Karonudib

Karonudib- rationale

  • Targeting the cancer phenotype (cancer can change genotype) by
    – exploiting the high level of endogenous DNA damage in cancer
    – exploiting oxidative stress in cancer
  • Causes DNA damage and mitotic arrest to kill cancer cells
  • Targeting the MTH1 enzyme required for tumour growth but is non- essential enzyme for healthy cells

Karonudib- potential benefits

  • Works on several cancer indications
  • Works on heterogeneous cancers
  • Less general cytotoxic side effects
  • Overcome existing chemotherapy resistance mechanisms
  • Mono-, combo-therapy
  • Oral treatment

Karonudib- has a dual mechanism

  1. Inhibits the activity of the DNA repair enzyme MTH1, 8-oxodGTPase, causing more DNA damage, resulting in cancer cell death.
  2. Karonudib increases free radicals (ROS) and thereby hindering the cancer by disturbing microtubule polymerisation.
  • MTH1 is non-essential for normal cells and therefore have potential to have less general side effects compared to chemotherapy used today.
  • Karonudib- key data

    • Karonudib has a broad anti-cancer activity
    • Well tolerated in human cancer patients, with reversible toxicity
    • Biomarkers show on-target signals and reduction of target tumor lesions in patients

    Background

    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 were identified and Thomas Helleday Foundation for Medical Research has filed patents. Oxcia holds an exclusive license for development and commercialization of the compounds.

    Preclinical findings

    The MTH1 inhibitors have been 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, Das et al., 2019; ).

    Karonudib has been shown to:

    • Hinders tumor growth in many different human cancers, both solid and hematological cancers
    • Shows as good as or better efficacy than standard treatments
    • Can be combined with standard of care treatments showing additive/synergistic effects
    • Effective in chemotherapy resistant tumors
    • Well tolerated in animals (mice, rat and dog) with no acute toxicity and reversible toxicity after repeat dosing
      • Reversible toxicity, mainly bone marrow and GI tract related
      • No cardiovascular, respiratory or CNS related toxicity observed.

     

    Clinical studies

    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. In 2019 approval for the MAATEO (A phase 1 study in MDS, AML and ALL patients to evaluate safety, tolerability and efficacy of Karonudib with EUDRACT no: 2019-001221-27) was obtained and started in December 2019.

    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 both the clinical trial MASTIFF and MAAETO, and are now managing it according to GCP, GMP, GLP and applicable regulations.