FDA Advisory Committee Votes 10-7 To Recommend Approval of Teplizumab For Delay Of Type 1 Diabetes
On May 27, 2021, the U.S. Food and Drug Administration (FDA) hosted an Endocrinologic and Metabolic Drugs Advisory Committee Meeting (EMDAC) to review Provention Bio, Inc.’s Biologics License Application (BLA) for Teplizumab, a monoclonal antibody and investigational candidate to delay the onset of Type 1 diabetes in at-risk individuals.
Provention Bio Makes Their Case
In Provention Bio Inc.’s clinical study, TN-10, they found that Teplizumab preserved beta cell function and delayed the onset of Type 1 diabetes by a median of two years among 76 trial participants between the ages of eight and 49. All study participants had two or more Type 1 diabetes autoantibodies, clinically known as stage two Type 1 diabetes. 43 percent of participants who were given Teplizumab developed clinical diabetes, compared to 72 percent of participants in the control group.
“Patients receiving Teplizumab or placebo were given daily intravenous infusions over at least 30 minutes for 14 consecutive days, Eleanor Ramos, MD, chief medical officer at Provention Bio Inc. said at today’s proceedings. She added that the doses were based on a participant’s body surface area.
While the study showed statistically significant findings, adverse events were observed, including short-term rash and low white blood cell count. Many of the adverse events reported were not serious or severe, according to Lauren Wood Heickman, MD, clinical reviewer.
Ramos explained that overall, Teplizumab had an acceptable safety profile. “Data from nearly 800 patients with approximately 1,500 patients years of follow up, comprised mostly of children who have the greatest disease burden, indicate that most of the adverse events related to the Teplizumab treatment are mechanism based, transient, generally limited to the time of exposure and manageable.”
The FDA Advisory Committee Weighs In
Presentations by the FDA advisory committee followed Provention Bio’s. The FDA advisory committee acknowledged the statistically significant findings of TN-10, however, concerns around the study sample size and efficacy arose. “Limitations included studied was an investigator initiated trial with small sample size. The study design limited for evaluation of treatment effects of Teplizumab on the secondary endpoint change from baseline,” Yu Wang, PhD, statistical reviewer said at EMDAC.
While the FDA advisory committee agreed that a two-year delay of Type 1 diabetes would be significant and clinically meaningful, there were some considerations and reservations regarding Teplizumab support. Committee members stated that they needed more safety data in order to adequately mitigate labeling and required postmarketing studies.
More specifically, committee members stressed that they couldn’t full grasp the long-term malignancies, including the risk of diabetic ketoacidosis (DKA) and three deaths documented in the study. The causes of death include DKA and anterior myocardial infarction. The last cause of death was unknown.”We don’t really know how safe this drug is and I’m not sure how much risk we can accept because the intended targeted population would be people who do not actually have a disease, they are at risk of the disease,” said Connie Newman, MD, endocrinologist and physician-scientist. “I think we need more safety data whether that can occur after approval is still a question for me and in terms of long-term malignancy, I think we don’t have enough data to make a decision about that.”
Throughout EMDAC’s open public hearing, individuals with Type 1 diabetes and family members of people with Type 1 diabetes stressed how burdensome living with Type 1 diabetes has been and how a treatment like Teplizumab would impact their lives. Many mentioned delaying the quivering process of insulin distribution and the process of diabetes management, especially for young children, where Type 1 diabetes can be diagnosed as early as infancy.
Madison Buff, senior at University of South Carolina stated “I was administered the drug five years ago and [saw] firsthand my blood sugar levels returned to a normal level and stayed at a a normal level…[making] me a strong advocate for this drug and others like me. During the past five years, I’ve been able to attend prom, graduate high school, I’ve moved out on my own and I’m set to graduate college in three and a half years. I can say this drug has made me more confident in the future of my health and wellbeing.”
Buff also recalled the fear of witnessing a family member struggle with diabetes complications: “One vivid memory I have is when my brother had a low blood sugar reading which caused him to go into a state of confusion. He had no idea where I was and when the ambulance came, he tried running away, and he eventually had a seizure. It was a super scary moment in my life and something that I never want to witness again nor do I want to happen to myself.”
Results of the Vote
Ultimately, the committee voted 10 to 7 in support of recommending Teplizumab, a drug shown to delay the onset of Type 1 diabetes among at-risk individuals for FDA approval.
The seven members who voted no, including Martha Nason, PhD, mathematical statistician for the National Institutes of Health, expressed the need for more replication of efficacy, safety data, and diversity in the trial population. Ten committee members voted in favor of the monoclonal antibody, mentioning that the study is a breakthrough and paradigm change in the diabetes space. However, those members recognized the limitation and recommended the following: more robust post marketing, safety evaluation, and long-term study follow up.
Currently, there is no disease modifying treatment that targets the underlying causes of Type 1 diabetes. The advisory committee’s decision will be reviewed by the FDA and will inform whether Teplizumab will be approved. If approved, Teplizumab would become the first disease modifying treatment to delay Type 1 diabetes.
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