Nirsevimab: A Promising Breakthrough in RSV Prevention
Respiratory syncytial virus (RSV) is a common and significant health concern, especially for infants and young children. It is one of the most common causes of childhood illness that often results in hospitalizations. According to the American Academy of Pediatrics (AAP), approximately 1% to 3% of children under 12 months of age in the United States are hospitalized each year due to RSV. RSV follows a seasonal pattern in the United States, typically starting in the fall and peaking during winter, though the exact timing may vary each year. This virus causes acute
respiratory infection in individuals of all age groups. While most infants and young children experience mild, cold-like symptoms, some infants, especially with their first infection, develop lower respiratory tract disease that often leads to an emergency department or physician office visit. Premature infants, and those with chronic lung disease of prematurity or significant congenital heart disease, are at the highest risk for severe RSV disease. This pervasive virus presents a significant
challenge to pediatric healthcare providers, emphasizing the importance of effective prevention and treatment strategies.
One of the primary prophylactic treatments for RSV is the monoclonal antibody Synagis ® (palivizumab). Palivizumab received approval from the Food and Drug Administration (FDA) in 1998, and since then has played a pivotal role in RSV prevention. This agent is recommended by the AAP for infants and young children who are at an elevated risk of developing severe RSV disease. Palivizumab is indicated for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients who fall into specific categories. It is administered through monthly intramuscular (IM) injections during the duration of the RSV season, offering protection to at-risk infants and children.
While Palivizumab has played a remarkable role in RSV prophylaxis, a significant development occurred on July 17, 2023, when the FDA approved Beyfortus ™ (nirsevimab-alip) for the prevention of RSV. This monoclonal antibody represents a notable advancement in RSV prevention. It’s designed to provide extended protection with just one dose that lasts for at least five months, essentially covering the duration of a typical RSV season. Nirsevimab-alip is indicated for the prevention of RSV in neonates and infants born during or entering their first RSV season. Additionally, it is also approved for use in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. Nirsevimab-alip works by specifically targeting the prefusion conformation of the RSV F protein. This recombinant human IgG1κ monoclonal antibody’s prolonged effectiveness is achieved through a triple amino acid substitution in the Fc region, which enhances its binding and extends its serum half-life (71 days).
The recommended dosing regimen for nirsevimab-alip offers effective protection based on different age groups and risk factors. For neonates and infants entering their first RSV season, nirsevimab-alip is administered right at birth or just before the season begins. The dosage is 50 mg for those weighing less than 5 kg and 100 mg for those weighing 5 kg or more. During the second RSV season, children up to 24 months old who remain at an increased risk for severe RSV disease receive 200 mg, divided into two IM doses. In the case of children undergoing cardiac surgery with cardiopulmonary bypass, an additional dose is recommended once the child is stable post-surgery. If the surgery occurs within 90 days after receiving nirsevimab-alip during the first RSV season, the additional dose depends on body weight. However, if it’s been more than 90 days since receiving nirsevimab-alip, a 50 mg additional dose is administered, regardless of body weight. Lastly, in the second RSV season following surgery within 90 days of nirsevimab-alip, a 200 mg additional dose is recommended, while if it’s been more than 90 days, a 100 mg additional dose is advised. This precise dosing regimen ensures optimal protection for pediatric patients in various scenarios and with different risk profiles.
The Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices/AAP (ACIP/AAP) have issued recommendations for nirsevimab-alip usage in the 2023 season, addressing its appropriate administration. Infants under 8 months entering their first RSV season are strongly advised to receive one nirsevimab-alip dose, while children aged 8 to 19 months at a higher risk of severe RSV should consider a dose at their second RSV season’s start. These guidelines also indicate that nirsevimab-alip and palivizumab should not be given in the same season. However, if less than five doses of palivizumab were given, one nirsevimab-alip dose is recommended, followed by discontinuing palivizumab. In cases where palivizumab was given in the first season and a child remains eligible for RSV prophylaxis in the second season, nirsevimab-alip should be administered in the second season if available. If not, continue with palivizumab as previously advised. These guidelines aim to ensure effective nirsevimab-alip and palivizumab use for infants and children at risk of RSV-related illnesses in the upcoming season.
Nirsevimab-alip demonstrates a favorable profile regarding drug interactions as it does not interfere with reverse transcriptase polymerase chain reaction or rapid antigen detection RSV diagnostic assays utilizing commercially available antibodies targeting antigenic sites on the RSV fusion protein. In contrast, palivizumab, may pose challenges as it can potentially interfere with immunological-based RSV diagnostic tests, especially certain antigen detection-based assays. Regarding safety, nirsevimab-alip should be used with caution in individuals with a history of serious hypersensitivity reactions, including anaphylaxis, either to nirsevimab-alip itself or any of its excipients. Additionally, special attention is warranted when considering nirsevimab-alip use in individuals with clinically significant bleeding disorders due to potential bleeding-related risks. Careful clinical management and monitoring are advised to address these considerations effectively.
Nirsevimab-alip’s safety and efficacy were evaluated in three clinical trials, a phase 2B trial (NCT02878330), the phase 3 MELODY trial, and in a phase 2–3 trial (NCT03959488). The phase 2B trial was a randomized, placebo-controlled trial that assessed the prevention of RSV-associated lower respiratory tract infections in 1453 healthy preterm infants. Infants were divided into two groups: nirsevimab-alip (969 infants) and placebo (484 infants). Included infants were one year or younger (eight months or younger for European Union participants) and born with gestational ages ranging from 29 weeks 0 days to 34 weeks 6 days. Notably, 53% of patients in the nirsevimab-alip group were 3 months or younger, and 13.7% were older than 6 months. Overall, baseline characteristics were similar between both the nirsevimab-alip and placebo group. The primary outcome, medically attended RSV-associated lower respiratory tract infections within 150 days, showed a significant 70.1% reduction with nirsevimab-alip compared to placebo (95% CI 52.3 to 81.2, p< 0.001). Hospitalization due to RSV-associated lower respiratory tract infections, the secondary outcome, saw a substantial 78.4% reduction with nirsevimab-alip compared to placebo (95% CI 51.9 to 90.3, p< 0.001).
Regarding safety, serious adverse events were less common in the nirsevimab-alip group (11.2%) than the placebo group (16.9%), with none related to the investigational product. Most adverse events were mild or moderate (grade 1 or 2), and grade 3 or higher events occurred in 8% of the nirsevimab-alip group and 12.5% of the placebo group. Adverse events of special interest, like hypersensitivity, immune complex disease, and thrombocytopenia, were reported in both groups, without significant anaphylaxis or severe hypersensitivity. Though there were a few deaths (5 in the nirsevimab-alip group vs. 3 in the placebo group), none were linked to RSV, nirsevimab-alip, or the placebo.
In the MELODY phase 3 randomized, placebo-controlled trial, 1490 healthy late-preterm and term infants were enrolled to assess nirsevimab-alip’s effectiveness against RSV-associated lower respiratory tract infections. Of these infants, 994 received nirsevimab-alip, and 496 received a placebo. Infants were randomized 2:1 to receive nirsevimab-alip IM injection or a placebo. Healthy infants who had been born at a gestational age of at least 35 weeks 0 days, were 1 year of age or younger, and were entering their first RSV season were included. The trial population included predominantly healthy infants who were born at term (86.0%), and baseline characteristics were similar in the two groups. The primary outcome, medically attended RSV-associated lower respiratory tract infections, showed a 74.5% reduction with nirsevimab-alip compared to placebo (95% CI 49.6 to 87.1, p< 0.001). Hospitalizations due to RSV-associated lower respiratory tract infections, the secondary outcome, had a 62.1% reduction (95% CI -8.6 to 86.8, p= 0.07). Safety-wise, most adverse events were mild to moderate (grade 1 or 2), with rare serious adverse events. Three deaths occurred, none related to the drug. Antidrug antibodies were detected in 6.1% of nirsevimab-ali precipients on day 361.
Due to these results from both trial, researchers concluded that a single injection of nirsevimab-alip significantly reduced medically attended RSV-associated lower respiratory tract infections and hospitalizations in healthy preterm infants, and in healthy late-preterm and term infants, throughout the RSV season. Additionally, Safety and efficacy were maintained through day 150, with consideration for antibody development post-day 361.
Lastly, an ongoing phase 2–3 trial (NCT03959488) spanning two RSV seasons, is evaluating nirsevimab-alip’s safety and pharmacokinetics in infants at risk for severe lower respiratory tract RSV infections, eligible for palivizumab. The study included infants eligible for palivizumab, born on or before 35 weeks of gestation, without congenital heart disease (CHD) or chronic lung disease (CLD) in the preterm cohort. Infants with uncorrected, partially corrected, or medically treated CHD or CLD requiring intervention within 6 months were part of the CHD–CLD cohort. Adverse events during treatment and special interest events were monitored up to day 361, and pharmacokinetics and antidrug antibody levels were analyzed. A total of 925 infants were included, with 310 in the CHD–CLD cohort and 615 in the preterm cohort. The primary analysis involved 886 infants with follow-up until day 151. Baseline characteristics were balanced between cohorts, reflecting standard neonatal care practices and palivizumab use in their respective countries. The incidence of adverse events was comparable across treatment groups and cohorts. Notably, two adverse events of special interest occurred in the nirsevimab-alip group: heparin-induced thrombocytopenia in an infant with CHD and a maculopapular rash following a placebo dose in a preterm infant.
In terms of safety, six deaths were recorded, with none attributed to treatment (5 in the nirsevimab-alip group vs. 1 in the palivizumab group). The trial also revealed that seven infants (0.6%) in the nirsevimab-alip group experienced medically attended RSV infections of the lower respiratory tract, compared to 1% of infants receiving palivizumab during the first RSV season. However, it’s essential to acknowledge that the trial was not specifically powered to assess efficacy, and the evaluation of efficacy was conducted as a secondary outcome. Serum nirsevimab-alip levels at day 151 demonstrated consistency between cohorts. Importantly, both groups exhibited a low antidrug-antibody response at day 151. Overall, these findings contribute valuable insights into nirsevimab-alip’s safety and pharmacokinetics in infants at risk for severe lower respiratory tract RSV infections, further informing its potential as an effective preventive measure in this vulnerable population.
The approval of nirsevimab-alip offers the potential to revolutionize the prevention of RSV, particularly for infants and young children. This monoclonal antibody offers extended protection throughout the RSV season with a single dose, providing a more convenient and effective option compared to the traditional monthly injections of palivizumab. Key findings from clinical trials have also showcased the efficacy and safety of nirsevimab-alip in preventing RSV-associated lower respiratory tract infections in both healthy preterm infants and late-preterm/term infants. This advancement in RSV prevention provides healthcare providers with a powerful tool to safeguard young patients from this seasonal health threat and offers hope for reduced hospitalizations and improved overall well-being. As healthcare providers continue to evaluate the best strategies for RSV prevention, the availability of nirsevimab-alip alongside palivizumab expands the options to tailor interventions to individual patient needs. However, ongoing research and surveillance are crucial to further refine these strategies and maximize the protection of vulnerable infants against RSV.
Written by Drug Information Fellow: Muna Said
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