In March, the biopharma company, headquartered in Pennsylvania, US, submitted an Investigational New Drug (IND) application to the US Food and Drug Administration (FDA) for trodusquemine (MSI-1436). The aminosterol compound is the first highly selective inhibitor of protein tyrosine phosphatase 1B (PTP1B), claims Genaera.
The company estimates there are 113m obese Americans and although 4m of these are treated for weight loss, three times as many are treated for obesity-related diseases such as Type II diabetes and dyslipidaemia.
Obesity and Type II diabetes are characterised by resistance to leptin and insulin, which may be caused by defects in the hormones' signalling pathways. Scientists believe that PTP1B reduces the amount of insulin and leptin signalling and inhibiting this effect could provide a useful therapy.
PTP1B can remove a phosphate group from the tyrosine residue of a protein. This, in conjunction with the tyrosine kinases that add the phosphate group to tyrosine residues, is an integral part of enzyme regulation. Although tyrosine kinases are a well established and popular drug target, the associated phosphatases are researched less often.
In preclinical testing on obese mice, Genaera found that trodusquemine acted as an appetite suppressant and caused weight loss and fasting blood glucose and cholesterol levels to return to normal.
"While the primary endpoint of this first Phase I study is safety and tolerability, we will be looking for evidence supporting our preclinical observations," said Jack Armstrong, CEO of Genaera.
At the moment, the only drugs approved to treat obesity are: Sanofi-Aventis' recently-introduced Acomplia (rimonabant), an oral appetite suppressant that is taken once a day and works by blocking cannabinoid binding to the CB-1 receptors found on the surface of cells; Abbott Laboratories' centrally-acting Reductil/Meridia (sibutramine) and Roche's Xenical (orlistat), a lipase inhibitor that prevents absorption of dietary fat in the gastrointestinal tract.
Having bought the US rights for Xenical off Roche last year, GlaxoSmithKline had its low dose, over the counter version, which will be marketed as Alli, approved by the FDA in February of this year.
Despite what are perceived as relatively modest effects on weight loss, Xenical and Meridia account for a market valued at a little over $1bn (€738m), while Sanofi-Aventis has high hopes for Acomplia, which debuted last year, predicting that sales will be in the 'billions of dollars' range at peak.
Ertiprotafib was developed by Wyeth several years ago to selectively inhibit PTP1B. However, the compound was dropped in Phase II development due to insufficient efficacy and concerns about side-effects.