karonudib (OXC-101) / Oxcia, Helleday Foundation - LARVOL DELTA

Pharmacological inhibition of MutT homolog 1 (MTH1) in allergic airway inflammation as a novel treatment strategy. (PubMed, Respir Res) - "MTH1 inhibition reduced proliferation and promoted apoptosis of T cells in vitro. In vivo, TH1579 dampened the type 2 associated immune response in a murine model. These findings suggest that MTH1 could serve as a novel target to treat allergic airway inflammation."

Journal • Asthma • Immunology • Inflammation • Oncology • Pulmonary Disease • Respiratory Diseases • CD4 • IL13

A Phase I/II Study Investigating Karonudib in Patients with Refractory Haematological Malignancies (ASH 2024) - P1 | "Five patients had AML, four MDS, 3 DLBCL, one AUL and one MM. The RP2D has been determined and the trial will now start recruiting the extension cohort with a possibility to combine Karonudib with Idarubicin in patients with R/R AML and high-risk MDS with an aim to optimize delivery of this combination."

Clinical • P1/2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • NUDT1

Oxcia is focusing the development of OXC-101 on hematological cancers (Cision) - "Following a strategy and data review, Oxcia has chosen to re-prioritize the clinical development of OXC-101 from solid tumors to hematological cancers, specifically acute myeloid leukemia (AML). The preclinical program for OXC-101 has shown good results in both AML and other forms of hematological cancers, and data to date from the phase I/II study MAATEO confirm the previous results. Oxcia has initiated an expansion part of the MAATEO study in patients with refractory/relapsed AML (R/R AML), where OXC-101 is administered in combination with idarubicin (an anthracycline)."

Pipeline update • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

MASTIFF: MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Thomas Helleday Foundation | N=35 ➔ 100 | Trial completion date: Jun 2022 ➔ Dec 2025 | Trial primary completion date: Dec 2021 ➔ Dec 2025

Enrollment change • Trial completion date • Trial primary completion date • Hepatocellular Cancer • Oncology

MAATEO: A Study in Leukemia Patients With Karonudib (clinicaltrials.gov) - P1 | N=9 | Recruiting | Sponsor: Thomas Helleday Foundation | Trial completion date: Jun 2022 ➔ Jan 2026 | Trial primary completion date: Dec 2021 ➔ Jan 2026

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Oncology

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway. (PubMed, Oncogenesis) - "An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-β and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner. In conclusion, TH1579 has the potential to improve ICI treatment by modulating immune checkpoint-related proteins and pathways."

IO biomarker • Journal • Inflammation • Melanoma • Oncology • Solid Tumor • CXCL10 • IFNB1

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway (Nature, Oncogenesis) - "An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-β and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner."

Preclinical • Melanoma

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway (Nature, Oncogenesis) - "An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-β and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner."

Preclinical • Melanoma

Mitotic MTH1 Inhibitors in Treatment of Cancer. (PubMed, Cancer Treat Res) - "Here, I discuss the leading mitotic MTH1 inhibitor TH1579 (OXC-101, karonudib), now being evaluated in clinical trials, and describe its dual effect on mitosis and incorporation of oxidative DNA damage in cancer cells...I discuss emerging roles of MTH1 in regulating tubulin polymerisation and mitosis and the necessity of developing the basic science insights along with translational efforts. I also give a perspective on how edgetic perturbation is making target validation difficult in the DDR field."

Journal • Oncology

MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma. (PubMed, Cancers (Basel)) - "Combined MTH1 and PD-L1 inhibition holds promise for the successful clinical management of mesothelioma."

Journal • Lung Cancer • Mesothelioma • Oncology • Respiratory Diseases • Solid Tumor • CD8

MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma (Multidisciplinary Digital Publishing Institute) - "Karonudib administration enhances M1 macrophage polarization, stimulates CD8 expansion and promotes the activation of DC and T cells. Combined administration of PD-L1 and MTH1 inhibitors impairs mesothelioma tumor growth and mesothelioma-associated pleural effusion accumulation more effectively compared to each monotherapy."

Preclinical • Mesothelioma

DNA-PK inhibition augment the cancer specific cytotoxicity of mitotic MTH1 inhibitor OXC-101 (AACR 2023) - "Based on the involvement of DNA-PK in mitosis, we hypothesized that depletion/inhibition of DNA-PK might enhance the DNA damage and mitotic catastrophic effect of OXC-101.To test our hypothesis, we performed an in vitro drug combination experiment using the DNA-PK inhibitor nedisertib with OXC-101 in non-small cell lung carcinoma NSCLC (H460,A549), uveal melanoma (MP -38, MP -41 and MP46), osteosarcoma (U2OS) and) and neuroblastoma (IMR32, Kelly, SKNFI) cancer cell lines and non-cancerous foreskin fibroblasts(VH-10, BjhTERT). These data suggest that the DNA-PK inhibitor may enhance the cytotoxic effect of OXC-101specifically in cancer cells. In addition, we will conduct an in-depth mechanistic study of how depletion/inhibition of DNA-PK enhances the cytotoxicity of OXC-101 and validate the drug combination in an appropriate preclinical mouse model."

CNS Tumor • Eye Cancer • Lung Cancer • Melanoma • Neuroblastoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • Uveal Melanoma • ANXA5

OXC-101 shows favorable safety profile in first in human phase 1 trial in patients with advanced solid cancer (AACR 2023) - P1 | "OXC-101 has a favorable safety profile with an RP2D of 900mg twice a week."

Clinical • Metastases • P1 data • Oncology • Solid Tumor

OXC-101 kills cancer by disturbing microtubule polymerization and inhibiting MTH1 (AACR 2023) - "Biomarker searches for genetic alterations explaining responders/non-responders are presently on-going. In summary, the dual mechanism of action of the mitotic MTH1 inhibitor OXC-101 explains its strong anti-cancer effect."

Head and Neck Cancer • Oncology • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

"Enrolment completed and recommended phase II dose reached for OXC-101 https://t.co/GFpXeIJUQY" (@CisionNews)

[PREPRINT] Overexpressed C-Myc Sensitize Cells to TH1579, an Mitotic Arrest and Oxidative DNA Damage Inducer (Preprints) - “To test this, we overex-pressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but interestingly not by nucleoside supplementation. This suggest that cancer selectivity is unrelated oncogene-induced replication stress. We conclude that the molecular toxi-cological mechanisms how TH588 and TH1579 kill c-Myc overexpressing cells have several com-ponents and involves MTH1-independent proteosomal degradation of c-Myc itself, c-Myc driven transcription and CDK activation, and is likely unrelated to oncogene-induced replication stress.”

Clinical • Preprint • Oncology

Inhibition of oxidized nucleotide sanitation by TH1579 and conventional chemotherapy cooperatively enhance oxidative DNA-damage and survival in AML. (PubMed, Mol Cancer Ther) - "We demonstrate that MTH1 is a potential druggable target expressed by the majority of AML patients and the inv(16)/KITD816Y AML mouse model mimicking the genetics of AML patients exhibiting poor response to standard chemotherapy (i.e. anthracycline & cytarabine). In conclusion, our study provides a rationale for future clinical studies combining standard AML chemotherapy with TH1579 to boost standard chemotherapy response in AML patients. Moreover, other cancer entities treated with ROS- and DNA damage-inducing chemo- or radiation therapies might benefit therapeutically from complementary treatment with TH1579."

Journal • Acute Myelogenous Leukemia • Oncology

MutT Homolog 1 Inhibitor Karonudib Attenuates Autoimmune Hepatitis by Inhibiting DNA Repair in Activated T Cells. (PubMed, Hepatol Commun) - "Lastly, we validated the protective effect of karonudib on the Con A-induced hepatitis model. MTH1 functions as a critical regulator in the development of AIH, and its inhibition in activated T cells reduces liver inflammation and damage."

IO biomarker • Journal • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Failure • Non-alcoholic Fatty Liver Disease

Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion. (PubMed, Cells) - "Disruption of redox homeostasis using PLN sensitized anoxia-tolerant cancer cells to MTH1 inhibition by TH1579 under both normoxic and acute hypoxic treatment conditions. Thus, we uncover a glutathione-driven compensatory resistance mechanism towards MTH1-inhibition in form of increased antioxidant capacity as a consequence of microenvironmental or therapeutic stress."

Journal • Oncology

MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia. (PubMed, Cancer Res) - "A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubicin. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the pre-clinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rational to investigate the clinical usefulness of TH1579 in AML in an on-going clinical phase 1 trial."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD34 • CD38 • PTPRC

MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells. (PubMed, Cell Death Differ) - "TH1579 does not affect resting T cells, as opposed to the established immunosuppressor Azathioprine, and no sensitivity among other major immune cell types regarding their function can be observed. In conclusion, we show proof of concept of the existence of MTH1 and MTH1 activated T cells, and that MTH1 inhibition by TH1579 selectively suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve as a novel treatment option against autoreactive T cells in autoimmune diseases, such as multiple sclerosis."

Journal • CNS Disorders • Immunology • Multiple Sclerosis • Oncology

Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma. (PubMed, Sci Rep) - "Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma."

Journal • Preclinical • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

MAATEO: A Study in Leukemia Patients With Karonudib (clinicaltrials.gov) - P1; N=9; Recruiting; Sponsor: Thomas Helleday Foundation; Trial completion date: Jun 2021 ➔ Jun 2022; Trial primary completion date: Mar 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology

MASTIFF: MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class (clinicaltrials.gov) - P1; N=35; Recruiting; Sponsor: Thomas Helleday Foundation; Trial completion date: Oct 2021 ➔ Jun 2022; Trial primary completion date: May 2021 ➔ Dec 2021

Trial completion date • Trial primary completion date • Oncology • ALB

Antitumour activity of TH1579, a novel MTH1 inhibitor, against castration-resistant prostate cancer. (PubMed, Oncol Lett) - "Moreover, TH1579 treatment increased 8-oxo-dG levels, as well as the number of 53BP1 and γH2A.X foci, resulting in increased DNA double-strand breakage and apoptosis in PC-3 and DU-145 cells. The findings of the present study demonstrated that TH1579 exerted strong antitumour effects on CRPC cells, and may therefore be used as a potential therapeutic agent for the clinical treatment of CRPC."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR