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Tackling an issue of our age: drug-resistant bacteria

Interview - March 8, 2022

Antibiotic-resistant bacteria (ARB) has become a global healthcare crisis, with as many as 700,000 people worldwide dying annually due to the growing problem. Japanese firm Miyarisan Pharmaceutical is leading the pack in the research and development of probiotics to treat the issue. We spoke to president Masayuki Uchida to learn more about Miyarisan's activities at the forefront of healthcare.

 

 

MASAYUKI UCHIDA, MIYARISAN PHARMACEUTICAL CO., LTD.
MASAYUKI UCHIDA | PRESIDENT OF MIYARISAN PHARMACEUTICAL CO., LTD.

Can you tell us a little more about some of the unique features of your manufacturing facilities?

We have two factories in Nagano. One is called the Sakaki Plant and the other is called the CBM Plant, which is dedicated to overseas exports. These factories are quite unique in that they have a total of six bio tanks, with a twenty-ton capacity in each factory. This large scale is quite unusual for Japanese manufacturers. The factory runs around the clock, 24 hours a day, and we have plans to develop a new plant in the same Nagano area in the near future. As our products are for people and animals, by having more factories we can tailor our production to the specific guidelines of a product or market. Since the standards for quality control are completely different depending on usage and application, this will enable more standard-compliant production.

 

Are there any new partnerships or co-creation ventures you’ve recently entered into that you’d like to tell us about? 

In August 2021, we were able to develop a new partnership with BASF of Germany, the world’s largest chemical company. Before signing the contract, they conducted a factory inspection for Miyarisan’s quality system. Through our contract with BASF we’re looking to expand into Southeast Asia, North America and South America in the future.

 

Can you tell us about your current R&D strategy?

With our Miya Gold animal feed, we’ve had a breakthrough in our Research and Development efforts which enabled us to double the volume of the bacteria in our feed while at the same time reducing the price by one-third from what it used to be. This high-volume, low-cost feed just went to market at the beginning of July 2021.

In Europe, regulations on antibiotics for livestock have been banned since 2006, and there is a growing trend towards alternative products, including probiotics, which has led to great interest in our products. Also, for the human body, our CBM strain is entering this market as a new type of probiotic.

 

Can you tell us a little more about the focus of your Research and Development?

We have a very diverse research network working alongside companies like BASF, Huvepharma in Bulgaria, and OSEL in the United States. We also work with various universities here in Japan and abroad such as Keio University, Aichi Medical University, Tokushima University and the University of Michigan.

There are three different areas in which we are doing research now. One is infectious diseases, another is digestive diseases, and the third is cancer. For our infectious disease research, we’re focused on the problem of antibiotic resistant bacteria (ARB). The development of new antibiotics around the globe is decreasing. There has been a huge rise in ARB but the development of antibiotics simply can’t keep up. I think this is a huge issue, and the ARB issue is an even larger issue than the COVID-19 pandemic we’re in right now. According to the WHO, currently, more than 700,000 people worldwide die annually because of ARBs. If we continue at this pace, by 2050, approximately 10 million people will die each year. In the future more people will die from this than even cancer. The WHO has already raised a global alert in regard to this and called out for different private and public institutions to conduct research and manufacturing, but it’s simply not enough and they are encouraging global partnerships to tackle this issue.

Another reason for the rise of ARB to this extent has been the widespread use of antibiotics in livestock as a growth promoter. Only 33% of all antibiotics are used for people, the largest majority is used for animals. Administering antibiotics to livestock disrupts the intestinal flora, allowing them to absorb more nutrients from the feed they eat and increase growth performance easily. This practice has already been banned in Europe since 2006 in the hope of reducing the risk of ARB strains in animal feed and also to reduce the risk of contamination into humans. In America, regulations have been set up only recently. In Europe they are looking for something to replace antibiotics in animal feed in a way that is much gentler and more ethical. That’s when they discovered our product, which doesn’t disrupt intestinal flora but actually helps to stabilize and normalize it, while still helping livestock growth performance. Antibiotics targeted at livestock are most prevalent in China, the United States, and Brazil. We’ve developed our new partnership with BASF for the exact reason to be able to expand into these areas and address this issue.

We have researched and discovered a substance that does not produce ARB based on a new way of thinking. We have filed a worldwide patent for this substance.

In terms of our research in the field of digestive diseases, the number of new drugs made to address them is decreasing year on year. The market is quite saturated for gastrointestinal medication so it’s difficult for new discoveries to take place. Yet there are digestive related illnesses on the rise for which there is no potent drug on the market yet. Recently, the number of patients with IBD such as Crohn’s disease and/or ulcerative colitis has been increasing year on year around the world, and we still don’t understand why. The number of medical and research related papers that have been published to address this issue is increasing with each passing year. We’re really putting a lot of R&D effort into this field.

The third field of our research, as I mentioned before, is cancer. Currently, the mainstays of cancer drugs are those related to immunity. It is said that this trend will continue to grow in the future. Since our specialty is also in the field of immunology, we would like to make use of our knowledge and experience to focus on research and development in this field. The results of clinical trials conducted in the U.S. have been published in Nature Medicine and are receiving significant acclaim.

We’re also looking to exceed our MIYAIRI strain and isolate or develop a hyper MIYAIRI strain. We’re looking to develop pharmaceutical substances that take advantage of the peptides from the MIYAIRI strain so we can isolate them and use them for different medical fields. To that extent all of our research is focused on micro biologics. More than 10 years ago when we tried to fill investigational drug application at  the U.S. FDA, at that time live microorganisms like probiotics were still not considered as pharmaceutical products in the U.S. We’re very interested in the different ways we can get microorganisms approved for medical use. We’re also starting to do something that, while quite established in North America and Europe, is completely under the radar here in Japan, and that is animal welfare. To this end we donated an entire research lab to Tokushima University so we could collaborate with them in this endeavor. We’ve started different trials in order to see how we can improve the welfare of pigs; if they are better off, they will produce tastier pork. We also want to focus on pets and their well-being as well. We believe that better pet care will not only make for happier pets but also contribute to the mental stability of pet owners.



I wanted to share all these different activities, to show that even though we are a company with a long history, we’re actively challenging ourselves in new arenas.

I believe and continue to emphasize to my staff that the extent that we are able to grow is the extent we will be able to deliver this very effective drug to the people of the world and in that sense, to deliver our product to as many countries and people as possible is part of our duty. Diarrhea for example, is the 4th leading cause of death in the world, with 1.4 million dying from it each year. Our product is mainly used for the treatment or prevention of diarrhea caused by with or without infections. We will not stop working until this 1.4 million goes to 0, and we no longer have preventable deaths in the world because of diarrhea. What I want to share is that we don’t look to profit from the sale and manufacture of pharmaceuticals, but we are rather in pursuit of our duty to treat those suffering from these illnesses.

 

Your CBM medicine was discovered by Dr. Miyairi in 1933 to regulate intestinal flora which improves digestion and prevents irritable bowel syndrome (IBS) or diarrhea amongst others. Nowadays, however, we have a lot of knowledge when it comes to intestinal problems, we have medicines like laxatives, muscle relaxants, dietary supplements, and antibiotics. Can you tell us, what is the difference between CBM and these other gastrointestinal treatments?

What’s very interesting about CBM and what sets it aside from other probiotics is that it works in a way that doesn’t harm or disrupt the intestinal flora. Without being inactivated by gastric acid and bile acid, CBM reaches the lower gut alive and works in the digestive tract. Some other probiotics do not survive their way to reach the gut. CBM also produces butyric acid, which is not produced by other probiotics such as lactic acid bacteria, and the butyric acid is very effective in the control of intestinal conditions and at reducing inflammation in the digestive tract.

I think therefore that the largest difference between CBM and other probiotics like lactic acid bacteria and bifidobacteria is that other probiotics die before reaching the gut and become food for the other intestinal bacteria, while CBM strains are properly delivered alive and then produce short-chain fatty acids, acetic acid, and butyric acid to enhance the natural function of the intestines.

 

Drug delivery methods are hugely important when it comes to effective pharmaceutical treatments. Can you tell us more about how your product's drug delivery method works?

Initially, CBM is encapsulated in a spore, which is referred to as a natural capsule. However, in an anaerobic condition where there is no oxygen, the spore germinates, and then CBM starts growing. In other words, when CBM passes through the stomach and bile ducts, it is encased in a capsule called a spore, so it can reach the intestines without being affected. You know many kinds of animals, humans, pigs, birds all have different lengths of intestines. Intestinal length often determines the ability for a drug to properly release and work. Since our product naturally germinates and grows in an anaerobic environment such as the lower intestinal tract, it can be used regardless of species.

 

You’ve already mentioned the many uses of CBM that range from animal feeds to novel cancer treatments. However, CBM was discovered in 1933, it’s been around for almost 100 years now. Why have these applications of CBM just being developed now? Why do you think it took so long for the world to start utilizing and understanding CBM?

It’s actually only recently that we’ve been able to go into more detail in inspecting the intestinal tract. Up until now, when trying to observe the intestines, there is usually no oxygen in the lower intestine, but when the intestines were taken out for research use, they were exposed to oxygen, so it was not possible to observe the actual condition of the intestinal tract. As a result, most of the past research about the intestinal flora was made by studying feces. It’s only recently through new research platforms, like molecular or genetic methods, that we are now able to inspect and look into the digestive tract in more detail. By being able to look more closely at the digestive tract, we have been able to understand the function of the microorganisms in the intestines, the intestinal flora, and the effect of drugs that work on these bacteria have been revealed and are now available to more people. This is just regarding the large intestine, but there are so many unknowns related to the small intestine.

A huge theme for us has been to what extent we can extend resources into research of the small intestine. This is an area which cameras are unable to reach, so there are still a large number of unknowns. We do know for sure that it is very important, it’s the place where the nutrients are absorbed. If you remove the small intestine from any animal it dies, so we know it’s vital. I think moving forwards for scientists and companies working in digestive fields, the small intestine will be the next area of focus. We still don’t understand where the different types of intestinal bacteria are proliferating within the small intestine. Studies have shown a huge correlation not only between the gut and the brain (so called gut-brain axis) but also between the gut and the liver. We believe that studying the gut will bring all kinds of new information about treating liver diseases as well. We hope that more and more research on the relationship between the intestines and various organs of the body will contribute to the treatment of more diseases.

 

You’ve said you're looking to increase the sales of CBM worldwide, but can you tell us what your focus will be? Will it be the medicine itself which accounts for 70% of your sales, or will it be the animal feed? What is your international strategy?

In the short term, Miya Gold as an animal feed additive product is our focus, as they are easier to get authorization from authorities of other countries. Our new BASF partnership was formed in part with the objective of expanding Miya Gold internationally. The pharmaceutical range of CBM is more of our long-term focus. It requires a lot more investment on our part to make sure that it meets the different medical standards of different countries. We’re looking to expand relationships with our global partners in the field of pharmaceutical CBMs.

 

You’ve emphasized the correlation between how bacteria are becoming resistant to antibiotics, and how the utilization of antibiotics has gone down. This is something we’ve seen occurring for the past 20 years in both humans and livestock. This is an international problem today, as even if Europe bans the use of antibiotics in cattle, if you travel to Brazil or Africa, it’s widespread. From a more macro perspective, what can be done between government and industry to better coordinate our efforts to combat resistant bacteria?

I can definitely share with you that it’s a huge issue of global concern. Even in Japan, it was one of the major policy themes during the time of Prime Minister Abe. This is not a problem that can be solved by pharmaceutical companies alone. As the WHO said before, industry, academia, and government need to work together.

 

We know that companies all around the world have been severely affected by COVID, sales in high street stores have plummeted, but at the same time it’s been a great opportunity for companies to pivot and take their business to e-commerce channels. We know that you’ve traditionally been B2B but you’ve engaged more recently in the B2C model with companies like Amazon or Ebay, can you tell us about how COVID has impacted your business, but also more broadly how you’ve increased your brand recognition through e-commerce?

Actually, we have zero experience working directly with consumers as all of our products were sold through wholesale distributors and business enterprises. We thought it would be very important for our future to have a channel to understand the actual needs of our consumers themselves directly, and in doing so get to know what kinds of products they want. We decided to venture into our new pet business to test and see what effect direct contact with our customers can have. As such, by listening to the real opinions of consumers through B2C channels, we hope to develop better and more effective products.

 

In the distant future, you will eventually have to hand over the company to a new generation. When that happens what vision would you like to have achieved and shared with your successor?

I believe that much more than the company brand, profits, or product itself; the people are most important. I’ve always put as much effort as I can into fostering the staff and really developing a solid array of talented individuals who can take on the company philosophy. If that is something we can retain, I will be very happy. Until today, I have always refused interview requests from various companies. One of the reasons I decided to accept your interview today is because I felt like it would be a good opportunity to reflect back on the company, its history, and our record of achievement. I also thought that global communication like yours would be the best way to let people know about our company, so I decided to take part in the interview.

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