A Double-Blind, Placebo-Controlled Comparator Study of LY2140023 monohydrate in patients with schizophrenia

Abstract

Background: Pomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia.

Methods: Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry. Patients (N = 1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2 mg BID for 6 weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461.

Results: Neither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p = .154 [0.01]; LY80, p = .698 [0.01], subpopulation: LY40, p = .033 [0.0025]; LY80, p = .659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p < .001 [0.05]). There were no statistically significant differences in the incidence of serious adverse events, and no seizures on LY2140023.

Conclusion: LY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed.

Clinical trials registration: A Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR SchizophreniaClinicalTrials.gov identifier: NCT01086748.

Figure 1

The unblinded study design. Study HBBM consisted of 3 periods: a screening phase, a 7-day placebo lead-in phase that was blinded to investigators and patients, and a 6-week randomized treatment phase. All patients were hospitalized from Visits 2–5. Patients could be discharged after that time based upon clinical presentation.

Figure 2

Patient disposition.

Figure 3

Kaplan-Meier time to discontinuation for any reason; intent-to-treat patients in the overall population.

Figure 4

Plot of weekly least-squares mean (+/−standard error [SE]) of efficacy measures by treatment. Repeated measures analysis of change from baseline to each postbaseline visit (MMRM), efficacy-evaluable intent-to-treat patients in the overall population (A) and in the predefined subpopulation (B). In the figures, Week 0 corresponds to study Visit 3, and Week 6 corresponds to study Visit 9.