Karyopharm Therapeutics FY Conference Summary Company Overview - **Company**: Karyopharm Therapeutics (NasdaqGS: KPTI) - **Key Product**: XPOVIO (selinexor), a first-in-class oral Exportin-1 inhibitor primarily for relapse refractory multiple myeloma and diffuse large B-cell lymphoma, with ongoing development for myelofibrosis and endometrial cancer [1][2] Core Points and Arguments Product and Mechanism - **Selinexor Mechanism**: Acts as an XPO1 inhibitor, blocking the Exportin-1 protein, which retains tumor suppressors like p53 within the nucleus, thereby inhibiting cancer cell proliferation [3][4] - **Myelofibrosis Context**: Current treatments mainly target the JAK-STAT pathway, but selinexor also addresses p53 and NF-B pathways, which are crucial in myelofibrosis [4] Financial Performance - **Q3 Revenue**: Reported revenues of approximately $32 million, with guidance for $110-$120 million for the year, indicating slight growth compared to the previous year [5][6] Market Utilization - **Multiple Myeloma**: Selinexor is primarily used in the community setting (60% of utilization) and academic settings (40%), positioned as a treatment option for patients post anti-CD38 therapy [6][7] - **Growth Strategy**: Focus on expanding usage in multiple myeloma while emphasizing the upcoming myelofibrosis opportunity [9][11] Myelofibrosis Opportunity - **Current Standard of Care**: Ruxolitinib has been the standard treatment for over a decade, but only 30% of patients achieve significant spleen volume reduction (SVR35) [15][17] - **Combination Therapy**: Selinexor combined with ruxolitinib aims to improve SVR35 rates and address symptoms and anemia more effectively than ruxolitinib alone [18][22] - **Clinical Trial Data**: The ESSENTIAL trial showed a nearly 30% SVR35 rate in heavily pretreated patients, while a phase 1 study indicated a 79% SVR35 rate in newly diagnosed patients [21][22] Upcoming Trials and Data - **Phase 3 SENTRY Trial**: Designed to evaluate the combination of selinexor and ruxolitinib in frontline myelofibrosis patients, with primary endpoints of SVR35 and total symptom score (TSS) [28][29] - **Expected Data Release**: Top-line data from the SENTRY trial is anticipated in March 2026 [11][54] Market Potential - **Revenue Opportunity**: Estimated peak revenue opportunity for myelofibrosis in the U.S. is approximately $1 billion, with a significant overlap in prescriber base from multiple myeloma [42][43] - **Patient Population**: Approximately 20,000 prevalent patients in the U.S. with 6,000 new intermediate to high-risk diagnoses annually [43][44] Endometrial Cancer Development - **Phase 3 XPORT-EC-042 Trial**: Focused on p53 wild type patients, leveraging previous positive data showing a median progression-free survival (PFS) of 40 months compared to 5 months for placebo [49][51] - **Data Expectations**: Results from this trial are expected in mid-2026 [51] Financial Position - **Debt and Cash Runway**: Karyopharm has $231 million in debt with deferred interest payments until Q2 2026, providing a cash runway to reach pivotal data readouts [54] Additional Important Points - **Safety Profile**: Combination therapy shows potential for improved gastrointestinal and hematologic safety compared to ruxolitinib alone [31][32] - **Commercialization Strategy**: Existing capabilities and market research indicate a strong intent to prescribe the combination therapy among physicians [44][45] This summary encapsulates the key insights from Karyopharm Therapeutics' FY conference, highlighting the company's strategic focus on myelofibrosis and endometrial cancer, alongside its financial positioning and market opportunities.

Financial Data and Key Metrics Changes - Total revenue for 2025 was $37.9 million, down from $42.8 million in 2024, primarily due to $6 million of non-recurring license-related revenue recognized in 2024 [38] - U.S. XPOVIO net product revenue for 2025 was $29.7 million, compared to $28 million in 2024, reflecting a 6% increase [32][39] - The gross to net provisions for XPOVIO in Q2 2025 were 26.8%, down from 45% in Q1 2025 and 29.3% in 2024 [39] - The company reported a net loss of $37.3 million or $4.32 per share on a GAAP basis, which includes $11.2 million in interest expense [42] Business Line Data and Key Metrics Changes - XPOVIO net product revenue was consistent, with the community setting driving approximately 60% of total U.S. sales [32] - The company expects net product revenue for the full year 2025 to be in the range of $110 million to $120 million [39] Market Data and Key Metrics Changes - The peak revenue potential for selinexor in myelofibrosis is estimated to be up to $1 billion annually in the U.S. alone [10][35] - Royalty revenue increased by 28% to $1.6 million in 2025 compared to 2024, reflecting increased global demand for XPOVIO and NexpoVIO [34] Company Strategy and Development Direction - The company is focused on enhancing liquidity and maximizing value while preparing for potential launches in myelofibrosis and endometrial cancer [6][45] - The company aims to redefine the standard of care for myelofibrosis with the combination of selinexor and ruxolitinib, pending positive data from ongoing trials [9][45] Management's Comments on Operating Environment and Future Outlook - Management acknowledged financial constraints with a near-term debt maturity in October and is actively engaged with lenders to enhance liquidity [6] - The company remains optimistic about the potential for selinexor plus ruxolitinib to improve treatment outcomes for myelofibrosis patients [9][45] Other Important Information - The company announced a 20% reduction in workforce to optimize costs, expecting to lower annual spend by approximately $13 million in 2026 [43] - The company exited 2025 with cash and equivalents of $52 million, down from $109.1 million at the end of 2024 [43] Q&A Session Summary Question: Concerns about myelofibrosis readout and preparation for multiple data readouts - Management expressed excitement about the upcoming readouts and confidence in leveraging existing commercial capabilities to prepare for potential launches in myelofibrosis and endometrial cancer [50][51] Question: Impact of higher baseline TSS on trial results - Management indicated that higher baseline TSS could lead to more meaningful outcomes in the trial, with ongoing monitoring of patient characteristics [60][61] Question: Reasons for lower rates of grade three anemia with combination therapy - Management attributed lower rates of grade three anemia to potential disease modification effects of selinexor, including reductions in key cytokines [62][63] Question: Confidence in blinded safety data holding once unblinded - Management expressed optimism about the safety profile observed in blinded data, noting consistency with historical ruxolitinib safety data [71][72]