Toxic at Best
In September, the White House released the 2018 National Biodefense Strategy, a biennial report that lays out the president’s priorities for managing the risk of biological agents. Biological threats - whether naturally occurring, accidental or deliberate - are among the most serious risks facing the US and the international community. Multiple nations have pursued biological weapons programmes and a number of terrorist groups have sought to acquire biological warfare agents.
One of the National Biodefense Strategy’s goals is to ensure the federal government is prepared to reduce the impacts of bio incidents. The strategy calls for prioritising the development of platform and innovative technologies that accelerate the development, production, and availability of medical countermeasures against biological threats.
The Department of Defense’s (DoD) chemical biological defence programme is responding to this call to action through the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense’s (JPEO-CBRND) Joint Project Management Office for Medical Countermeasure Systems (JPM-MCS), along with the Defense Threat Reduction Agency’s Joint Science and Technology office (DTRA-JSTO). The initial research and early stage development of medical countermeasures against CBRN threats is provided by DTRA-JSTO, ultimately transferring products to JPM-MCS, which facilitates the advanced development and fielding of the medical countermeasures.
Medical countermeasures include vaccines, treatments and diagnostic equipment that are critical to a multilayered defence strategy to protect warfighters from CBRN threats. The medical solutions JPM-MCS and DTRAJSTO develop prevent disease, accurately diagnose exposure to biological agents, and provide post exposure treatments that save the lives of US and allied service members.
Platform technologies accelerate medical countermeasure development
While known threats remain a priority, the threat environment is constantly changing. Operational necessity may exposbe the warfighter to deadly emerging or engineered agents, and current medical countermeasures may not be available to respond to these novel agents in a relevant timeframe. The JPEO-CBRND, JPMMCS and DTRA-JSTO are seeking to leverage platform technologies to accelerate fielding of medical countermeasures to the warfighter, in line with the administration’s National Biodefense Strategy.
As defined by the president’s council in 2016, a platform system can counter a variety of threat agents using standardised discovery, design, manufacturing and testing technologies that may accelerate medical countermeasure development. A platform provides a base structure for different antiviral, antibacterial and antitoxin medical countermeasure products. The system reduces developmental risk and cost while accelerating medical countermeasure development and fielding to troops. Established platforms are also a rapid response capability to accelerate the manufacturing and development of medical countermeasures in the event of a national security emergency to respond to novel threats in a relevant timeframe. Rapid response platforms leverage well understood and characterised technologies to deliver safe and effective medical countermeasures to the warfighter in an emergency.
The first platform - proof of concept The key aspect that enables platforms to be used for rapid response is the use of standardised discovery, design, manufacturing and testing technologies. JPEO-CBRND, JPM-MCS and DTRAJSTO are building that standardisation through an establishment and validation process. In the establishment phase, the first platform candidate is run through the process to create standardised procedures and assays. A second candidate is then run through the standardised process to validate that system as a platform. The development of any subsequent medical candidate is thereby greatly accelerated by utilising a proven process. This standardisation and repeated use of the platform builds familiarly and confidence with the US Food and Drug Administration (FDA), which reviews regulatory submissions.
This concept is being put to the test by the JPEO-CBRND, JPM-MCS and DTRA-JSTO through investment in the advanced development and manufacturing of antibody technologies, or Adamant, platform to develop medical countermeasures against botulinum toxin. Adamant is based on monoclonal antibodies, which are manufactured human antibodies engineered to bind and neutralise a specific target. Instead of antibodies being made over time in the body either by vaccination or following exposure to an infectious agent, these manufactured antibodies can be administered to serve as a pre-exposure prophylactic or post exposure treatment.
The potential of monoclonal antibodies to rapidly provide pre-baseexposure protection and post exposure therapy makes them a valuable medical countermeasure technology to explore. Monoclonal antibodies do not replace the long term protection provided by vaccinations; however, they do offer a unique alternative in situations where service members require rapid onset of protection or treatment. In a crisis response, monoclonal antibodies offer the unique ability to rapidly protect troops who have not previously been vaccinated.
“Selecting monoclonal antibodies as our first platform technology was an easy choice. We are taking advantage of the significant work already done by industry to mature this technology while adapting the products to the unique needs of the warfighter,” said Ms Rebecca Kurnat of JPM-MCS. “Monoclonal antibodies are well known to the FDA, with over 80 FDA approved monoclonal antibody drugs available on the market. This provides us with a straightforward regulatory pathway toward FDA approval, and allows us to quickly develop medical countermeasures with monoclonal-based platforms.”
The Adamant platform is currently being established at the DoD’s advanced development and manufacturing, or DOD ADM, facility in Florida, its dedicated manufacturing facility for medical countermeasures. The botulinum toxin monoclonal antibody product being developed fully utilises the Adamant platform and manufacturing processes established at the facility.
The threat of Botulinum toxin
There is a considerable need to develop medical countermeasures against botulinum toxin. It is the world’s most toxic poison and poses a major bioweapon threat due to its extreme potency and lethality. A single gram of the toxin disseminated via aerosol or through contaminated food and water supplies could kill more than one million people. There are eight types of botulinum toxins, but types A and B are the most likely to be engineered into biological weapons. The toxin affects the nervous system, leading to paralysis, respiratory failure and death in a matter of hours.
Botulinum toxin gained public attention after a vial of the bacteria that produce the toxin was found by investigators in Iraq after Saddam Hussein was ousted. At the end of the 1991 Gulf War, Iraq claimed it had produced 19,000litres (5,020gallons) of the toxin, enough to kill the entire global population, which was confirmed by an independent UN commission. The Japanese cult Aum Shinrikyo attempted to disperse botulinum toxin on at least three occasions between 1990 and 1995 at multiple sites in downtown Tokyo, as well as at US military installations in Japan.
Development of a Botulinum toxin medical countermeasure
The medical countermeasure being developed at the DOD ADM facility will provide prophylaxis, or preventative treatment, and therapy for warfighters exposed to aerosolised botulinum neurotoxin types A and B. The drug product is being designed with improved logistics for the warfighter: intramuscular administration rather than traditional intravenous administration to allow for use in and out of theatre, as well as a lyophilised, or freeze-dried, drug product in order to extend shelf life and maintain stability.
Since its development started, the botulinum toxin medical countermeasure has passed a number of developmental milestones and remains on schedule to file an investigational new drug application in 2019 and begin phase one clinical trials in 2020. Several proof of concept and nonclinical efficacy studies have demonstrated 100% protection against high doses of aerosolised botulinum toxin when the medical countermeasure is delivered intramuscularly.
The botulinum toxin medical countermeasure is being used as the establishment product for the Adamant-based manufacturing process at the DOD ADM facility. The standardised manufacturing process is being set up at the 500litre (132gallon) bioreactor scale. Maintaining this production scale throughout the development stages eliminates the need for costly and lengthy scale up efforts and reduces significant risks. Each drug product manufacturing batch is expected to provide monoclonal antibodies sufficient to support 8,000 to 16,000 doses. This product is expected to receive FDA approval in 2025, which is already much faster than traditional medical product development. After a second medical product is run through the platform validation process, development time is expected to be even shorter.
While threats remain, service members can rest assured that the JPEO-CBRND, JPM-MCS and DTRAJSTO are actively working to protect them from biological warfare agents like botulinum toxin and accelerating development schedules to deliver products into the warfighters’ hands faster. By using the established procedures within the Adamant platform technology, novel threats can be addressed as they arise to deliver medical countermeasures to the warfighter in an operationally relevant timeframe.