This is the follow-on Phase II SBIR proposal to continue the project "Novel Neurotensin Analogs as Antischizophrenics" (MH-65099) under PA-06-079 (Pharmacological Agents and Drugs for Mental Disorders). There exists a critical clinical need for the identification and development of novel therapies for psychosis, a major unmet medical need. Low levels of the brain peptide neurotensin (NT) have been linked to schizophrenia, hence NT receptor agonists that can be delivered to the brain have significant potential for development as a new class of antipsychotics that might not have the side- effects associated with current drugs. In Phase I and the first year of Phase II of this program, ABS201, a derivative of the active fragment of NT, NT[8-13], was identified as the most promising lead for development from a comprehensive screen of over 50 NT[8-13] analogs. This compound showed strong efficacy in the key rat models of psychosis, did not cause catalepsy, and animals did not develop resistance to it. Most notably, it is active at a "druggable" dose when administered orally. During the rest of the Phase II proposal, a detailed preclinical and clinical plan was completed for further development of ABS201, and many of the IND-enabling experiments were completed with successful outcomes. In addition, a critical set of experiments to define the site and mechanism of action of the compound was completed successfully. The goal of this follow-on Phase II is to perform activities necessary for advancing ABS201 through Phase I of clinical trials. This will be achieved through completion of four Specific Aims.
In Specific Aim 1, GMP synthesis of sufficient amounts of the compound to finish preclinicals and bridge it into the Phase I clinical trial will be performed.
In Specific Aim 2 the outstanding preclinical experiments will be completed enabling preparation and submission of the IND, the goal of Specific Aim 3. Completion of the Phase I clinical trial is the objective of Specific Aim 4.
Specific Aim 1 will be completed at Genzyme Pharmaceuticals, the designated GMP synthesis laboratory.
Specific Aim 2 will be managed by Argolyn in collaboration with Summit Drug Development (who wrote the clinical plan) using high quality CROs to perform the experiments.
Specific Aims 3 and 4 will be managed by Argolyn and Summit with the site(s) of the Phase I trials to be determined. Evidence linking NT to schizophrenia has accumulated over the last 30 years, the proposed clinical trial would be the first in which a NT derivative is evaluated in humans.
During Phase I and II of this project a derivative of the endogenous brain peptide neurotensin, ABS-201, has demonstrated the characteristics necessary for development as an orally available, first-in-class antipsychotic. Completion of various activities designed to take ABS201 through Phase I of clinical trials, including synthesis of GMP-grade material, completion of preclinicals, and the preparation and submission of an IND, is the goal of this proposal.