Nirsevimab significantly protected infants against RSV disease in Phase III MELODY trial

Nirsevimab showed 74.5% efficacy against medically attended lower respiratory tract infections caused by RSV in healthy infants.

Nirsevimab is the first potential immunisation for all infants to demonstrate sustained protection across the entire RSV season with a single dose.

MELODY and MEDLEY trial results were published in the New England Journal of Medicine.

Detailed results from the positive MELODY Phase III trial showed a single dose of AstraZeneca and Sanofi’s nirsevimab met the primary efficacy endpoint reducing the incidence of medically attended lower respiratory tract infections (LRTI) caused by respiratory syncytial virus (RSV) by 74.5% (95% CI 49.6, 87.1; p<0.001), compared to placebo.^1-2

The trial involved healthy term and late preterm (gestational age ≥35 weeks) infants entering their first RSV season.^1-2

Additionally, the MEDLEY Phase II/III trial, which evaluated safety and pharmacokinetics of nirsevimab in infants with congenital heart disease (CHD), chronic lung disease (CLD) and prematurity entering their first RSV season, demonstrated nirsevimab had a similar safety and tolerability profile compared to Synagis (palivizumab).^3-4

Serum levels of nirsevimab following dosing (on day 151) in this trial were comparable with those observed in the MELODY Phase III trial, indicating similar protection in this population to that in the healthy term and late preterm infants is likely.^1-4 Synagis is currently the only available preventative option for RSV.

Nirsevimab is an investigational long-acting antibody designed to protect all infants through their first RSV season with a single dose. It is the first potential immunisation to show protection against RSV in the general infant population in a Phase III trial.^1-2

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, US and primary investigator of the MELODY Phase III trial, said: “We know that respiratory syncytial virus 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 respiratory syncytial virus 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.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “Respiratory syncytial virus is a leading cause of lower respiratory tract infections, such as bronchiolitis or pneumonia, as well as hospitalisations in infants. These data show for the first time, the potential to significantly protect all infants through their first respiratory syncytial virus season with a single dose immunisation and we look forward to working with health authorities to bring nirsevimab to infants as quickly as possible.”

Jean-François Toussaint, Global Head of Research and Development Vaccines, Sanofi, said: “With three pivotal late-stage trials, our research has been focused on delivering a first-in-class respiratory syncytial virus prevention for all infants. Our Phase III 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 respiratory syncytial virus season, with only a single dose.”

A prespecified pooled analysis of the MELODY and Phase IIb trials demonstrated a reduction of hospitalisations caused by RSV with the proposed dose of nirsevimab.^1-2,5 In term and preterm infants (greater than 28 weeks gestational age), 21 of 786 (2.7%) infants in the placebo arm compared to nine of 1,564 (0.6%) in the nirsevimab arm experienced an RSV-associated hospitalisation, giving an estimate of efficacy of 77.3% (95% CI 50.3, 89.7; P<0.001) through 150 days postdose.^1,2,5 There was numerical reduction, although not statistically significant, of the risk of RSV associated hospitalisations observed in the MELODY trial alone (62.1%, 95% CI: -8.6, 86.8, p=0.07).^1-2 In the nirsevimab arm, six of 994 (0.6%) infants were hospitalised for RSV LRTI, while eight of 496 infants (1.6)% were hospitalised in the placebo arm.^1-2

The overall safety profile of nirsevimab remains consistent with previously reported results. No clinically meaningful differences in safety results between the nirsevimab and placebo groups were seen in MELODY and Phase IIb.^1-2,5-6

MELODY trial results were published in the New England Journal of Medicine (NEJM). Details from the MEDLEY trial were also published in the NEJM. Regulatory submissions began in the first half of 2022.

Notes

RSV

RSV is a common, contagious virus that causes seasonal epidemics of lower respiratory tract infections (LRTI), leading to bronchiolitis and pneumonia in infants.^7-9 It is also a leading cause of hospitalisations in all infants.⁹ 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.^9-10 In recent months, there has been a resurgence of RSV following the easing of COVID-19 public health measures.^11-12 Most hospitalisations for RSV occur in otherwise healthy infants born at term.^13-17 Medically attended LRTIs are associated with increased costs to the healthcare system.¹⁸

MELODY

MELODY is a randomised, placebo-controlled Phase III trial conducted across 21 countries designed to determine the incidence of medically attended LRTI due to RSV confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) testing through 150 days after dosing, versus placebo, in healthy infants entering their first RSV season.^1-2 Healthy late preterm and term infants (gestational age ≥35 weeks 0 days) 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 February 2021, 1,490 infants were randomised to either nirsevimab or placebo at the RSV season start.^1-2 Pooled analyses of the RSV LRTI hospitalisation endpoint from both of the MELODY and the Phase IIb trials were prespecified under a multiplicity-protected hierarchical testing strategy.

The evaluation of the primary efficacy 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 enrolment. 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

Medically Attended LRTI and Hospitalisation for RSV LRTI Through 150 Days Postdose (ITT population)

^*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 trial and the Phase IIb trial demonstrate that nirsevimab provides protection against RSV in all infants with a single dose. This all-infant population includes preterm, healthy late preterm and term infants, as well as infants with CLD and CHD.^2,4-5 These trials will form the basis of AstraZeneca’s regulatory submissions planned from the first half of 2022.

MEDLEY

MEDLEY is a Phase II/III, randomised, double-blind, Synagis-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 Synagis.^3-4 Between July 2019 and May 2021 approximately 918 infants entering their first RSV season were dosed with either nirsevimab or Synagis. Safety is assessed by monitoring the occurrence of treatment emergency adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) through 360 days post-dose.^3-4

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 Synagis based on a sufficient number of infants being enrolled and followed through their first RSV season.

Nirsevimab

Nirsevimab is an investigational long-acting antibody, being developed by AstraZeneca and Sanofi using AstraZeneca’s proprietary YTE technology, designed to protect all infants through their first RSV season. 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 congenital heart disease or chronic lung disease, entering their first and second RSV season.^2,4,19 The current anti-RSV antibody, AstraZeneca’s Synagis, is limited to high-risk infants and provides one-month protection, requiring five injections to cover an RSV season.²⁰

Nirsevimab is an immunisation designed to provide direct prophylactic 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.²¹

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 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). Nirsevimab is currently under clinical investigation and has not been approved by any regulatory authority.

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.

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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References

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