Sometimes – for no obvious reason – there is a flurry of publications from a particular area which has been quiet for a long time. RSV is such an area where new drug development had a hard time getting started. There was always the lure of big money: an infection as prevalent as influenza which causes significant disease in the newborn is clearly a high-need area. Prophylaxis in high-risk children has already made palivizumab/Synagis a 1 billion USD drug. This disease should either be preventable with a vaccine or at least become more manageable with an antiviral. Even significant symptomatic improvement would be progress and create a blockbuster.
The label for Synagis is quite restrictive and it is quite amazing that this antibody has become so lucrative. Clearly, Medimmune was anxious to replace palivizumab with motavizumab (MEDI-524, Numax) ahead of the patent expiry for Synagis last month (October 2015), but things did not work out as planned. Although Numax was a monoclonal antibody with 20-times higher affinity for the F-(fusion) glycoprotein of RSV, this affinity advantage did not translate into higher clinical efficacy when compared to Synagis. Even more unfortunately, Numax was associated with rashes and hypersensitivity reactions, including urticarial, in approx. 1% of patients. Despite some theoretical benefits, the 2010 Antiviral Drugs Advisory Committee voted against approval, and FDA followed that advice. Now, years after that decision, we learn about a study conducted with motavizumab which is truly impressive. And the clinical findings are very impressive as well.
O’Brien and the team at MedImmune report the results of an RSV disease prevention study conducted with motovizumab (Numax) in a large population of infants from the Navajo and Apache nations, a particularly high-incidence population for RSV [1]. Over 4 consecutive fall/winter seasons, they were able to enroll 2127 evaluable infants who received motavizumab in 5 monthly injections. The results were impressive: Overall, treatment with motavizumab prevented 87% of infections that would have led to hospitalization for lower tract respiratory disease due to RSV. Even in the outpatient setting, treatment with motavizumab was highly effective in preventing RSV-related lower tract respiratory disease: here 71% was the protection level.
No significant safety issues were identified; in fact, the placebo arm looked numerically worse than the Numax group. However, the authors mention that some children developed hypersensitivity reactions to motavizumab that required urgent care, a reminder of the concerns raised at the Antiviral Drugs Advisory Committee.
With 20/20 hindsight, similar results could have been achieved by Synagis in this population had the same study been done. It would have broadened the indications for palivizumab and provided a new prophylaxis option which currently does not exist.
This was a beautifully executed trial; it had all the quality markers you could wish for: Central lab processing, long-term f/u, interim analysis, blinded data review, independent data monitoring committee. It showed (again) that monoclonal antibody prophylaxis works: RSV incidence can be reduced significantly, even if disease severity – once illness strikes – is not improved.
It is a pity publication of study results was delayed by 5 years. A trial like this creates a lot of good will towards industry; it deserves to be highlighted as an example of excellence in study design and execution.
With Numax no longer being developed and not getting much attention in-house at MedImmune, this publication had a long gestation period. First results were communicated to ‘the community’ in 2011, i.e., 1 year after the end of the trial. Unfortunately, it took 4 more years for this publication to appear in print.
Just as this article is being published, we learn that Novavax has initiated a large placebo-controlled Phase 2 trial of its candidate RSV vaccine, directed against the F-gp as well. This is a study of immunogenicity in elderly patients. And we have not even mentioned the Alios compound yet, ALS-008176 (aka AL-8176) which after the merger is now being developed by Johnson & Johnson.
We will keep an eye on these and other anti-RSV therapeutics and report progress in future blogs.
References:
[1] O’Brien, K. Efficacy of motavizumab for the prevention of respiratory syncytial virus disease in healthy Native American infants: a phase 3 randomised double-blind placebo-controlled trial Lancet Infect Dis 2015; 15: 1398–408
