Mortality and morbidity of hospitalized patients with severe COVID-19 infection at high risk of progression to ARDS remain high despite the availability of the antiviral agent (remdesivir), anti-inflammatory (dexamethasone), anti-interleukin-6 receptor antibodies (tocilizumab), and Janus kinase inhibitors (baricitinib).
The COVID-19 virus enters the cell through the attachment of the S protein to the ACE-2 receptors, hijacking the internal transportation system (the microtubules in the cytoskeleton) to replicate and release new viruses for infection.
Sabizabulin is an oral agent under investigation for treating breast and prostate cancers. The agent targets the colchicine binding site on β-tubulin and a unique site on α-tubulin. It crosslinks these α and β subunits inhibiting microtubule polymerization. As a result, sabizabulin is both antiviral and anti-inflammatory as it targets and disrupts microtubules, halting the transport of viruses in the cell and inhibiting cytokine release.
A Phase II interim analysis of oral sabizabulin investigated the safety and efficacy of 18 mg of Sabizabulin in 40 patients with moderate to severe COVID-19 infection. The proportion of patients alive without respiratory failure at Day 29 was 70% in the placebo group, compared to 94.7% in the Sabizabulin group. There were no treatment-related adverse events or serious adverse events observed in the study.
The encouraging result from the phase II trial led to investigating the agent in a phase III, multicenter, randomized placebo-controlled clinical trial. The research question was whether Sabizabulin improves the outcome in moderate to severe COVID-19 patients at risk for progression into ARDS and death compared to placebo. The study planned to randomize a total of 210 patients with a 2:1 assignment. It was conducted at 27 participating sites in 5 countries (USA, Brazil, Bulgaria, Argentina, and Mexico) with the majority of patients enrolled in the USA and Brazil.
A total of 204 patients with moderate to severe COVID-19 infection at high risk of ARDS and death were randomized to receive either 9 mg of oral sabizabulin (134 patients) or placebo (70 patients) daily for 21 days or until discharge. Key inclusion criteria included high risk for ARDS, hospitalized, WHO Ordinal Scale for Disease Progression ≥4, and oxygen saturation <94% on room air. Exclusion criteria included pregnancy or breastfeeding, WHO score ≥7 (on mechanical ventilation with one more organ support), LFTs >3X upper normal, elevated bilirubin above the upper limit of normal, or creatinine clearance <60 ml/min.
60-day all-cause mortality was significantly lower in the sabizabulin group compared to the placebo group (20.2% vs. 45.1%, 24.9-point difference and 55.2% relative reduction in death, OR, 3.23; 95% CI: 1.45-7.22, p=0.0042), and the number needed to treat (NNT) is 4. Sabizabulin resulted in a relative reduction of 43% in ICU days, 49% in ventilator days, and 26% in hospital days compared to placebo. The benefit is detected regardless of sex, BMI, geographical area, age, WHO ordinal score, treatment received, or baseline comorbidities. Sabizabulin has an acceptable side effect and safety profile in the first 150 patients who were analyzed.
The trial was stopped early due to efficacy but was only short of 6 patients (planned for 210 with >92% power to detect a 50% relative reduction in death). Similar results occurred when the analysis included all 204 patients. The study concluded that sabizabulin reduces 60-day all-cause mortality in hospitalized patients with moderate to severe COVID-19 infection who are at high risk of progression to ARDS or death with fewer incidences of adverse events compared to placebo.
The study results were submitted to FDA for Emergency Use Authorization. If approved, this agent will be the first with significant outcome benefits in hospitalized patients with moderate to severe COVID-19 infection.
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