Researchers Demonstrate Promise of Dicerna Investigational Therapy in Preclinical Model of Primary Hyperoxaluria Type 1 (PH1)

DCR-PH1 Uses Proprietary Dicer Substrate RNAi Technology to Inhibit Enzyme Implicated in Rare Liver Disorder

WATERTOWN, Mass.--Dicerna Pharmaceuticals, Inc. (DRNA), a leader in the development of RNAi-based therapeutics, today announced the presentation of preclinical data demonstrating the promise of DCR-PH1, the Company’s therapeutic candidate for the treatment of primary hyperoxaluria type 1 (PH1), a rare inherited liver disorder that often results in progressive and severe kidney damage. The research was presented at the 11^th International Primary Hyperoxaluria Workshop in Chicago by Eduardo Salido, Ph.D., Professor of Pathology at the University of La Laguna in Santa Cruz de Tenerife, Spain.

The preclinical studies showed that DCR-PH1 provides potent and long-term inhibition of HAO1, a gene implicated in the pathogenesis of PH1. In 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 significant reduction in urinary oxalate levels, a key marker of the disease. In mice treated with DCR-PH1, urinary oxalate levels returned to near baseline levels, similar to normal mice.

“Physicians, patients and families managing PH1 currently have limited to no effective treatment for this severe and progressive disease,” noted Craig B. Langman, M.D., chair of the workshop and the Isaac A. Abt, M.D., Professor of Kidney Diseases, and Head, Kidney Diseases, at the Ann & Robert H. Lurie Children’s Hospital of Chicago and the Feinberg School of Medicine of Northwestern University. “Based on these encouraging preclinical data, we look forward to beginning clinical trials to determine the potential role of DCR-PH1 in the treatment of PH1.”

PH1 occurs when a liver enzyme called AGT does not function properly due to a genetic defect, inducing the liver to over-produce a metabolite called oxalate. While oxalate has no clinical effect in a healthy population, it is concentrated in the urine by the kidneys of patients with PH1, forming calcium oxalate crystals that can lead to chronic and painful cases of kidney stones, scarring of the kidney and end-stage renal disease.

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

“Our preclinical studies indicate that inhibition of the gene HAO1 prevents expression of glycolate oxidase, as expected, and may therefore reduce significantly the abnormally high oxalate production found in patients with PH1,” commented Dr. Salido. “By blocking production of glycolate oxidase in the liver, DCR-PH1 may prevent the severe kidney damage that is characteristic of PH1.”

“Dr. Salido’s data lend further support to the use of the Dicer Substrate RNAi technology platform, which we believe improves upon existing RNAi technologies in the treatment of rare, genetically defined diseases involving the liver,” stated Pankaj Bhargava, M.D., Chief Medical Officer of Dicerna. “We look forward to initiating clinical trials of DCR-PH1 to validate these preclinical findings in humans.”

About PH1

PH1 is a rare, serious, inherited liver disorder that often results in oxalosis, a rare metabolic disorder that causes 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. Even 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 AGT (alanine:glyoxalate aminotransferase), 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, the estimated prevalence of PH1 is 1 to 3 cases per 1 million people.¹ Fifty percent of patients with PH1 reach ESRD by their late 30s.²

About EnCore^TM Technology

Dicerna uses EnCore lipid nanoparticles, the company’s proprietary delivery system, to deliver the Dicer Substrate RNA (DsiRNA) molecule DCR-PH1 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 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 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 Form 10-Q dated May 14, 2014, 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 June 25, 2014.