The story feels like a Hollywood flick, not reality—at least to University of Massachusetts Medical School molecular medicine professor and Nobel Prize winner Craig Mello.
Nearly 20 years ago, Mello, Stanford University pathologist Andrew Fire, and their colleagues co-discovered RNA interference, a method of switching off or “silencing” genes before they can make potentially damaging proteins. In 2006, Fire and Mello won a Nobel Prize for their work. And now, within the next month, the first RNA interference drug could be on the horizon.
An RNAi drug from Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY)—patisiran, for the rare nerve disease familial amyloid polyneuropathy—will produce Phase 3 data in September. If successful, patisiran will head to the FDA for a review. If not, fresh questions will arise for a field that has had years of ups and downs. And Alnylam would likely be years away from getting back to this spot.
“I certainly never would’ve predicted that we would have a therapy based on” RNAi, Mello (pictured) says. “It’s almost science fiction, it’s so great.” (Mello isn’t involved with Alnylam.)
Around the year 2000, beginning with Mello and Fire’s work, RNAi electrified scientists across the globe because it offered, at least in theory, a way to create a new class of drugs that could treat diseases that other medications—like monoclonal antibodies, or small molecule drugs—couldn’t touch. Yet it’s been a bumpy road turning theory into reality. Over the past two decades, large pharmaceutical companies like Roche, Abbott Laboratories, Pfizer, and Novartis have fallen in and out of love with RNAi. Promising projects ended in failure. Technological challenges—like safely delivering large RNA molecules into the right tissue, without causing unintended problems—took years to figure out.
Some smaller developers have struggled mightily. Marlborough, MA-based RXi Pharmaceuticals (NASDAQ: RXII), which Mello co-founded in 2003, had to split in two in 2011. Its surviving RNAi work, still under the RXi name, currently trades at less than a dollar a share. (The other part of its business, renamed Galena Biopharma, recently merged with another company after a trial failure.) And once high-flying Sirna Therapeutics, based in San Francisco, had its lab shut down after being acquired by Merck. Alnylam bought its remnants in 2015.
Thanks to several early partnerships that raked in a pile of cash, Alnylam was able to weather the storm and become the largest RNAi company in the world. During its darkest days in 2010, Alnylam’s shares bottomed out around $6 apiece. They’re now close to $90, but the storm clouds will gather once again if patisiran doesn’t come through. “The opening of [that] envelope is probably the biggest pivotal moment for us,” Alnylam president Barry Greene told Xconomy earlier this year.
In a year in which the first U.S. gene therapy is now under review at the FDA, the first CAR-T cell therapy has been approved, and treatments using CRISPR-Cas9 gene editing are heading into clinical testing, it’s easy to overlook RNAi—especially since pharma has largely abandoned it. Even Mello is in on CRISPR; he’s a co-founder of CRISPR Therapeutics (NASDAQ: CRSP), which raised $56 million in an IPO last year.
Yet Mello believes the best is yet to come. RNAi is now capable of things that seemed impossible in the early 2000s, he says. Experimental drugs are lasting weeks or months at a time between injections. Early work is progressing to help deliver RNAi therapies to a variety of tissues, not just the liver, as is the case for the most advanced treatments. “I think the fundamentals are strong,” he says. “This is just the beginning.”
Xconomy spoke with Mello about his thoughts on the past, present, and future of RNAi, and his perspective on the field’s development. (Fire declined to be interviewed for this story.) Edited excerpts of the conversation follow below.
Xconomy: Looking back to the time you, Andrew Fire, and your colleagues published some of the seminal papers on RNAi, did you think you were on to something big?
Craig Mello: To be honest, I’m an optimistic person. Even when I was in high school I probably thought I was on to something big. I just always liked science. I always feel like there’s some major discovery just waiting over the horizon.
X: What were you trying to do with those initial experiments?
CM: We were not directly studying gene silencing. We were trying to use gene silencing just as a tool, and noticed that there were really surprising things going on. And that’s how a lot of discoveries get made, when you notice something unexpected and you decide to pursue it. If you notice something unexpected you might ignore it, too, or think that you made a mistake, but in this case it was obvious there was something interesting going on. It was just a matter of trying to figure out what it was and how the mechanism works. And we’re still working on it today. There’s still a lot to learn.
X: Once the initial discoveries were made, did you get involved in forming a company?
CM: I stayed very centered on the basic research. I don’t think I really appreciated [commercializing discoveries] until my own daughter developed type 1 diabetes back in 2001, when she was 1 year old. It was of course heartbreaking and scary to have a child who is absolutely dependent on science and medicine to stay alive. It really gets brought home to you when someone you love is alive because of molecular or genetic medicine.
X: Once you made your initial discoveries, what did you do with your patents?
CM: We made the decision to license very broadly. We wanted to make it available to researchers at the lowest cost possible. We really didn’t expect there were going to be drugs for a long time anyway, but if they came, then we’d worry about royalty streams at that point. So we made a very cheap license, and frankly didn’t make that much money off of the foundational IP, which is about to expire.
It was a learning curve, because making a patent easy to license isn’t necessarily the best way to commercialize. It actually creates an opportunity for someone to make a follow-on discovery and make a huge amount of money off of what you might call an improvement in an existing technology. That is kind of what MIT was able to do around the technology that Alnylam ended up licensing—essentially they were able to make that the franchise for the company. I don’t know what MIT got, but I bet it’s a lot more than what UMass got for its role in the more foundational IP.
X: Do you regret that?
CM: I don’t regret it personally, because I think there were positive aspects, too, about making the IP easy for people to license. But some folks on the business side of the university probably regret it. I think it could’ve made the university a lot more money than it did. That part I kind of do regret.
X: You did ultimately form one RNAi company, RXi Pharmaceuticals. But it hasn’t distinguished itself in the same way that, say, Alnylam has. Why not, and what did you take from it?
CM: Unfortunately, we didn’t have investors with the vision needed to go through all the ups and downs. We never raised the kind of money that Alnylam raised. The field definitely requires a lot of continued investment and reinvestment. In an academic setting we can make those investments through federally funded and privately funded research. It’s harder for a small company. Unless it can raise a lot of money and run a big research team, it can’t keep pace with what’s being done in academia.
X: Did you think the RNAi field moved too fast?
CM: I can’t blame anybody because hindsight is always much better, 20/20 as they say. But at the time that companies first began to invest directly in RNA interference, they were investing in delivering these natural RNAs that were incredibly unstable. They were almost guaranteed to fail. I think a lot of people underestimated the hurdle that delivery represented. In retrospect it should’ve been pretty clear that a lot of investment in chemistry was going to be necessary to get a potent molecule over the finish line.
In the whole field there was a lot of hyperbole, because it was really cool from a science side that cells could do this and that they had these mechanisms. But everyone I advised, I told them, look: there are obstacles. Maybe that’s why we couldn’t raise much money [at RXi], because I was too honest or something.
X: Are you worried that if Alnylam fails here, it will set the field back once again?
CM: The only thing that would concern me at this point is surprising toxicity or something. That would be very bad, there’s no nice way to put it. But if there are problems, I don’t think it’s going to end this field. One trial failing would just be another one failing. But I think it’s going to be successful—and it’s just the beginning.
X: As gene therapy, CRISPR, and other methods advance, is RNAi being surpassed?
CM: The nice thing about RNAi is you can withdraw the drug and you haven’t permanently modified the individual, whereas with gene therapy [and gene editing technologies] you’re stuck with any kind of negative ramifications. The fact is that the delivery problems have been solved for some target tissues and are being solved for others like the brain. In the meantime we found out that the duration of effect is surprisingly long. So I’d say the upside is much bigger than the downside in all of this.
X: What does the future hold for RNAi?
CM: It’s a whole new ballgame now. The hard work has been done, or a lot of it. It’s time to start making drugs. And that requires a big investment, but now it’s an investment that’s much more likely to see a return.