AZ COVID-19 Vaccine Scores 79% In Pivotal US Trial – Any Hope For A Fresh Start?
Brain Clot Safety Issue Addressed
Executive Summary
The US FDA will now have the full efficacy data that it wanted from AstraZeneca, but the company still has to deal with concerns over safety and global supply issues.
AstraZeneca’s COVID-19 vaccine has achieved a 79% efficacy in preventing symptomatic cases of the disease in its Phase III trial conducted in the US.
The interim results from the trial are a long-awaited validation for the vaccine AZD1222 in the US, and set it up for a possible emergency use authorization (EUA) from the US Food and Drug Administration.
That is because the US regulator had made it clear that earlier pivotal trials carried out by AZ's partner Oxford University would not be enough for it to grant clearance, as they did not include sufficient numbers of people over 65, and also included a range of dosing schedules and sub-group results.
This has been addressed in the US trial, which used a standard two-dose regimen over four weeks and where 20% of participants were over 65, and in whom the efficacy was found to be 80%.
Despite playing a large part in the UK's very successful COVID-19 vaccination campaign, the product has been bedeviled by controversy over its safety and efficacy in Europe, so it is yet to be seen whether these results can give it a fresh start in the US.
The interim safety and efficacy analysis on the US study was based on 32,449 participants accruing 141 symptomatic cases of COVID-19. The trial had a 2:1 randomization of vaccine to placebo.
Vaccine efficacy was consistent across ethnicity and age and most notably in those participants aged 65 and over.
The interim data also showed a 100% efficacy against severe or critical disease and hospitalization, plus a favorable reactogenicity and overall safety profile.
The results are strong, but nevertheless put it some way behind the 90% plus efficacy scores achieved by Pfizer/BioNTech and Moderna’s in the pivotal trials for their mRNA-based vaccines.
AZ’s results do, however, surpass those of the single-shot vaccine from J&J, which showed it to be 66% effective in preventing moderate to severe/critical disease at least 28 days after vaccination, the most comparable endpoint to that in the AZ study.
Moreover, results from real-world data generated in the UK show that the longer 12-week dosing interval used there can generate superior efficacy results, and also help accelerate the number of people who receive the first dose.
However, given the conservative approach of the US regulator on following trial protocols for EUAs, the FDA is unlikely to authorize a longer dosing schedule as seen in the UK. (Also see "More Encouraging Real World Data From UK – But Can It Turn Around European Sentiment On AZ COVID-19 Vaccine?" - Scrip, 3 Mar, 2021.)
The US government signed a deal with AZ in July 2020 for 100 million doses of the vaccine, which have already been delivered while an EUA is awaited. The US last week announced it was 'loaning' 4 million doses to its neigbors Mexico and Canada.
Safety Question Tackled
The other ongoing talking point hanging over the AZ vaccine is its safety. Last week, the European Medicines Agency gave it the all-clear after 13 EU nations decided to suspend its use after a possible link with blood clots emerged.
Fears of a raised risk of general thrombosis events have been dismissed, however a link to rare but potentially fatal brain blood clots called cerebral venous sinus thrombosis (CVST) has not yet been ruled in or out.
In order to tackle these concerns, the data safety monitoring board (DSMB) for the US trial conducted a specific review of thrombotic events, as well as CVST with the assistance of an independent neurologist.
It found no increased risk of thrombosis or events characterized by thrombosis among the 21,583 participants receiving at least one dose of the vaccine. The specific search for CVST found no events in this trial.
However, given the rarity of this adverse event, patterns of cases are only likely to be picked up when used in a larger population. Whether or not the US regulator should put in place safety monitoring or restrictions over and above those required for the other COVID-19 vaccines will be a key talking point for the FDA committee reviewing the data.
Ann Falsey, professor of medicine, University of Rochester School of Medicine, US, and co-lead principal investigator for the trial, said: “These findings reconfirm previous results observed in AZD1222 trials across all adult populations but it’s exciting to see similar efficacy results in people over 65 for the first time.
"This analysis validates the AstraZeneca COVID-19 vaccine as a much-needed additional vaccination option, offering confidence that adults of all ages can benefit from protection against the virus.”
Mene Pangalos
Mene Pangalos, executive vice president, BioPharmaceuticals R&D, said: “These results add to the growing body of evidence that shows this vaccine is well tolerated and highly effective against all severities of COVID-19 and across all age groups,” adding that he believed it can play an important role in immunizing the world against the virus.
He confirmed that the company was preparing to submit the interim results to the US FDA, and said millions of doses could be quickly deployed in the US should it gain an EUA.
A row is also brewing over a shortage of the vaccine in the European Union, and the Phase III results come just one day after AstraZeneca announced the sad and unexpected news that its oncology research chief José Baselga has passed away. (Also see "Shock As AstraZeneca’s Oncology R&D Head José Baselga Dies" - Scrip, 21 Mar, 2021.)