In a key clinical trial, an experimental drug delays type 1 diabetes | Science

Marking the culmination of a 33-year odyssey, scientists today report a milestone in type 1 diabetes: the first time that the disease is significantly delayed in high-risk youth. During the presentation at the meeting of the American Diabetes Association in San Francisco and the simultaneous publication in the New England Journal of Medicine, the researchers found that two weeks of experimental intravenous treatment delayed the two-year disease on average.

The basic treatment for type 1 diabetes is insulin, discovered 97 years ago. These results open a new chapter, says Jeffrey Bluestone, an immunologist at the University of California at San Francisco and part of the research team. "On the one hand, the result is" rather exciting, "says Bluestone. "On the other hand, the real work begins now." This will involve considering how to advance this treatment and determine who it is most likely to help.

The clinical trial began 8 years ago and included 76 people, the youngest of whom was 8 years old and the oldest in their forties. Nearly three-quarters were 18 years old or younger. Everyone had an extremely high risk of type 1 diabetes. In this autoimmune disease, the body attacks the pancreatic cells that make insulin, which helps control blood sugar levels. By the time diabetes is diagnosed, most of these insulin-producing cells, called beta cells, have disappeared.

In the United States, more than one million people have type 1 diabetes, which requires constant attention to blood glucose and insulin injections to stay alive. The disease carries a risk of long-term complications, including heart disease, blindness and kidney failure. (People with type 2 diabetes, more common, usually produce their own insulin, but their body can not use it properly.)

Over time, scientists have learned that type 1 diabetes begins years before it is diagnosed. The subtle attacks on the pancreas are directed by the sentinels of the immune system, the T cells. These attacks are detectable via antibody markers in the blood. During this quiet battle, the beta cells of the pancreas are still largely intact, providing a crucial window in which to intervene and save them.

When researchers began to predict the risk of diabetes in people whose loved ones had the disease, prevention was the next obvious step. But a series of preventative tests conducted in the US and Europe – ranging from oral insulin to high doses of a vitamin B form – has proven daunting: although There are signs of hope in some subgroups of people, no study has been successful. . "This field has been completely disappointing," says Kevan Herold, endocrinologist at Yale University, who led the new clinical trial.

It was a flourishing friendship between Herold and Bluestone several decades ago, while they were both newly struck researchers at the University of Chicago, who set the stage for scientific success. Bluestone had designed an anti-activated T-cell antibody in his laboratory. To do this, it targets a molecule called CD3 on the surface of cells. By annihilating activated T cells, this anti-CD3 antibody could stop autoimmune attacks, Bluestone thought.

When he started work, Bluestone devised therapy to treat kidney transplant recipients because the body's T cells often attack a new organ. However, effective drugs for transplant patients had just arrived on the market and pharmaceutical companies were not interested. "He was abandoned," says Bluestone.

Herold has launched another idea for Bluestone. And if anti-CD3 could counter the attacks of T cells on the pancreas, which lead to type 1 diabetes? In the early 1990s, they injected anti-CD3 antibody into a mouse model of diabetes before the animals became ill. The treatment prevented many of them from developing diabetes.

Another highlight came in 1994, when French immunologists Lucienne Chatenoud and Jean-François Bach of Necker Children's Hospital in Paris reported that anti-CD3 reversed diabetes in newly diagnosed mice. The couple also indicated the timing of the treatment: it seemed to work better in animals whose T cells were stimulated and about to be attacked by the pancreas, and about to become or had developed diabetes. "If you do not have a lot [T cell] For activation, nothing is blocked, "says Jay Skyler, endocrinologist at the University of Miami and a member of the test team reporting today. "If you leave too late, it's too overwhelming" for the drug to succeed.

In 2000, Herold went from mice to people – but prevention research with anti-CD3 came with ethical concerns. Efforts to predict who would develop diabetes were nascent, and the idea of ​​giving a potentially risky experimental drug to people who might never get sick was worrying. In addition, diabetes is a childhood disease – half of patients are diagnosed before the age of 12 – complicating the ethical dilemmas of prevention trials.

Herold therefore focuses more on newly diagnosed people. His hope was that the anti-CD3 could help preserve the few beta cells that they still have, which would be destroyed as their disease progresses. This conservation, he concluded, could mean injecting less insulin and better controlling glucose levels. His team reported in the 2002 New England Journal of Medicine that more than a year after treatment, nine of the 12 treated patients had maintained or increased their insulin production. Other tests on anti-CD3 antibodies have progressed in newly emerged patients and have been largely successful.

And then, in 2010, the program was stopped: Two pharmaceutical companies announced that two different anti-CD3 antibodies, one of which had been designed by Bluestone, had not achieved their goals in large trials. scale on newly diagnosed people. "It was devastating," says Bluestone. "Everyone sort of said," OK, that does not work. "

Still, Herold, Bluestone, Skyler and a few others were optimistic about skepticism. In particular, they claimed that the pharmaceutical laboratories' trials were too low and included participants who did not have the autoimmune form of diabetes.

Herold has convinced a network of clinical trials on diabetes called TrialNet, which Skyler later chaired, to support a study to prevent anti-CD3 antibodies. It opened to volunteers in 2011 and tested the version of Bluestone, then called teplizumab. The trial team focused on the recruitment of mouse-like individuals that Chatenoud and Bach had successfully found years earlier: those with a combination of unstable blood sugar and antibodies in the body. blood shaking at the dawn of diabetes. Based on this combination, the researchers estimated that participants had a 75% chance of getting diabetes over the next 5 years. They were identified by an extensive network of screening centers in North America, Europe and Australia, set up years ago by TrialNet, which aims in part to trace the natural history of diabetes-type 1 and includes thousands of parents of people with the disease.

Forty-four volunteers received teplizumab and 32 received placebo. Treatment in both groups included an intravenous infusion of 14 consecutive days. The inscription was slow. Screening was laborious and, according to Herold, there may have been some hesitation, as other prevention trials had failed, as had teplizumab as part of a study conducted by a large pharmaceutical company . The planned trial of 144 people was reduced to 76, which means that teplizumab had to shine so as to differentiate between treatment and placebo.

At the end of last year, Herold procrastinated when badyzing the data. "I kept pushing," he says, because he worried about failure. Instead, the difference between the two groups was statistically striking. In the treatment group, the median time to diagnosis of diabetes was just over 4 years; in the placebo group he was 2 years old. Forty-three percent of those who received the experimental drug developed diabetes after five years, compared with 72% of those receiving placebo. Participants with teplizumab and carriers of certain gene variants appeared particularly likely to avoid the disease.

"I thought it would be difficult" to show an effect with so few patients, says Chatenoud, who did not participate in the trial. "That's why I think it makes so much sense that it worked … These data are the first to show that it is possible to prevent the progression of type 1 diabetes."

Although some researchers have described the study as a prevention trial, Herold is quick to point out that it was designed, strictly speaking, to check for delayed onset, not prevention. Preventing testing may mean waiting for participants to die to confirm that they do not have diabetes, which is obviously impossible. Yet he and others wonder if there is a subset for which real prevention is possible; it will take several years to find out.

Doctors say that even a two-year delay in the disease is important. "Living two years without insulin, … I think it's important," says Mark Atkinson, a pathologist at the University of Florida's Institute of Diabetes in Gainesville, who investigated the origins of the disease and conducted trials. clinics. "You have to think of mom or dad who are 2 years younger than getting up at night" to check their child's blood sugar level, he adds, and a potentially lower risk of complications long-term. Two weeks of teplizumab "is a small price to pay" for extra time without diabetes, he says.

This is especially true because teplizumab's safety fears in the early years have not disappeared. Chatenoud says that, to date, more than 800 people have received the treatment and that "the side effects are not what people feared". During the trial, common side effects included rash and decreased white blood cells; both resolved in a few weeks.

The big question now is, what's next? Some think that it might be difficult to conduct a larger scale trial on the prevention of teplizumab, as giving a placebo to young people might be difficult to justify now. One of the main hurdles is that even though Herold's trial focuses on people with a first-degree relative with diabetes, at least 85% of people with diabetes do not have this family history, which means that a large-scale screening would be needed to reach everyone. at risk. "Who will pay for this? And will the public even participate? Wonders Atkinson.

The next steps will come in part from the company that currently holds teplizumab rights, Provention Bio, in Oldwick, New Jersey; experimental treatment has been in the hands of many companies over the years.

No matter what happens next, Herold hopes his study will mark a turning point. He thinks of the first test volunteer, who enrolled at Yale's Herold Center. At the time, the teenager was in college; after graduating, he moved to New York. By the time Herold finalized the test data, he noticed that this participant, whom Herold would later learn he had obtained teplizumab, had disappeared from the surveillance.

"I called him and said," What's going on? "" Remembers Herold. Not much, admitted the young man. he felt good and forgot to follow up with the researchers. It was an answer that delighted Herold. "It's great, it's great," he thought. Forgetting is what people with diabetes can not afford – so for this young man who does not suffer from illness, it meant everything.