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). Both cytokines are expressed at increased levels in rheumatoid synovial tissue and are believed to contribute to joint inflammation and structural damage to bone and cartilage that are hallmarks of rheumatoid arthritis (RA). Drugs individually neutralizing TNFα and IL-17 have demonstrated efficacy in patients with RA. The objective of this work was to quantitatively characterize the relationship between ABT-122 serum concentrations and time course of ACR20/50/70 and DAS28 (CRP) response following treatment with ABT-122 in subjects with RA who had an inadequate response to methotrexate in a Phase 2 study.

Methods:  ABT-122 doses of 60 mg every other week (EOW; N=55), 120 mg EOW (N=56) and 120 mg every week (EW; N=55) were evaluated in this 12-week Phase 2, randomized, double blind, active comparator [adalimumab, 40 mg EOW (N=56)] study. Serial ABT-122 and adalimumab serum concentrations, collected every week and time course of efficacy data collected at baseline and weeks 2, 4, 6, 8, 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 ACR20/50/70 responses were characterized using a Markov model, 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 DAS28 (CRP) scores were utilized.

Results:  ABT-122 dose of 120 mg EOW provided comparable molar serum exposures to adalimumab 40 mg EOW, whereas the 60 mg EOW dose and the 120 mg EW doses provided exposures lower and higher than adalimumab, respectively. The EC₅₀ (the concentration associated with 50% of maximal effect) on the transition rates to higher ACR response for ABT-122 and adalimumab were estimated to be 2.6 nM and 7.2 nM, respectively, with largely overlapping confidence intervals. The IC₅₀ values, the concentrations associated with 50% of maximal reduction of DAS28 (CRP) scores for ABT-122 and adalimumab were both estimated to be 8 nM, with maximum inhibition of the baseline DAS28(CRP) level fixed to 60% based on observed data. These analyses indicate that the ACR20/50/70 and DAS28 (CRP) responses of ABT-122 plateau at exposures associated with 120 mg EOW dose in RA patients.

Conclusion:  ABT-122 dose range evaluated in this Phase 2 study was adequate to describe the exposure-response relationships for ACR and DAS28 (CRP). ABT-122 and adalimumab potency values were not distinguishably different and Week 12 efficacy was comparable for the two agents at similar molar exposures (i.e. after pharmacokinetic differences are accounted for, both agents appear to provide similar efficacy). No significant increment in ABT-122 efficacy is estimated at doses higher than 120 mg EOW in patients with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exposure-response-analyses-of-efficacy-of-abt-122-a-dual-variable-domain-immunoglobulin-dvd-ig-targeting-tnf-%ce%b1-and-il-17a-compared-with-adalimumab-in-subjects-with-rheumatoid-arthrit/