Pfizer and BioNTech have advanced their front-running, four-candidate COVID-19 vaccine program into an up-to-30,000 patient, nearly global Phase II/III trial—with the companies switching their lead vaccine candidate from one nucleoside modified mRNA (modRNA) candidate to the other, citing stronger clinical data.
The companies opted to advance BNT162b2, saying that preliminary Phase I/II data from nearly 120 patients showed a more favorable overall tolerability profile than BNT162b1, with no serious adverse events and generally mild to moderate and transient systemic events such as fever, fatigue, and chills.
Two other reasons cited by Pfizer and BioNTech: Participants who were vaccinated with BNT162b2 showed a favorable breadth of epitopes recognized in T-cell responses specific to the SARS-CoV-2 antigen, compared to BNT162b1. Also, BNT162b2 elicited T-cell responses against the receptor-binding domain (RBD) and against the remainder of the spike glycoprotein that is not contained in BNT162b1. BNT162b2 showed concurrent induction of high magnitude CD4+ and CD8+ T-cell responses.
“The companies believe that immune recognition of more spike T-cell epitopes may have the potential to generate more consistent responses across diverse populations and in older adults,” Pfizer and BioNTech stated late yesterday.
The companies also said they continue to collect data from the Phase I/II trials for all four vaccine candidates and expect to submit data on BNT162b2 for peer review and potential publication in the near future: “In keeping with their commitment to transparency, the companies intend to also post the manuscript on a preprint server at that time.”
In the statement, BioNTech CEO Ugur Sahin, M.D., added: “We selected BNT162b2 as our lead candidate for this Phase II/III trial upon diligent evaluation of the totality of the data generated so far.”
That totality began with promising preclinical data: In a primate SARS-CoV-2 challenge model, both BNT162b2 and BNTb1 induced favorable viral antigen-specific CD4+ and CD8+T cell responses, high levels of neutralizing antibody in various animal species, and beneficial protective effects.
News of the Phase II/III trial launch, anticipated for several days, did not appear to faze investors. Shares of BioNTech rose 5% in after-hours trading as of 7:45 p.m., to $91.13 from the closing price of $86.53, before settling down to $87.08 at 10 a.m. today. Pfizer shares inched up 1.7% after hours to $38.25, from a close of $37.54, and rose again to $38.30 at 10 a.m.
BNT162b2 encodes an optimized SARS-CoV-2 full-length spike glycoprotein antigen. BNT162b1 encodes an optimized SARS-CoV-2 RBD antigen. Both constructs were granted the FDA’s Fast Track designation earlier this month.
The two candidates are among four developed by Pfizer and BioNTech based on differing constructs in their BNT162 COVID-19 vaccine clinical program, which the companies have dubbed “Project Lightspeed.” The other two candidates are a uridine containing mRNA (uRNA) candidate; and a candidate using self-amplifying mRNA (saRNA).
All four candidates will continue to be studied, the companies said.
The Phase II/III trial is designed to evaluate two BNT162b2 in up to 30,000 participants aged 18–85 years, using a protocol developed through feedback from global regulators that included the FDA and the German Paul-Ehrlich-Institut.
The companies cited clinical data showing that two 30 µg doses of BNT162b2 elicited neutralizing geometric mean titers (GMTs) generally similar to the GMTs that were elicited by BNT162b1 and detailed in a preprint study posted July 20 in medRxiv. In older adults (65–85 years of age), two 30 µg doses, spaced three weeks apart, elicited a neutralizing antibody GMT higher than the GMT in a panel of 38 sera from subjects who had contracted SARS-CoV-2.
The companies said they plan to enroll a diverse population, including participants from areas that have seen high levels of SARS-CoV-2 transmission.
Participants will be randomized 1:1, vaccine candidate to placebo in the observer-blinded study, whose primary endpoints will be prevention of COVID-19 in those who have not been infected by SARS-CoV-2 prior to immunization, and prevention of COVID-19 regardless of whether participants have previously been infected by SARS-CoV-2. The trial’s secondary endpoints include prevention of severe COVID-19 in both groups.
The study will also explore prevention of infection by SARS-CoV-2. The primary efficacy analysis will be based on the number of participants with symptomatic COVID-19 disease, Pfizer and BioNTech added. The trial design also allows for interim analyses and unblinded reviews by an independent external Data Monitoring Committee.
120 sites, 39 U.S. states
The Phase II/III trial has been launched in the United States and is expected to include approximately 120 sites worldwide—except China, where Pfizer and BioNTech are partnering with Fosun Pharma to jointly develop BNT162. The global sites will include 39 U.S. states and countries that include Argentina, Brazil, and Germany.
If the Phase II/III trial is successful, Pfizer and BioNTech said, they expect to be ready to seek Emergency Use Authorization or other regulatory approval as early as October 2020. Upon obtaining such authorization or approval, the companies plan to supply up to 100 million doses by the end of this year, and approximately 1.3 billion doses by the end of 2021.
“The initiation of the Phase II/III trial is a major step forward in our progress toward providing a potential vaccine to help fight the ongoing COVID-19 pandemic, and we look forward to generating additional data as the program progresses,” stated Kathrin U. Jansen, PhD, senior vice president and head of vaccine research & development at Pfizer.