Virus World

The FDA has for the first time approved an emergency use authorization for a long-acting monoclonal antibody cocktail designed to prevent symptomatic COVID-19 among adults and children aged 12 years and older. According to data submitted to the FDA, AstraZeneca’s Evusheld (tixagevimab plus cilgavimab), also known as AZD7442, can reduce the risk for developing symptomatic COVID-19 by 77%, compared with placebo, among unvaccinated adults without prior SARS-CoV-2 infection at increased risk for inadequate immunization response.  Alfred H.J. Kim, MD, PhD, assistant professor of medicine in the division of rheumatology at the Washington University School of Medicine, in St. Louis, Missouri, noted that Wednesday’s approval represents a significant step forward in the protection of immunocompromised patients. “This is really great news for the immunosuppressed in general, but particularly those on medications that put them at high risk for very poor or absent antibody responses,” Kim told Healio Rheumatology. “These patients now have a way to have protective antibodies. The timing of this is especially good, since cases are spiking due to colder weather — and the holidays are coming up. If it can be administered prior to holiday engagements, this will provide an extra layer of protection for them.” According to Kim, the Evusheld EUA will have a particularly profound impact on patients receiving TNF inhibitors, as these individuals appear unable to neutralize the delta variant of the SARS-CoV-2 virus, even when vaccinated. Although COVID-19 booster shots can alleviate this concern, they may not be an option for patients who experienced adverse reactions to the vaccine.

“This pre-exposure prophylaxis (PrEP) can neutralize delta in these patients,” Kim said. “Given the number of people on TNF inhibitors, for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and more, this could help provide an extra protection that they don’t quite have right now. I should add that patients on TNF inhibitors who receive the booster dose can generate a response to delta. However, if they had a reaction to the vaccine, PrEP solid alternative.” Kim added that he and his colleagues will now focus on administering the newly available cocktail to their B-cell depleted patients, as well as those receiving mycophenolate, considering both populations are at risk for having an inadequate response to COVID-19 vaccines. The FDA’s EUA authorizes the drug only for adults and children aged 12 years and older, weighing at least 40 kg, who are not currently infected with SARS-CoV-2, and who have not recently been exposed to COVID-19. The emergency authorization also requires that individuals either have moderate to severely compromised immune systems, due to a medical condition or immunosuppressive medications or treatments, leading to a potentially inadequate immune response to COVID-19 vaccination, or a history of severe adverse reactions to a COVID-19 vaccine and/or components of the vaccines. Evusheld is not authorized for individuals to treat COVID-19 or for post-exposure prevention of COVID-19. The FDA also stressed that Evusheld is not a substitute for vaccination among those for whom vaccination is recommended.

The FDA based their approval on data from the phase 3 PROVENT trial, which examined the efficacy and safety of Evusheld in 5,197 participants across 87 sites in the United States, United Kingdom, Spain, France and Belgium. Participants were unvaccinated adults without prior SARS-CoV-2 infection who had an increased risk for inadequate response to active immunization, or an increased risk for COVID-19, including those whose location or circumstances increased their chances of infection. According to AstraZeneca, more than 75% of those enrolled demonstrated baseline comorbidities and other characteristics associated with an increased risk for severe COVID-19, including immunosuppressive disease or receiving immunosuppressive medications, diabetes, severe obesity or cardiac disease, chronic obstructive pulmonary disease, and chronic kidney and chronic liver disease. Participants were randomly assigned 2:1 to receive either a single, intramuscular 300 mg dose of Evusheld or a saline placebo, administered in two sequential injections. According to the PROVENT researchers, Evusheld reduced the risk for symptomatic COVID-19 by 77% (95% CI, 46% to 90%), compared with placebo. None of the participants who received the monoclonal cocktail developed severe COVID-19, and none died. Meanwhile, the placebo arm saw three cases of severe COVID-19, including two deaths. The trial reported a total of 25 cases of symptomatic COVID-19 across both groups at the primary analysis. Regarding safety, Evusheld was well tolerated, with the preliminary analyses demonstrating balanced adverse events between the placebo and treatment groups. AstraZeneca’s request for an EUA also included data from the phase 3 STORM CHASER trial, which analyzed efficacy and safety among more than 1,100 unvaccinated adults who were exposed to SARS-CoV-2 within the past 8 days. The study suggested that the cocktail shrunk the risk for symptomatic COVID-19 by 33% (95% CI, –26% to 65%), compared with placebo. However, this result was not significant, and the trial did not meet its primary endpoint.

The malaria drug hydroxychloroquine did not help prevent people who had been exposed to others with Covid-19 from developing the disease, according to the results of an eagerly awaited study that was published Wednesday in the New England Journal of Medicine. Despite a lack of evidence, many people began taking the medicine to try to prevent infection early in the Covid-19 pandemic, following anecdotal reports it could be effective and claims by President Trump and conservative commentators. Trump, too, said he took hydroxychloroquine to prevent infection. But the new study, the first double-blind randomized, placebo-controlled trial of hydroxychloroquine, found otherwise.

“I think in the setting of post-exposure prophylaxis, it doesn’t seem to work,” said Sarah Lofgren, an assistant professor at the University of Minnesota who is a co-author of the study. Other studies of hydroxychloroquine are ongoing. Also Wednesday, the World Health Organization said it is resuming a clinical trial testing hydroxychloroquine as a treatment after pausing it over safety concerns. “This is not the end of the story with hydroxychloroquine,” said Ashish Jha, the director of the Harvard Global Health Institute. But given the data, he said, if there is any benefit to giving the drug to prevent infection, “it’s going to be small.” “This is not the end of the story with hydroxychloroquine,” said Ashish Jha, the director of the Harvard Global Health Institute. But given the data, he said, if there is any benefit to giving the drug to prevent infection, “it’s going to be small.”

The latest trial enrolled 821 patients who were either living in the same household as someone with Covid-19 or who were health care workers who had been exposed to someone with Covid-19 without adequate protective gear. While the initial infections had to be confirmed with a diagnostic test, the researchers also counted patients who had symptoms consistent with disease, in part because testing wasn’t available. Approximately 12% of those given hydroxychloroquine developed Covid-19, compared to 14% who were given the vitamin folate as a placebo. There was no further benefit among patients who chose to take zinc or vitamin C. Nearly 40% of patients on hydroxychloroquine experienced side effects such as nausea, upset stomach, or diarrhea. However, the study did not see a significant increase in disturbances of heart rhythms, or an imbalance of deaths.

Published in New England J. Medicine (June 3, 2020):

https://doi.org/10.1056/NEJMoa2016638