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FDA panel recommends monoclonal antibody to protect infants from RSV

June 8, 2023

An expert panel is recommending federal approval of a product to protect infants and high-risk young children from respiratory syncytial virus (RSV), the leading cause of infant hospitalization.

The Food and Drug Administration’s (FDA’s) Antimicrobial Drugs Advisory Committee voted Thursday 21-0 in favor of using monoclonal antibody nirsevimab for infants during or entering their first RSV season. It voted 19-2 on using it for children up to 24 months who remain at risk of severe disease in their second RSV season.

“I thought that the studies as presented showed clear evidence of efficacy and reassuring evidence of safety across all subgroups presented, and I think this could be a real game changer,” said committee member George K. Siberry, M.D., M.P.H., FAAP, a pediatric infectious disease expert and a medical officer for the U.S. Agency for International Development who voted yes on both questions.

The group focused on efficacy and safety and did not address many of the outstanding logistical considerations such as cost and optimal timing.

The FDA advisory panel included numerous pediatricians, including AAP members, but the AAP does not have formal representation on the committee. If the product receives formal approval from the FDA and Centers for Disease Control and Prevention (CDC), AAP experts will confer on the clinical indications and practice implementation guidance to recommend to AAP members. AAP will continue to update members.

Nirsevimab is an RSV F protein inhibitor monoclonal antibody developed by AstraZeneca in partnership with Sanofi. The product is intended to protect children against lower respiratory tract disease caused by RSV. It is a form of passive immunization.

RSV can cause severe lower respiratory tract disease such as bronchiolitis or pneumonia. There are about 58,000 to 80,000 hospitalizations and 100 to 300 deaths per year in children under 5 years, according to CDC data. No vaccines are licensed in the U.S. to prevent RSV in children. Another monoclonal antibody, palivizumab, is available only for certain high-risk infants and young children.

AstraZeneca has proposed giving nirsevimab, an intramuscular injection, as a single dose to infants born during the RSV season at birth before hospital discharge. Those born before the RSV season would get a single dose in their pediatrician’s office at the beginning of the season, which starts in fall, peaks in winter and ends in spring in temperate climates. RSV circulates year-round in tropical climates.

Double-blind, placebo-controlled clinical trials in preterm infants born from 29 weeks’ to less than 35 weeks’ gestation showed efficacy of 70.1% against medically attended lower respiratory tract infection from RSV and 78.4% against hospitalization five months after a dose, according the FDA’s data analysis.

In term and late preterm infants, efficacy was 74.9% against medically attended disease and 60.2% against hospitalization after five months. The latter figure had broad confidence intervals that went below 0.

“This is one of the most important infectious diseases resulting in significant illness in the pediatric population,” said committee member Mary Anne Jackson, M.D., FAAP, a pediatric infectious disease physician at Children’s Mercy in Kansas City who voted in favor of administering nirsevimab to protect infants in their first RSV season. “… I think the presentations we saw assured me there is good immune-based data, there’s good safety data and there’s good efficacy data that shows the product will prevent a significant number of cases of RSV lower respiratory tract disease.”

In high-risk children, trial populations were not large enough to determine efficacy, so investigators established efficacy by extrapolating data from term and preterm infants in the previously mentioned trials.

Most committee members said they were comfortable with this methodology and voted in favor of using nirsevimab for children up to 24 months who remain at risk of severe disease in their second RSV season. Two panelists who voted no for this group, including Dr. Jackson, said they would like more data.

Safety of nirsevimab was studied in just over 3,000 infants and children, and no major safety concerns were seen. The most common adverse events reported were upper respiratory tract infection, fever and nasopharyngitis. The differences between the nirsevimab group and placebo group were small.

There were no cases of anaphylaxis or serious skin reactions in the trials, and the incidence of rash was low. However, the FDA noted anaphylaxis, hypersensitivity reactions and rash have been reported with palivizumab and other monoclonal antibodies, so it expects to see some cases if approved and used more widely.

There were 12 deaths in the nirsevimab group and four in the placebo group, but none were deemed to be related to nirsevimab.

If it approves nirsevimab, the FDA plans to track safety using the FDA Adverse Event Reporting System and leverage its partnership with the CDC.

“Safety in 3,000 is not safety in 3 million,” said committee Chair Lindsey R. Baden, M.D., an infectious disease specialist at Brigham and Women’s Hospital in Boston who voted yes on both questions. “Safety for a year is not safety for a longer time, although that should be much less of a risk in this setting.”

AstraZeneca representatives said they do not expect nirsevimab to interfere with other childhood immunizations and pointed to the long safety record of palivizumab with childhood vaccines. An FDA analysis found there may be a slight increase in fever among those who received another childhood immunization within two weeks, but the percentages were small.

Clinical trials also did not find evidence that getting nirsevimab as an infant made children more susceptible to the disease or to severe disease in their second RSV season, but the FDA said the small numbers in the trials made it difficult to reach a definitive conclusion.

FDA consideration of nirsevimab came less than a month after another FDA committee endorsed an RSV vaccine for pregnant women that would protect their infants. The FDA has not made a final decision on whether to license that vaccine, and data are not available on how maternal immunization would impact use of nirsevimab.

The FDA committee on Thursday focused largely on safety and efficacy, but logistical questions remain on cost, optimal timing, inclusion in immunization records and restrictions on which health care providers can administer a monoclonal antibody.

If approved by the FDA, the CDC likely would take up some of these and other logistical issues.



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