SINE compound shows promise in blood malignancies

NATICK, Mass.—Karyopharm Therapeutics Inc., a clinical-stage pharmaceutical company focused on the discovery and development of novel first-in-class drugs directed against nuclear transport targets for the treatment of cancer and other major diseases, presented clinical data from an ongoing Phase 1 clinical trial of its lead oral SINE compound, Selinexor (KPT-330), in patients with relapsed and/or refractory non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) at the recent annual meeting of the American Society of Hematology (ASH) in New Orleans.

Selinexor is a first-in-class, oral SINE compound that is undergoing Phase 1 studies in patients with advanced hematologic malignancies, solid tumors and sarcomas. Selinexor functions by blocking the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies the tumor suppressor function. This is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells.

“Our founder, who is also my wife, is a computational biophysicist who began the discovery process with five million compounds,” says Dr. Michael Kauffman, CEO of Karyopharm. “From there she characterized 50 potential candidates for bioassays; eight worked. Structures were modified one at a time and Selinexor resulted.”

Thus far, the data show that oral Selinexor demonstrates preliminary evidence of anticancer activity as a single agent in the majority of heavily pretreated, relapsed and/or refractory NHL and CLL patients in the study cohort who had progressive disease on study entry. “Under these circumstances, when anyone responds you’re excited,” Kauffman notes, and several of these patients have remained on the study with Selinexor as their only anticancer treatment for between six and 12 months.

About a month prior to the ASH meeting, Karyopharm conducted an initial public offering that was fully subscribed and, after which, underwriters fully exercised their option to purchase an additional million-plus shares at the public offering prices of $16 per share. “The favorable IPO results were largely based on the clinical data,” Kauffman opines. He adds that Karyopharm’s patent position is based both on composition of matter and methods of use and runs through 2032.

Coming out of the ASH meeting, Dr. Sharon Shacham, founder, chief scientific officer and president of R&D at Karyopharm, said: “We believe the data presented at ASH further demonstrate the potential of Selinexor as a single-agent treatment for heavily pretreated, relapsed and/or refractory hematologic malignancies. The patients in our Phase 1 study have hematologic malignancies that have progressed after multiple previous treatments, including combinations of highly active agents. These data support our plans to conduct future studies of Selinexor alone and in combination with standard of care chemotherapy regimens and other approved therapies.

“We plan to continue to evaluate new indications for potential treatment with Selinexor based on these initial results as well as to assess the maximum tolerated dose and dosing schedule, and expect to report more data from the Phase 1 trial and investigator-sponsored single-agent and combination studies in the first half of 2014,” she added. “ In addition, we expect to initiate randomized studies in the first half of next year designed to potentially serve as the basis for an application seeking regulatory approval of Selinexor.”

“We plan to use the 2014 studies to seek approval for Selinexor as a single agent,” Kauffman states, “probably in blood cancer first. We are also looking at the drug in a topical version for wound healing where it has shown good effects and surprising potential. Beyond that both Selinexor (KTP330) and its ‘cousin’ KTP350 are being looked at for their anti-inflammatory properties and as antivirals against influenza and HIV. We expect to be in the clinic for these indications in the next year or so.”