Intra-Cellular Therapies and Takeda to Develop PDE1 Inhibitors for Schizophrenia

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DEAL WATCH Intra-Cellular Therapies and Takeda to develop PDE1 inhibitors for schizophrenia

Takeda and Intra-Cellular Therapies, Inc. hippocampus and frontal cortex, which (ITI) have recently entered into an exclusive suggests that PDE1 inhibition might have collaboration to discover, develop and greater efficacy for cognitive enhancement commercialize phosphodiesterase type 1 than PDE10A inhibition.” Greengard adds that (PDE1) inhibitors for treating cognitive “PDE1 is the only PDE that is calcium/ impairment associated with schizophrenia — calmodulin-dependent. As such, PDE1 a deal that could be worth US$750 million inhibitors have little or no effect on basal for ITI. cyclic nucleotide levels; rather, they enhance “Cognitive impairment associated with cyclic nucleotide signalling in neurons under schizophrenia is chronic, highly prevalent and conditions that are associated with increased not addressed by current therapies,” says Paul intracellular calcium levels. Other PDE Greengard, who is the Vincent Astor Professor inhibitors, including those directed at at the Laboratory of Molecular and Cellular PDE10A, override the endogenous system by Neuroscience, The Rockefeller University, New increasing the basal state of cyclic nucleotide York, USA, and co-founder and chairman of signalling, which could be associated with the scientific advisory board of ITI. All of these unwanted side effects.” therapies are thought to act by modulating ITI currently have a series — named ITI‑002 monoamine receptors (in particular the striatal — of novel potent, orally available PDE1

dopamine D2 receptor), and their limitations inhibitors that are in preclinical development, have stimulated interest in alternative although which of the three isoforms of PDE1 strategies such as those targeting downstream (A, B or C) are being targeted has not been intracellular signalling molecules. disclosed. This could be important for the PDE1 belongs to the PDE superfamily of biological effects sought, and represents a enzymes, which degrade cyclic AMP and challenge in achieving the selectivity desired. cyclic GMP — these are key second “If PDE1B is the selective target, the effects messenger molecules, and their intracellular will be more associated with striatal concentrations are affected by modulation of pathways, whereas if PDE1A is selectively G protein-coupled receptors such as the targeted, the effects could differ

dopamine D2 receptor. “In total, there are substantially,” says Akira Sawa, Director and more than 100 PDE isoforms, but selective Professor of the Program in Molecular PDE inhibitors could allow a more targeted Psychiatry at Johns Hopkins Hospital, approach [for treating schizophrenia] because Maryland, USA. “The distribution and role of of the specific localization of certain PDE PDE1A are thought to be more associated isoforms in the brain,” explains Jos Prickaerts, with the cerebral cortex than those of PDE1B, an associate professor at the Department of and the cortex is one of the most important Psychiatry and Neuropsychology, Maastricht brain areas involved in the pathophysiology of University, the Netherlands. schizophrenia,” he adds. Indeed, a PDE10A inhibitor that is being As well as potentially ameliorating the developed by Pfizer (PF‑2545920) for the cognitive deficits in schizophrenia, PDE1 treatment of schizophrenia is currently in inhibitors might have utility in other Phase II trials. “PDE10A is expressed mostly in neurological disorders. “PDE1 inhibitors may the striatum, but it is also expressed in the also be useful for treating cognitive hippocampus and frontal cortex, and impairment associated with Alzheimer’s preclinical studies have shown that PDE10A disease and Parkinson’s disease. Moreover, inhibition has procognitive effects,” says they may also be useful as a form of Prickaerts. “However, PDE1 is expressed adjunctive therapy to reduce the motor side mostly in the striatum as well, but it is more effects of antipsychotic treatment in patients abundantly expressed than PDE10A in the with schizophrenia,” says Greengard.