Orphan Drug Designation by the EMA provides regulatory and financial
incentives under Regulation (EC) No. 141/2000 for companies to develop
and market therapies that treat a life-threatening or chronically
debilitating condition affecting no more than five in 10,000 persons in
DCR-PH1 is Dicerna's proprietary therapeutic candidate in development for the treatment of PH1. Preclinical experiments indicate that DCR-PH1 knocks down hydroxyacid oxalyase-1 (HAO1), the gene transcript that encodes for the enzyme glycolate oxidase (GO), which, in turn, reduces the excretion of oxalate in the urine.
"We are very pleased to have received Orphan Drug Designation in the EU
for DCR-PH1. This is an important regulatory milestone for our team
working to bring this therapy to patients with PH1," said
DCR-PH1 incorporates a proprietary, lipid nanoparticle (LNP) technology
that allows for efficient delivery to the liver after intravenous (IV)
administration. Dicerna obtained rights to this delivery technology by
way of a licensing agreement with
About Primary Hyperoxaluria Type 1 (PH1)
PH1 is a rare, inherited disorder of the liver in which excess oxalate production can result in severe damage to the kidneys and other organs. Patients with this disease often undergo combined liver and kidney transplant, a major surgical procedure, and subsequently must take immunosuppressant drugs for the rest of their lives. Currently there are no approved therapies for the treatment of PH1 in the EU.
PH1 is characterized by a genetic mutations in the AGXT gene, which encodes for the liver enzyme alanine:glyoxylate-aminotransferase (AGT). AGT deficiency causes overproduction of oxalate by the liver, which can result in the deposition of calcium oxalate crystals in the kidneys. The deposition of calcium oxalate crystals can lead to both nephrolithiasis (the presence of kidney stones in the kidney) and nephrocalcinosis (calcification in the renal parenchyma, the functional part of the kidney), the latter of which has been linked to more rapid progression to end-stage renal disease (ESRD) and the need for intensive hemo- and/or peritoneal dialysis and a kidney transplant. In addition, PH1 patients in ESRD also need an orthotopic liver transplant (liver removal followed by replacement in the normal position) to correct the overproduction of oxalate. 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. It is estimated that up to three people per one million have PH1.1 The median age at first symptoms is 5.8 years.2 The median age at diagnosis is between 4.2 and 11.5 years depending on whether or not nephrocalcinosis is present.3 Fifty percent of patients with PH1 reach ESRD by their mid-30s.4
Dicerna is developing DCR-PH1, which is in preclinical development, for the treatment of PH1. DCR-PH1 is engineered to address the pathology of PH1 by targeting and destroying the messenger RNA (mRNA) produced by HAO1, a gene implicated in the pathogenesis of PH1. HAO1 encodes glycolate oxidase (GO), an enzyme involved in producing oxalate. By reducing oxalate production, this approach seeks to prevent the complications of PH1. Preclinical studies indicate that DCR-PH1 induces potent and long-term inhibition of HAO1 and significantly reduces levels of urinary oxalate, while demonstrating long-term efficacy and tolerability in animal models of PH1.
About Dicerna's Dicer Substrate Technology
Dicerna's proprietary RNAi molecules are known as Dicer substrate short-interfering RNA molecules, 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 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 preclinical development, and
the process by which a preclinical therapeutic candidate could
potentially lead to an approved drug is long and subject to significant
risks and uncertainties. Orphan Drug Designation does not assure a
faster or more probable regulatory path. 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
Cochat, P, Rumsby, G. Primary hyperoxaluria.
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 Ducth cohort. Nephrology, Dialysis, Transplantation 2012; 27(10):3855-3862.
Tang X, Bergstrath EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske
JC. Nephrocalcinosis is a risk factor for kidney failure in
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