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ARD Online First, published on June 2, 2015 as 10.1136/annrheumdis-2014-206090 Basic and translational research
EXTENDED REPORT
A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE) Kenneth C Kalunian,1 Joan T Merrill,2 Romeo Maciuca,3 Jacqueline M McBride,3 Michael J Townsend,3 Xiaohui Wei,3 John C Davis Jr,3 William P Kennedy3 Handling editor Tore K Kvien ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ annrheumdis-2014-206090). 1
Department of Medicine, University of California San Diego, La Jolla, California, USA 2 Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA 3 Genentech, South San Francisco, California, USA Correspondence to Dr Kenneth C Kalunian, Rheumatology, Allergy, and Immunology, UC San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0943, USA;
[email protected] Received 13 June 2014 Revised 6 March 2015 Accepted 22 March 2015
ABSTRACT Objectives To examine the safety and efficacy of rontalizumab, a humanised IgG1 anti-interferon α (anti-IFN-α) monoclonal antibody, in patients with moderate-to-severe systemic lupus erythematosus (SLE). Methods Patients with active SLE were randomised (2:1) to 750 mg intravenous rontalizumab every 4 weeks or placebo (Part 1), and 300 mg subcutaneous rontalizumab every 2 weeks or placebo (Part 2). Background Hydroxychloroquine and corticosteroids were allowed. Patients taking immunosuppressants at baseline were required per protocol to discontinue. Efficacy end points included reduction in disease activity by British Isles Lupus Disease Activity Group (BILAG)2004 ( primary), and SLE response index (SRI, secondary) at Week 24. Efficacy was also examined by an exploratory measure of IFN-regulated gene expression (interferon signature metric, ISM). Results Patients (n=238) received rontalizumab (n=159) or placebo (n=79). At baseline, the mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) score in all cohorts was ∼10, and 75.6% of patients had a high ISM (ISM-High). Efficacy response rates by BILAG and SRI were similar between rontalizumab and placebo groups. However, in the exploratory subgroup of ISM-Low patients, SRI response was higher and steroid use was lower in the rontalizumab-treated patients. There was also a reduction in SELENA-SLEDAI flare index rates (HR 0.61, 0.46 to 0.81, p=0.004) in this subgroup. Adverse events were similar between placebo and rontalizumab groups. Conclusions The primary and secondary end points of this trial were not met in all patients or in patients with high ISM scores. In an exploratory analysis, rontalizumab treatment was associated with improvements in disease activity, reduced flares and decreased steroid use in patients with SLE with low ISM scores. Trial registration number NCT00962832.
INTRODUCTION
To cite: Kalunian KC, Merrill JT, Maciuca R, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/annrheumdis2014-206090
Systemic lupus erythematosus (SLE) is characterised by activation of the innate and adaptive immune systems and by autoantibody production.1 Although current management of SLE has decreased patient mortality,2 disability from accelerated atherosclerosis,3 and accumulation of tissue damage4 contributes to earlymortality.5 Therefore, newer more targeted treatments with improved safety profiles are still needed.6 7
A large body of evidence has implicated interferon α (IFN-α) in SLE.8 9 Elevated serum levels of IFN-α in patients with SLE correlate with disease activity and flares in cross-sectional studies.10–15 Therapeutic use of recombinant IFN-α(2a) can lead to a reversible form of drug-induced lupus,16 and genome-wide association studies have identified risk polymorphisms in SLE within IFN-regulated genes.17–19 Microarray of mononuclear cell RNA has shown IFN-inducible gene overexpression in both adult20 21 and paediatric22 patients. Rontalizumab is a human anti-IFN-α monoclonal antibody that neutralises all 12 IFN-α subtypes, preventing signalling through the type I IFN receptor. Rontalizumab does not bind to IFN-β or IFN-ω. Based on acceptable safety and pharmacodynamic effects in a Phase I study in patients with mild SLE,23 a multicentre, randomised, placebocontrolled Phase 2 efficacy and safety trial (ROSE: Rontalizumab in Systemic Lupus Erythematosus) was conducted with rontalizumab.
METHODS Study design This multicentre, randomised, double-blind, placebocontrolled trial comprised two sequential placebocontrolled substudies (figure 1) (Part 1 and Part 2; 24 weeks each), followed by an open-label safety extension study (Part 3, up to 144 weeks). Part 1 started in September 2009; Part 2 started in August 2010. Patients completing Part 1 or Part 2 were eligible for the open-label safety extension (Part 3). Patients who did not enter Part 3 returned for monthly safety follow-up visits for 48 weeks.
Entry criteria Eligible patients met ≥ four of the revised American College of Rheumatology classification criteria for SLE,24 and had current or past evidence of an antinuclear antibody titre of ≥1:80. Active disease as defined by the British Isles Lupus Disease Activity Group (BILAG) index25 was required: either severe activity (BILAG A) in ≥ one domain or moderate (BILAG B) disease in ≥ two domains.26 27 Key exclusion criteria included active lupus nephritis, unstable neuropsychiatric lupus, severe or unstable antiphospholipid antibody syndrome, current or recent history of systemic bacterial, fungal, viral or parasitic infections, or prior B cell directed therapy (within 12 months). Immunosuppressants were discontinued at randomisation (24–36% of patients).
Kalunian KC, et al. Ann Rheum Dis 2015;0:1–7. doi:10.1136/annrheumdis-2014-206090
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Basic and translational research Figure 1 Schema for the two part Phase 2 trial (ROSE) in patients with SLE. FPI, first patient; IV, intravenous; ROSE, Rontalizumab in Systemic Lupus Erythematosus; SC, subcutaneous.
This clinical trial approach has been discussed previously.28 29 Patients could receive a short course of oral steroids, 0.25– 0.5 mg/kg/day prednisone (or equivalent), during screening followed by a taper to ≤10 mg/day by Week 6 after randomisation. Permitted background treatments included non-steroidal antiinflammatory drugs, antimalarials, ACE inhibitors, angiotensin receptor-blocking agents, osteoporosis therapies and statins. Additional rescue treatment for SLE could be provided, but this use constituted a treatment failure. After randomisation, steroid increases exceeding the lowest achieved dose by ≥20 mg for ≥14 days, or any increase exceeding the lowest achieved dose by ≥10 mg for ≥28 days, constituted a treatment failure. At Weeks 20–24, ≥20 mg of prednisone equivalent on any day during this 4-week period, or 10–20 mg/day prednisone equivalent for ≥7 days (cumulative), constituted treatment failure.
Randomisation After screening, patients in Part 1 were separately randomised 2:1 to receive intravenous rontalizumab 750 mg or placebo intravenous infusion monthly until Week 20. In Part 2, patients were randomised 2:1 to receive subcutaneous rontalizumab 300 mg or a placebo every 2 weeks until Week 22. Randomisation was managed by a central interactive web response system vendor using a permuted blocks randomisation schedule. Patients were stratified by prior use of immunosuppressants within the preceding 12 months and by race/ethnicity.
Efficacy evaluations Measures of disease activity were the BILAG index, SELENA-SLEDAI, (SLE Disease Activity Index modified for the Safety of Estrogens in Lupus National Assessment trial) and the Physician Global Assessment (PGA). Trial investigators completed extensive training on the use of BILAG and SELENA-SLEDAI scoring, including investigator meeting training, web-based training and verification of training. Enrolment of patients using BILAG criteria was adjudicated by a committee of SLE experts. Evaluations were performed every 4 weeks through Week 36 and every 12 weeks thereafter. Randomised patients with ≥ one postbaseline efficacy assessment were included in all efficacy analyses. The primary end point was the proportion of patients who at Week 24 achieved reduction of all BILAG A domains present at randomisation to BILAG B or better and all BILAG B domains to BILAG C or better with no new BILAG A or more than one new BILAG B and without being classified as treatment failure due to additional therapies. The key secondary outcome measure was proportion of patients who achieved the SLE response index (SRI)-4 response30 31 at Week 24. A prespecified exploratory analysis of the treatment response by these end 2
points in patients stratified by baseline interferon signature metric (ISM) status was conducted. Other exploratory objectives included percentage of patients with a decreased use of steroids and flare rates defined by the SELENA-SLEDAI Flare Index.32 33
Safety assessments Safety was evaluated by the incidence, nature, severity and drug relatedness of adverse events (AEs), graded according to the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI–CTCAE) V.3.0. Lupus flares were captured with the flare outcome measures and not as AEs unless they were serious events.
Diagnostic, pharmacodynamic and other biomarkers Anti-dsDNA, C3, C4 and antinuclear antibody levels were reported by Covance central laboratories (see online supplementary methods). A bridging-antibody ELISA was validated to detect antibodies to rontalizumab (antitherapeutic antibodies) in human SLE serum.34 Exploratory measures included baseline evaluation of the gene expression ISM, a 3-gene set of IFN-regulated genes used as a surrogate for the global IFN gene expression signature in patients with SLE (Townsend et al,35 submitted). The ISM surrogate (HERC5, EPSTI and CMPK2) for the IFN signature was optimised to detect overall differences in gene expression between identifiable subgroups of patients with lupus. Specific pharmacodynamic evaluations of rontalizumab blockade on IFN-gene expression were assessed by quantitative PCR gene expression changes from seven IFN-regulated genes (IFI27, IFI44, IFIT1, MX1, OAS1, OAS2 and OAS323) at baseline and post dose on Weeks 2, 4, 8, 12, 16, 20, and 24.
Statistical methods The sample size was selected for adequacy (0 Dose >10 ISM-High BILAG index (screening) ≥2A ≥1A BILAG index global score SELENA-SLEDAI score PGA score Immunoserology ANA positive (≥1:80) Complement C3 Low (
