Background/Purpose:  ABT-122 is a novel dual-variable domain immunoglobulin (DVD-IgTM), which specifically neutralizes both TNF alpha (TNFα) and interleukin-17A (IL-17). Drugs individually neutralizing TNFα or IL-17 have demonstrated efficacy in patients with Psoriatic Arthritis (PsA). The objective of this work was to quantitatively characterize the relationship between ABT-122 or adalimumab serum concentrations and the respective ACR20/50/70, PASI50/75/90 and DAS28 (CRP) responses following treatment in subjects with PsA who have had an inadequate response to methotrexate.

Methods:  Subcutaneous (SC) doses of ABT-122 120 mg every week (EW; N=71) and 240 mg EW (N=73) were evaluated in this 12-week randomized, double blind, placebo (N=24) controlled Phase 2 study, with adalimumab 40 mg SC every other week (EOW, N=71) as an active comparator. Serial ABT-122 and adalimumab serum concentrations collected every other week and time course of efficacy data collected at weeks 3, 5, 7, 10, and 12, were analyzed using non-linear mixed-effects modeling. The relationships of ABT-122 and adalimumab average serum concentrations (C_avg) during the dosing interval and the ACR20/50/70 and PASI50/75/90 responses as well as dropouts were characterized using Markov models, where active therapies enhanced transition of the status of patients to higher levels of response (e.g. no response to ACR20, ACR20 to ACR50, ACR50 to ACR70). For DAS28 (CRP), indirect response models with ABT-122 and adalimumab suppressing the response were utilized.

Results: The 120 and 240 mg EW doses of ABT-122 provided 2-fold and 4-fold higher molar serum concentrations compared with adalimumab 40 mg EOW dose. There was no evidence of different maximal effects between ABT-122 and adalimumab with available data. The EC₅₀ values (the concentrations associated with 50% of maximal effect) on the transition rates between ACR responses for ABT-122 and adalimumab were 6.5 nM (relative standard error [RSE]= 170%) and 13.0 nM (RSE = 61% ), respectively. Analyses provided similar results for PASI responses with EC₅₀ for the transition rates to higher PASI response (no response to PASI50, PASI50 to PASI75) for ABT-122 and adalimumab as 27 nM (RSE= 91%) and 34 nM (RSE = 58%), respectively. The IC₅₀, concentrations associated with 50% of maximal reduction of DAS28(CRP) responses, for ABT-122 and adalimumab were 60 nM (RSE = 18%) and 32 nM (RSE = 24%), respectively, with maximum inhibition of the baseline DAS28(CRP) level fixed to 45% based on observed data. These analyses indicate that the ACR, PASI and DAS28 (CRP) responses of ABT-122 approximately plateau at an ABT-122 dose of 120 mg EW in PsA patients. Combined analyses across studies in subjects with background MTX and either rheumatoid arthritis or PsA (ABT-122 dose range of 60 mg EOW and 240 mg EW) provided similar results.

Conclusion: The exposure-response relationships of efficacy for ABT-122 and adalimumab were not distinguishably different in subjects with PsA on background MTX. Overall, there was no clear evidence that inhibition of the IL-17 pathway provides significant incremental efficacy benefit in presence of TNF inhibition.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abt-122-an-immunoglobulin-targeting-both-tnf-%ce%b1-and-il-17a-does-not-provide-significantly-greater-efficacy-compared-with-adalimumab-in-subjects-with-psoriatic-arthritis-results-from-exposure-re/