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First RNAi drug approved
C R E D I T: A L N YL A M
Nod for Alnylam’s Onpattro comes two decades after the discovery of RNA interference 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 (hATTR). “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,” Alnylam CEO John Maraganore says. 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 small 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, has 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 founder and chair of the 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. 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,
A two-decade roller coaster for RNAi ▸ 1998: Craig Mello and Andrew Fire publish a Nature article demonstrating that double-stranded RNA could turn off specific genes in C. elegans. ▸ 2002: Alnylam is formed with $2 million in investor funding. ▸ 2005: Novartis and Alnylam establish a broad pact to develop RNAi therapeutics. The deal becomes a key source of research funding for Alnylam. ▸ 2006: Mello and Fire win the Nobel Prize in Physiology or Medicine for the discovery of RNA interference and gene silencing. ▸ 2010: Alnylam lays off a third of its staff after Novartis decides not to extend their R&D pact. ▸ 2016: Alnylam ends development of revusiran after unexplained patient deaths in a Phase III clinical study in people with hATTR with cardiomyopathy. The firm’s stock price fell by half. ▸ 2018: Alnylam wins FDA approval for Onpattro.
although Alnylam will refund the cost if a patient does not benefit. 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.—LISA JARVIS, with reporting
by Ryan Cross AUGUST 13/20, 2018 | CEN.ACS.ORG | C&EN
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