RXC004 – best-in-class porcupine inhibitor

Porcupine is a key enzyme in the Wnt signalling pathway and plays a key role in immune resistance to treatment with immune-oncology agents such as anti-PD-1 checkpoint inhibitors. Our Porcupine inhibitor, RXC004, is a potent inhibitor of this enzyme and WNT-ligand pathway.

RXC004 has the potential to be used as a combination partner in immune-oncology treatment paradigms with immune-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, biliary and gastric cancers.

RXC004 clinical development – Phase I trial update

The first-in-man clinical phase 1 trial of RXC004 aims to evaluate the safety and tolerability of the RXC004 in patients with advanced malignancies (ClinicalTrials.gov Identifier: NCT03447470). In preclinical models of cancer RXC004 has demonstrated the potential to deliver benefit to cancer patients lacking alternative  treatment options.

As previously announced, we suspended recruitment of patients in March 2018 following treatment of the first patient. The study was paused due to the observation of clinically significant adverse events, which were related to the on-target effects of RXC004 on the inhibition of the Wnt pathway.  Clinical data from this first patient confirmed significant Wnt pathway inhibition and indicated that RXC004 exposure was higher than that predicted from preclinical studies.

Together with our clinical investigators, we believe that the desired RXC004 exposure can be achieved using a significantly lower starting dose and dose-escalation. Following a positive scientific advice meeting with the MHRA, a protocol amendment incorporating a lower dose and additional safety monitoring will be submitted to the regulatory agency, with the aim of treating the next patient in the first half of 2019.

In the remaining Phase I component of the clinical programme, we will establish the optimal dose of RXC004 to use going forward. As a part of this, we will look at side effects of the drug as well as the pharmacokinetics of the drug in cancer patients.

RXC004 Clinical investigators:

Professor Sarah P Blagden, PhD, FRCP, 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. More information.

Dr. Natalie Cook, MBchB, MRCP, PhD, Senior Clinical Lecturer in Experimental Cancer Medicine and Honorary Consultant, Christie Hospital. More information.

Professor Ruth Plumber, MA, DPhil, BMBch, MD, FRCP,  Clinical Professor of Experimental Cancer Medicine, Northern Institute of Cancer Research, Newcastle University. 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” that is, 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, (recently reviewed by 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 already been presented at the recent American Association of Cancer Research 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 and 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 genetic alterations in the RNF43 gene in cancers such as colorectal pancreatic and gastric cancer which 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, working with diagnostic testing experts at NewGene Ltd, 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 2017. In addition to RNF43, our scientists are also working with other institutions and providers to developed further genetic predictors of response to RXC004.

Case study:

Liquid biopsy assay for testing RNF43 mutated gastric and pancreatic cancer