Mark Offerhaus, Micreos CEO:

Phages: the natural enemy of bacteria that help tackle skin conditions

Staphylococcus aureus is a nasty little creature. This bacterium plays a sinister role in all sorts of chronic skin conditions, including eczema, acne and psoriasis. But how do you fight this bacterium without also killing all good bacteria that are important to our health? And how do you combat the MRSA variant, more commonly known as the hospital bacterium or ‘superbug’, which is resistant against most antibiotics and can therefore also be deadly? Micreos took a leaf out of the book of bacteriophages - a name that literally means ‘bacteria-eating viruses’ - which have been the natural enemies of bacteria for billions of years.

"We had our ‘Eureka’ moment when we discovered exactly how phages kill bacteria," says CEO Mark Offerhaus. “This insight allows us for the first time to provide an alternative to antibiotics that is actually selective and to which the bacteria are not expected to become resistant. We are talking about endolysin technology, which involves the use of little enzymes to cut the cell wall of target bacteria, like little scissors.”

Micreos is not a normal biotech company for a number of reasons. Within ten years of its foundation, it had grown into two divisions, each of which has marketed a number of products: Micreos Human Health, widely known for producing Gladskin™, and Micreos Food Safety, a pioneer in the field of phage technology for improving food safety. The company is currently involved in registering a number of medicines.

"We are a bit different from the others," Offerhaus explains. "We have always adhered to the discipline imposed by the market. We wanted to go from technology to product as quickly as possible. There is a lot you can learn during the last 10% of the phase before a product is out on the market. Moreover, it's an inspiring process, as it allows you to see, for the first time, what your technology means to society and the individual patient. We have already been able to help around 100,000 persons suffering from skin conditions and resistant wound infections using Gladskin™. To many of them, our technology was life-changing. And it worked quickly to boot. They might have suffered from eczema severe enough for the itch to keep them from sleeping properly for decades and suddenly their suffering was over. We are talking a matter of days here. Inflammatory skin conditions are now dominating the lives of tens of millions of patients - one in five children suffers from eczema in developed countries, for instance - while parents try and avoid corticosteroids due to the possible side effects and urgently look for a less harmful alternative for their children.

But we are also conducting a study into the application of our product to treat patients suffering from Netherton syndrome, a serious hereditary skin disorder. While there are only about 15 patients with Netherton in the Netherlands, the impact may be enormous for this small group. This fits in nicely with the core characteristic of our company culture: care.

HAMAPASAP as leitmotiv

For a year now, this Micreos culture has been encapsulated in the HAMAPASAP slogan. The term was born during a meeting between Offerhaus and a number of employees to discuss the strategy. "Scalability is one of the themes most important to us. Our technology has so much potential and there is so much we can do that we need to upscale to be able to help as many people as possible. So I wrote down on the whiteboard that our objective should be to Help As Many As Possible As Soon As Possible - HAMAPASAP in short. We liked this acronym and it has since become our leitmotiv."

It has now been turned into a verb within Micreos. ‘HAMASAPing recently gathered considerable momentum in response to a Dokters van Morgen broadcast. This popular television show about medical innovation had focused on a number of patients suffering from eczema who had used Gladskin™. "The broadcast resulted in a flood of orders. We had experienced this before when the BBC discussed our technology. Things became a madhouse then and we were virtually out of stock for weeks on end." All this interest shows how massive the problems are that we are tackling and how urgent the need is for new treatment methods.

A game changer in the treatment of skin conditions

Well over a million persons in the Netherlands suffer from eczema, an often chronic skin condition involving red rashes, severe itching, infection and inflammations that may be triggered by all kinds of external influences and stress. "People generally have no idea about how much of an impact eczema has on quality of life," says Offerhaus. "For small children in particular, this impact is more massive than it is for almost any other condition." Gladskin™ does not help against eczema alone; in principle, it is effective against all skin conditions involving Staphylococcus aureus. This is true for about 70% of all persons suffering from eczema, but also for rosacea, psoriasis, specific types of acne and diabetic wounds.

Gladskin™ works differently from the antibiotics or corticosteroids that are currently used as the standard treatment for these conditions. "Our technology is the first to provide a way to selectively kill unwanted bacteria without them becoming resistant (see the text box). While Staphylococcus aureus is destroyed within a matter of seconds, its benign sibling Staphylococcus epidermis remains unaffected. And because bacteria do not become resistant to Gladskin™ and it does not impact the immune system, patients are able to use it for as long as they need to. It truly is a game changer."

Our ‘Eureka’ moment

This is also how Micreos was presented on the front page of The Times in 2014, the headline declaring: "Scientists create drug to replace antibiotics - Breakthrough in fight against superbugs". For Micreos's endolysin technology was first and foremost intended to be used to combat MRSA, a resistant variant of S. aureus. Turning such a weapon into an approved medicine is a very long process. However, creams, ointments or gels based on virtually the same active ingredient are not considered medicines, but medical aids. And having such aids approved for release on the market is a lot less complex and can be done much more quickly. "In 2011, we had our ‘Eureka’ moment and realised how we could turn phage technology using endolysins into something humans can use. Our first products hit the market in 2013. Such rapid development was really unheard of."

Not a last resort, but a primary choice

To speed up their adoption by the market, it is of primary importance for Micreos's endolysins to be accepted as a medicine. For only then can it be covered by insurance policies. Offerhaus is convinced of success. "We will start conducting animal tests this year and will launch the first clinical trials for the medicines next year. It will still take a few years before it can be registered as a medicine. That's just how the system works. But I have no doubt that we will succeed. The results so far using Gladskin™ are indicative for what the medicine will do." Will the Micreos product remain something of a last resort, to be used only when the customary treatments no longer work? "Absolutely not! To the contrary, in fact. It would be far more logical to actually start with only targeting the harmful bacteria. Why would you use antibiotics or corticosteroids if there's a medicine available that does not have any side effects and leaves the body's immune system in peace?"

Ambitions for growth while keeping things fun

It is Micreos's ambition to continue to grow independently, only engaging partners where relevant - such as for marketing and distribution purposes - so as to proceed at full speed. A new office was opened in Zurich to boost the research side, while the incorporation of Micreos USA is scheduled for this year in order to service the largest market in the world. To be able to fund all these ambitions, Micreos has raised 30 million euros from investors in the past two years.

Will there still be room for HAMAPASAP when Micreos becomes even bigger? “Absolutely! One of the privileges I grant myself as founder of the company is to continue guiding the company in adhering to this keystone. This requires special attention and I'm focusing on it on a daily basis. There are few things that are more satisfying than building up a company and helping thousands of people at the same time."

Using phage technology to fight bacteria

During the last century, humanity launched a full-on assault against bacteria. While antibiotics form the primary tools in our arsenal, disinfectant soaps and wipes and chemicals are also used to kill as much bacteria as possible. Though this fight has resulted in enormous health benefits for mankind, the chosen strategy also has certain downsides, which are becoming ever more prominent.

The rise in resistant bacteria due to the often excessive use of antibiotics is considered one of the premier threats to public health by the World Health Organisation. According to a British study, over 50,000 persons die each year as a consequence of infection by resistant bacteria in Europe and the U.S. alone. Moreover, it has become clear that bacteria in the intestinal tract and on the skin make a vital contribution to a person's health. Untargeted attacks against this microbiome may result in new health problems.

While humans only started fighting bacteria in the last century, bacteriophages have been at war with them for billions of years. These phages (bacteria-eating viruses) require a bacterium as a host in order to procreate. Once a phage recognises it has found the cell wall of a bacterium and attaches to it, it injects its genetic material into the bacterial host. The bacteria's own systems are then used to reproduce the phage's offspring. As a result, "a breeding ground with baby phages", to quote Offerhaus, comes into being, locked inside the bacterium. In order to break free, they produce an enzyme, also known as an endolysin, which is a molecular pair of scissors that cuts open the cell wall of the bacterium, resulting in one deceased bacterium and a host of freed phages that go out and search for a new host. This entire process of attacking, conquering and destroying a bacterium plays out in about 20 minutes.

Two processes

The evolutionary success of phages therefore revolves around two processes. Firstly, the phages must be able to recognise a specific species of bacteria. This is possible because they have co-evolved with the mutating bacteria species that have developed over the course of history. In addition, new phages must be able to escape from their host. That they have remained able to do so for billions of years – i.e. that the bacteria have not become resistant to them – is due to the fact that endolysins attack genetically unalterable parts of the bacterial cell wall. These two processes render endolysins both selective and deadly.

Food safety

One of Micreos's product groups uses phages to increase food safety. Phages specifically targeting bacteria like Salmonella, Listeria and E. coli are employed by producers of chicken, turkey, salmon, cheese and other foodstuffs.

Human use

The phages themselves are no longer used for human health products. Instead, only the endolysins, the enzymes that cut the bacterial cell wall like little scissors, are used. The first endolysin available for human use in the world is called Staphefekt™ SA.100 and it is the active ingredient in Gladskin™. A variant, XZ.700, is being registered as a medicine for certain conditions by Micreos.

Using only Staphefekt™ instead of the entire phage provides a number of benefits. While a phage requires around 20 minutes to kill a bacterium, Staphefekt™ takes only a few milliseconds. And because Gladskin™does not use phages, it more easily meets the requirements for registration as a medicine and Good Manufacturing Practices.

Basis for the patent strategy

Combining the essential components is the core trick of the trade, Offerhaus explains. "Ever since Micreos was founded, we have been cooperating exclusively with Professor Loessner's research group at ETH in Zurich. Micreos holds the right of first development to all therapeutic applications of endolysins and phages discovered by his research group.

This is why Micreos was the first company in the world able to create endolysins. It also provided us with the basis to patent our discovery. Such a basis is lacking when using a phage that originated through evolution. Together with NLO, we have very precisely described the order of the amino acids that allow our products to work the way they do. Should a competitor create endolysins that are overly similar to ours, we will be able to see this and demonstrate that our rights have been infringed upon."

Broad protection

In addition to the parent patent that protects this ‘composition of matter’, Micreos broadened its protection by acquiring various other patents, such as for applications in which the use of its antibacterial product, in combination with other substances, produces a specific benefit. "The importance of protection is beyond question. If you don't have it, you simply don't get funding in this sector. However, parading a patent that is later successfully challenged in front of shareholders makes no sense. This is why we are happy with the fact that the Munich District Court dismissed a challenge to our parent patent late last year. This shows that our argumentation is solid and that we have the freedom to move our company where we want it to go. And, at the end of the day, that should be the basis for your patent strategy."