Disease Analysis: Respiratory Syncytial Virus (RSV) Prevention

Latest key takeaways

• The RSV prophylaxis market is expected to expand rapidly over the next 10 years, triggered by the anticipated launches of nirsevimab and various vaccine approaches from the 2023/24 and 2024/25 seasons, respectively. The RSV pipeline remains active with vaccines being developed for the three major risk groups, namely the elderly, infants, and pregnant women (to protect infants via passive transfer of neutralizing antibodies across the placenta).
• Synagis is currently the only marketed preventive agent in the RSV space and generates blockbuster sales. Notably, the use of Synagis is severely restricted to niche risk groups in infants because pivotal trial data showed only moderate efficacy against RSV hospitalization in patients with chronic lung disease (CLD) or congenital heart disease (CHD), as well as by its very high cost per dose. With no competition in the near term, and no biosimilars likely to enter clinical development, Synagis’s sales are expected to remain stable until the 2022/23 season, after which the anticipated approval of AstraZeneca/Sanofi’s next-generation antibody nirsevimab in time for the 2023/24 season threatens to render Synagis redundant.
• Nirsevimab, a next-generation monoclonal antibody with an improved once-per-season dosing schedule, is likely to succeed Synagis as the new standard of care in the 2023/24 season if ongoing pivotal trials are successful. Sanofi is intending to price nirsevimab comparably to other pediatric vaccines to facilitate reimbursement for universal use as an at-birth dose. In April 2021, AstraZeneca and Sanofi announced that nirsevimab had met the primary endpoint of a statistically significant reduction in the incidence of medically attended lower respiratory tract infections (LRTIs) due to RSV in the pivotal MELODY trial in healthy infants, but details on an important secondary endpoint, a reduction in RSV-related hospitalization, are yet to be released. Previously, Phase IIb data in healthy infants demonstrated a promising reduction in RSV hospitalizations compared to placebo (78%), which was comparable to the reduction in RSV hospitalization observed with Synagis in the IMPACT trial (also 78%). Recently, AstraZeneca and Sanofi announced that nirsevimab met the primary safety endpoint in the MEDLEY trial in at-risk infants. Details on key secondary endpoints, namely incidence of medically attended LRTIs and serum concentrations of antibodies, are yet to be reported.
• Nirsevimab also poses a severe threat to maternal vaccines, which aim to provide protection during the first six months of life (the highest risk period for RSV hospitalization). Additionally, the public health impact of the latter will be hampered by poor vaccination coverage rates in pregnant women.
• Vaccines in development for maternal immunization include Novavax’s ResVax, Pfizer’s RSVpreF, and GlaxoSmithKline’s GSK3888550A. ResVax narrowly missed its primary efficacy endpoint in the pivotal PREPARE study, and while it hit key secondary endpoints, the EMA and FDA have requested an additional confirmatory efficacy study before considering approval. While Novavax is seeking funding from a willing development partner, Pfizer and GlaxoSmithKline have taken the lead with ongoing pivotal trials expected to reach primary completion in August 2023, paving the way for potential launch in time for the 2024/25 RSV season. Both GSK3888550A and RSVpreF have shown promise in Phase II trials, including strong immunogenicity data in infants in the first six months of life for the former and an 85% reduction in medically attended LRTIs for the latter.
• Maternal vaccines are under threat from AstraZeneca/Sanofi’s nirsevimab, which Phase IIb data suggest will be able to provide protection from RSV hospitalization for the first five to six months of life after a single at-birth dose. This approach could be preferred because much higher coverage rates could be achieved than with maternal vaccination, potentially leading to a greater reduction in clinical morbidity and mortality.
• The elderly segment offers the most commercial potential because of the large population size, high coverage rates that can be achieved, and the likely requirement for repeat seasonal vaccination. ResVax also failed to meet its primary efficacy endpoint in this subgroup in the RESOLVE study, leaving the door open for a host of challengers to steal first-to-market status. The new frontrunner in the elderly segment, GlaxoSmithKline, initiated patient dosing in its Phase III trial in February 2021, in time for the 2021/22 RSV season. The trial will reach primary completion in 2022, and GlaxoSmithKline has guided that it will gain approval by 2024, with use beginning from the 2024/25 season onwards. Though Johnson & Johnson’s JNJ-64400141 demonstrated only modest efficacy in its Phase II human challenge study (50%), the vaccine exceeded expectations in a Phase IIb study showing vaccine efficacy of 70% against symptomatic RSV infection and 80% efficacy against confirmed RSV-associated LRTI. Johnson & Johnson initiated the Phase III EVERGREEN trial in June 2021, with a data readout expected in mid-2023. Given that RSVpreF achieved compelling data in a Phase II human challenge study, Pfizer chose to accelerate its development by initiating a Phase III trial in September 2021. Although Bavarian Nordic was previously the frontrunner, it has chosen to defer its Phase III trial to the 2022/23 season due to low enrollment during the COVID-19 pandemic. Subsequently, MVA-BN RSV will launch behind major rivals in the elderly segment.
• With GlaxoSmithKline abandoning development of former frontrunner GSK3389245A due to a lack of efficacy in its pivotal trial, pediatric vaccines currently in the pipeline include Johnson & Johnson’s JNJ-64400141, Sanofi’s live-attenuated vaccines (LAVs), and Meissa Vaccines’ MV-012-968. Johnson & Johnson’s vaccine seems to be the most promising because of its ability to be administered at two to three months of age, while Sanofi’s LAVs are limited to six months of age because of the risk of neutralization by pre-existing anti-RSV antibodies (transferred to infants via the placenta). Johnson & Johnson’s vaccine has been in Phase II trials, and reached primary completion in November 2021 (results are yet to be released). With a Phase III trial yet to be announced, JNJ-64400141 is unlikely to gain approval in the pediatric setting until 2025/26 at the earliest.