ABSTRACT
Introduction: In the setting of viral infections, including infection with SARS-CoV-2, lymphocyte exhaustion and lymphopenia are common. Patients with COVID-19 who develop lymphopenia, particularly low numbers of circulating natural killer (NK) cells, are at high risk for disease progression. Thus, strategies that overcome profound lymphopenia and restore innate immune function may reduce the severity of COVID-19. One approach is the direct infusion of an exogenous source of healthy, functional NK cells intended to boost the patient’s immune system during the viral infection, enabling elimination of infected cells. “DVX201” is a cord blood-derived allogeneic NK cell therapy that is cryopreserved and intended for “off-the-shelf use” without HLA-matching. Objective: The primary objective of this study is to investigate the safety and to identify the recommended phase II dose and/or the maximum tolerated dose (MTD) of DVX201 in patients hospitalized with COVID-19. Methods: We are conducting an open-label, nonrandomized phase I safety and dose-finding (modified 3+3) study of DVX201 at three dose levels in patients hospitalized with COVID-19. Adult patients with documented SARS-CoV-2 infection were eligible if they were admitted to the hospital, were receiving ≤6 L supplemental oxygen by low flow delivery, and did not have other evidence of cytokine storm based on levels of serum IL-6, C-reactive protein, and ferritin. Results: To date, 9 patients have been enrolled: 3 subjects at each dose level. All dose levels have been well tolerated, with no dose-limiting toxicities, infusion toxicities, or cytokine release syndrome observed. All patients were discharged from the hospital at an average of 5 days post infusion. Blood samples were drawn for correlative studies including persistence of DVX201, pre- and post-infusion immune system characterization, and cytokine panels. Accrual is continuing at the MTD. Discussion: This trial will serve as the proof of concept for the use of DVX201 as an anti-viral treatment for COVID-19. These results will inform the potential role of DVX201 for treatment of other life-threatening viral infections by harnessing NK cells’ innate function to kill virally infected cells, regardless of the etiology of the infection.
ABSTRACT
Background. Remdesivir (RDV) is a potent nucleotide prodrug inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase that has demonstrated efficacy in the treatment of patients hospitalized with moderate to severe COVID-19. This Phase 3 (GS-US-540-9012) double-blind, placebo-controlled study compared the efficacy and safety of 3 days of RDV to standard of care in non-hospitalized, high-risk participants with confirmed COVID-19. Methods. Participants were randomly assigned 1:1 to receive intravenous (IV) RDV (200 mg on day 1, 100 mg on days 2 to 3) or placebo. The primary efficacy endpoint was composite COVID-19 hospitalization or all-cause death by day 28 and compared using Cox proportional hazards model with baseline stratification factors as covariates. The primary safety endpoint was proportion of participants with treatment-emergent adverse events. Study enrollment was terminated early for administrative reasons in light of the evolving pandemic. Results. 562 patients underwent randomization and started their assigned treatment (279, RDV;283, placebo). Baseline demographics and characteristics were balanced across arms. Overall, 52% were male, 44% were Hispanic/Latino ethnicity and 30% were ≥ 60 years old. The most common comorbidities were diabetes mellitus (62%), obesity (56%;median BMI, 30.7), and hypertension (48%). Median baseline SARS-CoV-2 RNA nasopharyngeal viral load was 6.2 log10 copies/mL. Treatment with RDV significantly reduced COVID-19 hospitalization or all-cause death by day 28 (HR, 0.13;95% CI, 0.03 - 0.59;p = 0.008;Table 1) compared to placebo. Participants receiving RDV also had significantly lower risk for COVID-19-related medically attended visits or all-cause death by day 28 compared to placebo (HR, 0.19;95% CI, 0.07 - 0.56;p = 0.002;Table 1). No deaths occurred in either arm by day 28. There was no difference between arms in time-weighted average change in nasopharyngeal viral loads from baseline up to day 7. The proportion of patients with AEs was similar between arms (Table 1);the most common AEs in the RDV arm were nausea (11%), headache (6%), and diarrhea (4%). Conclusion. A 3-day course of IV RDV was safe, well tolerated and highly effective at preventing COVID-19 related hospitalization or death in high-risk non-hospitalized COVID-19 patients.