Teplizumab: Can We Delay the Onset of Type 1?
Provention Bio’s new injectable drug, which was recommended by an FDA committee for approval on May 25, 2021, has had a tumultuous journey through the FDA application process. Studies showed that teplizumab can delay the onset of type 1 diabetes – for people already at high risk – for two years or more.
Editor’s Note: After the FDA Advisory Committee meeting voted in favor of teplizumab's approval in May 2021, the FDA issued a Complete Response Letter (CRL). This letter addressed several concerns from the FDA and the Advisory Committee – specifically regarding a lack of comparability between the intended commercial product and the drug product used in clinical trials. This temporarily halted the process for teplizumab’s approval until all the concerns were addressed.
Since the CRL was issued, the drug manufacturer, Provention Bio, has worked to address the FDA’s concerns, and it has conducted an additional study (using a subset of participants enrolled in the ongoing phase 3 PROTECT trial) to address the concerns regarding drug comparability. The company resubmitted the marketing application to the FDA before the end of March and in March 2022, the resubmission was accepted by the FDA.
What follows is an update of the article that diaTribe published at the time of the May hearing to answer basic questions about the medication and the ongoing approval process.
What is teplizumab?
Rarely does one get to witness the potential for an entirely new therapeutic or preventive drug to come onto the medical horizon. But that is the threshold we have now reached with the possible upcoming FDA approval of the first drug to delay the onset of type 1 diabetes (T1D) – teplizumab – in high risk individuals.
Teplizumab is a drug (specifically, an anti-CD3 monoclonal antibody) that binds to cells in the immune system called T-cells (these are one type of infection-fighting cell). Scientists hope that teplizumab will change the T-cells in a person’s body so that autoimmunity – or the destruction of body tissue by one’s own immune system – is reduced. This would hopefully reduce the damage and destruction of the insulin-producing cells of the pancreas, called beta-cells, that lead to T1D.
What’s next for teplizumab?
The FDA has to determine if teplizumab can help beta-cells survive. The FDA also must determine if teplizumab is safe and whether there are not too many side effects (the “safety” of the drug). In the FDA’s response letter, there were no indications that it had any major concerns about the drug’s effectiveness or safety.
How did we get here?
The drug manufacturer, Provention Bio Inc., applied to the FDA to approve teplizumab as a way to delay the onset of T1D in high-risk individuals. Even before Provention Bio’s TN-10 clinical trial, other studies were conducted with different forms of this medication.
Macrogenics (the company that previously owned teplizumab) evaluated whether anti-CD3 could be used at the onset of T1D to preserve some of the insulin producing beta-cells. If people with T1D could still make some insulin on their own, in addition to the insulin they needed to take, diabetes management could be made easier, with less hyperglycemia, lower A1C levels, and less risk of diabetes complications. However, the data did not show good enough outcomes needed for the FDA to approve anti-CD3 for new-onset diabetes. Perhaps it was simply too late in the diabetes process for the drug to make a significant difference. So, the focus turned to prevention – and to “delaying” the onset of T1D.
The TN-10 trial, sponsored by the National Institutes of Health, compared teplizumab to a placebo in 79 people with type 1 diabetes ranging from eight to 49 years old. A single intravenous infusion (IV) of Teplizumab or placebo was given daily for 14 days. To assure that study participants and research staff did not know who received teplizumab or the placebo, the placebo was given through IV in the same manner.
After two years, 43% of those given teplizumab developed clinical diabetes compared to 72% of participants in the placebo group. The health outcomes between the treatment and placebo groups were significant and in favor of teplizumab, but the number of people in the trial was small (only 79 people). Similarly, TN-10 showed teplizumab to be safe, but it is hard to be sure about both the short- and long-term safety profile of the drug. Provention Bio is asking the FDA to allow teplizumab to be approved for children and adults who are at high risk for (but do not yet have) diabetes. Because of this, understanding the safety and effectiveness of the drug is even more important.
What happened at the FDA meeting last year?
The FDA convened an Endocrinologic and Metabolic Drugs Advisory Committee Meeting (EMDAC) on May 27, 2021.
The EMDAC panel was asked to analyze the data and provide a recommendation on teplizumab to the FDA, but the final decision, as always, rests with FDA. The panel was composed of 17 highly regarded endocrinologists, rheumatologists, cardiologists, biostatisticians and mathematical statisticians, a consumer representative, and a patient representative. All panelists agreed that teplizumab showed benefit to the participants of the TN-10 study by delaying the onset of diabetes by two years. However, there was concern about some of the data from prior studies on teplizumab which did not reveal a significant effect on glucose management in people with new-onset T1D.
The panel focused on safety concerns, mainly in terms of long-term risks. The data from TN-10 and the five previous studies in those with newly diagnosed T1D showed higher rates of diabetic ketoacidosis, viral infections, and cytokine release syndrome (which can can cause flu-like symptoms and more serious reactions) in the anti-CD3 groups than in the placebo groups. There were also three total deaths in the treatment groups and none in the placebo groups. The EMDAC panel agreed that long-term surveillance studies would be required to better understand the safety of this treatment, if approved by the FDA.
Although five previous studies were submitted as evidence about teplizumab, the manufacturing and the rate at which the drug was cleared from the bloodstream are not the same as what has been seen with the teplizumab under FDA review. This brings up the concern that the prior studies don’t truly support the present submission. The panel also agreed that if the FDA approved teplizumab, it could only be indicated for use in people with the same characteristics as those evaluated in TN-10 – people over the age of eight, with a family history of T1D, and similar glucose profiles. Therefore, because about 80% of people who develop T1D have no affected relative, that target population would be a subsection of the actual number of people it could help. However, this could be reconsidered once more safety data is available.
Of the 17 EMDAC panel members, 10 voted in favor and seven voted against recommending FDA approval of teplizumab for the delay of T1D.
What does this mean in the diabetes community?
During the Open Public Hearing that helped influence the EMDAC’s decision, diabetes community leaders and organizations provided input, shared perspectives, and advocated for approval. The experts talked compellingly about the benefit of a two-year delay in diabetes diagnosis and what that would mean with regards to health. Several endocrinologists described the burdens of managing diabetes despite improvements in medications and technology, and the unmet needs that are still present. The speakers included:
JDRF CEO Aaron Kowalski
Dr. Mark Atkinson (University of Florida)
Dr. Louis Phillipson (University of Chicago)
Jeff Hitchcock (Children with Diabetes)
Dr. Jeremy Pettus (University of California San Diego)
Dr. Jennifer Sherr (Yale University)
Korey Hood (Stanford University)
diaTribe founder Kelly Close (Close Concerns) and Jackie Tait (dQ&A), who detailed results from a dQ&A survey of 1,078 people with T1D.
These speakers were supported by 187 letters posted to the FDA website, as well as the dQ&A survey of adults with T1D. Survey participants reflected upon how a two-year delay before needing to start insulin would have positively affected their life with diabetes.
If approved, teplizumab would become the first disease-modifying, preventive drug for T1D, and it could have the potential to change the paradigm of how the condition is managed. Stay tuned as we aim to keep you updated on this drug’s journey through the FDA approval process.