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.

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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/