LB-020 - MODEL-INFORMED DRUG DEVELOPMENT APPROACH FOR APPROVAL OF INTRAVENOUS FORMULATION OF SECUKINUMAB IN PSORIATIC ARTHRITIS (PSA), ANKYLOSING SPONDYLITIS (AS) AND NON-RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS (NR-AXSPA)

T. Dumortier¹, A. Marathe², R. Martin³, J. Ng³, G. Bruin⁴, D. Renard⁵, R. Woessner⁴, L. Pricop³, H. Richards³, J. Mijatovic⁵; ¹Novartis Pharma AG, Basel, Switzerland, , , ²Novartis Biomedical Research, East Hanover, USA, , , ³Novartis Pharmaceutical Corporation, East Hanover, USA, , , ⁴Novartis Biomedical Research, Basel, Switzerland, , , ⁵Novartis Pharma AG, Basel Switzerland, , .

Background: The US Food and Drug Administration (FDA) approved the intravenous (IV) formulation of secukinumab in PsA, AS and nr-axSpA on 6 October, 2023. The approved maintenance IV regimen of 1.75 mg/kg q4w (with or without a single loading dose of 6 mg/kg) was based on a pharmacokinetic bridging approach where modeling and simulation was utilized to determine the IV regimen that would approximate the PK of the previously approved subcutaneous (SC) regimens of 150 mg q4w and 300 mg q4w. The approval of the SC regimens was based on efficacy and safety data from Phase 3 studies.

Methods: A population pharmacokinetic (popPK) model was developed using data from 5270 patients (PsA, AS and nr-axSpA) treated with secukinumab IV or SC in 14 studies. The population PK model was qualified via internal and external validation.

Results: The popPK model was used to select 1.75 mg/kg q4w IV regimen as maintenance dose such that at steady state the regimen resulted in minimum, average, and peak drug concentrations (Cmin,ss, Cavg,ss, and Cmax,ss, respectively) that lie between the two approved SC regimens. This allowed for leveraging the efficacy and safety data from the approved SC regimens for the approval of 1.75 mg/kg q4w IV regimen. Additionally, exposure-response analysis for key efficacy and safety endpoints including ACR20, ASAS40, Candida infections and serious adverse events from 9 pivotal SC studies indicated that the efficacy and safety of the selected IV regimen are expected to be similar to the approved SC regimens. The key assumption that same drug concentration results in similar efficacy and safety regardless of the route of administration was validated by showing that the exposure-response models, built from SC data only, could predict well the efficacy and safety of a higher IV regimen of 3 mg/kg q4w in patients. The predictions were consistent with the observed data. The option of loading regimen of 6 mg/kg was included to align with the approved SC regimen with weekly loading SC injections for 4 weeks. The 6 mg/kg IV loading dose achieved generally comparable concentration levels to the approved SC dose with loading.

Conclusion: A model-based approach was used for the approval of the 1.75 mg/kg q4w IV regimen of secukinumab in PsA, AS and nr-axSpA and obviated the need of conducting any Phase 3 study utilizing this regimen.