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Every cell in the human body relies on a constant flow of proteins moving between two compartments, the nucleus and the surrounding cytoplasm. That traffic is managed by a small group of transport proteins, and one of them, called exportin 1, has become an unlikely focal point in cancer research. Exportin 1, often abbreviated as XPO1, acts as a kind of delivery vehicle. Its job is to carry other proteins out of the nucleus once they have finished their work inside it.
In many cancers, that delivery system runs into trouble. Tumor cells frequently produce far more XPO1 than healthy cells do, and the excess activity pushes important regulatory proteins out of the nucleus faster than they should leave. Among the proteins caught up in this outbound traffic are tumor suppressors, the molecules whose entire function is to sense damaged or abnormal cells and stop them from multiplying. When those tumor suppressors get exported out of the nucleus prematurely, they lose the ability to do that job, and cancer cells gain a growth advantage. A class of medicines known as XPO1 inhibitors was developed specifically to interrupt this process. By blocking the export pathway, these drugs trap tumor suppressor proteins inside the nucleus, restoring their ability to slow or halt abnormal cell division. The best known XPO1 inhibitor on the market today is selinexor, sold under the brand name Xpovio, which is already approved in the United States for multiple myeloma and a form of lymphoma.
The company behind that drug, Karyopharm Therapeutics Inc. (NASDAQ: KPTI), spent years testing whether the same mechanism could work against a much different cancer, an advanced or recurrent form of endometrial cancer. The trial, called XPORT-EC-042, tested selinexor as a maintenance therapy given after patients had already responded to earlier chemotherapy. Karyopharm announced that the study missed its primary goal of extending progression free survival, the length of time before a patient’s cancer worsens or returns. Among the 236 patients evaluated, those taking selinexor had a median progression free survival of 12.75 months compared with 7.43 months for those on placebo, a gap of more than five months. Despite that numerical edge, the result landed at a one-sided p value of 0.0791 against a hazard ratio of 0.76, just short of the threshold needed to call it a statistical success.
Markets rarely forgive a near miss in oncology. Shares of Karyopharm, already trading as a microcap stock with a market value under $200 million, plunged 68.47% from $7.01 in after hours trading once the news broke to around $2.35, and that is where it is trading on the open of the market today. For a company whose value rests heavily on a handful of programs, there is little room to absorb that kind of shock.
Rather than walk away from selinexor entirely, Karyopharm said it will scale back investment in the endometrial cancer program and redirect resources toward two areas where its data has looked stronger, myelofibrosis and multiple myeloma. The company pointed to its Phase 3 SENTRY trial in myelofibrosis, which produced a statistically significant benefit, and said it plans to submit an application to the U.S. Food and Drug Administration later this year.
As demonstrated, a single trial result can rewrite years of strategy almost overnight, and this week’s numbers are a reminder of how thin the margin between a promising trend and a failed endpoint can be.
