For RNAi, 2013 proved to be a year largely marked by incremental successes that, while not always the most attention grabbing, reflect the maturity of the gene-silencing technology and have helped it begin to reignite the interest of big pharma in RNA therapeutics.
It was during the past year that RNAi — indeed, RNA therapeutics in general — "have come of age," Regulus Therapeutics CEO Kleanthis Xanthopoulos told Gene Silencing News. "There is no longer skepticism about whether the … approach works."
One of the biggest validations for RNA drugs came in late January when the US Food and Drug Administration approved Isis Pharmaceuticals' antisense-based hypercholesterolemia treatment Kynamro (mipomersen).
Although Isis had previously gotten regulatory clearance for an antisense drug, this was the first time the FDA okayed a systemically administered one, which was a major positive for all those developing nucleic acid therapies, Miragen Therapeutics President and CEO William Marshall noted.
Of major importance to the RNAi field specifically has been Alnylam Pharmaceuticals ongoing work with its TTR-mediated amyloidosis drugs patisiran, which is systemically administered, and ALN-TTRsc, which is delivered subcutaneously, Marshall said.
In July, the company reported positive phase II data showing that patisiran, formerly known as ALN-TTR02, could cut levels of its target protein by as much as 93 percent. By November, Alnylam had begun enrolling patients in a phase III study of the drug, marking the first ever pivotal trial for the industry-leading company.
These achievements, University of Texas Southwestern researcher David Corey said, have gone a long way in increasing optimism in RNAi, showing that delivery isn't an insurmountable hurdle and that it's "likely that someone will ultimately make some money on one of these drugs."
Meanwhile, ALN-TTRsc just weeks ago moved into phase II testing — a critical milestone for a field that has long struggled to find new ways to effectively deliver its therapeutic payloads. While most RNAi drugs have heretofore used lipid-based delivery vehicles, ALN-TTRsc employs Alnylam's proprietary GalNAc technology, which facilitates liver delivery of siRNAs via uptake through the asialoglycoprotein receptors expressed on the surface of hepatocytes.
The uptake mechanism behind the GalNAc approach has been known for a long time, Marshall said, but making it efficient enough for drug delivery has been problematic. Alnylam's efforts show that "continuing to look at systems … can really result in some game-changing opportunities."
Arrowhead Pharmaceuticals has also been blazing its own trail away from lipid nanoparticle delivery with its hepatitis B treatment ARC-520, which uses the company's so-called dynamic polyconjugates (DPCs).
Originally developed by Mirus Bio, which was later acquired by Roche, DPCs are composed of endosomolytic polymers linked to siRNAs and combined with a tissue-specific targeting ligand. After the molecule is taken into a cell via endocytosis, the decreasing pH of the maturing endosome unmasks the polymer, which disrupted the endosomal membrane and releases the siRNA into the cytoplasm.
After acquiring the RNA drug assets of Roche, Arrowhead has run with DPCs and the HBV program, reporting in October positive phase I data on the drug and last month filing to move it into a phase IIa study.
The company also disclosed in 2013 that, going forward, it would focus exclusively on drug candidates that use DPCs and that it had dropped a phase I cancer drug delivered with an older cyclodextrin-based polymer nanoparticle delivery technology.
Amid the work of Alnylam, Arrowhead, and other RNAi companies with drugs in the clinic, big pharma has once again begun warming up to the technology, as well as related modalities including antisense and microRNAs.
The RNAi space was particularly hard hit in late 2010 and early 2011 when Roche and Pfizer announced that they dropping their in-house efforts with nucleic acid drugs, which contributed to a general sense that these molecules had failed to live up to their potential. Even this year, Merck announced that it was reorganizing to reduce its focus on platform technologies, of which RNAi is one.
Nevertheless, the pharmaceutical industry is once again viewing RNA therapeutics as "very worthwhile," but is expressing that sentiment in ways other than large internal research and development initiatives, such as alliances and, potentially, acquisitions, according to Xanthopoulos.
Marshall agreed. "The divestiture of internal research efforts does not mean abandonment of interest in the portfolio," he said. "This is not unique to nucleic acid therapeutics; you're seeing it everywhere," Marshall said. "It's a sort of realignment in the way big pharma is spending cash."