Virus World

BACKGROUND

Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications.

METHODS

In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19–related hospitalization or death from any cause by day 29.

RESULTS

A total of 1035 patients underwent randomization and received an infusion of bamlanivimab–etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab–etesevimab group had a Covid-19–related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, −4.8 percentage points; 95% confidence interval [CI], −7.4 to −2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab–etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19–related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, −1.20; 95% CI, −1.46 to −0.94; P<0.001).

CONCLUSIONS

Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19–related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501. opens in new tab.)

Published in NEJM (July 14, 2021):

https://doi.org/10.1056/NEJMoa2102685 

The authorization raised immediate questions about who would get access to the antibody treatments, which are in short supply. The Food and Drug Administration has granted emergency authorization of a Covid-19 antibody treatment made by Eli Lilly that is similar to a therapy given to President Trump shortly after he contracted the coronavirus. The decision, announced on Monday by the agency, is likely to be seen as a valuable tool to treat patients with Covid-19 at a time when the pandemic is raging across the United States, hospitals are overwhelmed and doctors have few options to treat the disease. Eli Lilly said that its treatment, called bamlanivimab, should be administered as soon as possible after a positive coronavirus test, and within 10 days of developing symptoms. The authorization applies only to people newly infected with the virus, and the agency said it should not be used in hospitalized patients. It is authorized for people who are 12 and older and at risk for developing a severe form of Covid-19 or being hospitalized for the condition. The F.D.A. said that included people who were over 65 and obese — a key group that early studies have shown can benefit the most from the treatment. “It’s a great day for science and medicine — sort of a feat of what’s possible,” said Dr. Daniel M. Skovronsky, the chief scientific officer of Eli Lilly. The company and its collaborators, including the National Institutes of Health, he said, were able “to create a new drug, manufacture it, test it in clinical trials, and get it authorized for use in just seven months.”

In October, the company announced that it had reached a $375 million deal to sell 300,000 doses of the treatment to the U.S. government. The emergency authorization for Eli Lilly raised immediate questions about who would get access to the treatment at a time when emergency authorizations for coronavirus vaccines might still be weeks or months away. The news came on the same day that Pfizer announced positive early results from its coronavirus vaccine trial. That vaccine might get emergency authorization sometime this year, but even then it would not be available to most Americans until well into 2021.  In a statement on Monday, Alex M. Azar II, the health secretary and a former executive at Eli Lilly, said the F.D.A.’s emergency authorization for bamlanivimab was a “step forward” in “bridging us to the rollout of safe and effective vaccines.” Eli Lilly has said that it expects to have enough doses to treat up to one million people by the end of the year, and that it will be able to significantly increase production thereafter. But that means that even in the best-case scenario, there won’t initially be enough to curb a virus that is now infecting more than 110,000 people a day in the United States. “It’s kind of the best times for these therapies to enter, because they can have an impact,” said Dr. Walid F. Gellad, who leads the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “It’s also the worst time because we don’t have enough doses, and it’s going to add to the backlog of testing.”...

Lilly's press release (Nov. 9, 2020): 

https://investor.lilly.com/news-releases/news-release-details/lillys-neutralizing-antibody-bamlanivimab-ly-cov555-receives-fda

FDA letter of authorization (Nov. 9, 2020):

https://www.fda.gov/media/143602/download

The Food and Drug Administration (FDA) rescinded its emergency use authorization for the monoclonal antibody bamlanivimab to be used on its own as treatment against COVID-19 due to variants' resistance to the therapy. The federal agency declared its cancelation of bamlanivimab-only COVID-19 therapy hours after the company Eli Lilly requested the FDA revoke the emergency authorization because the variants resistant to the treatment have become more common. With the number of resistant infections growing, the agency concluded that the benefits of treating COVID-19 with only bamlanivimab “no longer outweigh the known and potential risks for its authorized use.”   The FDA cited data that as of mid-March about 20 percent of variants in the U.S. were expected to be resistant to bamlanivimab, compared to 5 percent in January. But the FDA still grants bamlanivimab and another monoclonal antibody, etesevimab, to be used together to treat COVID-19 under an emergency use authorization. In a March study, Eli Lilly determined the combination of monoclonal antibodies — lab-created proteins that copy how the immune system responds to viruses — reduced the risk of hospitalization and death from COVID-19 by 87 percent.

“Other monoclonal antibody therapies authorized for emergency use remain appropriate treatment choices when used in accordance with the authorized labeling and can help keep high risk patients with COVID-19 out of the hospital,” Patrizia Cavazzoni, the director of the FDA’s Center for Drug Evaluation and Research, said in a release.  “We urge the American public to seek out these therapies when needed while we continue to use the best data available to provide patients with safe and effective treatments during this pandemic,” Cavazzoni added.  The emergency use authorization for bamlanivimab-only COVID-19 treatment, granted in November, was the first monoclonal antibody approved to treat mild to moderate COVID-19 cases. It originally allowed it to be used alone for mild-to-moderate COVID-19 adult patients and some children at high risk of severe coronavirus illness or hospitalization.   The federal agency said it will work with the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) to monitor how variants impact the treatments authorized for emergency use.  Eli Lilly called for the FDA to end emergency authorization for bamlanivimab-only COVID-19 treatment “due the evolving variant landscape in the U.S. and the full availability of bamlanivimab and etesevimab together.” The company noted its request for authorization to be revoked was “not due to any new safety concern.”

Eli Lilly & Co. is ending a clinical trial of its antibody drug bamlanivimab in hospitalized COVID-19 patients after federal researchers concluded the therapy produced no marked improvement.  The study of the monoclonal antibody called bamlanivimab was initially paused by the company on Oct. 13 out of "an abundance of caution," because of a potential safety concern. For this particular study the therapy was being used in combination with remdesivir, an antiviral with emergency use authorization for the virus. Remdesivir was among the medications President Trump received after contracting the coronavirus. 

On Monday, the National Institutes of Health, which sponsored the trial, found the antibody treatment posed no significant safety risks for patients. However, researchers said, "bamlanivimab is unlikely to help hospitalized COVID-19 patients recover from this advanced stage of their disease." The decision to end this study does not put an end to Lilly's investment in the experimental therapy. Company officials said they "remain confident ... that bamlanivimab monotherapy may prevent progression of disease for those earlier in the course of COVID-19." The company and the NIH are pursuing several additional trials involving the antibody, which is designed to stop the virus from infecting cells. The trials target patients with less advanced stages of the disease.

Lilly's public release (October 26, 2020) available at: 

https://www.lilly.com/news/stories/statement-activ3-clinical-trial-nih-covid19