CGX1321 / Curegenix - LARVOL DELTA

Synergism between inhibitors of the EGFR-RAS-RAF-MEK pathway and the WNT pathway (AACR 2023) - P1b | "We tested MAPK pathway inhibitors, such as cetuximab, selumetinib and cobimetinib (MEK1/2 inhibitors), encorafenib (BRAFV600E inhibitor), and AMG510/sotorasib (KRASG12C inhibitor). Secondary endpoints included PK, overall response rate, CR and PR rate, and duration of response by RECIST 1.1 and irRECIST 1.1. The clinical protocol and available data of CGX1321 in combination with encorafenib and cetuximab in CRC patients with RSPO fusions and BRAFV600E mutations will be discussed."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • APC • AXIN1 • KRAS • RNF43 • RSPO3

Phase 1 study of WNT pathway Porcupine inhibitor CGX1321 and phase 1b study of CGX1321 + pembrolizumab (pembro) in patients (pts) with advanced gastrointestinal (GI) tumors. (ASCO 2023) - P1, P1b | "Bone resorption, the main on-target AE, was manageable and preventable by prophylactic administration of denosumab or zoledronic acid. CGX1321 has demonstrated potent inhibition of the WNT pathway with manageable side effects. Promising efficacy signals have been observed in pts whose tumors harbor RSPO fusion, supporting further development of CGX1321 monotherapy and CGX1321 + anti-PD-1/L1 in a defined patient population that is historically known to be refractory to standard therapies and immune checkpoint inhibitors. Clinical trial information: NCT02675946, NCT03507998."

Clinical • IO biomarker • Metastases • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Immune Modulation • Oncology • Small Intestinal Carcinoma • Solid Tumor • AXIN2 • RNF43 • RSPO3

Dr Giannakis on the Initial Efficacy of CGX1321 With or Without Pembrolizumab in GI Cancers (OncLive) - P1 | N=72 | Keynote 596 (NCT02675946) | P1 | N=39 | NCT03507998 | Sponsor: Curegenix Inc. | "Marios Giannakis, MD...discusses preliminary efficacy data from a phase 1 study conducted in the United States (NCT02675946); and in China (NCT03507998) of CGX1321 with or without pembrolizumab (Keytruda) in advanced gastrointestinal (GI) tumors....A total of 77 patients were evaluated, including 38 patients with solid tumors in the single-agent CGX1321 dose-escalation cohort, and 19 patients with microsatellite stable (MSS) CRC in the CGX1321/pembrolizumab escalation cohort....CGX1321 was well-tolerated and had significant inhibitory activity in WNT-mutated tumors, Giannakis reports. Patients who received CGX1321 monotherapy experienced sustained stable disease and significant ctDNA reduction, with a disease control rate (DCR) of 77%, Giannakis states."

P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling. (PubMed, Acta Pharmacol Sin) - "In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • CTNNB1 • NFATC3

CGX1321 in Subjects With Advanced Solid Tumors and CGX1321 With Pembrolizumab or Encorafenib + Cetuximab in Subjects With Advanced GI Tumors (Keynote 596) (clinicaltrials.gov) - P1b; N=72; Recruiting; Sponsor: Curegenix Inc.; Trial completion date: Dec 2022 ➔ Mar 2023; Trial primary completion date: Dec 2022 ➔ Mar 2023

Combination therapy • Trial completion date • Trial primary completion date • Cholangiocarcinoma • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • AXIN1 • BRAF • CTNNB1 • RNF43 • RSPO2 • RSPO3

Sequential modulation of the Wnt/β-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance. (PubMed, Gynecol Oncol) - "Wnt/β-catenin pathway modulation increases MHC I expression and promotes tumor leukocytic infiltration, facilitating a pro-immune TME associated with decreased tumor burden. This intervention overcomes common tumor immune-evasion mechanisms and may render ovarian tumors susceptible to immunotherapy."

IO biomarker • Journal • Gynecologic Cancers • Immune Modulation • Inflammation • Oncology • Ovarian Cancer • Solid Tumor • CXCL10 • DKK1

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

"Results: In the ID8par model, sequential DKN-01/CGX-1321 resulted in the greatest macrophage influx into the TME. CGX-1321 monotherapy increased the M2:M1 macrophage ratio (pro-tumor) while DKN-01 monotherapy resulted in decreased M2:M1 ratio (anti-tumor.)" (@Brownynut)

Monotherapy • Oncology

[VIRTUAL] Modification of intrinsic ovarian cancer tumor factors by Wnt-pathway agents influences macrophage recruitment and activity. (ASCO 2021) - " Syngeneic murine models harboring ID8 parental (ID8par) tumors were treated with DKN-01 and CGX-1321 as single agents or in sequence (DKN-01 followed by CGX-1321.) Flow cytometry analyses were performed on harvested omenta and blood . Macrophage activity influences immune responses and tumor behavior . For example, M2 macrophages are pro-tumor and can enhance tumor growth and immune evasion . In our studies, we demonstrated that macrophage recruitment and polarization (M1 vs M2) are influenced by genetic alterations that can be modified by treatment ."

IO biomarker • Oncology • Ovarian Cancer • Solid Tumor • CSF1 • IL13 • IL4 • TNFA

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

CGX1321 in Subjects With Advanced Solid Tumors and CGX1321 With Pembrolizumab in Subjects With Advanced GI Tumors (Keynote 596) (clinicaltrials.gov) - P1b; N=72; Recruiting; Sponsor: Curegenix Inc.; Trial completion date: Jun 2020 ➔ Dec 2022; Trial primary completion date: Jun 2020 ➔ Dec 2022

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor

Manipulating the Wnt/β-catenin signaling pathway to promote anti-tumor immune infiltration into the TME to sensitize ovarian cancer to ICB therapy. (PubMed, Gynecol Oncol) - "CGX-1321 significantly reduced tumor burden and enhanced CD8+ T cell levels in ovarian cancer, nevertheless the addition of DKN-01 or anti-PD-1 therapies did not enhance these effects of CGX-1321. Further investigation is needed to determine if CGX-1321 + DKN-01 combination treatment sensitizes pre-clinical ovarian cancer to ICB therapy."

Journal • Immune Modulation • Inflammation • Oncology • Ovarian Cancer • Solid Tumor • CD8

Phase 1 Dose Escalation Study of CGX1321 in Subjects With Advanced Gastrointestinal Tumors (clinicaltrials.gov) - P1; N=39; Recruiting; Sponsor: Curegenix Inc.; Trial completion date: Apr 2020 ➔ Apr 2021; Trial primary completion date: Apr 2020 ➔ Apr 2021

Clinical • Trial completion date • Trial primary completion date • Biliary Cancer • Cholangiocarcinoma • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

The Delivery of a Wnt Pathway Inhibitor Toward CSCs Requires Stable Liposome Encapsulation and Delayed Drug Release in Tumor Tissues. (PubMed, Mol Ther) - "CGX1321 is a porcupine inhibitor that can effectively block Wnt ligand synthesis and is currently undergoing clinical trials...We showed it is feasible to use such a CSC elimination approach to treat malignant cancers prone to rapid progression using a LoVo tumor model as well as a GA007 patient derived xenograft (PDX) model. Nano drug delivery systems may be required for precision medicine in cancer therapy."

Journal • Oncology • Solid Tumor

[VIRTUAL] Utilizing porcupine (PORCN) and DKK1 inhibition to improve anti-tumor immunity in a murine model of ovarian cancer. (ASCO 2020) - "CGX-1321 decreased omental weight and ascites volume, while DKN-01 increased the cellular percentage of NK cells. Both DKN-01 and CGX-1321 increased CD8+ T cells. Wnt-inhibition is therapeutically promising in EOC, and the combination of a PORCN inhibitor with DKN-01 could improve the response to immune checkpoint blockage and further investigation is warranted."

Preclinical • Gynecologic Cancers • Immune Modulation • Inflammation • Oncology • Ovarian Cancer • Solid Tumor • CD8 • CTNNB1 • DKK1

Inhibition of PORCN in a p53-/- knockout syngeneic ovarian cancer model (SGO 2020) - "CGX1321 treatment inhibited tumor growth in ID8p53-/--luciferase tagged tumors; this was not seen in ID8p53-/-nonluciferase-tagged mice. Immune changes in the TME were not significant in this model, but were not measured in the luciferase-tagged model. There was no difference in tumor burden in ID8p53-/- injected DC-intrinsic β-catenin absent model."

Preclinical • CD8 • CTNNB1

Inhibition of PORCN in a p53-/- knockout syngeneic ovarian cancer model (SGO 2020) - "CGX1321 treatment inhibited tumor growth in ID8p53-/--luciferase tagged tumors; this was not seen in ID8p53-/-nonluciferase-tagged mice. Immune changes in the TME were not significant in this model, but were not measured in the luciferase-tagged model. There was no difference in tumor burden in ID8p53-/- injected DC-intrinsic β-catenin absent model."

Preclinical • CD8 • CTNNB1

Inhibition of PORCN in a p53-/- knockout syngeneic ovarian cancer model (SGO 2020) - "CGX1321 treatment inhibited tumor growth in ID8p53-/--luciferase tagged tumors; this was not seen in ID8p53-/-nonluciferase-tagged mice. Immune changes in the TME were not significant in this model, but were not measured in the luciferase-tagged model. There was no difference in tumor burden in ID8p53-/- injected DC-intrinsic β-catenin absent model."

Preclinical • CD8 • CTNNB1

Inhibition of PORCN in a p53-/- knockout syngeneic ovarian cancer model (SGO 2020) - "CGX1321 treatment inhibited tumor growth in ID8p53-/--luciferase tagged tumors; this was not seen in ID8p53-/-nonluciferase-tagged mice. Immune changes in the TME were not significant in this model, but were not measured in the luciferase-tagged model. There was no difference in tumor burden in ID8p53-/- injected DC-intrinsic β-catenin absent model."

Preclinical • CD8 • CTNNB1

Inhibiting WNT Ligand Production for Improved Immune Recognition in the Ovarian Tumor Microenvironment. (PubMed, Cancers (Basel)) - "When CD8 T cells were depleted, CGX1321 treatment did not have the same magnitude of effect on tumor growth. Our investigation confirmed an increase in Wnt activity correlated with a decreased T-cell-inflamed environment; a relationship that was further supported in our pre-clinical model that suggests inhibiting the Wnt/β-catenin pathway was associated with decreased tumor growth and improved survival via a partial dependence on CD8 T cells."

Biomarker • Journal • Tumor microenvironment • CD8 • CTNNB1

Identification of RSPO2 Fusion Mutations and Target Therapy Using a Porcupine Inhibitor. (PubMed, Sci Rep) - "Finally, we used a Wnt pathway Porcupine inhibitor CGX1321 to treat PDX mouse models containing RSPO2 fusion genes...Our data show that Wnt pathway inhibition could provide an effective treatment for cancers containing RSPO2 fusion. The RSPO2 fusion will serve as a good biomarker for screening patients to support clinical treatment of digestive system cancers using Wnt pathway inhibitors."

Biomarker • Journal

A novel porcupine inhibitor blocks WNT pathways and attenuates cardiac hypertrophy. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "We conclude that CGX1321 inhibits both canonical and non-canonical WNT pathways, and attenuates cardiac hypertrophy. Our findings support the porcupine inhibitors as a class of new drugs to be potentially used for treating patients with cardiac hypertrophy."

Journal

The effects of Wnt inhibition on tumor progression and the tumor microenvironment in a syngeneic mouse model of ovarian cancer. (ASCO 2019) - "... We used a small molecule inhibitor, CGX-1321, in C57Bl6 mice, an immunocompetent mouse model, injected intraperitoneally with either ID8 cells, a murine ovarian cancer cell line, or ID8-p53-/- cells... In the syngeneic mouse model with a murine ovarian cancer cell line, with p53 knocked out, tumor size and proliferation were decreased with treatment with Wnt inhibition. Surprisingly, the TME changes were inconclusive via flow cytometry. Perhaps these cells do not rely upon the Wnt/ β-catenin pathway as heavily, as seen in changes to baseline β-catenin levels, or perhaps tumors progress quicker and the critical time point of TME change is being overlooked."

Tumor microenvironment

Phase 1 Dose Escalation Study of CGX1321 in Subjects With Advanced Gastrointestinal Tumors (clinicaltrials.gov) - P1; N=39; Recruiting; Sponsor: Curegenix Inc.; Trial completion date: Apr 2019 ➔ Apr 2020; Trial primary completion date: Apr 2019 ➔ Apr 2020

Clinical • Trial completion date • Trial primary completion date

Evaluation of WNT/β-catenin pathway inhibitor CGX-1321 in a syngeneic ovarian cancer mouse model (SGO 2019) - "This study indicates that inhibition of the Wnt/β-catenin pathway using CGX-1321 combined with administration of paclitaxel significantly reduced tumor burden in a syngeneic mouse model. Further investigation is required to fully understand any potential effect on T cell function."

IO Biomarker • PD(L)-1 Biomarker • Preclinical