CBRN Antivirals & Antitoxins MEDICAL COUNTERMEASURES Program

Although 2020 was a year defined by SARS-CoV-2, the Antivirals and Antitoxins program remained focused on the advancement of all products within its portfolio while simultaneously making significant contributions to the COVID-19 response.  A case in point is the approval of the first therapeutics for the treatment of patients with Ebolavirus Disease (EVD) caused by Zaire ebolavirus.

During the 2014-2016 Ebola outbreak in West Africa, BARDA supported Regeneron Pharmaceutical’s development of a cocktail of monoclonal antibodies targeting the Zaire ebolavirus glycoprotein.  The program leveraged Regeneron’s VelocImmune® platform and quickly advanced to Project BioShield in 2017.  In late 2018, BARDA and Regeneron collaborated closely with USG and international partners to ensure that the Regeneron product would be evaluated in the Pamoja Tulinde Maisha (PALM) randomized controlled trial in The Democratic Republic of The Congo (DRC).  Ultimately, the Regeneron product, Inmazeb™, met the pre-defined early stopping criteria within the PALM trial due to its superior efficacy relative to the control arm.  Based on this human efficacy data and an abundance of prior nonclinical and manufacturing data collected under the BARDA-supported program, Inmazeb became the first therapeutic approved by the FDA for treatment of EVD in October 2020.  The partnership forged by the Antivirals and Antitoxins programand Regeneron also paved the way for the development of Regeneron’s COVID-19 therapeutic (casirivimab/imdevimab) that was granted Emergency Use Authorization in November 2020.

In parallel with BARDA’s development of Inmazeb™, two of BARDA’s medical countermeasure transition partners (NIAID and DARPA) developed mAb114, a single monoclonal antibody candidate for treatment of EVD.  Analysis of the final data set from the PALM trial showed that mAb114 also demonstrated superior efficacy in humans relative to the control arm and that it performed equally well as Inmazeb™.  The product was licensed to Ridgeback Biotherapeutics in December 2018 and BARDA subsequently partnered with Ridgeback in 2019 to support continued advanced development, including submission of a Biologics License Application.  This collaboration proved highly successful when, in December 2020, mAb114 – now known as Ebanga™ – was approved by the FDA for the treatment of EVD.

Since clinical efficacy was demonstrated for Inmazeb™ and Ebanga™, the Antivirals and Antitoxins program has worked with Regeneron and Ridgeback; USG partners; international entities such as the World Health Organization and Médecins Sans Frontières (Doctors Without Borders); and the governments of DRC, Guinea and surrounding countries to ensure that these life-saving products can be made available as part of the overall USG response to mitigate the effects of this devastating disease.

Although smallpox was eliminated as an endemic disease by 1980, the potential re-emergence of smallpox from natural sources, clandestine stocks, or other sources means that smallpox is still a considerable threat to the safety of our nation. The Antivirals and Antitoxins program has supported the advanced development and licensure of two products (TPOXX,^® and TEMBEXA^®) to protect the United States against this threat.

In 2009, BARDA partnered with SIGA Technologies to support the advanced development of a smallpox antiviral, TPOXX^®, which was approved on July 13^th, 2018. The approval of TPOXX^® provided the USG with a potent first step in assembling the therapeutic armamentarium against smallpox. Consistent with an Institute of Medicine panel of experts assessment of the development of smallpox antivirals, BARDA pursued development of additional therapeutics with distinct mechanisms of action to obviate the potential for the evolution of viral resistance through selective pressure against TPOXX^®. 

As such, in 2011, BARDA embarked on a partnership with Chimerix, Inc. to support the advanced development of a second smallpox antiviral, TEMBEXA^®, which was approved on June 4^th, 2021. TEMBEXA^® is an antiviral drug with a distinct mechanism of action from TPOXX^®, which inhibits activity of a critical viral enzyme, preventing the ability of the virus to replicate and cause disease.

The success of this program demonstrates an integrated government and industry effort to drive medical countermeasures from bench to bedside. The approval of TEMBEXA^® has enhanced the USG capabilities to respond to a smallpox emergency, mitigated the risk of evolving resistance to TPOXX^®, and provided healthcare professionals with multiple options for therapeutic intervention. From the initial development of the antiviral drug to its ultimate 2021 FDA approval as a second smallpox therapeutic, we are honored to be a part of this endeavor which helps enhance the nation’s preparedness.

Additional Resources:

1. BARDA announcement
2. FDA announcement

On February 7^th 2021, the DRC Ministry of Health announced a confirmed case of Ebola virus disease (EVD) in the North Kivu Province of the Democratic Republic of Congo (DRC). Sequencing results from samples sent to Institut National de Recherche Biomédicale (INRB) in Kinshasa confirmed these new cases were caused by Zaire ebolavirus and were linked to some form of viral persistence within a survivor of the 2018-2020 EVD outbreak in North Kivu, which was the largest outbreak in DRC’s history.

Less than a week later, samples sent to the national laboratory in Conakry were also confirmed positive for EVD, and on February 14^th the Guinea Ministry of Health officially declared an outbreak of EVD in the N'Zérékoré Prefecture. Institut Pasteur de Dakar (IP Dakar) and Centre de Recherche et de Formation en Infectiologie de Guineé (CERFIG) in Conakry completed viral sequencing from four clinical samples, confirming the outbreak was caused by Zaire ebolavirus. In addition, given the limited number of mutations accumulated relative to viruses from the 2014 to 2016 West Africa outbreak, they concluded that the initiation of this 2021 outbreak was most likely a result of viral persistence (sexual transmission or recrudescence) in a survivor of the West Africa outbreak. In a paradigm shift for filovirus research, this finding would push the longest known period of viral persistence from 500 days to 5-7 years. However, the lack of data about the rate of mutation of the virus in its animal host means there is still the possibility this outbreak was caused by a new introduction from an animal reservoir.

BARDA and its interagency partners quickly jumped into the response for these new outbreaks. By the end of April, 1,989 individuals, including 542 front-line workers, in DRC were vaccinated with the Ebola vaccine Ervebo^TM (rVSV-ZEBOV), and eight confirmed cases received monoclonal antibody therapeutics Inmazeb^TM or Ebanga^TM (6/8 recovered). In Guinea, 10,833 individuals were vaccinated (including 2,876 front line workers) by the end of May and eight patients received Inmazeb^TM (8/8 recovered). The critical role that BARDA supported products played in the 2021 DRC and Guinea outbreaks is clear. Ring vaccination efforts limited transmission and the case fatality rates among patients receiving the FDA approved Ebola therapeutics Inmazeb^TM or Ebanga^TM were reduced to 25% in the DRC and 0% in Guinea.

On May 3^rd, the Ministry of Health of the DRC declared the end of human-to-human transmission of EVD over in North Kivu Province as more than 42 days (two maximum incubation periods) had elapsed since the date of the second consecutive negative test of the last confirmed case. In this outbreak, there was a total of 12 cases (11 confirmed, 1 probable), and six deaths (case-fatality proportion = 50.0%). Shortly thereafter on June 19th, the Guinea Ministry of Health and WHO announced the Guinea outbreak was over as well. There was a total of 23 cases (16 confirmed, 7 probable), and 12 deaths (case-fatality proportion = 52.2%).

BARDA/CBRN’s objective for the development of Ebola medical countermeasures is to

i) develop vaccines to reduce transmission of this deadly virus and protect healthcare workers, contacts and the communities at large, and

ii) develop drugs to provide healthcare workers with a strong therapeutic intervention to complement the supportive care available in Ebola treatment units and increase the patients’ chance for survival.

The 2014-2016 West Africa outbreak and the 2018-2020 Eastern DRC outbreaks combined to infect over 30,000 people, over 13,000 of whom ultimately succumbed to the disease.  In contrast, the 2021 responses have had the benefit of a strong medical countermeasure arsenal to complement the evolving and improving infection prevention and control measures implemented by our USG and global partners. We are cautiously optimistic that the rapid containment of the 2021 outbreaks in the DRC and Guinea is indicative of coming successes as we move swiftly to stop future outbreaks.

References:
1. Release - 4 EBOV genomes from Guinea 2021 outbreak
2. Resurgence of Ebola Virus Disease in Guinea Linked to a Survivor With Virus Persistence in Seminal Fluid for More Than 500 Days