Interesting for the treatment of positive and negative symtoms, apparently in specific genetic populations of patients.
DB103: psychiatric drug Pomaglumetad
Currently the drugs used in the clinical treatment of psychosis mainly work on dopamine (DA) D2 receptor in central nervous system. DB103 selectively acts on the glutamic acid mGlu2/3 receptor and has no cross-reaction with other receptors in the central nervous system, and hence can avoid some usual side effects of psychiatric drugs on the market. Lilly completed 37 clinical trials with more than 3,800 subjects. DB103 showed significant efficacy in Phase II clinical trial (p<0.05), but failed to achieve the desired effect in the Phase III clinical trial. March 2015, Denovo licensed DB103 development rights from Lilly. After Phase II clinical trial by Denovo, Lilly has priority repurchase right. Financial terms have been defined in the agreement. If Lilly repurchase DB103, Denovo will receive a success fee, back milestone and sales royalties. Denovo is currently conducting biomarker discovery, progress to date is encouraging. Phase 2 clinical study to initiate in 2018 with possible exit by 2020."
Interest in targeting mGlu2/3 for the treatment of schizophrenia began with the initial findings that the selective group II mGlu receptor orthosteric agonists LY354740 and LY379268 can reverse the ability of NMDAR antagonists to induce hyperlocomotion, stereotypies, deficits in working memory, cortical glutamate efflux, and increased firing of PFC neurons in rats [114, 127, 128] (Table 2). One of the most intriguing results of these studies was that activation of group II mGlu receptors had no effect on the NMDAR antagonist-induced rise in extracellular dopamine in the CNS . Despite this, group II mGlu receptor agonists still retained antipsychotic-like efficacy in a range of animal models, suggesting the possibility of treating psychosis without the extrapyramidal or other adverse effects associated with dopaminergic antipsychotics. On the other hand, when the mGlu2/3 agonist LY404039 was administered to rats, it caused an increase in extracellular dopamine, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the PFC [129, 130]. In contrast to the hyperdopaminergic state in the striatum thought to underlie the positive symptoms of schizophrenia, it is hypothesized that the negative symptoms of the disease are contributed to by a dearth of dopamine and serotonin release in cortical regions [131, 132, 133, 134]. Therefore, the increased dopamine as well as dopamine and serotonin turnover observed in the rat PFC in response to LY404039  may predict efficacy in treating some aspects of the negative symptoms of schizophrenia.