The U.S. Food and Drug Administration (FDA) regulatory review is now under way for teplizumab—a therapy that blocks the blood marker CD3, which activates immune cells—to prevent or delay type 1 diabetes (T1D) in at-risk individuals. The target action date is July 2, 2021.

Teplizumab could become the first disease-modifying therapy approved for T1D.

Breakthrough T1D had a hand in the development of teplizumab from nearly the beginning:

Teplizumab, now called PRV-031, is also being tested in a phase III clinical trial in people who have been recently diagnosed, headed by Provention Bio, a company with an investment from the Breakthrough T1D T1D Fund.

If successful, and the FDA review results in approval, we will be moving ever closer to a world without this disease.

Many scientists enter their fields hoping that their work will directly impact people’s lives. That is exactly what Thomas Kay, M.B.B.S., and Helen Thomas, Ph.D., at the St. Vincent’s Institute of Medical Research (SVI), in Australia, wanted to do for type 1 diabetes (T1D).

Through their research, they discovered that inhibition of a protein, called JAK, may work in slowing down or preventing beta cell loss.

JAK—otherwise known as Janus kinase—is critical to signaling pathways within both immune cells and beta cells in T1D. It is therefore a very attractive target for the correction of both immune and beta cell defects in T1D.

Kay and Thomas now have a clinical trial, funded by Breakthrough T1D, to find out if a JAK inhibitor, called baricitinib, will preserve beta cell function in children and young adults with recently diagnosed T1D. (It’s called BANDIT, which stands for BAricitinib in New-onset type 1 DIabeTes.)

“It is tremendously exciting for us to be the first group anywhere in the world to test the efficacy of baricitinib as a potential type 1 diabetes treatment,” says Dr. Kay. “Our BANDIT trial will determine if the treatment can protect insulin-producing cells of people recently diagnosed with type 1 diabetes from further immune attack. If it proves successful, production of insulin will be maintained and people with type 1 diabetes will be significantly less dependent on insulin treatment. Making more insulin after diagnosis of diabetes has benefits that are increasingly recognised.”

JAK inhibitors are a type of therapeutic that do what the name says—stop or inhibit the activity of a JAK protein in your body.

It is a bench-to-bedside research project—that has gone from basic research at the laboratory through a clinical trial in people with T1D—that Breakthrough T1D has had a hand in for more than a decade.

“We are very excited to support this trial, led by Dr. Thomas Kay and colleagues,” says Simi Ahmed, Ph.D., director of research at Breakthrough T1D. “We are grateful to Eli Lilly and company for providing the investigational drug, and to our colleagues at Breakthrough T1D Australia for their partnership in launching this trial.”

Preservation of a Body’s Own Beta Cells

The trial aims to recruit approximately 85 participants, aged 12-30 years, who have been recently diagnosed with T1D and will test if baricitinib can slow the loss of insulin-producing beta cells in people with the disease.

Baricitinib is already approved for the treatment of rheumatoid arthritis and is currently in clinical trials for other autoimmune diseases (T1D is an autoimmune disease, too). This is because JAKs are often associated with over-reactive immune systems. Recently, the FDA approved it in combination with remdesivir for the emergency treatment of people who have been hospitalized with severe COVID-19 and whose immune systems are on over drive.

Other JAK inhibitors have been approved for treating blood cancer, which is a cancer of the immune system. This is the first time, however, that a JAK inhibitor is being tested in T1D.

A Reversal of T1D. Wait…What?!?

One might say that T1D can’t be reversed. Well, that’s not true now.

On October 8, a letter to the New England Journal of Medicine revealed that doctors had reversed T1D in a young man. This was a precision medicine treatment that corrects the effect of a mutation of a gene product that is directly activated by JAKs, and he has been off insulin treatment for more than 2 years.

What drug was it? Another JAK inhibitor. (This time, it was ruxolitinib.)

We don’t know whether JAK inhibition will help others with T1D, who don’t have this genetic mutation. However, we do know that cell pathways that involve the JAKs are aberrant in T1D and in many other diseases. We’ll have to see the results of this clinical trial to know.

“Breakthrough T1D remains very hopeful that the results will propel future commercial development of this class of therapies for type 1 diabetes,” says Ahmed.

Stay tuned.

Clinical Trial Information

If you are interested in participating in the BANDIT (BAricitinib in New-onset type 1 DIabeTes) trial, contact the trial coordinator via email at [email protected] or by mobile on +61 3 0450 323 962 in Australia.

Targeting Immune Cell Protein May Prevent Type 1 Diabetes

Immune cells are so clever. They can detect any foreign material that they encounter. They have memory and will remember past invaders. But they can also be destructive, harming the body’s own tissues, and memory is a known culprit.

Repeated encounters with a known molecule—called an antigen—in the body are a key feature of autoimmunity, including type 1 diabetes (T1D).

But what if you could halt immune cell memory? Meaning that you can present the immune cell to an antigen that it’s already seen, and it remains inactive.

Breakthrough T1D-funded researchers have discovered a protein on immune cells that, when it is disabled, might just do that. It’s called OCA-B.

Normally, OCA-B helps ensure that immune cells can easily be reactivated if they reencounter the same antigens at a later date. But blocking the activity of OCA-B put the immune cells in a non-responsive state. What’s more: Those that were prone to developing T1D were protected from the disease if they lacked OCA-B!

These results were published in the Journal of Experimental Medicine. Breakthrough T1D-funded researchers who were involved include the lead author, Dean Tantin, Ph.D., Brian D. Evavold, Ph.D., Danny H.-C. Chou, Ph.D., three of whom have received grants from Breakthrough T1D, and all based at the University of Utah.

When Breakthrough T1D was founded in 1970, there were no types of diabetes. There was no type 1, no type 2, no gestational (which, as we now know, happens when you are pregnant). It was all diabetes.

Until 1974. Two teams showed—for the first time—that insulin-dependent diabetes is associated with the development of antibodies directed against insulin-producing beta cells in the pancreas.1,2 This was instrumental in establishing type 1 diabetes (T1D) as an autoimmune disease.

Using this, investigators were able to:

1. Describe the presence of more antibodies, besides the islet cell antibodies, that were associated with type 1 diabetes. There are now 5 antibodies connected with the disease.

 What’s more, studies have shown that T1D begins well before its symptoms appear—and it includes the presence of 2 or more T1D-specific antibodies. This allowed us to conduct clinical trials before the presence of symptoms, to prevent or delay the progression to clinical onset of the disease.

2. Refine the tests for T1D-related antibodies, for more widespread study. This led to TrialNet—an international NIH-funded and Breakthrough T1D-supported network of leading academic institutions, endocrinologists, physicians, scientists, and healthcare teams dedicated to finding cures for T1D—who began its Pathway to Prevention study in 2004. This study identifies people at risk for T1D with the aim to conduct clinical trials to stop the disease.

3. Conduct clinical trials targeting several immune pathways and mechanisms, including teplizumab—a drug that blocks CD3, a blood marker that helps activate immune cells. In a clinical trial conducted by TrialNet, it was the first study to significantly delay the onset of T1D, for nearly 3 years, in individuals at-risk of developing the disease.

Recently, Breakthrough T1D also launched a community-based education and awareness program to expand screening to the general population. The program’s aim is to make people understand what type 1 diabetes is, how screening is advantageous to the public, how they can be involved, and what to do if you are positive for T1D-specific antibodies.

Learn more about the Breakthrough T1D Early Detection Program.

  1. Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974 Nov 30; 2 (7892): 1279-83. PMID: 4139522.
  2. MacCuish AC, Irvine WJ, Barnes EW, Duncan LJ. Antibodies to pancreatic islet cells in insulin-dependent diabetics with coexistent autoimmune disease. Lancet. 1974 Dec 28; 2 (7896): 1529-31. PMID: 4140978.

In the words of Colin Dayan, M.D., Ph.D., professor of clinical diabetes and metabolism at Cardiff University: “Type 1 diabetes is almost the only major autoimmune disease now that does not have a licensed immunotherapy.” And he’s going to change that.

Dr. Dayan conducts clinical trials in the development of immune therapies, which aims to re-train the immune system to stop the attack on insulin-producing beta cells. These therapies could be given to people when they are first diagnosed with type 1 diabetes (T1D), and still have surviving insulin-producing cells, or when they have a high risk of T1D, before their insulin-producing cells have been destroyed, to try and stop the condition from developing (as is the case with the immune therapy teplizumab, which was able to delay T1D for nearly 3 years).

Dr. Dayan set up the Type 1 Diabetes UK Immunotherapy Consortium (T1D UK), backed by Diabetes UK and Breakthrough T1D, to coordinate immunotherapy trials and improve the way in which they are carried out. So far, the consortium has increased the number of people with T1D taking part in vital clinical trials ten-fold, and is paving the way toward cures.

But what keeps him motivated as a scientist? People with T1D.

“Just one hour in the clinic reminds me why this work is important,” says Dr. Dayan, “and when I meet a person who has just heard that they have been diagnosed, I long to be able to offer something different from the treatments we already have.”

So do we.

Find out from his video why being a clinician is both challenging and gratifying in T1D research:

Breakthrough T1D’s funding enables promising scientists, like Colin, to focus their talent, ambition and passion on improving life with T1D. Learn more about the researchers we fund, and learn how you can support their work to prevent, treat and—one day—find cures for T1D.

Last year, at the American Association for Diabetes (ADA) Scientific Sessions, a drug, called teplizumab, was able to significantly delay—for over two years—the onset of type 1 diabetes (T1D) in participants with a high risk of developing the disease. This was the first ever study in humans to show a delay in the onset of T1D. But it doesn’t stop there. Breakthrough T1D has updated results, and this is big. The investigators were able to follow up on the individuals who didn’t develop clinical diabetes, and the effect of teplizumab had been sustained: 50% of those treated with teplizumab remain diabetes-free, compared to only 22% of those taking placebo, and the delay in diabetes onset was close to 3 years (35 months). These were presented by Emily Sims, M.D., an assistant professor of pediatrics at Indiana University and a Breakthrough T1D-funded investigator, at ADA’s Scientific Sessions.

Additionally, the participants, both the teplizumab and placebo groups, had a progressive decline in the biomarker that measure’s the body’s ability to produce insulin—C-peptide—preceding the trial. But the teplizumab team found that production of C-peptide actually went up following treatment with teplizumab, especially in the first 6 months after treatment. Like, teplizumab could reverse the downward trajectory of C-peptide loss that was there before the trial.* Um, wow. And there’s more: the increases in C-peptide were correlated with induction of a state of “exhaustion” in “bad” immune cells. Like, they literally took a punch and lost the ammo to keep on attacking the beta cells. Wow (again).

So, could the exhaustion of “bad” immune cells result in not getting T1D or significantly slowing down the time to getting it? Well, we’re not there yet, but we’re close, and closer to a day when T1D might be prevented, forever.

Breakthrough T1D Leadership: Breakthrough T1D funded one of the first clinical trials of this drug, results of which were integral to the teplizumab prevention trial. The study in this report was conducted by TrialNet, a T1D trial consortium funded by NIDDK and by the NIH’s Special Diabetes Program for which Breakthrough T1D is the leading advocate. Multiple studies involving samples and data from teplizumab trials have continued to receive Breakthrough T1D funding. Teplizumab (now called PRV-031) is currently being tested in a phase 3 clinical trial in people recently diagnosed with T1D, headed by Provention Bio, a company with an investment from the Breakthrough T1D T1D Fund. If successful, this could become the first immune therapy approved for T1D.

*In the placebo group, C-peptide still declined.

Carla Greenbaum, M.D., chair of TrialNet—an international Breakthrough T1D-supported network that is dedicated to finding cures for type 1 diabetes (T1D)—and a professor at Benaroya Research Institute, discussed T1D research in the time of COVID-19, including what TrialNet is up to, on Breakthrough T1D’s Facebook Live event. She chats about:

Watch the full, recorded livestream below:

The idea of heterogeneity—a disease having different or diverse pathways to the same disease type—has been gaining ground in type 1 diabetes (T1D). It was iterated by almost all of the presenters at the 12th Network for Pancreatic Organ Donors with Diabetes (nPOD) Annual Meeting (February 23-26), and a new publication gives further support to the concept as a way to better understand T1D. In the paper, Breakthrough T1D-funded researchers—including Sarah Richardson, Ph.D., and Richard Oram, MBBCh, of the University of Exeter—found that T1D is comprised of two different subtypes, called endotypes by the scientific community, which are dependent upon the age at diagnosis.

The researchers used samples from nPOD and the Exeter Archival Diabetes Biobank (EADB), and looked at co-localization of insulin and proinsulin—the precursor to insulin—in the pancreas. They found that people under the age of 7 do not process proinsulin properly, leading to a highly aggressive attack on beta cells. The investigators propose this aggressive subtype should be defined as “type 1 diabetes endotype 1” or T1DE1. People diagnosed at 13+ years of age have lower levels of infiltrating immune cells and they retain more insulin-containing islets. Investigators call this subtype “type 1 diabetes endotype 2” or T1DE2. The field is now working hard to figure out which T1D pathways govern this.

In clinical research, the authors say, it will be important to design future immune therapies based on the distinct endotypes of T1D.

Breakthrough T1D funded other authors of the study, as well, including Andrew T. Hattersley, FRS, Noel G. Morgan, Ph.D., Bart O. Roep, Ph.D., and Timothy I. Tree, Ph.D.