ARISAPH PHARMACEUTICALS, INC. — Department of Health and Human Services STTR Phase II: 102

Description

DESCRIPTION provided by applicant Cancer is the second leading cause of death after heart disease in the US Chemotherapy is a mainstay of treatment after surgical removal of tumors but the balance of clinical benefit versus disabling or life threatening side effects is often uncertain Genotyping of cancers to identify mutated oncogenes has enabled an era of targeted therapy Drugs targeting the mutated proteins that drive tumor growth promised to revolutionize cancer treatment but the genetic plasticity inherent in cancer limits the numbers of patients who can respond to treatment and those that do often relapse due to development of drug resistance This proposal describes prodrugs intended to kill tumors with reduced damage to healthy tissues The prodrugs are designed to remain harmless until they are cleaved by the enzyme fibroblast activation protein FAP Short peptides are linked to cytotoxic molecules tumor killing warheads to create prodrugs that only release their warheads when a specific peptide bond is cleaved enzymatically by FAP FAP is expressed by nonmalignant fibroblasts in the connective tissue stroma of epithelial tumors therefore prodrugs enable tumors to be targeted with cytotoxic agents independently of the mutational status of the cancer cell Prodrug feasibility was demonstrated in STTR Phase I for ARI which delivers a Velcade like proteasome inhibitor to the tumor and confirmed with ARI DOX which delivers the chemotherapeutic agent doxorubicin DOX ARI DOX and ARI are both promising drug candidates Before proceeding to IND enabling studies however further work which is planned for STTR Phase II will be required in order to improve prodrug half life in vivo evaluate the possible safety risk that might result from killing FAP cells that have recently been discovered in normal tissues and understand whether by a new mechanism of action prodrugs can relieve tumoral immune suppression to activate the immune system to kill tumors Arisaph has developed chemistry required to make prodrugs that are unique in that they are cleaved to release cytotoxic warheads by FAP but not by a closely related enzyme prolyl endopeptidase which would otherwise present a major risk of toxicity to the patient because it is expressed in many healthy tissues Developmental risk is mitigated by ability to make back up compounds and clinical risk by patient selection with a simple biopsy assay for FAP activity in tumor samples Arisaphandapos s collaborator Dr H Borghaei Fox Chase Cancer Center has developed a model of endogenous lung cancer for testing the possible immunological effects of prodrugs The goal of STTR Phase II is to select the most efficacious prodrug candidate based on preclinical efficacy and safety for IND enabling studies that will be conducted by Arisaph in Phase III PUBLIC HEALTH RELEVANCE Epithelial tumors in lung colorectum prostate and breast account for almost half of all cancers and the incidence of pancreatic cancer and melanoma is increasing Chemotherapeutic agents are a mainstay of treatment but are limited by toxicity and the use of newer agents that target oncogene products is restricted to subsets of patients whose cancers harbor specific genetic alterations and suffers the major drawback of unavoidable drug resistance The development of prodrugs that are specifically activated by fibroblast activation protein in the tumor stroma to deliver cytotoxic warheads promises a new class of anticancer agent that can reduce the toxicity associated with conventional chemotherapy and avoid the problem of genetic resistance faced by anticancer agents that target oncoproteins