OXC-101, a mitotic MTH1 inhibitor, is based on many years research at the Helleday lab at Karolinska Institute and in collaboration with academic groups worldwide such as Mayo clinic, University of Manchester, Uppsala University, Université de Nantes, Shanghai Jiao Tong University, Netherlands Cancer Institute, Sahlgrenska University Hospital, University of Copenhagen, National and Kapodistria University of Athens and Sanger Institute. OXC-101 is investigated in cancer patients with advanced solid cancers and blood cancers.
Despite targeted medicine and immune-oncology drugs, cancer is still one of the leading causes of death. Globally 19.3 million cancer cases in 2020 and 10 million deaths. There is still an increasing incidence, due to our lifestyle and aging population, which is devastating for patients and places a burden on the healthcare system. Cancers are heterogenous diseases, not only between indications but also within same indication, between patients and within tumor and cancer cells. Furthermore, therapy resistance is a major problem. It is responsible for most relapses of cancer, one of the major causes of death of the disease. Approximately 90% of failures in chemotherapy are related to drug resistance.
Chemotherapy is effective, but in addition to resistance development, severe side-effects is a major concern as it affects both cancer cells and healthy cells. Targeted medicine and immune-oncology drugs have contributed with substantial clinical benefits but unfortunately do not work for all patients. In other words, the medical need is still huge for a safe and effective drug that works in the majority of patients and works in heterogenous and resistant cancers.
Oxcia is developing OXC-101, a mitotic MTH1 inhibitor, fighting cancer by taking advantage of one of the Achilles heels of cancer cells- the high endogenous oxidative stress and DNA damage. OXC-101 both stops cell division resulting in additional oxidative stress to the cancer cell and ensures that cancer cells cannot repair the oxidized DNA damage. The cancer cell cannot grow and subsequently dies. This dual synergistic mechanism is unique for OXC-101; increasing efficacy, tolerability and size of applicable patient population.
Mode of Action
Background to Mode of Action
Oxygen is vital for life. In the body’s cells, oxygen can easily form ROS (i.e. Reactive Oxygen Species). This is a normal process in living cells, which is usually highly controlled.
If an imbalance in these control systems occurs, we call it oxidative stress. Then ROS levels can accumulate, and ROS will react with cellular components like DNA and cell membranes and cause damage. This damage can lead to the onset of various diseases like cancer and inflammation. DNA damage is controlled and repaired in the body by DNA Damage Response (DDR) proteins.
Cancer cells suffers from oxidative stress and elevated levels of ROS and DNA damage. The DNA damage are usually controlled by production of increased numbers of DDR repair proteins so that oxidative DNA damage is kept below a lethal threshold and the cancer cell is able to survive and multiply.
Unique synergistic dual action makes the difference
OXC-101 is a so-called “mitotic MTH1 inhibitor”. Mitotic MTH1 inhibitors is a completely new class of drugs. No similar compound exists in the pipeline of other companies. OXC-101 is fighting cancer by taking advantage of one of the Achilles heels of cancer cells – the high endogenous oxidative stress and DNA damage. OXC-101 has a unique synergistic dual mechanism of action, stopping cell division and the DNA repair protein MTH1. To facilitate understanding of how it actually works, Oxcia has made an animation which you can find below.
In short, OXC-101 introduces additional oxidative stress and ensures the cancer cells cannot repair the oxidized DNA damage.
In more detail, OXC-101 stops the division of the cancer cell by disturbing microtubule function. This generates additional oxidative stress (i.e. ROS) and increased oxidative DNA building blocks (e.g. 8-oxodGTP). By inhibiting MTH1, a DNA repair protein that cleanses oxygen-damaged DNA building blocks in the cancer cell, more oxidative DNA building blocks are available for incorporation into DNA causing DNA damage. The resulting DNA damage becomes so high that the cancer cell is beyond repair and dies.
Healthy cells are only marginally impacted (as they have limited oxidative DNA damage and therefore no need to repair), which forms the foundation for OXC-101’s excellent tolerability. (For more in depth reading see references 1,2,3)
Notes: (1) Gad et al Nature 2014 (2) Warpman Berglund et al Annals Oncology 2016 (3) Gad et al BioRxive 2019
Key supporting data
OXC-101 was developed at Karolinska Institutet in Prof. Thomas Helleday’s laboratory. In collaboration with KI and other national and international academic groups, extensive preclinical research has been performed. OXC-101 has been shown to have a broad anti-cancer effect in various disease models, including chemotherapy resistant cancers. This data has been published in several highly-ranked journals. The anticancer activity is equally good or better compared to standard of care in disease models. Therefore OXC-101 has great potential for many cancer indications, cancer types and in many phases of the disease – as a single agent or in combination.It is well tolerated in animals (mice, rat and dog) with no acute toxicity.
OXC-101 alters immune checkpoint markers on cancer cells and recruits cytotoxic T cells to the tumour. Thus, OXC-101 has potential to improve immune-oncology therapy by making cold tumours hot.
Clinical phase I trials in advanced cancer patients also show that OXC-101 is well tolerated. There are preliminary signs of clinical benefits with OXC-101 in these heavily pretreated advanced cancer patients. A recommended phase 2 dose in advanced solid cancers has been established.
OXC-101 has the potential to increase survival and has fewer adverse effects as compared to chemotherapy.
In various cancer disease models, OXC-101 has been shown to have potential for a broad anti-cancer effect, can be given both alone and in combination with other approved anticancer treatment and can function in chemotherapy-resistant tumours.
OXC-101 has potential to increase the response of immuno-oncology treatment (making cold tumours hot).
Works on several cancer indications ✓ Works on heterogeneous cancers ✓ Healthy cells are not affected ✓ Less general cytotoxic side effects ✓ Potential to overcome existing chemotherapy resistance mechanisms ✓ Mono-, combination-therapy ✓ Oral treatment ✓
The patent protection for OXC-101 is strong with large geographical coverage. The major patent covers pyrimidine-2,4-diamine derivatives for treatment of cancer. The patent portfolio also includes patents for other indications and patents for back-up compounds.