Treatment with a low dose of the immunosuppressant antithymocyte globulin (ATG) did not affect C-peptide modified quantitative response (mQR) in patients with early type 1 diabetes (T1D), in preliminary results of an ongoing real-world study.

Low-dose ATG offers a less expensive and less complicated alternative to the monoclonal antibody teplizumab for slowing disease progression and preserving beta cells in early-stage diabetes, according to David Weber, MD, of the Diabetes Institute at the University of Florida in Gainesville, Florida, and colleagues.

ATG has demonstrated effectiveness in clinical trials, Weber and his colleagues noted. For example, the phase 2 MELD-ATG trial showed that ATG significantly preserved beta-cell function as assessed by C-peptide compared with placebo. However, real-world data are lacking.

In a study published in Diabetes Care, the researchers evaluated the real-world feasibility of ATG by assessing its impact on C-peptide mQR.

Real-World Clinical Cohort

The study population included six individuals with stage II and 33 with stage III T1D, all of whom were treated in a clinical setting with 2.5 mg/kg low-dose ATG, then requested to obtain C-peptide via a commercial laboratory 90 minutes after consuming a 6 mL/kg Boost beverage. Participants also were asked to obtain baseline C-peptide data.

The ATG treatment consisted of peripheral intravenous infusion delivered over 4-6 hours in an outpatient setting, divided over 2 days. The researchers used baseline estimated area under the curve C-peptide (based on the 90-minute values) to calculate mQR.

Of the 39 participants, 30 had completed a year of follow-up, and 22 had provided baseline C-peptide data from 6 mL/kg Boost. The 22 patients with complete data included 15 responders (positive mQR) and seven nonresponders (negative mQR). The mean age of the patients at the time of infusion was 13 years, six were in stage II and 16 were in stage III T1D. The average mQR after 1 year was 0.072, with a SD of 0.292, and the average A1c decreased from 7.1% (54 mmol/mol) to 6.0% (42 mmol/mol).

ATG was well tolerated overall; the most common infusion reactions, nausea and headache, occurred in 19 patients, 11 of whom met the criteria for grade 1 cytokine release syndrome. A total of 18 patients experienced grade 2-3 serum sickness, 15 of whom took oral prednisone to manage their symptoms. All patients developed clinician-expected short-term lymphopenia that resolved by 3 months post-infusion. No drug-related adverse events were reported for the rest of the follow-up period.

The study also supports the use of mQR (with additional validation in larger studies) as a reliable measure of beta-cell function that could identify ATG responders and nonresponders, the study authors noted.

The findings were limited by several factors including the small sample size and potential selection bias, as well as the relatively high socioeconomic status of the study population, who had commercial insurance or were self-paying, the researchers wrote. Other limitations included the variation in C-peptide assays and the potential uncertainty of regression analyses, they added.

However, the results, along with those from ATG clinical trials, support the value of ATG in preserving C-peptide and reducing A1c in T1D in a real-world setting.

Observations Support Further Study

Although ATG has, in some settings, shown beta-cell preservation in trials, “real-world effectiveness data have been rather limited,” said Charles E. Leonard, PharmD, MSCE, MPH, associate professor of epidemiology at the Perelman School of Medicine, University of Pennsylvania in Philadelphia, who was not involved in the study.

“This study begins to address that gap, using a more pragmatic approach to outcome assessment,” he said, adding that the current study findings were not unexpected, as the magnitude and heterogeneity of response are consistent with prior ATG and related immunotherapy trials, and largely reinforce what is known about ATG.

The takeaway from the current study is that ATG can be delivered in routine care with a signal that tracks with trial data, and with potentially fewer logistical barriers than teplizumab, but the observational design of the study means that the evidence is as yet insufficient to guide routine use, said Leonard.

“The priority now is comparative and combination trials, along with identifying who benefits and whether short-term C-peptide effects translate into durable clinical outcomes,” he added.

The study was funded by the McJunkin Family Foundation, the Silverstein Family Chair, and the National Institutes of Health. Disclosure information for the authors is available in the original study publication. Leonard had no financial conflicts to disclose.