Research to develop small-molecule drug that blocks excess iron absorption

While most people are familiar with anemia - or lack of iron in the blood - they are less familiar with diseases of too much iron.

Excess iron in the body, if left unchecked, can form toxic deposits in major organs leading to serious conditions including heart failure, diabetes, liver cirrhosis, arthritis, and even infertility. Iron overload can be a consequence of a genetically mutated gene known as hereditary hemochromatosis, or a consequence of red blood cell transfusions, required as life saving treatments, for patients with diseases such as thalassemia.

Patients with hemochromatosis and thalassemia both absorb too much iron from their diet which either causes or exacerbates their iron overloading to levels that are toxic.

The mutated gene for hemochromatosis is carried by 1 in 9 Canadians. Currently over 100,000 Canadians and several million people in the US have hemochromatosis, with many of these patients still undiagnosed.

"Part of the problem is that this condition of hemochromatosis will present itself in disguised ways and is often unrecognized by physicians. A patient may have arthritis, or extreme fatigue or even diabetes, but often it's not linked to the real genetic cause, which is iron overload," says Dr. Paul Goldberg of Xenon Pharmaceuticals.

Goldberg is the lead investigator on the $7.5 million project entitled Enabling Studies for a DMT1 inhibitor - A Novel Therapeutic Approach for Treatment of Iron Overload Disorders.

The research, funded by Xenon Pharmaceuticals and Genome BC will tackle the disease, by creating a small-molecule drug to block excess iron absorption at its source: directly in the gut.

Currently, hemochromatosis patients are treated with lifelong phlebotomies - invasive and sometimes painful treatments that require regular trips to the hospital or clinic to remove about half a litre of blood, allowing the patient to produce new blood with less iron.

While phlebotomies work well in many of the patients, they can be problematic, causing recipients to feel unwell for a while following the procedure. "Patients are rendered anemic temporarily so the procedure is not suitable for people with heart conditions or needle intolerance," says Goldberg. He also points out that patient compliance can be a problem with this form of treatment.

As such, Goldberg's research is focused on creating a safe and effective oral therapy as an alternative or adjunctive treatment for those affected by iron overload.

"Patients with hemochromatosis are hyper-absorbing iron he says. The drug that we are developing would block the key transporter for this excess iron uptake, known as DMT1."

Thalassemia patients may also directly benefit from the DMT1 blockers. These patients become severely iron overloaded at a young age due to the requirement for regular life saving blood transfusions and the additive complication of excessive iron absorption from their diet.

Patients who chronically receive blood transfusions are currently treated with iron chelators to control their iron levels. However chelators have severe dose limiting side effects and it remains challenging for clinicians to maintain normal iron balance in these patients. In addition, chelation therapy is extremely expensive, sometimes costing up to $50,000 per patient and may require for some patients frequent and prolonged intravenous administration.

"The Xenon drug provides an oral alternative and is being optimized for patient safety," says Dr. Simon Pimstone, President and CEO of Xenon Pharmaceuticals. "Our DMT1 blockers could lower the dosage of iron chelator drugs making them safer or could make them more effective, either way, improving patient outcomes. Our goal is to test this drug in iron overload patients within two to three years."

"Genome BC is pleased to co-support this innovative research, which may develop an innovative, safe and valuable treatment alternative to patients suffering from iron overload disorders," says Dr. Alan Winter, President and CEO of Genome BC.

http://www.xenon-pharma.com/