CD40L blockade shows promise for RA
medwireNews: Findings from a proof-of-concept study provide preliminary evidence that the CD40 ligand (CD40L) binding agent VIB4920 may be a promising treatment option for rheumatoid arthritis (RA).
“The centrality of the CD40 pathway in humoral immunity has long made it an attractive target for the treatment of autoimmune diseases and transplant rejection,” but previous investigations with monoclonal antibodies (mAbs) targeting the ligand “were halted because of thromboembolic events observed in the clinical trials,” explain Jodi Karnell (Viela Bio, Gaithersburg, Maryland, USA) and co-investigators.
They add that VIB4920 blocks the CD40 binding site on CD40L, thereby inhibiting ligand–receptor binding and representing “an approach to suppress CD40L-mediated signaling events with a non-mAb scaffold protein.”
As reported in Science Translational Medicine, the researchers demonstrated that VIB4920 inhibited CD40-dependent signaling events in primary human B cells, including proliferation and plasma cell differentiation. They then carried out a phase I study in 56 healthy volunteers, showing that the compound resulted in dose-dependent suppression of antigen-specific immunoglobulin G after priming and boosting with KLH, a T-dependent antigen.
Following these findings, the compound progressed into a phase Ib trial involving 57 patients with RA and moderate-to-severe disease activity (DAS28-CRP score ≥3.2 at screening with four or more swollen and four tender joints at screening and randomization) who were randomly assigned to receive one of four doses of intravenous VIB4920 (1500, 1000, 500, or 75 mg) or placebo every other week for 12 weeks. Participants received methotrexate throughout the study, and those with methotrexate intolerance were given another conventional DMARD.
Karnell and team demonstrated that VIB4920 treatment resulted in dose-dependent reductions in DAS28-CRP, with adjusted mean decreases from baseline to week 12 of 2.3, 2.2, and 1.2 points in the 1500 mg, 1000 mg, and 500 mg groups, respectively. Conversely, patients given the 75 mg dose had an adjusted mean increase in DAS28-CRP score of 0.1 points, while those in the placebo group experienced a 0.1-point reduction.
The researchers say that the reduction in disease activity relative to placebo over 12 weeks was “clinically and statistically meaningful” for participants receiving the two highest doses of VIB4920, with adjusted mean differences versus placebo of 1.4 and 1.2 points for the 1500 mg and 1000 mg groups, respectively.
Moreover, 75% of patients in the 1500 mg group and 50% of those in the 1000 mg group achieved remission or low disease activity (DAS28-CRP ≤3.2) by the 12-week follow-up, while a respective 30%, 0%, and 13% of participants in the 500 mg, 75 mg, and placebo groups achieved this endpoint.
The investigators report that VIB4920 had “a good overall safety profile” in both the phase I and Ib studies, with “a balanced distribution of treatment-emergent adverse events” between the VIB4920 and placebo groups. No platelet or coagulation abnormalities were observed, and administration of the compound was not associated with an increased risk for infection.
“Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions,” the team concludes.
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