The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).
Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).
The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.
“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.
In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.
About selinexor
Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).
This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.
Selinexor combos in MM
In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.
The study included 9 evaluable patients who received selinexor at 45 mg/m2 twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.
The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.
The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.
During the dose-evaluation part of the study, the 60 mg/m2 selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m2 is the recommended future study dose.
In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.
The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.
