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Abstract Number: 2951

Ustekinumab Treatment Response in SLE Is Associated with Changes in Type II but Not Type I Interferons

Jarrat Jordan1, Kristen Sweet2, Matteo Cesaroni1, Keying Ma2, Carol Franks2, Loqmane Seridi2, Jessica Schreiter3, Robert Gordon2, Peter E. Lipsky4, Shawn Rose2, Frédéric Baribaud2, Matthew Loza2 and Kim Campbell2, 1Janssen Research and Development, LLC., Spring House, PA, 2Janssen Research & Development, LLC, Spring House, PA, 3Estrela Lupus Venture, Janssen Research and Development, LLC., Spring House, PA, 4AMPEL BioSolutions, Charlottesville, VA

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Disease Activity, Interferons and systemic lupus erythematosus (SLE)

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Session Information

Date: Wednesday, October 24, 2018

Title: 6W024 ACR Abstract: SLE–Etiology & Pathogenesis II (2946–2951)

Session Type: ACR Concurrent Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose: We previously reported that treatment with ustekinumab (UST), an anti-IL-12/23 p40 neutralizing monoclonal antibody, improved global and organ-specific measures of disease activity in a randomized, placebo (PBO)-controlled study of patients with active SLE (NCT02349061)1. Type I interferon (IFN-I) and type II IFN (IFN-g) are elevated in a subset of SLE patients. The comparative effects of IFN-I and IFN-g in SLE remain uncertain, although targeting IFN-I (anifrolumab) has demonstrated clinical efficacy, whereas a preliminary study with anti-IFN-g mAb (AMG811) failed to establish benefit2,3. Given the potential importance of the IFN-I and IFN-g pathways in SLE pathogenesis, we studied the effects of UST treatment on both IFN-I and IFN-g in patients with active SLE.

Methods: We conducted a phase 2, PBO-controlled study in 102 adults with seropositive SLE by SLICC criteria and active disease (baseline SLEDAI score ≥6 and ≥1 BILAG A and/or ≥2 BILAG B scores) despite standard-of-care therapy1. Gene expression analysis using a previously published 21 gene IFN-I gene signature (IGS)4 was performed by microarray analysis using whole blood PAXgene RNA samples. Analysis of serum protein levels of IFN-g and IFN-α was performed using MSD (IFN-g) and Quanterix (IFN-α) platforms.

Results: Serum levels of IFN-g and IFN-α and the IGS were significantly elevated at baseline versus healthy controls (p<0.0001). Approximately 67% of the SLE patients were IGS high at baseline. At 4 weeks, patients who received UST, but not PBO, exhibited decreased IFN-g protein levels (p=0.0032). Despite non-significant differences at baseline, there was a trend toward greater reduction in IFN-g levels in UST-treated patients who achieved an SRI-4 response at wk24 compared to non-responders. There was no decrease in IFN-α protein levels or the IGS after treatment with either UST or PBO. Whereas the proportion of patients achieving an SRI-4 response at wk24 was numerically greater in the IGS low patients (81.8% UST vs. 54.5% PBO) versus the IGS high (48.6% UST vs. 20% PBO) population, the magnitude of the treatment effect (UST vs. PBO) was similar in both subsets (IGS low effect size= 27.3% vs. IGS high effect size = 28.6%).

Conclusion: In this SLE trial population which had significant upregulation of IFN-I protein and IGS at baseline, clinical response to UST was not associated with IFN-I reduction. In contrast, a significant decrease in IFN-g protein levels was associated with UST treatment. These findings suggest that a broad population of SLE patients may respond to UST regardless of baseline IFN status. Moreover, an effect of UST treatment on TH1 responses manifested by IFN-g levels in SLE patients was suggested, a finding that will be tested in a phase 3 trial.

1ACR 2017 Abstract # 6L

2Furie, R., et al., Arthritis Rheumatol, 2017. 69(2): p. 376-386.1.

3Boedigheimer, M.J., et al., Lupus Sci Med, 2017. 4(1): p. e000226.

4Yao, Y., et al., HGP, 2009.


Disclosure: J. Jordan, Janssen Research Development, LLC, 3; K. Sweet, Janssen Research and Development, LLC, 3; M. Cesaroni, Janssen Research and Development, LLC, 3; K. Ma, Janssen Research and Development, LLC, 3; C. Franks, Janssen Research and Development, LLC, 3; L. Seridi, Janssen Research and Development, LLC, 3; J. Schreiter, Janssen Research and Development, LLC, 3; R. Gordon, Janssen Research & Development, LLC, 3; P. E. Lipsky, Janssen Research and Development, LLC, 2; S. Rose, Janssen Research & Development, LLC, 3; F. Baribaud, Janssen Research and Development, LLC, 3; M. Loza, Janssen Research and Development, LLC, 3; K. Campbell, Janssen Research and Development, LLC, 3.

To cite this abstract in AMA style:

Jordan J, Sweet K, Cesaroni M, Ma K, Franks C, Seridi L, Schreiter J, Gordon R, Lipsky PE, Rose S, Baribaud F, Loza M, Campbell K. Ustekinumab Treatment Response in SLE Is Associated with Changes in Type II but Not Type I Interferons [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/ustekinumab-treatment-response-in-sle-is-associated-with-changes-in-type-ii-but-not-type-i-interferons/. Accessed .
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