New Preclinical Data Show Potential of Dicerna GalXC™ Subcutaneous Delivery Platform as RNAi Drug Discovery Engine

Business Wire: June 29, 2016 – CAMBRIDGE, MA, U.S.A. – Dicerna Pharmaceuticals, Inc. (NASDAQ: DRNA), a leading developer of investigational RNA interference (RNAi) therapeutics, today will unveil preclinical data showing the promise of its proprietary GalXC™ subcutaneous (SC) delivery platform as an RNAi drug discovery engine. At the company’s Investor Day conference in New York City, Dicerna management will present preclinical data both from nonhuman primates and from rodent disease models showing that GalXC enables direct delivery of RNAi-based therapy to the liver via SC injection, with potential utility against diverse therapeutic targets, based on consistent, potent, and durable silencing of multiple disease-causing genes in the liver.

“The GalXC platform significantly strengthens our capabilities to develop next-generation RNAi-based therapies that silence diseasedriving genes in the liver. Evidence presented today spans GalXC conjugates in various states of optimization targeting a dozen gene targets implicated in various rare diseases, chronic liver diseases, cardiovascular disease, and hepatitis B virus,” said Douglas Fambrough, PhD, president and chief executive officer of Dicerna. “We expect to file an investigational new drug application for our first GalXC therapy in late 2017. We also anticipate identifying three clinical candidates annually starting in 2016, both on our own and potentially in collaboration with development partners.”

At the Investor Day conference, Dicerna will report on the preclinical application of GalXC RNA duplexes to achieve gene silencing of well-characterized hepatic disease genes such as HAO1, Alpha-1-antitrypsin (SERPINA1), and numerous undisclosed targets, as well as updated tolerability data, molecular details of the GalXC platform, and the history of GalNAc-mediated delivery of oligonucleotides to the liver. Use of the GalXC platform has yielded gene silencing of greater than 90% for multiple genes in nonhuman primates after a single dose. In a nonhuman primate experiment, the maximum HAO1 gene silencing after a single 3 mg/ kg dose was 94%, with an average gene silencing of approximately 88%. Another single 3 mg/kg dose nonhuman primate study resulted in an average of 97% silencing of an undisclosed rare disease gene target. Duration of effect data suggest a monthly preclinical dosing interval, or even less frequently for select gene targets.

The GalXC platform relies on Dicerna’s GalNAc DsiRNA-EX conjugate technology platform to deliver RNAi therapies by SC administration. Dicerna scientists attach small drug delivery agents, known as N-acetylgalactosamine (GalNAc) sugars, directly to the extended region of a Dicer substrate short-interfering RNA (DsiRNA-EX) molecule, a chemically optimized, double-stranded RNA developed by Dicerna. The GalNAc sugars specifically bind to receptors on target cells in the liver, leading to effective delivery and silencing of specific gene targets within the cells. Many of the conjugates produced using the GalXC platform incorporate a folded motif known as a tetraloop, which stabilizes the RNA duplex and provides multiple conjugation points for the addition of GalNAc sugars. The tetraloop configuration, which is unique to Dicerna’s conjugates, interfaces effectively with the RNAi machinery within target cells.

“The longer RNAi duplexes of our GalXC molecules provide greater flexibility to enhance their pharmaceutical properties, including increased potency and reduced toxicity,” explained Bob D. Brown, PhD, chief scientific officer and senior vice president of research at Dicerna. “The GalXC platform allows us to screen and optimize therapeutic leads in mice and monkeys with remarkable efficiency. Within a month of nominating a gene target expressed in the liver, we are able to design, synthesize, and validate GalXC duplexes in animal models.”

GalXC™ is a proprietary technology platform invented by Dicerna to advance the evaluation of next-generation RNAi-based therapies designed to silence disease-driving genes in the liver. Compounds produced via the GalXC technology are intended to be broadly applicable across multiple therapeutic areas including cardiovascular disease, nonalcoholic steatohepatitis (NASH) and related fibrotic conditions of the liver, hepatitis B virus (HBV), and various rare diseases. Using GalXC, Dicerna scientists attach N-acetylgalactosamine (GalNAc) sugars directly to the extended region of a Dicer substrate short-interfering RNA (DsiRNA-EX) molecule, yielding multiple proprietary conjugate delivery configurations. GalXC enables subcutaneous delivery of Dicerna’s RNAi therapies to hepatocytes in the liver, where they are designed to specifically bind to receptors on target cells, potentially leading to internalization and access to the RNAi machinery within the cells. The technology may offer several distinct benefits, as suggested by robust preclinical data. These benefits include potent silencing of gene targets; highly specific binding to hepatocytes; long duration of action; and an infrequent subcutaneous dosing regimen, while retaining the potential for intravenous dosing, allowing for flexibility in mode of administration. Conjugates produced via the GalXC platform can be administered as simple saline solutions and do not need transport technologies (such as lipid nanoparticles) to facilitate delivery.

Dicerna Pharmaceuticals, Inc., is an RNA interference-based biopharmaceutical company focused on the discovery and development of innovative treatments for rare, inherited diseases involving the liver, for other therapeutic areas in which the liver plays a key role, and for cancers that are genetically defined. The company is using its proprietary RNA interference (RNAi) technology platform to build a broad pipeline in these therapeutic areas. In many cases, Dicerna is pursuing targets that have historically been difficult to inhibit using conventional approaches, but where connections between targets and diseases are well understood and documented. The company intends to discover, develop, and commercialize these novel therapeutics either on its own or in collaboration with pharmaceutical partners. For more information, please visit www.dicerna.com.