Diabetes: Finding a Panacea

In 2013, world leaders came together to develop an action plan to address the global rise in noncommunicable diseases (1). Among the goals was to prevent further increases in the number of cases of diabetes mellitus (types 1 and 2). But adequately addressing the current epidemiological situation is a challenge; over 400 million people worldwide live with diabetes (5-10 percent of individuals live with type 1) and estimates suggest that the number will continue to rise (2,3). The high disease burden has placed significant stress on countries’ economic and healthcare infrastructure.

According to Kiran Mazumdar-Shaw, Founder and Executive Chairperson of Biocon, ensuring proper disease management is crucial to curbing this global healthcare problem. “Diabetes is often described as a disease of halves – only half of the people living with it get diagnosed; only half this group receive treatment; and, among this group, only half are compliant with their medication,” she says. “Although early insulinization is regarded as an efficient aid to improve long-term control and the quality of patient lives, this method of treatment fails to address certain problems.” Needle anxiety and issues related to cold chain supply, particularly in rural areas of developing countries, may delay the onset of treatment, she adds – problems exacerbated by the stunted growth of the treatment pipeline.

“Insulin has been used as a life-saving treatment for close to 100 years,” says Stephan Kissler, Associate Professor of Medicine at Harvard Medical School. “Though the types of insulin preparations available have continuously improved, as have methods of administering them – with smaller needles, insulin pens, and automated pumps available today – we still don’t have a treatment to prevent or cure diabetes.”

This leaves the door for innovation wide open. But before new options can be developed, Mazumdar-Shaw believes that the pharmaceutical industry can do more to improve access to existing treatments.

The immunotherapy approach

According to Kissler, researchers have spent decades trying to understand type 1 diabetes and devise effective therapies. “In recent years, the field has recognized that, instead of solely targeting the immune system that causes the destruction of insulin-producing cells, an alternative approach might be to protect these cells from the immune system instead. This is a relatively new strategy that holds much promise,” he says.

According to Kissler, researchers have spent decades trying to understand type 1 diabetes and devise effective therapies. “In recent years, the field has recognized that, instead of solely targeting the immune system that causes the destruction of insulin-producing cells, an alternative approach might be to protect these cells from the immune system instead. This is a relatively new strategy that holds much promise,” he says.

For Lucy Walker, Professor of Immune Regulation at University College London, immunotherapy may hold the key to tackling type 1 diabetes. Leading a team of researchers, she has begun to investigate how existing immunosuppressive therapies can be applied to the disease. “Immunotherapy has completely changed the landscape of cancer care and I am really excited to see it starting to come to the fore in autoimmunity,” she says. “There are, understandably, more barriers to testing new therapies in people with type 1 diabetes, who are often young and otherwise healthy, than in people with advanced cancer. However, recent studies show that T cell-directed immunotherapy could delay the development of the condition by two years.” Last year, the EMA awarded Priority Medicines designation to teplizumab – a drug that binds to the proinflammatory T cell co-receptor CD3, preventing it from killing insulin-producing cells. It also received a breakthrough designation from the FDA. The drug was shown to slow the onset of type 1 diabetes in at-risk patients by two to three years (4). The potential of this therapy, coupled with other recent results, has been a source of inspiration for Walker, whose work on abatacept – an immunosuppressive drug – could help treat the condition. In 2014, she found that T follicular helper cells were partly responsible for the destruction of the pancreatic beta cells that produce insulin. Now, in a project funded by Diabetes UK and AstraZeneca, Walker is exploring the role of abatacept in reducing T follicular helper cell numbers and thereby protecting insulin-producing cells. So far, the drug – currently used to treat rheumatoid arthritis – has been shown to help some people with type 1 diabetes, but not others, but the study must be expanded for its full potential to be realized.

Walker’s work is just one example of the innovative research taking place to help people living with diabetes; many others are working on new treatments. Researchers at Texas A&M University’s College of Medicine, for example, have reported on an immunotherapy that was shown to reduce inflammation and halt immune attacks on beta cells (5).

The Type 1 Diabetes UK Immunotherapy Consortium is also conducting several trials to investigate the potential of immunotherapies. This includes the USTEKID Phase II trial, which is investigating whether ustekinumab – a drug first produced by Janssen to treat psoriasis – will be effective in preventing pancreatic damage (6).

Other research teams are approaching the problem by using currently available small molecules to their advantage. “Repurposing an old drug that is off-patent has the benefit of potentially making a very cheap drug available to patients,” Kissler says. “Because a repurposed drug does not have to undergo lengthy preclinical development and the many stages of toxicity and safety testing, its cost can remain low.”

Though scientists have developed methods of creating insulin-producing cells by resetting the pluripotency of blood and skin cells – allowing them to be converted into pancreatic beta cells – the risk of their destruction by the immune system still remains. With this in mind, Kissler and his colleague Peng Yi at the Joslin Diabetes Center are investigating how a drug first developed in the 1950s could prevent the autoimmune killing of beta cells.

Using a genetic screening approach, the researchers discovered an enzyme, renalase, that had previously been associated with the risk of type 1 diabetes, but whose function in disease was unknown. They found that the enzyme modifies beta cells’ ability to withstand cellular stress and autoimmune killing (7).

“We went on to search for a small molecule that could inhibit renalase function to mimic the protection we observed in cells whose RNLS gene we had inactivated with a mutation,” Kissler says.  “This search yielded the drug pargyline, which was developed as a treatment for hypertension. Although it is no longer being made, the patent has long since expired, which should make it inexpensive to produce.” The team now plan to test the drug in newly diagnosed diabetic patients but, because this drug and others like it are not specifically designed to treat diabetes, questions arise as to the challenges associated with their use.

“Because the drug was originally designed for a different purpose – in this case, the treatment of hypertension – one has to make sure that the original effect of the drug does not pose a safety issue for the new application of the drug,” Kissler says.

In the years to come

Whether companies and researchers are pursuing new drugs or repurposing old ones, funding is still vital. Walker says that sustained funding – particularly for those in academic environments – is crucial to making headway in diabetes research.

“High-quality research takes time and, therefore, requires consistent funding to help move it forward,” she says. “I have been lucky to have received long-term support, enabling me to build a sustainable program of work. Ultimately, there is a human capital that goes into making research findings and it would be hugely satisfying to  take this project to the point where people can benefit.”

Although new therapeutic solutions will help inform the future landscape of diabetes management, Mazumdar-Shaw believes that digital therapeutics will also help “achieve optimal outcomes for diabetic patients.” These software-driven interventions are currently used across a variety of disease indications to help patients manage the conditions they live with. She says, “Digital therapeutics will emerge as part of the new standard of care for diabetes. By pairing insulin with a digital solution we hope to improve treatment outcomes thus lowering the chances of patients developing co-morbidities, which will reduce costs to healthcare systems in the long term.” 

The biggest question of all, however, is: will a cure for diabetes be found in our lifetimes? Kissler is optimistic. “It’s definitely possible. We all look forward to working on this with optimism, knowing that there may be failures and challenges ahead, but hoping that we can help cure all forms of diabetes as well as their complications.”