FDA approves teplizumab to delay type 1 diabetes onset

Kevan Herold, MD

We are very excited about the approval of teplizumab. This has been a long time in coming beginning with preclinical studies three decades ago. I like to think of this as the beginning of a new frontier for the prevention and perhaps treatment of type 1 diabetes – to stop the disease from eliminating all beta cells. There is much work still to be done but this approval opens the door on our path to reaching that goal.

The recent approval by the FDA of teplizumab represents exciting passage past a major milestone along the road to prevention and reversal of type 1 diabetes. It has been known for decades that type 1 diabetes results from an unwanted attack in people with the disease by their own dysregulated immune cells on the insulin-producing beta cells in the pancreas.

The trick here has been to find an immunomodulatory drug that would prevent the immune system from attacking one’s own beta cells, but not interfere with the immune system’s principal function: protecting people from infection with viruses, bacteria and other pathogens. This has proven far more difficult than most diabetes researchers had hoped or predicted. The road to effective immunomodulatory therapy of type 1 diabetes is littered with failed attempts over several decades, so this is cause for great celebration.

But much more work remains. For example, teplizumab delays disease onset by several years in some high-risk individuals — meaning close relatives of people who already have established type 1 diabetes — but it does not work in all. It is also unknown how long this preventive effect will last in those whose disease has been prevented. As another example, volunteers enrolled in the study received a single 2-week treatment course, and subjects were followed for 5 or more years. This was effective in many people, but begs the question whether prevention would have been more effective in those who did not respond, if they had had a second dose 6 or 12 or 24 months after the first. As another example, might teplizumab be an even more effective preventive drug if it were combined with other immunomodulatory drugs that work through complimentary mechanisms? These questions and many others are no doubt being addressed by the investigators.

The study was performed in subjects who were at risk, but had not yet developed type 1 diabetes because the goal of tepilizumab treatment is prevention of anticipated disease, not treatment of established disease. It is not likely that tepilizumab will return high glucose and low insulin levels to normal, reversing established type 1 diabetes. This, in turn, is because insulin-producing beta cells, once lost, cannot regenerate. Thus, restoring a depleted “beta-cell tank” will require replacing beta cells through pancreas, islet or stem cell transplants, or through the use of beta-cell regenerative drugs, such as harmine, first identified and developed by our laboratories at Icahn School of Medicine at Mount Sinai, and currently in early-stage human trials. Part of the excitement in the teplizumab story is that it may predict a future when type 1 diabetes can not only be prevented by teplizumab, but also reversed by a combination of teplizumab together with beta-cell regenerative drug treatment.

It is important to understand that subjects enrolled in this project were selected because they were at high genetic risk: They had a close relative with type 1 diabetes. This highlights the facts that type 1 diabetes is, to some extent, genetic. But many people with type 1 diabetes have family trees that are devoid of the disease. This and other data highlight the point that not all type 1 diabetes is the same — there are likely multiple varieties. Thus, one must ask, “Is teplizumab the right treatment for all people with type 1 diabetes, or is it best used in particular (as yet undefined) subsets of people in early stages?” At present, we have no answer to this important question.

Another important concern with any immunosuppressive treatment is safety, particularly with respect to infections with bacteria, for example, pneumonia, or viruses, for example mononucleosis. In studies to date, this risk seems low, probably reflecting the moderate dose and brief teplizumab treatment duration. This concern will no doubt be followed carefully by the researchers and regulators as teplizumab use expands and will also play into the design of future studies.

Finally, it is important to note that this work was driven by individuals and groups of academic investigators at universities with decades of support from the government: NIH, the National Institute of Diabetes Digestive and Kidney Disease and its TrialNet Program, as well as private foundations such as JDRF. As success became apparent, and as the project has increased in cost and scale, commercial entities, such as Provention, have expanded the scope and scale of the research, so that it can finally reach its target population: people at risk. These are exciting times, indeed, and the teplizumab story is a beautiful illustration of how the federally and privately funded basic, translational and clinical research pipeline can progress to pharma and eventually to people with unmet medical needs such as those with type 1 diabetes.

Andrew F. Stewart, MD

Director of the Diabetes Obesity and Metabolism Institute

Professor of medicine, endocrinology, diabetes and bone disease

The Icahn School of Medicine at Mount Sinai

Adolfo Garcia-Ocaña, PhD

Professor of medicine, endocrinology, diabetes and bone disease

The Icahn School of Medicine at Mount Sinai

Robert J. DeVita, PhD

Professor in the department of pharmacological sciences

Director of medicinal chemistry

The Icahn School of Medicine Drug Discovery Institute