Eli Lilly reported today that its investigational compound LY2140023 showed a statistically significant improvement in schizophrenia positive and negative symptoms in a phase II study. The study was published in the journal Nature Medicine.
LY2140023 is a drug under development for treatment of schizophrenia. LY2140023 is an oral “prodrug,” meaning it is devoid of intrinsic biological activity and, once administered, is metabolized to provide the active mGlu2/3 receptor agonist called LY404039. Most currently approved antipsychotic medications work by affecting the neurotransmitters dopamine or serotonin. For LY2140023, the active substance, LY404039, is thought to work by reducing the presynaptic release of another neurotransmitter, glutamate, in brain regions where mGlu2/3 receptors are expressed.
One-hundred and ninety six patients were assigned in the study to four weeks of treatment with either compound LY2140023, olanzapine, an atypical antipsychotic medication that targets dopamine and serotonin receptors as an active control, or a placebo (a sugar pill). A placebo is used in studies like this so that both researchers and patients don’t know which pills are filled with “active” ingredients (either LY2140023 or olanzapine) or sugar. This helps ensure neither researchers nor patients inadvertently bias the results.
Patients in the LY2140023 group showed a rapid response to the treatment, improving on a scale that measures both negative and positive symptoms of schizophrenia (PANSS) usually within a week. The group also appeared to suffer from fewer side effects typically associated with atypical antipsychotics, such as an increase in involuntary movements or muscle stiffness, or weight gain.
The patients with schizophrenia were randomly assigned to LY2140023 (40 mg twice daily), olanzapine (15 mg daily) or placebo. All participants were hospitalized to ensure patient safety, tapered off from any pre-trial antipsychotic medications (no therapeutically stable patients were included in the trial), and treated in a double-blind manner for four weeks. In all, 118 patients completed four weeks of the planned study treatment.
Treatment with LY2140023 or olanzapine resulted in statistically significant improvement in PANSS (Positive and Negative Syndrome Scale) total score (primary outcome) compared to placebo.
After four weeks of treatment, the study showed that both the LY2140023 group and the olanzapine group demonstrated significantly greater response rates compared to the placebo group. Response was measured primarily by the PANSS, the most common scale used for measuring symptoms of patients with schizophrenia.
Results showed that the placebo arm experienced the highest rate of study discontinuation due to lack of efficacy, however, discontinuation due to adverse events was not significantly different across the three treatment groups.
Overall, the study showed that LY2140023 40mg, given twice daily, was found to be safe and well-tolerated, with most adverse events being mild to moderate in severity and not treatment-limiting.
The most common treatment-emergent adverse events in the LY2140023 group were insomnia, affect lability, nausea, headache, somnolence and blood creatine phosphokinase increase.
Although mood lability seems to represent the most important potential adverse event, it should be noted that this outcome was observed primarily at one clinical site. In the olanzapine group, treatment-emergent adverse events included elevation in blood triglyceride levels, insomnia, weight gain, somnolence, akathisia, agitation and periodontitis.
More longer-term studies are needed to confirm and extend these initial findings.
A phase II study includes early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of a particular drug for a particular indication or indications in patients with the disease or condition. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well-controlled, closely monitored, and conducted in a relatively small number of patients, usually involving several hundred people.
Before U.S. Food and Drug Administration (FDA) approval can be had for a drug, drug makers must also pass phase III clinical trials. Phase III studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in Phase II, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Phase III studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. Phase III studies usually include several hundred to several thousand people.
Sources: Eli Lilly, Nature Medicine & FDA