NEWS & ANALYSIS

Nature Reviews Drug Discovery | Published online 28 Feb 2018; doi:10.1038/nrd.2018.20 “We’ve had our near-death experiences,” concedes Maraganore. Alnylam prepares to land first Merck continued to outwardly express enthusiasm for RNAi for a few years longer, but never moved any RNAi therapies into its RNAi drug approval publicly disclosed pipeline, and eventually With Alnylam’s rare disease drug candidate patisiran nearing the regulatory sold its Sirna intellectual property (IP) to finish line, the RNA interference community is now turning its attention to once-arch-rival Alnylam in early 2014 for less next-generation delivery technology to solidify the future of the emerging modality. than a sixth of the Sirna purchase price. “I think that large companies, and large pharma in particular, really stink at Chris Morrison start-ups captured the imaginations and innovation around platforms, and we saw enthusiasm of venture capitalists and public that with RNAi,” Maraganore says. The Drug developers have been fishing in the investors, and industry’s largest companies near-death experiences that strengthened bumpy RNA interference (RNAi) waters for eventually bought into the hope and hype as Alnylam’s resolve are culturally incompatible years without a catch in sight. They probably well. Novartis committed hundreds of millions with large organizations, he argues. And so won’t have to wait much longer. In December of US dollars for access to Alnylam’s platform when early generation RNAi candidates 2017, RNAi pioneer Alnylam Pharmaceuticals in 2005, and Roche followed suit in 2007. In failed to deliver on their promise, it was finalized its regulatory submissions to the 2006, Merck & Co. paid $1.1 billion to acquire unsurprising to see big companies cut back FDA and the European Medicines Agency Alnylam’s main rival Sirna Therapeutics, which or abandon the space. of patisiran, for the treatment of hereditary prior to that deal had signed pacts with Alnylam was able to persevere, however, transthyretin-mediated (ATTR) amyloidosis, GlaxoSmithKline and others. The scientists with support from hold-out partner Sanofi. a rare and potentially fatal disease who discovered RNAi won the Nobel Prize Sanofi first signed on in 2012, and expanded characterized by the build-up of amyloid in in 2006. this alliance in 2014 by buying $700 million peripheral nerves, the heart and other organs. But owing to difficulties delivering RNAi worth of Alnylam stock in exchange for The breakthrough-designated drug could hit therapeutics to systemic targets, RNAi’s status options to license rights to Alnylam’s leading the US and European markets this summer. as the next big thing in drug development pipeline assets outside of North America and An approval will be a “landmark moment in subsequently waned. “When Sirna was sold to Western Europe. In January 2018, the a 15‑year journey to harness the RNAi Merck, we were expecting the first generation partners renegotiated the deal such that pathway as a source of medicines,” says John of programmes to pan out in the clinic,” Alnylam gained worldwide rights to patisiran Maraganore, CEO of Alnylam. It will also says Douglas Fambrough, CEO of the RNAi as well as to ALN‑TTRsc02, a subcutaneously “facilitate new approvals in the future,” therapeutics company Dicerna administered ATTR amyloidosis follow-on he adds, providing regulators with an Pharmaceuticals and an early Sirna investor programme that will enter phase III in 2018. opportunity to come to grips with the and board member. But those programmes Sanofi now has worldwide rights to phase III modality. were unsuccessful. Naked delivery of RNAi candidate fitusiran, a once-monthly, Drug developers have of course already candidates to the eye to treat conditions such subcutaneously administered antithrombin had success with oligonucleotide-based as age-related macular degeneration failed. RNAi for haemophilia A and haemophilia B. drugs. Regulators approved Ionis Early iterations of lipid nanoparticle (LNP) Pharmaceuticals’ and Sanofi’s high cholesterol delivery platforms — designed to encase and … and flows treatment mipomersen in 2013, for example, protect RNA from degradation before it With RNAi now on the verge of its first highlighting the ability of single-stranded reaches its target — required extremely high approval, the biopharma industry is DNA-based oligonucleotides to silence mRNA dosing to show even modest efficacy, and re-engaging with this technology. Amgen via antisense mechanisms. And Ionis has also then only worked in liver-mediated diseases. partnered with Arrowhead Pharmaceuticals filed its mRNA-silencing antisense inotersen “None of the respiratory stuff worked, none of (which in 2011 acquired Roche’s RNAi for hereditary TTR amyloidosis, as a potential the cardiovascular stuff worked, and as that programmes and IP) in 2016 in a deal that competitor to patisiran. But patisiran — became clear the big pharma partners began could be worth up to $675 million, for which uses a double-stranded RNA-based to peel away,” says Fambrough. example, to work on cardiovascular projects. oligonucleotide to dampen protein In late 2010, Novartis and Roche both cut And Boehringer partnered with Dicerna in expression via the RNA-induced silencing ties with Alnylam, delivering a combination 2017, pledging up to $200 million, to work on complex — now stands to broaden the punch that forced the biotech to restructure. non-alcoholic fatty liver disease and other biological range of oligonucleotide agents chronic liver diseases. In part, says and add another option to the therapeutic Maraganore, the interest is driven by the tool box. ability to evaluate the potential of experimental candidates like they would a Enthusiasm ebbs … Targeting liver RNAs with small molecule or an antibody. “When these RNAi, a natural process for gene silencing, single-stranded or double- medicines start coming forward and start was discovered in 1998 (see Nature’s RNAi stranded RNA? Boy, I pretty showing high-impact results like patisiran has, animation). It quickly became a powerful [large companies] will be interested in specific research tool to control protein expression, well think we have it nailed products,” Maraganore says. and by 2002 a field of start-ups emerged to But renewed enthusiasm is also a product turn RNAi oligonucleotides into drugs. Those of how quickly the RNAi field is moving.

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NEWS & ANALYSIS

Table 1 | Select late-stage RNA interference programmes Drug candidate Developer Clinical stage Target Therapeutic indication Delivery method Patisiran Alnylam Pharmaceuticals Registration TTR Hereditary ATTR amyloidosis Lipid nanoparticle QPI‑1002 Quark Pharmaceuticalsa Phase III p53 Delayed graft function Naked QPI‑1007 Quark Pharmaceuticals Phase III Caspase 2 Non-arteritic anterior ischaemic Naked optic neuropathy Tivanisiran Sylentis/PharmaMar Phase III TRPV1 Moderate to severe dry eye Naked Fitusiran Sanofi/Alnylam Phase III Antithrombin Haemophilia A, haemophilia B GalNAc conjugate Pharmaceuticals Givosiran Alnylam Pharmaceuticals Phase III ALAS1 Acute hepatic porphyrias GalNAc conjugate Inclisiran The Medicines Company/ Phase III PCSK9 Hypercholesterolaemia GalNAc conjugate Alnylam Pharmaceuticals Source: Biomedtracker. ALAS1, 5-aminolevulinic acid synthase 1; GalNAc, N-acetylgalactosamine; PCSK9, proprotein convertase subtilisin/kexin type 9; TRPV1, transient receptor potential vanilloid 1; TTR, transthyretin. aNovartis holds an option to license QPI‑1002 following a phase III study.

Patisiran uses an intravenous LNP delivery Getting RNAi to work in other therapeutic $170 million since 2015 to harness technology that Alnylam and other RNAi areas is still challenging, says Art Krieg, CEO membrane sacs called exosomes to deliver hopefuls have almost entirely abandoned of Checkmate Pharmaceuticals and former oligonucleotides. Whereas LNPs are synthetic in favour of next-generation alternatives. head of oligonucleotide therapeutics at Pfizer. lipid-based vehicles, exosomes are naturally The leaders in this field are instead now “But targeting liver RNAs with single-stranded secreted from cells and are part of what conjugating RNAi to N-acetylgalactosamine or double-stranded RNA? Boy, I pretty well Codiak CEO Doug Williams calls a (GalNAc) or similar ligands to generate think we have it nailed. And there are a lot of “fascinating and ancient communication products with better therapeutic indices, liver targets,” he says. system”. Codiak’s lead drug candidate, which which can be injected subcutaneously, at And for these targets, RNAi exhibits should enter the clinic in late 2018, is an higher doses and with better side-effect extraordinary drug-like properties that rival anti-KRAS RNAi designed to treat pancreatic profiles. or exceed those of antibodies, argues cancer. “We’re letting the exosomes lead the The most advanced GalNAc-conjugated Fambrough. The technology is “incredibly way,” says Williams, “and the pancreas seems RNAis are now in phase III (see TABLE 1). safe”, with a high therapeutic index and a to be a tissue to which exosomes go in The biotech Arrowhead shut down multiple long duration of effect. At least in the liver, abundance.” The reasons for this trafficking intravenously delivered RNAi programmes in Fambrough says, “there’s now a comfort level pattern remain unknown, he says. 2016 when the FDA placed a clinical hold on that this probably works and it’s got a bunch Other companies are working to exploit its lead experimental hepatitis B treatment of uses in some interesting areas in exosomes for drug delivery as well. Several due to toxicity in a non-human primate cardiovascular disease, chronic liver disease pharma and biotech companies “have been study, and has shifted instead to a new and rare disease.” exploring exosomes in many cases to solve pipeline of ligand-conjugated products. Indeed patisiran met all primary and delivery problems for payloads they have Dicerna, too, has transitioned to secondary end points in its phase III pivotal access to,” says Williams. “This is an idea that subcutaneous delivery using a GalNAc-based trial, and common side effects including has come of age,” he says. platform, and dosed its first patient with its injection-site reactions and peripheral Arrowhead is meanwhile developing an new line of product candidates near the end oedema after 18 months of dosing were inhaled formulation of RNAi, to act in the of 2017. mild or moderate. The follow-on lung, which is set to enter clinical trials this These products, which make a bee-line GalNAc-conjugated candidate ALN‑TTRsc02 year. for hepatocyte receptors, play to the should theoretically achieve even better RNAi therapies are also just one piece of biological tendency of oligonucleotides to results. the broader ecosystem of oligonucleotide traffic to the liver. And, notes Maraganore, Executives still hope however that the liver technologies, which include antisense and “the entirety of the modern pharmacopeia” is just the beginning for RNAi. “We have data exon-skipping drugs, viral-mediated gene for liver-mediated diseases represents more in extrahepatic delivery that we think are very therapies, mRNA-based drugs and than $50 billion worth of marketed products, promising and that might open up the door genome-editing CRISPR therapeutics. And not including long-genericized drugs such as further, for RNAi therapy in cancers, in central development and delivery success with these statins. In other words, even if RNAi remains nervous system disease and other areas,” oligonucleotides could lift the RNAi tide. confined to liver targets, the opportunity Maraganore says. Some companies have also “I really am feeling more confident than here is significant. RNAi drugs are on the persevered in the development of late-stage ever that oligonucleotide therapeutics are horizon for rare liver-mediated diseases such products that use naked RNAi to target the going to represent the third major platform of as haemophilia as well as more common eye and the kidney. drug development,” says Krieg, placing the liver-associated diseases including hyper- Emerging technologies may yet extend the emerging modality alongside small molecules cholesterolaemia (PCSK9 is predominantly reach of RNAi and other oligonucleotide and biologics. “At the beginning, I was expressed in the liver) and hepatitis B therapies further still. The biotech Codiak skeptical about RNAi. But the progress in that infection. BioSciences, for example, has raised nearly field has been extraordinary.”

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