EFFICACY AND SAFETY OF THE PROPOSED BIOSIMILAR AFLIBERCEPT, SDZ-AFL, IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: 52-Week Results From the Phase 3 Mylight Study.

PURPOSE: The Phase 3 Mylight study was designed to confirm clinical equivalence of proposed biosimilar aflibercept (SOK583A1; Sandoz [proposed biosimilar aflibercept, SDZ-AFL]) to its reference biologic (Eylea; Regeneron Pharmaceuticals, Inc; Bayer AG [reference aflibercept, Ref-AFL]). METHOD: Mylight was a prospective, double-masked, 2-arm, parallel Phase 3 study. Participants with neovascular age-related macular degeneration were randomized 1:1 to receive eight injections of SDZ-AFL (n = 244) or Ref-AFL (n = 240) over 48 weeks. The primary endpoint was mean change in best-corrected visual acuity score from baseline to Week 8. Secondary endpoints included anatomical outcomes, best-corrected visual acuity at Weeks 24 and 52, safety, and pharmacokinetics. RESULTS: Similarity in mean change in best-corrected visual acuity score was established between SDZ-AFL (n = 235) and Ref-AFL (n = 226) at Week 8 (difference: -0.3 [90% CI, -1.5 to 1.0]) and Week 52. No clinically meaningful differences occurred between groups in anatomical outcomes. Safety profiles were similar, with comparable incidences of treatment-related adverse events (SDZ-AFL: 2.5%; Ref-AFL: 2.9%). The incidence of anti-drug antibodies was similar between groups. Systemic free aflibercept concentrations 24 hours postdose were low and comparable between SDZ-AFL and Ref-AFL. CONCLUSION: Proposed biosimilar aflibercept matched reference aflibercept in efficacy, safety, and pharmacokinetics in participants with neovascular age-related macular degeneration. Therefore, this Phase 3 study confirmed biosimilarity of SDZ-AFL to Ref-AFL.

The tyrosine kinase BMX is an essential mediator of inflammatory arthritis in a kinase-independent manner.

Inflammatory cytokines like TNF play a central role in autoimmune disorders such as rheumatoid arthritis. We identified the tyrosine kinase bone marrow kinase on chromosome X (BMX) as an essential component of a shared inflammatory signaling pathway. Transient depletion of BMX strongly reduced secretion of IL-8 in cell lines and primary human cells stimulated by TNF, IL-1ß, or TLR agonists. BMX was required for phosphorylation of p38 MAPK and JNK, as well as activation of NF-κB. The following epistasis analysis indicated that BMX acts downstream of or at the same level as the complex TGF-ß activated kinase 1 (TAK1)-TAK1 binding protein. At the cellular level, regulation of the IL-8 promoter required the pleckstrin homology domain of BMX, which could be replaced by an ectopic myristylation signal, indicating a requirement for BMX membrane association. In addition, activation of the IL-8 promoter by in vitro BMX overexpression required its catalytic activity. Genetic ablation of BMX conferred protection in the mouse arthritis model of passive K/BxN serum transfer, confirming that BMX is an essential mediator of inflammation in vivo. However, genetic replacement with a catalytically inactive BMX allele was not protective in the same arthritis animal model. We conclude that BMX is an essential component of inflammatory cytokine signaling and that catalytic, as well as noncatalytic functions of BMX are involved.

The lysosomal transmembrane protein 9B regulates the activity of inflammatory signaling pathways.

The intracellular signaling pathway by which tumor necrosis factor (TNF) induces its pleiotropic actions is well characterized and includes unique components as well as modules shared with other signaling pathways. In addition to the currently known key effectors, further molecules may however modulate the biological response to TNF. In our attempt to characterize novel regulators of the TNF signaling cascade, we have identified transmembrane protein 9B (TMEM9B, c11orf15) as an important component of TNF signaling and a module shared with the interleukin 1beta (IL-1beta) and Toll-like receptor (TLR) pathways. TMEM9B is a glycosylated protein localized in membranes of the lysosome and partially in early endosomes. The expression of TMEM9B is required for the production of proinflammatory cytokines induced by TNF, IL-1beta, and TLR ligands but not for apoptotic cell death triggered by TNF or Fas ligand. TMEM9B is essential in TNF activation of both the NF-kappaB and MAPK pathways. It acts downstream of RIP1 and upstream of the MAPK and IkappaB kinases at the level of the TAK1 complex. These findings indicate that TMEM9B is a key component of inflammatory signaling pathways and suggest that endosomal or lysosomal compartments regulate these pathways.

The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells.

Since the identification of the p38 mitogen-activated protein kinase (MAPK) as a key signal-transducing molecule in the expression of the proinflammatory cytokine tumor necrosis factor (TNF) more than 10 years ago, huge efforts have been made to develop inhibitors of p38 MAPK with the intent to modulate unwanted TNF activity in diseases such as autoimmune diseases or sepsis. However, despite some anti-inflammatory effects in animal models, no p38 MAPK inhibitor has yet demonstrated clinical efficacy in human autoimmune disorders. One possible reason for this paradox might relate to the fact that the p38 MAPK signaling cascade is involved in the functional regulation of several different cell types that all contribute to the complex pathogenesis of human autoimmune diseases. In particular, p38 MAPK has a multifaceted role in CD4 T cells that have been implicated in initiating and driving sustained inflammation in autoimmune diseases, such as rheumatoid arthritis or systemic vasculitis. Here we review recent advances in the understanding of the role of the p38 MAPK signaling cascade in CD4 T cells and the consequences that its inhibition provokes in T cell functions in vitro and in vivo. These new data suggest that p38 MAPK inhibitors may elicit several unwanted effects in human autoimmune diseases but may be useful for the treatment of allergic disorders.

The p38 mitogen-activated protein kinase regulates effector functions of primary human CD4 T cells.

The role of p38 mitogen-activated protein kinase in primary human T cells is incompletely understood. We analyzed in detail the role of p38 in the regulation of effector functions and differentiation of human CD4 T cells by using a p38-specific inhibitor and a dominant-negative mutant of p38. p38 was found to mediate expression of IL-10 and the Th2 cytokines IL-4, IL-5, and IL-13 in both, primary naive and memory T cells. In contrast, inhibition of p38 activity did not affect expression of the Th1 cytokines IFN-gamma and TNF induced by TCR-stimulation, but decreased IL-12-mediated IFN-gamma expression. Cytokine expression from established Th2 effector cells was also regulated by p38, however, the role of p38 was less pronounced compared to primary CD4 T cells. p38 MAPK regulated cytokine gene expression at both, the transcriptional level by activating gene transcription and the post-transcriptional level by stabilizing cytokine mRNA. As a result of the effect of p38 on IL-4 expression, p38 activity modulated differentiation of naive precursor T cells by inducing a shift of the Th1/Th2 balance toward the immuno-modulatory Th2 direction. Together, the data suggest that p38 plays a key role in human Th2 cell immune responses.