This phase I trial tests the safety, side effects, and best dose of eltanexor in combination with venetoclax for the treatment of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Eltanexor works by trapping "tumor suppressing proteins" within the cell, thus causing the cancer cells to die or stop growing. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving eltanexor together with venetoclax may be safe, tolerable and/or effective in treating patients with relapsed or refractory MDS or AML.

Start Date30 Sep 2024

Sponsor / Collaborator

The Vanderbilt-Ingram Cancer Center

[+2]

NCT05918055 / RecruitingPhase 1/2IIT

A Phase I/II Trial of Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes

Background:
Myelodysplastic syndromes (MDS) are diseases that affect the bone marrow. They can inhibit the blood formation process and reduce blood cell counts. High-risk MDS can lead to leukemia. People with high-risk MDS have a low survival rate. Better treatments are needed.
Objective:
To test a study drug (KPT-8602), combined with another drug (Inqovi), in people with MDS.
Eligibility:
Adults aged 18 years and older with high-risk MDS that did not respond to treatment.
Design:
Participants will be screened. They will have a physical exam. They will have blood and urine tests and tests of their heart function. They may have a bone marrow biopsy: Their hip will be numbed; then a needle will be inserted to draw out a sample of soft tissue from inside the bone. They will answer questions about their quality of life. Genetic tests may be performed.
KPT-8602 and Inqovi are both tablets taken by mouth. Participants will take these drugs at home on a 28-day cycle. They will take Inqovi once a day on days 1 to 5. They will take KPT-8602 on a schedule assigned by the researcher. Participants will be given a drug diary to record each dose.
Participants will visit the clinic for an exam at least once in each cycle. Some tests, including the bone marrow biopsy, may be repeated.
Participant will continue treatment for at least 6 cycles. If their disease improves, they may continue taking the drugs after 6 cycles.
Participants will have follow-up visits at the clinic for about 8 years.

Start Date14 Nov 2023

Sponsor / Collaborator

National Cancer Institute

EUCTR2021-003810-38-IT / Not yet recruitingPhase 1/2

Phase 1/2 Open-Label Study of the Safety, Tolerability and Efficacy of the Selective Inhibitor of Nuclear Export (SINE) Compound Eltanexor (KPT-8602) in Patients with Newly Diagnosed and Relapsed/Refractory Cancer Indications - Phase 1/2 Open-Label Study of Eltanexor in Patients with high risk nonresponsive MDS

Start Date30 Aug 2022

Sponsor / Collaborator

Karyopharm Therapeutics, Inc.

100 Clinical Results associated with Eltanexor

100 Translational Medicine associated with Eltanexor

100 Patents (Medical) associated with Eltanexor

Literatures (Medical) associated with Eltanexor

01 Sep 2024·Leukemia

Altered RNA export by SF3B1 mutants confers sensitivity to nuclear export inhibition

Article

Author: Chirino, Alexandra ; Sondhi, Anya K ; Nicholls, Miah ; Taylor, Justin ; Tamiro, Francesco ; Chaudhry, Sana ; Nimer, Stephen D ; Robayo, Paola ; Wang, Eric ; Cornista, Alyssa Mauri ; Montoya, Skye ; Rodríguez, Jose Antonio ; Totiger, Tulasigeri M ; Jasdanwala, Shaista Shabbir ; Lawal, Abimbola Eunice ; Bhatt, Shruti ; Afaghani, Jumana ; Adams, Andrew ; Beckedorff, Felipe ; Tonini, Olivia ; Bilbao, Daniel ; Affer, Maurizio ; Noudali, Stephen

AbstractSF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using Sf3b1K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS.

29 Oct 2023·Scientific reports

The synergy of the XPO1 inhibitors combined with the BET inhibitor INCB057643 in high-grade B-cell lymphoma via downregulation of MYC expression.

Article

Author: Zhao, Haijun ; Fang, Xiaosheng ; Tan, Jinshui ; Xu, Bing ; Zhu, Feng ; Young, Kenh ; Deng, Manman ; Pham, Lan V ; Fan, Ziying

High grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH) represents an uncommon B-cell lymphoma (BCL) with aggressive clinical courses and poor prognosis. Despite revolutionary therapeutic advances in BCL, there has been limited treatment progress in HGBCL-DH, thus necessitating additional therapeutic strategies for HGBCL-DH. This study demonstrated that the BET antagonist INCB057643 synergized with the XPO1 inhibitors (selinexor and eltanexor) to decrease cell viability and increase cell apoptosis in HGBCL-DH cells with or without TP53 mutations. As anticipated, the combined treatment of INCB057643 with selinexor slowed tumor growth and reduced the tumor burden in TP53-mutated HGBCL-DH xenografts. Mechanistically, MYC functional inhibition was a potential molecular mechanism underlying the synergy of the combined INCB057643 and selinexor treatment in HGBCL-DH cells independent of TP53 mutation status. In TP53 mutated HGBCL-DH cells, inducing DNA damage and impairing the DNA damage response (DDR) were involved in the therapeutic interaction of the combined regimen. In TP53 wild-type cells, the molecular mechanism was linked with upregulation of p53 levels and activation of its targeted pathways, rather than dysregulation of the DDR. Collectively, we might provide a potential promising combination therapy regimen for the management of HGBCL-DH. Clinical evaluations are warranted to confirm this conclusion.

01 Sep 2023·Cell biochemistry and biophysics

Nuclear Export Inhibitors Selinexor (KPT-330) and Eltanexor (KPT-8602) Provide a Novel Therapy to Reduce Tumor Growth by Induction of PANoptosis.

Review

Author: Lockey, Richard ; Camilli, Samuel ; Kolliputi, Narasaiah

Programmed cell death (PCD) is a process that occurs naturally in cells in response to different endogenous or exogenous factors and facilitated by specific proteins. The three common pathways are pyroptosis, necroptosis, and apoptosis. Each pathway has its own unique proteins, mechanisms, and byproducts. Dysregulated PCD can lead to abnormal growth of cells causing tumor growth, a hallmark feature of many cancer pathologies. Recently, the PCD pathways have been considered to be activated simultaneously in a combined nature defined as PANoptosis (pyroptosis, apoptosis, and necroptosis). An integral protein, Z-DNA binding protein 1 (ZBP1) aids in the initiation of the NOD-like receptor protein 3 (NLRP3) inflammasome, a known facilitator of pyroptosis. It also is known to bind to a regulator of necroptosis, receptor-interacting protein kinase 3 (RIPK3). A unique binding partner to ZBP1, adenosine deaminase acting on RNA 1 (ADAR1), is involved in RNA editing, stress mechanisms, and disease. In murine bone marrow-derived macrophages (BMDMs) treatment with nuclear export inhibitors (NEIs) has allowed for sequestering of ADAR1 to the nucleus, and increased incidence of cell death. Additionally, the use of interferons (IFNs) to induce ZBP1 has increased the incidence of cell death. Emerging therapies are looking at the efficacy of using a combination of NEI and IFN treatment to rapidly reduce tumor size and growth by inducing PANoptosis. KPT-330 and KPT-8602 are two different NEIs, both of which have shown efficacy in the reduction of tumor size and inhibition of Exportin 1 (XPO1), a transport protein. However, this article posits KPT-8602 as the better of the two. KPT-8602 is more tolerable for the patient and should be pushed to human trials.

News (Medical) associated with Eltanexor

01 Jun 2024

·www.prnewswire.com

Karyopharm Presents Updated Exploratory Subgroup Analyses from SIENDO Study in Patients with Advanced or Recurrent TP53 Wild-Type Endometrial Cancer During 2024 ASCO Plenary Series: Rapid Abstract Updates

Long-Term Follow-Up Data Signal Promising Progression-Free Survival (PFS) for Selinexor in the Maintenance Setting with Median PFS of 28.4 Months in the TP53 Wild-Type and 39.5 Months in the Proficient Mismatched Repair Status (pMMR) TP53 Wild-Type Exploratory Subgroups Q-TWiST, an Important Metric Assessing Both Quality and Quantity of Clinical Benefit, Suggests Improvement with Selinexor versus Placebo, which is Critical in the Maintenance Setting Company Highlights Additional Presentations in Endometrial Cancer and Myelofibrosis at ASCO 2024 NEWTON, Mass., June 1, 2024 /PRNewswire/ -- Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced the presentation of updated exploratory subgroup analyses from the SIENDO study (NCT03555422), in patients with advanced or recurrent TP53 wild-type endometrial cancer at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. The data were presented in a special ASCO plenary series rapid abstract update session on June 1 at 12:30pm CT and simultaneously published in the Gynecologic Oncology Journal. The primary analysis of the Phase 3 SIENDO study of selinexor maintenance therapy in advanced or recurrent endometrial cancer showed improvements in median PFS for the intent-to-treat (ITT) population but were not clinically meaningful. However, an exploratory analysis of a pre-specified subgroup of patients with TP53 wild-type endometrial cancer showed a promising efficacy signal. In the exploratory subgroup analysis, 113 patients with TP53 wild-type advanced/recurrent endometrial cancer were randomized to receive selinexor (n=77) vs placebo (n=36) as maintenance therapy after 1L platinum-based chemotherapy. As of the April 1, 2024 data cut-off date, and a median duration of follow-up of 36.9 months, selinexor-treated patients had a median PFS of 28.4 months compared to 5.2 months for patients receiving placebo. In selinexor-treated patients with TP53 wild-type/pMMR and TP53 wild-type/dMMR endometrial cancer, median PFS was 39.5 months and 13.1 months compared to 4.9 months and 3.7 months in those treated with placebo, respectively. Although immature, preliminary overall survival (OS) in the TP53 wild-type subgroup was promising with a hazard ratio of 0.65; median OS for selinexor has not been reached. The updated analyses also highlighted findings from a quality-adjusted time without symptoms or toxicity analysis (Q-TWiST) used to assess quality and toxicity-adjusted PFS. The findings showed the restricted mean Q-TWiST for selinexor to be 26 months compared to 15 months for placebo, resulting in a difference of nearly 11 months. "The approximately 40 months median PFS observed with selinexor in patients whose tumors are both TP53 wild-type and pMMR, coupled with the robust QTWiST analysis, suggests that selinexor may be an optimal maintenance therapy in endometrial cancer," said Reshma Rangwala, MD, PhD, Chief Medical Officer and Head of Research at Karyopharm. "Our ongoing Phase 3 trial will definitively assess these benefits and may lead to a new standard of care in the novel subgroup of patients defined by TP53 wild-type status." No new safety signals were identified as of the data cut-off date of April 1, 2024. The most common treatment-emergent adverse events (TEAEs) in selinexor treated TP53 wild-type patients were nausea (90%), vomiting (60%) and diarrhea (45%), the majority of which were grades 1-2. The most common reported grade 3-4 TEAEs included neutropenia (20%), nausea (13%), and thrombocytopenia (10%). TEAEs leading to discontinuations were reported in 17% of patients. "It is exciting to see the emerging data around progression free survival, as well as an encouraging trend in overall survival and the Q-TWiST metric in the TP53 wild-type subgroup analysis from the SIENDO study," said Vicky Makker, MD, Gynecologic Oncologist, Memorial Sloan Kettering Cancer Center. "The long-term follow-up data further reinforce how selinexor could benefit patients with endometrial cancer, including patients with mismatch repair-proficient disease, and add to the growing body of evidence supporting the potential role of selinexor as a maintenance treatment option for patients whose options are limited." A copy of the presentation from the "ASCO Plenary Series: Rapid Abstract Updates" special session can be accessed under "Publications and Presentations" in the Investor section of the Company's website, . Selinexor is being evaluated in a global, Phase 3, randomized, double-blind study, EC-042 (XPORT-EC-042; NCT05611931), as a maintenance therapy following systemic therapy in patients with TP53 wild-type advanced or recurrent endometrial cancer. Karyopharm expects to report data from this trial in the first half of 2025. The following Karyopharm abstracts will also be presented at ASCO: About the EC-042 Study EC-042 (XPORT-EC-042; NCT05611931) is a global, Phase 3, randomized, double-blind study evaluating selinexor as a maintenance therapy following systemic therapy in patients with TP53 wild-type advanced or recurrent endometrial cancer. The EC-042 study was initiated in November 2022 and is expected to enroll up to 220 patients who will be randomized 1:1 to receive either a 60 mg, once-weekly, administration of oral selinexor or placebo until disease progression. The primary endpoint of the study is progression free survival (PFS), as assessed by an investigator, with overall survival as a key secondary endpoint. Further, in connection with the EC-042 Study, Karyopharm entered into a global collaboration with Foundation Medicine, Inc. to develop FoundationOne®CDx, a tissue-based comprehensive genomic profiling test to identify and enroll patients whose tumors are TP53 wild-type. About the SIENDO Study Karyopharm's evaluation of selinexor to treat patients with TP53 wild-type advanced or recurrent endometrial cancer is supported by data from an exploratory subgroup analysis from its ongoing SIENDO Study, a European Network of Gynaecological Oncological Trial Groups (ENGOT)-led trial in collaboration with the Gynecologic Oncology Group (GOG) Foundation, Inc. The SIENDO Study is a multicenter, randomized, double-blinded Phase 3 study evaluating the efficacy and safety of oral selinexor versus placebo as a front-line maintenance therapy in patients with advanced or recurrent endometrial cancer following at least one prior platinum-based combination chemotherapy treatment (NCT03555422). Participants in this study with advanced or recurrent disease who had a partial response or a complete response after at least 12 weeks of taxane-platinum combination chemotherapy were randomized in a 2:1 manner to receive either maintenance therapy of 80 mg of selinexor or placebo taken once per week, until disease progression. The primary endpoint in the study was PFS from time of randomization until death or disease progression as assessed by an investigator, with the goal of the study demonstrating a HR of 0.6. In the first quarter of 2022, Karyopharm presented top-line data from the SIENDO study, including preliminary exploratory subgroup analyses. Selinexor-treated patients had a median PFS of 5.7 months compared to 3.8 months for patients on placebo in the full trial population, which was not clinically meaningful. There were no new safety signals identified, and a discontinuation rate of 10.5% due to adverse events (AEs). The most common treatment-emergent AEs in the SIENDO study of any grade were: nausea (84%), vomiting (52%), constipation (37%) and thrombocytopenia (37%). The most common grade 3 treatment-emergent AEs were nausea (10%), neutropenia (9%), thrombocytopenia (7%) and asthenia (6%). About Endometrial Cancer Endometrial cancer is the most common cancer of the female reproductive organs in the U.S., with approximately 67,880 new cases expected in 2024 leading to nearly 13,250 deaths.1 In 2022, there were approximately 124,874 new cases and 30,272 deaths in Europe from endometrial cancer, while on a global scale there were 420,368 new cases and approximately 97,723 deaths.2 Since 2000, the incidence of new cases and deaths from endometrial cancer have risen.3 Risk factors include obesity, Type 2 diabetes, high-fat diets, use of tamoxifen and oral estrogens, and delayed menopause.4 About XPOVIO® (selinexor) XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm's Selective Inhibitor of Nuclear Export (SINE) compounds approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade® (bortezomib) and dexamethasone (XVd) in adult patients with multiple myeloma who have received at least one prior therapy; (ii) in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody; and (iii) in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO® in certain countries) has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including but not limited to the European Union, the United Kingdom, China, South Korea, Canada, Israel and Taiwan. XPOVIO and NEXPOVIO is marketed by Karyopharm's partners, Antengene, Menarini, Neopharm and FORUS, in China, South Korea, Singapore, Australia, Hong Kong, Germany, Austria, Israel and Canada. Please refer to the local Prescribing Information for full details. Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis. For more information about Karyopharm's products or clinical trials, please contact the Medical Information department at: Tel: +1 (888) 209-9326 Email: [email protected] SELECT IMPORTANT SAFETY INFORMATION Warnings and Precautions Thrombocytopenia: Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care. Neutropenia: Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony‐stimulating factors. Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care. Hyponatremia: Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care. Serious Infection: Monitor for infection and treat promptly. Neurological Toxicity: Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes. Embryo‐Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with a female partner of reproductive potential, of the potential risk to a fetus and use of effective contraception. Cataract: Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract. Adverse Reactions The most common adverse reactions (≥20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract and vomiting. Grade 3‐4 laboratory abnormalities (≥10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON trial, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients. Treatment discontinuation rate due to adverse reactions was 19%. The most common adverse reactions (≥20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea and upper respiratory tract infection. In the STORM trial, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%. The most common adverse reactions (incidence ≥20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3‐4 laboratory abnormalities (≥15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. In the SADAL trial, fatal adverse reactions occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reactions was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients; the most frequent serious adverse reaction was infection (21% of patients). Discontinuation due to adverse reactions occurred in 17% of patients. Use In Specific Populations Lactation: Advise not to breastfeed. For additional product information, including full prescribing information, please visit . To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1‐888‐209‐9326 or FDA at 1‐800‐FDA‐1088 or . About Karyopharm Therapeutics Karyopharm Therapeutics Inc. (Nasdaq: KPTI) is a commercial-stage pharmaceutical company whose dedication to pioneering novel cancer therapies is fueled by a belief in the extraordinary strength and courage of patients with cancer. Since its founding, Karyopharm has been an industry leader in oral compounds that address nuclear export dysregulation, a fundamental mechanism of oncogenesis. Karyopharm's lead compound and first-in-class, oral exportin 1 (XPO1) inhibitor, XPOVIO® (selinexor), is approved in the U.S. and marketed by the Company in three oncology indications. It has also received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including Europe and the United Kingdom (as NEXPOVIO®) and China. Karyopharm has a focused pipeline targeting indications in multiple high unmet need cancers, including in multiple myeloma, endometrial cancer, myelofibrosis, and diffuse large B-cell lymphoma (DLBCL). For more information about our people, science and pipeline, please visit , and follow us on Twitter at @Karyopharm and LinkedIn. Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the ability of selinexor to treat patients with endometrial cancer; and expectations related to the clinical development of selinexor and potential regulatory submissions of selinexor. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm's control, that may cause actual events or results to differ materially from Karyopharm's current expectations. For example, there can be no guarantee that Karyopharm will successfully commercialize XPOVIO or that any of Karyopharm's drug candidates, including selinexor and eltanexor, will successfully complete necessary clinical development phases or that development of any of Karyopharm's drug candidates will continue. Further, there can be no guarantee that any positive developments in the development or commercialization of Karyopharm's drug candidate portfolio will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: the adoption of XPOVIO in the commercial marketplace, the timing and costs involved in commercializing XPOVIO or any of Karyopharm's drug candidates that receive regulatory approval; the ability to obtain and retain regulatory approval of XPOVIO or any of Karyopharm's drug candidates that receive regulatory approval; Karyopharm's results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, including with respect to the need for additional clinical studies; the ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respective obligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm's ability to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development or regulatory approval of drug candidates by Karyopharm's competitors for products or product candidates in which Karyopharm is currently commercializing or developing; the direct or indirect impact of the COVID-19 pandemic or any future pandemic on Karyopharm's business, results of operations and financial condition; and Karyopharm's ability to obtain, maintain and enforce patent and other intellectual property protection for any of its products or product candidates. These and other risks are described under the caption "Risk Factors" in Karyopharm's Quarterly Report on Form 10-Q for the quarter ended March 31, 2024, which was filed with the Securities and Exchange Commission (SEC) on May 8, 2024, and in other filings that Karyopharm may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and, except as required by law, Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. XPOVIO® and NEXPOVIO® are registered trademarks of Karyopharm Therapeutics Inc. Any other trademarks referred to in this release are the property of their respective owners. References 1American Cancer Society, About Endometrial Cancer: (accessed May 22, 2024) 2International Agency for Research on Cancer, World Health Organization. "Top 15 Cancer Sites) (accessed May 22, 2024) 3Seer Cancer Incidence Rate Estimates, National Cancer Institute. Bethesda, MD. (accessed May 22, 2024) 4American Cancer Society, Endometrial Cancer Risk Factors. (accessed May 22, 2024) SOURCE Karyopharm Therapeutics Inc.

Clinical ResultPhase 3Drug ApprovalASCO

08 May 2024

·www.prnewswire.com

Karyopharm Announces Significant Refinancing Transactions and Amended Royalty Agreement Extending Vast Majority of Its Debt Maturities into 2028 and 2029

– $148.0 Million (86%) of Existing Convertible Notes due in 2025 to be Exchanged for $111.0 Million of New Convertible Notes due in 2029 and Warrants – – Issues New $100.0 Million Senior Secured Term Loan due in 2028 – – Repays Principal Portion and Amends Royalty Agreement with HealthCare Royalty – NEWTON, Mass., May 8, 2024 /PRNewswire/ -- Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, announced today that it has entered into a series of financing transactions that will extend the Company's debt maturities into 2028 and 2029, well beyond the Company's planned Phase 3 data readouts in 2025. "We are extremely pleased to have accomplished several important objectives for Karyopharm and our shareholders with this refinancing. We successfully strengthened our balance sheet by extending the maturity of the vast majority of our debt obligations well beyond the planned readouts and potential approvals of our three ongoing Phase 3 programs," said Richard Paulson, President and Chief Executive Officer of Karyopharm. "With the demonstrated strong commitment from HealthCare Royalty and our top convertible note holders, we have enhanced our ability to unlock the potential of selinexor." Convertible Notes Exchange As part of these refinancing transactions, on May 8, 2024, the Company entered into privately negotiated agreements with certain funds managed by each of Braidwell LP, Highbridge Capital Management, LLC, Davidson Kempner Capital Management LP and Context Capital Management, the top four holders of the Company's outstanding 3.0% Convertible Notes due 2025 (the 2025 Convertible Notes) to exchange approximately $148.0 million aggregate principal amount out of the $172.5 million aggregate principal amount of the 2025 Convertible Notes then outstanding for approximately $111.0 million aggregate principal amount of the Company's newly issued 6.0% Convertible Notes due 2029 (the 2029 Convertible Notes), plus warrants to purchase up to approximately 46.0 million shares of the Company's common stock, at an exercise price of $1.10 per share. Exchanging holders will receive 2029 Convertible Notes having a principal amount equal to 75% of the principal amount of 2025 Convertible Notes exchanged by them (i.e., $750 in principal amount of 2029 Convertible Notes for each $1,000 in principal amount of 2025 Convertible Notes surrendered in exchange). The 2029 Convertible Notes will be secured on a second-lien basis by the same collateral that secures the Secured Term Loan. The exchange transactions are anticipated to close on or around May 13, 2024, subject to customary closing conditions. In addition, certain entities managed by HealthCare Royalty Management, LLC (HCRx) will purchase $5.0 million of the 2029 Convertible Notes in satisfaction of $5.0 million of the Company's existing obligations to HCRx. The 2029 Convertible Notes will be convertible into shares of the Company's common stock at the option of holders of the 2029 Convertible Notes at an initial conversion rate of 444.4444 shares of the Company's common stock per $1,000 principal amount of the 2029 Convertible Notes (which is equivalent to an initial conversion price of $2.25 per share, a premium of approximately 105% above the closing price of the Company’s common stock on May 7, 2024). New $100.0 Million Senior Secured Term Loan On May 8, 2024 (the Term Loan Closing Date), the Company also entered into a new $100.0 million first lien senior secured term loan facility (the Secured Term Loan). The lenders under the Secured Term Loan include certain holders of the 2025 Convertible Notes and HCRx, with existing holders of the 2025 Convertible Notes funding $85.0 million and HCRx funding $15.0 million through satisfaction of approximately $15.0 million of the Company's existing obligations to HCRx. The Secured Term Loan matures in May 2028 and accrues interest at a rate of Secured Overnight Financing Rate (SOFR) plus 9.25%. Amortization payments will commence 24 months after closing. Karyopharm intends to use $49.5 million of the proceeds from the Secured Term Loan to repay royalty payment obligations owed to HCRx under its existing Revenue Interest Financing Agreement (the Financing Agreement), as described below, which, together with the satisfaction of HCRx obligations through the delivery of $5.0 million in 2029 Convertible Notes and $15.0 million of the Secured Term Loan to HCRx, will reduce the maximum amount owed to HCRx thereunder to $128.3 million. The remainder of the proceeds of approximately $30.0 million from the Secured Term Loan are intended to be used to pay transaction expenses and for general corporate purposes, including to support the Company's ongoing and planned clinical trial activities. Amended HealthCare Royalty Agreement In addition, on the Term Loan Closing Date, the Company entered into an amendment to the Financing Agreement with HCRx pursuant to which the Company (i) made a $49.5 million cash payment to HCRx; (ii) agreed to deliver a $15.0 million Secured Term Loan note to HCRx in a cashless exchange of existing obligations under the Financing Agreement with HCRx; (iii) agreed to deliver $5.0 million of 2029 Convertible Notes to HCRx. Further, the royalty rate on Karyopharm's worldwide net revenue of selinexor and any other future products was reduced from a tiered schedule resulting in a rate of 12.5% just prior to the Term Loan Closing Date to a flat 7.0%. The Financing Agreement with HCRx will be secured on a second-lien basis. The transactions described in this press release are further described in a Current Report on Form 8-K to be filed today with the U.S. Securities and Exchange Commission. J. Wood Capital Advisors LLC acted as financial advisor to Karyopharm and Wilmer Cutler Pickering Hale and Dorr LLP acted as legal counsel to Karyopharm in connection with these transactions. This press release does not constitute an offer to sell or the solicitation of an offer to buy the 2029 Convertible Notes or any other securities, nor shall there be any offer, solicitation or sale of the 2029 Convertible Notes or any other securities (including the shares of Karyopharm's common stock issuable upon conversion of the 2025 Convertible Notes, if any) in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful. Conference Call Information Karyopharm will host a conference call on May 8, 2024, at 8:00 a.m. Eastern Time, to discuss the first quarter 2024 financial results, the transactions described herein and other company updates. To access the conference call, please dial (800) 836-8184 (local) or (646) 357-8785 (international) at least 10 minutes prior to the start time and ask to be joined into the Karyopharm Therapeutics call. A live audio webcast of the call, along with accompanying slides, will be available under "Events & Presentations" in the Investor section of the Company's website, . An archived webcast will be available on the Company's website approximately two hours after the event. About Karyopharm Therapeutics Karyopharm Therapeutics Inc. (Nasdaq: KPTI) is a commercial-stage pharmaceutical company whose dedication to pioneering novel cancer therapies is fueled by a belief in the extraordinary strength and courage of patients with cancer. Since its founding, Karyopharm has been an industry leader in oral compounds that address nuclear export dysregulation, a fundamental mechanism of oncogenesis. Karyopharm's lead compound and first-in-class, oral exportin 1 (XPO1) inhibitor, XPOVIO® (selinexor), is approved in the U.S. and marketed by the Company in three oncology indications. It has also received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including Europe and the United Kingdom (as NEXPOVIO®) and China. Karyopharm has a focused pipeline targeting indications in multiple high unmet need cancers, including in multiple myeloma, endometrial cancer, myelofibrosis, and diffuse large B-cell lymphoma (DLBCL). For more information about our people, science and pipeline, please visit , and follow us on LinkedIn and on X at @Karyopharm. Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the anticipated benefits of and activities under the refinancing transactions, expectations for our use of proceeds from the Secured Term Loan and our expected cash runway; the expected closing date for the exchange transactions and the Company's ability to complete the exchange transactions; expectations with respect to commercialization efforts; the ability of selinexor to treat patients with multiple myeloma, endometrial cancer, myelofibrosis, diffuse large B-cell lymphoma, and other diseases; and expectations with respect to the clinical development plans and potential regulatory submissions of selinexor. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm's control, that may cause actual events or results to differ materially from Karyopharm's current expectations. For example, there can be no guarantee that Karyopharm will successfully commercialize XPOVIO or that any of Karyopharm's drug candidates, including selinexor and eltanexor, will successfully complete necessary clinical development phases or that development of any of Karyopharm's drug candidates will continue. Further, there can be no guarantee that any positive developments in the development or commercialization of Karyopharm's drug candidate portfolio will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: the adoption of XPOVIO in the commercial marketplace, the timing and costs involved in commercializing XPOVIO or any of Karyopharm's drug candidates that receive regulatory approval; the ability to obtain and retain regulatory approval of XPOVIO or any of Karyopharm's drug candidates that receive regulatory approval; Karyopharm's results of clinical trials and preclinical trials, including subsequent analysis of existing data and new data received from ongoing and future trials; the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, including with respect to the need for additional clinical trials; the ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respective obligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm's ability to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development or regulatory approval of drug candidates by Karyopharm's competitors for products or product candidates in which Karyopharm is currently commercializing or developing; the direct or indirect impact of the COVID-19 pandemic or any future pandemic on Karyopharm's business, results of operations and financial condition; and Karyopharm's ability to obtain, maintain and enforce patent and other intellectual property protection for any of its products or product candidates. These and other risks are described under the caption "Risk Factors" in Karyopharm's Annual Report on Form 10-K for the year ended December 31, 2023, which was filed with the Securities and Exchange Commission (SEC) on February 29, 2024, and in other filings that Karyopharm may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and, except as required by law, Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. SOURCE Karyopharm Therapeutics Inc.

Drug ApprovalPhase 3

29 Feb 2024

·www.biospace.com

Karyopharm Reports Fourth Quarter and Full Year 2023 Financial Results and Highlights Recent Company Progress

– Total Revenue of $146 Million and U.S. XPOVIO® (selinexor) Net Product Revenue of $112 Million for Full Year 2023, Meeting Company's Guidance – – Top-Line Data Readouts from Three Pivotal Phase 3 Trials Evaluating Selinexor in Endometrial Cancer, Myelofibrosis and Multiple Myeloma Expected in 2025 – – Company Provides Full-Year 2024 Total Revenue Guidance of $140 Million to $160 Million, Including U.S. XPOVIO Net Product Revenue Guidance of $100 Million to $120 Million; Cash Runway to Late 2025 – – Conference Call Scheduled for Today at 8:00 a.m. ET — NEWTON, Mass., Feb. 29, 2024 /PRNewswire/ -- Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today reported financial results for the fourth quarter and full year ended December 31, 2023. In addition, Karyopharm highlighted select corporate milestones and provided an overview of its key clinical development programs. "We made significant progress in 2023 across our clinical pipeline and continued to build on our foundation in the highly competitive multiple myeloma space. The encouraging clinical results that we presented last year reinforce the potential of our three ongoing pivotal Phase 3 trials in addressing critical unmet needs of cancer patients," said Richard Paulson, President and Chief Executive Officer of Karyopharm. "Our drive for innovation and progress will continue into 2024, by focusing our resources to advance our Phase 3 trials. We are enthusiastic about the upcoming top-line read-outs from these trials and what they could mean for patients and selinexor's growth potential." Fourth Quarter 2023 and Recent Highlights Research and Development (R&D) Highlights Long-term exploratory analysis of the pre-specified subgroup of patients with advanced or recurrent TP53 wild-type endometrial cancer (EC) from the Phase 3 SIENDO trial (NCT03555422) was presented at the International Gynecological Cancer Society Annual Global Meeting in Seoul, South Korea, with updated progression-free survival (PFS). As of the September 1, 2023 data cut-off date, median PFS was 27.4 months in the selinexor treatment arm (n=77) as compared to 5.2 months (n=36) in the placebo arm. Immature overall survival data showed an encouraging signal and corroborated the PFS results. Oral presentation at the 65th American Society of Hematology 2023 Annual Meeting of the updated results from the Phase 1 trial (XPORT-MF-034) evaluating selinexor in combination with ruxolitinib in patients with treatment-naïve myelofibrosis (MF) showed encouraging long-term durability. 79% of intent-to-treat (ITT) patients (11 out of 14) treated with 60mg selinexor achieved ≥35% reduction in spleen volume (SVR35) at week 24, and continued to remain in radiographic response as of the August 1, 2023 data cut-off date. In addition, 58% of the ITT patients (7 out of 12) who achieved symptom improvement of ≥ 50% (TSS50) at week 24 also remained in response as of the data cut-off. In general, early cytokine reduction at week 4 was associated with spleen volume reduction at week 24, was sustained until the end of treatment, and is a potential sign of disease modification. Clinical trial collaboration agreement executed with Bristol Myers Squibb (BMS) to evaluate selinexor in combination with BMS' proprietary investigational cereblon E3 ligase modulator (CELMoD™) agent mezigdomide in patients with relapsed/refractory multiple myeloma (MM) progressing after T-cell immunotherapies, potentially adding to the growing body of evidence that selinexor has the potential to show meaningful benefit in combination with MM therapies with differing mechanisms of action; the study of selinexor/mezigdomide enables further evaluation of selinexor's role in maintaining an optimal T-cell environment. XPOVIO Commercial Performance Achieved U.S. net product revenue for the year ended December 31, 2023 of $112 million, compared to $120 million for the year ended December 31, 2022. U.S. net product revenue for the fourth quarter of 2023 was $25 million, compared to $31 million for the fourth quarter of 2022. Although demand for XPOVIO continued its growth in the community setting in 2023, it was adversely impacted in the academic setting due to increased competition in the later-lines. Continued progress in shifting selinexor use into earlier lines of therapy, with patient mix approaching 70% in the second to fourth lines in 2023 versus 55% in 20221. XPOVIO net product revenue was adversely impacted year-over-year by increased utilization of the KaryForward Patient Assistance Program (PAP), due to MM foundation closures2, contributing to ~10% of total demand in 2023 as compared to ~5% in 2022, leading to an estimated impact of ~$6 million. Additionally, increased competition and higher gross-to-net, driven by increased 340B discounts and Medicaid rebates during the year, adversely impacted XPOVIO net product revenue in 2023. Intellectual Property The U.S. Patent and Trademark Office issued patents directed toward the polymorphic form of selinexor present in XPOVIO, pharmaceutical compositions comprising the polymorphic form and methods of treatment using the polymorphic form and the pharmaceutical compositions. The newly issued patents will expire in August 2035. Anticipated Catalysts and Operational Objectives in 2024 and 2025 Present updated exploratory subgroup analysis results in patients with TP53 wild-type EC from the Phase 3 SIENDO trial in 2024. Complete enrollment in pivotal XPORT-EC-042 Phase 3 trial in TP53 wild-type EC in 2H 2024 and report top-line results in 1H 2025. Report updated results from the Phase 1 trial of selinexor in combination with ruxolitinib in patients with treatment-naïve MF in 2024. Report preliminary results from the Phase 2 trial evaluating the efficacy and safety of selinexor monotherapy in subjects with JAK inhibitor-naïve MF and moderate thrombocytopenia in 2H 2024. Report top-line results from pivotal Phase 3 trial of selinexor in combination with ruxolitinib in treatment-naïve MF in 2H 2025. Publish and present efficacy and safety data on selinexor 40mg in combination with pomalidomide and dexamethasone from ongoing STOMP/028 Phase 2 trials in patients with MM in 2024. Report additional data on selinexor's impact on T-cell fitness and potential combinability with multiple agents pre- or post-T-cell therapy in patients with MM in 2024. Complete enrollment in pivotal Phase 3 trial evaluating an oral combination of 40mg selinexor, pomalidomide and dexamethasone in patients with previously treated MM in 2H 2024 and report top-line results in 1H 2025. Maintain the Company's commercial foundation in the competitive MM marketplace, driving increased XPOVIO revenues. Continue global launches and reimbursement approvals for selinexor by partners in ex-U.S. territories. 2024 Financial Outlook Based on its current operating plans, Karyopharm expects the following for full year 2024: Total revenue to be in the range of $140 million to $160 million. Total revenue consists of U.S. XPOVIO net product revenue and license, royalty and milestone revenue earned from partners. U.S. XPOVIO net product revenue to be in the range of $100 million to $120 million. R&D and SG&A expenses to be in the range of $260 million to $280 million, which includes approximately $20 million to $25 million of estimated non-cash stock-based compensation expense. The Company expects that its existing cash, cash equivalents and investments, and the revenue it expects to generate from XPOVIO net product sales, as well as revenue generated from its license agreements, will be sufficient to fund its planned operations into late 2025. Full Year and Fourth Quarter 2023 Financial Results Total revenue: Total revenue for the fourth quarter of 2023 was $33.7 million, compared to $33.6 million for the fourth quarter of 2022. Total revenue for the year ended December 31, 2023 was $146.0 million, compared to $157.1 million for the year ended December 31, 2022. Net product revenue: Net product revenue for the fourth quarter of 2023 was $25.1 million, compared to $31.1 million for the fourth quarter of 2022. Net product revenue for the year ended December 31, 2023 was $112.0 million, compared to $120.4 million for the year ended December 31, 2022. License and other revenue: License and other revenue for the fourth quarter of 2023 was $8.7 million, compared to $2.5 million for the fourth quarter of 2022. License and other revenue for the year ended December 31, 2023 was $34.0 million, compared to $36.6 million for the year ended December 31, 2022. Cost of sales: Cost of sales for the fourth quarter of 2023 was $1.5 million, compared to $1.9 million for the fourth quarter of 2022. Cost of sales for the year ended December 31, 2023 was $4.9 million, compared to $5.2 million for the year ended December 31, 2022. Cost of sales reflects the costs of XPOVIO units sold and third-party royalties on net product revenue. R&D expenses: R&D expenses for the fourth quarter of 2023 were $39.4 million, compared to $30.9 million for the fourth quarter of 2022. R&D expenses for the year ended December 31, 2023 were $138.8 million, compared to $148.7 million for the year ended December 31, 2022. The decrease in R&D expenses in 2023 compared to 2022 was primarily due to a decrease in personnel costs and stock-based compensation attributable to a reduction in headcount and contractors, including severance-related expenses incurred in 2022. These decreases were partially offset by an increase in clinical trial and related costs primarily due to the advancement of the Company's three pivotal Phase 3 trials and the timing of purchases of comparator drug used in the Company's clinical trials. SG&A expenses: SG&A expenses for the fourth quarter of 2023 were $30.7 million, compared to $34.6 million for the fourth quarter of 2022. SG&A expenses for the year ended December 31, 2023 were $131.9 million, compared to $145.4 million for the year ended December 31, 2022. The decrease in SG&A expenses in 2023 compared to 2022 was primarily due to a decrease in stock-based compensation because of severance-related expenses incurred in 2022. Interest expense: Interest expense for the fourth quarter of 2023 was $6.2 million, compared to $5.9 million for the fourth quarter of 2022. Interest expense for the year ended December 31, 2023 was $23.8 million, compared to $25.0 million for the year ended December 31, 2022. Net loss: Karyopharm reported a net loss of $41.8 million, or $0.36 per basic and diluted share, for the fourth quarter of 2023, compared to a net loss of $38.5 million, or $0.43 per basic and diluted share, for the fourth quarter of 2022. Net loss includes non-cash stock-based compensation expense of $5.2 million and $6.2 million for the fourth quarters of 2023 and 2022, respectively. Karyopharm reported a net loss of $143.1 million, or $1.25 per basic and diluted share, for the year ended December 31, 2023, compared to a net loss of $165.3 million, or $2.02 per basic and diluted share, for the year ended December 31, 2022. Net loss includes non-cash stock-based compensation expense of $21.7 million and $35.4 million for the years ended December 31, 2023 and 2022, respectively. Cash position: Cash, cash equivalents, restricted cash and investments as of December 31, 2023 totaled $192.4 million, compared to $279.7 million as of December 31, 2022. Conference Call Information Karyopharm will host a conference call today, February 29, 2024, at 8:00 a.m. Eastern Time, to discuss the fourth quarter and full year 2023 financial results and the financial outlook for 2024 and to provide other business updates. To access the conference call, please dial (800) 836-8184 (local) or (646) 357-8785 (international) at least 10 minutes prior to the start time and ask to be joined into the Karyopharm Therapeutics call. A live audio webcast of the call, along with accompanying slides, will be available under "Events & Presentations" in the Investor section of the Company's website. An archived webcast will be available on the Company's website approximately two hours after the event. About XPOVIO® (selinexor) XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm's Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade® (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO® in certain countries) has received regulatory approvals in a growing number of ex-U.S. territories and countries, including Europe, the United Kingdom, South Korea, Israel, Singapore, Hong Kong, Mainland China, Australia, Canada, Taiwan and Macau and is marketed in those areas by Karyopharm's global partners. Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis. For more information about Karyopharm's products or clinical trials, please contact the Medical Information department at: Tel: +1 (888) 209-9326, Email: medicalinformation@karyopharm.com XPOVIO® (selinexor) is a prescription medicine approved: In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (XVd). In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti‐CD38 monoclonal antibody (Xd). For the treatment of adult patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). SELECT IMPORTANT SAFETY INFORMATION Warnings and Precautions Thrombocytopenia: Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care. Neutropenia: Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony‐stimulating factors. Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care. Hyponatremia: Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care. Serious Infection: Monitor for infection and treat promptly. Neurological Toxicity: Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes. Embryo‐Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with a female partner of reproductive potential, of the potential risk to a fetus and use of effective contraception. Cataract: Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract. Adverse Reactions The most common adverse reactions (≥20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract and vomiting. Grade 3‐4 laboratory abnormalities (≥10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON trial, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients. Treatment discontinuation rate due to adverse reactions was 19%. The most common adverse reactions (≥20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea and upper respiratory tract infection. In the STORM trial, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%. The most common adverse reactions (incidence ≥20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3‐4 laboratory abnormalities (≥15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. In the SADAL trial, fatal adverse reactions occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reactions was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients; the most frequent serious adverse reaction was infection (21% of patients). Discontinuation due to adverse reactions occurred in 17% of patients. Use In Specific Populations Lactation: Advise not to breastfeed. For additional product information, including full prescribing information, please visit . To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1‐888‐209‐9326 or FDA at 1‐800‐FDA‐1088 or About Karyopharm Therapeutics Karyopharm Therapeutics Inc. (Nasdaq: KPTI) is a commercial-stage pharmaceutical company pioneering novel cancer therapies. Since its founding, Karyopharm has been an industry leader in oral Selective Inhibitor of Nuclear Export (SINE) compound technology, which was developed to address a fundamental mechanism of oncogenesis: nuclear export dysregulation. Karyopharm's lead SINE compound and first-in-class, oral exportin 1 (XPO1) inhibitor, XPOVIO® (selinexor), is approved in the U.S. and marketed by the Company in three oncology indications and has received regulatory approvals in a growing number of ex-U.S. territories and countries, including Europe, the United Kingdom, China, South Korea, Israel, Singapore, Hong Kong, Mainland China, Australia, Canada, Taiwan and Macau, and is marketed in those areas by Karyopharm's global partners. Karyopharm has a focused pipeline targeting multiple high unmet need cancer indications, including in multiple myeloma, endometrial cancer and myelofibrosis. For more information about our people, science and pipeline, please visit , and follow us on Twitter at @Karyopharm and LinkedIn. Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding Karyopharm's guidance on its 2024 total revenue, 2024 U.S. net product revenue and 2024 R&D and SG&A expenses; Karyopharm's expected cash runway; expectations with respect to commercialization efforts; the ability of selinexor to treat patients with multiple myeloma, endometrial cancer, myelofibrosis, diffuse large B-cell lymphoma, and other diseases; and expectations with respect to the clinical development plans and potential regulatory submissions of selinexor and eltanexor. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm's control, that may cause actual events or results to differ materially from Karyopharm's current expectations. For example, there can be no guarantee that Karyopharm will successfully commercialize XPOVIO or that any of Karyopharm's drug candidates, including selinexor and eltanexor, will successfully complete necessary clinical development phases or that development of any of Karyopharm's drug candidates will continue. Further, there can be no guarantee that any positive developments in the development or commercialization of Karyopharm's drug candidate portfolio will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: the adoption of XPOVIO in the commercial marketplace, the timing and costs involved in commercializing XPOVIO or any of Karyopharm's drug candidates that receive regulatory approval; the ability to obtain and retain regulatory approval of XPOVIO or any of Karyopharm's drug candidates that receive regulatory approval; Karyopharm's results of clinical trials and preclinical trials, including subsequent analysis of existing data and new data received from ongoing and future trials; the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, including with respect to the need for additional clinical trials; the ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respective obligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm's ability to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development or regulatory approval of drug candidates by Karyopharm's competitors for products or product candidates in which Karyopharm is currently commercializing or developing; the direct or indirect impact of the COVID-19 pandemic or any future pandemic on Karyopharm's business, results of operations and financial condition; and Karyopharm's ability to obtain, maintain and enforce patent and other intellectual property protection for any of its products or product candidates. These and other risks are described under the caption "Risk Factors" in Karyopharm's Quarterly Report on Form 10-Q for the quarter ended September 30, 2023, which was filed with the Securities and Exchange Commission (SEC) on November 2, 2023, and in other filings that Karyopharm may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and, except as required by law, Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. XPOVIO® and NEXPOVIO® are registered trademarks of Karyopharm Therapeutics Inc. Any other trademarks referred to in this release are the property of their respective owners. References: 1 Based on Komodo claims data analysis, accessed in November 2023 2 Four multiple myeloma foundations provide financial support to Medicare patients with multiple myeloma Company Codes: NASDAQ-NMS:KPTI

Clinical ResultDrug ApprovalPhase 3Phase 2Financial Statement

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 2	FR	Karyopharm Therapeutics, Inc.	01 Jan 2016
Acute Myeloid Leukemia	Phase 2	CA	Karyopharm Therapeutics, Inc.	01 Jan 2016
Acute Myeloid Leukemia	Phase 2	CN	Karyopharm Therapeutics, Inc.	01 Jan 2016
Acute Myeloid Leukemia	Phase 2	US	Karyopharm Therapeutics, Inc.	01 Jan 2016
Acute Myeloid Leukemia	Phase 2	ES	Karyopharm Therapeutics, Inc.	01 Jan 2016
Metastatic castration-resistant prostate cancer	Phase 2	CN	Karyopharm Therapeutics, Inc.	01 Jan 2016
Prostatic Cancer	Discovery	CA	Karyopharm Therapeutics, Inc.	01 Jan 2016
Prostatic Cancer	Discovery	US	Karyopharm Therapeutics, Inc.	01 Jan 2016
Rectal Cancer	Discovery	US	Karyopharm Therapeutics, Inc.	01 Jan 2016
Rectal Cancer	Discovery	CA	Karyopharm Therapeutics, Inc.	01 Jan 2016

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02649790 (EHA2021)	Phase 1/2	Refractory Myelodysplastic Syndrome	20	Eltanexor 10 mg	(mapabqcrll) = yahxmelhdh idfzusivvg (wodlrvtpwq )	-	09 Jun 2021
				Eltanexor 20 mg	(mapabqcrll) = bfosxnvraw idfzusivvg (wodlrvtpwq )
NCT02649790 (ASCO2021)	Phase 1/2	Refractory Myelodysplastic Syndrome	20	Eltanexor 10 mg	dglkfddknx(azysslduvu) = cczeinskgc dqgakswyml (bbgptmbcpt ) View more	-	28 May 2021
				Eltanexor 20 mg	(maedwvuoup) = aakrztkrxq nvmvqcylwk (zdoomdixlg )
NCT02649790 (AACR2020)	Phase 1/2	Acute Lymphoblastic Leukemia	90	Eltanexor 12.5 mg/kg	(qsthxjzsyp) = vfqbynuevm rwyvsbwntk (gagvkvfnhb )	Positive	15 Aug 2020
EHA2020	Not Applicable	Acute myeloid leukemia with mutated NPM1	-	Eltanexor 10mg/kg 5d/w	kmocqkktgz(jrtwqzucnh) = lmgulaomdc vrqkcpdnuy (tuazonhovl )	Positive	14 May 2020
				Selinexor 5mg/kg 5d/w	kmocqkktgz(jrtwqzucnh) = juatkotvnf vrqkcpdnuy (tuazonhovl )
NCT02649790 (ASCO_GU2019)	Phase 1/2	Metastatic castration-resistant prostate cancer	30	Eltanexor (20 mg)	(zfruktnglh) = 33% (7% Gr≥3) wzylyabmeh (tnnlhvqmym ) View more	Positive	26 Feb 2019
				Eltanexor (30 mg)
NCT02649790 (ASH2016) Manual	Phase 1/2	Plasma cell myeloma refractory	6	dexamethasone+KPT-8602	(dwcrhxspsa) = none yepaxzdeca (wuewzyegza ) View more	Positive	02 Dec 2016

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