-- Company to Host First R&D Webcast on
In the R&D webcast, the company will discuss details of its DCR-PH1 program, its treatment for the orphan disease primary hyperoxaluria type 1 (PH1). Expected to enter the clinic in 2015, DCR-PH1 incorporates a new and proprietary extended Dicer substrate molecule (DsiRNA-EX) and in-licensed lipid nanoparticle (LNP) delivery technology from Tekmira Pharmaceuticals. The company will also describe, for the first time, its proprietary conjugate-mediated delivery technology, which will enable subcutaneous delivery of RNAi therapy and will be featured in future liver-targeted programs. These liver delivery technologies complement Dicerna's proprietary oncology-focused EnCore LNP delivery system.
"Dicerna continues to make rapid progress in engineering highly precise
and targeted RNAi-based treatments for rare, inherited diseases
involving the liver and for cancers that are genetically defined," said
Dicerna management will also include a summary of recent developments in
the company's presentations at the Stifel 2014 Healthcare Conference in
Update on the DCR-PH1 Development Program
Dicerna expects to release initial data from a phase 1 clinical trial of DCR-PH1 in patients with PH1 by the end of 2015. DCR-PH1 is an investigational extended Dicer substrate RNA (DsiRNA-EX) molecule delivered via LNP technology. In the DCR-PH1 DsiRNA-EX molecule, one of the two RNA strands carries a 10-base extension. This extended structure improves the immunosilencing and stability properties of the DsiRNA-EX molecule. DsiRNA-EX technology is covered by Dicerna patent 8,349,809 and other Dicerna patent applications and is distinct from other existing RNAi patent estates. As announced earlier today, the DCR-PH1 delivery system has been in-licensed from Tekmira. This system has been demonstrated in both non-human primate studies and human clinical studies to provide potent, safe and effective RNA delivery to hepatocytes (liver cells). Use of the Tekmira LNP is expected to streamline the development path for DCR-PH1 and allow Dicerna to focus its proprietary EnCore LNP delivery platform on its oncology pipeline.
DCR-PH1 addresses the pathology of PH1 by seeking to target and destroy the messenger RNA produced by HAO1, a gene implicated in the excessive production of oxalate in PH1 patients. Oxalate is the key driver of pathogenesis in PH1. By reducing oxalate production, this approach is expected to prevent the kidney damage and other complications associated with PH1. In preclinical studies, DCR-PH1 induces potent and long-term inhibition of HAO1 and significantly reduces urinary oxalate levels, while demonstrating long-term tolerability in animal models of PH1.
First Disclosure of the DsiRNA-EX Conjugate-Mediated Subcutaneous Delivery Platform
Dicerna has developed a proprietary DsiRNA-EX conjugate-based delivery system to advance the development of its pipeline of liver-targeted RNAi therapies. These conjugates do not involve lipid nanoparticles and are built on the DsiRNA-EX platform, using an extension to one strand of the double-stranded DsiRNA molecule. DsiRNA-EX conjugates can be delivered subcutaneously, while still retaining capability for intravenous administration, allowing flexibility in mode of administration. The DsiRNA-EX conjugate technology is covered by Dicerna patent 8,349,809 and other Dicerna patent applications and is distinct from other existing RNAi conjugate-mediated delivery patent estates.
Identification of Additional Liver-Targeted RNAi Therapies
Following an extensive review of rare diseases with gene targets expressed in the liver, Dicerna has prioritized a broad portfolio of research and development opportunities. The company is currently pursuing discovery research on several rare diseases involving the liver and intends to add additional programs over time. Dicerna expects to declare its first DsiRNA-EX conjugate clinical candidate in 2015 for an undisclosed rare disease involving the liver. For competitive reasons, the company does not plan to specify disease areas or therapeutic targets until a program has reached a late preclinical stage.
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 which carries
substantial risk. 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. Currently, there are no
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. 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
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.
RNAi therapeutics have the potential to treat a number of human diseases by "silencing" disease-causing genes. The discoverers of RNAi, a gene silencing mechanism used by all cells, were awarded the 2006 Nobel Prize for Physiology or Medicine.
About Dicer Substrate Technology
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.
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
that LNP technology may fail to deliver DCR-PH1 to the liver in human
beings or otherwise fail to accelerate clinical development, clinical
trials may not demonstrate the effectiveness of DCR-PH1, and the
DsiRNA-EX conjugate-based delivery system may fail to advance the
development of Dicerna's pipeline of liver-targeted RNAi therapies.
Additional risks, including those relating to Dicerna's preclinical
research and clinical development and other risks, are identified under
the heading "Risk Factors" included in our most recent Form 10-Q filing
and in other future filings with the
1 Cochat, P, Rumsby, G. Primary Hyperoxaluria.
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