Tuesday, January 24, 2006

Something borrowed...something blue…something old…something new: The obesity therapeutics market evolves

Today's edition (Jan 24th) of DailyUpdates highlights major advances in the treatment of obesity

The problem of obesity is well recognized. Defined as a BMI of above 30 (compared to 18.5-25 for healthy individuals), obesity is generally caused by poor dietary habits resulting in the ingestion of excessive eat sugar and fat. When intake exceeds requirement the individual becomes overweight. Although diet is the major influence on weight gain there is a genetic influence and genes are thought to contribute 25–40% to obesity. A number of gene defects have been linked to obesity such as mutations in the genes encoding leptin, the melanocortin-4 receptor, cholesterol side-chain cleavage enzyme and PPAR gamma.

Something old….In our recent feature Obesity - commercial opportunities and therapeutic pipeline analysis it is estimated that there are 127 million obese people in the seven major markets and numbers are expected to increase. In 1997 the FDA approved Abbott’s Meridia (sibutramine) for the treatment of obesity and of the currently available approved therapeutics, this agent has been on the market the longest. Meridia acts centrally, inhibiting the reuptake of norepinephrine, serotonin and dopamine.

Something blue….More recently, the FDA approved a second therapeutic, Roche’s Xenical (Orlistat). In contrast to Meridia, this blue tablet acts peripherally by blocking lipase activity thus reducing lipid absorption. Approved in April 1999 Orlistat has now grown to one of Roche’s most successful drugs. In 2004 it ranked #8 amongst Roche’s bestsellers bringing in 593 million Swiss Francs (approx $0.5 billion). Roche generates roughly a quarter of Xenical's worldwide sales in the US.

Something borrowed….In the same year, Roche and GSK penned an agreement under which the North American Consumer Healthcare division of GSK agreed to pay Roche Holdings $100 million for the rights to sell Orlistat over the counter in the US. Roche retained control of the prescription versions (GSK currently markets Orlistat in the US) and will retain over-the-counter rights outside the United States. GSK in-licensed Orlistat prior to winning FDA approval for the OTC version and today’s announcement that this approval has been recommended represents a major advance.

Press releases posted on the websites of GSK and Roche (and which headline today’s edition of DailyUpdates), announce that the FDA joint Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committee recommended that Orlistat 60 mg capsules be approved for over-the-counter use in the US to promote weight loss in overweight adults, when used along with a reduced calorie, low-fat diet. If approved by FDA, OTC Orlistat (named Alli) would be the only FDA-approved weight loss drug available over the counter.

Something new….In addition to highlighting the developments around Alli, today’s edition of DailyUpdates also reports on a potential new molecular target for future obesity treatments. This target, aquaporin 7 is investigated in a paper in this month’s edition of BBRC. The paper (Biochem Biophys Res Commun. 2006 Jan 20;339(3):785-9) reports that the gene encoding aquaporin 7, AQP7, is down-regulated in obese compared to lean subjects.

Aquaporins are integral membrane proteins that facilitate water movement across the cell membrane. Some of the aquaporins are also known to permeabilize glycerol as well as water. AQP7 is one such protein (also known AQP adipose AQPap) first identified in 1997. Triglycerides in adipocytes are hydrolyzed to fatty acids and glycerol, and both are released into the circulation. Loss of AQP7 results in reduced release of glycerol both in humans and mice. Loss of AQP7 also produces adult-onset obesity and insulin resistance in rodents, a finding that was mirrored by adipocyte hyperplasia and triglycerides accumulation. The molecular mechanism underlying these events appears to involve elevated adipose glycerol kinase activity and accelerated triglycerides synthesis in adipocytes.

The BBRC findings highlighted today suggest that AQP7 may also be implicated in human obesity suggesting that activators of this channel could be of interest therapeutically.


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