PharmaShots Interview: Jon Heinrichs of Sanofi Pasteur & Tonya Villafana of AstraZeneca Shares Insights on Nirsevimab in Healthy Infants Born at Term or Late Preterm

In an interview with PharmaShots, Jon Heinrichs, Associate, Vice President, and the Head of Innovation and Emerging Sciences at Sanofi Pasteur & Tonya Villafana, Vice President, Global Franchise Head, Infection at AstraZeneca share their views on the data of Nirsevimab in P-III (MELODY) trial to protect infants against Respiratory Syncytial Virus

Shots:

The P-III (MELODY) trial evaluates nirsevimab (50/100mg, IM) vs PBO in a ratio (2:1) in 1490 infants at term or late preterm with RSV
The trial met its 1EPs i.e., 74.5% reduction in LRTI. In terms & of preterm infants (≥28wks. gestational age), 77.3% efficacy against RSV-associated hospitalizations @150 days postdose, reduction in risk of RSV-associated hospitalizations & the safety profile was consistent with prior reported results with no differences in safety results in the P-III (MELODY) & P-IIb study
Additionally, 6 of 994 infants were hospitalized for RSV LRTI in nirsevimab & 8 of 496 infants in PBO. The (MEDLEY) trial results were published in the NEJM with expected regulatory submissions in H1’22

Tuba: Tell us about Nirsevimab (its MOA, ROA, formulation, pathway, etc.)

Jon & Tonya: Nirsevimab, being developed in partnership with AstraZeneca and Sanofi, is the first investigational long-acting antibody aiming to protect all infants across the RSV season with a single dose. Nirsevimab is designed to provide direct and rapid prophylactic RSV protection to all infants via an antibody to help prevent lower respiratory tract infections (LRTI) caused by RSV. Monoclonal antibodies do not require the activation of the immune system to help offer protection against disease.

RSV is a common, contagious seasonal virus that infects the respiratory tract. In most cases, RSV causes cold-like symptoms, but it is also the most common cause of lower respiratory tract infections like bronchiolitis and pneumonia. RSV is a leading cause of hospitalizations in all infants, with most hospitalizations occurring in healthy infants born at term.

Despite 60 years of research, there is no RSV preventative option for all infants. Nirsevimab has the potential to change the healthcare system approach to RSV prevention by providing rapid and direct protection for all infants for the RSV season with a single-dose immunization.

As 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.”

AstraZeneca and Sanofi are committed to reducing the impact of RSV disease through the protection of all infants (healthy, premature, and those with underlying conditions) experiencing their first RSV season with nirsevimab, which we anticipate to be offered at a price in line with a full series of other innovative pediatric vaccines. These price intentions are contingent on the recognition by public health authorities of the need and the value to pursue an all-infant approach.

Tuba: Discuss the results from both MELODY and the MEDLEY trials.

Jon & Tonya: These recent clinical trial results contribute to the body of evidence demonstrating nirsevimab’s potential to protect all infants with one dose across the RSV season. This all-infant population includes preterm, healthy late preterm, and term infants, as well as infants with CLD and CHD.

MELODY: The detailed results from the Phase 3 trial published in The New England Journal of Medicine (NEJM) demonstrate that nirsevimab met its primary endpoint in healthy infants born at term or late preterm (35 weeks gestational age or greater) entering their first RSV season.

Nirsevimab showed a 74.5% reduction in lower respiratory tract infections caused by RSV requiring medical care in healthy infants.
A prespecified pooled analysis of RSV-associated hospitalizations of Phase 3 and Phase 2b trial data was also conducted. In term and pre-term infants (greater than 28 weeks gestational age), the proposed dose of nirsevimab demonstrated the efficacy of 77.3% (95% CI 50.3 to 89.7; P<0.001) against RSV-associated hospitalizations. 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).
COVID-19 contributed to a lack of circulation of RSV during the trial, which also led to fewer hospitalizations for the virus among infants and children (e.g., Spain, Australia, Brazil, New Zealand). The Phase 3 study was powered for the primary endpoint of reducing the incidence of medically attended LRTI, such as bronchiolitis or pneumonia, caused by RSV. The Phase 3 trial was not powered for the secondary endpoint of hospitalization. Of note, changes to the clinical trial protocols due to COVID-19 were made in partnership with regulators.

MEDLEY: Detailed results from the Phase 2/3 trial were published in The New England Journal of Medicine (NEJM). Results showed nirsevimab demonstrated similar safety and tolerability profile compared to palivizumab when administered to infants with chronic lung disease (CLD), congenital heart disease (CHD), or prematurity (35 weeks gestational age or less) entering their first RSV season. The serum levels of nirsevimab following dosing on 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 pre-term infants are likely.

Tuba: Can we discuss the safety of Nirsevimab overall beyond these mentioned studies?

Jon & Tonya: 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.

Tuba: Are you developing any other drugs for lower respiratory tract infections?

Jon & Tonya: We cannot comment at this time.

Tuba: In what other indication does Nirsevimab work for infants?

Jon & Tonya: At this time, Nirsevimab is being developed by AstraZeneca and Sanofi for the prevention of medically attended LRTI in all infants through their first RSV season.

Tuba: Can you give us a brief comparative view of the MELODY trial vs the MEDLEY trial?

Jon & Tonya: MELODY: The Phase 3 study is a randomized, placebo-controlled trial conducted across 21 countries designed to determine the incidence of medically attended LRTI due to Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) confirmed RSV through 150 days post-dose versus placebo in healthy late preterm and term infants entering their first RSV season. Healthy late preterm and term infants born at 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.

MEDLEY: MEDLEY is a Phase 2/3, randomized, double-blind, palivizumab-controlled trial with the primary objective of assessing the safety and tolerability of nirsevimab in preterm infants and infants with CHD and/or chronic lung disease of prematurity (CLD) eligible to receive palivizumab. Safety was assessed by monitoring the occurrence of adverse events (AEs) and serious AEs through 360 days post-dose. The focus of this study was on safety and tolerability rather than efficacy because nirsevimab has already shown efficacy in a broader population of infants in other trials. We have evaluated nirsevimab in two efficacy trials and demonstrated it is effective in preventing RSV in both full-term and preterm infants born at greater than 29 weeks gestational age.

Q7- In what other places were the results shown other than the NEJM publication?

Jon & Tonya: Results for the MELODY trial were presented at IDWeek and RSVVW’21 and results for the MEDLEY trial were presented at RSVVW’21 in late 2021.

Tuba: What are your additional plans regarding Nirsevimab?

Jon & Tonya: The Phase 2b trial (already completed), Phase 3 and Phase 2/3 trials form the basis of regulatory submissions that have begun in the first half of 2022.

We are conducting a Phase I clinical trial investigating the pharmacokinetics, safety, tolerability, and anti-drug antibody (ADA) of nirsevimab compared to placebo in healthy adults and a phase III trial evaluating the safety and efficacy of nirsevimab in healthy preterm and term infants in China.

We are also conducting MUSIC, a Phase 2, open-label, uncontrolled, single-dose study to evaluate the safety and tolerability, PK, the occurrence of ADA, and efficacy of nirsevimab in immunocompromised children who are ≤ 24 months of age at the time of dose administration.

In February 2022, the European Medicines Agency (EMA) accepted our Marketing Authorization Application (MAA) for nirsevimab under an accelerated procedure for the prevention of medically attended LRTI in all infants through their first RSV season.

Source: Ochsner Health

About Author:

Jon Heinrichs

Jon Heinrichs is an Associate Vice President and the Head of Innovation and Emerging Sciences at Sanofi Pasteur. Dr. Heinrichs earned his doctoral degree in microbiology and molecular genetics from Rutgers University and the University of Medicine and Dentistry of New Jersey and completed a post-doctoral fellowship in the Laboratory of Bacterial Pathogenesis and Immunology at The Rockefeller University.

Tonya Villafana

Tonya Villafana is the Vice President, Global Franchise Head, Vaccine & Immune Therapies at AstraZeneca. Dr. Villafana leads the late-stage development of a number of vaccine and monoclonal antibody infectious disease programs including nirsevimab, a novel monoclonal antibody for the prevention of RSV disease in all infants. She received a Ph.D. in immunology from Weill Cornell University Graduate School of Medical Sciences and an MPH from Harvard School of Public Health.