Selinexor COVID-19 Global Trial Launching

Thomas J. Walsh, MD, professor of Medicine, Pediatrics, and Microbiology & Immunology, Weill Cornell Medicine, Cornell University

Thomas J. Walsh, MD

Selinexor (Xpovio), an FDA-approved drug for the treatment of patients with relapsed/refractory multiple myeloma, is being evaluated in a global randomized clinical trial as a potential treatment for hospitalized patients with severe COVID-19.¹

Karyopharm Therapeutics Inc., the manufacturer of selinexor, a selective inhibitor of nuclear export (SINE) compound which blocks the cellular protein XPO1, explained the rationale behind the trial in a press release.

"One of the most important aspects of COVID-19 is the marked pulmonary inflammation with high levels of cytokines such as IL6, IL1, IFNg and others. Along these lines, selinexor and other SINE compounds have demonstrated potent anti-inflammatory activity through the inhibition of NF-kB, leading to reductions in all of these cytokines in a variety of models, and this may be particularly beneficial to hospitalized patients with COVID-19,” the company explained.

Thomas J. Walsh, MD, professor of Medicine, Pediatrics, and Microbiology & Immunology, Weill Cornell Medicine, Cornell University, commented in the press release on the decision to explored selinexor for COVID-19.

“Given the globally devastating impact of the COVID-19 pandemic, innovative strategies and collaborative efforts are critically needed to bring effective treatment options to patients, who are so desperately in need. I am highly encouraged by the scientific rationale of studying selinexor, which targets both virus and immune-mediated injury, for treatment of patients with severe COVID-19. My staff, colleagues, and I and look forward to working with Karyopharm to better understand the role of this novel approach in improving patient outcomes of COVID19.”

In July 2019, the FDA granted an accelerated approval to selinexor for use in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory drugs, and a CD38-targeted monoclonal antibody.²

The approval was based on data from a prespecified subgroup analysis of 83 patients of Part 2 of the multicenter, single-arm, open-label, phase II STORM trial. In this subpopulation, patients’ disease was refractory to bortezomib, carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), and daratumumab (Darzalex), and the benefit-risk ratio appeared to be greater in this more heavily pretreated subgroup than in the overall population with an ORR of 25.3%. Thirty-seven percent (n = 31) of patients had a minimal response or better to selinexor.

Safety findings of the 202 total patients enrolled in Parts 1 and 2 of the STORM trial who received the combination of selinexor/dexamethasone showed that the most common (≥20%) adverse events (AEs) were thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infections.

Twenty-seven percent of patients discontinued due to AEs, and 53% of patients experienced dose reductions; 65.3% had selinexor dose interruptions. The most frequent AEs requiring permanent discontinuation in ≥4% of patients who received selinexor included fatigue, nausea, and thrombocytopenia. Fatal AEs occurred in 8.9% of patients.

Also in myeloma, selinexor in combination with bortezomib (Velcade) and low-dose dexamethasone led to a statistically significant increase in progression-free survival (PFS) compared with bortezomib/dexamethasone alone in patients with multiple myeloma who have received 1 to 3 prior lines of therapy, according to topline findings from the phase III BOSTON trial.³

Results showed that the median PFS in the selinexor arm was 13.93 months compared with 9.46 months with bortezomib/dexamethasone alone, leading to a 30% reduction in the risk of disease progression or death (HR, 0.70; P = .0066). Karyopharm plans to submit a supplemental new drug application to the FDA based on these data.

Beyond myeloma, the FDA has granted a priority review designation to a supplemental new drug application for selinexor (Xpovio) as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma, not otherwise specified, who have received ≥2 prior therapies.⁴

The application includes updated results from the phase IIb SADAL trial, in which the agent demonstrated a 28.3% ORR in patients with relapsed/refractory DLBCL, including an 11.8% complete response rate and a median duration of response of over 9 months.

References

1. Karyopharm to Evaluate Low Dose Selinexor as a Potential Treatment for Hospitalized Patients with COVID-19. Published April 7, 2019. https://bit.ly/2yKMmfr. Accessed April 7, 2019. Selinexor Prescribing Information. FDA. Published July 3, 2019. https://bit.ly/309qeU6. Accessed July 3, 2019.
2. Karyopharm Announces FDA Approval of XPOVIO™ (selinexor) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. Karyopharm. Published July 3, 2019. https://bit.ly/2XMo1k0. Accessed July 3, 2019.
3. Karyopharm announces phase 3 BOSTON study meets primary endpoint with significant increase in progression-free survival in patients with multiple myeloma following one to three prior lines of therapy [news release]: Newton, MA. Karyopharm Therapeutics. Published March 2, 2020. https://bit.ly/3csGuXA. Accessed March 2, 2020.
4. Karyopharm reports updated data from the phase 2b SADAL study at the 2019 International Conference on Malignant Lymphoma [news release]: Newton, MA. Karyopharm Therapeutics, Inc. Published June 19, 2019. https://bit.ly/2PO7qrc. Accessed December 23, 2019.

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“SINE XPO1 inhibitors have demonstrated activity against over 20 different viruses, including the RNA viruses, influenza, respiratory syncytial virus and other common causes of respiratory infection. XPO1 inhibition has been identified in several assays as having potential activity against SARS-CoV-2, although specific animal models have not been available to date.