Abatacept Misses Mark for Preventing Type 1 Diabetes in Phase 2 Trial

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In a recent phase 2 trial, abatacept failed to significantly reduce progression to diabetes or abnormal glucose tolerance among a cohort of stage 1 relatives of people with type 1 diabetes considered to be at risk of progression.

William Russell, MD | Courtesy: Vanderbilt University Medical Center

William Russell, MD
Courtesy: Vanderbilt University Medical Center

Despite showing promise in earlier studies, new data from a phase 2 clinical trial provide new insight into the effects of abatacept use for delay or preventing the progression of type 1 diabetes (T1D).1

A trial of more than 200 stage 1 relatives at risk of T1D, results of the study indicate abatacept use did not significantly delay progression to abnormal glucose intolerance of diabetes in at-risk individuals but did have an effect on immune cell subsets as well as insulin secretion, which investigators purport provides additional insight into the effects of costimulation blockade on progression of T1D.1

“This trial of 1-year treatment with abatacept in participants with stage 1 type 1 diabetes did not show a statistically significant effect on progression to stage 2 or stage 3 type 1 diabetes. The treatment caused the anticipated biologic changes in immune cells and an effect on metabolic function in these early-stage participants,” wrote investigators.2 “Had there been higher rates of progression in the placebo group or a longer period of treatment, we may have seen a greater effect on metabolic function and a statistically significant effect on the primary outcome.”

Sponsored by Type 1 Diabetes TrialNet and the National Institutes of Diabetes and Digestive Kidney Diseases, the Abatacept Prevention Study was designed based on results from previous studies indicating inhibition of lymphocyte costimulation reduces declining b-cell function in individuals newly diagnosed with type 1 diabetes. Conducted at 51 sites in North America and Europe from April 2013-December 2021, the phase 2 trial enrolled and randomized 212 patients with a primary endpoint of abnormal glucose tolerance or diabetes, which was assessed by oral glucose tolerance tests. Of the 212 participants included, 101 received abatacept and 111 received placebo.1

Upon analysis, 81 of the 212 patients met the primary endpoint of abnormal glucose tolerance or type 1 diabetes, with an incidence rate of 34.65% (n=35) among the abatacept arm and 41.44% (n=46) among the placebo arm (Hazard ratio [HR], 0.702 [95% confidence interval [CI], 0.452-1.09]; P=.11). However, investigators called attention to the C-peptide response to oral glucose tolerance tests, which were higher in the abatacept arm than the placebo arm (P <.03).1

Further analysis suggested abatacept use was associated with frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P <.0001), increased naïve CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells(Tregs) from the baseline (P=.0067). Investigators pointed out the frequency of ICOS+ Tfh, naïve CD4+ T cells, and Tregs returned to baseline levels 12 months after treatment.1

“Looking at these findings alongside those from a previous TrialNet study testing abatacept in people newly diagnosed with T1D (stage 3), helped us learn more about how the drug works and its impact on disease progression,” wrote William Russell, MD, lead investigator of the Abatacept Prevention Study and director of the Division of Endocrinology and Diabetes at the Vanderbilt University Medical Center.2 “Together, these findings open the door to additional research asking: Would continued treatment make a difference? Would waiting to start abatacept until stage 2 be more effective? Could combining abatacept with another therapy prolong its impact?”

References

  1. Russell WE, Bundy BN, Anderson MS, et al. 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
  2. Russell WE. Abatacept Prevention Study. Type1DiabetesTrialNet. https://www.trialnet.org/our-research/completed-studies/abatacept. Accessed March 20, 2023.
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