8-K: Karyopharm Therapeutics Adjusts Primary Endpoint for Phase 3 Myelofibrosis Trial Following FDA Feedback

Karyopharm Therapeutics has changed a co-primary endpoint in its Phase 3 SENTRY trial for myelofibrosis treatment, replacing total symptom score improvement with absolute total symptom score after discussions with the FDA.

Summary

• Karyopharm Therapeutics has modified a co-primary endpoint for its Phase 3 SENTRY trial evaluating selinexor in combination with ruxolitinib for myelofibrosis.
• The original co-primary endpoint, a 50% improvement in total symptom score (TSS50), has been replaced with absolute total symptom score (Abs-TSS).
• This change was made following feedback from the U.S. Food and Drug Administration (FDA).
• The other co-primary endpoint, spleen volume response rate of 35% (SVR35), remains unchanged.
• The Phase 1 trial data showed a 79% SVR35 rate and an average 18.5 point improvement in Abs-TSS at week 24.
• The company is increasing the total sample size of the SENTRY trial to approximately 350 patients to enhance statistical power.
• Top-line data from the SENTRY trial is still expected in the second half of 2025.

Sentiment

Score: 7

Explanation: The document presents a positive adjustment to the clinical trial based on FDA feedback and promising Phase 1 data, but also includes standard risk disclosures.

Positives

• The change to Abs-TSS is supported by key investigators and patient advocacy groups.
• Phase 1 trial data showed promising results with a 79% SVR35 rate and an average 18.5 point improvement in Abs-TSS.
• The increased sample size of the Phase 3 trial should improve statistical power.
• The safety profile of the combination therapy remains consistent with no new safety signals identified.

Risks

• There is no guarantee that Karyopharm will successfully commercialize XPOVIO.
• There is no guarantee that any of Karyopharm's drug candidates will successfully complete necessary clinical development phases.
• The company's expectations could be affected by risks and uncertainties relating to 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 could impact the company.
• The ability to obtain and retain regulatory approval of XPOVIO or any of Karyopharm's drug candidates that receive regulatory approval is not guaranteed.
• The company's results of clinical trials and preclinical trials, including subsequent analysis of existing data and new data received from ongoing and future trials, could impact the company.
• The content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities could impact the company.
• The ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respective obligations under the applicable agreement could impact the company.
• Karyopharm's ability to enroll patients in its clinical trials could impact the company.
• Unplanned cash requirements and expenditures could impact the company.
• Development or regulatory approval of drug candidates by Karyopharm's competitors could impact the company.
• The direct or indirect impact of the COVID-19 pandemic or any future pandemic on Karyopharm's business, results of operations and financial condition could impact the company.
• Karyopharm's ability to obtain, maintain and enforce patent and other intellectual property protection for any of its products or product candidates could impact the company.

Future Outlook

The company expects top-line data from the Phase 3 SENTRY trial in the second half of 2025.

Management Comments

• Dr. Raajit Rampal stated that there remains a tremendous unmet need in myelofibrosis.
• Dr. Rampal believes the Phase 1 data are meaningful and impressive and provide a strong rationale for the Phase 3 SENTRY trial.
• Reshma Rangwala, MD, PhD, stated that the company's confidence in the success of the Phase 3 SENTRY trial increases based on the change in the co-primary endpoint, the increased sample size and the data previously presented from the Phase 1 trial.
• Dr. Ruben Mesa stated that improving symptomatic burden for patients with myelofibrosis is an important goal in therapy.
• Kapila Viges stated that growing data that support a newer outcome measure like Abs-TSS that is also meaningful to patients is very encouraging.

Industry Context

The change in endpoint reflects a broader trend in myelofibrosis clinical trials to focus on patient-reported outcomes and symptom improvement, aligning with the views of key investigators and patient advocacy organizations. The use of Abs-TSS is becoming more common in this space.

Comparison to Industry Standards

• The document references the Phase 3 MANIFEST trial and the Phase 3 TRANSFORM-1 trial, which are both relevant to the myelofibrosis treatment landscape.
• The Phase 1 trial data for selinexor plus ruxolitinib showed a 79% SVR35 rate, which is significantly higher than the less than 50% SVR35 rate typically seen with ruxolitinib monotherapy.
• The Phase 1 trial also showed an average 18.5 point improvement in Abs-TSS, compared to the 11 to 14 point improvement seen with ruxolitinib monotherapy.

Stakeholder Impact

• The change in endpoint may lead to a more accurate assessment of symptom improvement for patients in the SENTRY trial.
• The increased sample size of the trial may increase the likelihood of a statistically significant result.
• The potential success of the trial could lead to a new treatment option for myelofibrosis patients.

Next Steps

• Karyopharm will continue to enroll patients in the Phase 3 SENTRY trial.
• The company will report top-line results from the SENTRY trial in the second half of 2025.

Key Dates

Keywords

myelofibrosis, selinexor, ruxolitinib, clinical trial, FDA, SENTRY trial, Abs-TSS, SVR35, JAK inhibitor, cancer therapy