Redx Pharma Plc announced data from all Phase 2 clinical trial modules of zamaporvint (RXC004), a potent, selective, orally-active Porcupine inhibitor in development for Wnt-ligand dependent, hard-to-treat GI cancers at the European Society for Medical Oncology Gastrointestinal Cancers (ESMO GI) Congress. These data were from small, signal searching patient cohorts in the PORCUPINE study, investigating genetically-selected patients (RNF43_mutant/RSPO-fusion subgroup) with microsatellite stable metastatic colorectal cancer (MSS mCRC) as monotherapy and in combination with anti-PD-1 (NCT04907539); and the PORCUPINE2 study investigating all-comers biliary tract cancer (BTC) as monotherapy and anti-PD-1 combination, as well as genetically-selected pancreatic cancer as monotherapy (NCT04907851). Zamaporvint has been shown to have a tolerable safety profile and is the first Porcupine inhibitor to demonstrate efficacy across this hard-to-treat RNF43/RSPO patient subgroup.

Partial responses observed in approximately 30% (2/7) of genetically-selected patients when combined with nivolumab in the PORCUPINE MSS mCRC module is encouraging in a late-line patient population who have previously undertaken a median of two prior lines of therapy, and where anti-PD-1 alone is not effective. This suggests activity levels potentially better than late-line standard of care in this setting. Furthermore, a disease control rate =16 weeks of 57% (4/7), higher than zamaporvint monotherapy at 15% (2/13), indicates the potential for zamaporvint in combination with immune checkpoint inhibition to drive durable efficacy outcomes.

Consistent with this, robust metabolic (FDG-PET) and molecular (ctDNA) responses were observed in all patients that achieved disease control (partial response or stable disease) following zamaporvint treatment with or without nivolumab. The results from the PORCUPINE2 study also showed some durable clinical benefit in the BTC module in an all-comers (unselected) patient group, albeit at a lower level than that observed in genetically-selected MSS mCRC. In the RNF43 mutated pancreatic ductal adenocarcinoma (PDAC) cohort, although one partial response was observed in the monotherapy module, participant numbers in the present study are too low to support any conclusion on efficacy.

However, further investigator sponsored studies in this indication are being planned. In both the PORCUPINE and PORCUPINE2 studies all patients received prophylactic denosumab that successfully prevented any treatment related bone effects, a known effect of Wnt inhibition. Overall, the data from these signal searching studies show enhanced activity of zamaporvint within the RNF43/RSPO MSS subgroup of GI cancers.

Furthermore, they support clinical development in this subgroup in combination with anti-PD-1 where see an exciting opportunity for Wnt pathway inhibition by zamaporvint to reverse innate anti-PD-1 resistance. Other rational zamaporvint combination opportunities to enhance patient benefit, such as with early line chemotherapies or with EGFR/MAPK pathway inhibitors, also exist in wider GI cancer patient populations. Redx is seeking a partner to support ongoing clinical development.