Twenty years after scientists found that double-stranded RNA can turn off genes, a drug based on the discovery, known as RNA interference, has been approved. The U.S. Food & Drug Administration has given its blessing to Alnylam Pharmaceuticals’ Onpattro, an RNAi therapeutic for people with a rare and deadly genetic disorder called hereditary transthyretin-mediated amyloidosis.
“This is a very large, and in some ways historic, breakthrough,” says Phillip A. Sharp, a geneticist at MIT and one of Alnylam’s founders.
Indeed, news of the approval rippled through the biotech community, many members of which had closely watched—or lived through—the cycle of hype and disappointment around RNAi. “Everybody loves it when tough science gets solved and gets to the finish line,” says Alnylam CEO John Maraganore.
The concept behind RNAi therapeutics is simple enough: prevent a protein of interest from being made by intercepting its related messenger RNA. To do that, researchers design complementary “silent interfering” RNA, or siRNA, which are double-stranded molecules running 20 to 25 nucleotides in length.
But turning that idea into a drug was easier said than done. Since its formation in 2002, Alnylam, and RNAi therapeutics more broadly, experienced multiple challenges and setbacks—clinical disappointments, legal drama, and the loss of high-profile partnerships, to name a few. Many big pharma firms that had invested in the technology abruptly withdrew, while several RNAi-focused biotech companies either shifted focus or shut down altogether. And the price of innovation was steep: Alnylam alone spent more than $2 billion in its pursuit of an approved drug.
Maraganore sees history repeating itself in other emerging technologies, particularly the gene-editing technology CRISPR. “I look at CRISPR/Cas9, and it reminds me exactly of Alnylam a decade ago,” he says. “There’s IP stuff, technical hurdles that have to be solved, there are moments in time in which a new scientific piece of data emerges and people say, ‘Oh, this will never work.’ We lived through all of that with RNAi.”
One technical hurdle was figuring out how to safely deliver siRNA to the right tissues. To reach its target in the liver, the siRNA in Onpattro is packaged in a lipid nanoparticle, a vessel that required years of engineering. Still more work went into optimizing the chemistry of the RNA molecules themselves.
“It just took a lot of tinkering with delivery,” says Phillip Zamore, another Alnylam cofounder and chair of University of Massachusetts Medical School’s RNA Therapeutics Institute. “Thank god for the lipid nanoparticle chemists and nucleic acid chemists. In a lot of ways, they are the heroes of the story.”
Although a victory for science, Onpattro’s approval is far from the closing chapter in the RNAi therapeutics saga. Many technical hurdles remain to making RNAi broadly applicable. Lipid nanoparticles have a tendency to head straight to the liver—limiting their use to diseases in which the target genes are expressed there. Alnylam focuses on diseases that manifest in the liver, but Maraganore points to recent work showing its molecules could reach the central nervous system if delivered to the spinal cord.
Meanwhile, the number of people this first RNAi therapeutic will reach is small. FDA approved Onpattro for a more narrow portion of the hATTR patient population than Alnylam had hoped for, putting its initial market at about 3,000 people. As such, it is breathtakingly expensive: the list price for an annual course is $450,000, although Alnylam will refund the cost if a patient does not benefit. And a competing product from Ionis Pharmaceuticals could be approved in the U.S. later this year.
But for now, the researchers who ushered in the RNAi era are relishing the approval. “To see it come to fruition and for patients to really significantly benefit—and the promise that there will be many more patients that will benefit from this technology—is just a dream come true,” Sharp says.