The two companies will make use of ObeTherapy's platform of in vitro biological tests aimed at identifying small-molecule drugs that interact with a molecular target involved in intestinal lipid absorption.
This approach offers numerous advantages over currently available therapies, such as Roche's lipase inhibitor Xenical (orlistat) and Abbott's central nervous system stimulant Reductil (sibutramine). For example, drugs targeting this target will be peripherally acting, potentially without systemic toxicity and highly selective, according to the two partners.
ObeTherapy has already validated and has a pending patent on the new target - which is related to the absorption of lipids via chylomicrons in they gastrointestinal tract - and has set up and patented various assays for screening purposes, including a cellular high-throughput screening assay. It has also generated a list of potential hit compounds obtained by virtual screening.
Itzik Harosh, chairman and chief scientific officer of ObeTherapy, told DrugResearcher.com that screening is already underway at Zambon, with the capability to examine several hundred compounds a week. Once a few leads are identified, they will be returned to ObeTherapy for validation.
Thereafter, Zambon will conduct the structure-activity relationship work needed to develop focused libraries for secondary screening, and will conduct medicinal chemistry and other development work on any resulting leads.
ObeTherapy's approach to research in this area has been to identify genes that are pivotal in keeping people slim - the so-called 'lean phenotype' - in contrast to the focus on the obese phenotype adopted by other research teams.
The rationale behind this is that if you can find one gene that results in a deficiency fat absorption, then the gene implicated in this malfunction is critical to the absorptive process. And this gene, which is not compensated by other mechanisms, should be a much better target for obesity treatment than the genes responsible for obesity in obese patients, as it is proven that they are neither specific nor redundant.
ObeTherapy has identified such a gene in patients suffering from a rare form of apolipoproteinaemia. If patients are homozygotes - in other words both copies of the gene in question are faulty - they are unable to absorb any fatty acids at all.
This rare condition, affecting about one in a million individuals, is a deeply unhealthy state with serious symptoms, including very bad diarrhoea. However, patients with only one mutation in the gene - heterozygotes - have a very desirable outcome: they are slim and protected from elevated blood lipids that could lead to heart disease. So partial agonists of the product of this gene could mimic the latter phenotype and treat metabolic syndrome and obesity.
Xenical is the only drug on the market that adopts a similar type of approach, blocking the absorption of triglycerides by inhibiting pancreatic lipases. But this drug is not very effective, and has some rather unpleasant side effects, including diarrhoea and anal leakage. Harosh said that drugs blocking its target should be more effective as they will inhibit the absorption of not just triglycerides but also cholesterol and other sources of fatty acids.