A US Food and Drug Administration (FDA) advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.
The 10-7 vote of the FDA's Endocrinologic and Metabolic Drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.
Regardless of their vote, nearly all panel members advised FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.
If approved, teplizumab, which interferes with T-cell mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.
That "stage 2" or "at-risk" condition is associated with a nearly 100% lifetime risk of progression to clinical ("stage 3") type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
What's the Evidence to Support Approval So Far?
In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.
While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.
Although the FDA typically requires companies to demonstrate a drug's effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.
In this case, Provention's submission included as "confirmatory" evidence a meta-analysis of data from five earlier randomized trials (three placebo-controlled, two open-label) of a total 942 individuals with newly diagnosed type 1 diabetes ("stage 3") who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.
Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
Safety: Adverse Events Mostly Transient, but Unanswered Questions
Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs 9.4% placebo; relative risk [RR], 8.2), leukopenia (82.1% vs 24.1%; RR, 3.4), and rash (44.5% vs 9.0%; RR, 4.9).
"Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable," Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.
Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.
Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.
Approximately 10% of patients were not able to complete the treatment course due to protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.
There was only one malignancy, a melanoma in a patient with a pre-existing lesion, but malignancy is a theoretical concern with long-term immunosuppression, Heickman said.
Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.
Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
Panel Members Describe "Struggle" With Vote Decision
Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, Maryland, voted in favor of teplizumab approval. However, he said, "I was very conflicted on this one and my 'yes' is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial...Patients who don't fit the criteria could hopefully be enrolled in a second confirmatory trial."
He also advised an extensive Risk Evaluation and Mitigation Strategies (REMS) program to look for both short- and long-term adverse effects.
"My overall take on this is that I do think it's a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I'm excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval," Blaha said.
Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.
"I really struggled with it...I was pushed by the very encouraging results of what is admittedly a very small study and something I can't feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous post-marketing program, preferably including another controlled trial, should be carried out."
But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.
"I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes...but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly."
A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, North Carolina. She voted yes, pointing out that she's accustomed to prescribing biologics for chronic conditions in children.
"I was unconflicted in my vote, which was yes. I thought the data...were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease...and I would require post-marketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it."
FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.
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