If the previous pivotal studies of Astrazeneca’s Covid-19 vaccine AZD1222 were confusing, the results from its US phase III trial are clear: the vaccine works and does not increase the risk of blood clots.
AZD1222 showed efficacy of 79% in preventing symptomatic Covid-19, rising to 100% against severe disease and hospitalisations. There are still some questions to be answered, including how the vaccine performs against different variants, but the findings will be a boost to Astra after a week that saw many European countries halt its use after fears over thromboses.
Astra plans to file AZD1222 in the US in the first half of April, its head of biopharmaceuticals, Ruud Dobber, said on a media call today. An emergency use authorisation looks like a foregone conclusion given that Johnson & Johnson’s one-shot version of JNJ-78436735 got the go-ahead on apparently weaker data, although the usual caveats about cross-trial comparisons apply.
There will also be pressure on the agency to push AZD1222 through quickly as the US has pre-ordered 300m doses of the Astra jab, on a par with the contribution from Pfizer/Biontech and Moderna. If and when Astra’s shot gets the green light, the company is ready to deliver 30m doses immediately, with another 20m to follow later the same month, Mr Dobber said.
Blood clot fears assuaged
The latest data have important read-across to Europe, where a storm has been raging about blood clot risk. Many EU countries have now started using Astra’s shot again, following a review by the EMA last week that concluded that the benefits of the vaccine outweighed its risks.
However, the agency stopped short of ruling out a link between AZD1222 and blood clots, and a Yougov poll published today shows that confidence in the Astra shot specifically has fallen.
Hopefully, the new US data will go some way towards rehabilitating the jab. The study, in 32,449 participants, found no increased risk of thrombosis among the 21,583 subjects receiving at least one dose of the vaccine. In addition, no cerebral venous sinus thrombosis events were seen.
Another question going into the readout concerned AZD1222’s performance in the over-65s, and here any doubts seem to have been squashed: in this age group the jab’s efficacy was 80%. Around 20% of the trial’s participants were aged 65 or older.
Apart from these nuggets, details were thin on the ground, with Astra merely saying that the interim analysis was based on 141 symptomatic cases of Covid-19. The group did not give a breakdown of how many of these were seen in the vaccine versus the placebo cohorts, and execs dodged several questions about this during today’s briefing.
Mene Pangalos, Astra’s head of biopharmaceuticals R&D, did confirm that five cases of severe Covid-19 had been seen in the placebo arm, compared with none in the vaccine arm. 2:1 randomisation meant that twice as many people in the study received AZD1222 as placebo, and Mr Pangalos said more cases had accrued since the interim analysis.
The Covid-19 case numbers will be closely watched upon publication of the FDA’s briefing documents.
The biggest unanswered question, though, concerns AZD1222’s efficacy against emerging variants. Astra had no data to share here today, but the trial is sequencing confirmed Covid-19 cases to determine which variant is responsible, with data to be reported “in due course”, a spokesperson told Evaluate Vantage.
Mr Pangalos was optimistic here, given that there were “undoubtedly variants of concern in circulation in this study”. He concluded that the latest data boosted his belief that, “against severe disease, our vaccine will be effective against all variants of concern”.
That said, given data published in the NEJM last week from a South Africa study, hopes cannot be high that AZD1222 will provide high levels of protection against mild to moderate Covid-19 caused by the B.1.351 variant.
As for new vaccines against emerging variants, on which Astra has so far been quiet, the spokesperson said Oxford University had already started developing next-generation candidates, and that the company was also looking at this.
A final and less pressing question for Astra is what dosing schedule the FDA might recommended. The US trial tested a four-week dosing interval, but in other studies a 12-week schedule has been shown to be more effective.
And Astra stuck to this script, saying that an interval of more than four weeks could increase efficacy beyond that reported today. Some immunogenicity data from the US trial could support this, as there was a cohort of patients whose second dose was delayed when the study was paused last year.
But the decision will ultimately be down to the FDA. For the agency this is probably a nice problem to have, especially given the doubts that had previously swirled around AZD1222.
|Selected upcoming Covid-19 vaccine readouts of interest|
|Medicago/Glaxosmithkline||CoVLP (coronavirus-like particle Covid-19 vaccine)||US/Canada ph2/3 (NCT04636697)||31,000||Ph2 data due Apr 2021; ph3 portion began Mar 2021|
|Johnson & Johnson||JNJ-78436735||Ensemble-2, US ph3 (two-dose regimen, NCT04614948)||30,000||Data expected May 2021|
|Novavax||NVX-CoV2373||Prevent-19, US/Mexico ph3 (NCT04611802)||30,000||Interim data due Q2 2021|
|Curevac||CVnCoV||Herald, Europe & LatAm ph2/3 (NCT04652102)||36,500||Data due Q2 2021 (from Q1 previously)|
|Europe ph3, healthcare workers (NCT04674189)||2,500||Primary completion Jun 2021|
|Clover/Dynavax||SCB-2019 (Covid-19 S-Trimer)||Europe/ROW ph2/3 (NCT04672395)||22,000||Interim analysis due mid-2021|
|Sanofi/Glaxosmithkline||SARS-CoV-2 vaccine||Ph2 trial||720||If positive, ph3 to start Q2 2021|
|Moderna||mRNA-1273.351 (next-gen candidate against S Africa variant)||Ph1 NIAID trial (NCT04785144)||210||Primary completion Aug 2021|
|Source: Evaluate Pharma & company statements.|