Milestone for DsiRNA Therapeutic Follows Receipt of Orphan Drug Designation in US and EU
"Dosing of our first patient with PH1 is an important milestone for
DCR-PH1, as it brings us a step closer to offering a potentially
meaningful therapeutic option to this underserved patient population,"
In patients with PH1, 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-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. In preclinical models, DCR-PH1 also increased the excretion of glycolate, a metabolite that is the substrate of the GO enzyme, and as a result, a pharmacodynamic marker of effective knockdown.
"There is a significant unmet medical need for a treatment option for
patients with primary hyperoxaluria type 1, a devastating disease that
often causes early-onset renal failure," said
The DCR-PH1-101 clinical trial is testing single ascending doses of DCR-PH1 in patients who have a genetically confirmed diagnosis of PH1, 24-hour urine oxalate excretion ≥ 0.7 mmol per 1.73 m2 body surface area (BSA), and an estimated glomerular filtration rate (eGFR) of ≥ 40 mL/min/1.73 m2 BSA. Investigators will monitor patients for 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 that will include a pharmacokinetic analysis to identify an appropriate dose for future studies of DCR-PH1.
"The successful dosing of the first patient in the DCR-PH1-101 trial is
a major event in the clinical development program for this promising
product candidate," commented
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
About Primary Hyperoxaluria Type 1 (PH1)
PH1 is a severe, rare, 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 In patients with PH1, 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 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 have the disease.2 The median age at the first appearance of 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
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. DsiRNA-EX Conjugate-mediated delivery
technology is in preclinical development, and the process by which a
preclinical technology 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
1. Cochat, P, Rumsby, G. Primary hyperoxaluria.
2. Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype
correlations and estimated carrier frequencies of primary hyperoxaluria.
3. 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.
4. 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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