Developers of two leading COVID-19 vaccine candidates announced plans to ramp up their Phase III trials, with AstraZeneca and the University of Oxford resuming the clinical study they paused last week after one U.K. participant developed a “potentially unexplained illness,” while Pfizer and BioNTech requested FDA approval to add 14,000 participants to their late-stage study.

AstraZeneca said the Phase III trial of AZD1222—the vaccine it is co-developing with the University of Oxford and a spinout company—was resumed after receiving confirmation from the U.K.’s Medicines Health Regulatory Authority (MHRA) that it was safe to do so. The MHRA acted after the trial’s U.K. independent data and safety monitoring committee concluded its investigation and recommended to the MHRA that the trials in the U.K. were safe to resume.

“The standard review process triggered a voluntary pause to vaccination across all global trials to allow review of safety data by independent committees, and international regulators,” AstraZeneca stated on Saturday. “The company will continue to work with health authorities across the world and be guided as to when other clinical trials can resume to provide the vaccine broadly, equitably, and at no profit during this pandemic.”

The pause is one of two that has occurred during the trial, AstraZeneca disclosed on Wednesday. The company said “a brief pause” occurred in July after a volunteer participant “was confirmed to have an undiagnosed case of multiple sclerosis, which the independent panel concluded was unrelated to the vaccine.”

The U.K. committee joined data and safety monitoring committees and regulators worldwide in reviewing the trial’s safety data to date, AstraZeneca said, after the U.K. patient became ill.

AstraZeneca has not disclosed the nature of the patient’s illness—and said in a statement Saturday that it “cannot” do so—for now: “All trial investigators and participants will be updated with the relevant information and this will be disclosed on global clinical registries, according to the clinical trial and regulatory standards.”

The New York Times reported Tuesday that the patient developed transverse myelitis, citing an unnamed source—while STAT later reported AstraZeneca CEO Pascal Soriot told investors on a private conference call organized by J.P. Morgan that the patient had neurological symptoms consistent with the disorder.

“No final diagnosis”

AstraZeneca responded with a statement saying: “There is no final diagnosis and there will not be one until more tests are carried out.” However, NIH director Francis S. Collins, MD, PhD, seemed to give credence to the Times’ report when he told a Senate committee last week that the reason for the trial pause was a “spinal cord problem.”

The Biomedical Advanced Development Authority (BARDA) has committed up to $1.2 billion toward development, production, and delivery of AZD1222 via Operation Warp Speed, 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.

BARDA and the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) are funding the 30,000-patient Phase III trial (NCT04516746), which AstraZeneca launched September 1 in the United States. The study is intended to account for most of the 50,000 participants on which the company intends to assess the vaccine.

In a separate statement, the University of Oxford added given the trial’s large participant population, “it is expected that some participants will become unwell and every case must be carefully evaluated to ensure careful assessment of safety.”

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.

AZD1222 and BNT162 are among 19 “Front Runner” candidates among the approximately 300 COVID-19 therapeutics under study in GEN’s “COVID-19 Drug & Vaccine Candidate Tracker.”

Amended protocol submitted

Also on Saturday, BNT162’s co-developers BioNTech and Pfizer said they submitted an amended protocol to the FDA seeking approval to add 14,000 participants to their up-to-30,000 participant, nearly global Phase II/III clinical trial (NCT04368728) evaluating BNT162b2, the lead vaccine candidate of the BNT162 program.

“The proposed expansion would allow the companies to further increase trial population diversity; and include adolescents as young as 16 years of age and people with chronic, stable HIV (human immunodeficiency viruses), Hepatitis C, or Hepatitis B infection; as well as provide additional safety and efficacy data,” Pfizer and BioNTech stated.

They said enrollment in their trial had proceeded as planned, and that they expected to meet their initial population target of 30,000 participants this week.

“Based on current infection rates, the companies continue to expect that a conclusive readout on efficacy is likely by the end of October,” BioNTech and Pfizer added.

Two SVB Leerink analysts said in a tracker of upcoming events for investors that they expect the price of both Pfizer and BioNTech shares to react strongly to the results of an interim data readout expected next month, based on how solidly they support an emergency use authorization for the companies’ vaccine.

“If BNT-162b2 generates positive efficacy (>50% reduction in disease vs placebo) without additional unexpected safety liabilities, we expect PFE stock to gain +3–5%,” wrote Geoffrey C. Porges, MBBS, director of therapeutics research and a senior research analyst.

Daina M. Graybosch, PhD, another senior research analyst who is also managing director, immuno-oncology, noted that the FDA is set to hold an advisory committee meeting on October 22 to discuss vaccines for COVID-19, “where we expect available data to be discussed and statements made in support of rapid approval for high-risk populations.”

“Phase III data that show clean safety and meet 50% efficacy bar could cause BNTX shares to retest the ~$85/share price plateau made in July after data from Phase I were reported and supply contracts with U.S. government were signed,” Graybosch wrote.

BioNTech’s share price could go even higher, she added, if AstraZeneca’s vaccine resumes a clinical hold—and if, as she expects, BNT162b2 generates stronger data than another leading COVID-19 vaccine candidate, Moderna’s mRNA-1273.

“Shares should settle down afterwards with greater acknowledgment of the level of competition, cold-chain distribution challenges, and uncertain long-term economic opportunity,” Graybosch added.

Pfizer and BioNTech are studying four constructs of BNT162: Two nucleoside modified mRNA (modRNA) candidates (BNT162b1 and BNT162b2); a uridine containing mRNA (uRNA) candidate; and a candidate using self-amplifying mRNA (saRNA).

BNT162b2, the construct under study in the Phase II/III trial, encodes an optimized SARS-CoV-2 full-length spike protein antigen. It has received the FDA’s Fast Track designation, as has the other advanced construct under study, BNT162b1, which encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen.

$1.95B order from Washington

The BNT162 program has also attracted a funding commitment from Washington: In July, the U.S. Department of Health and Human Services (HHS) and Department of Defense (DoD) ordered an initial 100 million doses of the vaccine for $1.95 billion—which the companies agreed to offer for free under an agreement signed as part of Operation Warp Speed.

Under that agreement, the U.S. federal government has the option to purchase 500 million additional doses.

The companies have not disclosed the price of those additional 500 million doses should Washington agree to order them—but have said their agreement is subject to Pfizer successfully manufacturing and obtaining approval or emergency use authorization for the vaccine.

Pfizer and BioNTech have said they expect to manufacture globally up to 100 million doses by the end of 2020, and potentially more than 1.3 billion doses by the end of 2021, subject to final dose selection from their clinical trials.

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