Will the COVID-19 Pandemic Finally Fuel Drug Repurposing Efforts?

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has turned the health care world upside down. Research and medical institutions have delved deeply into health care arsenals to identify some unlikely heroes that have helped to treat a disease that seemingly evolves with each passing day. In a controlled, open-label trial of hospitalized COVID-19 patients, the Randomized Evaluation of COVID-19 Therapy (RECOVERY) Collaborative Group found that the use of dexamethasone, a cheap generic drug commonly used to treat a variety of inflammatory conditions, resulted in lower 28-day mortality in COVID-19 patients receiving respiratory support.1 This is not the only incidence of older generic drugs being repurposed to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus; however, it is one of the more successful stories. The urgency to find effectiveness in older drugs has come with some serious pitfalls. Chloroquine phosphate and hydroxychloroquine sulfate, 2 drugs originally used for malaria, were broadcast at the beginning of the pandemic as possible “cures” for the new virus. Ensuing demand for these products threatened to interrupt chronic therapy among patients using the drugs for evidence-based indications such as lupus, only for the Food and Drug Administration (FDA) to revoke their Emergency Use Authorization (EUA) for COVID-19 because of reports of ineffectiveness and serious cardiac adverse events.2 Drug repurposing is a process that involves identifying an alternative use for medications that are already on the market or investigational medications that are being studied for a different indication. For patients with limited life expectancy or few treatment options, earlier access to potential new therapeutics is a benefit of repurposing older, cheaper drugs that are already on the market. For example, glucagon-like peptide 1 (GLP-1) agonists, indicated for type 2 diabetes, are being integrated into clinical practice for patients with nonalcoholic steatohepatitis based on evidence from a mix of clinical trials and observational studies.3 A major advantage of drug repurposing is that preclinical and safety studies have already been conducted, and for medications that have been approved, there exists a body of real-world evidence on utilization and safety.4 Therefore, the safety profile of the medications is already well understood and fewer studies will need to be conducted for regulatory approval, which may shorten the notoriously long drug development process significantly. This decreases the cost of development and reduces the risk of failure in the later stages of clinical development to much lower levels compared with a completely new molecular entity.4 Although less costly, 3 years of market protection provided by the FDA is often not enough time to recover accumulated expenses and may leave the company open to competition from off-label use of generics.5 Consequently, there have been relatively few instances of pharmaceutical companies seeking and gaining approval for new indications of repurposed generic drugs. There are different methods to identify candidate drugs for repurposing, including computational approaches and experimental approaches. Computational approaches include analysis of genomic and proteomic data, chemical structure, and retrospective observational studies.5 Observational studies occupy a critical intermediary position in the drug repurposing process. They are one of the more accessible pathways for developing evidence to support the drug repurposing efforts, capitalizing on already existing data that only need to be extracted and not created. Once drugs are identified as potential candidates for repurposing (eg, based on an understanding of their mechanisms of action), observational studies that leverage existing data sources can identify signals of clinical effectiveness (or a lack thereof) to support or refute the need for expensive clinical trials, while also informing trial design. Positive signals from observational studies should be confirmed with 1Jefferson College of Population Health, Thomas Jefferson University, Walnut Street, Philadelphia, PA 2Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA