Session Type: Poster Session D
Session Time: 9:00AM-11:00AM
Background/Purpose: JNJ-839 is a fully human neutralizing antibody selective to human IFN-ω and IFN-α subtypes. Here we report the exploratory biomarker analyses of a Phase 1 study in mild to moderate SLE participants with elevated baseline IFN-I scores.
Methods: A screening strategy was implemented to enroll participants exhibiting elevated IFN-I scores using a whole blood qPCR 10 gene signature. The signature was calculated based on the following genes: DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1, and SAMD9L. Patients with a score below the pre-defined signature cutoff were excluded, resulting in 28 SLE participants randomized (3:1) to receive six bi-weekly IV treatments of JNJ-839 (10 mg/kg) or placebo (PBO), response was defined as a ≥4-point improvement of SRI-4 at Day 100. The IFN-I gene signature was measured longitudinally using RNAseq analysis of PAXgene blood samples to assess the pharmacodynamic (PD) effect of treatment vs. PBO. A novel precision medicine tool, in vitro perturbation assay, was developed to assess ex vivo exposure as a means to potentially predict clinical response. Participant blood was collected directly into a tube resulting in a final concentration of 200 μg/mL JNJ-839 or null tubes prior to dosing patients with PBO or JNJ-839 and incubated in vitro for 24h, followed by transcriptome profiling using microarray.
Results: At baseline, in vivo IFN-I signature levels were not significantly different between treatment groups, irrespective of response status. IFN-I signature suppression was observed in treated participants vs. PBO. IFN-I suppression was similar in JNJ-839 non-responders (NR) and responders (R) throughout the dosing period. After the final dose of JNJ-839 at Day 71, R exhibited a sustained suppression through Day 86, reaching PBO levels only at Day 130, while the NR promptly returned to PBO levels at Day 79. In the in vitro perturbation assay, using blood from participants prior to in vivo dosing, the magnitude of IFN-I signature suppression between JNJ-839 treated vs. untreated samples was statistically significant (p=0.032) using blood from R. In contrast, IFN-I signature suppression was not statistically significant between JNJ-839 treated vs. untreated samples in NR blood.
Conclusion: A sustained PD effect on the IFN-I signature was noted in JNJ-839 treated participants relative to PBO. Transient longitudinal PD differences were observed between R and NR only after the final dose. Differential expression analyses using samples from the in vitro perturbation assay indicated downmodulation of IFN-inducible transcripts in treated samples relative to untreated, suggesting that the IFN-I signature is perpetuated under these in vitro conditions. Further, in vitro exposure revealed a significant change between treated and untreated blood in R, indicating that this assay may have utility for future use to identify R to anti-IFN-I agents without exposing patients to these immunomodulatory agents. Despite the limitations of sample size, these results support further testing with inhibitors of the IFN-I pathway in SLE.
To cite this abstract in AMA style:Orillion A, Seridi L, Cesaroni M, Schreiter J, Benson J, Stohl W, Chatham W, Furie R, Migone T, Marciniak S, Yao Z, Srivastava B, Chevrier M, Jordan J. Biomarker Analysis of IFN-I Modulation in JNJ-839: First-in-Human Study for Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/biomarker-analysis-of-ifn-i-modulation-in-jnj-839-first-in-human-study-for-systemic-lupus-erythematosus/. Accessed November 26, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biomarker-analysis-of-ifn-i-modulation-in-jnj-839-first-in-human-study-for-systemic-lupus-erythematosus/