Johnson & Johnson said today its Janssen Pharmaceutical Cos. has advanced its COVID-19 vaccine candidate JNJ-78436735 into a Phase III trial designed to assess the safety and effectiveness of the single-dose vaccine compared with placebo in up to 60,000 volunteers across three continents.

JNJ-78436735—also called Ad26.COV2.S—is under study in the Phase III ENSEMBLE trial (NCT04505722), which will enroll volunteers at up to nearly 215 clinical research sites in the U.S. and worldwide.

Janssen is funding the trial along with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA).

BARDA has committed up to nearly $1.5 billion toward supporting JNJ-78436735, from development through licensure—an award of more than $456.2 million in February, followed August 5 by approximately $1 billion to support a manufacturing demonstration project including the ability to deliver vaccine doses to government-designated locations nationwide.

ENSEMBLE is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of a single vaccine dose versus placebo in up to 60,000 adults ages 18 years old and older, including what J&J said would be “significant” representation from participants over age 60. The trial will include participants both with and without comorbidities associated with an increased risk for progression to severe COVID-19.

J&J aims to enroll participants in the U.S. as well as in Argentina, Brazil, Chile, Colombia, Mexico, Peru, and South Africa—countries and clinical trial sites which according to the company have a high incidence of COVID-19 and the ability to achieve rapid initiation.

J&J has also committed to including a “significant” representation of populations that have been disproportionately impacted by the pandemic—which in the U.S. will include Black, Hispanic/Latinx, American Indian, and Alaskan Native participants.

ENSEMBLE’s primary outcome measure is the number of participants with first occurrence of molecularly confirmed moderate to severe/critical COVID-19 with seronegative status up to 2.1 years following injection.

The trial also has three secondary outcome measures:

  • Number of participants with first occurrence of molecularly confirmed moderate to severe/critical COVID-19 regardless of serostatus.
  • Number of participants with first occurrence of molecularly confirmed moderate to severe/critical COVID-19 with seronegative status.
  • Number of participants with first occurrence of COVID-19 requiring medical intervention.

“As COVID-19 continues to impact the daily lives of people around the world, our goal remains the same—leveraging the global reach and scientific innovation of our company to help bring an end to this pandemic,” J&J chairman and CEO Alex Gorsky said in a statement. “This pivotal milestone demonstrates our focused efforts toward a COVID-19 vaccine that are built on collaboration and deep commitment to a robust scientific process.”

J&J has posted the clinical protocol of ENSEMBLE on its website: “We are committed to clinical trial transparency and to sharing information related to our study, including details of our study protocol,” Gorsky added.

Aiming for 2021 EUA

In the same statement, Paul Stoffels, MD, vice chairman of J&J’s Executive Committee and CSO, expressed the company’s goal of delivering a vaccine for emergency use authorization (EUA) in early 2021.

That would appear to place J&J’s vaccine on a slower path to an EUA compared with three other leading COVID-19 vaccine candidates now in Phase III trials, all of which have been discussed as potentially pursuing emergency authorizations later this year: AstraZeneca/University of Oxford’s AZD1222; Moderna’s messenger RNA (mRNA) vaccine mRNA-1273; and Pfizer/BioNTech’s nucleoside modified mRNA (modRNA) vaccine BNT162b2.

“Four COVID-19 vaccine candidates are in Phase III clinical testing in the United States just over eight months after SARS-CoV-2 was identified. This is an unprecedented feat for the scientific community made possible by decades of progress in vaccine technology and a coordinated, strategic approach across government, industry and academia,” said NIAID Director Anthony S. Fauci, MD, in a separate NIH statement. “It is likely that multiple COVID-19 vaccine regimens will be required to meet the global need. The Janssen candidate has showed promise in early-stage testing and may be especially useful in controlling the pandemic if shown to be protective after a single dose.”

Janssen launched the Phase III trial after reporting positive interim data from a Phase I/IIa trial (NCT04436276) showing that the safety profile and immunogenicity after a single vaccination of JNJ-78436735 supported further development of the vaccine. That study was originally planned to start in September but was accelerated to July, with J&J citing the strength of its preclinical data and interactions with regulators.

Earlier this month, researchers from Janssen, BIDMC, and clincal partners published a study in Nature showing that Ad26.COV2.S, a single immunization of an Ad26 vector encoding a full-length prefusion stabilized S immunogen (S.PP), protected against severe clinical disease after high-dose SARS-CoV-2 challenge in Syrian golden hamsters.

“Front runner” candidate

JNJ-78436735 is a recombinant vector vaccine that uses a human adenovirus to express the SARS-CoV-2 spike protein in cells. JNJ-78436735 emerged from vaccine constructs created and tested by J&J with Beth Israel Deaconess Medical Center (BIDMC), part of Harvard Medical School, using Janssen’s AdVac® and PER.C6® vaccine technology platforms, designed for accelerated vaccine development.

AdVac is based on the development and production of adenovirus vectors (gene carriers), and can be used together with Janssen’s PER.C6 technology to develop recombinant vaccines against life-threatening infectious diseases.

J&J says AdVac offers a key advantage: The vaccine would, at launch, remain stable for two years at -20 °C and at least three months at 2–8° C. This makes the vaccine candidate compatible with standard vaccine distribution channels and would not require new infrastructure to get it to patients, the company asserts.

Ad26.COV2-S, recombinant, is among 18 “front runner” candidates among the approximately 300 COVID-19 therapeutics detailed in GEN’s updated “COVID-19 DRUG & VACCINE CANDIDATE TRACKER.”

In parallel with ENSEMBLE, J&J has also agreed in principle to collaborate with the U.K. government on a separate Phase III clinical trial in multiple countries to explore a two-dose regimen of JNJ-78436735.

J&J said today it was continuing to scale up its manufacturing capacity and remained on track to meet its goal of providing 1 billion doses of a vaccine annually. The company has committed to making its vaccine affordable on a not-for-profit basis for emergency pandemic use, adding that it anticipates the first batches of a COVID-19 vaccine to be available for emergency use authorization in early 2021, if JNJ-78436735 proves to be safe and effective.

Trial sites participating in the ENSEMBLE trial are part of the NIAID-supported COVID-19 Prevention Network (CoVPN). The CoVPN consists of existing NIAID-supported clinical research networks with infectious disease expertise and designed for rapid and thorough evaluation of vaccine candidates and monoclonal antibodies for the prevention of COVID-19.

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