Use of dose–exposure–response relationships in Phase 2 and Phase 3 guselkumab studies to optimize dose selection in psoriasis. (6th June 2019) - Lebwohl, M.
Abstract: Background: Guselkumab is an anti‐interleukin‐23 monoclonal antibody for the treatment of moderate‐to‐severe psoriasis. Objective: To evaluate the association between dose–response and exposure–response of guselkumab in Phase 2 and Phase 3 studies to optimize dose selection. Methods: Serum guselkumab concentrations in Phase 2 and Phase 3 studies (VOYAGE 1 and VOYAGE 2) were measured using a validated immunoassay. Efficacy assessments included Physician's Global Assessment (PGA), Investigator's Global Assessment (IGA) and Psoriasis Area and Severity Index (PASI). Results: In Phase 2, a positive dose–response relationship was observed for PASI and PGA (5‐mg through 100‐mg dose regimens). Exposure–response analysis showed that patients with steady‐state trough serum guselkumab concentrations ≥0.67 μg/mL achieved the highest levels of efficacy (PGA 0/1: 90.0%; PGA 0: 70.0%). The guselkumab 100‐mg every 8‐week (q8w) dose regimen, safe and well‐tolerated in Phase 2, provided the highest serum guselkumab concentrations among all regimens studied and was selected for Phase 3. In Phase 3, 72.5% of patients achieved guselkumab concentrations ≥0.67 μg/mL at week 28, the level associated with the highest clinical responses in Phase 2, with patients achieving response rates of IGA 0/1: 91.2%, IGA 0: 55.3%, PASI 90: 83.8% and PASI 100: 49.1% at week 28. Conclusion: The 100‐mg guselkumab q8w dose regimen, based on the dose–exposure–response relationship from the Phase 2 study, produced the target serum concentration associated with high‐level efficacy in the majority of patients in Phase 3. Phase 3 data further confirmed that guselkumab 100mg q8w is the optimum dosing regimen for treating patients with moderate‐to‐severe psoriasis.