AstraZeneca to conduct further study to answer questions over COVID-19 vaccine

AstraZeneca CEO Pascal Soriot said Thursday that the company is likely to conduct a further global study of its COVID-19 vaccine candidate AZD1222 to address questions arising from its current late-stage trials, Bloomberg reported. He indicated that the new study, which would evaluate an initial low-dose of the vaccine, would be conducted instead of adding another arm to the ongoing US Phase III study testing a regimen of two full doses.

"Now that we've found what looks like a better efficacy, we have to validate this, so we need to do an additional study," Soriot remarked, adding that the trial "could be faster because we know the efficacy is high, so we need a smaller number of patients." Soriot suggested that the additional study is not expected to delay regulatory approval of AZD1222 in the UK and Europe, although authorisation in the US is anticipated to take longer as the FDA is unlikely to accept the current data.

On the defensive

Soriot's comments came after AstraZeneca fended off criticism of data released earlier this week in which the lower dose of AZD1222, given to study participants in error, performed better than the full amount. Mene Pangalos, executive vice president for biopharmaceuticals R&D, remarked "whichever way you cut the data -- even if you only believe the full-dose/full-dose data....we still have efficacy that meets the thresholds for approval with a vaccine that's over 60% effective."

When AstraZeneca and its partner the University of Oxford presented the results, they highlighted a combined interim analysis from two late-stage studies conducted in the UK and Brazil suggesting that AZD1222 had an average efficacy of 70%. However, the data showed that efficacy of the vaccine when administered as a half dose followed by a full dose in 2741 people was 90%, dropping to 62% in 8895 participants given two full doses. The parties later disclosed that the regimen in which subjects initially received a half dose of AZD1222 was in fact due to a dosing error.

Pangalos explained that the mistake was only identified after a trial investigator noticed that volunteers in this group were having a lower inflammatory response, prompting researchers to analyse their vaccine supply and find that they had miscalculated the dose. AstraZeneca and the University of Oxford subsequently informed regulators in the UK, US and the EU, with the study design amended to include the half-dose group in their analysis. "The methods for measuring the concentration are now established and we can ensure that all batches of vaccine are now equivalent," the University of Oxford said.

Dosing mistake "irrelevant"

"The mistake is actually irrelevant," Pangalos remarked, adding "I'm not going to pretend it's not an interesting result, because it is -- but I definitely don't understand it and I don't think any of us do." Although it is currently unknown why the half-dose/full-dose regimen may be more effective, researchers have suggested that the lower dose more accurately reflects the natural immune response to viruses. Pangalos said "I'm not going to hand wave with the immunologists. Until I see some data that gives me some science behind it, I'm going to say 'I don't know.'"

Other factors could also be at play, with Moncef Slaoui, chief scientific adviser to the US government's Operation Warp Speed initiative, noting that the half-dose regimen was only given to volunteers 55 and younger, whereas the full-dose group also included older participants. "There are a number of variables that we need to understand," said Slaoui, adding "it's unlikely but it's still possible that it's a random difference."

Commenting on the data for AZD1222, Bloomberg Intelligence analyst Sam Fazeli said "the most likely explanation for the divergent efficacy in its interim analysis is either chance or patient demographics." Fazeli added "either way, approval based on current data means people will be inoculated with a vaccine the true efficacy of which is unknown."

For related analysis, see ViewPoints: Leading expert weighs in on AstraZeneca's serendipitous COVID-19 vaccine finding.

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