FDA advisory committee recommends approval of immunotherapy to delay type 1 diabetes
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An FDA advisory panel voted 10-7 in favor of recommending approval of teplizumab to delay development of type 1 diabetes in high-risk children and adults, with most committee members expressing some concerns about trial size and safety.
In casting their votes, most members of the Endocrinologic and Metabolic Drugs Advisory Committee said they struggled with whether to recommend approval of teplizumab (Provention Bio), a humanized anti-CD3 monoclonal antibody, which was shown in a randomized clinical trial to delay development of type 1 diabetes by a median of up to 2 years in children as young as age 8 years after a single, 14-day course of the drug. Members weighed the importance of reducing the well-known disease burden and complications of type 1 diabetes with questions of efficacy and potential safety concerns.
“I voted yes; however, I was very conflicted on this one, and my ‘yes’ is very qualified,” Michael J. Blaha, MD, MPH, professor of cardiology and epidemiology and director of clinical research at the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, said after the vote. “In my opinion, the risk-benefit is very narrow here, and I would only approve this drug for the exact indication of the trial. ... I do think this is a promising, paradigm-shifting therapy that needs to move forward, but I have a lot of skepticism about the entire body of data to make even more than just the most narrow approval.”
Committee member David M. Nathan, MD, director of the Massachusetts General Hospital Diabetes Center and professor of medicine at Harvard Medical School, who voted “no,” said the small study size makes it difficult to balance risks vs. benefit, and the significance of a delay in diagnosis remains unknown.
“I struggled with this vote tremendously, having listened carefully to the patients with type 1 diabetes,” Nathan said after the vote. “That said, having done clinical trials for 40 years in type 1 diabetes, we need to have more data, both in terms of efficacy and safety. I would hate to figure out, years down the road, that we actually caused more harm than good, especially keeping in mind that the treatment of diabetes is evolving rapidly.”
Study data
As Healio previously reported, data published in The New England Journal of Medicine in 2019 showed children and adults most likely to develop type 1 diabetes were able to stave off the disease for up to 2 years after receiving a single 14-day course of teplizumab.
Within a cohort of 76 participants aged at least 8 years, researchers found that during a median follow-up of 745 days, 43% vs. 72% of participants who received teplizumab vs. placebo, respectively, developed type 1 diabetes. The annualized rate of diagnosis was 14.9% vs. 35.9% for those assigned teplizumab and placebo, respectively. Overall, 25 participants in the teplizumab group avoided type 1 diabetes altogether compared with the nine who received placebo. For those who developed the disease, the time from baseline to diagnosis was nearly twice as long for those in the teplizumab cohort compared with the placebo cohort (48.4 months vs. 24.4 months; P < .006).
In a more extended follow-up of the randomized controlled trial (median, 923 days), published in Science Translational Medicine in March and also reported by Healio, researchers observed a persistent delay in the development of type 1 diabetes among participants assigned teplizumab, as well as improved beta-cell function for high-risk individuals.
During follow-up, 50% of teplizumab-treated participants and 78% of the placebo group developed type 1 diabetes, for an HR of 0.457 (P = .01). Median times to type 1 diabetes diagnosis were 59.6 months and 27.1 months, respectively.
“If you ask anyone who has type 1 diabetes, they will tell you that every day that you can delay the clinical diagnosis is important,” Kevan Herold, MD, the C.N.H. Long Professor of Immunobiology and Medicine at Yale School of Medicine, said when presenting on behalf of Provention Bio during the meeting. “People who have type 1 diabetes need to manage the disease 24 hours a day, 7 days a week, 365 days a year. It goes well beyond a diagnosis. It is a constant burden to patients and anyone who lives with them.”
Questions of study size, safety
In briefing documents released before the meeting, the FDA noted that the study, TN-10, was “relatively small,” with only 44 patients exposed to teplizumab; however, more than 750 patients with new-onset type 1 diabetes were exposed to teplizumab in other controlled clinical studies included in a meta-analysis.
“The low prevalence of stage 2 type 1 diabetes makes it challenging to identify ‘at-risk’ patients for clinical studies, and studies of relatively long duration are needed to observe outcomes and quantify treatment benefits,” the FDA stated. “Furthermore, there are no approved therapies to delay the onset of type 1 diabetes, indicating an unmet need in this therapeutic area. Thus, given the severity and rarity of the disease, the lack of treatments to delay its onset, and the impracticality of conducting a second long-term clinical trial, it seems appropriate to consider this single trial plus confirmatory evidence as potentially meeting the standard for substantial evidence of effectiveness.”
Safety concerns were also highlighted. In both TN-10 and the new-onset type 1 diabetes population, risks identified related to teplizumab treatment included cytokine release syndrome (CRS), transient hepatic enzyme elevations, and occasionally bilirubin increases, often as a part of CRS and transient lymphopenia. Additionally, slightly more than 10% of trial participants were not able to receive the full course of teplizumab secondary to meeting protocol-specified withdrawal criteria, usually related to laboratory abnormalities. “In addition, teplizumab affects T-cell signaling and has the potential to cause immunosuppression,” the FDA stated. “A possible result of immunosuppression may be a greater risk of infection, and theoretically, a higher risk of future malignancy. Aside from a higher frequency of serious infections in the TN-10 trial safety database, the overall safety database did not suggest infection as an important risk of treatment.”
A ‘win’ for patients
Despite safety concerns, clinicians, people with type 1 diabetes and their family members spoke passionately about the possibility of delaying the daily burdens of the disease and the risks they already take on with insulin therapy.
“A ‘win’ for type 1 diabetes has been difficult to come by,” Jeremy H. Pettus, MD, assistant clinical professor of medicine in the School of Health Sciences at the University of California, San Diego, in La Jolla, California, who also has type 1 diabetes, said during the public comment portion of the meeting. “This therapy is not only a win, but also a landmark for diabetes care. We all talk about the cure like it will be handed to us in some pill. Diseases are rarely, if ever, cured that way. The cure starts with a paradigm shift ... and that is exactly what teplizumab is. It is a very literal first step, finally addressing type 1 diabetes at its root cause.”
Mark Atkinson, PhD, the Jeffrey Keene Family Professor at the University of Florida and director of the University of Florida Diabetes Institute, said teplizumab achieves the goal of delaying disease with minimal safety concerns and will be welcomed by patients and clinicians alike.
“For many, the term ‘diaversary’ is used to describe the date when their diagnosis occurs, as it represents a day when their life changed forever,” Atkinson said during public comment. “If teplizumab receives approval from this regulatory body, I firmly believe that the ‘diaversary’ for individuals destined to develop type 1 diabetes will be delayed, and for some, this date will not even be registered on any calendar.”
The advisory panel’s recommendations are nonbinding, although the FDA often follows its suggestions.
Reference:
Provention Bio briefing information. Available at: https://www.fda.gov/media/149389/download.
Perspective
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The panel’s decision (10-7) is exciting and surprising. Most panel members were skeptical about the small sample size and only one large clinical trial with some heterogeneity in response to the treatment.
There were many great stories from patients and their family members and physicians affected by type 1 diabetes on burden of living with this disease and a need for drugs to prevent or delay the disease onset. On that side, I completely agree — yes, we need something to delay type 1 diabetes. It matters.
The other side of the story is concern about the study findings and long-term safety of this drug. In my personal opinion, the main concern I have is whether the TN-10 study is strong enough to affirmatively conclude delaying the development of diabetes by 2 years. The data also suggest that people with HLA-DR3 haplotypes are not good responders to this treatment; however, HLA-DR4 haplotypes are good responders.
I am both excited and cautious about the panel’s decision. How FDA will construct the label indication for this drug is going to be very important, as we know that once the drug is approved, there may be a possibility of increasing off-indication use without much evidence. We do not want that. Another study and long-term follow-up of the TN-10 study cohort is definitely warranted.
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FDA Briefing Document: Endocrinologic and Metabolic Drugs Advisory Committee Meeting. May 27, 2021. Available at: www.fda.gov/media/149388/download.
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