A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia

Abstract

BackgroundWe compared the time to discontinuation due to lack of tolerability over 24 weeks in patients suffering from schizophrenia treated with pomaglumetad methionil (LY2140023 monohydrate, the prodrug of metabotropic glutamate 2/3 receptor agonist, LY404039) or standard of care (SOC: olanzapine, risperidone, or aripiprazole).MethodsStudy HBBR was a multicenter, randomized, open-label study comparing the long-term safety and tolerability of LY2140023 with SOC for schizophrenia. Patients had moderate symptomatology with prominent negative symptoms and evidence of functional impairment. Those who met entry criteria were randomized to open-label treatment with either LY2140023 (target dose: 40 mg twice daily [BID]; n = 130) or SOC (n = 131).ResultsThere was no statistically significant difference between LY2140023 and SOC for time to discontinuation due to lack of tolerability (primary objective; P = .184). The Kaplan-Meier estimates revealed comparable time to event profiles. Only 27% of LY2140023 and 45% of SOC patients completed the 24-week open-label, active treatment phase. Twenty-seven patients (20.8%) in the LY2140023 group and 15 patients (11.5%) in the SOC group discontinued due to lack of efficacy (P = .044). Twenty-three patients (17.7%) in the LY2140023 group and 19 patients (14.5%) in the SOC group discontinued due to adverse events (physician and subject decision combined, P = .505). The incidence of serious adverse events was comparable between groups. LY2140023-treated patients reported significantly more treatment-emergent adverse events of vomiting, agitation, and dyspepsia, while SOC-treated patients reported significantly more akathisia and weight gain. The incidence of treatment-emergent parkinsonism (P = .011) and akathisia (P = .029) was significantly greater in SOC group. Improvement in PANSS total score over the initial 6 to 8 weeks of treatment was similar between groups, but improvement was significantly greater in the SOC group at 24-week endpoint (P = .004). LY2140023 and SOC groups had comparable negative symptom improvement at 24-week endpoint (P = .444).ConclusionThese data provide further evidence that the potential antipsychotic LY2140023 monohydrate, with a glutamatergic mechanism of action, may have a unique tolerability profile characterized by a low association with some adverse events such as extrapyramidal symptoms and weight gain that may characterize currently available dopaminergic antipsychotics.Trials registrationA Long-term, Phase 2, Multicenter, Randomized, Open-label, Comparative Safety Study of LY2140023 Versus Atypical Antipsychotic Standard of Care in Patients with DSM-IV-TR SchizophreniaClinicalTrials.gov identifier: NCT00845026.

Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor

“…This receptor, a class C GPCR, has emerged as therapeutic target for various psychiatric diseases amongst which schizophrenia, depression and anxiety, which are characterized by glutamatergic dysfunction [10,11]. A variety of glutamate-like agonists that can dampen glutamate hyperfunction was developed, of which LY2140023 of Eli Lilly, a prodrug of LY404039 showed improvement in positive and negative symptoms in schizophrenic patients, which could not be confirmed in later clinical studies [12,13]. Inhibition of the mGlu 2 receptor can be beneficial for glutamate hypofunction in depression, and when considering the orthosteric binding site antagonist LY341495 has been the most studied for this purpose [14,15].…”

A Real-Time Method for Measuring cAMP Production Modulated by Gαi/o-Coupled Metabotropic Glutamate Receptors

“…Although no selective agonists exist, several nonselective mGluR agonists have entered late-stage clinical trials (Patil et al, 2007;Adams et al, 2013), but none has successfully reached the market. These clinical setbacks may be attributed to the lack of subtype selectivity, as studies suggest that even within groups, individual mGluR can play opposing physiological roles (Conn and Pin, 1997;Caraci et al, 2011).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…However, there is preclinical evidence to suggest that fenobam (an mGluR5 negative allosteric modulator) may effectively treat cocaine addiction (Keck et al, 2013), and fenobam has shown promising results in an open-label trial for fragile X (Berry-Kravis et al, 2009). LY404039 [(2)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid] is an mGluR2/3 agonist that partly attenuates an animal model of alcohol addiction (Rodd et al, 2006) and has been investigated in a phase 2 trial for schizophrenia (Adams et al, 2013). It remains to be seen whether trials of drugs targeting mGluRs for treating addiction will be successful.…”