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

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 Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • NUDT1

Pharmacological inhibition of MutT homolog 1 in allergic airway inflammation (ERS 2025) - "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."

Asthma • Inflammation • Respiratory Diseases • CD4 • IL13

Topical MTH1 inhibition suppresses SKP2-WNT5a-driven psoriatic hyperproliferation (ESDR 2025) - "Topically applied TH1579 alleviated the psoriatic phenotype in the imiquimod-induced psoriasis mouse model, by decreasing CD45+, Ly6b+, and CD3+cell infiltration and downregulating expression of the proliferation marker PCNA. The therapeutic effects depended on the SKP2/WNT5a pathway, which mediates psoriatic hyperproliferation. This study introduces a conceptually innovative topical treatment for psoriasis patients with mild-to-moderate disease who have limited therapeutic options."

Dermatology • Immunology • Psoriasis • IL17A • PCNA • PTPRC • SKP2

MASTIFF: MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class (clinicaltrials.gov) - P1 | N=63 | Completed | Sponsor: Thomas Helleday Foundation | N=100 ➔ 63 | Trial completion date: Dec 2025 ➔ Dec 2024 | Trial primary completion date: Dec 2025 ➔ Dec 2024 | Recruiting ➔ Completed

Enrollment change • Trial completion • 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: Jan 2026 ➔ Dec 2026 | Trial primary completion date: Jan 2026 ➔ Dec 2026

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

Scientific advances in psoriasis research with OXC-101 [Google translation] (Cision) - "The results show that topically applied OXC-101 effectively inhibits several hallmarks of psoriasis, including keratinocyte hyperproliferation and infiltration of IL-17-producing γδ T cells. In addition, levels of key cytokines involved in the inflammatory response in the skin were reduced. The underlying mechanism involves the MTH1-SKP2-WNT5a signaling pathway."

Preclinical • Psoriasis

Topical MTH1 Inhibition Suppresses SKP2-WNT5a-Driven Psoriatic Hyperproliferation. (PubMed, Int J Mol Sci) - "Topically applied TH1579 alleviated the psoriatic phenotype in the imiquimod-induced psoriasis mouse model by decreasing CD45+, Ly6b+, and CD3+ cell infiltration and downregulating the expression of the proliferation marker PCNA. The therapeutic effects depended on the SKP2/WNT5a pathway, which mediates psoriatic hyperproliferation. This study introduces a conceptually innovative topical treatment for psoriasis patients with mild-to-moderate disease who have limited therapeutic options."

Journal • Dermatology • Immunology • Inflammation • Psoriasis • IL17A • PCNA • PTPRC • SKP2

EMA approves ODD for OXC-101 in AML (TradingView)

Orphan drug • Acute Myelogenous Leukemia

Oxcia enters a research collaboration with LEO Pharma to explore OXC-101 in medical dermatology (Cision) - "Oxcia today announces that it has entered into an early research collaboration with LEO Pharma to explore OXC-101 in topical formulations for medical dermatology indications including psoriasis....This collaboration, aimed at exploring OXC-101 for medical dermatology, aligns with Oxcia’s vision of extending the application of its technology platform beyond cancer. LEO Pharma’s proven expertise and long-standing success in developing dermatology treatments that deliver significant therapeutic advancements make them the ideal partner to help explore the potential of Oxcia’s OXC-101."

Licensing / partnership • Dermatology • Psoriasis

Mitotic MTH1 inhibitor karonudib kills epithelial ovarian cancer independent of platinum sensitivity. (PubMed, Exp Hematol Oncol) - "This cytotoxicity was blunted by overexpression of the pre-mitotic checkpoint protein CHFR, which inhibits other anti-mitotics, or treatment with the antioxidant N-acetylcysteine, which diminishes nuclear 8-oxo-dG staining, suggesting a role for both mitotic stalling and increased nuclear incorporation of oxidized nucleotides in karonudib efficacy. Moreover, addition of karonudib to carboplatin doubled median overall survival in two models and prolonged survival for the duration of the study (110 days) in the third. These results demonstrate activity of mMTH1is as monotherapy and in combination with carboplatin in OC that warrants further investigation."

Journal • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

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

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