Dicerna Expands Lead GalXC™ Development Program to Encompass All Forms of Primary Hyperoxaluria (PH) and Reveals New Therapeutic Target for DCR-PHXC
Jul 17, 2017
DCR-PHXC Achieved Broad, Durable, and Consistent Knockdown of LDHA and Reduction of Oxalate in Multiple Animal Models of PH
New Data Presented at 12th International PH Workshop Also Include Update from PHYOS Trial of Patients with PH1
Management to Host Conference Call Today at
"These research findings are particularly exciting as they show that
inhibition of LDHA reduces oxalate production in animal models of
all forms of primary hyperoxaluria, establishing LDHA as a
potentially ideal therapeutic target and opening the door to a new
treatment approach for this family of diseases," noted
In patients with PH, 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-PHXC, the lead investigational product candidate in Dicerna's pipeline of therapies targeting rare diseases of the liver, yields potent, liver-specific LDHA inhibition in animal models of PH, an effect that reduces oxalate to near-normal levels, which may prevent the damage caused to kidneys and other organs by oxalate accumulation.
At the 12th
LDHA reduction has a linear correlation with oxalate reduction and offers a minimal metabolic intervention, unlike GO reduction. These benefits of LDHA inhibition may translate into consistent therapeutic activity even in the event of a missed dose. There are numerous case reports of LDHA deficiency naturally occurring in humans, with no reported adverse effects due to deficiency in the liver.
"Our data suggest that targeting LDHA results in thorough
suppression of oxalate production," commented
DCR-PHXC is the most advanced product candidate utilizing Dicerna's GalXC technology, a proprietary platform that advances the development of next-generation RNAi-based therapies designed to silence disease-driving genes in the liver. GalXC compounds are intended to be broadly applicable across multiple therapeutic areas, including rare diseases, chronic liver diseases, cardiovascular diseases, and viral infectious diseases. GalXC enables subcutaneous delivery of RNAi therapies to hepatocytes in the liver and offers several distinct potential benefits, as extensively demonstrated in various animal models. Such benefits could include potent silencing of LDHA and other genes; highly specific targeting to hepatocytes, sparing other cell types in the body; a long duration of action; and a simple, infrequent dosing regimen.
"The primary hyperoxalurias are characterized by significant unmet
medical need, as there are no approved treatment options for patients
living with any of these devastating diseases," said
To learn more about PH, the unmet need for a treatment option and Dicerna's recent update on DCR-PHXC and its new therapeutic target, here is a link to an explanatory video.
Conference Call Details
Management will host a conference call at
The call can also be accessed by dialing (855) 453-3834 or (484)
756-4306 (international), and referencing conference ID 54633420 prior
to the start of the call. After the conference call, a replay will be
About Primary Hyperoxaluria (PH)
Primary hyperoxaluria (PH) is a family of severe, rare, genetic liver disorders characterized by overproduction of oxalate, a natural chemical in the body that is normally eliminated as waste through the kidneys. In patients with PH, 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 PH in the US.
There are three known types of PH, each of which results from a mutation in a specific gene, as well as PH for which the molecular basis remains unknown, often referred to as idiopathic PH (IPH) or "no mutation detected" (NMD) PH. The known PH mutations cause a decrease in the activity of a specific enzyme in the liver, triggering an increase in oxalate production. In each case the decreased enzyme activity changes the balance of intermediary metabolites, resulting in overproduction of oxalate. The three genetically known types of PH are: 1,2
- PH1, which is caused by a mutation in the AGXT gene, causing a deficiency of the enzyme alanine:glyoxylate-aminotransferase (AGT)
- PH2, which is caused by a mutation in the GRHPR gene, causing a deficiency of the enzyme glyoxylate/hydroxypyruvate reductase (GR/HPR)
- PH3, which is caused by a mutation in the HOGA1 gene, causing a deficiency of the enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA)
Patients with PH 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 incidence of PH1, the most common type of PH, is 1 in 151,887 births, which implies more than 5,000 patients in the US and EU have the disease.3 The median age at the first appearance of PH1 symptoms is 5.8 years.4 The median age at diagnosis of PH1 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.5 Fifty percent of patients with PH1 reach end-stage renal disease (ESRD) by their mid-30s.2
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. GalXC-mediated delivery technology and
pipeline programs, including DCR-PHXC, are in preclinical development,
and the process by which a preclinical technology and product candidates
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
3. Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype
correlations and estimated carrier frequencies of primary hyperoxaluria.
4. 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.
5. Tang X, Bergstrath EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske JC.
Nephrocalcinosis is a risk factor for kidney failure in primary
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