Repurposing Licensed Drugs for Use Against the Zika Virus
Robert W. Malone, MD, MS, has identified several already-licensed drugs that would be successful in blocking Zika virus replication in human tissues.
Updated at March 2, 2017 at 4:42 PM EST
On Friday, February 24, 2017, at the First International Conference on Zika Virus, Robert W. Malone, MD, MS, discussed repurposing licensed drugs to serve as both therapy and prophylaxis for Zika. Contagion® sat down with Dr. Malone to discuss his research.
It is a truth universally acknowledged that drug production is not only a costly feat, but also a time-consuming one. On average, it takes approximately $1 billion and 10 years to get a new drug or vaccine on the market. With the Zika virus rapidly spreading across multiple countries, bringing with it a wide array of devastating complications, there is no doubt that time is of the essence to bring a viable treatment option to market. Given the constraints of time and money, however, repurposing approved drugs that have already shown clinical significance against other pathogens has proven to be a practical alternative, particularly when not much funding is available for the disease in question.
Emerging infectious diseases, such as Zika, are areas of focus where “pharmaceutical companies can’t make much profit,” according to Dr. Malone. “The whole business model of how we develop medical countermeasures of emerging infectious diseases is broken,” he stressed. He referred to this phenomenon as, “outbreak fatigue,” and stated that “one of the only ways out of the woods that many people have started to think about and develop—both for oncology and infectious disease—is to recognize that we now have a rich pharmacopeia of compounds with different mechanisms of action.”
To this end, Dr. Malone and his team took a four-step approach to identifying such compounds to repurpose. The four steps included: gathering background knowledge on pathogen, defining the target for licensure, carrying out investigational research, and finally, using high-throughput tools to test compound activity against the pathogen.
Dr. Malone’s approach differed from approaches past researchers have used to repurpose compounds against the Zika virus. Whereas past research jumped straight to high-throughput screening of all currently available compounds; Dr. Malone’s team first identified how the Zika virus infects primary skin cells and causes cellular autophagy, and then worked to identify licensed autophagy inhibitors that would be safe for use in pregnant women. These inhibitors were tested under a cooperative research agreement with the US Army Medical Research Institute of Infectious Diseases.
Next, the research team sought to determine the level of effectiveness an anti-arbovirus drug truly needs. Dr. Malone discussed this factor in an exclusive interview with Contagion®.
From there, the research team was able to define their target product profile. According to Dr. Malone, the team aimed to answer the question, “what drugs are available that work by these mechanisms of action that are already licensed that are compatible with what we know about the virus pathology and what we want to use as the end-point for licensure?”
The research team then used the “best available” high-throughput tools to test which compounds were active with multiple different viral isolates and multiple human cell types. They narrowed these down to 5 compounds and a few combinations that were suitable for animal testing.
In his interview with Contagion®, Dr. Malone discussed the various combinations and compounds his team identified to be used against Zika.
According to Dr. Malone, testing a drug’s efficacy in a cohort of pregnant women would not only be time-consuming, but also expensive and would require a large number of participants. One reason that testing drugs and vaccine efficacy for use in pregnant women is so time-consuming is that researchers need to test the drug during pregnancy, and then follow the infants after birth to see if any complications arise.
Because Zika viral shedding in semen is prolonged, Dr. Malone and his team plan to enroll male participants in their clinical trials. Study power calculations indicate that this approach may reduce study enrollment requirements to prove antiviral activity from approximately 10,000 subjects in a prophylactic efficacy trial to only around 600 male participants for this type of a therapeutic clinical trial design; this may also cut the costs and length of the trials. The research team hopes to be able to administer the identified drugs to their study cohort, and measure how long the Zika virus is able to persist in semen samples thereafter.
Through this novel approach to repurposing drugs, Dr. Malone and his team propose that a “shortened pathway to potential licensure,” can be implemented by identifying already licensed drugs that could be potentially effective against the Zika virus.
Editor's note: This article has been updated to reflect that the human semen shedding trials have yet to be initiated.