況，以投資我們正在進行的三項第三階段研究，並預計在我們的現金跑道內公佈頂線數據。

Now on slide 29, I will focus on the quarter's financial highlights. Total revenue for the third quarter of 2023 was $36 million compared to $36.1 million for the third quarter of 2022. Net product revenue from US commercials of XPOVIO for third quarter of 2023 was $30.2 million compared to $32 million for the third quarter of 2022.

現在，在投影片 29 上，我將重點介紹本季的財務亮點。 2023 年第三季的總營收為3,600 萬美元，而2022 年第三季為3,610 萬美元。2023 年第三季XPOVIO 美國廣告的產品淨收入為3,020 萬美元，而2022 年第三季為3,200 萬美元。

As Sohania discussed, net product revenue continued to be adversely affected by more patients using our patient assistance program, as well as higher gross-to-net discounts. Gross-to-net discounts were 20% in the third quarter of 2023 as compared to 18% in the third quarter of 2022. Turning to cost, with our continued focus on cost management, we are pleased to be delivering a combined 12% year-over-year reduction in our R&D and SG&A expenses for the nine months ended September 30, 2023.

正如 Sohania 所討論的，產品淨收入繼續受到更多患者使用我們的患者援助計劃以及更高的毛淨折扣的不利影響。 2023 年第三季的毛淨折扣為 20%，而 2022 年第三季為 18%。談到成本，隨著我們繼續關注成本管理，我們很高興實現全年 12% 的綜合折扣-截至2023 年9 月30 日的九個月，我們的研發和銷售、一般管理費用年減。

R&D expenses for the third quarter of 2023 were $35.6 million compared to $31.4 million for the third quarter of 2022. We expect fourth quarter 2023, R&D expenses to be relatively consistent to the third quarter, as we continue to invest in our three ongoing Phase 3 studies with each representing a large addressable market with unmet patient needs.

2023 年第三季的研發費用為3,560 萬美元，而2022 年第三季為3,140 萬美元。我們預計2023 年第四季的研發費用將與第三季相對一致，因為我們將繼續投資正在進行的三個第三階段項目每項研究都代表了一個巨大的潛在市場，但患者的需求尚未得到滿足。

We have reduced SG&A expenses in the third quarter of 2023 by 12% at $30.8 million compared to $34.6 million for the third quarter of 2022. Cash, cash equivalents, restricted cash and investments as of September 30, 2023, total $209.2 million compared to $279.7 million as of December 31, 2022. Based on our current operating plans, we are reaffirming revenue guidance for the full year of 2023 as follows.

我們將2023 年第三季的銷售管理及行政費用減少了12%，達到3,080 萬美元，而2022 年第三季為3,460 萬美元。截至2023 年9 月30 日，現金、現金等價物、限制性現金和投資總額為2.092 億美元，而2022 年第三季為279.7 美元截至 2022 年 12 月 31 日，我們的收入為 100 萬。根據我們目前的營運計劃，我們重申 2023 年全年的收入指引如下。

Total revenue expected to be in the range of $145 million to $160 million. XPOVIO net US product revenue is expected to be in the range of $110 million to $125 million. We are also reaffirming our expense guidance for the full year of 2023 as follows.

總收入預計在 1.45 億美元至 1.6 億美元之間。 XPOVIO 美國產品淨收入預計介於 1.1 億至 1.25 億美元之間。我們也重申 2023 年全年的費用指引如下。

Non-GAAP R&D and SG&A expenses, which exclude stock-based compensation expense is expected to be in the range of $240 million to $255 million. And importantly, coming to our cash guidance, our existing cash, cash equivalents and investments, as well as the revenue, we expect to generate from our XPOVIO product sales and other license revenues will be sufficient to fund our planned operations through late 2025, excluding maturity of our convertible bonds in October 2025.

非 GAAP 研發和 SG&A 費用（不包括基於股票的薪酬費用）預計將在 2.4 億至 2.55 億美元之間。重要的是，根據我們的現金指導，我們現有的現金、現金等價物和投資以及收入，我們預計從XPOVIO 產品銷售和其他許可收入中獲得的收入將足以為我們到2025 年底的計劃運營提供資金，不包括我們的可轉換債券將於 2025 年 10 月到期。

I will now turn to slide 13 and some final thoughts from Richard.

我現在將轉向幻燈片 13 以及理查德的一些最後的想法。

Thank you, Mike. Turning to Slide 31. As we have discussed today, we are rapidly advancing our pipeline, concentrating our investments in three Phase 3 programs that are expected to read out through '24 and '25, as we work to create near and long-term value for all our stakeholders. We are well prepared for the next stage of growth, as we continue to expand on our foundation and multiple myeloma with our proven commercialization and late stage development capabilities.

謝謝你，麥克。轉向幻燈片31。正如我們今天所討論的，我們正在快速推進我們的管道，將我們的投資集中在三個第3 階段項目上，這些項目預計將在“24”和“25”期間實施，同時我們致力於創造近期和長期價值為了我們所有的利害關係人。我們已為下一階段的成長做好了充分準備，我們將憑藉成熟的商業化和後期開發能力，繼續擴大我們的基礎和多發性骨髓瘤。

I would like to thank our teams who continue to execute in a disciplined manner and who strive each day for patients with high unmet needs. 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

我要感謝我們的團隊，他們繼續以嚴格的方式執行任務，並每天為有高度未滿足需求的患者而努力。再次感謝您今天加入我們。我現在想請接線生打開今天通話的問答部分，接線員

We will now begin the question and answer session. (Operator Instructions)

我們現在開始問答環節。 （操作員說明）

Peter Lawson, Barclays.

彼得·勞森，巴克萊銀行。

Good morning, This is [Sharon] Peter, thanks for taking our question. Congratulations on the new MF data and help today maybe contextualize for us, as we think about getting in that top line data from Phase 3 in 2025, maybe with the more appropriate bar is to be looking at rather than just check inhibitor monotherapy?

早安，我是[莎倫]彼得，感謝您提出我們的問題。恭喜新的 MF 數據，今天的幫助可能會為我們提供背景信息，當我們考慮在 2025 年獲得第 3 階段的頂線數據時，也許更合適的標準是關注而不是僅僅檢查抑製劑單一療法？

And then secondly, just a quick add-on questions for selinexor and MMS, I believe, we are potentially going to get an update on development plans here. Is that still on track for something we could learn about more in this quarter versus something we should be thinking as de-prioritized (inaudible) Karyopharm at this point? Thank you.

其次，關於 selinexor 和 MMS 的快速附加問題，我相信，我們可能會在這裡獲得有關開發計劃的最新資訊。與我們目前應該考慮取消優先事項（聽不清楚）的 Karyopharm 相比，這是否仍然是我們在本季度可以了解更多的東西？謝謝。

I appreciate your question, I will turn Reshma for that, Reshma

我很感激你的問題，我會為此轉向雷什瑪，雷什瑪

Thank you, [Sharon]. A lot of excitement around the new MF data that we are presenting today at the NPN Congress in New York, it only builds upon the impressive efficacy that we see with the combination of selinexor and ruxolitinib in this JAKi naive patient population.

謝謝你，[莎倫]。我們今天在紐約 NPN 大會上展示的新 MF 數據令人興奮，它只是建立在我們在未經 JAKi 治療的患者群體中使用 selinexor 和 ruxolitinib 組合所取得的令人印象深刻的療效的基礎上。

As you mentioned, we have already presented data at week 24 for both SVR, as well as TSS50, 79% SVR rate, it was 58% TSS50 rate. What patients and physicians really want to know is that how long are those SVR and TSS data response is going to last, and that's the durability data that we are presenting today, what you see is a very impressive durability for both of these endpoints.

正如您所提到的，我們已經在第 24 週提供了 SVR 和 TSS50 的數據，SVR 率為 79%，TSS50 率為 58%。患者和醫生真正想知道的是，這些 SVR 和 TSS 數據響應將持續多久，這就是我們今天展示的耐久性數據，您看到的是這兩個端點的非常令人印象深刻的耐久性。

In fact, as of the data cut-off of August 1st, none of the patients experienced radiographic progression for, either SVR or TSS50 would again just builds upon the body of evidence that really suggest that this combination could be a game changer for patients, who are JAKi naive myelofibrosis and will continue to evaluate this as part of our Phase 3 study.

事實上，截至 8 月 1 日數據截止，沒有任何患者經歷放射學進展，無論是 SVR 還是 TSS50 都只是建立在大量證據的基礎上，真正表明這種組合可能會改變患者的遊戲規則，他們是JAKi幼稚骨髓纖維化患者，並將繼續對此進行評估，作為我們3 期研究的一部分。

Right now, the focus is very much on SVR, TSS50 at week 24, but as you mentioned, we will continue to look at durability, as well as multiple other efficacy endpoints that are relevant to this patient population. In regards to your question about the appropriate comparator, it still remains ruxolitinib. So, ruxolitinib is the standard of care for patients who are JAKi naive myelofibrosis, who have platelet counts above 100.

目前，重點主要放在第 24 週的 SVR、TSS50，但正如您所提到的，我們將繼續關注耐久性以及與該患者群體相關的多個其他療效終點。關於您關於合適的比較藥物的問題，仍然是魯索替尼。因此，魯索替尼是血小板計數高於 100 的 JAKi 初治性骨髓纖維化患者的標準治療方法。

So, the study design is appropriate and evaluates again, the efficacy with this combination relative to the current standard of care. In terms of your question about selexinor, great question, I am very enthusiastic about those data as well, specifically observed from the Phase 1, Phase 2 study. We have been evaluating our selexinor and a very hard to treat patient population, specifically relapse refractory, higher risk MDS patients.

因此，研究設計是適當的，並再次評估了這種組合相對於當前護理標準的療效。關於你關於 selexinor 的問題，很好的問題，我也對這些數據非常感興趣，特別是從第一階段、第二階段研究中觀察到的數據。我們一直在評估我們的 sexinor 和非常難以治療的患者群體，特別是復發難治性、高風險 MDS 患者。

Overall survival is very poor in this patient population around four to six months. And as, we have disclosed previously, the survival that we have seen as part of both the Phase 1 and Phase 2 are very encouraging, right? 9 month to 10 month median overall survival. We are in the process of optimizing our next steps in this program and look forward to updating everybody probably around the Q4 call.

該患者族群的總存活期非常差，約四到六個月。正如我們之前所揭露的，我們在第一階段和第二階段看到的生存情況非常令人鼓舞，對吧？ 9 個月至 10 個月的中位總存活期。我們正在優化該計劃的後續步驟，並期待在第四季度電話會議期間向大家通報最新情況。

Was there a follow-up, ma'am?

女士，有後續嗎？

That's it. Thanks so much.

就是這樣。非常感謝。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特，傑弗里斯。

Hi, good morning. Congrats on the progress, and thanks for taking my questions. I was going to ask one on endometrios, so for selinexor as maintenance and endometrial, when do you think you could show the initial overall survival data from the C&O Phase 3 study? And then also separately, how is the export Phase 3 in the TP53 wild-type patients enrolling? And you have a sense of how many patients are getting anti-PD-1 therapy with chemo upfront, if you can provide any perspective on that?

早安.恭喜您的進展，並感謝您提出我的問題。我本來想問一個關於子宮內膜的問題，那麼對於作為維持和子宮內膜的 selinexor，您認為什麼時候可以顯示 C&O 3 期研究的初始總體生存數據？另外，TP53 野生型患者的出口 3 期招募情形如何？您知道有多少患者正在接受預先化療的抗 PD-1 治療，您能否對此提供任何看法？

Great question, Maury. So, as you know, so we continue to follow overall survival. We are very excited. We are going to be presenting overall survival data for the first time from the C&O trials physically from the P53 wild-type subgroup later this year. So, more to come in the next couple of months. Obviously a key endpoint in addition to the progression free survival for more to come over there.

好問題，莫里。所以，如您所知，我們繼續關注整體存活率。我們非常興奮。我們將在今年稍後首次提供 P53 野生型亞組的 C&O 試驗的整體存活數據。因此，接下來的幾個月還會有更多的事情發生。顯然，除了無惡化存活期之外，還有更多的關鍵終點。

In terms of the question around the PD-1 inhibitors in combination with chemotherapy. So, there is a new standard, as I mentioned on the call, it is just starlimab in combination with chemotherapy, followed by the starlimab maintenance. Keep in mind that the approval is only for patients, who are MMR deficient. So, they represent the minority of patients at only 20%.

關於PD-1抑制劑與化療合併的問題。所以，有一個新的標準，正如我在電話會議中提到的，它只是starlimab與化療結合，然後是starlimab維持。請記住，該批准僅適用於 MMR 缺陷的患者。因此，他們只佔患者的少數，僅佔 20%。

The remaining patients who are pMMR proficient in their MMR, as well as TP53 do not have a new standard of care, continues to remain chemotherapy, followed by watch and wait.

其餘的 pMMR 和 TP53 熟練的患者沒有新的護理標準，繼續保持化療，然後觀察和等待。

Got it. That's helpful. And any other perspective into enrollment and how that's going. And then also, wanted to ask a separate question on multiple myeloma commercial. You said there were approximately 20%, there is 20% year-over-year growth in second line to fourth line new starts. Can you give us some color on how refill rates have evolved, specifically in these earlier-line patients versus when you were just in the later line setting?

知道了。這很有幫助。以及對入學情況以及進展的任何其他看法。然後，我想就多發性骨髓瘤廣告提出一個單獨的問題。你說大約有20%，二線到四線的新開工量年增了20%。您能否向我們介紹一下補充率的變化情況，特別是在這些早期第一線患者與您剛剛處於後期一線的患者中？

Maybe, I will turn it over to Reshma, just to follow up on the trial question and Sohania on the progress in multiple myeloma, Reshma?

也許，我會把它交給 Reshma，只是為了跟進試驗問題和 Sohania 多發性骨髓瘤的進展，Reshma？

Yes, thank you. So, enrollment is going well, there is a lot in largely, that's due from the enthusiasm around these data and I think that was highlighted most recently, (inaudible) Couple of weeks ago in Spain, a lot of enthusiasm largely because, the benefit that we are demonstrating is, again in the high unmet need patient population that doesn't have a new standard of care, that is translating to activation in sites and enrollment on to our clinical trials.

是的，謝謝。因此，入學進展順利，很大程度上是由於對這些數據的熱情，我認為最近強調了這一點，（聽不清楚）幾週前在西班牙，人們熱情高漲，主要是因為，我們正在證明的是，在沒有新的護理標準的高未滿足需求的患者群體中，這正在轉化為站點的激活和我們臨床試驗的註冊。

We in fact, have 70 plus sites that are already active and enrolling patients onto the study. So, the study is going, it's proceeding quite nicely.

事實上，我們有 70 多個站點已經活躍並正在招募患者參加研究。所以，研究正在進行中，進展順利。

Sohanya?

索漢亞？

I can address the question around the 20% year-over-year growth. So, when you look at our mix of XPOVIO new starts, over 60% of that is in the second to fourth line, which represents in Q3 year-over-year, a 20% growth. Now, the shift into earlier lines, as you pointed out is a huge growth driver for us. Primarily because of the benefit of duration that we see.

我可以回答關於 20% 年成長的問題。因此，當您查看我們的 XPOVIO 新產品組合時，您會發現其中超過 60% 位於第二至第四線，這意味著第三季度同比增長了 20%。現在，正如您所指出的，向早期生產線的轉變對我們來說是一個巨大的成長動力。主要是因為我們看到了持續時間的好處。

Now, as we think about duration of therapy data, as we have discussed previously, the data can be choppy takes time to mature, but as we triangulate multiple data sources, we are seeing a nice upward trend in our duration of therapy and refills and this is largely driven by this increasing patients on the earlier lines and also better management of patients on the lower dose and supportive care.

現在，當我們考慮治療數據的持續時間時，正如我們之前討論的那樣，數據可能會不穩定，需要時間才能成熟，但當我們對多個數據源進行三角測量時，我們看到治療持續時間和補充量呈現良好的上升趨勢，這主要是由於早期第一線患者的增加以及較低劑量和支持性護理對患者的更好管理所致。

Got it. That's helpful. Thanks for taking my questions.

知道了。這很有幫助。感謝您回答我的問題。

Thanks, Maury.

謝謝，莫里。

(Operator Instructions) Colleen Kusy, Baird.

（操作員說明）Colleen Kusy，Baird。

Great. Thanks, good morning and thanks for taking our questions. First one on a multiple myeloma, with the elevation of the NCCN guideline recommendation for XVd to Category 1, can you help us understand how much of a tailwind that could be through the end of the year? And then I will follow.

偉大的。謝謝，早安，謝謝您提出我們的問題。第一個關於多發性骨髓瘤的問題，隨著 NCCN 指南對 XVd 的建議提升至 1 類，您能否幫助我們了解到今年年底可能會有多大的推動力？然後我會跟隨。

So, as we think about the evolving competitive landscape in multiple myeloma, XPOVIO has become established as a foundational mechanism. Now this elevation from XPOVIO, from category 1, which used to be other recommended regimens to now category 1 and preferred regimens is meaningful, particularly in the community setting, where it's a large driver of treatment decisions.

因此，當我們考慮多發性骨髓瘤不斷變化的競爭格局時，XPOVIO 已成為一種基本機制。現在，XPOVIO 從 1 類（曾經是其他推薦方案）提升到現在的 1 類和首選方案是有意義的，特別是在社區環境中，它是治療決策的重要驅動因素。

So, notably, the NCCN guidelines made two updates that were favorable for XPOVIO, as I mentioned, one was recommending class switching, again supports a novel class of therapy like XPOVIO, as well as the elevation of XPOVIO [velcade] Dex into the category 1 and preferred status. In terms of impact, we are not going to see an impact overnight.

因此，值得注意的是，NCCN 指南做出了兩項有利於XPOVIO 的更新，正如我所提到的，其中一項是建議轉換類別，再次支持XPOVIO 等新型療法，以及將XPOVIO [velcade] Dex 提升到該類別1、優先地位。就影響而言，我們不會在一夜之間看到影響。

However, with multiple myeloma, it is an area that is highly promotionally sensitive, and we see steady growth over time. So, we are excited that our field team is now able to actively promote this update today and moving forward. And we believe this strengthens our position in the community and in the earlier lines.

然而，對於多發性骨髓瘤，這是一個宣傳高度敏感的領域，我們看到隨著時間的推移穩步增長。因此，我們很高興我們的現場團隊現在能夠積極推動這項更新並繼續前進。我們相信這會加強我們在社區和早期產品線中的地位。

That's helpful. Thank you. And then for endometrial, given the evolution of the treatment landscape with starlumab and dMMR and you are really encouraging results in pMMR, have you pre-specified any sort of analysis in this PMM, TP53 wild-type patient population for the ongoing Phase 3 study?

這很有幫助。謝謝。然後對於子宮內膜，考慮到starlumab 和dMMR 治療前景的演變，並且pMMR 的結果確實令人鼓舞，您是否為正在進行的3 期研究預先指定了對這個PMM、TP53 野生型患者群體的任何類型的分析？

Yes, it's a great question, Colleen. Similar to C&O in which we had, endpoint looking specifically at the dMMR versus pMMR will continue to do that in our ongoing Phase 3 as well. It's not a stratification factor. We assume that the vast majority of patients are going to be MMR proficient, given the fact that they represent 80%, that will ensure balanced likely, but again, we will be looking, specifically at the efficacy across these two MMR subgroup.

是的，這是一個很好的問題，科琳。與我們的 C&O 類似，專門關注 dMMR 與 pMMR 的端點將在我們正在進行的第 3 階段中繼續這樣做。這不是分層因素。我們假設絕大多數患者將精通 MMR，因為他們佔 80%，這將確保可能的平衡，但我們將再次特別關注這兩個 MMR 亞組的療效。

Great. Thanks for taking our questions.

偉大的。感謝您回答我們的問題。

Eric Joseph, JPMorgan.

艾瑞克‧約瑟夫，摩根大通。

Thanks to your question. This is (inaudible) Eric. A quick one from. I was just on the combination with the BMS, just know that goes on what the rationale there in terms of the combination of selinexor?

謝謝你的提問。這是（聽不清楚）艾瑞克。快速的一個。我剛剛與BMS結合，只知道selinexor結合的理由是什麼？

Yes, absolutely. Great question. We are really, really excited about this novel combination. Just to give you a little bit of insight, right? this combination was pushed for some of our key KOLs coming out of Dana Farber Cancer Institute, specifically, Paul Richardson, he just thought that this builds upon the number of combinations of selinexor has already shown remarkable efficacy in patients with multiple myeloma.

是的，一點沒錯。很好的問題。我們對這種新穎的組合感到非常非常興奮。只是為了給你一點洞察力，對嗎？這種組合是由來自Dana Farber 癌症研究所的一些關鍵KOL 推動的，特別是Paul Richardson，他只是認為這種建立在selinexor 組合數量的基礎上，已經在多發性骨髓瘤患者中顯示出顯著的療效。

The other aspect that is intriguing to him and also, BMS and, of course, us, is the fact that both of these drugs XPO1 inhibition with selinexor, as well as this novel CELMoD mezigdomide has individually and potentially in combination shown that it can reverse T-cell resistance.

令他、BMS，當然還有我們感興趣的另一個方面是，這兩種藥物對 XPO1 的抑制與 selinexor 以及這種新型 CELMoD mezigdomide 單獨和潛在的組合顯示，它可以逆轉T細胞抵抗。

And this concept piece of resistance is, of course, becoming more and more important for multiple myeloma treaters, given the fact that they are now introducing T-cell therapies into the multiple myeloma arsenal, this novel combination potentially give them a really important tool to help with sequencing of these therapies for their multiple myeloma patients.

當然，這種抗藥性的概念對於多發性骨髓瘤治療者來說變得越來越重要，因為他們現在正在將T 細胞療法引入多發性骨髓瘤庫中，這種新穎的組合可能為他們提供一個非常重要的工具幫助多發性骨髓瘤患者對這些療法進行排序。

That's helpful. Thank you. And I just wanted on your mind quickly on the patient assistance program, and I kind of see the impact of these foundation closures going forwards and then kind of a medical on T-design might be affecting us in 2024?

這很有幫助。謝謝。我只是想讓你們盡快了解病患援助計劃，我有點看到這些基金會關閉對未來的影響，然後 T 型設計的醫療可能會在 2024 年影響我們？

Yes. Thank you for the question. I can take that. So, in terms of path, as we know, we saw an increase utilization of path of free drug this year due to foundation closures now, year-to-date through Q3, the impact of path has been roughly $5 million to $6 million, which includes about a $1million to $2 million PAP impact in Q3.

是的。感謝你的提問。我可以接受。因此，就路徑而言，正如我們所知，由於現在基金會關閉，今年迄今為止，到第三季度，我們看到免費藥物路徑的利用率有所增加，路徑的影響約為500 萬至600 萬美元，其中包括第三季約 100 萬至 200 萬美元的 PAP 影響。

Now in Q3, there were two of the foundations that were open and we as a result saw new patient starts in PAP normalize, but the refill impact remained. Now in Q4, these two of the four foundations remain open to date, and we anticipate the PAP impact being very similar in Q4, as it was in Q3 assuming the foundation dynamic does not change.

現在在第三季度，有兩個基金會開放，因此我們看到新患者的 PAP 開始正常化，但補充影響仍然存在。現在在第四季度，四個基金會中的這兩個仍然開放，我們預計 PAP 的影響在第四季度非常相似，與第三季度的影響非常相似，假設基金會的動態沒有改變。

Now, as we move forward into 2024, where we are encouraged by the IRA related change to the design of the Medicare Part D, which eliminates the patient burden of the 5% beneficiary coinsurance requirement, and we expect, therefore, significantly less need for these patients to utilize our patient assistance program for co-pay assistance.

現在，隨著我們邁入2024 年，我們對IRA 相關的醫療保險D 部分設計變更感到鼓舞，該變更消除了5% 受益人共同保險要求的患者負擔，因此我們預計，對醫療保險D 部分的需求將大大減少這些患者利用我們的患者援助計劃獲得共同支付援助。

Great. Thanks for taking questions.

偉大的。感謝您提出問題。

(Operator Instructions). This concludes our question and answer session. I would like to turn the conference back over to Richard Paulson for any closing remarks.

（操作員說明）。我們的問答環節到此結束。我想將會議轉回理查德·保爾森（Richard Paulson）發表閉幕詞。

Thank you, operator, and thank you, everyone, for joining us today. As we mentioned, we are well prepared for the next stage of growth, as we continue to expand on our foundation of multiple myeloma with our proven commercialization late stage development capabilities and, as we continue to rapidly advance our pipeline, concentrating investments in our three Phase 3 programs that are expected to read out through '24 and '25, as we work to create near and long-term value for all stakeholders. Thanks for joining and have a wonderful day.

謝謝運營商，也謝謝大家今天加入我們。正如我們所提到的，我們已為下一階段的成長做好了充分準備，我們將憑藉成熟的商業化後期開發能力，繼續擴大多發性骨髓瘤的基礎，並繼續快速推進我們的產品線，集中投資於我們的三個領域第三階段計劃預計將在 24 年和 25 年期間實施，我們致力於為所有利益相關者創造近期和長期價值。感謝您的加入，祝您有個愉快的一天。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連線。