Candidates: BNT162a1, BNT162b1, BNT162b2, and BNT162c2

Category: RNA, VAX

Types: Two nucleoside modified mRNA (modRNA) candidates (BNT162a1 and BNT162b2); a uridine containing mRNA (uRNA) candidate; and a candidate using self-amplifying mRNA (saRNA). BNT162b1 encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen, while BNT162b2 encodes an optimized SARS-CoV-2 full-length spike protein antigen.

Each mRNA format is combined with a lipid nanoparticle (LNP) formulation. The larger spike sequence is included in two of the candidates, while the smaller optimized receptor binding domain (RBD) from the spike protein is included in the other two candidates.

Status: Pfizer Canada and BioNTech on August 5 said they agreed to supply their BNT162 vaccine candidate to the Government of Canada. The companies did not disclose financial details but did say they were based on the timing of delivery and the volume of doses. Deliveries of the vaccine candidate are planned for over the course of 2021, at Canadian government request.

On July 31, Pfizer and BioNTech said they will supply 120 million doses of a BNT162 candidate in Japan beginning in 2021, subject to clinical success and regulatory approval, under an agreement signed with Japan’s Ministry of Health, Labour and Welfare (MHLW). While financial details were not disclosed. The companies said terms were based on the timing of delivery and the volume of doses.

“We are proud to help support Japan in its steadfast determination to bring the world together at the 2020 Tokyo Olympics, in a celebration of solidarity, friendship and the power of sport as a global force for good,” said Pfizer Chairman and CEO Albert Bourla, DVM, PhD. The Tokyo Olympics were postponed due to COVID-19, but has been rescheduled for July 23-August 8, 2021.

Four days earlier, Pfizer and BioNTech said they had advanced the four-candidate BNT162 program into an up-to-30,000 patient, nearly global Phase II/III trial—after 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.

The Phase II/III trial is designed to evaluate two BNT162b2 in up to 30,000 participants aged 18–85 years, at approximately 120 sites globally—including in regions with significant expected 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 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.”

Five days earlier, the companies said that the U.S. Department of Health and Human Services (HHS) and Department of Defense (DoD) ordered an initial 100 million doses of BNT162 for $1.95 billion, with the option to purchase 500 million additional doses. The companies agreed to offer BNT162 for free under an agreement signed as part of 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.

The companies did not announce the price Washington would pay for the additional 500 million doses should they be ordered—but did say the agreement is subject to Pfizer successfully manufacturing and obtaining approval or emergency use authorization for the vaccine. Pfizer and BioNTech said they expect to be ready to seek emergency use authorization or some form of regulatory approval as early as October.

Pfizer and BioNTech 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.

Two days earlier, Pfizer and BioNTech published initial data from an ongoing German Phase I/II, open-label, non-randomized, non-placebo-controlled, dose-escalation trial of then-lead candidate BNT162b1, (EU Clinical Trials Registry EudraCT number 2020-001038-36). The preliminary data—from a preprint study published in medRxiv—showed BNT162b1 to have elicited high, dose level-dependent SARS-CoV-2-neutralizing titers and receptor binding domain (RBD)-binding immunoglobulin G (IgG) concentrations after the second dose.

At Day 43, SARS-CoV-2 neutralizing geometric mean titers were in the range of 0.7-fold (1 µg) to 3.2-fold (50 µg) compared to that of a panel of SARS-CoV-2 infection convalescent human sera. Furthermore, sera of vaccinated subjects displayed broadly neutralizing activity in pseudovirus neutralization assays across a panel of 16 SARS-CoV-2 RBD variants represented in publicly available SARS-CoV-2 sequences and against the newly dominant D614G strain. The initial German trial results also showed for the first time a concurrent induction of high level CD4+ and CD8+ T cell responses against the SARS-CoV-2 RBD for BNT162b1—thus indicating a strong potential for cell mediated anti-viral activity, according to BioNTech and Pfizer.

“The preliminary data indicate that our mRNA-based vaccine was able to stimulate antibody as well as T-cell responses at remarkably low dose levels. We believe both may play an important role in achieving effective clearance of a pathogen such as SARS-CoV-2,” Özlem Türeci, MD, CMO and Co-founder of BioNTech, said in a statement.

BioNTech and Pfizer also announced July 20 that they committed to supply the U.K. with 30 million doses of their BNT162, to be delivered this year and next. Financial terms were not disclosed. The companies plan to seek regulatory review as early as October 2020, manufacture globally up to 100 million doses by the end of 2020, and more than 1.3 billion doses by the end of 2021.

On July 14, Fosun Pharma said its subsidiary Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd. received acceptance of its clinical trial application for BNT162b1 by China’s National Medical Products Administration. A day earlier, Pfizer and BioNTech received the FDA’s Fast Track designation for BNT162b1 and BNT162b2, which are the two most advanced vaccine candidates in the BNT162 program. Both are under study in ongoing Phase I/II clinical trials in the U.S. and Germany. The designation was granted based on preliminary data from those studies, as well as animal immunogenicity studies.

Bourla told Time magazine on July 7 that he expects FDA approval for a vaccine from the BNT162 program this fall: “We should be able in the September time frame to have enough data to say if the vaccine works or not. And to submit that to the FDA. So for a potential approval in October, if we are lucky. It’s feasible.”

Pfizer and BioNTech said July 1 the most advanced of four constructs of their messenger RNA (mRNA) vaccine candidate for COVID-19 showed encouraging immunogenicity and a favorable safety profile in preliminary Phase I/II data published in a preprint study.

“These clinical findings for the BNT162b1 RNA-based vaccine candidate are encouraging and strongly support accelerated clinical development and at-risk manufacturing to maximize the opportunity for the rapid production of a SARS-CoV-2 vaccine to prevent COVID-19 disease,” researchers concluded in the preprint study, published in medrRxiv.

Bourla told Time: “For me, it was the moment when I saw the data, plus many other data that we haven’t published yet, [that] made me say that until now I was thinking if we have a vaccine. Now I’m discussing when we’re going to have a vaccine.

BioNTech and Pfizer are evaluating four vaccine constructs of BNT162 in an mRNA-based clinical program the companies have dubbed “Project Lightspeed.”

Data in the preprint came from the ongoing U.S. Phase I/II trial (NCT04368728; EU Clinical Trials Registry EudraCT number 2020-001038-36), a randomized, placebo-controlled, observer-blinded study designed to assess the safety, tolerability, and immunogenicity of escalating dose levels of BNT162b1.

BioNTech said June 29 it launched a $250 million private placement by new investor by Temasek and other unnamed “accredited investors.” The private placement includes an investment of approximately $139 million in ordinary shares and a $112 million investment in four-year mandatory convertible notes.

Upon closing, private placement investors will receive 2,595,996 ordinary shares in BioNTech, subject to a 180-day lock-up agreement. The four-year mandatory convertible notes will come with a coupon of 4.5% per annum and a conversion premium of 20% above the reference price. The investment is expected to close in early- to mid-August, subject to customary closing conditions, BioNTech said.

On June 3, The New York Times reported that Pfizer was among developers of five COVID-19 vaccines identified by President Donald Trump’s administration as most likely to produce a vaccine for the virus, citing unnamed “government officials.” According to the report, the five will receive additional government funding, assistance with clinical trials, and financial and logistical support for manufacturing. A formal announcement is expected in coming weeks.

Bourla predicted May 29 that “if things go well, and the stars are aligned, we will have enough evidence of safety and efficacy so that we can… have a vaccine around the end of October,” during a virtual briefing organized by International Federation of Pharmaceutical Manufacturers and Associations (IFPMA).

Pfizer and BioNTech said they planned to scale up production for global supply, through a manufacturing program designed to allow production of millions of vaccine doses in 2020, increasing to hundreds of millions in 2021. At its own risk, Pfizer said, it will produce COVID-19 vaccines in Puurs, Belgium and sites it owns three U.S. states—with “critical” raw material manufacturing to take place in St. Louis; drug substance manufacturing in Andover; and formulation and fill in Kalamazoo, MI. BioNTech added that plans to provide further capacity for a global supply of the potential vaccine through its existing mRNA production sites in Mainz and Idar-Oberstein, Germany.

In April, CEO Bourla told analysts on the company’s quarterly conference call that his company planned to manufacture “millions of doses” of BNT162 at its own risk by the end of 2020 “to accelerate availability in the event the development program is successful and we obtain regulatory approval” for emergency use authorization. Pfizer plans to rapidly scale up its production capacity “to produce potentially hundreds of millions of doses in 2021,” he said.

BioNTech CEO Ugur Sahin told the German newspaper Welt am Sonntag April 25 that his company had ruled out being acquired after being approached by several potential acquirers he did not name: “Takeovers are out of the question for the majority shareholders and for us anyway. Our vision is to build a biopharmaceutical company that addresses the medical needs of the 21st century.”

Three days earlier, BioNTech and Pfizer said the German regulatory body Paul-Ehrlich-Institut approved the companies’ Phase I/II clinical trial for BNT162—the first clinical trial of a COVID-19 vaccine candidate to start in Germany. The companies said earlier that month they intended to launch their first clinical trials for an mRNA COVID-19 vaccine initially in the U.S. and Europe across multiple sites, with plans to advance multiple candidates.

“Given mRNA vaccine technology is in its infancy, with most data from animal studies, we like the risk diversification of this approach,” SVB Leerink Senior Research Analyst Daina M. Graybosch, PhD, and Associate Dilip Joseph wrote in an April 22 investor note. “The fact that the field has not settled on a lead mRNA technology also reminds us how early we are in development of mRNA vaccines.”

Pfizer agreed to pay BioNTech $185 million upfront—including $72 million in cash and a $113 million equity investment—and up to $563 million in payments tied to achieving milestones. Pfizer will initially fund 100% of the development costs, and BioNTech will repay Pfizer its 50% share of these costs during commercialization of the vaccine.

The companies announced their up-to-$748 million COVID-19 vaccine development partnership in March and in April revealed plans to launch a clinical trial, initially focusing on BNT162, the first treatment to emerge from BioNTech’s accelerated COVID-19-focused development program, “Project Lightspeed.” Three other candidates have since emerged.

The BioNTech-Pfizer partnership is worldwide except China, where BioNTech is partnering with Fosun Pharma to jointly develop BNT162. Fosun has agreed to make a $50 million equity investment, and pay BioNTech up to $85 million in additional upfront and milestone payments. The companies will share future gross profits from the sale of the vaccine in China.


COVID-19: 200 Candidates and Counting

To navigate through the >200 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:

FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.

DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data

KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.

TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.

GEN has also tagged the most common treatment types:

● ANTIVIRAL
● VAX
● ANTIBODY
● RNA

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