Miriam E. Tucker
June 25, 2020
Prevention or delay of type 1 diabetes could become a reality in the next few years, with teplizumab (PRV-031, Provention Bio) likely to become the first agent commercially available to halt disease progression.
New data show that a single 14-day infusion of teplizumab, an anti-CD3 monoclonal antibody, leads to a median 3-year delay in type 1 diabetes onset among high-risk individuals compared with placebo, and follow last year's "game-changing" results showing a 2-year delay.
These latest findings were presented at the recent virtual American Diabetes Association (ADA) 80th Scientific Sessions.
Data for other interventions aimed at halting type 1 diabetes progression were also reported during the meeting, including anti-interleukin-21 (anti-IL-21) with and without the glucagon-like peptide-1 (GLP-1) agonist liraglutide and the immunosuppressive monoclonal antibody golimumab, both in newly diagnosed individuals.
"We are in very exciting times, I think, in terms of disease-modifying therapies for type 1...We are really at an inflection point in the ability to affect disease course," Jessica L. Dunne, PhD, former senior director of research at JDRF, told Medscape Medical News.
Dunne said that multiple different agents will likely be needed, as well as biomarkers to enable prediction of individual patient response and tailoring of treatment.
"Not everyone responds to the same therapies in the same way...We're making advances, but it's not a one-size-fits-all approach...I think there will be different therapies and ways to personalize treatment."
Teplizumab Shows Extended Benefit in Type 1 Diabetes Prevention
The pivotal phase 2 "At-Risk" TN-10 study was conducted by TrialNet, an international network of type 1 diabetes researchers, and funded by the US National Institute of Diabetes and Digestive and Kidney Diseases.
It was a randomized, placebo-controlled trial of 76 pediatric and adult relatives of patients with type 1 diabetes, all of whom were at high risk for the condition themselves because they had two or more type 1 diabetes-associated autoantibodies and subclinical abnormal glucose tolerance.
Primary results, presented at the American Diabetes Association (ADA) 2019 Scientific Sessions and published in the New England Journal of Medicine, showed that a single 14-day infusion of teplizumab produced a 2-year delay in the onset of type 1 diabetes.
Data showing that benefit extending another year were presented during the virtual ADA meeting by Emily K. Sims, MD, a pediatric endocrinologist at Riley Hospital for Children and physician scientist at the Indiana University Center for Diabetes and Metabolic Diseases and the Herman B. Wells Center for Pediatric Research, Indianapolis.
As of now, 50% of the teplizumab-treated group versus 22% of the placebo group remain diabetes-free, compared with 53% and 28%, respectively, last year.
Median time to diabetes is now approximately 5 years in the teplizumab group versus 2 years with placebo. Teplizumab resulted in a 54% reduced risk of progression to insulin-dependent type 1 diabetes (hazard ratio, 0.457; P = .01).
Sims also presented data showing that C-peptide levels, a marker of endogenous insulin production, were significantly higher for the teplizumab group versus placebo (P = .009). Those levels had been similar and declining in both groups prior to the trial. The decline continued in the placebo group while C-peptide levels increased with teplizumab relative to study entry (P = .02).
There have been no new safety events since last year.
"The pronounced early efficacy of the drug followed by stabilization of beta-cell function suggest that repeated treatment with teplizumab or the addition of other complementary agents at key timepoints in the clinical course may be valuable to extend the delay, or even prevent the diagnosis, of type 1 diabetes," Sims said.
Teplizumab has been granted a breakthrough therapy designation by the US Food and Drug Administration and PRIME designation by the European Medicines Agency.
Provention Bio has initiated a rolling submission of the biologic license application for teplizumab "for the delay or prevention of insulin-dependent type 1 diabetes for use in presymptomatic patients." Completion of the submission is expected in the fourth quarter of 2020.
The company is currently conducting a phase 3 study of teplizumab in patients with newly diagnosed type 1 diabetes called PROTECT.
Anti-IL-21 Plus Liraglutide: A Disease-Modifying Option?
Reporting on a different approach, Thomas Pieber, MD, head of the Division of Endocrinology and Metabolism at the Medical University of Graz, Austria, presented data from an international multicenter trial funded by Novo Nordisk of anti-IL-21 in combination with liraglutide in adults recently diagnosed with type 1 diabetes.
The idea behind this combination in newly diagnosed individuals, Pieber said, is as an adjunct to insulin that could maintain residual endogenous insulin production, leading to improved glycemic control, reduced insulin requirements, and potentially reduced risk of long-term complications and improved quality of life.
Anti-IL-21 is expected to reduce IL-21-mediated inflammation, while liraglutide confers beta-cell protection against cytokine-mediated apoptosis. The combination, Pieber said, should "maintain immunological tolerance, allowing beta-cell mass to survive, regain functionality, and eventually control blood glucose in patients with type 1 diabetes."
In the 54-week trial, a total of 304 adults aged 18-45 years diagnosed with type 1 diabetes in the prior 20 weeks were randomized to one of four groups: 12 mg/kg intravenous anti-IL-21 given every 6 weeks, 1.8 mg/day subcutaneous liraglutide, the combination of both, or placebo. All patients received insulin as needed.
At week 54, the primary endpoint, C-peptide area under the curve (AUC) after a mixed-meal tolerance test, was a significant 48% higher for the combination treatment compared with placebo (P < .01) and 33% higher compared with liraglutide alone, also significant (P = .02).
With anti-IL-21 alone, C-peptide secretion increased by 23%, a trend that didn't achieve significance (P = .14). The difference between liraglutide alone versus placebo wasn't significant (P = .38).
After an additional 26-week observation period, C-peptide secretion was 59% higher for the combination versus liraglutide alone (P < .01) but a significant 32% lower for liraglutide alone versus placebo (P < .01).
Total daily insulin dose at 54 weeks was reduced by 32% with the combination therapy versus placebo (P < .01), and also with liraglutide alone versus placebo (P = .01), but not with anti-IL-21 alone (P = .09) or any of the treatments by the end of the extended 80-week observation period.
And while A1c levels were lower by about 0.4 percentage points at week 54 for all three treatment groups compared with placebo, that difference wasn't significant.
Hypoglycemic events were significantly reduced by 50% with liraglutide alone (P = .01), and there was also a trend for both the combination (P = .12) and the anti-IL-21 alone (P = .16). The significance was lost by week 80. Other treatment-emergent events didn't differ significantly across the groups, including activation of viruses.
"The combination of anti-IL-21 and liraglutide could constitute a potential novel disease-modifying therapy for adults with recently diagnosed type 1 diabetes," Pieber concluded.
Another Immune-Modulating Agent Already on the Market: Golimumab
In a late-breaking poster, Teresa Quattrin, MD, professor of pediatrics at the University of Buffalo, New York, and colleagues presented data from a phase 2a, double-blind, placebo-controlled trial of the monoclonal antibody golimumab (Simponi, Janssen) in 84 participants aged 6-21 years with newly diagnosed type 1 diabetes.
Participants were randomized to receive either subcutaneous golimumab (weight-based dosing) or placebo for 52 weeks. The primary endpoint, C-peptide AUC at 52 weeks after a 4-hour mixed-meal tolerance test, was 0.64 pmol/mL with golimumab versus 0.43 pmol/mL for placebo, a significant difference (P < .001).
The drug also resulted in lower insulin use, hypoglycemia rates, and proinsulin/C-peptide ratio compared with placebo.
There were no safety signals.
Other Agents Being Investigated, Screening Approaches Will Be Needed
Dunne said that if these agents are tested and shown effective in preclinical (stage 2) type 1 diabetes, as has been demonstrated with teplizumab, then screening to identify individuals at risk will become an important component of intervention.
Initially, this could be done in first-degree relatives of people with type 1 diabetes, but most people with the condition don't have family members with it so ultimately screening would need to be expanded.
"We need to do more wide screening. Initially, we can screen family members until we can get payers on board, but ultimately, we have to figure out better ways to screen universally for type 1 diabetes risk," she commented.
Another approach, she said, could be to screen people with autoimmune diseases that often co-occur with type 1 diabetes, specifically thyroid and celiac disease.
However, Dunne said, "The long-term goal will be to screen all infants at birth for genetic risk, then follow them a few times during childhood for autoantibodies." The feasibility of that approach was demonstrated in a recent German study.
Overall, she said, "I'm just very excited about where we go next, and the fact that companies like Novo Nordisk, Janssen, and Provention are in this space tells you something about where the field is going. All the hard work built on the shoulders of the academics over the years is really starting to show the fruits of their labor."
Dunne is an employee of Janssen Research & Development. Sims has reported no relevant financial relationships. Pieber has reported being on advisory panels for, speakers bureaus for, and/or receiving research support from Arecor, Adocia, AstraZeneca, Novo Nordisk, Lilly, Sanofi, and Roche Diagnostics. Quattrin is a consultant for Janssen and receives research support from Provention Bio.