Sapience Therapeutics, Inc. has received Orphan Drug Designation (ODD) from the U.S. Food and Drug Administration (FDA) for ST316, a first-in-class β-catenin antagonist, for the treatment of familial adenomatous polyposis (FAP). This regulatory milestone supports the development of a novel therapeutic approach for this rare, pre-malignant condition.
FAP is a genetic disorder characterized by the development of numerous polyps in the colon, often starting in adolescence. Without intervention, FAP invariably leads to colorectal cancer (CRC) by the age of 40. The development of FAP is considered an early event in the progression to CRC, with approximately 150,000 new cases of CRC expected to be diagnosed in the United States next year.
ST316: Targeting the Wnt/β-Catenin Pathway
ST316 is designed to selectively shut down the Wnt/β-catenin signaling pathway by antagonizing β-catenin and its co-activator, BCL9. This pathway is a key driver in FAP and is implicated in over 80% of CRC cases. By disrupting the interaction between β-catenin and BCL9, ST316 inhibits the formation of the Wnt enhanceosome protein complex, suppressing the transcription of oncogenic Wnt target genes.
According to Dr. Abi Vainstein-Haras, Sapience's Chief Medical Officer, the ODD is an important regulatory milestone. "Other than high morbidity surgery and intensive colonoscopy surveillance, patients with FAP have no available treatment options to prevent their disease from progressing to CRC, the second-leading cause of cancer death in the United States," she stated.
Clinical Development and Orphan Drug Designation Benefits
ST316 is currently being evaluated in a Phase 2 study for the treatment of CRC. The Phase 1-2 study (NCT05848739) is an open-label, dose-escalation and expansion study assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and early efficacy of ST316 in patients with advanced solid tumors, including CRC, known to harbor abnormalities in the Wnt/β-catenin signaling pathway.
Orphan Drug Designation is granted to therapies targeting rare diseases affecting fewer than 200,000 people in the U.S. The designation provides incentives such as eligibility for federal grants, research and development tax credits, waiver of filing fees, and potential for seven years of market exclusivity upon approval.
Mechanism of Action and Preclinical Data
Preclinical models suggest that ST316 creates a pro-immune tumor microenvironment and has shown synergistic effects with checkpoint inhibition. ST316 exposure in cancer cells prevents BCL9-driven nuclear localization of β-catenin and inhibits formation of the Wnt enhanceosome protein complex. Disruption of this interaction selectively suppresses the transcription of oncogenic Wnt target genes that regulate proliferation, migration, invasion and the metastatic potential of tumor cells, as well as genes that regulate the immunosuppression of the tumor microenvironment. Its selectivity allows for targeting Wnt/β-catenin driven pathologies without the toxicities seen with other Wnt pathway agents.
