It’s an exciting time for type 1 diabetes (T1D) research with several big breakthroughs poised to make a significant impact on the lives of people with the disease, writes Dr Dorota Pawlak, chief scientific officer at JDRF Australia.
Up to the early 20th century, a T1D diagnosis meant a shortened lifespan and ultimately a death sentence. An autoimmune disease, T1D occurs when the immune system mistakenly attacks the insulin-producing beta cells of the pancreas. This leaves patients with insulin deficiency and without the ability to regulate blood glucose levels, which, left untreated, can causes serious and often fatal complications.
The outlook changed in July 1921 at the University of Toronto, when Canadian doctors Frederick Banting and Charles Best achieved a breakthrough, successfully isolating insulin from canines. A mere six months later, insulin was administered to the first ever human patient with severe diabetes: 14-year-old Leonard Thompson.
This year marks the 100th anniversary of this game changing discovery. The impact of insulin on the lives of millions around the world cannot be understated.
Today, more than 120,000 Australians use insulin to treat T1D and keep their blood glucose levels within target range, avoiding life-threatening complications in the process. While insulin is undoubtedly a lifesaving, clinically important drug, it’s also still the only available treatment option for the disease, 100 years on. Plus, its administration through multiple daily injections or bulky devices can have a big impact on the lives of people who depend on it.
With this in mind, it’s unsurprising that this significant milestone is bittersweet for much of the global T1D community. A recent report titled ‘The Challenges of T1D’ found that 95% of Australians living with T1D saw living with the disease as a burden.1 More than half experienced feelings of depression.
As many of you will have seen in your careers, living with T1D requires significant management, planning and understanding. The opportunity for pharmacy is to continue to be a supportive healthcare professional through the patient’s life stages and maintain a watching brief on advances, as some of the most exciting advancements are pharmacological.
Closing in on a cure
There are no approved disease-modifying therapies for T1D, but several promising candidates have been identified that can prevent beta cell loss, or even restore the body’s natural insulin production.
The most high-profile of these is teplizumab, an anti-CD3 monoclonal antibody currently under priority review in the US. In late-stage clinical trials, teplizumab was shown to delay the onset of clinical T1D by three years in people at high risk of developing the disease. Patients receiving teplizumab also had increases in C-peptide levels, indicating that the drug restores natural insulin production in the early stages of T1D, essentially reversing the course of disease.2
This breakthrough therapy is one of several that have begun human trials in the past few years. ATG (anti-thymocyte globulin) has been approved by the FDA for anaemia and preventing transplant rejection for more than 50 years. For more than a decade, research has been underway to investigate ATG as a potential therapeutic for T1D. In 2019, results showed that ATG can prolong the “honeymoon” phase—the period of early-stage T1D when some insulin production is retained—by two years.3 A next generation, humanised ATG has been developed in response to this, to be investigated in a clinical trial in 2021.
In Australia, the janus kinase (JAK) inhibitor baricitinib has shown a similar effect, extending the honeymoon phase of T1D in animal models. Baricitinib entered a clinical trial in 2020, the first study of its kind in Australia. Read more about this clinical trial in our interview with Professor Tom Kay, below.
Cell therapies—directly replacing the damaged beta cells with healthy insulin-producing cells—is another promising avenue for a functional cure for T1D. Until recently, islet transplants have been reserved for the most high-risk patients due to the scarcity of donor cells and the need for lifelong immunosuppression. Research is underway to address these limitations and make cell therapies for T1D much more accessible. Therapies like PEC-Direct, developed by ViaCyte, use pluripotent stem cells with the potential to differentiate into insulin-producing cells as an alternative cell source, encapsulating them in a vascularised pouch to promote engraftment. PEC-Direct is in clinical trials for high-risk T1D, with additional stem cell products in development that would also reduce the need for immunosuppressants.
Technology to make insulin treatment easier and safer
Insulin delivery and glucose monitoring systems are evolving, as technology like continuous glucose monitors, insulin pumps, and hybrid closed-loop (HCL) systems becomes more advanced and accessible. An HCL system uses a specialised algorithm to connect a continuous glucose monitor with an insulin pump, ensuring that blood glucose is monitored round the clock and precise amounts of insulin are delivered when needed.
HCL systems revolutionise T1D treatment by automating the delivery of basal insulin. Those using HCL technology have better glucose management, as well as improved mental health and quality of life, compared to those using traditional finger pricks and insulin injections.4 Now, the focus is shifting to making this life-changing technology available to those who will benefit from it the most, as well as enhancing its efficacy with additional therapeutics.
A clinical trial, CLVer, is assessing HCL technology in combination with verapamil—a repurposed pharmaceutical originally approved to treat blood pressure. In clinical trials in people with early-stage T1D, verapamil has been shown to reduce beta cell stress and stop cells from dying in response to the autoimmune attack.5 It’s hoped that in combination with HCL, verapamil can extend the honeymoon phase of T1D and preserve insulin production for longer.
It’s an exciting time for T1D research, with several big breakthroughs poised to make a significant impact on the lives of people with the disease. By continuing to support research, we can ensure that T1D treatment and prevention continues to evolve for future generations as well.
Find out more about T1D research at jdrf.org.au/research
If you’d like to read JDRF Australia’s report on The Challenges of T1D, it’s available to download at jdrf.org.au/100years
Tapping the potential of baricitinib to treat early-stage type 1 diabetes
Professor Tom Kay is director of St Vincent’s Institute of Medical Research in Melbourne, and principal investigator of the Baricitinib in new-onset T1D (BANDIT) clinical trial. BANDIT is investigating the JAK inhibitor baricitinib as a potential therapeutic for people with newly diagnosed T1D.
JAK inhibitors are widely used to treat other autoimmune diseases, including rheumatoid arthritis. Professor Tom Kay and his team at St Vincent’s Institute demonstrated that the JAK-STAT pathway is a critical part of immune-mediated beta cell destruction, and that blocking this pathway can prevent the development of T1D in mice. BANDIT is the first clinical trial in the world to repurpose a JAK inhibitor as a T1D therapeutic.
Here, Prof Kay shares more about the BANDIT trial and some of the JDRF-supported work leading up to this point.
What’s really exciting about the BANDIT trial?
T1D is an immune disease, but we still treat it by replacing insulin, not by addressing the underlying mechanisms. Insulin is essentially a band aid treatment for the disease. Momentum has been building to transform our approach to T1D treatment.
The BANDIT trial represents an opportunity to test a new treatment that may help people retain their insulin-producing capacity for longer, by protecting the cells from the immune system attack. If the trial is successful, the body will make more of its own insulin that will make T1D easier to manage.
How did your team first discover that baricitinib could be used to treat T1D?
My colleague and co-investigator on BANDIT, Professor Helen Thomas, and I have been working on understanding the pathways that control the immune response in T1D for more than three decades. That work has given us a lot of insight into what is happening in the immune system of people who develop the disease and has involved great support from JDRF over that time.
We found that blocking the JAK-STAT pathway could be useful for treating T1D, but our ways of doing this in the lab could not be used clinically in people. We had to wait for industry to develop drugs that target this same pathway—JAK inhibitors.
The drugs work virtually identically to the methods we used before, but give us the opportunity to test our findings in people with diabetes for the first time.
What outcomes are you hoping to see in this clinical trial?
We used JAK inhibitors in the laboratory to show that they would prevent immune cells from destroying insulin-producing beta cells. We found that the drugs do this partly by blocking effects of the immune system on the beta cell and partly by acting on the immune cells themselves. The fact that both are affected makes the treatment especially effective in our studies.
The drug we are testing has already been approved for the treatment of rheumatoid arthritis, so we know that it is safe and that it is effective in that disease setting. Our experimental results indicate that it modifies the course of T1D in the lab. We are hopeful that we will see the same effect in the trial participants.
What are the next steps for baricitinib after this trial?
We are hopeful that the results of the trial will be positive and that baricitinib or other related drugs will become approved for people newly diagnosed with T1D. We then will look at trials in people at different stages of the disease to test the disease-modifying effect. We imagine that the ultimate treatment for T1D might involve combining a number of different strategies and we will continue working on these in the meantime.
The BANDIT trial is funded by JDRF Australia through its Type 1 Diabetes Clinical Research Network. For more information, visit svi.edu.au/resources/bandit_trial/ or email firstname.lastname@example.org.
- Lonergan Foundation, 2020. JDRF Australia Study Report—Insights into T1D people in Australia.
- Herold KC, et al. T1D TrialNet Study Group. An anti-cd3 antibody, teplizumab, in relatives at risk for T1D. N Engl J Med. 2019 Aug 15;381(7):603-613. doi: 10.1056/NEJMoa1902226. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586.
- Haller MJ, et al. T1D TrialNet ATG-GCSF Study Group. Low-dose anti-thymocyte globulin preserves c-peptide, reduces hba1c, and increases regulatory to conventional t-cell ratios in new-onset t1d: two-year clinical trial data. Diabetes. 2019 Jun;68(6):1267-1276. doi: 10.2337/db19-0057.
- McAuley SA, et al. Six months of hybrid closed-loop versus manual insulin delivery with fingerprick blood glucose monitoring in adults with T1D: a randomized, controlled trial. Diabetes Care. 2020 Dec;43(12):3024-3033. doi: 10.2337/dc20-1447.
- Ovalle F, et al. Verapamil and beta cell function in adults with recent-onset T1D. Nat Med. 2018 Aug;24(8):1108-1112. doi: 10.1038/s41591-018-0089-4.