Is Abatacept effective in preventing type 1 diabetes in at-risk individuals? Phase 2 trial provides insights

The trial provided new insight into the effects of abatacept use for delaying or preventing the progression of type 1 diabetes (T1D). The trial, whose findings were published in Diabetes Care, comprised more than stage 1 relatives at risk of T1D.

Previous studies have reported that inhibiting lymphocyte costimulation reduces β-cell function in people newly diagnosed with type 1 diabetes. William E. Russell, Vanderbilt University Medical Center, Nashville, TN, and colleagues tested whether abatacept would prevent or delay the progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or diabetes and the effects of treatment on metabolic and immune responses.

For this purpose, they conducted a phase 2, placebo-controlled, randomized, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The endpoint was abnormal glucose tolerance or diabetes, evaluated by oral glucose tolerance tests.

The study led to the following findings:

• A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the endpoint of AGT or type 1 diabetes diagnosis (hazard ratio 0.702).
• The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm.
• Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ Tfh (T-follicular helper cells) during treatment, raised naïve CD4+ T cells, and also decreased the frequency of CD4+ regulatory T cells (Tregs) from the baseline.
• Twelve months after treatment, the frequency of ICOS+ Tfh, Tregs, and naïve CD4+ T cells returned to baseline.

“This trial of 1 year of abatacept treatment in people with stage 1 type 1 diabetes did demonstrate a statistically remarkable effect on advancing to stage 2 or stage 3 type 1 diabetes. In these early-stage participants, the treatment caused an effect on metabolic function and anticipated biologic changes in immune cells,” wrote investigators.

“Had there been higher progression rates in the placebo group or a longer treatment period, we may have observed a greater effect on metabolic function and a statistically significant effect on the primary outcome.”

They concluded, "the findings suggest that costimulation blockade may modify the progression of type 1 diabetes."

Reference:

William E. Russell, Brian N. Bundy, Mark S. Anderson, Laura A. Cooney, Stephen E. Gitelman, Robin S. Goland, Peter A. Gottlieb, Carla J. Greenbaum, Michael J. Haller, Jeffrey P. Krischer, Ingrid M. Libman, Peter S. Linsley, S. Alice Long, Sandra M. Lord, Daniel J. Moore, Wayne V. Moore, Antoinette M. Moran, Andrew B. Muir, Philip Raskin, Jay S. Skyler, John M. Wentworth, Diane K. Wherrett, Darrell M. Wilson, Anette-Gabriele Ziegler, Kevan C. Herold, Type 1 Diabetes TrialNet Study Group; Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial. Diabetes Care 2023; dc222200. https://doi.org/10.2337/dc22-2200