As the COVID-19 pandemic surged in early 2020, the FDA created the emergency Coronavirus Treatment Acceleration Program (CTAP), which “uses every available method to move new treatments to patients as quickly as possible while ensuring the safety and efficacy of these therapies,” said Nikolay Nikolov, MD, director of the FDA’s Division of Rheumatology and Transplant Medicine.
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Approximately 15% of COVID-19 patients progress to serious disease, and about 5% could advance to critical disease with effects seen in multiple organ systems, including possible cytokine-related syndromes or hyperinflammation, Dr. Nikolov said.15 A few cases of life-threatening, multi-system inflammatory syndrome in children have also been reported, so finding effective, safe treatments quickly is of paramount importance. Developing new therapies for COVID-19 has been challenging because scientists still lack clear understanding of the disease course in both adults and children.
“The underlying inflammation is complex and still not yet well understood, including when a protective inflammation becomes destructive,” Dr. Nikolov said. Several types of therapies have been studied for use in COVID-19 patients, including antivirals like remdesivir, immune-based therapies like corticosteroids and targeted biologics, and adjunctive therapies to prevent complications. In 2020, the FDA allowed 110 investigational drug clearances to proceed in the fight against COVID-19.
Patients who develop severe COVID-19 often have elevated levels of inflammatory cytokines and other biomarkers, including tumor necrosis factor alpha, IL-1, IL-6, C-reactive protein, ferritin and others, but the exact reasons for this hyperinflammation remain unclear, and “when is the right time to intervene with immunomodulators? More trials and clinical studies were needed to find out,” Dr. Nikolov said.
One successful such trial to date was a large, randomized controlled trial of hospitalized COVID-19 patients, in which 2,104 received 6 mg daily of either oral or IV dexamethasone and 4,321 received usual care for up to 10 days.16 The primary outcome was 28-day mortality. Dexamethasone resulted in lower mortality in patients receiving either invasive mechanical ventilation or oxygen support only at randomization, but patients with less severe respiratory problems did not benefit as much, Dr. Nikolov said. “These data suggest that dexamethasone is a more appropriate intervention in more severely affected individuals instead of early in the disease course.”
Early results from other phase 3 trials of targeted therapies have been mixed, he said. In November, the FDA issued an emergency use authorization for baricitinib in combination with the antiviral drug remdesivir for treatment of suspected or laboratory-confirmed COVID-19 in adults and children age 2 or older who require supplemental oxygen, invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), based on preliminary results of a trial of more than 1,000 patients.17 Two phase 3 trials of IL-6-receptor inhibitors, sarilumab and tocilizumab, did not meet their primary endpoints.18,19 However, in September, early results of another phase 3 trial of tocilizumab were more promising.20 Patients who took one IV infusion of 8 mg/kg of tocilizumab plus standard of care were 44% less likely to progress to mechanical ventilation or death compared to those on placebo, meeting the trial’s primary endpoint.