Prezalumab

Sjögren's syndrome (SS) is a prototype autoimmune disease characterized by oral and ocular mucosal dryness following chronic inflammation of salivary and lachrymal glands, respectively. Profound B cell hyperactivity along with systemic manifestations including fatigue, musculoskeletal complaints, features related to hepatic, pulmonary, renal and nervous system involvement, as well as lymphoma development can be also present. Despite that activation of both innate and adaptive immune pathways has been long well documented in SS pathogenesis, systemic immunosuppression in SS, in contrast to other autoimmune diseases, has been largely inefficacious. Biological agents previously implemented in successful therapeutic outcomes in rheumatoid arthritis (RA), such as anti-TNF agents, anakinra, tocilizumab and rituximab failed to reach primary outcomes in randomized double-blind controlled trials in the context of SS. Abatacept and belimumab, already licensed for the treatment of RA and lupus respectively, as well combination regimens of both rituximab and belimumab hold some promise in alleviation of SS-specific complaints, but data from large controlled trials are awaited. Recent advances in dissecting the molecular pathways underlying SS pathogenesis led to an expanding number of novel biological compounds directed towards type I interferon system, antigen presentation, costimulatory pathways, B and T cell activation, as well as germinal center formation. While targeting of cathepsin-S (Petesicatib), inducible costimulator of T cells ligand (prezalumab), and lymphotoxin beta receptor (baminercept) failed to fulfil the primary outcome measures, preliminary results from two randomized placebo controlled trials on CD40 blockade (Iscalimab) and B-cell activating factor receptor (Ianalumab) inhibition resulted in significant reduction of SS disease activity, with a favorable so far safety profile. Results from administration of other kinase inhibitors, a transmembrane activator and calcium-modulator and cytophilin ligand interactor TACI fusion protein (RC18), as well as low dose recombinant interleukin-2 to expand T-regulatory cells are currently awaited.

To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis.

In this phase Ib, randomized, double‐blind, placebo‐controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1‐letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4‐point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (–36.3% versus –24.7%) and the SLEDAI score (–47.8% versus –10.7%) and in tender (–22.8% versus –13.5%) and swollen (–62.1% versus –7.8%) joint counts on day 169.

AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.