Ann Rheum Dis: first published as 10.1136/annrheumdis-2012-202794 on 23 February 2013. Downloaded from Basic and translational research EXTENDED REPORT A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients Brandon W Higgs,1 Wei Zhu,1 Chris Morehouse,1 Wendy I White,1 Philip Brohawn,1 Xiang Guo,1 Marlon Rebelatto,1 Chenxiong Le,1 Anthony Amato,2 David Fiorentino,3 Steven A Greenberg,2 Jorn Drappa,1 Laura Richman,1 Warren Greth,1 Bahija Jallal,1 Yihong Yao1 Handling editor Tore K Kvien ABSTRACT immunosuppressant drugs associated with a wide ▸ Objective To assess the pharmacodynamic effects range of side effects. There is a strong unmet Additional material is α 4–6 published online only. To view of sifalimumab, an investigational anti-IFN- monoclonal medical need for better therapeutic alternatives. please visit the journal online antibody, in the blood and muscle of adult The role of type I IFN in the pathogenesis of myo- (http://dx.doi.org/10.1136/ dermatomyositis and polymyositis patients by measuring sitis has been well documented. Immunohistochemical annrheumdis-2012-202794). neutralisation of a type I IFN gene signature (IFNGS) studies demonstrate that IFN is elevated in muscle 7 1MedImmune, LLC, following drug exposure. tissue, and plasmacytoid dendritic cells (DC) are Gaithersburg, Maryland, USA Methods A phase 1b randomised, double-blinded, present in the muscle and skin of dermatomyositis 2 Department of Neurology, placebo controlled, dose-escalation, multicentre clinical patients.89Measuring free IFN-α in the serum is less Brigham and Women’s trial was conducted to evaluate sifalimumab in sensitive compared to measuring type I IFN-inducible Hospital, Harvard Medical 10–13 School, Boston, Massachusetts, dermatomyositis or polymyositis patients. Blood and transcripts, as has been reported in many studies. USA muscle biopsies were procured before and after ThesetypeIIFN-inducibletranscriptsmeasuredinthe 3 Department of Dermatology, sifalimumab administration. Selected proteins were blood of myositis patients correlate with disease activ- – Stanford University School of measured in patient serum with a multiplex assay, in the ity in dermatomyositis.14 18 Reports have recently Medicine, Redwood City, California, USA muscle using immunohistochemistry, and transcripts were indicated that the type I IFN signature in the blood of profiled with microarray and quantitative reverse dermatomyositis patients correlates with IFN-β,not Correspondence to transcriptase PCR assays. A 13-gene IFNGS was used to IFN-α protein expression.19 Dr Brandon W Higgs, measure the pharmacological effect of sifalimumab. In a phase 1b clinical trial (MI-CP151) in adult One MedImmune Way, LLC, Gaithersburg, MD 20878, Results The IFNGS was suppressed by a median of patients with dermatomyositis or polymyositis 53–66% across three time points (days 28, 56 and 98) evaluating the safety and tolerability of multiple USA; http://ard.bmj.com/ [email protected] in blood (p=0.019) and 47% at day 98 in muscle intravenous doses of sifalimumab, an investigational specimens post-sifalimumab administration. Both anti-IFN-α monoclonal antibody (MI-CP151), we Received 6 October 2012 IFN-inducible transcripts and proteins were prevalently report here the clinical utility of the type I IFN Revised 3 January 2013 Accepted 3 February 2013 suppressed following sifalimumab administration. gene signature (IFNGS) as a pharmacodynamic Published Online First Patients with 15% or greater improvement from baseline marker in both blood and muscle of patients 23 February 2013 manual muscle testing scores showed greater treated with sifalimumab, similar to the approach 10 20–23 neutralisation of the IFNGS than patients with less than used in systemic lupus erythematosus (SLE). on September 24, 2021 by guest. Protected copyright. 15% improvement in both blood and muscle. Pathway/ Blood and/or muscle tissues from a total of 26 functional analysis of transcripts suppressed by dermatomyositis and 25 polymyositis patients were sifalimumab showed that leucocyte infiltration, antigen transcript profiled at baseline (pre-dose) and up to presentation and immunoglobulin categories were most 98 days post initial dose with either placebo or one suppressed by sifalimumab and highly correlated with of four dose levels for sifalimumab. We also exam- IFNGS neutralisation in muscle. ined the effects of sifalimumab on pathways down- Conclusions Sifalimumab suppressed the IFNGS in stream of type I IFN. Finally, correlative trends blood and muscle tissue in myositis patients, consistent were examined between neutralisation of the with this molecule’s mechanism of action with a positive IFNGS and changes in disease activity following correlative trend between target neutralisation and clinical administration of sifalimumab. improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy. Open Access METHODS Scan to access more Myositis patients and controls free content MI-CP151 was a phase 1b randomised, double-blind, INTRODUCTION placebo controlled, dose-escalation, multicentre fl To cite: Higgs BW, Zhu W, The in ammatory myopathies dermatomyositis and study to evaluate multiple intravenous doses of sifali- Morehouse C, et al. Ann polymyositis are rare autoimmune disorders mumab, in adult patients with dermatomyositis or – Rheum Dis 2014;73: affecting skeletal muscle function.1 3 Conventional polymyositis (NCT00533091). Primary trial objec- – 256 262. treatment options for these diseases include tives were to evaluate the safety and tolerability of 256 Higgs BW, et al. Ann Rheum Dis 2014;73:256–262. doi:10.1136/annrheumdis-2012-202794 Ann Rheum Dis: first published as 10.1136/annrheumdis-2012-202794 on 23 February 2013. Downloaded from Basic and translational research sifalimumab in dermatomyositis or polymyositis patients, while The same 13 type I IFN-inducible genes were also used to evalu- one of the exploratory objectives included the assessment of the ate the pharmacodynamics of sifalimumab on target neutralisation effects of sifalimumab on pharmacodynamic markers in blood and in IFNGS-positive patients. The total numbers of dermatomyositis disease tissue. A description of the latter objective is the scientific or polymyositis patients who had specimens available for correla- focus of this paper. Fifty-one patients were enrolled with seven, tive studies at baseline were 26 and 21 for blood, and 23 and 25 eight, 16 and eight patients dosed with sifalimumab at 0.3, 1, 3 for muscle, respectively (see supplementary material, available and 10 mg/kg, respectively, and 12 received placebo. Patients online only, for patient counts at each time point). received treatment for 6 months with 14 doses (every other week In blood, target neutralisation was observed in sifalimumab- dosing), while patients receiving placebo were dosed for 3 months, dosed patients in three dose groups relative to placebo-dosed then switched to sifalimumab for 3 months with seven doses patients after the first dose and sustained to day 98 (figure 1A,B). beginning at day 98. After day 98, placebo-dosed patients crossed over and received Sixty-one different immunosuppressant agents or corticoster- sifalimumab. Graphs displaying target neutralisation up to day oids were used among 37 patients, with prednisone (n=30) and 196 post initial dosing are provided in supplementary figure S3 methotrexate (n=15) being the two most common. No correl- (available online only). The IFNGS in the blood is maximally ation was observed between baseline prednisone or methotrex- neutralised in the 0.3 mg/kg cohort (91% at day 98; p=0.002 ate dose and baseline IFNGS. at all time points). At day 98, the IFNGS is neutralised from MI-CP151 was conducted in accordance with the Declaration 54% to 91% in 0.3, 1.0 and 3.0 mg/kg cohorts (p=0.002, 0.05 of Helsinki, and the study protocol was approved by the institu- and 0.014, respectively). The 10 mg/kg cohort did not show a tional review board at each site. All patients provided written significant difference from placebo at day 98 (p=0.28), informed consent before study-related procedures were per- although this cohort had the smallest sample size (n10mg/kg=4 vs formed. IFNGS scores in blood were prescreened to stratify nplacebo=4). As expected, the placebo-dosed patients showed no patients. The baseline clinical characteristics and IFNGS status target neutralisation across all times points. The median of all summaries are provided in table 1. four dose cohorts combined show that the IFNGS is neutralised For the detailed study inclusion and exclusion criteria, IFNGS from 53% to 66% across the three time points, compared to the calculation, RNA extraction, transcript and protein assays, and placebo (figure 1B; Hotelling’sT2 p=0.019). Dose-dependent immunohistochemistry see supplementary material (available target neutralisation was not observed in the blood. online only). All four sifalimumab cohorts show dose-dependent target neutralisation in muscle that differs from the placebo cohort (figure 1C) with a median for combined sifalimumab cohorts of RESULTS fi Safety profile of sifalimumab 47% target neutralisation ( gure 1D), although the difference was not statistically significant. The medians do, however, show Before day 98, a total of 49 treatment-emergent adverse event a trend towards a difference from placebo, noting that the (TEAE) occurred in 10/12 subjects (83.3%) in the placebo sample sizes for the muscle specimens were generally lower than group and 172 TEAE occurred in 34/39 subjects (87.2%) in the those available from the blood. any sifalimumab group. The most frequent adverse event in The neutralisation of the IFNGS was represented in a heat either group was headache. During open-label sifalimimumab map for each patient at days 28, 56 and 98 post-administration administration on or after day 98, 306 TEAE occurred in 47/51 in blood and day 98 in muscle specimens with either sifalimu- (92.2%) subjects in all cohorts. Anti-drug antibodies to sifalimu- mab or placebo (figure 2).