Sweet medicine

By Frances Davies, Deputy Editor

For people with diabetes a lack of insulin means regulating the body's blood sugar levels is a challenge. As the prevalence of the disease continues, reversing the trend is a focus for Novo Nordisk.

“We're not against stem cell research, but we think it should be done under strict ethical guidelines”
-Kare Schulz of Novo Nordisk

With 48 million sufferers, Europe has the highest incidence of diabetes worldwide and as the population ages numbers are only set to increase. With these figures in mind, finding new treatments is more important now than ever. Leading the way is Novo Nordisk who have been diabetes pioneers for the past 80 years with the sole aim of improving living conditions and outlooks for people with the disease. The company have roughly more than 20% of the total of the diabetes market worldwide and more than half of the insulin market.

Those with Diabetes are unable to produce or properly use insulin in their body, thus sugar and other food cannot be turned into energy. Manufacturing insulin is technologically difficult, but the company achieved this feat and then made it available to those with Type 1 diabetes. “We’ve been instrumental in finding safer and better insulins many times,” says Kare Schultz, COO.

Bright ideas

The first long-acting NPH insulin was developed by Novo Nordisk. It also developed a totally pure mono-component insulin. “To fully understand the benefit of these inventions, you had to imagine having Type 1 diabetes,” pinpoints Schultz. “Patients have to inject themselves every day with insulin to survive. These inventions have been improving the lives of millions of people.”

Later, Novo Nordisk invented inject device systems, first with a durable pen, then later with a pre-filled pen. The company succeeded in making the products very precise and created a fast-acting insulin analogue. This meant patients could take the insulin with their meal instead of having to plan meals and taking the insulin before eating.

One of the drawbacks with insulin is if you get too much of it there is a risk of getting hypoglycemia. On the other hand, too little causes high blood sugars and can lead to late complications such as kidney failure, blindness, or amputations. Schultz explains how it's a delicate balance to treat the disease in an optimal way, and how inventions over the last 80 years have been making it more possible to treat diabetes so patients can minimise or avoid the negative effects of the disease. “We have spent nearly 20 years making it possible to take a human hormone called GLP-1 and to modify it into a longer action profile. We filed the drug, liraglutide, for approval with the FDA and EMEA in May. This is a major research milestone and it will be a major benefit for people with Type 2 diabetes.”

Protein-based figures

The company is committed to engineering proteins into safe and effective therapies and developing new and improved protein delivery systems. Schultz describes some of the history behind the company’s protein-based figures. He describes how when insulin was discovered back in the 1920’s, it was based on animal raw materials and extracted from the glands of pigs and cows. During this era, Denmark had a strong agricultural tradition and it was a Nobel Prize winning Dane who happened to be in Canada when insulin was discovered that took the invention back to Denmark. Once back, he started insulin manufacturing out of animal-based raw materials. Over many years there was a growth in hormone manufacturing based on biological starting materials. When the biotech technological revolution happened in the 1980’s, the system changed into biotech manufacturing of these proteins. Most big pharma companies in Europe and the US are based out of the chemical industry.

“We came out of biological manufacturing and research,” recalls Schultz, “Today, this has led us to be among the biggest manufacturer of biotech products because most of our insulin, growth hormones, and Factor VII for hemophilia are all products produced by having different cells grow in fermenters. These are harvested, purified then used for different kinds of therapies.

“This way of developing, manufacturing and researching new products is totally different from what big pharma does with chemical compounds. Fundamentally and technologically this is a different technology and scientific base.”

Due to the biotech industry growing in the last 20 years there are many other companies applying the same techniques in different areas. Novo Nordisk has combined this protein focus with a strong focus on diabetes. Proteins are characterized by the fact that they are not really orally available, so cannot be taken as a tablet, whereas all chemical compounds are basically taken as tablets. “If you take the top five pharma companies worldwide, you will see how much of their sales are injection therapy and how much are tablet therapy,” highlights Schultz. “ Most of their sales will be tablets, and they are characterised by the fact that they are extremely easy to copy. The moment they go off patent, most of these sales will be lost. With our proteins, it's not enough to make the protein; a delivery system needs to be made so that it can, in a convenient and safe way, be injected.

“This is what we've been doing at Novo Nordisk for many years, and today, we are by far the world’s leader in easy-to-use, safe and efficient injection systems for therapeutic proteins. Millions are using our insulin pens and our pre-filled insulin injection devices every day. In order to have an effective product offering in this area, there is a need to have research, development, manufacturing skills and then skills within the device area so that devices that are competitive are delivered. We’ve built this over many years, and believe are leading in this area.”

World Diabetes Foundation

Those in developing countries are often at most risk of the adverse effects of diabetes, which is why the World Diabetes Foundation, set up with the help of Novo Nordisk, contributes enormously to saving the lives of those effected by the disease. The foundation was created six years ago and the company has committed around $200 million to it.

Novo Nordisk donates the money to the foundation, and the foundation is then managed by an independent board. Several people from the company are on the board along with people from independent organisations. The board then drives projects and donates money to projects in many developing countries to build sustainable improvements. “It’s very important for us to deliver support for those in developing countries with diabetes,” stresses Schultz. “With our help we are able to develop better healthcare for people.”

The work is always carried out in close collaboration with local authorities, local hospitals because as Schultz emphasises, “we believe that what we have to do is through support and education. We have to build more awareness and capacity to treat diabetes. We cannot do the job totally without a local foundation that can carry the job forward when we, or our project, ends.”

More than 100 projects have now been approved and are up and running. These have provided millions of people with better care. In fact, there are now many interesting examples of building diabetes clinics and huge education programs in many countries around the world.

Human stem cell research

Human stem cell research continues to provoke a lot of ethical debate. Novo Nordisk takes the view that it is vital to ensure that all aspects of research is undertaken following the highest ethical standards. The company has been carrying out stem cell research in collaboration with many international experts. They have their own centre in Copenhagen, and are very positive about the possibilities of stem cell research. “If it's done in the correct way then we don't think there's a ethical issue that cannot be managed in a responsible way,” reassures Schulz. “We’re not against stem cell research, but we think it should be done under strict ethical guidelines. Stem cell research might help find a cure for Type 1 diabetes conceptually is if it is possible to take stem cells and then have them naturally converge into insulin producing feeder cells. As stem cells are the origin of all cells, if we can guide the growth of them into being insulin producing feeder cells then we might have a treatment option which might be closer to a cure than the current treatment options.”

The company is already doing a lot of research in this area. Schultz does not believe that the idea of taking feeder cells not compatible with a patient’s own immune system will be a sustainable solution. Current research indicated that when feeder cells are not taken from an individual’s own stem cells then their immune system will react. The only way these therapies can be used is by heavy immuno-depressing medication. According to Schultz: “This is not the way forward because diabetes is a disease you live with for many years. It is impossible to be on this immune system suppression therapy for many years without running major risks. The strong solution would be to grow feeder cells from the body's own human cell that can be re-entered into the person in question.”

Working as one

The company actively engages in partnerships and sees them as a way to help build trust among its key stakeholders and to reach a better understanding of a variety of important issues . Schultz tells us why this emphasis on partnership is so important: “The way to find new, interesting targets that are following our overall strategy of being in biotech and protein-based products is to be in constant touch with the international research community and then spot research organizations who come up with interesting early-stage innovation.

“These are typically organisations who do not have the capability to take this through to manufacturing. Therefore, we would like to enter into collaborations with these partners with the aim of developing the innovations into real products.”

Many people believe that genome-based medicine, also known as personalised medicine, is the future of healthcare. However, according to Schultz there is still a lot of work that needs to be done before this field can really breakthrough. He believes that sophisticated technology such as stem cell research has to come to fruition first. Until progress is made in this then developments in this area could still be as far away as 10 or 20 years away. “An element of this is happening already,” he says. “In a certain disease area, there will be different physiological responses to different treatments among different groups of people. Certain products have very much the same response, such as some of our key products. Some products will be well suited for 10% of the target group but not for the other 90%.”

“Scientists will need to work on discovering what is it that predicts that a drug will work well for some but not others. This is not really personalised medicine to the extreme, but this is what I think will happen in the next 10 years. There will be some segments in the marketplace where you see this, and it might be genome-based determination of who can use the product.”

On the horizon

The development of the human GLP-1 has been on of the most exciting projects at the company over the past 20 years. This is a hormone that regulates both blood sugar levels and appetite. GLP-1 is a natural hormone, which can be found in our body. “Whenever we eat, it is released,” informs Schultz. “It has a very strong effect so whenever we eat it's released but then disappears again. It’s half-life is extremely short.”

The company has now been able to make it in a long-acting version, liraglutide, with a much longer duration of action, that means it only needs to be injected once daily. It only works if a patient’s blood sugar is too high, minimising the risk that the patient’s blood sugar might get too low. Apart from lowering glucose, it has also shown to have a weight-lowering effect. As Schultz correctly identifies: “The biggest problem typically for people with Type 2 diabetes is that their blood sugar level is too high as is their body weight. At the same time they are afraid of getting too-low blood sugar because there is the risk of being hospitalised. Having too low blood sugar levels can carry grave consequences.”

Schultz predicts that this product will come to market in the next year and is excited about the effect it has shown to have in the body to regulate blood sugar and appetite.

One of the most difficult challenges Novo Nordisk has had to deal with has been a complicated business model due to the difficulties associated with manufacturing proteins. Despite these problems it appears that these hurdles have been turned into advantages. “We are now in a niche that’s different from all the tablet-based, chemical-based products. We seem to be in an area where all the complexity of development, manufacturing, distribution, delivery, has created a specific know-how that keeps our business model growing very nicely.”

The company’s growth over the last 5o years has been very strong and Schultz envisions this will continue into the future. He is hopeful that having worked very hard in this area they are lucky that the market is also still going their way. “As a company owned by a foundation, we have been given the freedom and opportunity to focus on diabetes,” he concludes. “We have a very holistic long-term view where we intend to spend substantial resources on securing both our commitment to the worldwide community within diabetes, but also our commitment to the environment, our employees, and the areas where we operate.”