AstraZeneca acknowledged that it has paused the up-to-30,000 patient Phase III trial of its closely-watched COVID-19 vaccine candidate AZD1222—which it is co-developing with the University of Oxford and a spinout company—to investigate a “potentially unexplained illness” involving a participant from the U.K.
“As part of the ongoing randomized, controlled global trials of the Oxford coronavirus vaccine, our standard review process was triggered and we voluntarily paused vaccination to allow review of safety data by an independent committee,” AstraZeneca stated. “This is a routine action which has to happen whenever there is a potentially unexplained illness in one of the trials, while it is investigated, ensuring we maintain the integrity of the trials.”
“We are working to expedite the review of the single event to minimize any potential impact on the trial timeline,” AstraZeneca added. “We are committed to the safety of our participants and the highest standards of conduct in our trials.”
AstraZeneca later stated that it initiated the pause—but has not disclosed specifics on the adverse reaction and when it took place. The New York Times reported that the adverse event was a diagnosis of transverse myelitis, citing an unnamed “person familiar with the situation, who spoke on the condition of anonymity.” Transverse myelitis is an inflammation of both sides of one section of the spinal cord that often damages the insulating material covering nerve cell fibers (myelin), according to the Mayo Clinic.
Testifying before the U.S. Senate Committee on Health, Education, Labor & Pensions on Wednesday, NIH Director Francis S. Collins, MD, PhD, appeared to confirm that report when he described the reason for the trial pause as a “spinal cord problem.”
The timing of the diagnosis and its link if any to AstraZeneca’s vaccine is unknown, the New York Times reported. Also not known is the length of the pause in enrollment, though the Financial Times reported Wednesday that the trial could resume early next week, citing unnamed “people familiar with the matter.”
“If adenovirus can cause transverse myelitis, perhaps the adverse event that halted $AZN’s Phase III #COVID19 vaccine trial is specific to the adenoviral delivery strategy used by AZ/Oxford,” tweeted David R. Liu, PhD, of the Broad Institute of Harvard and MIT, as well as Harvard University and the Howard Hughes Medical Institute. “Still, a reminder of the challenge of vaccine-making at warp speed.”
Liu was alluding to Operation Warp Speed, the program through which President Donald Trump’s administration has committed the nation to delivering 300 million vaccine doses protecting against SARS-CoV-2 by January 2021.
Up to $1.2B from “Warp Speed”
The Biomedical Advanced Development Authority (BARDA) has committed up to $1.2 billion toward development, production, and delivery of AZD1222 via Operation Warp Speed.
BARDA and the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) are funding the 30,000-patient Phase III trial, which AstraZeneca launched last week in the United States—a study intended to account for most of the 50,000 participants on which the company intends to assess the vaccine. Participants had been randomized to receive two doses of either AZD1222 or a saline control, four weeks apart, with twice as many participants receiving the potential vaccine than the saline control. Local and systemic reactions and immune responses are set to be assessed in 3,000 of the participants.
In addition to co-funding the U.S. Phase III trial, BARDA also agreed to fund another trial designed to evaluate the vaccine in children. AstraZeneca has agreed to furnish BARDA with 300 million doses of the vaccine.
“We believe that it is obvious that AZN’s vaccine program will be delayed by several weeks, if not months, to get to the bottom of this unfortunate event. If there are any more such events (i.e., even one) in the safety database, then the program will be halted permanently,” Geoffrey C. Porges, MBBS, Director of Therapeutics Research and a senior research analyst at SVB Leerink predicted today in an investor note.
“Other adenovirus vaccine programs are likely to experience some slowdown, most likely days to weeks, but not months. The direct spillover to other COVID vaccine programs should be modest,” Porges added. However, this will serve as an important reminder to politicians, public health officials, and industry executives about the risks of the current compressed and accelerated development programs.”
AZD1222 is based on an adenovirus vaccine vector and the COVID-19 spike protein. After vaccination, the surface spike protein of the coronavirus is produced, which primes the immune system to attack the coronavirus if it later infects the body.
“For the moment, we don’t see any reason to implicate the use of the Spike protein target in this event, but a similar occurrence in another vaccine study targeting the Spike protein (especially one utilizing a different vector/technology platform) would be grounds for concern,” added Mani Foroohar, MD, a senior research analyst and managing director, genetic medicines with SVB Leerink.
Investors responded to news of the pause in trial patient recruitment, which emerged after the close of trading on Tuesday, by sending AstraZeneca shares on the New York Stock Exchange down 8.14% in after-hours trading as of 7:59 p.m. ET, to $50.25 from the closing price of $54.71. The share price dipped another 1.4% on Wednesday as of 2:12 p.m., to $53.94.
U.K. health secretary Matt Hancock said Tuesday on the national radio news/talk station LBC that the AZD1222 vaccine would “most likely” be available in the first few months of 2021.
“We have got 30 million doses already contracted with AstraZeneca. In fact, they are starting to manufacture those doses already, ahead of approval, so should that approval come through—and it’s still not certain but it is looking up—should that approval come through, then we are ready to roll out,” Hancock said. “The best-case scenario is that it happens this year. I think more likely in the early part of next year—in the first few months of next year is the most likely.”
Earlier in the day, AstraZeneca CEO Pascal Soriot was one of nine CEOs of leading developers of vaccine candidates against COVID-19 who signed a statement that pledged “a united commitment to uphold the integrity of the scientific process” by pursuing approvals or emergency use authorizations (EUAs) only for vaccines that pass muster in Phase III trials by proving safety and effectiveness.
“Need more details. But based on this info I’m not alarmed. Side effects, stops, and re-starts are part of a GOOD careful process,” tweeted Faheem Younus, MD, chief of infectious diseases at the University of Maryland Medical System. “1 ‘potential’ side effect vs 35,000 COVID patients hospitalized in U.S. today. That’s the perspective we need to keep in mind.”
Brad Loncar, CEO of Loncar Investments, which tracks developments in the biopharma industry, tweeted a rhetorical question on Tuesday: “Did you really think vaccine development was going to go totally smoothly?”
Loncar added: “The Astra trial participant may end up being nothing and unrelated to the trial, but at least it’s a reminder of how risky and unpredictable biology can be.”