Exposure–Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit–Risk Assessment in Rheumatoid Arthritis

Abstract

Exposure–response analyses of upadacitinib (UPA) key efficacy and safety end points (3,685 and 4,577 subjects for efficacy and safety, respectively) using data from phase II and phase III rheumatoid arthritis (RA) studies were conducted to support benefit–risk assessment. Percentage of subjects achieving American College of Rheumatology (ACR)20/50/70, disease activity score 28 (C‐reactive protein) (DAS28‐CRP) ≤ 3.2, and DAS28‐CRP < 2.6 increased with increasing UPA plasma exposures. With the small number of observed safety events, no clear trends for exposure–response relationships were identified for pneumonia, herpes zoster infection, changes in platelet count, lymphopenia (Grade ≥ 4), or neutropenia (Grade ≥ 3) up to Week 26. Shallow exposure–response relationships were observed for > 2 g/dL decrease in hemoglobin, lymphopenia Grade ≥ 3 at Week 12/14, and serious infections at Week 24/26. Exposure–efficacy analyses demonstrate that UPA 15 mg q.d. (once daily) dose provided the optimal benefit–risk in RA through maximizing efficacy with only small incremental benefit with 30 mg q.d.; and with consistency across RA subpopulations and with UPA monotherapy or combination with conventional synthetic disease‐modifying antirheumatic drugs.

Exposure‐Response Analyses for Upadacitinib Efficacy in Subjects With Atopic Dermatitis—Analyses of Phase 2b Study to Support Selection of Phase 3 Doses

“…Differences have been observed in the maximally efficacious upadacitinib plasma concentrations across different autoimmune diseases. In subjects with moderate to severe RA, upadacitinib plasma exposures associated with 15 mg once daily achieved the plateau for efficacy 35,36 ; upadacitinib exposures associated with 30 mg once daily were estimated to result in a <5% increase in the percentage of subjects achieving the efficacy end‐points ACR 20/50/70 responses or DAS‐28 low disease activity and clinical remission, compared with 15 mg once daily exposures 36 . Therefore, the 15 mg once daily dose of upadacitinib was selected as the clinical dose, and this dose received regulatory approval for treatment of RA.…”

Exposure–Response Analyses for Upadacitinib Efficacy and Safety in the Crohn's Disease CELEST Study and Bridging to the Extended‐Release Formulation

“…regimen. 15,16,18,26 However, in subjects with CD, upadacitinib doses higher than 30 mg q.d. using the ER formulation (or 12 mg b.i.d.…”

“…The relationships between upadacitinib plasma concentration and clinical efficacy end points were characterized using a continuous-time Markov modeling approach, 25 similar to the approach used previously to analyze the efficacy for upadacitinib in patients with RA. 26 The relationships between upadacitinib plasma exposures and endoscopic end points (endoscopic response 25%, endoscopic response 50%, and endoscopic remission at week 12 of 16) were characterized using regression analyses.…”

Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy

“…Short-term impacts of venetoclax and ibrutinib as single agents have been described in some cohorts. [25][26][27] Analysis of the cellular immunology of patients with relapsed MCL before salvage therapy has not been described in detail. Venetoclax inhibits BCL2, which is an important survival mechanism in activated T cells and innate subsets.…”