Background/Purpose:

Dysregulation of interferon alpha (IFN) activity and/or signaling is implicated in systemic lupus (SLE).    This randomized, double-blind, placebo-controlled, two part Phase 2 study (ROSE) evaluated the efficacy and safety of intravenous (IV) and subcutaneous (SC) rontalizumab, a humanized IgG1 antibody against all anti-interferon alpha isoforms, in adults with moderate to severe extrarenal SLE. 

Methods: Subjects were randomized 2:1 in sequential cohorts to: 750 mg IV q4wk rontalizumab or placebo (pbo) (part 1) and 300 mg SC q2wk rontalizumab or pbo (part 2).  Immunosuppressants were stopped at randomization, and steroids were to be tapered to ≤10mg/day by Week 8.  Rescue therapy was allowed for worsening of disease but defined as treatment failure. Efficacy endpoints included reduction in disease activity by the BILAG (primary), and the SLE Response index (SRI, secondary) at week 24.   Exploratory measures included the Interferon Signature gene expression as Metric (ISM) at baseline. Pharmacokinetics (PK) and immunogenicity of rontalizumab were assessed. 

Results:

159 subjects received rontalizumab (81 IV and 78 SC) and 79 received pbo.  Subjects were 94% female with mean age of 39 years. At baseline, the mean SELENA-SLEDAI (SS) was 9.8, and the most common disease manifestations involved musculoskeletal and mucocutanenous systems. 76% of subjects were ISM-High.  Baseline disease activity was comparable in ISM-High and ISM–Low subjects except for higher likelihood of autoantibodies and low complement in ISM-High subjects vs ISM-Low: (anti-dsDNA 71% vs 34%, anti-ENA 73% vs 19% and low C3 43% vs 16%, respectively).  Overall, response rates by BILAG and SRI were similar between rontalizumab and pbo groups.  However, rontalizumab vs pbo SRI response was 55% vs 31% in those on >10 mg prednisone at baseline (56% vs 23% and 54% vs 38% in the IV and SC groups, respectively).  In a biomarker-defined pre-specified subgroup, ISM-Low subjects, rontalizumab vs pbo SRI response rates were 75% vs. 18%, and 75% vs. 62% in the IV and SC groups, respectively. The estimated treatment difference of SRI response in rontalizumab and pbo ISM-Low arms was 31% (90% CI: 9-51%, p=0.0285).  A reduction in SS flare rates occurred in rontalizumab subjects vs. pbo: hazard ratio 0.61 (0.46-0.81, p=0.0040), driven by ISM-Low subjects.  A greater percentage of subjects achieved prednisone reduction (≤10 mg/day) by week 24 in the rontalizumab ISM-Low group:  91% vs. 67% pbo.   Incidence of adverse events (AE) was comparable between pbo and rontalizumab-treated subjects.  The most common AEs were UTI, URI, headache, and nausea.  There were more SAEs from SLE flares in the active group (n=10, 6%) vs. pbo (n=1, 1%), which occurred only in ISM-High subjects.  Treatment emergent anti-therapeutic antibodies were uncommon (1/159, 0.6%) and did not appear to affect safety or PK.

Conclusion: Rontalizumab treatment in the absence of immunosuppressants was associated with improvement in signs and symptoms of SLE, flare rates and steroid burden at week 24 in a pre-specified biomarker defined group of ISM-Low moderate to severely active lupus subjects.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-and-safety-of-rontalizumab-anti-interferon-alpha-in-sle-subjects-with-restricted-immunosuppressant-use-results-of-a-randomized-double-blind-placebo-controlled-phase-2-study/