Treatment with a new 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 found.
The 60-day mortality, the primary endpoint of the international study, was more than halved in the group assigned to study sabizabulin compared to 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 had a high risk of acute respiratory distress syndrome (ARDS) or death, and this difference represented a 55% relative reduction in the risk of death (relative risk [RR] 0.45, 95% CI 0.27-0.74), according to the findings in NEJM Records†
“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 analyzes of the primary endpoint.”
Results in key secondary endpoints also favored sabizabulin, with significantly fewer mean days spent in intensive care (ICU; 17 vs. 31 in the placebo group), on mechanical ventilation (14 vs. 29) and in hospital (26 vs. 35).
David Boulware, MD, MPH, of the University of Minnesota at Minneapolis, warned: on Twitter that the trial had an “unexpectedly high” mortality in the control group. He noted that with 35% of the control group participating in the study on nasal cannula and 54% on high-flow oxygen, “mortality should be much lower.”
On day 29, the death rate was 35.3% in the placebo group. In comparison, death rates at comparable time points among the control arms of studies of hospitalized COVID-19 patients ranged from 7.8% in ACTT-2, 15.2% in ACTT-1, to 25.7% in the control group of the segment of the RECOVERY trial that resulted in dexamethasone being established as standard of care 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 induce microtubule depolymerization in cells,” noted Barnette and colleagues.
“Microtubules are intracellular transport structures critical for the entry, transport, replication and exit of the coronavirus, as well as triggering the innate inflammatory response and cytokine storm responsible for ARDS, septic shock and often death,” the group added. ready.
A smaller phase II study of sabizabulin in COVID-19 patients at high risk for ARDS supported the drug’s efficacy and showed a reduction in deaths and days in the ICU on mechanical ventilation. In early June, Veru filed an emergency authorization application with the FDA for the use of sabizabulin in this setting.
The current phase III study enrolled 204 hospitalized patients with moderate to severe COVID-19 at high risk for ARDS in the US (44%), Brazil (42%), Bulgaria (12%), Colombia, Argentina and Mexico during the Delta and Omicron waves. Patients were required 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 dose of 9 mg sabizabulin for 21 days or placebo.
The pre-specified interim analysis was performed after 60 days of follow-up in the first 150 randomized patients. The study was discontinued due to efficacy after the interim data, although 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.
The mean patient age in the interim analysis population was 60 years, slightly more than two-thirds were male, and the mean body mass index (BMI) was 32.8. For comorbidities, 60% had hypertension, 63% had respiratory problems, 51% had pneumonia and 37.3% had diabetes.
One-third of patients had a WHO ordinal scale score of 4 (mask oxygen or nasal teeth), 60% used non-invasive ventilation or high-flow oxygen, and 7.3% required mechanical ventilation. Most patients received standard treatments, including dexamethasone at 83%, remdesivir (Veklury) at 33%, tocilizumab (Actemra) at 10%, and either baricitinib (Olumiant) or tofacitinib (Xeljanz) at 12%.
As noted, subgroup analyzes for the primary endpoint – including age, gender, baseline comorbidities or BMI, whether standard of care was received and WHO rank score – all favored the sabizabulin group.
Barnette’s team also looked at geographic location and patients in the US receiving sabizabulin had a 55.5% relative mortality reduction at 60 days (RR 0.44, 95% CI 0.24-0.81). Note that vaccination status (45% had received one to three doses) was not included in the subgroup analysis, leaving the question of drug 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 adverse events (29% vs. 46%).
The study was funded by Veru and multiple authors are employed by the company or have disclosed relationships with the company. Co-authors also revealed relationships with Atea, Fujifilm, HD Research, Incyte, Kinevant, RedHill BioPharma and Syndax.