Eli Lilly opens door for next-generation antipsychotics

The trial results, published in the journal Nature Medicine​​, suggest that Eli Lilly's latest antipsychotic drug candidate, LY2140023, acts by targeting the metabotropic glutamate 2/3 (mGlu2/3) receptor. In addition, treatment with the drug was found to be safe and well tolerated with patients showing statistically significant improvement in both positive and negative symptoms of schizophrenia compared to placebo. Schizophrenia is a debilitating mental illness that effects more than 24m people worldwide with symptoms including hallucinations, delusions, disordered thinking, movement disorders, social withdrawal and cognitive defects. There are two main classes of schizophrenia therapies, antipsychotics and atypical antipsychotics, with both classes causing extrapyramidal side effects (involuntary movements or muscle stiffness). This has been cited as a major reason for non-compliance by schizophrenia patients. According to the authors, the trial "provides strong new evidence for the role of glutamate modulation in treating psychosis, and specifically for mGlu2/3 receptor activation as a viable therapeutic approach to treat schizophrenia." ​ Crucially, LY2140023 has a very different adverse effect (AE) profile than the company's blockbuster antipsychotic Zyprexa (olanzapine), which had 2005 sales of over $4bn (€2.9bn). Eli Lilly has been hit by a series of lawsuits over the side effects of olanzapine and has agreed to pay at least $1.2bn to 25,000 claimants. Earlier this year, Janssen's Invega (paliperidone) became the first new prescription drug to be approved by the US Food and Drug Administration (FDA) since 2003 and Lilly will be keen to hold on to its market leading position in face of the new competition and lawsuits. Most antipsychotic and atypical antipsychotic drugs, including olanzapine, work by affecting the dopamine and serotonin neurotransmitter pathways. In contrast, LY2140023 works as a receptor agonist for the glutamate system, specifically targeting the metabotropic glutamate 2/3 (mGlu2/3) receptor to reduce the presynaptic release of the glutamate neurotransmitter in brain regions where mGlu2/3 receptors are expressed. LY2140023 is a methionine amide oral pro-drug which is readily hydrolysed to form Eli Lilly's earlier candidate LY404039 which suffered from poor human oral absorption. The trial, that included 196 patients suffering from schizophrenia, compared the effects of the new drug to placebo, as well as including olanzipine as an active control. Treatment with LY2140023 was not observed to cause certain common AEs associated with schizophrenia treatments such as increased prolactin elevations, extrapyramidal symptoms and weight that occur with currently approved schizophrenia medications. "These data provide compelling new evidence that mGlu2/3 receptor agonists have antipsychotic properties and may provide a completely new therapeutic approach for treating schizophrenia and, perhaps, other neuropsychiatric disorders,"​ said Dr Steven Paul, Eli Lilly's executive vice president of science and technology. "Additional and longer-term studies are needed to confirm and extend these exciting initial findings. However, these data suggest that LY2140023 may provide a new alternative for the treatment of this often devastating condition." ​ ​