Andecaliximab (GS-5745): A Comprehensive Monograph on a Selective MMP9 Inhibitor from Oncology and Inflammation to Rare Bone Disorders

Section 1: Executive Summary

Andecaliximab, also known by its development code GS-5745, is an investigational recombinant chimeric IgG4 monoclonal antibody engineered for high-affinity, selective inhibition of matrix metalloproteinase-9 (MMP9).[1] Initially developed by Gilead Sciences, the therapeutic was positioned as a promising agent for a broad spectrum of diseases, including advanced cancers and chronic inflammatory conditions, based on the pathological upregulation of its target in these settings.[2] Early-phase clinical trials in oncology, particularly in combination with chemotherapy for gastric and pancreatic cancers, showed encouraging signals of antitumor activity, prompting advancement into large-scale pivotal studies.[3]

However, the extensive clinical development program ultimately met with significant setbacks. The cornerstone Phase III GAMMA-1 trial, which evaluated Andecaliximab with mFOLFOX6 chemotherapy in first-line gastric or gastroesophageal junction (GEJ) adenocarcinoma, failed to meet its primary endpoint of improving overall survival.[3] Concurrently, development programs in inflammatory diseases were discontinued following definitive evidence of futility. A combined Phase II/III study in patients with moderate-to-severe ulcerative colitis was terminated after an interim analysis revealed a complete lack of efficacy, a result mirrored in a parallel Phase II trial for Crohn's disease.[2] These failures, despite consistent evidence of robust target engagement, suggested a fundamental flaw in the therapeutic hypothesis that MMP9 was a critical, non-redundant driver of these complex, multifactorial diseases.