RNAi-mediated beta-catenin knockdown in the gastrointestinal mucosa (GI) of patients with familial adenomatous polyposis (FAP): Results of START-FAP trial.

Abstract

e15065 Background: FAP is an inherited GI disorder that predisposes patients to early-onset of colorectal cancer due to mutations in the APC gene resulting in accumulation of β-catenin contributing to the formation of polyps. CEQ508 is a novel agent using live-attenuated bacteria genetically engineered to produce and deliver β-catenin short-hairpin RNA into the GI mucosa. Methods: A dose-escalating Phase I study (START-FAP) evaluated the safety and tolerability of single daily oral doses of CEQ508 in FAP patients (3 each in Cohort 1 and 2 with 108 and 109 CFU for 28 days). The primary objective was to establish safety of oral CEQ508. The secondary objective was to test the effectiveness of CEQ508 in targeting β‐catenin gene in GI mucosa. GI tissues (duodenum, ileum, colon, antrum) obtained during endoscopy exam at baseline and end-of-treatment (EOT) were measured using qPCR and analyzed with ViiA™ 7 Real-Time system. Ct values were normalized to 2 of 3 housekeeping genes (EIF2B1, HPRT1, GUSβ). A mixed Nested-ANOVA model was used to evaluate β-catenin knockdown in normal mucosa and polyps. Results: Oral dosing of 108 and 109 CFU of CEQ508 for 28 days was well-tolerated. Histological evaluation of polyps and normal mucosa at baseline and EOT indicated minimal changes in tissue morphology or inflammation. β-catenin knockdown differed significantly between tissue types, with duodenum exhibiting the highest and antrum with the lowest (~2-fold difference). No significant effects from CEQ508 treatment were observed in normal mucosa. Significant reduction was observed in overall β-catenin expression in polyps at EOT (P = 0.0005). Patient to patient variation accounted for 8.2% of total variations. Reduction was observed primarily in the duodenum (39.3% decrease, P < 0.0001) and ileum (28.8% decrease, P = 0.012). Conclusions: Bacterial delivery of RNAi via CEQ508 in FAP patients demonstrated an acceptable safety profile at the two bacterial dose levels tested, with no MTD having been identified. START-FAP achieved both the primary endpoint of safety and secondary endpoint of β-catenin knockdown. Clinical development of CEQ508 with Celecoxib/Lisinopril (IT-102) for FAP is planned.