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Diabetes has become an epidemic, sentencing over 422 million people worldwide to lifelong medication. Science is striving to find a diabetes treatment that can cure this chronic disease, but how close are we? Diabetes is the major cause of blindness, kidney failure, heart attack, and stroke. The number of people affected by all types of diabetic disorders is now over four times higher than just 40 years ago. This has led the World Health Organization to consider diabetes an epidemic, predicting it will soon be the seventh biggest cause of death worldwide. Despite its huge impact, there is still no cure for any type of diabetes. Most treatments help patients manage the symptoms to a certain extent, but diabetics still face multiple long-term health complications. Diabetes affects the regulation of insulin, a hormone required for glucose uptake in cells, resulting in high levels of blood sugar. While there are some similarities in symptoms, the two main types of diabetes develop in different ways. Type 1 diabetes is an autoimmune disease that destroys insulin-producing beta-pancreatic cells. In contrast, patients with type 2 diabetes develop insulin resistance, meaning that it has less and less effect on reducing blood sugar. The biotech industry has seen this opportunity and is striving to develop new diabetes treatments and chasing the holy grail: a cure. Let’s have a look at what’s brewing in the field and how it will change the way diabetes is treated. Type 1 diabetes Replacing missing cells with cell therapy Although still in the very early stages of development, cell therapy is one of the biggest hopes towards developing a cure for diabetes, especially for type 1 diabetes. Replacing the missing insulin-producing cells could potentially recover normal insulin production and cure patients. However, early attempts to transplant pancreatic cells have largely failed, mostly due to immune reactions that reject and destroy the implanted cells. The lack of donors is also a limitation. One of the most advanced alternatives comes from the Diabetes Research Institute in the US, which is developing a bioengineered mini-organ where insulin-producing cells are encapsulated within a protective barrier. In 2016, the DRI announced that the first patient in Europe treated with this approach in an ongoing phase I/II trial no longer requires insulin therapy. “This can be the beginning of a new era in islet transplantation. Our ultimate goal is to prevent the need for lifelong anti-rejection therapy,” stated Camillo Ricordi, Director of the DRI. A similar device is being developed by the US company Viacyte, in collaboration with JDRF. After a phase I trial where the device proved safe, the company is now working on improving the engraftment of insulin-producing cells. The Belgian company Orgenesis is pursuing an approach where cells from the patient’s liver are transformed into insulin-producing cells to avoid the issues of sourcing cells from donors. Islexa, in the UK, is developing a similar procedure sourcing cells from the pancreas. Big pharma are still in earlier stages of developing their own cell therapy approaches for diabetes. Novo Nordisk, one of the largest providers of diabetes treatments, is bidding for stem cells and an encapsulation device, stating that the first clinical trial could take place in the “next few years.” Sanofi, also a big name in diabetes, is working with the German Evotec in a beta cell replacement therapy for diabetics. Although the promises are big, these technologies are still far from the market. First, clinical trials have to show they do work. In addition, the price could be steep, as cell therapies for other applications, such as oncology, come with six-figure price tags and are finding it difficult to get reimbursement from health insurance companies. Considering that compared to cancer, diabetes is, for the most part, not an immediately life-threatening disease, health insurers in some countries might be reluctant to cover the treatment. Attacking the origin with immunotherapy In type 1 diabetes, insulin-producing cells are progressively destroyed by the immune system. Stopping this process early enough could preserve the cells and provide a cure. That is the goal of Imcyse, a Belgian company running a clinical trial with an immunotherapy designed to stop type 1 diabetes by specifically killing the immune cells that destroy the pancreas. “Early after diagnosis, between 3 to 6 months, it is estimated that around 10% of the insulin-producing cells are still alive and producing insulin. After stopping the autoimmune process, the remaining beta cells would be protected and could continue producing insulin,” Pierre Vandepapelière, CEO of Imcyse, told me. ActoBio Therapeutics, a company in Belgium, is now running a phase I/II clinical trial with an unusual approach to stop the progression of type 1 diabetes. The company uses cheese-producing bacteria to deliver two drugs that stimulate regulatory T cells to instruct the immune system not to attack insulin-producing cells. “It is potentially a safe oral treatment that will be given for a limited period of time and could lead to patients who develop type 1 diabetes not needing to use insulin, or delay the need for insulin after diagnosis” said Pieter Rottiers, CEO of ActoBio. In France, the company Neovacs is developing a vaccine for type 1 diabetes that stimulates the immune system to lower the levels of an inflammatory protein that is thought to be involved in multiple autoimmune diseases. The vaccine can immunize patients with lupus for 5 years, and the next step is to test whether this effect is also achieved in people with type 1 diabetes. “This would make treatment with insulin no longer necessary, and of course reduces the cost considerably compared to a lifetime treatment,” Miguel Sieler, CEO of Neovacs, told me. Automated treatment with an artificial pancreas For people that have already lost their insulin-producing cells, a shorter-term solution could be the ‘artificial pancreas’ — a fully automated system that can measure glucose levels and inject the right amount of insulin into the bloodstream, just like a healthy pancreas would. “Type 1 diabetes is very different from your standard disease. Insulin requirements vary greatly from one day to another and there is no way patients can know what they need,” Roman Hovorka, Professor at the University of Cambridge, told me. His research group is working on the development of an algorithm that can accurately predict insulin requirements for a specific patient at any moment. Replacing humans with computers could help patients better control their sugar levels and suffer less complications in the long term. However, in order to fully automate insulin therapy, there are several challenges yet to be addressed. First of all, faster forms of insulin are needed to react quickly enough to changes in sugar blood. In addition, current algorithms need to significantly improve to be able to make accurate predictions. Type 2 diabetes Stimulating insulin production “During the past decade over 40 new pills and injections were approved for diabetes. However, the scary reality is that the majority of patients with type 2 diabetes still have poor glycemic control,” said Kurt Graves, CEO of Intarcia. One of the biggest hits in type 2 diabetes treatment is glucagon-like peptide (GLP)-1 receptor agonists, which induce insulin production in beta-pancreatic cells while suppressing the secretion of glucagon, a hormone with the opposite effect to insulin. All big pharma have GLP-1 drugs on the market or their pipelines, including Sanofi, Eli Lilly, Roche, AstraZeneca and Boehringer Ingelheim. But Novo Nordisk is going a step further with the first oral version of a GLP-1 drug, which is now on the market. The French company Poxel is going after a different approach with a drug that simultaneously targets the pancreas, the liver and the muscles to reduce blood sugar. The drug has proved this effect in a phase III trial in Japan, where Poxel will be seeking approval before Europe and the US. In Sweden, Betagenon and Baltic Bio are working on a first-in-class drug with the potential to simultaneously control sugar levels and reduce blood pressure, a big risk factor in patients with type 2 diabetes who are also obese. Tackling the obesity component of type 2 diabetes is also the German Morphosys, which is running Phase II trials with an antibody designed to reduce fat, prevent insulin resistance and control excessive eating. Targeting the microbiome Just in the past decade, scientists have realized the big role that the microbes living inside and on us play in our health. The human microbiome, and especially the gut microbiome, has been linked to multiple chronic diseases, including diabetes. An unbalanced microbiome composition has been found in patients with diabetes, who tend to have a less diverse gut microbiome as compared to healthy people. Researchers from the University of Amsterdam recently showed that fecal transplants, used to transfer the microbiome of a healthy person to the gut of one with diabetes, can result in a short-term improvement of insulin resistance in obese patients with type 2 diabetes. Some companies are developing diabetes treatments targeting the microbiome. The French Valviotis is currently conducting preclinical testing of a drug aimed at increasing the microbiome diversity as a treatment for type 2 diabetes. Although promising, the microbiome field is very young and its complexity makes it difficult to establish causation after finding correlation. Until more diabetes treatments are tested in the clinic, it will be difficult to determine the real potential of the microbiome in this space. The needle-free revolution “In a perfect world, blood sugar testing would be quick and painless,” said Avner Gal, CEO of Integrity Applications, in an interview. That world may not be so far away, as many companies are developing non-invasive methods to substitute finger pricking. Integrity Applications has developed a device called GlucoTrack that can measure glucose using electromagnetic waves and is already available in Europe. Similar technologies are popping up, with GlucoSense in London using laser light to measure sugar levels and MediWise making use of radio waves. ”The device could reduce costs for healthcare, which in the case of diabetes account for €90Bna year in Europe,” MediWise co-founder Panos Kosmas told me. Patches are also becoming a popular form of measuring blood glucose without needles, such as FreeStyle Libre, an inch-wide patch that can be worn for up to 2 weeks. At the University of Bath, researchers are developing a graphene patch that could provide greater accuracy by measuring sugar levels individually in multiple hair follicles. Dutch firm NovioSense is going for a tiny device that is placed under the eyelid and would be more affordable than current continuous glucose monitors. Meanwhile, Senseonic and Roche are working on a device that is implanted under the skin. Still, non-invasive options to measure blood sugar often face issues regarding accuracy. The famous glucose-measuring contact lens that Google announced in 2014 was dismissed as “technically infeasible” and further developments will be needed to reach the degree of accuracy of finger-pricking methods. What’s next in diabetes treatment? The diabetes market is expected to reach a massively big €86Bn by 2025 combining both type 1 and type 2, and we can expect all sorts of revolutionary technologies to come forward and claim their market share. Researchers are already speculating about microchips that can diagnose diabetes type 1 before the symptoms appear or nanorobots traveling in the bloodstream while they measure glucose and deliver insulin. “There’s little fiction left in this. I strongly believe that microrobotics will come and will be part of our drug delivery within the next 10 years,” said Tomas Landh, Director of Strategy and Innovation Sourcing at Novo Nordisk, at the 2013 Medicon Valley Alliance Annual Meeting Whatever the future brings, it will undoubtedly make a huge difference in the lives of millions of people worldwide. This article was originally published in November 2016 and has since been updated to reflect the latest developments in diabetes treatment. Images via DRI Biohub; MaSTherCell; MediWise; A. N. Zaykov et al., Nature Reviews Drug Discovery 15,425–439 (2016); Ktsdesign/Shutterstock

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