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Genetic Tests And Rimonabant: Coulda, Woulda, Shoulda

Here’s something I missed while finishing up that blood thinner cover story. Last week Reuters reported that genetic testing might have helped save rimonabant, the ill-fated obesity medication once touted as a future blockbuster. Rimonabant, which blocks the cannabinoid-1 receptor, the target of marijuana’s psychoactive ingredient, appeared to help people lose weight. But it also increased the risk of psychiatric side effects, as we wrote back in 2009. The drug never won US approval and was pulled from the market in Europe in 2008.

Reuters’ story was based on this report from The Lancet. The report (and accompanying press release) decribe CRESCENDO, a large clinical trial of rimonabant which was halted midway through because regulatory authorities were concerned about suicides in people taking the drug.

The story actually focused on a small part of the Lancet paper’s discussion section, where Topol describes the lessons drugmakers should take away from the CRESCENDO trial.

Endocannabinoid blockade could have proven viable, if a genome-wide association study had been done to establish what sequence variants are linked with suicides, suicide attempts, or significant neuropsychiatric side-effects.

And here’s what Topol told Reuters about genetic testing.

“Finding the gene for severe adverse drug reactions is a lot easier than we ever thought it would be,” Topol said in a telephone interview.
Topol thinks if they had thought to collect genetic information on the study’s more than 18,000 participants, they might have spared the drug.
“We probably could have figured out genomically who was susceptible and that drug could be quite viable,” Topol said in a telephone interview.

I guess a genome-wide association study might have been interesting. It’s a shame one doesn’t seem to have been conducted. Still, I’m not sure it would have been guaranteed to determine which patients were more susceptible to suicide. These types of studies have limitations, which this article from JAMA describes best:

GWA studies are an important advance in discovering genetic variants influencing disease but also have important limitations, including their potential for false-positive and false-negative results and for biases related to selection of study participants and genotyping errors.

Image:C&EN

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