Nirsevimab-alip (Beyfortus) Form

U.S. Food and Drug Administration (FDA)-Approved Indications

Beyfortus is a respiratory syncytial virus (RSV) F protein‑directed fusion inhibitor indicated for the prevention of RSV lower respiratory tract disease in:

Neonates and infants born during or entering their first RSV season

Children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.

Respiratory syncytial virus (RSV) is an enveloped single-stranded, negative-sense ribonucleic acid (RNA) virus of the

Pneumovirdae

family that can cause acute respiratory tract illness in persons of all ages. RSV is considered a common respiratory pathogen typically resulting in self-limited, mild, cold-like symptoms that can last around one to two weeks. However, for some people, the virus can lead to an infection that spreads to the lower respiratory tract, causing bronchiolitis or pneumonia, resulting in a severe or life-threatening illness. Those who are most vulnerable for severe infection include infants (especially premature infants), older adults (especially those 65 years and older), people with certain comorbid conditions (e.g., cardiac and pulmonary disease), and those who are immunocompromised. In most parts of the United States, RSV circulation is seasonal, typically starting during the fall and peaking in the winter. It is transmitted from person to person through close contact with someone who is infected.

Currently, there is not a "vaccine" readily available to prevent RSV in infants and children less than 2 years of age. However, since 1998, palivizumab, a humanized monoclonal antibody against the RSV F glycoprotein, has been available for the prevention of serious RSV lower respiratory tract disease in children, but only for those at high risk of RSV disease, and is only administered during RSV season. In July 2023, the FDA approved nirsevimab-alip (Beyfortus) (Sanofi Pasteur and AstraZeneca), a monoclonal antibody against the RSV F glycoprotein with an extended half-life, to protect all infants through their first RSV season. Approval also included use for children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. Palivizumab and nirsevimab are classified as an immunoprophylactic drug, not a vaccine. They act similarly to a vaccine; however, instead of prompting the immune system to develop antibodies to the virus (considered active immunization), they deliver the antibodies directly to the bloodstream (considered passive immunization).

FDA approval for Beyfortus is based on three multicenter, placebo-controlled randomized trials of otherwise healthy infants born at 29 weeks gestation or more, in which a single injection of nirsevimab was evaluated during the 150 days after administration and found to be safe and effective in preventing RSV lower respiratory tract infection that requires medical attention (e.g., emergency department or clinic/office visit) and RSV-associated hospitalization.

Griffin et al (2020) evaluated single-dose nirsevimab for the prevention of RSV in preterm infants. The study randomly assigned 1453 healthy infants who had been born preterm (29 weeks 0 days to 34 weeks 6 days of gestation) in a 2:1 ratio to receive nirsevimab (n=969), at a dose of 50 mg in a single intramuscular injection, or placebo (n=484) at the start of an RSV season. The primary end point was medically attended RSV-associated lower respiratory tract infection through 150 days after administration of the dose. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after administration of the dose. The authors found that the incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower with nirsevimab prophylaxis than with placebo (p<0.001), and that the incidence of hospitalization for RSV-associated lower respiratory tract infection was 78.4% lower with nirsevimab than with placebo (p<0.001). These differences were consistent throughout the 150-day period after the dose was administered and across geographic locations and RSV subtypes. Adverse events were similar in the two trial groups, with no notable hypersensitivity reactions. The authors concluded that a single injection of nirsevimab resulted in fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV season in healthy preterm infants (ClinicalTrials.gov Identifier: NCT02878330).

Hammitt et al (2022) evaluated nirsevimab for prevention of RSV in healthy late-preterm and term infants. The authors randomly assigned, in a 2:1 ratio, 1490 infants who had been born at a gestational age of at least 35 weeks to receive a single intramuscular injection of nirsevimab (n=994) or placebo (n=496) before the start of an RSV season. The primary efficacy end point was medically attended RSV-associated lower respiratory tract infection through 150 days after the injection. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after the injection. The authors found that medically attended RSV-associated lower respiratory tract infection occurred in 12 infants (1.2%) in the nirsevimab group and in 25 infants (5.0%) in the placebo group, which correspond to an efficacy of 74.5% (p<0.001) for nirsevimab. Hospitalization for RSV-associated lower respiratory tract infection occurred in 6 infants (0.6%) in the nirsevimab group and in 8 infants (1.6%) in the placebo group (efficacy, p = 0.07). Among infants with data available to day 361, antidrug antibodies after baseline were detected in 58 of 951 (6.1%) in the nirsevimab group and in 5 of 473 (1.1%) in the placebo group. Serious adverse events were reported in 67 of 987 infants (6.8%) who received nirsevimab and in 36 of 491 infants (7.3%) who received placebo. The authors concluded that a single injection of nirsevimab administered before the RSV season protected healthy late-preterm and term infants from medically attended RSV-associated lower respiratory tract infection (ClinicalTrials.gov Identifier: NCT03979313).

Domachowske et al (2022) conducted a phase 2/3 randomized, double-blind, palivizumab-controlled, multicenter study that evaluated the safety and pharmacokinetics (PK) of nirsevimab in preterm infants born less than 35 weeks gestational age (GA) and infants with chronic lung disease (CLD) of prematurity or hemodynamically significant congenital heart disease (CHD). This trial was not powered for efficacy, but efficacy was assessed as a secondary endpoint. The efficacy of nirsevimab in preterm infants during their first RSV season and in pediatric subjects up to 24 months of age with CLD or CHD during their first and second RSV season was established by extrapolation of efficacy from prior trials based on similar nirsevimab exposures. For RSV season one, a total of 925 infants were randomized 2:1 in each of the preterm (n=615) and CLD/CHD (n=310) cohorts to receive nirsevimab or palivizumab. Infants received a single IM dose of nirsevimab (50 mg if less than 5 kg body weight or 100 mg if greater than 5 kg body weight at the time of dosing), followed by 4 once-monthly intramuscular (IM) doses of placebo, or 5 once-monthly IM doses of 15 mg/kg palivizumab, respectively. In the first RSV season, the incidence of medically attended RSV-associated lower respiratory tract infection through 150 days post dose was 0.6% (4/616) in the nirsevimab group and 1.0% (3/309) in the palivizumab group. Pediatric subjects with CLD of prematurity or hemodynamically significant CHD up to 24 months of age continued in the trial for a second RSV season (n=262). Subjects who received nirsevimab during their first RSV season also received a single dose of 200 mg nirsevimab entering their second RSV season followed by 4 once-monthly IM doses of placebo (n=180). Subjects who received palivizumab during their first RSV season were re-randomized 1:1 to either receive nirsevimab or palivizumab entering their second RSV season. Forty subjects who received palivizumab in the first RSV season received a single IM dose of nirsevimab followed by 4 once-monthly IM doses of placebo in their second RSV season; and 42 subjects received palivizumab (5 once-monthly IM doses of 15 mg/kg palivizumab) in both first and second RSV seasons. In the second RSV season of trial, there were no cases of medically attended RSV-associated lower respiratory tract infection through Day 150 post-dose in subjects who received either nirsevimab or palivizumab (ClinicalTrials.gov Identifier: NCT03959488).

Beyfortus is a single-dose long-acting monoclonal antibody, providing protection for at least 5 months (the average length of one season), which is administered intramuscularly by a healthcare provider, and can be given concomitantly with childhood vaccines. It is contraindicated in infants and children with a history of serious hypersensitivity reactions, including anaphylaxis, to nirsevimab-alip or to any of the excipients. Labeled warnings and precautions include serious hypersensitivity reactions, including anaphylaxis, which have been observed with other human IgG1 monoclonal antibodies. The most common adverse reactions were rash (0.9%) and injection site reactions (0.3%). The safety and effectiveness of Beyfortus in children older than 24 months of age have not been established.

On August 3, 2023, the Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) voted unanimously to recommend routine use of Beyfortus for: (i) newborns and infants below 8 months of age born during or entering their first RSV season, and (ii) children aged 8 to 19 months who are at increased risk of severe RSV disease and entering their second RSV season. In addition, the ACIP voted unanimously to include Beyfortus in the Vaccines for Children program. "The official recommendations will be published in the CDC’s

Morbidity and Mortality Weekly Report (MMWR)

. Once approved, routine use of Beyfortus would be included in the CDC’s Child and Adolescent Immunization Schedule" (CDC, 2023a).

On August 25, 2023, the CDC's ACIP published their recommendations for use of nirsevimab in the

MMWR.

The recommendations are as follows (not all-inclusive list):

Only a single dose of nirsevimab is recommended for an RSV season

1 dose of nirsevimab for all infants aged less than 8 months born during or entering their first RSV season;

1 dose of nirsevimab for infants and children aged 8 through 19 months who are at increased risk for severe RSV disease and entering their second RSV season

Children with chronic lung disease of prematurity who required medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) any time during the 6-month period before the start of the second RSV season

Children with severe immunocompromise

Children with cystic fibrosis who have either (i) manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest imaging that persist when stable), or (ii) weight-for-length <10th percentile

American Indian or Alaska Native children

For infants born during the RSV season, nirsevimab should be given within 1 week after birth. This can be given either in the hospital before discharge or at the doctor’s clinic after discharge.

Infants younger than 8 months who were born outside the RSV season should receive nirsevimab before the start of their first RSV season

Infants with prolonged birth hospitalizations related to prematurity or other causes should receive nirsevimab shortly before or promptly after hospital discharge

No evidence is available to support use of nirsevimab for prevention of hospital-acquired RSV infection, and nirsevimab is not recommended for this indication.

On September 22, 2023, the CDC's ACIP voted, 11-1, to recommend maternal RSV vaccine (Pfizer’s bivalent RSVpreF, Abrysvo) for pregnant people during 32 through 36 weeks gestation, using seasonal administration, to prevent RSV lower respiratory tract infection in infants. They also voted to approve the Abrysvo vaccine for the Vaccines for Children Program (applying to pregnant people under 19 years of age).

Per the CDC's ACIP, fourteen days or more are likely needed for development and transplacental transfer of maternal antibodies to protect the infant. Therefore, nirsevimab is not needed for most infants born 14 or more days after maternal vaccination; meaning, most infants will likely only need protection from either the maternal RSV vaccine (Abrysvo) or infant immunization (nirsevimab), but not both. However, there may be circumstances for which nirsevimab can be considered when pregnant mother has received the RSV vaccine greater than or equal to 14 days prior to birth (CDC, 2023; Jones, 2023). Nirsevimab can be considered for the following rare circumstances even though the mother received an RSV vaccine when, per the clinical judgment of the healthcare provider, the potential incremental benefit of administration is warranted: (CDC, 2023; Jones, 2023a, 2023b)

Pregnant people who may not mount an adequate immune response to vaccination (e.g., people with immunocompromising conditions) or have conditions associated with reduced transplacental antibody transfer (e.g., people living with HIV infection)

Infants who have had cardiopulmonary bypass leading to loss of RSV antibodies

Infants with substantially increased risk for severe RSV disease (e.g., hemodynamically significant congenital heart disease, intensive care admission, and requiring oxygen at discharge).

Nirsevimab can be considered for some children between the ages of 8 and 19 months who are at increased risk of severe RSV disease before their second RSV season. These include:

Children who have chronic lung disease of prematurity who required medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) any time during the 6-month period before the start of the second RSV season

Children with severe immunocompromise

Children with cystic fibrosis who have either 1) manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest imaging that persist when stable) or 2) weight-for-length less than 10th percentile

American Indian and Alaska Native children.

"Children at increased risk for severe disease should not receive more than two doses of nirsevimab (one dose [50mg or 100 mg depending on weight] for the first RSV season and one dose [two 100 mg injections] for the second RSV season). Only one dose of nirsevimab is recommended per season (with exception for children who undergo cardiac surgery with cardiopulmonary bypass). Nirsevimab is recommended for children at increased risk for severe disease during their first RSV season, including if aged 8-11 months if the child has not received nirsevimab during that RSV season" (Jones, 2023b).

RSV Seasonality

RSV epidemic in the U.S. typically follows a seasonal pattern. The RSV seasonality, which can vary by geographical region,

usually occurs from October to April, peaking in December or January. Disruption of the typical seasonal pattern may result in off-season outbreaks, which was the case du

ring the 2020-2022 seasons due to the coronavirus disease 2019 (COVID-19) pandemic. The CDC's RSV circulation data for the 2022-2023 RSV season in the U.S. indicates a return to pre-COVID-19 pandemic seasonality. However, the CDC's ACIP cautions that a

lthough an eventual return to pre-pandemic RSV seasonality is expected, clinicians should be aware that off-season (atypical) RSV circulation might continue (Hamid et al, 2023). "While the timing of the onset and duration of RSV season may vary, nirsevimab may be administered October through the end of March in the majority of the continental United States. Providers may adjust timing of administration based on guidance from public health authorities (e.g., CDC, health departments) or regional medical centers. Although optimal timing of administration is just before the start of the RSV season, nirsevimab may also be administered during the RSV season to infants and children who are age-eligible. Infants born shortly before or during RSV season should receive nirsevimab within one week of birth. Nirsevimab administration can occur during the birth hospitalization or in the outpatient setting. Infants with prolonged birth hospitalizations related to prematurity or other causes should receive nirsevimab shortly before or promptly after hospital discharge" (Jones, 2023)

Criteria for Approval

Aetna considers the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recommendations for a single intramuscular injection nirsevimab-alip (Beyfortus) medically necessary for the prevention of lower respiratory tract disease (LRTD) caused by RSV when

any

of the following criteria is met:

For infants less than 8 months old born during or entering their first RSV season, or children 8 to 11 months old who are at increased risk for severe disease during their first RSV season (e.g., hemodynamically significant congenital heart disease, intensive care admission, and requiring oxygen at discharge), and the following criteria are met: (For maternal RSV vaccine, see

CPB 1027 - Respiratory Syncytial Virus (RSV) Vaccine

)

Maternal RSV vaccine was not received or maternal RSV vaccine status is unknown;

or

Maternal RSV vaccine was received and infant was born less than 14 days after maternal vaccination;

and

Infant has not previously received a nirsevimab-alip or palivizumab dose;

or

Per the CDC’s ACIP, most infants will only need protection from either the maternal RSV vaccine (Pfizer’s bivalent RSVpreF, Abrysvo) or infant immunization (nirsevimab), but not both. For maternal RSV vaccine with Abrysvo, see

CPB 1027 - Respiratory Syncytial Virus (RSV) Vaccine

. However, there may be circumstances for which infant immunization with nirsevimab can be considered when maternal RSV vaccine was received 14 or more days prior to birth. The following indications may be considered per clinical judgment of the healthcare provider and infant has not previously received a nirsevimab-alip or palivizumab dose before or during their first RSV season:

When pregnant individual may not have mounted an adequate immune response to vaccination (e.g., members with immunocompromising conditions) or have conditions associated with reduced transplacental antibody transfer (e.g., members living with HIV infection);

or

Infant who has had cardiopulmonary bypass leading to loss of RSV antibodies;

or

Infant with substantially increased risk for severe RSV disease (e.g., hemodynamically significant congenital heart disease, intensive care admission, and requiring oxygen at discharge);

or

For children between the ages of 8 and 19 months who are at increased risk of severe RSV disease prior to or during their second RSV season and have not received palivizumab in the same season. Nirsevimab-alip (Beyfortus) may be administered if palivizumab was received in the member's first RSV season. Conditions at increased risk of severe RSV disease include the following:

Children with chronic lung disease of prematurity who required medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) any time during the 6-month period before the start of the second RSV season;

Children with severe immunocompromise;

Children with cystic fibrosis who have severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest imaging that persist when stable), or weight-for-length less than 10th percentile;

American Indian or Alaska Native children; or

For children undergoing cardiac surgery with cardiopulmonary bypass, an additional dose of Beyfortus may be administered soon as the child is stable after surgery to ensure adequate nirsevimab-alip serum levels and when the following criteria is met:

First RSV season:

Surgery is within 90 days after receiving initial Beyfortus dose;

or

More than 90 days have elapsed since receiving initial Beyfortus dose;

or

Second RSV season:

Surgery is within 90 days after receiving second Beyfortus dose;

or

More than 90 days have elapsed since receiving second Beyfortus dose.

Aetna considers all other indications as experimental and investigational.