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Background and Aims

Joint involvement, a frequent manifestation of SLE, can be assessed using global lupus disease activity indices (SLEDAI-2K, BILAG-2004) and/or by assessing joint tenderness and swelling (28-joint count).¹ This post-hoc analysis evaluated changes in joint manifestations in the LILAC Part A trial of BIIB059 versus placebo (NCT02847598)² using various definitions.

Methods

The randomized, double-blind, placebo-controlled LILAC Part A study included SLE participants with ≥4 tender and ≥4 swollen joints, active skin disease, and positive lupus antibodies (ANA and/or anti-dsDNA). “Joint-50” response was defined as a 50% reduction from baseline in active joint count at Week-24. Three definitions of total active joint count were used: (1) sum of total tender plus total swollen joints; (2) sum of joints that were tender and/or swollen; (3) sum of joints that were both tender and swollen. Arthritis scored on SLEDAI-2K and BILAG-2004 was also analyzed.

Results

The analysis included 56 and 46 participants treated with BIIB059 450mg and placebo, respectively. At Week-24, a greater proportion of BIIB059-treated participants achieved a Joint-50 response compared to placebo; findings were consistent across the 3 definitions (Figure). The percentage of participants with resolution of arthritis by SLEDAI-2K was greater in BIIB059-treated participants (48.2%) versus placebo (21.7%); similar findings were seen with the BILAG-2004 arthritis (musculoskeletal domain) evaluation. Incidence and severity of AEs were similar with BIIB059 versus placebo in LILAC Part A.

Conclusions

BIIB059 treatment was associated with improvement in SLE arthritis. More participants achieved a Joint-50 response with BIIB059 versus placebo, regardless of how active joint count was defined.

1.Mahmoud.CurrOpinRheumatol.2017;29(5):486-492.

2.Furie.ArthRheumatol.2020;72(S10):0935

Background and Aims

Baricitinib, a Janus kinase (JAK)1/JAK2 inhibitor, improved disease activity in systemic lupus erythematosus (SLE) adults receiving standard background therapy in a phase 2 trial (NCT02708095).¹ The aim of this study was to elucidate the mechanism of action of baricitinib in SLE.  

Methods

Patients with SLE were treated with baricitinib-2mg or -4mg in a phase 2, randomized, placebo-controlled study. Sera from 68 patients (baricitinib-2mg: n=29; baricitinib-4mg: n=25; placebo: n=14) were collected at baseline and Week 12 and analyzed for cytokines using a Proximity Extension Assay (PEA) with 87 detectable analytes (Target 96 Inflammation Panel (Olink)). Interferon (IFN) scores were determined using a Modaplex assay. Spearman correlations were computed. Analyte changes from baseline at Week 12 were compared between baricitinib-4mg and placebo groups by Wilcoxon rank-sum or t-tests. Adjusted p<0.05 was considered significant.

Results

At baseline, CXCL10 (r=0.50), CXCL11 (r=0.38), and CCL19 (r=0.45) correlated with the IFN signature. Confirming previous findings using Quanterix assays², PEA analysis indicated that baricitinib-4mg, but not placebo, reduced IL-6 and IL-12p40 in SLE. Additionally, baricitinib-4mg significantly downregulated 1) serum cytokines that mediate lymphocyte and monocyte/macrophage recruitment (CCL19, TNFRSF9, TNF-β/Lymphotoxin-α), and 2) cytokines that induce bone turnover and augment joint pain (TRANCE/RANKL and Artemin).

Conclusions

These results suggest that downregulation of key cytokines that have proinflammatory and/or regulatory functions may play a role in the mechanism by which baricitinib acts to improve SLE disease activity.

References

1) Wallace DJ, et al. Lancet. 2018;392(10143):222-31.

2) Dörner T, et al. Lupus Sci Med. 2020;7(1).

Background and Aims

Toll-like receptors 7 and 8 (TLR7/8) detect single-stranded viral RNA, initiating immune cell activation, differentiation, cytokine secretion, antibody production and NETosis. M5049, a highly potent and selective TLR7/8 inhibitor, is being investigated for autoimmune conditions such as SLE, in which aberrant TLR7/8 activation by endogenous RNA is implicated.

Methods

Compound potency was optimized in TLR7/8-stimulated cells. Pharmacokinetic and pharmacodynamic (PK/PD) activity and efficacy in lupus models were assessed in mice. Population PK/PD models were developed from first-in-human (FIH) data of M5049 in healthy participants receiving single or multiple daily doses from 1–200mg (NCT03676322). Dose simulations were performed to identify regimens achieving target PD inhibition with adequate safety margins.

Results

In mice, M5049 demonstrated dose-dependent inhibition of cytokine release, long duration of action, and ≥1mg/kg suppressed disease development in BXSB-Yaa and interferon-α accelerated NZB/W lupus models. In humans, simulations suggested 25 and 100mg M5049 twice daily (BID) would maintain concentrations above 60% and 90% PD (cytokine) inhibition, respectively, throughout the dosing interval. Supported by non-clinical and FIH safety data, M5049 doses of 25mg and up to 150mg BID are investigated to assess safety, PK and PD in lupus patients.

Conclusions

M5049 effectively reduces lupus pathogenesis in mice. Based on PK, PD and safety data from a successfully completed FIH study, and model-informed dose selection guided by preclinical knowledge, a Phase Ib study was initiated investigating oral M5049 as a novel therapy for SLE and CLE patients (NCT04647708).

Acknowledgements: Merck KGaA, Darmstadt, Germany, fund M5049 development. Bioscript, Macclesfield, UK, provided medical editing support.