Quality drugs are important to us since they will show greater drug efficacy and reduce adverse drug reactions. We use a clinical genetics approach to drug discovery that identifies the right gene target for the right disease treatment. We study the phenotypes of human genetic diseases and mouse models to identify root cause of diseases of interest to Xenon.

At the core of Xenon's technologies is the careful selection of the relevant rare single gene diseases for drug discovery. These key genes identified in rare genetic disorders represent drug targets for common complex diseases. Published retroactive studies support this approach to quality drug target selection. For example, rare families with mutations in the LDL receptor have hypercholesterolemia, supporting the development of the statin drugs for cholesterol lowering. Glanzmann thrombasthenia is a very rare platelet bleeding disorder caused by mutations in the genes for glycoprotein IIb/IIIa. By inducing a milder phenotype than the exaggerated genetic disorder, inhibitors of these glycoprotein targets are used to treat common forms of arterial thrombosis. Male patients with the rare disease 5 a-reductase deficiency have an absent prostate gland. Again, by inducing a milder phenotype than the exaggerated genetic disorder, inhibitors of the 5 a-reductase enzyme are widely used to reduce prostate size in the common condition of benign prostatic hypertrophy.

These examples and others validate our approach to identifying the right families for the discovery of the right target for drug development for the right disease. We have built a worldwide network of over 40 clinical collaborators to find and access the rare families with diseases of relevance to drug discovery.

Our clinical genetic approaches are:

Extreme Genetics TM: the analysis of rare families that have multiple cases of a severe (extreme) clinical picture of a common disease with unmet medical need. The genes for the extreme form of a common disease will identify targets that can have a major impact on the disease pathophysiology. By modulating these major pathways, we should discover drugs that will effectively treat the patients with the common version of the disease.

For example, Xenon discovered that mutations in the ABCA1 gene were causal for the very rare disorder Tangiers disease, which is characterized by an absence of plasma HDL (good cholesterol). Further investigations have shown that up regulation of ABCA1 raises plasma HDL and could provide protection against atherosclerosis in the general population. more

Opposite Phenotype: the analysis of rare genetic disorders, which have the opposite clinical features to a common disease. For example, rare families with sclerosteosis have severely increased bone density, which is in stark contrast to the common low bone density disease, osteoporosis. The disease gene identified in these rare families represents a drug target that when inhibited should create the protective opposite phenotype (i.e. increased bone density), treating patients with the common low bone density disease, osteoporosis.

As another example, we cloned the gene for the rare disorder of highly elevated plasma iron concentrations, juvenile hemochromatosis. This disorder is characterized by a hyperabsorption of iron in the gut and an inability to store iron in macrophages. This phenotype is the opposite for the common condition of anemia of inflammation, which is characterized by hypoabsorption of iron in the gut and high iron storage in macrophages. Our goal is to treat anemia of inflammation patients by inhibiting the juvenile hemochromatosis gene returning their serum iron to normal levels.more

Genetically Modified Models: Xenon creates novel models representative of human disease through utilizing loss-of-function (knockout) and over-expression (transgenic) strategies. For example, we characterized the knockout for SCD1, which has features opposite to the common disorders of metabolic syndrome. more

To take our high quality targets forward we have built an internal small molecule drug discovery and development platform. Through adopting ‘best practices’ from both traditional pharmaceutical as well as biotechnology industries, Xenon has used our productive integrated platform to advance our drug discovery programs. 

We have assembled a highly diverse chemical compound library of drug-like molecules, which in combination with our broad assay development capabilities and high throughput screening (HTS) technologies enables us to identify early compound hits. To take these hits forward we have an experienced team of synthetic and medicinal chemists who work closely with in vitro pharmacology, ADME and in vivo pharmacology groups. This combined approach enables multiple cycles of synthesis and testing and results in the rapid progression of hits to lead compounds and clinical candidates.

Rigorous criteria have been established for good drug-like properties that include detailed assessments for both potency and safety. Compounds that meet these required criteria are taken forward into full preclinical and clinical development. We have significant internal expertise for GLP preclinical studies, regulatory submissions and clinical development. Our clinical genetic and biomarker approach can be applied to design early proof-of-concept decision studies in man providing cost effective options for clinical trials. We are readying our clinical capabilities, as we will be entering clinical trials in the near-term with our internal programs.

The quality of our drug discovery capabilities has been validated by partnerships Novartis, Pfizer, Roche and Takeda. more