Dicerna Pharmaceuticals
Dec 21, 2015

Dicerna Updates Progress on the Development of DCR-MYC for the Treatment of Solid Tumors

- Company Expects to Achieve Proof-of-Concept for DCR-MYC in 2H 2016 -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Dicerna Pharmaceuticals, Inc. (NASDAQ:DRNA), a leading developer of investigational RNA interference (RNAi) therapeutics, today reported continued progress in the clinical development of DCR-MYC, Dicerna's investigational Dicer substrate short interfering RNA (DsiRNA) therapeutic designed to silence MYC, an oncogene implicated in multiple tumor types. Dicerna plans to report proof-of-concept data for DCR-MYC in the second half of 2016 based on anticipated results from a Phase 1 clinical trial of DCR-MYC in patients with advanced solid tumors, multiple myeloma, or lymphoma, and a Phase 1b/2 trial in patients with hepatocellular carcinoma (HCC).

"We are pleased with the progress, enrollment, and initial clinical trial results seen to date in our DCR-MYC program," said Douglas Fambrough, Ph.D. chief executive officer of Dicerna. "Taken together, the DCR-MYC 101 and 102 studies will allow us to explore anti-tumor activity of DCR-MYC in two focused patient populations, specifically patients with HCC and pancreatic neuroendocrine tumors, where we have seen indications of activity in clinical or pre-clinical settings. Investigators have not yet identified the maximum tolerated dose of DCR-MYC in either trial. We look forward to completing this step, advancing the trials, and reporting additional results in the second half of 2016."

DCR-MYC utilizes Dicerna's EnCoreTM lipid nanoparticle (LNP) tumor delivery system, which delivered DsiRNA molecules to multiple tumor types, including hepatocellular carcinoma, in preclinical disease models.

DCR-MYC-101 Study, a Phase 1 Study in Advanced Solid Tumors and Hematological Malignancies

The ongoing Phase 1 study, initiated in April 2014, is a multi-center, dose escalation trial designed to assess the safety and tolerability of DCR-MYC in patients with advanced solid tumors, multiple myeloma, or lymphoma who are refractory or unresponsive to standard therapies. The study is also designed to identify the compound's maximum tolerated dose (MTD), the pharmacokinetic (PK) profile, potential pharmacodynamic (PD) effects using F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, and anti-tumor activity based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1). In the study, DCR-MYC is administered as a two-hour intravenous (IV) infusion once-weekly for two weeks, followed by a one week break (3 weeks = 1 cycle). All patients receive premedications with dexamethasone, diphenhydramine, and an H-2 blocker.

As of December 15, 2015, 37 patients have been treated with DCR-MYC, in nine dose cohorts from the starting dose of 0.1 mg/kg to the current dosing level of 1.25 mg/kg. The MTD has not been determined. We have observed anti-tumor activity in two of three patients with advanced, treatment refractory low-to-intermediate grade pancreatic neuroendocrine tumors (PNET), including a partial tumor response (34% reduction in tumor size) based on RECIST 1.1 criteria. A second PNET patient achieved a complete metabolic response based on imaging with FDG-PET. This patient had a drug holiday lasting 12 months before demonstrating recurrence, based on increased metabolic activity as seen on FDG-PET scan. This patient resumed treatment with DCR-MYC, and again achieved a complete metabolic response based on imaging with FDG-PET while demonstrating stable disease (28.6% reduction in tumor size) based on RECIST 1.1 criteria. Both patients were treated with multiple therapies for PNET prior to starting the study. Overall, four patients in this study have received treatment for six months or more with stable disease.

Based on clinical activity observed in patients with PNET, Dicerna announced in May 2015 an expansion of the ongoing DCR-MYC Phase 1 trial to include a cohort of patients with PNET. This multi-center expansion cohort will enroll up to 20 patients with low- to intermediate-grade PNET who have demonstrated disease progression after treatment with standard therapies such as Sutent® or Afinitor®. Dicerna will initiate enrollment in this expansion cohort in early 2016. Dana-Farber Cancer Institute, MD Anderson Cancer Center, and Stanford University Cancer Center will join the study to participate in the expansion cohort, in addition to the two existing sites, START San Antonio and University of Chicago Cancer Center.

Once the MTD of DCR-MYC has been determined, Dicerna plans to initiate enrollment of a cohort of patients who will undergo pre- and post-treatment tumor biopsies. Molecular analysis of the MYC gene transcript in these biopsies will allow direct observation of the RNAi-mechanism of action of DCR-MYC.

"The preliminary Phase 1 safety and efficacy results are encouraging and support further study of DCR-MYC for use as a new treatment option for patients with cancer," said Pankaj Bhargava, M.D., Dicerna chief medical officer. "We look forward to determining the MTD of DCR-MYC and to dosing patients in both the PNET and biopsy cohorts during 2016. By demonstrating the DCR-MYC mechanism of action in tumor biopsies, and in conjunction with FDG-PET and RECIST 1.1 criteria responses, we hope to attain proof-of-concept for the clinical activity of DCR-MYC in patients. We expect to be able make this determination in the second half of 2016."

DCR-MYC-102 Study, a Phase 1b/2 Study in Hepatocellular Carcinoma (HCC)

The ongoing Phase 1b/2 study is a multi-center, dose escalation trial designed to assess the safety and tolerability of DCR-MYC in patients with advanced HCC who do not respond to or do not tolerate standard-of-care sorafenib, or patients who lack access to sorafenib or for whom no suitable therapy is available. The study is also designed to identify the compound's MTD, the PK profile, and anti-tumor activity based on modified RECIST. As in the DCR-MYC-101 study, DCR-MYC is administered as a two-hour intravenous (IV) infusion once-weekly for two weeks, followed by a one week break (3 weeks = 1 cycle). All patients receive premedications with dexamethasone, diphenhydramine, and an H-2 blocker. The study was initiated in December 2014.

As of December 15, 2015, 14 patients have been treated with DCR-MYC, in five dose cohorts from the starting dose of 0.125 mg/kg to the current dosing level of 0.68 mg/kg. Dose escalation will continue until determination of the MTD, at which point Dicerna will initiate an expansion cohort at MTD that includes pre- and post-treatment biopsies, as well as the Phase 2 portion of the study. Molecular analysis of the MYC gene transcript in tumor biopsies will allow direct observation of the RNAi-mechanism of action of DCR-MYC in HCC.

About Pancreatic Neuroendocrine Tumors (PNETs)

PNETs are a group of rare tumors that develop in endocrine cells found in the pancreas. Although PNETs are rare, their incidence has been rising significantly over the last 20 years.1 In the United States, the incidence of PNET has increased approximately 80% from 2007-2012, with an estimated 3,000 new patients diagnosed annually; about half of them are diagnosed with metastatic disease.2 Similar epidemiology trends are also reported in Europe and Japan. 3, 4 The median age of presentation is approximately 60 years old and the five-year survival is reported to be less than 43%.5, 6 Surgical resection, when feasible, is the primary treatment for patients. However, most patients with PNETs are diagnosed in advanced stages of the disease when surgical resection is no longer an option. Patients with non-resectable disease are generally treated with approved medical therapies including the two targeted therapies approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with advanced PNET.

About Hepatocellular Carcinoma (HCC)

Liver cancer is the second leading cause of cancer-related deaths worldwide, with 745,000 deaths per year.7 Hepatocellular carcinoma (HCC) is the most common form of liver cancer in adults. In the United States, an estimated 25,000 new patients are diagnosed annually and HCC is the fastest rising cause of cancer mortality with a five-year survival reported to be approximately 12%.8 Most cases of HCC result from infection with the hepatitis B or C virus, which can lead to cirrhosis of the liver.9 However, non-alcoholic fatty liver disease, associated with obesity and diabetes, is also an important risk factor for HCC.10 Early-stage HCC is generally treated with surgery, which is potentially curative; however, given the nonspecific symptoms that are characteristic of HCC, the substantial majority of patients are diagnosed only after HCC is at an advanced stage. Patients with advanced HCC have limited treatment options, and the disease is associated with poor patient outcomes and high mortality.

About MYC

MYC genomic duplications and amplifications are associated with a large number of cancers. Disruption of MYC activity has been associated with anti-tumor efficacy in a wide variety of tumor types in animal models. As a result, a drug that inhibits MYC has long been a goal for the pharmaceutical industry. However, due to the nature of the MYC protein, MYC is considered an undruggable target, recalcitrant to direct inhibition by traditional pharmaceutical approaches. By utilizing the RNAi mechanism targeted to the MYC transcript, Dicerna seeks to directly target MYC. In preclinical research involving human tumors implanted in mice, and in mice that were genetically engineered to develop tumors, Dicerna's DCR-MYC substantially reduced the level of MYC expression and slowed or halted tumor progression.

About RNAi

RNA interference (RNAi) is a biologic process in which certain double-stranded RNA molecules inhibit the expression of disease-causing genes by destroying the messenger RNAs (mRNAs) of those genes. This approach may enable the development of specific and powerful therapies for genetic cancers and rare inherited diseases involving the liver. RNAi has the potential to treat these diseases through some of the most promising, yet previously inaccessible drug targets.

Traditional classes of drugs, small molecules and antibodies, have been used successfully for diseases with well-defined targets and proteins, encoded by disease-associated genes. However, both of those classes are limited by the nature of the targets they can inhibit. RNAi offers the potential to overcome these limitations. Rather than targeting and binding to proteins to inhibit their activity, RNAi exerts its effects one step earlier in the process by targeting the mRNA, the instruction set that directs the building of the protein. In this manner, RNAi can potentially attack any target. Potential targets include disease-causing genes that are expressed exclusively inside cells and which lack good small-molecule binding pockets, putting them beyond the reach of traditional antibody and small molecule technology.

About Dicer Substrate Technology

Dicerna's innovative Dicer substrate short-interfering RNA (DsiRNA) technology platform fuels a pipeline of promising, precisely targeted drug candidates designed to potentially overcome many of the challenges of earlier generations of RNAi therapeutics. Dicerna's DsiRNA and DsiRNA-EX molecules are at the core of its therapeutic candidates. Dicerna seeks to chemically optimize its double-stranded RNAs to potently induce RNAi. Dicerna has further developed the ideas behind DsiRNAs to create its DsiRNA-EX molecules, which potentially carry additional benefits.

Dicerna's proprietary RNAi molecules are known as Dicer substrates because they are designed to be processed by the Dicer enzyme, which is the initiation point for RNAi in the human cell cytoplasm. Dicerna's discovery approach seeks to maximize RNAi potency through optimized structuring of DsiRNA 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. Dicerna's DsiRNA Extended (DsiRNA-EX) molecules resemble DsiRNA molecules but have an extended region at one end which is engineered to provide additional functionality to the DsiRNA-EX molecules. Dicerna can also use this extended region to generate its DsiRNA-EX Conjugates, whereby a drug delivery agent is linked directly to the extended region of the DsiRNA-EX molecule, potentially enabling the delivery of DsiRNA-EX Conjugates to patients through a subcutaneous injection.

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-MYC 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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10. Gambarin-Gelwan M. Viral hepatitis,non-alcoholic fatty liver disease and alcohol as risk factors for hepatocellular carcinoma. Chin Clin Oncol 2013;2(4):32. doi:10.3978/j.issn.2304-3865.2013.09.02


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Source: Dicerna Pharmaceuticals, Inc.



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