15 Sep 23
By Dave Griffin
Respiratory virus infections represent a significant threat to global public health. Many viruses can rapidly evolve into new strains via antigenic drift and antigenic shift which can become tolerant of large and small molecule treatments, as recently seen with the H7N9 influenza virus that became resistant to amantadines.[1] Such events greatly limit treatment options and increase the probability of an unfavourable outcome.
In July this year, the United States Food and Drug Administration (FDA) approved AstraZeneca’s monoclonal antibody, nirsevimab-alip (Beyfortus), for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants born during or entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.[2] Beyfortus has a 150-day coverage so a single shot covers the whole RSV season, compared with AstraZeneca’s other anti-RSV monoclonal antibody, paviluzimab (Synagis), which has only a 28-day coverage. The approval of Beyfortus follows FDA’s approval in May 2023 of GSK’s Arexvy, the first vaccine for prevention of lower respiratory tract disease caused by RSV in individuals ≥ 60 years of age.[3]
Whilst this is good news for preventing these life-threatening infections, treatments remain limited once an infection is established and development of much needed new agents has become more difficult due to changes in regulatory guidelines.
Influenza and bacterial pneumonia was the sixth most common cause of death in the UK in 2018. Apart from a small decrease in mortality that occurred after the introduction of antibacterial vaccines in the first decade of this century, the rate of death has remained constant.[4] RSV is the most commonly identified cause of acute lower respiratory tract infection in children, immunocompromised adults, and the elderly.[5]
Infection also frequently drives exacerbations of chronic respiratory conditions and, therefore, has a critical role not only in influenza and pneumonia mortality but also in chronic respiratory disease. We also now know through post-coronavirus disease 19 (COVID-19) symptomatic monitoring that some long-term pulmonary diseases, such as idiopathic pulmonary fibrosis, is a consequence of viral infection. This emphasises the importance of not only developing new antiviral and antibacterial agents, but ensuring effective guidance is available for their development.
The emergence of COVID-19 in December 2019 led to a re-evaluation of the development of treatments for respiratory virus infection by regulators, academics, and the World Health Organization. As a result, both the FDA and the European Medicines Agency (EMA) published guidance documents which built on existing guidance for influenza antiviral development.[6–9] However, changes made to the original guidance have made the development of new antiviral drugs for the treatment of non-COVID-19 respiratory infections problematic and may, in fact, prohibit their development.
This issue has arisen because, in the new guidance, whilst the inclusion criteria for Phase 3 studies in COVID-19 and influenza patients remain similar, the primary endpoint has changed. For influenza treatments, the primary endpoint was symptom improvement, but this has been replaced with hospitalisation and/or all-cause mortality, with measures of disease progression being relegated to a secondary endpoint. Whilst hospitalisation and mortality are certainly hard endpoints, they are only numerically large enough to be measured practically during a pandemic, such as the COVID-19 pandemic, where mortality is mostly due to the infection. For non-COVID-19 respiratory infections, such as influenza, that are associated with lower rates of mortality and hospitalisation, and where mortality is confounded by many other non-infection-related causes, such endpoints are less reliable. Furthermore, both mortality and hospitalisation endpoints only address acute infection and outcome within 28 days, whereas the burden of consequent illness that may or may not require further hospitalisation or that may relate to long-term care or exacerbations of other comorbidities, has become an overlooked important aspect of outcome.
Prior to the COVID-19 pandemic, the need for new drug development guidance was acknowledged for influenza. The EMA had stated that there was a need to clarify the European regulatory expectations regarding data that should be generated to support the approval of novel influenza treatments and the FDA produced guidance for development of both small molecules and biologicals for influenza.[10,11] COVID-19, unsurprisingly and necessarily, distracted efforts to provide clear guidance for developing antiviral agents for other respiratory infections. However, now that the impact of the pandemic is declining, it is time to revisit these guidance documents to ensure that they allow efficient and meaningful evaluation and progression of potential new treatments and agents for prevention for non-COVID-19 antiviral agents.
tranScrip has a team of pharmaceutical physicians and scientists who have a wealth of experience in developing antimicrobial agents, including those for respiratory use, and in interacting with regulatory agencies across the world to obtain scientific advice at each stage of a product’s development. If this is something that you believe may be beneficial in your drug development programme, please contact us.
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