Redx Pharma reports on zamaporvint cancer treatment trials 

Gastrointestinal tract

Redx Pharma has announced data from all Phase II clinical trial modules of zamaporvint (RXC004), a potent, selective, orally-active Porcupine inhibitor in development for Wnt-ligand dependent, hard-to-treat gastrointestinal (GI) cancers.  

These data, presented at the European Society for Medical Oncology Gastrointestinal Cancers (ESMO GI) Congress, 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 as monotherapy and anti-PD-1 combination, as well as genetically-selected pancreatic cancer as monotherapy (NCT04907851). 

Natalie Cook, Chief Investigator for the Zamaporvint Study Programme, commented: “It is very encouraging to see the data returned from this signal-searching study. The indications targeted are in populations with a particularly poor prognosis and limited treatment options. Wnt inhibition has long held promise for this genetically-selected patient group and a tolerable, clinically active Porcupine inhibitor in combination with anti-PD-1 could potentially offer a new treatment option for patients with these particularly hard to treat cancers.”  

Dr Helen Timmis, Interim Chief Medical Officer, Redx Pharma, commented: “We are delighted to report the Phase II data from our zamaporvint study programme which shows a disease control rate of 57% including partial responses in ~30% of the patients treated with zamaporvint in combination with nivolumab in MSS mCRC. Real world evidence shows that the prognosis for the RNF43/RSPO mutant subgroup of MSS mCRC is significantly worse than in MSS mCRC patients without these Wnt aberrations, where outcomes are already poor. This early signal indicates that, in the right patient groups, the combination of Porcupine and immune checkpoint inhibition has the potential to provide a much-needed improvement on the current standard of care.” 

Wnt inhibition  

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 ~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 effective1. This suggests activity levels potentially better than late-line standard of care in this setting2. 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 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 Redx see an 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. 

References 
  1.  Le et al (2015) 
  2. (Fruquintinib ORR 1.5% [FRESCO]; trifluridine/tipiracil + bevacizumab ORR 6.1% [SUNLIGHT]) 

 

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