Diabetes has become an epidemic, with over 422 million people affected worldwide sentenced to lifelong medication. Science is striving to find a cure to 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 (WHO) 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 diabetes. Most treatments help patients manage the symptoms to a certain extent, but diabetics still face multiple long-term health complications.
Both type 1 and type 2 diabetes affect the regulation of insulin, a hormone required for glucose uptake in cells, resulting in high levels of blood glucose. Over time, high sugar levels deteriorate the body, especially the eyes, kidneys, heart and blood vessels.
While type 1 diabetes is an autoimmune disease that destroys the insulin-producing beta-pancreatic cells, in patients with type 2 diabetes these cells still function but the body develops insulin resistance as a consequence of genetics, obesity, highly caloric diets and lack of exercise.
The biotech industry has seen this opportunity and is striving to develop new diabetes treatments and chasing for 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
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 has the potential to recover normal insulin production and cure patients.
However, early attempts at the transplantation of pancreatic cells have largely failed, mostly due to immune reactions against donor cells that cause complications and eventually destroy the implanted cells. The lack of donors is also a limitation.
One of the most advanced alternatives comes from the Diabetes Research Institute (DRI) in the US, which is developing a bioengineered mini-organ where insulin-producing cells are encapsulated within a protective barrier. Two years ago, the DRI announced that the first patient treated 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 life-long anti-rejection therapy,” stated Camillo Ricordi, Director of the DRI.
A similar device is being developed by Viacyte, in collaboration with the Juvenile Diabetes Research Foundation (JDRF) in the UK. After a Phase I trial where the device proved safe, the company is now working on improving the engraftment of insulin-producing cells.
Big pharma are in the early 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.
The Belgian Orgenesis is pursuing an approach where the implanted cells are derived from the patient’s liver and reprogrammed 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.
Although the promises are big, these technologies are still far from the market. First, clinical trials will have to show they do work. Then, the price could be steep, as cell therapy precedents for other applications, such as oncology, come with price tags that reach the six figures and are finding difficulties to get reimbursed. Considering that compared to cancer, diabetes is not an immediately life-threatening disease, health insurers in some countries might be reluctant to cover the treatment.
Countering the immune system
In type 1 diabetes, insulin-producing cells are progressively destroyed until none are left and the patient fully depends on insulin injections. Stopping the progression of the disease early in the process could preserve the cells and provide a cure for patients diagnosed early enough.
That is the goal of Imcyse, a French company running a clinical trial with an immunotherapy designed to stop type 1 diabetes. Patients that have been diagnosed within the last 6 months, who still retain some insulin-producing cells, are given a treatment designed to make the immune system destroy the specific immune cells that are attacking insulin-producing cells. Results are expected later this year and will reveal whether the treatment has the potential to become a cure.
ActoBio Therapeutics, in Belgium, is about to start another clinical trial with an unusual approach to stop 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.
Also getting close to the clinic is Neovacs, developing a vaccine for type 1 diabetes intended to delay the progression of type 1 diabetes after an early diagnosis. The treatment is focused on lowering the levels of an inflammatory protein that is thought to be involved in multiple autoimmune diseases, including type 1 diabetes but also lupus.
The artificial pancreas
Efforts to cure or stop type 1 diabetes are still in the early stages, and these approaches will also not be suitable for people that have already lost their insulin-producing cells. A solution could be the creation of an “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.
“Diabetes type 1 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, explained to me during an interview. 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 make patients better control their sugar levels and suffer less complications in the long term. The French company Cellnovo has already shown that just a partially automated system, where blood sugar levels can be monitored wirelessly but patients still select insulin amounts, can reduce the chances of reaching life-threatening low sugar levels up to 39%. The company is now working towards developing a fully automated artificial pancreas in collaboration with Imperial College, the Diabeloop consortium and the Horizon2020 program.
Type 2 diabetes
Inducing 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,” stated Kurt Graves, CEO of Intarcia, in a press release.
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. 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 close to 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, where it helps recover the lost function of mitochondria, which is thought to drive the progression of type 2 diabetes.
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.
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 found to be linked to multiple chronic diseases, including diabetes.
An unbalanced microbiome composition, known as dysbiosis, has been found in patients with diabetes, for whom the diversity of the gut microbiome is often reduced 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 the insulin resistance found in obese patients with type 2 diabetes.
Some companies are now starting taking the concept into a treatment, with the French Valviotis currently conducting preclinical testing of a drug aimed at increasing the microbiome diversity as a treatment for 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.
Gal’s company, 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 €90Bn a year in Europe,” MediWise co-founder Panos Kosmas told us in an interview.
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.
Others are going for implants, such as NovioSense’s eye implant or Senseonic’s subcutaneous device, which will be distributed by Roche.
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 (€32Bn) and type 2 (€54Bn) treatments, and we can expect all sort 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; MMediWise; A. N. Zaykov et al., Nature Reviews Drug Discovery 15,425–439