Zamaporvint (RXC004, Porcupine Inhibitor) - Redx (2024)

Designed to unlock the potential of Wnt pathway blockade in oncology

Phase 2 programme combination data expected 2024

Zamaporvint (RXC004), is a potent, selective, oral small molecule inhibitor of the enzyme, Porcupine, a key activator of Wnt-ligands in the Wnt signalling pathway.

Aberrant Wnt signalling contributes directly to tumour growth and plays an important role in immune resistance to treatment with immuno-oncology agents such as anti-PD-1 checkpoint inhibitors.

Wnt-ligand activation is common in GI cancers and by selecting patients with tumours that have high Wnt-ligand dependency, such as tumours with mutations in the RNF43 gene and fusions in the RSPO gene family, zamaporvint has an opportunity to directly target tumour in addition to having an immune-enhancing effect by potentially reversing or delaying resistance to multiple conventional and targeted cancer therapies.

Our primary efficacy hypothesis for zamaporvint is in combination, which we are initially exploring clinically with anti-PD-1 therapy, where it has potential to overcome immune evasion and anti-PD-1 resistance in late-stage hard-to-treat tumour types. Additionally, due to its mechanism of action, there is exciting potential to combine with MAPK pathway inhibitors given the significant co-occurrence of both BRAF and KRAS mutations in Wnt-ligand dependent tumours, such as microsatellite metastatic colorectal cancer (MSS mCRC) and pancreatic cancer , as well as with chemotherapy.

There is a significant unmet need GI cancers which together cause more deaths that another other cancer, with MSS mCRC being the second most common cause of cancer mortality in the US and Europe. Other GI cancers, such as pancreatic, gastric, small bowel or appendiceal also have a poor prognosis and limited treatment options are known to be driven by RNF43/ RSPO genetic aberrations.

Our Phase 2 exploratory signal-searching modules are in genetically-selected patients with MSS mCRC (monotherapy and immuno-oncology combination), genetically selected pancreatic cancer (monotherapy) and all-comers biliary cancer (monotherapy and immuno-oncology combination).

Zamaporvint Highlights to date

In the Phase 1 study zamaporvint was found to have a well tolerated and clinically active profile as a monotherapy and in combination with anti-PD-1:

• Well tolerated and active as a monotherapy, having differential clinical efficacy in Wnt-ligand dependent tumours (ESMO, 2021)
• Well tolerated in combination with nivolumab (SITC, 2022)
• Pharmaco*kinetic profile suitable for once daily oral dosing.
• Showed target engagement (Axin-2 reduction) at all doses.

About the Phase 2 Programme:

The first trial, PORCUPINE, evaluates zamaporvint as a monotherapy and in combination with nivolumab (OPDIVO®¹), an anti-PD-1 checkpoint immunotherapy in genetically selected MSS mCRC. The second trial, PORCUPINE2, evaluates zamaporvint as monotherapy in genetically selected pancreatic cancer and as monotherapy and in combination with pembrolizumab (KEYTRUDA®²), anti-PD-1 checkpoint immunotherapy in biliary tract cancer, given biliary tract cancer has high Wnt-ligand expression. In December 2022, a clinical trial collaboration and supply agreement with Merck was announced for the supply of pembrolizumab for this trial.

The Phase 2 data will be presented at a scientific congress during 2024.

Zamaporvint offers a unique opportunity to unlock the efficacy of Wnt pathway inhibition with a tolerable, clinically active porcupine inhibitor, that has demonstrated preclinical efficacy in a number of treatment combinations to address genetically-selected, hard-to-treat GI cancers.

¹ OPDIVO® is a registered trademark of Bristol-Myers Squibb Company
² KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

Clinical Investigators

Porcupine as an oncology target – why target Porcupine?

Signalling through the Wnt pathway is highly regulated at the level of ligand (Wnt), receptors (Fzd/LRP) and downstream components. The pathway is initiated by the binding of Wnt-ligands to Frizzled (Fzd) receptors resulting in activation of both the classical canonical and non-canonical signalling pathways.

Aberrant activation of the Wnt signalling pathway is involved in the initiation and progression of cancer. Activation of the Wnt pathway is also associated with poor prognosis and resistance of cancers to current therapies, including immune checkpoint inhibitors (ICIs). The pathway is initiated by the binding of Wnt-ligands to Frizzled (Fzd) receptors resulting in activation of both the classical canonical and non-canonical signalling pathways (see Fig. 1). Porcupine is a key enzyme required for the release of all active Wnt-ligands and its inhibition will affect signalling via both canonical and non-canonical pathways, which are both involved in disease progression.

Clinical Development: RXC004 has a dual mechanism of action

RXC004 has a dual mechanism of action, directly targeting tumour cells, in addition to having an immune-enhancing effect.

References