New repository may speed COVID-19 drugs to market

By Samantha Black, PhD, The Science Advisory Board staff writer

May 28, 2020 -- As researchers race to find vaccines and treatments for COVID-19, drug repurposing has emerged as potentially the fastest route to get drugs to market. A new research effort aims to speed up the process by creating a repository for data on drugs that have already been used off-label to treat COVID-19.

Called Covid19 Registry of Off-label and New Agents (CORONA), the effort aims to build a central repository of information about repurposed drugs that physicians have used to treat COVID-19. The effort will help public health agencies and pharmaceutical companies make informed decisions about drug repurposing, according to a paper published in Infectious Diseases & Therapy on May 27.

COVID-19 patients exhibit clinical symptoms ranging from mild flu-like symptoms to respiratory and multiorgan failure from cytokine storm. With no approved therapies for the disease, physicians have administered treatments off-label and through clinical trials. Although thousands of papers have been published in medical journals and preprint servers, only some of the treatments have undergone randomized controlled trials; others have not experienced the same regulatory scrutiny.

Drug repurposing can help identify the best drug candidates to repurpose for COVID-19. As part of the process, it's important to identify and build consensus on indicators of effectiveness such as time to clinically meaningful response (TCMR). These types of insights could be invaluable to governments, public health organizations, and pharmaceutical companies.

Yet, no systematic effort has been made to organize and consolidate drug repurposing efforts for COVID-19 to date. In the new paper, researchers sought to identify and inventory the full range of treatments that have been reported for use in treating COVID-19 patients.

"We can't win this fight if we don't take stock of the tools that are already being used and search for new ones that could be effective. While off-label use is happening all over the world, there's currently no system in place to track it, so we felt like we had to create one," said the study's lead author, Dr. David Fajgenbaum, an assistant professor of translational medicine and human genetics and director of the Center for Cytokine Storm Treatment and Laboratory (CSTL) at the University of Pennsylvania Perelman School of Medicine.

Dr.
Dr. David Fajgenbaum. Image courtesy of Penn Medicine.

The researchers first performed a systematic literature review to identify all the treatments reported for use on COVID-19 patients. The team searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles published between December 1, 2019, and March 27, 2020. From over 2,700 articles, 155 studies met the researchers' inclusion criteria, consisting of more than 9,000 patients. Nearly all patients were reported to be hospitalized (98%) and 18% required ventilation.

Fourteen therapeutic categories represented a total of 115 reported treatments. The most frequently administered classifications of treatments were antivirals, antibiotics, and corticosteroids. The most frequently administered individual drugs were lopinavir/ritonavir, interferon-alpha/beta, and immunoglobulins. Interferon treatments had the highest amount of available response data and were associated with the shortest TCMR (11.7 days).

Based on their analysis, they built a framework through which treatments may be exerting effects based on COVID-19 pathogenesis. For example, several treatments -- including N-acetylcysteine, heparin, meplazumab, umifenovir, and hydroxychloroquine -- limit entry of SARS-CoV-2 by blocking it from binding to the human angiotensin-converting enzyme 2 (ACE2) receptor. Others may inhibit viral replication (interferon-alpha/beta, ritonavir/lopinavir, oseltamivir, ganciclovir, ribavirin, favipiravir, remdesivir, and danoprevir).

Another popular off-label treatment that has been employed, using convalescent plasma, may prevent viral dissemination via antibody-mediated neutralization by increasing SARS-CoV-2-specific antibodies. More generally, some drugs may prevent or control hyperimmune responses (corticosteroids, hydroxychloroquine, and tocilizumab).

The data analysis provided by the researchers focuses on drugs being used by clinicians and could assist and harmonize high-throughput drug screening efforts. The goal of the CORONA project is not to point toward the most effective treatment, but rather to provide a resource for what may be candidates for further study, Fajgenbaum noted.

"We hear a lot about the same handful of drugs, but we show here that there are many more currently in use than those that have already made headlines. Anything that shows promise anecdotally still needs to be rigorously tested in a clinical trial to see if it is effective and safe," he said.

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