Xenon is developing small molecule inhibitors against DMT1 as a novel treatment for iron overload disorders. The primary indications for DMT1 inhibitor monotherapy include the idiopathic iron overload disorder hereditary hemochromatosis (HH) and thalassemia intermedia (TI). These disorders are characterized by a relatively rapid and progressive iron overloading of tissues leading to significant morbidities such as cardiomyopathy, diabetes, cirrhosis and liver cancer eventually leading to premature death. The iron overload in these conditions is caused by the hyperabsorption of iron as a result of up-regulation of the target DMT1 in the intestine. Secondary indications include those disorders where patients acquire iron overload as a result of regular therapeutic blood transfusions but in which there may also be an up-regulation of iron uptake by DMT1. Examples include patients with thalassemia major, sickle cell disease, MDS and rare genetic disorders such as congenital dyserythropoetic anemia. Furthermore, broader clinical utilities may include the treatment of other neurodegenerative diseases whre intracellular iron metabolism has been implicated.

Genetic studies of DMT1 using mk/mk knockouts have demonstrated the essential role of DMT1 in iron uptake, and when combined with the genetic model of hemochromatosis the iron hyperabsorption is prevented. Likewise, studies of human patients with HH show that DMT1 is inappropriately up-regulated at the intestinal brush border. This aberrant excess expression of DMT1 in HH is fundamental to the primary pathophysiology of this condition, thus underscoring the importance of targeting DMT1 for the treatment of disorders with iron hyperabsorption and overload.

Compounds from the lead series XEN600 have shown good in vitro and in vivo potency and are in the clinical candidate selection phase.