Old Drugs, New Tricks: The Power of Medication Repurposing

As COVID-19 rapidly evolved from an outbreak to a pandemic, researchers, clinicians, governments, and the public were all desperately seeking solutions. In the setting of this urgency, drug repurposing emerged as a powerful strategy for identifying potential treatments — utilizing medications already available on pharmacy shelves around the world.

Some proved effective, while others did not. In the end, it was the lesser-known repurposed drugs that received far less attention that ended up saving the most lives: dexamethasone, tocilizumab (Actemra), and baricitinib (Olumiant). These drugs quietly saved, and continue to save, countless lives, demonstrating the immense potential of repurposing to unlock additional life-saving uses of existing drugs.

We believe that the lessons learned from these repurposed drugs have the potential to save millions more lives in the future.

The Search for Solutions

At the start of the pandemic, no treatments were available, and drug repurposing presented the opportunity to utilize FDA-approved drugs that were already accessible, and often relatively inexpensive, to address critical gaps in our response to a novel viral infection. However, this was not a new approach; for example, sildenafil (Viagra) was originally developed for cardiac disease but was successfully repurposed for erectile dysfunction and a rare pediatric lung disease.

Groups like ours at the University of Pennsylvania have been dedicated to exploring new uses for existing drugs. In fact, one of the authors (Fajgenbaum) is alive thanks to a repurposed drug that we identified.

The initial focus on repurposing early in the pandemic sparked a sudden surge of interest in drugs like hydroxychloroquine and ivermectin. These drugs, an antimalarial and an antiparasitic, gained attention through limited, early observational studies and widespread political and media endorsements.

However, more rigorous interventional studies ultimately revealed that the initial optimism surrounding these drugs was premature. Larger clinical trials demonstrated no significant benefit in treating or preventing COVID-19 with hydroxychloroquine or ivermectin. Unfortunately, public discourse disproportionately focused on these drugs, potentially overshadowing more promising treatments that were emerging from the medical research community.

Dexamethasone: The Game-Changer

The first true success of drug repurposing in treating COVID-19 came with the discovery that dexamethasone significantly lowered mortality among severely ill patients. This was particularly noteworthy, as organizations like the World Health Organization (WHO) and other agencies initially recommended against the use of corticosteroids like dexamethasone when the pandemic emerged.

Published in July 2020, the RECOVERY trial, a controlled, open-label trial, found that dexamethasone reduced the 28-day mortality rate among hospitalized COVID-19 patients who were receiving invasive mechanical ventilation or oxygen. The reduction was most significant among patients receiving mechanical ventilation, with a 29% relative risk reduction compared to those who did not receive dexamethasone.

This finding quickly led to dexamethasone being incorporated into treatment protocols worldwide, likely saving millions of lives. These results have been bolstered by subsequent studies like large national cohort studies, and dexamethasone continues to save the lives of severely ill patients with COVID-19.

However, the challenges of repurposing were highlighted by the fact that dexamethasone was found to be ineffective at treating COVID-19 patients with more mild disease, potentially even increasing mortality. The timing of administration and the appropriate dosage are critical factors in its effectiveness.

Tocilizumab: Taming the Cytokine Storm

As the number of infections increased and more data were obtained, it became evident that some of the most severe cases of COVID-19 were accompanied by cytokine storm, which also underlies other pathologies such as autoinflammatory diseases, hemophagocytic lymphohistiocytosis, and idiopathic multicentric Castleman disease.

Tocilizumab, an anti-IL-6 receptor monoclonal antibody originally developed for idiopathic multicentric Castleman disease and also approved for use in rheumatoid arthritis, was one of the early drugs studied in patients with severe COVID-19 infections. The RECOVERY trial that identified dexamethasone’s role in treating COVID-19 was expanded to include tocilizumab. The results showed that in hospitalized COVID-19 patients with hypoxia and signs of systemic inflammation, tocilizumab administration resulted in a 14% decrease in 28-day mortality.

Additionally, patients treated with tocilizumab were less likely to require invasive mechanical ventilation and were more likely to be discharged within 28 days than those who did not receive the medication. Importantly, this benefit appeared to be additive to the survival advantage from dexamethasone.

Baricitinib: Highlighting the Power of Knowledge Graphs

In one of the first successful AI-assisted identifications of potential treatments for COVID-19, researchers applied machine learning algorithms to a biomedical knowledge graph to uncover the potential of baricitinib. This JAK inhibitor, originally developed for rheumatoid arthritis, was already recognized to have anti-inflammatory properties, but BenevolentAI’s algorithms predicted it would also have antiviral effects.

The COV-BARRIER trial demonstrated that adding baricitinib to standard care reduced mortality by 13% in hospitalized COVID-19 patients, proving particularly effective in treating moderate to severe cases of the disease. Baricitinib not only continues to save lives but also highlights the immense potential of AI algorithms and biomedical knowledge graphs to drive drug repurposing efforts.

The Power and Potential of Drug Repurposing

The success of dexamethasone, tocilizumab, and baricitinib in providing clinicians with life-saving therapies for patients with moderate to severe COVID-19 highlights the incredible potential of drug repurposing. These drugs were not originally designed to combat a novel virus; rather, they were existing treatments with established safety profiles and mechanisms of action that were effectively leveraged for new uses. Often, the best solutions are already within our reach, waiting to be re-discovered.

The COVID-19 pandemic provided a powerful reminder of the effectiveness of repurposing, but its implications extend far beyond this single virus. There are thousands of diseases, affecting millions of people, for which no approved, effective treatments currently exist. This highlights the untapped potential of drugs that are already sitting on pharmacy shelves, and underscores the importance of unlocking new uses for existing medicines. We’ve already seen how AI can be a powerful partner in such efforts to analyze global biomedical knowledge and uncover previously unseen connections, and we’re working to harness this power to identify the most promising drug repurposing opportunities.

As we aim to identify treatments for a broad range of diseases, the ability to repurpose existing drugs will be an essential tool in our medical arsenal. We can unlock new treatments for diseases that currently lack effective therapies, drive innovation, and make a meaningful impact on millions of patients worldwide.

David Fajgenbaum, MD, MBA, MSc, is associate professor of medicine in the Translational Medicine & Human Genetics department at the University of Pennsylvania. He is founding director of the Center for Cytokine Storm Treatment & Laboratory (CSTL), and associate director of Patient Impact and the Orphan Disease Center at the University of Pennsylvania. He is also co-founder and president of the Castleman Disease Collaborative Network (CDCN) and co-founder of Every Cure, a nonprofit biotech working to unlock additional uses for existing medicines by harnessing the power of AI. Reece Williams is a fourth-year medical student at Emory University and a member of the medical team at Every Cure.

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