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U.S., U.K. volume bets on AZD1222 come into question with vaccine efficacy data 

As U.K.’s MHRA readies review of AZ’s COVID vaccine, company weighs additional trial

As the U.K.’s MHRA prepares to review AstraZeneca and Oxford’s COVID vaccine, AZ is weighing running an additional trial.

By stephen hansen and Karen Tkach Tuzman, Associate Editors
Nov 28, 2020 | 12:08 AM GMT
Updated on Dec 1, 2020 at 2:48 AM GMT

As the U.K. moves to review AZD1222 from AstraZeneca and Oxford, efficacy data from the three front-runner COVID-19 vaccines provides an opportunity to take stock of governments’ bets on which candidates warranted the most investment, and of how the landscape could shift if AZ opts for a second trial.

Both the U.S. and U.K. made AZD1222 their biggest investments by volume, largely due to its lower price. But as emerging data raises questions about its relative efficacy and optimal dosing regimen, the adenoviral vector vaccine could see its role in the COVID-19 response dwindling, with the possibility that it may never become available stateside.

The U.K.’s government Friday formally requested that MHRA start a review of AZD1222, making the country a clear front-runner to host the debut of the vaccine.

The news came on the heels of last week’s readout showing a full-dose regimen of AZD1222 performed worse than a partial-dose regimen, and raised the possibility of AstraZeneca plc (LSE:AZN; NASDAQ:AZN) needing to run another trial.

That data might affect the timing for Operation Warp Speed’s distribution of the vaccine in the U.S., if AZ waits to gather more data before filing for emergency use authorization (EUA) to FDA. But should higher performing vaccines become widely available during that time period, the candidate could miss the boat for a U.S. EUA entirely.

On Nov. 23, AZD1222 from AZ and partner University of Oxford became the third COVID-19 vaccine to meet FDA’s threshold for efficacy, behind mRNA-1273 from Moderna Inc. (NASDAQ:MRNA) and BNT162b2 from Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX). 

A May deal with OWS secured 300 million doses of AZD1222, or about 37% of the total vaccine doses slated to be procured by the U.S. government, not including the exercise of any options.

But AZD1222’s performance fell short of the 95% efficacy demonstrated by mRNA-1273 and BNT162b2. (On Nov. 30, Moderna reported its vaccine had prevented 94.1% of symptomatic and 100% of severe cases of COVID-19.) Operation Warp Speed has procured 100 million doses of each of those vaccines.

The  U.K. has ordered 100 million doses of AZD1222, out of a total of 357 million across seven manufacturers. AZ has said it may have 4 million doses available in the U.K. by year-end and 40 million by March.

The U.K. Department of Health has also called upon MHRA to review Pfizer and BioNTech’s BNT162b2, of which the country ordered 40 million doses; the mRNA vaccine could be available in the country as early as next month.

The U.K. also has an agreement to procure Moderna’s mRNA vaccine. On Nov. 16, the U.K. signed an agreement for 5 million doses of mRNA-1273, updated to 7 million on Nov. 29. The earliest delivery of that vaccine would be next spring. 

Among vaccines without data on protection from infection, the U.S. has procured a total of 300 million doses from Novavax Inc. (NASDAQ:NVAX), Johnson & Johnson (NYSE:JNJ) and partners Sanofi (Euronext:SAN; NASDAQ:SNY) and GlaxoSmithKline plc (LSE:GSK; NYSE:GSK). The U.K. has procured 210 million doses from the above plus Valneva SE (Euronext:VLA; VSE:VLA).

Trial, trial again

The data reported Monday came from an interim analysis of two Phase III studies and were based on accrual of 131 confirmed cases. Across the two trials, AZD1222 was 70% effective (p<0.0001) in preventing symptomatic COVID-19 disease, clearing FDA’s 50% efficacy threshold.

But the studies’ readouts differed markedly. The better data came from the Phase II/III COV002 trial, in which a cohort of 2,741 U.K. volunteers received a half dose of AZD1222 followed by a full dose one month later. The regimen, which was deployed due to an error that was later fixed, was 90% effective in preventing development of symptomatic COVID-19 disease.  The other study, the COV003 trial, showed 62% efficacy on the primary endpoint in 8,895 participants in Brazil who received two full doses of the vaccine.

AZ has not yet disclosed the breakdown of the 131 cases between the trials, nor whether or how the results will affect the path forward.

Following the readout, CEO Pascal Soriot said the U.K. pharma may run another trial of the lower dose regimen, according to a report by Bloomberg. 

An AZ spokesperson declined to confirm to BioCentury that the company was considering conducting another trial, but did reiterate comments from earlier in the week that the company is weighing next steps for the regimen even as it readies regulatory submissions.

“There is strong merit in continuing to further investigate the half-dose/full dose regimen,” the spokesperson said via email. “We are further evaluating the data and will work with regulators on the best approach for further evaluation. This would add to data from existing trials which are currently being prepared for regulatory submission.”

If the better efficacy of the partial-dose regimen holds up with further scrutiny or another trial, it would stretch the vaccine supplies farther.

Although the U.K. remains under EMA’s jurisdiction until the Brexit transition period ends on Dec. 31, European law allows the government to bypass EMA’s review and ask its own regulator to review safety and efficacy data to approve a temporary supply when a public health need exists.

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