Background/Purpose: The CD40L/CD40 co-stimulatory pathway is important for T-cell-dependent antibody production. Previous clinical programs with intact monoclonal antibodies against CD40L have been discontinued due to thromboembolic events (TE) despite preliminary evidence of clinical efficacy in autoimmune diseases such as systemic lupus erythematosus and idiopathic thrombocytopenic purpura. MEDI4920 is an engineered Fc-deficient CD40L antagonist that is being developed for treatment of numerous autoimmune diseases.

Methods: A Phase 1, randomized, double-blinded, placebo-controlled study was conducted to evaluate the safety and tolerability of single-ascending intravenous doses of MEDI4920 in healthy subjects. Secondary endpoints were T-cell‒dependent antibody response (TDAR) inhibition, pharmacokinetic (PK) parameters, and anti-drug antibodies (ADAs) to MEDI4920. To assess TDAR, titers of IgG and IgM antibodies to neoantigen keyhole limpet hemocyanin (KLH) were quantified at Day 43 post-dose. A dose-response model was generated for TDAR inhibition. Fifty-six healthy adult male subjects were randomized and treated in this study: 3 subjects each in a 2:1 ratio in Cohorts 1 and 2 (3 and 10 mg of MEDI4920, respectively, or placebo) and 10 subjects each in a 4:1 ratio in Cohorts 3 through 7 (30, 100, 300, 1,000, and 3,000 mg of MEDI4920, respectively, or placebo).

Results: There were no deaths, no TE events or clinically significant coagulation or platelet function abnormalities, no severe or serious hypersensitivity reactions, no severe or serious infection events, and no infusion-related reactions. Only 1 serious adverse event of fractured tibia was reported in the placebo arm. No safety signals were identified overall. TDAR dose-response analysis at Day 43 demonstrated a statistically significant E_max dose response (P < 0.001; ED₅₀ = 491 mg) with the 3,000 mg dose showing 86% inhibition of the TDAR IgG response compared to placebo (95% CI: 68%, 94%; Figure 1). PK parameters (C_max and AUC) increased dose proportionally. Most subjects in the lower dose cohorts (3, 10, 30, and 100 mg) developed ADAs to MEDI4920, whereas a decreasing trend was observed for the higher doses (300, 1,000, and 3,000 mg).

Conclusion: MEDI4920 demonstrated an acceptable safety and tolerability profile while showing significant dose-dependent inhibition of TDAR. These encouraging results support further exploration of the safety and efficacy of repeat administration of MEDI4920 in an autoimmune disease in which the CD40/CD40L pathway activation plays a significant role.    

  Figure 1: Plot of dose-response model for TDAR inhibition (anti-KLH IgG at Day 43).