Preclinical studies suggest that drug improves cognition and could ameliorate extrapyramidal side effects associated with antipsychotics.

Takeda Pharmaceutical and Intra-Cellular Therapies (ITI) inked a global collaboration agreement to develop the latter’s preclinical-stage oral phosphodiesterase type 1 (PDE1) inhibitors for the treatment of cognitive impairment associated with schizophrenia. As part of the deal, Takeda will have sole responsibility for developing, manufacturing, and commercializing the drugs, although ITI retains the option to co-promote resulting products in the U.S. The firm will receive an up-front cash payment from Takeda and could earn development milestones of up to $500 million, plus potentially another $250 million in sales-related milestones.

Takeda says the agreement will allow it to bolster its central nervous system (CNS) pipeline, which is one of the firm’s core therapeutic areas. “We believe that ITI’s PDE1 inhibitors have the potential to be a novel drug with a new mechanism of action which will satisfy unmet needs for the millions of patients suffering from schizophrenia,” remarks Shigenori Ohkawa, executive vp and CSO at Takeda.

“This program represents a unique approach to the treatment of cognitive impairment associated with schizophrenia and other disorders,” adds Sharon Mates, chairman and CEO at ITI. “Takeda’s strength in CNS drug development and commercialization complements ITI’s innovative approach to discovery, research, and development.”

ITI is focused on developing novel drugs for the treatment of neuropsychiatric and neurologic diseases and other disorders of the CNS. The firm’s lead early clinical-stage schizophrenia candidate, ITI-007, combines 5-HT2A receptor antagonism with dopamine receptor phosphoprotein modulation and serotonin reuptake inhibition. The firm aims to conduct a Phase II proof-of-efficacy trial in patients with acutely exacerbated schizophrenia and will also look at other potential CNS indications for ITI-007. In July 2010 it reported promising data from a Phase Ib/II study in schizophrenia patients. The results showed that treatment with ITI-007 yielded clinical signs consistent with antipsychotic and antidepressant efficacy, including a reduction in the total positive and negative syndrome scale and the Calgary depression scale for schizophrenia.

ITI’s preclinical PDE1 inhibitor program is designated ITI-002 and encompasses a family of candidates. The firm claims the target enzyme regulated by ITI-002 plays an important role in modulating dopamine receptor signaling pathways that in turn play a critical role in the control of cognition and motor behavior. Studies in preclinical models suggest ITI-002 demonstrates broad efficacy in terms of improving multiple facets of cognition including acquisition (learning), consolidation (memory storage), and retrieval (remembering), which ITI maintains support further development of ITI-002 for the treatment of cognitive deficits occurring in a range of CNS disorders including schizophrena. ITI-002 has in addition been found to normalize movement and enhance wakefulness.

In the field of schizophrenia, ITI-002 is being developed to help improve the cognitive deficits associated with the disease, but ITI suggests that when used as an adjunctive therapy to existing antipsychotic drugs, the candidate may also help reduce antipsychotic-induced extrapyramidal side effects and sedation by normalizing movement and enhancing daytime wakefulness. The firm speculates that the combined effects of targeting PDE1 may allow the development of drugs for the treatment of a range of disorders including schizophrenia, Alzheimer disease, ADHD, Parkinson disease, and sleep disorders.

ITI has in addition developed a CNSProfile™ technology platform that generates a molecular signature of drug compound activity on phosphoproteins. The platform uses selective antibodies as probes to track subtle changes in disease-relevant phosphoproteins before and after drug treatment, generating a molecular snapshot of a nerve cell’s integrated response. The platform is being exploited to help select and optimize internally derived drug candidates and to evaluate potential in-licensing candidates.

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