With much of the recent news on vaccine development focused on Covid-19, it might have been easy to miss Glaxosmithkline's announcement earlier this week that it was moving its maternal respiratory syncytial virus vaccine into phase III.
Glaxo is not alone in trying to prevent this intractable yet highly prevalent seasonal disease – unsurprisingly, given that any successful product could be expected to meet high demand.
Glaxo is not alone in trying to prevent this intractable yet highly prevalent seasonal disease – unsurprisingly, given that any successful product could be expected to meet high demand.Pfizer and Sanofi also have candidates in late-stage development and there are several more in phase II; all the companies involved will hope to avoid the missteps that have jinxed previous contenders.
Worldwide, RSV is the leading cause of acute lower respiratory infections in children; while many of these are mild and do not cause too much distress, severe infections can lead to bronchitis, pneumonia and hospitalisation. Leerink analysts estimate that of the approximately 33 million RSV infections in children under five annually, more than 10% result in a trip to the hospital and 60,000 lead to death.
At present there is only one approved treatment for RSV in infants, Abbvie and Sobi’s Synagis, which was originally developed by Medimmune. The steep $6,000 price tag, a complex treatment regimen involving five monthly doses, and restrictions on its use mean that the antibody is not widely used. Despite all this sales are forecast to hit $735m in 2026, according to EvaluatePharma.
The fact that only one product has been approved in 21 years – Synagis was launched in 1999 – highlights the challenges that RSV presents. Recent failures include Novavax’s Resvax, which has bombed in two pivotal studies, and Regeneron’s suptavumab, which also made it to phase III before being abandoned in 2017. A decade ago a potential follow-on to Synagis, motavizumab, made it as far as regulators but was rebuffed on safety grounds.
A vaccine developed in the 1960's that aggravated the disease in infants following natural infection deterred research into prophylactic approaches for decades. However t he large potential market has persuaded the likes of Glaxo and others to try again.
he large potential market has persuaded the likes of Glaxo and others to try again.
Riders and runners
In Glaxo's newly-started Grace study, 10,000 expectant mothers will either be given GSK3888550A or placebo, with the primary endpoint being the reduction in lower respiratory tract infections (LRTIs) in infants during the first six months of life. The study is expected to complete in early 2024 with an interim readout in 2022.
This passive approach to vaccination, designed to ensure children are born with protection against RSV through their mother’s inoculation, is also being utilised by Pfizer, Merck and Moderna.
Pfizer is currently slightly ahead: the pivotal trial of PF-06928316 (RSVpreF) started in June and is expected to complete in late 2023. This also is primarily evaluating LRTIs in the first six months of life, and could also have an interim readout in 2022.
If either vaccine hits its interim this could not only give an indication of which could reach the market first, but also the potential commercial opportunity. Secondary endpoints such as reducing hospitalisations will also be closely watched.
Merck and Moderna, having recently ended a collaboration on adult RSV vaccines, are now working on separate projects.
Moderna is planning on combining its mRNA RSV candidate mRNA-1345 with mRNA-1653, its vaccine candidate against human metapneumovirus and parainfluenza virus type 3, with the goal of preventing all three diseases in one shot. Work is very early stage, however.
|Selected RSV treatments|
|Product||Company||Mechanism of Action||WW 2026e sales ($m)||Current clinical focus|
|Synagis||Abbvie/Sobi||Fusion antibody||735||Indicated for prevention of RSV infections in high-risk infants|
|SP0232 (nirsevimab)||Sanofi/Astrazeneca||Fusion antibody||455||Prevention of RSV infections in healthy and high-risk infants|
|RSVpreF (PF-06928316)||Pfizer||Vaccine||128||Prevention of RSV infections in the infants of vaccinated mothers|
|GSK3888550A||Glaxosmithkline||Vaccine||86||Prevention of RSV infections in the infants of vaccinated mothers|
|Mid-early stage development|
|Ad26.RSV.preF||Johnson & Johnson||Vaccine||not available||Prevention of RSV infections in vaccinated elderly adults and toddlers|
|EDP-938||Enanta Pharmaceuticals||Nucleoprotein inhibitor||306||Treatment for RSV infection in adults and stem cell transplant patients (infant study to start 2021)|
|MK-1654||Merck & Co||Fusion antibody||94||Safety trial in high-risk infants|
|mRNA-1345||Moderna||mRNA vaccine||10||Safety trial in adults and infants|
|Source: EvaluatePharma, company statements.|
Perhaps the most interesting infant RSV approach is nirsevimab (SP0232), an antibody that is being developed under a collaboration between Sanofi and Astrazeneca. Like Synagis, the project is intended for infants shortly after birth, also in a preventative setting.
Phase II results with nirsevimab looked good, with a reduction in serious LRTIs of 70% and hospitalisations of 78%. Nirsevimab uses extension technology to increase its half-life; Sanofi claims that it can provide protection from RSV-associated LTRIs for at least six months – equivalent to passive vaccinations – and potentially out to 12 months.
The company also says that protection is immediate, versus the two to three weeks needed to generate protective immunity after vaccination.
This could make nirsevimab a better fit with the seasonal nature of RSV, compared with maternal vaccines: its use could be targeted more accurately to the times of year when the virus is more prevalent.
Nirsevimab is currently in two phase III trials, one running against Synagis in high-risk pre-term infants, called Medley, and another against placebo in healthy infants, called Melody. These are due to read out in 2022 and 2023 respectively.
The history of development in RSV shows that this is a high-risk area. But for now, at least, there are several promising approaches in late-stage trials. Although given most infants recover from RSV on their own, companies might have to work hard to develop a substantial market outside of the high-risk category, particularly in more price-sensitive regions.