RXC004 – best-in-class porcupine inhibitor
RXC004 is a potent, selective and orally bioavailable inhibitor of the enzyme Porcupine and ligand-dependant Wnt signalling pathway. Porcupine is a key enzyme in the Wnt signalling pathway. Aberrant Wnt signalling contributes directly to tumour growth and plays a key role in immune resistance to treatment with immuno-oncology agents such as anti-PD-1 checkpoint inhibitors.
RXC004 has the potential to be used in immuno-oncology treatment paradigms as monotherapy or in combination with immuno-oncology agents such as anti-PD-1 checkpoint inhibitors. Anti-PD-1 checkpoint inhibitors have been approved in a broad array of tumour types, for example non-small cell lung cancer (NSCLC), melanoma, and colorectal cancer. Additionally, RXC004 has potential as a biomarker-guided, targeted therapy in genetically defined cancers, such as colorectal, pancreatic and biliary cancers.
Genetic alterations of interest include mutations in the RNF43 gene and fusions in the RSPO gene family which are present in multiple tumour types. By selecting patients with these genetic alterations, RXC004 has a unique opportunity to target tumour proliferation directly, in addition to having an immune-enhancing effect.
RXC004 clinical development – Phase I update
The first-in-man clinical phase 1 trial of RXC004 aims to evaluate the safety and tolerability of RXC004 in patients with advanced malignancies (ClinicalTrials.gov Identifier: NCT03447470). Based on preclinical models of cancer, RXC004 has demonstrated the potential to deliver benefit to cancer patients lacking alternative treatment options.
Initial results from the unblinded clinical study are encouraging. RXC004 was well tolerated in both 0.5mg and 1mg patient cohorts treated so far, with no Dose Limiting Toxicities (DLTs) reported. Measured pharmacokinetic parameters were compatible with once daily dosing and importantly, there was strong target engagement detected in markers in skin tissue. A third patient cohort at 1.5mg, was initiated in 2019 and is ongoing. Despite a recruitment pause resulting from COVID-19, Redx still anticipates full safety and tolerability results from this phase 1 study will be available during 2020, with the initiation of Phase 2 studies in early 2021.
RXC004 Clinical investigators:
Dr. Natalie Cook, Senior Clinical Lecturer in Experimental Cancer Medicine and Honorary Consultant, Christie Hospital, Manchester, England. More information.
Professor Sarah P Blagden, Associate Professor of Experimental Cancer Medicines & Consultant Medical Oncologist/ Director of Early Phase Cancer trails unit & Oxford ECMC lead, University of Oxford, Department of Oncology, England. More information.
Professor Ruth Plumber, Clinical Professor of Experimental Cancer Medicine, Northern Institute of Cancer Research, Newcastle University, England. More information.
Dr. Debashis Sarker, Senior Lecturer and Honorary Consultant in Medical Oncology, King’s College Hospital & Guy’s and St Thomas hospital, London, England. More information
Dr. Juanita Lopez, Consultant Medical Oncologist, Royal Marsden Hospital, Institute Cancer Research, Surrey, England. More Information
Future development of RXC004
RXC004: Enhancing immuno-oncology drug response.
Immune checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1 antibodies, have revolutionised the treatment of cancer; but they do not work in all patients. Many tumours are described as “cold”, meaning that tumour-killing immune cells are not present at the tumour site. There is now strong scientific evidence that the Wnt signalling pathway plays a key role in immune evasion and resistance to checkpoint inhibitors across multiple tumour types, (reviewed by Luke et al. 2019, Spranger et al. 2018, Wang et al. 2018).
Our scientists have demonstrated the ability of RXC004 to enhance the immune system response to cancer in preclinical models. Some of this data has been presented at the American Association of Cancer Research (AACR) Annual meeting (Bhamra et al., 2018). These data suggest RXC004 in combination with checkpoint inhibitors (such as anti-PD-1, anti-PD-L1 antibodies) may enhance the already impressive results observed for this exciting class of therapies by increasing the response rates and the duration of the response. In line with these data, Redx is exploring clinical opportunities for a RXC004 combination approach with anti-PD-1 or anti-PD-L1, with the ultimate aim of increasing patient response rates to immuno-oncology therapy.
Targeted therapy in genetically defined cancers– Development of a predictive clinical response biomarkers
Our scientists have identified specific mutations in the RNF43 gene and fusions in the RSPO gene family in cancers such as colorectal and pancreatic cancer. These targeted aberrations can be used to predict which patients are most likely to benefit from treatment with RXC004. In order to translate these finding to the clinic, our scientists worked with diagnostic testing experts at NewGene Ltd, and have developed a cutting edge clinical biomarker assay which will be used to guide patient selection during clinical trials. This test analyses small fragments of DNA released by tumour cells into the patient’s blood to detect cancer-specific RNF43 mutations which are predictive of drug response. This technology, which only requires a simple blood sample from patients, allows a precision medicine approach to be taken for our RXC004 clinical programme, benefiting patients and also improving the efficiency with which studies can be carried out. Initial data describing aspects of test development were presented at the ESMO congress. Our scientists are continuing to with other institutions and providers to develop further genetic predictors of response to RXC004.