UAB Researchers Answer Questions About Antiviral Work

Dr. Richard Whitley. Source; UAB.

Q&A with Richard Whitley, MD, director, and Stephanie Moore, PhD, associate director, of the Antiviral Drug Discovery and Development Center (AD3C)

What was the background for UAB’s antiviral expertise?

WHITLEY: UAB’s work on viruses began when we first started publishing data from, arguably, the first efficacious antiviral drug, vidarabine, in the mid-70s, and it’s been forging ahead since then. The Antiviral Drug Discovery and Development Center (AD3C) was born out the experience of studying and developing antiviral therapies. It provided a framework that allowed us to bring together individuals who I thought were the best virologists in the country in order to focus on the development of antivirals for emerging infections.

(UAB pediatric infectious diseases physician) Charlie Alford set the stage for it. But the difference is that people involved in this grant aren’t all in Birmingham. They’re at Vanderbilt; Oregon Health and Sciences University; Galveston; Washington University, St. Louis; University of Colorado, Denver and the University of North Carolina – plus a pharmaceutical collaborator, Gilead Sciences.

The model came about when I was about 75 percent out the door of UAB, about to accept the position of chairman of the pediatrics department at Stanford University and on sabbatical at the University of Chicago. Bob Rich (UAB medical school dean) flew to Chicago and basically offered me funds to drive my research agenda. So, with Jack Secrist (then Southern Research CEO), we decided the one thing that’d be good for the UAB/SR community was to build the Alabama Drug Development Alliance (ADDA). The idea was to recruit UAB basic scientists working in areas with therapeutic potential and harness their energy and scientific acumen to develop targets of pharmaceutical interest in their research programs.

That was pretty complex. It was multidisciplinary and required not only good scientists at UAB but also the scientific talent at Southern Research to screen libraries of compounds with high-throughput assays against unique targets. With successful conformation of the hits, a medicinal chemistry was instituted.

That gave us a model that I was able to adopt for the first AD3C grant – we got funded, and we’re now in our second five-year cycle. The AD3C model recognized the fact that some absolutely super virologists around the country wanted to participate in this drug discovery program.

It was incredibly exciting when AD3C was funded, because I’d been involved in antiviral drug discovery my entire career. This was the first grant that I applied for that was not studying drugs in clinical trials. (It called for) doing the basic developmental work, so it provided a brand-new opportunity that was incredibly successful. It led to the work on remdesivir, and we’re very grateful that is now in clinical studies.


Very few drugs in clinical trials make it to FDA approval — what about remdesivir?

WHITLEY: That’s right, and we still don’t know if remdesivir is going to cross the line (to approval). We’ll know soon. The studies in China should be completed in a relatively short period of time – the next month. This is short-term therapy, so given the nature of this disease and the imperative to get something to people, I would think it could move to at least Emergency Use Approval fairly quickly.

Is this search different from previous searches for therapy for AIDS, H2N1 influenza, SARS, MERS?

WHITLEY: This is very different from the search for a drug for HIV infection. HIV slowly unrolled. Yes, it was associated with mortality, but one, two, three, four years after patients were diagnosed.  What’s striking about COVID-19 is the rapidity with which this virus is spreading around the world. The mortality is lower than many diseases, but the rapidity of spread is unprecedented. As a consequence, it has resulted in incredible economic morbidity and social disruption. Hospital resources are stretched. Diagnostics are only becoming available late in the disease, and patients are dying. Mortality is greatest in people over the age of 70, particularly those with risk factors – and that’s most individuals over 70. Remember, in the mid-80s the first drug out of the starting block for HIV was AZT, and that, at least, temporized the disease for a bit. But HIV was a much, much slower rollout than this pandemic with COVID-19.

With H1N1 in 2009, we already had drugs available as two of them were licensed in 2000. So, we could take drugs into the field for use.

The original AD3C funding came through the National Institute of Allergy and Infectious Diseases (NIAID) following a Request for Applications. NIAID was interested in three distinct areas. One was diagnostics for emerging infections, another was vaccines and adjuvants (to increase immune response), and, lastly, therapies for emerging infections. I chose to respond to therapies request. Thus, I began talking to my colleagues around the country to see if they were interested in throwing their hats in the ring. The viruses we chose to target were in the alpha- and flavi-virus families as well coronaviruses and influenza.

What other COVID-19 Work is the center involved in?

MOORE: We are coordinating the submission of an administrative supplement for AD3C between our coronavirus project leaders at Vanderbilt University and the University of North Carolina at Chapel Hill. They, along with the Southern Research experts, who run the high-throughput screening and medicinal chemistry cores, are working extremely hard to quickly discover and develop potential therapeutics. Supplemental support will be instrumental to aid and expand the response of our teams. For example, we have other compound libraries we’re going to be screening. If we find any (biologically active compounds), we’ll send them to our coronavirus project leaders. We are trying to rapidly get things screened and through the pipeline and get them to testing for the COVID-19-related virus, SARS CoV-2.

In addition, the Gates Foundation has a partnership with Scripps-Calibr, which has a library of about 13,000 compounds that we are negotiating to have screened at Southern Research to look for anything that’s active against SARS CoV-2.

Is Gilead the only entity producing remdesivir?

WHITLEY: Yes, Gilead has committed many people to the production of the drug.

Any last comments?

WHITLEY: Gilead Sciences is our pharmaceutical partner in AD3C. Early on, they weren’t interested at all in developing drugs for emerging infections. But they became interested and we’re in a partnership that’s allowed us – through this grant and through the terrific science of Mark Denison at Vanderbilt, Ralph Baric at UNC-Chapel Hill and our screening people at Southern Research – to get a better understanding of how remdesivir works in cell culture and in animal models. We provided those data to Gilead, and they, in turn, included it their application for an IND (Investigational New Drug from the FDA) for controlled studies in MERS. It’s just that COVID-19 came along and trumped studies of MERS as all the drug (remdesivir) commandeered for COVID-19 studies.