Clin Pharmacol Ther . 2020 Apr;107(4):994-1003. doi: 10.1002/cpt.1671.UPA 15 mg provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg, and with consistency across RA subpopulations and with UPA monotherapy or combination with csDMARDs. Exposure-response analyses were conducted using combined data from two Phase 2b and five Phase 3 studies in order to characterise the relationship between plasma exposure and efficacy, as well as to select safety parameters using the totality of the data in subjects with RA. The analysis also aimed to predict changes in efficacy response or safety variables with increased UPA exposures in certain scenarios such as hepatic or renal impairment. Exposure-efficacy models were run for ACR response, achievement of low disease activity, and remission, which showed that UPA efficacy increases with increasing plasma exposures. These exposure-efficacy results were consistent across subpopulations, and with UPA both as monotherapy and in combination with csDMARDs.Due to the small number of observed safety events, there was no clear trend observed in exposure-response relationships for pneumonia, HZ infection, changes in platelet count, lymphopenia (Grade ≥4), or neutropenia (Grade ≥3) up to Week 26. Simulation results in safety events of special interest showed that increases in UPA exposures up to 75% are predicted to result in an increase of 0.67% of subjects experiencing serious infections up to Week 24, and an increase of up to 1.33% in lymphopenia Grade ≥3 or haemoglobin decreases >2 g/dL at Week 12.These analyses demonstrate that once-daily extended-release UPA 15 mg provides optimal benefit-risk in RA through maximizing efficacy.