The First Nuclear Export Inhibitor Xpovio Was Approved For New Indications In The United States

- Jul 02, 2020-

Deqi Medical Partner Karyopharm Therapeutics recently announced that the US Food and Drug Administration (FDA) has approved the second tumor indication for Xpovio (selinexor) for the treatment of relapsed or refractory diffuseness of at least 2 systemic therapies Adult patients with large B-cell lymphoma (DLBCL), including DLCBL caused by follicular lymphoma (FL).


The indication was approved through the FDA’s accelerated approval process based on remission rate data. Continued approval for this indication may depend on the verification and description of clinical benefits in confirmatory trials. Karyopharm also plans to submit a marketing authorization application (MAA) for Xpovio to treat relapsed or refractory DLBCL to the European Medicines Agency (EMA) in 2021.


It is worth mentioning that Xpovio is currently the only monotherapy oral therapy approved for the treatment of relapsed or refractory DLBCL. Previously, the FDA has granted Xpovio the orphan drug qualification and fast-track qualification for this indication. In addition, Xpovio is the first and only drug approved by the FDA for both myeloma and DLBCL.


Xpovio is a first-in-class, selective nuclear export inhibitor (SINE). In August 2018, Deqi Pharmaceuticals and Karyopharm Therapeutics reached a strategic cooperation to jointly develop 4 innovative oral drugs, including 3 SINE XPO1 antagonists Xpovio (selinexor), eltanexor, verdinexor and a PAK4 and NAMPT dual-target inhibitor KPT -9274. In January 2019, ATG-010 (Xpovio) was approved in China for clinical treatment of refractory and relapsed multiple myeloma. The drug is also the first selective nuclear export inhibitor developed for multiple myeloma in the Chinese market (SINE).


In July 2019, Xpovio received accelerated approval from the US FDA in conjunction with dexamethasone for use in at least 4 therapies and at least 2 proteasome inhibitors (PI), at least 2 immunosuppressants (IMiD), one An anti-CD38 monoclonal antibody refractory relapsed refractory multiple myeloma (RRMM) patient.


It is worth mentioning that Xpovio is the first and only nuclear export inhibitor (SINE) approved by the FDA. In addition, Xpovio is also the first drug approved for a new target of myeloma (XPO1) since 2015.

Xpovio

This indication for DBLCL is based on the positive results of a multicenter, single-arm phase IIb SADAL study. The study was conducted in 134 patients with relapsed or refractory DLBCL who had previously received a median of 2 systemic therapies (range: 1-5). In the study, patients received a fixed 60mg dose of Xpovio, orally twice daily for a period of 4 weeks. Patients with germinal center B cells (GCB) or non-GCB subtypes of DLBCL were also included in the study.


The data shows that the total response rate (ORR) of Xpovio treatment is 29%, the complete response rate (CR) is 13%, and the partial response rate (PR) is 16%. Among patients with remission, the median duration of remission (DOR) exceeded 9 months, 56% of patients had duration of remission ≥3 months, 38% of patients ≥6 months, and 15% of patients ≥12 months. These data highlight the potential of Xpovio as a new and first oral therapy in a population of patients with relapsed or refractory DLBCL who have previously received at least two multi-drug regimens, are not suitable for stem cell transplantation, and have extremely limited treatment regimens.

1393477-72-9 selinexor

 selinexor CAS NO:1393477-72-9 Structural formula

The active pharmaceutical ingredient of Xpovio is selinexor, a first-in-class, oral, selective nuclear export inhibitor (SINE) compound that acts by binding and inhibiting nuclear export protein XPO1 (also known as CRM1), resulting in tumor suppressor proteins in the nucleus Accumulation, which will restart and amplify their tumor suppressor function, leading to selective apoptosis of cancer cells, while not causing significant effects on normal cells.


In May of this year, Karyopharm submitted another Xpovio supplemental new drug application (sNDA) to the US FDA seeking approval for Xpovio as a new therapy for the treatment of multiple myeloma (MM) that had previously received at least one therapy. )patient.


This sNDA is based on the positive top-line results of the Phase III BOSTON study. The study was conducted in patients with relapsed or refractory MM who had previously received 1-3 therapies and evaluated the weekly combination of Xpovio and weekly once-a-week combination of Velcade (bortezomib, bortezomib) and low-dose dexamethasone ( SVd), the efficacy and safety of the combination of Velcade and low-dose dexamethasone twice a week (Vd). Vd is a standard therapy for clinical treatment of MM.


The results showed that the study reached the primary endpoint: compared with the Vd treatment group, the progression-free survival (PFS) of the SVd treatment group increased by 4.47 months and an increase of 47% (median PFS: 13.93 months vs 9.46 months) , And the risk of disease progression or death was significantly reduced by 30% (HR=0.70, p=0.0066). Previously, compared with the Vd treatment group, the overall response rate (ORR) of the SVd treatment group also increased significantly. In this study, no new safety signals were observed in the SVd treatment group, and there was no imbalance in deaths between the two groups.


If approved, Xpovio will provide an important supplement to the treatment model for patients with relapsed or refractory MM. Karyopharm is currently evaluating the potential of selinexor in the treatment of a range of hematological malignancies and solid tumors in multiple mid-to-late clinical studies, including multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), and liposarcoma (SEAL Research), endometrial cancer, recurrent glioblastoma.