Session Type: Poster Session D
Session Time: 9:00AM-11:00AM
Background/Purpose: Clinical and biological heterogeneity pose a significant hurdle in SLE, making biomarkers that define patient subsets crucial for developing tailored therapies. Interventional SLE trials using inhibitors of the IL-12/IL-23 and type I interferon (IFN-I) pathways revealed gene signatures linked with each mechanism. We reported that response to the IL-12/IL-23 p40 inhibitor (Ustekinumab, UST) associates with baseline expression of a cytotoxic-cell associated gene signature (CTS). IFN-I gene signature (IGS) may serve as a patient selection tool and pharmacodynamic biomarker for IFN-I inhibitors. Here, we examined the expression of IGS and CTS signatures in two SLE trials: UST Ph2 (NCT02349061) and JNJ-839, anti-IFN-α/ω antagonist, Ph1B (NCT02609789) to test whether the CTS association with response was specific to the mechanism of action of UST.
Methods: We conducted Gene Set Variation Analysis (GSVA) of CTS and IGS on whole blood transcriptomes from moderate-to-severe SLE patient samples collected in two distinct randomized, double-blind, placebo (PBO)-controlled trials (UST Ph2 [N=102] and JNJ-839 Ph1B [N=28]). In UST Ph2, patients were randomized (3:2) to receive UST IV ~6 mg/kg or PBO at Week 0, then UST SC ~90 mg or PBO every 8 weeks. In JNJ-839 Ph1B, IFN positive patients were randomized (3:1) to receive JNJ-839 IV 10 mg/kg or PBO every 2 weeks. Clinical response was defined by SLE Responder Index (SRI)-4 at Week 24 and Day 100, respectively.
Results: Unlike in UST Ph2, where CTS was lower at baseline in UST-nonresponders (NR) compared to UST-responders (R) (p=0.0087), CTS expression did not correlate with response to, nor was it modulated by JNJ-839. UST did not modulate IGS, and the treatment effect (difference in response rate UST vs. PBO) was similar between IFN-I high and IFN-I low patients. IGS expression was comparable in JNJ-839-R and JNJ-839-NR at baseline and rapidly decreased after JNJ-839 treatment and throughout the dosing period (Day 1-71). After the last dose, JNJ-839-R exhibited durable IGS suppression through Day 86 before returning to baseline levels and was comparable to levels observed in patients receiving PBO at Day 130. In contrast, JNJ-839-NR IGS levels rapidly reached PBO levels by Day 79.
Conclusion: Biomarkers linked to UST response did not associate with anti-IFN-α/ω response in SLE. Likewise, IFN-I pathway biomarkers did not specifically associate with UST response. These data support a distinct mechanism of action between UST and agents targeting IFN-I and provide a foundation for future biomarker response-based studies using additional therapies in SLE.
To cite this abstract in AMA style:Dörner T, Tsokos G, Kalunian K, van Vollenhoven R, Orillion A, Cesaroni M, Benson J, Chevrier M, Rose S, Marciniak S, Yao Z, Srivastava B, Schreiter J, Baribaud F, Ort T, Jordan J, Seridi L. Biomarkers Linked to Anti-IFN-I and Ustekinumab Suggest Distinct Mechanism of Action in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/biomarkers-linked-to-anti-ifn-i-and-ustekinumab-suggest-distinct-mechanism-of-action-in-systemic-lupus-erythematosus/. Accessed November 26, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biomarkers-linked-to-anti-ifn-i-and-ustekinumab-suggest-distinct-mechanism-of-action-in-systemic-lupus-erythematosus/