Genetic Liver-Targeted Diseases
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.
Learn more about PH, the unmet need for a treatment option and an update on Dicerna’s DCR-PHXC development program
PH can be fatal unless the patient undergoes a dual liver and kidney transplant, a major surgical procedure that is often difficult to perform due to the lack of donors and the threat of organ rejection. Even in the event of a successful transplant, the patient must endure the risks and complications of major surgery and face a lifetime of therapy with immunosuppressant drugs, which have substantial associated risks.
What Causes PH?
There are three known types of PH, each of which results from a mutation in a specific gene. The mutation causes 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 how the liver makes oxalate, resulting in overproduction of oxalate. The three types of PH are: 1,2
- PH1, which results from 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, leading to decreased activity of the glyoxylate/hydroxypyruvate reductase (GR/HPR) enzyme
- PH3, caused by a mutation in the HOGA1 gene, resulting in a deficiency of the 4-hydroxy-2-oxoglutarate aldolase (HOGA) enzyme
In some patients with PH, a genetic mutation has not been identified. These individuals are often referred to as having idiopathic PH (IPH) or “no mutation detected” (NMD) PH.
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 prevalence of PH1, the most common type of PH, is 1 in 151,887, which suggests 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
Why Focus on PH?
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. Currently there are no FDA-approved treatments for the disease in the US. 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. Dicerna’s new preclinical data suggests the potential utility of DCR-PHXC, a GalXC-based investigational therapy, for treating all forms of PH.
Dicerna is preparing to file a clinical trial application in the EU in the fourth quarter, 2017, and plans to begin Phase 1 clinical trials in early 2018.
In a series of presentations at the 12th International Workshop on Primary Hyperoxaluria for Professionals, Patients and Families in Tenerife, Spain from July 14-16, 2017, Dicerna scientists presented research from animal models demonstrating how DCR-PHXC inhibits the lactate dehydrogenase A (LDHA) gene, which Dicerna has identified as potentially being an optimal therapeutic target in patients with PH.
- 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.
- 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.
- 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.
- 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.