Teplizumab is a proposed treatment which, if given to someone at-risk for type-1 diabetes (T1D), can delay or possibly prevent the onset of T1D symptoms. At-risk has a specific meaning here: it is someone who has tested positive for two or more autoantibodies for T1D, but has not yet shown symptoms of T1D (i.e. a lack of blood glucose control). These are people not yet in their honeymoon phase. In TrialNet terminology, they are in stage 1 of T1D. Teplizumab works by targeting one specific part of the immune system which is involved in the attack on beta-cells which leads to T1D.
Scientifically, Teplizumab is a monoclonal antibody targeting CD3. What does that mean? It means Teplizumab starts out as an antibody aimed at neutralizing a specific part of the immune system called CD3. Because CD3 is part of the process that leads to type-1 diabetes, the hope is by neutralizing it, T1D can be delayed or maybe even prevented. Provention Bio starts out with one of these cells, and clones it repeatedly to create a large number of cells, all of which target CD3 (and only CD3) in exactly the same way. This is a very common way to create new medicines. Roughly 1/3 of the new medicines approved in recent years have been monoclonal antibodies. If you see a treatment with a generic name ending in "mab" that is a Monoclonal AntiBody.
The full history of Teplizumab is long and complex, and I covered it in a previous blog:
https://cureresearch4type1diabetes.blogspot.com/2019/09/teplizumab-phase-ii-results-for.html
As very quick summary is as follows: Teplizumab was developed in the 1990s, and had its first clinical trial 1999-2005. In 2008 it started a phase-III trial, which could have led to approval, but was unsuccessful, and was stopped in 2010. A similar treatment, also targeting CD3, was also in phase-III trials at the same time and was also unsuccessful. Other clinical trials on Teplizumab continued however, and in 2018 a different company, Provention Bio, restarted clinical trials. Provention believed that the previous phase-III trials had failed because of a poor choice of primary end point (i.e. they measured the wrong thing to prove success).
In 2019, Provention Bio announced plans to submit Teplizumab for FDA approval based on three sets of data: 1. from the long ago completed studies. 2. from the long running, recently completed study, and 3. from their own recently completed study.
Press Releases:
These proceedings are described from Provention's point of view by various press releases here:
http://investors.proventionbio.com/news?l=100&year=2021
I'm not going to describe the back-and-forth, except to point out that it lasted 9 months.
I'm going to discuss why the approval of Teplizumab is important from two different points of view. First the "tactical", how it would change the life of families with T1D right now, and second the "strategic", how it would change the research landscape of trying to cure T1D.
For the tactical part of the discussion, I'm going to assume that Teplizumab does exactly what the existing research says it does: delay the onset of T1D by about 3 years on average. I think that will have two important good effects. First, I think, in some cases, delaying the onset, even for just 3 years, is a good thing all by itself. In practical terms, that means that someone who would normally be diagnosed in college, might actually be diagnosed after college. Or someone in high school might be diagnosed in college. Everything I've heard from families diagnosed in the teenage years, is that later diagnoses would be better. I don't think this would be true for everyone. My daughter was diagnosed at 18 months, and I actually think it would have been worse to be diagnosed at 4 years, but for many families, a delay would be a good thing. If approved, Teplizumab would give families and patients that choice.
Second, I think that a 3 year delay may cushion the psychological impact of diagnosis. Right now, a person goes from healthy to having a chronic, incurable disease in a week or two. As a parent, I experienced this shock, and it was very jarring, but I'm sure it is much worse for the patients themselves. Teplizumab would give people a few years to transition from not-T1D to T1D. We have no experience with this, but I'm hopeful that it will lead to better psychological outcomes, because people will have more time to adjust.
The approval of Teplizumab will also have a huge impact on future research aimed at curing T1D. For example:
Right now, there is a lot of uncertainty, in terms of getting drugs approved to cure T1D. Since no drug has been approved, no one knows (for sure) how much evidence the FDA will require in order to do the approval. We can read generic FDA policy documents, but it is not the same thing. But if Teplizumab is approved, then from now on, everyone will know how much data is required and what results are good enough. This makes the whole approval process less risky. And less risky means more companies will try.
Second, the first drug approved to treat a disease, is almost never the best drug. Once one is approved, improvements follow. So I think it is fair to view Teplizumab as being the first in a series of improving drugs. Having one drug, makes the development of other drugs easier in several different ways. It shows researchers where to focus their efforts, it encourages more researchers to enter this field, and it shows companies how much money is available.
Third, I think it will encourage people to participate in trials like TrialNet. One of the things I hear over and over is parents who say "Why should I participate in TrialNet, even if they tell me my son/daughter will get T1D, there is nothing we can do." Right now, that is not true because they can participate in research, but if Teplizumab were approved, then it would be even less true, because they would have the option of delaying their T1D.
Definitions
[d1] The technical term for this is "disease-modifying" treatment. This
is very different from a treatment like insulin which treats the
symptoms, but does not change the underlying cause of the disease.
Teplizumab has the potential to change T1D itself in ways that insulin
does not.
[d2] This is called "pharmacokinetics/pharmacodynamics" (or PKs/PDs) which refers to how quickly a medicine is absorbed into the body, how quickly it is distributed to different parts of the body, and how quickly it is used up.
[d3] To over simplify a little, the FDA regulates three things: drugs, biologicals, and devices. Drugs are chemicals, biologicals are cells and parts of cells, devices are electromechanical objects. Since Teplizumab is a cloned cell, it is a biological. The rules for approval for drugs and biologicals are similar. The rules for devices are different and generally "looser". The concept of a "generic" applies only to drugs, since the 1960s. The same idea for biologicals is called "biosimilar" and has been in use only since 2015. Devices do not have anything similar to generics or biosimilars for other companies, but do have a simplified approval system for newer versions of a previously approved device.
