Despite a February adcom meeting urging the agency to wait for more data, the FDA has approved Karyopharm Therapeutics Inc.'s selinexor, in combination with dexamethasone (dex), as a new treatment for certain adults with relapsed refractory multiple myeloma (MM). The approval covers patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.
"Sadly, often over time, patients [with multiple myeloma] can exhaust all available treatments and still see their disease progress," said Richard Pazdur, director of the FDA's Oncology Center of Excellence and acting director of its Office of Hematology and Oncology Products. Selinexor "provides a treatment option for patients with multiple myeloma with no available therapy," he said.
The medicine, to be marketed as Xpovio, arrived without any black box safety warnings, which J.P. Morgan analyst Eric Joseph said "had been a lingering concern given renewed safety/tolerability focus coming away from the panel in February." Warning and precaution language included in the label cite risks of thrombocytopenia, neutropenia, gastrointestinal toxicity and hyponatremia.
Karyopharm said Xpovio is expected to be commercially available in the U.S. on or before July 10, with a recommended starting dose of 80 mg, taken twice per week. To support dosing flexibility, the company will launch Xpovio in four different four-week dosing package sizes of Xpovio 20-mg tablets, all four of which will be priced at the same wholesale acquisition cost of $22,000 per month, independent of the dosing regimen. The drug will be distributed via three oncology specialty pharmacy providers.
On July 2, following the buildout of the company's commercial organization and development of its product launch strategy, the company's chief commercial officer, Anand Varadan, resigned. Karyopharm promoted Perry Monaco to take charge of sales.
Full approval awaits Boston data
The accelerated approval was granted following a priority review of data from Karyopharm's phase IIb Storm study and partial data from the company's ongoing randomized phase III Boston study, which will now serve as the confirmatory trial required by the accelerated approval. Members of the FDA's Oncologic Drugs Advisory Committee had voted 8-5 in support of delaying the approval until data on progression-free survival (PFS), the Boston study's primary endpoint, were available. (See BioWorld, Feb. 27, 2019.)
The Boston trial, which is expected to read out by the end of this year or in 2020 depending on PFS events, is evaluating 100 mg of selinexor dosed once weekly in combination with the proteasome inhibitor Velcade (bortezomib) and low-dose dex vs. twice-weekly Velcade and low-dose dex in patients with MM who have had one to three prior lines of therapy. Data from the study, if positive, would be used to support regulatory submissions to the FDA and EMA requesting the use of selinexor in patients with MM who received at least one prior therapy.
An FDA summary of the data supporting its decision cited efficacy from an evaluation of Xpovio in 83 patients with relapsed refractory MM who were treated with the drug in combination with the corticosteroid dex. At the end of the study, the overall response rate was measured at 25.3%. The median time to first response was four weeks, with a range of one to 10 weeks. The median duration of response was 3.8 months. The agency said its efficacy evaluation was also supported by additional information from the Boston study.
A first-in-class compound
Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE). It functions by binding with and inhibiting the nuclear export protein XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus, Karyopharm said. The change reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells, according to the company.
Karyopharm was co-founded by Sharon Shacham, the company's president and chief scientific officer, in 2008 to focus on the discovery and development of nuclear transport modulators. She discovered SINE compounds in 2010, with selinexor becoming the first example of the class to enter clinical development in 2012. Karyopharm's other co-founder is CEO Michael Kauffman.
Company shares (NASDAQ:KPTI) rose 36% to close at $8.90 on Wednesday.
According to the National Cancer Institute (NCI), MM is the second most common cancer of the blood in the U.S., with more than 32,000 new cases each year and more than 130,000 patients living with the disease, of which about 69,000 are treated with drug therapy annually. Karyopharm's team estimates that there are about 6,000 patients being treated with their fourth or later line of therapy.
Patients with penta-refractory multiple myeloma are those who have previously received the two proteasome inhibitors, Velcade (bortezomib) and Kyprolis (carfilzomib), the two immunomodulatory drugs, Revlimid (lenalidomide) and Pomalyst (pomalidomide), and the anti-CD38 monoclonal antibody Darzalex (daratumumab), as well as alkylating agents.
The median age of diagnosis for MM is 69. There is no cure. According to the NCI, nearly 13,000 deaths due to MM are expected in the U.S. in 2019.
A marketing authorization application for selinexor at the EMA remains under review, with a decision on conditional approval for the treatment of heavily pretreated MM patients expected late this year. Karyopharm is still evaluating whether to go it alone or enlist a partner should that approval come through.
The company could also file for approval to market selinexor in earlier lines of MM should the Boston study return positive data. It also has plans for regulatory submissions in the U.S. and Europe seeking accelerated and conditional approvals in relapsed or refractory diffuse large B-cell lymphoma based on data generated from its recent phase IIb Sadal study.