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An FDA advisory committee on Thursday will consider whether to recommend a shot of a monoclonal antibody against respiratory syncytial virus (RSV) to prevent lower respiratory tract disease in both infants and in at-risk children up to age 2 years.

The will examine a biologics license application approval for nirsevimab, a long-acting RSV fusion protein inhibitor monoclonal antibody that's delivered via intramuscular injection. Nirsevimab's developer is AstraZeneca.

Its proposed indication will be prevention of lower respiratory tract disease due to RSV in neonates and infants born during or entering their first RSV season, and in children up to 24 months who remain vulnerable to severe RSV disease through their second RSV season.

Panelists will vote on two questions about the risk-benefit profile of the drug for both populations, and will consider two additional discussion questions. One is to consider the risk-benefit by chronological or gestational age group and determine whether there is a population or subpopulation for whom the prophylactic is most appropriate.

The other discussion question asks panelists to assess what additional data may be helpful to inform future recommendations about the drug's use in infants born to mothers who were vaccinated against RSV. Indeed, another FDA advisory committee recently voted to recommend approval of Pfizer's RSV vaccine in the second or third trimester of pregnancy to prevent respiratory tract illness in infants.

In addition, the FDA recently approved the first-ever RSV vaccines for adults ages 60 and up: GlaxoSmithKline's Arexvy and Pfizer's Abrysvo.

Nirsevimab was for preventing RSV disease in infants. It is a recombinant neutralizing humanized immunoglobulin G1 kappa monoclonal antibody directed against the prefusion conformation of the RSV fusion (F) protein. Essentially, it binds to the F protein to prevent viral entry into cells. Nirsevimab also has a three amino acid substitution to extend its half-life and enable it to be long-acting.

Currently, only one drug -- palivizumab (Synagis) -- is approved for prevention of serious lower respiratory tract disease due to RSV in certain high-risk infants and children. According to FDA review documents, palivizumab is administered monthly, while nirsevimab would be given once as a single dose prior to or during RSV season.

Infants weighing under 5 kg would get a single 50-mg dose, while those weighing 5 kg and up would get a 100-mg dose. Kids less than age 24 months entering their second RSV season would get a single 200-mg shot.

Safety and efficacy data come mainly from three trials: Trial 03, Trial 04 (MELODY), and Trial 05 (MEDLEY). The first two assessed infants in their first RSV season, while the third was conducted in high-risk infants over two RSV seasons.

Trial 03 was a phase IIb double-blind, placebo-controlled trial that randomized 1,453 participants to a 50-mg dose regardless of their weight. The incidence of medically attended lower respiratory tract disease due to RSV through day 150 post-dose was 2.6% in the treated group and 9.5% in placebo group (RR 70.1%, 95% CI 52.3%-81.2%, P<0.0001). Also, a significantly smaller proportion of patients in the treated group were hospitalized (0.8% vs 4.1% with placebo, RR 78.4%, 95% CI 51.9%-90.3%, P=0.0002).

The double-blind, placebo-controlled Trial 04 had to be paused due to the COVID pandemic. A total of 1,490 participants comprised the "primary cohort" that enrolled before the pandemic, and an additional 1,522 were enrolled when the trial resumed. In the interim, the statistical plan was revised so that the primary analysis could be based on those 1,490 participants, according to FDA review documents.

In that cohort, the incidence of medically attended lower respiratory tract disease through day 150 was 1.2% in the nirsevimab group and 5% in the placebo group (RR 74.9%, 95% CI 50.6%-87.3%, P<0.0001). The incidence of hospitalization, a secondary endpoint, was not statistically significant (0.6% vs 1.6%).

In its review, the FDA said that efficacy was demonstrated in both trials, but noted that few infants older than 8 months were enrolled in the studies, and that the risk-benefit analysis in this age group "may need additional consideration."

In terms of efficacy for high-risk children, the FDA said it "agreed with the applicant" that data could be extrapolated from Trials 03 and 04 to the "highest-risk" infants in yet another study, Trial 05, that was designed to assess safety. In addition, pharmacokinetic data could be considered "bridging evidence" to support efficacy in this population, FDA said.

Trial 05 was a double-blind, active-controlled trial that enrolled 925 infants, comparing the safety of nirsevimab with palivizumab in infants at high risk for severe disease over two RSV seasons. This at-risk population included premature infants born at less than 35 weeks' gestation and infants with chronic lung disease of prematurity or hemodynamically significant congenital heart disease.

During the first RSV season, incidence of medically attended lower respiratory tract infection was similar in the nirsevimab and palivizumab groups (0.6% and 1%). There were no cases of disease in the second RSV season since it was conducted in 2020 during the COVID pandemic, FDA said.

Trial 05 also showed that over 360 days, the most common adverse effects (AEs) for nirsevimab were agitation or irritability (0.7%), increased temperature (0.5%), and rash (0.3%). Additional safety data came from Trials 01, 02, and 08, FDA said.

There were no reports of anaphylaxis or immune complex disease in the trials, according to the FDA review document. There were two cases of thrombocytopenia, deemed an AE of special interest, and both were in the nirsevimab group. One was in a patient with congestive heart disease (CHD) who experienced heparin-induced thrombocytopenia; the other occurred in a patient with CHD who was septic at the time. Neither event was assessed to be related to nirsevimab.

FDA noted an "imbalance of deaths" in the nirsevimab group. Over five trials, there were 12 deaths among those on nirsevimab compared with four deaths among controls. The agency wrote that the number of deaths in the nirsevimab arms "exceeds what one would expect with the 2:1 randomization in Trials 03, 04, and 05." In those three trials alone, there were 11 deaths in the nirsevimab arms versus four in control arms (0.32% vs 0.22%). There was an additional death in Trial 08.

The most common causes of death included cardiac, infection, malignancy, and accidental causes. In the nirsevimab group, eight patients' cause of death was "clearly unrelated," FDA wrote. Another two patients died of lower respiratory tract infection. One had underlying severe protein calorie malnutrition, and the other had multiple underlying conditions, FDA said.

Two patients in the nirsevimab group were reported as dying of an unknown cause, as they were found dead in their cribs. One had multiple prior hospitalizations and a healthcare provider hypothesized the child had an underlying congenital metabolic or chromosomal anomaly. The other child, whose death occurred 123 days post-dose, was healthy, without previous issues, and the death was consistent with sudden infant death syndrome (SIDS) but the cause remains unknown and autopsy data were not available, according to the FDA.

None of the deaths were deemed to be related to the study drug, FDA said, noting that the rate of child mortality in the study overall was much lower than global infant mortality rates reported in 2021.

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