RXC004 (Porcupine Inhibitor)
Designed to unlock the potential of Wnt pathway blockade in oncology
Phase 2 programme underway, topline data expected from H2 2023
Target/Product
Indications
Research
Preclinical
Phase 1
Phase 2
Phase 3
Upcoming Milestones
Potential best-in-class
Porcupine Inhibitor
(RXC004)
Genetically selected MSS mCRC
Topline data in combination with anti-PD-1 – from H2 2023
Biliary tract cancer and pancreatic cancer
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-PD1 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 the 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 (monotherapy and immuno-oncology combination) are underway.
Our Pipeline
Potential best-in-class
Porcupine Inhibitor
(RXC004)
UPCOMING MILESTONES
Topline data in combination with anti-PD-1 – from H2 2023
RXC004 clinical development
About the Phase 1 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 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 dependent cancers. These data were presented at the European Society of Medical Oncology (ESMO) Congress in September 2021.
We evaluated RXC004 in a second module of our Phase 1 clinical trial in combination with nivolumab, an anti-PD-1 antibody. The primary objective of this module was to evaluate the safety and tolerability of this combination in patients with unselected advanced malignancies. The results from this combination trial were presented at the Society for Immunotherapy of Cancer (SITC) Conference in November 2022 and confirmed that the combination was well tolerated, and a dose of 1.5mg of RXC004 was selected to be used in combination arms of the Phase 2 study.
A third module, in which patients are given RXC004 monotherapy on an intermittent schedule, is ongoing.
About the Phase 2 Programme
We are running two Phase 2 proof-of-concept clinical trials in genetically selected patients with microsatellite stable metastatic colorectal cancer (MSS mCRC), as well as in genetically selected patients with pancreatic cancer, and in biliary cancer. The first trial, PORCUPINE, evaluates RXC004 as a monotherapy and in combination with nivolumab (OPDIVO® – Bristol Myers Squibb), an anti-PD-1 checkpoint immunotherapy in genetically selected MSS mCRC. The second trial, PORCUPINE2, evaluates RXC004 as monotherapy in genetically selected pancreatic cancer and as monotherapy and in combination with pembrolizumab (KEYTRUDA® – MSD International Business GmbH), anti-PD-1 checkpoint immunotherapy in biliary cancer, given biliary cancer is a highly Wnt-ligand driven cancer.
These indications have significant unmet medical need given poor survival outcomes and limited safe and effective treatment options. The addressable patient population for these initial indications aggregates to approximately 74,000 new cases per year in the United States, the five major markets in Europe, or EU5, and Japan.
Clinical InvestigatorsWhy 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 have demonstrated that Porcupine inhibition has had significant anti-cancer effects in genetically defined cancer cells harbouring upstream Wnt pathway alterations such as RNF43 LoF mutations and RSPO-fusions. RNF43 LoF mutations and RSPO-fusions both result in increased levels of cell-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 particularly sensitive to Porcupine inhibition 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 has potential to 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 the American Association of Cancer Research Annual Meeting 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 has potential to 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 AACR and is published here Phillips et al. 2019.
Programme summary
RXC004 (Porcupine Inhibitor)