Development of highly potent human monoclonal for RSV immunoprophylaxis

PROJECT SUMMARY Globally, respiratory syncytial virus (RSV) causes over 3 million hospitalizations of neonates/infants. While there are licensed vaccines in the U.S. for use in elderly populations, they are neither approved nor appropriate for use in neonates/infants who have immature immune systems. Palivizumab, a prophylactic monoclonal antibody (mAb) marketed by AstraZeneca and Sobi as Synagis™, has been available since 1998, but due to high cost and modest efficacy, its use has been restricted to high-risk infants. The recently approved single dose, long-acting mAb, nirsevimab (previously known as MEDI8897 and marketed as Beyfortus™ by Sanofi), has improved efficacy compared to palivizumab and was approved for use in all children up to 24 months of age. However, severe shortages and cost barriers have limited its availability in countries where it is currently approved (EU, US, Japan, Australia, Canada and China). In October 2023 the CDC issued Health Alert Network CDCHAN-00499 that recommended limiting the use of nirsevimab to higher risk children in the 2023- 2024 season due to the shortages, resulting in many eligible infants not receiving prophylaxis. In addition, nirsevimab is not currently available in any low- or middle-income countries (LMICs) and is unavailable in 8/10 of the most populous countries in the world. Mapp Biopharmaceutical, Inc. is developing a fully human mAb product, MBP002, that like nirsevimab, can be administered in a single dose per RSV season. Mapp’s objective is to dramatically lower the price and increase the global availability of RSV immunoprophylaxis. Further, unlike nirsevimab and Merck’s Phase 3 candidate, MK-1654, Mapp’s product is a two mAb cocktail, reducing the risk not only of clinical development of resistance, but also of a naturally occurring strain evading a single mAb. Indeed, this method of product failure occurred during a recent Phase 3 trial with Regeneron’s RSV mAb candidate and is the reason several mAb candidates lost their emergency use authorization for use against COVID-19. While nirsevimab resistant mutations were rare in a survey of 5675 RSV strains between 2015 and 2021, several mutations in the nirsevimab binding site have increased since 2020, including the resistant RSV-B variant K68N present in the U.S. and Australia. The impact of widespread use of nirsevimab on the frequency of resistant variants is under close post-marketing surveillance due to the potential for selection of escape mutants. Mapp has screened 70+ RSV clinical strains and found neutralization resistant strains to palivizumab, nirsevimab (MEDI8897) and Regeneron’s candidate, but no resistant strains to one of the MBP002 mAbs. In addition, the MBP002 mAbs are dramatically more potent in vitro and in vivo than palivizumab and have comparable neutralization and in vivo activity to nirsevimab. The requested SBIR support, together with significant in-kind contributions by Mapp, will allow for the advancement of MBP002 to IND submission (Investigational New Drug Application) and initiation of a Phase 1 clinical trial.