Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis

Introduction

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.¹ There are now effective vaccines for the general population² and antiviral agents (molnupiravir and nirmatrelvir) for symptomatic patients in the nonhospitalized setting.^3,4 However, despite the availability of the antiviral remdesivir⁵ and anti-inflammatory/immunomodulators including dexamethasone,⁶ anti-interleukin-6 receptor antibodies,⁷ and Janus kinase inhibitors^8,9 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.^10-12 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-19.¹³ 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.^14,15 Microtubules are intracellular transport structures critical for coronavirus cellular entry, trafficking, replication, and egress^16-21 as well as for triggering the innate inflammatory response and cytokine storm responsible for ARDS, septic shock, and frequently death.^22-24 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.²⁵ Preclinical studies demonstrate that sabizabulin has both significant antiviral and anti-inflammatory activities by disrupting microtubule dynamics.²⁶

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.²⁷ 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.

Methods

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 improvement²⁸ score 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.

PROCEDURES

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).²⁸ 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 Supplementary Appendix available with the full text of this article at evidence.nejm.org.

EFFICACY

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 Holm²⁹ step-down procedure was used to control multiplicity for selected key secondary end points.

SAFETY

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.

STATISTICAL ANALYSIS

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).

https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200145

Créditos: Comité científico Covid