Op0250 efficacy and Safety of Romilkimab in Diffuse Cutaneous Systemic Sclerosis (Dcssc): Randomized, Double-Blind, Placebo-Controlled, 24-Week, Proof of Concept Study

Abstract

Background:Systemic sclerosis (SSc) is a progressive, multi-organ disease with limited treatment options. Interleukin-4 (IL-4) and IL-13 have been implicated in the fibrotic pathway and pathogenesis of SSc and are promising targets. Romilkimab (RKB) is an engineered humanized bispecific Ig-G4 antibody that binds and neutralizes both IL-4/IL-13. We report a Phase IIa randomized, double-blind, placebo-controlled trial (NCT02921971, Sanofi funded) employing RKB in SSc.Objectives:To evaluate the efficacy and safety of RKB in dcSSc.Methods:Patients with dcSSc duration ≤36 months, mRSS 10-35, with or without immunosuppressive background therapy were randomized (1:1) to subcutaneous RKB 200mg or placebo (PBO) for 24 weeks and stratified on history of SSc-ILD. Primary endpoint was mean change in mRSS at Week 24 and FVC/DLco and HAQ-DI were secondary endpoints. All analyses used a 1-sided p-value <0.05 as reaching statistical significance.Results:Ninety-seven patients with similar baseline characteristics between arms, including use of background therapy (RKB 59.2% vs. PBO 52.1%) were randomized. Six (12.2%) and 4 (8.3%) patients discontinued study treatment early in the PBO and RKB arms, respectively. Primary endpoint showed an absolute change in mRSS of -2.45 (0.85) and -4.76 (0.86) for PBO and RKB groups, respectively with a difference of -2.31 (1.21) favoring RKB (p=0.029). Subgroup analysis based on background therapy showed a similar treatment effect with a PBO subtracted difference in mRSS of -2.69 (1.83) and -2.38 (1.59), suggesting an additive effect between background therapy and RKB. Secondary endpoints did not show a statistically significant difference between RKB vs. PBO arms, although there was numerically less decline in FVC with RKB with a PBO subtracted difference of 70ml (p=0.06). Exploratory endpoints suggested possible effect of RKB on overall pain, Raynaud’s, digital ulcers, and EQ-5D-5L. Post-hoc analysis was undertaken to determine time to progression (first event defined as death, ≥10% relative decline in % predicted FVC, ≥15% relative decline in % predicted DLCO, ≥20% increase or +5 in mRSS, or other events: cardiac, SRC, PAH development) and showed a benefit for RKB (HR: 0.47 p=0.04). Adverse events were balanced between the two groups (RKB 83.3% vs. PBO 83.7%). There were 5 and 4 SAEs in the PBO and RKB arms, respectively. One death occurred in each arm (SRC – RKB, cardiomyopathy – PBO).Conclusion:Patients with dcSSc who were treated with RKB showed a statistically significant reduction in mRSS compared to those receiving PBO. Secondary outcomes were not met, although RKB was associated with a smaller decline in FVC than PBO. Post-hoc analysis showed a possible reduction on time to progression with RKB. RKB was well tolerated with no major safety concerns.References:None.Disclosure of Interests:Yannick Allanore Grant/research support from: Yannick Allanore has received grants from Inventiva, Roche and Sanofi, Consultant of: Yannick Allanore has received fees from Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Curzion, Inventiva, Roche, Sanofi, Peter Wung Shareholder of: I own Sanofi stock, Employee of: I work for Sanofi, Christina Soubrane Employee of: I work for Sanofi., Corinne Esperet Employee of: I work for Sanofi., MARRACHE Frederic Employee of: I work for Sanofi, Raphael Bejuit Employee of: I work for Sanofi., Amel Lahmar Employee of: I work for Sanofi., Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer

Generation of a novel CD30+ B cell subset producing GM-CSF and its possible link to the pathogenesis of systemic sclerosis

“…We here clearly show that IL-4 and IL-13 generate a novel B cell subset (GM-Beffs) which was increased in patients with SSc. It should be noted that romilkimab, a humanized bispecific IgG4 antibody that binds and neutralizes both IL-4/IL-13, was effective for diffuse cutaneous SSc in a phase Ⅱa randomized, double-blind, placebo-controlled trial (NCT02921971) [41]. This treatment thus would in theory selectively suppress the induction of GM-Beffs.…”

Recent advances in the treatment of systemic sclerosis associated interstitial lung disease

“…Future possibilities for the treatment of CTD-ILD arise from elucidating the role Th2-driven immune response plays in the pathogenesis of systemic sclerosis. Romilkimab, an anti-IL-4 and anti-IL-13 antibody (79,80), has shown promising results in animal models and is currently undergoing Phase II trials (Effectiveness and Safety of SAR156597 in Treating Diffuse Systemic Sclerosis, NCT02921971). Aside from using immunomodulatory therapies on their own, future directions for combined antifibrotic and immunomodulatory therapies in CTD-ILD will hopefully come from the Scleroderma Lung Study-3 (SLS-3) trial, which will compare the effect of the combination of pirfenidone and mycophenolate with mycophenolate and placebo on FVC at 18 months 55 .…”

Recent progress in treatments of rheumatoid arthritis: an overview of developments in biologics and small molecules, and remaining unmet needs

“…However, ABT-122, which is a bispecific antibody against TNF and IL-17, has not been demonstrated to be equivalent or superior to anti-TNF antibodies with respect to efficacy in the treatment of MTX-refractory RA [ 20 ]. Although a study has shown that romilkimab, a bispecific antibody against IL-4 and IL-13, inhibits the progression of sclerema in systemic scleroderma, the study was discontinued because it was less effective on lung function [ 21 ]. Rozibafusp (AMG 570), a bispecific antibody against inducible T cell costimulator ligand expressed by follicular T cells and soluble B cell activating factor stimulating B cells, is currently being examined in phase II clinical trials on RA and SLE [ 22 ].…”