The coronavirus disease 2019 (Covid-19) pandemic is in its third year, with more than 509 million confirmed cases and 6.2 million deaths worldwide thus far.There are now effective vaccines for the general population and antiviral agents (molnupiravir and nirmatrelvir) for symptomatic patients in the nonhospitalized setting. , However, despite the availability of the antiviral remdesivir and anti-inflammatory/immunomodulators including dexamethasone, anti-interleukin-6 receptor antibodies, and Janus kinase inhibitors , for hospitalized patients at high-risk for acute respiratory distress syndrome (ARDS), mortality and morbidity rates remain significantly high.
The principal therapy for hospitalized patients with moderate to severe Covid-19 is supportive care and oxygen, with mechanical ventilation in cases of respiratory failure and hemodynamic support for the management of septic shock.Complicating matters, Covid-19 case surges create an undue strain on hospital capacity that results in excess deaths in all types of critical care patient populations beyond individuals with Covid-19. Effective and safe therapies are greatly needed to reduce the risk of death in hospitalized patients with Covid-19 thereby reducing the impact of Covid-19 on critical care delivery.
Sabizabulin is an orally available, novel microtubule disruptor that targets, binds, and crosslinks both the α- and β-tubulin subunits to inhibit polymerization and to induce depolymerization of microtubules in cells., Microtubules are intracellular transport structures critical for coronavirus cellular entry, trafficking, replication, and egress as well as for triggering the innate inflammatory response and cytokine storm responsible for ARDS, septic shock, and frequently death. ARDS is one of the primary causes of mortality in Covid-19 infection, as infiltration of immune cells in both lungs leads to alveolar-capillary membrane injury and edema; increased lung permeability leads to exudates filling the air sacs, with resultant hypoxemia. Preclinical studies demonstrate that sabizabulin has both significant antiviral and anti-inflammatory activities by disrupting microtubule dynamics.
In a phase 2, double-blind, placebo-controlled, clinical trial of 39 patients with moderate to severe Covid-19 at high risk for ARDS, sabizabulin treatment resulted in reductions in deaths, respiratory failure, days in the intensive care unit (ICU), and days on mechanical ventilation. Sabizabulin had an acceptable side-effect and safety profile with no clinically meaningful differences in safety observations compared with placebo, except for a higher incidence of respiratory failure and death in the placebo group.Accordingly, a randomized, double-blind, multicenter, global placebo-controlled phase 3 clinical trial was conducted with hospitalized patients with moderate to severe Covid-19 infection who were at high risk for ARDS and death. Here, the sabizabulin efficacy and safety results from this study are reported.
Objectives, Patients, and Oversight
Eligible patients were required to meet the following criteria: to be at least 18 years of age with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection; to have a World Health Organization (WHO) 9-point ordinal scale for clinical improvementscore of 4 (oxygen by mask or nasal prongs) with a documented comorbidity (asthma, chronic lung disease, diabetes, hypertension, severe obesity with a body-mass index [BMI] of 40 or greater, 65 years of age or older, primarily reside in a nursing home or long-term care facility, or immunocompromised status), WHO 5 (noninvasive ventilation or high-flow oxygen), or WHO 6 (intubation and mechanical ventilation); and to have a baseline oxygen saturation (SpO2) level of 94% or lower on room air. This study was approved by an institutional review board or ethics committee for each site, and written informed consent was required from the patient or legally authorized representative.
The key exclusion criteria for the study were as follows: pregnant or currently breast feeding; WHO 7 score (required ventilation plus additional organ support such as long-term pressors, renal replacement therapy, or extracorporeal membrane oxygen), alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal, total bilirubin above the upper limit of normal, creatinine clearance of less than 60 ml/min, and hepatic impairment. The Protocol (available with the full text of this trial at evidence.nejm.org) contains the full clinical trial protocol, which provides the complete inclusion and exclusion criteria for the study and information on prohibited prior or concomitant therapies, trial blinding, ethical conduct, and responsibilities of the sponsor, as well as the statistical analysis plan. The study was designed by Veru, Inc. Clinical data were gathered and analyzed by Worldwide Clinical Trials (Raleigh, NC). Manuscript decision and first draft authors were Drs. Barnette and Steiner (Veru, Inc.). All of the data were available to all authors, who vouch for the accuracy and completeness of the data as well as the adherence of the trial to the protocol.
Patients were randomly assigned to receive Sabizabulin or placebo in a 2:1 ratio. Randomization was stratified by WHO COVID-19 ordinal clinical severity score (0 to 8).Supplementary Appendix available with the full text of this article at evidence.nejm.org.Study drug was administered daily at approximately the same time each day for up to 21 days or until the patient was discharged from the hospital, whichever came first. Dose selection of sabizabulin was derived from the no adverse effect level observed in nonclinical toxicity studies. Sabizabulin (9-mg) capsules and matching placebo capsules were manufactured and tested by CoreRx (Clearwater, FL). The schedule of assessments is provided in the
The primary efficacy end point of the study was 60-day all-cause mortality (proportion of patients who died during the study up to day 60) compared with placebo in the intent-to-treat (ITT) population. The key secondary end points were differences in days in the ICU, days on mechanical ventilation, and days in the hospital between the two treatment groups. The multivariate analysis of the primary end point included treatment, geographic region, WHO ordinal scale score at baseline, standard-of-care therapy use, and sex. Prespecified subgroup analyses of the primary end point was performed by region (country), by WHO ordinal scale score at baseline, and by standard-of-care use during the study (dexamethasone and remdesivir). The Holmstep-down procedure was used to control multiplicity for selected key secondary end points.
Safety assessment included treatment-emergent adverse events, serious adverse events, and adverse events leading to discontinuation from the study starting at randomization into the study through day 60. Medical Dictionary for Regulatory Activities version 24.0 was used for safety coding. The incidence of events was provided for each treatment group and included all randomized patients.
The planned enrollment into the study was approximately 210 patients. In the primary efficacy analysis, the sample size was calculated so there was 92.8% power to detect an approximately 50% relative reduction in deaths in the sabizabulin-treated group compared with placebo (expected mortality rate of 30% for the placebo group). Randomization was stratified by oxygen supplementation requirement at baseline. A prespecified interim efficacy analysis was planned to occur when the first 150 randomized patients had been followed through day 60. This analysis was focused on the primary efficacy end point of all-cause mortality according to prospectively set stopping boundaries that were reviewed by regulatory agencies. The primary efficacy analysis used logistic regression with covariates of treatment, site and region, standard of care at baseline, sex, and WHO ordinal scale score at baseline. At the time of the interim efficacy analysis, a two-sided P value of less than 0.0160 was needed to demonstrate early efficacy (superiority of sabizabulin over placebo) on the basis of the prespecified alpha spending function. Missing data were handled by multiple imputation. Statistical analyses were performed by Worldwide Clinical Trials. Efficacy and safety results of this interim analysis were reviewed by the independent data monitoring committee (Advarra, Indianapolis, IN).
Although a total enrollment of approximately 210 patients was planned, 204 participants had been randomly assigned to treatment when the study was stopped for efficacy at the direction of the independent data monitoring committee. The 150 randomized patients in the interim analysis were enrolled at 27 participating sites in five countries (66 patients in the United States [44.0%], 63 patients in Brazil [42.0%], 18 in Bulgaria [12.0%], 2 in Argentina [1.3%], and 1 in Mexico [0.7%]) and underwent random assignment (between May 18, 2021 and January 31, 2022), with 98 randomly assigned to sabizabulin and 52 to placebo (Fig. 1). Of the 150 patients in the interim analysis, 145 patients completed the study with known vital status at day 60. Baseline demographic and clinical characteristics were similar in the two groups in the interim efficacy analysis (Table 1). Enrolled patients had moderate to severe Covid-19 infection with a mean SpO2 on ambient air at baseline of 92.5% and required supplemental oxygen. The proportion of patients requiring oxygen by mask or nasal prongs, noninvasive ventilation or high-flow oxygen, or intubation and mechanical ventilation was similar between the treatment groups. The distribution of common risk factors for ARDS and death was similar between treatment groups and included hypertension (59.2% for sabizabulin vs. 61.5% for placebo), 65 years of age or older (45.9% for sabizabulin vs. 50.0% for placebo), diabetes (35.7% for sabizabulin vs. 40.4% for placebo), and obesity (defined as a BMI of 35 or greater; 34.7% for sabizabulin vs. 27.5% for placebo). Covid-19 nonvaccinated rates were also similar (54.1% for sabizabulin vs. 57.7% for placebo). Receipt of standard of care was also similar between the two groups, in which dexamethasone (83.7% for sabizabulin vs. 80.7% for placebo) and remdesivir (34.7% for sabizabulin vs. 28.8% for placebo) were the most common treatments. Overall, the demographics of the patients included in this study were similar to the ranges reported by the Centers for Disease Control and Prevention for hospitalized patients with Covid-19 (Table S2), except the proportion of male patients in this study was slightly higher than expected and the proportion of patients of Black race was slightly lower than expected.
Primary Efficacy Outcomes: All-Cause Mortality
Sabizabulin met the prespecified superiority criterion for efficacy at the time of the interim analysis. In the primary efficacy end point of mortality up to day 60, a statistically significant 24.9 percentage point absolute reduction and a 55.2% relative reduction in mortality was observed in the sabizabulin-treated group compared with placebo (odds ratio, 3.23; 95% confidence interval [CI], 1.45 to 7.22; P=0.0042) (Fig. 2 and Table 2). The beneficial effects of sabizabulin were observed starting as early as day 3 after dosing; by day 15, statistically significant reductions in mortality were observed. The beneficial effects of sabizabulin treatment on mortality were maintained through day 29, a standard time point that other studies have used as the efficacy end point, with mortality rate of 35.3% for placebo compared with 17% for sabizabulin — an absolute reduction of 18.3 percentage points and a relative reduction of 51.8 percentage points. From days 29 to 60, the death rate increased by 9.8 percentage points in the placebo group and by 3.2 percentage points in the sabizabulin-treated group. Results of subgroup analyses evaluating the relative risk of death (Fig. 3) were consistent with the overall study results favoring sabizabulin treatment regardless of standard-of-care treatment received, baseline WHO ordinal clinical score, sex, age, baseline comorbidities, BMI, or geographic location.
In the United States, a 34.4 percentage point absolute reduction in mortality at day 60 (55.5% relative reduction) was observed in the sabizabulin group compared with placebo. In the rest of the world (Brazil, Bulgaria, Mexico, and Argentina), a 18.5 percentage point absolute reduction in mortality at day 60 (55.6% relative reduction) was observed in the sabizabulin group compared with placebo. At the time of this publication, all-cause mortality for the full final data set (ITT population) of 204 randomized patients was similar to that result observed in the interim efficacy analysis population, with sabizabulin treatment resulting in a 51.6 percentage point relative reduction in deaths compared with placebo.
Secondary Efficacy Outcomes
Sabizabulin treatment resulted in a statistically significant reduction in key secondary end points compared with placebo (Table 3). There was a 43 percentage point relative reduction in days in the ICU (least-squares [LS] mean of −13.4 days; 95% CI, −21.5 to −5.3; P=0.0013), a 49 percentage point relative reduction in days on mechanical ventilation (LS mean of −14.1 days; 95% CI, −22.4 to −5.6; P=0.0013), and a 26 percentage point relative reduction in days in the hospital (LS mean of −8.4 days; 95% CI, −15.8 to −0.9; P=0.0277). In these analyses, the values of days were imputed to the maximum (60 days) for all patients who died during the study.
The adverse events and serious adverse events observed in this study were consistent with patients with serious Covid-19 illness. The proportion of patients who experienced any adverse event was lower in the sabizabulin-treated group (61.5%) compared with the placebo group (78.3%) (Tables 4 and 5). The most frequently reported adverse events in either group were respiratory failure (9.2% for sabizabulin vs. 17.4% for placebo), acute kidney injury (8.5% for sabizabulin versus 11.6% for placebo), pneumothorax (0.8% for sabizabulin vs. 10.1% for placebo), bacterial pneumonia (0.8% for sabizabulin vs. 7.2% for placebo), and hypotension (2.3% for sabizabulin vs. 11.6% for placebo). The proportion of patients with a serious adverse event observed during the study was also lower for the sabizabulin-treated group (29.2%) compared with placebo (46.4%) (Tables 4 and 5). The most frequently reported serious adverse events in either group were respiratory failure (9.2% for sabizabulin vs. 17.4% for placebo), acute kidney injury (3.8% for sabizabulin vs. 8.7% for placebo), pneumothorax (0.8% for sabizabulin vs. 8.7% for placebo), septic shock (1.5% for sabizabulin vs. 5.8% for placebo), and acute respiratory failure (4.6% for sabizabulin vs. 5.8% for placebo). Adverse events leading to discontinuation were 4.7% for sabizabulin versus 5.9% for placebo.
Vaccinations remains the mainstay for prevention of serious Covid-19 infection and death. Most patients will recover from an acute Covid-19 illness.New antiviral agents molnupiravir and nirmatrelvir reduce the incidence of Covid-19–related hospitalization or death when taken in a nonhospital setting within 3 to 5 days after Covid-19 symptom onset. , For patients who progress to moderate to severe Covid-19 illness requiring hospitalization, the risk of death remains high. In this setting, however, the antiviral molnupiravir did not demonstrate clinical benefit.
Sabizabulin is a novel microtubule disruptor that has dual antiviral and anti-inflammatory activities. Sabizabulin appears to be a member of a novel class of drugs that targets, binds, and crosslinks both the α- and β-tubulin subunits of microtubules to inhibit polymerization and to induce depolymerization of microtubules, which alters microtubule dynamics., Sabizabulin has a different chemical structure and unique physicochemical properties compared with the more familiar drug, colchicine. Although sabizabulin does bind to the β-tubulin subunit in the “colchicine binding” pocket, it inserts deeper and tighter in the pocket with more hydrogen bonding than colchicine. Sabizabulin inhibits tubulin polymerization better than colchicine in in vitro studies. Unlike colchicine, sabizabulin is not a substrate for P-glycoprotein or CYP3A4, which may result in higher and more consistent intracellular and blood concentrations of sabizabulin than colchicine. Thus, sabizabulin has a different chemical structure and unique physicochemical properties compared with colchicine.
Oral daily dosing of 9 mg of sabizabulin up to 21 days demonstrated significant efficacy in this interim analysis of a randomized, double-blind, placebo-controlled global phase 3 clinical trial in hospitalized adult patients with moderate to severe Covid-19 who were at high risk for ARDS and death. Sabizabulin demonstrated a statistically significant 24.9% absolute reduction and a 55.2% relative reduction in all-cause mortality by day 60, the primary efficacy end point of the study. The cumulative mortality analysis showed that the reduction in deaths with sabizabulin started within the first week of treatment and the relative reduction in deaths reached 51.8% at day 29. This efficacy was further supported by the consistency of the subgroup analyses of the primary end point: a reduction in deaths with sabizabulin treatment compared with placebo regardless of standard-of-care treatment received, baseline WHO ordinal score, sex, age, baseline comorbidities, BMI, or geographic location. Furthermore, the secondary efficacy end points demonstrated that sabizabulin treatment resulted in a significant reduction in days in the ICU, days on mechanical ventilation, and days in the hospital compared with placebo. With 130 patients treated, sabizabulin had an acceptable side-effect and safety profile. Significantly fewer serious adverse events and adverse events were reported for sabizabulin compared with placebo. There were also fewer treatment discontinuations due to adverse events in the sabizabulin group compared with placebo. The phase 3 reported safety profiles suggest that sabizabulin treatment may have resulted in fewer Covid-19–related morbidities, especially respiratory failure, acute kidney injury, cardiac arrest, septic shock, and hypotension.
In this study, sabizabulin was evaluated in hospitalized patients with moderate to severe Covid-19 illness. The inclusion criteria were selected by design to include patients who were at the highest risk for ARDS and death due to Covid-19. Enrolled hospitalized patients had to demonstrate moderate to severe Covid-19 illness (at least oxygen supplementation with SpO2 of 94% or less while breathing ambient air). Patients with a WHO score of 4 (receiving supplemental oxygen) had to have a comorbidity that placed them at high-risk for death; and no limitation was placed on the duration of Covid-19 symptoms before enrollment. Accordingly, the mortality rate in the placebo group for this study was 35.3% at day 29; by day 60, the mortality rate in this group further increased to 45.1%. It is apparent that the mortality rate for hospitalized patients with moderate to severe Covid-19 remains high even with available therapies, such as antiviral agent remdesivir, immunomodulators, or anti-inflammatory agents., , , , , By targeting microtubule trafficking, sabizabulin has both dual anti-inflammatory and antiviral activity. These data demonstrate that sabizabulin treatment significantly reduced mortality with an acceptable side-effect and safety profile in hospitalized patients with moderate to severe Covid-19 at high risk for ARDS.
This study was funded by Veru, Inc.
Disclosure forms provided by the authors are available with the full text of this article.
A data sharing statement provided by the authors is available with the full text of this article.
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