RXC004 (Porcupine Inhibitor)

Designed to unlock the potential of Wnt pathway blockade in oncology

Phase 2 start in H2 2021

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 combo safety
completion – H2 2021

Phase 2 start H2 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.

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 during the second half of 2021.

RXC004 clinical development

About the Phase 2 Programme

The selection of a dose and decision to move RXC004 into Phase 2, follows the successful recruitment of all patients to the monotherapy arm of the Company’s ongoing open label dose escalation Phase 1 study (NCT03447470). The primary objective of the Phase 1 study was to establish the safety and tolerability of RXC004 in patients. Preliminary data from the study in patients with unselected advanced solid tumours, showed that RXC004 2mg once daily was safe, tolerated and provided target coverage at levels required to assess monotherapy efficacy in Phase 2 clinical trials in selected patients with Wnt-ligand driven cancers. These data will be presented at EMSO in Sept 2021.

Redx now plans to commence a global Phase 2 monotherapy programme in three tumour types to assess RXC004 efficacy in patients with Wnt-ligand driven cancers. In two tumour types, microsatellite stable metastatic colorectal cancer (MSS mCRC) and pancreatic cancer, the studies will enrol only patients whose tumours have high Wnt-ligand dependency resulting from specific genetic aberrations (RNF43 mutations and/or RSPO fusions). A third proof of concept study will enrol patients diagnosed with biliary tract cancer, a tumour known to have high Wnt-ligand dependency. All three of these cancer types have high unmet need with limited treatment options and poor 5-year survival rates of less than 3% for biliary and pancreatic cancer and 14% for mCRC. All three studies are planned to commence in H2 2021 and initial results could be available from 2022.

RXC004 is also currently being investigated in a Phase 1 study in combination with nivolumab (OPDIVO® – Bristol Myers Squibb, an anti-PD-1 antibody). The primary objective of this arm of the study is to evaluate the safety and tolerability of this combination in patients with unselected advanced malignancies. The results from this combination study are expected in H2 2021 and will be used to define a dose of RXC004 to be used in combination with standard dose nivolumab in a Phase 2 study in patients with genetically selected microsatellite stable (MSS) metastatic colorectal cancer (MSS mCRC).

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 monotherapy complete, with anti-PD1 ongoing

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 H2

Phase 2 start – IO combo MSS mCRC