One of the wilder ideas in biotechnology just got a vote of confidence from the people who gave the world the Internet.
Cambridge, MA-based Moderna Therapeutics is announcing later today it has snagged a grant worth as much as $24.6 million over the next five years from the Defense Advanced Research Projects Agency (DARPA). The U.S. military’s futuristic technology agency is committing the cash now to further develop Moderna’s messenger RNA drug technology to fight infectious diseases.
By making this grant, the agency is betting on what could become a superfast, cheap, and unusually adaptable method for fighting today’s known pandemic threats, and the unknown threats of the future.
The deal is the latest coup for Moderna, a three-year-old startup that turned heads in the biotech industry in March when it secured a huge $240 million upfront payment from AstraZeneca (NYSE: AZN) to collaborate on 40 different mRNA drug candidates. Moderna, which has grown to 80 employees and aspires to be the first mover in the field of injectable messenger RNA drugs, hasn’t yet taken any drug candidates into clinical trials. But it has quietly been doing work behind the scenes on a small $700,000 DARPA grant this year to prove that its mRNA technology is more than just science fiction.
After 18 months of talks, scientists at Moderna showed the agency that its modified mRNA molecules, which carry the instructions for making specific proteins, could get inside cells of live animals. Not only that, but once there, the mRNA could coax the cellular machinery to churn out therapeutic-quality antibodies like Genentech’s trastuzumab (Herceptin), and make more than enough of the antibody to have a therapeutic effect. That was enough for DARPA to double down and ask whether Moderna can make more mRNAs that can help people produce all kinds of other antibodies, particularly ones of national security interest.
Scientifically, it means Moderna has shown animals can serve as their own drugmaking factories. Next step: carefully marching ahead to prove it can do the same thing in human beings.
“This is a big technology validation for us,” said Stephane Bancel, Moderna’s CEO, one of the speakers tonight at the Xconomy event titled “Boston’s Life Science Disruptors.”
If Moderna is successful in getting its mRNA drugs through clinical trials, it could radically change the way public health officials think about pandemics. Today, most officials think of combatting these threats with vaccines, which stimulate antibody production through different means. Vaccines can be highly effective, but they often suffer from limited manufacturing capacity and long production cycles. That means it’s usually not practical to react nimbly, and scale up massive production, during a fast-moving pandemic. Similarly, there are a few injectable antibody drugs that officials can turn to in that kind of situation, but those products, including one from Baxter Healthcare derived from human blood plasma, also face manufacturing cost and capacity constraints.
The idea of using mRNA drugs is quite different. These are synthetic compounds that can be designed and manufactured in just about three weeks, with a customized genetic sequence for making any protein of interest. Theoretically, a new pathogen could be discovered, scientists could sequence the new genome in a day, and turn around almost immediately with a sequence for an mRNA molecule that makes antibodies to fight the bug. Scaling up the manufacturing is relatively easy, because mRNA drugs are made through a common chemical process. These compounds don’t need to go through the time-consuming process of being incubated in living cells and purified, like how today’s engineered antibodies are made.
Once the mRNA drug is injected into a person, it should take no more than 24 hours for the person to start producing the protective antibody that’s desired. So, at least in theory, a completely new and deadly strain of flu could be identified one day, and millions of people could find themselves able to fend it off with protective antibodies stirred by mRNA within a month.
Other biotech companies with RNA-based drug technologies have secured big support from the U.S. military. Cambridge-based Sarepta Therapeutics (NASDAQ: SRPT) is working on experimental drugs for the Marburg and Ebola viruses, as does Vancouver, BC-based Tekmira Pharmaceuticals (NASDAQ: TKMR). But those technologies work in different ways than Moderna’s.
Mike Houston, the former vice president of chemistry and formulation at Bothell, WA-based Marina Biotech, said he was “amazed” that Moderna has shown it can use mRNA molecules to produce not just small, relatively simple therapeutic proteins, but also larger, more structurally complex molecules like Y-shaped antibodies. Houston, now a consultant in the RNA therapeutics field, is familiar with Moderna’s work because he interviewed for a job there earlier this year, but chose not to move his family across the country to join the company.
Making mRNA drugs to coax antibody production “is really important because the time it takes to make an antibody from scratch is really long,” Houston says.
“We’ve had to go as an industry from chimeric human monoclonal antibodies to fully human monoclonal antibodies. Now you’re essentially bypassing all that by having the mRNA and injecting it into the human so they make the antibody themselves,” he says. “It’s really cool. It’s like we’re in the future almost. This blows my mind.”
Besides its scientific and public health implications, the government work could provide a meaningful secondary revenue stream for Moderna’s business. DARPA is providing the grant to develop the technology, and to help Moderna work on mRNA drugs against three specific infectious diseases that Bancel said he can’t publicly identify. DARPA has further agreed to pick up the tab for clinical trial expenses should any of the Moderna molecules get that far. If Moderna can pass all the necessary trials in human beings, it will still own the intellectual property, and could be in position to sell stockpiles of its mRNA drugs to the government, which may want to keep them in freezers just in case they’re needed to fight a pandemic. Or, it could hire Moderna to turn on a dime and start making mRNA drugs against a newly identified pathogen.
Bancel wouldn’t say what the biggest technical challenge is that Moderna must solve to fulfill the DARPA grant. But in the past, he has noted that Moderna must make sure its compounds don’t provoke any nasty immune system reactions—what’s known as immunogenicity. On a recent visit to his office, he also discussed how dosing must be figured out for various mRNA drugs. That’s because tiny doses of mRNA can prompt the body to produce large amounts of therapeutic proteins—perhaps more than necessary or desirable in some situations.
With the validation of AstraZeneca and DARPA, Bancel has options. He almost surely could whip up an IPO road show and take Moderna public if he wanted to, given the investor appetite for new offerings this year. But he has demurred, saying the main goal is to get strong assurance that the compounds are safe before they go into clinical trials. A stumble by Moderna there could be devastating to this entire new area of biology, he says.
“The last thing we want to do is rush and make a mistake,” Bancel says. “We have a big responsibility to society. We believe we can bring forward new drugs to patients. Remember gene therapy? They rushed it to the clinic in the ‘90s, and an 18-year-old died in a clinical trial. It set back the field for a decade. mRNA is brand new, and we don’t want to damage it—it’s our responsibility to society. We are being very responsible and careful, especially now that we have cash. It would be criminal to make a mistake now. We still don’t know what we don’t know. It’s science, so we can never check every box, but in terms of improving product purity, integrity, so that we go in [to clinical trials] knowing as much as we can, it’s very important to us.”