Doing things naturally…
Core business: Drug development – diseases of oxidative stress and mitochondrial dysfunction
Company founded: 2006
Number of full-time employees: 2
Doing things naturally
The next time you bite into an apple, eat raspberries or blueberries, or knock back a glass of red wine, you will be treating yourself to some of nature's most effective therapies – the antioxidants or flavonoids that help to protect against the development of major illnesses such as cardiovascular disease, neurodegenerative conditions and certain cancers. And a small company in Aberdeen is using these natural “remedies” as a chemical platform to develop a new range of more powerful drugs to treat established disease and provide novel small molecules for use in the regenerative medicine industry...
For Donald McPhail, the founder and chief scientific officer of Antoxis, the ultimate achievement would be to see the company's products being used in clinics all around the world in the fight against serious medical conditions with substantial unmet need – the end result of work which started a number of years ago at the Rowett Research Institute, now part of the University of Aberdeen, when scientists set out to understand the role that plant polyphenols, such as flavonoids, play in human health and the prevention of disease.
A major focus of this work was to establish the mechanisms by which certain members of the flavonoid family could act as antioxidants, thereby protecting cells from free radical attack. Free radicals are atoms or molecules that contain an unpaired electron, making them highly reactive and damaging towards cell membranes and a host of important biomolecules necessary for maintaining health. They are continually produced in the body as a by-product of the conversion of oxygen to energy. This ‘oxidative stress’ is controlled by the body’s elaborate antioxidant defence mechanisms. However, these are not fool-proof and a level of damage inevitably occurs, which can result in disease and the degenerative changes seen in ageing. The paradox is that we need oxygen to live, but ultimately it can also lead to our demise.
There is now a substantial body of epidemiological evidence that diets high in polyphenol antioxidants – for example, apples, red berries and certain vegetables, as well as tea, coffee and wine (in moderation) – are associated with a reduction in a range of chronic illnesses. These include cardiovascular disease, inflammatory disorders, Type 2 diabetes, neurodegenerative conditions such as Parkinson’s disease, and certain forms of cancer.
However, once the disease is established, much higher levels of oxidative stress can be generated that overwhelm the body's natural defences and result in cell death. So the challenge for scientists is how to amplify the therapeutic properties of flavonoids and get them into the cells to have beneficial effects – increase the bioactivity and target specific, susceptible locations inside the cell.
Antoxis describes this as “the rational design and synthesis of entirely new flavonoid-like molecules which demonstrate a step change in activity compared with the natural compounds.”
A chemist by background, McPhail has developed a range of techniques (using electron spin resonance spectroscopy), to determine the antioxidant potency of foodstuffs such as wine, tea, berry juices and even whiskies. “Although there has been a great deal of interest in identifying dietary sources high in antioxidants, it was understanding the complex relationships between molecular structure, antioxidant activity and bio-potency which really intrigued me,” McPhail says. “By understanding these effects, the logical next step was to design new synthetic molecules that combine antioxidant potency along with the additional molecular features needed to produce drug-like characteristics. Developing a successful therapeutic is not just about a molecule’s ability to destroy free radicals; it is dependent on many factors, including stability, accessing the disease site and the ability to be absorbed by the cell and target key locations, such as the mitochondria, where oxidative stress occurs.”
It is this valuable know-how that lies at the heart of Antoxis and the company was recently granted its second patent in the US and beyond, covering over 100 million molecular variants of the flavonoid family.
Using this rational design approach, compound libraries have now been developed that combine antioxidant potency with rapid cell uptake and targeting of key areas involved in oxidative stress and free radical damage.
McPhail explains: “Our goal is to design in drug-like characteristics to these novel product scaffolds that will make them suitable for use in clinical conditions which the natural compounds are not optimised for – for example, by increasing the amount of compound that can cross from the bloodstream into the brain and slowing its rate of metabolism.”
Of particular interest are antioxidants within the company’s pipeline that target the energy ‘power house’ of the cell – the mitochondria. “This would allow us to intervene in the cycle of oxidative stress, free radical damage and mitochondrial dysfunction that is a major component of many diseases such as Parkinson’s, Huntington’s and sepsis,” adds McPhail.
The company is also looking at wider applications for its compounds and is undertaking studies in the field of regenerative medicine. “Results indicate that several of our proprietary molecules can effectively preserve stem cell viability in situations where they are exposed to high levels of oxidative stress, and once the compounds are incorporated into the cell, there is a good time window of protection, which is of huge benefit clinically.
After transplantation, therapeutic cell therapies are exposed to reperfusion and immune response effects that can result in significant generation of oxygen-derived, free radical species (which in layman’s terms means that over 80% of the transplanted cells can die within 24 h). As recent evidence has shown that treatment with dietary antioxidants can help reverse this loss of viability and functionality, the company believes its antioxidants have far better characteristics to improve treatment outcomes, as they are almost 1000 times more potent than their natural cousins. Early evidence in a number of regenerative medicine applications would tend to support this view.
The use of Antoxis’ compounds in regenerative medicine is seen as a quicker route to market because it's likely that the compounds would not be given as a drug but be categorised as a medical device (cells loaded with protective agents outside the body and pre-implantation), thereby reducing the long and costly regulatory development pathway associated with mainstream therapeutics. This would provide the company with a much earlier income stream, potentially within two years, that would then be re-invested into higher-value, but longer-term drug development programmes.
The business plan
The key to commercial success for Antoxis, according to McPhail, will be the “patent space” the company controls – and this is what will ramp up the company's value over the next few years. Antoxis now has patents protecting over 100 million synthetic variants of the natural flavonoid scaffold. These patents are not just about a single product – they encompass a platform technology from which different molecular variants can be optimised for specific clinical and stem cell applications.
The ‘on-the-bench’ data is very encouraging, so far. According to McPhail, the lead compounds provide an “exceptional ability” to keep a wide range of cell types alive, including neuronal cells, when they are exposed to otherwise lethal levels of oxidative stress. The company is now undertaking in vivo disease models to identify which particular clinical indications and compound combinations are most suitable to move into clinical trials. McPhail says he is also confident that Antoxis’ products out-perform the natural products, and also other antioxidant molecules in clinical trials or on the market.
For McPhail, swapping the white coat for the business world has been an interesting experience, and one he is enjoying. “Setting up the company has been very exciting – especially the prospect of taking the science to market and, hopefully, of providing some kind of health benefit. I was fortunate in securing a Royal Society of Edinburgh/ Scottish Enterprise Enterprise Fellowship, prior to company formation, which was of immense benefit.”
Like many other biomedical start-ups, Antoxis operates as a semi-virtual company. When the company needs to produce any chemical compounds or undertake pre-clinical research and development, it simply sub-contracts the project to a specialist firm, thus avoiding costly overheads. This makes for greater flexibility and enables the company to respond rapidly to new challenges, rather than being locked into an infrastructure that may not be appropriate a few years down the line. “Unlike large pharma, biotechs need to be highly-adaptable, with a more dynamic business model,” says McPhail.
Antoxis does not operate alone, however, and has partnerships and collaborative agreements with several other organisations, including large pharma and mid-sized bio-pharma. In particular, the company has fostered excellent links with Scotland’s universities, including Aberdeen, Edinburgh and Glasgow and, in some respects, is replicating the ‘open innovation’ model that is becoming more common in big pharma.
Aberdeen University is a shareholder in the company, while Glasgow University provided the medicinal chemistry expertise needed to generate the first-generation, flavonoid-like molecules, supported by funding through the Scottish Enterprise Proof of Concept scheme. Antoxis has also been supported through SULSA (the Scottish Universities Life Sciences Alliance) with post-doctoral posts in oncology and regenerative medicine at the University of Edinburgh.
“The key in Scotland,” says McPhail, “is to create an environment where academics can be more commercially focused as well as do blue-sky research.” Thanks to Scottish Enterprise, funding initiatives that encourage high-tech SMEs and the universities to work together, along with an excellent investor network (in Antoxis's case, Genomia Fund, Grampian BioPartners, TriCap and Kapital Assets), the blue-sky thinking which led to the birth of Antoxis, and continues to power its commercial development programme, will not just lead to better medical treatments, but also to a healthy return on investment.
One of the chief aims of Antoxis has been to “carve out a swathe of IP protecting millions of synthetic variants of the flavonoid family” and to increase the value of its intellectual property assets by “generating compound efficacy data in a range of disease state models covering cancer, neurodegenerative and cardiovascular conditions as well as regenerative medicine applications.”
After completing these studies, the company will choose the most compelling indications and promising compounds to move forward into clinical Phase I studies.
The flavonoid-like molecules developed by Antoxis address eight key characteristics:
Rapid cell uptake
Increased metabolic stability
Membrane lipid solubility
Optimal antioxidant potential
Improved access to the brain
Substantially enhanced bio-potency