The U.S. Food and Drug Administration (FDA) has granted priority review to Karyopharm Therapeutics’ application requesting accelerated approval of its investigational therapy selinexor as a treatment for multiple myeloma patients who have failed five prior myeloma therapies. A final decision is expected by April 6, 2019.
“As a potential new therapy with a novel mechanism and compelling clinical profile, we believe oral selinexor, if approved, will provide a meaningful therapeutic option for patients battling highly resistant, penta-refractory myeloma,” Sharon Shacham, PhD, founder, president and chief scientific officer of Karyopharm, said in a press release.
“The acceptance of this [New Drug Application] for review and grant of Priority Review mark significant milestones for the selinexor program, and further underscores the high level of unmet need in this patient population,” Shacham said. “We look forward to working with the FDA during the review process.”
Tumor suppressor proteins prevent the abnormal proliferation or induce the death of abnormal cells. To escape the effect of these proteins, tumors often increase the levels of XPO1, a protein that exports tumor suppressor proteins from the nucleus into the cytoplasm.
Selinexor, Karyopharm’s lead oral therapy, works against this tumor evasion mechanism by suppressing the function of XPO1 — called a Selective Inhibitor of Nuclear Export, or SINE. This results in the accumulation of tumor-suppressor proteins inside the nucleus of the cell, leading to the selective induction of cell death in cancer cells while sparing normal ones.
The application was based on clinical data from the STORM Phase 2b trial (NCT02336815), where selinexor was given, in combination with low-dose dexamethasone, to quad-refractory and penta-refractory myeloma patients.
Quad-refractory patients are those who received prior treatment with two immunomodulatory drugs, Revlimid (lenalidomide) and Pomalyst (pomalidomide), and two proteasome inhibitors, Velcade (bortezomib) and Kyprolis (carfilzomib).
Also, quad-refractory patients did not respond to at least one proteasome inhibitor and one immunomodulatory drug, and progressed following their most recent therapy.
Those with penta-refractory disease are similar to patients with quad-refractory disease, but are also refractory to an anti-CD38 monoclonal antibody, such as Darzalex (daratumumab), or isatuximab.
The most recent results in penta-refractory patients have shown that selinexor shrank tumors in 25.4% of these patients, including two patients whose tumors were completely gone. Responses lasted a median of 4.4 months.
If approved, Karyopharm plans to commercialize selinexor in the first half of 2019. The company is also planning to submit a similar application to the European Medicines Agency for conditional approval.
Accelerated approvals in the U.S. and conditional approvals in Europe are often based on promising response rates in early-stage clinical trials. However, regulatory agencies require that these results are confirmed in larger Phase 3 clinical trials after the medicines are approved.
To this end, Karyopharm is already conducting a Phase 3 trial, called BOSTON (NCT03110562), to determine whether a combination of selinexor, low-dose dexamethasone and Velcade is better at delaying disease progression and extending patients’ lives than Velcade and dexamethasone alone. The trial is recruiting patients who have received one to three prior therapies.