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: [[ticker: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: [[ticker: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: [[ticker: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
