To date, efforts to identify effective antiviral drugs to combat Covid-19 have been disappointing. Only one, remdesivir, has been approved, and it appears to be only modestly effective. We must and can better prepare for the next pandemic. It involves identifying the families of viruses that pose the biggest threats, developing an array of potential small-molecule, antiviral drugs that could be quickly moved to human trials at the first signs of an outbreak, and making a societal commitment to this effort.
The unprecedented speed with which Covid-19 vaccines were developed is a testament to both the scientific research that laid the groundwork and the herculean effort of public-private partnerships to bring them to market.
In stark contrast, efforts to identify effective antiviral drugs that can prevent Covid-19 infections or stop it from worsening have proven far less fruitful. To date, only one such drug, remdesivir, has been approved for treating Covid-19, but its use is limited to clinical settings, and at best it appears to be only modestly effective.
How can the United States and the rest of the world do better next time around? As any leader knows, efforts to prepare for crises must begin before the crisis occurs. This applies as much to the global threat of highly infectious diseases as to the threat of armed conflict (in which countries have collectively invested massive resources). Part of the preparation should be to preemptively develop effective and readily available drugs to combat viruses most likely to cause the next — inevitable — global pandemic.
The case for antiviral drugs. The emergence of Covid-19, which is caused by the SARS-CoV-2 virus, was far from a total surprise. SARS-CoV-1, which struck in 2002 to 2003, and the MERS-CoV outbreak, which happened in 2012, were warning shots across our bow that another coronavirus could emerge as a global threat. And well before them, of course, there was the 1918-1919 influenza pandemic, which is believed to have killed at least 50 million worldwide. But prior to early 2020, nations did little to support research for a drug that would combat these and other families of highly infectious viruses with pandemic potential.
Yet there are many good reasons to pursue antiviral drugs alongside vaccines. For one, there will always be a lag between the outbreak of a new pandemic and the delivery of an effective vaccine. During that delay, antiviral drugs serve as primary tools to keep us safe. Recent reports of new strains of SARS-CoV-2 are a stark reminder of how viruses can evolve to become more transmissible and harder to contain. Existing vaccines can also become less effective when a virus mutates. In cases where effective vaccines have been challenging to create — such as HIV, the virus that causes AIDS, and HCV, the virus that causes hepatitis C — antiviral drugs are the cornerstone of our therapeutic arsenal. Furthermore, these drugs can be rapidly distributed globally without cold chain — keeping them cold while they move through the supply chain — and at modest cost.
Scientists have been doing everything within their powers to find effective antiviral drugs for Covid-19. At Scripps Research, for example, we led a major effort to mine existing drugs, leveraging our collection of 13,000 known medicines that we built in collaboration with the Bill and Melinda Gates Foundation. We screened these and other drugs against the live SARS-CoV-2 virus, both in-house and in partnerships with dozens of academic and industry partners. We have not yet identified a highly effective existing drug to repurpose for Covid-19.
However, we have identified several drugs (nucleosides and protease inhibitors) that show immense potential if they are chemically modified to increase their potency against SARS-CoV-2. Indeed, with a relatively modest investment we have already shown that we can significantly improve the activity and pharmacological properties of these drugs. Even with the accelerated testing and approval process put in place by the U.S. Food and Drug Administration (FDA) for Covid-19, it still takes time to carry out the optimization, formulation, and testing (for both efficacy and safety) for a new drug. And that is too late for too many people.
There are several steps we can take to better prepare for future pandemics by developing antiviral drugs, all of which are entirely achievable.
1. Identify the primary threats. We can’t predict exactly which virus will spark the next pandemic, but we can focus on families of known viruses with concerning qualities, such as their ability to be highly transmitted through respiratory droplets and aerosols. Among the most worrisome are coronaviruses, such as SARS-CoV-1, MERS-CoV, and SARS-CoV-2; orthomyxoviruses, such as influenza; and paramyxoviruses, including Nipah and Hendra.
Let’s proactively prepare for the next major viral threat by continually monitoring outbreaks of these viruses, develop the ability to rapidly test for infection on a massive scale, and have drugs ready to combat them.
2. Focus on developing small-molecule antiviral drugs. Once we have identified which families of viruses to prioritize, we should pursue the development of small-molecule drugs that stop the viruses from replicating in the human body or avert community spread in high-risk settings. These drugs can often be derived from existing drugs, especially those known to already have at least a modest impact against a specific member of that viral family or a related one.
This is a highly doable undertaking given the structural homology of many essential viral proteins, modern structural and computational tools, and our ability to develop cellular and animal models of viral disease. The goal should be to create an arsenal of drugs with demonstrated efficacy and safety in relevant disease models that could quickly be advanced into clinical human trials at the first signs of an outbreak.
3. Make a societal commitment to this type of research. The cost of such an effort would be a very small fraction of the economic price of a global pandemic like Covid-19 that overwhelmed our hospitals, shut down our schools, and stifled our economy. But given that few incentives currently exist for companies to develop drugs before a market is evident, this effort will require the financial support of governments and philanthropy.
In addition, given its scope and complexity, this effort will need to be guided with clear goals, milestones, and incentives. It will also require a high degree of coordination among scientists involved — from fundamental researchers to drug development experts. Although historically it has been difficult to bridge all the cultures, activities, and motivations of those involved in making modern drugs, the remarkable response of the scientific community to Covid-19 gives us a great deal of encouragement
Leveraging our experience from addressing cancer, neurodegeneration, age-related and infectious disease, Scripps Research has been developing a model that breaks down these barriers. This model combines basic research, drug discovery, and development — all under one roof. And with support from pharma and foundations like the Bill & Melinda Gates Foundation, Scripps Research is able to accelerate the development of new medicines and bring them to market quicker.
As I write this, more than 2 million people around the world have lost their lives to Covid-19. And given that it will take many more months to inoculate significant portions of the global population, many more will succumb to the virus. Imagine how many lives we could have saved, how much economic distress we could have mitigated, if, at the onset of Covid-19, we had one or more safe drugs that were highly potent against coronaviruses and could be immediately advanced into human trials. Investing proactively in the search for antiviral drugs is a calculated and modest measure we must take given the terrible global health and financial impact of one simple virus. Doing so will render a tremendous service to ourselves and future generations.