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TH9619 is a first-in-class, potent small-molecule inhibitor of MTHFD1 and MTHFD2 — enzymes that are among the most consistently overexpressed genes in cancer compared to normal tissue. By inhibiting both enzymes simultaneously, TH9619 induces toxic folate trapping: starving cancer cells of the DNA building block thymidine, triggering replication stress and DNA damage, and causing cancer cell death. Because normal cells do not express MTHFD2, they do not generate the folate trap.
TH9619 started to be investigated in the ODIN Phase 1/2 clinical study in 2025 ( NCT07151040 ; EudraCT No. 2024-519639-40-00). This is a first-in-human, multicenter, open label, dose escalation and expansion study, aiming at evaluating safety, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of TH9619 as monotherapy in subjects with advanced refractory solid tumors, including colorectal cancer, non-small cell lung cancer, head & neck squamous cell carcinoma, gastric cancer or gastroesophageal junction cancer.
The trial is currently being conducted across leading academic and clinical research centers in the United Kingdom, France, and Spain, with expansion planned across additional European sites in the coming months.
TH9619 is a first-in-class, potent, small-molecule, and dual inhibitor of MTHFD1/2 , highly overexpressed and cancer-specific enzymes within the one-carbon metabolic pathway. TH9619 kills cancer cells via a dual mechanism of action (1) inhibition of MTHFD1 traps folate leading to thymidine depletion (2) inhibition of nuclear MTHFD2 disrupts DNA damage response and repair pathways. With its unique characteristics, TH9619 kills tumor cells while sparing healthy tissue.
TH9619 started to be investigated in the ODIN Phase 1/2 clinical study in 2025 ( NCT07151040 ; EudraCT No. 2024-519639-40-00). This is a first-in-human, multicenter, open label, dose escalation and expansion study, aiming at evaluating safety, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of TH9619 as monotherapy in subjects with advanced refractory solid tumors, including colorectal cancer, non-small cell lung cancer, head & neck squamous cell carcinoma, gastric cancer or gastroesophageal junction cancer.
The trial is currently being conducted across leading academic and clinical research centers in the United Kingdom, France, and Spain, with expansion planned across additional European sites in the coming months.
Role of MTHFD1 & MTHFD2 in cancer
Supporting fast growth through DNA building blocks
One-carbon metabolism is central to cancer survival. Cancer cells depend on this pathway to sustain the rapid DNA synthesis and repair activity that fuels their proliferation. MTHFD2 — one of the most consistently overexpressed genes in cancer — is an oncofetal protein: expressed during embryonic development to enable rapid cell growth, silenced in healthy adult tissue, and re-expressed in tumours, where high levels are associated with poor disease outcomes. MTHFD1, its isoenzyme, is also upregulated in malignancy. Simultaneous inhibition of both isoenzymes is what unlocks the unique mode of action of TH9619, with strong anti-tumour activity demonstrated across in vitro cell line panels, patient-derived organoids, and in vivo models — including standard-of-care–resistant settings. This makes the MTHFD1/2 axis one of the most compelling and well-validated dependencies in oncology.
Many one-carbon metabolizing enzymes, including methylenetetrahydrofolate dehydrogenase 1 and 2 (MTHFD1/2), are associated with the development of cancers. MTHFD2 is an oncofetal protein; under normal circumstances, it does not exist in healthy adult tissue; it is present only in embryos before cells mature into specialized organs. It is re-expressed in cancers and associated with poor disease outcomes. While not oncofetal, MTHFD1 is also associated with malignancy, and depletion of both MTHFD1 and 2 proteins abrogates malignant phenotypes, such as proliferation, migration, invasion, and metastasis in various cancer models. More recent research shows that both MTHFD1 and 2 have additional non-enzymatic and metabolism-related functions that are important for epigenetic and DDR processes in cancer cells. Since the expression and functions of MTHFD1/2 proteins are cancer-specific, our MTHFD1/2 inhibitor is causing replication stress and death in cancer cells while sparing normal cells.
The one-carbon metabolism pathway refers to a network of biochemical reactions that transfer single-carbon units for essential cellular processes. Cancer cells rely heavily on this pathway for nucleotide supply and general regulation of nucleotide pools. Cancer cells are more sensitive to nucleotide pool imbalances than normal cells, and such imbalances also lead to DNA damage.
At One-carbon Therapeutics, our scientific edge is not simply what we target — it is how we target it. We have developed a deep understanding of the one-carbon metabolic pathway that previous programmes lacked: a granular, structure-guided insight that allowed us to design a molecule where others had failed. That precision is the foundation on which TH9619 and the ODIN Phase 1/2 study are built.
The one-carbon metabolism pathway refers to a network of biochemical reactions that transfer single-carbon units for essential cellular processes. Cancer cells rely heavily on this pathway for nucleotide supply and general regulation of nucleotide pools. Cancer cells are more sensitive to nucleotide pool imbalances than normal cells, and such imbalances also lead to DNA damage.
At One-carbon therapeutics, we take advantage of our deep biological understanding of metabolism and DNA repair processes to develop novel therapeutic approaches targeting both. This is resulting in more efficient, cancer-specific drugs and novel synthetic lethal combination approaches.
Solna, Sweden, March 17h, 2026. One-carbon Therapeutics, a clinical-stage oncology company pioneering first-in-class targeted therapies based on deep understanding into cancer biology, today announced a
Solna, Sweden, December 1, 2025. One-carbon Therapeutics AB, a clinical-stage biotechnology company pioneering first-in-class cancer therapies, announced today the closing of an oversubscribed 153 million