We are currently working on

Oxcia is currently engaged in development or commercialization of projects concerning the following targets:

KARONUDIB

In the end of 2016, the Medical Product Agency (MPA) approved a clinical phase 1 trial, MASTIFF (MTH1, A phase) ... I, Study on Tumors Inhibition, First in human, First in class with EudraCT no: 2016-002624-80), investigating safety and tolerability of Karonudib in cancer patients with advanced solid malignancies. Thomas Helleday Foundation for Medical Research is the sponsor of the MASTIFF trial, but has appointed Oxcia AB to assist in the clinical development and commercialization.

Many cancers have a dysfunctional redox status and upregulated levels of MTH1, suggesting that MTH1 is necessary for the cancer cell to survive the high load of oxidative stress and oxidized nucleotides. MTH1 (NUDT1) is a sanitizing enzyme, hydrolysing oxidized nucleotides into their monophosphates, thereby hindering them to be incorporated into DNA and cause mutations (Nakabeppu et al., 2010). By knocking down MTH1, cancer cells can no longer survive, while normal cells still divide and live (Gad et al., Nature 2014; Rai et al., 2011, Ling et al., 2016 etc). In Professor Thomas Helleday laboratory at Karolinska Institute, small molecule inhibitors against MTH1 was identified and shown to kill a variety of cancer cells in vitro and reduce tumour growth in mice xenograft disease models (Gad et al., Nature 2014; Warpman Berglund et al., Annals of Oncology 2016).

Oxcia AB has been crucial for patent strategies and clinical development strategies for the MTH1 project. Oxcia AB has, been responsible for planning, preparing, initiating the clinical trial MASTIFF, and are now managing it according to GCP, GMP, GLP and applicable regulations.)

OGG1 INHIBITOR

Oxcia is developing OGG1 inhibitors against severe lung diseases in collaboration with Swedish academia, Karolinska Institutet, Lund University, Uppsala University) ... and Stockholm University.

Proof of principle has been demonstrated in mice, showing that therapeutic treatment with our tool compound, an OGG1 inhibitor, TH5487 significantly reduces lung inflammation.

Targeting OGG1 is a completely novel approach for treatment of inflammatory. The pro-inflammatory immune cells that drive auto-immunity and inflammation suffer from high level of oxidative stress and therefore require specific detoxification enzymes for survival and function. One enzyme of specific interest is OGG1, 8oxo guanine glycosylase1. Through binding to promoter regions, enriched in oxidized guanines, this enzyme recruits other proteins such as transcription factors, e.g. NF-Ƙβ to form complexes, promoting transcription of pro-inflammatory genes. Our OGG1 inhibitor TH5487 prevents OGG1 from binding to DNA and thereby dampening the inflammatory responses in animal models (Visnes et al, Science, Nov 16, 2018). http://science.sciencemag.org/content/362/6416/834

Helleday lab at the Karolinska Institute is advancing the lead optimization of OGG1 inhibitors to develop novel therapies for severe lung inflammation diseases with large medical need such as ARDS, COPD, severe non allergic asthma and idiopathic pulmonary fibrosis (IPF).

Oxcia is responsible for the business and market strategies, IPR and regulatory strategies of the project. Oxcia is open for partnership to enable development of potential therapies and launch of novel products.

Oxcia in collaboration with Karolinska Institutet, Lund University and Uppsala University, have been granted 5 Million SEK by Swelife and Vinnova in support of the OGG1 project. Swelife is a strategic innovation programme, funded by the Programme Partners and the Swedish Government via the Swedish innovation agency, Vinnova. Swelife support collaboration within academia, industry and healthcare, with the goal to strengthen Life Science in Sweden and to improve public health.)

NUDT5 INHIBITOR

Breast cancer represents the most common cancer in women and is a leading cause of cancer-related death in Sweden and) ... globally. Most breast cancers use hormones (estrogen and progesterone) to promote the growth of the tumor (so-called hormone receptor positive (HR+) breast cancers). This process requires vast amount of cellular energy in the form of adenosine triphosphate (ATP) which allows the cancer cell to respond to hormone stimulation.

NUDT5 protein allows the cancer cell to produce large amounts of ATP following hormone stimulation. This molecular energy fuels the production of hormone-dependent genes which tells the cancer cell to proliferate. Without NUDT5, hormone-dependent gene expression is blocked, which halts the growth response following hormone stimulation in breast cancer cells.

Together, the Helleday and Page Laboratories at the Karolinska Institute have developed potent NUDT5 inhibitors that have promising effects against breast cancer cell lines. These compounds were designed to specifically bind to NUDT5 in cancer cells using state-of-the-art chemical biology techniques, with a concerted effort to avoid cytotoxic and off-target effects. Lead NUDT5 inhibitors have been formulated for in vivo testing, have excellent pharmacokinetic properties and are well-tolerated in repeated dose mouse studies. Ongoing efforts aim to show proof of concept in mouse breast cancer models.

Oxcia AB is working collaboratively with the Karolinska Institute Innovation Office to assist in commercial strategies for the project. The aim is to outlicense the project with the first inhibitors of the NUDT5 protein representing promising anti-cancer agents that could help treat and prevent the recurrence of breast cancer in patients.)

MTHFD2 INHIBITOR

Altered cellular metabolism is a hallmark of cancer and reflects differential metabolic requirements between normal and malignant cells that can) ... be exploited for anti-cancer therapies. Consequently, anti-folates such as methotrexate have formed the cornerstone of chemotherapy since they were introduced in the 1950s. Thus, disturbing the folate metabolism can effectively kill cancer cells. Unfortunately, the enzymes targeted by these chemotherapies are also expressed in normal proliferative tissues, causing toxic long term-effects, thereby limiting their therapeutic utility. It is therefore of great interest to further characterize cancer metabolism to identify novel potential therapeutic targets.

The mitochondrial MTHFD2 was recently identified to be the most consistently overexpressed metabolic enzyme in multiple cancers, while being weakly expressed or absent in normal proliferating cells (Nilsson et al. 2014). Genetic silencing of MTHFD2 inhibits cancer cell proliferation, as well as tumor burden and progression in animal models (Pikman et al 2016). Given its expression profile, MTHFD2 inhibitors may provide a cancer lethal phenotype with a large therapeutic window, however no inhibitors targeting MTHFD2 exist on the market today.

The Helleday laboratory has initiated a drug discovery program to develop first in class MTHFD2 inhibitors. In collaboration with the lab of Pål Stenmark at Stockholm University they have solved the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor (Gustafsson et al 2017), as well as discovered that MTHFD2 localizes at replication sites in the nucleus (Gustafsson et al 2015). Through intense drug discovery efforts, the project is now in a stage with MTHFD2 inhibitors with low-nanomolar potency on target and in cells. The inhibitors stop proliferation of cancer cell lines and induce apoptosis, while leaving normal proliferating cells such as CD34+ bone marrow cells from healthy individuals largely unaffected. Proof of concept studies using human samples and mouse disease models are currently ongoing.

Oxcia is responsible for the business and market strategies, IPR and regulatory strategies of the project. Oxcia is open for partnership to enable development of potential therapies and launch of novel products.

Oxcia in collaboration with Karolinska Institutet and Uppsala University, have been granted 1 Million SEK by Swelife and Vinnova in support of the MTHFD2 project. Swelife is a strategic innovation programme, funded by the Programme Partners and the Swedish Government via the Swedish innovation agency, Vinnova. Swelife support collaboration within academia, industry and healthcare, with the goal to strengthen Life Science in Sweden and to improve public health.)