A randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis

Abstract

ObjectivesRecent advances in systemic sclerosis (SSc) show that it involves a T-helper type-2-oriented immune response with interleukin (IL)-4 and IL-13. Romilkimab is an engineered, humanised, bispecific immunoglobulin-G4 antibody that binds and neutralises IL-4/IL-13 making it ideal for exploration in fibrosis.MethodsPatients aged ≥18 years diagnosed with diffuse cutaneous SSc (dcSSc), and with or without immunosuppressive background therapy, were randomised (1:1) to subcutaneous romilkimab 200 mg or placebo one time per week for 24 weeks in this double-blind, proof-of-concept, phase II study. The primary endpoint was change in modified Rodnan skin score (mRSS) from baseline to week 24.ResultsNinety-seven patients were randomised to romilkimab (n=48) or placebo (n=49) for 24 weeks. Least-squares mean (SE) change in mRSS was –4.76 (0.86) for romilkimab versus –2.45 (0.85) for placebo yielding a mean (SE) (90% CI) difference of –2.31 (1.21) (–4.32 to –0.31; p=0.0291, one-sided). Treatment-emergent AEs were balanced between placebo (n=41; 84%) and romilkimab (n=40; 80%). Most were mild-to-moderate and discontinuations were low (three overall). There were two deaths (one scleroderma renal crisis (romilkimab) and one cardiomyopathy (placebo)), neither were considered treatment related. Two patients in the placebo group had a cardiovascular treatment-emergent SAE (one cardiac failure, one cardiomyopathy), but there were no cardiac safety signals with romilkimab.ConclusionThis study demonstrated significant effects on skin changes with romilkimab in early dcSSc that require confirmation with a longer and more comprehensive phase III study to determine clinical relevance.Trial registration numberNCT02921971.

Distinct T cell chromatin landscapes in scleroderma subtypes

“…The Th2 cytokines IL-4 and IL-13 are both detected at higher serum levels in SSc patients (Allanore et al, 2020), and have been implicated as drivers of PAH (Christmann et al, 2011;Kumar et al, 2015;Soon et al, 2010;Sweatt et al, 2019). Combined with the clinicallydocumented association between ACA+ and PAH development, these results support our proposed model that ACA carriage is connected to the Th2 fibrosis-promoting pathway whereas RNAIII carriage is associated with an alternative pathway involving less Th2 activity ( Figure 6D).…”

“…Our study results suggest that targeted therapies to modulate Th2 activity can potentially be a specific and effective treatment option for ACA+ and/or for male patients with high levels of Th2-cytokines. In particular, IL-4 and IL-13 have emerged as promising therapeutic targets in SSc (Gasparini et al, 2020), and two drugs are in clinical trials: (1) Dupilumab (DB12159), an anti-IL-4 and IL-13 monoclonal antibody used to treat atopic dermatitis, is currently in Phase II trials for localized SSc (trial identifier: NCT04200755, 2019-002036-90, Uni-Koeln-3815) and (2) romilkimab (SAR156597), an IL-4 and IL-13 neutralizing IgG bi-specific antibody that appears to significantly improve skin fibrosis based upon the results of a Phase II trial in patients with early dcSSc (Allanore et al, 2020). It is important to note that neither trial published the autoantibody profile of enrolled patients and thus, it is unclear if targeted IL-4/IL-13 therapy was more effective in ACA+ than RNAIII+ patients or whether study outcomes were affected by a preponderance of ACA+ or RNAIII+ subjects in these Phase II trials.…”

Idiopathic pulmonary fibrosis and systemic sclerosis: pathogenic mechanisms and therapeutic interventions

“…2 ). However, a recent study involving the therapeutic blockade of two of the key cytokines of type 2 immunity, IL-4 & IL-13, underscores the importance of type 2 inflammation in dermal fibrosis [ 133 ]. This study establishes one of the first direct lines of evidence to connect type 2 inflammation in human fibrosis.…”

Pharmacological Interventions for Pulmonary Involvement in Rheumatic Diseases

“…A phase 2 RCT of bortezomib plus MMF versus MMF alone on patients with SSc-ILD is currently ongoing ( number, NCT02370693). Romilkimab, a monoclonal antibody targeting IL-4 and IL-13, showed efficacy after 24 weeks on skin fibrosis associated with diffuse SSc under background immunosuppressive agents in a phase 2 pilot study [ 82 ]. However, it failed to show benefits in the of IPF after 52 weeks [ 83 ].…”