Dicerna Presents Preclinical Data for Investigational RNAi Therapeutic DCR-PH1 in Primary Hyperoxaluria Type 1 (PH1) at the 10th Annual Meeting of the Oligonucleotide Therapeutics Society

Dicerna Pharmaceuticals, Inc. (NASDAQ:DRNA), a leader in the development of RNAi-based therapeutics, presented data from its preclinical program in primary hyperoxaluria type 1 (PH1) in a poster session at the 10th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held in San Diego, October 12-15, 2014. The data confirm the therapeutic potential of DCR-PH1, the company’s investigational treatment for PH1, a rare, inherited liver disorder that often results in kidney failure.

“These additional data provide a more complete understanding of the mechanism of our Dicer Substrate RNAi technology in preclinical models of PH1,” said Douglas Fambrough, Ph.D., chief executive officer of Dicerna. “We hope to validate these preclinical findings in humans and are on track to enter the clinic with DCR-PH1 in 2015.”

The latest findings add to the preclinical evidence of potent and long-term inhibition of HAO1, a central target gene for the treatment of PH1, and provide evidence of long-term efficacy and tolerability of DCR-PH1 in mice. In a separate study of genetically modified mice, researchers observed a significant reduction in levels of urinary oxalate, the metabolite responsible for kidney disease in PH1 patients.

“The additional data provide further evidence of the rapid and durable activity of DCR-PH1, as well as long-term tolerability after four-month chronic dosing,” said Bob D. Brown, Ph.D., chief scientific officer of Dicerna. “By reducing production of the enzyme that converts glycolate to oxalate, DCR-PH1 treatment lowers oxalate levels and increases glycolate levels, two independent molecular markers that confirm reduction of HAO1 expression.”

In a previous presentation of data from a genetically modified mouse model of PH1, researchers reported a 97 percent reduction of the HAO1 transcript in the liver after a single dose of DCR-PH1 and a reduction in urinary oxalate to near-normal levels.

About Primary Hyperoxaluria Type 1 (PH1)

PH1 is a rare, inherited liver disorder that often results in severe damage to the kidneys. The disease can be fatal unless the patient undergoes a liver-kidney transplant, a major surgical procedure that is often difficult to perform due to the lack of donors and the threat of organ rejection. In the event of a successful transplant, the patient must live the rest of his or her life on immunosuppressant drugs, which have substantial associated risks.

PH1 is characterized by a genetic deficiency of the liver enzyme alanine:glyoxalate-aminotransferase (AGT), which is encoded by the AGXT gene. AGT deficiency induces overproduction of oxalate by the liver, resulting in the formation of crystals of calcium oxalate in the kidneys. Oxalate crystal formation often leads to chronic and painful cases of kidney stones and subsequent fibrosis (scarring), which is known as nephrocalcinosis. Many patients progress to end-stage renal disease (ESRD) and require dialysis or transplant. Aside from having to endure frequent dialysis, PH1 patients with ESRD may experience a build-up of oxalate in the bone, skin, heart and retina, with concomitant debilitating complications. Currently, aside from dual liver and kidney transplant, there are no highly effective therapeutic options for most patients with PH1. While the true prevalence of primary hyperoxaluria is unknown, it is estimated to be one to three cases per one million people.1 Fifty percent of patients with PH1 reach ESRD by their mid-30s.2

About DCR-PH1

DCR-PH1 is engineered to address the pathology of PH1 by targeting and destroying the messenger RNA (mRNA) produced by HAO1, a gene implicated in the pathogenesis of PH1. HAO1 encodes glycolate oxidase, a protein involved in producing oxalate. By reducing oxalate production, this approach is designed to prevent the complications of PH1.

About EnCoreTM Technology

Dicerna uses EnCore lipid nanoparticles, the company’s proprietary delivery system, to deliver the Dicer substrate RNA (DsiRNA) molecule to liver tissues. Once in the liver, the DsiRNA leads to the specific destruction of the gene transcript that encodes the enzyme glycolate oxidase, which is responsible for the pathologic accumulation of oxalate in PH1. This process is highly specific for the targeted gene.

About RNAi

RNAi is a highly potent and specific mechanism for regulating the activity of a targeted gene. In this biological process, certain double-stranded RNA molecules known as short interfering RNAs (siRNAs) bind to complementary messenger RNAs (mRNAs) and recruit proteins that break the chemical bonds that hold mRNAs together, preventing the mRNAs from transmitting their protein-building instructions.

Dicerna’s proprietary RNAi molecules are known as Dicer substrates, or DsiRNAs, so called because they are processed by the Dicer enzyme, which is the initiation point for RNAi in the human cell cytoplasm. Dicerna’s discovery approach is believed to maximize RNAi potency because the DsiRNAs are structured to be ideal for processing by Dicer. Dicer processing enables the preferential use of the correct RNA strand of the DsiRNA, which may increase the efficacy of the RNAi mechanism, as well as the potency of the DsiRNA molecules relative to other molecules used to induce RNAi.

About Dicerna Pharmaceuticals, Inc.

Dicerna is a biopharmaceutical company focused on the discovery and development of innovative treatments for rare, inherited diseases involving the liver 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 both rare diseases and oncology, Dicerna is pursuing targets that have been difficult to address using conventional approaches, but where connections between targets and diseases are well understood and documented. The company intends to discover, develop and commercialize novel therapeutics either on its own or in collaboration with pharmaceutical partners.

Cautionary Contact on Forward-Looking Statements

This press release includes forward-looking statements. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Applicable risks and uncertainties include those relating to our preclinical research and other risks identified under the heading "Risk Factors" included in our most recent Form 10-Q filing and in other future filings with the SEC. The forward-looking statements contained in this press release reflect Dicerna's current views with respect to future events, and Dicerna does not undertake and specifically disclaims any obligation to update any forward-looking statements.

References

1 Cochat, P, Rumsby, G. Primary hyperoxaluria. The New England Journal of Medicine 2013; 369(7): 649-658.

2 Rare Kidney Stone Consortium. Primary Hyperoxaluria. 2010. Available at: http://www.rarekidneystones.org/hyperoxaluria/physicians.html. Accessed October 14, 2014.