Dicerna Begins Dosing in First Clinical Trial of Therapy for Primary Hyperoxaluria Type 1 (PH1) in Healthy Volunteers

Dicerna Pharmaceuticals, Inc. (NASDAQ:DRNA), a leading developer of investigational RNA interference (RNAi) therapeutics, today announced it has initiated dosing in the first clinical trial of DCR-PH1, its investigational therapy for the treatment of primary hyperoxaluria type 1 (PH1). In addition to this Phase 1 study in healthy volunteers, Dicerna expects to begin the first Phase 1 study of DCR-PH1 in patients with PH1 in early 2016. The Company also initiated an international, multicenter, observational study designed to measure biomarkers implicated in PH1 and to identify patients who may be eligible for the Phase 1 trial. Lastly, Dicerna reported that it has identified several DsiRNA-EX-Conjugate candidates for subcutaneous (SC) administration for the treatment of PH1 that meet the Company’s criteria for clinical development.

PH1 is a severe, rare, inherited liver disorder that has no approved therapies. Patients with PH1 over-produce 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. DCR-PH1 also increases the excretion of glycolate, a metabolite involved in oxalate production, providing further proof of inhibition of the GO enzyme, the target of DCR-PH1.

“Initiation of dosing in the first human trial with DCR-PH1 is an important milestone in our robust clinical development program targeting PH1,” said Pankaj Bhargava, M.D., chief medical officer at Dicerna. “Our progress underscores our commitment to rapidly advance this agent for the treatment of PH1, a rare and debilitating disease.”

“PH1 is an aggressive cause of chronic kidney disease that affects thousands of patients and has no approved therapy,” noted Ted Ashburn, M.D., Ph.D., senior vice president of product strategy and operations at Dicerna and the leader of its DCR-PH1 program. “Our efforts are guided by our passion to quickly address the unmet needs of the PH1 community.”

Normal Healthy Volunteer Study (DCR-PH1-102)

DCR-PH1-102 is a two-part, randomized, double-blind, placebo-controlled trial with the primary objective of determining the safety profile of DCR-PH1 in healthy adults following its intravenous (IV) infusion. Part 1 will assess single ascending doses (SAD) of DCR-PH1 and part 2 will examine multiple ascending doses (MAD) of the drug candidate. The study will also investigate the pharmacodynamics (PD) of DCR-PH1 by monitoring changes in plasma and urinary glycolate, the key PD marker of the activity of the oxalate-generating metabolic pathway that causes the pathology associated with PH1. Data from this trial are expected to be available in the second half of 2016.

“This study in healthy volunteers is an important milestone in the development of desperately needed new therapies for patients with PH1, a devastating disease that often causes early onset of renal failure, which is treated today with highly invasive, combined kidney and liver transplants,” commented Sally-Anne Hulton, M.D., speaking on behalf of OxalEurope, a consortium of leading experts in the disease. “We therefore eagerly anticipate results from this trial, and look forward to forthcoming trials of DCR-PH1 in patients with PH1,” added Dr. Hulton, who is a consultant paediatric nephrologist at Birmingham Children’s Hospital in Birmingham, U.K., and a member of the scientific advisory board of the Oxalosis and Hyperoxaluria Foundation (OHF).

First Phase 1 Trial in Patients with PH1 (DCR-PH1-101)

In early 2016, Dicerna expects to initiate enrollment in this open-label study of DCR-PH1 in patients with PH1. The study will be conducted at multiple sites globally and will initially test single ascending doses of DCR-PH1 in patients as young as 12 years old. The DCR-PH1-101 trial will monitor 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.

“The two studies in normal healthy volunteers and patients could usher in a new era of treatment for patients with PH1,” said Craig Langman, M.D., a pediatric nephrologist and the Isaac A. Abt, M.D. Professor of Kidney Diseases at the Feinberg School of Medicine, Northwestern University and Head, Kidney Diseases, at Lurie Children's Hospital. “Positive results from these trials would bring us a step closer to making a viable and novel therapeutic option available to patients living with this devastating disease.”

Observational Study of PH1 Patients

Dicerna also announced initiation of the Primary HYperoxaluria Observational Study (PHYOS), an international, multicenter, observational study that is measuring changes in oxalate, glycolate, and other metabolites over a six-month period in patients with PH1. PHYOS investigators are also collecting data on the clinical manifestations of PH1, fluid intake, and quality of life. Although the study will not include investigational drugs or other interventions, its participants may be considered for enrollment in planned clinical trials of DCR-PH1.

"By collecting data on key biochemical parameters implicated in the pathogenesis of PH1, PHYOS supports our efforts to understand the baseline disease state and presentation of PH1 and will help us roll out our Phase 1 trial,” noted Dr. Bhargava.

Investigators are now enrolling PH1 patients for the PHYOS study, which will eventually include up to 50 patients at as many as 12 sites worldwide. Further details of the DCR-PH1-101, DCR-PH1-102, and PHYOS trials are available at www.dicerna.com.

Identification of DsiRNA-EX-Conjugates as Clinical Candidates for Subcutaneous (SC) Administration for PH1

Dicerna also reported that it has identified multiple DsiRNA-EX-Conjugates that meet key criteria the Company has established for selection of clinical candidates for the subcutaneous (SC) delivery of RNAi therapies to key cells in the liver (hepatocytes), targeting the HAO1 gene. Dicerna is developing DsiRNA-EX-Conjugates in parallel with DCR-PH1, with the goal of providing physicians and patients the option of either IV or SC therapy for their PH1 treatment. Preclinical data across multiple targets suggest that DsiRNA-EX-Conjugates can potently silence genes in the liver. A study presented at the recent EuroTIDES conference indicated an ED50 (a dose that produces a defined effect in 50% of a population) of 0.6 mg/kg in mice receiving DsiRNA-EX-Conjugate therapy with SC administration. Additionally, multiple DsiRNA-EX-Conjugates showing high potency in mice have been tested in non-human primates and have shown excellent translation of activity from mice to the non-human primate model, as expected.

“Based on our preclinical data, there are multiple DsiRNA-EX-Conjugate molecules that meet key criteria we have established for selection of a clinical candidate to follow our DCR-PH1 program, and we plan to take a conjugate to treat PH1 into clinical development in 2017,” noted Bob D. Brown, Ph.D., chief scientific officer and senior vice president at Dicerna. “Thus we are well-positioned for clinical lead selection and development in other therapeutic areas as well.”

“This is truly an exciting time for the PH1 community, as decades of painstaking work are now yielding important research advances that may bring us viable therapeutic options, which the community currently lacks and urgently needs,” said Kim Hollander, executive director of OHF. “We applaud all researchers, including the scientists at Dicerna, for working to gain a deeper understanding of PH1 and to identify and develop potential therapeutic options. We encourage patients and families affected by PH1 to learn more about clinical trials and international patient registries that are planned and underway, and to participate in these ground-breaking research initiatives, which will strengthen the scientific foundation for potential therapies for PH1.”

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, inherited 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 Kidneys are unable to eliminate the large amount of oxalate that is produced in PH1 patients, and its accumulation 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.2 The median age at first 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

Dicerna Pharmaceuticals, Inc., 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 genetically defined cancers, 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 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. DCR-PH1 is in early clinical development, and the process by which an early clinical therapeutic candidate could potentially lead to an approved drug 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.

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