番茄社区

Treatment with a novel, oral microtubule disruptor significantly reduced the risk of death in hospitalized COVID-19 patients with severe disease, an interim analysis of a phase III study indicated.

Mortality at 60 days, the international trial's primary endpoint, was more than halved in the group assigned to investigational sabizabulin versus those randomized to placebo (20.2% vs 45.1%, P=0.0042), reported K. Gary Barnette, PhD, of drug developer Veru in Miami.

Patients in the study were at high risk for acute respiratory distress syndrome (ARDS) or death, and this difference represented a 55% relative reduction in the risk for death (relative risk [RR] 0.45, 95% CI 0.27-0.74), according to the findings in .

"The reduction in deaths with sabizabulin started within the first week of treatment," the authors noted. "This efficacy was further supported by the consistency of the subgroup analyses of the primary endpoint."

Outcomes in key secondary endpoints landed in sabizabulin's favor as well, with significantly fewer average days spent in the intensive care unit (ICU; 17 vs 31 in the placebo group), on mechanical ventilation (14 vs 29), and in the hospital (26 vs 35).

David Boulware, MD, MPH, of the University of Minnesota in Minneapolis, cautioned that the trial had an "unexpectedly high" mortality in the small control group, given that about 90% entered on nasal cannula or high-flow oxygen.

"This level of mortality is significantly higher than expected," he told 番茄社区.

At day 29, the mortality rate was 35.3% in the placebo group. By comparison, mortality rates at similar time points among the control arms of trials involving hospitalized COVID-19 patients have ranged from 7.8% in , 15.2% in , to 25.7% in the control group of the segment of the RECOVERY trial that led to dexamethasone being established as a standard treatment in this setting.

"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," noted Barnette and colleagues.

"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," the group added.

A smaller phase II study of sabizabulin in COVID-19 patients at high risk for ARDS supported the drug's efficacy, demonstrating reductions in death and days in the ICU on mechanical ventilation. In early June, Veru to the FDA for use of sabizabulin in this setting.

"By standard FDA metrics, this new medicine has shown superiority over placebo in a randomized trial, thus it should merit an EUA," said Boulware.

The current phase III trial enrolled 204 hospitalized patients with moderate to severe COVID-19 at high risk for ARDS across the U.S. (44%), Brazil (42%), Bulgaria (12%), Colombia, Argentina, and Mexico during the Delta and Omicron waves. Patients needed to have a score of 4-6 on the World Health Organization (WHO) ordinal scale and were randomized 2:1 to either an oral daily 9-mg dose of sabizabulin for 21 days or placebo.

The prespecified interim analysis was conducted after 60 days of follow-up had occurred in the first 150 patients randomized. The trial was halted for efficacy following the interim data, though the study authors noted that the intent-to-treat (ITT) population had a 51.6% relative reduction in all-cause mortality with sabizabulin compared to placebo.

Mean patient age in the interim analysis population was 60 years, just over two-thirds were men, and mean body mass index (BMI) was 32.8. For comorbidities, 60% had hypertension, 63% had respiratory issues, 51% had pneumonia, and 37.3% had diabetes.

A third of the patients had a WHO ordinal scale score of 4 (oxygen by mask or nasal prongs), 60% were on noninvasive ventilation or high-flow oxygen, and 7.3% required mechanical ventilation. Most patients received standard-of-care treatments, including dexamethasone in 83%, remdesivir (Veklury) in 33%, tocilizumab (Actemra) in 10%, and either baricitinib (Olumiant) or tofacitinib (Xeljanz) in 12%.

As noted, subgroup analyses for the primary endpoint -- including age, sex, baseline comorbidities or BMI, whether standard of care was received, and WHO ordinal scale score -- all favored the sabizabulin group.

Barnette's team also looked at geographic location, and patients in the U.S. receiving sabizabulin had a 55.5% relative mortality reduction at 60 days (RR 0.44, 95% CI 0.24-0.81). Of note, vaccination status (45% had received one to three doses) was not included in the subgroup analysis, leaving the question of the drug's efficacy in this large subpopulation somewhat open.

In the ITT population, treatment-emergent adverse events (AEs) were lower in the sabizabulin arm (62% vs 78%), as were serious AEs (29% vs 46%).

Comment