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Eagle Pharmaceuticals, Inc , a New Jersey-based pharmaceutical company announced that its product RYANODEX for injectable suspension inhibited the growth of SARS-CoV-2, the virus causing the COVID-19 pandemic, in a controlled in vitro laboratory test. On Tuesday, April 14, Eagle submitted its Investigational New Drug application to the U.S. FDA for a Phase 2 clinical trial in partnership with Hackensack University Medical Center to evaluate the efficacy of RYANODEX in patients infected with SARS-CoV-2. Eagle has been in contact with the FDA’s Coronavirus Treatment Acceleration Program to request potential expedited review of the IND application and aims to begin the clinical trial as soon as possible.
Eagle is working to increase production of RYANODEX in advance of clinical results and to potentially shorten the supply chain lead time if necessary. To that end, Eagle is forming a partnership for strategic manufacturing support with Amneal Pharmaceuticals, Inc. (NYSE: AMRX) based in Bridgewater, N.J., one of the largest U.S.-based pharmaceutical manufacturers. Eagle is also working with its existing manufacturing partner, Durham, N.C.-based Alcami Corporation, a leading provider of contract manufacturing services for pharmaceutical and biotechnology clients around the globe to increase its production.
RYANODEX is approved by the FDA for the treatment of patients with malignant hyperthermia (“MH”) in conjunction with appropriate supportive measures, and for the prevention of MH in patients at high risk. MH is a life-threatening condition experienced by susceptible individuals exposed to certain medications. MH is characterized by high body temperature, muscle hyperactivity, rapid heart rate and other symptoms.
RYANODEX acts by modulating free intracellular calcium levels to restore calcium homeostatic balance inside cells. Eagle has worked for many years to understand how RYANODEX impacts calcium regulation in cells. This work has served as the basis for Eagle to study a number of different diseases and disorders in which intracellular calcium dysregulation may be an important factor.
Eagle is now exploring the relationship between viral infection and the regulation of calcium levels inside cells. Viruses can exploit host cells to replicate by creating dysfunction in the intracellular environment. Depending on the virus type, an altered intracellular calcium balance may enhance virus entry, replication and release. As a result, intracellular calcium levels may be an important factor in viral-host interactions and viral infections. Dysregulation of the intracellular calcium homeostasis may benefit the virus lifecycle leading to cell death and worsening of the disease.
“The results of Eagle Pharmaceuticals’ virus neutralization assay demonstrated a lack of viral growth in RYANODEX-treated cells compared to those not treated with RYANODEX. This outcome suggests that RYANODEX may have antiviral activity against SARS-CoV-2, which we believe represents a novel approach to impeding the virus lifecycle by modulating free intracellular calcium levels of host cells,” said Adrian Hepner, M.D., Ph.D., Chief Medical Officer of Eagle Pharmaceuticals. “We now plan to conduct a clinical trial in partnership with Hackensack University Medical Center to evaluate the efficacy and safety of RYANODEX as a potential treatment for patients hospitalized with COVID-19.”
“Effective treatments for patients with COVID-19 are needed urgently,” said Scott Tarriff, Chief Executive Officer of Eagle Pharmaceuticals. “Our years of research have resulted in a deep knowledge of how RYANODEX works and insights into the potential of RYANODEX to address unmet needs for multiple diseases in which calcium dysregulation plays a significant role. We believe the antiviral effect observed in the laboratory suggests RYANODEX may be useful in combating the COVID-19 public health crisis our world now faces.”
In Vitro Laboratory Viral Neutralization Assay Results
The viral neutralization assay demonstrated the in vitro antiviral activity and lack of cytotoxicity of RYANODEX at concentrations observed in humans after administration of recommended doses.
The assay was performed using Vero E6 cells, which are susceptible to SARS-CoV-2 infection. After determining the median tissue culture infection dose of the SARS-CoV-2 isolate, a standardized viral dose was added to cells preincubated with different concentrations of RYANODEX, ranging between 5 to 100 micromolar (“µM”). After removal of the virus-RYANODEX mixtures, the cells were incubated further and evaluated for viral effects by observation under a phase-contrast inverted microscope for the presence or absence of SARS-CoV-2 cytopathic effects (“CPE”) in the cells.
The assay had several controls, including cells infected with the same virus that did not receive any RYANODEX treatment, and cells exposed to RYANODEX without viral infection. The cells were then analyzed over six days for CPE as evidence of viral growth.
Specifically, on day 2 post-infection, no CPE (indicating no virus growth) was observed in any of the infected cell cultures containing RYANODEX. On day 4 and day 6 post-infection, no CPE was observed in cells incubated with 20 to 40 µM of RYANODEX. Based on this experiment, it was concluded that the minimum concentration of RYANODEX needed to inhibit SARS-CoV-2 infection in incubated cell cultures is 20 µM.
No CPE was observed with the 20 and 40 µM RYANODEX concentrations at all time points. Toxic effects on the cells only were observed at the two highest RYANODEX concentrations (100 and 50 µM), both in infected and uninfected cell cultures. In contrast, at the lower RYANODEX dilutions (less than 50 µM), both infected and uninfected cell cultures showed good cell viability. Further, the control cells without RYANODEX all had CPE, evidencing viral growth causing marked cytotoxicity and cell death.
Clinical Trial of RYANODEX for the Treatment of COVID-19
Eagle is partnering with Hackensack University Medical Center to conduct a controlled Phase 2 clinical trial in patients with COVID-19, which will evaluate the effectiveness and safety of RYANODEX for the treatment of COVID-19 as adjunctive treatment to current standard of care. The World Health Organization Ordinal Scale of Severity, the Sequential Organ Failure Assessment (“SOFA”) and other relevant clinical measurements will be used as efficacy endpoints. The trial will enroll approximately 60 adult COVID-19 patients with confirmed SARS-CoV-2 infection.
“Hackensack Meridian Health, the largest provider of patient services in New Jersey, is committed to helping address the COVID-19 pandemic. Not only are we providing patient care but our collaboration with Eagle Pharmaceuticals addresses our mission to help establish the scientific basis for therapies that might alleviate symptoms or address the root cause of the disease,” said Ihor S. Sawczuk, M.D., FACS, Regional President and Chief Research Officer, Hackensack Meridian Health, which owns Hackensack University Medical Center.
Pending FDA authorization of Eagle’s IND application, the trial will begin enrolling participants at Hackensack University Medical Center with initial results anticipated in May 2020.
“As partners with Eagle Pharmaceuticals, we look forward to conducting this clinical trial to determine if the in vitro evidence of antiviral activity seen in the lab can be replicated in patients with COVID-19. We believe the data generated will add to our understanding of how best to address COVID-19 disease,” said David S. Perlin, Ph.D., Chief Scientific Officer and Senior Vice President of the Center for Discovery and Innovation, Hackensack Meridian Health.
About RYANODEX
RYANODEX® (dantrolene sodium) for injectable suspension is indicated for the treatment of malignant hyperthermia in conjunction with appropriate supportive measures, and for the prevention of malignant hyperthermia in patients at high risk.
Eagle’s RYANODEX is a proprietary formulation of dantrolene sodium that is reconstituted within 10 seconds with sterile water for a single injection and administered as IV push in less than one minute. In most cases, a single dose of RYANODEX requires a single vial. RYANODEX therefore requires significantly less preparation and administration time compared to other dantrolene sodium formulations, which require multiple vials and larger infusion volume to deliver a single dose.
This news release discusses investigational uses for an FDA-approved product. The information is not intended to convey conclusions about the efficacy or safety of investigational use. RYANODEX has not been demonstrated to be safe or effective for the treatment of COVID-19. There is no guarantee that any investigational uses of RYANODEX will gain FDA approval.
About Eagle Pharmaceuticals, Inc.
Eagle is a fully integrated pharmaceutical company with research and development, clinical, manufacturing, and commercial expertise. Eagle is committed to developing innovative medicines that result in meaningful improvements in patients’ lives. Eagle’s commercialized products include RYANODEX®, BENDEKA®, BELRAPZOTM, and its oncology and CNS/metabolic critical care pipeline includes product candidates with the potential to address underserved therapeutic areas across multiple disease states.
