Dicerna Pharmaceuticals
May 13, 2016

Dicerna Announces Dosing of First Patient in Phase 1 Clinical Trial of DCR-PH1 in Patients with Primary Hyperoxaluria Type 1 (PH1)

Milestone for DsiRNA Therapeutic Follows Receipt of Orphan Drug Designation in US and EU

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Dicerna Pharmaceuticals, Inc. (NASDAQ:DRNA), a leading developer of RNA interference (RNAi) therapeutics, today announced that the Company has dosed the first patient in its DCR-PH1-101 trial, the first Phase 1 clinical trial of DCR-PH1 in patients with primary hyperoxaluria type 1 (PH1). A severe, rare, inherited disorder of the liver, PH1 often results in kidney failure, and there are no approved therapies for the disease.

The U.S. Food and Drug Administration (FDA) designated DCR-PH1, an investigational Dicer substrate short interfering RNA (DsiRNA) therapeutic, as an Orphan Drug in April 2015. In August 2015, the European Medicines Agency (EMA) granted Orphan Drug Designation to DCR-PH1 in the European Union (EU). More recently, in December 2015, Dicerna initiated dosing in a Phase 1 trial of DCR-PH1 in healthy volunteers.

"Dosing of our first patient with PH1 is an important milestone for DCR-PH1, as it brings us a step closer to offering a potentially meaningful therapeutic option to this underserved patient population," said Pankaj Bhargava, M.D., chief medical officer of Dicerna. "We eagerly await the first clinical readout from this study, as well as from the normal healthy volunteer study, and we look forward to sharing the results with the PH1 community."

In patients with PH1, the liver over-produces oxalate, a metabolite that can accumulate throughout the body and particularly in the kidneys, often resulting in end-stage renal disease (ESRD) and the need for both kidney and liver transplants. DCR-PH1, the lead investigational product candidate in Dicerna's pipeline of therapies targeting rare diseases of the liver, is based on the Company's proprietary DsiRNA-EX technology. In a genetic mouse model of PH1, DCR-PH1 markedly knocked down HAO1, the gene transcript that encodes for the enzyme glycolate oxidase (GO), causing near normalization of oxalate levels. In preclinical models, DCR-PH1 also increased the excretion of glycolate, a metabolite that is the substrate of the GO enzyme, and as a result, a pharmacodynamic marker of effective knockdown.

"There is a significant unmet medical need for a treatment option for patients with primary hyperoxaluria type 1, a devastating disease that often causes early-onset renal failure," said Bernd Hoppe, M.D., Head of the Division of Pediatric Nephrology in the Department of Pediatrics at the University of Bonn, Germany. "Currently, patients with PH1 must resort to combined transplantation of the kidney and liver, a highly invasive and burdensome procedure. Given the encouraging inhibitory activity of DCR-PH1 in animal studies, we are excited to begin dosing in humans, as we hope this clinical trial will produce similarly positive results."

The DCR-PH1-101 clinical trial is testing single ascending doses of DCR-PH1 in patients who have a genetically confirmed diagnosis of PH1, 24-hour urine oxalate excretion ≥ 0.7 mmol per 1.73 m2 body surface area (BSA), and an estimated glomerular filtration rate (eGFR) of ≥ 40 mL/min/1.73 m2 BSA. Investigators will monitor patients for changes in urinary and plasma glycolate and oxalate, key efficacy markers in PH1. Once safety has been demonstrated with single doses, the trial will transition to a multi-dose study that will include a pharmacokinetic analysis to identify an appropriate dose for future studies of DCR-PH1.

"The successful dosing of the first patient in the DCR-PH1-101 trial is a major event in the clinical development program for this promising product candidate," commented Douglas Fambrough, Ph.D., president and chief executive officer of Dicerna. "If successful, the trial will validate our DsiRNA-EX technology platform as a vehicle for inducing RNA interference, and it will provide important justification for our innovative approach to treating rare and debilitating diseases."

About DCR-PH1

DCR-PH1 is being developed by Dicerna for the treatment of PH1 by addressing its pathology through the targeting and destruction of the messenger RNA (mRNA) produced by the HAO1 gene. HAO1 encodes glycolate oxidase (GO), an upstream enzyme involved in the production of oxalate, the mediator of pathogenesis and progression of PH1. Preclinical studies have shown that DCR PH1 inhibited HAO1 and significantly increased levels of glycolate and reduced levels of urinary oxalate.

DCR-PH1 incorporates small interfering RNA (siRNA) formulated in a proprietary lipid nanoparticle (LNP) technology that is being investigated as a system for efficient delivery to the liver after intravenous (IV) administration. Dicerna obtained rights to this delivery technology through a licensing agreement with Arbutus Biopharma Corporation, formerly known as Tekmira Pharmaceuticals Corporation.

About Primary Hyperoxaluria Type 1 (PH1)

PH1 is a severe, rare, genetic liver disorder that causes excess oxalate production due to mutations in the AGXT gene, which encodes for the liver enzyme alanine:glyoxylate-aminotransferase (AGT).1 In patients with PH1, the kidneys are unable to eliminate the large amount of oxalate that is produced, and the accumulation of oxalate can result in severe damage to the kidneys and other organs. Currently, there are no approved therapies for the treatment of PH1 in the US.

Patients with PH1 often undergo both liver and kidney transplants, which are major surgical procedures, and subsequently must take immunosuppressant drugs for the rest of their lives. Patients with decreased renal function may also experience oxalosis, which involves a build-up of oxalate in other organs such as the bone, skin, heart, and retina, possibly causing other concomitant, debilitating complications.

The estimated genetic prevalence of PH1 is 1 in 151,887, which suggests more than 5,000 patients in the US and EU have the disease.2 The median age at the first appearance of symptoms is 5.8 years.3 The median age at diagnosis is between 4.2 and 11.5 years, depending on whether nephrocalcinosis (calcification in the renal parenchyma, the functional part of the kidney) is present.4 Fifty percent of patients with PH1 reach end-stage renal disease (ESRD) by their mid-30s.5

About Dicerna Pharmaceuticals, Inc.

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.

Cautionary Note 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. DsiRNA-EX Conjugate-mediated delivery technology is in preclinical development, and the process by which a preclinical technology could potentially lead to an approved product is long and subject to significant risks and uncertainties. Applicable risks and uncertainties include those relating to our preclinical and clinical research and other risks identified under the heading "Risk Factors" included in our most recent Form 10-K 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. Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. Journal of the American Society of Nephrology 2015; 26(10):2559-2570.

3. van der Hoeven SM, van Woerden CS, Groothoff JW. Primary hyperoxaluria type 1, a too often missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of the Dutch cohort. Nephrology, Dialysis, Transplantation 2012; 27(10):3855-3862.

4. Tang X, Bergstrath EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske JC. Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria. Kidney International 2015; 87:623-631.

5. Rare Kidney Stone Consortium. Primary hyperoxaluria. 2010. Available at: http://www.rarekidneystones.org/hyperoxaluria/physicians.html. Accessed March 28, 2016.

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Source: Dicerna Pharmaceuticals, Inc.

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