Formulary Drug Reviews: Nirsevimab

Abstract

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Generic Name: NIRSEVIMAB

Proprietary Name: Beyfortus (Sanofi Pasteur, Inc.)

Approval Rating: BLA

Therapeutic Class: Immune Globulin; Monoclonal Antibody

Similar Drugs: Palivizumab

Sound-/Look-Alike Names: Niraparib, Nivolumab

Indications

Nirsevimab-alip is indicated for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants born during or entering their first RSV season and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. ¹

Nirsevimab-alip and palivizumab, another monoclonal antibody for RSV prevention, are compared in Table 1.^1,2

Table 1.

Comparison of Monoclonal Antibodies for RSV Prevention.^a,1,2

	Nirsevimab-alip	Palivizumab
Brand name (manufacturer)	Beyfortus (Sanofi Pasteur)	Synagis (Sobi Inc)
Indication: Prevention of RSV lower respiratory tract disease in the following populations:
Neonates and infants born during or entering their first RSV season	X
Infants ≤6 months of age with a history of premature birth (≤35 weeks’ gestational age)		X
Children ≤24 months of age c who remain vulnerable to severe RSV disease through their second RSV season	X
Children ≤24 months of age c with bronchopulmonary dysplasia that required medical treatment within the previous 6 months		X
Children ≤24 months of age c with hemodynamically significant congenital heart disease		X
How supplied	50 mg per 0.5 mL prefilled syringe and 100 mg/mL prefilled syringe	50 mg per 0.5 mL single-dose vial and 100 mg/mL single-dose vial
Route	IM	IM
Frequency	Once per RSV season b	Monthly during the RSV season b

^aIM = intramuscular.

^bAdminister an additional dose in children undergoing cardiac surgery with cardiopulmonary bypass.

^cGuidelines recommend an age cutoff of 19 months for nirsevimab-alip, in contrast to the 24-month cutoff described in the nirsevimab-alip prescribing information. (^11,12).

Clinical Pharmacology

Nirsevimab-alip is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that provides passive immunity by targeting the prefusion conformation of the RSV fusion (F) protein. It binds to a conserved epitope in antigenic site Ø on the prefusion protein, with dissociation constants K_D = 0.12 nM and K_D = 1.22 nM for RSV subtype A and B strains, respectively. Nirsevimab-alip neutralizes RSV by inhibiting conformation changes in the F protein necessary for fusion of the viral and cellular membranes and viral entry. It is long-acting due to a triple amino acid substitution in the Fc region, which increases binding to the neonatal Fc receptor, thereby extending the serum half-life. Nirsevimab-alip is produced in Chinese hamster ovary cells by recombinant DNA technology.^1,3,4 In cell culture, nirsevimab-alip neutralized RSV A and B strains with more than 50-fold greater activity compared with palivizumab. In rats infected with RSV A or B, prophylactic nirsevimab-alip was 9-fold more potent than palivizumab at reducing pulmonary viral loads. ⁵

A positive correlation was observed between a serum nirsevimab-alip AUC above 12.8 mg•day/mL and a lower incidence of medically attended RSV lower respiratory tract infection. Following IM administration of nirsevimab-alip in adults, RSV-neutralizing antibody levels in serum were approximately 4 times higher than baseline at 8 hours after nirsevimab-alip dosing, and maximum levels were reached by day 6. ¹ In 97.9% of preterm infants with available data in one study (833 of 851 infants), serum concentrations remained above a targeted 90% effective concentration threshold of 6.8 µg/mL at day 151 after administration. ³ In an earlier pharmacokinetic study enrolling healthy preterm infants, 87% of infants in the 50 mg group had a serum concentration >6.8 µg/mL at day 151. ⁶ In data from 2143 infants in phase 2b and phase 3 studies, nirsevimab-alip–treated infants had RSV-neutralizing antibody levels more than 140-fold higher than baseline at day 31 after administration, more than 50-fold higher at day 151, and more than 7-fold higher at day 361. ⁷ Based on clinical data, the duration of protection offered by a single dose extends through 5 months. ¹

In cell culture, some recombinant RSV variants have demonstrated reduced susceptibility to nirsevimab-alip compared with the reference strain, including RSV A with substitutions N67I+N208Y (103-fold reduction) as well as RSV B with substitutions N208D (>90 000-fold change), N208S (>24 000-fold change), K68N+N201S (>13 000-fold change), and K68N+N208S (>90 000-fold change). All resistance-associated substitutions identified among neutralization escape variants were located in the nirsevimab-alip binding site (amino acids 62-69 and 196-212) and were shown to reduce binding affinity to RSV F protein. ¹

In isolates collected from 1956 to 2014, polymorphisms conferring large-fold reductions in nirsevimab-alip susceptibility were not observed for RSV A and were seen rarely for RSV B (<1%). Polymorphisms conferring reduced susceptibility included K65Q+K68N (1239-fold change), K65Q+S211N (36-fold change), and L203I (3005-fold change). In prospective, observational, global epidemiologic studies, RSV variants harboring known nirsevimab-alip resistance–associated substitutions have been rare (<1%) and have included RSV B substitutions N201T (>406-fold change) and N201T+I206M+Q209R (>418-fold change). Variants with reduced susceptibility include RSV A substitutions K68E (13-fold change) and S275F (6-fold change), and RSV B substitutions K68N (30-fold change), K68Q+I206M+Q209R (46-fold change), and N201S (127-fold change). The clinical significance of these reductions in susceptibility is unknown. In a clinical trial of patients with RSV infection receiving a single dose of nirsevimab-alip, 2 of 40 patients had a variant containing nirsevimab-alip resistance–associated substitutions; both patients had received less than the recommended nirsevimab-alip dose and had RSV B variants harboring I64T+K68E+I206M+Q209R co-occurring substitutions or an N208S substitution. I64T, K68E, and N208S substitutions individually have reduced susceptibility to nirsevimab-alip (>496-fold change, >283-fold change, and >387-fold change, respectively). RSV B variants harboring these substitutions were also observed in 2 subjects in another trial. ¹ An observed RSV B binding site substitution I206M:Q209R increased nirsevimab-alip susceptibility. Overall, more than 99% of isolates from the phase 2b and phase 3 trial retained susceptibility to nirsevimab. ⁸ The FDA is requiring genotype and phenotype surveillance from ongoing clinical studies, including reporting of new variants and substitutions showing 5-fold or greater reductions in susceptibility. ⁹

Limited data are available on cross-resistance between nirsevimab-alip and palivizumab. Palivizumab retained full neutralization potency against resistance-associated substitutions identified in nirsevimab-alip trials. Nirsevimab-alip retained activity against recombinant RSV harboring palivizumab resistance–associated substitutions, although susceptibility was reduced 6-fold in the presence of the S275F substitution. ¹

In clinical trials, antidrug antibodies were observed in a small number of subjects (<10%) receiving nirsevimab-alip, and subjects with anti–nirsevimab-alip antibodies had 50% to 60% reduced nirsevimab-alip concentrations at day 361 compared with subjects who did not develop antidrug antibodies. The effect of antidrug antibodies on nirsevimab-alip effectiveness could not be determined. ¹ There is limited experience with treatment for a second season; however, antidrug antibodies were observed in 1 of 90 participants (1.1%) at day 31 and in zero of 158 participants at day 151 in a phase 2/3 trial including retreatment for a second season. ¹⁰

Pharmacokinetics

Dose-proportional pharmacokinetics have been observed following single IM doses ranging from 25 mg (0.5 times the lowest approved dose) to 200 mg in pediatric subjects. Following the recommended dose, nirsevimab-alip serum exposures were similar in neonates and infants born during or entering their first RSV season, in neonates and infants born before 35 weeks’ gestational age in their first RSV season, and in pediatric subjects up to 24 months of age with chronic lung disease or chronic heart disease in their first and second RSV season. ¹

Nirsevimab-alip absolute bioavailability is estimated to be 84%, and median T_max is 6 days (range, 1-28 days). For an infant weighing 5 kg, the estimated total volume of distribution is 477 mL, the terminal half-life is approximately 71 days, and the estimated clearance is 3.42 mL/day. Nirsevimab-alip is degraded into small peptides by catabolic pathways. ¹ Serum concentrations decreased linearly over time. ⁴

No significant differences in pharmacokinetics were observed based on race or vulnerability to severe RSV disease (ie, chronic lung disease, chronic heart disease, gestational age <29 weeks, or immunocompromised states). Renal or hepatic impairment is not expected to alter nirsevimab-alip pharmacokinetics. ¹

Comparative Efficacy

Indication: Prevention of Respiratory Syncytial Virus Lower Respiratory Tract Infection

Guidelines

• Guideline: Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) recommendations for nirsevimab

• Reference: American Academy of Pediatrics, 2023 ¹¹

• Comments: Nirsevimab-alip is recommended for all infants younger than 8 months born during or entering their first RSV season, including those recommended by the AAP to receive palivizumab, and for infants and children 8 through 19 months of age who are at increased risk of severe RSV disease and entering their second RSV season, including those recommended by the AAP to receive palivizumab. The ACIP of the Centers for Disease Control and Prevention recommends that nirsevimab-alip be used as indicated in the FDA-approved labeling and has voted to include it in the Vaccines for Children program. If nirsevimab-alip is not available or not feasible to administer, high-risk infants who are recommended to receive palivizumab in the first or second year of life should receive palivizumab until nirsevimab-alip becomes available. If nirsevimab-alip is administered for the RSV season, palivizumab should not be administered later that season. If palivizumab was administered initially for the season and fewer than 5 doses were administered, the infant should receive one dose of nirsevimab-alip, with no further palivizumab administered. If palivizumab was administered for the infant’s first RSV season and the child is eligible for RSV prophylaxis in their second season, the child should receive nirsevimab-alip in season 2 if it is available or palivizumab if nirsevimab-alip is not available. Nirsevimab-alip should be administered during the first week of life in infants born shortly before or during the RSV season. It can be administered during the birth hospitalization or in the outpatient setting. Infants with a prolonged birth hospitalization should receive nirsevimab-alip shortly before or promptly after discharge. If not administered shortly before the start of the RSV season, nirsevimab-alip may be given at any time during the RSV season to age-eligible infants and children who have not yet received a dose. Healthy infants born at the end of the RSV season who received nirsevimab-alip around the time of delivery should not receive a second dose entering the second RSV season, even if they are younger than 8 months. Healthy infants born at the end of the RSV season who did not receive nirsevimab-alip and are younger than 8 months entering their second RSV season may receive one nirsevimab-alip dose. Nirsevimab-alip is recommended for children entering their second RSV season who are 8 through 19 months of age with chronic lung disease of prematurity requiring medical support at any time during the 6 months prior to the start of their second RSV season, are severely immunocompromised, have cystic fibrosis with manifestations of severe lung disease or weight-for-length less than the 10th percentile, or are American Indian or Alaska Native. Simultaneous administration of nirsevimab-alip with age-appropriate vaccines is recommended. CDC Advisory Committee on Immunization Practices–specific recommendations support the AAP guideline recommendations regarding nirsevimab-alip for prevention of RSV in infants and young children. ¹²

Studies

• Drug: Nirsevimab-alip versus Palivizumab

• Reference: Domachowske J, et al, 2022 (MEDLEY trial; NCT03959488)^1,13,14

• Study Design: Phase 2/3, randomized, double-blind, multicenter study

• Study Funding: AstraZeneca

• Patients: 925 infants born at or before 35 weeks’ gestational age (preterm cohort; n = 615) and infants born with chronic lung disease or chronic heart disease (CHD/CLD cohort; n = 310) entering their first RSV season, as well as 262 infants with chronic lung disease or chronic heart disease entering their second RSV season. Participants were excluded from the first-season cohorts if they had previously had an RSV infection, or had received palivizumab or an investigational RSV monoclonal antibody or vaccine, including a maternal RSV vaccine. In the preterm cohort, gestational age was <29 weeks in 13% and 29 weeks to <35 weeks in 81%. In the CHD/CLD cohort, 70% had chronic lung disease of prematurity; 34% had hemodynamically significant chronic heart disease; 40% were <29 weeks’ gestational age, 28% were 29 weeks’ to <35 weeks’ gestational age, and 32% were at least 35 weeks’ gestational age. In the combined cohorts, 54% of patients were male; 79% were White and 10% were Black; and 57% weighed <5 kg. Median age was 3.5 months; 45% of patients were 3 months or younger, 34% were older than 3 to 6 months, and 21% were older than 6 months.

• Intervention: Subjects were randomized (2:1) to receive a single IM injection of nirsevimab-alip (50 mg for weight <5 kg, or 100 mg for weight of 5 kg or more) followed by 4 once-monthly IM doses of placebo, or to receive 5 once-monthly IM doses of palivizumab 15 mg/kg during the first season. Subjects continuing in the second RSV season who had received nirsevimab-alip in the first season received a single dose of nirsevimab-alip 200 mg followed by 4 once-monthly doses of placebo (n = 180). Those treated with palivizumab in the first season were rerandomized (1:1) to nirsevimab-alip or palivizumab for the second season.

Results:

Primary End Point(s):

• Adverse reactions reported in children who received nirsevimab-alip in their first RSV season were similar to those reported in children who received nirsevimab-alip in placebo-controlled trials. Safety profile of nirsevimab-alip in these children during their second RSV season was consistent with the safety profile observed during their first RSV season.

• Following the recommended dose, nirsevimab-alip serum exposures were similar in neonates and infants born during or entering their first RSV season; in neonates and infants born at <35 weeks’ gestational age (including <29 weeks’ gestational age) in their first RSV season; and in children up to 24 months of age with chronic lung disease or chronic heart disease in their first and second RSV season.

Secondary End Point(s):

• In the first RSV season, medically attended RSV-associated lower respiratory tract infections through 150 days post dose occurred in 0.6% of infants in the nirsevimab-alip group and 1% of infants in the palivizumab group (statistical analysis not conducted).

• In the second RSV season, there were no cases of medically attended RSV-associated lower respiratory tract infections through 150 days post dose in the nirsevimab-alip or palivizumab groups.

Comments: The study was conducted at 128 study sites in 25 countries in the northern hemisphere and 1 country in the southern hemisphere.

Limitations: The study was not powered for efficacy, but efficacy was assessed as a secondary end point. Results are only available in the prescribing information and a published letter.

Drug: Nirsevimab-alip versus Placebo

Reference: Hammitt LL, et al, 2022 (MELODY trial; NCT03979313) ⁴

Study Design: Phase 3, randomized, double-blind, multicenter study

Study Funding: MedImmune/AstraZeneca; Sanofi

Patients: 1490 healthy infants born at a gestational age of at least 35 weeks 0 days and who were 1 year or younger entering their first RSV season. Participants were excluded if they met guidelines to receive palivizumab prophylaxis; had previously had an RSV infection; or had received palivizumab or an investigational RSV monoclonal antibody or vaccine, including a maternal RSV vaccine. Most subjects were enrolled in the northern hemisphere (69%). Median patient age was 2.6 months; 86% of infants were born at term (37 weeks or later). Mean weight was <5 kg in 40.6% of infants in the nirsevimab-alip group and 38.7% of infants in the placebo group. Females comprised 46.8% of the nirsevimab-alip cohort and 51.8% of the placebo cohort. Most subjects were White (52.9% in the nirsevimab-alip group and 54.8% in the placebo group) or Black (28.9% and 27.4%, respectively).

Intervention: Subjects were randomized (2:1) to a single IM injection of nirsevimab-alip (50 mg for weight <5 kg, or 100 mg for weight 5 kg or more; n = 994) or normal saline placebo (n = 496). Randomization was stratified by hemisphere (northern or southern) and by age (3 months or younger, older than 3 to 6 months, or older than 6 months). Seven subjects in the nirsevimab-alip group and 5 subjects in the placebo group did not receive an injection.

Results:

Primary End Point(s):

• Medically attended RSV-associated lower respiratory tract infection through 150 days after administration occurred in 1.2% of infants in the nirsevimab-alip group and 5% of infants in the placebo group (relative risk reduction, 74.5%; 95% CI, 49.6%-87.1%; P < .001).

  • Over the entire 150-day efficacy period after administration of the dose, nirsevimab-alip–treated infants had a lower risk of medically attended RSV-associated lower respiratory tract infection than placebo-treated infants (HR, 0.23; 95% CI, 0.12-0.47).

Secondary End Point(s):

• Hospitalization due to RSV-associated lower respiratory tract infection through 150 days after administration was not significantly reduced (0.6% of infants in the nirsevimab-alip group and 1.6% of infants in the placebo group; P < .07).

Other End Point(s):

• Medically attended RSV-associated lower respiratory tract infection on any test result through 150 days in the northern hemisphere cohort occurred in 2.5% of infants in the nirsevimab-alip group and 10.8% of infants in the placebo group (relative risk reduction, 77%; 95% CI, 59.8%-86.8%).

• Medically attended lower respiratory tract infection of any cause through 150 days in the northern hemisphere cohort occurred in 8.7% of infants in the nirsevimab-alip group and 18.1% of infants in the placebo group (relative risk reduction, 51.5%; 95% CI, 32.6%-65.2%).

• Hospitalization for any respiratory illness due to RSV on any test result through 150 days in the northern hemisphere cohort occurred in 1.3% of infants in the nirsevimab-alip group and 3.2% of infants in the placebo group (relative risk reduction, 59%; 95% CI, 2.1%-82.9%).

• Hospitalization for any respiratory illness of any cause through 150 days in the northern hemisphere cohort occurred in 2.3% of infants in the nirsevimab-alip group and 4.1% of infants in the placebo group (relative risk reduction, 42.8%; 95% CI, −15.8% to 71.7%).

Comments: The primary cohort was enrolled in 2019 at 150 sites in 20 countries in the northern hemisphere and in 2020 at 10 sites in 1 country in the southern hemisphere. Efficacy analyses were conducted in the intention-to-treat population. Overall, 98.3% of participants completed 150 days of follow-up, and 91.7% completed 360 days of follow-up. Subgroup analysis according to age at randomization, sex, race, weight, and gestational age showed consistent efficacy of nirsevimab-alip compared with placebo for the primary end point; however, relatively lower estimates of efficacy were observed among younger infants (3 months and younger) and for those weighing <5 kg. Enrollment and follow-up for an additional safety cohort of 1500 infants was ongoing at the time of the primary analysis.

Additional data have been reported for the full enrollment of the MELODY trial (3012 randomized participants enrolled at a total of 211 sites in 31 countries [n = 2009 for nirsevimab-alip and n = 1003 for placebo]). Overall, medically attended RSV-associated lower respiratory tract infection through 150 days occurred in 1.2% in the nirsevimab-alip group and 5.4% in the placebo group, for a relative risk reduction of 76.4% (95% CI, 62.3%-85.2%). Hospitalization for RSV-associated lower respiratory tract infection through 150 days occurred in 0.4% in the nirsevimab-alip group and 2% in the placebo group (relative risk reduction, 76.8%; 95% CI, 49.4%-89.4%). Very severe medically attended RSV-associated lower respiratory tract infection through 150 days occurred in 0.3% in the nirsevimab-alip group and 1.7% in the placebo group (relative risk reduction, 78.6%; 95% CI, 48.8%-91%). ¹⁵

Limitations: Efficacy was not able to be assessed in the cohort enrolled in 2020 in the southern hemisphere (South Africa) due to the low incidence of RSV during the COVID-19 pandemic. Target enrollment was not reached, impacting power for the assessment of hospitalization.

Reference: Griffin MP, et al, 2020 (NCT02878330) ³

Study Design: Phase 2, randomized, double-blind, multicenter study

Study Funding: MedImmune/AstraZeneca; Sanofi Pasteur

Patients: 1453 healthy infants born preterm (gestational age, 29 weeks 0 days through 34 weeks 6 days) and who were 1 year or younger entering their first full RSV season. Infants enrolled in the European Union had to be 8 months or younger. Participants were excluded if they met guidelines to receive palivizumab prophylaxis; had previously had an RSV infection; or had received palivizumab or an investigational RSV monoclonal antibody or vaccine, including a maternal RSV vaccine. Most subjects were enrolled in the northern hemisphere (68%). Mean patient age was 3.29 months in the nirsevimab-alip group and 3.28 months in the placebo group; mean gestational age was 32.7 weeks in both groups. Mean weight was 4.6 kg in the nirsevimab-alip group and 4.51 kg in the placebo group. Females comprised 48.3% of the nirsevimab-alip cohort and 46.3% of the placebo cohort. Most subjects were White (71.6% in the nirsevimab-alip group and 73.3% in the placebo group) or Black (19.5% and 13.8%, respectively). Approximately one-third of patients had a sibling enrolled in the trial (34.7% in the nirsevimab-alip group and 35.5% in the placebo group).

Intervention: Subjects were randomized (2:1) to a single IM injection of nirsevimab-alip 50 mg (n = 969) or normal saline placebo (n=484) during a 2-month period immediately before the RSV season. Randomization was stratified by hemisphere (northern or southern) and by age (3 months or younger, older than 3 to 6 months, or older than 6 months). Three subjects in each treatment group did not receive an injection.

Results:

Primary End Point(s):

• Medically attended (inpatient or outpatient) RSV-associated lower respiratory tract infection through 150 days after administration occurred in 2.6% of infants in the nirsevimab-alip group and 9.5% of infants in the placebo group (relative difference, 70.1%; 95% CI, 52.3%-81.2%; P < .001).

  • Over the entire 150-day efficacy period after administration of the dose, nirsevimab-alip–treated infants had a lower risk of medically attended RSV-associated lower respiratory tract infection than placebo-treated infants (hazard ratio [HR], 0.26; 95% CI, 0.16-0.43).

Secondary End Point(s):

• Hospitalization due to RSV-associated lower respiratory tract infection through 150 days after administration occurred in 0.8% of infants in the nirsevimab-alip group and 4.1% of infants in the placebo group (relative difference, 78.4%; 95% CI, 51.9%-90.3%; P < .001).

  • Over the entire 150-day efficacy period after administration of the dose, nirsevimab-alip–treated infants had a lower risk of hospitalization for RSV-associated lower respiratory tract infection than placebo-treated infants (HR, 0.19; 95% CI, 0.08-0.44).

• Incidence of medically attended lower respiratory tract infection of any cause through 150 days was 19.7% in the nirsevimab-alip group and 25.8% in the placebo group (relative difference, 23.5%; 95% CI, 7.1%-37%).

• Incidence of hospitalization for lower respiratory tract infection of any cause through 150 days was 5.5% in the nirsevimab-alip group and 9.5% in the placebo group (relative difference, 42.5%; 95% CI, 16.3%-60.5%).

Other End Point(s):

• Among infants with medically attended RSV-associated lower respiratory tract infection, fewer nirsevimab-alip–treated patients than placebo recipients required supplemental oxygen (16%vs 32.6%).

• Of infants hospitalized for RSV infection, intensive care unit admission was required for 5 infants in the placebo group and none in the nirsevimab-alip group, and assisted ventilation was required for 4 infants in the placebo group and none in the nirsevimab-alip group.

Comments: The study was conducted at 164 sites in 23 countries. Efficacy analyses were conducted in the intention-to-treat population. Overall, 97.5% of subjects (1417 participants) completed the 150-day efficacy period; 94.2% of subjects in the nirsevimab-alip group and 93.8% in the placebo group completed the entire 360-day follow-up. Subgroup analysis according to hemisphere, age at randomization, sex, race, gestational age, and enrolled sibling showed consistent efficacy of nirsevimab-alip compared with placebo for primary and secondary end points.

A similar ongoing phase 3, randomized, open-label, multicenter study (HARMONIE; NCT05437510) sponsored by Sanofi Pasteur and conducted in France, Germany, and the United Kingdom is assessing 8058 infants born at or after 29 weeks’ gestational age and who are 0 to 12 months of age (calendar age) entering their first RSV season. Exclusion criteria included immunodeficiency, receipt of immunosuppressants, bleeding disorder or receipt of an anticoagulant, eligibility for palivizumab treatment, or maternal receipt of RSV vaccine during pregnancy. Patients were randomized to a nirsevimab-alip single IM dose or no intervention. The primary end point is overall incidence of hospitalization for RSV lower respiratory tract infection up to 180 days post randomization. Secondary end points include incidence of very severe RSV lower respiratory tract infection, incidence of hospitalization for lower respiratory tract infection through the RSV season in each country, and overall hospitalization for all-cause lower respiratory tract infection in all 3 countries combined throughout the RSV season. This is an ongoing study with anticipated completion in March 2024.^9,16 A long-term extension of this study will be conducted in the UK cohort through day 511 post dosing, with completion anticipated in April 2025. A long-term observational study is also to be conducted in the United States, with study completion anticipated in March 2028. ⁹

Limitations: Racial diversity was limited.

Contraindications, Warnings, and Precautions

Contraindications

Nirsevimab-alip is contraindicated in infants and children with a history of serious hypersensitivity reactions, including anaphylaxis, to nirsevimab-alip or to any component of the formulation (ie, arginine hydrochloride, histidine, L-histidine hydrochloride monohydrate, polysorbate 80, sucrose). ¹

Warnings and Precautions

Serious hypersensitivity reactions, including anaphylaxis, have been observed with other human IgG monoclonal antibodies. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, appropriate medications and/or supportive therapy should be initiated. ¹

As with all IM injections, nirsevimab-alip should be administered with caution to infants and children with thrombocytopenia or any coagulation disorder, or who are receiving anticoagulant therapy. ¹

Safety and effectiveness of nirsevimab-alip have not been established in pediatric patients older than 24 months. ¹ The FDA has waived requirement for study in this age group because children older than 24 months have a lower incidence of medically attended RSV disease, with fewer hospitalizations and less severe disease, and would therefore be unlikely to benefit from the use of nirsevimab-alip for the prevention of RSV lower respiratory tract disease. ⁹

Nirsevimab-alip is not indicated for use in females of reproductive potential. ¹ There are no data regarding nirsevimab-alip use during pregnancy or lactation.

Adverse Reactions

The most common adverse reactions with nirsevimab-alip in clinical trials were rash (0.9% vs 0.6% with placebo) and injection-site reactions (0.3% vs 0% with placebo). Adverse reactions reported in children receiving nirsevimab-alip during their second RSV season were consistent with those observed during their first RSV season.^1,10

Drug Interactions

No formal drug interaction studies have been conducted with nirsevimab-alip. Nirsevimab-alip is not expected to be a substrate, inhibitor, or inducer of CYP-450 enzymes or transporter systems. ¹

Nirsevimab-alip may be given concomitantly with childhood vaccines, although experience is limited. When nirsevimab-alip was given concomitantly with routine childhood vaccines in clinical trials, the safety and reactogenicity profile of the coadministered regimen was similar to that of the childhood vaccines given alone.^1,11,17

Nirsevimab-alip does not interfere with reverse transcriptase polymerase chain reaction (RT-PCR) or rapid antigen detection RSV diagnostic assays that use commercially available antibodies targeting antigenic site I, II, or IV on the RSV F protein. If immunologic assay results are negative in the presence of clinical observations consistent with RSV infection, confirmatory testing using an RT-PCR–based assay is recommended. ¹

Recommended Monitoring

Observe for severe hypersensitivity reactions; RSV infection.

Dosing

Nirsevimab-alip is administered by a health care provider as an IM injection, preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used as an injection site due to the risk of damage to the sciatic nerve. ¹

For neonates and infants born during or entering their first RSV season, the recommended dose is 50 mg for those weighing <5 kg and 100 mg for those weighing 5 kg or more. For neonates and infants born during or entering the RSV season, nirsevimab-alip should be administered starting from birth. For infants born outside the RSV season, nirsevimab-alip should be administered once before the start of the RSV season, considering the duration of protection provided by the product. ¹

For children up to 24 months of age who remain at risk for severe RSV disease through their second RSV season, the recommended dose is 200 mg (two 100 mg IM injections). ¹

For children undergoing cardiac surgery with cardiopulmonary bypass, an additional dose of nirsevimab-alip is recommended as soon as the child is stable after surgery to ensure adequate nirsevimab-alip serum levels. During the first RSV season, if surgery is within 90 days after receiving nirsevimab-alip, the additional dose should be based on body weight at the time of the additional dose (according to previously described weight-based dosing); if surgery is more than 90 days after receiving nirsevimab-alip, the additional dose should be 50 mg regardless of body weight. During the second RSV season, if surgery is within 90 days after receiving nirsevimab-alip, the additional dose should be 200 mg regardless of body weight; if surgery is more than 90 days after receiving nirsevimab-alip, the additional dose should be 100 mg regardless of body weight. ¹

Nirsevimab-alip may be given concomitantly with childhood vaccines. When administered concomitantly, nirsevimab-alip and other injectable vaccines should be given with separate syringes and at different injection sites. Nirsevimab-alip should not be mixed with any vaccines or medications in the same syringe or vial. ¹

There is no information regarding coadministration of nirsevimab-alip with other immunoglobulin products. Palivizumab should not be administered to infants who have already received nirsevimab-alip in the same season. There are no data regarding substitution of nirsevimab-alip for palivizumab once prophylaxis has been initiated with palivizumab for the RSV season; however, the AAP and ACIP recommend that nirsevimab-alip be used if 5 doses of palivizumab have not yet been administered. ¹¹ Nirsevimab-alip may be administered prior to and during the second RSV season to children for whom it is indicated and who received palivizumab in their first RSV season. ¹

Product Availability and Storage

Nirsevimab-alip was approved by the Food and Drug Administration on July 17, 2023.^1,9 Nirsevimab-alip is available as a sterile, preservative-free solution for IM injection. It is supplied in cartons containing one or five 50 mg per 0.5 mL single-dose prefilled syringes or one or five 100 mg/mL single-dose prefilled syringes. Each milliliter contains 100 mg of nirsevimab-alip; the formulation has a pH of 6. ¹

The syringes should be stored refrigerated at 2°C to 8°C (36°F-46°F) in the original carton to protect from light until time of use. After removal from the refrigerator, nirsevimab-alip must be used within 8 hours or discarded. Do not freeze, shake, or expose to heat. ¹

Drug Safety/REMS

No REMS is required for nirsevimab-alip. ⁹

Conclusion

Nirsevimab-alip, a monoclonal antibody that provides passive immunity for RSV, is approved for prevention of RSV lower respiratory tract disease in neonates and infants born during or entering their first RSV season and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. According to ACIP and AAP recommendations, nirsevimab-alip is recommended for all infants younger than 8 months born during or entering their first RSV season, including those recommended by the AAP to receive palivizumab, and for infants and children 8 through 19 months of age who are at increased risk of severe RSV disease and entering their second RSV season, including those recommended by the AAP to receive palivizumab. Nirsevimab-alip is administered as a single IM injection, offering an advantage over palivizumab, which must be administered monthly during the RSV season.