AstraZeneca has released positive safety and efficacy results from a large Phase III study in the United States, Chile, and Peru for its COVID-19 vaccine—and specifically, no increased risk of blood clots along the lines of the 30 reported in Europe earlier this month.

The pharma giant released results from the Phase III D8110C00001 trial (NCT04516746), showing the vaccine to be 79% effective at preventing symptomatic COVID-19 and 100% effective at preventing severe disease or hospitalization in the whole cohort. It was also 80% effective at preventing symptomatic disease in over 65s who made up 20% of the participants, the company said.

The non-replicating adenoviral vector vaccine targeting SARS-CoV-2 is called AZD1222 in the United States, where it has not been approved or authorized for emergency use. The positive results should propel the vaccine toward eventual FDA approval, one analyst predicted yesterday.

“Given this favorable read-out, barring manufacturing issues or other issues discovered during the review process, we think the FDA is likely to grant access to the drug,” Andrew Berens, MD, managing director, targeted oncology, and a senior research analyst with SVB Leerink, wrote with a colleague in a research note.

However, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), issued a statement early Tuesday morning citing concerns raised by the study’s Data and Safety Monitoring Board (DSMB), which notified NIAID; the U.S. Biomedical Advances Research and Development Authority (BARDA), which funded the trial; and AstraZeneca that the company “may have included outdated information from that trial, which may have provided an incomplete view of the efficacy data.”

“We urge the company to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible,” NIAID added.

AstraZeneca responded Tuesday with a statement saying that its data was based on a pre-specified interim analysis with a data cut-off of February 17, and that its preliminary assessment of its primary analysis showed results consistent with the interim analysis: “We are now completing the validation of the statistical analysis.”

Peter Welford, equity analyst at Jefferies, called the results “surprisingly positive” in a research note. He also offered two possible explanations why AstraZeneca’s effectiveness rate lagged behind the 95% final efficacy reported by Pfizer and BioNTech for their vaccine BNT162b2, and the 94.1% final efficacy reported by Moderna for its mRNA-based COVID-19 vaccine (mRNA-1273). Both have been authorized for U.S. emergency use by the FDA.

“(1) Weekly swabbing was performed to detect COVID-19 and not just confirmation of suspected cases by symptoms as in the U.S. trials; and (2) meningococcal vaccine MenACWY used as a comparator and not placebo,” Welford wrote.

Welford added, however, that AstraZeneca’s vaccine offered an important advantage over the other two COVID-19 vaccines when it came to ease of storage:

“Importantly, AZD1222 offers the convenience of a simple supply chain, with the vaccine able to be stored and transported at normal refrigerator conditions (2–8ºC) for at least six months, with no specialist setting required for administration. This compares favorably to supply chain logistics for mRNA vaccines from Pfizer/BioNTech and Moderna, which can only be stored at refrigerator temps for 5 and 30 days, respectively, and require transport at -70ºC and -20ºC, respectively.”

Controversy over clots

AstraZeneca’s vaccine has been renamed COVID-19 Vaccine AstraZeneca in Europe and the U.K., where it was first developed through a collaboration between the University of Oxford and its spin-out company, Vaccitech, before AstraZeneca joined the collaboration.

The AstraZeneca/Oxford vaccine has generated significant controversy in Europe in recent months, initially due to a lack of data in over 65s, and more recently over concerns that it might increase the risk of blood clots, based on what the World Health Organization said earlier this month were reports of 30 patients who developed thrombotic events following vaccination.

The reports led more than a dozen European nations to pause their vaccination of patients using the AstraZeneca two-dose vaccine. But on Thursday, both the European Medicines Agency and the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) concluded that the vaccine’s benefits outweighed its risks.

AstraZeneca’s COVID-19 vaccine has been granted a conditional marketing authorization or emergency use in more than 70 countries across six continents. Also, the World Health Organization has granted the vaccine an Emergency Use Listing, accelerating access in up to 142 countries through the COVAX Facility.

32,449 participants

D8110C00001 was a large trial, with 32,449 participants randomly assigned to vaccine—two doses with a four-week interval—or placebo in a 2:1 ratio, with approximately 21,583 participants receiving the vaccine. Overall, 141 symptomatic cases of COVID-19 occurred during the trial.

The vaccine was well tolerated with no major safety concerns raised by the trial. The trial’s independent data safety monitoring board reviewed thrombotic events as well as cerebral venous sinus thrombosis (CVST) with the assistance of an independent neurologist, only to find no increased risk of such events or CVST in the 21,583 participants who received at least one dose of the vaccine.

Among participants in the interim analysis of the U.S.-Chile-Peru trial, approximately 79% were white/Caucasian, 8% black/African American, 4% Native American, 4% Asian, and 22% Hispanic.

In addition, AstraZeneca said, approximately 20% of participants were 65 years and over, and approximately 60% had co-morbidities associated with an increased risk for progression of severe COVID-19, such as diabetes, severe obesity, or cardiac disease.

“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,” said Ann Falsey, MD, a professor at the University of Rochester School of Medicine, and co-lead principal investigator for the trial.

Added Mene Pangalos, executive vice president, biopharmaceuticals R&D, AstraZeneca: “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. We are confident this vaccine can play an important role in protecting millions of people worldwide against this lethal virus.”

To that end, AstraZeneca said, it is preparing to submit its data to the FDA “in the coming weeks” as it pursues emergency use authorization (EUA) for its vaccine. A primary analysis of the U.S. Phase III trial will be submitted for publication in a peer-reviewed journal, the company added.

The positive results achieved in D8110C00001 were higher than those in the original trials of the vaccine.

“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,” said Falsey.