Results from a prespecified pooled analysis of the pivotal MELODY Phase III and Phase IIb trials showed AstraZeneca and Sanofi's nirsevimab demonstrated an efficacy (relative risk reduction versus placebo) of 79.5% (95% Confidence Interval [CI] 65.9 to 87.7; P<0.0001) against medically attended lower respiratory tract infections (LRTI), such as bronchiolitis or pneumonia, caused by respiratory syncytial virus (RSV) in infants born at term or preterm entering their first RSV season. The pooled analysis studied healthy preterm and term infants who received the optimised dose of nirsevimab compared to placebo through Day 151 and showed an efficacy of 77.3% (95% CI 50.3, 89.7; P<0.001) against RSV LRTI hospitalisations.1
In a separate pooled post-hoc analysis of the trials, blood samples taken from infants dosed with nirsevimab exhibited RSV neutralising antibodies that were approximately 50-fold higher than baseline at Day 151 postdose. RSV neutralising antibody levels remained greater than 19-fold higher than placebo recipients with no known RSV infection through Day 361, suggesting protection may extend beyond Day 151.2
These findings contribute to the growing body of evidence that nirsevimab has the potential to protect all infants entering their first RSV season with a single dose.1-5
Eric Simões, MD, Clinical Professor, Pediatrics-Infectious Diseases, UC Denver School of Medicine, said: "Respiratory syncytial virus remains the most common cause of lower respiratory tract infection in infants and results in seasonal epidemics globally each year. These new analyses strengthen nirsevimab's potential to protect all infants across the respiratory syncytial virus season with a single dose, which may lead to a paradigm shift in respiratory syncytial virus prevention."
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: "Each year, respiratory syncytial virus causes seasonal epidemics of lower respiratory tract infections in infants. These analyses add to nirsevimab's compelling body of evidence as the first potential single-dose preventative immunisation for all infants against respiratory syncytial virus, addressing a clear unmet need in the respiratory syncytial virus preventative landscape."
Jean-François Toussaint, Global Head of Research and Development Vaccines, Sanofi, said: "These new analyses are very consistent with and confirm the strong results observed in all Phase II and Phase III studies that evaluated nirsevimab in diverse paediatric populations. We take pride in the progress made to develop a potential solution to address this long unmet need for all infants."
The overall safety profile of nirsevimab in the two trials have previously been reported, and no clinically meaningful differences in safety results were seen between the nirsevimab and placebo groups.6,7
The data are being presented at the 40th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID) from 9th-13th May in Athens, Greece.
Notes
Nirsevimab
Nirsevimab is an investigational long-acting antibody, being developed by AstraZeneca and Sanofi using AstraZeneca's proprietary YTE technology, designed to help protect all infants from birth entering their first RSV season with a single dose. Due to its extended half-life technology, nirsevimab is being developed as a single dose from birth for all infants experiencing their first RSV season and infants who remain vulnerable to severe RSV entering their first and second RSV season.3,5,8
Nirsevimab is an immunisation designed to provide direct RSV protection to all infants via an antibody 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.9
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 US Food and Drug Administration; and access granted to the European Medicines Agency (EMA) PRIority MEdicines (PRIME) scheme; 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). The safety and efficacy of nirsevimab is currently being evaluated under an accelerated assessment procedure by the EMA. Nirsevimab has not been approved by any regulatory authority.
Pivotal nirsevimab clinical trials
The Phase IIb study was a randomised, placebo-controlled trial designed to measure the efficacy of nirsevimab against medically attended LRTI through 150 days postdose. Healthy preterm infants of 29–35 weeks' gestation were randomised (2:1) to receive a single 50mg intramuscular injection of nirsevimab or placebo. Between November 2016 and December 2017, 1,453 infants were randomised (nirsevimab, n=969; placebo, n=484) at the RSV season start. Research was conducted by AstraZeneca in both hemispheres, at 164 sites in 23 countries.4 Data was published in the New England Journal Medicine (NEJM) in July 2020. The dosing regimen was optimised based on further exploration of this data. The subsequent Phase III study MELODY applied the optimised dosing regimen.1,3
The Phase III MELODY study was a randomised, placebo-controlled trial conducted across 21 countries designed to determine efficacy of nirsevimab against medically attended LRTI due to RSV confirmed by reverse transcriptase polymerase chain reaction testing through 150 days after dosing, versus placebo, in healthy late preterm and term infants (35 gestational age or greater) entering their first RSV season. Infants were randomised (2:1) to receive a single 50mg (in infants weighing <5kg) or 100mg (in infants weighing ≥5kg) intramuscular injection of nirsevimab or placebo. Between July 2019 and March 2020, 1,490 infants were randomised to either nirsevimab or placebo at the RSV season start.3 Data was published in NEJM in March 2022.
The prespecified pooled analysis of the MELODY and Phase IIb trials looked at infants receiving the optimised dosing regimen (infants <5 kg at dosing and receiving the 50 mg dose from Phase IIb and the infants from Phase III). The analysis was based on 2,350 infants of which 1,564 infants were randomised to receive nirsevimab and 786 infants randomised to receive placebo.1
Medically Attended LRTI and Hospitalisation for RSV LRTI Through 150 Days Postdose (ITT population)
Endpoints and analyses, n (%) | Nirsevimab
(N = 1564) | Placebo
(N = 786) | Efficacy (Relative Risk Reduction)
(95% CI) | P value |
Medically attended RSV LRTI | | | 79.5 (65.9, 87.7) | <0.0001 |
| Participants with observed Events n (%) Participants requiring
imputation of data* n (%) | 19 (1.2) 25 (1.6) | 51 (6.5) 10 (1.3) | | |
Hospitalisation for RSV LRTI | | | 77.3 (50.3, 89.7) | <0.001 |
| Participants with observed Events n (%) Participants requiring
imputation of data* n (%) | 9 (0.6) 25 (1.6) | 21 (2.7) 10 (1.3) | | |
*Data were imputed for participants who had no events and were not followed through 150 days postdose. Analyses were conducted using Poisson regression with robust variance. CI, confidence interval; ITT, intent-to-treat; LRTI, lower respiratory tract infection; RRR, relative risk reduction; RSV, respiratory syncytial virus.
The results of MELODY, MEDLEY Phase II/III and the Phase IIb trials demonstrate that nirsevimab provides protection against RSV in all infants entering their first RSV season with a single dose.1-5 This all-infant population includes preterm, healthy late preterm and term infants, as well as infants with specific conditions.
These trials form the basis of regulatory submissions that began in 2022.
RSV
RSV is the most common cause of lower respiratory tract infections (LRTI), including bronchiolitis and pneumonia in infants.10 It is also a leading cause of hospitalisation in all infants, with most hospitalisations for RSV occurring in healthy infants born at term.11-17 Globally, in 2015, there were approximately 30 million cases of acute lower respiratory infections leading to more than three million hospitalisations, and it was estimated that there were 60,000 in-hospital deaths of children younger than five years.18-19 In recent months, there has been a resurgence of RSV following the easing of COVID-19 public health measures.20-21 Globally, in 2017, RSV-related direct medical costs – including hospital, outpatient and follow-up care – were estimated at €4.82 billion.22
Sanofi Alliance
In March 2017, AstraZeneca and Sanofi announced an agreement to develop and commercialise nirsevimab. Under the terms of the agreement, AstraZeneca leads all development and manufacturing activities and Sanofi will lead commercialisation 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.
Sobi agreement
Related, in November 2018, AstraZeneca divested US commercial rights for Synagis to Swedish Orphan Biovitrum AB (publ) (Sobi) in addition to the right to participate in payments that may be received by AstraZeneca from the US profits or losses for nirsevimab. Under the agreement AstraZeneca received upfront consideration of $1.5bn, consisting of $1.0bn in cash and $500m in ordinary shares of Sobi upon completion, and received a total of $60m in non-contingent payments for nirsevimab during 2019-2021. AstraZeneca will also receive up to $470m in sales-related payments for Synagis, a $175m milestone following the submission of the Biologics License Application (BLA) for nirsevimab and potential net payments of approximately $110m on achievement of other nirsevimab profit and development-related milestones. Upon payment of the $175m milestone on BLA submission, Sobi's ongoing participation will amount to AstraZeneca's share of profits or losses under the aforementioned agreement with Sanofi for nirsevimab in the US. AstraZeneca will continue to manufacture and supply nirsevimab globally and is entitled to an additional royalty from Sobi if profits from nirsevimab in the US exceed a pre-specified level.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.
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