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Dicerna Doses First Primary Hyperoxaluria Patient with DCR-PHXC in Group B Portion of PHYOX Phase 1 Clinical Trial
FDA Grants Orphan Drug Designation for DCR-PHXC for the Treatment of Primary Hyperoxaluria
“The Orphan Drug Designation for DCR-PHXC for the treatment of primary
hyperoxaluria and the dosing of the first primary hyperoxaluria patient
in the Group B portion of the PHYOX trial are important milestones for
the Company as we seek to develop the first GalXC-based RNAi therapeutic
to treat patients with all forms of this serious, life-threatening
The PHYOX trial is a Phase 1, single-ascending dose study of DCR-PHXC in normal healthy volunteers (NHVs) and patients with PH. The study is divided into two groups: Group A is a placebo-controlled, single-blind, single-center study that has enrolled 25 NHVs; Group B is an open-label, multi-center study enrolling up to 16 patients with PH type 1 (PH1) and PH type 2 (PH2).
The primary objective of the PHYOX study is to evaluate the safety and tolerability of single doses of DCR-PHXC in both groups. The secondary objectives are to evaluate the pharmacodynamic effect of single doses of DCR-PHXC on biochemical markers, including but not limited to, changes in urine oxalate concentrations, and to characterize the pharmacokinetics of single doses of DCR-PHXC in NHVs and patients with PH.
“Primary hyperoxaluria is a family of devastating diseases for which
there are currently no approved treatment options,” said Pierre Cochat,
M.D., Ph.D., professor at the
The Company has completed the Group A portion of the PHYOX study. While the study is still blinded and only topline results from Group A are available, there were no serious adverse events (SAEs) and no discontinuations. Out of 25 participants, there have been two mild-to-moderate transient injection site reactions at doses of 6 and 12 mg/kg involving erythema and tenderness, lasting no more than 36 hours. The highest dose level in the Group A portion of the trial was 12 mg/kg, while the highest dose level in the Group B portion is 6 mg/kg.
Dicerna also recently announced that the Company received a notice from
DCR-PHXC is an investigational drug in development for the treatment of all forms of primary hyperoxaluria (PH), and the most advanced product candidate utilizing Dicerna's GalXCTM technology. GalXC is 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. 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 might 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.
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.
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 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 U.S. 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, including, for
example, Dicerna's expected timeline and plans for development of
DCR-PHXC and other pipeline programs, as well as expected regulatory
results and timing. 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 risks relating to Dicerna's clinical and
preclinical research and other risks identified under the heading "Risk
Factors" included in the Company's most recent Form 10-K filing and in
other future filings with the
Oxalosis & Hyperoxaluria Foundation. Overview of hyperoxaluria. 2017. Available at: https://ohf.org/overview/. Accessed July 6, 2017.
Rare Kidney Stone Consortium. Primary hyperoxaluria. 2010. Available at: http://www.rarekidneystones.org/hyperoxaluria/physicians.html. Accessed July 6, 2017.
|3.||Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. Journal of the American Society of Nephrology 2015; 26(10):2559-2570.|
|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 hyperoxaluria. Kidney International 2015; 87:623-631.|