059: Pharmacokinetics & Immunogenicity of Combination Therapy of Guselkumab & Golimumab in Patients With Moderately to Severely Active Ulcerative Colitis

Statement of Purpose: A study of guselkumab (an IL-23 inhibitor) and golimumab (a TNF-α inhibitor) suggested that the combination therapy achieved greater efficacy than either guselkumab or golimumab monotherapy. This work is to investigate the pharmacokinetics (PK) and immunogenicity of guselkumab and golimumab administered alone or in combination.

Description of Methods & Materials: VEGA was a Phase 2b, double-blind, active-controlled, proof-of-concept study in patients with moderate-to-severely active ulcerative colitis who were naïve to anti-TNF-α therapy. Patients were randomly assigned (1:1:1) to guselkumab monotherapy (n=71), or golimumab monotherapy (n=72) or combination therapy (n=71) with guselkumab and golimumab administered for 12 weeks (combination comparison phase), followed by a transition to guselkumab monotherapy for 26 weeks (monotherapy phase). Blood samples were collected for 38 weeks to assess the PK and immunogenicity of guselkumab and golimumab. Patient demographic and disease characteristics were also collected and evaluated as covariates in the population pharmacokinetic (PPK) analysis. PPK models were individually developed for guselkumab and golimumab using the non-linear mixed effects modeling software NONMEM to describe their PK in the respective monotherapy and combination therapy

Data & Results: Serum guselkumab concentrations were comparable between guselkumab monotherapy and combination therapy [e.g. median trough 10.9 μg/mL (49.5%CV) vs 11.3 μg/mL (46.2%CV) at Week 12]. Similarly, the incidence of antibodies (ADA) to guselkumab was generally low and comparable between guselkumab monotherapy [0% (0/71)] and combination therapy [7.1% (5/71)] through Week 12, and through Week 38 [7.1% (5/71) in the guselkumab monotherapy group vs 11.3% (8/71) in the group of combination therapy - > guselkumab monotherapy]. The guselkumab PK was further described by a two-compartment PPK model with linear elimination which confirmed the observations. In contrast, serum golimumab concentrations in patients who received combination therapy were slightly higher than those in patients who received golimumab monotherapy [e.g. median trough 2.3 μg/mL (62%CV) vs 1.4 μg/mL (69%CV) at Week 10]. The slightly higher golimumab concentrations seen in the combination therapy group can likely be attributed to lower immunogenicity in the combination setting [5.6% (4/71)] as compared to the golimumab monotherapy [25.4% (18/72)] through Week 12. In the monotherapy phase (through Week 38), the ADA incidence of golimumab was 42.3% (30/71) and 64.8% (46/72) for the golimumab monotherapy group and the group that initially received combination therapy, respectively. The golimumab PK was further assessed using covariate analysis in the PPK analysis. The effect of combination therapy on the apparent clearance of golimumab (effect size -16%) relative to monotherapy can at least be partially attributed to the effect of immunogenicity (effect size: +8%) although the effect of immunogenicity might not have been reliably estimated due to limitations in sample size, sampling scheme and short duration of combination treatment.

Interpretation, Conclusion or Significance: The PK of guselkumab was similar between the combination therapy and the monotherapy groups, while combination therapy resulted in slightly higher golimumab concentrations than the monotherapy. The higher golimumab concentration from the combination therapy was likely due to lower immunogenicity as a result of guselkumab and golimumab combination therapy.

Disclosures: The authors received no financial support in the writing of this abstract Some authors were employees of Janssen Research & Development, LLC., a subsidiary of Johnson & Johnson at the time of the study and may own stock and/or stock options in the company.