pomaglumetad was known to be active in neurocircuits within the brain, and this information was used to develop the pharmacogenetic strategy to generate hypotheses that could be tested in the clinic. Furthermore, it was felt that any new therapeutic would need to differentiate itself from the available generic and branded competition, leading to significant interest in identifying response markers that could be used to identify patients who would respond better to treatment.

In the original proof-of-concept study, both pomaglumetad and the existing standard-of-care treatment olanzapine significantly decreased the number of symptoms experienced by patients relative to placebo treatment (Patil et al., 2007). However, pomaglumetad did not distinguish itself, based on efficacy, from the standard of care. The developers therefore investigated whether a segment of the population might respond differently to this new type of treatment of schizophrenia. Fortunately, the proof-of-concept study included optional DNA collection for patients, and the collection rate was roughly 70 percent, Nisenbaum stated. Using these DNA samples, a candidate gene association study revealed 16 genetic variants in the serotonin 2A receptor that were associated with differential response to pomaglumetad. In particular, patients who were either homozygous for the rare allele or were heterozygous for a particular single nucleotide polymorphism (SNP) in the receptor had a greater response than patients who were homozygous for the common allele. Similar results were observed in a second clinical trial. This kind of discovery is relatively rare in psychiatric genetics, Nisenbaum said, in that few studies have repeated a finding prospectively in a second clinical trial.

Eli Lilly and Company researchers are now trying to validate the marker in larger registration studies. “You’ll have to stay tuned to see how the story plays out,” Nisenbaum said.1 “But we are very excited at the prospect of potentially being able to help tailor something in the psychiatric space where we know that the response rate for these types of drugs is modest.”

As genetic markers related to the serotonin 2A receptor are considered for further use in clinical trials, it is necessary to understand additional factors regarding receptor expression, Nisenbaum said. The serotonin variants identified in the proof-of-concept study are all located within a large intron of the serotonin 2A receptor, and the variants do not have an obvi-

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1 Eli Lilly and Company announced results from the first of these studies, H8Y-MC-HBBM, subsequent to the workshop on July 11, 2012. Results indicated that the primary efficacy endpoint had not been met and that neither pomaglumetad nor the active control used, risperidone, had separated from placebo “in either the overall or predefined genetic subpopulation” for the two doses that had been investigated. Further trials are ongoing. Details of the announcement can be found at http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=690836 (accessed August 7, 2012).



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