Obesity is epidemic in many countries worldwide. This disease is now a major cause of diabetes, heart disease and other disorders, such as cancer and sleep apnea. Xenon is pioneering a novel approach for treating obesity through the development of small molecules inhibiting Stearoyl-CoA Desaturase-1 (SCD1).

We studied a knockout of SCD1 that had an opposite phenotype to obesity and metabolic syndrome. These knockouts were lean and resistant to weight gain induced genetically (by leptin deficiency) or by diet, showed increased insulin sensitivity and reduced plasma triglycerides.

Further investigations showed that SCD1 enzyme activity largely determines whether fatty acids are processed for fat deposition (energy storage) or for energy usage through beta-oxidation. SCD1 acts like a switch to control fat storage. When SCD1 activity is ‘up’, the switch is flipped in the direction of storing fat, and when its activity is ‘down’, the switch is flipped in the direction of burning fat.

Xenon then undertook human clinical validation studies of the SCD1 gene using our plasma biomarker for SCD1 activity. We significantly correlated decreased SCD1 activity with reduced obesity and reduced cardiovascular risk profile (decreased plasma triglycerides and increased plasma HDL) in several human populations.

The validation data tell us that small molecules inhibiting the enzyme activity of SCD1 should replicate these desirable clinical effects, and provide a potential novel mechanism for treating obesity and metabolic syndrome.

Xenon has made significant advances in its discovery of small molecule inhibitors of SCD1. We developed a proprietary HTS assay, optimized our leads for potency and good drug-like properties, and demonstrated in vivo efficacy using “gold standard” preclinical models of obesity. We have generated a significant patent portfolio protecting our intellectual property for this program. We are actively pursuing our molecules into the clinic.

In September 2004, Xenon entered into partnership with Novartis Pharma AG to develop novel drugs targeting SCD1.