A Phase 2 (2a) Randomized Trial of Iscalimab in Adolescents and Young Adults with New-Onset Type 1 Diabetes

<b><i>Purpose:</i></b> Iscalimab is a fully human, monoclonal anti-CD40 antibody that blocks CD154-induced CD40 signaling. <b><i>Method:</i></b> In a Phase 2 (2a) study, new-onset stage 3 type 1 diabetes mellitus (T1DM) participants were randomized 2:1 to iscalimab or placebo administered as a single intravenous dose followed by weekly subcutaneous injections for 1 year to evaluate safety and effects on β cell function. <b><i>Results:</i></b> At 14 centers in 6 countries, 44 participants (29 M/15 F, mean age 16 years [range 12-21 years]) were randomized; 39 completed the study (26 active:13 placebo). Treatment was discontinued prematurely in seven, two of these due to a temporary trial halt during the COVID-19 pandemic. No difference in C-peptide area under the curve (C-peptide_(AUC)) during a mixed meal tolerance test was observed after 52 weeks (ratio active:placebo 1.173 [80% confidence interval (CI) 0.94, 1.47], <i>P</i>_(one-sided) = 0.18). The yearly rate of change of normalized stimulated C-peptide_(AUC) suggests a slower decline of β cell function: iscalimab -0.14 (80% CI -0.23, -0.05) versus placebo -0.33 (-0.42, -0.23) nmol/L per year (<i>P</i>_(one-sided) = 0.04). The estimated geometric mean ratio to baseline of hemoglobin A1c at week 52 was lower with iscalimab than placebo (0.95 [80% CI 0.92-0.99] versus 1.05 [80% CI 1.00-1.11], respectively). Leukocytes, neutrophils, and monocytes were lower, whereas T and B lymphocytes were higher in iscalimab-treated participants compared with placebo. Iscalimab was generally safe and well tolerated. Five serious adverse events (AEs) occurred under iscalimab (urinary tract infection, diabetic metabolic decompensation, traumatic fracture, hypoglycemia, and large intestine infection [3.4% each]) and one under placebo (mastoiditis [6.7%]). The most common AEs were hypoglycemia, nasopharyngitis, injection site reaction, COVID-19, and neutropenia. The majority of AEs were mild-to-moderate in intensity and resolved. <b><i>Conclusion:</i></b> Iscalimab has an acceptable safety and tolerability profile. The sample size limits interpretation of efficacy results. CD40:CD154 inhibition warrants further investigation in T1DM.