Gateway for Drug Development is in Key Cytokines

Key therapeutic targets for rheumatic diseases have been explored in the past decade, including targets for agents with robust clinical efficacy, as well as those with preliminary or preclinica data that supports their further development, according to a review published in a recent issue of Nature Reviews Rheumatology.

Translational studies in rheumatology have been particularly promi­nent in the field of cytokine biology, stated the authors, led by Nunzio Bottini of La Jolla Institute for Allergy and Immunology in La Jolla, Calif. In 2005, IL‑17 producing T helper 17 cells were first characterized and then IL‑23 was defined as a critical cytokine for their differentiation. Now, “abundant data implicate this pathway in rheumatic diseases,” they stated.

The anti-IL‑17 antibody secukinumab is effective in psoriasis and psoriatic arthritis. The anti-IL‑12 and IL‑23 antibody ustekinumab received FDA approval for psoriasis in 2009 and for psoriatic arthritis in 2013, and changed the therapeutic landscape of psoriasis, they stated. These agents have only modest efficacy in rheumatoid arthritis.

In the past decade, researchers discovered a critical role for IL‑1  in the inflammasome and autoinflammatory diseases.

“IL-1 inhibition lost its luster owing to the disappointing results in RA, but enthusiasm re-emerged into the past decade with the discovery of a critical role for Il-1 in the inflammasome and the autoinflammatory diseases,” the authors of the review wrote. Three anti-IL‑1 agents showed “remarkable efficacy” in cryopyrin-associated periodic syndromes (CAPS) were approved for use in the U.S., they wrote.

In 2003, researchers observed that leukocytes from patients with systemic lupus erythematosus (SLE) have a type I interferon (IFN) transcriptome signature. Multiple translational studies have focused on validating type I IFN as a drug target for SLE and other autoimmune diseases.

Targeting granulocyte-macrophage colony-stimulating factor, first described in rheumatoid arthritis more than 25 years ago, has now been validated using blocking antibodies in rheumatoid arthritis.

Approaches that target cell lineages implicated in pathogenesis have also shown progress. In 2011, rituximab received FDA approved based on studies demonstrating the critical role of antibodies and B cells in anti-neutrophil cytoplasmic antibody-positive vasculitis.

B cells also received much attention in systemic lupus erythematosus (SLE) research, in particular B cell stimulating factors (BAFF), what the authors call a tumor necrosis factor “superfamily member.” The anti-BAFF antibody belimumab received FDA approval for SLE in 2011, however, the authors state its benefits are limited and clinical utilization is modest.

“Neutrophils have also emerged as criti­cal players in SLE and RA,” they stated. They pointed out that NETosis – the process by which neutrophils from patients with SLE extrude portions of their nuclei and cytoplasm (neutrophil extracellular traps) - is now recognized as a critical pathway for presentation of altered antigens and self-antigens, and is a key mediator of innate immunopathology in lupus.

The janus kinus inhibitor tofacitinib was developed and approved for the treatment of rheumatoid arthritis in 2012. Although other results in signaling research have been mixed, kinases remain high-profile targets in rheumatology, they stated.

​Genome-wide association studies (GWAS) have identified clear associations with IL-23 in ankylosing spondylitis and CD40 in rheumatoid arthritis, leading to exploration into drug targets. However, GWAS have been unable to capture the influences on complex rheumatic diseases.

Current biomarker research is increasingly driven by knowl­edge of disease mechanisms, they stated.

“Translational studies will hopefully provide clues on the best ways to select patients for ‘personalized’ approaches to therapy,” they concluded.

References:

Nunzio Bottini and Gary S. Firestein, “

Ten years after: rheumatology research from bench to bedside

,” 

Nature Reviews Rheumatology

 11, 623–624 (2015) doi:10.1038/nrrheum.2015.126. Published online 22 September 2015.