Kronos Bio, Inc. (Nasdaq: KRON) has announced the selection of KB-7898, a p300 lysine acetyltransferase (KAT) inhibitor, as a development candidate for the treatment of Sjögren’s disease. This marks the company's first foray into autoimmune disease therapeutics, leveraging its proprietary discovery engine focused on transcription factor regulatory networks.
KB-7898 is designed as an orally available therapy to address the underlying mechanisms of Sjögren’s disease, a chronic autoimmune condition affecting an estimated two to four million people in the U.S. The disease is characterized by autoantibody production, chronic inflammation, and lymphocytic infiltration of exocrine glands, leading to dryness symptoms (sicca), systemic effects, fatigue, and chronic pain. Currently, there are no approved treatments that target the root cause of Sjögren’s disease.
Targeting p300 for Immune Modulation
KB-7898 inhibits p300, a cofactor crucial for interferon regulatory factor 4 (IRF4) in mediating immune responses across various cell types, including antibody-producing B cells and cytokine-producing T cells. By targeting p300, Kronos Bio aims to modulate the inflammatory pathways driving Sjögren’s disease.
"Our proprietary discovery engine has enabled us to decode the multifaceted role of p300 across multiple cell types that drive inflammation and to create our second p300 KAT inhibitor—one that may treat autoimmune diseases," said Nobert Bischofberger, Ph.D., president and chief executive officer of Kronos Bio. "Sjögren’s disease symptomatology can significantly impact quality of life and even be life threatening, and patients do not currently have access to an approved therapy that addresses the underlying disease mechanism."
Preclinical Evidence and Future Development
Preclinical data supporting the role of p300 inhibition in inflammatory conditions, including Sjögren’s disease, will be presented at ACR Convergence 2024. Key findings include:
- Inhibition of p300 KAT activity resulted in selective downregulation of pro-inflammatory cytokines such as TNFα, IL-23, IL-17A, and soluble IgG.
- Selective gene expression changes occurred at doses corresponding to partial inhibition of p300 KAT activity.
- p300 KAT inhibition significantly decreased inflammation in a rat collagen-induced arthritis (CIA) model, as evidenced by reduced joint swelling, clinical scores, and histopathology.
Furthermore, in vitro studies demonstrated a reduction in IL-17 transcript and protein levels in Th17 cells, while in vivo studies showed significant decreases in the secondary immune response (IgG production) in the KLH challenge model. Kronos Bio plans to initiate Investigational New Drug (IND)-enabling studies for KB-7898 in the fourth quarter of 2024, with potential exploration in other autoimmune diseases in the future.
