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12:00 AM
Jun 25, 2007
 |  BioCentury  |  Product Development

De-risking obesity strategies

Although an FDA advisory committee's negative vote on sanofi-aventis Group's Zimulti rimonabant signals a general increase in scrutiny of side effects resulting from centrally acting compounds in non-psychotropic indications, other companies in the space believe the concerns are largely specific to rimonabant.

Specifically, Zimulti acts on a target that is ubiquitous in the brain, is in a poorly characterized pathway and has a narrow therapeutic index. According to the other players, compounds with different characteristics shouldn't run into the same regulatory issues.

On June 13, FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 14-0 against recommending approval of Zimulti from sanofi-aventis (Euronext:SAN; SNY, Paris, France) to control weight. Although Zimulti (Acomplia in Europe) is approved in 37 countries, the committee was concerned about neurological and psychological effects that were closely associated with the compound's MOA (see BioCentury, June 18).

Zimulti targets the cannabinoid CB1 receptor, which affects appetite in the hypothalamus. The receptor is expressed in other regions of the brain, including regions involved with pain, movement, memory, stress and higher cognitive function. The ubiquitousness of the CB1 receptor likely explains why Zimulti showed a broad array of side effects, including depression, suicidality and seizures.

Whether the effects are a class issue remain to be seen. Karen Davis Bruno, a pharmacologist in the FDA division, noted that Zimulti's side effects begin to emerge in animals at the therapeutic dose. By comparison, she said CNS side effects in several other CB1 receptor antagonists are not observed until doses reach greater than...

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