The prospect of an emergency use authorization (EUA) for the new oral agent sabizabulin met with mixed reception from an FDA advisory panel that considered it a treatment for hospitalized adults with moderate to severe COVID-19 who have a high risk of acute respiratory distress syndrome (ARDS). ).
Although universally impressed by the size of the effect in reducing mortality, the panel was simply not convinced that the single phase III COVID-19 trial was robust enough to bear the burden of proving both efficacy and safety.
At the end of an all-day meeting Wednesday, the FDA Pulmonary Allergy Drug Advisory Committee they voted 8-5 that there was insufficient evidence for a positive benefit-risk balance that would support an EUA for a 21-day course of the oral drug, administered at 9 mg once daily.
“I don’t think we’re arguing that point estimates are impressive,” said committee member Janet Lee, MD, of the University of Pittsburgh Medical Center, who voted against an EUA recommendation. “I think it’s really the question about the robustness of the data affected by lingering uncertainties, mostly related to this small sample size.”
At issue was drug developer Veru’s main phase III trial, which enrolled a total of 204 patients out of a planned 300, far short of the 500 that FDA presenters stressed they repeatedly suggested were needed to get enough data from safety, and with 2:1 randomization to sabizabulin or placebo.
Initial EUAs for previous COVID-19 drugs were based on larger patient data sets, in the range of 500 to 3,000 for remdesivir (Veklury), baricitinib (Olumiant), and tocilizumab (Actemra), the presenter of the FDA, Robert Busch, MD, MMSc.
But the FDA considered this small trial because of the great benefit for the most difficult endpoints: intermediate analysis of the results of the first 150 of those patients, published in NEJM Evidence in July, showed a more than 20 percentage point drop in 60-day all-cause mortality with sabizabulin versus placebo (20.2% vs 45.1%, P=0.0042).
Veru presented data to the panel on the full dataset of 204 patients, noting that the mortality benefit was maintained. Sabizabulin reduced mortality by 51.6% relative compared to placebo at day 60 (19.2% vs. 39.7%, P=0.0046) which was significant in all sensitivity analyzes and directionally consistent across groups by vaccination, comorbidity, and other treatment received. The number needed to treat for this primary endpoint was five.
Along with “small but potentially clinically significant demographic differences,” the small placebo group also had an unusually high death rate compared to what was expected in the trial or seen in other trials, according to the presenters. from the FDA. For example, in the ACTIV-4a trial in COVID-19 that was conducted at the same time and with a population of 100% of the World Health Organization (WHO) ordinal scale 5 or 6, the placebo group had a higher rate mortality rate of 35% compared to approximately a 40% mortality rate in the placebo arm of the sabizabulin trial, where approximately two-thirds were WHO 5 or 6.
Veru’s team responded that the rate fell in line with the expected mortality for the proportion of patients with severe disease, compared with findings from contemporary drug studies with EUAs or part of the NIH COVID treatment guidelines. And, he added, in a real-world data set of a CDC study of 678 hospitals, high-risk ARDS patients hospitalized during the early Delta to Omicron periods had an overall mortality rate of 29.4% at day 29 and 39.7% at day 60.
The company’s trial enrolled hospitalized COVID-19 patients with WHO severity scale scores of 5 or 6 (requiring noninvasive ventilation, high-flow oxygen, or intubation and mechanical ventilation) and those with scores of 4 (oxygen by mask or nasal cannulas) if they had additional comorbidities that put them at risk for ARDS. Veru emphasized that this was a very sick group of WHO 4 patients included, noting that more than half of the patients had three or more comorbidities.
FDA staff raised another internal validity concern at the meeting, noting that the clinical care team had to open the capsules of patients with nasogastric tubes to administer them, which could unmask them given the difference in color between sabizabulin (yellow) and placebo (white).
Nearly a quarter of those receiving sabizabulin and a third of patients receiving placebo had nasogastric tubes, but Busch noted that data were not collected for other types of enteral tubes or for those unable to swallow, making unblinding possibly a bigger problem.
“While many of these issues are not unique to this critical care trial and may not influence the overall interpretation of results in a very large trial, all of these issues together in a small trial, which is more vulnerable to imbalances, raise questions about the results,” said Banu Karimi-Shah, MD, deputy director of the FDA’s Division of Pulmonology, Allergy and Critical Care.
However, “we still have this mortality benefit left,” argued panelist Lindsey Robert Baden, MD, of Brigham and Women’s Hospital and the Dana-Farber Cancer Institute in Boston, who voted in favor of sabizabulin. “Even in the face of these validity threats nipping at the sides and heels, I’m not sure they will vitiate the results.”
Explaining his ‘yes’ vote, Baden noted that the level of concern regarding the limited size of the safety database for a new molecular entity was “through the roof” but also could not outweigh the large mortality benefit, which is the most important safety concern.
The phase III trial plus another 39-patient trial of the drug in COVID-19 suggested lower overall rates of any serious or fatal adverse events with sabizabulin versus placebo, although too small to reliably pinpoint even common adverse events, they noted. panelists on both sides of the vote.
That sabizabulin’s mechanism of action in COVID-19 isn’t really clear “raises my level of concern even more,” said Scott Evans, MD, of the University of Texas MD Anderson Cancer Center in Houston, who voted against it. a US recommendation.
Sabizabulin, a new oral microtubule depolymerizing agent, was in phase III clinical development for castration-resistant prostate cancer when the COVID-19 pandemic began. But the drug targets rapidly forming microtubules that are not only vital for cancer cell division but also for virus transport within infected cells, and preclinical data suggest it could be an antiviral agent. and anti-inflammatory.
The drug does not attack the SARS-CoV-2 virus itself, but rather the cellular process that enables the virus to be transported, making it potentially variant-independent and even virus-type independent, said Mitchell Steiner, MD, chief executive officer. and medical director of Veru. The drug is also being investigated for the flu.
Steiner argued that the two drugs cannot be put in the same bucket, as they target microtubules differently, with differences in potency, pharmacology, and therapeutic index.
However, human data on COVID-19 provided little evidence to support antiviral or anti-inflammatory effects. It did not include biomarker monitoring of cytokine levels, for example. And in the phase III trial, the viral load results were described as “very unusual.” While viral shedding generally declines over time, viral load actually increased more than fourfold in the placebo group, again leading one panelist to express concern about how well the placebo group is understood.
Veru speakers noted that those markers could be part of later planned trials.
The FDA’s charge to the panel included a description of what might be desired from such a trial in COVID-19 and whether it would be necessary before or after the EUA is granted.
A superiority design and additional sample size would increase confidence in benefit, Lee noted. However, his fellow panelists could not agree on the population to study, whether it would be better to focus on the sickest patients with WHO disease 5 and 6, as a last resort after other clinical options had failed, or whether those were too late in the disease to maximize the benefit of potential antiviral aspects of the mechanism, suggesting that even WHO 3 patients might be worth studying.
The FDA does not have to follow the recommendations of its advisory panels, but often does.