RXC004 (Porcupine Inhibitor)

Designed to unlock the potential of Wnt pathway blockade in oncology

Phase 1 clinical study ongoing

Target/ Product

Indication(s)

Research

Preclinical Development

Clinical Phase 1/2

Expected Milestones

Porcupine Inhibitor
(RXC004)

Monotherapy in solid tumours
(genetically selected MSS mCRC and pancreatic cancer; biliary cancer)

Combination with anti-PD- (L)1
(genetically selected MSS mCRC)

Phase 1 mono safety
completion – H1 2021

Phase 2 start H1 2021

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.

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, RXC004 has an opportunity to directly target tumour in addition to having an immune-enhancing effect.

RXC004 is currently in Phase 1 clinical trials with data expected in H1 2021. Clinical proof-of-concept studies in genetically-selected patients with metastatic colorectal cancer (monotherapy and immuno-oncology combination), genetically selected pancreatic cancer and all comers biliary cancer are expected to initiate following completion of phase 1.

RXC004 clinical development

The first-in-human phase 1 trial of RXC004 aims to evaluate the safety and tolerability of RXC004 in patients with advanced malignancies, and is currently ongoing (ClinicalTrials.gov identifier: NCT03447470).

The first four patient cohorts (0.5mg, 1mg, 1.5mg, 2mg) have been successfully dosed such that the final cohort (3mg) was initiated in January 2021. Redx anticipates that full safety and tolerability results from this Phase 1 study will now be available in H1 2021 and RXC004 is on track to move into Phase 2 clinical studies in 2021.

Clinical Investigators

Why target porcupine for oncology?

Figure 1: 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.

RXC004 has a dual mechanism of action

Figure 2: RXC004 has a dual mechanism of action, directly targeting tumour cells, in addition to having an immune-enhancing effect.

Preclinical in vitro and in vivo data has demonstrated that RXC004 has significant anti-cancer effects in genetically defined cancer cells with upstream Wnt pathway alterations e.g. RNF43 loss of function (LoF) mutations and RSPO-fusions/translocations. RNF43 LoF mutations and RSPO-fusions/translocations both result in increased levels of surface Fzd receptors (see Fig. 1), and hence increased Wnt-ligand dependent signalling. Consistent with this, cancer cells carrying RNF43 LoF mutations and RSPO fusions/ translocations are sensitive to RXC004 in vitro and in vivo. In addition to targeting cancer cell growth directly, RXC004 has shown strong monotherapy efficacy in a mouse in vivo model that imitates a checkpoint inhibitor-resistant cancer patient. There is strong preclinical and clinical data linking Wnt pathway activation to immune evasion in cancer patients. Thus, in genetically defined cancer patients, RXC004 will have a dual action; by directly inhibiting cancer cell growth and stimulating the patient’s immune system to help fight the cancer.

Source: Redx Published data – full detail in Posters (Phillips et al. 2019),(Woodcock et al. 2019).

RXC004 in genetically-defined cancers

Cancers harbouring genetic alterations upstream in the Wnt pathway have demonstrated sensitivity to RXC004 monotherapy via a direct tumour targeting mechanism. Loss of function mutations in the RNF43 gene and fusions in RSPO, both result in an increase of Fzd receptors at the cell surface and an increased dependence on Wnt ligand for the tumour cell. These upstream Wnt pathway mutations are present in multiple cancer types. By selecting patients with these genetic alterations, RXC004 has an opportunity to directly target tumours, in addition to having an immune enhancing effect. Some supporting preclinical data was presented at American Association of Cancer Research and is published here Woodcock et al. 2019.

Enhancing immune-checkpoint response with RXC004

Immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-PD-L1 antibodies have revolutionised the treatment of cancer, but do not work in all patients. Many tumours that are not responsive to ICI therapy are described as “cold”, in that the tumour-killing immune cells are not present at the tumour site.

The role of the Wnt pathway in immune evasion by tumours (i.e. promoting “cold” tumours) has been the subject of several recent high-profile reviews (Kleeman et al. 2020). (Luke et al. 2019). There is strong preclinical evidence to support the hypothesis that RXC004 will block activation of the Wnt pathway and restore the ability of the immune system to fight the tumour. RXC004 can turn “cold” tumours “hot” by facilitating entry of tumour-fighting immune cells into the tumour microenvironment. Our scientists have demonstrated the ability of RXC004 to enhance the immune system response to cancer in preclinical models. These data suggest that RXC004 alone or in combination with ICIs may help to address the shortcomings of this exciting class of therapies by increasing the response rates and the duration of the response. Supporting preclinical data was presented at the American Association of Cancer Research (AACR) and is published here Phillips et al. 2019.

Programme summary

RXC004 (Porcupine Inhibitor)

Target

Porcupine inhibitor (RXC004) unlocking the potential of Wnt pathway for oncology

Status

Phase 1 clinical trial ongoing, read out in H1 2021

Indications

Monotherapy Genetically selected MSS mCRC & Pancreatic cancer

Biliary cancer

IO combination MSS mCRC

Future development

2021 H1

Phase 2 mono expansion (mCRC, biliary, Pancreatic cancer)

Future development

2021 H1

Phase 1 start – IO combo safety

Future development

2021 H2

Phase 2 start – IO combo MSS mCRC