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

Abstract

ObjectiveTo assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure.MethodsA phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab.ResultsThe IFNGS was suppressed by a median of 53–66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle.ConclusionsSifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.

Type I interferons mediate pancreatic toxicities of PERK inhibition

“…Current medical efforts are focused on the development of antibody-based drugs (sifalimumab, rontalizumab, etc.) for neutralizing IFNAR1 in patients with diverse inflammatory/ autoimmune syndromes (61,62). Our data suggest that a similar strategy could be potentially envisioned for relieving IFN-mediated pancreatotoxicity in patients with Wolcott-Rallison or patients who receive PERK inhibitors for treating tumors (22)(23)(24) and prion-mediated neurogenerative disorders (25).…”

Current pharmacological treatment of idiopathic inflammatory myopathies

“…Gevokizumab, a potent monoclonal antibody binding strongly to IL-1 beta, is currently being studied in a global clinical trial [89]. In a first phase 1b clinical trial [91], sifalimumab showed a moderate suppression of cluster of genes induced by type I IFN, highly over-expressed in IIM patients compared to controls. Positive correlation between gene neutralization and improvement of muscle strength by MMT8 was also recorded.…”

Immunotherapies for Immune-Mediated Myopathies: A Current Perspective

“…Therefore, MEDI-545 (Sifalimumab), an anti-IFN-α monoclonal antibody, was trialed in refractory PM/DM (NCT00533091). This phase 1B study found suppression of IFN in blood and muscle and some clinical improvement, suggesting that further studies may be worthwhile [106].…”