FAP is an inherited gastrointestinal (GI) disorder that predisposes patients to early-onset of colorectal cancer due a mutation in the APC gene resulting in nuclear accumulation of β-catenin. CEQ508 is a live-attenuated Escherichia coli genetically engineered to produce and deliver β-catenin short-hairpin RNA into the mucosa. This first-in-human study (START-FAP) aimed to assess the safety, tolerability, and efficacy in response to CEQ508 in FAP patients.
Six patients with FAP were orally administered (3 each in Cohort 1 and 2) with CEQ-508 (108 and 109 CFU/day for 28 days). The primary objective was to establish safety profile of oral CEQ508 and to determine the MTD. The secondary objective was the extent of knockdown of the target gene β‐catenin in GI tissues (duodenum, ileum, right and left colon, antrum) taken during endoscopy at baseline and at end-of-treatment (EOT). β-catenin expression levels were measured using qPCR and normalized to housekeeping genes (EIF2B1, HPRT1, GUSβ). A mixed-model nested-ANOVA was used to evaluate β-catenin knockdown.
Daily oral dosing of 108 and 109 CFU of CEQ508 for 28 days was well-tolerated. Histology of polyps and normal mucosa at baseline and EOT indicated no changes in tissue morphology or inflammation in cohort 1 patients. A slight inflammation (from score of 0 to 1 at EOT) was noted in normal colon mucosa of cohort 2 patients. Daily oral dosing of 109 CFU of CEQ508 for 28 days was well-tolerated with targeted β-catenin knockdown in polyps. β-catenin expression was highest in duodenum and lowest in antrum with no significant treatment effects in normal mucosa. Significant reduction was observed in overall β-catenin expression in polyps at EOT (P = 0.0005). Reduction was observed primarily in the duodenum (39.3%, P
Bacterial delivery of RNAi in FAP patients demonstrated an acceptable safety profile at the two dose levels tested. Without hitting MTD, START-FAP achieved both the primary endpoint of safety and secondary endpoint of b-catenin knockdown. CEQ508 is now being moved into clinical development in combination with Celecoxib/Lisinopril (IT-102) against FAP.
Clinical trial identification
Legal entity responsible for the study
V. Trieu, L. Hwang: Officers and own stocks for Marina Biotech. All other authors have declared no conflicts of interest