Technology

Using the power of detailed SARs (structure-activity relationship) analysis the Antoxis’ Kromex™ scaffold neatly reverses the drug-like deficiencies so seen for many secondary metabolites that demonstrated therapeutic potential. Key among these improvements has been an increase in the biological activity of a re-designed Kromex™ chemistry backbone that delivers 2-3 orders of magnitude improved potency. This scaffold can then be further designed to accommodate additional attributes including:   

    Rapid Cell Uptake     

    Mito targeting               

    Increased Potency

    Increased stability

    Optimal ClogP

    Control Redox Pot

    BBB permeability

    Pro-drug options

 

The mitochondria are organelles contained within the cell that have a key role in producing the cell's energy requirements along with other important functions such as cell signalling and differentiation. A cycle of oxidative stress, mitochondrial dysfunction and cell death is observed in a number of human diseases.Consequently,developing compounds that can target and protect the mitochondria has great potential in the treatment of a variety of clinical conditions.

In summary: Antoxis’ unique approach has delivered proprietary compounds with step-changing pharmacological properties that display efficacies substantially greater than natural and synthetic agents currently in the clinic. Their mode of action is via membrane stabilisation, protection against and prevention of lipid peroxidation and the inhibition of mitochondrial pathways of energy generation. In some cases all three activities are present within a single compound. 

 

Regenerative medicine

Whilst the potential of cell therapies to deliver real benefits to patients is unquestioned, there remain several significant hurdles to overcome before this approach can be considered reliable and routine. Reperfusion damage, a process that occurs during the first 24-48 h post transplantation, can often leave between 80- 97% of transplanted cells non-viable and limits or undermines any therapeutic benefits seen by patients. Our lead compound Proxison™ has been designed to reduce or prevent this reperfusion damage to the most fragile of cell types. In addition we are now able to use our compounds to influence stem cell differentiation and hold cells in both a pristine and protected state.

Beneficial effects include:

        Protection of stem cells from oxidative stress-induced loss of viability e.g. by reduction in membrane lipid peroxidation

     Enhanced viability and functional outcome of transplanted cells through amelioration of reperfusion and immune mediated ROS damage

     Creation of an optimal intracellular redox environment to keep cells in a pristine, undifferentiated state pre-transplantation

Excitingly all this can be achieved by pre-incubating cells, pre-transplantation. Compounds are rapidly taken up into the mitochondria, are retained after cell washing for 48 h and can protect over 90% of cells from damage. We believe that this type of approach will permit accelerated regulatory development of these compounds as a medical-device for a range of regenerative medicine applications.

 

The incredible protective potency of Proxison™ was demonstrated with the help of a time-lapse video. Thereby neural cells were stressed with tBHP, an oxidative stress inducer. Consequently, these sensitive cells undergo apopotosis, forming apoptotic bodies.

In the presence of only 1µM Proxison, however, the cells remain in a pristine state.

Videos: Courtesy of Tilo Kunath, University of Edinburgh

 

Oncology

Oncamex™ is derived from Antoxis’s patented chemistry scaffold – Kromex™ - has demonstrated antitumour effects in vivo as well as synergy with marketed oncology compounds.

Oncamex™ is a mitochondrial redox modulator that:

     Arrests tumour growth in a breast cancer xenograft mouse model

     Re-sensitises TRAIL-resistant ovarian cell lines to Paclitaxel inducing almost complete apoptosis

     In in-vitro studies, outperforms the chemotherapeutics (Etoposide, Cisplatin, Gemcitabine)

     Rapidly enters the mitochondrial compartment and remains present and active for over 48 h

     Demonstrates selective toxicity for cancer cells.

 

CNS

Proxison™ is derived from Antoxis’s Kromex™ patented chemistry scaffold with potent neuro-protective properties now seen in vivo.

Proxison™ is an inhibitor of the oxidative stress generated in mitochondrial dysfunction and demonstrates:

        Significant protection of dopaminergic neurons of zebra-fish embryos in a Parkinson’s model

     Protection of dopaminergic neurons in a transgenic mouse model (ex-vivo)

     Protection in a rat stroke model reducing infarct volume, improving neurological scores and significantly increasing survival rates

 

 


 

In summary, Antoxis is currently focused on increasing the value of its intellectual property assets by generating compound efficacy data in a range of disease state models. The Company will choose the most compelling compound and clinical indication combinations to move forward as a medical device in regenerative medicine or as an NCE into clinical Phase I studies.