Modernizing Medical Countermeasures to Face Evolving Threats

By Kaléo

U.S. pharmaceutical company Kaléo strives to set the new standard for medical countermeasures with its next-generation Aerio^TM Auto-Injector Technology Platform.

Although typically considered by the public as weapons of the distant past, chemical warfare agents remain an evolving and persistent threat today. As recently as May 2024, the United States accused Russia of deploying chloropicrin – a choking agent banned for military use by international law – on the battlefields of Ukraine¹. Nerve agents like sarin and Novichok have also been used in recent years by rogue states and terrorist groups². And, most recently, the threat from weaponized synthetic opioids such as carfentanyl is raising concerns within the U.S. government and among allies across the globe³.

History of Chemical Weapons

The modern use of chemical weapons made its debut during World War I. Between 1914 and 1918, many types of toxic chemicals were deployed, such as phosgene and chlorine (choking agents), and sulfur mustard (a blister agent). Since World War I, chemical weapons have caused more than one million casualties globally^2,5.

18 years later, while testing organophosphate molecules for potential insecticide use, a German chemist named Dr. Gerhard Schrader stumbled upon the compound that would become tabun, the world’s first nerve agent². Fortunately, while mass produced during World War II, these nerve agents were never intentionally used in combat. 

Nerve agents such as tabun, sarin, and VX block an enzyme called acetylcholinesterase (AChE) in the nervous system. This causes the accumulation of a neurotransmitter called acetylcholine (ACh) between nerve cells or across synapses leading to hyper-stimulation of muscles, glands, and other nerves. Without medical intervention, victims of nerve agents experience extreme sweating, cramps, salivation, vomiting, muscle contractions, and death from asphyxiation³. 

Nerve agents were widely used during the Iran-Iraq War in the 1980s and as recently as 2013 in Syria, resulting in the deaths of 200 to 1,800 people. The countermeasure against nerve agents is typically a combination of drugs used in concert which may include atropine, an oxime to reactivate the acetylcholine enzyme; and an anti-convulsant, such as diazepam or midazolam³. Auto-injectors with these medical countermeasures (MCMs) and in various combinations have been deployed by the U.S. military since as early as the 1960s.

Pharmaceutical-based agents (PBAs) are another chemical weapon category that poses a significant threat in the modern era. Unlike nerve agents that are extremely complicated to manufacture, PBAs are based on readily available pharmaceutical ingredients⁵. The PBA threat with the highest profile are synthetic opioids, molecules synthesized in a laboratory that act on the same targets in the brain as naturally occurring opioids. According to the Organisation for the Prohibition of Chemical Weapons, fentanyl homologues are powerful synthetic opiate analgesics similar to but more potent than morphine⁶.

For example, carfentanyl, a synthetic opioid made in a lab, is 10,000 times more potent than morphine and can be absorbed into the body through inhalation, ingestion, or oral exposure. The most well-documented use of ultra-potent synthetic opioids as a chemical weapon occurred in 2002 when Russian special forces are believed to have used aerosolized synthetic opioids against terrorists during a hostage rescue in Moscow that resulted in the deaths of 127 terrorists and hostages⁴. In 2018, leading law enforcement and homeland security agencies in the United States issued warnings that synthetic opioids remain “very likely a viable option for a chemical weapon attack in the United States” ⁷.

Modernizing Medical Countermeasures

Former U.S. Assistant Secretary of Defense for Nuclear, Chemical, and Biological Defense Programs Hon. Andy Weber said: “The threat of chemical weapons use against U.S. and allied military forces is increasing. In May my government sanctioned Russia’s NBC Defense Forces for facilitating the use of chemical weapons against Ukraine. North Korea is also known to stockpile nerve agents. In response, the Department of Defense has invested in advanced auto-injectors for the instant delivery of lifesaving medical countermeasures for soldiers serving in the EUCOM, CENTCOM, and INDO-PACOM areas of responsibility.”

In 2022, the U.S. Department of Defense’s Chemical and Biological Defense Program (CBDP) stated that investment in CBRN capabilities have been largely driven by the threat environment posed during the Cold War era⁷. However, the rapid evolution of technology and the expanding array of potential adversaries are driving a new reality that the nature of war is changing and evolving at an unprecedented rate. To face this new threat landscape, the U.S. government is taking steps to modernize MCM capabilities designed to protect military personnel, civilians, and other emergency responders⁸.

Central to this effort is the need to develop the next-generation auto-injector technology to deliver the latest, most advanced MCMs to protect the 21st-century warfighter. The new benchmark for future auto-injectors includes the highest standards for device reliability, durability, and ease of use on a foreign battlefield or at the scene of a national emergency at home.

“Modernizing medical countermeasures is critical,” said Major General Elder Granger, M.D., U.S. Army (Ret), former commander of Task Force 44th Medical Command and command surgeon for the Multinational Corps Iraq. “It is encouraging to see the government update their requirements for emergency use auto-injector designs to meet higher standards.”

Kaléo’s Aerio™ Auto-Injector Technology Platform

In 2018, the U.S. Department of Defense announced plans to develop a new MCM against synthetic opioids. The new auto-injector platform had to be compact and extremely durable to stand up to the rigors of large-scale combat operations where troops may be isolated and further away from definitive medical care than in past conflicts. Additionally, the auto-injector had to be intuitive to use and meet the latest quality requirements of the U.S. Food and Drug Administration (FDA) requiring 99.999% device reliability.

Out of a field of six candidate designs, Kaléo, a privately held pharmaceutical company based in Richmond, Virginia, was selected to develop the new medical countermeasure against the operational exposure of pharmaceutical-based agents, such as ultra-potent weaponized opioids, based on the company’s commercially proven Aerio™ Auto-Injector Platform. The patented Aerio platform is designed to deliver wet/dry drug formulations, large volumes, high viscosity fluids, and the simultaneous delivery of multiple drugs while the non-coaxial design maximizes space and enables a more compact auto-injector. 

Using rigorous human factors engineering processes in device development, Kaléo ensures that the needs of end-users are prioritized at every stage of design. This user-centered approach helps to ensure that the auto-injector is intuitive and user-friendly, even in critical situations. Kaléo’s Aerio auto-injectors are compact, intuitive to use, and the streamlined design allows for precise delivery of medications to ensure accurate dosage administration even in the most austere environments. This combination of engineering and design represents a pivotal advancement in auto-injectors.

The Naloxone Auto-Injector 10 mg, referred to as the Rapid Opioid Countermeasure System, or ROCS, was designed in partnership with the U.S. Department of Defense (DoD) in 2019. The product was developed for the Joint Project Manager for Chemical, Biological, Radiological, and Nuclear Medical (JPM CBRN Medical), a component of the DoD’s Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) in collaboration with the Chemical and Biological Defense Program (CBDP). The JPM CBRN Medical facilitates the advanced development and acquisition of medical countermeasures and systems to enhance the nation’s CBRN response capability.

“This was our first MCM program with the U.S. Department of Defense, and a pivotal moment in the history of our company,” said Ron Gunn, Kaléo’s Chief Operating Officer. “We successfully delivered a quality product under budget, and five months ahead of schedule.”

Designed to protect, the Rapid Opioid Countermeasure System is designed for military personnel and chemical incident responders that may come into contact with ultra-potent opioids such as fentanyl analogues. Approved by the U.S. Food and Drug Administration in February 2022, ROCS is currently fielded by the U.S. military and various allied countries across the globe.

Kaléo to Develop Innovative Rapid Reconstitution Technology

In July 2023, Kaléo was awarded a second development contract by the U.S. DoD. JPM CBRN Medical selected Kaléo to develop the Reconstitution Auto-Injector Device – Atropine (RAD-A). Atropine sulfate injection is used for the treatment of poisoning by susceptible organophosphorus nerve agents having cholinesterase activity as well as organophosphorus or carbamate insecticides. The RAD-A will be the first of a new generation of medical countermeasures utilizing an innovative rapid reconstitution technology.

“RAD-A is our second significant addition to a layered defense against CBRN threats for the warfighter,” said Mark A. Herzog, Kaléo’s Vice President, Global Corporate Affairs, Defense and Homeland Security. “An auto-injector capable of automatically reconstituting a range of military countermeasures has the potential to positively impact the lifespan of military and civilian stockpiles.”

Unlike the currently fielded atropine auto-injectors, the RAD-A will maintain the atropine in a dry format until the drug is automatically reconstituted into a liquid immediately prior to administration. This formulation is expected to significantly extend the shelf life of the drug as well as maintain its stability under extreme conditions.

Kaléo to Work with BARDA

In April 2024, the Biomedical Advanced Research and Development Authority (BARDA), part of the Administration for Strategic Preparedness and Response (ASPR) within the U.S. Department of Health and Human Services, selected Kaléo to develop the latest generation pralidoxime chloride (2-PAM) auto-injector as a countermeasure against organophosphate or nerve agent poisoning.

The contract tasks Kaléo with developing a 2-PAM auto-injector for FDA approval within three years, with an ultimate goal of enabling later procurement of the 2-PAM auto-injectors for the CHEMPACK program. The CHEMPACK program, an initiative of the ASPR, is designed to provide a comprehensive capability to communities for the effective use of medical countermeasures in the event of an attack with nerve agents on civilians.

Medical Countermeasures and the Future of CBRN Defense

“While the United States has not faced a peer-level adversary with the capability and willingness to use chemical weapons in many decades, the current geopolitical environment posed by adversary nations seen as acute threats or pacing challengers is demanding new attention to the future of CBRN defense measures,” said Herzog. “Of course, the hope is that these products are never needed. However, ensuring that these critical defensive capabilities exist, are of the highest quality and efficacy, and are actively deployed by those in harm’s way is essential to deterrence and, ultimately, survival in the case of a chemical attack by our adversaries in the 21st century.”

References: Please click here to see full reference list.

Kaléo is a fully integrated pharmaceutical company dedicated to inventing, manufacturing, and commercializing life- transforming products for certain serious and life-threatening medical conditions. Kaléo’s auto-injection technologies are protected by an extensive intellectual property portfolio of ~200 patents and patent applications as well as meeting the U.S. Food and Drug Administration (FDA) draft guidance standard for 99.999% device reliability. Kaléo is headquartered in Richmond, Virginia, in the United States.

_{Naloxone Auto-Injector Indication}

_{Naloxone Auto-Injector 10 mg is an opioid antagonist indicated for use by military personnel and chemical incident responders for:}

• _{The emergency treatment of patients 12 years of age and older where use of high potency opioids such as fentanyl analogues as a chemical weapon is suspected.}
• _{Temporary prophylaxis of respiratory and/or central nervous system depression in military personnel and chemical incident responders entering an area contaminated with high-potency opioids such as fentanyl analogues.}

_{Important Safety Information: Contraindications, Warnings, Precautions, and Adverse Events}

• _{Naloxone Auto-Injector 10 mg is contraindicated in individuals with hypersensitivity to naloxone hydrochloride or to any of the other ingredients in Naloxone Auto-Injector 10 mg.}
• _{Use in patients who are opioid dependent may cause abrupt opioid withdrawal. Use of a product that delivers a dose lower than 10 mg of naloxone HCl may be preferable in treatment of a patient with known opioid dependence.}
• _{Due to the duration of action of naloxone HCl relative to the opioid, keep the patient under continued surveillance and administer additional naloxone HCl, as necessary, while awaiting emergency medical assistance.}
• _{The following adverse reactions were observed in more than one subject in clinical studies evaluating NAI: dizziness, feeling hot, headache, and injection site erythema.}

_{To report suspected adverse reactions, contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For Full Prescribing Information visit www.naloxoneautoinjector.com}