Introduction

SARS-CoV-2 infection has evolved into a global health crisis and pandemic. SARS-CoV-2 infection can be accompanied by a marked inflammatory response which is associated with multi-organ dysfunction, respiratory failure, and death [1]. Both the SARS-CoV-2 lifecycle and pro-inflammatory transcription factors require functional host nuclear export mediated by Exportin 1 (XPO1), which was recently identified as a “hub” host protein for SARS-CoV propagation [2]. Selinexor is a potent, oral, selective inhibitor of nuclear export (SINE) compound that specifically blocks XPO1 [3]. SINE compounds reduce inflammation through inhibition of the NF-κB pathway, thereby reducing cytokines including IL-1, IL-6, and TNFα, which are associated with COVID-19 pathogenesis [4-6]. SINE compounds also block essential interactions between SARS-CoV-2 proteins and human XPO1 [7]. Selinexor demonstrates anti-SARS-CoV-2 activity in vitro with 90% inhibition of new virus production at 100nM (manuscript in preparation).

In addition, selinexor and related SINE compounds protect mice from endotoxin- and viral-induced lung injury by reducing pro-inflammatory cytokines and improving survival [8,9]. Selinexor received accelerated approval from the US FDA in combination with dexamethasone as a treatment for patients with advanced multiple myeloma, and >3,200 patients have received selinexor alone or in combination with other anti-neoplastic agents in clinical studies with adequate tolerability [10]. Given the urgency of the COVID-19 pandemic, the preclinical efficacy, and safety and tolerability observed in multiple early-phase clinical trials, selinexor may confer both anti-viral and anti-inflammatory activity in SARS-CoV-2 infected patients. Here, we report the first case of a COVID-19 patient treated with low dose selinexor (20 mg three times weekly) and his early clinical response following dosing.

Case Description

AA 69-year-old Hispanic male (80.2kg, 1.75m, ~1.95 m²) with a past medical history of hypertension presented to Lehigh Valley Hospital Allentown, PA on April 21, 2020 with complaints of increasing weakness, confusion, decreased appetite, and shortness of breath. The patient was found to be SARS-CoV-2 positive on April 13, 2020, which was confirmed during hospital admission on Day 1 and Day 3. The family reported that the patient had been febrile for 10 days and treated at home by his primary care physician with ivermectin. The patient was living with three additional family members reported to be ill. Upon arrival to the emergency room (Day 1), the patient was afebrile, tachypneic with a respiratory rate of 30-33 breaths per minute (bpm), blood pressure of 102/89mmHg, and heart rate of 133-88 beats per minute. He was hypoxic on room air, requiring 2L/min O₂ via Nasal Cannula (NC) to maintain his oxygen saturation (SaO₂ via pulse oximetry) >90%.

Laboratory tests showed an elevated white blood cell count (WBC, 13×109/L), creatinine (1.31μmol/L), Na (129mEq/L), and transaminitis with AST (101 U/L) and ALT (99 U/L). On Day 2 of the hospital admission, the patient became increasingly confused and was placed on 6 L/min O₂ via NC to maintain SaO₂ >90%. He developed progressive confusion and worsening hypoxia later that day and was switched to 70% FiO₂ via facemask. On Day 3 the patient’s respiratory rate was 21-25 bpm and the chest x-ray showed stable hazy bilateral infiltrates. On Day 4, the patient was more alert on 70% FiO₂ via facemask with the following vital signs: temperature 99.1°F, heart rate 99 beats per minute, blood pressure 146/89mmHg, respiratory rate 20bpm, and SaO₂ 94%. The patient subsequently decompensated and was transferred to the ntensive Care Unit (ICU) on Day 5, where he received 65- 70% FiO₂ via Nasal High Flow (NHF) therapy (Optiflow, NC) to maintain SaO₂ >90%. The patient became increasingly lethargic but did not require vasopressors or mechanical ventilation.

Methods

For analysis, the patient’s medical records - including clinical characteristics and treatment, laboratory parameters, chest X-rays, and treatment - were collected. This case study was approved by the institutional review board of the Lehigh Valley Health Network, and informed consent was obtained.

Selinexor Dosing

The patient received 6 doses of 20 mg oral selinexor over a period of 2 weeks.

Results

Upon admission to the ICU on hospital Day 5, the patient was receiving 60-70% FiO₂ via NHF therapy, and was afebrile, lethargic, and confused. The patient was ineligible for the clinical trial Evaluation of Activity and Safety of Oral Selinexor in Participants With Severe COVID-19 Infection (Coronavirus) (XPORT-CoV-1001, NCT04349098) due to a serum sodium level <135mmol/L (an exclusion criteria), and was subsequently enrolled on the Karyopharm Expanded Access Program (KEAP). The patient was characterized to a medium-risk group of developing critical illness among patients with COVID-19 based on 10 variables measured on admission [11]. On Day 8, the patient began oral selinexor 20mg three times per week (every other day). That afternoon, he improved sufficiently to receive 10L/min O₂ via NC. The patient’s O₂ requirement decreased to 8L/min NC O₂ on Day 9, further decreasing to 6L/min NC before transfer from the ICU to the COVID-19 hospital ward. The respiratory rate was 20-23 bpm on Day 8 and improved to <20 bpm on Day 9. His condition continued to improve and he became more interactive and ambulatory by Day 10, with O₂ requirements decreased to 5L/ min NC and then 4L/min NC.

Three days after the first dose of selinexor (Day 11), the patient was transferred to a regular floor and was able to talk and eat without desaturating while receiving 3L/min NC. In the evening of Day 11, with no assistance, his SaO₂ was 94-96% through discharge on Day 15, within 7 days after initiating selinexor treatment. Prior to starting therapy, the patient had elevated inflammatory markers which improved rapidly and significantly after starting selinexor. Most notably, C-Reactive Protein (CRP) decreased from 196.0mg/L upon admission (Day 1) to 13.9mg/L after 2 doses of selinexor (Day 10), with a further reduction to 5.5mg/L on Day 12. Comparable effects were observed for IL6: 11pg/mL on Day 8 prior to selinexor dosing to <5pg/mL on Day 10, and ferritin (5,735ng/mL to 1,214ng/mL) (Table 1). Other significant substantial improvements following initiation of selinexor included platelet count, which increased progressively throughout treatment from 203 × 10⁹/L to 466 × 10⁹. The transaminase elevations associated with severe COVID-19 present at hospital admission also improved with reductions in both ALT (99 U/L to 38 U/L) and AST (101 U/L to 32 U/L) (Table 2).

Discussion

Selinexor and related SINE compounds have shown potent in vitro and in vivo anti-viral activity against a broad range of RNA and DNA viruses. Here we report a case of a patient with severe COVID-19 and progressive hypoxia and at high risk for progressive respiratory failure who responded to low dose selinexor without any reported adverse effects. The changes observed following administration of selinexor-particularly the dramatic clinical improvements in a patient who was rapidly decompensating with profound hypoxia and mental status changes, as well as reductions in CRP and ferritin-suggest that selinexor may confer both antiviral and anti-inflammatory activity and may be a feasible approach to reducing overall disease burden and improving prognosis in patients with severe COVID-19.

Conclusion

This is the first report to demonstrate the possible activity of selinexor in a SARS-CoV-2-infected patient. Combined with the established safety and tolerability, these data may translate to the broader application of selinexor to the COVID-19 patient population. The safety and adverse event profile of selinexor in patients with severe COVID-19 is currently being assessed in a placebo-controlled randomized global trial (NCT04349098).

Acknowledgements

This study was supported by research funding from Karyopharm Therapeutics, Inc. JetPub Scientific Communications LLC, supported by Karyopharm Therapeutics, Inc., assisted in the preparation of this manuscript, in accordance with Good Publication Practice (GPP3) guidelines.

Conflict of Interest

The authors declare no competing financial interests.

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