Date: Sunday, November 5, 2017
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Upadacitinib, a selective JAK1 inhibitor, demonstrated favorable efficacy in two Phase 2 studies in subjects with moderate to severe rheumatoid arthritis (RA) who had inadequate response to prior treatment with anti-tumor necrosis factor (anti-TNF) therapy in BALANCE I or with methotrexate in BALANCE II. This work was done to characterize upadacitinib exposure-response relationships for effects on ACR responses in RA patients which supported dose selection for the ongoing Phase 3 RA trials.
The Analyses included data from 276 and 298 subjects in BALANCE I and BALANCE II, respectively. Subjects were randomized to receive 3, 6, 12, or 18 mg twice daily (BID) or matching placebo in BALANCE I and 3, 6, 12, 18 mg BID or 24 mg once daily or matching placebo in BALANCE II. Upadacitinib was administered in both studies as immediate-release formulation. Efficacy assessments and sparse blood samples for pharmacokinetic analyses were collected from over a 12-week period. ACR20, ACR50, and ACR70 responses as well as dropouts were collectively analyzed using a continuous-time Markov model, where upadacitinib enhanced transition of the status of patients to higher levels of response (e.g. no response to ACR20, ACR20 to ACR50, ACR50 to ACR70). The final model was used to predict the efficacy of different upadacitinib doses in both patient populations assuming 300 subjects for each dose. A separate model was utilized for simulation of placebo response in the anti-TNF inadequate responders population to better capture the lower placebo response in that population.
In the Markov analysis, point estimate for upadacitinib plasma concentrations associated with 50% of maximal effect on the transition rates to higher ACR responses was higher for anti-TNF inadequate responders compared with the methotrexate inadequate responders, however with overlapping confidence intervals between the populations. The predicted median (90% Prediction interval) ACR responses are shown in Table 1 compared to the observed ACR responses from BALANCE 1 and BALANCE II based on non-responder imputation.
Table 1. Predicted median (90% Prediction interval) ACR responses compared to the observed ACR responses based on non-responder imputation.
|Simulated dropouts are imputed with non-response.|
The exposure-response models adequately described upadacitinib exposure-response relationships for ACR20, ACR50, and ACR70 in the BLANACE I and II studies. Using the immediate-release formulation, upadacitinib exposures associated with 6 mg BID dose are predicted to achieve near maximal efficacy in methotrexate inadequate-responders, while exposures associated with 12 mg BID dose may provide additional efficacy benefit in anti-TNF inadequate responders.
To cite this abstract in AMA style:Klünder B, Mohamed MEF, Camp HS, Othman AA. Exposure-Response Analyses of the Effect of Upadacitinib on ACR Responses in the Phase 2b Rheumatoid Arthritis Trials in Patients with Inadequate Response to Methotrexate or to Anti-Tumor Necrosis Factor Therapy [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/exposure-response-analyses-of-the-effect-of-upadacitinib-on-acr-responses-in-the-phase-2b-rheumatoid-arthritis-trials-in-patients-with-inadequate-response-to-methotrexate-or-to-anti-tumor-necrosis-fac/. Accessed May 22, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exposure-response-analyses-of-the-effect-of-upadacitinib-on-acr-responses-in-the-phase-2b-rheumatoid-arthritis-trials-in-patients-with-inadequate-response-to-methotrexate-or-to-anti-tumor-necrosis-fac/