Karyopharm Therapeutics (NASDAQ:KPTI) executives used an H.C. Wainwright BioConnect Conference appearance to highlight upcoming clinical and regulatory milestones for selinexor, the company’s oral nuclear export inhibitor marketed as XPOVIO in multiple myeloma.
Chief Executive Officer Richard Paulson described Karyopharm as a commercial-stage pharmaceutical company focused on nuclear export inhibition for cancer. He said selinexor is approved in multiple myeloma in the U.S. and in more than 50 countries through partners, and that the company is guiding to approximately $130 million to $150 million in multiple myeloma revenue this year.
SENTRY Data Show Spleen Response and Early Survival Signal
Karyopharm’s chief medical officer, identified during the discussion as Reshma, reviewed the SENTRY trial, a randomized, double-blind Phase 3 study evaluating selinexor in combination with ruxolitinib versus ruxolitinib alone in front-line, JAK-naïve myelofibrosis patients. Patients were required to have baseline platelet counts above 100, and the trial used 2:1 randomization.
The co-primary endpoints were SVR35, defined as a spleen volume reduction of at least 35%, and absolute total symptom score, or TSS, both measured at week 24. The trial also included secondary endpoints such as overall survival and exploratory translational measures including variant allele frequency, a measure of clonal burden.
The CMO said the trial showed an “approximate doubling” of SVR35 for selinexor plus ruxolitinib compared with ruxolitinib alone. She said the spleen response was rapid, appearing as early as week 12, and sustained beyond week 24 into week 36.
The symptom endpoint was not statistically significant versus the control arm, though the company said it observed a meaningful improvement from baseline at week 24. The CMO said the overall survival data were a key point of interest, citing a preliminary signal at a median follow-up of 12 months with a hazard ratio of 0.43 and a nominal P value of 0.0222. She also pointed to a deep reduction in variant allele frequency as early as week 24 relative to ruxolitinib.
ASCO Presentation and Regulatory Context
Karyopharm said SENTRY was selected as a late-breaking abstract for presentation at ASCO. The company said John Mascarenhas, described as a leading key opinion leader in myelofibrosis, will present the data on behalf of SENTRY investigators. The presentation is expected to cover efficacy endpoints, secondary endpoints, disease-modification data, mechanism of action and safety context.
Asked about comparisons with other myelofibrosis development programs that showed SVR35 benefit but did not meet symptom endpoints, the CMO declined to comment on other companies’ regulatory interactions. She emphasized what she called a differentiated profile for selinexor plus ruxolitinib, citing rapid and sustained spleen volume reduction, no new safety signals and the preliminary overall survival signal.
She also said selinexor has been used in tens of thousands of patients and that Karyopharm has confidence in its safety profile. Confirmed rates of leukemic transformation were described as the same across the two arms of the SENTRY trial.
On regulatory precedent, the CMO cited pacritinib’s accelerated approval based on SVR35 in patients with very low platelet counts and momelotinib’s approval, which she said reflected FDA flexibility in considering clinically meaningful benefit beyond the original primary endpoint framework.
Paulson also discussed the possibility of NCCN compendia inclusion, saying such a listing could support reimbursement. He said myelofibrosis is a multi-billion-dollar market and that Karyopharm believes selinexor’s peak potential in myelofibrosis could be up to about $1 billion. He said the company and its partners are also interested in engaging regulatory agencies outside the U.S., including in Europe.
Endometrial Cancer Trial Builds on SIENDO Subgroup
The discussion then turned to Karyopharm’s endometrial cancer program. The CMO said the earlier Phase 3 SIENDO trial evaluated selinexor as maintenance therapy in an all-comers population of advanced or recurrent endometrial cancer patients. While the all-comers population did not show a clinically meaningful progression-free survival outcome at the early 2022 top-line readout, she said a subgroup of patients with p53 wild-type disease showed a median PFS of 13.7 months versus 3.7 months for placebo, with a hazard ratio of 0.44.
Those findings informed the ongoing XPORT-EC-042 study, also referred to as ECO42 during the discussion. The CMO said the trial is focused specifically on patients with p53 wild-type tumors and has enrolled 253 patients. Patients are randomized 1:1, with progression-free survival as the primary endpoint.
The study includes a modified intent-to-treat population of about 220 patients, described as p53 wild-type and MMR proficient, as well as a broader intent-to-treat population that includes all p53 wild-type patients. The CMO said that if the modified intent-to-treat population is positive for PFS, the statistical alpha would then roll down to the broader ITT population.
Paulson said p53 wild-type patients represent slightly more than 50% of endometrial cancer patients, and that about 80% of that group is pMMR while about 20% is dMMR. He said the company has been preparing commercially for a potential endometrial cancer launch, noting that many patients are treated in the community setting and that Karyopharm already has commercial, medical affairs, payer access and patient support capabilities in place.
The CMO said the current standard of care for the relevant patient population is generally chemotherapy, typically a taxane plus platinum doublet for four to six cycles, followed by monitoring until progression. She said there remains an urgent need for new therapies in this setting.
About Karyopharm Therapeutics (NASDAQ:KPTI)
Karyopharm Therapeutics (NASDAQ: KPTI) is a clinical-stage biopharmaceutical company focused on discovering and developing novel first-in-class drugs that target the nuclear export protein XPO1. The company’s lead product, selinexor (marketed as XPOVIO), is an oral selective inhibitor of nuclear export (SINE) compound approved for treatment of multiple myeloma and diffuse large B-cell lymphoma. In addition to selinexor, Karyopharm’s pipeline includes second-generation SINE compounds and combination studies in solid tumors and hematologic malignancies.
Founded in 2008 and headquartered in Newton, Massachusetts, Karyopharm has built a research platform around modulation of nuclear export pathways.
