the potential of stratified medicine. In many cases, today’s understanding of the biology of disease is severely limited. As a result, new treatments sometimes move into the clinic in response to hypotheses that are not sufficiently supported. Model organisms provide an opportunity to develop data to support a hypothesis about drug efficacy, whereas moving into the clinic too soon has created challenges for the industry.
“Ultimately, it all requires data,” Ho concluded. “One has to have good data to drive those decisions, and good data requires well-designed studies.”
Just as genetics is useful for informing drug development for cancers, it is also relevant for other disease states, said Laura Nisenbaum of Eli Lilly and Company. Like cancer, these other diseases can be polymorphic and arise through complex pathways. Diseases like schizophrenia also are polygenic and heritable, and patients have differential responses to treatments.
Schizophrenia is a chronic disabling psychiatric disorder with mortality rates two to three times higher than those in the general population. Even after five decades of modern pharmacotherapy, the clinical management of patients with schizophrenia remains challenging, Nisenbaum said. The efficacy of the currently available drugs to treat the symptoms associated with schizophrenia is still very limited, leading to poor outcomes for these patients, including suicide. Drugs with a greater level of efficacy are needed to increase compliance, reduce adverse effects, and give patients hope for the future.
Recent studies have begun to uncover both common and rare genetic variants that are associated with the disease. But there is as yet no clear understanding of the biological mechanisms that contribute to the disease, Nisenbaum said. Thus, instead of using knowledge of the molecular genetics of the disease, as has been done with cancer, Eli Lilly and Company researchers used knowledge of drug mechanisms to formulate a strategy for the discovery of drug-response markers.
The drug currently being developed for the treatment of schizophrenia by Eli Lilly and Company is called pomaglumetad methionil (hereafter referred to as pomaglumetad). It is an agonist of several group II metabotropic glutamate receptors, in contrast to other available antipsychotics, which target the dopamine D2 receptor, Nisenbaum said. It is thought to work by suppressing excitatory neurotransmission in brain neurocircuits that are dysregulated in schizophrenia.
No specific genetic data were available at the outset of the program to guide the development of the drug, Nisenbaum said. However,