WOODCLIFF LAKE, N.J.—Last month, Eagle Pharmaceuticals announced a new exclusive worldwide license agreement with the University of Pennsylvania under which they will explore the development of Ryanodex (dantrolene sodium) for the potential treatment of people living with Alzheimer’s disease. This agreement includes terms for funding additional research and provisions regarding commercialization of products developed under the license.
“Our collaboration with University of Pennsylvania builds on Eagle’s strategy to develop and commercialize therapies for critical care and disorders that have significant unmet patient needs, such as Alzheimer’s disease, the most common form of dementia,” stated Scott Tarriff, CEO of Eagle Pharmaceuticals. “Dantrolene sodium’s potential for use in treating Alzheimer’s patients represents novel thinking backed by years of proprietary Eagle research. Preclinical work around this has proven positive thus far, and builds on Eagle’s years of insight gained in multiple clinical and preclinical studies on dantrolene sodium.”
Eagle believes that the homeostatic balance of calcium inside cells is essential for the proper function of the nervous system. The company continues to look into how Ryanodex plays a role in restoring intracellular calcium regulation, and its extensive experience with the drug suggests that changes in intracellular calcium levels or calcium signaling, which involve complex cellular pathways, may be involved in neurological pathologies and may lead to neurodegeneration and neuron death.
A proof-of-concept preclinical study conducted at Penn with Eagle’s participation was presented in July at the 2019 Alzheimer's Association International Conference, and showed that intranasal dantrolene achieved a greater passage across the blood-brain barrier with higher brain concentrations compared to other routes of administration. Additionally, it showed a disease-modifying effect (improved cognition and memory) and no significant side effects in an animal model of Alzheimer’s disease.
Ryanodex is currently approved for the treatment of malignant hyperthermia, which is a life-threatening condition. Eagle’s advanced nanosuspension technology is combined with a lyophilized formulation that allows Ryanodex to be reconstituted with sterile water for injection and administered in significantly less time compared to other formulations of dantrolene sodium.
Years of research have lead to the conclusion that calcium dysregulation likely plays a role in Alzheimer’s disease as well as an understanding and focus on the drug’s role in intracellular calcium regulation. Much of this research focuses on the ryanodine receptor, which is an intracellular calcium channel. Ryanodine receptor dysfunction can lead to excessive calcium release from the endoplasmic reticulum in brain cells, which may trigger a subsequent signaling cascade that induces cell damage and/or cell death. Ryanodex's mechanism of action modulates intracellular calcium release by inhibiting ryanodine receptors in brain cells, and it appears to help restore intracellular calcium homeostasis. Eagle and University of Pennsylvania researchers independently concluded that dantrolene sodium has potential as a disease-modifier for Alzheimer’s disease.
“We are encouraged by the preliminary work we have done together and the potential of dantrolene as a first-in-class treatment option for this devastating disease,” said Dr. Huafeng Wei, an associate professor of the Department of Anesthesiology and Critical Care and principal investigator for the animal studies at University of Pennsylvania.
“Our approach—using dantrolene for Alzheimer’s disease—is unique,” Tarriff tells DDNews. “Results from this proof-of-concept preclinical study were presented at the July 2019 Alzheimer’s Association International Conference and support the next stages of our collaboration with University of Pennsylvania. We’re looking forward to continuing our work with University of Pennsylvania and sharing our results with the public as we progress.”
In addition to Alzheimer’s disease, Eagle is studying the role of intracellular calcium regulation in brain damage secondary to exertional heat stroke, nerve agent exposure, acute radiation syndrome and traumatic brain injury, which includes concussion. In some cases, this is the first and only research target available at this time. This marks the tenth project currently underway for Eagle, a pharmaceutical company focused on developing and commercializing innovative and differentiated injectable products that address the shortcomings, as identified by physicians, pharmacists and other stakeholders, of existing commercially successful injectable products.
Updates from the JPM Healthcare Conference in San Francisco last month touched on Eagle’s growth plan, outlining both the company’s financial stability and plans for five additional project launches in the next three years, including targets used for treatment of breast and pancreatic cancers. Moreover, it gave a detailed illustration of how Ryanodex works and the potential it has in treatment under nine different patents expiring between 2022 and 2025. Partnerships on these projects include The United States Army Medical Research Institute of Chemical Defense, NorthShore University HealthSystem and TYME Technologies.