zamaporvint (RXC004) / Redx - LARVOL DELTA

Study to Evaluate the Safety and Tolerability of RXC004 in Advanced Malignancies (clinicaltrials.gov) - P1 | N=46 | Completed | Sponsor: Redx Pharma Ltd | Active, not recruiting ➔ Completed

Trial completion • Oncology • Solid Tumor

Redx Pharma's cancer drug shows promising results in early trials (Proactiveinvestors) - P2 | N=25 | NCT04907539 | Sponsor: Redx Pharma Plc | "Redx Pharma PLC's...phase II data for its cancer drug, zamaporvint, showed a disease control rate of 57% along with around a 30% partial response rate when combined with an immune checkpoint inhibitor drug called nivolumab in people with a type of colorectal cancer called MSS mCRC....In the trial, zamaporvint was generally well tolerated, and the combination with nivolumab appeared to be more effective than zamaporvint alone."

P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Phase II results of the porcupine (PORCN) inhibitor zamaporvint (RXC004) in genetically selected microsatellite stable colorectal cancer patients (ESMO-GI 2024) - P2 | "RXC004 was tolerable; denosumab prevented BMD loss. In this poor prognosis subgroup, RXC004 monotherapy was comparable to late-line SoC in mCRC, whilst the nivolumab combination suggests improvement versus SoC and warrants further clinical investigation."

Clinical • IO biomarker • P2 data • Alopecia • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Immunology • Oncology • Solid Tumor • RNF43 • RSPO2

Phase II results of the porcupine (PORCN) inhibitor zamaporvint (RXC004) in patients with pancreatic and biliary tract cancer (ESMO-GI 2024) - "Pts received RXC004 monotherapy (2mg QD; M1 and M2) or in combination (1.5mg QD) with pembrolizumab (M3). RXC004 was tolerable; denosumab prevented BMD loss. No conclusions on efficacy can be drawn in PDAC due to insufficient recruitment. Whilst some durable clinical benefit was seen, efficacy results in unselected advanced BTC pts are not sufficient to support further development."

Clinical • P2 data • Biliary Cancer • Biliary Tract Cancer • Constipation • Fatigue • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • RNF43

PORCUPINE: A Study to Assess Efficacy of RXC004 +/- Nivolumab in Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer After Progression on Standard of Care (SOC) (clinicaltrials.gov) - P2 | N=25 | Completed | Sponsor: Redx Pharma Plc | Recruiting ➔ Completed | N=50 ➔ 25 | Trial completion date: Dec 2023 ➔ Apr 2024 | Trial primary completion date: Aug 2023 ➔ Apr 2024

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RNF43 • RSPO2

Clinical study assessing the preliminary efficacy and safety of RXC004, in Patients with Advanced Pancreatic Cancer that have Progressed following Therapy with Current Standard of Care (ANZCTR) - P2 | N=20 | Not yet recruiting | Sponsor: Australian Genomic Cancer Medicine Centre Ltd t/a Omico

Metastases • New P2 trial • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • RNF43

Final results of the first-in-human study of the porcupine (PORCN) inhibitor zamaporvint (RXC004) in patients with advanced solid tumors (AACR 2024) - P1 | "RXC004 has potential for efficacy in upstream Wnt pathway activated tumours: ~5% pancreatic cancer and ~8% microsatellite stable colorectal (CRC) cancer with RNF43 mutations or RSPO fusions, and tumors with high Wnt ligand expression.Methods In this Phase I study of RXC004 (NCT03447470), Module 1 investigated continuous monotherapy dosing, Module 2 investigated combination with nivolumab 480mg s.c. Q4W and Module 3 investigated intermittent monotherapy dosing (2 weeks on 1 week off). Denosumab prevented loss of BMD. Intermittent RXC004 dosing was well tolerated with no detrimental impact on efficacy."

Clinical • Metastases • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Small Intestinal Carcinoma • Solid Tumor • RNF43

Pre-clinical activity of the Wnt pathway inhibitor RXC004 in combination with MAPK pathway inhibitors in GI cancer models (AACR 2024) - "A striking co-occurrence of upstream Wnt pathway variants with MAPK pathway driver mutations (KRAS, BRAF, NRAS) was detected in 77% of Microsatellite stable (MSS) GI cancers, suggesting co-inhibiting these pathways could enhance clinical activity in these patients. In vitro proliferation assays were performed in pre-clinical models of upstream Wnt pathway mutated MSS GI cancer (SNU-1411, HPAF-II and AsPC-1) using Wnt (RXC004) or MAPK (Trametinib) pathway inhibitors at multiple concentrations as single agents or in combination. Wnt and MAPK pathways are frequently co-activated in GI cancers, particularly in the upstream Wnt pathway mutated sub-population. Pre-clinically we show that Wnt and MAPK pathways act as potential reciprocal resistance mechanisms following single agent inhibition of either pathway; co-inhibition of these pathways leads to synergistic effects in vitro and enhanced efficacy in vivo. This provides a clear rationale to assess this combination approach..."

Combination therapy • Preclinical • Gastrointestinal Cancer • Oncology • AXIN2 • BRAF • DUSP6 • KRAS • NRAS • RNF43

KEYNOTE-E86: A Study to Assess RXC004 Efficacy in Advanced Solid Tumours After Progression on Standard of Care (SoC) Therapy (PORCUPINE2) (clinicaltrials.gov) - P2 | N=45 | Completed | Sponsor: Redx Pharma Plc | Active, not recruiting ➔ Completed

Metastases • Trial completion • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RNF43

THIS ANNOUNCEMENT CONTAINS INSIDE INFORMATION FOR THE PURPOSES OF ARTICLE 7 OF EU REGULATION 596/2014 AS IT FORMS PART OF DOMESTIC LAW IN THE UNITED KINGDOM BY VIRTUE OF THE EUROPEAN UNION (WITHDRAWAL) ACT 2018. (Redx Pharma) - "Significant pipeline prioritisation review undertaken with strategic focus refined to the advancement of differentiated Rho Associated Coiled-Coil Containing Protein Kinase (ROCK) inhibitor portfolio through the next stages of clinical development, with RXC004 identified for partnership...In October 2023, confirmed that recruitment had been closed into all PORCUPINE and PORCUPINE2 modules, with data readout expected H1 2024."

P2 data • Trial status • Biliary Tract Cancer • Colorectal Cancer

Therapeutic opportunities for porcupine inhibition in gastrointestinal cancer (ESMO 2023) - "Preclinically, GI tumors with upstream Wnt pathway variants (RNF43 loss of function (LoF), RSPO gain of function (GoF)) are Wnt ligand dependent and exquisitely sensitive to RXC004, a small molecule Porcupine inhibitor...Conclusions Upstream Wnt pathway variants are enriched in GI cancer, in particular Small Bowel cancer, a rare subtype of high unmet need. In MSS CRC cancer, the poor prognosis and high BRAF_V600E co-occurrence with upstream Wnt pathway variants suggests benefit of co-targeting Wnt and MAPK pathways in this population."

Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Small Intestinal Carcinoma • Solid Tumor • RNF43 • RSPO2 • RSPO3

KEYNOTE-E86: A Study to Assess RXC004 Efficacy in Advanced Solid Tumours After Progression on Standard of Care (SoC) Therapy (PORCUPINE2) (clinicaltrials.gov) - P2 | N=45 | Active, not recruiting | Sponsor: Redx Pharma Plc | Recruiting ➔ Active, not recruiting | N=80 ➔ 45 | Trial primary completion date: Jun 2023 ➔ Nov 2023

Enrollment change • Enrollment closed • Metastases • Trial primary completion date • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RNF43

Study to Evaluate the Safety and Tolerability of RXC004 in Advanced Malignancies (clinicaltrials.gov) - P1 | N=46 | Active, not recruiting | Sponsor: Redx Pharma Plc | Completed ➔ Active, not recruiting | Trial completion date: Mar 2023 ➔ Sep 2023 | Trial primary completion date: Mar 2023 ➔ Sep 2023

Combination therapy • Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Study to Evaluate the Safety and Tolerability of RXC004 in Advanced Malignancies (clinicaltrials.gov) - P1 | N=50 | Completed | Sponsor: Redx Pharma Plc | Recruiting ➔ Completed | Trial completion date: Dec 2021 ➔ Mar 2023 | Trial primary completion date: Jul 2021 ➔ Mar 2023

Combination therapy • Metastases • Trial completion • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Pre-clinical activity of the Wnt/Beta-catenin pathway inhibitor RXC004 in models of biliary tract cancer (AACR 2023) - P2 | "Background: RXC004 is a potent and selective inhibitor of the Wnt pathway regulator Porcupine, and is currently being investigated in phase 2 studies in patients with advanced cancers, including Biliary Tract Cancers (BTCs) +/- Pembrolizumab (NCT04907851 and NCT04907539). These data demonstrate that (1) RXC004 is efficacious in pre-clinical PDX models of BTC, (2) RXC004 induces multiple PD effects in BTC models at the level of gene expression, cell proliferation and cell differentiation, and (3) PDX models of BTC can be clustered based on baseline transcriptomic profiles of Wnt signalling genes and predict RXC004 sensitivity."

Preclinical • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MUC2 • MUC4 • MUC5AC • MYC • RNF43

PORCUPINE: A Study to Assess Efficacy of RXC004 +/- Nivolumab in Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer After Progression on Standard of Care (SOC) (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Redx Pharma Plc | Trial completion date: Aug 2023 ➔ Dec 2023 | Trial primary completion date: Apr 2023 ➔ Aug 2023

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RNF43 • RSPO2

The Wnt Pathway Inhibitor RXC004 Blocks Tumor Growth and Reverses Immune Evasion in Wnt Ligand-dependent Cancer Models. (PubMed, Cancer Res Commun) - "RXC004 has demonstrated the potential to block both tumor growth and tumor immune evasion in a genetically defined, clinically actionable subpopulation of Wnt ligand-dependent gastrointestinal cancers. The clinical utility of RXC004, and other Porcupine inhibitors, in such Wnt ligand-dependent cancers is currently being assessed in patient trials."

IO biomarker • Journal • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • RNF43 • RSPO3

Redx Announces RXC004 Topline Data from a Phase 2 Monotherapy Module (Market Screener) - P2 | N=80 | PORCUPINE2 (NCT04907851) | Sponsor: Redx Pharma Plc | "Redx...announces topline monotherapy data from the biliary tract cancer (BTC) module of the RXC004 PORCUPINE2 Phase 2 clinical trial programme....Some patients received durable clinical benefit from RXC004 in this cohort, consistent with clinical activity seen in the Phase 1 trial, and the safety profile of RXC004 in this module was also consistent with the safety data previously reported in the Phase 1 trial. However, the overall results are not sufficient to support the further development of RXC004 as a monotherapy in this treatment setting."

P2 data • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Effective co-targeting of fibrotic and immune microenvironments to improve the overall anti-tumour response in models of advanced pancreatic cancer (SITC 2022) - P2 | "These alterations include decreased level of immunosuppressive regulatory T cells, improved CD8+ and CD4+ T cell infiltration and increased presence of M1 pro-inflammatory macrophages in KPC tumours post-treatment, evident both within the tumour body and the invasive edge. Conclusions These data demonstrate that therapeutic efficacy of RXC004 and select anti-fibrotics in preclinical development may be the result of targeting both tumour cells and key aspects of the fibrotic and immune PDA microenvironment and in addition provide scientific rationale for the design of future SoC chemotherapy as well as immunotherapy-based combinations in pancreatic cancer."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • FN1 • KRAS • PDX1 • POSTN

Pre-clinical efficacy of the Wnt pathway inhibitor RXC004 in combination with anti-cancer therapies (AACR 2022) - P2 | "RXC004, dosed at 5mg/kg QD (5 days on / 2 days off), was evaluated in combination with either the clinically relevant colorectal triplet chemotherapy regimen (5-fluorouracil 5-FU (25mg/kg), irinotecan (50mg/kg) and oxaliplatin (5mg/kg)) or doublet chemotherapy regimen (5-FU (25mg/kg), irinotecan (50mg/kg)). These data demonstrate that RXC004 in combination with clinically relevant standard of care chemotherapy regimens can lead to potential benefit over chemotherapy alone. The RXC004 induced downregulation of DNA repair pathway genes observed in vitro could contribute to the beneficial effect seen in combination with a PARP inhibitor in vitro as well as the combination effect observed in vivo with standard of care chemotherapy agents."

Combination therapy • Preclinical • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • BRCA1 • BRCA2 • RNF43

Precision medicine for pancreatic cancer in the UK national health service: Lessons learned from the Precision-Panc platform (AACR 2022) - "Somatic driver variants in RNF43 were detected in 15 patients (5.8%) (biomarker for PRIMUS-007, a second-line trial of porcupine inhibitor RXC004). Three patients (1.2%) were found to be MSI high and 18 (9.1%) had a TMB ≥ 4mutations/Mb (eligible for PRIMUS-008; Pembrolizumab/ Olaparib for patients with a high TMB)... We present the experience and real-world challenges in longitudinal fashion in delivering precision medicine for PC, with attrition along patient and tissue pathways. The majority of samples were successfully sequenced and embedding research activities into routine clinical practice is enabling drug and biomarker development.PS. Discrepancy of numbers is due to a real time snap shot of the pipeline."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRD • KRAS • RNF43 • TMB

[VIRTUAL] Mechanism of action of RXC004, a Wnt pathway inhibitor, in genetically-defined models of cancer (AACR 2021) - P1 | "These data demonstrate that RXC004 monotherapy results in tumour cell differentiation accompanied by reduced metabolic activity in genetically selected tumours. RXC004-induced cell differentiation may therefore continue to provide patient benefit even post dosing. Moreover, FDG-PET imaging in clinical studies may allow early detection of the positive effects of RXC004 in a non-invasive manner, and prior to any changes in tumour volume by conventional RECIST measurements."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CTNNB1 • FDG PET • RNF43

Wnt/â-Catenin pathway inhibitor RXC004 enhances the immunity of pre-clinical models of cancer (AACR 2019) - P1/2; "Taken together, Wnt pathway suppression by RXC004 treatment can enhance the immune response against tumors by 1) directly regulating levels of immune-relevant markers on cancer cells, and 2) enhancing the immunity of the TME by decreasing MDSCs and increasing chemokine and cytokine signaling.Spranger et al Cancer Cell 2017 8 31(5):711-723"

Efficacy of the Wnt/Beta-Catenin pathway inhibitor RXC004 in genetically-defined models of cancer (AACR 2019) - P1/2; "Taken together, these data demonstrate that RXC004 monotherapy has the potential to benefit patients with tumours bearing RNF43 mutations or RSPO fusions, supporting a genetically-defined patient selection strategy for ongoing RXC004 clinical studies."

Clinical

A Study to Assess RXC004 Efficacy in Advanced Solid Tumours After Progression on Standard of Care (SoC) Therapy (PORCUPINE2) (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: Redx Pharma Plc | N=40 ➔ 80 | Trial completion date: Jun 2023 ➔ Dec 2023 | Trial primary completion date: Mar 2023 ➔ Jun 2023

Enrollment change • Trial completion date • Trial primary completion date • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RNF43