For decades, scientists had been trying to prove the value of new medicines made with RNA, the single-stranded genetic information that tells cells what proteins to create. But it wasn't until a pandemic gripped the world that the potential of these therapies became undeniable.
Following the success of Moderna, BioNTech and their coronavirus vaccines, money is now pouring into RNA-focused companies, with the latest batch announced Wednesday. Backed by $40 million from the venture firm Apple Tree Partners, Replicate Biosciences has officially launched, attempting to treat diseases with the help of RNA that reproduces itself.
Replicate's approach is different from Moderna's and BioNTech's, which rely on so-called messenger RNA. Instead of just providing instructions on how to make certain proteins, Replicate aims to make medicines outfitted with the genetic code that some viruses use to turn cells into their own personal reproduction factories.
"The difference with self-replicating RNA is we're delivering a copy machine into the cell along with that instruction manual, so you can make a lot more copies and they last for a much longer period. And that creates a lot more protein," said Nathaniel Wang, an immunologist who co-founded Replicate in February 2020.
Wang and his team believe their self-replicating RNA medicines could hold significant advantages over other RNA-based therapies; longer-lasting protein expression, for example, may mean patients need treatment less often or at much smaller doses, which could improve convenience and reduce side effects.
"All those things together mean that you've got kind of a turbocharged RNA therapy," said Michael Ehlers, a well-known drug researcher and the chief scientific officer at Apple Tree. Ehlers is also the lead investor and co-founder of Replicate.
Ehlers joined Apple Tree in late 2019 after three years at Biogen, where he served as head of research and development. At Apple Tree, one of his initial roles was helming Limelight Bio, a young company working on gene therapies for inherited diseases of the brain, eye, liver and muscle.
But even before RNA was making headlines, Ehlers said he had been thinking about what a "truly signature RNA therapeutic company" would look like. He seemed to have found it by the late summer of 2020, when a mutual colleague connected Ehlers with Wang.
To Ehlers and later Apple Tree, one of the big draws to Replicate was the team. Wang was experienced at developing and applying synthetic biology after working with companies like Synthetic Genomics, Novartis and Johnson & Johnson. Andrew Geall, another co-founder, led messenger RNA vaccine development at Novartis before heading to Avidity Biosciences, where he served as vice president of formulations, analytics and chemistry. Avidity went public in June 2020, raising just shy of $260 million.
Replicate's two other co-founders, Hebert Kim Lyerly and Zachary Hartman, are professors of cancer research and immunology at Duke University.
Together, the team was knowledgeable not only about the molecular biology behind self-replicating RNA, but also about the ways to encapsulate and formulate these molecules so as to turn them into actual products. The four scientists collaborated, for example, on a self-replicating RNA application that they say is capable of combating drug-resistant cancer mutations.
"A big chunk of the future opportunity in medicine is going to be RNA therapeutics," Ehlers said. "And when I saw what Replicate was doing, I have to admit it was a ‘no-duh' moment, which was, 'Why on earth hasn't anyone really thought to do this in a more industrialized way?'"
With $40 million at its disposal, Replicate plans to advance multiple drug programs into human testing. Among the four most advanced programs, two are based on that drug resistance application and are targeting breast and lung cancers, according to Wang.
"Increasingly, we feel that the direction of oncology needs to be tackling earlier-stage disease and earlier lines of care, and instead of focusing on salvage therapies or things of that nature, to find new improvements to first-line therapies," Wang said. "And that's where we found this type of approach, which tries to catch tumors before they become a heterogeneous mess from multiple lines of therapy, to be attractive."
Replicate's other two leading programs are, respectively, directed at immunotherapy resistance in solid tumors and autoimmune and inflammatory diseases. Wang said that the company is on schedule to get at least its first drug into clinical testing in the second half of next year.
If Replicate sticks to that schedule, it could further emphasize the rapid early development timelines that have become synonymous with RNA medicines. Moderna, for instance, went from receiving the genetic code for the coronavirus to testing a vaccine in people in a matter of months.
Meanwhile, another newcomer to the space, Laronde, expects to have multiple "endless RNA" drugs cleared for human testing in 2023.
Drug development, however, doesn't often go as quickly or seamlessly as companies hope. With Moderna, it took many years just to refine the shell needed to protect the messenger RNA in its medicines. The fast progress it made with its coronavirus vaccine last year built on existing vaccine research from company and government scientists, too.
Replicate will almost certainly face challenges of its own. The company's new backer, though, doesn't appear too worried.
"This is a highly efficient, drug candidate producing machine. It's fast. It's cost effective. We can move quickly," Ehlers said. "And as we get programs advancing. I can't imagine us having any problem being able to raise the capital and resources to elaborate further."