Kronos Bio Selects Autoimmune Candidate for Sjögren's Disease

Kronos Bio, Inc. has announced the nomination of KB-7898, a p300 lysine acetyltransferase (KAT) inhibitor, as a development candidate for Sjögren’s disease, a chronic autoimmune disorder. This disease is characterized by the production of autoantibodies, chronic inflammation, and the infiltration of lymphocytes into exocrine glands, resulting in significant dryness and systemic effects that can impact the lungs, kidneys, and nervous system. Patients often suffer from severe fatigue and chronic pain, and there are currently no approved treatments that address the underlying cause of Sjögren’s disease.

KB-7898 is being developed as an oral therapy for individuals suffering from Sjögren’s disease. The p300 protein serves as a key cofactor for interferon regulatory factor 4 (IRF4), which plays a crucial role in immune responses across various cell types, including antibody-producing B cells and cytokine-producing T cells. Kronos Bio plans to begin Investigational New Drug (IND)-enabling studies for KB-7898 in the fourth quarter of 2024. The company also intends to explore the potential use of KB-7898 in other autoimmune diseases.

Dr. Nobert Bischofberger, President and CEO of Kronos Bio, highlighted the importance of their proprietary discovery engine in developing KB-7898. He emphasized that the multifaceted role of p300 in inflammation has been decoded, leading to the creation of this second p300 KAT inhibitor aimed at treating autoimmune diseases. Dr. Bischofberger noted the significant impact of Sjögren’s disease on quality of life and the lack of approved therapies that address the disease mechanism. Preclinical studies have shown that KB-7898 can reduce antibody production in B cells and cytokine production in T cells, which could potentially alter the course of Sjögren’s disease.

Kronos Bio will present preclinical data supporting the role of p300 in inflammatory conditions, including Sjögren’s disease, at the American College of Rheumatology's annual meeting, ACR Convergence 2024, on November 18, 2024, in Washington, DC. The data indicate that inhibiting p300's KAT activity, a crucial cofactor for proinflammatory transcription factors, leads to the selective downregulation of cytokines such as TNFα, IL-23, IL-17A, and soluble IgG. Selective gene expression changes were noted at doses corresponding to partial inhibition of p300 KAT activity. Additionally, p300 KAT inhibition resulted in decreased inflammation in a rat model of collagen-induced arthritis (CIA), as evidenced by reduced joint swelling, clinical scores, and histopathology findings.

Furthermore, in vitro studies showed that p300 KAT inhibition reduced IL-17 transcript and protein levels in Th17 cells. In vivo studies demonstrated significant decreases in the secondary immune response, such as IgG production, in the KLH challenge model.

Sjögren’s disease is a chronic autoimmune condition marked by autoantibody production, chronic inflammation, and lymphocytic infiltration of exocrine glands. Systemic effects can affect the lungs, kidneys, and nervous system, leading to issues such as pneumonia, bronchitis, kidney problems, hepatitis, cirrhosis, peripheral neuropathy, and lymphomas. The disease affects an estimated two to four million people in the U.S., with around one million diagnosed cases. It is more common in women, typically diagnosed after the age of 40. Currently, there are no approved treatments targeting the underlying cause of Sjögren’s disease.

Kronos Bio is a clinical-stage biopharmaceutical company focused on developing small molecule therapeutics that address deregulated transcription, a key factor in cancer and autoimmune diseases. The company’s proprietary discovery engine identifies druggable cofactors by decoding complex transcription factor regulatory networks. Kronos Bio has a pipeline of three drug candidates: Istisociclib (KB-0742) for ovarian cancer, KB-9558 for multiple myeloma and HPV-driven tumors, and KB-7898 for Sjögren’s disease. Kronos Bio is headquartered in San Mateo, California, with a research facility in Cambridge, Massachusetts.