The Company Expects to Initiate Clinical Dosing in Q1 2018
"The filing of this CTA marks an important milestone for Dicerna, for
our GalXC technology platform, and most importantly, for our pipeline of
GalXC product candidates," said
Once the CTA is authorized by the MHRA, Dicerna plans to conduct the Phase 1 trial as a randomized, single-blind, placebo-controlled, single-ascending dose study, enrolling up to 25 healthy volunteer subjects and up to 16 patients with PH. The primary objective of the study is to evaluate the safety and tolerability of single doses of DCR-PHXC, with participants being enrolled into as many as five sequential cohorts of increasing doses. Patients with PH will be dosed after safety has been established at the same dose level in normal healthy volunteers. Secondary endpoints include the pharmacokinetics of DCR-PHXC and its pharmacodynamic effects on oxalate biomarkers in plasma and urine.
DCR-PHXC is the most advanced product candidate utilizing Dicerna's GalXC technology, a proprietary platform invented by Dicerna scientists to discover and develop next-generation RNAi-based therapies designed to silence disease-driving genes in the liver. DCR-PHXC targets the lactate dehydrogenase A (LDHA) gene, a non-essential gene that Dicerna has identified as being a potentially optimal therapeutic target in patients with PH.
In animal models of PH, DCR-PHXC selectively silences LDHA in the liver, blocking the excess production of oxalate, a hallmark of the disease. In preclinical studies of DCR-PHXC, the compound was well tolerated with no adverse effects in the liver. Studies have shown that people who are completely deficient in LDHA show no liver dysfunction and can lead normal lives. LDHA deficiency in the liver should be beneficial for patients with PH, as the LDHA enzyme is implicated in the abnormal production of oxalate in PH, which in turn is responsible for the severe damage to kidneys and other organ systems in patients with PH.
"Based on pre-clinical data, LDHA has the potential to be an
ideal therapeutic target in patients with PH and we hope to replicate
the inhibitory effect on oxalate production in human clinical studies,"
"With this CTA filing, and the expected initiation of a first-in-human,
proof-of-concept Phase 1 trial of DCR-PHXC once the MHRA authorizes the
CTA, Dicerna is pursuing an exciting and important approach that may
address a high unmet medical need in primary hyperoxaluria," noted
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 or the EU.
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
Patients with severe 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.
PH affects an estimated 1 in 58,000 individuals around the world. PH1 is the most common form of the disease, accounting for approximately 80% of cases, whereas PH2 and PH3 each account for roughly 10% of cases.3 The estimated genetic incidence of PH1 is 1 in 151,887 births, which implies more than 5,000 patients in the US and EU have the disease.4 The median age at the first appearance of PH1 symptoms is 5.8 years.5 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.6 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. Examples of forward-looking statements
include, among others, statements we make regarding: (i) the therapeutic
and commercial potential of GalXC™; (ii) research and development plans
related to GalXC; and (iii) the potential of our technology and drug
candidates in our research and development pipeline. The process by
which early clinical technology and product candidates such as DCR-PHXC
could potentially lead to an approved product is long and subject to
highly significant risks. Applicable risks and uncertainties include
those relating to our preclinical research and other risks identified
under the heading "Risk Factors" included in our most recent Form 10-Q
filing and in other future filings with the
3. Genetics Home Reference. Primary hyperoxaluria.
4. Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype
correlations and estimated carrier frequencies of primary
|5. 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.|
6. 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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