Nirogacestat (Ogsiveo): A Comprehensive Monograph on a First-in-Class Gamma-Secretase Inhibitor for Desmoid Tumors

Executive Summary

Nirogacestat, marketed as Ogsiveo, is a first-in-class, oral, selective gamma-secretase inhibitor that represents a landmark therapeutic advance for the treatment of desmoid tumors. Its approval by the U.S. Food and Drug Administration (FDA) and the European Commission (EC) addresses a long-standing unmet medical need for a dedicated, mechanism-based therapy for this rare and debilitating condition. Nirogacestat functions by inhibiting the gamma-secretase enzyme complex, thereby blocking the activation of the Notch signaling pathway, which is aberrantly activated in desmoid tumors and contributes to their growth. The pivotal Phase 3 DeFi clinical trial demonstrated profound and statistically significant efficacy, with nirogacestat reducing the risk of disease progression or death by 71% compared to placebo. This was accompanied by a high objective response rate and meaningful improvements in patient-reported outcomes, including pain and overall quality of life. The safety profile is characterized by a set of common, manageable adverse events and notable class-related toxicities, particularly ovarian toxicity, which requires careful patient counseling. The drug's pharmacology is also defined by a secondary mechanism involving the modulation of B-cell maturation antigen (BCMA), which has positioned it as a promising combination agent for enhancing BCMA-targeted therapies in multiple myeloma. As a Category 1 recommended therapy in NCCN guidelines, nirogacestat has established a new standard of care for adult patients with progressing desmoid tumors requiring systemic treatment.

Introduction to Desmoid Tumors and the Therapeutic Landscape

Pathophysiology and Clinical Presentation of Desmoid Tumors (Aggressive Fibromatosis)