Partnering to Respond to a Possible Nuclear Threat

Originally posted on May 25, 2022 on PharmaceuticalExecutive.com.

Steve Scalia, Bob Mulroy, John L. McManus

Recent explosion at Zaporizhzhia nuclear power plant in Ukraine shows how pharma industry can pull together and take action in the face of adversity.

In early March, an explosion at Ukraine’s Zaporizhzhia nuclear power plant after intense Russian shelling had the world on edge, including executives from Partner Therapeutics (PTx), a Massachusetts-based commercial biotech company. But unlike many observers, these leaders realized there was more they could do than watch from afar.

PTx manufactures Leukine (sargramostim), and the company knew it could potentially play a life-saving role should the unthinkable happen, a nuclear attack or radiation leak at the hands of Russia. Leukine, developed originally to support cancer patients’ immune systems, is an FDA-approved immune system modulator for the treatment of the hematopoietic effects of acute radiation syndrome (ARS). Prior to its FDA approval, it was provided by Immunex, an earlier manufacturer of Leukine, to treat victims of the 1986 Chernobyl nuclear power plant accident.¹

After the Zaporizhzhia event, the PTx team decided to take action. They turned to their partner, Tanner Pharma Group, knowing the North Carolina–based international distributor of essential medicines could handle the complicated logistics of getting Leukine to a European warehouse quickly, where it could be deployed on short notice—an absolute necessity for this type of treatment. Since 2018, Tanner has handled all international requests for the drug and maintains an inventory under a program called Leukine Access Program (LeAP). Leveraging its global storage and distribution network, Tanner was able to transport a sizable quantity of the drug to a secure location in Europe in a matter of days.

Why Leukine?

Leukine is administered by injection and was approved by FDA in 1991 for acceleration of white blood cell recovery following autologous bone marrow transplantation in patients with non-Hodgkin’s lymphoma, acute lymphocytic leukemia, or Hodgkin’s disease. Subsequently, it received four more FDA approvals related to cancer, and in 2018, FDA signed off on Leukine as a treatment for ARS. It has been held for use by the US government as an ARS medical countermeasure since 2013.

High doses of radiation acutely damage the body’s immune system, including monocytes, macrophages, platelets, neutrophils, dendritic cells, and red blood cells. Leukine stimulates each of these cell types and accelerates recovery from pancytopenia, a deficiency of the cellular components of blood. Its broad impact enables increased survival from ARS without the need for blood transfusions—a critical advantage given the expectation that after a radiological or nuclear event, blood products would be limited or unavailable. It is also the only ARS countermeasure that has been shown to be effective when administered more than 24 hours after exposure, and studies have shown efficacy when given up to 96 hours after exposure.^2,3 In the aftermath of a radiological or nuclear event, a 48- to 96-hour treatment window is critical.^4,5 Leukine is also stable at room temperature for 12 months, eliminating the need for a refrigerated supply chain—a challenging requirement during a radiological crisis.

Yet despite the unique efficacy of Leukine for the treatment for ARS, it has not been approved for use for this indication in Europe; in fact, no medical countermeasure has been. Tanner is currently exploring ways to secure the needed regulatory sign-offs. An important part of Tanner and PTx’s strategy has been educating ministries of health in countries near Ukraine, specialized health agencies, and other organizations about Leukine and related topics.

The importance of education

Pharmaceutical and biotech companies, as well as distributors, spend significant time and effort on drug education, especially for medications that are being used outside of their core markets or that lack authorization by local regulators. Because the effects of radiation are not well understood in some parts of the world, this information as well as the mechanism of drug action and how Leukine compares to other ARS treatments have been the top talking points for Tanner and PTx. What has made education particularly challenging has been the undue media attention in Europe on potassium iodide (KI) and other inferior approaches as viable treatments for acute radiation sickness. KI helps prevent the thyroid from absorbing radioactive iodine after an exposure, but it does not protect the rest of the body. It also cannot reverse thyroid damage that has already occurred.

In addition to dispelling misperceptions about KI and other treatments, executives from Tanner and PTx also have been engaging in conversations about the importance of preparedness. One concern of stockpiling a drug that may or may not be used imminently is the fear of large quantities expiring, particularly in countries where healthcare infrastructure may be lacking. Tanner has been responding to these concerns of European governments and their representatives by educating them about vendor managed inventory. This approach is a way for the purchaser of a drug, in this case a government, to delegate management of inventory to a third party that distributes and replenishes stock based on customer demand, thus reducing or eliminating the risk of unused stock expiring.

Even in the best of times, medical preparedness is often not a high priority for governments dealing with immediate health crises. And insufficient health infrastructure can exacerbate the lack of long-term planning. Understandably, the conversations have taken place in fits and starts, as Ukraine’s neighbors have been preoccupied with the war on their doorsteps as well as the global pandemic.

Securing a regulatory-compliant pathway

While education has played a key role in helping to accelerate the pathway to authorization of Leukine in Europe, the drug has several things in its favor. First of all, in addition to being FDA-approved for the treatment of Hematopoietic Sub-Syndrome of Acute Radiation Syndrome (H-ARS), it also has been recommended by the International Atomic Energy Agency as well as the World Health Organization as a treatment for ARS. Additionally, Leukine is not completely unknown in Europe: Early in the COVID-19 pandemic, Tanner helped provide access to Leukine for a clinical trial in Belgium studying its ability to improve lung function in COVID patients.

Along the way to potential regulatory approval are a couple of promising guideposts. First, Tanner has extensive experience with named patient programs (NPPs), by which an FDA-approved medication can be made available to individual patients and physicians outside of the US if the drug is not approved and/or available in that country. These pathways could be utilized to obtain authorization for Leukine in certain cases and locations.

At the same time, the pandemic has brought attention to and showed the value of emergency use authorizations, the mechanism by which FDA expedites the availability of medical products such as tests, medicines, and vaccines during a public health emergency. The EU has an equivalent tool: a conditional marketing authorization issued by FDA’s European counterpart, the European Medicines Agency. Tanner and PTx believe that may be a promising avenue to secure authorization.

An obligation to act

Governments, even in the best of times, can be slow-moving and laser-focused on the present. Introduce war and a global pandemic, and the ability to respond to unprecedented threats to public health becomes even tougher. Tanner and PTx believe that at times, private industry can play an important role in addressing needs that governments are unable or unwilling to take on. In this case, the stakes couldn’t be higher: an existential threat that may affect the health of untold numbers of people. It’s also important for drug makers and distributors to look beyond their own backyards and think about ways to make their drugs available in corners of the world that struggle with access.

Our advice to others? Persist even in the face of obstacles; leverage pre-existing partnerships; take on responsibilities based on each partner’s expertise; and let your moral compass be your inspiration and guide. The Leukine story is far from over, but both companies believe the medication will ultimately be authorized for use in Europe and ready for patient use, should the unthinkable occur.

Steve Scalia is president of Tanner Pharm Group; Bob Mulroy is director and chief executive officer of Partner Therapeutics; and John L. McManus is chief business officer of Partner Therapeutics.

References

1. Dainiak N, Medical management of acute radiation syndrome and associated infections in a high-casualty incident, Journal of Radiation Research, Vol. 59, No. S2, 2018, p. ii54-ii64. Doi:10.1093/jrr/rry004
2. Clayton N, et al. (2021): Sargramostim (rhu GM-CSF) Improves Survival of Non-Human Primates with Severe Bone Marrow Suppression after Acute, High-Dose, Whole-Body Irradiation, Radiation Research 195:191-199. https://doi.org/10.1667/RADE-20-00131.1
3. Zhong Y, et al. (2020): Efficacy of delayed administration of sargramostim up to 120 hours post exposure in a non-human primate total body irradiation model, Int. J. Radiat. Biol.; https://doi.org/10.1080/09553002.2019.1673499
4. Yeddanapudi N, et. al., (2018): Informing CONOPS and medical countermeasure deployment strategies after an improvised nuclear device detonation: the importance of delayed treatment efficacy; Int. J. Radiat. Biol.
5. Pray L, et al., (2019): Exploring Medical and Public Health Preparedness for a Nuclear Incident: Proceedings of a Workshop; National Academies Press.