We believe the combination of being biomarker driven, treating life threatening diseases without effective treatment options, and a novel method of action will assist us in accelerating our development strategy.
Ag5 is our lead molecule and is targeted to treat KRas mutant type cancers through its catalytic mechanism of action in cancers with high levels of reactive oxygen species. Ag5 targets KRas mutant cancer cells downstream after the switch is stuck in the “on” position, whatever the proximate cause of the switch being thrown. The mechanism of action of Ag5 targets cancers with high levels of Reactive Oxygen Species (ROS). RAS mutant cancers are the largest group of high-ROS cancers, but many other cancers generate high levels of ROS, so will be amenable to treatment by Ag5, most notably primary and secondary brain cancers. Ag5 selectively kills cancer cells already exhibiting high levels of reactive oxygen species (ROS), while having no effect on non-cancer cells, via a novel mechanism that has been thoroughly investigated and defined by our academic team and founders (multiple academic publications and patents filed). Ag5 acts as a catalyst inside cells to increase the oxidation of proteins by ROS leading to cell death. A crucial advantage of this over previous ROS-dependent cancer killing therapies is that Ag5 does not induce ROS production, only amplifying the effect of tumor-produced ROS, meaning that non-tumor cells are unaffected. Ag5 is therefore non-toxic when administered long-term to rats, and we therefore expect a benign toxicology profile in humans. Preclinical testing of Ag5, in animal models, shows significant tumor killing efficacy in KRas mutant cancers. We are investigating biomarkers that allow us to identify cancers with the highest levels of ROS, and therefore the most sensitivity to Ag5. We have compelling evidence that these biomarkers will allow us to identify cancers for treatment with Ag5 beyond those with mutant KRas genes. We therefore believe that eventually, the patient population that is addressable by Ag5 treatment will go beyond KRas mutant cancers. Ag5 is currently in preclinical testing.
We believe that TMC Ag3 can be a potential new pharmacological agent based on a number of factors. We have shown that clusters of three atoms can augment chromatin accessibility. This effect only occurs during DNA replication. Administration of both our Therapeutic Molecular Cluster Ag3 with Cisplatin increases the cytotoxic effect of DNA-acting drugs on human lung carcinoma cells. In mice with orthotopic lung tumors, the co-administration of Ag3 increases the amount of Cisplatin (CDDP) bound to the tumor DNA by fivefold without modifying CDDP levels in normal tissues. As a result, CDDP co-administered with Ag3 more strongly reduces the tumor burden. Evidence of the significance of targeting chromatin compaction to increase the therapeutic index of chemotherapy is one of the future applications we are going to explore further in the new field of Therapeutic Molecular Clusters. Ag3 is currently in preclinical testing.
10.5 Million patients a year are given radiotherapy worldwide. Efficacy is limited by resistance of cancer cells to the radiation dose that is necessarily limited to prevent damage to surrounding tissue. The effects of this damage are huge-particularly where radiotherapy is administered to pediatric patients who then go on to develop radiation-induced cancers many years later. We have evidence that Ag3 and Ag5 can act together to make cancers more sensitive to radiation (by complementary mechanisms) as well as protecting non-cancer cells by inducing expression of anti-ROS genes (nrf2). This could allow more cells to be killed, or to allow less radiation to be given, reducing off-target effects. Of particular relevance is the fact that TMCs freely cross the blood brain barrier, making them ideal for augmenting cranial radiotherapy (radiotherapy is the most common treatment for intracranial malignancy). TMCs both sensitize tumors to radiotherapy up to 5x with our in vitro studies and protect non-dividing cells from harm from radiation. Ag3 is effective in unspooling DNA making cancer cells more prone to damage from radiation while simultaneously protecting non-dividing cells. This is an important discovery; we help protect healthy cells from the damage of radiation while we assist the radiological treatment in removing cancerous cells with higher efficacy. Either outcome provides clinical benefit. We augment radiotherapy so lower doses can be deployed, with greater efficacy and fewer side effects. Our combo therapy potentially increases efficacy of current treatments. Ag3/Ag5 combo may allow for lower doses of radiation to be administered.