Two decades passed between the discovery of RNA interference, a natural mechanism of gene control, and approval of the first drug built on the Nobel Prize-winning science.
The 2018 breakthrough of the rare disease drug Onpattro, and further advances in RNAi last year, has now set the stage for a trio of biotechs: Alnylam Pharmaceuticals, developer of Onpattro, Arrowhead Pharmaceuticals and Dicerna Pharmaceuticals.
As the just-wrapped J.P. Morgan Healthcare Conference sets the tone for 2020, all three look to build on their field's momentum, which has sparked resurgent interest from large pharmaceutical companies.
While gene therapy and editing drove headlines last year, RNAi drugmakers were some of the industry's best-performing stocks. Alnylam, the biggest of the three, was up 62%, while Dicerna's stock more than doubled and Arrowhead shares skyrocketed 422% in 2019. As Alnylam's CEO told BioPharma Dive last November, "RNAi has got its sexy back."
Such heady returns are unlikely to be replicable, Arrowhead CEO Christopher Anzalone conceded in an interview at the JPM conference. But, he said, expanding the RNAi platform into organs outside the liver could drive his company well beyond its nearly $6 billion market valuation, putting it out of reach of most companies interested in a takeover.
"I don't think we have alignment with any potential acquirer, because we can continue to grow this company organically very rapidly," Anzalone said. "It would shock me if anybody could write a big enough check to make sense to our shareholders."
"We are in the first out of the first inning of the lifespan of RNAi," he added.
That's true, at least, for RNAi as a medicine. The technology has emerged from a 20-year journey in which large drugmakers began research, lost interest and only now begun to reenter.
Less than two months ago, Novartis paid nearly $10 billion to acquire The Medicines Company, a deal driven by one asset, an RNAi heart drug called inclisiran. On the first day of JPM, the Swiss pharma announced ambitious plans alongside U.K. health officials to study inclisiran in a wide patient population and to ramp up manufacturing capacity for RNAi medicines.
"I believe inclisiran has the potential to be one of the largest, if not the largest, medicine at Novartis in our history," Novartis CEO Vas Narasimhan said Monday.
That optimism comes even as RNAi's commercial potential has yet to be proved out. Alnylam is still in early days of selling Onpattro, while Novartis will need to demonstrate it can avoid the fate of Amgen, Sanofi and Regeneron, which sell non-RNAi drugs targeting the same protein as inclisiran. Both therapies, Praluent and Repatha, have disappointed in their commercial launches.
Alnylam, the original developer of inclisiran, has led the field for years and can boast of being first to commercial marketing. Last year marked the first full year of sales for the Cambridge, Massachusetts-based biotech after 16 years of R&D and featured a Food and Drug Administration OK for its second drug, Givlaari.
By the end of 2020, the company anticipates having its third RNAi therapeutic on the market.
But the real test of RNAi as a broader drug category will be taking the technology outside of the liver, which has been the focus of all three companies.
Alnylam partnered with Regeneron last year to combine its tech with Regeneron's antibodies in central nervous system and eye diseases.
Dicerna, meanwhile, spent 2019 inking R&D partnerships with major industry players including Roche and Novo Nordisk, the latter of which effectively exhausted the last viable RNAi target in the liver, CEO Douglas Fambrough said in an interview.
This year will begin to bring early answers as to whether RNAi can have the same impact on diseases that develop elsewhere in the body. Arrowhead announced in December it will begin testing its RNAi platform in solid tumors.
"We've always preached the value of bringing RNAi outside of the liver," Anzalone said. "Now we're ready."
Anzalone's 2020 plans don't end there. The biotech plans to also test RNAI in lung diseases, starting with cystic fibrosis, and in muscle diseases. Anzalone said the goal is for Arrowhead to have 10 drugs in clinical testing by the end of the year. Three or four years from now, he thinks Arrowhead could have 20 therapeutic candidates in the clinic.
Yet as RNAi develops, other genetic medicine platforms are advancing rapidly. The first hemophilia gene therapy is expected to launch later this year, pending FDA approval, and gene editing approaches using CRISPR will begin to yield fuller clinical data.
Whether these technologies will compete or complement each other remains unclear. In 2018, Alnylam CEO John Maraganore suggested a symbiotic relationship, calling it a potential yin-and-yang pairing for gene therapy and RNAi in hemophilia, for instance.
But in recent interviews, Fambrough and Anzalone expressed skepticism gene therapy or gene editing will displace RNAi therapies.
Dicerna's chief executive compared gene therapy approaches to “getting a tattoo every time you go to the doctor's office." While it may make sense in certain diseases, he argued, the approach has limitations, too.
Anzalone voiced skepticism with CRISPR in particular, contrasting the genetic changes it effects with RNAi.
“The permanence of CRISPR and other technologies scares the heck out of me," he said. “Wait until the first patient who needs to be un-CRISPR-ized occurs, and that person will, and people will appreciate the real danger of that technology."
"Biology is funny. We don't know nearly as much as we think we do," he added, predicting that CRISPR will have a similarly lengthy journey to approved therapeutic as RNAi.
“People are forgetting that's the way new modalities work when they think about CRISPR," he said. “I don't know what's going to trip them up, but if history is prologue, CRISPR is going to have to go through that cycle as well."