Silenc(ing) disease-driving genes is golden

Dicerna unveils new preclinical data for GalXC delivery of RNAi-based therapy in fight vs. chronic liver disease

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CAMBRIDGE, Mass.—Targeted toward silencing multiple disease-causing genes in the liver, Dicerna Pharmaceuticals Inc. has unveiled preclinical data from primate and rodent disease models showing the promise of its proprietary GalXC platform, which enables direct delivery of RNAi-based therapy to the liver via subcutaneous injection. The optimistic news, delivered at the company’s first Investor Day conference in New York City, gives hope to 3 million U.S. liver disease patients, including the 17,000 adults and children awaiting liver transplants.
Use of GalXC has yielded gene silencing of greater than 90 percent for multiple genes in non-human primates after a single dose, Dicerna reports. In a non-human primate experiment, the maximum HAO1 gene silencing after a single 3 mg/kg dose was 94 percent, with an average gene silencing of approximately 88 percent. Another single 3 mg/kg dose non-human primate study resulted in an average of 97 percent silencing of an undisclosed rare disease gene target.
“The GalXC platform significantly strengthens our capabilities to develop next-generation RNAi-based therapies that silence disease-driving genes in the liver,” says Douglas Fambrough, president and CEO of Dicerna. “Evidence presented (to investors June 29) 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.”
The “longer RNAi duplexes of our GalXC molecules provide greater flexibility to enhance their pharmaceutical properties, including increased potency and reduced toxicity,” adds Bob D. Brown, Dicerna’s chief scientific officer and senior vice president of research. “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 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, Fambrough says.
“We expect to file an Investigational New Drug application for our first GalXC therapy in late 2017,” Fambrough adds. “We also anticipate identifying three clinical candidates annually, starting in 2016, with the potential to launch three new development programs each year. This includes DCR-PHsc for the treatment of primary hyperoxaluria (Dicerna has already launched this program), DCR-undisclosed for the treatment of an orphan genetic disorder and DCR-PCSK9 for the treatment of cardiovascular disease.”
Furthermore, the preclinical data demonstrate that the company’s GalXC technology is now a fully enabled drug discovery engine, with more than 29 disease targets qualified to date, he says.
“When you roll the clock forward, along with our ability to continue to produce them, we believe our pipeline could be five clinical-stage programs, including a late-stage program by 2019,” Fambrough says.
“This is target knockdown in the liver,” Fambrough told investors in a recent conference call. “The whole emerging field of chronic liver diseases—NASH, fatty liver disease, cholestatic diseases—these are ideal targets for a subcutaneous RNAi-based inhibitor.”
Liver disease affects millions of people and leads to more than 34,000 deaths each year, Fambrough says, emphasizing that the bottom line is Dicerna’s GalXC platform has the potential to generate investigational therapies for multiple liver diseases.
The company is also looking at hepatitis B. If you can knock that virus down 99 percent, Fambrough notes, “it is going to be easier to fully eliminate it and have a full HBV cure. I think it’s very likely we’re going to have RNAi as a component of a curative regimen in HBV.”
According to Fambrough, on the oncology side, “we are currently enrolling at maximum tolerated dose a focus cohort around pancreatic neuroendocrine tumors for our MYC-targeted program. We are enrolling our biopsy cohort and collecting data on the molecular destruction of the MYC transcript in tumors, and we are enrolling hepatocellular carcinoma patients as well.”
This data is underway and before the end of the year, “we would expect to provide a full update on outlook for that program, and whether we have achieved the proof of concept that justifies future development—and we’ll know whether it’s a go or a no-go,” he reports.
“Our program selection is based on looking at rare genetic diseases, where we think the probability of clinical success is very high because we understand the basis of the disease,” Fambrough says. “We can target just the right patients who contain the mutations.
“We intend to maintain substantial ownership for key rare disease programs where we feel a company of our scale is able to drive them into late-stage clinical development and maintain full or substantial commercial rights, and build our company forward to integrate around those programs while working with strategic collaborators for the large population size disorders.”

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