Background/Purpose:  MEDI4920 is a CD40 ligand (CD40L) antagonist under development for the treatment of autoimmune diseases. It is an engineered protein lacking a fragment crystallizable (Fc) moiety to avoid potential thromboembolic events associated with the Fc domain. The safety and tolerability of single ascending intravenous (IV) doses of MEDI4920 in healthy adults were studied in a Phase 1, randomized, blinded, placebo-controlled study. In addition, the pharmacokinetics (PK), immunogenicity, and PK/pharmacodynamic (PD) relationship were assessed and characterized in the study.

Methods:  Fifty-six healthy adult male subjects were randomized in the study at a single site and administered either placebo or MEDI4920 (3, 10, 30, 100, 300, 1000, 3000 mg). Blood samples were collected to evaluate the PK, anti-drug antibody (ADA), and PD profiles. MEDI4920 and total soluble CD40L (sCD40L) concentrations were determined using a validated immunoassay and a qualified enzyme-linked immunosorbent assay (ELISA) method, respectively. The presence of ADA to MEDI4920 was determined using a validated ELISA method. PK parameters were obtained using non-compartmental analysis, and a mechanism-based PK/PD model was developed to describe the relationship between MEDI4920 and total sCD40L accumulation in healthy subjects.

Results:   Following IV administration, MEDI4920 exposure increased in a dose-proportional manner. The clearance and terminal half-life ranged from 453 to 668 mL/day and 4.41 to 9.68 days, respectively, across the dose cohorts. Administration of MEDI4920 produced a dose-dependent increase in total sCD40L levels that reached a plateau at doses of 1000 mg and higher. A high incidence of ADA was observed in the lower dose cohorts (3, 10, 30, and 100 mg); ADA incidence and titers decreased with increasing dose. In subjects with high ADA titers, MEDI4920 was cleared faster from the circulation at concentrations lower than 1 µg/mL. A rapid decrease in total sCD40L accumulation was observed in subjects with high ADA titers. No association of ADA with clinical adverse events was established.

Conclusion:  The PK of MEDI4920 was linear and showed a dose-dependent increase in total sCD40L, consistent with target engagement. The decrease in ADA incidence and titers observed with increasing dose is consistent with the MEDI4920 immunosuppressive mechanism of action. Overall, MEDI4920 demonstrated safety and tolerability in a single ascending dose study in healthy subjects. These data support further investigation of MEDI4920 as a therapy for patients with rheumatoid arthritis. The mechanism-based PK/PD model can be used to explore the effects of various MEDI4920 doses and regimens on target engagement.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacokinetics-pharmacodynamics-and-immunogenicity-of-medi4920-a-novel-engineered-cd40-ligand-antagonist-in-healthy-volunteers/