FDA Approves First-Ever Agent to Delay Type 1 Diabetes Onset

Miriam E. Tucker

November 17, 2022

The US Food and Drug Administration (FDA) has approved the anti-CD3 monoclonal antibody teplizumab-mzwv (Tzield, Provention Bio) to delay the onset of clinical type 1 diabetes in people aged 8 years and older who are at high risk for developing the condition.

"Today's approval of a first-in-class therapy adds an important new treatment option for certain at-risk patients," said John Sharretts, MD, director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA's Center for Drug Evaluation and Research. "The drug's potential to delay clinical diagnosis of type 1 diabetes may provide patients with months to years without the burdens of disease."

The agent, which interferes with T-cell-mediated autoimmune destruction of pancreatic beta cells, is the first disease-modifying therapy for impeding progression of type 1 diabetes. It is administered by intravenous infusion once daily for 14 consecutive days.

The specific indication is "to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes." In type 1 diabetes staging, adopted in 2015, stage 1 is defined as the presence of beta-cell autoimmunity with two or more islet autoantibodies with normoglycemia, stage 2 is beta-cell autoimmunity with dysglycemia yet asymptomatic, and stage 3 is the onset of symptomatic type 1 diabetes.

Stage 2 type 1 diabetes is associated with a nearly 100% lifetime risk of progression to clinical (stage 3) type 1 diabetes and a 75% risk of developing the condition within 5 years.

The FDA previously rejected teplizumab for this indication in July 2021, despite a prior endorsement from an advisory panel in May 2021.

In clinical trials, use of teplizumab-mzwv has delayed development of stage 3 type 1 diabetes by approximately 2 years, on average. However, to identify eligible candidates to receive it, broader autoantibody screening would be needed because most people who develop type 1 diabetes do not have first-degree family members with the condition. 

A Historic Occasion…a Great Day for the Diabetes Community, a Seismic Shift

Regarding the FDA approval, Provention Bio co-founder and CEO Ashleigh Palmer said in a statement: "This is a historic occasion for the type 1 diabetes community and a paradigm-shifting breakthrough...It cannot be emphasized enough how precious a delay in the onset of stage 3 type 1 diabetes can be from a patient and family perspective; more time to live without and, when necessary, prepare for the burdens, complications, and risks associated with stage 3 disease."

Robert Gabbay, MD, PhD, chief scientific and medical officer for the American Diabetes Association (ADA), agreed: "The approval of teplizumab, the first-ever treatment approved for the delay of type 1 diabetes, is a significant step forward for everyone impacted by this chronic disease."

"People with type 1 diabetes require life-long insulin replacement therapy, so to be able to provide an individual with a 2-year delay from the symptoms and burden of type 1 diabetes is a tremendous accomplishment as we look towards finding a cure," noted Gabbay in an ADA statement.

"There will likely be long-term benefits for blood glucose management and the reduction or delay of acute and long-term complications. The immeasurable benefits of improved quality of life will be felt not only by those diagnosed with type 1 diabetes, but also by their families. Today is a great day for the diabetes community," he added. 

"The...decision represents a turning point in the field," concurred Kevan Herold, MD, Yale School of Medicine, New Haven, Connecticut, one of the clinical investigators involved in the research.

"First, it identifies a way in which an immune therapy to stop the disease process might be combined with cell replacements in those with type 1 diabetes. It also suggests that it is time to more broadly screen to identify those at risk for type 1 diabetes since now there is a therapy that can change its course," he noted in a JDRF press statement.  

Cory Wirt, MD, Rochester, New York, enrolled her daughter, Claire, who had biomarkers and was deemed at risk for type 1 diabetes, in a clinical trial for Tzield 7 years ago. Today, her daughter has yet to progress to clinical type 1 diabetes.

"As a mom, I appreciate 83 months of not checking blood sugars multiple times per day, worrying about life-threatening lows, and balancing my child/teen's independence with the importance of tight medical control," Wirt noted in the JDRF statement. "Not to mention the significant cost of supplies, office visits, and emotional stress. We don't know how long the effects of the treatment will last, but every day without insulin has been a gift!" 

This "landmark approval of teplizumab in the US is the start of a seismic shift in how type 1 diabetes is treated," added Chris Askew, chief executive at Diabetes UK.  The decision means that "for the first time, the root cause of the condition — an immune system attack — can be tackled, and type 1 diabetes potentially delayed for up to 3 years," he noted in a statement.

Preventative treatments for type 1 diabetes can only be effective when combined with screening programs to identify those at risk, and the launch of the ELSA screening trial in children in the UK this week "is perfectly timed to help unleash the benefits of teplizumab here in the UK," he said. "The licensing of teplizumab in the UK must now be accelerated."

Type 1 Diabetes Onset Delayed by 2 Years

In 2019, a pivotal phase 2, randomized, placebo-controlled 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.

Those "game changer" data were presented in June 2019 at the ADA annual meeting and simultaneously published in the New England Journal of Medicine.

Three-year data were presented in June 2020 at the ADA annual meeting and published in March 2021 in Science Translational Medicine by Emily K. Sims, MD, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, and colleagues.

At a median follow-up of 923 days, 50% of those randomly assigned to teplizumab remained diabetes free, compared with only 22% of those who received placebo infusions (hazard ratio, 0.457; P = .01). The teplizumab group had a greater average C-peptide area under the curve compared with placebo, reflecting improved beta-cell function (1.96 vs 1.68 pmol/mL; P = .006).

C-peptide levels declined over time in the placebo group but stabilized in those receiving teplizumab (P = .0015). 

"The mid-range time from randomization to stage 3 type 1 diabetes diagnosis was 50 months for the patients who received Tzield and 25 months for those who received a placebo. This represents a statistically significant delay in the development of stage 3 type 1 diabetes," according to the FDA statement.

The most common side effects of Tzield include lymphopenia (73% teplizumab vs 6% placebo), rash (36% vs 0%), leukopenia (21% vs 0%), and headache (11% vs 6%). Label warnings and precautions include monitoring for cytokine release syndrome, risk for serious infections, and avoidance of live, inactivated, and mRNA vaccines.

This approval is likely to accelerate discussion about universal autoantibody screening. Currently, most individuals identified as having preclinical type 1 diabetes are first-degree relatives of people with type 1 diabetes identified through the federally funded TrialNet program. In December 2020, the type 1 diabetes research and advocacy organization JDRF began offering a $55 home blood test to screen for the antibodies, and other screening programs have been launched in the United States and Europe.  

Previous studies have examined cost-effectiveness of universal screening in children and the optimal ages that such screening should take place.  

In October, Provention Bio announced a co-promotion agreement with Sanofi for the US launch of Tzield for delay in onset of clinical type 1 diabetes in at-risk individuals. Provention Bio offers financial assistance options (eg, copay assistance) to eligible patients for out-of-pocket costs.

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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