ETC-159 / Experimental Therapeutics Centre, A*Star, National University of Singapore - LARVOL DELTA

Porcupine inhibitors LGK-974 and ETC-159 inhibit Wnt/β-catenin signaling and result in inhibition of the fibrosis. (PubMed, Toxicol In Vitro) - "LGK-974 and ETC-159 may be a possible long-term therapeutic target for scleroderma."

Journal • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • TGFB1

A Study to Evaluate the Safety and Tolerability of ETC-1922159 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumours (clinicaltrials.gov) - P1 | N=89 | Active, not recruiting | Sponsor: EDDC (Experimental Drug Development Centre), A*STAR Research Entities | Trial completion date: May 2024 ➔ Oct 2024 | Trial primary completion date: Feb 2024 ➔ Oct 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RSPO2 • RSPO3

ETC-159-02: ETC-159 In Combination With Pembrolizumab In Advanced MSS/pMMR Ovarian Cancers (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: National University Hospital, Singapore

Combination therapy • Metastases • New P1 trial • Oncology • Ovarian Cancer • Solid Tumor

Examination of Wnt signaling as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using a pancreatic tumor organoid library (PTOL). (PubMed, PLoS One) - "Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Telocyte-Derived Exosomes Provide an Important Source of Wnts That Inhibits Fibrosis and Supports Regeneration and Repair of Endometrium. (PubMed, Cell Transplant) - "Results showed that, TCs (either TCM or TC-derived Exo) provide a source of Wnts that inhibit cellular fibrosis, as evidenced by significantly elevated VEGF and β-catenin with decreased fibrotic markers, whereas TCs lost salvage on fibrosis after being blocked with Wnt/β-catenin inhibitors (XAV939 or ETC-159). Results demonstrated that TC-Exo treatment effectively promotes regeneration repair of endometrium by relieving fibrosis, enhancing MET, and angiogenesis. These results confirmed new evidence for therapeutic perspective of TC-derived Exo in IUAs."

Journal • Fibrosis • Gynecology • Immunology • Infectious Disease • Obstetrics • Women's Health • CDH1 • CDH2 • COL1A1 • CTNNB1 • FN1

A Study to Evaluate the Safety and Tolerability of ETC-1922159 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumours (clinicaltrials.gov) - P1 | N=89 | Active, not recruiting | Sponsor: EDDC (Experimental Drug Development Centre), A*STAR Research Entities | Recruiting ➔ Active, not recruiting | Trial completion date: Aug 2024 ➔ May 2024 | Trial primary completion date: Dec 2022 ➔ Feb 2024

Combination therapy • Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RSPO2 • RSPO3

EFFICACY OF THE PORCUPINE INHIBITOR ETC-1922159 (ETC-159) PLUS PEMBROLIZUMAB IN MICROSATELLITE STABLE (MSS) OR PROFICIENT MISMATCH REPAIR (PMMR) PLATINUM RESISTANT OVARIAN CARCINOMAS (PROC) (IGCS 2023) - "Six PROC patients were treated with the combination in dose escalation & expansion. The majority (66%) were high- grade serous ovarian carcinomas with a median 4 lines (2-7) of previous treatments. SAEs were pneumonitis and erythema with fever (8 mg, 1 patient)."

Clinical • IO biomarker • Mismatch repair • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRCA2

A phase 1B dose escalation study of ETC-159 in combination with pembrolizumab in advanced or metastatic solid tumours. (ASCO 2023) - P1 | "Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was safe as a monotherapy at 16 mg or at 24 mg with the addition of preventive denosumab for bone protection. ETC-159 + pembrolizumab was well tolerated; 8 mg of ETC-159 in combination with pembrolizumab was determined to be the MTD/RD. Preliminary data suggest Wnt signaling inhibition in combination with checkpoint inhibition may provide clinical benefit in MSS patients. Clinical trial information: NCT02521844."

Combination therapy • Metastases • P1 data • Colorectal Cancer • Constipation • Dermatology • Endocrine Disorders • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Musculoskeletal Diseases • Oncology • Orthopedics • Pneumonia • Solid Tumor • Thrombocytopenia

ETC-159, an Upstream Wnt inhibitor, Induces Tumour Necrosis via Modulation of Angiogenesis in Osteosarcoma. (PubMed, Int J Mol Sci) - "Consistent with our hypothesis, we noted that ETC-159 treatment not only resulted in markedly decreased β-catenin staining in xenografts, but also increased tumour necrosis and a significant reduction in vascularity-a hereby yet undescribed phenotype following ETC-159 treatment. Through further understanding the mechanism of this new window of vulnerability, therapies can be developed to potentiate and maximize the effectiveness of ETC-159, further increasing its clinical utility for the treatment of OS."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CTNNB1

[VIRTUAL] Development of a qRT-PCR-based diagnostic test to identify colorectal cancer patients with recurrent R:Spondin gene fusions (ESMO Asia 2020) - P1 | "This CTA is currently used to pre-screen & select patients for the phase IB trial with the porcupine inhibitor ETC-1922159 (NCT02521844) ongoing in Singapore and USA...Funding: BMRC, NRF and NMRC Singapore. Clinical trial identification: NCT02521844."

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • NRAS • SPON1

[VIRTUAL] Development of a qRTPCRbased diagnostic test to identify colorectal cancer patients with recurrent RSpondin gene fusions (ESMO Asia 2020) - P1 | "This CTA is currently used to pre-screen & select patients for the phase IB trial with the porcupine inhibitor ETC-1922159 (NCT02521844) ongoing in Singapore and USA. BMRC, NRF and NMRC Singapore."

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • NRAS • SPON1

[VIRTUAL] Development of a qRTPCRbased diagnostic test to identify colorectal cancer patients with recurrent RSpondin gene fusions (ESMO Asia 2020) - P1 | "This CTA is currently used to pre-screen & select patients for the phase IB trial with the porcupine inhibitor ETC-1922159 (NCT02521844) ongoing in Singapore and USA. BMRC, NRF and NMRC Singapore."

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • NRAS • SPON1

EXAMINATION OF WNT SIGNALING AS A THERAPEUTIC TARGET FOR PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) USING A PANCREATIC TUMOR ORGANOID LIBRARY (PTOL) (APCM 2021) - "For confirmation of Wnt inhibition, organoids grown in minimal media were treated with Wnt inhibitors (ETC-159, ICG001, C59). Based on the results obtained, each pancreatic organoid demonstrated different niche factor dependencies providing an avenue for targeted therapy, particularly with Wnt inhibition, which was supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. WES and gene expression analysis of each organoid will be done as an additional avenue of analysis to comprehensively correlate genotype and Wnt (in)dependency observed in vitro."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

A Study to Evaluate the Safety and Tolerability of ETC-1922159 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumours (clinicaltrials.gov) - P1; N=89; Recruiting; Sponsor: EDDC (Experimental Drug Development Centre), A*STAR Research Entities; Trial completion date: Apr 2023 ➔ Aug 2024

Clinical • Combination therapy • Trial completion date • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PCR • RSPO2 • RSPO3

Structural model of PORCN illuminates disease-associated variants and drug binding sites. (PubMed, J Cell Sci) - "Drugs including ETC-159, IWP-L6 and LGK-974 dock in the PORCN catalytic site, providing insights into PORCN pharmacologic inhibition. This structural model enhances our mechanistic understanding of PORCN substrate recognition and catalysis as well as the inhibition of its enzymatic activity and can facilitate the development of improved inhibitors and the understanding of disease relevant PORCN mutants."

Journal • Oncology

Phase 1 extension study of ETC-159 an oral PORCN inhibitor administered with bone protective treatment, in patients with advanced solid tumours. (ESMO Asia 2018) - P1; "ETC-159 with prophylactic denosumab is safe; there are no compression fractures and β-CTX decreases in most pts. ETC-159 has PD activity and increases immune infiltration. ETC-159 dosing is ongoing at 24 mg."

Clinical • P1 data • Solid Tumor

Recent updates on Wnt signaling modulators: a patent review (2014-2020). (PubMed, Expert Opin Ther Pat) - "Lorecivivint, Wnt inhibitor, for the treatment of knee osteoarthritis and SM-04554, Wnt activator, for the treatment of androgenetic alopecia are currently under Phase III. Other molecules like LGK-974, RXC-004, ETC-159, CGX-1321, PRI-724, CWP-232291 and BC-2059 are also under different stages of clinical development for the treatment of cancer. Antibody based Wnt modulator, OTSA101-DTPA-90Y is currently under Phase I for the treatment of relapsed or refractory synovial sarcoma while OMP-18R5 is under Phase I for metastatic breast cancer. Ongoing preclinical and clinical trials will define the role of the Wnt pathway in different therapeutic areas and have opened new opportunities."

Journal • Review • Alopecia • Alzheimer's Disease • Breast Cancer • CNS Disorders • Hepatology • Immunology • Nephrology • Oncology • Osteoarthritis • Pain • Renal Disease • Rheumatology • Sarcoma • Solid Tumor • Synovial Sarcoma

Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer. (PubMed, J Med Chem) - "Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, β-catenin/coactivators, protein-protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (e.g., LGK-974, PRI-724, and ETC-159) in human clinical trials. Herein we summarize recent progress in the drug discovery and development of small-molecule inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochemical properties, and therapeutic potential. The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted."

Journal • Oncology

A Study to Evaluate the Safety and Tolerability of ETC-1922159 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumours (clinicaltrials.gov) - P1; N=83; Recruiting; Sponsor: EDDC (Experimental Drug Development Centre), A*STAR Research Entities; Trial completion date: Jul 2023 ➔ Apr 2023

Clinical • Combination therapy • Trial completion date • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PCR • RSPO2 • RSPO3

Amelioration of bone fragility by pulsed electromagnetic fields in type 2 diabetic KK-Ay mice involving Wnt/β-catenin signaling. (PubMed, Am J Physiol Endocrinol Metab) - "Moreover, PEMF-induced improvement in bone microstructure, mechanical strength and bone formation in KK-Ay mice was abolished after intragastric administration with the Wnt antagonist ETC-159. Together, our results suggest that PEMF can improve bone microarchitecture and quality by enhancing the biological activities of osteoblasts and osteocytes, which are associated with the activation of the Wnt/β-catenin signaling pathway. PEMF might become an effective countermeasure against T2DM-induced bone deterioration."

Journal • Preclinical • Diabetes • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • Type 2 Diabetes Mellitus

Porcupine Inhibitors: Novel and Emerging Anti-cancer Therapeutics Targeting the Wnt Signaling Pathway. (PubMed, Pharmacol Res) - "Clinically, Porcupine inhibitors have shown their potential in treating majorly colorectal cancer, pancreatic cancer, hepatocellular carcinoma, head and neck cancer etc. Till date, none of the Porcupine inhibitors have been in the market and only four molecules, LGK974, ETC159, CGX1321 and RXC004 have reached the Phase I clinical trial. Their physico chemical properties were also predicted using SwissADME server. Major concerns during their development have also been summarised which may throw some light for the future development of novel Porcupine inhibitors for the treatment of cancer."

Journal • Review • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer. (PubMed, EMBO Mol Med) - "In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers...Our findings suggest a general paradigm that Wnt/β-catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents."

Journal • Hematological Disorders • Oncology • APC • BRCA • BRCA1 • FANCD2 • MYBL2 • RAD51

A Study to Evaluate the Safety and Tolerability of ETC-1922159 in Advanced Solid Tumours (clinicaltrials.gov) - P1; N=83; Recruiting; Sponsor: EDDC (Experimental Drug Development Centre), A*STAR Research Entities; Active, not recruiting ➔ Recruiting; Trial completion date: Dec 2022 ➔ Jul 2023

Clinical • Enrollment open • Trial completion date • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor

Made-in-Singapore Cancer Drug ETC-159 Advances Further in Clinical Trials. - "'This study will help address a critical and unmet need in gastrointestinal cancers. The novel design to molecularly screening for R-spondin fusion colorectal cancers that may be driven by the Wnt pathway and to target them with ETC-159 and immunotherapy has never been done before. Furthermore, most gastrointestinal cancers particularly colorectal cancers do not respond to immunotherapy. This may be due to suppression of immune cells in the tumour by Wnt-related pathways. We hope that by combining ETC-159 and immunotherapy we can circumvent this problem and achieve long-lasting responses for our patients.'"

Media quote

[VIRTUAL] Sensitizing microsatellite stable colorectal cancer to immune checkpoint therapy utilizing Wnt pathway inhibition (AACR-II 2020) - "Lastly, VECTRA analysis corroborates the flow cytometry data showing a changing tumor immune landscape through an increase in CD4+ and CD8+ T cells in the tumor and surrounding stroma.Our data demonstrates the combination treatment of ETC-159 + nivolumab in MSS CRC hPDX show increased tumor infiltration of human immune cells. Further preclinical data is compulsory but these results support further development of this combination in clinical trials."

IO Biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • CTLA4 • GZMB • MSI • PD-1