2021-LB: FABULINUS—A Randomized, Controlled Trial with FrexalimAB, to Assess Endogenous Insulin Secretion in New-Onset Stage 3 Type 1 Diabetes Adults and Adolescents

Introduction: Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic β-cells. The CD40/CD40L immune checkpoint leads to activation of both innate and adaptive immune cells. Frexalimab is the first second-generation antibody against CD40L to be studied in T1D.

Objective: To demonstrate the efficacy and safety of different doses of frexalimab on endogenous insulin secretion in participants with newly diagnosed T1D.

Methods: FABULINUS (NCT06111586) is a 52-week randomized (2:1), double-blind, placebo-controlled phase 2b study with a 52-week blinded extension conducted in the US and Europe. It consists of 2 parts: Part A evaluates the safety of the highest dose of frexalimab in adults (18 - 35 years). In Part B, which is based on 3-month safety data from Part A, adolescents, and young adults (12 - 21 years) are treated with 3 sequentially escalated doses of frexalimab or placebo. Study entry criteria include diagnosis of Stage 3 T1D according to American Diabetes Association standards, initiation of insulin therapy <u><</u> 90 days prior to screening and random C-peptide levels ≥0.2 nmol/L. Change from baseline to Week 52 in the mean 2h stimulated AUC C-peptide concentration is used as a primary efficacy endpoint. Secondary endpoints include time in range (TIR, 70-180 mg/dL blood glucose), insulin dose, glycated hemoglobin A1c (HbA1c), remission, and safety.

Results: The study design of FABULINUS ensures the stepwise assessment of anti-CD40L antibodies in adults and then adolescents with type 1 diabetes.

Conclusion: FABULINUS is an innovative combined proof-of-concept and dose-finding study tailored to specific clinical development requirements for ß-cell preservation in T1D.