Rare Disease Report

New Treatment in Development Could Cure Primary Hyperoxaluria

AUGUST 30, 2017
James Radke
Primary hyperoxaluria are a group of rare, genetic liver disorders characterized by overproduction of oxalate.

Oxalate can typically be eliminated from the body via the kidneys, but the high amounts that accumulate in patients with primary hyperoxaluria cannot be efficiently removed. As a result, kidney stones are formed and severe kidney damage becomes a legitimate concern.

Currently, there are only 2 options to increase the elimination of oxalate: the first is to change the ionic concentrations in the kidney (usually via magnesium supplements). The second option is to reduce the concentration of oxalate by drinking excessively large amounts of water.

Unfortunately, neither treatment is particularly effective, and the development of newer treatment options are necessary.

Recently, Rare Disease Report spoke about this rare condition with Michelle Baum, MD, a pediatric nephrologist at Boston Children’s Hospital as well as Douglas Fambrough, PhD, who serves as the president and chief executive officer of Dicerna, a pharmaceutical company developing a potential treatment for patients with primary hyperoxaluria.

Rare Disease Report: What is the cause of primary hyperoxaluria?

Dr. Fambrough: Primary hyperoxaluria is a family of closely-related autosomal recessive genetic diseases, all of which result in the excess production of oxalate. This family of diseases is due to mutations in a particular pathway whose primary role is the catabolic, or breakdown metabolism, of hydroxyproline and that is a major constituent of collagen. This pathway operates in hepatocytes within the liver.

When all of the enzymes are working appropriately, hydroxyproline is metabolized in the liver to the amino acid glycine which can be recycled or reused in protein synthesis but when the various enzymes in the pathway are absent or not functioning due to genetic mutation, that pathway often results in the excess production of oxalate.

Oxolate is an end product of metabolism which means there's no enzyme in the body that can metabolize oxalate— so the only option is excretion and the oxalate which can pass through cell membranes is eliminated in the urine. And that would all be fine, but for the fact that oxalate is highly insoluble in the presence of calcium and so it combines with the calcium that's normally present to create calcium oxalate crystals. The presence of those crystals leads to kidney damage. This becomes a progressive kidney disorder and ultimately leads to end stage renal disease.

RDR: What are the 3 types of primary hyperoxaluria?

Dr. Fambrough: There are 3 forms of the disease: type 1, type 2, and type 3. There are also patients who don't fall in any of these 3 categories and they're sort of lumped together as idiopathic PH or PH of unknown mutation.

Type 1 is the most severe and most common form; approximately 50% of patients with primary hyperoxaluria type 1 will have end stage renal disease some time in their 20s. Liver transplantation ends up being the treatment paradigm for these patients.

Type 2 and type 3 are less severe— they lead to somewhat lower elevated levels of oxalate. They are still elevated to the extent that they have a problem with oxalate crystal formation but not as likely to proceed to end-stage renal disease as much as type 1 patients. For type 2, about 25% of the patients are believed to progress to end stage renal disease as some point. Type 3 is quite rare and these patients generally don't progress all the way to end stage renal disease.

For type 2 and type 3, the issue is mostly chronic stones that require surgical intervention.

Patients with type 1 or 2 that develop end-stage renal disease, there is another set of issues that we goes under the name systemic oxalosis. If the patient's kidneys aren't functioning to remove the excess oxalate then that excess oxalate builds up around the body in the form of oxalate crystals being deposited in other tissues. Accumulation in bone is very common leading to fractures. There's deposition in the skin that can also lead to skin necrosis. Deposition at the retina can cause blindness. And deposition heart valve can cause cardiac problems and generally all organ systems are going to be affected to one extent.

RDR: How is the treated?

Dr Baum: We manage the preventive aspect of the disease with a high fluid intake and the medications that help things dissolve better in the urine like the potassium citrate or phosphate or magnesium therapies.

Some patients with primary hyperoxaluria type 1 will respond to pyridoxone (vitamin B6). Some can have a complete reduction in their urine oxalate or have a smaller reduction in their urine oxalate. But that is only for primary hyperoxaluria type 1 and it only works in about 30% of patients.

The hardest part is the amount of water that we are asking patients, especially children, to take on a daily basis.

RDR: How much water do patients need to drink?

Dr. Fambrough: The amount of water varies depending on the size of the patient but for a full-sized adult you're probably talking 8 liters. For a smaller child it may 2 liters per day but that is still a lot. It's enough that these patients can't watch a movie without going to the bathroom.

It's very difficult to actually do long term and is extremely disruptive to the family.

RDR: How does DCR-PHXC work?

Dr Fambrough: The excess oxalate is produced by an enzyme called lactate dehydrogenase (LDHA). This is not why your body has an LDHA enzyme; it's an activity that LDHA enzyme can do when there is excess glyoxalate. So, if you take out the activity of LDHA then you take out the production of oxalate. “Lactate dehydrogenase” is called that for a reason –that is what it is normally doing that's what it's evolved to it. What we do is we turn off LDHA in the liver and nowhere else. Our drug (DCR-PHXC) is very specific to hepatocytes of the liver, turning off the action of a particular gene, in this case LDHA. We have no impact on LDHA activity in muscle. We're optimistic that by turning off LDHA in the liver we're not going to induce any negative effects and we're going to deal with essentially in its entirety, the problem associated with this disease.

RDR: Is other research being conducted?

Dr. Baum: At the recent workshop in July on primary hyperoxaluria hosted by the Oxalosis and Hyperoxaluria Foundation (OHF), the pharmaceutical industries were able to present the products that are in development and it's pretty amazing that there are several potential medications that are now going to be studied in patients with primary hyperoxaluria. To see something that can actually target the disease specifically and block the oxalate production and sort of shut off that pathway and prevent the development of a chronic kidney disease, or prevent the need for a liver and kidney transplantation is really exciting.

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