How open-source drug discovery could help us in the next pandemic

Cassandra Willyard

from MIT Technology Review on 2023-11-10 10:00 (#6G92G)

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When the covid pandemic hit, our antiviral coffers were essentially bare. Sure, pharmaceutical companies had developed drugs to combat influenza and a handful of chronic infections. But they hadn't had much of an incentive to develop drugs against other viruses with the potential to start pandemics. Developing drugs for diseases that don't pose an immediate threat isn't exactly lucrative.

But what would happen if we took profit out of the equation and made drug discovery a collaborative process rather than a competitive one? That was the idea behind the Covid Moonshot, an open-science initiative to develop antivirals against the coronavirus that began back in March 2020 with a Twitter plea for covid drug designs. "Calling all medicinal chemists!" wrote Nir London, an engineer at the Weizmann Institute of Science who works in drug discovery.

This week the researchers behind the project published their results in Science. The effort, which relied on more than 200 volunteer scientists from 25 countries, produced 18,000 compound designs that led to the synthesis of 2,400 compounds. One of those became the basis for what is now the project's lead candidate: a compound that targets the coronavirus's main viral enzyme. The enzyme, known as Mpro, snips long viral proteins into short chunks, a key step in viral replication. The compound stops this enzyme from working. Paxlovid, an antiviral developed by Pfizer after the pandemic began, hits the same target.

Maybe that doesn't feel like a huge win. Even if the compound works, it will likely take many more years to develop it into a drug. But it's still gone remarkably quickly if you were to compare that with most drug discovery stories," says Charles Mowbray, discovery director of the nonprofit Drugs for Neglected Diseases Initiative (DNDi), a Moonshot participant.

And although developing another drug now, in the waning days of the covid pandemic, might not seem as urgent as it once was, the need for another antiviral that's ready for the next pandemic or next outbreak or the next variant is still very relevant," he adds.

The US National Institute of Allergy and Infectious Diseases has identified 10 virus families that hold pandemic potential. Some of these families contain viruses that you've no doubt heard of-Ebola, West Nile, measles, hepatitis A. Other viruses are more obscure. For example, you probably haven't heard of La Crosse, Oropouche, or Cache Valley, all peribunyaviruses. We have antiviral drugs for smallpox, and now for the coronavirus, but for many of these families, we have no therapies at all. No pill. No antibody. Nothing. That may be a problem open-source drug development could solve.

There's another potential benefit to an open-source model: global access. The current covid therapies are under patent protection and are unaffordable for much of the globe. Even in the US, these drugs are pricey. When Paxlovid was introduced, in 2021, the US bought more than 20 million treatment courses for $529 each and made them available free of charge. But Pfizer says the price will more than double, to $1,390 per dose, when the company starts selling the drug in the commercial market in 2024.

Because the Covid Moonshot is developing drugs that won't be under patent protection, they'll go straight to generic. The drug can be made by more than one manufacturer, can be distributed to everybody who would need it when needed, and not have to wait for sometimes slow and painful licensing negotiations, which companies may or may not be willing to do," Mowbray says.

What happens next? DNDi will be taking the lead on developing the lead candidate, called DNDI-6501, shepherding it through preclinical development. And the Covid Moonshot team will continue its work too. Last year, the US National Institutes of Health awarded the consortium nearly $69 million to continue developing oral antivirals. They'll be developing drugs to treat not only the coronavirus but also West Nile, Zika, dengue, and enteroviruses.

No medicine has ever made it to market through an entirely open-source process. But that doesn't mean that the model can't make a difference in drug development. The pharma company Shionogi used data from the Covid Moonshot to help develop its antiviral ensitrelvir, which is already approved for emergency use in Japan. Contrary to what is often assumed, openness is not a barrier to translation of impactful molecules, either directly or by pharma," says Matthew Todd, a chemist at University College London and the founder of Open Source Pharma.

Mowbray would like to see more sharing in drug research and development. We don't know what virus will spark the next pandemic. Will it be a variant of something we've seen before, or an entirely new virus? The idea that a single entity would have enough antiviral drugs ready to manage the risks seems unrealistic, he says. If we're prepared to share what we're doing between us, we probably have a much better chance of having the right drug candidates ready."

Another thing

Preparing for the next pandemic requires more than a drug development overhaul. We also need to beef up our early warning system. In 2021, the Centers for DIsease Control and Prevention launched a surveillance project at a handful of major US airports to detect emerging SARS-CoV-2 variants.

Now the agency plans to expand that program to cover 30 new pathogens, including influenza and RSV. For now, the additional testing will take place at just four airports: San Francisco International, JFK, Logan, and Dulles.

Here's how it works:International travelers flying into airports where the surveillance program operates can volunteer to collect their own nasal swab samples. Those samples go to a lab for PCR testing. Positive samples undergo whole-genome sequencing. The program also collects samples of wastewater from individual planes and from the common drain into which all plane wastewater gets dumped.

One sample from an aircraft coming from a geographic destination afar can give us information potentially about 200 to 300 people that were on that plane," Cindy Friedman, who leads the CDC's traveler genomic surveillance program, told CNN.

As of last month, the surveillance program had tested more than 370,000 travelers from more than 135 countries and sequenced more than 14,000 samples.

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