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.

A phase 2b trial (NCT02345070) was conducted to evaluate the efficacy and safety of two dose levels/regimens of SAR156597 (a bispecific IgG4 antibody that binds and neutralises both circulating interleukin-4 and interleukin-13), in comparison with placebo, administered to patients with idiopathic pulmonary fibrosis (IPF) over 52 weeks.DRI11772 was a multinational randomised double-blind placebo-controlled phase 2b trial. Patients aged >40 years with a documented diagnosis of IPF received SAR156597 200 mg once every week (QW), SAR156597 200 mg once every 2 weeks (Q2W) or placebo, over 52 weeks. The primary efficacy end-point was absolute change from baseline in forced vital capacity (FVC) % predicted at 52 weeks.Of 327 randomised patients, 325 received treatment with placebo (n=109), SAR156597 Q2W (n=108) or SAR156597 QW (n=108). The mean change from baseline in FVC % pred at 52 weeks was –5.8%, –5.2% and –6.3% for the placebo, Q2W and QW arms, respectively (Q2W versus placebo, p=0.59; QW versus placebo, p=0.63). The safety profile observed in the three treatment arms was generally similar, although serious adverse events were more common in the QW arm than in the other arms.The DRI11772 study failed to demonstrate benefit of SAR156597 in the treatment of IPF.

The human ␣-globin gene complex includes three functional globin genes (5-2-␣2-␣1-3) regulated by a common positive regulatory element named HS-40 displaying strong erythroid-specific enhancer activity. How this enhancer activity can be shared between different promoters present at different positions in the same complex is poorly understood. To address this question, we used homologous recombination to target the insertion of marker genes driven by cytomegalovirus or long terminal repeat promoters in both possible orientations either upstream or downstream from the HS-40 region into the single human ␣-globin gene locus present in hybrid mouse erythroleukemia cells. We also used CRE recombinase-mediated cassette exchange to target the insertion of a tagged ␣-globin gene at the same position downstream from HS-40. All these insertions led to a similar decrease in the HS-40-dependent transcription of downstream human ␣-globin genes in differentiated cells. Interestingly, this decrease is associated with the strong activation of the proximal newly inserted ␣-globin gene, whereas in marked contrast, the transcription of the non-erythroid marker genes remains insensitive to HS-40. Taken together, these results indicate that the enhancer activity of HS-40 can be trapped by non-erythroid promoters in both upstream and downstream directions without necessarily leading to their own activation.Human ␣-globin genes are clustered on a single complex located in the telomeric region of the short arm of chromosome 16. This complex includes three functional genes, the embryonic 2 gene and the two fetal/adult ␣2 and ␣1 genes, which are arranged in the order 5Ј-2-␣2-

No 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