An investigational, phase II study published in the scientific journal Nature Medicine demonstrates that for the first time in humans a drug that acts on certain proteins in the brain called mGlu2/3 has antipsychotic activity. The study was sponsored by Eli Lilly and Company (NYSE: LLY).
In this study – a randomized, double-blind, placebo-controlled clinical trial – patients were assigned to four weeks of treatment with either Lilly’s investigational compound LY2140023; olanzapine, an atypical antipsychotic medication that targets dopamine and serotonin receptors as an active control; or placebo. The study demonstrated that:
– LY2140023 and olanzapine showed statistically significant improvement versus placebo in PANSS (Positive and Negative Syndrome Scale), the most common scale used for measuring symptoms of patients with schizophrenia. Both groups showed a rapid response, within one week.
– Treatment with LY2140023 was not observed to have certain adverse events that often occur with currently approved schizophrenia medications, including increased prolactin elevations, extrapyramidal symptoms (involuntary movements or muscle stiffness), or weight gain.
– Overall, LY2140023 40 mg 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.
“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 Steven Paul, M.D., 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.”
The trial was a proof of concept study designed to determine LY2140023 superiority versus placebo. Olanzapine was used as an active control. 196 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 (-20.8, P < 0.001; -26.7, P < 0.001; respectively), After four weeks of treatment, the study showed that both the LY2140023 group (32.0%, P < 0.001) and the olanzapine group (41.2%, P < 0.001) demonstrated significantly greater response rates compared to the placebo group (3.2%). Response was measured primarily by the PANSS, the most common scale used for measuring symptoms of patients with schizophrenia. A patient showing a 25% or more decrease in PANSS total score was defined as a responder. Additionally, a mean 0.51-kg weight reduction from baseline was observed in the LY2140023 group. A moderate but statistically significant weight gain was observed in the olanzapine group (0.74 kg, P = 0.017) relative to the placebo group.
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 (P = 0.66).
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 (P = 0.038), nausea, headache, somnolence and blood creatine phosphokinase increase. The adverse event profile of LY2140023 did not include prolactin increase or worsening of extrapyramidal symptoms (EPS). 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 (P = 0.005), insomnia, weight gain (P = 0.034), somnolence, akathisia, agitation and periodontitis (P = 0.03).