PARIS – MARCH 3, 2022 - The New England Journal of Medicine (NEJM) today published detailed positive primary results from a Phase 3 trial evaluating nirsevimab, the first investigational long-acting antibody designed to help protect all infants against lower respiratory tract infections (LRTI) caused by respiratory syncytial virus (RSV) across the RSV season (150 days) with a single dose.1,2
The trial met its primary endpoint, showing that nirsevimab achieved a relative risk reduction against placebo in the incidence of medically attended LRTI, such as bronchiolitis or pneumonia, caused by RSV, in healthy infants born at term or late preterm (35 weeks gestational age or greater) entering their first RSV season.1,2 Medically attended LRTI occurred in 12 (1.2%) of the 994 infants in the nirsevimab group and in 25 (5%) of the 496 infants in the placebo group, corresponding to a reduction of 74.5% (95% CI: 49.6 to 87.1; p<0.001).1,2
In the Phase 3 MELODY trial alone, a numerical reduction of the risk of RSV-associated hospitalizations was observed, although not statistically significant (62.1%, 95% CI: -8.6 to 86.8; p=0.07).1,2 In the nirsevimab arm, six (0.6%) of 994 infants were hospitalized for RSV LRTI, while eight (1.6%) of 496 infants were hospitalized in the placebo arm.1,2 A prespecified pooled analysis of RSV-associated hospitalizations in both the Phase 3 and Phase 2b trials was also conducted. In term and preterm infants (greater than 28 weeks gestational age), the proposed dose of nirsevimab demonstrated a reduction of 77.3% (95% CI 50.3 to 89.7, P<0.001) in RSV-associated hospitalizations.1-3 Nirsevimab is being developed by Sanofi and AstraZeneca.
Dr. William Muller
Associate Professor, Pediatrics, Northwestern University Feinberg School of Medicine and Scientific Director, Clinical and Community Trials, Ann & Robert H. Lurie Children’s Hospital of Chicago, Illinois
“We know that RSV has seen a resurgence with the easing of COVID-19 public health measures. This shows us a broad immunization approach is needed to help mitigate the substantial global burden RSV places on infants, their families and healthcare services. These exciting data show that nirsevimab has the potential to offer RSV protection for all infants, which would be a paradigm shift in the approach to this disease.”
The results of the Phase 3 and Phase 2/3 clinical trials, combined with the Phase 2b trial and conducted in different trial populations, demonstrate nirsevimab’s potential to help protect all infants against LRTI caused by RSV across the RSV season (150 days) with a single dose.1-6
Global Head of Research and Development Vaccines, Sanofi
“With three pivotal late-stage trials, our research has been focused on delivering a first-in-class RSV prevention for all infants. Our Phase 3 MELODY results in healthy late preterm and term infants represent a major milestone toward that goal. We are pleased nirsevimab has the potential to become the first immunization to protect all infants across the RSV season, with only a single dose.”
Potential to provide rapid protection
Nirsevimab is the first investigational long-acting antibody designed to help protect all infants during their first RSV season. With nirsevimab, the goal is to help provide rapid and direct protection to the infant through a single immunization. It is the first potential immunization to show protection against LRTI caused by RSV in infants in a Phase 3 trial.1,2 RSV is a very contagious virus that can lead to serious respiratory illness for infants, according to the Centers for Disease Control and Prevention (CDC).7 It is the leading cause of hospitalization in infants under 12 months, according to a study conducted between 1997 and 2000.8
Executive Vice President, BioPharmaceuticals R&D, AstraZeneca
“Respiratory syncytial virus is a leading cause of lower respiratory tract infections, such as bronchiolitis or pneumonia, as well as hospitalizations in infants. These data show for the first time, the potential to significantly protect all infants through their first RSV season with a single-dose immunization and we look forward to working with health authorities to bring nirsevimab to infants as quickly as possible.”
The safety and tolerability of nirsevimab compared to palivizumab was evaluated in the Phase 2/3 trial, which demonstrated nirsevimab had a similar safety and tolerability profile compared to palivizumab when administered to infants with congenital heart disease (CHD), chronic lung disease (CLD) and prematurity (35 weeks gestational age or fewer) entering their first RSV season.5,6 Safety was assessed by monitoring the occurrence of all treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) through 360 days post-dose.5,6 The serum levels of nirsevimab following dosing at Day 151 in this trial were comparable with those observed in the Phase 3 trial, indicating similar protection in this population to that in the healthy term and late preterm infants is likely.1,2,5,6 Details from the Phase 2/3 trial were also published in NEJM. The study is ongoing, and topline results were presented at ReSViNET Annual Conference 2021 (RSVVW’21).
Regulatory submissions in the U.S. are planned to begin in the second half of 2022.
About the Phase 3 trial
MELODY is a randomized, placebo-controlled Phase 3 trial conducted across 21 countries designed to determine the incidence of medically attended LRTI due to RSV confirmed by reverse transcriptase polymerase chain reaction testing through 150 days after dosing, versus placebo, in healthy infants entering their first RSV season.1,2 Healthy late preterm and term infants (35 weeks gestational age or greater) were randomized (2:1) to receive a single 50mg (in infants weighing <5kg) or 100mg (in infants weighing >5kg) intramuscular injection of nirsevimab or placebo.1,2 Between July 2019 and February 2021 1,490 infants were randomized to either nirsevimab or placebo, and 1,478 were dosed (987 received nirsevimab and 491 received placebo) at the RSV season start.1,2 Pooled analyses of the RSV LRTI hospitalization endpoint from both the MELODY and the Phase 2b trials were prespecified under a multiplicity-protected hierarchical testing strategy.
The overall safety profile of nirsevimab in the trial remains consistent with previously reported results.1-3 No clinically meaningful differences in safety results between the nirsevimab and placebo dosed groups were seen.1,2 Adverse events (AEs) were similar across the nirsevimab and placebo groups and occurred in 863 (87.4%) of the 987 nirsevimab recipients and 426 (86.8%) of the 491 placebo recipients.1,2 Only 10 (1%) of the nirsevimab recipients and 7 (1.4%) of the placebo recipients reported a treatment related AE. Serious AEs occurred in 67 (6.8%) of the nirsevimab recipients and 36 (7.3%) of the placebo recipients, with none considered product related.1,2 There was a total of 3 deaths on or after day 140 in the nirsevimab group, none of which were considered by the investigators to be related to nirsevimab.1,2
The evaluation of the primary endpoint in the MELODY trial was conducted earlier than anticipated. Global public health measures to control COVID-19 had reduced the circulation of all respiratory viruses, including RSV, at the time of trial enrollment. Sufficient cases had been accrued prior to the pandemic to evaluate nirsevimab’s ability to prevent RSV LRTI versus placebo. An additional 1,500 infants have been enrolled in the Northern and Southern Hemispheres to provide additional safety information.1,2
About the Phase 2/3 trial
MEDLEY is a Phase 2/3, randomized, double-blind, palivizumab-controlled trial with the primary objective of assessing safety and tolerability for nirsevimab in preterm infants and infants with CHD and/or CLD of prematurity eligible to receive palivizumab.5,6 Between July 2019 and May 2021 approximately 918 infants entering their first RSV season were dosed with either nirsevimab or palivizumab. Safety is assessed by monitoring the occurrence of TEAEs and TESAEs through 360 days post-dose.5,6
The evaluation of the safety and tolerability of nirsevimab in the MEDLEY trial was carried out earlier than anticipated. A primary analysis was conducted to allow earlier assessment of nirsevimab’s safety and tolerability versus palivizumab based on a sufficient number of infants being enrolled and followed through their first RSV season.
The results of MEDLEY, MELODY, and the Phase 2b trial demonstrate that nirsevimab helps to provide protection against LRTI caused by RSV in all infants (including preterm, healthy infants born at term or late preterm, as well as infants with CLD and CHD) with a single dose.1-6
These trials will form the basis of global regulatory submissions that have begun and are planned to begin in the U.S. in the second half of 2022.
What is RSV
RSV is a very contagious virus that can lead to serious respiratory illness for infants, according to the CDC.7 RSV is the leading cause of hospitalization in infants under 12 months, according to a study conducted between 1997 and 2000.8 Approximately 72% of infants hospitalized for RSV were born at term with no underlying conditions in a study conducted from 2014-2015.9 RSV symptoms can include runny nose, coughing, sneezing, fever, decrease in appetite, and wheezing.7 In recent months, there has been a resurgence of RSV following the easing of COVID-19 public health measures.10 Each year RSV infection leads to approximately 500,000 emergency department visits by children under 5 years of age, which represents 1 in 4 of all RSV-related doctor visits, according to the CDC.11
Nirsevimab is an investigational long-acting antibody designed to help protect all infants through their first RSV season with a single dose. Due to its extended half-life technology, nirsevimab is being developed as a single dose for all infants experiencing their first RSV season and infants with specific conditions, such as CHD or CLD entering their first and second RSV season.2,6,12
Nirsevimab is an immunization designed to help provide direct prophylactic RSV protection to all infants via an antibody given directly to an infant to help prevent LRTI caused by RSV. Monoclonal antibodies do not require the activation of the immune system to help offer rapid and direct protection against disease.13
In March 2017, Sanofi and AstraZeneca announced an agreement to develop and commercialize nirsevimab. Under the terms of the agreement, AstraZeneca leads all development and manufacturing activities and Sanofi will lead commercialization activities and record revenues. Under the terms of the global agreement, Sanofi made an upfront payment of €120m, has paid a development milestone of €30m and will pay up to a further €465m upon achievement of certain development and sales-related milestones. The two companies share all costs and profits. Revenue from the agreement is reported as Collaboration Revenue in the Company’s financial statements.
Nirsevimab has been granted regulatory designations to facilitate expedited development by several major regulatory agencies around the world. These include Breakthrough Therapy Designation by The China Center for Drug Evaluation under the National Medical Products Administration; Breakthrough Therapy Designation from the United States Food and Drug Administration; access granted to the European Medicines Agency PRIority Medicines scheme; Promising Innovation Medicine designation by the UK Medicines and Healthcare Products Regulatory Agency; and named “a medicine for prioritized development” under the Project for Drug Selection to Promote New Drug Development in Pediatrics by the Japan Agency for Medical Research and Development (AMED). Nirsevimab is currently under clinical investigation and its safety and efficacy have not been reviewed by any regulatory authority.
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