Schizophrenia affects roughly 1% of the world's population, with more than two million Americans afflicted in any given year, and an estimated 30-50 million people worldwide. Treatment with available antipsychotic medications often effectively attenuates the positive symptoms of schizophrenia without improvement in the negative symptoms or cognitive deficits. Fewer than 10% of schizophrenic patients are ever able to live independently or hold a regular job even with antipsychotic treatment. The social impact of this fact is that approximately 60% live in poverty and 1 in 20 end up homeless. Dopamine D1 agonists have been identified by most experts in the field as the most promising therapeutic target for improving the cognitive deficits and negative symptoms of schizophrenia. This conclusion has been further supported by a recent consensus panel conducted under the auspices of the NIMH-sponsored MATRICS program, which assigned the highest priority to dopamine D1 agonists as a novel therapy for treating cognitive deficits (working memory) in schizophrenia. DarPharma has developed DAR 0200A, a high affinity dopamine D1 full agonist with full intrinsic activity. DAR-0200A is an extremely promising drug candidate that already has extensive preclinical pharmacological and toxicological data. The overall goals of this SBIR application are to: 1. Complete preclinical development work to support a US Investigational New Drug Application (IND) for the subcutaneous (s.c.) administration of DAR-0200A (subcutaneous formulation, stability assessment, safety pharmacology studies, and additional toxicology studies); 2. Submit and receive approval for a US IND, followed by the initiation and completion of Phase I clinical studies to assess the tolerability and pharmacokinetics of DAR-0200A administered s.c. in humans over a wide dose range; 3. Initiate and complete a Phase II clinical investigation to study the effect of s.c. DAR-0200A on working memory in schizophrenia patients currently treated with antipsychotics.
